Untitled - Universidade do Porto

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Comportamento de Mediadores Inflamatórios e Hormonais na
Síndrome de Apneia Obstrutiva do Sono
Resposta ao APAP
Marta Susana Monteiro Drummond Freitas
2009
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Agradecimentos
Sr. Prof. Dr. Agostinho Marques
Sr. Prof. Dr. João Carlos Winck
Sra. Prof. Dra. Ana Cristina Santos
Sra. Dra. Cristina Gavina
Sra. Dra. Teresa Pinho
Sra. Dra. Patrícia Caetano Mota
Sr. Prof. Dr. João Tiago Guimarães
Sr. Prof. Dr. Henrique Barros
Sra. Dra Conceição Gonçalves
Sr. Dr. João Almeida
Sr. Prof. Dr. Venceslau Hespanhol
Técnico Cardiopneumologista Delfim Souteiro
Técnica Cardiopneumologista Carina Barros
Técnica Cardiopneumologista Cristina Carrondo Lourenço
Técnica Cardiopneumologista Elisabete Santa Clara
Técnica Cardiopneumologista Ermelinda Moreira
Técnico Cardiopneumologista Paulo Viana
Técnica Cardiopneumologista Teresa Santigo
Enfermeira Emília Araújo
Enfermeira Paula Martins
Auxiliar de Acção Médica Fátima Queirós
Auxiliar de Acção Médica Paula Garcia
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Índice
Introdução ............................................................................ 6
1- O Sono e as suas patologias ............................................................. 6
2- Síndrome de Apneia Obstrutiva do Sono........................................... 7
2.1- Definição ............................................................................................. 7
2.2- Diagnóstico ......................................................................................... 8
2.3- Factores de risco................................................................................. 10
2.3.1- Obesidade ................................................................................................ 10
2.3.2- Sexo ....................................................................................................... 11
2.3.3- Factores genéticos ................................................................................. 11
2.3.4- Etnia ....................................................................................................... 12
2.3.5- Álcool ..................................................................................................... 12
2.3.6- Tabaco ................................................................................................... 12
2.3.7- Obstrução nasal ..................................................................................... 13
2.4- Morbilidade e Mortalidade ................................................................... 13
2.5- SAOS e Doença Cardiovascular ......................................................... 15
2.5.1- Activação intermitente do Sistema Simpático .......................................... 16
2.5.2- Desordem do stress oxidativo................................................................ 17
2.5.3- Disfunção endotelial ............................................................................... 19
2.5.4- Resposta inflamatória ............................................................................ 20
2.5.5- Aterogénese e Aterosclerose................................................................. 21
2.5.6- Hipóxia intermitente ............................................................................... 23
2.5.7- Síndrome Metabólica ............................................................................. 25
2.5.8- Via do metabolismo lipídico ................................................................... 25
2.5.9- SAOS, Doença Cardiovascular e Obesidade ........................................ 28
2.6- Tratamento.......................................................................................... 29
3- Objectivos gerais .............................................................................. 32
122345-
Racionalidade ............................................................................................. 32
IL-6 e PCR .................................................................................................. 33
Leptina ....................................................................................................... 35
Pressão Arterial.......................................................................................... 36
Achados ecocardiográficos em doentes com SAOS moderada a grave ..... 37
Resposta Metabólica .................................................................................. 39
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4- Publicações .......................................................................... 40
Trabalho 1- Efecto a largo plazo de la presión positiva automática en
la via aérea sobre la proteína C reactiva y la interleucina-6 en varones
com síndrome de apnea obstructiva del sueño ........................................... 41
Trabalho 2- Autoadjusting-CPAP effect on serum Leptin concentrations
in Obstructive Sleep Apnoea patients ........................................................ 50
Trabalho 3- Long term effect of Auto-adjusting Positive Airway Pressure
on Ambulatory Blood Pressure in OSA patients ........................................... 58
Trabalho 4- Comparison of Echocardiographic findings between male
patients with OSA and community controls .................................................. 83
Trabalho 5- Echocardiographic findings in male patients with OSA:
before and after long term Autoadjusting Positive Airway Pressure ............ 107
Trabalho 6- APAP Impact on Metabolic Syndrome in Obstructive Sleep
Apnoea Patients .......................................................................................... 133
5- Discussão geral .................................................................... 160
6- Comentário Geral ................................................................. 172
7- Conclusões ........................................................................... 176
8 - Resumo ................................................................................ 221
9 - Summary .............................................................................. 223
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Introdução Geral
O Sono e as suas patologias
O sono é parte integrante da vida, estando longe de ser um período inútil e de
desperdício de tempo, como muitos apregoam, para se constituir num tempo
de regeneração dos processos fisiológicos, mentais e físicos, sendo certo o seu
inestimável contributo para a saúde física, psíquica e bem estar de todos e
cada um de nós (1).
O sono é, pela maioria, ainda hoje, conhecido como o período “em que não
estamos acordados”, sendo, assim, reconhecido não pelas suas características,
mas pela ausência delas, não pela positiva, mas pela negativa. Ora, o sono,
não obstante ser um estado de reduzida responsividade para estímulos
internos e externos (2), é caracterizado por processos biológicos activos
fundamentais para a homeostasia do meio interno e para o equilíbrio de
mecanismos fisiológicos tendentes à conservação do próprio (1).
As patologias do sono constituem-se como uma preocupação crescente dos
profissionais de saúde, bem assim, como uma área de curiosidade e busca
incessante de conhecimento por parte da população geral. Os fenómenos de
apneia durante o sono são conhecidos desde há séculos, tendo sido
redescobertos no início do século 20, mas foi, já, no final da década de 90, que
diferentes tipos de apneias foram destrinçados e definidos, no que concerne às
suas características, origem, consequências e comorbilidades, tendo sido
criada uma classificação pela American Academy of Sleep Medicine (3) que foi,
posteriormente,
confirmada
na 2ª
edição
do
documento International
Classification of Sleep Disorders (4).
A Síndrome de Apneia Obstrutiva do Sono (SAOS) é a mais frequente das
desordens relacionadas com o sono (4) sendo, actualmente, reconhecida como
um problema de saúde pública, afectando 9 a 24% dos adultos de meia idade,
do sexo feminino e masculino, respectivamente (5).
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Sindrome de Apneia Obstrutiva do Sono
Definição
Esta patologia é caracterizada pela recorrência de episódios de oclusão parcial
ou completa da via aérea superior, ao nível da hipofaringe, (Fig.1) durante o
sono, resultando em dessaturação intermitente de oxigénio e microdespertares
com, consequente, fragmentação do sono (3).
Fig. 1- Representação esquemática dos fenómenos de oclusão parcial ou completa da via
aérea superior, ao nível da hipofaringe, que se verificam durante o sono em doentes com
SAOS
A SAOS, enquanto quadro de manifestação clínica, é caracterizada por um
conjunto de sintomas e sinais, que quando em simultâneo devem fazer
suspeitar da sua presença. São eles, hipersónia diurna, roncopatia e pausas
respiratórias testemunhadas durante o sono, a mais das vezes, associados a
obesidade (3). Embotamento cognitivo caracterizado por diminuição da
memória, da atenção, da capacidade de concentração, da destreza manual, de
competências visuais e motoras, da fluência verbal e de funções executivas (6)
são também muito prevalentes nestes doentes.
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Diagnóstico
O quadro clínico é, via de regra, muito característico, pelo que a suspeição e o
encaminhamento destes doentes se faz de forma correcta e atempada, sendo
conseguida a confirmação da patologia, na maior parte dos doentes enviados
para estudo em laboratórios de patologia respiratória do sono (7).
O estudo polissonográfico durante a noite permanece o exame de eleição para
o diagnóstico da SAOS (8) (Fig. 2).
Fig.2- Exemplo de um estudo polissonográfico de tipo Split-night. O diagnóstico é feito nas 2
primeiras horas do estudo (sem sombreado) e nas horas seguintes faz-se a aferição
terapêutica (sombreado a amarelo).
A contabilização de eventos respiratórios, sejam eles apneias ou hipopneias
(Fig. 3), de acordo com os critérios de Rechtschaffen e Kales publicados em
1968 e recentemente validados para contabilizações automáticas (9), em
número superior a 5 por hora de sono, faz-se necessária para a afirmação
diagnóstica (3,4) que, assim, se baseia no Índice de Apneia- Hipopneia (IAH).
Episódios de microdespertares associados a eventos respiratórios que não
reúnam critérios para classificação como apneias ou hipopneias (RERAS8
Respiratory Events Related Arousals), devem, igualmente, ser tidos em
consideração na contabilização do índice de distúrbio respiratório (3,4).
A
B-
Fig. 3- Imagens de fluxo oronasal, adquiridas por cânula nasal e termistor, no contexto de um
estudo polissonográfico, mostrando eventos respiratórios (A- Apneia) (B-hipopneia)
O estudo cardio-respiratório do sono é um método de diagnóstico de SAOS em
crescente uso em todo o mundo, não só por permitir a realização do estudo no
domicílio obviando a maiores incómodos na rotina do doente, mas também, por
reduzir custos e listas de espera (10,11) (Fig. 4).
Fig. 4- Registo de estudo cardio-respiratório do sono, com cinco canais
Acresce, ainda, o facto deste exame contornar a problemática da noite de sono
em laboratório não ser representativa das noites habituais do doente, por efeito
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de mudança de hábitos e local de sono e, é, actualmente considerado um
exame fiável, reprodutível e custo-eficaz no que se refere ao diagnóstico de
SAOS quando comparado com a polissonografia (PSG) (10,11). Uma revisão
de sete artigos sobre sistemas de monitorização ambulatória cardio-respiratória
do sono permitiu verificar que estes sistemas apresentam, em comparação
com a PSG, sensibilidade de 78-100% e especificidade de 67-100% (12).
Assim, em doentes sem comorbilidades major e com forte suspeita de SAOS, o
estudo ambulatório é possível (13). No entanto, em doentes com patologias
pulmonar, neurológica e/ou cardíaca significativas, o estudo em laboratório
supervisionado por técnico qualificado é desejável (14).
Factores de risco
Obesidade
A obesidade, sobretudo central, cuja relação com a circunferência do pescoço
se encontra bem estabelecida, é o maior factor de risco para a SAOS (15-19).
É sabido que 70% dos doentes com SAOS são obesos (20) e que um
incremento de 10 kg no peso corporal aumenta para o dobro, o risco de SAOS
(21). São múltiplos os potenciais mecanismos pelos quais a obesidade
predispõe à SAOS: estreitamento da via aérea superior por deposição adiposa
e consequentes alterações funcionais da referida via aérea; redução de
volumes pulmonares e alterações no equilíbrio estímulo-trabalho ventilatório
(22-24).
Ademais, nos últimos anos, o tecido adiposo branco tem emergido como um
órgão secretor, sendo considerado, nos obesos, o maior órgão endócrino (25).
Este tecido expressa elevados níveis de citoquinas inflamatórias, induzindo a
um estado de inflamação crónica de baixo-grau (26).
A produção inflamatória do tecido adiposo nos doentes com SAOS, pode, no
entanto, ser alterada por fenómenos de hipóxia sustentada visto haver a
hipótese do tecido adiposo branco ser precariamente oxigenado nos obesos,
por haverem grupos de adipócitos muito distantes da vasculatura, durante o
processo de crescimento da massa adiposa ou por hipóxia intermitente, ela
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própria característica da SAOS (25). Os escassos estudos (27,28) existentes
que exploram estas hipóteses debruçam-se, principalmente, sobre os efeitos
da hipóxia sustentada, mas, sendo certos, a disfunção do tecido adiposo nos
obesos, a existência de hipóxia e mecanismos inflamatórios no próprio (29) e a
forte ligação da obesidade à SAOS, o estudo da hipóxia intermitente sobre o
metabolismo do tecido adiposo revestir-se-ia da maior relevância.
Sexo
O sexo masculino apresenta cerca de duas vezes mais risco de apresentar
SAOS do que o sexo feminino (30). Esta diferença poderá ser justificada por
vários factores, nomeadamente: maior comprimento da via aérea no homem,
apresentando, assim, maior número de pontos de vulnerabilidade ao colapso;
volume aumentado das estruturas de tecidos moles da via aérea superior que
se associa ao sexo masculino; pelo facto da obesidade, no homem, tender a
ser central e pelo papel protector dos estrogénios na mulher (30-32).
Factores Genéticos
O alelo 4-epsilon do gene Apolipoproteína E (APOE) tem vindo a ser associado
à presença de SAOS (33,34), mas não em todos os estudos (35).
Relatórios, publicados na década de 90, sugeriam relação entre a ocorrência
familiar de roncopatia e SAOS, verificando-se um risco relativo entre 3 e 5,
sendo particularmente elevado em indivíduos com ambos os progenitores
afectados (36, 37, 38).
Existe uma elevada probabilidade de serem herdadas as respostas de
receptores periféricos relativas à hipoxemia (39).
Também a causa genética da obesidade tem vindo a ser contabilizada em
vários e grandes estudos como se situando entre 25 a 40% (40) dos casos.
Os genes envolvidos na embriogénese, crescimento e desenvolvimento
poderão, igualmente, ter um importante papel na definição do complexo
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craniofacial,
incluindo
as
estruturas
ósseas
e
de
partes
moles,
e,
consequentemente na anatomia da via aérea superior (41,42).
É, igualmente, possível, a propensão genética para uma sobre-regulação dos
mecanismos moleculares e celulares envolvidos na resposta inflamatória nos
doentes com SAOS (43).
Há, certamente, um longo caminho a percorrer no esclarecimento do papel da
genética nesta patologia.
Etnia
Afro-americanos e asiáticos tendem a apresentar maior risco de SAOS para o
mesmo valor de Índice de Massa Corporal (IMC) (44) quando comparados com
os seus congéneres caucasianos e de entre aqueles, os que apresentam
SAOS, tendem a ser mais novos do que estes (44).
Álcool
O álcool relaxa os músculos dilatadores da faringe, aumentando a resistência
da via aérea superior e podendo induzir o aparecimento de SAOS (45). Aliás,
um mecanismo idêntico ao produzido pelas benzodiazepinas.
Tabaco
Existe evidência de que o tabaco aumenta o risco de aparecimento de SAOS,
possivelmente pela sua interferência na estabilidade do sono e pelos efeitos
inflamatórios locais sobre a via aérea (46). Kashyap e colaboradores (46)
demonstraram que os fumadores têm duas vezes e meia mais probabilidade de
desenvolverem SAOS do que os ex-fumadores e os não fumadores.
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Obstrução nasal
Estudos revelam que a presença de obstrução nasal (Fig. 5) aumenta o risco
de SAOS (47). Os vários mecanismos passíveis de explicar esta relação
incluem o aumento da pressão negativa na via aérea superior produzido pelo
esforço inspiratório contra uma via nasal parcialmente obstruída, a turbulência
do fluxo inspiratório nasal e a roncopatia geradas, as quais originam
fenómenos inflamatórios e de edema local que agravam a obstrução nasal (48),
funcionando como um ciclo vicioso que se auto-alimenta e perpetua.
Fig. 5- Corte coronal de TAC dos seios perinasais, revelando importante desvio dextro-convexo
do septo nasal, causando marcada obstrução nasal de predomínio direito em doente com
SAOS grave
Morbilidade e mortalidade
A SAOS não tratada pode contribuir para o aparecimento ou agravamento de
diversas entidades nosológicas.
Existe evidência crescente no sentido de relacionar a presença da SAOS ao
risco aumentado de complicações cardiovasculares (49,50), como hipertensão
arterial (51), insuficiência cardíaca (52), disfunção ventricular direita e/ou
esquerda (53,54), angina (55) alterações do ritmo cardíaco (56-57), hipertensão
pulmonar (58), acidente vascular cerebral (59,60) e morte súbita (61).
A associação entre SAOS e hipertensão arterial (HTA) é, de entre todas, a que
se encontra melhor estudada e documentada, existindo à data, grandes e
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recentes estudos epidemiológicos revelando ser a referida associação
independente e verificando-se, a mesma, quer na população geral quer em
população seguida em centros de diagnóstico e tratamento de desordens
relacionadas com o sono (62-66).
A evidência unindo estas duas entidades é tão forte que na última reunião do
Joint National Comittee Report on Prevention, Detection, Evaluation and
Treatment of High Blood Pressure, a SAOS foi assumida como a primeira
causa identificável e tratável de HTA (51).
Mais, encontra-se demonstrada a relação dose-resposta entre a gravidade da
SAOS e os valores de tensão arterial (TA) (65,67) e é conhecida a maior
propensão ao desenvolvimento de HTA resistente entre os doentes com SAOS
(63,68).
Também a SAOS não tratada se relaciona com a incidência aumentada de
acidentes de viação (69-71) que se constituem, provavelmente, como o maior
factor de impacte desta patologia na saúde pública e de alavancagem dos seus
custos sociais.
A SAOS configura-se como uma carga socio-económica significativa que se
deve à comorbilidade, especialmente, cardiovascular e à consequente
utilização de recursos primários e secundários da saúde, custos inerentes à
terapêutica, efeitos na actividade profissional, como a baixa rentabilidade, o
absentismo ou, mesmo, o desemprego e a consequente diminuição da
qualidade de vida (72). As consequências cardiovasculares e, indirectamente,
sociais desta doença, parecem ser mais pronunciadas entre doentes com baixo
nível socio-económico (73).
As consequências, claramente nefastas, da SAOS não se ficam pela
morbilidade e impacte sócio-económico negativo a nível pessoal, familiar e na
comunidade em que o indivíduo se insere, embora, tanto uma como outro
sejam, já, suficientemente importantes para que autoridades de saúde,
médicos e população em geral olhem para esta patologia com a seriedade
necessária mas, urge que vão mais além.
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Um estudo recente mostrou que os indivíduos com SAOS moderada a grave
apresentam um aumento do risco global de morte, sendo este risco
particularmente elevado em doentes do sexo masculino e com menos de 50
anos (74). Assim sendo, é em indivíduos activos, em idade produtiva e capazes
de contribuir para o crescimento de si próprios e da sociedade, que mais se faz
sentir a mortalidade devida a esta patologia. Sabe-se, ainda, que a
probabilidade de morte aumenta com o aumento da gravidade da síndrome
(74), tornando-se, pois, urgente o diagnóstico e o tratamento atempado desta
doença, sobretudo, nos seus casos mais graves.
SAOS e Doença Cardiovascular
Nos últimos 30 anos o nosso conhecimento sobre as características e as
consequências da SAOS conheceu um progresso assinalável e esta doença é,
hoje, considerada como um problema major de saúde pública (5). Sendo a
obesidade o principal factor de risco da SAOS (15-19) e, assistindo-se na
contemporaneidade e no mundo ocidental a uma evolução pandémica daquela
patologia, é previsível que no futuro, a SAOS venha a afectar um número ainda
mais elevado de indivíduos e venha a mobilizar uma quantia ainda mais
avultada de recursos da saúde.
A patogénese da doença cardiovascular (CV) na SAOS ainda não se encontra
completamente esclarecida, mas pensa-se que a sua origem seja multifactorial
(25,75). Ignorar os efeitos fisiopatológicos resultantes da hipóxia intermitente e
dos microdespertares repetidos que acontecem durante um terço do dia nos
doentes com SAOS não parece do mais elementar bom senso. Efectivamente,
a plausibilidade biológica destas alterações levarem ao desenvolvimento e/ou
agravamento da patologia CV é uma noção sustentada, a cada dia que passa,
por um número crescente de investigadores corroborados pelos seus
resultados experimentais, no domínio da experimentação in vitro, in vivo com
modelos animais e no domínio dos estudos clínicos e epidemiológicos.
O modelo, mais consensual, proposto como explicação para a predisposição
aumentada dos doentes com SAOS ao desenvolvimento de
doença CV
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assenta na activação e interacção de várias vias inflamatórias em resposta à
hipóxia intermitente que se constitui como a marca fisiopatológica desta doença,
sendo, igualmente, de realçar o papel da fragmentação do sono, da activação
intermitente do Sistema Simpático e do stress oxidativo na génese da
disfunção endotelial, precursor primeiro da doença CV (25) (Fig. 6).
Síndrome de Apneia Obstrutiva do Sono
Hipóxia intermitente
Inflamação
NF-kB
Stress
Oxidativo
Disfunção
Endotelial
HIF
Activação
S. Simpático
Doença cardiovascular
Fig. 6- Activação e interacção entre vias inflamatórias na resposta à hipóxia intermitente na
SAOS. NF-kB- Factor Nuclear kB; HIF- hypoxia-inducible factor. Adaptado do artigo de Garvey
JF, et al. Eur Respir J 2009
Activação intermitente do Sistema Simpático
Um evento respiratório durante o sono, em regra, é terminado por um
microdespertar, que funciona como um mecanismo de defesa do indivíduo
contra a hipoxemia, e que restaura a normal dinâmica ventilatória (75).
Imediatamente antes desse microdespertar, verifica-se uma activação do
Sistema Simpático (76), que num doente com SAOS, acontece em ondas
repetitivas durante o sono, e que, nos doentes mais graves, se mantém
também durante o dia, como documentado por microneurografia (76,77) e pela
elevação plasmática de catecolaminas (78,79). A par desta activação simpática
verificam-se subidas em pico e de carácter intermitente da tensão arterial (Fig.
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7), assim como, aumentos repetitivos do débito e da frequência cardíacos, tal
como, por nós, previamente, fora descrito (80).
A activação do S. Simpático é uma das características mais salientes da SAOS
(76,81,82) e sabe-se, actualmente, que esta activação pode induzir stress
oxidativo (83) e, de forma inversa, uma mudança no ambiente redox pode
activar neurónios ganglionares do S. Simpático induzindo vasoconstrição e
HTA (84).
Desta forma, a activação do S. simpático constitui-se, pelo menos, como um
dos mecanismos fisiopatológicos ligando a SAOS à doença CV.
Fig. 7- Equipamento Finapres® device (Finapres Medical Systems, The Netherlands),
permitindo o registo contínuo da TA, acoplado a PSG de 14 canais (Alpha Series, Vyasis. USA).
Nesta imagem é possível visualizar aumentos repetitivos da TA após dessaturações de 02.
Desordem do Stress oxidativo
A cada apneia, os níveis circulantes de oxigénio declinam após o que voltam a
subir aquando da reoxigenação devida à restauração da dinâmica ventilatória.
Este fenómeno mimetiza o mecanismo de isquemia-reperfusão, sendo que a
cada episódio de reoxigenação é produzida uma enorme quantidade de
radicais livres (75), os quais activam o factor nuclear kB, promovendo uma
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regulação positiva de genes pró-inflamatórios e moléculas de adesão, que
poderão conduzir à disfunção endotelial (25,75,85). Esta cascata inflamatória
conduz, paralelamente, à activação de monócitos e linfócitos (86,87),
aumentando a sua avidez para o endotélio e, assim, potenciando a disfunção
endotelial (Fig.8).
Os radicais livres de oxigénio são átomos ou moléculas que possuem um ou
mais electrões desemparelhados numa órbita externa, o que os torna
susceptíveis a reacções químicas (88) e capazes de causar dano em vários
componentes celulares e em biomoléculas como lípidos, proteínas, hidratos de
carbono e ADN, assim alterando as suas funções biológicas (83).
O desequilíbrio resultante do aumento de radicais livres de oxigénio e do ião
superóxido, por um lado, e a diminuição de anti-oxidantes, por outro, tornam o
conceito de ser a SAOS uma desordem do stress oxidativo num consenso
emergente (89-91).
Síndrome de Apneia Obstrutiva do Sono
Hipóxia intermitente
NF-kB
AS
SREBP
Stress oxidativo
GATA
HIF
NO
Inflamação: moléculas adesão; citoquinas- TNFα, PCR; Leptina
Leucócitos e Plaquetas
Disfunção Endotelial
Doença Cardiovascular
Fig. 8- Stress oxidativo como paradigma de união entre Síndrome de Apneia Obstrutiva do
Sono e Doença Cardiovascular. AS- Activação simpática; NF-kB- Factor Nuclear kB; SREBPsterol regulatory element binding protein; GATA- GATA transcription factor; NO- Óxido nítrico;
HIF- hypoxia-inducible factor. Adaptado do artigo Lavie L., et al. Eur Respir J 2009
18
Estudos conduzidos em doentes com SAOS suportam este modelo, quer
usando a comparação entre doentes com SAOS e controlos (92,93), quer, de
forma mais convincente, comparando doentes com SAOS antes e após o uso
de suporte ventilatório nocturno (94). Existe, no entanto, a convicção de que
este padrão isquemia/reperfusão só será relevante em doentes com SAOS
muito grave.
Em boa verdade, modelos animais não têm conseguido demonstrar a que
magnitude de declínio de 02 ou a que duração da hipóxia ou, ainda, a que
frequência do fenómeno isquemia- reperfusão se inicia a produção dos efeitos
adversos (95-97). É possível que existam, igualmente, diferenças individuais
geneticamente determinadas que induzam susceptibilidades e respostas
diversas ao desafio da hipóxia intermitente (75).
Disfunção endotelial
A disfunção endotelial é um marcador precoce de anomalia vascular que
precede a doença cardiovascular clinicamente manifesta (98).
O endotélio intacto regula o tónus vascular e a sua capacidade de autoreparação, mantendo o equilíbrio entre factores pró-inflamatórios, antiinflamatórios, pró-coagulantes e anti-coagulantes (99).
Doentes com SAOS, livres de comorbilidades CV, apresentam desordem do
stress oxidativo e reduzida capacidade de reparação endotelial (89-91,100)
sugerindo que a SAOS, por si só, e, de forma independente, prejudica a função
endotelial (101).
Para além da capacidade de reparação endotelial, as funções biológicas do
endotélio pressupõem a regulação do tónus vasomotor, da actividade próinflamatória/anti-inflamatória do endotélio e da homeostasia do mecanismo da
coagulação.
O endotélio saudável mantém o balanço entre as respostas vasodilatadora e
vasoconstrictora a estímulos bioquímicos (99).
Entre os doentes com SAOS, livres de outras patologias, para além de se
verificar uma redução dos níveis de óxido nítrico (NO)- vasodilatador
dependente do endotélio, no plasma e nas células endoteliais (102,103) e uma
19
resposta reduzida à acetilcolina, também ela, factor vasodilatador dependente
do endotélio (104,105), verifica-se, ainda, um aumento plasmático de
substâncias vasoconstrictoras, como aldosterona e angiotensina II (106),
quando comparados com controlos. Mais, a reactividade da artéria braquial
correlaciona-se
com
hipoxemia/reoxigenação
o
IAH,
mostrando
desempenham
um
que
papel
os
fenómenos
crucial
na
de
resposta
vasomotora do endotélio (107).
Ademais, a SAOS tem vindo a ser ligada a alterações da homeostasia da
coagulação e activação da agregação plaquetária (108) no sentido de contribuir
para a génese de um estado de pró-coagulabilidade que induz, ele próprio, a
formação e progressão de fenómenos ateroscleróticos (108,109).
Finalmente, o equilíbrio entre forças anti-inflamatórias e pró-inflamatórias
parece pender para o lado da produção e activação de factores inflamatórios,
assim como para a destruição precoce de mediadores anti-inflamatórios
(25,98,110).
O endotélio, como órgão funcional, encontra-se, então, numa posição
privilegiada na interface entre sangue circulante e os diversos tecidos
do
organismo humano, tornando-se assim, particularmente susceptível à hipóxia
intermitente.
Resposta Inflamatória
A resposta adaptativa à hipóxia é mediada, em larga escala, pelo factor de
transcrição do HIF-1 (hypoxia-inducible factor-1) (111), o qual induz a
expressão de numerosos genes codificadores de proteínas como eritropoetina,
VEGF (vascular endothelial growth factor) e sintétase de NO que têm por
função melhorar a oxigenação tecidular (110).
A hipóxia induz, de igual maneira, a activação de um outro factor de transcrição
de importância capital, o NF-kB (nuclear factor kB) (112), o qual se constitui
como o actor central em toda a resposta inflamatória, induzindo a produção de
citoquinas pró-inflamatórias como TNFα (tumour necrosis factor α), IL-6
(interleucina-6), IL-8 (interleucina-8), PCR (Proteína C reactiva), moléculas de
adesão, selectinas, entre outras (110). Estas citoquinas actuam como factores
20
de
sinalização
celular,
atraindo
ao
endotélio
células
inflamatórias,
especialmente macrófagos que se diferenciam, posteriormente, em monócitos
e induzem a libertação de mais citoquinas inflamatórias fazendo uma regulação
positiva e de perpetuação do ciclo inflamatório (111).
Mais, HIF-1α e NF-kB regulam-se mutuamente, na espiral inflamatória; a
indução pelo estímulo hipóxico da activação de NF-kB está dependente da
presença de HIF-1α, o qual se encontra directamente envolvido na regulação
da apoptose celular através da modulação dos sinais de NF-kB (Fig.9) (25).
Inflamação
HIF-1α
NF-kB
Hipóxia
Fig. 9- Interacção entre factor hipóxia-induzido (HIF)-1α e o factor nuclear (NF) kB na resposta
à hipoxia tecidular. Adaptado do artigo de Garvey JF, et al. Eur Respir J 2009
Aterogénese e Aterosclerose
A aterosclerose é caracterizada pela presença de lesões vasculares contendo
colesterol, infiltrados de células ligadas à imunidade e fibroblastos, formando
largas áreas de fibrose (113,114).
Os factores de risco clássicos da aterosclerose são a dislipidemia, a HTA, a
diabetes mellitus e o tabagismo (115).
As células imuno-inflamatórias dominam os processos ateroscleróticos
precoces, secretando várias moléculas pró-inflamatórias que aceleram a
progressão das lesões e propiciam eventos de ruptura da placa aterosclerótica,
precipitando quadros clínicos agudos (116).
21
A génese da placa aterosclerótica faz-se na íntima vascular com deposição de
colesterol LDL (low-density lipoprotein) que, subsequentemente, oxida e induz
a expressão e libertação de células inflamatórias como macrófagos e linfócitos
T e de factores pró-inflamatórios, nomeadamente, citoquinas e moléculas de
adesão (116) (Fig. 10). Tanto uns como outros são detectados em níveis
elevados nos indivíduos que apresentam SAOS (117,118) e correlacionam-se
directamente com a gravidade da patologia (118).
A
B
B
Fig. 10- Secções da aorta em grupos experimentais de ratos. A- controlo; B- ratos sujeitos a
12h por dia de hipóxia intermitente durante 12 semanas e dieta rica em gordura. Setas
apontam para as placas aterscleróticas. Adaptado Savransky V, et al. Am J Respir Crit Care
Med 2007
Uma vez, esta plêiade inflamatória instalada na íntima, as células do músculo
liso iniciam a secreção de componentes da matriz extracelular, originando
acúmulo de colagénio e proteoglicanos que se comprometem com a
estabilização da placa aterosclerótica recém-formada (118). Esta estabilização
pode ser ameaçada pela acção de metaloproteinases, dependentes de células
inflamatórias que laboram no sentido da vulnerabilidade e ruptura da mesma
(118).
O espessamento das íntima e média carotídeas, avaliado por ecografia, é, hoje,
reconhecido como um marcador de aterosclerose pré-clínica (116,119) e um
potente preditor de doença CV (120,121).
22
Estudos recentes e quase simultâneos revelaram evidência de que a SAOS
pode conduzir a fenómenos de aterosclerose precoce, reflectidos no
espessamento vascular e na ocorrência de placas de ateroma, na ausência de
qualquer outra comorbilidade significativa (93,122-124) e demonstraram, ainda,
correlação entre a gravidade da síndrome, mensurada pelo IAH, e o volume da
placa aterosclerótica (20).
Assim, a juntar aos factores de risco acima elencados, também a SAOS, à luz
do conhecimento actual, parece encontrar-se entre os factores de risco de
aterosclerose.
Hipóxia intermitente
A hipóxia intermitente é, sem sombra de dúvida, a marca fisiopatológica da
SAOS (Fig. 11).
Fig. 11- Traçado de oximetria nocturna em doente com SAOS grave, mostrando
dessaturações repetitivas ao longo da noite
Os ciclos curtos e repetitivos de hipóxia/reoxigenação são únicos e
característicos desta síndrome (25). No entanto, mesmo, entre os doentes que
apresentam
a
referida
patologia
se
verifica
uma
variabilidade
e
heterogeneidade de padrões de hipóxia intermitente, espantosas. Basta-nos
atentar nas apneias surgidas durante o sono REM (Rapid Eye Movement) para
verificarmos que são, caracteristicamente, mais longas e originam maiores
quedas de saturação de oxigénio do que outras acontecidas em diferentes
fases do sono (125) e no grande espectro de índices de gravidade da doença
(IAH entre 5 e infinito), para percebermos que na avaliação dos efeitos
23
biopatológicos desta hipóxia, muitos factores têm que ser tidos em conta, sob
pena de ao confundirmos todos nos ser impossível perceber o verdadeiro papel
da hipóxia intermitente no organismo humano.
Uma enorme variedade de modelos celulares, animais e humanos têm sido
criados no sentido de se tornarem ferramentas fiáveis na investigação do papel
da hipóxia intermitente na fisiopatologia da SAOS (126). No entanto, e, apesar
dos modelos criados mimetizarem a variação cíclica observada na oxigenação
dos doentes com SAOS, variam em duração e grau de hipóxia vivenciada e em
número de episódios, em regra, sendo mais grave em culturas celulares e mais
próxima da realidade em modelos animais (25).
Mais ainda, nestes modelos, a hipóxia não é associada a fases do sono nem se
acompanha de fragmentação do mesmo, não se relaciona com fenómenos
oclusivos da via aérea superior nem com variações da pressão intra-torácica o
que poderá fazer variar as respostas adaptativas (25) e torna tão difícil o
estudo deste fenómeno assim como a integração de todas as suas
consequências, na realidade.
Períodos prolongados de hipóxia sustentada permitem o desenvolvimento de
respostas adaptativas cujo objectivo é o restabelecimento da oxigenação e
perfusão tecidulares, em que a aclimatação à altitude é um exemplo
paradigmático (127), enquanto que, curtos períodos de hipóxia, de intensidade
variável, repetitivos, que acontecem durante várias horas, diariamente, como
os que se verificam na SAOS poderão diferir largamente daquelas respostas.
A indução de respostas protectoras em subgrupos de doentes com SAOS é
disso exemplo e pode parcialmente explicar o facto de nos doentes com mais
de 50 anos se verificar uma redução do risco de mortalidade (128), cuja
tendência se manteve mesmo entre os doentes mais graves ou, mesmo,
explicar o reduzido impacte CV da SAOS REM, onde a hipóxia é mais
prolongada,
podendo,
teoricamente
induzir
o
referido
fenómeno
de
condicionamento isquémico (25).
Efectivamente, na hipóxia intermitente, a resposta dos receptores do corpo
carotídeo é exagerada, contribuindo para o aumento da actividade simpática, o
aumento da TA e a diminuição da sensibilidade dos baro-receptores à periferia
24
(129). Por outro lado, esta resposta é largamente dependente do factor HIF-1α,
ele próprio interveniente privilegiado na cascata inflamatória induzida pela
própria hipóxia intermitente (25).
Estes fenómenos caracterizam a hipóxia intermitente e diferenciam-na da
hipóxia sustentada e são, eles próprios, que se vêem implicados na génese e
amplificação do risco CV, como atrás ficou demonstrado, pelo que há um
crescente número de dados que tornam a hipóxia intermitente na peça fulcral
de toda a fisiopatologia da própria síndrome e das suas consequências e
comorbilidades.
Resposta Metabólica
A SAOS pode afectar, indirectamente, a via metabólica devido à diminuição da
qualidade e /ou quantidade do sono a ela associada (130). De facto, muitos são
os estudos que implicam a privação do sono na génese de alterações
metabólicas, tais como, redução da leptina, aumento da grelina e aumento do
apetite (131-132), intolerância à glicose (133-135) e aumento do risco de
obesidade (136,137). Este último, permitindo a especulação sobre a
causalidade entre redução das horas de sono nas sociedades ocidentais e a
pandemia de obesidade (29). Têm surgido estudos reforçando este último
ponto, que referem regressão do IMC com o aumento das horas de sono (138)
e atribuem 5 a 13% da obesidade, em adultos, à falta deste (139).
A indução de um estado pró-inflamatório poderá ser um dos mecanismos por
detrás das consequências metabólicas da privação do sono (29), através da
activação do S. Simpático e da produção de cortisol (140-142).
Para além disso, a hipóxia intermitente e o stress oxidativo, nos seres humanos,
têm sido implicados na génese, através da regulação positiva de um grupo de
factores de transcrição SREBPs (sterol regulatory element binding protein), da
hiperlipidemia (83).
Modelos experimentais de hipóxia intermitente revelaram activação de genes
reguladores do metabolismo lipídico, pelos factores SREBPs (143,144) e HIF1α, o último causando regulação positiva dos níveis de triglicerídeos (145).
25
Vários estudos têm demonstrado a plausibilidade de ser a hiperlipidemia,
associada à SAOS e independente da obesidade, da responsabilidade de uma
regulação positiva das vias SREBPs e HIF-1α, já demonstrada em modelos
animais (146,147,148), as quais são responsáveis pela manutenção das
alterações da via do metabolismo lipídico.
A mais recente definição de Síndrome Metabólica (SM) (149), labora no sentido
de classificar esta síndrome como uma constelação de alterações metabólicas
nomeadamente dislipidemia, HTA, intolerância à glicose e obesidade central,
que se constituem, elas próprias, como factores de risco CV (Fig. 12).
Fig.12- in Grundy. Circulation 2005
Três metanálises recentes demonstraram associação entre a presença de SM
e o risco aumentado de doença CV (150-152) (Fig. 13).
26
Radicais livres de 02
Óxido Nítrico
Ião Superóxido
Disfunção Endotelial
Inflamação
SAOS e DCV:
Mecanismos potenciais
Leptina
Alterações do Metabolismo Lipídico
Obesidade
S. Metabólica
Fig.13- Fluxograma em que é possível ver a ligação entre SAOS e SM, seja como causa, seja
como consequência, desta feita, com mediação hormonal, nomeadamente da leptina. SAOSSíndrome de apneia Obstrutiva do Sono; DCV- Doença Cardiovascular. Adaptado do artigo de
Quan SF et al. Circulation 2004
Também estudos recentes têm vindo a apresentar evidência de que a SAOS se
associa, de forma independente, a prevalência aumentada de SM (153-155) e,
com
relação dose-resposta
(153-155) tendo, mesmo, Coughlin
(156)
conseguido demonstrar que aqueles doentes têm 9,1 vezes mais probabilidade
de apresentar SM versus controlos. Mais, a maioria dos doentes com SAOS,
apresentam SM (157,158), como nós próprios pudemos constatar em estudo
precedente (159).
Assim, há, já, autores que advogam ser a SAOS uma manifestação da SM
(160), em virtude daquela se encontrar associada, de forma independente, à
maioria dos critérios de diagnóstico para esta síndrome (15-19,51,156-158).
Estes autores propõem ser a SAOS não só uma mera causa de SM mas,
também, uma consequência desta (161).
Do exposto, facilmente se depreende que existe evidência experimental e
clínica que implica a SAOS no desenvolvimento da SM. Esta evidência, é, a
mais das vezes, circunstancial e o nexo de causalidade entre ambas
permanece por provar. Não deixam, no entanto, de ser curiosos e importantes,
trabalhos (162) que revelam diminuição do risco CV global e diminuição,
27
concomitante, da prevalência de SM após terapêutica eficaz para SAOS, sem
quaisquer terapias adicionais.
SAOS e comorbilidades
Dislipidemia,
diabetes,
HTA,
obesidade
podem
desenvolver-se
independentemente da SAOS graças a características genéticas, hormonais,
nutricionais ou variáveis relacionadas com o estilo de vida ou serem
consequências directas desta (Fig. 14) (83).
As desregulações metabólicas e a obesidade observadas nos doentes com
SAOS podem ser ditadas por consequência das alterações respiratórias
observadas durante a noite, como atrás exposto.
Mas, claro está, a obesidade pode constituir-se, igualmente, como uma séria
candidata a factor iniciador de todo este processo. A hipóxia sustentada a que
os adipócitos se encontram sujeitos por distantes à vasculatura (28), tornamnos produtores desregulados de adipocinas como leptina, TNF-α, adiponectina,
etc, resultando em processo inflamatório de baixo grau (163).
Ainda, obesidade e SAOS podem agravar-se mutuamente através da activação
de stress oxidativo via hipóxia sustentada ou intermitente, respectivamente,
induzindo activação de enzimas produtoras de radicais livres de oxigénio (83).
Independentemente de saber qual terá sido o factor iniciador, a partir do
momento que se desenvolve SAOS, a hipóxia intermitente e o stress oxidativo
que se gera noite após noite transformam-se nos factores centrais da
estimulação da cascata de eventos que conduz à morbilidade CV (83).
28
SAOS
Obesidade
Hipóxia intermitente
Hipóxia sustentada
Activação
Stress Oxidativo
Simpática
HTA
DM
Dislipidemia
Inflamação
Fig. 14.- Representação esquemática do papel central do stress oxidativo e da inflamação no
desenvolvimento das comorbilidades associadas à SAOS. HTA- Hipertensão arterial; DM-
Diabetes mellitus. Adaptado do artigo Lavie L., et al. Eur Respir J 2009
Tratamento
O suporte ventilatório nocturno com pressão positiva contínua da via aéreaCPAP (Continuous positive airway pressure) é a terapêutica de eleição para a
SAOS (164-166).
Trata-se de um tratamento simples cujo princípio é o da criação de uma
almofada de ar na via aérea superior, por forma a impedir o seu colapso (Fig.
15).
Fig.15- Modelo esquemático do princípio de actuação da Pressão Positiva Contínua da Via
Aérea, que deverá ser titulada durante um estudo polissonográfico ou apresentar algoritmo de
variação automática, a fim de impedir o colapso da via aérea superior.
O CPAP tem sido apontado como sendo eficaz e seguro, não só no controlo
dos sintomas associados à SAOS (164,167) como também na redução do risco
29
CV que lhe está inerente (168-178). Este efeito protector parece estar
relacionado com a eficácia do CPAP na normalização ventilatória durante o
sono, na estabilização dos padrões do sono de per se e na redução do tónus
adrenérgico (178).
Os dispositivos de pressão positiva automática, APAP (Auto-adjusting positive
airway pressure), são uma alternativa recente (Fig. 16) ao tratamento
tradicional com CPAP, demonstrando eficácia no controlo sintomático (179) e
na redução de custos (180,181), uma vez que dispensam titulação durante
estudo polissonográfico, enquanto permitem o aumento da aderência à
terapêutica a longo termo (182-184).
Fig. 16- Dispositivo APAP- REM Star Auto Respironics® Inc
O funcionamento destes dispositivos baseia-se na disponibilização de uma
pressão positiva variável durante o sono, dependendo do grau de obstrução da
via aérea, em cada ciclo respiratório, nos diferentes estadios do sono e de
posição corporal (185).
No entanto, diverso do CPAP, o impacte CV e metabólico da terapêutica com
APAP permanece precariamente estudado.
Dois estudos recentes (185,186) reportaram a incapacidade do APAP na
redução da TA sistólica e diastólica em doentes com SAOS, não, sem
demonstrarem importantes deficiências metodológicas, nomeadamente no que
concerne ao tempo de seguimento dos doentes.
Também é certo, que estudos houve (187), não demonstrando eficácia do
CPAP na redução da TA em subgrupos de doentes com SAOS.
30
Um outro estudo (188), comparando ambas as abordagens terapêuticas,
revelou que o APAP não conseguiu reduzir nem a TA nem a resistência à
insulina verificadas numa população de doentes com SAOS, mas revelou-se
eficaz na redução do estado inflamatório associado a esta doença,
conseguindo significativa diminuição dos valores séricos de PCR, enquanto
que o CPAP se mostrou capaz no controlo dos três factores de risco CV
estudados.
Tendo em conta o uso crescente, em todo o mundo, da opção terapêutica com
APAP e a aparente, mas débil, evidência de apresentar, este tratamento, uma
actuação díspar do CPAP no que concerne à redução do risco e,
consequentemente, da doença CV associados à SAOS, e, sendo esta, uma
das consequências mais debilitantes, incapacitantes e onerosas da referida
síndrome, parecem revestir-se de todo o interesse trabalhos desenhados,
elaborados e levados a cabo no sentido da clarificação da eficácia do APAP no
controlo do risco CV em doentes com SAOS.
31
Objectivos Gerais
Racionalidade
Da introdução atrás elaborada, se pode depreender da complexidade que
subjaz ao modelo hipotético, mas já, em larga escala, parcialmente
comprovado, que explica a ligação existente entre SAOS e Doença CV.
As relações entre ambas as entidades nosológicas parecem estabelecer-se,
em muitos casos, não de forma unívoca, mas biunívoca e havendo entre as
várias linhas de união uma inter-relação dinâmica e inter-moderadora
regulando a actividade e intensidade de cada uma.
Tendo em conta o uso crescente, em todo o mundo, da opção terapêutica
APAP, em grande parte, devido aos custos reduzidos, mas também por ser
eficaz no controlo sintomático e permitir uma aderência terapêutica, senão
melhor, pelo menos idêntica, à do suporte ventilatório convencional, é de
interesse o conhecimento dos seus efeitos na redução do risco CV inerente à
SAOS, que se constitui, não só, como uma das indicações mais prementes
para o tratamento activo da doença, mas também como uma das
consequências mais temíveis da mesma.
Partindo de ambas as premissas atrás enunciadas, o trabalho, nesta tese,
explanado, propõe-se avaliar a eficácia do APAP na redução do risco CV
associado à SAOS moderada a grave. Em virtude deste risco se materializar
através de variados e intercomunicantes mecanismos fisiopatológicos, foram
alvo deste estudo várias das disposições que entre ambas as entidades
nosológicas se desenrolam, nomeadamente: a resposta da pressão arterial à
activação intermitente do sistema simpático, a resposta inflamatória e as
alterações morfo-funcionais do coração à hipóxia intermitente, a resposta
hormonal associada à regulação do apetite e à obesidade e a resposta
metabólica global.
32
IL-6 e PCR
A resposta inflamatória foi estudada através de dois mediadores eleitos pela
sua representatividade e preponderância na iniciação e perpetuação da
cascata da inflamação.
A interleucina-6 (IL-6) é uma citoquina circulante secretada por diversas células
inflamatórias, incluindo macrófagos e linfócitos activados (189), que regula a
síntese hepática da Proteína C Reactiva (PCR) (190,191) e de muitos outros
mediadores inflamatórios, sendo crível que a própria se constitua como um
regulador major da resposta inflamatória aguda (190,191).
A PCR é um importante, embora inespecífico, marcador inflamatório que, ao
contrário de outras citoquinas se mantém sericamente estável ao longo de 24h
(192), permitindo espelhar o nível da resposta inflamatória durante esse tempo.
Para além do seu papel como marcador inflamatório, estudos epidemiológicos
têm , igualmente, demonstrado que níveis elevados de PCR em indivíduos
saudáveis são um forte preditor de risco CV (193,194), de forma independente,
como já demonstrado por alguns (195,196). As propriedades pró-inflamatórias
e pró- aterogénicas desta molécula, verificadas nas células vasculares do
músculo liso (197), nas células endoteliais (198), nos monócitos/macrófagos
(199)
e a sua associação com o stress oxidativo (200) fazem dela uma
personagem, também, na iniciação e progressão da aterosclerose (201).
Numerosos estudos têm demonstrado níveis séricos elevados de IL-6 (202204) e PCR (204-206) nos doentes com SAOS, mas, tanto quanto sabemos,
existe apenas um estudo avaliando o efeito do APAP nos valores séricos de
PCR (188) e nenhum sobre o efeito daquele nos níveis de IL-6.
Assim, elaborámos algumas questões:
Qual será o impacte a curto termo do tratamento com APAP nos níveis
séricos de IL-6 e PCR de alta resolução (h-PCR) nos doentes com SAOS
moderada a grave?
Esse impacte será sustentado a longo termo?
33
Correlacionar-se-ão os níveis basais de IL-6 e h-PCR com os índices de
gravidade da SAOS, independentemente de factores confundidores?
Serão os níveis de h-PCR nos doentes recém-diagnosticados com SAOS
moderada a grave diferentes dos níveis dos controlos comunitários?
34
Leptina
A Leptina é uma hormona com funções bem conhecidas na composição
corporal, homeostasia energética e comportamento alimentar dos seres
humanos (207-209). Trata-se de uma proteína com 167-aminoácidos,
produzida, predominantemente, no tecido adiposo branco (207-209) que circula
no plasma sob a forma livre ou associada a moléculas de ligação leptin-binding
proteins (210).
De facto, a leptina transmite informação ao cérebro, através da ligação a
receptores localizados no hipotálamo, sobre o tamanho das reservas de tecido
adiposo e regula o apetite e o gasto energético em face dessas informações
(211-215), funcionando como a hormona reguladora da obesidade (208).
Os níveis séricos de leptina relacionam-se com o aumento do peso corporal
(214-215), mas, também, com a hipóxia intermitente, como demonstrado sob
condições experimentais e em doentes com SAOS (216-221).
Estudos, revelando redução dos níveis séricos de leptina em doentes com
SAOS sob tratamento com CPAP (222-224), reforçam a ideia de que a hipóxia
intermitente, nesta patologia, independentemente da obesidade, poderá induzir
alterações nos níveis de leptina no soro. Não existem, até ao nosso
conhecimento, estudos avaliando o efeito do APAP sobre esta hormona.
Desta forma, este trabalho pretende responder às seguintes questões:
Os níveis séricos de leptina encontram-se elevados nos doentes com
SAOS, independentemente da obesidade? E relacionam-se com os
índices de gravidade da síndrome?
Qual é o efeito a curto e a longo prazo do APAP sobre os níveis séricos
de leptina nos doentes com SAOS moderada a grave, independentemente
dos factores confundidores?
35
Pressão Arterial
Diversos estudos (62,64,225-232) têm reportado uma elevada prevalência,
entre 40 a 70%, de HTA entre doentes com SAOS e, inversamente, cerca de
um terço dos doentes hipertensos apresentam SAOS (233).
Estudos
epidemiológicos
com
grande
número
de
doentes
incluídos,
demonstraram, recentemente, associação independente entre SAOS e HTA na
população geral e em doentes medicamente seguidos por patologia respiratória
do sono (62-67), a qual parece ser dose-dependente, após ajuste para factores
confundidores (67).
Apesar de alguns trabalhos (234-240) mostrarem dados claros ou, outros,
reflectirem um baixo impacte do tratamento da SAOS sobre a TA, duas
metanálises recentes concordaram no efeito positivo do CPAP na redução da
mesma (170,171), sendo que, tal benefício, não tem sido capaz de ser
mostrado pelo APAP (186,188).
Este estudo propõe-se juntar evidência, à débil havida até ao momento, no que
concerne ao efeito do APAP sobre a TA em doentes com SAOS.
Para tal, é postulada a seguinte interrogação:
Qual será o impacte do APAP sobre a TA, mensurada por monitorização
ambulatorial durante 24h, nos doentes com SAOS moderada a grave?
36
Achados ecocardiográficos em doentes com SAOS moderada a grave
Durante a obstrução da via aérea superior, que acontece ciclicamente nos
doentes com SAOS, pressão negativa intratorácica é gerada pelos esforços
inspiratórios desenvolvidos contra-obstáculo, o que induz um aumento de
pressão transmural do miocárdio e aumento do afterload (53). O aumento do
retorno venoso (53) que, também, se verifica pelo mesmo processo, atrás
exposto, contribui para o incremento do preload e da congestão pulmonar
(241,242).
Estes mecanismos, potencialmente, afectam a função cardíaca, sendo que, há
evidência crescente de aumento do risco de morbilidade e mortalidade CV
entre os doentes com SAOS (49,50). Insuficiência cardíaca (IC) (52), disfunção
ventricular direita e/ou esquerda (53,54), alterações do ritmo cardíaco (56,57),
hipertensão pulmonar (58) e morte súbita (61) são algumas das consequências
CV já descritas.
Dado que existem alterações morfológicas e funcionais cardíacas, silenciosas,
precoces e precursoras das consequências atrás mencionadas seria de todo o
interesse o despiste atempado destas alterações, a fim de que se possa alterar
o curso natural da doença, ou pelo menos, evitar as suas complicações.
O ecocardiograma transtorácico, sendo um método não invasivo, de
investigação da morfologia e função cardíacas direita e esquerda, poderá ser
usado neste rastreio, de forma vantajosa (Fig. 17).
A
B
Fig. 17- Imagens de ecocardiograma transtorácico:
A- janela epigástrica em modo bi-dimensional ;B- imagem em modo M
37
Ainda mais que, a função ventricular esquerda está intimamente relacionada
com a mortalidade e a morbilidade, sendo que o dano diastólico precede o
sistólico e, só ele, contribiu para 30-40% da insuficiência cardíaca esquerda
(243,244).
Assim, o reconhecimento (243-246) e a terapêutica apropriados da disfunção
VE diastólica, inicialmente, e, de ambas, numa fase mais avançada, é
aconselhável para prevenir futura progressão no sentido da IC e morte.
Alguns estudos, realizados recentemente, têm mostrado um número importante
de anomalias cardíacas presentes nos doentes com SAOS (53,247,248).
Poucos, são os trabalhos investigando o papel do CPAP nestas anomalias
(170,171), embora, indo, as suas conclusões no sentido positivo, mas nenhuns,
são os que investigam o efeito do APAP, que permanece desconhecido, neste
contexto.
Logo, foram desenhados, no âmbito desta tese, dois trabalhos que tentam
responder a questões que a todos, que trabalham com doentes com SAOS,
interessam ver respondidas:
Qual é a prevalência de anomalias cardíacas morfológicas e funcionais
nos doentes com SAOS e de, entre elas, qual a sua prevalência relativa?
Esta prevalência é diferente da encontrada em controlos comunitários,
independentemente de factores confundidores?
Estas anomalias relacionam-se com os índices de gravidade da SAOS?
O APAP tem algum efeito a longo prazo sobre estas anomalias?
38
Resposta Metabólica
Apesar de, desde há longo tempo, vários investigadores observarem e
descreverem a presença concomitante de obesidade central, HTA, intolerância
à glicose e dislipidemia num mesmo indivíduo, só em 1988 é que, pela primeira
vez, se integraram todas estas alterações como premissas de uma mesma
síndrome (249), actualmente chamada metabólica e, recentemente, definida
como tal (149).
Sendo que a SAOS se associa a obesidade (21), a HTA (51), a intolerância à
glicose (250,251) e a dislipidemia (144,252,253), é, sem espanto, que vemos
trabalhos revelando a associação daquela à presença da SM (153-155).
Dado que, cada um destes critérios, se constitui como um factor de risco CV,
torna-se de interesse discernir se é por cada um deles, em particular e,
sobretudo, pela sua constelação, no global, que a SAOS se associa à
morbilidade e mortalidade CV ou se tal associação se deve, também, à
fisiopatologia da própria síndrome e se esta, contribui, ela própria para a
génese e agravamento da SM. Assim sendo, o tratamento da SAOS poderia
reverter, pelo menos em parte, a presença da SM.
No sentido de clarificar alguns destes pontos, foram elaboradas as seguintes
questões, que se pretendem ver respondidas:
Qual a prevalência de Síndrome Metabólica nos doentes com SAOS
moderada a grave?
Qual o efeito do tratamento a longo prazo com APAP na prevalência da
referida síndrome nos doentes em estudo?
Existem critérios de definição da SM que sejam mais respondedores ao
tratamento com APAP?
39
Publicações
40
Trabalho 1
Efecto a largo plazo de la presión positiva automática en la via aérea
sobre la proteína C reactiva y la interleucina-6 en varones com síndrome
de apnea obstructiva del sueño
41
42
43
44
45
46
47
48
49
Trabalho 2
Autoadjusting-CPAP effect on serum Leptin concentrations in Obstructive
Sleep Apnoea patients
50
51
52
53
54
55
56
57
Trabalho 3
Long term effect of Auto-adjusting Positive Airway Pressure on
Ambulatory Blood Pressure in OSA patients
58
Artigo submetido à revista International Journal of Cardiology
Long term effect of Auto-adjusting Positive Airway Pressure on
Ambulatory Blood Pressure in OSA patients
Marta Drummond*, JC Winck*, AC Santos**,
JA Almeida*, JA Marques*
Pulmonology Department*, Epidemiology Department**
Hospital de São João
Faculdade de Medicina do Porto
Porto – Portugal
Alameda Hernâni Monteiro
4200-319 Porto
Abstract
IntroductionObstructive Sleep Apnoea (OSA) is independently associated with arterial
hypertension (AH).
Autoadjusting positive airway pressure (APAP) devices are an alternative
treatment for OSA patients.
Our aim is to determine the prevalence of AH in these patients and evaluate the
effect of long-term APAP therapy on those with AH.
Materials/ Patients and MethodsThis is a prospective, non-controlled study enrolling 98 male patients with
moderate to severe OSA confirmed by domiciliary sleep study. Blood pressure
was monitored with 24h-ABP (arterial blood pressure) device at baseline in all
patients and after 6 months of intervention in those with AH at baseline.
ResultsMean age 55.3±10.7 years, mean BMI 33.2±5.0 Kg/m2, mean AHI 51.7±21.3/h
and mean desaturation index (DI) 86.3±5.3/h. APAP compliance 91.27%±20.45
days and 5.76±1.59 hours/night. AHI positively correlates with mean overall (p=
0.004), systolic mean (p=0.005) and diastolic mean ABP (p=0.018). AH was
present in 47.2% patients at baseline and in 8.5% after therapy. Non-dipper
phenomenon was reduced by treatment from 38.7% to 21.7%. After 6 months a
59
statistical significant reduction in mean overall, mean systolic, mean diastolic,
daytime mean and nighttime mean ABP (all p=0.000) was achieved.
ConclusionsLong term APAP therapy significantly reduces ABP and contributes to
normalize the nighttime dipper phenomenon.
Patients with more severe OSA benefit more from APAP effect on ABP.
Keywords- Arterial hypertension, Auto-adjusting continuous positive airway
pressure, Obstructive sleep apnoea.
Introduction
Obstructive sleep apnoea (OSA) is an important public health problem, with an
estimated prevalence of 4% and 2% in middle-aged men and women,
respectively (1,2).
Large epidemiological studies have recently shown an independent association
between OSA and systemic hypertension in both general and sleep clinic
populations (3,4,5,6,7).
The evidence linking both entities is so compelling that the last Joint National
Committee report on Prevention, Detection, Evaluation and Treatment of High
Blood Pressure (8) defined OSA as the first identifiable cause of hypertension.
Nasal continuous positive airway pressure (CPAP) treatment is the most
effective therapy for mild-to-severe OSA (9,10).
Two recent meta-analysis agreed on the positive impact of CPAP in blood
pressure reduction (11,12).
Auto-adjusting positive airway pressure (APAP) devices are a recent alternative
treatment to traditional CPAP. However, different from CPAP, the impact of
APAP therapy on cardiovascular and metabolic outcomes in OSA patients
remains unknown, and two recent studies (13,14) have reported that APAP
therapy may not be able to reduce arterial blood pressure.
60
The present study was conducted to evaluate the impact of long-term APAP
therapy on 24-hours ambulatory blood pressure in hypertensive patients with
moderate to severe obstructive sleep apnoea.
Materials and Methods
Study design
This trial was designed as a prospective non-controlled study. All patients gave
written informed consent to participate in the trial. The study protocol was
approved by the Hospital Ethics Committee and the study was performed in
accordance with the guidelines of the Declaration of Helsinki and its current
revision.
Subjects
One hundred and two patients with moderate/ severe OSA (AHI>20/h)
confirmed by domiciliary sleep study were included between February 2005 and
March 2006.
All but four patients concluded the study (n=98). Those who failed to conclude
the protocol referred APAP intolerance as the reason to quit.
In only 46 patients, the 24-ABPM was performed 6 months after the treatment
initiation as these were those with previous uncontrolled hypertension.
Fat distribution was assessed according to waist/hip ratio at baseline and after 6
months.
Study procedures
Sleep Study
An overnight sleep study was performed using a five-channel recording device
(Alphascreen; Vyasis). This device produces a computerized recording of
variations in oronasal airflow (measured by nasal cannula), body position, wrist
actimetry, pulse rate, arterial oxygen saturation (measured by finger pulse
61
oximetry), thoracic and abdominal respiratory efforts. In all cases, sleep
technicians carried out a manual analysis of the recordings, by counting apnoea
(episodes of ≤ 20% of previous airflow with at least 10 seconds of duration) and
hypopnoea episodes (episodes showing 20 to 50% of the previous airflow, with
at least 10 seconds of duration joined with a 4% dip in oxygen saturation),
dividing the total number of these episodes by the sleep time in hours, thus
obtaining the manual respiratory disturbance index (15). Also the separation
between central and obstructive apnoeas was made and none of the patients
had a significant number of central apnoeas (all < 5/h).
APAP
Patients received APAP therapy by REM STAR AUTO® (Respironics, inc.
Murraysville, USA) device with pre-determined minimum and maximum
pressure of 4 and 15 cmH20, respectively.
Blood pressure monitoring
24-hour Ambulatory Blood Pressure was measured with validated ambulatory
recorders (Spacelab, Inc 90207 Neural) in all but 3 patients who refused, at
baseline, the examination as they considered the arm discomfort intolerable.
Those measures were performed before starting APAP treatment and repeated
6 months later in those who showed baseline abnormal 24 hour- Ambulatory
Blood Pressure (24-ABP).
A trained technician fitted an appropriately sized cuff on the patients nondominant arm, which was worn for the subsequent 24 hours, during normal
daily activities. Monitors were programmed for cuff inflation measurement every
20 minutes during the day and every 30 minutes during the night. Hypertension
was defined according to European and JNC-VII guidelines (16).
Dippers were defined as those patients presenting a minimum mean nocturnal
BP decrease of 10% or more with respect to the mean BP value.
Blood pressure (BP) parameters measured: overall mean arterial pressure
(MAP) min, overall MAP mean, overall MAP max, overall systolic min, overall
systolic mean, overall systolic max, overall diastolic min, overall diastolic mean,
overall diastolic max, daytime MAP min, daytime MAP mean, daytime MAP max,
daytime systolic min, daytime systolic mean, daytime systolic max, daytime
62
diastolic min, daytime diastolic mean, daytime diastolic max, night-time MAP
min, night-time MAP mean, night-time MAP max, night-time systolic min, nighttime systolic mean, night-time systolic max, night-time diastolic min, night-time
diastolic mean, night-time diastolic max.
Statistical Analysis:
Data were analyzed using SPSS, release 14.0, and described as mean values
and their respective standard deviation for normally, or as median values and
corresponding 25th and 75th centiles for clearly non-normally distributed
variables. Counts and proportions are reported for categorical variables.
Proportions were compared using Chi-square test or Fisher’s exact test
whenever appropriate. For comparison between median values at baseline and
at 6 months of treatment the non parametric Wilcoxon est for paired samples
was used.
Spearman correlations coefficients were computed to estimate the association
between blood pressure values and participants characteristics at baseline.
Receiver-operating characteristic (ROC) curve analysis was used to assess
threshold of the desaturation index above which arterial hypertension is
favoured.
Generalized linear models were used to estimate the association between blood
pressure and OSA severity.
Results
Sample Characteristics
The studied population (n=98) is depicted in table 1.
During the 6 months of the study, the patients compliance with APAP was good
(table 2- information retrieved from ENCORE® APAP software), pressure on
90% nighttime decreased significantly during the study (mean baseline p90=
10.8 cmH20; mean final p90= 10.1; p<0,001) and the residual AHI (from
ENCORE® APAP software) was 2.7/h ±1.7.
63
During the study, patients did not loose significant weight (mean baseline
weight= 94.4 Kg; mean final weight= 94.1 Kg; p= 0.545) nor changed their fat
distribution (p= 0.151) according to waist/hip data pre- and post-treatment.
Those under anti-hypertensive medication (n=56) did not change neither the
medication nor its dosage during the study, and the drugs were always taken in
the morning (Table 3).
Habits and Comorbidities
In this population 42.5% patients were non-smokers; 39.6% former- smokers (>
1 year without smoking habits) and 17.9% had active smoking habits.
Arterial Hypertension (AH) was observed in 47.2% of cases (n=46), being 2.8%
nocturnal AH only.
Congestive heart failure was present in 9.4% patients, according to clinical
symptoms and medication used. History of stroke, acute myocardial infarction
(AMI) and angina was present in 15.1%, 7.5% and 1.9% patients, respectively.
Blood analysis showed that 75.5% patients had high serum lipid values (total
cholesterol> 2.00 g/L; LDL> 1.30 g/L; triglicerides>1.50 g/L) and 34.9% showed
glucose intolerance (fasting glucose> 1.15 g/L; HgA1c> 6%).
Baseline Associations
At baseline, the vast majority of the studied blood pressure parameters
significantly correlated with BMI, waist/hip ratio and OSA severity indexes
(Fig.1).
Daytime hypersomnia (measured by Epworth Sleepiness Scale) positively
correlated with mean overall ABP and all nighttime BP parameters and age did
correlate with diastolic ABP parameters.
Hypertensive patients were more obese (p<0.001) and showed a predominantly
central fat distribution (p=0.001) when compared to the others.
We could not find any relation between baseline blood pressure values and
smoking habits, caffeine intake or elevated lipid serum levels, but there was a
significant positive correlation between glucose intolerance and global mean
arterial blood pressure (p=0.001).
Considering all confounding factors found for this population (age, BMI,
waist/hip ratio, daytime hypersomnia, glucose intolerance), we observed a clear
64
positive independent relationship between desaturation index and almost all
studied blood pressure parameters (results not shown).
It was also possible to determine with a sensitivity of 76% and a specificity of
69.6% that patients who show a dessaturation index above 51.9% have a
greater possibility of having AH (p<0.001) (Figure 2).
Effect of APAP on Blood Pressure
Uncontrolled AH was found, according to 24-hour ambulatory blood pressure
(24-ABP) in 47.2% (n=46) patients (some were under anti-hypertensive
medication) at baseline and only in 8.5% after APAP therapy.
At baseline 38.7% patients were non dippers and after therapy only 21.7% were.
Following six months of APAP therapy, there was a statistically significant fall in
mean overall ABP of 7 mmHg, in mean systolic ABP of 6 mmHg, in mean
diastolic ABP of 5 mmHg, in daytime mean ABP of 6 mmHg and in nighttime
mean ABP of 8 mmHg (all p< 0.001) (Fig. 3).
There was no association between blood pressure parameters variation and
weight loss, body fat distribution change, anti-hypertensive therapy introduction
or modification, or change in smoking habits as none of them occurred.
Daytime mean ABP variation during the study positively correlates with the
percentage days of APAP usage (p= 0.021).
Patients who benefit more from the APAP therapy were those with higher AHI
(p=0.004) and with higher mean ABP values (p< 0.001) at baseline.
More sleepy patients did not show further benefit from APAP use when
compared to the others (p= 0.600 and p=0.570, respectively).
Patients under anti-hypertensive medications could not get further benefit from
APAP use when compared to the patients naïve from that kind of medication
(p=0,115)
Patients under angiotensin converting enzyme inhibitors (ACEI) showed greater
overall (p= 0.025) and daytime (p= 0.03) ABP decrease when compared with
those under other anti-hypertensive medications (Table 4).
65
Discussion
The prevalence of hypertension in this studied population, diagnosed on the
basis of 24-ABP monitoring at baseline, was high (47.2%), corroborating the
association between AH and OSA previously reported in several studies
(1,17,18,19,20,21,22,23).
After an average of 6 months of treatment, we found a statistical significant
decrease in overall mean ABP, mean systolic ABP, mean diastolic ABP,
daytime mean ABP and nighttime mean ABP, all between 8 and 5 mmHg fall,
identical to positive results with CPAP (11,12,24,25,26,27,28,29,30) after
adjustment for confounding factors (age, BMI, waist/hip ratio, daytime
hypersomnia and glucose intolerance) determined for this population. We do
not see the fact that the ABPM was repeated after 6 months only in those who
shown baseline abnormal blood pressure values as a limitation of the study as
our purpose was precisely to observe the effect of APAP especially on elevated
blood pressure levels, because the patients with uncontrolled hypertension are
those who leave us with greater concerns and those who need the therapy to
be most efficacious.
The nighttime mean ABP was the parameter that achieved a greater decrease
which is in agreement with other studies (31,32,33,34) and with the hypothesis
of being the intermittent activation of sympathetic nervous system due to
repetitive hypoxemia episodes during night the responsible for the increase in
blood pressure, first during night and later on also during day.
In our study, mean diastolic ABP was the blood pressure parameter with
smaller absolute value response (5 mmHg), differently from what was found by
other authors (14). As diastolic ABP ranges between more narrowed values has
a smaller magnitude than the systolic ABP and is a parameter significantly
associated with aging, as we could also demonstrate, this variable may not be
changeable by APAP therapy.
This study, as far as we know, is the first demonstrating a positive and
significantly effect of APAP on BP. We consider these results important and
very useful for the medical community as APAP devices are a recent alternative
66
treatment to traditional CPAP, that has already proved clinical efficacy
(35,36,37) and capability of increasing long-term treatment compliance
(35,38,39) as it is preferred by patients (35). Proving this benefit can mean a
change in the way medical community see and prescribe this therapy and
possibly, also, a way of saving costs as this therapeutic approach do not need
laboratory titration (40).
This study was designed to produce data that could easily be applied to clinical
practice. The severity of sleep apnoea in the study sample is representative of
that for which CPAP/APAP are generally used and baseline blood pressure was
not an exclusion criterion, so our results should reflect the blood pressure
benefit likely to be seen across hypertensive patients with OSA receiving APAP.
Also the empirical APAP prescribed pressure was according to general
moderate-severe OSA patients need, and in none of the patients the upper limit
pressure had to be increased.
Patients under antihypertensive drugs were not excluded from the study, also
because we wanted the sample to be representative from the overall OSA
patients. In those already taking anti-hypertensive medications we could not see
further benefit from APAP use when compared to the patients naïve from that
kind of medication as others did (26), but with a small group of patients.
From large prospective studies (41), a blood pressure fall of 3.3 mmHg would
be expected to be associated with a stroke risk reduction of about 20% and a
coronary heart disease event risk reduction of about 15%. Such a reduction in
BP is similar to that seen in a study (42) of pharmacological treatments for
control of hypertension.
In this study the BP reduction is even greater than that referred above and is
seen both in systolic and diastolic BP, and during both wake and sleep,
suggesting that the fall is associated with a general change in vascular pressure
regulation and allowing us to speculate about the benefits regarding to
cardiovascular risk control.
This reduction can be even greater than we could demonstrate as it has been
shown that 24-ABP monitoring causes arousal from sleep in 64% of the
recordings and leads to an increase in systolic and diastolic blood pressure by
13.7±15.9 mmHg and 3.7±8.2 mmHg, respectively (43).
67
So the 24-ABP monitoring will therefore underestimate the changes in nighttime
blood pressure caused by APAP and this fact could also explain the reduced
number of non-dippers that have turned to dippers during the study period
(17%).
There was no relevant change in body weight, body fat distribution, antihypertensive therapy, or smoking habits, so these factors did not contribute to
our results.
Differently from these factors, APAP compliance contributed positively to a
greater decrease in daytime mean ABP, thus confirming our hypothesis of being
this nocturnal ventilatory treatment effective in controlling AH.
The choice to include only male in this study was made in order to get a more
homogeneous sample.
In the present study, patients with more severe daytime hipersomnia did not
show further benefit from APAP use concerning blood pressure values when
compared to the others.
Some authors showed that non sleepy patients did not benefit from CPAP
therapy neither in quality of life, attention, memory, visuomotor coordination (44)
nor in ABP control (44,45,46,47). Our data does not parallel these observations,
as the less symptomatic patients had a treatment response as good as the
more symptomatic ones. Our data is in accordance with that of some groups
(29,48) in which a very good therapy compliance could probably explain the
ABP decrease after therapy in mildly sleepy patients.
The lack of a control group is obviously a shortcoming of the study design, but
we had to use this approach as it would be unethical either to withhold
treatment of moderate to severe OSA patients or to treat a control group with
APAP for 6 months.
The authors do not consider the OSA diagnosis based on a domiciliary sleep
study a limitation of the present study as this diagnosis tool has already been
compared to polysomnography showing to be a viable, accurate, satisfactory,
useful and cost effective way of diagnosing OSA (39,40).
68
Also, the difference found between AHI and DI is not surprising as some of the
desaturation events have not the sufficient duration in time to be accounted as
apnoeas or hypopnoeas.
In summary, results from this trial demonstrated that AH is a prevalent condition
among OSA patients.
Long term APAP therapy significantly reduces ABP and contributes to
normalize the nighttime dipper phenomenon.
Patients with more severe OSA and higher mean ABP values benefit more from
APAP therapy.
Acknowledgments
The authors would like to sincerely thank Prof. Ted Witek Jr. for the critical
review of the manuscript.
We would also like to thank Cardiopulmonologist Delfim Souteiro for his
colaboration on ambulatory blood pressure monitoring, to all Sleep Technicians
who manually reviewed all sleep studies and to Linde Med® for lenting us the
ABPM recorder.
Corresponding author
Marta Drummond
Serviço Pneumologia Hospital São João
Alameda Hernâni Monteiro
4200-319 Porto
Portugal
Telef. 00351919361582
[email protected]
69
References
1-Young T, Palta M, Dempsey J, skatrud J, Weber S, Badr S. The occurrence
of sleep-disordered breathing among middle-aged adults. N Engl J Med 1993;
328(17): 1230-1235
2- Young T, Peppard P, Gottieb D. The epidemiology of obstructive sleep
apnoea: a population health perspective. Am J Respir Crit Care Med 2002; 165:
1217-1239
3- Nieto FJ, Young TB, Lind BK, Shahar E, Samet JM, Redline S, Dágostino RB,
Newman AB, Lebowitz MD, Pickering TG. Association of sleep-disordered
breathing, sleep apnea, and hypertension in a large community-based study.
Sleep Heart Health Study. JAMA 2000; 283(14): 1829-1836
4- Lavie P, Herer P, Hoffstein V. Obstructive sleep apnoea syndrome as a risk
factor for hypertension: population study. BMJ 2000; 320(7233): 479-482
5- Bixler EO, Vgontzas AN, Lin HM, Have TT, Leiby BE, Vela-Bueno A, Kales A.
Association of hypertension and sleep-disordered breathing. Arch Intern Med
2000; 160: 2289-2295
6- Grote L, Ploch T, Heitmann J, Knaack L, Penzel T, Peter JH. Sleep-related
breathing disorder is an independent risk factor for systemic hypertension. Am J
Respir Crit Care Med 1999; 160(6): 1875-1882
70
7- Young T, Peppard P, Palta M, Hla KM, Finn L, Morgan B, Skatrud J.
Population-based study of sleep-disordered breathing as a risk factor for
hypertension. Arch Intern Med 1997; 157: 1746-1756
8- Chobanian AV, bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr,
Jones DW, Materson BJ, Oparil S, Wright JT Jr., Rocella EJ. Report of the Joint
National Comittee on Prevention, Detection, Evaluation and Treatment of High
Blood Pressure. JAMA 2003; 289: 2560-2572
9- Sullivan CE, Issa FG, Berthon-Jones M, Eves L. Reversal of obstructive
sleep apnoea by continuous positive airway pressure applied through the nares.
Lancet 1981; 1: 862-865
10- Giles T, Lasserson T, Smith BJ, White J, Wright J, Cates CJ. Continuous
positive airways pressure for obstructive sleep apnoea in adults. Cochrane
Database Syst Rev 2006; 1: CD001106
11- Haentjens P, Van Meerhaeghe A, Moscariello A, De Weerdt S, poppe K,
Dupont A, Velkeniers B. The impact of continuous positive airway pressure on
blood pressure in patients with obstructive sleep apnea syndrome. Arch Intern
Med 2007; 167: 757-765
12- Alajmi M, Mulgrew AT, Fox J, Davidson W, Schulzer M, Mak E, Ryan CF,
Fleetham J, Choi P, Ayas NT. Impact of continuous positive airway pressure
71
therapy on blood pressure in patients with obstructive sleep apnea hypopnea: a
meta-analysis of randomized controlled trials. Lung 2007; 185: 67-72
13- Dursunoglu N, Dursunoglu D, Cuhadaroglu C, Kiliçaslan Z. Acute effects of
automated continuous positive airway pressure on blood pressure in patients
with sleep apnea and hypertension. Respiration 2005; 72: 150-155
14- Patruno V, Aiolfi S, Costantino G, Murgia R, Selmi C, Malliani A, Montano N.
Fixed and autoadjusting continuous positive airway pressure treatments are not
similar in reducing cardiovascular risk factors in patients with obstructive sleep
apnea. Chest 2007; 131: 1393-1399
15- The report of an American Academy of Sleep Medicine Task Force. Sleeprelated breathing disorders in adults: recommendations for syndrome definition
and measurement techniques in clinical research. Sleep-related breathing
disorders in adults: recommendations for syndrome definition and measurement
techniques in clinical research. The report of an American Academy of Sleep
Medicine Task Force. Sleep 1999; 22(5): 667-689
16- Mancia, Giuseppea; Co-Chairperson; De Backer, Guyb; Co-Chairperson;
Dominiczak, Annac; Cifkova, Renatad; Fagard, Roberte; Germano, Giuseppef;
Grassi, Guidog; Heagerty, Anthony Mh; Kjeldsen, Sverre Ei; Laurent,
Stephanej; Narkiewicz, Krzysztofk; Ruilope, Luisl; Rynkiewicz, Andrzejm;
Schmieder, Roland En; Boudier, Harry AJ Struijker; Zanchetti, Albertop; New
European Guidelines on Treatment of Hypertension. J Hypertens 2007; 25 (9):
1751-1762
17- Millman RP, Redline S, Carlisle CC, Asaf AR, Levinson PD. Daytime
hypertension in obstructive sleep apnoea: prevalence and contributing factors.
Chest 1991; 99: 861-866
72
18- Podszus T, Mayer J, Penzel T, Peter JH, von Wichert P. Nocturnal
hemodynamics in patients with sleep apnea. Eur J Respir Dis 1986; 69: 435442
19- Guilleminault C, Tilkian A, Dement WC. The sleep apnea syndrome. Ann
Rev Med 1976; 27:465-484
20- Lavie P, Alroy G, Halperin E. Apneic and nonapneic breathing disorders in
sleep. Isr J Med Sci 1982; 18: 523-533
21- Shepard JW Jr, Garrison MW, Grither DA, Dolan GF. Relationship of
ventricular ectopy to oxyhemoglobin desaturation in patients with obstructive
sleep apnea. Chest 1985; 88: 335-340
22- Partinen M, Jamieson A, Guilleminault C. Long-term outcome for
obstructive sleep apnea syndrome patients (mortality). Chest 1988; 94: 12001204
23- Hla KM, Young TB, Bidwell T, Palta M, Skatrud JB, Dempsey J. Sleep
apnea and hypertension. A population based study. Arch Int Med 1994; 120:
382-388
24- Sanner BM, Tepel M, Markmann A, Zidek W. Effect of continuous positive
airway pressure therapy on 24-hour blood pressure in patients with obstructive
sleep apnea syndrome. Am J Hypertens 2002; 15: 251-257
73
25- Faccenda JF, Mackay TW, Boon NA, Douglas NJ. Randomized placebocontrolled trial of continuous positive airway pressure on blood pressure in the
sleep apnea-hyppnea syndrome. Am J Respir Crit Care Med 2001; 163: 344348
26- Pepperell JCT, Ramdassingh-Dow S, Crosthwaite N, Mullins R, Jenkinson
C, Stradling JR, Davies RJ. Ambulatory blood pressure after therapeutic and
subtherapeutic nasal continuous positive airway pressure for obstructive sleep
apnea: a randomized parallel trial. Lancet 2002; 359: 204-210
27- Becker HF, Jerrentrup A, Ploch T, Grote L, Penzel T, Sullivan CE, Peter JH.
Effect of nasal continuous positive airway pressure treatment on blood pressure
in patients with obstructive sleep apnea. Circulation 2003; 107: 68-73
28- Campos-Rodriguez F, Grilo-Reina A, Perez-Ronchel J, Merino-Sanchez M,
Gonzalez-Benitez MA, Beltran-Robles M, Almeida-Gonzalez C. Effect of
continuous positive airway pressure on ambulatory BP in patients with sleep
apnea and hypertension. Chest 2006; 129: 1459-1467
29- Hui DS, To KW, Ko FW, Fok JP, Chan MC, Ngai JC, Tung AH, Ho CW,
Tong MW, Szeto C-C, Yu C-M. Nasal CPAP reduces systemic blood pressure
in patients with obstructive sleep apnoea and mild sleepiness. Thorax 2006; 61:
1083-1090
74
30- Hermida RC, Zamarrón C, Ayala DE, Calvo C. Effect of continuous positive
airway pressure on ambulatory blood pressure in patients with obstructive sleep
apnoea. Blood Pressure monitoring 2004; 9(4): 193-202
31- Becker HF, Jerrentrup A, Ploch T, Grote L, Penzel T, Sullivan CE, Peter JH.
Effect of nasal continuous positive airway pressure treatment on blood pressure
in patients with obstructive sleep apnoea. Circulation 2003; 107: 68-73
32- Dimsdale JE, Loredo JS, Profant J. Effect of Continuous positive Airway
Pressure on blood pressure- a placebo trial. Hypertens 2000; 35: 144-147
33- Mayer J, Backer H, Brandenburg U, Penzel T, Peter JH, Wichert PV. Blood
pressure and sleep apnea: results on long-term nasal continuous positive
airway pressure therapy. Cardiology 1991; 79. 84-92
34- Davies RJO, Crosby J, Prothero A, Stradling JR. Ambulatory blood pressure
and left ventricular hypertrophy in subjects with untreated obstructive sleep
apnoea and snoring, compared with matched control subjects, and their
response to treatment. Clin Sci 1994; 86: 417-424
35- Nussbaumer Y. Bloch KE, Genser T, Thurnheer R. Equivalence of
Autoadjusted and Constant Continuous Positive Airway Pressure in home
treatment of Sleep Apnea. Chest 2006; 129: 638-643
36- Rubinsztajn R, Kumor M, Byskiniewicz K, Bielicki P, Chazan R. Serum leptin
concentration and sympathetic activation estimated on the adrenalin and noradrenalin serum
75
concentration in patients with obstructive sleep apnea.
Pol Arch Med Wewn 2005; 113
(6): 544-551
37- Ip MS, Lam KS, Ho C, Tsang KW, Lam W. Serum leptin and vascular risk
factors in obstructive sleep apnea. Chest 2000; 118: 580-586
38- Konermann M, Sanner BM, Vyleta M, Laschwski F, Groetz J, Sturm A,
Zidek W. Use of conventional and self-adjusting nasal positive airway pressure
for treatment of severe obstructive sleep apnea syndrome: a comparative study.
Chest1998; 113: 714-718
39- Golpe R, Jiménez A, Carpizo R. Home sleep studies in the assessment of
sleep apnea/hypopnea syndrome. Chest 2002; 122: 1156-1161
40- Masa JF, Jiménez A, Durán J, Capote F, Monasterio C, Mayos M, Terán J,
Hernández L, Barbé F, Maimó A, Rubio M, Montserrat JM. Alternative methods
of titrating Continuous Positive Airway Pressure. Am J Respir Crit Care Med
2004; 170: 1218-1224
41- McMahon S, Peto R, Cutler J, Collins R, Sorlie P, Neaton J, Abbott R,
Godwin J, Dyer A, Stamler J. Blood pressure, stroke, and coronary heart
disease. Part 1, prolonged differences in blood pressure: prospective
observational studies corrected for the regression dilution bias. Lancet 1990;
335: 765-774
42- Collins R, Peto R, MacMahon S, hebert P, Fiebach NH, Eberlein KA,
Godwin J, Qizilbash N, Taylor JO, Hennekens CH. Blood pressure, stroke and
coronary heart disease. Part 2, short-term reductions in blood pressure:
76
overview of randomised drug trials in the epidemiological context. Lancet 1990;
335: 827-838
43- Heude E, Bourgin P, Feigel P, et al. Ambulatory monitoring of blood
pressure disturbs sleep and raises systolic pressure at night in patients
suspected of suffering from sleep-disordered breathing. Clin Sci 1996; 91: 4550
44- Barbé F, Mayoralas LR, Duran J, Masa JF, Maimó A, Montserrat JM,
Monasterio C, Bosch M, Ladaria A, Rubio M, Rubio R, Medinas M, hernandez L,
Vidal S, Douglas NJ, Agusti AGN. Treatment with continuous positive airway
pressure is not effective in patients with sleep apnea but no daytime sleepiness.
Ann Intern Med 2001; 134: 1015-1023
45- Barnes M, Houston D Worsnop CJ, Neil AM, Mykytyn IJ, Kay A, Trinder J,
Saunders NA, Douglas McEvoy R, Pierce RJ. A randomized controlled trial of
continuous positive airway pressure in mild obstructive sleep apnea. Am J
respir Crit Care Med 2002; 165: 773-780
46- Robinson GV, Smith DM, Langford BA, Davies RJ, Stradling JR. CPAP
does not reduce blood pressure in non-sleepy hypertensive OSA patients. Eur
Respir J 2006; 27: 1229-1235
47- Barnes M, Mc Evoy RD, Banks S, Tarquinio N, Murray CG, Vowles N,
Pierce RJ. Efficacy of positive airway pressure and oral appliance in mild to
77
moderate obstructive sleep apnea. Am J respir Crit Care Med 2004; 170: 656664
48- Norman D, Loredo JS, Nelesen RA, Ancoli-Israel S, Mills PJ . Effects of
continuous positive airway pressure versus supplemental oxygen on 24-hr
ambulatory blood pressure. Hypertension 2006; 47(5): 840-845
78
Table 1. Characteristics of the study group
Study group
Age (years)
55.3±10.7
BMI (Kg/m2)
33.2±5.0
Waist-to-hip ratio
1±0.1
Epworth Scale
12.34±5.38
AHI
51.7±21.3
02 Desaturation index
86.3±5.3
Lowest 02 (%)
70.8±9.7
Mean 02 (%)
86.3±5.3
1- Body Mass Index
Table 2. APAP compliance
Mean
% APAP days of
usage
Total APAP days
of usage
Hours per night
of APAP usage
91.27 ± 20.45
171.2 ± 44.9
5.76 ± 1.59
Table 3. Anti-hypertensive medications habits
Medications
1
ACEI
Ca+ Angiotensin
β Blockers
Nitrates
2
ARA
Patients n (%)
35 (54.7)
13 (20.3)
21 (32.8)
5 (7.8)
23 (35.9)
1 - Angiotensin converting enzyme inhibitors
2 - Angiotensin receptors antagonists
79
Fig.1 – Overall mean Arterial Blood Pressure (ABP) significantly correlates with
OSA severity indexes (AHI, desaturation index and Sa02 min)
160
p= 0.004
r= 0.285
150
Overall m ean ABP (mm Hg)
140
130
120
110
100
90
80
70
60
0
20
40
60
80
100
120
AHI
140
p<0.001
r= 0.404
Overall m ean ABP (mm Hg)
130
120
110
100
90
80
70
60
0
20
40
60
80
100
120
De satura tion Index
140
p=0.035
r= -0.215
Overall m ean ABP (mm Hg)
130
120
110
100
90
80
70
80
60
30
40
50
60
70
Sa O2 min (%)
80
90
100
Fig. 2- Desaturation index above 51.9% favours arterial hypertension
81
Fig. 3- Effect of APAP on overall, daytime and nighttime ABP parameters
p < 0.001
p < 0.001
Blood Pressure
103.50
101.95
105
p < 0.001
Without APAP
95.80
With APAP
98.35
100
95.33
95
88,27
90
85
80
Overall mean ABP
Daytime mean ABP
Nighttime mean ABP
p < 0.001
134.98
150
140
Blood Pressure
Without APAP
128.43
With APAP
p < 0.001
130
120
110
100
83.17
77.77
90
80
70
60
Systolic mean
Diastolic mean
Table 4. Anti-hypertensive medications effect on overall ABP
Medications
1
p
ACEI
0.0025
Ca+ Angiotensin
0.843
β Blockers
0.760
Nitrates
0.455
2
ARA
0.594
1 - Angiotensin converting enzyme inhibitors
2 - Angiotensin receptors antagonists
82
Trabalho 4
Comparison of Echocardiographic findings between male patients with
OSA and community controls
83
Artigo submetido à revista Journal of Clinical Sleep Medicine
Comparison of Echocardiographic findings between male
patients with OSA and community controls
Marta Drummond*#, JC Winck*#, AC Santos**# H Barros**#C Gavina***#,
T Pinho***,JA Almeida*, JA Marques*#
Pulmonology Department* Hospital São João,
Hygiene and Epidemiology Department** Faculdade de Medicina do Porto,
Cardiology Department*** Hospital de São João
Faculdade de Medicina da Universidade do Porto #
Porto – Portugal
Alameda Hernâni Monteiro
4200-319 Porto
Abstract
Introduction- Obstructive sleep apnea (OSA) might cause cardiovascular
morbidity and mortality. Few published echocardiographic studies have
investigated the abnormalities present at OSA diagnosis and its comparison to
a control group.
Objectives- Compare the prevalence of echocardiographic abnormalities
between OSA male patients and community controls. Assess its relation to OSA
severity indices.
Materials and Methods- This is a case-control study which enrolled 70 male
patients with moderate to severe newly diagnosed OSA and 70 community
controls matched by gender, age and BMI.
Results- Cases mean age was 53.2 (SD 9.7), mean BMI 33.6 (SD 5.2), mean
AHI 54.4 (SD 20.5), mean desaturation index 49.6 (SD 23.7) and mean lowest
02 saturation 70.5 (SD 8.8). Controls mean age was 54.3 (SD 9.6) and mean
BMI 29.4 (SD 4.01). Within patients, 20% had Left Ventricular Hypertrophy
(LVH) 64.3% had interventricular septum (IVS) thickness and 71.6% Ventricular
Diastolic Disfunction (VDD). Several echocardiographic parameters were out of
normal limits: IVS, LVESD (left ventricular end systolic diameter) E/A (Ratio of
early and lately mitral flow velocity), ARD (aorta root diameter) and LAD (left
atrial diameter). IVS and MDT significantly correlated with OSA.
84
ConclusionsThe majority of moderate to severe OSA male patients show cardiac
abnormalities.
IVS hypertrophy and LV diastolic disfunction were significantly more prevalent
in cases than in controls.
Keywords- Echocardiographic abnormalities, Obstructive sleep apnoea,
Community controls, Arterial Hypertension
IntroductionObstructive sleep apnoea (OSA) is a condition defined by repeated episodes of
upper airway obstruction while sleeping (1). During an obstructive apnoea, large
negative intrathoracic pressure are generated by inspiratory efforts, which
increase transmural pressures across the myocardium, thus increasing
afterload (2). Also, venous return is increased (2) contributing to the
augmentation of preload and pulmonary congestion that are accompanied by
hypertensive crises due to catecholamine release (3,4).
These mechanisms suggest that OSA by itself may significantly affect cardiac
function.
There is growing evidence that patients with OSA have an increased risk of
cardiovascular complications (5,6), such as hypertension (7), heart failure (8),
left/right ventricular disfunction (2,9), angina (10) cardiac arrythmia (11,12),
pulmonary hypertension (13), stroke (14,15) and sudden death (16). In the light
of these established associations, it seems logical that the prognosis of OSA
would be closely related with cardiovascular events (17,18).
Therefore, early detection of patients with a poor prognosis would be extremely
useful.
In clinical practice, transthoracic echocardiography is a non invasive diagnostic
tool commonly used to measure systolic and diastolic cardiac function.
The left ventricular systolic and diastolic functions are closely related to
mortality and morbidity. Diastolic dysfunction precedes left ventricular systolic
85
impairment and accounts alone for about 30-40% of patients with left ventricular
failure (19,20). Early recognition and appropriate therapy of left ventricular
diastolic disfunction are advisable to prevent further progression to heart failure
and death (19,20,21,22).
Previous studies have been showing association between OSA and numerous
echocardiographic abnormalities (23,24,25).
In the present study, we aimed to compare the occurrence of echocardiographic
abnormalities between OSA male patients and community controls and
determine its association with OSA severity indices.
Participants and Methods
Study design
This is a community based case-control study.
All patients (cases and controls) gave written informed consent to participate in
the study. The used protocol was approved by the Hospital Ethics Committee
and the study was performed in accordance with the guidelines of the
Declaration of Helsinki and its current revision.
Cases
Initially, 83 male patients newly diagnosed with moderate/ severe OSA
(AHI>20/h) were included in the study.
Exclusion criteria were: female gender, echocardiographic evidence of atrial
fibrillation (AF), presence of cardiac valvular prothesis, history of myocardial
ischemia and insufficient reliability of echocardiographic window.
Following application of all these criteria, 70 patients were included in the study
protocol.
A complete medical history was obtained, and a physical examination and
echocardiographic study were performed.
24h- ambulatory blood pressure monitoring (24-ABPM) was performed in all
patients (see below, “Arterial Hypertension” paragraph).
86
All patients completed a questionnaire to assess the Epworth Sleepiness Scale
(ESS) which is a rapid, easily administrated, low cost and validated method for
screening of daytime sleepiness (26, 27, 28).
Controls
As part of an ongoing health and nutrition survey of the adult population of Porto,
Portugal, community dwellers were selected as controls. Full details on
participants selection have been previously described (29). In brief, non
institutionalized inhabitants of Porto, Portugal were selected using random digit
dialing. The cohort comprised the evaluation of 2488 participants. The exclusion
criteria were: echocardiographic evidence of atrial fibrillation (AF), history of
myocardial ischemia and insufficient reliability of echocardiographic window.
Also, although no sleep study was performed in controls, the ESS was 0 in all
and none referred snoring, nocturnal gasping and/or witnessed respiratory
events. After the application of the exclusion criteria, 70 male participants were
selected and matched with cases by gender, age and BMI.
All participants were invited to visit the Department of Hygiene and
Epidemiology of Porto Medical School for an interview, which included a
questionnaire on social, demographic and clinical data. All participants had an
anthropometric evaluation, fasting blood sample collected, spirometry and a
resting 12-lead ECG. Also, a cardiovascular physical examination and a
transthoracic M-mode, 2D echocardiogram and pulsed Doppler evaluation of
transmitral inflow were performed. Blood pressure was measured on a single
occasion with a standard mercury sphygmomanometer with the cuff on the right
upper arm. Two blood pressure readings were taken with the participant fasting
and after an at least 10 minutes resting. The mean of the two reading was
calculated. If the two reading differed more than 5 mm Hg a third reading was
taken and the mean of the two closest readings kept.
87
Study procedures
Pulmonary Function Tests
Pulmonary function tests (Sensor medics 2400®, The Netherlands), were
performed in all cases and controls, and Chronic Obstructive Pulmonary
Disease (COPD) was excluded in all participants (FEV1/FVC > 70).
Sleep Study- cases
An overnight sleep study was performed, in all cases, using an Alphascreen;
Vyasis device which has been validated previously (30). This device produces a
computorized recording of variations in oronasal airflow (measured by nasal
cannula), body position, wrist actimetry, pulse rate, arterial oxygen saturation
(measured by finger pulse oximetry), thoracic and abdominal effort. The device
estimates the total sleep time from the wrist actimetry registry, eliminating those
periods with high activity. It automatically calculates the number of apnoeas
plus hypopnoeas per hour of estimated sleep time (automatic respiratory
disturbance index) and it also provides information of desaturations > 4% per
hour (Desaturation Index) of estimated sleep time and the cumulative
percentages of sleep time under 90% oxygen saturation. In all cases, sleep
technicians carried out a manual analysis of the recordings, by counting apnoea
(episodes of ≤ 20% of previous airflow with at least 10 seconds of duration)
and hypopnoea episodes (episodes showing 20 to 50% of the previous airflow,
with at least 10 seconds of duration joined with a 4% dip in oxygen saturation),
dividing the total number of these episodes by the sleep time in hours, thus
obtaining the manual respiratory disturbance index according to established
criteria (31).
Echocardiography- cases
All measurements were performed with the subjects (cases and controls) in the
left lateral decubitus position using M-mode, two dimensional and Doppler
ultrasound echocardiography by two experienced physicians blinded to patients
88
clinical characteristics, including comorbidities and medications used. The
ultrasound equipment used was Sonos 5500® echocardiograph and a 2.5-MHz
probe (Philips, Eindhoven, The Netherlands). The duration of the examinations
was at least 20 min. Three consecutive measurements were taken for each
parameter and its mean was used for the analysis. Measurements were
recorded in midexpiratory apnoea. The ventricular diameters, volumes and
functions were measured according to the recommendations of the American
Society of Echocardiography (32). Basic measurements of left ventricular
dimensions in diastole and systole, thickness of interventricular septum (IVS),
left ventricular posterior wall (LVPW) were performed by the M-mode technique.
Early (E) and Atrial (A) transmitral maximal flow velocities, its ratio (E/A) and
mitral deceleration time (MDT) were registered.
In patients, Tissue Doppler Imaging (TDI) was used to assess left ventricular
(LV) diastolic function.
Interventricular septum hypertrophy was defined as- mild (>11 and <14mm);
moderate (>14 and < 16mm) and severe (>16mm).
LV hypertrophy was defined as increased mass and relative wall thickness of
the LV (33).
LV diastolic disfunction was defined as the positive evidence of abnormal LV
relaxation, filling, diastolic distensibility and diastolic stiffness according to
European Study Group (34).
LV systolic disfunction was defined as the positive evidence of abnormal
contraction of muscle fibers in the LV midwall (35,36) as this may better reflect
intrinsic contractility than contraction of fibers at the endocardium (37).
Arterial Hypertension- cases
The presence of AH was assessed in all OSA patients, at baseline, using a 24ABPM recorder (Spacelab, Inc 90207 Neural). Patients with abnormal 24-ABPM
results and/ or under antihypertensive medications were considered to have AH.
A trained technician fitted an appropriately sized cuff on the patients nondominant arm, which was worn for the subsequent 24 hours, during normal
daily activities. Monitors were programmed for cuff inflation measurement every
89
20 minutes during the day and every 30 minutes during the night. Hypertension
was defined according to European and JNC-VII guidelines (38).
The measured Blood pressure (BP) parameters were: overall mean arterial
pressure (MAP), overall MAP min, overall MAP mean, overall MAP max, overall
systolic min, overall systolic mean, overall systolic max, overall diastolic min,
overall diastolic mean, overall diastolic max, daytime MAP min, daytime MAP
mean, daytime MAP max, daytime systolic min, daytime systolic mean, daytime
systolic max, daytime diastolic min, daytime diastolic mean, daytime diastolic
max, night-time MAP min, night-time MAP mean, night-time MAP max, nighttime systolic min, night-time systolic mean, night-time systolic max, night-time
diastolic min, night-time diastolic mean, night-time diastolic max.
Statistical Analysis
Data were described as mean and standard deviation (SD) or median and
interquartile range (IQR) for quantitative variables and compared using the
Student-t test or the Mann Whitney test as appropriate. Categorical variables
were described as counts and proportions, and compared using the chi-square
or Fisher’s exact test. Odds ratios (OR) and the respective 95% confidence
intervals (95% CI) were estimated using conditional logistic regression models.
These models were used to assess the independent association between OSA
and
echocardiographic
parameters,
after
adjustment for
the
potential
confounders.
Results
Sample Characteristics
The studied sample characteristics, habits and comorbidities are depicted in
Table 1.
In OSA patients, mean overall blood pressure (BP), mean systolic BP and mean
diastolic BP were, respectively, 98.8 (SD 11.4) mmHg, 130.4 (SD 12.4) mmHg
and 81.4 (SD 8.8) mmHg, being the AH prevalence 48.5%. In controls, mean
BP, mean systolic BP and mean diastolic BP were respectively 129.7 (SD 14.3)
90
mmHg, 140.1 (SD 21.2) mmHg and 87.4 (SD 9.5) mmHg. The AH prevalence in
controls was 58.6%.
OSA patients sleep characteristics are described in Table 2.
Echocardiographic parameters
Baseline characteristics and left ventricular structure and function indices in
OSA patients and controls are showed in Table 3. Several echocardiographic
left heart functional and structural parameters were out of the normal limits at
baseline, in cases: LVESD (left ventricular end systolic diameter) and E/A (Ratio
of early and lately mitral flow velocity) and IVS (interventricular septum) were
under the normal range; ARD (aorta root diameter) and LAD (paraesternal left
atrial diameter) were above the normal limits (see Tables 3 and 4).
Furthermore, LAD and IVS thickness were significantly higher in cases (both p<
0.001) as also LVPW (p=0.002) than in controls. MDT was significantly shorter
in OSA patients when compared to controls (p< 0.001), all independently of
confounders (BMI, AH, Dyslipidemia) (Table 4).
Right ventricular structure and function indices in OSA patients and controls are
depicted in Table 5. All these parameters are within the normal range, in cases
and controls.
Forty five patients (64.3%) showed IVS hypertrophy vs thirty controls (42.9%)
(p=0.005); 1.4% (n=1) of OSA patients showed Left Ventricular Systolic
Disfunction (LVSD) and none of the controls had such an abnormality; 71.6%
(n=48) OSA patients showed Left Ventricular Diastolic Dysfunction (LVDD) vs
19 controls (27.9%) (p< 0.001) and 14.3% OSA patients showed left ventricular
hypertrophy (LVH) vs 13 controls (18.8%) (p=0.494) (Fig.1).
Associations with Echocardiographic parameters in cases
Two of the abnormal left ventricular parameters (IVS, LVESD) at baseline
showed correlation with hypertension assessed by mean overall BP (Table 6).
91
Smoking habits did not correlate with echocardiographic parameters (all
parameters with p> 0.1).
None of the abnormal echocardiographic parameters found in cases (IVS,
LVESD, E/A, ARD and LAD) showed correlation with OSA severity indices
(Table 7).
Discussion
The cardiovascular repercussions of OSA have been recognized for some time
(3-5,10, 11, 14) and it seems clear that the prognosis of this disease is linked to
the incidence of cardiovascular events (17,18).
Studies (2,25,39) performed with noninvasive techniques, such as Doppler
Echocardiography have assessed the prevalence of heart disease in these
patients.
In the present study, several cardiac parameters (IVS, LVESD, LAD, ARD, E/A),
were out of the normal limits.
IVS and LVESD showed significant association with BP.
IVS positively correlates with OSA, independently of confounders (BMI,AH,
dyslipidemia).
Thus, we can state that some of the echocardiographic abnormalities found
might be explained by the elevated prevalence of AH among these patients
population. Others cannot; like IVS whose origin probably is dependent on OSA
pathophysiology itself.
Also, in the current study, 14.3% patients showed LVH and the majority (64.3%)
had slight IVS hypertrophy. Both findings may be explained by high BP and/or
nocturnal hypoxemia, as others reported (7, 8). In this study, only IVS, of both
parameters, showed association with BP, furthermore IVS hipertrophy was
significantly more prevalent in cases than in controls, independently of
confounders, so hypoxemia, an OSA landmarck, may play a predominant role in
cardiac abnormalities.
92
In what concerns right heart parameters, no abnormalities were seen in the
studied population, as reported in previous studies (18,40), in contrast to results
of Shivalkar (41) and Dursunoglu (39,42). The former author (41) reported
significantly larger right ventricular diameters, which correlated with OSA
severity, and attributed them to an increase of venous return and to transient
presence of nocturnal pulmonary hypertension. Both findings are only justifiable
if patients have associated pulmonary disease (43) or daytime hypercapnia due
to very severe OSA (44), that was not the case of our studied population.
The reason for the disparate conclusions of the prior studies examining right
ventricular mass and function may be the complexity of right ventricular diastolic
filling event that is influenced by several factors, such as right ventricular
relaxation and compliance, right atrium contraction and pulmonary artery
resistance, thus resulting the possible disfunction of a variety of impairments.
Concerning diastolic cardiac function in patients with OSA, previous studies
have yielded conflicting results (45,46,47,48). Furthermore one large clinic
population study (49) shown that OSA does not impair LV diastolic function.
These discrepancies may be related to the use of conventional Doppler
echocardiography and its limited value in diagnosing diastolic disfunction.
It is generally accepted that conventional Doppler alone is not accurate for
detecting early diastolic disfunction in patients with a normal ejection fraction
(50,51). Tissue Doppler Imaging (TDI) has emerged as a sensitive tool for
detecting early abnormalities of systolic and diastolic functions (52,53,54).
In our study, the prevalence of LV diastolic disfunction was significantly higher
in cases when compared to controls (p< 0.001) and E/A mitral flow velocity was
slightly decreased in moderate to severe OSA patients when compared to the
normal values. Our results can probably be explained by the usage of TDI
Doppler instead of conventional Doppler and 2-dimensional parameters as the
latter seem less sensitive (55,56).
MDT, a sensitive parameter for the assessment of LV diastolic function (57) was
within normal limits in OSA patients, however it correlates negatively with OSA,
independently of confounders. So we may hypothesize that we have diagnosed
LV diastolic disfunction at an early stage as not all the diastolic function markers
were abnormal.
93
Only IVS and MDT, among abnormal cardiac parameters found in OSA patients,
showed association with OSA as others have reported (42,58).
Our results suggest that the majority of OSA patients might have subclinical
myocardial disfunction, predisposing them to develop heart failure that can be
early detected by a non invasive technique. Echocardiograph is easily and
quickly performed, being a useful screening tool for silent myocardial disfunction.
So, it would be advisable to perform TDI echocardiography to all newly
diagnosed severe OSA patients, considering that diastolic disfunction is a major
risk factor for overt congestive heart failure development and subsequent
cardiac mortality.
There are some limitations in our study.
First, we included only men, so our results cannot be generalized to women
with this condition.
Second, the absence of a sleep study among controls can be seen as a
shortcoming of the present study despite all controls were evaluated in what
concerns OSA related symptoms and performed ESS that is the most accurate
and a validated tool to assess daytime sleepiness (25,26,27), a clinical
surrogate of OSA.
Third, the AH diagnosis, between cases and controls, was based on different
methods, as the former performed a 24-hour AMBP and the latter were
evaluated using an office sphygmomanometer.
Fourth, TDI was only available in OSA patients and not to controls, being
possible that some minor findings in controls were missed.
Conclusions
The majority of moderate to severe OSA male patients show echocardiographic
abnormalities.
IVS hypertrophy and left ventricular diastolic disfunction were significantly more
prevalent in cases than in controls, independently of confounders.
MDT and IVS showed association with OSA, independently of confounders.
94
Conflict of interests
There are no financial or personal relationship with other people or
organisations that could inappropriately influence this work.
Corresponding author
Marta Drummond
Serviço Pneumologia Hospital São João
Alameda Hernâni Monteiro
4200-319 Porto
Portugal
Telef. 00351919361582
[email protected]
References
1- Guilleminault C, Tilkian A, Dement WC. The sleep apnea syndromes. Annu
Rev Med 1976; 27: 465-484
2- Dursunoglu D, Dursunoglu N, Evrengül H, Özkurt S, Kuru Ö, Kiliç M, Fisekçi
F. Impact of obstructive sleep apnea on left ventricular mass and global function.
Eur Resp J 2005; 26: 283- 288
3- Bradley TD, Floras JS, Phil D. Sleep apnea and heart failure: Part I:
obstructive sleep apnea. Circulation 2003; 107: 1671-1678
4- Ferreira S, Winck J, Bettencourt P, Rocha-Gonçalves F. Heart failure and
sleep apnea: to sleep perchance to dream. Eur J Heart Fail 2006; 8: 227-236
95
5- Shahar E, Whitney CW Redline S, Lee ET, Newman AB, Javier Nieto F,
O´Connor GT, Boland LL, Schwartz JE, Samet JM. Sleep-disordered breathing
and cardiovascular disease: cross- sectional results of the Sleep Heart Health
Study. Am J Respir Crit Care Med 2001; 163: 19-25
6- Peker Y, Hedner J, Norum J, Kraiczi H, Carlson J. Increased incidence of
cardiovascular disease in middle-aged men with obstructive sleep apnea: a 7year follow-up. Am J Respir Crit Care Med 2002; 166: 159-165
7- Chobanian A, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr,
Jones DW, Materson BJ, Oparil S, Wright JT Jr, Roccella EJ. National Heart,
Lung and Blood Institute Joint National Committee on Prevention, Detection,
Evaluation and Treatment of High Blood Pressure and National High Blood
Pressure Education Program Coordinating Committee. The seventh report of
the Joint National Committee on Prevention, Detection, Evaluation and
Treatment of High Blood Pressure the JNC 7 report. JAMA 2003; 289:25602572
8- Javaheri S, Parker TJ, Liming JD, Corbett WS, Nishiyama H, Wexler L,
Roselle GA. Sleep apnea in 81 ambulatory male patients with stable heart
failure: types and their prevalences, consequences and presentations.
Circulation 1998; 97: 2154-2159
9- Hedner J, Ejnell H, Caidahl K. Left ventricular hypertrophy independent of
hypertension in patients with obstructive sleep apnea. J Hypertens 1990; 8:
941-946
10- Franklin K, Nilsson JB, Sahlin C, Näslund U. Sleep apnea and nocturnal
angina. Lancet 1995; 345: 1085-1087
11- Hoffstein V, Mateika S. Cardiac arrythmias, snoring and sleep apnea. Chest
1994; 106: 466-471
96
12- Gami AS, Pressman G, Caples SM, Kanagala R, Gard JJ, Davison DE,
Malouf JF, Ammash NM, Friedman PA, Somers UK.
Association of atrial
fibrillation and obstructive sleep apnea. Circulation 2004; 110: 364-367
13- Marrone O, Bonsignore MR. Pulmonary haemodynamics in obstructive
sleep apnea. Sleep Med Rev 2002; 6: 175-193
14- Parra O, Arboix A, Montserrat JM, Quinto L, Bechich S, García-Eroles L.
Sleep-related breathing disorders: impact on mortality of cerebrovascular
disease. Eur Respir J 2004; 24: 267-272
15- Yaggi HK, Concato J, Kernan WN, Lichtman JH, Brass LM, Mohsenin V.
Obstructive sleep apnea as a risk factor for stroke and death. N Engl J Med
2005; 353: 2034-2041
16- Gami AS, Howard DE, Olson EJ, Somers UK. Day-night pattern of sudden
death in obstructive sleep apnea. N Engl J Med 2005; 352: 1206-1214
17- Baguet JP, Pepin JL, Hammer L, Levy P, Mallion JM. Cardiovascular
consequences of obstructive sleep apnea syndrome. Med Intern 2003; 24: 530537
18- Marín JM, Carrizo SJ, Vicente E, Agustí AG. Long-term cardiovascular
outcomes in men with apnoea-hypopnoea with or without treatment with
continuous positive airway pressure: an observational study. Lancet 2005; 365:
1046-1053
19- Bonow RO, Udelson JE. Left ventricular diastolic dysfunction as a cause of
congestive heart failure. Mechanisms and management. Ann intern Med 1992;
117: 502-510
20- Fischer M, Baessler A, Hense HW, Hengstenberg C, Muscholl M, Holmer S,
Döring A, Broeckel U, Riegger G, Schunkert H. Prevalence of left ventricular
diastolic dysfunction in the community. Results from a Doppler
97
echocardiographic-based survey of a population sample. Eur Heart J 2003; 24:
320-328
21- Petrie MC, Caruana L, Berry C, McMurray JJ. “Diastolic heart failure” or
heart failure caused by subtle left ventricular systolic dysfunction? Heart 2002;
87: 29-31
22-
Cohen GI, Bietrolungo JF, Thomas JD, Klein AL. A practical guide to
assessment of ventricular diastolic function using Doppler echocardiography. J
Am Coll Cardiol 1996; 27: 1753-1760
23- Cloward TV, walker JM, Farney RJ, Anderson JL. Left ventricular
hypertrophy is a common echocardiographic abnormality in severe obstructive
sleep apnea and reverses with nasal continuous positive airway pressure.
Chest 2003; 124: 594-601
24- Fung JWH, Li TST, Choy DKL, Yip GWK, Ko FWS, Sanderson JE, Hui DSC.
Severe obstructive sleep apnea is associated with left ventricular diastolic
dysfunction. Chest 2002; 121: 422-429
25- Romero-Corral A, Somers VK, Pellikka PA, Olson EJ, Bailey KR, Korinek J,
Orban M, Sierra-Johnson J, Kato M, Amin RS, Lopez-Jimenez F. Decreased
right and left ventricular myocardial performance in obstructive sleep apnea.
Chest 2007; 132: 1863-1870
26- Johns MW. A new method for measuring dytime sleepiness: the Epworth
slepiness scale. Sleep 1991; 14: 540-545
27- Johns MW. Sleepiness in different situations measured by the Epworth
Sleepiness Scale. Sleep 1994; 17: 703-710
28- Johns MW. Reliability and factor analysis of the Epworth Sleepiness Scale.
Sleep 1992; 15: 376-381
98
29- Santos AC, Ebrahim S, Barros H. Alcohol intake, smoking, sleeping hours,
physical activity and the metabolic syndrome. Prev Med 2007; 44: 328-34
30- García-Díaz E, Quintana-Gallego E, Ruiz A, Carmona-Bernal C, SanchézArmengol A, Botebol-Benhamou G, Capote F. Respiratory Poligraphy with
actigraphy in the diagnosis of Sleep Apnea-Hypopnea Syndrome. Chest 2007;
131 (3): 725-732
31- The report of an American Academy of Sleep Medicine Task Force. Sleeprelated breathing disorders in adults: recommendations for syndrome definition
and measurement techniques in clinical research. Sleep-related breathing
disorders in adults: recommendations for syndrome definition and measurement
techniques in clinical research. The report of an American Academy of Sleep
Medicine Task Force. Sleep 1999; 22(5): 667-689
32- Schiller NB, Shah PM, Crawford M, DeMaria A, Devereux R, Feigenbaum H,
Gutgesell H, Reichek N, Sahn D, Schnittger I. American Society of
Echocardiography Committe on standards, Subcommitte on quantitation of two
dimensional echocardiograms: recommendations for quantitation of the left
ventricle by two-dimensional echocardiography. J Am Soc Echocardiogr 1989;
2: 358-367
33- Nagueh SF, Appleton CP, Gillebert TC, Marino PN, Oh JK, Smiseth OA,
Waggoner AD, Flachskampf FA, Pellikka PA, Evangelista A. Recommendations
for the evaluation of Left Ventricular Diastolic Function by Echocardiographyguidelines and standards. J Am Soc Echocardiogr 2009; 22(2): 107-133
34- European Study Group on Diastolic Heart Failure. How to diagnose diastolic
heart failure. Eur Heart J 1998; 19: 990-1003
35- de Simone G, Devereux RB, Roman MJ, Ganau A, Saba PS, Alderman MH,
Laragh JH. Assessment of left ventricular function by the midwall fractional
shortening/end-systolic stress relation in human hypertension. J Am Coll Cardiol
1994; 23: 1444-1451
99
36- Shimizu G, Zile MR, Blaustein AS, Gaasch WH. Left ventricular chamber
filling and midwall fiber lengthening in patients with the left ventricular
hypertrophy: overestimation of fiber velocities by conventional midwall
measurements. Circulation 1985; 71: 266-272
37- Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA,
Picard MH, Roman MJ, Seward J, Shanewise JS, Solomon SD, Spencer KT,
Sutton MSJ Stewart WJ. Recommendations for chamber quantification: a report
from the American Society of Echocardiography´s Guidelines and Standards
Committee and the Chamber quantification Writing Group, developed in
conjunction with the European Association of Echocardiography, a branch of
the European Society of Cardiology. J Am Soc Echocardiogr 2005; 18: 14401463
38- Mancia, Giuseppea; Co-Chairperson; De Backer, Guyb; Co-Chairperson;
Dominiczak, Annac; Cifkova, Renatad; Fagard, Roberte; Germano, Giuseppef;
Grassi, Guidog; Heagerty, Anthony Mh; Kjeldsen, Sverre Ei; Laurent,
Stephanej; Narkiewicz, Krzysztofk; Ruilope, Luisl; Rynkiewicz, Andrzejm;
Schmieder, Roland En; Boudier, Harry AJ Struijker; Zanchetti, Albertop; New
European Guidelines on Treatment of Hypertension. J Hypertens 2007; 25 (9):
1751-1762
39- Dursunoglu N, Dursunoglu D, Ozturk S, Gur S, Ozalp G, Evyapn F. Effects
of CPAP on right ventricular myocardial performance index in obstructive sleep
apnea patients without hypertension. Resp Res 2006; 7: 22-29
40- Hanly P, Sasson Z, Zuberi N, Alderson M. Ventricular function in snorers
and patients with obstructive sleep apnea. Chest 1992; 102: 100-105
41- Shivalkar B, Van de Heyning C, Kerremans M, Rinkevich D, Verbraecken J,
De Backer W, Vrints C. Obstructive sleep apnea syndrome: more insights on
structural and functional cardiac alterations, and the effects of treatment with
continuous positive airway pressure. J Am Coll Cardiol 2006; 47: 1433-1439
100
42- Dursunoglu N, Dursunoglu D, Kiliç M. Impact of obstructive sleep apnea on
right ventricular global function: sleep apnea and myocardial performance index.
Respiration 2005; 72(3): 278-284
43- Bradley TD, Rutherford R, Grossman RF, Lue F, Zamel N, Moldofsky H,
Phillipson EA. Role of daytime hypoxemia in the pathogenesis of right heart
failure in the obstructive sleep apnea syndrome. Am Rev Respir Dis 1985; 131:
835-839
44- Nahmias J, Lao R, Karetzky M. Right ventricular dysfunction in obstructive
sleep apnoea: reversal with nasal continuous positive airway pressure. Eur
Respir J 1996; 9: 945-951
45- Arias MA, García-Río F, Alonso-Fernández A, Mediano O, Martínez I,
Villamor J. Obstructive sleep apnea syndrome affects left ventricular diastolic
function: effects of nasal continuous positive airway pressure in men.
Circulation 2005; 112: 375-383
46- Kraiczi H, Caidahl K, Samuelsson A, Peker Y, Hedner J. Impaiment of
vascular endothelial function and left ventricular filling: association with the
severity of apnea-induced hypoxemia during sleep. Chest 2001; 119: 10851091
47- Fung JW, Li TS, Choy DK, Yip GW, Ko FW, Sanderson JE, Hui DS. Severe
obstructive sleep apnea is associated with left ventricular diastolic dysfunction.
Chest 2002; 121: 422-429
48- Sidana J, Aronow WS, Ravipati G, Di Stante B, McClung JA, Belkin RN,
Lehrman SG. Prevalence of moderate or severe left ventricular diastolic
dysfunction in obese persons with obstructive sleep apnea. Cardiology 2005;
104: 107-109
101
49- Niroumand M, Kuperstein R, Sasson Z, Hanly PJ. Impact of obstructive
sleep apnea on left ventricular mass and diastolic function. Am J Respir Crit
Care Med 2001; 163: 1632-1636
50- Yamamoto K, Nishimura RA, Chaliki HP, Appleton CP, Holmes DR Jr,
Redfield MM. Determination of left ventricular filling pressure by Doppler
echocardiography in patients with coronary artery disease: critical role of left
ventricular systolic function. J Am Coll Cardiol 1997; 30: 1819-1826
51- Ommen SR, Nishimura RA, Appleton CP, Miller FA, Oh JK, Redfield MM,
Tajik AJ. Clinical utility of Doppler echocardiography and tissue Doppler imaging
in the estimation of left ventricular filling pressures: a comparative simultaneous
Doppler-catheterization study. Circulation 2000; 102: 1788-1794
52- Rodriguez L, Garcia M, Ares M, Griffin BP, Nakatani S, Thomas JD.
Assessment of mitral annular dynamics during diastole by Doppler tissue
imaging: comparison with mitral Doppler inflow in subjects without heart disease
and in patients with left ventricular hypertrophy. Am Heart J 1996; 131: 19821987
53- Dokainish H. Tissue Doppler imaging in the evaluation of left ventricular
diastolic function. Curr Opin Cardiol 2004; 19: 437-441
54- Khouri SJ, Maly GT, Suh DD, Walsh TE. A practical approach to the
echocardiographic evaluation of diastolic fnction . J Am Soc Echocardiogr
2004;17: 290-29
55- Temporelli PL, Giannuzzi P, Nicolosi GL, Latini R, Franzosi MG, Gentile F,
Tavazzi L, Maggioni AP and GISSI- 3 Echo Substudy Investigators. J Am Coll
Cardiol 2004; 43: 1646-1653
56- Osranek M, Steward JB, Buschenreithner B, Bergler-Klein J, Heger M,
Klaar U, Binder T, Maurer G, Zehetgruber M. Diastolic function assessment in
102
clinical practice: the value of 2-dimensional echocardiography. Am Heart J
2007; 154: 130-136
57- Rodriguez L, Garcia M, Ares M, Griffin BP, Nakatani S, Thomas JD.
Myocardial wall velocity assessment by pulsed Doppler tissue imaging:
characteristic findings in normal subjects. Am Heart J 1996; 132: 648-656
58- Kim SH, Cho GY, Shin C, Lim HE, Kim YH, Song WH, Shim WJ, Ahn JC.
Impact of obstructive sleep apnea on left ventricular diastolic function. Am J
Cardiol 2008; 101: 1663-1668
Table 1. Characteristics of the study group (n=70) and the control group
(n=)
Variables
Mean age (years)
BMI1 (Kg/m2)
Waist/hip
Habits and
comorbidities
Arterial Hypertension
History of Stroke
Dyslipidemia 2
Smokers
Non-smokers
Former Smokers3
Cases
Mean
53.2
33.6
0.99
n (%)
36 (51.5)
7 (10)
53 (76.9)
13 (18.6)
26 (37.1)
31 (44.3)
sd
9.7
5.2
0.06
Controls
Mean
54.3
29.4
0.96
n (%)
41 (58.6)
0 (0)
26 (37.7)
18 (25.7)
17 (24.3)
35 (50.0)
1-
Body Mass Index
2-
Total cholesterol> 2.00 g/L and/or LDL> 1.30 g/L and/or triglycerides>1.50 g/L
3-
Former smoker > 1 year without smoking habitus
p
sd
9.6
4.01
0.05
0.943
< 0.001
0.003
0.075
0.013
< 0.001
103
Table 2- Sleep characteristics of the OSA population
1
AHI
DI2
Sat02 min3
ESS4
Mean
54.4
49.6
70.5
12.8
Standard deviation
20.5
23.7
8.8
5.7
1- Apnoea/ Hypopnoea Index
2- Desaturation Index
3- Lowest oxygen saturation
4- Epworth Sleepiness Scale
Table 3. Echocardiographic measures and left ventricular structure and
function indices in OSA patients and controls
Basic measurements
Aorta root (mm) (20-30 mm)*
LAD1 (mm) (19-40)*
Left Ventricular Structure
IVS2 thickness (mm) (6-11)*
LVPW 3 (mm) (6-11)*
LVEDD4 (mm) (37-56)*
Diastolic Functions
E/A6 (>1)*
MDT7 (m/s) (<220)*
*
Cases
Mean (SD)
33.3 (6.50)
40.3 (3.88)
Controls
Mean (SD)
33.5 (2.64)
38.0 (4.32)
p value
0.405
< 0.001
12.1 (2.00)
10.1 (1.84)
48.5 (5.10)
10.3 (1.48)
9.13 (1.52)
49.23 (5.09)
< 0.001
0.002
0.481
0.99 (0.37)
200.1 (41.3)
1.06 (0.30)
237.43 (52.93)
0.102
< 0.001
Normal values
1.
LAD= paraesternal left atrial diameter
2.
IVS= interventricular septum
3.
LVPW= left ventricular posterior wall
4.
LVEDD= left ventricular end diastolic diameter
5.
LVESD= left ventricular end systolic diameter
6.
E/A= ratio of early and lately mitral flow velocity
7.
MDT= Mitral deceleration time
104
Table 4. Multivariate analysis
Crude OR (95%
CI)
1.15 (1.05-1.27)
2.2 (1.52-3.1)
1.37 (1.10-1.69)
0.98 (0.97-0.99)
LAD
IVS
LVPW
MDT
OR (95% CI)*
OR (95% CI)**
1.05 (0.94-1.17)
1.97 (1.33-2.91)
1.14 (0.86-1.50)
0.97 (0.95-0.99)
1.08 (0.95-1.22)
2.15 (1.29-3.57)
1.24 (0.85-1.81)
0.98 (0.95-1.00)
*OR adjusted for body mass index.
**OR adjusted for body mass index, hypertension and dyslipidemia.
Table 5. Right ventricular structure and function indexes in OSA patients
and controls
Variables
E-velocity1 (m/s)
2
A- velocity (m/s)
3
E/ A (>1)*
Cases
Mean (SD)
71.4 (17.6)
Controls
Mean (SD)
73.9 (15.4)
p value
0.362
77.1 (17.6)
73.2 (17.1)
0.386
1.00 (0.37)
1.06 (0.30)
0.308
E-velocity= early tricuspid flow velocity
A-velocity= lately tricuspid flow velocity
E/A= ratio E-velocity/ A- velocity
Table 6. Associations of Left Ventricular Abnormal echocardiographic
parameters to Mean overall BP in cases
Variables
IVS1
LVESD2
E/A3
MDT4
LVPW5
LAD6
p
0.001
0.049
0.062
0.161
0.336
0.107
r
0.379
0.286
-0.227
-0.173
0.117
0.194
1- IVS= interventricular septum
2- LVESD= left ventricular end systolic diameter
3- E/A= ratio E-velocity/ A- velocity
4- MDT= mitral deceleration time
5- LVPW= left ventricular posterior wall
6- LAD= paraesternal left atrial diameter
105
Table 7. Associations of Abnormal echocardiographic parameters in
cases and OSA severity indices
Echocardiographic AHI5
AHI
DI6
DI
Sat min 027
Sat min 02
findings
r
p
r
p
r
p
ARD1
-0.016
0.895
-0.036
0.778
-0.198
0.112
IVS2
-0.082
0.502
-0.097
0.436
0.087
0.479
LAD3
-0.123
0.312
-0.168
0.174
0.107
0.387
LVESD4
0.045
0.767
-0.046
0.762
0.157
0.304
1- ARD= Aorta root diameter
2- IVS= interventricular septum
3- LAD= Left Auricular diameter
4- LVESD= left ventricular end systolic diameter
5- AHI= Apnoea Hypopnoea Índex
6- DI= Desaturation Índex
7- Sat min 02= minimum oxygen saturation
Fig. 1 – Interventricular Septum Hypertrophy, Left Ventricular Hypertrophy
and Left Ventricular Diastolic Dysfunction Prevalence in cases and
controls.
80
71.7%
70
64.3%
60
50
42.9%
40
C as es
27.9%
30
C ontrols
18.8%
20
1 4.3%
10
0
IVS hypertrophy
p= 0.005
L V hy pertrophy
p= 0.494
L V D ias tolic Di s func tion
p< 0.001
106
Trabalho 5
Echocardiographic findings in male patients with OSA: before and after
long term Autoadjusting Positive Airway Pressure
107
Artigo submetido à revista Portuguesa de Cardiologia
Echocardiographic findings in male patients with OSA: before
and after long term Autoadjusting Positive Airway Pressure
Marta Drummond*#, JC Winck*#, C Gavina**#, T Pinho**, AC Santos***#,
JA Almeida*, JA Marques*#
Pulmonology Department*, Cardiology Department**, Hospital São João
Hygiene and Epidemiology Department*** Faculdade de Medicina do Porto
Faculdade de Medicina da Universidade do Porto#
Porto – Portugal
Alameda Hernâni Monteiro
4200-319 Porto
Abstract
Introduction- Obstructive sleep apnea (OSA) might cause cardiovascular
morbidity and mortality. However, the effect of OSA on ventricular function,
especially diastolic function, is not clear.
Objectives- Determine the prevalence of echocardiographic abnormalities in
OSA patients, assess its correlations with OSA severity and determine long
term Auto-adjusting positive airway pressure (APAP) therapy impact on
echocardiographic findings.
Materials and Methods- This is a prospective, descriptive study in 70 male
patients with moderate to severe OSA confirmed by cardio-respiratory
domiciliary sleep study. Echocardiography was performed before and 6 months
after APAP therapy.
Results- Mean age was 53.2 (SD 9.7), mean BMI 33.6 (SD 5.2), mean Epworth
12.8 (SD 5.7), mean AHI 54.4 (SD 20.5), mean dessaturation index 49.6 (SD
23.7) and mean lowest 02 saturation 70.5 (SD 8.8). APAP compliance was
good: 96.6% of days usage, 6.4h/night. At baseline, 20% had LVH (Left
Ventricular Hypertrophy) 64.3% had IVS (Interventricular septum) thickness and
71.6% Ventricular Diastolic Dysfunction (VDD). Various echocardiographic
parameters were out of normal limits: LVESD (left ventricular end systolic
diameter) E/A (Ratio of early and lately mitral flow velocity), ARD (aorta root
108
diameter), LAD (left atrial diameter), MAE (mitral annular excursion) and Tei
index. IVS and LVESD correlated positively with hypertension, at baseline
(p<0.05). No significant correlations were seen between OSA severity indices
and echocardiographic abnormalities.
Of the studied parameters, only Mitral deceleration time (MDT) changed
significantly after APAP (p=0.031).
ConclusionsIn the studied population both systolic and diastolic left ventricular dysfunctions
were very prevalent.
Tei Index was clearly altered in this population.
Mitral deceleration time changed significantly after 6 months of APAP therapy.
A longer-term usage of APAP might achieve complete improvement of left
ventricular dysfunction in OSA patients.
Keywords- Obstructive sleep apnoea, Echocardiography, Auto-adjusting
positive airway pressure.
IntroductionObstructive sleep apnoea (OSA) is a condition defined by repeated episodes of
upper airway obstruction while sleeping (1). During an obstructive apnoea, large
negative intrathoracic pressures are generated by inspiratory efforts, which
increase transmural pressures across the myocardium, thus increasing
afterload (2). Preload increase and pulmonary congestion may also occur due
to greater venous return (2), together with hypertensive crises due to
catecholamine release (3,4).
These mechanisms suggest that OSA by itself may significantly affect cardiac
function.
There is growing evidence that patients with OSA have an increased risk of
cardiovascular complications (5,6), such as hypertension (7), heart failure (8),
left/right ventricular dysfunction (9,10), cardiac arrythmia (11,12,13), pulmonary
hypertension (14), stroke (15,16) and sudden death (17). In the light of these
established associations, it seems reasonable that the prognosis of OSA would
109
be closely related with cardiovascular events (18,19). Therefore, early detection
of patients with a poor prognosis would be extremely useful.
In clinical practice, ventricular function is commonly evaluated using
transthoracic echocardiography to measure systolic and diastolic function.
The Tei index is an easily determined echocardiographic parameter that allows
evaluation of systolic and diastolic ventricular function (20,21). This index has
proved to be useful for both the left and the right ventricle and it correlates with
the severity of the clinical symptoms and survival of cardiac failure (20,22).
Baseline echocardiograms showed that severe OSA is associated with
numerous cardiovascular abnormalities (9,23,24,23). Some recent studies have
reported positive effects of Continuous Positive Airway pressure (CPAP)
therapy on right ventricular myocardial performance (2) and on left ventricular
hypertrophy (25) in OSA patients.
Auto-adjusting positive airway pressure (APAP) devices are a recent alternative
treatment to traditional CPAP and are able to improve symptoms (26,27) while
increasing long-term treatment compliance (28,29,30) without the high costs of
CPAP titration (31, 32). However, differently from CPAP, the impact of APAP
therapy on cardiovascular outcomes in OSA patients remains unknown.
In
the
present
study,
we
aimed
to:
determine
the
prevalence
of
echocardiographic abnormalities in patients with newly diagnosed OSA, assess
whether there is an association between the severity of OSA and the degree of
abnormalities and determine the effect of long term APAP therapy on
echocardiographic findings in these patients.
Materials and Methods
Study design
This is a prospective study.
All patients gave written informed consent to participate in the study. The used
protocol was approved by the Hospital Ethics Committe and the study was
performed in accordance with the guidelines of the Declaration of Helsinki and
its current revision.
110
Subjects
Initially, 83 male patients with newly diagnosed moderate/ severe OSA
(AHI>20/h) were included in the study.
Exclusion criteria were: echocardiographic evidence of atrial fibrillation (AF),
presence of cardiac valvular prothesis, history of myocardial ischemia and
insufficient reliability of echocardiographic window, abnormal pulmonary
function tests and abnormal daytime arterial blood gases. Following application
of all these criteria, 70 patients were included in the study protocol (Fig.1).
Patients received APAP therapy by REM STAR™ Auto device (Philips
Respironics, inc., Murraysville, USA) with pre-determined minimum and
maximum pressure of 4 and 15 cmH20, respectively. Pressure on 90% of APAP
time (P90), residual AHI
were analysed using ENCORE® APAP software
(Philips Respironics, inc., Murraysville, USA).
Echocardiograms were repeated, on average, 180 days after APAP initiation.
Study procedures
Sleep Study
An overnight sleep study was performed using a five-channel recording device
(Alphascreen; Vyasis). This device produces a computorized recording of
variations in oronasal airflow (measured by nasal cannula), body position, wrist
actimetry, pulse rate and arterial oxygen saturation (measured by finger pulse
oximetry). The device estimates the total sleep time from the wrist actimetry
registry, eliminating those periods with high activity. It automatically calculates
the number of apnoeas plus hypopnoeas per hour of estimated sleep time
(automatic respiratory disturbance index) and it also provides information of
desaturations > 4% per hour of estimated sleep time and the cumulative
percentages of sleep time under 90% oxygen saturation. In all cases, sleep
technicians carried out a manual analysis of the recordings, by counting apnoea
(episodes of ≤ 20% of previous airflow with at least 10 seconds of duration)
and hypopnoea episodes (episodes showing 20 to 50% of the previous airflow,
with at least 10 seconds of duration joined with a 4% dip in oxygen saturation),
dividing the total number of these episodes by the sleep time in hours, thus
111
obtaining the manual respiratory disturbance index according to established
criteria (33).
Echocardiography
All measurements were performed with the subjects in the left lateral decubitus
position using M-mode, two dimensional and tissue Doppler ultrasound
echocardiography by two experienced physicians blinded to the clinical data
and to the APAP compliance of the patients. The ultrasound equipment used
was Sonos 5500® echocardiograph and a 2.5-MHz probe (Philips, Eindhoven,
The Netherlands). The duration of the examinations was at least 20 min. Three
consecutive measurements were taken for each parameter and its mean was
used for the analysis. Measurements were recorded in midexpiratory apnoea.
The ventricular diameters, volumes and functions were measured according to
the recommendations of the American Society of Echocardiography (34). Basic
measurements of left ventricular dimensions in diastole and systole, thickness
of interventricular septum (IVS), left ventricular posterior wall (LVPW) were
performed by the M-mode technique. Early (E) and Atrial (A) transmitral
maximal flow velocities, its ratio (E/A) and mitral deceleration time (MDT) were
registered. Tei index also known as myocardial performance index was
calculated as (isovolumic contraction time + isovolumic relaxation time)/ aortic
ejection time using Doppler.
Interventricular septum hypertrophy was defined as- mild (>11 and <14mm);
moderate (>14 and < 16mm) and severe (>16mm).
LV hypertrophy was defined as increased mass and relative wall thickness of
the LV (35).
LV diastolic disfunction was defined as the positive evidence of abnormal LV
relaxation, filling, diastolic distensibility and diastolic stiffness according to
European Study Group (36).
LV systolic disfunction was defined as the positive evidence of abnormal
contraction of muscle fibers in the LV midwall (37,38) as this may better reflect
intrinsic contractility than contraction of fibers at the endocardium (39).
112
Statistical Analysis:
Data were analyzed using SPSS, release 14.0, and described as mean values
and their respective standard deviation for normally, or as median values and
corresponding 25th and 75th centiles for clearly non-normally distributed
variables. Counts and proportions are reported for categorical variables.
Proportions were compared using Chi-square test or Fisher's exact test
whenever appropriate. For the comparison of the two moments of evaluation
the McNemar Chi square test, was used for categorical variables.
Pearson and Spearman correlations coefficients were computed to estimate the
association between independent continuous variables and the variation
between the two moments of the cardiac variables.
For comparison between mean or median values at the two moments studied,
the paired sample t-test or the non parametric Wilcoxon test for paired samples
were used.
Results
Sample Characteristics
The studied population (n=70) is depicted in table 1.
During the 6 months of the study, APAP patients compliance was good (table 1).
Pressure on 90% nighttime (P90) decreased significantly during the study
(mean initial at one week of therapy 10.8 cmH20 (SD 4,7) ; mean final 10.1
cmH20 (SD 4.2); p<0,001) and the residual Apnoea Hypopnoea Index (AHI) at
the end of the protocol was 2.7 (SD 1.7).
During the study patients did not loose significant weight (mean baseline
weight= 94.4 Kg; mean final weight= 94.1 Kg; p= 0.545) nor changed their fat
distribution according with waist/hip ratio (p= 0.151).
Habits and Comorbidities
Data is depicted in table 2.
The diagnosis of Arterial Hypertension (AH), according to European and JNCVII guidelines (40), was based on 24-hour ambulatory blood pressure
monitoring (24-ABPM) results.
113
The baseline mean overall blood pressure (BP), mean systolic BP and mean
diastolic BP were, respectively, 98.8 (SD 11.4) mmHg, 130.4 (SD 12.4) mmHg
and 81.4 (SD 8.8) mmHg. The prevalence of AH was at baseline 48.5% and
declined to 38.5% at the end of the protocol, with a statistical significant
decrease on mean overall BP (p= 0.002). All hypertensive patients in our
population have maintained their anti-hypertensive medications.
Metabolic syndrome (MS) diagnosis was based on National Heart, Lung and
Blood Institute/ American Heart Association (NHLBI/AHA) definition and clinical
criteria (41).
Echocardiographic abnormalities find before and after APAP therapy
Left Heart Indices
Baseline characteristics and left ventricular structure and function indices in
OSA patients before and after 6 months of APAP treatment are shown in Table
3. Many of the echocardiographic left heart functional and structural parameters
were out of normal limits at baseline. IVS (interventricular septum), LVESD (left
ventricular end systolic diameter) and E/A (Ratio of early and lately mitral flow
velocity), were under the normal range and none have significantly changed
after APAP; ARD (aorta root diameter), LAD (paraesternal left atrial diameter),
MAE (mitral annular excursion) and Tei Index were above the normal limits and,
also, none of them changed after APAP. MDT (mitral deceleration time) that
was, at baseline, within the normal range, was the only echocardiographic
parameter showing a significant change after 6 months of APAP therapy
(p=0.031).
Also a decline in mitral annular excursion (MAE) (p=0.065) was observed after
therapy.
Echocardiographic abnormalities found before and after APAP therapy are
showed in Fig.2, and their prevalence did not change during the study period.
Forty five patients (64.3%) had, at baseline, IVS hypertrophy, 1.4% (n=1) Left
Ventricular Systolic Disfunction (LVSD) and 71.6% (n=48) shown Left
Ventricular Diastolic Dysfunction (LVDD).
114
At baseline, 24.3% patients shown left atrium dilation (LAD), 14.3% left
ventricular hypertrophy (LVH) and 5.7% both abnormalities. After 6 months of
APAP therapy, these values changed to 21.4%, 24.3% and 7.1%, respectively,
which is not a significant variation (p= 0.460).
Right Heart Indices
Right ventricular structure and function indices in OSA patients before and after
APAP are depicted in Table 4. All these parameters were within the normal
range, and none has changed significantly during the study period.
Associations with Echocardiographic parameters at baseline
Several of the abnomal left ventricular parameters at baseline showed
correlation with hypertension assessed by mean overall BP (Table 5).
All the other echocardiographic parameters within the normal range at baseline
did not show correlation with BP.
In this study no association was observed between the presence of LVH and
arterial hypertension (p= 0.133) assessed by mean overall BP.
None of the abnormal echocardiographic parameters at baseline (IVS, LVESD,
E/A, aorta root diameter, LAD, MAE and Tei Índex) showed an association with
OSA severity indices assessed by AHI, Desaturation Index and Minimum 02
saturation.
Associations of Echocardiographic parameters variation after APAP
therapy
Significant negative associations were found between Early tricuspid flow
velocity (E-velocity) variation and APAP compliance measured by total days
usage (p= 0.026; r= -0.277) and between E/A and total APAP days usage (p=
0.003; r= -0.137).
MDT variation correlated positively with the presence of MS (Metabolic
Syndrome) (p= 0.017). Patients with MS showed smaller mean MDT values, at
baseline (216.3 SD 34.8 vs 224.8 SD 44.2), and also a smaller decline of MDT
values after APAP usage (216.3±34.8 to 215.6±51.8 vs 224.8±44.2 to
216.1±33.7).
115
Discussion
The cardiovascular repercussions of OSA have been recognized for some time
(3-5,11, 12, 15) and it seems clear that the prognosis of this disease is
associated with the incidence of cardiovascular events (18,19). Studies
(2,9,21,42,43) performed with noninvasive techniques, such as Doppler
Echocardiography have assessed the prevalence of heart disease in these
patients, as well as the response to CPAP therapy. CPAP is known to maintain
upper airway patency during sleep by increasing transmural pressure of upper
airways, thus improving cardiac function and quality of life (44). Beneficial
effects of Positive Airway Pressure on cardiac function may be explained by
several factors: improvement on myocardial oxygen delivery; decrease on
sympathetic activity, decrease on left ventricular transmural pressure and
afterload (24,45).
However, there is no study evaluating the effects of APAP, a rising therapy
option for OSA patients, on structural and functional cardiac parameters. In the
present study, we aimed to determine echocardiographic abnormalities in a
number of patients diagnosed with moderate to severe OSA in whom treatment
had not yet been initiated and, then, assess the long-term APAP impact on
those echocardiographic findings.
In the present study, at baseline, left cardiac structure (IVS, LVESD, LAD, ARD,
MAE) as also left diastolic (E/A) and left global function (Tei Index) , were out of
the normal limits. IVS and LVESD showed significant association with BP and
the direction of the association observed between E/A and ARD towards BP
could have reached statistical significance, there was enough sample size.
All of the left heart parameters that were within the normal range (LVPW,
LVEDD, MDT) did not show an association with BP.
None of the left heart parameters measured showed association with OSA
severity.
In face of this, the authors could hypothesize that hypertension might play a
predominant role in cardiac abnormalities seen in OSA patients, but this
relationship may be not so straightforward. Indeed, the Tei Index, a measure of
myocardial performance, independent from heart rate and BP (46) was above
116
the values reported in healthy individuals (22,42) as was also observed in
previous studies (2,21,43). Despite this index did not correct with APAP therapy
nor showed relation to OSA severity, as others have stated (9,21,42), its origin
probably is not independent from OSA pathophysiology, as its baseline increase
can not be explained by the presence of hypertension or other cardiovascular
impairment.
Furthermore, E/A and E-velocity variation had a significant negative relation
with APAP compliance measured by total days usage (p= 0.026; r= -0.277; p=
0.003; r= -0.137, respectively), what means that apnoeas correction can signify
amelioration in heart parameters.
In the current study, 20.0% OSA patients showed LVH and the majority (64.3%)
had slight IVS hypertrophy. Both findings may be explained by high BP and/or
nocturnal hypoxemia, as others reported (9, 10). Ou results also confirm this
hypothesis, by the presence of a positive association between IVS and mean
overall BP (p= 0.001) but not between LVH and BP (p= 0.133).
The great majority of the studied patients (71.6%) showed LVDD, as well as
global dysfunction, supported by the increased Tei Index. These findings are
quite impressive and are in accordance with previous data (9). Since the
systolic and diastolic dysfunctions frequently coexist, these findings suggest
that OSA patients might have subclinical myocardial dysfunction, predisposing
them to develop heart failure, that can be early detected by a non invasive
technique. Moreover, the Tei index is easily and quickly calculated, and is a
useful and sufficiently reliable indicator to screen for silent myocardial
dysfunction.
In what concerns right heart parameters, no abnormalities were seen in the
studied population, as reported in previous studies (9,21,47), in contrast to
results of Shivalkar (42) and Dursunoglu (2). The former author (42) reported
significantly larger right ventricular diameters, which correlated with OSA
severity, and attributed them to an increase of venous return and to transient
presence of nocturnal pulmonary hypertension. Both findings are only justifiable
117
if patients have associated pulmonary disease (48) or daytime hypercapnia due
to very severe OSA (49), that is not the case of our studied patients.
MAE is a well-established parameter of the left ventricle systolic and diastolic
function (50, 51). At baseline, this index was more than twice the normal value
and 6 months of APAP determined a decline of this value (p= 0.065), almost
reaching the statistical significance.
MDT is an ideal parameter for the assessment of LV diastolic function (52), with
a particular accuracy in post-infarct patients (53,54). This was the only
evaluated echocardiographic parameter showing a significant change after 6
months of APAP therapy (p=0.031).
The authors may hypothesize on the beneficial effects of APAP on LV diastolic
dysfunction. MDT decrease can not be explained by the decrease in BP, as
these two parameters are not related (p= 0.161) but MS prevalence could
influence this value as MDT variation correlated positively with the presence of
MS (p= 0.017).
We can speculate about the necessity of longer treatment time to achieve
complete reversal of the echocardiographic abnormalities in OSA patients under
APAP when compared to patients under CPAP therapy, due to its autoadjusting
algorithm and a larger sample could enhance the statistical power.
Controlled studies are required to further clarify the importance of OSA on
cardiac alterations.
Not only the small sample size can be seen as a limitation of this study but also
the possibility that this sleep clinic population may not reflect general OSA
patients. Furthermore, we included only men, so our results cannot be
generalized to women with this condition.
118
Conclusions
In the studied population LVH, LVDD and IVS thickness were highly prevalent
abnormalities and the majority of left ventricular parameters were out of the
normal limits.
Tei Index was clearly altered in this population.
No significant associations were seen between OSA severity indices and
echocardiographic abnormalities.
MDT changed significantly after 6 months of APAP therapy.
We speculate that longer-term usage of APAP might achieve complete
improvement of left ventricular dysfunction in OSA patients.
Acknowledgments
The authors would like to sincerely thank nurses Emília Araújo and Paula
Martins for their colaboration on blood sample collections and to all Sleep
Technicians who manually reviewed all sleep studies.
Conflict of interests
There are no financial or personal relationship with other people or
organisations that could inappropriately influence this work.
Corresponding author
Marta Drummond
Serviço Pneumologia Hospital São João
Alameda Hernâni Monteiro
4200-319 Porto
Portugal
Telef. 00351919361582
[email protected]
119
References-
1- Guilleminault C, Tilkian A, Dement WC. The sleep apnea syndromes. Annu
Rev Med 1976; 27: 465-484
2- Dursunoglu N, Dursunoglu D, Özkurt S, Gür S, Özalp G, Evyapan F. Effects
of CPAP on right ventricular myocardial performance index in obstructive sleep
apnea patients without hypertension. Resp Res 2006; 7:22-29
3- Bradley TD, Floras JS, Phil D. Sleep apnea and heart failure: Part I:
obstructive sleep apnea. Circulation 2003; 107: 1671-1678
4- Ferreira S, Winck J, Bettencourt P, Rocha-Gonçalves F. Heart failure and
sleep apnea: to sleep perchance to dream. Eur J Heart Fail 2006; 8: 227-236
5- Shahar E, Whitney CW Redline S, Lee ET, Newman AB, Javier Nieto F,
O´Connor GT, Boland LL, Schwartz JE, Samet JM. Sleep-disordered breathing
and cardiovascular disease: cross- sectional results of the Sleep Heart Health
Study. Am J Respir Crit Care Med 2001; 163: 19-25
6- Peker Y, Hedner J, Norum J, Kraiczi H, Carlson J. Increased incidence of
cardiovascular disease in middle-aged men with obstructive sleep apnea: a 7year follow-up. Am J Respir Crit Care Med 2002; 166: 159-165
7- Chobanian A, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr,
Jones DW, Materson BJ, Oparil S, Wright JT Jr, Roccella EJ. National Heart,
Lung and Blood Institute Joint National Committee on Prevention, Detection,
Evaluation and Treatment of High Blood Pressure and National High Blood
Pressure Education Program Coordinating Committee. The seventh report of
the Joint National Committee on Prevention, Detection, Evaluation and
Treatment of High Blood Pressure the JNC 7 report. JAMA 2003; 289:25602572
120
8- Javaheri S, Parker TJ, Liming JD, Corbett WS, Nishiyama H, Wexler L,
Roselle GA. Sleep apnea in 81 ambulatory male patients with stable heart
failure: types and their prevalences, consequences and presentations.
Circulation 1998; 97: 2154-2159
9- Dursunoglu D, Dursunoglu N, Evrengül H, Özkurt S, Kuru Ö, Kiliç M, Fisekçi
F. Impact of obstructive sleep apnea on left ventricular mass and global function.
Eur Resp J 2005; 26: 283- 288
10- Hedner J, Ejnell H, Caidahl K. Left ventricular hypertrophy independent of
hypertension in patients with obstructive sleep apnea. J Hypertens 1990; 8:
941-946
11- Franklin K, Nilsson JB, Sahlin C, Näslund U. Sleep apnea and nocturnal
angina. Lancet 1995; 345: 1085-1087
12- Hoffstein V, Mateika S. Cardiac arrythmias, snoring and sleep apnea. Chest
1994; 106: 466-471
13- Gami AS, Pressman G, Caples SM, Kanagala R, Gard JJ, Davison DE,
Malouf JF, Ammash NM, Friedman PA, Somers UK.
Association of atrial
fibrillation and obstructive sleep apnea. Circulation 2004; 110: 364-367
14- Marrone O, Bonsignore MR. Pulmonary haemodynamics in obstructive
sleep apnea. Sleep Med Rev 2002; 6: 175-193
15- Parra O, Arboix A, Montserrat JM, Quinto L, Bechich S, García-Eroles L.
Sleep-related breathing disorders: impact on mortality of cerebrovascular
disease. Eur Respir J 2004; 24: 267-272
16- Yaggi HK, Concato J, Kernan WN, Lichtman JH, Brass LM, Mohsenin V.
Obstructive sleep apnea as a risk factor for stroke and death. N Engl J Med
2005; 353: 2034-2041
121
17- Gami AS, Howard DE, Olson EJ, Somers UK. Day-night pattern of sudden
death in obstructive sleep apnea. N Engl J Med 2005; 352: 1206-1214
18- Baguet JP, Pepin JL, Hammer L, Levy P, Mallion JM. Cardiovascular
consequences of obstructive sleep apnea syndrome. Med Intern 2003; 24: 530537
19- Marín JM, Carrizo SJ, Vicente E, Agustí AG. Long-term cardiovascular
outcomes in men with apnoea-hypopnoea with or without treatment with
continuous positive airway pressure: an observational study. Lancet 2005; 365:
1046-1053
20- Tei C,Nishimura RA, Seward JB, Tajik AJ. Noninvasive Doppler-derived
myocardial performance index: correlation with simultaneous measurements of
cardiac catheterization measurements. J Am Soc Echocardiogr 1997; 10: 169178
21- Moro JA, Almenar L, Fernández-Fabrellas E, Ponce S, Blanquer R,
Salvador A. Relationship between echocardiographic abnormalities and sleep
apnea-hypopnea syndrome severity. Rev Esp Cardiol 207; 60: 589-596
22- Tei C, Dujardin KS, Hodge DO, Bailey KR, McGoon MD, Tajik AJ, Seward
JB. Doppler echocardiographic índex for assessment of global right ventricular
function. J Am Soc Echocardiogr 1996; 9: 838-847
23- Cloward TV, walker JM, Farney RJ, Anderson JL. Left ventricular
hypertrophy is a common echocardiographic abnormality in severe obstructive
sleep apnea and reverses with nasal continuous positive airway pressure.
Chest 2003; 124: 594-601
24- Fung JWH, Li TST, Choy DKL, Yip GWK, Ko FWS, Sanderson JE, Hui DSC.
Severe obstructive sleep apnea is associated with left ventricular diastolic
dysfunction. Chest 2002; 121: 422-429
122
25- Romero-Corral A, Somers VK, Pellikka PA, Olson EJ, Bailey KR, Korinek J,
Orban M, Sierra-Johnson J, Kato M, Amin RS, Lopez-Jimenez F. Decreased
right and left ventricular myocardial performance in obstructive sleep apnea.
Chest 2007; 132: 1863-1870
26- Nussbaumer Y, Block KE, Genser T, Thurneer R. Equivalence of
autoadjusted and constant continuous positive airway pressure in home
treatment of sleep apnea. Chest 2006; 129: 638-643
27- Ip MS, Lam KS, Ho C, Tsang KW, Lam W. Serum leptin and vascular risk
factors in obstructive sleep apnea. Chest 2000; 118: 580-586
28- Konermann M, Sanner BM, Vyleta M, Laschwski F, Groetz J, Sturm A,
Zidek W. Use of conventional and self-adjusting nasal positive airway pressure
for treatment of severe obstructive sleep apnea syndrome: a comparative study.
Chest1998; 113: 714-718
29- Massie CA, McArdle N, Hart RW, Schmidt-Nowara WW, Lankford A, Hudgel
DW, Gordon N, Douglas NJ. Comparison between automatic and fixed positive
airway pressure therapy in the home. Am J Respir Crit Care Med 2003; 167: 2023
30- Series F, Marc I. Efficacy of automatic continuous positive airway pressure
therapy that uses an estimated required pressure in the treatment of obstructive
seep apnea syndrome. Ann Intern Med 1997; 127: 588-595
31- Lloberes P, Ballester E, Montserrat JM, Botifoll E, Ramirez A, Reolid A,
Gistau C, Rodriguez-Roisin R. Comparison of manual and automatic CPAP
titration in patients with sleep apnea/hypopnea syndrome. Am J Respir Crit
Care Med 1996; 154: 1755-1758
32- Stradling JR. Reducing the cost of treating obstructive sleep apnoea: good
news for the patients. Am J Respir Crit Care Med 2004; 170: 1143-1144
123
33- The report of an American Academy of Sleep Medicine Task Force. Sleeprelated breathing disorders in adults: recommendations for syndrome definition
and measurement techniques in clinical research. Sleep 1999; 22(5): 667-689
34- Schiller NB, Shah PM, Crawford M, DeMaria A, Devereux R, Feigenbaum H,
Gutgesell H, Reichek N, Sahn D, Schnittger I. American Society of
Echocardiography Committe on standards, Subcommitte on quantitation of two
dimensional echocardiograms: recommendations for quantitation of the left
ventricle by two-dimensional echocardiography. J Am Soc Echocardiogr 1989;
2: 358-367
35- Nagueh SF, Appleton CP, Gillebert TC, Marino PN, Oh JK, Smiseth OA,
Waggoner AD, Flachskampf FA, Pellikka PA, Evangelista A. Recommendations
for the evaluation of Left Ventricular Diastolic Function by Echocardiographyguidelines and standards. J Am Soc Echocardiogr 2009; 22(2): 107-133
36- European Study Group on Diastolic Heart Failure. How to diagnose diastolic
heart failure. Eur Heart J 1998; 19: 990-1003
37- de Simone G, Devereux RB, Roman MJ, Ganau A, Saba PS, Alderman MH,
Laragh JH. Assessment of left ventricular function by the midwall fractional
shortening/end-systolic stress relation in human hypertension. J Am Coll Cardiol
1994; 23: 1444-1451
38- Shimizu G, Zile MR, Blaustein AS, Gaasch WH. Left ventricular chamber
filling and midwall fiber lengthening in patients with the left ventricular
hypertrophy: overestimation of fiber velocities by conventional midwall
measurements. Circulation 1985; 71: 266-272
39- Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA,
Picard MH, Roman MJ, Seward J, Shanewise JS, Solomon SD, Spencer KT,
Sutton MSJ Stewart WJ. Recommendations for chamber quantification: a report
from the American Society of Echocardiography´s Guidelines and Standards
Committee and the Chamber quantification Writing Group, developed in
124
conjunction with the European Association of Echocardiography, a branch of
the European Society of Cardiology. J Am Soc Echocardiogr 2005; 18: 14401463
40- Mancia, Giuseppea; Co-Chairperson; De Backer, Guyb; Co-Chairperson;
Dominiczak, Annac; Cifkova, Renatad; Fagard, Roberte; Germano, Giuseppef;
Grassi, Guidog; Heagerty, Anthony Mh; Kjeldsen, Sverre Ei; Laurent,
Stephanej; Narkiewicz, Krzysztofk; Ruilope, Luisl; Rynkiewicz, Andrzejm;
Schmieder, Roland En; Boudier, Harry AJ Struijker; Zanchetti, Albertop; New
European Guidelines on Treatment of Hypertension. J Hypertens 2007; 25 (9):
1751-1762
41- Grundy SM, Brewer HB Jr, Cleeman JI, Smith SC Jr, Lenfant C; American
Heart Association; National Heart, Lung, and Blood Institute.
Definition of
Metabolic Syndrome: Report of the National Heart, Lung and Blood Institute/
American Heart Association Conference on Scientific Issues Related to
Definition. Circulation 2004; 109; 433-438
42- Shivalkar B, Van de Heyning C, Kerremans M, Rinkevich D, Verbraecken J,
De Backer W, Vrints C. Obstructive sleep apnea syndrome: more insights on
structural and functional cardiac alterations, and the effects of treatment with
continuous positive airway pressure. J Am Coll Cardiol 2006; 47: 1433-1439
43- Dursunoglu N, Dursunoglu D, Özkurt S, Kuru O, Gür S, Kiter G, Evyapan F.
Effects of CPAP on left ventricular structure and myocardial performance índex
in Malé patients with obstructive sleep apnoea. Sleep Med 2007: 8; 51-59
44- Sullivan CE, Issa FG, Berthon-Jones M, Eves L. Reversal of obstructive
sleep apnoea by continuous positive airway pressure applied through the narres.
Lancet 1981; 1: 862-865
45- Bradley TD, Floras JS. Pathophysiologic and therapeutic implications of
sleep apnea in congestive heart failure. J Card Fail 1996; 2: 223-240
125
46- Lind L, Andren B, Ärnlöv. The Doppler-derived myocardial performance
index is determined by both left ventricular systolic and diastolic function as well
as by afterload and left ventricular mass. Echocardiography. 2005;22:211-6
47- Hanly P, Sasson Z, Zuberi N, Alderson M. Ventricular function in snorers
and patients with obstructive sleep apnea. Chest 1992; 102: 100-5
48- Bradley TD, Rutherford R, Grossman RF, Lue F, Zamel N, Moldofsky H,
Phillipson EA. Role of daytime hypoxemia in the pathogenesis of right heart
failure in the obstructive sleep apnea syndrome. Am Rev Respir Dis 1985; 131:
835-839
49- Nahmias J, Lao R, Karetzky M. Right ventricular dysfunction in obstructive
sleep apnoea: reversal with nasal continuous positive airway pressure. Eur
Respir J 1996; 9: 945-951
50- Carlhäll C, Lindström L, Wranne B, and Nylander E. Atrioventricular plane
displacement correlates closely to circulatory dimensions but not to ejection
fraction in normal young subjects. Clin Physiol 21: 621–628, 2001
51- Henein MY and Gibson DG. Normal long axis function. Heart 81: 111–113,
1999
52- Temporelli PL, Giannuzzi P, Nicolosi GL, Latini R, Franzosi MG, Gentile F,
Tavazzi L, Maggioni AP and GISSI- 3 Echo Substudy Investigators. J Am Coll
Cardiol 2004; 43: 1646-1653
53- Cerisano G, Bolognese L, Carrabba N, Buonamici P, Santoro GM, Antiucci
D, Santini A, Moschi G, Fazzini PF. Doppler derived mitral deceleration : an
early strong predictor of left ventricular remodeling after reperfused anterior
acute myocardial infarction. Circulation 1999; 99: 230-236
126
54- Cerisano G, Bolognese L, Buonamici P, et al. Prognostic implications of
restrictive left ventricular filling in reperfused anterior acute myocardial infarction.
J Am Coll Cardiol 2001; 37: 793-799
127
Fig. 1- Patients inclusion organigram
83 patients enrolled
70 patients
included
13 patients
excluded
3 Atrial Fibrillation
2 Cardiac valvular
prothesis
5 myocardial
ischaemia
3 no reasonable
reliability on
echocardiographic
window
128
Table 1. Characteristics of the study group at baseline (n=70)
Variables
Mean age (years)
BMI1 (Kg/m2)
Waist/hip
AHI2per hour)
ESS3
Desaturation index (per hour)
Lowest 02 saturation (%)
Variables
APAP usage (% days)
APAP usage (total days)
APAP usage (h/night)
4-
Body Mass Index
5-
Apnoea/ Hypopnoea Index
6-
Epworth Sleepiness Scale
Mean
53.2
33.6
0.99
54.4
12.8
49.6
70.5
Median
96.6
180.0
6.4
Standard Deviation
9.7
5.2
0.06
20.5
5.7
23.7
8.8
Interquartile range
13.2
27.8
6.4
Table 2. Habits and comorbidities
Habits and comorbidities
Smokers
Non-smokers
Former Smokers1
Arterial Hypertension
Congestive Heart Failure
History of Stroke
Metabolic Syndrome
Dislypidemia 2
Glucose intolerance 3
n (%)
13 (18.6)
26 (37.1)
31 (44.3)
36 (51.5)
3 (4.3)
7 (10)
27 (40.3)
53 (76.9)
25 (36.8)
1-
Former smoker- > 1 year without smoking habitus
2-
Total cholesterol> 2.00 g/L and/or LDL> 1.30 g/L and/or triglycerides>1.50 g/L
3-
Fasting glucose> 1.15 g/L; HgA1c> 6%
129
Table 3. Basic echocardiographic measurements and left ventricular
structure and function indices in OSA patients before and after
Autoadjusting Positive Airway Pressure (APAP)
Basic measurements
Aorta root (mm) (20-30 mm)*
LAD1 (mm) (19-40)*
MAE2 (ml) (10±2)*
Left Ventricular Structure
IVS3 thickness (mm) (6-11)*
LVPW 4 (mm) (6-11)*
LVESD5 (mm) (19-40)*
LVEDD6 (mm) (37-56)*
Diastolic Functions
E/A7 (>1)*
MDT8 (m/s) (<220)*
Global Function
Tei Index (%) (0.28±0.04)*
Before APAP
33.3 (SD6.50)
40.3 (SD 3.88)
27.2 (SD 4.80)
After APAP
33.5 (SD 4.37)
40.6 (SD 4.09)
25.8 (SD 4.04)
p value
0.709
0.331
0.065
12.1 (SD 2.00)
10.1 (SD 1.84)
8.42 (SD 1.76)
48.5 (SD 5.10)
12.6 (SD 1.91)
10.3 (SD 1.67)
8.29 (SD 1.52)
48.0 (SD 5.74)
0.798
0.536
0.838
0.463
0.99 (SD 0.37)
200.1 (SD 41.3)
0.97 (SD 0.23)
218.9 (SD 42.2)
0.727
0.031
0.43 (SD 0.12)
0.47 (SD 0.14)
0.117
Data are presented as mean ± SD. * Normal values.
1- LAD= paraesternal left atrial diameter
2- MAE= mitral annular excursion
3- IVS= interventricular septum
4- LVPW= left ventricular posterior wall
5- LVESD= left ventricular end systolic diameter
6- LVEDD= left ventricular end diastolic diameter
7- E/A= Ratio of early and lately mitral flow velocity
8- MDT= Mitral deceleration time
130
Fig. 2 – Interventricular Septum Hypertrophy, Left Ventricular Systolic and
Diastolic Dysfunction Prevalence before and after APAP.
60
Interventricular Septum Hypertrophy
54,3
50
42,9
40
35,7
No
Mild
Moderate
Severe
30
24,3
21,4
18,6
20
10
2,9
p= 0,114
0
0
Before APAP
6 months after
APAP
200
Ventricular Systolic Disfunction
180
160
140
120
100
100
98,6
No
80
Yes
60
40
20
1,4
0
0
Before APAP
6 months after
APAP
80
Ventricular Diastolic Disfunction
70
60
54,3
47,8
50
No
Class 1
40
Class 2
31,4
30
28,4
Class 3
22,4
20
14,3
10
1,5
0
Before APAP
p= 0,143
0
6 months after
APAP
131
Table 4. Right ventricular structure and function indices in OSA patients
before and after Autoadjusting Positive Airway Pressure (APAP)
Variables
E-velocity1 (m/s)
2
A- velocity (m/s)
3
E/ A (>1)*
4
RVEDD (mm) (9-26)*
Before APAP
After APAP
p value
74.3 (SD 17.6)
73.4 (SD 14.4)
0.665
77.1 (SD 17.6)
79.0 (SD 15.9)
0.294
10.1 (SD 3.23)
9.80 (SD 3.33)
0.412
13.6 (SD 2.43)
14.4 (SD 4.35)
0.443
Data are presented as mean ± SD. * Normal values.
1- E-velocity= early tricuspid flow velocity
2- A-velocity= lately tricuspid flow velocity
3- E/A= ratio E-velocity/ A- velocity
4- RVESD= right ventricular end diastolic diameter
Table 5. Associations of Left Ventricular Abnormal echocardiographic
parameters to Mean overall BP
Variables
IVS1
LVESD2
E/A3
MDT4
1234-
p
0.001
0.049
0.062
0.161
r
0.379
0.286
-0.227
-0.173
IVS= interventricular septum
LVESD= left ventricular end systolic diameter
E/A= ratio E-velocity/ A- velocity
MDT= mitral deceleration time
132
Trabalho 6
APAP Impact on Metabolic Syndrome in Obstructive Sleep Apnoea
patients
133
Artigo submetido à Revista International Journal of Sleep Research
APAP impact on metabolic syndrome in obstructive sleep apnoea patients
Running Head: APAP and metabolic syndrome
Patrícia Caetano Mota1, Marta Drummond1,2, João Carlos Winck1,2, Ana Cristina
Santos3, João Almeida1, José Agostinho Marques1,2
1
Department of Pulmonology, Hospital de São João
2
Faculdade de Medicina da Universidade do Porto
3
Department of Hygiene and Epidemiology, Faculdade de Medicina da
Universidade do Porto
Correspondence:
Patrícia Caetano Mota, MD, Department of Pulmonology, Hospital de São João,
Alameda Professor Hernâni Monteiro, 4202-451 Porto, Portugal. Tel.: +351 22
5512100; fax number: +351 22 5512214; e-mail: [email protected]
Conflict of interest
Dr. Patrícia Caetano Mota has no conflict of interests that could inappropriately
influence this study.
Dr. Marta Drummond has participated in speaking activities related to industry
sources, receiving honoraria from Astrazeneca, MerckSharpDohme and
GlaxoSmithKline.
Prof. João Carlos Winck was sponsored by Respironics to attend a Sleep
conference in Canada 2006 and has received honoraria from GlaxoSmithKline
134
and Boehringer Ingelheim related to speaking activities about COPD and from
Respironics about NIV.
Prof. Ana Cristina Santos has no conflict of interests that could inappropriately
influence this study.
Dr. João Almeida has participated in speaking activities related to industry
sources, receiving honoraria from Boeheringer Ingelheim, Astrazeneca,
MerckSharpDohme and GlaxoSmithKline.
Prof. José Agostinho Marques has no conflict of interests that could
inappropriately influence this study.
135
Summary
Prevalence of metabolic syndrome (MS) in obstructive sleep apnoea (OSA)
patients is high. The effect of autoadjusting positive airway pressure (APAP) on
MS remains unclear. This study aimed to determine the prevalence of MS in
OSA patients before and 6 months after APAP, and to identify potential
determinants of metabolic status change. Seventy-four male patients with
moderate to severe OSA were enrolled. MS diagnosis was established
according to the National Cholesterol Education Program/Adult Treatment
Panel III. APAP was prescribed to all patients. In the studied population mean
age was 55.9 (SD 10.7) years, median body mass index (BMI), Epworth
sleepiness scale (ESS) and apnoea-hypopnoea index (AHI) were 33.4 (IQR
8.4) Kg/m2, 12.0 (IQR 8.0) and 46.9 (IQR 33.6)/hour, respectively. Prevalence
of MS before and 6 months after APAP was 63.5% and 47.3%, respectively,
and this difference was statistically significant (P = 0.004). In the subgroup of
patients with MS at baseline (n=47), 14 didn't present MS after APAP. In these
patients, a significant negative association with AHI (P = 0.016) and a positive
association with % of total days of usage (P = 0.014) were found. Blood
pressure (P = 0.018) and serum triglycerides (P = 0.001) had a statistically
significant reduction during this period. In patients that still had MS, 22.2%
presented a reduction of the number of MS criteria. To conclude, after 6 months,
APAP reduced the prevalence of MS, mainly in patients with less severe OSA
and with a better therapeutic compliance. Blood pressure and serum
triglycerides reduction contributed to this metabolic status change.
Key words: autoadjusting positive airway pressure, metabolic syndrome,
obstructive sleep apnoea
136
Introduction
Obstructive sleep apnoea (OSA) is a common disorder with a prevalence of 2 to
4% in adult middle-aged population (Young et al., 1993). It is characterised by
repeated episodes of upper airway obstruction during sleep, associated with
increasing respiratory efforts, intermittent arterial oxygen desaturation, systemic
and pulmonary arterial blood pressure surges and sleep disruption (McNicholas
et al., 2007). Current knowledge on the natural history of the disease is still
limited, but the long-term consequences of OSA appear relevant. Patients with
OSA have a higher incidence of cardiovascular morbidity and mortality
(McNicholas et al., 2007; Shahar et al., 2001). Recent data suggest that OSA
may be associated with a number of cardiovascular risk factors, independently
of obesity, such as hypertension, insulin resistance, impaired glucose tolerance
and dyslipidemia, which together comprise the metabolic syndrome (MS) (JeanLouis et al., 2008; McNicholas et al., 2007). This syndrome affects millions of
people worldwide and since its first description in the 1920s, the definition of MS
has undergone several modifications. They all share similar definitional criteria,
although they differ somewhat regarding etiology of the MS and degree of
importance assigned to each of its components (Grundy et al., 2005; JeanLouis et al., 2008). According to MS definition used, its prevalence in USA
varies between 22-39% (Ford et al., 2002; Ford, 2005), affecting 26.8% of men
and 16.6% of women (Wilson et al., 2005). The overall prevalence of the MS in
nondiabetic adult Europeans is 15% (15.7% in men and 14.2% in women) (Hu
et al., 2004).
A growing recognition of the presence of various metabolic abnormalities in
subjects with OSA has been observed during the past two decades, and the
137
association of OSA and MS was highlighted as “syndrome Z” in the late 1990s
(Wilcox et al., 1998). Prevalence of MS in OSA patients is high, varying
between 60 and 90% (Ambrosetti et al., 2006; Jean-Louis et al., 2008;
Kostoglou-Athanassiou and Athanassiou, 2008; Parish et al., 2007). Despite the
rather prolific data that suggest a contributing role of OSA towards the various
components of MS and the entity itself, the exact relationship between OSA and
MS remains controversial (Ambrosetti et al., 2006; Coughlin et al., 2004; Gruber
et al., 2006; Jean-Louis et al., 2008; Kostoglou-Athanassiou and Athanassiou,
2008; Lam et al., 2006; Parish et al., 2007; Tasali and Ip, 2008).
There are multiple mechanistic pathways involved in the interaction between
OSA and MS. Chronic intermittent hypoxia and sleep fragmentation with sleep
loss present in OSA can lead to generation of reactive oxygen species and
neurohumoral changes, respectively. These likely key triggers initiate or
contribute to the inflammation, a prominent phenomenon of this interaction
(Jean-Louis et al., 2008; McNicholas et al., 2007; Tasali and Ip, 2008).
Continuous positive airway pressure (CPAP) is the primary treatment for OSA
since it eliminates upper airway collapse during sleep, and improves sleep
fragmentation, daytime symptoms, and quality of life (Malhotra et al., 2000).
Accumulative evidence supports that CPAP also reduces cardiovascular
morbidity, through alterations in each of the components of MS (Ambrosetti et
al., 2006; Bazzano et al., 2007; Börgel et al., 2006; Coughlin et al., 2007;
Dorkova et al., 2008; Harsch et al., 2004; Jean-Louis et al., 2008; Steiropoulos
et al., 2007; Tasali and Ip, 2008). However, these results are not consistent,
and some studies only reveal a positive effect of CPAP in highly compliant
138
patients and in different treatment time courses (Börgel et al., 2006; Coughlin et
al., 2007; Harsch et al., 2004; Steiropoulos et al., 2007;Tasali and Ip, 2008).
Autoadjusting positive airway pressure (APAP), an alternative treatment to
CPAP, can reduce OSA symptoms while increasing long-term CPAP
compliance without the high costs of CPAP titration. However, one study
suggested that CPAP and APAP, despite significant effects on OSA indexes
and symptoms, do not improve cardiovascular risk factors into the same extent
(Patruno et al., 2007).
Data on the impact of OSA treatment, mainly with APAP, on MS entity are
scanty.
Thus, this study aimed to evaluate the prevalence of MS in OSA patients before
and after 6 months of APAP. This study had also the purpose of identifying the
potential determinants of metabolic status change.
Methods
Study design
This is a prospective observational study. All patients gave written informed
consent to participate in the study. The study protocol was approved by the
Hospital Ethics Committee and the study was performed in accordance to the
guidelines of the Declaration of Helsinki and its current revision.
Subjects
Seventy-four male patients with newly diagnosed moderate/severe OSA
(apnoea-hypopnoea index – AHI > 20/hour), confirmed by domiciliary sleep
139
study, referred to our Sleep Disordered Breathing Clinic, were included in the
study.
Exclusion criteria were established previously: neoplastic diseases, systemic
inflammatory chronic diseases, active infectious diseases, systemic long term
corticotherapy, female gender, a weight loss greater than 10%, changes in
current medication regimens (antihypertensive, antidiabetic and antidyslipidemic
drugs), and major changes in smoking habits.
Study procedures
An overnight sleep study was performed using a five-channel recording device
(Alphascreen®, Vyasis). This device produces a computerized recording of
variations in oronasal airflow (measured by nasal cannula), body position, wrist
actimetry, pulse rate and arterial oxygen saturation (measured by finger pulse
oximetry). The device estimates the total sleep time from the wrist actimetry
registry, eliminating those periods with high activity. It automatically calculates
the number of apnoeas plus hypopnoeas per hour of estimated sleep time
(automatic respiratory disturbance index) and it also provides information of
desaturations > 4% per hour of estimated sleep time and the cumulative
percentages of sleep time under 90% oxygen saturation. In all cases, Sleep
Technicians carried out a manual analysis of the recordings, by counting
apnoea (events of airflow cessation lasting for at least 10 seconds) and
hypopnoea episodes (events of airflow reduction to 20 to 50% of the previously
observed lasting for at least 10 seconds, joined with a 4% dip in oxygen
saturation), dividing the total number of these episodes by the sleep time in
140
hours, thus obtaining the manual AHI according to established criteria (Kushida
et al., 2005).
APAP (REMstarTM Auto, Respironics Inc., Murrysville, PA, USA) therapy was
prescribed to all patients with a mean minimum pressure of 4 cmH2O and a
mean maximum pressure of 17 cmH2O.
At baseline, 24-hour ambulatory blood pressure (Spacelab, Inc 90207 Neural)
was performed in all but 2 patients who refused the examination as they
considered the arm discomfort intolerable. Hypertension was considered
according to established criteria (Grundy et al., 2005).
Fasting morning venous blood samples were collected between 8-10 a.m.
before treatment and 6 months after the treatment initiation. Blood samples
were immediately sent to the laboratory for estimation of glucose and lipids.
Determination of Metabolic Syndrome
The clinical identification of MS was performed according to the National
Cholesterol Education Program/Adult Treatment Panel III (NCEP/ATPIII) criteria,
which were updated in 2005 in a statement from the American Heart
Association (AHA)/National Heart, Lung, and Blood Institute (NHLBI) (Grundy et
al., 2005). Patients were classified as having MS when three or more of the
following constituent components were present: abdominal obesity, defined as a
waist circumference ≥ 102 cm; serum triglycerides ≥ 150 mg/dL or drug
treatment for elevated triglycerides; serum high-density lipoprotein cholesterol
(HDL-C) < 40 mg/dL or drug treatment for low HDL-C; fasting blood glucose ≥
100 mg/dL or drug treatment for elevated blood glucose; elevated blood
141
pressure defined as a systolic blood pressure ≥ 130 mmHg or diastolic blood
pressure ≥ 85 mmHg or antihypertensive drug treatment.
Statistical Analysis
Statistical analysis was performed using the SPSS version 17.0 software (SPSS
Inc., Chicago, Illinois, USA). All probabilities were two tailed and P values <
0.05 were regarded as significant.
Data were described as mean and standard deviation (SD) or as median and
interquartile range (IQR) for quantitative variables and as counts and
proportions. For comparison of quantitative variables the Mann-Whitney test
was used. The Chi-square test or the Fisher exact test were used to compare
categorical variables whenever was appropriate.
In comparison with the study baseline and after 6 months of APAP, the
Wilcoxon test and the McNemar test were used for quantitative variables and
for categorical variables, respectively.
Results
Overall studied population characteristics at baseline are presented in table 1
and according to its initial metabolic status in table 2. Patients with MS at
baseline (n=47) were significantly younger (54.0 (SD 10.7) years versus 59.2
(SD 10.1) years; P = 0.041), presented a higher body mass index (BMI) (35.4
(IQR 6.0) Kg/m2 versus 28.0 (IQR 5.0) Kg/m2; P < 0.001) and a more severe
sleep-disordered breathing ((AHI - 56.6 (IQR 36.8)/hour versus 33.2 (IQR
20.3)/hour; P < 0.001), (desaturation index - 55.3 (IQR 35.7)/hour versus 28.1
(IQR 22.3)/hour; P < 0.001), (lowest arterial oxygen saturation - 67.0 (IQR
142
17.5)% versus 77.0 (IQR 8.0)% ; P < 0.001)), compared to those without MS
(n=27) (Table 2). The severity of daytime sleepiness (evaluated by Epworth
sleepiness scale (ESS)), smoking habits and presence of comorbidities did not
significantly differ between both groups.
During the 6 months of APAP treatment, patients did not lose significant weight
(median baseline weight: 92.0 (IQR 22.3) Kg versus median final weight: 93.3
(IQR 22.8) Kg; P = 0.992) nor changed their fat distribution evaluated by waisthip ratio (WHR) (median baseline and final WHR=1.00 (IQR 0.1); P = 0.110),
and no change in their current medication was performed.
The prevalence of MS at baseline and after 6 months of APAP was 63.5% and
47.3%, respectively, and this difference was statistically significant (P = 0.004).
Regarding the participants that were defined as having MS at study entry
(n=47), the subgroup of patients that ameliorate from its metabolic profile (n=14)
presented a significant lower median AHI, comparing to the subgroup of
patients that maintained MS at 6 months (n=33) (50.2 (IQR 35.9)/hour versus
62.1 (IQR 37.4)/hour; P = 0.016). No significant differences were found between
both subgroups regarding age, BMI, ESS, desaturation index and lowest arterial
oxygen saturation. Also, participants that ended without MS had significantly
higher percentage (%) of total days of usage of APAP (98.1 (IQR 7.3) % versus
88.2 (IQR 17.7) %; P = 0.014) (Table 3). Residual AHI did not differ between
both subgroups, and its value was under 5 events/h for both (data not shown).
The MS components that significantly improved, taking into account the cut-offs
of MS criteria, during the 6 months of treatment and among those that were
defined as having MS at baseline were high blood pressure (P = 0.018) and
high serum triglycerides (P = 0.001) (Table 4).
143
Evaluating the components of MS individually, 6 months of APAP therapy
reduced significantly median systolic (P < 0.001) and diastolic blood pressure
(P < 0.001) and median serum triglycerides levels (P = 0.010) (Table 5).
A reduction of the number of criteria accounted for MS diagnosis was observed
among 6 patients (22.2%) who maintained MS after treatment. Most of them
changed from a total of 4 to 3 criteria (n=5). An improvement in HDL-C (n=3)
and fasting blood glucose (n=2) contributed to that change (data not shown).
Two patients with no MS at baseline developed it after treatment, determining a
cumulative incidence of MS at 6 months of 7.5%. Comparing with patients that
maintained or resolved MS, these two patients presented a significant worse
APAP compliance in what concerns median values of % of total days of usage
of APAP (52.0%; P = 0.022) and number of hours per night (2.3 hours; P =
0.017) (data not shown).
Discussion
MS is a constellation of cardiovascular risk factors consisting of abdominal or
central obesity, hypertension, dyslipidemia and hyperglycemia (Grundy et al.,
2005). Patients with OSA have been found to have abnormalities of each of the
components of MS (Jean-Louis et al., 2008; McNicholas et al., 2007). Obesity,
particularly visceral obesity, is an important factor in the assessment of the
adverse metabolic outcome in OSA. A growing body evidence supports an
association between OSA, MS and cardiovascular morbidity (Ambrosetti et al.,
2006; Coughlin et al., 2004; Jean-Louis et al., 2008; Kostoglou-Athanassiou and
Athanassiou, 2008; Parish et al., 2007; Peled et al., 2007; Tasali and Ip, 2008;
Vgontzas et al., 2005; Wilcox et al., 1998). According to literature, the direction
144
of this causality relationship remains to be elucidated. It is not clear whether
OSA is observed as part of the basic pathophysiology of the MS or whether the
OSA through repetitive night hypoxemia and other mechanisms induces the
appearance of the characteristics of MS (Ambrosetti et al., 2006; Coughlin et al.,
2004; Gruber et al., 2006; Jean-Louis et al., 2008; Kostoglou-Athanassiou and
Athanassiou, 2008; Lam et al., 2006; Lam and Ip, 2007; Parish et al., 2007;
Tasali and Ip, 2008).
As it was expected, the studied patients presented a high prevalence of MS
(63.5%). Those with MS presented a more severe OSA, confirming the positive
association between the severity of OSA and the presence of MS, which has
been shown in previous studies (Bento et al., 2007; Parish et al., 2007; Peled et
al., 2007).
Our study addressed the long-term effect of APAP on MS, as a complete entity,
in a group of patients with moderate to severe OSA. Prevalence of MS
decreased significantly, from 63.5% to 47.3%, after 6 months of APAP
treatment. Compared to patients that maintained MS (n=33), the 14 patients
that improved their metabolic status presented less severe sleep-disordered
breathing, as it was shown by their lower median AHI, and were more compliant
to APAP, presenting a significant greater % of total days of usage. Despite
absence of statistically significance, these patients also presented a greater
number of hours of APAP usage per night. The found results cannot be due to
weight loss or changes in current medication regimens, as they were not
observed.
To date, some studies have investigated the relative time courses of the
response to CPAP treatment and their impact on the number of individuals
145
classified as having MS, and some results are contradictory. Dorkova et al.
(2008) demonstrated in an observational study, which enrolled 32 patients, that
8 weeks of CPAP therapy reduced the global cardiovascular risk in patients with
severe OSA and concurrent MS. Reductions in cardiovascular risk were linked
to reductions in blood pressure and in serum total cholesterol levels. In addition,
patients effectively treated with CPAP had reductions in insulin resistance,
tumor necrosis factor-α, and oxidative stress markers. Nevertheless, these
beneficial effects of therapy were confined to the group of patients who used
CPAP for more than 4 hours per night. On the other hand, Coughlin et al.
(2007) showed that 6 weeks of CPAP therapy reduced only blood pressure,
without change glucose, insulin resistance, lipids and the proportion of patients
accounted with MS. Other studies showed a reduction in insulin resistance after
3 months of CPAP therapy in patients with a BMI > 30 Kg/m2 (Harsch et al.,
2004), and a significant improvement in HDL-C after 6 months of therapy (most
evident in those with abnormal initial values) (Börgel et al., 2006). These
discordant results can probably be attributed to differences in the studied
populations.
In our population, considering MS definition and its criteria cut-offs (Grundy et
al., 2005) along with final metabolic status, APAP conducted to an improvement
in metabolic profile through changes in blood pressure and lipid profile (serum
triglycerides), which comes against one study that suggested CPAP superiority
through APAP on this issue (Patruno et al., 2007). We must note that the small
sample size of the study (n=31) could affect the results.
146
In our study the metabolic improvement found with long-term APAP treatment
was through significant reductions of median systolic and diastolic blood
pressure and also median serum triglycerides levels.
If the effect of CPAP and APAP on blood pressure and its physiologic
mechanisms has already been described (Bazzano et al., 2007; Coughlin et al.,
2007; Dorkova et al., 2008; Drummond et al., 2008; Dursunoğlu et al., 2005;
Haentjens et al., 2007), the effects on lipid metabolism, mainly in serum
triglycerides, are less well understood. To date there is only one study that
showed a positive influence of 6 months of CPAP treatment on serum
triglycerides (Ip et al., 2000). The exact mechanisms of this relationship have
not been clearly underlined, however experimental studies have shown that
intermittent hypoxia, a key clinical manifestation of OSA, led to increases in
fasting serum levels of total cholesterol, HDL-C and triglycerides in lean mice,
but not in obese mice, through mechanisms that implicate the up-regulation of
enzymes of lipid biosynthesis, such as sterol element binding protein (Ip et al.,
2000; Li et al., 2005; Li et al., 2005; Steiropoulos et al., 2007). In addition,
intermittent re-oxygenation, another integral feature of OSA, resembles
reperfusion injury and may result in the activation of several inflammatory
pathways (Steiropoulos et al., 2007). OSA treatment can abolish these
mechanisms and potentially result in the amelioration of the lipid profile.
Despite we found a slight reduction in HDL-C in patients with MS at baseline
(see Table 5), this cannot be overemphasized as a negative impact of APAP, as
those patients presented high mean initial and final values of HDL-C above the
cut-off considered in MS definition. This finding is in accordance with a previous
study in which the authors found that the magnitude of HDL-C serum levels
147
change was most evident in patients with abnormal initial HDL-C levels (Börgel
et al., 2006).
We detected that 2 patients aggravated their metabolic status after 6 months,
but this could be explained by their poor compliance to APAP, showed by lower
median values of % of total days of usage and number of hours per night, and
not as a negative treatment effect. In this context, we can speculate about the
potential benefits of APAP on cardiovascular morbidity and mortality and
underline the importance of compliance with APAP treatment.
We do not consider the selection criteria by gender a limitation of this study as
risk factors for MS differ concerning this characteristic; in males, age, BMI and
OSA were significantly associated with MS, whereas in females, BMI was the
only risk factor (Sasabane et al., 2006; Teramoto et al., 2007). Additionally, MS
criteria and their cut-offs, namely waist circumference and HDL-C, differ
according to gender (Grundy et al., 2005).
This study could have benefit from an experimental study design. However, for
ethical reasons, it would be inadequate to leave patients with confirmed OSA
untreated.
Also, we do not consider the OSA diagnosis based on a domiciliary sleep study
a limitation of the present study as this tool has already been compared to
polysomnography, showing to be a viable, accurate, satisfactory, useful and
cost effective way of diagnosing OSA (Dingli et al., 2003; Golpe et al., 2002).
In summary, in this sample of Portuguese moderate/severe OSA patients,
63.5% of them presented MS. After 6 months, APAP reduced the prevalence of
MS in the studied population, mainly in patients with less severe OSA and with
a better therapeutic compliance. The reduction in blood pressure and serum
148
triglycerides levels seemed to be the most important contributors to that
metabolic status change.
Acknowledgements
The authors would like to sincerely thank nurses Emília Araújo and Paula
Martins for their collaboration on blood sample collections, Technician Delfim
Souteiro for the 24-hour ambulatory blood pressure measurements, as well as
to all Sleep Technicians who manually reviewed all sleep studies.
References
Ambrosetti, M., Lucioni, A.M., Conti, S., Pedretti, R.F. and Neri, M. Metabolic
syndrome in obstructive sleep apnea and related cardiovascular risk. J.
Cardiovasc. Med., 2006, 7: 826-829.
Bazzano, L.A., Khan, Z., Reynolds, K. and He, J. Effect of nocturnal nasal
continuous positive airway pressure on blood pressure in obstructive sleep
apnea. Hypertension, 2007, 50: 417-423.
Bento, J., Drummond, M., Almeida, J. and Winck, J.C. Obstructive sleep
apnoea and metabolic syndrome. Rev. Port. Pneumol., 2007, 13 (Suppl 3):
S48-49 (Abstract).
Börgel, J., Sanner, B.M., Bittlinsky, A. et al. Obstructive sleep apnoea and its
therapy influence high-density lipoprotein cholesterol serum levels. Eur. Respir.
J., 2006, 27: 121–127.
149
Coughlin, S.R., Mawdsley, L., Mugarza, J.A., Calverley, P.M. and Wilding, J.P.
Obstructive sleep apnoea is independently associated with an increased
prevalence of metabolic syndrome. Eur. Heart J., 2004, 25: 735-741.
Coughlin, S.R., Mawdsley, L., Mugarza, J.A., Wilding, J.P. and Calverley, P.M.
Cardiovascular and metabolic effects of CPAP in obese males with OSA. Eur.
Respir. J., 2007, 29: 720-727.
Dingli, K., Coleman, E.L., Vennelle, M. et al. Evaluation of a portable device for
diagnosing the sleep apnoea/hypopnoea syndrome. Eur. Respir. J., 2003, 21:
253-259.
Dorkova, Z., Petrasova, D., Molcanyiova, A., Popovnakova, M. and Tkacova, R.
Effects of continuous positive airway pressure on cardiovascular risk profile in
patients with severe obstructive sleep apnea and metabolic syndrome. Chest,
2008, 134: 686-692.
Drummond, M., Winck, J.C., Santos, A.C., Almeida, J. and Marques, J.A. Long
term effect of APAP on blood pressure in obstructive sleep apnea. Am. J.
Respir. Crit. Care Med., 2008, 177: A805 (Abstract).
Dursunoğlu, N., Dursunoğlu, D., Cuhadaroğlu, C. and Kiliçaslan, Z. Acute
effects of automated continuous positive airway pressure on blood pressure in
patients with sleep apnea and hypertension. Respiration, 2005, 72: 150-155.
Ford, E.S., Giles, W.H. and Dietz, W.H. Prevalence of the metabolic syndrome
among US adults: findings from the third National Health and Nutrition
Examination Survey. JAMA, 2002, 287: 356-359.
Ford, E.S. Prevalence of the metabolic syndrome defined by the International
Diabetes Federation among adults in the US. Diabetes Care, 2005, 28: 27452749.
150
Golpe, R. Jiménez, A. and Carpizo, R. Home sleep studies in the assessment
of sleep apnea/hypopnea syndrome. Chest, 2002, 122: 1156-1161.
Gruber, A., Horwood, F., Sithole, J., Ali, N.J. and Idris, I. Obstructive sleep
apnoea is independently associated with the metabolic syndrome but not insulin
resistance state. Cardiovasc. Diabetol., 2006, 5: 22.
Grundy, S.M., Cleeman, J.I., Daniels, S.R. et al. Diagnosis and management of
the metabolic syndrome: an American Heart Association/National, Heart, Lung
and Blood Institute Scientific Statement. Circulation, 2005, 112: 2735-2752.
Haentjens, P., Van Meerhaeghe, A., Moscariello, A. et al. The impact of
continuous positive airway pressure on blood pressure in patients with
obstructive sleep apnea syndrome: evidence from a meta-analysis of placebocontrolled randomized trials. Arch. Intern. Med., 2007, 167: 757-764.
Harsch, I.A., Schahin, S.P., Radespiel-Tröger, M., et al. Continuous positive
airway pressure treatment rapidly improves insulin sensitivity in patients with
obstructive sleep apnea syndrome. Am. J. Respir. Crit. Care Med., 2004, 169:
156-162.
Hu, G., Qiao, Q., Tuomilehto, J., Balkau, B., Borch-Johnsen, K. and Pyorala, K.,
DECODE Study Group. Prevalence of the metabolic syndrome and its relation
to all-cause and cardiovascular mortality in nondiabetic European men and
women. Arch. Intern. Med., 2004, 164: 1066-1076.
Ip, M.S., Lam, K.S., Ho, C., Tsang, K.W. and Lam, W. Serum leptin and
vascular risk factors in obstructive sleep apnea. Chest, 2000, 118: 580-586.
151
Jean-Louis, G., Zizi, F., Clark, L.T., Brown, C.D. and McFarlane, S.I.
Obstructive sleep apnea and cardiovascular disease: role of the metabolic
syndrome and its components. J. Clin. Sleep Med., 2008, 4: 261-272.
Kostoglou-Athanassiou, Ι. and Athanassiou, P. Metabolic syndrome and sleep
apnea. Hippokratia, 2008, 12: 81-86.
Kushida, C.A., Littner, M.R., Morgenthaler, T. et al. Practice parameters for the
indications for polysomnography and related procedures: an update for 2005.
Sleep, 2005, 28: 499-521.
Lam, J.C., Lam, B., Lam, C.L. et al. Obstructive sleep apnoea and the metabolic
syndrome in community-based Chinese adults in Hong-Kong. Respir. Med.,
2006, 100: 980-987.
Lam, J.C. and Ip, M.S. An update on obstructive sleep apnea and the metabolic
syndrome. Curr. Opin. Pulm. Med., 2007, 13: 484-489.
Li, J., Thorne, L.N., Punjabi, N.M. et al. Intermittent hypoxia induces
hyperlipidemia in lean mice. Circ. Res., 2005, 97: 698-706.
Li, J., Grigoryev, D.N., Ye, S.Q. et al. Chronic intermittent hypoxia upregulates
genes of lipid biosynthesis in obese mice. J. Appl. Physiol., 2005, 99: 16431648.
Malhotra, A., Ayas, N.T. and Epstein, L.J. The art and science of continuous
positive airway pressure therapy in obstructive sleep apnea. Curr. Opin. Pulm.
Med., 2000, 6: 490-495.
McNicholas, W.T., Bonsigore, M.R. and Management Committee of EU COST
ACTION B26. Sleep apnoea as an independent risk factor for cardiovascular
disease: current evidence, basic mechanisms and research priorities. Eur.
Respir. J., 2007, 29: 156-178.
152
Parish, J.M., Adam, T. and Facchiano, L. Relationship of metabolic syndrome
and obstructive sleep apnea. J. Clin. Sleep Med., 2007, 3: 467-472.
Patruno, V., Aiolfi, S., Costantino, G. et al. Fixed and autoadjusting continuous
positive airway pressure treatments are not similar in reducing cardiovascular
risk factors in patients with obstructive sleep apnea. Chest, 2007, 131: 13931399.
Peled, N., Kassirer, M., Shitrit, D. et al. The association of OSA with insulin
resistance, inflammation and metabolic syndrome. Respir. Med., 2007, 101:
1696-1701.
Sasanabe, R., Banno, K., Otake, K. et al. Metabolic syndrome in Japanese
patients with obstructive sleep apnea syndrome. Hypertens. Res., 2006, 29:
315-322.
Shahar, E., Whitney, C.W., Redline, S. et al. Sleep-disordered breathing and
cardiovascular disease: cross-sectional results of the Sleep Heart Health Study.
Am. J. Respir. Crit. Care Med., 2001, 163: 19-25.
Steiropoulos, P., Tsara, V., Nena, E. et al. Effect of continuous positive airway
pressure treatment on serum cardiovascular risk factors in patients with
obstructive sleep apnea-hypopnea syndrome. Chest, 2007, 132: 843-851.
Tasali, E. and Ip, M.S. Obstructive sleep apnea and metabolic syndrome:
alterations in glucose metabolism and inflammation. Proc. Am. Thorac. Soc.,
2008, 5: 207-217.
Teramoto, S., Kume, H., Yamaguchi, Y. et al. Improvement of endothelial
function with allopurinol may occur in selected patients with OSA: effect of age
and sex. Eur. Respir. J., 2007, 29: 216-217.
153
Vgontzas, A.N., Bixler, E.O. and Chrousos, G.P. Sleep apnea is a manifestation
of the metabolic syndrome. Sleep Med. Rev., 2005, 9: 211-224.
Wilcox, I., McNamara, S.G., Collins, F.L., Grunstein, R.R. and Sullivan, C.E.
“Syndrome Z”: the interaction of sleep apnoea, vascular risk factors and heart
disease. Thorax, 1998, 53 (Suppl 3): S25-28.
Wilson, P.W., D'Agostino, R.B., Parise, H., Sullivan, L. and Meigs, J.B.
Metabolic syndrome as a precursor of cardiovascular disease and type 2
diabetes mellitus. Circulation, 2005, 112: 3066-3072.
Young, T., Palta, M., Dempsey, J., Skatrud, J., Weber, S. and Badr, S. The
occurrence of sleep-disordered breathing among middle-aged adults. N. Engl. J.
Med., 1993, 328: 1230-1235.
154
Table 1 Sample characteristics at baseline
Variable
n=74
Age (years), mean (SD)
55.9 (10.7)
BMI (Kg/m2), median (IQR)
33.4 (8.4)
ESS, median (IQR)
12.0 (8.0)
AHI (events/hour), median (IQR) 46.9 (33.6)
Smoking habits, n (%)
-
Non-smokers
29 (39.2)
-
Former smokers
31 (41.9)
-
Current smokers
14 (18.9)
Congestive Heart Failure, n (%)
7 (9.5)
Stroke, n (%)
10 (13.5)
Acute myocardial infarction, n
5 (6.8)
(%)
Angina, n (%)
3 (4.1)
BMI, body mass index; ESS, Epworth sleepiness scale; AHI, apnoeahypopnoea index.
Quantitative variables are expressed as mean and standard deviation (SD) or
as median and interquartile range (IQR).
155
Table 2 Sample characteristics according to baseline metabolic status
Variable
P-value
With MS at
Without MS at
baseline
baseline
(n=47)
(n=27)
Age (years), mean (SD)
54.0 (10.7)
59.2 (10.1)
0.041
BMI (Kg/m2), median (IQR)
35.4 (6.0)
28.0 (5.0)
<0.001
ESS, median (IQR)
14.0 (9.0)
11.0 (5.5)
0.059
AHI (events/hour), median (IQR) 56.6 (36.8)
33.2 (20.3)
<0.001
Desaturation index
55.3 (35.7)
28.1 (22.3)
<0.001
67.0 (17.5)
77.0 (8.0)
<0.001
0.408
(events/hour), median (IQR)
Lowest O2 saturation (%),
median (IQR)
Smoking habits, n (%)
-
Non-smokers
18 (38.3)
11 (40.7)
-
Former smokers
18 (38.3)
13 (48.1)
-
Current smokers
11 (23.4)
3 (11.1)
Congestive Heart Failure, n (%)
6 (12.8)
1 (3.7)
0.411
Stroke, n (%)
9 (19.1)
1 (3.7)
0.082
Acute myocardial infarction, n
3 (6.4)
2 (7.4)
1.000
1 (2.1)
2 (7.4)
0.550
(%)
Angina, n (%)
MS, metabolic syndrome; BMI, body mass index; ESS, Epworth sleepiness
scale; AHI, apnoea-hypopnoea index.
156
Quantitative variables are expressed as mean and standard deviation (SD) or
as median and interquartile range (IQR).
Table 3 Characteristics of participants with MS at baseline concerning their
metabolic status after 6 months of APAP
Variable
P-value
With MS after
Without MS after
6 months of
6 months of
APAP
APAP
(n=33)
(n=14)
Age (years)
53.0 (12.0)
56.5 (14.0)
0.073
BMI (Kg/m2)
35.3 (4.2)
36.9 (10.3)
0.843
ESS
15.0 (9.0)
11.5 (7.3)
0.382
AHI (events/hour)
62.1 (37.4)
50.2 (35.9)
0.016
Desaturation index
54.9 (44.5)
55.6 (33.1)
0.410
67.5 (13.8)
63.0 (21.3)
0.327
P90 (cmH2O)
10.6 (2.5)
10.6 (2.6)
0.635
% total days of usage
88.2 (17.7)
98.1 (7.3)
0.014
Hours per night
5.3 (2.0)
6.4 (1.8)
0.075
(events/hour)
Lowest O2 saturation (%)
APAP compliance variables
MS, metabolic syndrome; APAP, autoadjusting positive airway pressure; BMI,
body mass index; ESS, Epworth sleepiness scale; AHI, apnoea-hypopnoea
index; P90, pressure on 90% nighttime.
Variables are expressed as median and interquartile range (IQR).
157
Table 4 MS components status in with and without MS after 6 months of APAP
MS components
With MS after
Without MS
P-
6 months of
after 6 months
value
APAP
of APAP
Yes, n (%)
31 (96.9)
11 (84.6)
No, n (%)
1 (3.1)
2 (15.4)
Yes, n (%)
19 (76.0)
4 (30.8)
No, n (%)
6 (24.0)
9 (69.2)
Yes, n (%)
4 (44.4)
2 (66.7)
No, n (%)
5 (55.6)
1 (33.3)
Yes, n (%)
22 (95.7)
4 (40.0)
No, n (%)
1 (4.3)
6 (60.0)
Yes, n (%)
19 (82.6)
5 (62.5)
No, n (%)
4 (17.4)
3 (37.5)
High waist circumference (n=45)
0.196
High blood pressure (n=38)
0.018
Low HDL-C (n=12)
1.000
High triglycerides (n=33)
0.001
High fasting glucose (n=31)
0.335
MS, metabolic syndrome; OSA, obstructive sleep apnoea; APAP, autoadjusting
positive airway pressure; HDL-C, high-density lipoprotein cholesterol
158
Table 5 Effect of APAP on the MS components in patients with MS at baseline
Variable
Baseline
6 months after
P-value
APAP
Waist circumference (cm)
114.0 (13.0)
114.0 (13.0)
0.134
Systolic
137.0 (16.0)
130.0 (13.0)
< 0.001
Diastolic
84.0 (8.0)
77.0 (11.0)
< 0.001
HDL-C (mg/dL)
46.0 (16.0)
45.0 (13.0)
0.045
Triglycerides (mg/dL)
199.0 (134.0)
163.0 (77.0)
0.010
Fasting glucose (mg/dL)
110.5(56.0)
106.0 (48.0)
0.152
Blood pressure (mmHg)
MS, metabolic syndrome; APAP, autoadjusting positive airway pressure; HDL-C,
high-density lipoprotein cholesterol.
Variables are expressed as median and interquartile range (IQR).
159
Discussão geral
A SAOS é uma patologia muito comum, cuja prevalência é comparável à de
outras doenças crónicas como Asma, DPOC (Doença Pulmonar Obstrutiva
Crónica), Diabetes mellitus tipo 2 e Doença Coronária (254), situando-se entre
9 a 24% dos adultos de meia idade (5).
Esta síndrome apresenta elevada morbilidade (66-68,146-148), especialmente
cardiovascular (49,50), sinistralidade não dispicienda (70,71), diminuição da
qualidade de vida (72) e, consequentemente, constitui-se como um factor de
consumo de elevados recursos da saúde (254). A esta, já vasta e negativa,
lista de comorbilidades associadas à SAOS, junta-se, ainda, o aumento da
mortalidade de todas as causas (74), sobretudo entre os indivíduos de meia
idade e do sexo masculino.
Apesar do atrás exposto, nem tudo são contrariedades, uma vez que esta
síndrome dispõe de um tratamento eficaz, seguro e capaz de reverter as suas
mais frequentes e preocupantes complicações (103,164,166-178) e, bem assim,
a aderência à terapêutica não é baixa, cifrando-se em valores semelhantes
áqueles que se admitem para outras terapêuticas a longo termo (255,256).
A patologia CV, é, sem sombra de dúvida, a mais importante das
comorbilidades associadas à SAOS, não só pela frequência (257), mas
também pela sua gravidade sendo, por si só, motivo para iniciação de
terapêutica activa, mesmo, nos casos mais ligeiros da doença (165).
Pelas permissas atrás explanadas, parece ser de todo o interesse o
conhecimento aprofundado e consistente dos mecanismos que subjazem às
ligações que se desenrolam entre SAOS e doença CV. Muitos destes
mecanismos já se encontram perfeitamente conhecidos e clarificados, mas
muitos, há, que são, ainda, obscuros e alguns apresentam-se, só, no domínio
do hipotético.
É certo que o conhecimento sobre estas ligações tem vindo a crescer, de forma
considerável, nos últimos anos mas, mantém-se, no entanto, muito aquém do
aceitável e mais ainda, do desejável.
É este interesse, em aprofundar o conhecimento vigente, que move os
trabalhos aqui apresentados.
160
Assim, esta tese, propõe-se dar um contributo para o entendimento sobre a
interligação que se desenvolve entre SAOS e Doença CV.
Certo é, que o avanço do conhecimento nesta área apresenta dificuldades
várias. A associação entre as duas entidades nosológicas, SAOS e doença CV,
apresenta elevada complexidade, baseando-se em várias vias díspares mas
inter-actuantes, que se modulam e se potenciam entre si. Não só a
complexidade das ligações entre as duas entidades fazem desta relação, uma
matéria difícil de estudar, mas também outros factores concorrem para a manto
de obscuridade que sobre ela recai, nomeadamente os vários e importantes
confundidores existentes.
Assim, tratando-se de ser a obesidade uma pandemia em crescendo (258) e o
principal factor de risco para SAOS (15-19) e, sendo sabido que, tanto uma
entidade como outra afectam vias biológicas semelhantes, como sejam a da
resistência à insulina (259-261), a do stress oxidativo e a via inflamatória (262265), torna-se fundamental a separação entre ambas a fim de que se possa
estudar o real efeito da SAOS sobre estas e outras vias que jogam um papel
fulcral na génese da patologia CV. Não ter este factor confundidor em atenção,
desvirtua dados, mas eliminá-lo implica uma metodologia rigorosa que
possibilite resultados sem viés e comparáveis entre diferentes estudos.
Por outro lado, verifica-se que investigadores da patologia cardiovascular, têm,
sistematicamente, ignorado as desordens respiratórias do sono como factor de
risco de doença CV em detrimento do estudo único dos efeitos da obesidade,
como verificado numa metanálise recente (266). Parte da justificação para este
procedimento reside no fardo económico que representa a criação de
protocolos que avaliem as desordens respiratórias do sono.
Neste ponto, seria de enorme importância a aceitação, por parte da
comunidade científica, dos dados que caracterizam os estudos cardiorespiratórios domiciliários do sono como sendo fiáveis, reprodutíveis e custoeficazes no despiste da patologia respiratória do sono em doentes com elevada
suspeita e sem outras patologias associadas (10-13). Um estudo dinamarquês
realizado recentemente, mostrou, mesmo, superioridade na abordagem estudo
cardio-respiratório domiciliário do sono e tratamento com APAP versus uso de
PSG e titulação de CPAP em laboratório (267).
161
O fundamentalismo científico pode tornar-se tão pernicioso quanto o laxismo,
impedindo que o conhecimento evolua por ficar agarrado a valores que o
tempo já se encarregou de esbater e ultrapassar.
Também os modelos de culturas de células e os modelos animais se tornam
difíceis de elaborar, sobretudo no que concerne à dificuldade em mimetizar
fenómenos de hipóxia intermitente que na realidade, é única e típica dos
doentes com patologia respiratória do sono (25).
Por último, mas não por fim, existem limitações nos estudos clínicos e
epidemiológicos da SAOS que se prendem com a deontologia e a ética
médicas. Randomizar doentes entre grupos de tratamento activo e grupos de
placebo é questionável, sendo duvidoso que seja legítimo atrasar o início de
um tratamento que é reconhecidamente eficaz e capaz de reduzir
significativamente as comorbilidades associadas à doença (164) em nome da
realização de estudos científicos.
Se atentarmos no facto de serem os doentes mais sintomáticos e, claro, mais
sonolentos, aqueles que mais interessa estudar, à luz de conhecimentos que
revelam os menos sintomáticos como detendo um qualquer mecanismo
protector, não só, contra os sintomas próprios da SAOS mas também, e
sobretudo, contra o desenvolvimento de consequências CV (187) e, sendo
certo, que os mesmos apresentam um risco elevado de acidentes (268),
nomeadamente de viação, pondo em risco a sua integridade física, a sua vida e,
mais, colocando em perigo os seus concidadãos, menos legítimo, ainda, se
afigura o adiamento da terapêutica.
Mais, o maior estudo de mortalidade na SAOS, revelou que os doentes graves,
deixados sem terapêutica apresentam mortalidade CV e de todas as causas
superior aos indivíduos tratados (269), pelo que o modelo de estudos
controlados, mormente com placebo, tão em voga na comunidade científica
actual, parece de prática duvidosa nos doentes que apresentam SAOS grave.
Ainda, muitos são os resultados contraditórios de estudos realizados neste
campo, o que à luz de tamanha complexidade problemática e tão difícil
desenho metodológico não parece de estranhar, antes, os espelha e torna a
caminhada científica, embora mais lenta, aliciante.
162
Ainda assim, e com todas as limitações conhecidas, é possível e desejável
percorrer o caminho de aprofundamento e evolução do conhecimento científico
nesta área.
Com este propósito foram desenhados os 6 estudos acima apresentados.
Trabalho 1
A PCR tem-se vindo a revelar um importante biomarcador na determinação do
risco CV (196), havendo forte e consistente associação entre os valores desta
proteína e a presença de doença CV (270).
Por seu lado, a IL-6 é um bom indicador de activação da cascata inflamatória
(271) e valores elevados desta citoquina predizem a cinco anos, a mortalidade
CV, independentemente dos tradicionais factores de risco e, de modo mais
forte, mas aditivo, ao da PCR (272).
Dado que a SAOS se tem vindo a associar, de forma independente da
obesidade, em vários estudos, a valores séricos elevados de IL-6 (202204,273) e de PCR (203-206), embora não em todos (274,275) e em virtude de
existirem dados discordantes, na literatura, quanto ao efeito normalizador do
CPAP sobre estas citoquinas (190,204,276,277), levámos a cabo um estudo
prospectivo de avaliação destes níveis após uso, a curto e longo prazo de
APAP, a nova e crescente alternativa (179) de suporte ventilatório no
tratamento da SAOS.
Realizámos também um estudo comparativo, com controlos comunitários, dos
valores séricos de PCR previamente ao uso de suporte ventilatório nocturno.
Ao arrepio da literatura existente, este trabalho não encontrou correlação entre
os índices de gravidade da SAOS e os níveis séricos de IL-6 e de Proteína C
Reactiva de alta sensibilidade (h-PCR), após análise multivariada, controlada
para os vários factores confundidores e não verificou decréscimo dos mesmos
após tratamento eficaz da SAOS com APAP.
No entanto, diferenças nos valores séricos das citoquinas, poderão ficar a
dever-se ao facto de não terem sido incluídos doentes com SAOS ligeira,
163
sugerindo que a partir de determinado nível de gravidade da doença, uma
correlação linear não possa ser encontrada entre esta e aqueles, sendo
possível especular sobre o papel de outros mecanismos, interferindo nos níveis
das citoquinas estudadas.
Ademais, os doentes incluídos eram mais velhos do que os de outros estudos
(205) e, sendo conhecida a relação positiva existente entre os valores séricos
de h-PCR e a idade, podemos inferir que os nossos doentes teriam valores
mais elevados desta citoquina, tornando a relação entre estes e a gravidade da
SAOS mais fraca.
Por outro lado, este trabalho confirma que a SAOS se encontra associada a
valores séricos elevados de h-PCR, tal como outros demonstraram (205),
sendo que, este aumento não pode ficar a dever-se a factores demográficos ou
comorbilidades, pois que casos e controlos haviam sido emparelhados e
ajustados para essas variáveis.
Os autores podem, igualmente, afirmar que os doentes estudados apresentam
um risco duas vezes superior aos controlos de risco moderado de doença CV e
mais de duas vezes superior de risco grave da mesma doença, com base nos
valores séricos de h-PCR.
Tanto quanto sabemos, existe apenas um outro trabalho estudando o efeito do
APAP sobre a h-PCR (188) e nenhum sobre a IL-6.
É certo que podemos especular sobre o facto da pressão variável ser o motivo
da não descida dos valores das citoquinas estudadas, mas, também é certo
que, alguns autores não têm referido resposta dos mesmos ao uso de CPAP
(276,278) e que o APAP no único estudo existente (188), para além deste, foi
eficaz nessa redução.
Finalmente, podemos especular sobre o facto de múltiplos factores poderem
jogar um papel determinante nos valores séricos de PCR e IL-6,
nomeadamente a obesidade, e não só a SAOS, como estudos recentes têm
vindo a sustentar (279).
164
Trabalho 2
No sentido de tentar esclarecer se os níveis de leptina sérica são alterados
pelo tratamento da SAOS, desenhámos um estudo prospectivo comparando
valores séricos da referida hormona em 98 doentes recém diagnosticados com
SAOS moderada a grave e após o tratamento com APAP, sendo este segundo
momento desdobrado em terapêutica de curto termo e de longo termo, aos 9
dias e aos 6 meses, respectivamente.
O maior factor regulador dos valores de leptina é a obesidade (280-282), a qual
é, também, influenciada pelo sexo e pela idade (218,283), daí que o estudo
tenha abrangido apenas homens, no sentido de homogeneizar a amostra, e,
que os factores Índice de Massa Corporal (IMC) e idade tenham sido tidos em
conta na análise estatística.
Vários estudos prévios (218-220,284) reportaram elevação de valores séricos
de leptina em doentes com SAOS, mas a questão está longe de ser resolvida,
sobretudo, pelo efeito confundidor da obesidade e a disparidade metodológica
entre os vários estudos existentes. O nosso trabalho confirmou a elevação
destes valores nos doentes do sexo masculino com SAOS moderada a grave
quando comparados com o intervalo de normalidade para o referido sexo, mas
não detectámos associação entre a grandeza destes e a gravidade da doença,
tal como outros autores (210,285). No entanto, alguns autores (215219,221,286,287) demonstraram relação entre os valores séricos de leptina e a
gravidade da SAOS, mas nem sempre controlando para os vários
confundidores.
No nosso trabalho, usando modelos analíticos de regressão múltipla, o IMC
constituiu-se como o único preditor dos valores séricos de leptina nos doentes
estudados.
Além disso, encontrámos uma redução, apenas, marginal e sem significância
estatística nos valores séricos de leptina após uso a curto e longo termo de
APAP. Estes resultados contrastam com os de outros autores (222224,284,286,288) que usaram pressão positiva contínua para tratamento de
SAOS. Certo é, que nesses estudos as alterações encontradas foram, em
regra, ténues em valor absoluto e não muito diferentes das por nós
165
encontradas. Ainda assim, apesar da comprovada eficácia fisiológica e clínica
do APAP (179,213,220), não se pode descartar que a variação da pressão
nocturna possa afectar os níveis de leptina de maneira diversa da conseguida
pelo tratamento com pressão fixa.
Por fim, e de acordo com os nossos resultados e a maioria dos precedentes, os
níveis
séricos
de
leptina
nos
doentes
com
SAOS
parecem
estar,
predominantemente, na dependência da obesidade e não na da própria
patologia respiratória do sono, pelo que, também parece lógico e justificado o
diminuto efeito do suporte ventilatório nocturno com APAP sobre os referidos
valores.
Trabalho 3
Grandes e recentes estudos epidemiológicos têm vindo a mostrar a presença
de associação independente entre a HTA e a SAOS (63-66).
Duas metanálises recentes concordaram no impacte positivo do tratamento
com CPAP na redução da TA nestes doentes (170,171).
No entanto, diferente do CPAP, o efeito do APAP nas consequências
cardiovasculares da SAOS permanece por estudar e dois autores reportaram,
recentemente, a ineficácia deste modo de tratamento na redução dos valores
da TA (186,188).
Este nosso trabalho pretendeu avaliar o efeito a longo termo do APAP na TA
dos doentes com SAOS moderada a grave, medida através de monitorização
ambulatória de 24h.
Foi possível verificar uma elevada prevalência de HTA entre a população
estudada (47.2%), corroborando os resultados de estudos anteriores (226-232).
Reportámos um decréscimo estatisticamente significativo da TA global média,
da TA sistólica média, da TA diastólica média, da TA diurna média e da TA
nocturna média, após ajuste para factores confundidores. A queda tensional
verificada, para todos os parâmetros referidos, situa-se entre os 8 e os 5 mmHg,
idêntica a resultados positivos publicados para o uso de CPAP (171,235240,289).
166
Dos parâmetros estudados, a TA nocturna média foi o que apresentou maior
decréscimo, estando em linha com anteriores publicações (234,237,290,291) e
com a hipótese de ser a activação intermitente do S. Simpático durante a noite
consequente à hipóxia intermitente, a responsável pela elevação da TA em
doentes com SAOS. A TA diastólica média foi o parâmetro com resposta
menos exuberante, mas, ainda assim, com uma descida de 5 mmHg. A menor
resposta deste parâmetro ao APAP poderá associar-se ao facto de variar entre
valores mais apertados, logo, com menor margem absoluta de correcção e ao
envelhecimento, nomeadamente arterial, que diminui a capacidade moduladora
dos vasos sobre a pressão sanguínea e, logo, o efeito terapêutico da ventilação
com pressão positiva contínua.
As reduções observadas são, ainda, superiores às descritas para a terapêutica
farmacológica (292) e verificam-se quer na TA sistólica, quer na diastólica, na
TA diurna e também na nocturna, sugerindo uma alteração global na regulação
da pressão pela vasculatura e permitindo-nos especular sobre os benefícios
CV desta terapêutica, actualmente em crescente uso.
Os resultados encontrados poderão ser, ainda, mais significativos, tendo em
linha de conta o facto da monitorização ambulatorial da TA durante 24h
promover despertares frequentes durante a noite aquando das insuflações do
braçal e consequentes aumentos da TA (293). Desta forma, o nosso estudo
poderá estar a subestimar o efeito regulador do APAP sobre a TA, mormente
sobre o fenómeno dipper que vimos normalizado em apenas 17% dos doentes.
Os resultados encontrados não poderão ser explicados por alterações do IMC
ou da distribuição da gordura corporal, por mudanças na terapêutica antihipertensora, ou nos hábitos tabágicos dos doentes, pois em nenhuma destas
permissas se verificou modificação durante o estudo.
Não observámos um benefício acrescido em doentes sob medicação antihipertensora, que outros haviam observado (236) mas, apenas, em pequenas
amostras.
Alguns autores têm reportado que os doentes assintomáticos, nomeadamente,
no que concerne à hipersónia diurna, não beneficiam de redução da TA pelo
CPAP (187,294-296).
Os nossos resultados são díspares destes, tendo os doentes assintomáticos
demonstrado uma resposta tão positiva quanto os mais sintomáticos, estando,
167
nós, desta forma, em paralelo com achados (240,297) de amostras com muito
boa aderência ao CPAP, tal como a que verificámos para o APAP. Os doentes
assintomáticos são reconhecidamente menos aderentes ao tratamento e essa
pode ser a explicação de não terem resultados tão positivos em estudos
precedentes. No nosso estudo os doentes assintomáticos apresentaram
aderência tão boa quanto os mais sintomáticos, o que poderá justificar os
resultados alcançados.
Este estudo é o primeiro, de acordo com o nosso conhecimento, a demonstrar
um efeito positivo e significativo do APAP sobre a TA em doentes com SAOS.
Sabemos do facto da ausência de grupo controlo ser uma limitação, mas
também temos noção de serem estes resultados conseguidos numa população
representativa da realidade destes doentes: a gravidade dos doentes é aquela
para a qual prescrevemos, na prática clínica, suporte ventilatório nocturno, os
valores iniciais de TA não foram factor de exclusão, tal como o não foi, o facto
dos doentes se encontrarem sob medicação anti-hipertensora.
Trabalho 4 e 5
Com os objectivos de comparar a prevalência de anomalias ecocardiográficas
entre doentes com SAOS moderada a grave e controlos comunitários,
determinar a sua relação com a SAOS e avaliar o efeito do APAP a longo
termo
nas
referidas
anomalias,
foram
elaborados
dois
trabalhos,
complementares entre si, que nos permitiram verificar e poder afirmar que a
maioria
destes
doentes
apresentam
alterações
ecocardiográficas
nomeadamente no coração esquerdo, verificando-se uma prevalência de
disfunção diastólica ventricular esquerda e hipertrofia do septo interventricular
estatisticamente aumentada nos casos versus controlos, independentemente
dos confundidores (71.7% vs 27.9% p< 0.001; 64.3% vs 42.9% p= 0.005).
Para além disso, um dos parâmetros concernentes ao coração esquerdo, o
tempo de desaceleração mitral (TDM), relacionou-se de forma estatisticamente
significativa
com
a
SAOS,
independentemente
dos
confundidores
e,
coerentemente, sofreu alteração após 6 meses de APAP.
168
Assim, e atentando, nestes resultados, parece clara a existência de um impacte
negativo da SAOS na morfologia e função cardíacas, mormente à esquerda e,
é-nos, neste momento, possível especular sobre se o prolongamento da
terapêutica permitiria uma completa reversão das alterações funcionais e, quiçá,
morfológicas do coração esquerdo.
É certo que alguns dos parâmetros encontrados fora dos limites normais,
nomeadamente espessura do septo interventricular e diâmetro ventricular
esquerdo no fim da sístole, se relacionam com a TA, mas essa relação poderá
não ser tão linear uma vez que parâmetros há, como por exemplo a espessura
do
septo
interventricular,
que
se
relacionaram
com
a
SAOS,
independentemente de confundidores (entre os quais a TA) e mais, o Índice de
Tei, um parâmetro ecocardiográfico que permite a avaliação das funções
ventriculares diastólica e sistólica (298-301), reconhecidamente independente
da TA e da frequência cardíaca, foi encontrado elevado nos doentes estudados,
tal como previamente descrito (299,302), pelo que a fisiopatologia da síndrome
não parece ser alheia às alterações encontradas.
A enorme prevalência de disfunção diastólica nos doentes estudados contrasta
com trabalhos anteriores (53), podendo esta discrepância ser justificada pelo
uso de Doppler convencional e não de Doppler tecidular, como no nosso caso,
sendo o primeiro conhecido como ineficaz na detecção de disfunção diastólica
precoce em doentes com fracção de ejecção normal (303,304) e o segundo
reconhecido como uma ferramenta sensível nessa detecção (305-308).
O facto do Tempo de Desaceleração Mitral (TDM), um parâmetro sensível na
avaliação da disfunção diastólica ventricular esquerda (309), se encontrar
dentro dos limites da normalidade nos doentes estudados, permite-nos reforçar
a ideia de termos diagnosticado disfunção diastólica na sua fase inicial, dado
que nem todos os parâmetros, com ela relacionados, se encontravam alterados.
Os nossos estudos, em contraste com relatos prévios (53,310), não mostraram
alterações ecocardiográficas à direita nos doentes com SAOS moderada a
grave. Estes relatos atribuíam ao aumento do retorno venoso e à presença de
hipertensão arterial pulmonar transitória nocturna, os resultados encontrados.
169
Ambos os achados só são justificáveis em doentes com patologia pulmonar
associada (311) ou hipercapnia diurna (312), que, obviamente, não era o caso
dos nossos doentes, cuja função pulmonar fora avaliada previamente.
Não somos, naturalmente, insensíveis às limitações dos nossos estudos, mas
estamos certos que a complementaridade entre ambos minora os efeitos
daquelas.
Trabalho 6
Dados recentes sugerem que deverá haver uma relação entre a SAOS e várias
entidades nosológicas que se constituem como riscos cardiovasculares, que
em associação formam a Síndrome Metabólica (SM) (313). A prevalência de
SM entre os doentes com SAOS, de acordo com estudos recentemente
publicados (147,150,313-316), é elevada, variando entre 60 a 90%.
Evidência acumulada, embora não uniforme, suporta a eficácia do CPAP na
redução da morbilidade CV nestes doentes através de alterações nos variados
componentes constituintes da SM (156,317-320).
São escassos, os dados concernentes à eficácia do APAP nesta matéria.
Assim, conduzimos este estudo no sentido de avaliar a prevalência de SM em
doentes com SAOS moderada a grave recentemente diagnosticada e 6 meses
após tratamento com APAP.
Encontrámos uma prevalência de SM na população estudada de 63,5%, o que
se encontra dentro dos valores descritos na literatura (147,150,313-316), a qual
sofreu uma redução estatisticamente significativa, para 47.3%, após 6 meses
de terapêutica com APAP.
Os doentes que melhoraram o seu estado metabólico apresentavam SAOS
menos grave e melhor aderência à terapêutica, quando comparados com os
outros.
Aqueles que reverteram a SM, fizeram-no devido a redução da TA e alteração
no perfil lipídico, o que contraria estudos anteriores (188) revelando ineficácia
do APAP na alteração destas características.
170
Esta mudança de estado não pôde ser devida a perda significativa de peso ou
mudanças na medicação prévia visto tal ter sido mantido imutável por exigência
do protocolo de estudo.
Não consideramos dispicienda a limitação deste estudo quanto à inexistência
de grupo controlo mas salientamos o seu carácter inovador na avaliação da
eficácia terapêutica de um novo meio de suporte ventilatório nocturno na SAOS,
com resultados positivos, que se podem comparar aos observados com CPAP.
171
Comentário Geral
Da análise global dos vários trabalhos ressaltam as conclusões de não haver
associação entre os valores séricos de PCR, IL-6, leptina e os índices de
gravidade da SAOS e, de forma coerente, não haver efeito do tratamento desta
patologia nos valores séricos dos referidos mediadores. Verificámos, mesmo,
que em relação à leptina, a obesidade se revelou como o único preditor dos
valores séricos desta hormona e não quaisquer características associadas à
patologia respiratória do sono.
Também, já, outros autores (21,22) discutiram o facto de ser o tecido adiposo,
nos obesos, o maior órgão secretor, logo, condicionando directamente a maior
parcela de produção de PCR (279) e, indirectamente, induzindo a mesma
através da produção de IL-6, ela própria também aumentada.
Assim, apesar da PCR e IL-6 se encontrarem elevadas nos doentes com SAOS,
em muitos estudos (202-206), essa realidade poderá reflectir, também, a
disfunção do tecido adiposo sob efeito da hipóxia intermitente e não, sómente,
um efeito linear desta.
Actualmente, a SAOS é considerada uma doença sistémica resultante do
stress oxidativo (89) e do estado inflamatório (92,93,122,123,175,321,322).
Este, está, na sua vasta maioria, confinado ao compartimento vascular, sendo
a inflamação sistémica ausente ou ligeira (323) e, parecendo a obesidade,
associada à SAOS, ser o determinante mais poderoso da inflamação sistémica
(278), o que está de acordo com os resultados por nós encontrados.
Também,
nos
nossos
estudos,
quando
analisamos
parâmetros
cardiovasculares e metabólicos a conclusão parece ser antagónica da
encontrada para os mecanismos inflamatórios: foi possível observar uma
queda significativa em todos os parâmetros da TA após uso de APAP a longo
termo; a prevalência de alterações ecocardiográficas como a disfunção
diastólica do ventrículo esquerdo e a hipertrofia do septo interventricular foram
claramente mais prevalentes entre os doentes quando comparados com os
controlos e o tratamento com APAP foi capaz de diminuir, com significância
estatística, a prevalência de hipertrofia SI, assim como, a prevalência da SM.
172
Em modelos animais, a hipóxia intermitente, durante longos períodos, foi
implicada no desequilíbrio da família GATA, um conjunto de factores de
transcrição
redox-sensitivos
(83).
Alguns
membros
desta
família,
nomeadamente os factores GATA-4 e GATA-6, regulam o desenvolvimento e
crescimento cardíacos (324). Dados mostram que o factor GATA-4 pode ser
um importante mediador de sobrevida dos miócitos, prevenindo efeitos
apoptóticos, quando em presença pontual de stress oxidativo (325-327).
Quando a exposição quer ao stress oxidativo quer à hipóxia intermitente, se
torna prolongada, o referido factor passa de cardioprotector a cardiotóxico,
induzindo hipertrofia cardíaca e aumento da morbilidade cardiovascular.
Os nossos resultados revelaram que doentes com SAOS mostraram maior
prevalência de hipertrofia ventricular esquerda e de septo interventricular, maior
diâmetro da AE e maior espessura da parede posterior do VE, quando
comparados com controlos comunitários, o que está em linha com os
conhecimentos fisiopatológicos acima explanados.
Não foi, no entanto, o APAP capaz de reverter estes efeitos cardiotóxicos.
Mas é questionável se o uso mais prolongado deste suporte ventilatório
nocturno poderia contrariar estes achados, na medida em que verificámos, por
exemplo, que deixaram de existir no fim do estudo doentes com hipertrofia
grave do septo interventricular.
Na redução da prevalência de SM, foram determinantes a resposta tensional
ao
APAP,
como,
consistentemente,
havíamos
observado
e
descrito
previamente e a redução dos níveis séricos de triglicerídeos que não havíamos,
ainda, encontrado descrita na literatura, tendo sido, apenas, reportada a
eficácia do CPAP sobre os valores de colesterol sérico (162).
Assim,
poderemos
especular
sobre
o
facto
das
consequências
cardiovasculares e metabólicas serem mais sensíveis e, mais rapidamente,
reversíveis pelo tratamento da SAOS com APAP do que as alterações
inflamatórias.
173
Ou será que as alterações inflamatórias encontradas na dependência da
patologia respiratória do sono, por outros autores, não por nós, requerem uma
terapêutica mais prolongada para ser eficaz?
Ou será que essas alterações não se encontram, efectivamente, na
dependência da patologia respiratória do sono, mas das comorbilidades que
lhe estão associadas, como a obesidade?
Ou ainda, será que a pressão positiva da via aérea tem que ser contínua e não
variável para se verificar resposta destes parâmetros?
Presumivelmente, a pressão automática positiva contínua da via aérea será
diversa do CPAP no que concerne à persistência e, até, agravamento de
despertares e microdespertares por subidas mais ou menos bruscas de
pressão durante todo o sono e, consequentemente, podendo originar
fragmentação do sono e desarranjo autonómico (186,188). Estudos recentes
não têm feito eco deste receio (328, 329) e, até, num deles, houve melhoria da
microestrutura do sono com uso de APAP (330).
No sentido de esclarecer um possível efeito pernicioso do APAP sobre a
estrutura do sono, a realização de PSG sob tratamento com APAP poderia ser
benéfico e aclarar dúvidas.
Mas, também é certo que os algoritmos dos diversos equipamentos de pressão
positiva automática da via aérea diferem entre si e apresentam modos diversos
de funcionamento, com tempos de reacção e rapidez de subida de pressão
díspares (331) o que dificulta o estudo e a assunção da sua eficácia.
Seria de todo o interesse regulamentar a fabricação e a divulgação de
características dos diversos equipamentos de APAP disponíveis no mercado
de modo a que profissionais de saúde ao prescreverem determinado
tratamento possam saber exactamente o que prescrevem e que expectativas
ter e, sobretudo, transmitir aos seus doentes, nessa prescrição.
Do nosso trabalho, podemos afirmar, que o APAP REM Star Auto da
Respironics®, inc foi capaz de promover uma descida global da TA, uma
redução dos valores séricos de triglicerídeos e, consequentemente da
prevalência da SM e, finalmente, induzir melhoria e até normalização de
parâmetros ecocardiográficos alterados em doentes com SAOS moderada a
grave.
174
Claro está, que do modelo experimental de efeitos da hipóxia intermitente
ressalta
a
interação,
presumivelmente
existente,
entre
alterações
hemodinâmicas, metabólicas, inflamatórias e o fundo genético de cada
indivíduo.
Na patologia respiratória do sono, o factor genético, embora, até ao momento,
só superficialmente abordado, terá, certamente, no futuro, muito a oferecer
quanto a explicações causais e surgimento de novas opções terapêuticas.
Estudos moleculares e celulares estão, actualmente, em curso no sentido de
clarificar a importância do património genético no desenvolvimento da doença e
suas consequências e/ou comorbilidades, nem sempre da mesma magnitude e
de natureza semelhante nos diferentes indivíduos acometidos e, também, no
sentido de ilucidar a comunidade científica sobre o papel da informação
genética nas respostas, metabólica, hemodinâmica, inflamatória e outras, à
terapêutica com pressão positiva contínua da via aérea, apresentadas pelos
diversos doentes, a mais das vezes, também, diversas entre si.
O caminho da genética parece, então, ser um trilho aliciante e promissor, a
seguir pelos investigadores da área da patologia respiratória do sono.
175
Conclusões
Os níveis séricos de h-CRP, embora significativamente aumentados nos
doentes versus controlos, não se relacionaram com os índices de gravidade da
SAOS, tal como se verificou para os valores séricos de IL-6 e leptina.
Os valores séricos de leptina apresentaram-se elevados nos doentes com
SAOS, quando comparados com os limites de normalidade, mas a obesidade
constituiu-se como único factor preditor dos referidos valores.
A terapêutica com APAP, quer a curto quer a longo termo, não apresentou
impacte sobre os valores séricos de h-CRP, IL-6 e leptina.
Seis meses de tratamento com APAP reduziram, globalmente e com
significância estatística, os valores de TA nos doentes com SAOS moderada a
grave, entre 5 a 8 mmHg e foi verificada uma normalização marginal do
fenómeno dipper nestes doentes.
A população estudada apresentou 63,5% de prevalência ad initium de SM, a
qual desceu para 47,3% após 6 meses de terapêutica com pressão positiva
contínua automática da via aérea. Descida, esta, que se afigurou significativa
do ponto de vista estatístico.
Tensão arterial e valores séricos de triglicerídeos foram, de entre os critérios de
definição da SM, os mais respondedores ao tratamento da SAOS com APAP.
A terapêutica com APAP parece ser eficaz na reversão dos efeitos
hemodinâmicos, cardíacos e metabólicos nos doentes do sexo masculino com
SAOS moderada a grave, mas não das suas alterações inflamatórias.
176
Bibliografia Geral
1- Shneerson JM. Handbook of Sleep Medicine. Blackwell Science Ltd, 2000
2- Velluti RA. Interactions between sleep and sensory physiology. J Sleep Res
1997; 6: 61-77
3- American Academy of Sleep Medicine Task Force. Sleep-related breathing
disorders in adults: recommendations for syndrome definition and measurement
techniques in clinical research. The Report of an American Academy of Sleep
Medicine Task force. Sleep 1999; 22: 667-689
4- International Classification of Sleep Disorders. Diagnostic and Coding
Manual. 2nd Edition. Rochester, American Academy of Sleep Medicine, 2005
5- Young T, Palta M, Dempsey J, Skatrud J, Weber S, Badr S. The occurrence
of sleep disordered breathing among middle-aged adults. N Engl J Med 1993;
328: 1230-1235
6- Engleman HM, Kingshott RN, Martin SE, Douglas NJ. Cognitive function in
the sleep apnea/hypopnea syndrome (SAHS). Sleep 2000; 23(4): s102- s108
7- Drummond M, Barroso AS, Machado A, Winck JC, Almeida J. How do
Primary Care Physicians recognize Obstructive Sleep Apnoea. Rev Port Pneum
2002; vol. VIII, nº3: 262
8- Lopez-Jimenez F, Kuniyoshi FHS, Gami A, Somers VK. Obstructive Sleep
Apnea. Chest 2008; 133: 793-804
9- Anderer P, Gruber G, Parapatics D, Dorffner G. Automatic sleep
classification according to Rechtschaffen and Kales. Conf Proc IEEE Eng Med
Biol Soc 2007: 3994-3997
177
10- Golpe R, Jiménez A, Carpizo R. Home sleep studies in the assessment of
sleep apnea/hypopnea syndrome. Chest 2002; 122: 1156-1161
11- Dingli K, Coleman EL, Nennelle M, Finch SP, Wraith PK, Mackay TW,
Douglas NJ. Evaluation of a portable device for diagnosing the sleep
apnea/hypopnoea syndrome. Eur respir J 2003; 21: 253-259
12- Feber R, Millman R, Coppola M, Fleetham J, Murray CF, Iber C, McCall V,
Nino-Murcia G, Pre M. Portable recording in the assessment of obstructive
sleep apnea. ASDA standards of practice. Sleep 1994; 17: 378-392
13- Collop NA, Anderson WM, Boehlecke B, Claman D, Goldberg R, Gottlieb
DJ, Hudgel D, Sateia M, Schwab R. Clinical guidelines for the use of
unattended portable monitors in the diagnosis of obstructive sleep apnea in
adult patients. Portable Monitoring Task Force of the American Academy of
Sleep Medicine. J Clin Sleep Med 2007; 3: 737-747
14- Jennum P, Santamaria J. Report of an EFNS task force on management of
sleep disorders in neurologic disease (degenerative neurologic disorders and
stroke). Eur J Neurol 2007; 14: 1189-1200
15- Vgontzas NA, Tan TL, Bixler EO, Martin LF, Shubert D, Kales A. Sleep
apnea and sleep disruption in obese patients. Arch Intern Med 1994; 154: 17051711
16-
Young T, Shahar E, Nieto FJ, Redline S, Newman AB, Gottlieb DJ,
Walsleben JA, Finn L, Enright P, Samet JM. Predictors of sleep-disordered
breathing in community-dwelling adults. Arch Intern Med 2002; 162(8): 893-900
17-
van Boxem TJM, de Groot GH. Prevalence and severity of sleep
disordered breathing in a group of morbidly obese patients. Neth J Med 1999;
54(5): 202-206
178
18- Richman RM, Elliott LM, Burns CM, Bearpark HM, Steinbeck KS, Caterson
ID. The prevalence of obstructive sleep apnoea in an obese female
population. Int J Obes Relat Metab Disord 1994; 18(3): 173-177
19- Resta O, Foschino-Barbaro MP, Legari G, Talamo S, Bonfitto P, Palumbo
A, Minenna A, Giorgino R, Pergola GD. Sleep-related breathing disorders, loud
snoring and excessive daytime sleepiness in obese subjects. Int J Obes Relat
Metab Disord 2001; 25(5): 669-675
20- Malhotra A, White DP. Obstructive sleep apnoea. Lancet 2002; 360(9328):
237-245
21- Gami AS, Caples SM, Somers VK. Obesity and obstructive sleep
apnea. Endocrinol Metab Clin N Am 2003; 32. 869-894
22- Strobel RJ, Rosen RC. Obesity and weight loss in obstructive sleep apnea:
a critical review. Sleep 1996; 19: 104-115
23- Stanchina ML, Malhotra A, Fogel RB, Trinder J, Edwards JK. The influence
of lung volume on pharyngeal mechanisms, collapsibility and genioglossus
muscle activation during sleep. Sleep 2003; 26: 851-856
24- Al Lawati NM, Patel SR, Ayas NT. Epidemiology, risk factors and
consequences of obstructive slep apnea and short sleep duration. Prog in Card
Dis 2009; 51(4): 285-293
25- Garvey JF. Taylor CT, McNicholas WT. Cardiovascular disease in
obstructive sleep apnoea syndrome: the role of intermittent hypoxia and
inflammation. Eur Respir J 2009; 33: 1195-1205
26- Coppack S. Pro-inflammatory cytokines and adipose tissue. Proc Nutr Soc
2001; 60: 349-356
179
27- Trayhurn P, Wood IS. Adipokines: inflammation and the pleiotropic role of
white adipose tissue. Br J Nutr 2004; 92: 347-355
28- Trayhurn P, Wang B, Wood IS. Hypoxia in adipose tissue: a basis for the
dysregulation of tissue function in obesity? Br J Nutr 2008; 100: 227-235
29- Lévy P, Bonsignore MR, Eckel J. Sleep, sleep disordered breathing and
metabolic consequences. Eur Respir J 2009; 34: 243-260
30- Schwab R. Sex differences and sleep apnoea. Thorax 1999; 54: 284-285
31-Young T, Finn L, Austin D, Peterson A. Menopausal status and sleepdisordered breathing in the Wisconsin Sleep Cohort Study. Am J Respir Crit
Care Med 2003; 167: 1181-1185
32- Shahar E, Redline S, Young T, Boland LL, Baldwin CN, Nieto FJ, O´Connor
GT, Rapoport DM, Robbins JA. Hormone replacement therapy and sleepdisordered breathing. Am J Respir Crit Care Med 2003; 167: 1186-1192
33- Kadotani H, Kadotani T, Young T, Peppard PE, Finn L, Colrain IM, Murphy
Jr GM, Mignot E. Association between apolipoprotein E epsilon 4 and sleepdisordered breathing in adults. JAMA 2001; 285: 2888-2890
34- Gottlieb DJ, DeStefano AL, Foley DJ, Mignot E, Redline S, Givelber RJ,
Young T. APOE epsilon4 is associated with obstructive sleep apnea/hypopnea:
The Sleep Heart Health Study. Neurology 2004; 63: 664-668
35-Larkin EK, Patel SR, Redline S, Mignot E, Elston RC, Hallmayer J.
Apolipoprotein E and obstructive sleep apnea: evaluating whether a candidate
gene explains a linkage peak. Genet Epidemiol 2006; 30: 101-110
36- Jennum P, Hein HO, Suadicani P, Sorensen H, Gyntelberg F. Snoring,
family history, and genetic markers in men. The Copenhagen Male Study.
Chest 1995; 107: 1289-1293
180
37- Carmelli D, Bliwise DL, Swan GE, Reed T. Genetic factors in self-reported
snoring and excessive daytime sleepiness: a twin study. Am J Respir Crit Care
Med 2001; 164: 949-952
38- Ovchinsky A, Rao M, Lotwin I, Goldstein NA. The familial aggregation of
pediatric obstructive sleep apnea syndrome. Arch Otolaryngol Head Neck Surg
2002; 128: 815-818
39- Thomas DA, Swaminathan S, Beardsmore CS, McArdle EK, MacFadyen
UM, Goodenough PC, Carpenter R, Simpson H. Comparison of peripheral
chemoreceptor responses in monozygotic and dizygotic twin infants. Am Rev
Respir Dis 1993; 148: 1605-1609
40- Bouchard C. Genetics of human obesity: recent results from linkage studies.
J Nutr 1997; 127: 1887s-1890s
41- Schwab RJ, Pasirstein m, Kaplan L, Pierson R, Mackley A, Hachadoorian R,
Arens R, Maislin G, Pack AI. Family aggregation of upper airway soft tissue
structures in normal subjects and patients with sleep apnea. Am J respir crit
Care Med 2006; 173: 453-463
42- Francis-West P, Ladher R, Barlow A, Graveson A. Signalling interactions
during facial development. Mech Dev 1998; 75: 3-28
43- Riha RL, Brander P, Vennelle M, , McArdle N, Kerr SM, Anderson NH,
Douglas NJ. Tumour necrosis factor-alpha (-308) gene polymorphism in
obstructive sleep apnoea-hypopnoea syndrome. Eur Respir J 2005; 26: 673678
44- Redline S, Tishler PV, Hans MG, Tosteson TD, Strohl KP, Spry K. Racial
differences in sleep-disordered breathing in African-Americans and caucasians.
Am J Respir Crit Care Med 1997; 155: 186-192
181
45- Mitler MM, Dawson A, Henriksen SJ, Sobers m, Bloom FE. Bedtime ethanol
increases resistance of upper airways and produces sleep apneas in
asynptomatic snorers. Alcohol Clin Exp Res 1988; 12: 801-805
46- Kashyap R, Hock LM, Bowman TJ. Higher prevalence of smoking in
patients diagnosed as having obstructive sleep apnea. Sleep Breath 2001; 4:
167-172
47- Carskadon MA, Bearpark HM, Sharkey KM, Millman RP, Rosenberg G,
Cavallo A, Carlisle C, Acebo C. Effects of menopause and nasal obstruction on
breathing during sleep. Am J Respir Crit Care Med 1997; 155: 205-210
48- Mirza N, Lanza DC. The nasal airway and obstructed breathing during sleep.
Otolaryngol Clin North Am 1999; 32: 243-262
49- Shahar E, Whitney CW Redline S, Lee ET, Newman AB, Javier Nieto F,
O´Connor GT, Boland LL, Schwartz JE, Samet JM. Sleep-disordered breathing
and cardiovascular disease: cross- sectional results of the Sleep Heart Health
Study. Am J Respir Crit Care Med 2001; 163: 19-25
50- Peker Y, Hedner J, Norum J, Kraiczi H, Carlson J. Increased incidence of
cardiovascular disease in middle-aged men with obstructive sleep apnea: a 7year follow-up. Am J Respir Crit Care Med 2002; 166: 159-165
51- Chobanian A, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr,
Jones DW, Materson BJ, Oparil S, Wright JT Jr, Roccella EJ. National Heart,
Lung and Blood Institute Joint National Committee on Prevention, Detection,
Evaluation and Treatment of High Blood Pressure and National High Blood
Pressure Education Program Coordinating Committee. The seventh report of
the Joint National Committee on Prevention, Detection, Evaluation and
Treatment of High Blood Pressure the JNC 7 report. JAMA 2003; 289:25602572
182
52- Javaheri S, Parker TJ, Liming JD, Corbett WS, Nishiyama H, Wexler L,
Roselle GA. Sleep apnea in 81 ambulatory male patients with stable heart
failure: types and their prevalences, consequences and presentations.
Circulation 1998; 97: 2154-2159
53- Dursunoglu D, Dursunoglu N, Evrengül H, Özkurt S,
Kuru Ö, Kiliç M,
Fisekçi F. Impact of obstructive sleep apnea on left ventricular mass and global
function. Eur Resp J 2005; 26: 283- 288
54- Hedner J, Ejnell H, Caidahl K. Left ventricular hypertrophy independent of
hypertension in patients with obstructive sleep apnea. J Hypertens 1990; 8:
941-946
55- Franklin K, Nilsson JB, Sahlin C, Näslund U. Sleep apnea and nocturnal
angina. Lancet 1995; 345: 1085-1087
56- Hoffstein V, Mateika S. Cardiac arrythmias, snoring and sleep apnea. Chest
1994; 106: 466-471
57- Gami AS, Pressman G, Caples SM, Kanagala R, Gard JJ, Davison DE,
Malouf JF, Ammash NM, Friedman PA, Somers UK.
Association of atrial
fibrillation and obstructive sleep apnea. Circulation 2004; 110: 364-367
58- Marrone O, Bonsignore MR. Pulmonary haemodynamics in obstructive
sleep apnea. Sleep Med Rev 2002; 6: 175-193
59- Parra O, Arboix A, Montserrat JM, Quinto L, Bechich S, García-Eroles L.
Sleep-related breathing disorders: impact on mortality of cerebrovascular
disease. Eur Respir J 2004; 24: 267-272
60- Yaggi HK, Concato J, Kernan WN, Lichtman JH, Brass LM, Mohsenin V.
Obstructive sleep apnea as a risk factor for stroke and death. N Engl J Med
2005; 353: 2034-2041
183
61- Gami AS, Howard DE, Olson EJ, Somers UK. Day-night pattern of sudden
death in obstructive sleep apnea. N Engl J Med 2005; 352: 1206-1214
62- Nieto FJ, Young TB, Lind BK, Shahar E, Samet JM, Redline S, D´Agostino
RB, Newman AB, Lebowitz MD, Pickering TG. Association of sleep-disordered
breathing, sleep apnea, and hypertension in a large community-based study.
Sleep Heart Health Study. JAMA 2000; 283(14): 1829-1836
63- Lavie P, Herer P, Hoffstein V. Obstructive sleep apnoea syndrome as a risk
factor for hypertension: population study. BMJ 2000; 320(7233): 479-482
64- Bixler EO, Vgontzas AN, Lin HM, Have TT, Leiby BE, Vela-Bueno A, Kales
A. Association of hypertension and sleep-disordered breathing. Arch Intern Med
2000; 160: 2289-2295
65- Grote L, Ploch T, Heitmann J, Knaack L, Penzel T, Peter JH. Sleep-related
breathing disorder is an independent risk factor for systemic hypertension. Am J
Respir Crit Care Med 1999; 160(6): 1875-1882
66- Young T, Peppard P, Palta M, Hla KM, Finn L, Morgan B, Skatrud J.
Population-based study of sleep-disordered breathing as a risk factor for
hypertension. Arch Intern Med 1997; 157: 1746-1756
67- Peppard PE, Young T, Palta M, Skatrud J. Prospective study of the
association between sleep-disordered breathing and hypertension. N Engl J
Med 2000; 342: 1378-1384
184
68- Lavie P, Hoffstein V. Sleep apnea syndrome. A possible contributing factor
to resistant hypertension. Sleep 2001; 24: 721-725
69- Tan MC, Ayas NT, Mulgrew A, Cortes L, Fitzgerald JM, Fleetham JA,
Schulzer M, Ryan CF, Ghaeli R, Cooper P, Marra CA. Cost- effectiveness of
continuous positive airway pressure therapy in patients with obstructive sleep
apnea-hypopnea in British Columbia. Can Respir J 2008; 15: 159-165
70- Pack AI, Pien GW. How much do crashes related to obstructive sleep
apnea cost? Sleep 2004; 27: 369-370
71- Gurubhagavatula I, Nkwuo JE, Maislin G, Pack AI. Estimated cost of
crashes in commercial drivers supports screening and treatment of obstructive
sleep apnea. Accid Anal Prev 2000; 40: 104-115
72- Jennum P, Riha RL. Epidemiology of sleep apnoea/hypopnoea syndrome
and sleep disordered breathing. Eur Respir J 2009; 33: 907-914
73- Tarasiuk A, Greenberg-Dotan S, Simon T, Tal A, Oksenberg A, Reuveni H.
Low socioeconomic status is a risk factor for cardiovascular disease among
adult obstructive sleep apnea syndrome patients requiring treatment. Chest
2006; 130: 766-773
74- Lavie P, Lavie L, Herer P. All-cause mortality in males with sleep apnoea
syndrome. Declining mortality rates with age. Eur Respir J 2005; 25: 514-520
185
75- Pack AI, Gislason T. Obstructive Sleep Apnea and Cardiovascular Disease:
a perspective and future directions. Progr Cardio Dis 2009; 51(5): 434-451
76- Somers VK, Dyken ME, Clary MP, Abboud FM. Sympathetic neural
mechanisms in obstructive sleep apnea. J Clin Invest 1995; 96: 1897-1904
77- Waradekar NV, Sinoway LI, Zwillich CW, Leuenberger UA. Influence of
treatment on muscle sympathetic nerve activity in sleep apnea. Am J Respir Crit
Care Med 1996; 153 (4): 1333-1338
78- Ziegler NG, Mills PJ, Loredo JS. Effect of continuous positive airway
pressure and placebo treatment on sympathetic nervous activity in patients with
obstructive sleep apnea. Chest 2001; 120: 887-893
79- Hedner J, Darpo B, Ejnell H, Carlson J, Caidahl K. Reduction in sympathetic
activity after long-term CPAP treatment in sleep apnoea: cardiovascular
implications. Eur Respir J 1995; 8: 222-229
80- Winck JC, Sequeiros M, Drummond M, Pipa J, Magalhães S, Simões P,
Gouveia S, Rocha AP. Avaliação da pressão arterial durante o sono- um
estudo piloto. Rev Port Pneum 2008; vol XIV (4): s48
81- Somers VK, Mark AL, Abboud FM. Sympathetic activation by hypoxia and
hypercapnia- implications for sleep apnea. Clin exp Hypertens A 1988; 10 (1):
413-422
82- Carlson JT, Hedner J, Elam M, Ejnell H, Sellgren J, Wallin BG. Augmented
resting sympathetic activity in awake patients with obstructive sleep apnea.
Chest 1993; 103: 1763-1768
83- Lavie L. Lavie P. Molecular mechanisms of cardiovascular disease in
OSAHS: the oxidative stress link. Eur Respir J 2009; 33: 1467-1484
186
84- Dai X, Galligan JJ, Watts SW, Fink GD, Kreulen DL. Increased 02production and upregulation of ETB receptors by sympathetic neurons in
DOCA-salt hypertensive rats. Hypertension 2004; 43: 1048-1054
85- Dyugovskaya L, Lavie P, Lavie L. Increased adhesion molecules expression
and production of reactive oxygen species in leukocytes of sleep apnea patients.
A M J Respir Crit Care Med 2002; 165: 934-939
86- Lavie L, Dyugovskaya L, Lavie P. Sleep-apnea-related intermittent hypoxia
and atherogenesis. Adhesion molecules and monocytes/endothelial cells
interactions. Atherosclerosis 2005; 183: 183-184
87-
Dyugovskaya
L,
Lavie
P,
Lavie
L.
Phenotypic
and
functional
characterization of blood γδ T-cells in sleep apnea. Am J Respir Crit Care Med
2003; 168: 242-249
88- Valko M, Leibfritz D, Moncol J, Gronin MT, Mazur M, Telser J. Free radicals
and antioxidants in normal physiological functions and human disease. Int J
Biochem Cell Biol 2007; 39: 44-84
89- Lavie L. Obstructive sleep apnoea syndrome- an oxidative stress disorder.
Sleep Med Rev 2003; 7: 35-51
90- Suzuki YJ, Jain V, Park AM, Day RM. Oxidative stress and oxidant signaling
in obstructive sleep apnea and associated cardiovascular diseases. Free Radic
Biol Med 2006; 40: 1683-1693
91- Lavie L. Oxidative stress- a unifying paradigm in obstructive sleep apnea
and comorbidities. Prog Cardiov Dis 2009; 51(4): 303-312
92- Ryan S, Taylor CT, McNicholas WT. Predictors of elevated nuclear factor
kB dependent genes in obstructive sleep apnea syndrome. Am J Respir Crit
Care Med 2006; 174: 824-830
187
93- Minoguchi K, Yokoe T, Tazaki T, Minoguchi H, Tanaka A, Oda N, Okada S,
Ohta S, Naito H, Adachi M. Increased carotid intima-media thickness and serum
inflammatory markers in obstructive sleep apnea. Am J Respir Crit Care Med
2005; 172: 625-630
94- Kobayashi K, Nishimura Y, Shimada T, Yoshimura S, Funada Y, Satouchi
M, Yokoyama M. Effect of continuous positive airway pressure on soluble CD40
ligand in patients with obstructive sleep apnea syndrome. Chest 2006; 129:
632-637
95- Fletcher EC, Lesske J, Behm R, Miller CC, Strauss H, Unger T. Carotid
chemoreceptors, systemic blood pressure, and chronic episodic hypoxia
mimicking sleep apnea. J Appl Physiol 1992; 72: 1978-1984
96- Veasey SC, Davis CW, Fenik P, Zhan G, Hsu Y. Long-term intermittent
hypoxia in mice: protracted hypersomnolence with oxidative injury to sleepwake brain regions. Sleep 2004; 27: 194-201
97- Xu W, Chi L, Row BW, Xu R, Ke Y, Xu B, Luo C, Liu R. Increased oxidative
stress is associated with chronic intermittent hypoxia-mediated brain cortical
neuronal cell apoptosis in a mouse model of sleep apnea. Neuroscience 2004;
126: 313-323
98- Atkeson A, Yeh SY, Malhotra A, Jelic S. Endothelial function in obstructive
sleep apnea. Prog Cardiov Dis 2009; 51(5): 351-362
99- Aird WC. Phenotypic heterogeneity of the endothelium: representative
vascular beds. Circ Res 2007; 100: 174-190
100- Schulz R, Mahmoudi S, Hattar K. Enhanced release of superoxide from
polymorphonuclear neutrophils in obstructive sleep apnea. Am J Respir Crit
Care Med 2000; 162: 566-570
188
101- Jelic S, Padeletti M, kawut SM, Higgins C, Canfield SM, Onat D, Colombo
PC, Basner RC, Factor P, Lejemtel TH. Inflammation, oxidative stress and
repair capacity of the vascular endothelium in obstructive sleep apnea.
Circulation 2008; 117: 2270-2278
102- Ip MS, Lam B, Chan LY, Zheng L, Tsang KWT, Fung PCW, Lam WK.
Circulating nitric oxide is supressed in obstructive sleep apnea and is reversed
by nasal continuous positive airway pressure. Am J Respir Crit Care Med 2000;
162: 2166-2171
103- Schulz R, Schmidt D, Blum A, Lopes-Ribeiro X, Lücke C, Mayer K,
Olschewski H, Seeger W, Grimminger F. Decreased plasma levels of nitric
oxide derivatives in obstructive sleep apnea. Response to CPAP therapy.
Thorax 2000; 55: 1046-1051
104- Kato M, Roberts-Thomson P, Phillips BG, Maynes WG, Winnick M,
Accurso V, Somers VK. Impairment of endothelium-dependent vasodilation of
resistance vessels in patients with obstructive sleep apnea. Circulation 2000;
102: 2607-2610
105- Carlson J, Rangemark C, Hedner J. Attenuated endothelium-dependent
vascular relaxation in patients with sleep apnea. J Hypertens 1996; 14: 577-584
106- Moller DS, Lind P, Strunge B, Pedersen EB. Abnormal vasoactive
hormones and 24-hour blood pressure in obstructive sleep apnea. Am J
Hypertens 2003; 16: 274-280
107- Nieto FJ. Herrington DM, Redline S, Benjamin EJ, Robbi JA. Sleep apnea
and markers of vascular endothelial function in a large community sample of
older adults. Am J Respir Crit Care Med 2004; 169: 354-360
108- Von Känel R, Dimsdale JE. Hemostatic alterations in patients with
obstructive sleep apnea and the implications for cardiovascular disease. Chest
2003; 124: 1956-1967
189
109- Davies MJ. The contribution of thrombosis to the clinical expression of
coronary atherosclerosis. Thromb Res 1996; 82: 1-32
110- McNicholas WT. Obstructive sleep apnea and inflammation. Prog Cardiov
Dis 2009; 51 (5): 392-399
111- Cummins EP, Taylor CT. Hypoxia-responsive transcription factors.
Pflugers Arch 2005; 450: 363-371
112- Greenberg H, Ye X, Wilson D, Htoo AK, Hendersen T, Liu SF. Chronic
intermittent hypoxia activates nuclear factor-kappaB in vascular tissues in vivo.
Biochem Biophys res Commun 2006; 343: 591-596
113- Hansson GK. Inflammation, atherosclerosis, and coronary artery disease.
N Engl J Med 2005; 352: 1685-1695
114- Libby P. Inflammation in atherosclerosis. Nature 2002; 420: 868-874
115- Lusis AJ. Atherosclerosis. Nature 2000; 407: 233-241
116- Lévy P, Pépin JL, Arnaud C, Baguet JP, Dematteis M, Mach F. Obstructive
sleep apnea and atherosclerosis. Prog Cardiov Dis 2009; 51 (5): 400-410
117- Dyugovskaya L, Polyakov A, Lavie P, Lavie L. Delayed neutrophil
apoptosis in patients with sleep apnea. Am J Respir Crit Care Med 2008; 177:
544-554
118- Ohga E, Tomita T, Wada H. Effects of obstructive sleep apnea on
circulating ICAM-1, IL-8, and MCP-1. J Appl Physiol 2003; 94: 179-184
119- Pignoli P, Tremoli E, Poli A, Roeste P, Paoletti R. Intimal plus medial
thickness of the arterial wall: a direct measurement with ultrasound imaging.
Circulation 1986; 74: 1399-1406
190
120- O´Leary DH, Polak JF, Kronmal RA, Manolio TA, Burke GL, Wolfson SK,
for the Cardiovascular Health Study Collaborative Research Group. Carotidartery intima and media thickness as a risk factor for myocardial infarction and
stroke in older adults. Cardiovascular Health Study Collaborative Research
Group. N Engl J Med 1999; 340: 14-22
121- Fathi R, Haluska B, Isbel N, Short L, Marwick TH. The relative importance
of vascular structure and function in predicting cardiovascular events. J Am Coll
Cardiol 2004; 43: 616-623
122- Drager LF, Bortolotto LA, Lorenzi MC, Figueiredo AC, Krieger EM,
Lorenzi-Filho G. Early signs of atherosclerosis in obstructive sleep apnea. Am J
Respir Crit Care Med 2005;172: 613-618
123- Baguet JP, Hammer L, Lévy P, Pierre H, Launois S, Mallion JM, Pépin JL.
The severity of oxygen desaturation is predictive of carotid wall thickening and
plaque ocurrence. Chest 2005; 128: 3407-3412
124- Turmel J, Series F, Boulet LP, Poirier P, Tardif JC, Rodes-Cabeau J,
Larose E, Bertrand OF. Relationship between atherosclerosis and the sleep
apnea syndrome: an intravascular ultrasound study. Int J Cardiol 2008; 132 (2):
203-209
125- Krieger J, Sforza E, Boudewijns A, Zamagni M, Petiau C. Respiratory
effort during obstructive sleep apnea: role of age and sleep state. Chest 1997;
112: 875-884
126- Foster GE, Poulin MJ, Hanly PJ. Intermittent hypoxia and vascular function.
Implications for obstructive sleep apnea. Exp Physiol 2007; 92: 51-65
127- Robbins P. Role of the peripheral chemoreflex in the early stages of
ventilatory acclimatization to altitude. Respir Physiol Neurobiol 2007; 158: 237242
191
128- Lavie L, Lavie P. Ischemic preconditioning as a possible explanation for
the age decline relative mortality in sleep apnea. Med Hypotheses 2006; 66:
1069- 1073
129- Ryan S, Ward S, Heneghan C, McNicholas WT. Predictors of decreased
spontaneous baroreflex sensitivity in obstructive sleep apnea syndrome. Chest
2007; 131: 1100-1107
130- Knutson KL, Spiegel K, Penev P, van Cauter E. The metabolic
consequences of sleep deprivation. Sleep Med Rev 2007; 11: 163-178
131- Spiegel K, Tasali E, Penev P, van Cauter E. Brief communication: sleep
curtailment in healthy young men is associated with decreased leptin levels,
elevated ghrelin levels, and increased hunger and appetite. Ann Intern Med
2004; 141: 846-850
132- Taheri S, Lin L, Austin D, Young T, Mignot E. Short sleep duration is
associated with reduced leptin, elevated ghrelin, and increased body mass
index. Plos Med 2004; 1: e62
133- Nilsson PM, Roost M, Engstrom G, Hedblad B, Berglund G. Incidence of
diabetes in middle-aged men is related to sleep disturbances. Diabetes Care
2004; 27: 2464-2469
192
134- Mallon L, Broman J-E, Hetta J. High incidence of diabetes in men with
sleep complaints or short sleep duration: a 12-year follow-up study of a middleaged population. Diabetes Care 2005; 28: 2762-2767
135- Tasali E, Leproult R, Ehrmann DA, van Cauter E. Slow-wave sleep and the
risk of type 2 diabetes in humans. Proc Natl Acad Sci USA 2008; 105: 10441049
136- Chaput JP, Despres JP, Bouchard C, Tremblay A. Short sleep duration is
associated with reduced leptin levels and increased adiposity: results from the
Quebec family study. Obesity 2007; 15: 253-261
137- Hasler G, Buysse DJ, klaghofer R, Gamma A, Ajdacic V, Eich D, Rossler
W, Angst J. The association between short sleep duration and obesity in young
adults: a 13 year prospective study. Sleep 2004; 27: 661-666
138- Young T. Increasing sleep duration for a healthier (and less obese?)
population tomorrow. Sleep 2008; 31: 593-594
139- Cappuccio FP, Taggart FM, Kandala NB, Currie A, Peile E, Stranges S,
Miller MA. Meta-analysis of short sleep duration and obesity in children and
adults. Sleep 2008; 31: 619-626
140- Bierhaus A, Wolf J, Andrassy M, Rohleder N, Humpert PM, Petrov D,
Ferstl R, von Eynatten M, Wendt T, Rudofsky G, Joswig M, Morcos M,
193
Schwaninger M, McEwen B, Kirschbaum C, Nawroth PP. A mechanism
converting psychosocial stress into mononuclear cell activation. Proc Natl Acad
Sci USA 2003; 100: 1920-1925
141- Irwin M, Thompson J, Miller C, Gillin JC, Zieger M. Effects of sleep and
sleep deprivation catecholamine and interleukin-2 levels in humans. Clinical
implications. J Clin Endocrinol Metab 1999; 84: 1979-1985
142- Irwin MR, Ziegler M. Sleep deprivation potentiates activation of
cardiovascular
and
catecholamine
responses
in
abstinent
alcoholics.
Hypertension 2005; 45: 252.257
143- Li J, Grigoryev DN, Ye SQ, Thorne L, Scwartz AR, Smith PL, O´Donnell
CP, Polotsky VY. Chronic intermittent hypoxia upregulates genes of lipid
biosynthesis in obese mice. J Appl Physiol 2005; 99 (5): 1643-1648
144- Li J, Thorne LN, Punjabi NM, Sun CK, Schwartz AR, Smith PL, Marino RL,
Rodriguez A, Hubbard WC, O´Donnell CP, Polotsky VY. Intermittent hypoxia
induces hyperlipidemia in lean mice. Circ Res 2005; 97 (7): 698-706
145- Li J, Bosch- Marce M, Nanayakkara A, et al. Altered metabolic responses
to intermittent hypoxia in mice with partial deficiency of hypoxia-inducible factor
α1. Physiol Genomics 2006; 25: 450-457
194
146- Newman AB, Nieto FJ, Guidry U, Lind BK, Redline S, Shahar E, Pickering
TG, Quan SF. Relation of sleep disordered breathing to cardiovascular disease
risk factors: The Sleep Heart Health Study. Am J Epidemiol 2001; 154: 50-59
147- Mc Ardle N, Hillman D, Beilin L, Watts G. Metabolic risk factors for
vascular disease in obstructive sleep apnea: a matched controlled study. Am J
Respir Crit Care Med 2007; 175: 190-195
148- Robinson GV, Pepperell JC, Segal HC, Davies RJO, Stradling JR.
Circulating cardiovascular risk factors in obstructive sleep apnoea: data from
randomised controlled trials. Thorax 2004; 59 (9): 777-782
149- International Diabetes Federation.The IDF consensus worldwide definition
of the metabolic syndrome. International Diabetes Federation, Brussels 2005
150- Ford ES. Risks for all-cause mortality, cardiovascular disease, and
diabetes associated with the metabolic syndrome: a summary of the evidence.
Diabetes Care 2005; 28: 1769- 1778
151- Galassi A, Reynolds K, He J. Metabolic syndrome and risk of
cardiovascular disease: a meta-analysis. Am J Med 2006; 119: 812- 819
152- Gami AS, Witt BJ, Howard DE, Erwin PJ, Gami LA, Somers VK, Montori
VM. Metabolic syndrome and risk of incident cardiovascular events and death:
195
a systematic review and meta-analysis of longitudinal studies. J Am Coll Cardiol
2007; 49: 403- 414
153- Sasanabe R, Banno K, Otake K, et al. Metabolic syndrome in Japanese
patients with obstructive sleep apnea syndrome. Hypertens Res 2006; 29: 315322
154- Lam JCM, Lam B, LamC-L, et al. Obstructive sleep apnea and the
metabolic syndrome in community-based Chinese adults in Hong Kong. Respir
Med 2006; 100: 980-987
155- Shiina K, Tomiyama H, Takata Y, usui Y, Asano K, Hirayama Y, Nakamura
T, Yamashina A. Concurrent presence of metabolic syndrome in obstructive
sleep apnea syndrome exacerbates the cardiovascular risk: a sleep clinic cohort
study. Hypertens Res 2006; 29: 433-441
156- Coughlin SR, Mawdsley L, Mugarza JA, Calverley PMA, Wilding JPH.
Obstructive sleep apnoea is independently associated with an increased
prevalence of metabolic syndrome. Eur Heart J 2004; 25: 735-741
157- Kono M, Tatsumi K, Saibara T, Nakamura A, Tanabe N, Takiguchi Y,
Kuriyama T. Obstructive sleep apnea syndrome is associated with some
components of metabolic syndrome. Chest 2007; 131. 1387-1392
196
158- Peled N, Kassirer M, Shitrit D, Kogan Y, Shlomi D, Berliner AS, Kramer
MR. The association of OSA with insulin resistance, inflammation and metabolic
syndrome. Resp Med 2007; 101: 1696-1701
159- Bento J, Drummond M, Winck JC, Almeida J, Marques JA. Metabolic
Syndrome in OSA patients. Eur Respir J 2007; 30(51):493s
160- Vgontzas AN, Bixler EO, Chrousos GP. Sleep apnea is a manifestation of
the metabolic syndrome. Sleep Med Rev 2005; 9: 211-224
161- Ambrosetti M, Lucioni AM, Conti S, Pedretti RFE, Neri M. Metabolic
syndrome in obstructive sleep apnea and related cardiovascular risk. J Cardiov
Med 2006; 7: 826-829
162- Dorkova Z, Petrasova D, Molcanyiova A, Popovnakova M, Tkacova R.
Effects of CPAP on cardiovascular risk profile in patients with severe obstructive
sleep apnea and metabolic syndrome. Chest 2008; 134: 686-692
163- Hosogai N, Fukuhara A, Oshima K, Miyata Y, Tanaka S, Segawa K,
Furukawa S, Tochino Y, Komuro R, Matsuda M, Shimomura L. Adipose tissue
hypoxia in obesity and its impact on adipocytokine dysregulation. Diabetes
2007; 56: 901-911
197
164- Sullivan CE, Issa FG, Berthon-Jones M, Eves L. Reversal of obstructive
sleep apnoea by continuous positive airway pressure applied through the nares.
Lancet 1981; 1: 862-865
165- Giles T, Lasserson T, Smith BJ, White J, Wright J, Cates CJ. Continuous
positive airways pressure for obstructive sleep apnoea in adults. Cochrane
Database Syst Rev 2006; 1: CD001106
166- Loube DI, Gay PC, Strohl KP, Pack AI, White DP, Collop NA. Indications
for positive airway pressure treatment of adult obstructive sleep apnea patients:
a consensus statement. Chest 1999; 115: 863-866
167- Drummond M, Winck JC, Marques JA. CPAP therapy impact in OSA
related symptoms- a prospective study. Eur Respir J, September 2006; 411s
168- Milleron O, Pilliere R, Foucher A, de Roquefeuil F, Aegerter P, Jondeau G,
Raffestin BG, Dubourg O. Benefits of obstructive sleep apnoea treatment in
coronary artery disease: a long-term follow-up study. Eur Heart 2004; 25: 728734
169- Arias MA. García-Río F, Alonso-Fernández A, Hernanz A, Hidalgo R,
Martínez-Mateo V, Bartolomé S, Rodríguez-Padial L. CPAP decreases plasma
levels of soluble tumour necrosis factor-α receptor 1 in obstructive sleep apnoea.
European Respiratory Journal 2008; 32: 1009-1015
198
170- Haentjens P, Van Meerhaeghe A, Moscariello A, De Weerdt S, poppe K,
Dupont A, Velkeniers B. The impact of continuous positive airway pressure on
blood pressure in patients with obstructive sleep apnea syndrome. Arch Intern
Med 2007; 167: 757-765
171- Alajmi M, Mulgrew AT, Fox J, Davidson W, Schulzer M, Mak E, Ryan CF,
Fleetham J, Choi P, Ayas NT. Impact of continuous positive airway pressure
therapy on blood pressure in patients with obstructive sleep apnea hypopnea: a
meta-analysis of randomized controlled trials. Lung 2007; 185: 67-72
172- Dursunoglu N, Dursunoglu D, Ozkurt s, Gur S, Ozalp G, Evyapan F.
Effects of CPAP on right ventricular myocardial performance index in
obstructive sleep apnea patients without hypertension. Resp Res 2006; 7: 2229
173- Romero-Corral A, Somers VK, Pellikka PA, Olson EJ, Bailey KR, Korinek J,
Orban M, Sierra-Johnson J, Kato M, Amin RS, Lopez-Jimenez F. Decreased
right and left ventricular myocardial performance in obstructive sleep apnea.
Chest 2007; 132: 1863-1870
174- Steiropoulos P, Tsara V, Nena E, Fitili C, kataropoulou M, Froudarakis M,
Christaki P, Bouros D. Effect of continuous positive airway pressure treatment
on serum cardiovascular risk factors in patients with obstructive sleep apneahypopnea syndrome. Chest 2007; 132 (3): 843-851
175- Drager LF, Bortolotto LA, Figueiredo AC, Krieger EM, Lorenzi-Filho G.
Effects of continuous positive airway pressure on early signs of atherosclerosis
in obstructive sleep apnea. Am J Respir Crit Care Med 2007; 176: 706-712
199
176- Marin JM, Carrizo SJ, Vicente E, Agusti AGN. Long-term cardiovascular
outcomes in men with obstructive sleep apnoea-hypopnoea with or without
treatment with continuous positive airway pressure: an observational study.
Lancet 2005; 365: 1046-1053
177- Lattimore JL, Wilcox I, Skilton M, Langenfeld M, Celermajer DS. Treatment
of obstructive sleep apnoea leads to improved microvascular endothelial
function in the systemic circulation. Thorax 2006; 61: 491-495
178- Narkiewicz K, Kato M, Phillips BA, Pesek CA, Davison DE, Somers VK.
Nocturnal continuous positive airway pressure decreases daytime sympathetic
traffic in obstructive sleep apnoea. Circulation 1999; 100: 2332-2335
179- Nussbaumer Y, Block KE, Genser T, Thurneer R. Equivalence of
autoadjusted and constant continuous positive airway pressure in home
treatment of sleep apnea. Chest 2006; 129: 638-643
180- Stradling JR. Reducing the cost of treating obstructive sleep apnoea: good
news for the patients. Am J Respir Crit Care Med 2004; 170: 1143-1144
181- Lloberes P, Ballester E, Montserrat JM, Botifoll E, Ramirez A, Reolid A,
Gistau C, Rodriguez-Roisin R. Comparison of manual and automatic CPAP
titration in patients with sleep apnea/hypopnea syndrome. Am J Respir Crit
Care Med 1996; 154: 1755-1758
182- Massie CA, McArdle N, Hart RW, Schmidt-Nowara WW, Lankford A,
Hudgel DW, Gordon N, Douglas NJ. Comparison between automatic and fixed
positive airway pressure therapy in the home. Am J Respir Crit Care Med 2003;
167: 20-23
200
183- Konermann M, Sanner BM, Vyleta M, Laschwski F, Groetz J, Sturm A,
Zidek W. Use of conventional and self-adjusting nasal positive airway pressure
for treatment of severe obstructive sleep apnea syndrome: a comparative study.
Chest 1998; 113: 714-718
184- Series F, Marc I. Efficacy of automatic continuous positive airway pressure
therapy that uses an estimated required pressure in the treatment of obstructive
sleep apnea syndrome. Ann Intern Med 1997; 127: 588-595
185- Berry RB, Parish JM, Hartse KM. The use of auto-titrating continuous
positive airway pressure for treatment of adult obstructive sleep apnea: an
American Academy of Sleep Medicine Review. Sleep 2002; 25: 148-173
186- Dursunoglu N, Dursunoglu D, Cuhadaroglu C, Kiliçaslan Z. Acute effects
of automated continuous positive airway pressure on blood pressure in patients
with sleep apnea and hypertension. Respiration 2005; 72: 150-155
187- Robinson GV, Smith DM, Langford BA, Davies RJO, Stradling JR.
Continuous positive airway pressure does not reduce blood pressure in nonsleepy hypertensive OSA patients. Eur Respir J 2006; 27: 1229-1235
188- Patruno V, Aiolfi S, Costantino G, Murgia R, Selmi C, Malliani A, Montano
N. Fixed and autoadjusting continuous positive airway pressure treatments are
not similar in reducing cardiovascular risk factors in patients with obstructive
sleep apnea. Chest 2007; 131(5): 1393-1399
189- Yudkin JS, kumari M, Humphries SE, Mohamed-Ali V. Inflammation,
obesity, stress and coronary heart disease: is interleukin-6 the link?
Atherosclerosis 2000; 148: 209-214
201
190- Pasulka P, Bristian BR, Blackburn GL. Obesity and erythrocyte
sedimentation rates. Ann Intern Med 1985; 103: 304
191- Roytblat L, Rachinsky M, Fisher A, Greemberg L, Shapira Y, Douvdevani
A, Gelman S. Raised interleukin-6 levels in obese patients. Obesity Research
2000; 8: 673-675
192- Meier-Ewert HK, Ridker PM, Rifai N, Price N, Dinges DF, Mullington JM.
Absence of diurnal variation of C-reactive protein concentrations in healthy
human subjects. Clin Chem 2001; 47: 426-430
193- Lindhal B, Toss H, Siegbahn A, Venge P, Wallentin L. Markers of
myocardial damage and inflammation in relation to long-term mortality in
unstable coronary heart disease. FRISC Study Group. N Engl J Med 2000; 343:
1139-1147
194- Ridker PM, Rifai N, Pfeffer MA, Sacks F, Braunwald E. Long term effects
of pravastatin on plasma concentration of C-reactive protein. The Cholesterol
and Recurrent Events (CARE) Investigators. Circulation 1999; 100: 230-235
195- Ridker PM. Clinical Application of C-Reactive Protein for Cardiovascular
Disease Detection and Prevention. Circulation 2003; 107: 363-369
196- Danesh J, Whincup P, Walker M, Lennon L, Thomson A, Appleby P,
Gallimore JR, Pepys MB. Low grade inflammation and coronary heart disease:
prospective study and updated meta-analysis. BMJ 2000; 321: 199-204
197- Calabro P, Willerson JT, Yeh ET. Inflammatory cytokines stimulated Creactive protein production by human coronary artery smooth muscle cells.
Circulation 2003; 108: 1930-1932
198- Devaraj S, Xu DY, Jialal I. C-reactive protein increases plasminogen
activator inhibitor-1 expression and activity in human aortic endothelial cells:
202
implications for the metabolic syndrome and atherothrombosis. Circulation
2003; 107: 398-404
199- Han KH, Hong KH, Park JH, Ko J, Kang DH, Choi KJ, Hong MK, Park SW,
Park SJ. C-reactive protein promotes monocyte chemoattractant protein-Imediated chemotaxis through upregulating CC chemokine receptor 2
expression in human monocytes. Circulation 2004; 109: 2566-2571
200- Fichlscherer S, Breuer S, Schachinger V, Dimmeler S, Zeiher AM. Creactive protein levels determine systemic nitric oxide bioavailability in patients
with coronary artery disease. Eur Heart J 2004; 25: 1412-1418
201- Jialal I, Devaraj S, Venugopal SK. C-reactive protein: risk marker or
mediator in atherothrombosis? Hypertension 2004; 44: 6-11
202- Liu H, Liu J, Xiong S, Shen G, Zhang Z, Xu Y. The change of interleukin-6
and tumor necrosis factor in patients with obstructive sleep apnea syndrome. J
Tongji Med Univ 2000; 20(3): 200-202
203- Vgontzas AN, Papanicolaou DA, Bixler EO, Hopper K, Lotsikas A, Lin H,
Kales A, Chrousos GP. Sleep apnea and daytime sleepiness and fatigue:
relation to visceral obesity, insulin resistance, and hypercytokinemia. J Clin
Endocrinol Metab 2000; 85(3): 1151-1158
204- Yokoe T, Minoguchi K, Matsuo H, Oda N, Minoguchi H, Yoshino G, Hirano
T, Adachi M. Elevated levels of C-Reactive Protein and Interleukin-6 in patients
with Obstructive Sleep Apnea Syndrome are decreased by Nasal Continuous
Positive Airway Pressure. Circulation 2003; 107(8): 1129-1134
205- Shamsuzzaman ASM, Winnicki M, Lanfranchi P, Wolk R, Kara T, Accurso
V, Somers VK. Elevated C-Reactive Protein in patients with Obstructive Sleep
Apnea. Circulation 2002; 105: 2462-2464
203
206- Kokturk O, Ciftci TU, Mollarecep E, Ciftci B. Elevated C-reactive protein
levels and increased cardiovascular risk in patients with obstructive sleep apnea
syndrome. Int Heart J 2005; 46: 801-809
207- Auwerx J, Staels B. Leptin. The Lancet 1998; 351:737-742
208- Lima J. Leptin and neuroendocrinology. Arqu Med 2002; 16(2): 115-120
209- Haynes WG, Morgan DA, Walsh SA, Mark AL, Sivitz WI. Receptormediated regional sympathetic nerve activation by leptin. J Clin Invest 1997;
100: 270-278
210- Marik PE. Leptin, obesity, and obstructive sleep apnea. Chest 2000;
118(3): 569-571
211- Hakansson ML, Brown H, Ghilardi N,
Skoda RC, Meister B. Leptin
receptor immunoreactivity in chemically defined target neurons of the
hypothalamus. J Neurosci 1998; 1881): 559-572
212- Patel SR, Palmer LJ, Larkin EK, Jenny NS, White DP, Redline S, MD.
Relationship
between
obstructive
sleep
apnea
and
diurnal
leptin
rhythms. Sleep 2004; 27(2): 235-239
213- Rubinsztajn R, Kumor M, Byskiniewicz K, Bielicki P, Chazan R. Serum
leptin concentration and sympathetic activation estimated on the adrenalin and
noradrenalin serum concentration in patients with obstructive sleep apnea. Pol
Arch Med Wewn 2005; 113 (6): 544-551
214- Friedman JM, Halaas JL. Leptin and the regulation of body weight in
mammals. Nature 1998; 395 : 763-770
215- Ostlund RE, Yang JW, Klein S, Gingerich R. Relation between plasma
leptin concentration and body fat, gender, diet, age, and metabolic covariates. J
Clin Endocrinol Metab 2005; 81(11): 3909-3913
204
216- Manzella D, Parillo M , Razzino T, Gnasso P, Buonanno S, Gargiulo A,
Caputi M, Paolisso G. Soluble leptin receptor and insulin resistance as
determinant of sleep apnea. Int J Obes Relat Metab Disord 2002; 26(3): 370-5
217- Ozturk L, Ünal M, Tamer L, Celikoglu F. The association of the severity of
obstructive sleep apnea with plasma leptin levels. Arch Otolaryngol Head Neck
Surg 2003; 129(5): 538-540
218- Phillips BG, Kato M, Narkiewicz K, Choe I, Somers VK. Increases in leptin
levels, sympathetic drive, and weight gain in obstructive sleep apnea. Am J
Physiol Heart Circ Physiol 2000; 279(1): H234-237
219- Ciftci TU, Kokturk O, Bukan N, Bilgihan A. Leptin and ghrelin levels in
patients with obstructive sleep apnea syndrome. Respiration 2005; 72(4): 395401
220- Ip MS, Lam KS, Ho C, Tsang KW, Lam W. Serum leptin and vascular risk
factors in obstructive sleep apnea. Chest 2000; 118: 580-586
221- Barceló A, Barbé F, Llompart E, de la Peña M, Durán-Cantolla J, Ladaria
A, Bosch M, Guerra L, Agustí AG. Neuropeptide Y and leptin in patients with
obstructive sleep apnea syndrome. Am J respir Crit Care Med 2005; 171(2):
183-187
222- Harsch I, Konturek PC, Koebnick C, Kuehnlein PP, Fuchs FS, Pour
Schahin S, Wiest GH, Hahn EG, Lohmann T, Ficker JH. Leptin and ghrelin
levels in patients with obstructive seep apnoea: effect of CPAP treatment. Eur
Respir J 2003; 22(2): 251-257
223- Sanner BM, Kollhosser P, Buechner N, Zidek W, Tepel M. Influence of
treatment on leptin levels in patients with obstructive sleep apnoea. Eur Respir
J 2004; 23(4): 601-604
205
224- Shimizu K, Chin K, Nakamura T, Masuzaki H, Ogawa Y, Hosokawa R,
Niimi A, Hattori N, Nohara R, Sasayama S, Nakao K, Mishima M, Nakamura T,
Ohi M. Plasma leptin levels and cardiac sympathetic function in patients with
obstructive sleep apnoea-hypopnoea syndrome. Thorax 2002; 57(5) : 429-434
225- Tharaux PL. Effect of sleep apnea syndrome on the vascular endothelium.
Rev Neurol 2003; 159(11): 6s102-106
226- Millman RP, Redline S, Carlisle CC, Assaf AR, Levinson PD. Daytime
hypertension in obstructive sleep apnoea: prevalence and contributing factors.
Chest 1991; 99: 861-866
227- Podszus T, Mayer J, Penzel T, Peter JH, von Wichert P. Nocturnal
hemodynamics in patients with sleep apnea. Eur J Respir Dis 1986; 69: 435442
228- Guilleminault C, Tilkian A, Dement WC. The sleep apnea syndrome. Ann
Rev Med 1976; 27:465-484
229- Lavie P, Alroy G, Halperin E. Apneic and nonapneic breathing disorders in
sleep. Isr J Med Sci 1982; 18: 523-533
230- Shepard JW Jr, Garrison MW, Grither DA, Dolan GF. Relationship of
ventricular ectopy to oxyhemoglobin desaturation in patients with obstructive
sleep apnea. Chest 1985; 88: 335-340
206
231- Partinen M, Jamieson A, Guilleminault C. Long-term outcome for
obstructive sleep apnea syndrome patients (mortality). Chest 1988; 94: 12001204
232- Hla KM, Young TB, Bidwell T, Palta M, Skatrud JB, Dempsey J. Sleep
apnea and hypertension. A population based study. Arch Int Med 1994; 120:
382-388
233- Fletcher EC, DeBehnke RD, Lovoi MS, Gorin AB. Undiagnosed sleep
apnea in patients with essential hypertension. Ann Intern Med 1985; 103: 190195
234- Dimsdale JE, Loredo JS, Profant J. Effect of continuous positive airway
pressure on blood pressure: a placebo trial. Hypertension 2000; 35: 144-147
235- Faccenda JF, Mackay TW, Boon NA, Douglas NJ. Randomized placebocontrolled trial of continuous positive airway pressure on blood pressure in the
sleep apnea-hypopnea syndrome. Am J Respir Crit Care Med 2001; 163: 344348
236- Pepperell JCT, Ramdassingh-Dow S, Crosthwaite N, Mullins R, Jenkinson
C, Stradling JR, Davies RJ. Ambulatory blood pressure after therapeutic and
subtherapeutic nasal continuous positive airway pressure for obstructive sleep
apnea: a randomized parallel trial. Lancet 2002; 359: 204-210
207
237- Becker HF, Jerrentrup A, Ploch T, Grote L, Penzel T, Sullivan CE, Peter
JH. Effect of nasal continuous positive airway pressure treatment on blood
pressure in patients with obstructive sleep apnea. Circulation 2003; 107: 68-73
238- Monasterio C, vidal S, Duran J, Ferrer M, Carmona C, Barbé F, Mayos M,
Ganzalez-Mangado N, Juncadella M, Navarro A, Barreira R, Capote F,
Mayoralas LR, Peces-Barba G, Alonso J, Montserrat JM. Effectiveness of
continuous positive airway pressure in mild sleep apnea-hypopnea syndrome.
Am J Respir Crit Care Med 2001; 164: 939-943
239- Campos-Rodriguez F, Grilo-Reina A, Perez-Ronchel J, Merino-Sanchez M,
Gonzalez-Benitez MA, Beltran-Robles M, Almeida-Gonzalez C. Effect of
continuous positive airway pressure on ambulatory BP in patients with sleep
apnea and hypertension. Chest 2006; 129: 1459-1467
240- Hui DS, To KW, Ko FW, Fok JP, Chan MC, Ngai JC, Tung AH, Ho CW,
Tong MW, Szeto C-C, Yu C-M. Nasal CPAP reduces systemic blood pressure
in patients with obstructive sleep apnoea and mild sleepiness. Thorax 2006; 61:
1083-1090
241- Bradley TD, Floras JS, Phil D. Sleep apnea and heart failure: Part I:
obstructive sleep apnea. Circulation 2003; 107: 1671-1678
242- Ferreira S, Winck J, Bettencourt P, Rocha-Gonçalves F. Heart failure and
sleep apnea: to sleep perchance to dream. Eur J Heart Fail 2006; 8: 227-236
208
243- Bonow RO, Udelson JE. Left ventricular diastolic dysfunction as a cause of
congestive heart failure. Mechanisms and management. Ann Intern Med 1992;
117: 502-510
244- Fischer M, Baessler A, Hense HW, Hengstenberg C, Muscholl M, Holmer
S, Döring A, Broeckel U, Riegger G, Schunkert H. Prevalence of left ventricular
diastolic
dysfunction
in
the
community.
Results
from
a
Doppler
echocardiographic-based survey of a population sample. Eur Heart J 2003; 24:
320-328
245- Petrie MC, Caruana L, Berry C, McMurray JJ. “Diastolic heart failure” or
heart failure caused by subtle left ventricular systolic dysfunction? Heart 2002;
87: 29-31
246- Cohen GI, Bietrolungo JF, Thomas JD, Klein AL. A practical guide to
assessment of ventricular diastolic function using Doppler echocardiography. J
Am Coll Cardiol 1996; 27: 1753-1760
247- Cloward TV, walker JM, Farney RJ, Anderson JL. Left ventricular
hypertrophy is a common echocardiographic abnormality in severe obstructive
sleep apnea and reverses with nasal continuous positive airway pressure.
Chest 2003; 124: 594-601
248- Fung JWH, Li TST, Choy DKL, Yip GWK, Ko FWS, Sanderson JE, Hui
DSC. Severe obstructive sleep apnea is associated with left ventricular diastolic
dysfunction. Chest 2002; 121: 422-429
249- Reaven G. Banting lecture 1988. Role of insulin resistance in human
disease. Diabetes 1988; 37 (12): 1595-1607
250- Polotsky VY, Li J, Punjabi NM, Rubin AE, Smith PL, Schwartz AR,
O´Donnell CP. Intermittent hypoxia increases insulin resistance in genetically
obese mice. J Physiol 2003; 552: 253-264
209
251- Liyori N, Alonso LC, Li J, Sanders MH, Garcia-Ocana A, O´Doherty RM,
Polotsky VY, O´Donnell CP. Intermittent hypoxia causes insulin resistance in
lean mice independent of automatic activity. Am J Respir Crit Care Med 2007;
175: 851-857
252- Li J, Savransky V, Nanayakkara A, Smith PL, O´Donnell CP, Polotsky VY.
Hyperlipidemia and lipid peroxidation are dependent on the severity of chronic
intermittent hypoxia. J Appl Physiol 2007; 102: 557-563
253- American Heart Association: Heart and stroke facts: 1995 Statistical
Supplement. Dallas, TX: American Heart Association; 1994
254- Young T, Peppard PE, Gottlieb DJ. Epidemiology of Obstructive Sleep
Apnea- a population health perspective. Am J Respir Crit Care Med 2002; 165:
1217-1239
255- Meurice JC. Predictive factors of long-term compliance with nasal
continuous positive airway pressure treatment in sleep apnea syndrome. Chest
1994; 105: 429-433
256- Reeves-Hoche MK, Meck R, Zwillich CW. Nasal CPAP: an objective
evaluation of patient compliance. Am J Respir Crit Care Med 1994; 149 (1):
149-154
257- Drummond M, Winck JC, Pereira S, Almeida J, Marques JA. Síndroma de
Apneia Obstrutiva do Sono e Doença Cardiovascular- Estudo retrospectivo.
Rev Port Pneu 2003; IX (4): 327-335
210
258- Mokdad AH, Ford ES, Bowman BA, et al. Prevalence of obesity, diabetes,
and obesity-related health risk factors. JAMA 2001; 289: 76-79
259- Rader DJ. Effect of insulin resistance, dyslipidemia, and intra-abdominal
adiposity on the development of cardiovascular disease and diabetes mellitus.
Am J Med 2007; 120: s12-s18
260- Ip MS, Lam B, Ng MMT, Lam WK, Tsang KWT, Lam KSL. Obstructive
sleep apnea is independently associated with insulin resistance. Am J Respir
Crit Care Med 2002; 165: 670-676
261- Punjabi NM, Shahar E, Redline S, Gottlieb DJ, Givelber R, Resnick HE for
the Sleep Heart Health Study Investigators. Sleep-disordered breathing,
glucose intolerance, and insulin resistance; The Sleep Heart Health STUDY:
Am J Epidemiol 2004; 160: 521-530
262- Vincent HK, Taylor AG. Biomarkers and potential mechanisms of obesityinduced oxidant stress in humans. Int J Obes 2006; 30: 400-418
263- Vincent HK, Innes KE, Vincent KR. Oxidative stress and potential
interventions to reduce oxidative stress in overweight and obesity. Diabetes
Obes Metab 2007; 9: 813-839
264- Arnardottir E, Mackiewicz M, Gislason T, Teff K, Pack AI. Molecular
signatures of obstructive sleep apnea in adults: a review and perspective. Sleep
2009; 32(4): 447-470
265- McNicholas WT, Bonsignore MR. Sleep apnoea as an independent risk
factor for cardiovascular disease: current evidence, basic mechanisms and
research priorities. Eur Respir J 2007; 29: 156-178
266- Romero-Corral A, Montori VM, Somers VK, Korinek J, Thomas RJ, Allison
TG, Mookadam F, Lopez-Jimenez F. Association of body weight with total
211
mortality and with cardiovascular events in coronary artery disease: a
systematic review of cohort studies. Lancet 2006; 368: 666-678
267- Bing MH, Moller LA, Jennum P, Mortensen S, Skovgaard LT, Lose G.
Prevalence and bother of nocturia, and causes of sleep interruption in a Danish
population of men and women aged 60-80 years. BJU Int 2006; 98: 599-604
268- Sassani A, Findley LJ, Kryger M, Goldlust E, George C, Davidson TM.
Reducing motor-vehicle collisions, costs, and fatalities by treating obstructive
sleep apnea syndrome. Sleep 2004; 27: 453-458
269- Young T, Finn L, Peppard PE, Szklo-Coxe M, Austin D, Nieto FJ, Stubbs R,
Hla KM. Sleep disordered breathing and mortality: eighteen-year follow-up of
the Wisconsin Sleep Cohort. Sleep 2008; 31: 1071-1078
270- Ridker PM. High-sensitivity C-reactive protein: potential adjunct for global
risk assessment in the primary prevention of cardiovascular disease. Circulation
2001; 103: 1813-1818
271- Biffl WL, Moore EE, Moore FA, Peterson VM. Interleukin-6 in the injured
patient. Ann Surg 1996; 224: 647-664
272- Harris TB, Ferruci L, Tracy RP, Corti MC, Wacholder S, Ettinger WH Jr,
Heimovitz H, Cohen HJ, Wallace R. Association of elevated interleukin-6 and Creactive protein levels with mortality in the elderly. Am J Med 1999; 106: 506512
273- Vgontzas AN, Papanicolaou DA, Bixler EO, Kales A, Tyson K, Chrousos
GP. Elevation of plasma cytokines in disorders of excessive daytime
sleepiness: role of sleep disturbance and obesity. J Clin Endocrinol Metab
1997; 82: 1313-1316
274- Barceló A, Barbé F, Llompart E, Mayoralas LR, Ladaria A, Bosch M,
Agustí AG. Effects of obesity on C-reactive protein level and metabolic
212
disturbances in male patients with obstructive sleep apnea. Am J Respir Crit
Care Med 2004; 117: 118-121
275- Guilleminault C, Kirisoglu C, Ohayon MM. C-reactive protein and sleepdisordered breathing. Sleep 2004; 27: 1507-1511
276- Ahashiba T, Akahoshi T, Kawahara S, Majima T, Horie T. Effects of longterm nasal continuous positive airway pressure on C-reactive protein in patients
with obstructive sleep apnea syndrome. Intern Med 2005; 44: 899-900
277- Ryan S, Nolan G, Hannigan E, Cunningham S, Taylor C, McNicholas WT.
Cardiovascular risk markers in obstructive sleep apnoea syndrome and
correlation with obesity. Thorax 2007; 62: 509-514
278- Vgontzas AN, Zoumakis E, Bixler EO, Lin HM, Collins B, Basta M, Pejovic
S, Chroussos GP. Selective effects of CPAP on sleep apnoea-associated
manifestations. Eur J Clin Invest 2008; 38 (8): 585-595
279- Sharma SK, Mishra HK, Sharma H, Goel A, Sreenivas V, Glati V, Tahir M.
Obesity, and not obstructive sleep apnea, is responsible for increased serum
hs-CRP levels in patients with sleep disordered breathing in Delhi. Sleep Med
2008; 9 (2): 149-156
280- Maffei M, Halaas J, Ravussin E, Pratley RE, Lee GH, Zhang Y, Fei H, Kin
S, Lallone R, Ranganathan S, Kern PA, Friedman JM. Leptin levels in human
and rodent: measurement of plasma leptin and ob RNA in obese and weightreduced subjects. Nature Medicine 1995; 1 : 1155-1161
281- Considine RV, Sinha MK, Heiman ML, Kriauciunas A, stephens TW, Nyce
MR, Ohanneslan JP, Marco CC, Mkee LJ, Bauer TL, Caro JF. Serum
immunoreactive-leptin concentrations in normal-weight and obese humans. N
Engl J Med 1996; 334 : 292-295
213
282- Mantzoros CS. The role of leptin in human obesity and disease: a review
of current evidence. Ann Intern Med 1999 ; 130 : 671-680
283- Rosenbaum M, Nicolson M, Hirsch J, Heymsfield SB, Gallagher D, Chu F,
Leibel RL. Effects of gender, body composition, and menopause on plasma
concentrations of leptin. J Clin Endocrinol Metab 1996; 81: 3424-3427
284- Chin K, Shimizu K, Nakamura T, Narai N, Masuzaki H, Ogawa Y, Mishima
M, Nakamura T, Nakao K, Ohi M. Changes in intra-abdominal visceral fat and
serum leptin levels in patients with obstructive sleep apnea syndrome following
nasal continuous positive airway pressure therapy. Circulation 1999 ; 100 : 706712
285- Schafer H, Pauleit D, Sudhop T, Gouni-Berthold I, Ewig S, Berthold HK.
Body fat distribution, serum leptin, and cardiovascular risk factors in men with
obstructive sleep apnea. Chest 2002; 122(3): 829-839
286- Jin G, Wang W, Kang J, Wu Y, Hou X, Yu R. Study of serum leptin level in
patients with obstructive sleep apnea. Zonghua Jie He He Hu Xi Za Zhi 2002 ;
25(4): 204-206
287- O´Donnell CP, Schaub CD, Haines AS, Berkowitz DE, Tankersley CG,
Schwartz AR, Smith PL. Leptin prevents respiratory depression in obesity. Am J
Respir Crit Care Med 1999; 159: 1477-1484
288- Huang R, Huang XZ, Wang HG, Li M, Xiao Y. Effects of nasal continuous
positive airway pressure on serum leptin concentration and the metabolic
parameters in obstructive sleep apnea hypopnea syndrome. Zhongguo Yi Xue
Ke Xue Yuan Xue Bao 2004; 26(2): 168-171
289- Hermida RC, Zamarrón C, Ayala DE, Calvo C. Effect of continuous
positive airway pressure on ambulatory blood pressure in patients with
obstructive sleep apnoea. Blood Pressure monitoring 2004; 9(4): 193-202
214
290- Mayer J, Backer H, Brandenburg U, Penzel T, Peter JH, Wichert PV.
Blood pressure and sleep apnea: results on long-term nasal continuous positive
airway pressure therapy. Cardiology 1991; 79. 84-92
291- Davies RJO, Crosby J, Prothero A, Stradling JR. Ambulatory blood
pressure and left ventricular hypertrophy in subjects with untreated obstructive
sleep apnoea and snoring, compared with matched control subjects, and their
response to treatment. Clin Sci 1994; 86: 417-424
292- Collins R, Peto R, MacMahon S, hebert P, Fiebach NH, Eberlein KA,
Godwin J, Qizilbash N, Taylor JO, Hennekens CH. Blood pressure, stroke and
coronary heart disease. Part 2, short-term reductions in blood pressure:
overview of randomised drug trials in the epidemiological context. Lancet 1990;
335: 827-838
293- Heude E, Bourgin P, Feigel P, Escourrou P. Ambulatory monitoring of
blood pressure disturbs sleep and raises systolic pressure at night in patients
suspected of suffering from sleep-disordered breathing. Clin Sci 1996; 91: 4550
294- Barbé F, Mayoralas LR, Duran J, Masa JF, Maimó A, Montserrat JM,
Monasterio C, Bosch M, Ladaria A, Rubio M, Rubio R, Medinas M, Hernandez L,
Vidal S, Douglas NJ, Agusti AGN. Treatment with continuous positive airway
pressure is not effective in patients with sleep apnea but no daytime sleepiness.
Ann Intern Med 2001; 134: 1015-1023
215
295- Barnes M, Houston D Worsnop CJ, Neil AM, Mykytyn IJ, Kay A, Trinder J,
Saunders NA, Douglas McEvoy R, Pierce RJ. A randomized controlled trial of
continuous positive airway pressure in mild obstructive sleep apnea. Am J
Respir Crit Care Med 2002; 165: 773-780
296- Barnes M, Mc Evoy RD, Banks S, Tarquinio N, Murray CG, Vowles N,
Pierce RJ. Efficacy of positive airway pressure and oral appliance in mild to
moderate obstructive sleep apnea. Am J Respir Crit Care Med 2004; 170: 656664
297- Norman D, Loredo JS, Nelesen RA, Ancoli-Israel S, Mills PJ . Effects of
continuous positive airway pressure versus supplemental oxygen on 24-hr
ambulatory blood pressure. Hypertension 2006; 47(5): 840-845
298- Tei C, Nishimura RA, Seward JB, Tajik AJ. Noninvasive Doppler-derived
myocardial performance index: correlation with simultaneous measurements of
cardiac catheterization measurements. J Am Soc Echocardiogr 1997; 10: 169178
299- Moro JA, Almenar L, Fernández-Fabrellas E, Ponce S, Blanquer R,
Salvador A. Relationship between echocardiographic abnormalities and sleep
apnea-hypopnea syndrome severity. Rev Esp Cardiol 2007; 60: 589-596
300- Tei C, Dujardin KS, Hodge DO, Bailey KR, McGoon MD, Tajik AJ, Seward
JB. Doppler echocardiographic índex for assessment of global right ventricular
function. J Am Soc Echocardiogr 1996; 9: 838-847
216
301- Dursunoglu N, Dursunoglu D, Özkurt S, Kuru O, Gür S, Kiter G, Evyapan F.
Effects of CPAP on left ventricular structure and myocardial performance índex
in male patients with obstructive sleep apnoea. Sleep Med 2007: 8; 51-59
302- Sidana J, Aronow WS, Ravipati G, Di Stante B, McClung JA, Belkin RN,
Lehrman SG. Prevalence of moderate or severe left ventricular diastolic
dysfunction in obese persons with obstructive sleep apnea. Cardiology 2005;
104: 107-109
303- Niroumand M, Kuperstein R, Sasson Z, Hanly PJ. Impact of obstructive
sleep apnea on left ventricular mass and diastolic function. Am J Respir Crit
Care Med 2001; 163: 1632-1636
304- Yamamoto K, Nishimura RA, Chaliki HP, Appleton CP, Holmes DR Jr,
Redfield MM. Determination of left ventricular filling pressure by Doppler
echocardiography in patients with coronary artery disease: critical role of left
ventricular systolic function. J Am Coll Cardiol 1997; 30: 1819-1826
305- Ommen SR, Nishimura RA, Appleton CP, Miller FA, Oh JK, Redfield MM,
Tajik AJ. Clinical utility of Doppler echocardiography and tissue Doppler imaging
in the estimation of left ventricular filling pressures: a comparative simultaneous
Doppler-catheterization study. Circulation 2000; 102: 1788-1794
306- Rodriguez L, Garcia M, Ares M, Griffin BP, Nakatani S, Thomas JD.
Assessment of mitral annular dynamics during diastole by Doppler tissue
imaging: comparison with mitral Doppler inflow in subjects without heart disease
and in patients with left ventricular hypertrophy. Am Heart J 1996; 131: 19821987
307- Dokainish H. Tissue Doppler imaging in the evaluation of left ventricular
diastolic function. Curr Opin Cardiol 2004; 19: 437-441
217
308- Rodriguez L, Garcia M, Ares M, Griffin BP, Nakatani S, Thomas JD.
Myocardial wall velocity assessment by pulsed Doppler tissue imaging:
characteristic findings in normal subjects. Am Heart J 1996; 132: 648-656
309- Temporelli PL, Giannuzzi P, Nicolosi GL, Latini R, Franzosi MG, Gentile F,
Tavazzi L, Maggioni AP and GISSI- 3 Echo Substudy Investigators. Dopplerderived mitral deceleration time as a strong prognostic marker of left ventricular
remodelling and survival after acute myocardial infarction: Results of the GISSI3 Echo Substudy. J Am Coll Cardiol 2004; 43: 1646-1653
310- Shivalkar B, Van de Heyning C, Kerremans M, Rinkevich D, Verbraecken
J, De Backer W, Vrints C. Obstructive sleep apnea syndrome: more insights on
structural and functional cardiac alterations, and the effects of treatment with
continuous positive airway pressure. J Am Coll Cardiol 2006; 47: 1433-1439
311- Bradley TD, Rutherford R, Grossman RF, Lue F, Zamel N, Moldofsky H,
Phillipson EA. Role of daytime hypoxemia in the pathogenesis of right heart
failure in the obstructive sleep apnea syndrome. Am Rev Respir Dis 1985; 131:
835-839
312- Nahmias J, Lao R, Karetzky M. Right ventricular dysfunction in obstructive
sleep apnoea: reversal with nasal continuous positive airway pressure. Eur
Respir J 1996; 9: 945-951
313- Jean-Louis G, Zizi F, Clark LT. Obstructive sleep apnea and
cardiovascular disease: role of the metabolic syndrome and its components. J
Clin Sleep Med 2008;4:261-272
314- Parish JM, Adam T, Facchiano L. Relationship of metabolic syndrome and
obstructive sleep apnea. J Clin Sleep Med 2007;3(5):467-72
315- Kostoglou-Athanassiou ΙS, Athanassiou P. Metabolic syndrome and sleep
apnea. Hippokratia 2008;12:81-86
218
316- Tasali E, Ip M. Obstructive Sleep Apnea and metabolic syndrome –
alterations in glucose metabolism and inflammation. Proc Am Thorac Soc
2008;5:207-217
317- Coughlin SR, Mawdsley L, Mugarza JA, Wilding JP, Calverley PM.
Cardiovascular and metabolic effects of CPAP in obese men with OSA. Eur
Resp J 2007;29:720-727
318- Borgel J, Sanner BM, Bittlinsky A, Keskin F, Bartels NK, Buechner N, et al.
Obstructive sleep apnoea and its therapy influence high-density lipoprotein
cholesterol serum levels. Eur Respir J 2006; 27: 121–127
319- Harsch IA, Schalin SP, Radespiel-Troger, Weuntz O, Jahreiß H, Fuch FS,
Wiest GH, Hahn EG, Lohmann T, Konturek PC, Ficker JH. Continuous positive
airway pressure treatment rapidly improves insulin sensitivity in patients with
obstructive sleep apnea syndrome. Am J Respir Crit Care Med 2004;169:156162
320- Bazzano LA, Khan Z, Reynolds K, He J. Effect of nocturnal nasal
continuous positive airway pressure on blood pressure in obstructive sleep
apnea. Hypertension 2007; 50: 417-423
321- Ryan S, Taylor CT, McNicholas WT. Selective activation of inflammatory
pathways by intermittent hypoxia in obstructive sleep apnea syndrome.
Circulation 2005; 112: 2660-2667
322- Lorenzi-Filho G, Drager LF. Obstructive sleep apnea and atherosclerosis:
a new paradigm. Am J Respir Crit Care Med 2007; 175: 1219-1221
323- Taheri S, Austin D, Lin L, Nieto FJ, Terry. Correlates of serum C-reactive
protein (CRP)-no association with sleep duration or sleep disordered breathing.
Sleep 2007; 30: 991-996
219
324- Pikkarainen S, Tokola H, Kerkela R, Ruskoaho H. GATA transcription
factors in the developing and adult heart. Cardiovasc Res 2004; 63: 196-207
325- Suzuki YJ. Growth factor signaling for cardioprotection against oxidative
stress-induced apoptosis. Antioxid Redox Signal 2003; 5: 741-749
326- Park AM, Nagase H, Kumar SV, Suzuki YJ. Acute intermittent hypoxia
activates myocardial cell survival signaling. Am J Physiol Heart Circ Physiol
2007; 292: H751-H757
327- Park AM, Nagase H, kumar SV, et al. Effects of intermittent hypoxia on the
heart. Antioxid Redox Signal 2007; 9: 723-729
328- Hudgel DW, Fung C. A long-term randomized, cross over comparison of
auto-titrating and standard nasal continuous airway pressure. Sleep 2000;
23(5): 645-648
329- Ayas NT, Patel SR, Malhotra A, Schulzer M, Malhotra M, Jung D, Feetham
J, White DP. Auto-titrating versus standard continuous positive airway pressure
for the treatment of obstructive sleep apnea: results of a meta-analysis. Sleep
2004; 27(2): 249-253
330- Randerath WJ, Schraeder O, Galetke W, Feldmeyer F, Rühle KH.
Autoadjusting CPAP therapy based on impedance efficacy, compliance and
acceptance. Am J Respir Crit Care Med 2001; 163(3): 652-657
331- Rigau J, Montserrat JM, Wöhrle H, Plattner D, Schwaibold M, Navajas D,
Farré R. Bench model to simulate upper airway obstruction for analyzing
automatic continuous positive airway pressure devices. Chest 2006; 130 (2):
312-314
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RESUMO
A Síndrome de Apneia Obstrutiva do Sono (SAOS) é a mais frequente das
desordens relacionadas com o sono, sendo, actualmente, reconhecida como
um problema de saúde pública, afectando 9 a 24% dos adultos de meia idade,
do sexo feminino e masculino, respectivamente.
Esta patologia é caracterizada pela recorrência de episódios de oclusão parcial
ou completa da via aérea superior, ao nível da hipofaringe, durante o sono,
resultando em dessaturações intermitentes de oxigénio e microdespertares
com, consequente, fragmentação do sono.
Os efeitos fisiopatológicos resultantes da hipóxia intermitente e dos
microdespertares parecem conduzir ao desenvolvimento e/ou agravamento de
patologia cardiovascular (CV), como demonstrado em estudos experimentais in
vitro, in vivo com modelos animais e no domínio dos estudos clínicos e
epidemiológicos.
O modelo, mais consensual, proposto como explicação para a predisposição
aumentada dos doentes com SAOS ao desenvolvimento de doença CV
assenta na activação e interacção de várias vias inflamatórias em resposta à
hipóxia intermitente, sendo, igualmente, de realçar o papel da fragmentação do
sono, da activação intermitente do Sistema Simpático e do stress oxidativo na
génese da disfunção endotelial, precursor da doença CV.
De entre a panóplia de doenças CV, a hipertensão arterial (HTA) é, sem dúvida,
a
patologia
melhor
estudada
nos
doentes
com
SAOS
e
estudos
epidemiológicos demonstraram, recentemente, associação independente entre
SAOS e HTA, a qual parece ser dose-dependente.
Também alterações metabólicas como a obesidade, a dislipidemia e a
intolerância à glicose se encontram associadas à SAOS.
A Síndrome Metabólica (SM), sendo uma constelação de todas as alterações
acima referidas, juntamente com a HTA, apresenta-se, sem espanto, associada
à SAOS e constitui-se, ela própria, como factor de risco para DCV.
O tratamento de eleição da patologia respiratória do sono é o suporte
ventilatório nocturno com pressão positiva contínua da via aérea- CPAP
(Continuous positive airway pressure), o qual tem sido apontado como eficaz e
221
seguro, não só no controlo dos sintomas associados à SAOS como também na
redução do risco CV que lhe está inerente.
Os dispositivos de pressão positiva automática, APAP (Auto-adjusting positive
airway pressure), são uma alternativa recente ao tratamento tradicional com
CPAP, demonstrando eficácia no controlo sintomático, mas com resultados
contraditórios quanto à redução do risco CV.
Assim, foi nosso propósito estudar o efeito a curto e a longo prazo do APAP
nos doentes do sexo masculino com SAOS moderada a grave, no que
concerne ao risco CV, mensurável através da prevalência de HTA, SM,
alterações ecocardiográficas e dos valores séricos de interleucina 6 (IL-6),
proteína C reactiva (PCR) e leptina.
Fomos capazes, nestes estudos, de demonstrar que o tratamento a longo
termo com APAP reduz a prevalência de HTA, permite a normalização do
fenómeno dipper, reduz a prevalência de SM e tende a normalizar alterações
ecocardiográficas nos doentes com SAOS.
No entanto, quanto aos níveis séricos de citoquinas inflamatórias e de leptina, o
APAP não se mostrou eficaz na sua redução, aliás de forma coerente, pois
umas e outra não se correlacionaram com a presença e/ou gravidade da
patologia respiratória do sono, mas sim, com a obesidade.
Em conclusão, podemos afirmar, com base nos resultados obtidos, que a
terapêutica
com
APAP
parece
ser
eficaz
na
reversão
dos
efeitos
hemodinâmicos, cardíacos e metabólicos da SAOS, mas não das alterações
inflamatórias que lhe estão associadas.
222
Summary
Obstructive sleep apnoea (OSA) is the most prevalent sleep disorder, being an
important public health problem, with an estimated prevalence of 24% and 9%
in middle-aged men and women, respectively.
This disease is characterized by an intermittent occurrence of upper airway
occlusion, during sleep, resulting in oxygen desaturations and arousals causing
sleep fragmentation.
The physiopathologic effects of intermittent hypoxia and arousals seem to
conduct to the development and/or aggravation of the cardiovascular (CV)
diseases, as showed by experimental studies in vitro, in vivo with animal
models and in epidemiologic and clinical studies.
The most consensual model explaining the increased predisposition of OSA
patients to CV diseases is that of an activation and interaction between several
inflammatory pathways due to intermittent hypoxia combined with intermittent
sympathetic system activation after the arousals and the oxidative stress
inducing endothelial dysfunction.
Arterial hypertension (AH) is the most well-studied CV disease associated with
OSA. Recently, large epidemiological studies have shown an independent
association between these two entities, on a dose-response basis.
The Metabolic Syndrome (MS) known as a constellation of CV risk factors,
namely AH, dyslipidemia, diabetes and central obesity has also a higher
prevalence in OSA patients than in general population.
Nasal continuous positive airway pressure (CPAP) treatment is the most
effective therapy for mild-to-severe OSA.
Auto-adjusting positive airway pressure (APAP) devices are a recent alternative
treatment to traditional CPAP and are able to improve symptoms while
increasing long-term treatment compliance without the high costs of CPAP
titration. However, different from CPAP, the impact of APAP therapy on
cardiovascular and metabolic outcomes in OSA patients remains unknown.
223
In the present study we aimed to evaluate the impact of short and long-term
APAP therapy on CV risk in male patients with moderate to severe OSA.
AH prevalence, dipper phenomenon, MS prevalence, echocardiographic
findings and Interleucin- 6 (IL-6), C- Reactive Protein (CRP) and leptin serum
levels were used as CV risk factors and or CV markers.
Based on our results, we are able to say that APAP therapy was efficacious in
reducing AH and MS prevalence and in normalizing dipper phenomenon and
some echocardiographic findings. On the other hand, this treatment did not
show efficacy in reducing IL-6, CRP and leptin serum levels, but as these
cytokines were not related to OSA severity but to obesity, we can interpret the
results as being consistent.
In conclusion, we can state that long term APAP therapy in moderate to severe
OSA patients seems to be effective in reversing the hemodynamic, cardiac and
metabolic consequences, but not in what concerns normalization of
inflammatory characteristics associated with the disease.
224