pdf 12 MB - Cardio Symposium 2011

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Ceva Santé Animale
is very pleased
to welcome you to
the 2nd
Human and Veterinary
Crosstalk Symposium
on Aldosterone.
Sylvie BourrelierEmilie Guillot
DVM, Operational Director Western Europe Companion Animal
DVM, Technical Manager Cardiology
Place de la Bourse, City of Bordeaux, France
Preface
Two years ago we hosted what we billed as the first crossover symposium
and I am delighted to welcome you back to this second “Human and
Veterinary Crosstalk Symposium on Aldosterone”.
The first meeting had a profound impact in developing our thinking and new
vision, which we eventually summarised in the slogan “Together, beyond
animal health”.
What do we mean by that? Firstly, we are very proud that Ceva is an
independent business that we have built together. But if we are to address
the major health issues facing a largely urbanised population of 9 billion
in 2050 – it is only together with our scientific and business partners in all
aspects of the health profession that we will able to do this. Ceva will remain
a pure veterinary business but we are convinced that there is much to be
gained by reaching out to our fellow health professionals involved in both
human medicine and public health. This is why we were proud sponsors
of the first “One Health Congress” held in Australia earlier this year; yet if
we are to make “One Health” a reality, we need to promote more concrete
actions at a ground level.
That is why I am so excited, that so many of you that were here before have
seen value to come again and that we have also been able to persuade
many more experts in cardiology to join us.
In the 2009 preface I set down a challenge that we should all be more
entrepreneurial in the way that we approach innovation “it is important that
our own scientists together with their network of scientific partners move
quickly and take the reasoned risks and decisions in order to improve our
knowledge of animal health”.
I’m delighted to say that in the interim this is exactly what has happened
and we now have several active collaborative projects that will improve our
ability to treat cardiac problems in dogs. Some of these initiatives – aside
from involving researchers outside traditional veterinary boundaries, also
take us further into the field of applied diagnostics. I think for example of
the advances in our knowledge of bio markers, where the combination of
being able to predict the development of cardiac failure and the feedback
of accurate information to clinicians will vastly improve our ability to care
for companion animals.
This is exactly what we mean by and I hope you will join us in our mission
to go “Together, beyond animal health”.
Marc Prikazsky
Président and CEO, Ceva Santé Animale
2nd HUMAN and VETERINARY CROSSTALK SYMPOSIUM on ALDOSTERONE
SCIENTIFIC PROGRAM ON SATURDAY 1ST OCTOBER 2011
MORNING SESSION
9:00 am - 10:30 am
CLINICAL ASPECTS OF ALDOSTERONE AND THE
“ALDOSTERONE-ESCAPE” CONCEPT: WHAT IS THE ROLE
OF ALDOSTERONE RECEPTOR BLOCKADE?
Aldosterone receptor antagonists clinical interest: beyond the
“aldosterone escape” concept
Allan Struthers
Relationship between Aldosterone and clinical parameters in dogs
with Mitral Valve Disease
Adrian Boswood
Where Are We With Aldosterone Escape (Break-through) in 2011?
Clarke E. Atkins
11:00 am - 12:30 pm
CLINICAL TRIALS, WHERE ARE WE 10 YEARS
AFTER RALES STUDY?
Targeting the aldosterone pathway in cardiovascular disease
Faiez Zannad
Treatment of Preserved Cardiac function Heart Failure with an Aldosterone
Antagonist: The NHLBI TOPCAT Trial
Bertram Pitt
THE DELAY Study (DELay of Appearance of sYmptoms of canine degenerative
mitral valve disease treated with Spironolactone and Benazepril)
Michele Borgarelli
All lectures will be held in english
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AFTERNOON SESSION
2:00 pm – 2:30 pm
CEVA EUROPEAN STUDENTS CARDIOLOGY AWARD
2:30 pm – 4:00 pm
BIOMARKERS: WHAT ARE THE PRACTICAL USES
AND WHAT CAN BE EXPECTED IN THE COMING YEARS?
How to use biomarkers in cardiology?
Adriaan A. Voors
Potential Markers of Cardiac Remodeling and Function
Mark A. Oyama
4:30 pm – 6:00 pm
CARDIO-RENAL SYNDROME, WHAT IS BEHIND IT?
A Rock and a Hard Place: Cardiorenal Syndrome in Clinical Canine
Veterinary Patients
Rebecca L. Stepien
Cardio-Renal Syndromes: Lessons from human pathophysiology
Claudio Ronco
Mineralocorticoid receptor antagonists: New therapeutic opportunities
in chronic kidney diseases
Frédéric Jaisser
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CHAIRMEN FOR SCIENTIFIC PROGRAM
JONATHAN ELLIOTT
MA, VetMB, PhD, CertSAC, DipECVPT, MRCVS
Vice Principal – Research
Professor of Veterinary Clinical Pharmacology
Royal Veterinary College
London, UK
Contact: [email protected]
JENS HÄGGSTRÖM
DVM, PhD, DipECVIM (Cardiology)
Professor Internal Medicine
Department of Clinical Studies, Faculty of Veterinary
Medicine and Animal Science, Swedish University
of Agricultural Sciences
Uppsala, Sweden
CLARKE EDWARD ATKINS
DVM, DipACVIM (Internal medicine and Cardiology)
Jane Lewis Seaks Distinguished Professorship of Companion
Animal Medicine
Department of Clinical Sciences, College of Veterinary Medicine
North Carolina State University.
Raleigh, North Carolina. USA
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Jonathan Elliott graduated from Cambridge Veterinary School in 1985. After a year as an Intern
at the University of Pennsylvania, he undertook a PhD in vascular pharmacology in Cambridge.
In 1990 he was appointed to a lectureship in Veterinary Pharmacology at the Royal Veterinary
College and developed research interests in feline kidney disease and hypertension, canine mitral
valve disease and Equine Laminitis. He was awarded the Pfizer Academic Award in 1998 and the
BSAVA Amoroso Award in 2001, the Petplan Scientific Award in 2005 and the ESVNU Award in
2007 for contributions to companion animal medicine. He was a member of the ACVIM Consensus
Statement Panels on Proteinuria and Hypertension and chaired the International Renal Interest
Society from 2002-2004.
Jonathan is a Diplomate of the European College of Pharmacology and Toxicology. He is a past
member of the UK Government’s Veterinary Products Committee. He is currently Professor in
Veterinary Clinical Pharmacology and Vice Principal for Research and Innovation at the RVC.
Jens Häggstrom is a Professor in the Department of Clinical Studies, Faculty of Veterinary Medicine
and Animal Science. His main interests in clinical research concern heart disease in dogs and cats
(MMVD, DCM and cardiomyopathy in cats), diagnostic techniques, pathophysiology and therapy of
heart failure, and genetic risk factors for heart disease in dogs and cats.
Jens Häggström was born and brought up in Uppsala, Sweden, where he also completed his basic
veterinary training in 1990. He achieved his Doctorate degree in 1996 with a thesis concerning
MMVD in dogs. In 2000, Jens became an Associate Professor in Uppsala and in 2003 became
full Professor in Internal Medicine. He earned his status as Diplomate of the European College of
Veterinary Internal Medicine in 1998 and served in different Committees in the period 1999-2006
and as Chairman of the Cardiology subspeciality during 2003-2006. Since 2009 he is a co-lecturer
of the European School of Advanced Veterinary Studies for the Cardiology program.
Professor Häggström is also author and co-author of a large number original papers in
internationally distributed peer-viewed journals, congress abstracts and textbook chapters. He
resides in Uppsala with his family, wife and 2 sons, and enjoys running, racket sports, golf and
skiing during his spare time.
Clarke Atkins, DVM, Professor of Medicine and Cardiology at North Carolina State University is a
1972 graduate of the University of California, Davis and an Angell Memorial Animal Hospital intern.
He is board-certified by the ACVIM in internal medicine and in cardiology.
Dr. Atkins is known for his research and teaching in small animal cardiology, he is the 2004
Norden-Award recipient for excellence in teaching, and was recently named the Jane Lewis Seaks
Distinguished Professor.
He is the author of over 150 publications and his research involves canine and feline heartworm
disease and pharmacologic therapies of cardiac disease in dogs, cats and horses.
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Professor Allan D Struthers
BSc, MD, FRCP, FESC, FRSE, FMedSci
Professor of Cardiovascular Medicine
Division of Medical Sciences
University of Dundee,
Centre for Cardiovascular & Lung Biology
Mail Box 2,
Ninewells Hospital & Medical School
Dundee, UK.
Dr. Allan Struthers graduated MB (Hons) from Glasgow University in 1977. After junior
hospital posts in Glasgow, he was Senior Registrar at the Royal Postgraduate Medical School
and Hammersmith Hospital in London in 1982-1985. He was then appointed Wellcome
Senior Lecturer/Consultant Physician in Dundee and is currently Professor of Cardiovascular
Medicine and runs the Heart Failure service at Ninewells Hospital in Dundee.
He was Chairman of the SIGN Guidelines in Heart Failure (2007) and is now Chairman of
NHS-QIS Standards (2010) for Heart Failure. In addition, he is also Chairman of Tenovus
NSAC and Senior Regional Advisor for SACDA. Professor Struthers runs a large clinical
research programme and has supervised over 40 MD/PhDs.
He pioneered the use of plasma BNP to identify heart failure patients and the use of
aldosterone blockers to reduce their mortality. Another research interest is in allopurinol
and he has recently shown it to have antianginal oxygen sparing effects. He is also using
cardiac MRI to assess novel ways to regress left ventricular hypertrophy, e.g. Vitamin D. He
is currently funded (as PI) by the British Heart Fundation, Medical Research Council, CSO,
Diabetes (UK) and Chest, Heart & Stroke. In total he has held 30 BHF grants.
He has published over 400 papers which are cited around 600 times every year. His
research «h» factor is high at 51.
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Clinical aspects of aldosterone and the «aldosteroneescape» concept: what is the role of aldosterone
receptor blockade?
ALDOSTERONE RECEPTOR ANTAGONISTS CLINICAL
INTEREST: BEYOND THE “ALDOSTERONE ESCAPE”
CONCEPT
Aldosterone escape: background.
ACE inhibitors began to be used in human
heart failure in the late 1980s. The main
impetus for their use were the CONSENSUS I,
SOLVD and SAVE trials.1,2,3 Thereafter it began
to be realised that neither angiotensin II nor
aldosterone were fully suppressed by ACE
inhibitors. The latter phenomenon was called
“Aldosterone Escape” whereby the initial
decrease in aldosterone produced by an ACE
inhibitor was reversed and aldosterone levels
returned to normal.
Bomback and Klemmer 4 summarize the
results of eight studies indicating that
aldosterone breakthrough occurs in a
significant proportion of patients on long-term
ACE inhibitor and/or ARB therapy, and that
the phenomenon might be associated with
important cardiovascular and renal outcomes,
including left ventricular hypertrophy, poor
exercise tolerance, refractory proteinuria, and
declining glomerular filtration rate.
The phenomenon of aldosterone escape
could perhaps have been expected since
aldosterone has two principal secretagogues:
angiotensin II and potassium. Although
ACE inhibitors decrease angiotensin II, they
also increase potassium and the latter, as
a secretagogue for aldosterone, would be
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expected to offset the tendency for a low
angiotensin II level to produce a low level of
aldosterone.
Interest of using aldosterone receptor
blockers in Heart Failure (HF).
Consequently, the concept of aldosterone
escape led to the exploration of whether adding
spironolactone to an ACE inhibitor in human
heart failure would produce any benefits.
Barr et al5 showed that spironolactone had
beneficial cardiac effects (on sympathetic
activity and on ventricular arrhythmias) when
added to an ACE inhibitor in human heart failure.
Aldosterone blockade was then shown clearly
to reduce total mortality in both the RALES
and EPHESUS studies.6,7 In the RALES study,
a 30% reduction in all cause mortality was
shown in patients with chronic severe HF
(NYHA class III-IV) due to systolic dysfunction
(SLVD) receiving spironolactone whereas the
EPHESUS trial showed that the addition of
eplerenone to optimal medical therapy reduces
morbidity and mortality among patients with
acute myocardial infarction complicated by
SLVD and HF.6-8 Aldosterone blockade hence
became a mainstay of therapy in human heart
failure and was included as mandatory in all
heart failure guidelines.
Clinical aspects of aldosterone and the «aldosterone-escape»
concept: what is the role of aldosterone receptor blockade?
ALDOSTERONE RECEPTOR ANTAGONISTS CLINICAL INTEREST: BEYOND THE
“ALDOSTERONE ESCAPE” CONCEPT
Beyond the aldosterone escape concept.
The question then arose, especially in
hypertension, as to whether patients would
benefit from aldosterone blockade, whatever
their aldosterone plasma levels. Parthasarathy
et al 9 showed that spironolactone reduced
blood pressure in patients with both high
and low plasma levels of aldosterone. It then
became clear that aldosterone blockade
was beneficial irrespective of the individual’s
plasma aldosterone level.
Similarly, Palmer et al 10 demonstrated that
plasma aldosterone levels in the upper tertile,
but within normal limits, are predictive of an
increase in mortality and morbidity in patients
with post myocardial infarction independent of
the presence of HF, suggesting an important
role of aldosterone blockade in patients with
post myocardial infarction without HF or
SLVD.
In the EMPHASIS-HF trial, conducted in
NYHA Class II HF due to SLVD patients, i.e.
patients with systolic heart failure and mild
symptoms, eplerenone, as compared with
placebo, reduced both the risk of death and
the risk of hospitalization.11
Hence, the results of the RALES, EPHESUS
and EMPHASIS-HF studies allow to conclude
that, aldosterone blockade reduces mortality
in both mild and severe heart failure.6,7,11
In addition, these studies may help to support
that aldosterone blockade is beneficial
irrespective of the individual’s plasma
aldosterone level.12
Therefore in humans with heart failure due to left
ventricular systolic dysfunction, aldosterone
blockade is strongly indicated, irrespective of
the patient’s aldosterone levels and irrespective
of the severity of their heart failure.
References.
1.
The CONSENSUS Trial Study Group. Effects of enalapril
on mortality in severe congestive heart failure. Results
of the Cooperative North Scandinavian Enalapril
Survival Study (CONSENSUS). N Engl J Med. 1987 Jun
4;316(23):1429-35.
5.
Barr CS, Lang CC, Hanson J, Arnott M, Kennedy N,
Struthers AD. Effects of adding spironolactone to an
angiotensin-converting enzyme inhibitor in chronic
congestive heart failure secondary to coronary artery
disease. Am J Cardiol. 1995. 76 (17). 1259-65.
2.
Domanski M, Norman J, Pitt B, Haigney M, Hanlon
S, Peyster E; Studies of Left Ventricular Dysfunction.
Diuretic use, progressive heart failure, and death in
patients in the Studies Of Left Ventricular Dysfunction
(SOLVD). J Am Coll Cardiol. 2003 Aug 20;42(4):705-8.
6.
3.
Lamas GA, Flaker GC, Mitchell G, Smith SC Jr,
Gersh BJ, Wun CC, Moyé L, Rouleau JL, Rutherford
JD, Pfeffer MA, et al. Effect of infarct artery patency
on prognosis after acute myocardial infarction. The
Survival and Ventricular Enlargement Investigators.
Circulation. 1995 Sep 1;92(5):1101-9.
Pitt B., Zannad F., Remme W.J., Cody R., Castaigne
A., Perez A., Palensky J., Wittes J. The effect of
spironolactone on morbidity and mortality in patients
with severe heart failure. Randomized Aldactone
Evaluation Study Investigators. The New England
Journal of Medicine. 1999. 341 (10). 709-717.
7.
4.
Bomback AS and Klemmer PJ. The incidence and
implications of aldosterone breakthrough Nature
Clinical Practice. Nephrology. 2007. 3 (9). 486-492.
Pitt B, Remme W, Zannad F, Neaton J, Martinez F,
Roniker B, Bittman R, Hurley S, Kleiman J, Gatlin M;
Eplerenone Post-Acute Myocardial Infarction Heart
Failure Efficacy and Survival Study Investigators.
Eplerone, a selective aldosterone blocker, in patients
with left ventricular dysfunction after myocardial
infarction. N Engl J Med. 2003 Apr 3;348(14):1309-21.
Epub 2003 Mar 31. Erratum in: N Engl J Med. 2003 May
29;348(22):2271.
10
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8.
9.
Pitt B, White H, Nicolau J, Martinez F, Gheorghiade M,
Aschermann M, van Veldhuisen DJ, Zannad F, Krum
H, Mukherjee R, Vincent J; EPHESUS Investigators.
Eplerenone reduces mortality 30 days after
randomization following acute myocardial infarction in
patients with left ventricular systolic dysfunction and
heart failure. J Am Coll Cardiol. 2005. 46 (3). 425-31.
Parthasarathy HK, Alhashmi K, McMahon AD, Struthers
AD, McInnes GT, Ford I, Connell JM, MacDonald
TM. Does the ratio of serum aldosterone to plasma
rennin activity predict the efficacy of diuretics in
hypertension? Results of RENALDO. J Hypertens.
2010 Jan;28(1):170-7.
11
10. Palmer BR., Pilbrow AP., Frampton CM., Yandle TG.,
Skelton L., Nicholls M.G. and Richards A.M. Plasma
aldosterone levels during hospitalization are predictive
of survival post-myocardial infarction. Eur. Heart J.
2008. 29. 2489-2496.
11. Zannad F, McMurray JJ, Krum H, van Veldhuisen DJ,
Swedberg K, Shi H, Vincent J, Pocock SJ, Pitt B;
EMPHASIS-HF Study Group. Eplerenone in patients
with systolic heart failure and mild symptoms. N Engl J
Med. 2011 Jan 6;364(1):11-21. Epub 2010 Nov 14.
12. Guglin M, Kristof-Kuteyeva O, Novotorova I, Pratap P.
Aldosterone antagonists in heart failure. J Cardiovasc
Pharmacol Ther. 2011 Jun;16(2):150-9. Epub 2010 Dec
15.
Notes
12
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Notes
13
Adrian Boswood
MA, VetMB, DVC, DipECVIM-CA (Cardiology),
MRCVS
Professor of Veterinary Cardiology
Royal Veterinary College
London, UK
Adrian Boswood graduated from Cambridge University Veterinary School in 1989.
He has worked at the Royal Veterinary College since joining as an Intern in 1990. He
obtained the European College of Veterinary Internal Medicine Cardiology Diploma
in 2001 and is a European Specialist in Veterinary Cardiology.
Adrian is Professor of Veterinary Cardiology and his main area of interest is small
animal cardiorespiratory medicine. His research interests include the clinical uses
of cardiac biomarkers and the treatment of heart disease and failure.
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receptor blockade?
Relationship between aldosteRone and CliniCal
paRameteRs in dogs with mitRal ValVe disease
Adrian Boswood and Melanie Hezzell
Background.
The renin-angiotensin-aldosterone system
(RAAS) is one of the biological systems that
is stimulated in patients with heart disease. 1
Increased concentrations of aldosterone
are thought to underlie the development of
detrimental changes to the myocardium and
vasculature, as well as resulting in sodium
and water retention. Favourable effects of
mineralocorticoid receptor blockade have
been seen in human 2,3 and canine 4 patients
with heart disease and heart failure.
Previous studies have evaluated circulating
concentrations of aldosterone in canine heart
disease patients, but findings have been
somewhat contradictory and confounded
by the effects of therapy. 5,6 It has recently
b e e n p r o p o s e d t h a t m e a s u re m e n t o f
urinary aldosterone to creatinine ratio may
provide a reliable estimate of 24 hour urinary
aldosterone secretion and therefore give an
indication of average aldosterone production
less subject to the rapid fluctuations of
plasma concentrations.7
The aims of this study were to measure the
urine aldosterone to creatinine ratio (UAC)
in a large population of dogs with naturally
occurring degenerative mitral valve disease
15
(DMVD) and to investigate the relationship
between UAC and clinical variables including
echocardiographic measurements.
Materials and Methods.
The dogs included in this study are part of an
ongoing longitudinal study of dogs with DMVD
which began in 2004. The study is approved by
the ethics and welfare committee of the Royal
Veterinary College. Dogs were prospectively
recruited through two first opinion practices
in Central London. In order to be included in
the study dogs needed to have demonstrable
DMVD and be free of other significant systemic
disease at the time of recruitment.
Dogs were examined at approximately six
month intervals and at each examination
they were weighed, underwent a physical
examination and a series of diagnostic tests.
Owners were asked to collect a free catch
urine sample the evening prior to a patient’s
appointment and on the morning of the
appointment.
An age and weight matched population
of normal dogs was also recruited. These
dogs were normal on the basis of a physical
examination.
Relationship between aldosteRone and CliniCal paRameteRs
in dogs with mitRal ValVe disease
Echocardiographic examination was carried
out on all dogs affected by valvular disease.
In some dogs it was carried out on multiple
occasions. Standard 2-D, M-mode and
Doppler examination was undertaken with
patients conscious and restrained in lateral
recumbency. This was in order to confirm the
diagnosis of the underlying disease process
and also to obtain the measurements used in
the analysis.
LVEDDN and LVESDN were calculated using
the left ventricular internal diameter in diastole,
the left ventricular internal diameter in systole
and the bodyweight according to the formulae
described by Cornell and others.8
In dogs which were examined three times the
second visit was designated as the “baseline”
visit. The prior percentage changes in
LVEDDN and LVESDN per month were
calculated by comparing the measurements
from the baseline and previous examinations
as follows:
Prior percentage change per month = ((Visit
2 – Visit 1)/Visit 1) * 100)/ time between visit 1
and visit 2 (months).
Similarly, the subsequent percentage changes
in LVEDDN and LVESDN were calculated
by comparing the measurements from the
baseline and subsequent examinations as
follows:
Subsequent percentage change per month =
((Visit 3 – Visit 2)/Visit 2) * 100)/ time between
visit 2 and visit 3 (months)
If the dog was only examined twice, either the
first or the second visit was designated the
baseline visit at random. If the first visit was
designated the baseline visit, subsequent
percentage changes were calculated. If the
second visit was designated the baseline visit,
prior percentage changes were calculated.
Urine was centrifuged and then the
supernatant frozen at -80 o centigrade until
undergoing analysis. Urinary aldosterone was
measured following mild acid hydrolysis and
extraction into ethyl acetate. Aldosterone was
measured (in pg/mL) using a commerciallyavailable radioimmunoassay, validated for
use in dogs.9 Urine creatinine was measured
in (µmol/L) by a commercial laboratory.
Statistical analysis
UAC values were compared between dogs
with different classes of DMVD using one way
ANOVA.
Univariable and multivariable regression
analyses were used to assess associations
in dogs with MMVD between UAC and
clinical characteristics (age, breed (CKCS:
yes/no), body weight, HR obtained from
the electrocardiogram, echocardiographic
measurements (LA/Ao ratio, LVEDD/ LVFWd
ratio, LVEDDN, LVESDN, prior percentage
change in LVEDDN and LVESDN per month
and subsequent percentage change in
LV E D D N a n d LV E S D N p e r m o n t h ) a n d
treatment with angiotensin converting enzyme
inhibitors (ACEi: yes/no), pimobendan (yes/
no) or diuretics (yes/no)). CKCS was chosen
as the comparator breed since this was the
most frequently represented breed, and this
breed is particularly prone to MMVD and
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previous studies have suggested differences
in the natural history of the disease in this
breed. Variables associated with UAC with P
< 0.2 in the univariable analysis were entered
into the multivariable analyses. Separate
multivariable analyses were run excluding
and then including the percentage change in
normalised ventricular dimensions.
In the multivariable regression models,
analyses were performed in a backward
stepwise manner. All variables were initially
included, and the variable with the highest
P-value was removed until all remaining
variables had a value of P < 0.05.
of the influence of age and stage of disease.
UAC also seems to be higher at times of
active ventricular remodelling; showing a
significant relationship with prior change in
ventricular diastolic diameter and subsequent
change in ventricular systolic diameter.
Our findings suggest that aldosterone
production, as indicated by the UAC, is
increased at times of active ventricular
remodelling in dogs with DMVD.
Abbreviations.
ACEi
angiotensin converting enzyme
inhibitor
Results.
CKCS
cavalier King Charles spaniel
Numerical results will be presented at the
meeting.
HR
heart rate
LA/ Ao
ratio of left atrial diameter to aortic
root diameter
LVEDD/
diastolic
LVFWd
ratio of left ventricular end
In the multivariable model which included
rate of change data, age was negatively
associated with UAC whereas being a CKCS,
prior percentage change in LVEDDN and
subsequent percentage change in LVESDN
were positively associated with UAC.
LVEDDN
left ventricular end-diastolic
diameter, normalised for body
weight
LVESDN
left ventricular end-systolic
diameter, normalised for body
weight
Discussion.
MMVD
myxomatous mitral valve disease
RAAS
renin-angiotensin-aldosterone
system
UAC
urinary aldosterone to creatinine
ratio
In the multivariable model which excluded
rate of change data, age was negatively
associated with UAC, whereas being a
CKCS and receiving diuretics were positively
associated with UAC.
Our study has demonstrated a number of
novel and interesting findings. UAC appears
to be higher in CKCS by comparison to other
breeds and this effect seems independent
17
diameter to left ventricular free
wall thickness in diastole
Relationship between aldosteRone and CliniCal paRameteRs
in dogs with mitRal ValVe disease
References.
1.
Oyama MA. Neurohormonal activation in canine
degenerative mitral valve disease: implications on
pathophysiology and treatment. J Small Anim Pract
2009;50 Suppl 1:3-11.
5.
Knowlen GG, Kittleson MD, Nachreiner RF, et al.
Comparison of plasma aldosterone concentration
among clinical status groups of dogs with chronic heart
failure. J Am Vet Med Assoc 1983;183:991-996.
2.
Pitt B, Zannad F, Remme WJ, et al. The effect of
Evaluation Study Investigators. N Engl J Med
1999;341:709-717.
6.
Haggstrom J, Hansson K, Kvart C, et al. Effects of
naturally acquired decompensated mitral valve
regurgitation on the renin-angiotensin-aldosterone
system and atrial natriuretic peptide concentration in
dogs. Am J Vet Res 1997;58:77-82.
3.
Zannad F, McMurray JJ, Krum H, et al. Eplerenone
in patients with systolic heart failure and mild
symptoms. N Engl J Med 2011;364:11-21.
7.
Gardner SY, Atkins CE, Rausch WP, et al. Estimation of
24-h aldosterone secretion in the dog using the urine
aldosterone:creatinine ratio. J Vet Cardiol 2007;9:1-7.
4.
Bernay F, Bland JM, Haggstrom J, et al. Efficacy of
spironolactone on survival in dogs with naturally
occurring mitral regurgitation caused by myxomatous
mitral valve disease. J Vet Intern Med 2010;24:331341.
8.
Cornell CC, Kittleson MD, Della Torre P, et al. Allometric
scaling of M-mode cardiac measurements in normal
adult dogs. J Vet Intern Med 2004;18:311-321.
9.
Syme HM, Fletcher MG, Bailey SR, et al. Measurement
of aldosterone in feline, canine and human urine. J
Small Anim Pract 2007;48:202-208.
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Notes
19
Clarke Edward Atkins
DVM, DipACVIM
(Internal medicine and Cardiology)
Jane Lewis Seaks Distinguished
Professorship of Companion Animal Medicine
Department of Clinical Sciences
College of Veterinary Medicine
North Carolina State University
Raleigh, North Carolina, USA.
Clarke Atkins, DVM, Professor of Medicine and Cardiology at North Carolina State
University is a 1972 graduate of the University of California, Davis and an Angell
Memorial Animal Hospital intern. He is board-certified by the ACVIM in internal
medicine and in cardiology.
Dr. Atkins is known for his research and teaching in small animal cardiology, he is the
2004 Norden-Award recipient for excellence in teaching, and was recently named
the Jane Lewis Seaks Distinguished Professor.
He is the author of over 150 publications and his research involves canine and feline
heartworm disease and pharmacologic therapies of cardiac disease in dogs, cats,
and horses.
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receptor blockade?
WHERE ARE WE WITH ALDOSTERONE ESCAPE
(BREAK-THROUGH) IN 2011?
Clarke Atkins, DVM, Andrea Lantis, DVM, Marisa Ames, DVM.
Cardiovascular disease in dogs produces
significant morbidity and mortality and ranks
2nd in importance, behind only neoplastic
disease as a cause of non-traumatic death
in dogs. 1 The most important non-parasitic
cardiovascular disease affecting dogs is
degenerative mitral valvular disease with
mitral regurgitation (MR). 1
An ACVIM consensus panel has unanimously
indicated that chronic pharmacologic
management of heart failure in dogs
caused by MR should include furosemide,
pimobendan, and an angiotensin convertingenzyme inhibitor (ACE-I), with the majority of
panelists also recommending a mineralocorticoid receptor blocker (MRB), such
as spironolactone. 2 The use of the latter
2 drugs (ACE-I and MRB) demonstrates
the priority placed upon suppression of
the renin-angiotensin-aldosterone system
(RAAS) in canine cardiovascular disease.
The ACE-I, utilized in veterinary medicine,
blunt plasma ACE activity maximally by
approximately 75%, when administered as
directed, and the benefits of ACE-inhibition
have been demonstrated in multiple clinical
trials in dogs with CHF due to chronic
degenerative valvular disease and dilated
cardiomyopathy.3-7
21
Definition and Incidence.
These above-mentioned benefits are also
appreciated in human cardiovascular and
renal patients.8 It is recognized in human heart
failure-patients, however, that a percentage of
the population experiences a recrudescence of
aldosterone and angiotensin II secretion with
chronic ACE-inhibition.9 Persistent aldosterone
secretion, despite a significant reduction in
plasma ACE activity and presumed removal
of angiotensin II, its major secretagogue, is
then referred to as “aldosterone escape” or
preferably “aldosterone breakthrough”. 10
Aldosterone escape has been defined in the
human literature as any increase in serum
aldosterone concentration that exceeds a
baseline value after initiation of RAAS-blocking
therapy.11 To date, no study has been reported
which precisely assesses the time from
onset of treatment until breakthrough or the
percentage of patients affected. However, a
recent meta-analysis revealed varying results,
depending the exact definition that aldosterone
breakthrough was present in ~10% patients in
the first 6 months of ACE-inhibition therapy and
in 40-50% after 12 months of therapy (Fig 1).9
There appears, however, to be no consensus
within the human literature regarding the time
course of aldosterone escape as some authors
WHERE ARE WE WITH ALDOSTERONE ESCAPE (BREAK-THROUGH) IN 2011?
describe it as a serum level that exceeds a
baseline (pre-ACEI and/or ARB therapy) value
6-12 months after initiation of RAAS-blocking
therapy 11 while others have documented
aldosterone escape in human patients 4-6
weeks after initiation of an ACEI. 9, 12-13 Some
investigators have directly addressed whether
the incidence of aldosterone breakthrough
was related to the dosage or class of RAAS
blockade and found no apparent differences.
As examples, Tang et al. found no significant
difference in the incidence of breakthrough
between groups of patients randomly assigned
to low dose or high-dose enalapril and Horita et
al. demonstrated equal rates of breakthrough
among subjects on ACE inhibitors, ARBs, or a
combination.14
The frequency, degree and importance
of aldosterone breakthrough are not well
understood in humans, let alone animals.
Nevertheless, several studies have revealed
the likelihood of aldosterone breakthrough in
veterinary patients and experimental animals.1517,a
Cats with hypertrophic cardio-myopathy
receiving ramipril (0.5 mg/kg q24h) experienced
97% suppression of plasma ACE activity at 3,6,9,
and 12 months, however, plasma aldosterone
was not different in cats treated with ramipril
compared with those receiving placebo.16 A
pacing-induced CHF model in dogs receiving an
intravenous bolus of fosinoprilat (1µmol/kg) and
intravenous furosemide (40 mg administered
over 20 minute) resulted in a significant increase
in plasma aldosterone concentration at 30, 60,
90, and 150 minutes.17
In a clinical study of 22 Cavalier King Charles
Spaniels with naturally-occurring MR and “early”
signs of heart failure (modified NYHA class III),
12 dogs receiving enalapril monotherapy (0.4
mg/kg PO,q12h) had significant reductions
in plasma ACE activity at 3 weeks (-83%).
Furosemide was subsequently added to the
treatment regimen at the time of the 3-week
re-evaluation. Significant reductions in plasma
ACE activity (-81%) were again noted 6 months
after the initial examination. However, while
administration of enalapril led to a significant
decrease in plasma aldosterone concentration
after 3 weeks of treatment, the 6-month plasma
aldosterone concentration in dogs receiving
enalapril and furosemide were significantly
increased as compared to initial and 3-week
examination (P<0.05). 15 This demonstrates
aldosterone breakthrough occurring with
the addition of the known RAAS-activator,
furosemide.
Finally, in short-term study of normal hound
dogs, carried out in our laboratory, furosemideinduced RAAS activation (maximum mean
increase at 7 days of ~300%) was not
suppressed with concurrent benazepril
administration, even though plasma ACE
activity was suppressed by approximately 67%
six hours post-administration.a These final 2
studies argue for alternative RAAS suppressant
strategies, such as addition of MRB and/or ARB,
possibly earlier in the course of heart failure than
previously considered necessary.
Escape vs Breakthrough.
Aldosterone “escape”, the original term for
this phenomenon in the cardiology literature8,
has been largely replaced with the term
“Aldosterone breakthrough”. The former term
(escape) had been previously coined to describe
the phenomenon in which the kidneys “escape”
the sodium retaining effects of aldosterone
to achieve a sodium balance and stable
arterial blood pressure, without severe volume
expansion and edema.8 This is contradistinction
to the observation of restoration of aldosterone
blood or urine concentrations toward baseline
22
4
after being initially decreased during RAAS
blockade (with either ACE-I or angiotensin II
receptor blockers (ARBs).8
Mechanism.
The mechanism(s) by which aldosterone
breakthrough occurs are not yet well understood
and is probably multi-factoral.8,9,18 The most
popular explanation is that alternative pathways
and enzymes for conversion of Angiotensin
I to Angiotensin II are evoked, including
chymase and cathepsin G. Renin plasma
concentrations are elevated in the presence of
ACE-I therapy with subsequent elevations in
AgII concentrations, which may contribute to
aldosterone breakthrough. Increase in plasma
potassium values has also been suggested
as a potential mechanism for aldosterone
breakthrough, but the available evidence
does not support this hypothesis. Three
studies reported that potassium levels did not
change during an ACE inhibitor therapy longer
than 6 months, regardless of breakthrough
status.19-21 Finally, endogenous factors, such
as corticotrophin, catecholamines, endothelin,
prolactin, sertitonin, and vasopressin, as well as
diuretics, sodium restriction and vasodilators
stimulate aldosterone secretion and may
therefore contribute to breakthrough.21a To the
authors knowledge, compliance failure has not
been evaluated as a contributor to aldosterone
breakthrough.
Clinical Relevance.
Chronic exposure to high concentrations
of aldosterone results in excessive sodium
retention with expansion of extracellular volume,
favors potassium and magnesium wasting,
inhibits myocardial norepinephrine uptake,
diminishes heart rate variability, produces
cardiac arrhythmias, decreases baroreceptor
sensitivity, contributes to endothelial
23
dysfunction and vascular inflammation, and is
independently associated with renal, vascular
and cardiac remodeling and heart failure.9,22-25
Plasma aldosterone levels at presentation are
known to be significantly predictive of mortality
after myocardial infarction.26
Increasing evidence links aldosterone
excess and/or activation of mineralocorticoid
receptors to the development and progression
of various cardiovascular disease processes
in humans.26-29 The Randomized Aldactone
Evaluation Study (RALES) revealed a 31%
reduction in mortality due to cardiac causes
in human patients with NYHA class III and IV
CHF receiving spironolactone when added
to conventional therapy (ACE-I, loop diuretic,
and digoxin) as compared to a placebo
cohort. Pro-collagen markers decreased in
the spironolactone group but did not change
in the placebo cohort, indicating the benefit of
aldosterone blockade paralleled the reduction
of cardiac fibrosis. Serum levels of three
pro-collagen markers were independently
associated with increased risk of death and
the beneficial effects of spironolactone on
patient survival were predominantly seen
among patients with the highest baseline levels
of collagen markers.28 The EPHESUS study
compared eplerenone to placebo, each with
standard therapy, in post-infarct patients with
diminished left ventricular function, resulting
in significant survival benefit (17% reduction
in cardiovascular mortality). 27 This benefit
was noted early, within 30 days of initiation
of therapy. Finally, the EMPHASIS-HF study
demonstrated that eplerenone in a population
of mild (NYHA II) heart failure patients with left
ventricular dysfunction, significantly reduced
cardiac death and hospitalization by 29%, as
compared to placebo.29 This study importantly
demonstrated benefits of MRB early in the
course of heart failure.
Evidence of the harmful effects of RAAS
activation the benefits of RAAS suppression
are evident in veterinary patients as well. In
a prospective veterinary study by Hezzell
et al b, urinary aldosterone concentrations
were found to be negatively associated with
survival (P=0.005) in 54 dogs with mitral
valve disease. A recent double-blinded,
field study in 212 dogs demonstrated a 69%
reduction in risk of cardiac morbidity and
mortality in dogs with chronic degenerative
mitral valve disease that were treated with
spironolactone in addition to an ACEI with
furosemide +/- digoxin when compared to
furosemide, an ACEI +/- digoxin alone. 30
Previous studies in cats 16 , experimental
models of heart failure in dogs 17, and dogs
with naturally occurring chronic degenerative
valve disease 15,b have revealed persistent
aldosterone secretion despite ACEI therapy.
Studies in authors’ laboratory revealed that
furosemide-induced RAAS activation of
10 days duration was not attenuated with
concomitant benazepril administration.a The
therapeutic implications of these studies are
that aldosterone breakthrough appears to
occur in animals as it does in man and that
aldosterone and angiotensin II are important
negative prognostic indicators for dogs and
humans suffering from cardiac disease and
failure. To counteract this, a MRB, such
as spironolactone is probably necessary
in many heart failure patients and may be
necessary earlier than previously thought.
The use of renin antagonists may play a
future role in treatment of cardiovascular
disease in dogs.
Figure 1. The left panel demonstrates 2 definitions of aldosterone breakthrough, with definition 1 defined as a rise above baseline plasma
aldosterone concentrations after initial suppression by an angiotensin converting-enzyme inhibitor (ACE-I). The second, more conservative
definition, requires that the plasma aldosterone rebound and exceed a certain level (in this example, 80 pg/ml [red line], one of several
thresholds chosen by various investigators9). The hypothetical patient in the left panel meets definition #1 when checked at 6 months and
definition #2 when tested at 12 months after initiation of ACE-I.9
The right panel schematically demonstrates possible ways in which aldosterone breakthrough might or might not be manifested. This is
derived from the meta-analysis of Bomback and colleagues9 and the work from North Carolina State University in an experimental model of
RAAS activation b The ideal response to an ACE-I is that it falls and stays suppressed (~50% of human cases; red dashed line). In aldosterone
breakthrough, RAAS suppression fails after a period of time (red and blue lines) and there is recrudescence of plasma (or urinary) aldosterone
concentrations. This is observed in approximately 40-50% of human patients after 1 year of ACE-I therapy.9 There is evidence in experimental
RAAS activation that aldosterone excretion in normal dogs is not demonstrably suppressed 6 hours post-treatment with ACE-I on days 1, 5
and 10 (represented in the black dashed line [a]), despite dramatic reduction in ACE activity b.
Aldo = aldosterone; Mo = month.
24
4
Footnotes.
a
b
Hezzell MJ, Boswood A, Elliott J. Relationships
between serum and urinary aldosterone, ventricular
remodeling and outcome in dogs with mitral valve
disease. J Vet Intern Med 2010;24(3):672 (abstract).
Lantis A, Atkins CE, DeFrancesco TC, Keene
BW. Aldosterone escape in furosemide-activated
circulating renin-angiotensin-aldosterone
system (RAAS) in normal dogs. J Vet Intern Med
2010;24(3):672 (abstract).
References.
1.
Häggström, J. Angiotensin-converting-enzymeinhibitor therapy in canine heart failure. Waltham
Focus, 2002; 12:4-14.
2.
Atkins, C, Bonagura, J, Ettinger S, et al. Guidelines for
the diagnosis and treatment of canine chronic valvular
heart disease. J Vet Intern Med 2009;23:1142-1150.
3.
Amberger C, Chetboul V, Bomassi E, et al. on behalf of
the FIRST group. Comparison of the effects of imidapril
and enalapril in a prospective, multicentric randomized
trial in dogs with naturally acquired heart failure. J Vet
Cardiol 2004;6(2):9-16.
4.
Ettinger SJ, Benitz AM, Ericsson GF et al. for the LIVE
Study Group. Effects of enalapril maleate on survival
of dogs with naturally acquired heart failure. J Am Vet
Med Assoc 1999;11:1573-1577.
5.
The BENCH Study Group. The effect of Benazepril on
survival times and clinical signs of dogs with congestive
heart failure: Results of a multicenter, prospective,
randomised, double-blinded, placebo-controlled, long
term clinical trial. J Vet Cardiol 1999;1:7-18.
6.
The COVE Study Group. Controlled clinical evaluation
of enalapril in dogs with heart failure: Results of the
Cooperative Veterinary Enalapril Study Group. J Vet
Intern Med 1995;9:243-252.
7.
Hamlin RL, Nakayama T. Comparison of some
pharmacokinetic parameters of 5 angiotensinconverting enzyme inhibitors in normal beagles. J Vet
Intern Med 1998;12:93-95.
8.
9.
Waanders F, de Vries LV, van Goor H, Hillebrands JL,
Laverman GD, Bakker SJ, Navis G. Aldosterone, From
(Patho)Physiology to Treatment in Cardiovascular and
Renal Damage. Curr Vasc Pharmacol. 2011 May 2.
Bomback AS, Klemmer PJ. The incidence and
implications of aldosterone breakthrough. Nat Clin
Pract Nephrol. 2007 Sep;3(9):486-92.
10. MacFadyen RJ, Lee AF, Morton JJ, et al. How often are
angiotensin II and aldosterone concentrations raised
during chronic ACE inhibitor treatment in cardiac
failure? Heart 1999;82(1):57-61.
25
11. Bomback AS, Klemmer PJ. The incidence and
implications of aldosterone breakthrough. Nat Clin
Pract Nephrol 2007;3(9):486-492.
12. Staessen J, Lijnen P, Fagard R, et al. Rise in plasma
concentration of aldosterone during long-term
angiotensin II suppression. J Endocrinol 1981;91(3):457465.
13. Cleland JG, Dargie HJ, Hodsman GP, et al. Captopril in
heart failure. A double blind controlled trial. Br Heart J
1984;52(5):530-535.
14. Spät A, Hunyady L. Control of aldosterone secretion: a
model for convergence in cellular signaling pathways.
Physiol Rev 2004;84:489-539.
15. Häggström J, Hansson K, Karlberg BE et al. Effects of
long term treatment with enalapril or hydralazine on
the renin-angiotensin-aldosterone system and fluid
balance in dogs with naturally acquired mitral valve
regurgitation. Am J Vet Res 1996;57(11):1645-1651.
16. MacDonald KA, Kittleson MD, Larson RF, et al. The effect
of ramipril on left ventricular mass, myocardial fibrosis,
diastolic function, and plasma neurohormones in Maine
coon cats with familial hypertrophic cardiomyopathy
without heart failure. J Vet Intern Med 2006;20:10931105.
17. Cataliotti A, Boerrigter G, Chen HH, et al. Differential
actions of vasopeptidase inhibition versus angiotensinconverting enzyme inhibition on diuretic therapy in
experimental congestive heart failure. Circulation
2002;105:639-644.
18. Nobakht N, Kamgar M, Rastogi A, Schrier R. Limitations
of angiotensin inhibition. Nat. Rev. Nephrology, 2011;
7:356-359.
19. Cicoira M et al. Relation of aldosterone “escape” despite
angiotensin-converting enzyme inhibitor administration
to impaired exercise capacity in chronic congestive
heart failure secondary to ischemic or idiopathic dilated
cardiomyopathy. Am J Cardiol, 2002; 89: 403–407.
20. Sato A et al. Effectiveness of aldosterone blockade in
patients with diabetic nephropathy. Hypertension, 2003;
41: 64–68.
21. Sato A and Saruta T Aldosterone escape during
angiotensin-converting enzyme inhibitor therapy in
essential hypertensive patients with left ventricular
hypertrophy. J Int Med Res, 2001; 29: 13–21.
21a. Rossi GP. Aldosterone Breakthrough during RAS
blockade: A role for endothelins and their antagonists?
Curr Hypertens Rep 2006;8(3):262-268.
22. Weber KT. Aldosterone in congestive heart failure. N
Eng J of Med 2001;345(23):1689-1697.
23. Wang W, McClain JM, Zucker IH. Aldosterone
Reduces Baroreceptor Discharge in the Dog.
Hypertension 1992;19:270-277.
24. Brilla CG, Rupp H, Funck R, et al. The reninangiotensin-aldosterone system and myocardial
collagen matrix remodeling in congestive heart
failure. Eur Heart J 1995;16 (Supp O):107-109.
25. M a r t i n e z , FA . A l d o s t e r o n e i n h i b i t i o n a n d
cardiovascular protection: More important than it
once appeared. Cardivasc Drugs Ther 2010; 24:345350.
26. Palmer BR, Pilbrow AP, Frampton CM, et al. Plasma
aldosterone levels during hospitalization are
predictive of survival post-myocardial infarction.
Europ Heart Jour 2008; 29:2489-2496.
27. Suzuki G, Morita H, Mishima T, et al. Effects of
long-term monotherapy with Eplerenone, a novel
aldosterone blocker, on progression of left ventricular
dysfunction and remodeling in dogs with heart failure.
Circulation 2002;106:2967-2972.
28. Pitt B, Zannad F, Remme WJ, et al. The effect of
with severe heart failure. N Eng J Med 1999;341:709717.
29. Zannad F, John JV, McMurray MD, et al. Eplerenone in
patients with systolic heart failure and mild symptoms.
N Eng J Med 2011; 364:11-21.
30. Bernay F, Bland JM, Häggström J, et al. Efficacy of
mitral valve disease. J Vet Intern Med 2010;24:331-341.
26
4
Notes
27
Faiez Zannad
MD, PhD
Professor of Therapeutics and Cardiology
Director, Clinical Investigation Centre, INSERM
Head, Heart Failure and Hypertension Unit
Department of Cardiology, CHU and University
Henri Poincaré,
Nancy, France.
Faiez Zannad is Professor of Therapeutics and Cardiology. He is at the Head of the
Division of Heart Failure, Hypertension and Preventive Cardiology for the department
of Cardiovascular Disease of the Academic Hospital (CHU) in Nancy and the Director
of the Clinical Investigation Centre (Inserm-CHU) of Nancy since 1995. He entered
the European Society of Cardiology (ESC) in 1996 and is currently the Chairman
of the ESC Working group on Pharmacology and Drug Therapy as well as a Board
member of the ESC Heart Failure Association. He is Past-President of the French
Society of Hypertension.
As the Coordinator of French Cardiovascular Clinical Investigation Centres, he has
participated in various famous large scale trials in human cardiology such as RALES,
VALIANT, CIBIS, CAPRICORN, EPHESUS or EMPHASIS-HF. In these trials, he has
been involved either as a member of the Steering Committees or in the Protocol
Writing Groups.
He is Co-Editor-in-Chief for Fundamental and Clinical Pharmacology, the official
journal of the European Pharmacology Societies Federation (EUPHAR). He chairs
and organises annual international meetings on CardioVascular Clinical Trials (CVCT)
and on Biomarkers in Heart Failure.
28
4
Clinical trials, where are we 10 years after RALES study?
TARgETing ThE ALdoSTERonE pAThwAy in
CARdiovASCuLAR diSEASE
Aldosterone is a key player in the pathogenesis
of cardiovascular (CV) disease. Many details
about the role of aldosterone in CV disease
have, however, only recently been discovered
and debate exists as to the relative importance
of glucocorticoids and aldosterone in terms
of mineralocorticoid receptor (MR) activation,
which aldosterone modulator to use, which
timing of treatment to aim for, and in which
population to intervene. Accordingly, clinical
trials have documented that blocking the MRdependent effects of aldosterone can improve
mortality and CV morbidity in patients with
heart failure or myocardial infarction.
The greatest success with aldosterone
blockade so far has clearly been in patients
with heart failure (HF). Plasma aldosterone
levels have been shown to be predictive of
outcome in patients’ heart failure, irrespective
of NYHA class, etiology and left ventricular
ejection fraction. In the RALES trial severely
symptomatic patients with systolic HF (NYHA
III-IV), already treated with diuretics and an ACE
inhibitor were randomized to receive either
spironolactone 25-50 mg daily or placebo.
Treatment with spironolactone was associated
with a large reduction in both mortality and
cardiovascular hospitalizations. Aldosterone
blockade is a class I recommendation in North
American and European HF guidelines as an
important part of the treatment in patients with
persistent class III-IV symptoms despite ACEinhibitors and beta-blockers. Until recently, it
29
was unclear if aldosterone antagonists would
be effective in less advanced heart failure, and
also if an effect similar to that seen in RALES
would be evident in patients adequately treated
with both ACE inhibitors and beta-blockers. In
fact, a recent study in 226 HF patients in NYHA
class II-III found that 9 months of eplerenone
treatment on top of ACE inhibitors and betablockers did not improve symptoms nor did
it reduce left ventricular dimensions. The
levels of natriuretic peptides, were, however,
decreased by eplerenone. In contrast, a
clear effect on mortality and morbidity in
this group was recently demonstrated in the
much larger EMPHASIS trial. In the trial 2723
class II/III patients with LVEF ≤ 35 % and a
recent hospitalization for HF or elevated
levels of natriuretic peptides were randomized
to eplerenone or placebo. The trial was
stopped prematurely because eplerenone
reduced the primary endpoint (CV death or
HF hospitalizations) significantly by 34 %.
Indeed, total mortality was also significantly
reduced by eplerenone by 22 %. Although
the precise position of aldosterone blockers
in the treatment of less advanced heart failure
is still debated, it is clear that a much larger
role for these agents in class II patients than
previously recommended is reasonable.
The mechanism behind the impressive effect
of aldosterone blockade in chronic HF has
been studied extensively. A recent metaanalysis of 9 randomized clinical trials showed
TARgETing ThE ALdoSTERonE pAThwAy in CARdiovASCuLAR diSEASE
a significant effect of drug treatment on left
ventricular (LV) ejection fraction. Such an
effect of aldosterone blockade has been
documented also for patients who are
already treated with angiotensin II blocking
agents. In an MRI based study in 51 HF
patients, treatment with spironolactone
in addition to candesartan resulted in a
significant improvement in LV end-diastolic
diameter as well as in LVEF after 12 months.
The effects of aldosterone blockade are not
confined to LV volumes and systolic function.
Indeed, an effect on measures of diastolic
function of spironolactone in HF patients with
preserved ejection fraction (HFPEF) has been
documented. In experimental HF induced by
chronic L-NAME infusion in rats, eplerenone
further normalized diastolic function as
measured by E/A ratio, independent of any
effect on blood pressure. This would indicate
that aldosterone blockade reverses early
phases of HF and would emphasize the
need for early intervention in the disease
process. Similarly, administration of the active
metabolite of spironolactone, canrenone,
reduced myocardial norepinephrine content
and increased the threshold for ventricular
fibrillation in rats with experimental HF.
Recently published experimental evidence
supports that the myocardium becomes
increasingly sensitized to mineralocorticoid
excess in a setting of pressure overload
leading rapidly to cardiac changes similar to
those seen in HFPEF. In addition to the direct
cardiac effect, aldosterone blockade might
confer protection against development of the
cardio-renal syndrome. Such an effect would
be of tremendous clinical interest, since
impairment of renal function in HF patients
markedly increases mortality and morbidity.
In an experimental HF model in rats, the
combination of spironolactone and an ACEinhibitor was more effective than either alone,
or than vehicle, to increase urine output and
lower urinary protein excretion. Convincing
data to prove a similar effect in humans are
not yet available.
Following the publication of positive trials
on aldosterone blockade in HF and rapid
translation of trial results into clinical
practice, concerns have been raised over
the risks of adverse events, particularly
hyperkalemia. The risk of hyperkalemia is
highest in patients with renal dysfunction,
high pre-treatment S-potassium, diabetes or
prior use of antiarrythmics. However, if the
inclusion criteria from RALES and EPHESUS
are followed and appropriate monitoring is
performed, the risk for serious hyperkalemia is
very low if correct monitoring of S-potassium
is performed. In the EPHESUS trial short term
increase in S-potassium was not predictive
of mortality and no deaths were adjudicated
to hyperkalemia. Recent studies even
indicate that the risk of serious hyperkalemia
during treatment with spironolactone is low
in oligouric hemodialysis patients. Taken
together, the data suggest that the fear for
clinically important hyperkalemia associated
with aldosterone blockade may have been
overemphasized. Probably even patients with
tendency to hyperkalemia can be treated with
aldosterone blockers if correct measures are
taken.
Therapeutic tools and targets?
The CV consequences of MR activation may
be overcome or reduced either by blockade at
the receptor levels or by lowering the levels of
30
4
circulating agonists. As discussed above the
vast majority of clinical evidence is based on
the use of the MR blockers spironolactone
and eplerenone. Very few direct studies
comparing efficacy of spironolactone and
eplerenone have been published, but a
recent trial in hypertension due to primary
hyperaldosteronism suggested that
spironolactone might be more potent than
eplerenone. This contrasts the findings of a
previous smaller trial showing no difference.
A recent study suggested that eplerenone
was more effective than spironolactone in
preventing hyperglycemia in HF patients,
but doses used in the two arms were likely
not comparable, in turn complicating the
interpretation of the trial. There are no studies in
HF comparing the effect on clinical outcomes
of the two drugs. The main difference between
the two drugs exists in the lack of sex steroid
effect of eplerenone reducing or eliminating
the risk of gynecomastia with this drug.
While treatment with MR receptor blockers
is effective in reducing the effects of MR
activation, it is also clear that treatment with
for instance spironolactone or eplerenone
increases levels of circulating aldosterone,
and this could increase the degree of non-MR
(non-genomic) mineralocorticoid effects. This
feedback mechanism could be overcome by
reducing aldosterone synthesis by inhibition
of the CYP11B2 enzyme in the adrenal zona
glomerulosa, which in turn would reduce
mineralocorticoid MR activation. While
aldosterone synthase inhibition represents
an interesting potential target in the
mineralocorticoid pathway, several questions
remain to be answered. Firstly, there are
potential risks which are not well described in
large populations with CV disease, particularly
31
the risks of hyponatremia and hyperkalemia.
Secondly, it should be kept in mind that
aldosterone synthase inhibition does not
prevent glucocorticoids from activating
the MR as discussed above, which could
limit the utility of the drug in the absence of
concomitant MR blockade. Further studies
are required to address the potential of this
group of compounds in the treatment of CV
disease.
In clinical medicine the greatest development
in the field has been initiating trials to test if
expanding the indications for MR blockade
will improve outcome in the entire spectrum
of CV disease. Multiple hypertension trials
have been completed or are enrolling, and
trials in diabetic nephropathy are completed
and underway. Given the multiple beneficial
actions of MR blockers early in the processes
leading to CV damage as discussed above, it
appears that an outcome based trial targeting
high risk individuals would be of considerable
interest. As a consequence of the published
evidence for using ACE-I and ARBs for
this indication the trial should likely be a
comparative study evaluating an aldosterone
blocker to a blocker of the angiotensin II
pathway, in a clinical setting of high CV risk,
similar to the ONTARGET trial.
Evidence based treatment for heart failure
with preserved ejection fraction (HFPEF)
is essentially non-existing despite several
trials attempting to demonstrate benefit
from various pharmacological interventions.
Most researchers consider HFPEF a vascular
disease where longstanding increased
peripheral resistance induces myocardial
fibrosis and reduced ventricular and vascular
compliance, in turn leading to non-systolic
TARgETing ThE ALdoSTERonE pAThwAy in CARdiovASCuLAR diSEASE
heart failure. Given the well-described effects
of MR blockade on both blood pressure and
myocardial fibrosis, it could be hypothesized
that MR blockers would be beneficial in
HFPEF. This hypothesis is being tested in the
large TOPCAT study randomizing patients
with HF and LVEF > 45 % to spironolactone or
placebo. Another trial in HFPEF, the Aldo-DHF
trial, is currently recruiting patients with class
II-III HF, LVEF > 50 % and echocardiographic
evidence of abnormal diastolic filling. Patients
are randomized to spironolactone 25 mg OD
or placebo and the primary outcome measure
is change in peak VO2.
Conclusion.
Considerable amounts of knowledge about
the importance of aldosterone and MR
activation by aldosterone and glucocorticoids
have emerged over the last decade. While
intervention in the aldosterone pathway
is already a crucially important step in the
management of hypertension and HF, drugs
to block the MR or interfere with aldosterone
synthesis show promise in the treatment of
other CV disease entities. Ongoing studies
will address the optimal strategy to intervene
successfully in the aldosterone pathway and
in turn reduce the burden of CV disease.
References.
1.
Mihailidou AS, Loan Le TY, Mardini M, Funder JW.
Glucocorticoids activate cardiac mineralocorticoid
receptors during experimental myocardial infarction.
Hypertension 2009;54:1306-12.
2.
Lacolley P, Safar ME, Lucet B, Ledudal K, Labat C,
Benetos A. Prevention of aortic and cardiac fibrosis
by spironolactone in old normotensive rats. J Am Coll
Cardiol 2001;37:662-7.
3.
Schafer A, Vogt C, Fraccarollo D, et al. Eplerenone
improves vascular function and reduces platelet
activation in diabetic rats. J Physiol Pharmacol
2010;61:45-52.
4.
Tomaschitz A, Pilz S, Ritz E, Meinitzer A, Boehm BO,
Marz W. Plasma aldosterone levels are associated with
increased cardiovascular mortality: the Ludwigshafen
Risk and Cardiovascular Health (LURIC) study. Eur
Heart J 2010;31:1237-47.
5.
Hayashi M, Tsutamoto T, Wada A, et al. Immediate
administration of mineralocorticoid receptor antagonist
spironolactone prevents post-infarct left ventricular
remodeling associated with suppression of a marker
of myocardial collagen synthesis in patients with
first anterior acute myocardial infarction. Circulation
2003;107:2559-65.
6.
Pitt B, Zannad F, Remme WJ, et al. The effect of
Evaluation Study Investigators. NEnglJ Med 1999;
341:709-17.
7.
Pitt B, Remme W, Zannad F, et al. Eplerenone, a
selective aldosterone blocker, in patients with left
ventricular dysfunction after myocardial infarction. N
Engl J Med 2003;348:1309-21.
8.
Zannad F, McMurray JJ, Krum H, et al. Eplerenone in
patients with systolic heart failure and mild symptoms.
N Engl J Med 2011;364:11-21.
32
4
Notes
33
Bertram Pitt
MD
Professor of Medicine Emeritus,
University of Michigan, School of Medicine,
Ann Arbor, Michigan, USA.
Bertram Pitt is Professor of Medicine Emeritus at the University of Michigan School
of Medicine. He is diplomate of the American Board of Internal Medicine and of the
American Board of Cardiology.
He is a member of several professional societies such as the American College
of Cardiology, the American Society for Clinical Investigation, the American
Physiological Society – Circulation Group, the American Federation for Clinical
Research and the American Heart Association. He has received awards like the
Forest Dewey Dodrill Award for Excellence in 2001 and the James B. Herrick
Award in 2005 (both from the American Heart Association).
Dr. Pitt has published more than 500 papers in the most important peer-reviewed
journals dealing with cardiovascular diseases (Circulation, American Heart Journal,
Journal of the American College of Cardiology, Hypertension, European Heart
Journal, New England Journal of Medicine, and Lancet…). He was the principal
investigator of RALES and EPHESUS, the co-principal investigator of EMPHASIS-HF
and he is currently leading the large scale NHLBI TOPCAT trial investigating the
clinical benefit of mineralocorticoid receptor blockade in patients with heart failure
and a preserved left ventricular ejection fraction.
34
4
TREATmEnT of PRESERvEd CARdiAC funCTion
HEART fAiLuRE wiTH An ALdoSTERonE AnTAgoniST:
THE nHLBi ToPCAT TRiAL
The mortality and morbidity of patients with
heart failure and a reduced left ventricular
ejection fraction (HFREF) has decreased over
the past decade due to the use of angiotensin
converting enzyme inhibitors (ACE-Is) and or
angiotensin receptor blocking agents (ARBs),
beta adrenergic receptor blocking agents
(BBs), mineralocorticoid receptor antagonists
(MRAs), and implantation of devices including:
implanted automatic cardiac defibrillators,
cardiac resynchronization therapy (CRT), and
most recently left ventricular assist devices
(LVADs) for destination therapy. In contrast,
the mortality and morbidity of patients with
a preserved left ventricular ejection fraction
(HFPEF) has changed relatively little. 1
Unfortunately the incidence of HFPEF is
increasing due to the aging of the population
and the epidemic of visceral obesity in the
western world.1 ACE-Is and/or ARBs and BBs
while effective in patients with HFREF 2,3 have
had only equivocal results in patients with
HFPEF. The effect of MRAs on mortality and
morbidity in patients with HFPEF has however
not been systematically evaluated. There is
however reason to believe that a MRA both
through its effects on the pathophysiology of
HFPEF as well as on mechanisms associated
wit h a n u m b e r of i m p orta n t c omo r bid
conditions may influence the outcome of
these patients including: atrial fibrillation,
diabetes mellitus, resistant or uncontrolled
hypertension, obstructive sleep apnea, and
chronic renal disease might be effective in
35
altering the natural history of patients with
HFPEF. The National Heart Lung and Blood
Institute (NHLBI) has therefore initiated the
TOPCAT trial4,5 the design and background of
which will be briefly discussed below.
TOPCAT: study design.
3315 patients with a history of HFPEF will be
randomized to the MRA spironolactone or
placebo using a double blind protocol. To be
eligible patients must be >/= 50 years of age
with a LVEF </= 45% and either a history of
hospitalization for HF within the previous year
or a BNP >/= 100 pg/ml or NT-proBNP>/=
360 pg/ml within 60 days of randomization.
Major exclusion criteria include uncontrolled
hypertension, a prior history of serious
hyperkalemia, an estimated glomerular
filtration rate (e GFR) </= 30 ml/min/1.73 m 2,
and or a serum potassium >/= 5.0 mmol/l).
The primary endpoint is the composite of
cardiovascular death, hospitalization for HF,
or aborted cardiac arrest.
Randomized patients will be initiated on a
starting dose of 15 mg/day of study drug and
will be up titrated to 30 mg after one month if
the serum potassium remains < 5.0 mmol/l. An
additional up titration is allowed after 4 months
at the investigators discretion if the serum
potassium remains < 5.0 mmol/l and there are
signs or symptoms of progressive HF. If at any
time the serum potassium is > /= 6.0 mmol/l the
study drug will be discontinued and if the serum
TREATmEnT of PRESERvEd CARdiAC funCTion HEART fAiLuRE wiTH An
ALdoSTERonE AnTAgoniST: THE nHLBi ToPCAT TRiAL
potassium is between 5.5 and 6.0 mmol/l the
study drug will be down titrated to 15 mg /day.
The study drug will also be discontinued in
patients with an increase of serum creatinine to
>/= 3.0 mg/dl.
Important ancillary studies include
determination of ventricular function by
echocardiography, determination of vascular
stiffness by tonometry, and measurement of
selected cardiac biomarkers. To date, more
than > 3000 patients have been randomized
into the study with a planned end of recruitment
on January 31st 2012 and a subsequent follow
up of one year so that the final results can be
anticipated to be available in early 2013.
It should be emphasized that the dosing
regimen in this trial is different from that
with spironolactone in the RALES trial 6. In
RALES6 patients were randomized to 25 mg
of spironolatone or placebo and up titrated
to 50 mg at one month whereas in TOPCAT
patients will be started on 15 mg of study
drug and up titrated to 30 mg at one month,
and possibly to 45 mg at 4 months. An initial
dose of spironolactone of 15 mg was chosen
for this study since it was anticipated that
many of the patients would be elderly and have
concomitant diabetes mellitus and/or CKD, all
of which could predispose to hyperkalemia.
Rationale to use Spironolactone in the
treatment of HFPEF.
Prior data both from preclinical and clinical
studies provide a strong rational for the use
of a MRA in patients with HFPEF. Increasing
evidence shows that myocardial fibrosis is
critical in the transition from hypertensive or
diabetic heart disease to HFPEF. Myocardial
fibrosis is an early manifestation in patients
with hypertension, visceral obesity, and or
diabetes mellitus. 7 Studies both in animals
and man have shown that MRAs alone and or
in conjunction with an ACE-I and/or ARB are
effective in preventing myocardial fibrosis.8
There is a good correlation between serum
levels of aldosterone and the degree of
myocardial and vascular fibrosis as well as left
ventricular mass.9,10
The MRA spironolactone has been shown
to improve the echocardiographic indices of
diastolic function in patients with HFPEF. 11
MRAs have also been shown to improve
antioxidant reserves; reduce the formation
of reactive oxygen species (ROS); reduce
the formation of inflammatory cytokines
and signaling through the NF kappa B and
AP1 pathways; improve nitric oxide (NO)
availability, endothelial function, and the
number of circulating endothelial progenitor
cells (EPCs); and reduce vascular stiffness and
remodeling.12
In addition MRAs have been shown to
have a beneficial effect on the mechanisms
associated with a number of important
comorbid conditions in patients with HFPEF.
For example, the MRA eplerenone has recently
been shown to reduce the onset of atrial
fibrillation /flutter in patients with NYHA class
II HFREF in the EMPHASIS–HF trial,13 likely by
preventing left atrial fibrosis and remodeling.
Since atrial fibrillation is an important trigger
for the transition from hypertensive or diabetic
heart disease to HFPEF this finding may have
important implications for the outcome of
TOPCAT.
Aldosterone also appears to be of importance
in patients with uncontrolled or resistant
hypertension in that a MRA has been shown
to significantly reduce blood pressure in
these individuals 14 at high risk for recurrent
36
4
HFPEF. Visceral obesity as mentioned above
is also an increasingly important comorbid
condition in elderly patients with HFPEF. The
adipocyte releases substances such as Rac1
which stimulate the adrenal production of
aldosterone with its potential adverse effects
as outlined above. Serum aldosterone levels
are also elevated in patients with obstructive
sleep apnea, which is increasingly frequent in
patients with HFPEF and visceral obesity.
Aldosterone has also been shown to increase
albuminuria, podoycte damage, and
mesangial cell fibrosis while MRAs decrease
these pathological mechanisms 16,17 which
are important in CKD which is a frequent
comorbid condition in patients with HFPEF.
Aldosterone and/or MR activation are also
important in diabetes mellitus and have been
shown to cause pancreatic beta cell damage
and insulin resistance.18
Aldosterone and/or MR activation have also
been shown to be important in atherosclerosis
and MRAs have been shown to reduce the
extent of experimental atherosclerosis in
non-human primates 19 as well as reducing
the consequences of atherosclerosis such as
stroke.
The fact that many patients with HFPEF are
elderly and aldosterone levels are known to
decrease with age20 has led to the speculation
that a MRA might not be as effective in the
very old as in younger patients despite their
benefits as outlined above. However, there is
also a decrease with age in the expression of
the enzyme 11 Beta HSD2 21 which converts
cortisol, which can activate the MR, to
cortisone, which can not, such that in the
elderly cortisol may be an important activator
of the MR. Recent data has also shown that
MR expression in the vascular wall is increased
37
with age. 22 Thus, it is likely that despite a
reduction in serum aldosterone levels, that
activation of the MR is as or more important
in elderly patients with HFPEF than in younger
patients.
While as outlined above there is reason to
believe that a MRA will be effective in reducing
mortality and morbidity in patients with HFPEF
the relatively high incidence of comorbid
diabetes mellitus and or CKD in these patients
increases the risk of hyperkalemia. Therefore,
elderly patients with HFPEF need to be
carefully screened for diabetes mellitus and or
CKD, serially monitored for serum potassium
and renal function, and the dose of the MRA
adjusted accordingly. The development of
new oral non-absorbable potassium binding
polymers 23 and new non-steroidal MRAs, 24
which in preclinical studies appear to have a
more favorable sodium/potassium ratio than
either spironolactone or eplerenone, hold
the promise that in the near future the risk of
hyperkalemia associated with the use of a
MRA might be reduced and that this strategy
can be safely used in even higher risk patients
with HFPEF and CKD.
Conclusion.
In conclusion, the TOPCAT4,5 trial holds the
promise of altering the outcome of patients
with HFPEF. Its success will however depend
not only on the effectiveness of MRAs on
the myocardium and vascular wall, the
mechanisms associated with its important
comorbid conditions as outlined above, the
risk of hyperkalemia, but also on the conduct of
the trial, which will be analyzed using the intent
to treat principle, in maintaining compliance to
the protocol and in preventing patients from
dropping out.
TREATmEnT of PRESERvEd CARdiAC funCTion HEART fAiLuRE wiTH An
ALdoSTERonE AnTAgoniST: THE nHLBi ToPCAT TRiAL
References.
1.
Owan TE et al. Trends in prevalence and outcome of
heart failure with preserved ejection fraction. N Eng J
Med 2006;355:251-259.
2.
Yusuf S et al . Effects of Candesartan in patients with
chronic heart failure and preserved left-ventricular
ejection fraction: the CHARM-Preserved Trial. Lancet
2003;362:2338-45.
3.
4.
Massie BM et al. Irbersartan in patients with heart
failure and preserved ejection fraction. N Eng J Med
2008;359:2456-67.
Desai AS et al. Rationale and design of the treatment
of preserved cardiac function heart failure with an
aldosterone antagonist (TOPCAT ) trial: A randomized,
controlled study of spironolactone in patients with
symptomatic heart failure and preserved ejection
fraction. Submitted for publication.
in mild patients hospitalization and survival study in
heart failure (Emphasis-HF). Submitted for publication.
14. Chapman N et al . Effect of spironolactone on blood
pressure in subjects with resistant hypertension.
Hypertension 2007; 49: 839-845.
15. Pratt-Ubunama MN et al. Plasma aldosterone is related
to the severity of obstructive sleep apnea in subjects
with resistant hypertension. Chest 2007;131:453-459.
16. Shibata S et al. Podocyte as the target for aldosterone:
Roles of oxidative stress and sgk1. Hypertension 2007;
49:355-364.
17. Remuzzi G et al. The aggravating mechanisms of
aldosterone on kidney fibrosis. J Am SocNephrol. 2008;
19:1459-1462.
18. Mosso LM et al. A possible association between
primary aldosteronism and a lower beta cell function. J
Hypertension 2007; 25: 2125-2130.
5.
Clinical trials.gov. NCT 00094302
6.
Pitt B et al . The effect of spironolactone on morbidity
and mortality in patients with severe heart failure.
Randomized aldactone evaluation study investigators.
N Eng J Med 1999;341: 709-717.
7.
Martos R et al. Diastolic heart failure: Evidence of
increased myocardial collagen turnover linked to
diastolic dysfunction. Circulation 2007;115: 888-895.
20. Weidmann P et al. Effect of aging on plasma renin and
aldosterone in normal man. Kidney Int. 1975; 8: 325333.
8.
Brilla C. Renin-angiotensin-aldosterone system and
myocardial fibrosis. Cardiovascular Res 2000; 47:1-3.
9.
Yoshida C et al. Role of aldosterone concentration
in regression of left ventricular mass following
antihypertensive medication. Journal of Hypertension
2011;29: 367-363.
21. Henschowski J et al. Age-dependent decrease
in 11beta-hydroxysteroid dehydrogenase type 2
(11beta HSD2) activity in hypertensive patients. Am J
Hypertension 2008; 21: 644-649.
10. Duprez D et al. Inverse relationship between
aldosterone and large artery compliance in chronically
treated heart failure patients. European Heart Journal
1998;19:1371`-1376.
11. MottramPM et al. The effect of aldosterone antagonism
on myocardial dysfunction in patients with diastolic
heart failure. Circulation 2004;110:558-565.
12. Pitt B. The role of mineralocorticoid receptor
antagonists (MRAs) in very old patients with heart
failure. In press Heart failure reviews.
13. Swedberg K et al. Eplerenone and atrial fibrillation in
mild systolic heart failure–results from the eplerenone
19. Takai S et al. Eplerenone inhibits atherosclerosis in
nonhuman primates. Hypertension 2005; 46: 11351139.
22. Krug AW et al. Elevated mineralocorticoid receptor
activity in aged rat vascular smooth muscle
cells promotes a proinflammatory phenotype via
extracellular signal -regulated kinase ½ mitogen–
activated protein kinase and epidermal growth factor
receptor–dependent pathways. Hypertension 2010; 55:
1476-1483.
23. Pitt B et al. Evaluation of the efficacy and safety of
RLY5016, a polymeric potassium binder, in a doubleblind, placebo-controlled study in patients with chronic
heart failure (the Pearl-HF) trial. European Heart J 2011;
32: 820-828.
24. Fagart J et al. A new mode of mineralocorticoid receptor
antagonism by a potent and selective nonsteroidal
molecule. J Biol. Chem. 2010; 285: 29932-29940.
38
4
Notes
39
Michele Borgarelli
DVM, PhD, DipECVIM-CA (Cardiology)
Associate Professor
Kansas State University
College of Veterinary Medicine
1800 Denison Avenue
Manhattan, Kansas, USA.
contact: [email protected]
Michele Borgarelli is Doctor in Veterinary Medicine, graduate of the Veterinary School
of Torino in 1989. Since 1990 he has developed cardiology, abdominal ultrasound and
internal medicine training in Italy, Europe and the USA. From 1995 to 2007 he was
temporary Professor and then Assistant Professor (internal medicine and cardiology)
at the Faculty of Veterinary Medicine University of Torino. Since 2009 he is Associate
Professor of cardiology at Kansas State University. Diplomate of the European College
Veterinary Internal Medicine (Cardiology) in 1999, Dr. Borgarelli earned in 2005 his
PhD in clinical sciences with a thesis on “Mitral Valve Disease in dogs”.
Since 1991, he is member of the board of the European Society of Veterinary
Cardiology (ESVC). From 2004 until 2007 he was President of Italian Society of
Veterinary Cardiology. Since 2009, he is the President of the European College of
Veterinary Internal Medicine.
Author of 60 scientific publications, Dr. Borgarelli is actually in clinical research
programs on pathophysiology and therapy of heart failure, and chronic mitral valve
disease in dogs.
40
4
THE DELAY STUDY
(DELay of Appearance of sYmptoms of canine degenerative mitral
valve disease treated with Spironolactone and Benazepril)
Chronic degenerative mitral valve disease
(Cdvd or dmvd) is the most common
acquired cardiovascular disease in the dog
representing 75% of all cardiovascular
disease in these species. The disease is
characterized by a long pre-clinical period.
Asymptomatic dogs are a non homogeneous
group, including patients with very mild
disease and others that present a more
advance disease and are more likely to
develop clinical signs of HF, even though they
have never developed HF. The heterogeneity
of this group of dogs may be an important
reason for the conflicting data concerning
neuro-hormonal activation and efficacy
of early treatment for dmvd presented
in the veterinary literature for dogs with
asymptomatic disease. Preliminary data
from our laboratory showed that plasma
aldosterone levels are significantly more
elevated in asymptomatic affected dogs
compared to a control group of healthy dogs.
This observation suggests that aldosterone
escape mechanism can be present in the early
course of Cdvd, and that aldosterone can
play a role in the progression of the disease.
It would also confirm data from dogs with
experimentally induced Cdvd suggesting that
blocking renin-angiotensin system (RAAS) in
dogs may necessitate multiple drugs such an
association of an ACE-I and spironolactone.
41
The recognition that asymptomatic dogs are
an heterogeneous group of dogs underline the
importance of developing some biomarkers
able to identify the patients at higher risk
for developing CHF, these patients could be
the patients who may benefit from an early
treatment. Proposed prognostic indicators
for increased risk of death or progression
of Cdvd are represented by age, gender,
intensity of heart murmur, degree of valve
prolapse, severity of valve lesions, degree
of mitral valve regurgitation and left atrial
enlargement. data from our group suggest
that the left atrial enlargement represent the
most independent predictor of progression
or death for dogs with both symptomatic
and asymptomatic disease. A recent study
conducted on 72 asymptomatic dogs with
mmdv showed that the N-terminal fragment
of proBNP (NT-proBNP) is correlated with the
severity of mitral regurgitation. In this study a
cut off of 466 ρmol/L had 80% sensitivity and
76% specificity with an area under the curve
of 0.81 in predicting 12-month progression
(cardiac death or HF). Recently troponin I
(TnI) has been reported being associated
with the severity of Cdvd in dogs. In this
study TnI has been suggested representing
a biomarker of myocardial remodeling for
this disease. Although this data appear
very promising, further studies are needed
THE DELAY STUDY
to confirm the value of BNP and TnI in
distinguishing, among asymptomatic dogs,
those that will progress to HF.
These observations justify the investigation
of benefit of spironolactone plus benazepril,
through aldosterone blockade and ACE
inhibition, in delaying the onset of HF caused
by dmvd (positive effect on the clinical signs
and mortality).
The dELAY study will include 240 dogs
with advanced pre-clinical Cdvd ISACHC
class 1b or ACvIm consensus stage B2. The
primary aims for this study are to evaluate the
efficacy of spironolactone in combination with
benazepril on delaying time of onset of overt
heart failure and to evaluate if NT-proBNP and
TnI are clinically relevant biomarkers to predict
time of onset of heart failure. The study has
started on November 2010 and enrollment will
terminate on december 2012. End of the study
is december 2015.
References.
1.
Häggström J, Höglund K, Borgarelli M. An update on
treatment and prognostic indicators in canine myxomatous
mitral valve disease. J Small Anim Pract. Sep 2009;50 Suppl
1:25-33.
2.
Häggström J, Kvart C, Pedersen HD. Acquired valvular
heart disease. In: Ettinger SJ, Feldman EC, eds. Textbook
of Veterinary Internal Medicine. 6th ed. St. Louis: Elsevier
Saunders; 2005:1022-1039.
3.
Borgarelli M, Savarino P, Crosara S, et al. Survival
characteristics and prognostic variables of dogs with mitral
regurgitation attributable to myxomatous valve disease. J Vet
Intern Med. Jan-Feb 2008;22(1):120-128.
4.
Kvart C, Häggström J, Pedersen HD, et al. Efficacy of
enalapril for prevention of congestive heart failure in dogs
with myxomatous valve disease and asymptomatic mitral
regurgitation. J Vet Intern Med. Jan-Feb 2002;16(1):80-88.
5.
6.
Chetboul V, Serres F, Tissier R, et al. Association of plasma
N-terminal pro-B-type natriuretic peptide concentration
with mitral regurgitation severity and outcome in dogs with
asymptomatic degenerative mitral valve disease. J Vet Intern
Med. Sep-Oct 2009;23(5):984-994.
Atkins CE, Keene BW, Brown WA, et al. Results of the
veterinary enalapril trial to prove reduction in onset of heart
failure in dogs chronically treated with enalapril alone for
compensated, naturally occurring mitral valve insufficiency. J
Am Vet Med Assoc. Oct 1 2007;231(7):1061-1069.
7.
Atkins C, Bonagura J, Ettinger S, et al. Guidelines for the
Diagnosis and Treatment of Canine Chronic Valvular Heart
Disease. J Vet Intern Med. Sep 22 2009.
8.
Häggström J, Hansson K, Kvart C, Pedersen HD,
Vuolteenaho O, Olsson K. Relationship between different
natriuretic peptides and severity of naturally acquired
mitral regurgitation in dogs with chronic myxomatous valve
disease. J Vet Cardiol. May 2000;2(1):7-16.
9.
Moesgaard SG, Pedersen LG, Teerlink T, Häggström J,
Pedersen HD. Neurohormonal and circulatory effects of
short-term treatment with enalapril and quinapril in dogs with
asymptomatic mitral regurgitation. J Vet Intern Med. Sep-Oct
2005;19(5):712-719.
10. Bernay F., Bland J., Häggström J., et al. Efficacy of
Spironolactone on Survival in Dogs with Naturally Occuring
Mitral Regurgitation Caused by Myxomatous Mitral Valve
Disease. J Vet Intern Med 2010; Jan 25.
11. Hansson K, Häggström J., Kvart C and Lord P. Left atrial
to aortic root indices using two-dimensional and M-mode
echocardiography in Cavalier King Charles Spaniels with and
without left atrial enlargement Vet Radiol Ultrasound 2002,
43(6): 568-575.
12. Cornell C.C. Kittleson M.D., Della Torre P. et al. Allometric
scaling of M-mode cardiac measurements in normal adult
dogs J Vet Intern Med 2004; 18: 311-318.
42
4
Notes
43
Notes
44
4
Ceva European
Students
Cardiology
Award
1st - 2nd of October 2011
Bordeaux - France
The Ceva European Students Cardiology Award is designed to help improve
cardiology knowledge among students with an interest in companion animal
internal medicine throughout Europe. This cardiology award is specifically
designed for veterinarians currently in residency or internship.
Jury
The Jury is made up of 6 independent international experts in cardiology
from Veterinary and Human medicine.
The selection has been made based on the originality of the case,
description of and follow up (scientific evaluation) and literature review.
Two awards are offered during the Cardiology Symposium:
The Resident Award is a registration to the ECVIM Congress in Maastricht,
including flight tickets and accommodation for the duration of the congress
and following weekend.
The Internship Award is a registration to the SEVC (Southern European
Veterinarian Conference) in Barcelona, including flight tickets and
accommodation for the duration of the congress and following weekend.
Jury members
Rebecca STEPIEN
DVM, MS, DipACVIM
(Cardiology) - USA
Nuala SUMMERFIELD
BVM&S, DipACVIM
(Cardiology), MRCVS - UK
Michele BORGARELLI
DVM, PhD, DipECVIM-CA
(Cardiology) - USA
Frédéric JAISSER
MD, PhD, Research
Director - France
Mark OYAMA
DVM, DipACVIM
(Cardiology) - USA
Faiez ZANNAD
MD, PhD
France
FIRST AWARDED
Jordi López-Alvarez
LltVet MRCVS
Resident ECVIM (Cardiology),
April 2008 - May 2011
University of Liverpool,
Small Animal Teaching Hospital
Leahurst, Chester High Road,
Neston, UK
[email protected]
TUTOR
Joanna Dukes-McEwan
BVMS (Hons), MVM, PhD, DVC,
DipECVIM-CA(Cardiology), MRCVS
Senior Lecturer in Veterinary Cardiology
University of Liverpool, UK
[email protected]
Jordi graduated as Licenciat in Veterinary Medicine from the Universitat Autònoma
de Barcelona (Spain) in 2003. During his studies, he spent 2 years in the École
Nationale Vétérinaire d’Alfort, Paris (France) and worked in first opinion practice
there, before going back to Spain. He then completed an 18-months internship at the
Hospital Clínic Veterinari (HCV-UAB) in Barcelona, finishing in October 2004. After
3½ years working in private practice in Barcelona he moved to Liverpool to take the
position as Resident in small animal Cardiology. Jordi is currently working towards his
PhD about the natural history of mitral valve disease in dogs, at the Royal Veterinary
College in London.
46
4
Chasing fluid away! - Treating the progressive congestive
heart failure patient.
Case study of myxomatous degenerative valvular disease
in a German Shepherd dog
Jordi López-Alvarez a, b
Abstract.
Myxomatous degenerative valvular disease
(MDVD) is the most common acquired cardiac
disease in small breed dogs, characterized
b y s l o w a n d p ro g re s s i v e d e g e n e r a t i v e
thickening of the valvular leaflets, frequent
rupture of minor order chordae tendinae
and secondary valvular prolapse. The loss
of leaflet coaptation generates a regurgitant
orifice that results in the regurgitation volume
flowing backwards into the atrium in each
ventricular systole, causing progressive
volume overload, increased diastolic filling
pressures and eventual development of
congestive heart failure. German Shepherd
dogs (GSD) show less florid mitral valve
thickening and the main cause of their valvular
incompetence may be primary valvular
prolapse. In large breeds compared with small
breed dogs, MDVD has faster progression
with worse hemodynamic consequences,
leading frequently to myocardial failure,
arrhythmias and poor outcomes. It is very
important to consider this valvular cause
of volume overload in large breed dogs
to avoid misdiagnosing idiopathic dilated
cardiomyopathy, as both conditions share
similarities in their clinical presentation.
Treating congestive heart failure (CHF) is
palliative. The underlying disease will continue
to progress and different strategies to control
edema, effusions and clinical signs are
47
required. Different diuretic classes to perform
sequential nephron blockade, up-titration of
heart rate medication, afterload reduction and
improvement of abdominal discomfort are
some of the available options. This case, a 4
years old GSD with MDVD, atrial fibrillation,
myocardial failure, post-capillary pulmonary
hypertension and CHF, demonstrates this
approach.
Running header: MDVD in a GSD
Keywords: Congestive heart failure, diuretics, sequential
nephron blockade, atrial fibrillation, torasemide.
a
Small Animal Teaching Hospital, University of Liverpool,
School of Veterinary Science, Leahurst, Chester High
Road, Neston, CH64 7TE, UK
b
Present address: The Royal Veterinary College,
Hawkshead Lane, North Mymms, Hatfield, Herts AL9
7TA, United Kingdom.
Case.
A 4 years old, neutered male German Shepherd
dog (GSD) was referred for progressive
exercise intolerance and tachypnoea over the
previous month. No history of previous illnesses
was reported and he was fully wormed and
vaccinated.
On physical examination, the dog was bright,
alert and responsive and the body condition
was adequate. He was tachypnoeic (50 rpm)
and presented marked abdominal distension
with positive fluid thrill and hepatojugular reflux.
The mucous membranes were pink and moist,
Chasing fluid away! - Treating the progressive congestive heart
failure patient.
Case study of myxomatous degenerative valvular disease in a German Shepherd dog
with normal capillary refill time. He presented
irregularly irregular tachycardia (240 bpm) with
variable pulse volume and significant pulse
deficits (pulse rate <100/minute). Auscultation
of the chest revealed a variable grade II-III/
VI left apical systolic heart murmur, and no
adventitious but harsh bronchovesicular lung
sounds. The body temperature was normal at
38.4°C.
Systolic blood pressure, indirectly assessed
with a Doppler device, was adequate at
150 mmHg. Hematology and biochemistry
profile were within normal ranges, showing
only mild elevation of liver enzymes. Severe
cardiomyocyte damage was confirmed
with cTnI measurement of 1.18 ng/mL (ref
val. <0.15). Six lead electrocardiogram was
diagnostic of atrial fibrillation, and presented
ST segment coving with border-line high
QRS complex duration, considered a nonspecific sign of left ventricular enlargement/
hypertrophy and myocardial hypoxia
(Figure 1). Abdominocentesis revealed the
presence of a modified transudate. Doppler
echocardiography showed subjectively mild
thickening and prolapse of the mitral valve
leaflets, severely hypokinetic and dilated left
ventricle and severe left atrium and pulmonary
venous dilation. Color Doppler showed
moderate to severe mitral regurgitation (Figure
2). Mild tricuspid regurgitation with slightly
elevated velocities was suggestive of mild
post-capillary pulmonary hypertension. The
left ventricular systolic function was severely
impaired. The diastolic left ventricular filling
pressures were estimated to be elevated,
suggestive of left sided congestive heart failure
(CHF). Mild pleural and pericardial effusions
were present, consistent with right sided
CHF. The final diagnosis was myxomatous
degenerative valvular disease (MDVD) with
atrial fibrillation, myocardial failure, mild
pulmonary hypertension and biventricular
CHF.
The dog was admitted to the Hospital
for stabilization. A cephalic catheter was
placed and intravenous furosemide (1 mg/
kg) administered hourly until improvement of
the respiratory clinical signs was detected.
Adjunctive therapy for CHF at this stage
consisted of topical nitroglycerine 2% unguent
applied every 4 hours, pimobendan (0.3 mg/
kg twice daily) and spironolactone (2 mg/kg
once daily). The dog was started on digoxin
(3 μg/kg twice daily) and diltiazem (2 mg/kg
three times daily) for heart rate control. Once
the respiratory rate reduced to <40 rpm,
nitroglycerine was stopped and furosemide
reduced to four times daily and subsequently
changed to oral furosemide tablets (2 mg/kg
three times daily). At this stage the heart rate
was stable at 140-150 bpm, and improved
peripheral pulses (<130/min), reduced body
weight and decreased abdominal distension
were noted.
Thoracic radiographs revealed cardiomegaly
(predominantly left sided), generalized mild
interstitial lung pattern and mildly congested
lobar veins, all suggestive of residual left sided
CHF (Figure 3). Biochemistry profile showed
mild azotemia (iatrogenic pre-renal) and
benazepril treatment was initiated (0.5 mg/
kg once daily). The dog was discharged three
days later with oral medication.
The owner was instructed to monitor signs of
progression at home, assessing body weight,
respiratory and heart rates, which were also
recorded at each revisit. An initial Holter
monitor was performed to assess ventricular
rate control at home in order to adjust the
antiarrhythmic medication. Biochemistry
48
4
profile, mainly to assess kidney function and
electrolytes, was monitored after each new
diuretic introduction or increase of their doses.
cTnI was measured to assess severity of
disease and as prognostic indicator. Digoxin
dose was optimized to achieve trough levels
between 0.5 and 0.9 ng/mL. The consequent
follow-ups were planned bearing this scheme
in mind (see Figure 4).
The dog showed no CHF signs for five months,
although increased left ventricular filling
pressures on echocardiography four months
after initial stabilization suggested subclinical
decompensation, and the doses of benazepril
and furosemide were increased. Signs of
right sided CHF were present 5 months after
initial presentation and consequently the
furosemide dose was increased and a low
dose of amlodipine (0.1 mg/kg) started, aiming
to further reduce mitral regurgitant fraction by
lowering afterload. At 6 months, the heart rate
was stable but the clinical signs had progressed
(increased body weight and respiratory rate)
and the doses of amlodipine and furosemide
were increased again. At 7 months, right sided
CHF worsened and abdominocentesis was
performed to improve the comfort of the animal.
Hydrochlorothiazide was added (1 mg/kg twice
daily); this improved the clinical signs but mild
dilutional hyponatremia was suspected and
diuretic therapy was slightly modified. At 8
months, increased pulmonary hypertension was
evident on echocardiographic examination and
the right sided CHF was considered refractory to
standard therapy. Torasemide (0.2 mg/kg once
daily) was started. Sildenafil was also proposed
but the owners refused due to economic
constrains. The clinical signs improved and
remained in stable right sided CHF for five
months. One year after initial presentation the
dog returned with marked ascites, reduction in
49
body condition and paroxysms of soft cough.
Abdominocentesis was then performed and
repeated one month later. Torasemide dose
was increased and, due to impoverishment of
body condition, fish oil capsules were begun.
The dog continued to be moderately ascitic
but the owner was satisfied with the dog’s
quality of life during the subsequent revisits.
However, the dog was euthanized 2 years after
initial presentation due to refractory CHF and
deterioration of the quality of life.
Discussion.
Myxomatous degenerative valvular disease is
the most common cardiac disease in small breed
dogs. It is a relatively benign condition in these
breeds, characterized by an unpredictable but
usually slowly progressive degeneration of the
valvular apparatus.1 Histologically, this process
is characterized by an absence of inflammatory
infiltrates, proliferation of valvular interstitial
and endothelial cells, abnormal deposition of
extracellular matrix and disorganization of the
collagen network. These structural changes
are responsible for the typical disrupted
macroscopic aspect of the affected valves, with
thickening of the leaflets, loss of coaptation
and chordae tendinae rupture. This valvular
incompetence generates hemodynamic
consequences consistent with volume
overload and increased filling pressures that
can eventually lead to CHF. Large breed dogs
also suffer MDVD, but the progression seems
to be much faster and more severe for these
breeds, with less valvular structural changes
but worse hemodynamic consequences,
leading frequently to myocardial dysfunction,
arrhythmias and poor outcomes. Valvular
prolapse rather than chronic degeneration of
the leaflets might be the cause of their valvular
incompetence. 2 This is a relatively subtle
failure patient.
change that requires careful evaluation by an
experienced and observant echocardiographist
for its diagnosis. The resulting volume overload
increases preload, stimulating contraction by
the Frank-Starling mechanism, and the mitral
regurgitation reduces afterload. Increased
preload and reduced afterload results in
hyperdynamic ventricular contraction and
reduced peak systolic wall stress. 3 This
stimulates replication of sarcomeres in series
(eccentric hypertrophy), but this mechanism
is still insufficient to normalize the increased
diastolic wall stress,4 and might explain why
large breed dogs develop myocardial systolic
dysfunction more prematurely and acutely than
small breeds.5
Dilated cardiomyopathy is a disease of the
cardiac muscle characterized by reduced
systolic function. It manifests as progressive
dilation of the cardiac chambers due to
volume overload, which frequently leads to
supraventricular arrhythmias, namely atrial
fibrillation. Familial predisposition has been
suspected in large breed dogs for a long time,
and in recent years increasing evidence points
towards a genetic origin, with a few genetic
mutations already published.6,7 However, until
more accurate genetic tests are available, its
diagnosis still needs to be done by exclusion of
diseases sharing similar clinical presentation.8
Neither a genetic basis nor a familial
predisposition for DCM has been suspected
in GSDs, and furthermore some studies found
that DCM is a rare condition for this breed, 9
suggesting that exquisite attention is required
to avoid misdiagnosis.
Heart failure is a clinical syndrome characterized
by the inability of the heart pump to make blood
advance, and CHF is the result of backwards
accumulation of fluid and the neuro-hormonal
compensatory mechanisms activated. Due
to the distribution of the vascular system,
detection of CHF from the right side of the
heart is performed by clinical examination
(eg: distension of the jugular veins, positive
hepatojugular reflux, ascitis). Left sided CHF
can be first suspected by clinical examination
and auscultation, but the definitive assessment
of the severity of the condition relies on
radiology or echocardiography. It has now been
shown that the diastolic filling pressures of
the left ventricle can be estimated by Doppler
echocardiography, measuring the transmitral
inflow pattern velocities (E and A waves) and
the duration of the isovolumic relaxation time
(IVRT). Those parameters are dependent on
loading conditions and heart rate,10 but the ratio
E:IVRT is not, and seems to be very accurate
for the detection of CHF. 11 We used this
echocardiographic measurement to monitor left
sided CHF in this case, which was very practical,
as it limited the amount of thoracic radiographs,
which due to the presence of pleural effusion,
would not have always been easy to interpret.
Applying the Bernouilli equation on the systolic
tricuspid regurgitation and the diastolic
pulmonic insufficiency velocities gives a
good indication of the pulmonary circulation
pressures and allows them to be followed up
over time. This is another interesting application
of echocardiography, which helped in the
assessment of this case, as it negates the need
for invasive right sided cardiac catheterization.
Pulmonary hypertension can be classified
as either pre-capillary, when primary lung
pathology increases arterial resistance, or postcapillary, when there is increased pressures
in the left atrium that increase the pressure
in the pulmonary circulation. Post-capillary
hypertension is recognized in 14-31% of cases
of chronic left sided cardiac dysfunction in
dogs. 12 This is best treated by reducing the
50
4
left atrial pressures, but in some advanced
cases this is deemed to be difficult and adding
arterial vasodilators selective for pulmonary
circulation (ie: phosphodiesterase V inhibitors)
can be beneficial. In this case, sildenafil was
recommended, but due to economic reasons
the owner decided against it.
In the presence of CHF, several compensatory
neuro-hormonal mechanisms are activated
in response to low cardiac output. Those
alleviate the clinical signs in first instance,
but contribute with the progression of the
disease when chronically activated inducing
vasoconstriction, edema and increased
blood volume.13 These mechanisms include:
sympathetic system activation, with
vasoconstriction and positive chronotropic
a n d i o n o t ro p i c c a rd i a c e ff e c t s ; re n i n angiotensin-aldosterone system (RAAS)
activation, with sodium and water retention,
cardiac remodeling and vasoconstriction;
secretion of vasopressin promoting
dilutional hyponatremia (correlating with
adverse outcome in CHF) may aggravate
cardiac remodeling and peripheral vascular
resistance; 14 release of endothelin-1 in
response to shear stress, hypoxia, angiotensin
and vasopressin eliciting vasoconstriction
contributing to systemic and pulmonary
hypertension amongst others.15 The treatment
goal for CHF is triple: alleviate clinical signs,
stop progression of the disease and prevent
complications. To achieve this goals is required
the use of diuretics, inotropic support and RAAS
blockers. High dose diuretic monotherapy
often yields inadequate natriuretic response
and resistance (distal nephron hypertrophy,
R A A S a c t i v a t i o n , re d u c e d re n a l f l o w,
decreased GI absorption) and combination of
different diuretic classes, named sequential
51
nephron blockade, is recommended to avoid
this resistance. Spironolactone is a weak
diuretic and does not significantly increases
urine production,16 but it might potentiate the
effect of other diuretics. It has been shown that,
probably due to its anti-aldosterone effects, it
confers improved survival. 17 Torasemide is a
loop diuretic with longer action duration than
furosemide, adjunctive anti-aldosterone effects,
better GI absorption and it has been associated
with reduced mortality in people. There are
just a couple of studies in veterinary medicine
supporting its use,18,19 but in this case it resulted
in marked improvement of the clinical signs.
A t r i a l f i b r i l l a t i o n i s t h e m o re c o m m o n
supraventricular arrhythmia in large dogs 9 in
part because of their bigger atrial mass. 20 It
is caused by multifocal ectopic triggers with
reentrant waves,21 and enhanced by fibrosis,
inflammation and wall stretch. Atrial fibrillation
suppresses around 20% of the atrioventricular
filling by preventing atrial contraction, which
can precipitate or worsen CHF, and also can
induce myocardial failure 22 due to the fast
heart rate (tachycardiomyopathy). Rate rather
than rhythm control is the favorite strategy
in the presence of structural heart changes,
and this is best achieved combining digoxin
and diltiazem.23 Digoxin dose was optimized
to achieve trough levels between 0.5 and 0.9
ng/mL, which is lower than the laboratory
reference value, but it has been shown to have
optimal parasympathetic effect and reduced
toxicity compared with higher levels.24,25
Treatment of chronic cases of MDVD can be
somehow frustrating, but knowledge of the
pathophysiological mechanisms involved and
anticipation of possible complications can
alleviate clinical signs and offer an adequate
quality of life to our patients.
failure patient.
Figure & Legends.
Figure 1: ECG at presentation: standard six lead ECG diagnostic of atrial fibrillation, at the origin of the irregular tachycardia with pulse deficits
detected on physical examination. Notice ST segment coving with border-line QRS complex duration, considered unspecific signs of LV
enlargement/hypertrophy and myocardial hypoxia.
Leads I, II and III, paper speed 50 mm/s, sensitivity 1 mV= 1 cm. Six lead ECG recorded with the patient in right lateral recumbency.
ECG report:
Parameter
Presentation
Reference values
Heart rate
220 bpm
70-160 bpm
Rhythm
Irregularly irregular
SR/SA
P wave
Absent
<0.4 mV x 0.04 s
P-R interval
n/a
0.06 – 0.13 s
R wave height
2.8 mV
<3.0 mV
QRS duration
0.06 s
<0.06 s
Q-T interval
0.16 s
0.15 – 0.25 s
ST Segment
Coving
Not elevated or depressed
T wave
<25%, negative
<25% height R wave
MEA
+80o
+40o - +100o
ECG diagnostic
Atrial fibrillation
52
4
Figure 2: Doppler echocardiography at presentation. End diastolic (A) and end-systolic (B) frames obtained from the right parasternal, long
axis, 4 chamber view; these images show a rounded, volume overloaded left ventricle with nodular thickening of the atrioventricular valves and
prolapse. (C) Left ventricular M-mode obtained from the right parasternal, short axis view at the base of the papillary muscles; this image show
reduced radial motion. (D) Doppler color map of the left atrium in mid systole obtained from the left apical, 4 chamber view; this image show
moderate to severe MR.
Figure 3:
Dorsoventral (A) and
lateral (B) radiographic
projections
obtained after
initial stabilization.
These films show
cardiomegaly
(predominant left
sided enlargement)
with dorsal
displacement of the
trachea, generalized
mild interstitial lung
pattern (predominantly
perihilar) and mildly
congested lobar
veins (black arrow),
suggestive of residual
left-sided CHF.
53
failure patient.
Figure 4: Graph representing the progression of the body weight and the different actions taken during the follow up of the case. The blue arrows
represent cTnI measurement, the green arrows trough digoxin seric levels and the thick red arrows abdominocentesis (with the amount of
abdominal fluid retrieved in litres). The capital letters indicate treatment modifications. The purple * symbol represents 24 hours Holter monitor
recordings.
Abbreviations.
bpm
Beats per minute
CHF
Congestive heart failure
cTnI
Cardiac troponin I
DCM
Dilated cardiomyopathy
GSD
German Shepherd dog
MDVD
Myxomatous degenerative valvular
disease
RAAS
Renin-angiotensin-aldosterone
system
rpm
Respirations per minute
References.
1.
Borgarelli M, Haggstrom J. Canine degenerative
myxomatous mitral valve disease: natural history, clinical
presentation and therapy. Vet Clin North Am Small Anim
Pract 2010;40:651-663.
2.
Borgarelli M, Zini E, D’Agnolo G, et al. Comparison of
primary mitral valve disease in German Shepherd dogs
and in small breeds. J Vet Cardiol 2004;6:27-34.
3.
Bonagura JD, Schober KE. Can ventricular function be
assessed by echocardiography in chronic canine mitral
valve disease? J Small Anim Pract 2009;50 Suppl 1:1224.
4.
Grossman W, Jones D, McLaurin LP. Wall stress and
patterns of hypertrophy in the human left ventricle. J Clin
Invest 1975;56:56-64.
5.
Borgarelli M, Tarducci A, Zanatta R, et al. Decreased
systolic function and inadequate hypertrophy in large and
small breed dogs with chronic mitral valve insufficiency.
J Vet Intern Med 2007;21:61-67.
6.
Meurs K. A Splice Site Mutation in a Gene Encoding for a
Mitochondrial Protein Associated With the Development
of Dilated Cardiomyopathy in the Doberman Pinscher. In:
Proceedings ACVIM Forum, Anaheim 2010.
54
4
7.
8.
9.
M a u s b e rg T B , We s s G , S i m a k J , e t a l . A l o c u s
on chromosome 5 is associated with dilated
cardiomyopathy in Doberman Pinschers. PLoS One
2011;6:e20042.
Dukes-McEwan J, Borgarelli M, Tidholm A, et al.
Proposed Guidelines for the Diagnosis of Canine
Idiopathic Dilated Cardiomyopathy. J Vet Cardiol
2003;5:7-19.
Tidholm A, Jonsson L. A retrospective study of canine
dilated cardiomyopathy (189 cases). J Am Anim Hosp
Assoc 1997;33:544-550.
10. S c h o b e r K E , B o n a g u r a J D , S c a n s e n B A , e t a l .
Estimation of left ventricular filling pressure by use of
Doppler echocardiography in healthy anesthetized
dogs subjected to acute volume loading. Am J Vet Res
2008;69:1034-1049.
11. Schober KE, Hart TM, Ster n JA, et al. Detection
o f c o n g e s t i v e h e a r t f a i l u re i n d o g s b y D o p p l e r
echocardiography. J Vet Intern Med 2010;24:13581368.
12. Stepien RL. Pulmonary arterial hypertension secondary
to chronic left-sided cardiac dysfunction in dogs.
J Small Anim Pract 2009;50 Suppl 1:34-43.
13. Oyama MA. Neurohormonal activation in canine
degenerative mitral valve disease: implications on
pathophysiology and treatment. J Small Anim Pract
2009;50 Suppl 1:3-11.
14. Chatterjee K. Neurohormonal activation in congestive
heart failure and the role of vasopressin. Am J Cardiol
2005;95:8B-13B.
15. Ray L, Mathieu M, Jespers P, et al. Early increase in
pulmonary vascular reactivity with overexpression of
endothelin-1 and vascular endothelial growth factor
in canine experimental heart failure. Exp Physiol
2008;93:434-442.
16. Jeunesse E, Woehrle F, Schneider M, et al. Effect of
spironolactone on diuresis and urine sodium and
55
potassium excretion in healthy dogs. J Vet Cardiol
2007;9:63-68.
17. Bernay F, Bland JM, Haggstrom J, et al. Efficacy of
mitral valve disease. J Vet Intern Med 2010;24:331-341.
18. Hori Y, Takusagawa F, Ikadai H, et al. Effects of oral
administration of furosemide and torsemide in healthy
dogs. Am J Vet Res 2007;68:1058-1063.
19. Caro-Vadillo A, Ynaraja-Ramirez E, Montoya-Alonso
JA. Effect of torsemide on serum and urine electrolyte
levels in dogs with congestive heart failure. Vet Rec
2007;160:847-848.
20. Guglielmini C, Chetboul V, Pietra M, et al. Influence of left
atrial enlargement and body weight on the development
of atrial fibrillation: retrospective study on 205 dogs. Vet
J 2000;160:235-241.
21. Brundel BJ, Melnyk P, Rivard L, et al. The pathology of
atrial fibrillation in dogs. J Vet Cardiol 2005;7:121-129.
22. Ravens U, Davia K, Davies CH, et al. Tachycardiainduced failure alters contractile properties of canine
ventricular myocytes. Cardiovasc Res 1996;32:613621.
23. Gelzer AR, Kraus MS, Rishniw M, et al. Combination
therapy with digoxin and diltiazem controls ventricular
rate in chronic atrial fibrillation in dogs better than digoxin
or diltiazem monotherapy: a randomized crossover
study in 18 dogs. J Vet Intern Med 2009;23:499-508.
24. Slatton ML, Irani WN, Hall SA, et al. Does digoxin provide
additional hemodynamic and autonomic benefit at
higher doses in patients with mild to moderate heart
failure and normal sinus rhythm? J Am Coll Cardiol
1997;29:1206-1213.
25. Borgarelli M, Tarducci A, Tidholm A, et al. Canine
i d i o p a t h i c d i l a t e d c a r d i o m y o p a t h y. P a r t I I :
pathophysiology and therapy. Vet J 2001;162:182-195.
Adriaan A. Voors
MD, PhD
Professor of Cardiology
University Medical Center Groningen
Director of the Heart Clinic
Director of the Department of
Echocardiography of the University Medical
Center,
Groningen, Netherlands.
Adriaan Voors completed medical school in 1994 in Utrecht, the Netherlands. In 1997, he
defended his PhD thesis entitled “Risk Factors, Endothelial Function and Clinical outcome after
Coronary Bypass Surgery” (promotor: Professor W.H. van Gilst, University of Groningen, the
Netherlands). He completed his training in internal medicine in Utrecht (Professor J.B.L.
Hoekstra) and his training in cardiology in Nieuwegein, the Netherlands (Dr W. Jaarsma).
In July 2003, Dr. Voors started working as a Cardiologist, and became staff member of the
department of cardiology of the University Medical Center Groningen. Currently, Dr. Voors
is director of the Heart Failure Clinic and director of the Department of Echocardiography
of the University Medical Center Groningen. In 2007, he became Established Clinical
Investigator of the Netherlands Heart Foundation, Associate Professor of Cardiology,
President of the Working group of Heart Failure and a board member of the Working
group of Pharmacotherapy of the Dutch Society of Cardiology. In May 2010, he
became Professor of Cardiology at the University Medical Center Groningen.
Professor Voors (co)authored more than 200 peer-reviewed papers and several books
and chapters, mainly on heart failure, and he is deputy editor of the European Journal
of Heart Failure and an editorial board member of the Journal of the American College
of Cardiology, Netherlands Heart Journal and Cardiovascular Drugs and Therapy. He is
principal investigator of 3 phase II heart failure trials, and executive/steering committee
member of another 8 heart failure trials.
56
4
Biomarkers: what are the practical uses and what can
be expected in the coming years?
How to use Biomarkers in cardiology?
B i o m a r k e r s h a v e b e c o m e i n c re a s i n g l y
i m p o r t a n t i n the treatment of patients
with cardiovascular disease. Due to major
technological advances, it has become easier
to find novel biomarkers that are increased in
specific patients and their diseases. In heart
failure, a large amount of biomarkers have
become available and are can be used for
several purposes.(1)
1. Diagnosis.
Biomarkers might be of help in the diagnosis
of several diseases, including heart failure. For
example, in response to stretch or pressure,
the heart releases natriuretic peptides. (2)
Therefore, greater concentrations of natriuretic
peptides, such as BNP or NT-proBNP, indicate
that the heart is “under pressure”. In patients
that are admitted to the hospital with acute
breathlessness, natriuretic peptides can be
used to diagnose heart failure. In addition,
several groups of markers might indicate the
underlying disease. For example, heart failure
is a syndrome of typical signs and symptoms,
such as breathlessness and fatigue, caused
by a functional or structural abnormality of
the heart.(3) However, there might be multiple
causes for the impaired cardiac function.
Biomarkers may help in finding the cause
of heart failure. For example, an increase
in inflammatory markers might indicate an
inflammatory cause. Also, several markers
of remodeling and collagen formation can
be found in patients with hypertrophic heart
disease. So, biomarkers might not only help in
57
the diagnosis of heart failure, but its cause as
well.
2. Hemodynamic status.
Several biomarkers might be used as indicators
of hemodynamic status. For example, renal
function (glomerular filtration rate) is strongly
linked to the severity and prognosis of heart
failure. A higher creatinine (lower GFR) indicates
that there is either a decrease in cardiac output
or an increase in central venous pressure. (4)
In addition, changes in natriuretic peptides
might indicate changes in hemodynamic
status. (2) Several liver function tests might
indicate whether there is an increased central
venous pressure, or whether there is a decreased
cardiac output. (5) So, markers might help
us to determine hemodynamic status of
patients.
3. Prognosis.
Several biomarkers are elevated in patients
with heart failure, and are strongly related to a
poorer prognosis. For example, a higher level
of serum sodium is an important predictor
of a poorer prognosis. In addition, a poorer
renal function is also clearly associated with
increased mortality. Natriuretic peptides play
an important role in the determination of
the prognosis of patients with heart failure.
Other markers, such as adrenomedullin (6)
and galactin-3 (7) might be even better in
predicting prognosis in these patients. In
the meantime, there are a large number of
markers indicating prognosis, mainly due
How to use Biomarkers in cardiology?
to improving technologies to detect low
abundant proteins. Therefore, a multimarker
approach is currently advocated leading
to better prognostic evaluation. With this
approach, distinct biomarkers as a group
might indicate those patients at the highest
risk.
4. Biomarker-guided treatment.
Biomarkers, and natriuretic peptides in
particular, can be used to guide treatment. (8)
Patients with elevated levels of natriuretic
peptides might be treated more aggressively
in order to improve their prognosis. Several
studies have been performed with mixed
results. (9) In particular, several studies have
sought to investigate whether targeting
natriuretic peptides would improve outcome.
In other words, patients were randomized to
standard treatment or to treatment related
to natriuretic peptide levels. Some of these
studies showed that BNP-guided therapy
resulted in a better outcome, but others did
not. The final goal of each marker predicting
prognosis is to change clinical practice. In
other words, it should be proven that when
a biomarker is used to select or uptitrate
therapy, that it improves outcome as well.
5. Guidance for type of treatment.
Biomarkers might also be used to select
patients for a specific treatment. For example,
in patients with high renin levels, treatment
of ACE-inhibitors is highly effective to reduce
blood pressure, while in patients with low levels
of renin, diuretics are much more effective.(10)
References.
1.
Braunwald E. Biomarkers in Heart Failure. N Engl J
Med. 2008;358:2148-59.
2.
S c h r i e r R W, A b r a h a m W T. H o r m o n e s a n d
hemodynamics in heart failure. N Engl J Med. 1999
Aug 19;341(8):577-85.
3.
Dickstein K, Cohen-Solal A, Filippatos G, McMurray
JJ, Ponikowski P, Poole-Wilson PA, Strömberg A, van
Veldhuisen DJ, Atar D, Hoes AW, Keren A, Mebazaa A,
Nieminen M, Priori SG, Swedberg K; ESC Committee
for Practice Guidelines (CPG). ESC guidelines for the
diagnosis and treatment of acute and chronic heart failure
2008: the Task Force for the diagnosis and treatment
of acute and chronic heart failure 2008 of the European
Society of Cardiology. Developed in collaboration with the
Heart Failure Association of the ESC (HFA) and endorsed
by the European Society of Intensive Care Medicine
(ESICM). Eur J Heart Fail. 2008 Oct;10(10):933-89.
4.
5.
Damman K, Voors AA, Navis G, van Veldhuisen DJ,
Hillege HL. Current and novel renal biomarkers in heart
failure. Heart Fail Rev. 2011 May 22. [Epub ahead of
print]
van Deursen VM, Damman K, Hillege HL, van Beek AP,
van Veldhuisen DJ, Voors AA. Abnormal liver function
in relation to hemodynamic profile in heart failure
patients. J Card Fail. 2010 Jan;16(1):84-90.
6.
Klip IT, Voors AA, Anker SD, Hillege HL, Struck J,
Squire I, van Veldhuisen DJ, Dickstein K; OPTIMAAL
investigators. Prognostic value of mid-regional
pro-adrenomedullin in patients with heart failure after
an acute myocardial infarction. Heart. 2011 Jun;
97(11):892-8.
7.
de Boer RA, Voors AA, Muntendam P, van Gilst WH, van
Veldhuisen DJ. Galectin-3: a novel mediator of heart
failure development and progression. Eur J Heart Fail.
2009 Sep;11(9):811-7.
8.
Adams KF Jr, Felker GM, Fraij G, Patterson JH,
O’Connor CM. Biomarker guided therapy for heart
failure: focus on natriuretic peptides. Heart Fail Rev.
2010;15:351-70.
9.
Felker GM, Hasselblad V, Hernandez AF, O’Connor CM.
Biomarker-guided therapy in chronic heart failure: a
meta-analysis of randomized controlled trials. Am Heart
J. 2009 Sep;158(3):422-30.
10. Preston RA, Materson BJ, Reda DJ, Williams DW,
Hamburger RJ, Cushman WC, Anderson RJ. Age-race
subgroup compared with renin profile as predictors of
blood pressure response to antihypertensive therapy.
Department of Veterans Affairs Cooperative Study
Group on Antihypertensive Agents. JAMA. 1998 Oct
7;280(13):1168-72.
58
4
Notes
59
Mark A. Oyama
DVM, DipACVIM (Cardiology)
Associate Professor of Cardiology
Department of Clinical Studies, School
of Veterinary Medicine, University of
Pennsylvania,
Philadelphia, USA.
Mark Oyama is an Associate Professor in the Department of Clinical Studies,
School of Veterinary Medicine, University of Pennsylvania. His main clinical and
research interests concern canine myocardial disease, mitral valve disease and
cardiac biomarkers. He is currently involved in several research projects dealing
with investigation of biomarkers in dogs and cats as well as studies investigating
serotonin-related molecular mechanisms of canine valve disease.
He is a past President of the American College of Veterinary Internal Medicine,
Specialty of Cardiology and member of the ACVIM Board of Regents. He has served
as a member of the NIH-Center for Scientific Review Bioengineering, Technology, and
Surgical Sciences study section and is a member of the University of Pennsylvania
Institute of Translational Medicine and Therapeutics.
Dr. Oyama has published over 90 scientific manuscripts and abstracts and has
given over 150 national and international lectures. He serves on veterinary advisory
boards for a variety of biotechnology, pharmaceutical, and diagnostic laboratory
companies and is the Translational Sciences section editor for the Journal of
Veterinary Cardiology.
He resides in Philadelphia with his wife, a Golden Retriever, and two very mischievous
cats.
60
4
Potential Markers of CardiaC reModeling
and funCtion
Biomarker testing represents an attractive
diagnostic and monitoring technique in
dogs with mitral valve disease (MVD) and
dilated cardiomyopathy (DCM). Compared to
echocardiography and radiography, marker
testing is potentially more cost effective and
accessible to general practitioners. Pertinent
to the topic of this symposium, markers of
cardiac stress, remodeling, and function
might offer a means to stage disease severity,
monitor response to therapy, and provide
information regarding risk of morbidity and
mortality. Studies involving NT-proBNP have
already demonstrated utility in stratification of
risk for morbidity and mortality (Moonarmart et
al., Serres et al., Chetboul et al.). These studies
are particularly important as they move beyond
the simple description of elevated markers in
dogs and cats with heart disease. They offer
information that is otherwise unavailable from
conventional diagnostics.
Currently investigated biomarkers
in canine medicine.
An incomplete list of candidate markers in
dogs includes markers of necrosis (troponin
and high sensitivity troponin [Ljungvall et
al.(a)]), remodeling and fibrosis (N-terminal
procollagen type III [Hezzell et al.]; matrix
metalloproteinases [Ljungvall et al.(b)]);
serotonin [Arndt et al.]), calcium handing
(sodium-calcium exchanger [Nam et al.] ;
phospholamban [Lee et al.]), neurohormonal
61
activation (copeptin [Oyama et al.]; urocortin
[Veloso et al.]), and inflammation (C-reactive
protein [Rush et al.; Ljungvall et al.(a)]). To date,
most veterinary studies have been limited
to description of marker concentrations in
populations of affected animals or the use of
markers to diagnose presence or absence of
heart disease. As previously mentioned, the
next stage of investigation, wherein markers are
found to offer risk stratification and treatment
guidance, has just begun. In this respect,
veterinary medicine is not so far behind our
physician colleagues (see below).
Biomarkers for guided therapy.
The validation of markers is relatively laborious,
insofar as studies evaluating their prognostic
value requires longitudinal follow-up of relatively
large cohorts of animals. In addition, for such
markers to have the greatest clinical impact,
validation of markers requires simultaneous
advances in therapy such that once identified,
the natural history of at-risk individuals can be
altered by therapy or intervention. For instance,
in dogs with MVD and persistently elevated
NT-proBNP, would additional diuretics, betablockade, AT receptor blockade (or any other
drug for that matter) improve outcome? Would
this improvement be reflected in lower NTproBNP concentration so that clinicians would
know they have mitigated risk? In humans,
meta-analysis indicates that marker-guided
therapy reduced all-cause mortality by 30%
Potential Markers of CardiaC reModeling and funCtion
(Felker et al.). The benefits appear greatest
in patients that are younger and with systolic
dysfunction vs. those >75yrs of age or with
preserved ejection fraction.
mortality that any of the three alone (Damman
et al.).
The multimarker approach.
One challenge facing biomarker science
involves the unique nature of canine MVD as
compared to ischemic Mitral Regurgitation
( M R ) , D C M , o r m y o c a rd i a l i n f a r c t i o n .
Interestingly, experimental canine MVD is
devoid of the extensive degree of remodeling
and fibrosis that is seen in ischemic disease
(Dell’italia et al.). Studies in canine MR
demonstrate a net loss of collagen structure,
and serum pro-collagen III concentrations are
decreased in dogs with advanced MVD and
eccentric hypertrophy (Zheng et al., Hezzel
et al.). In dogs with naturally-occurring MVD,
myocardial fibrosis is related to the presence
and extent of arterial narrowing, and both
parameters appear related to survival (Falk
et al.). Thus, it is possible that myocardial
fibrosis in MVD is actually related to small
vessel hypertrophy and ischemia rather than
an intrinsic characteristic of volume overload
hypertrophy itself. Additional studies are
required to determine if markers of fibrosis (and
ischemia) will be useful in dogs with MVD.
In human medicine, much attention has been
given to the potential utility of combinations
of markers (the so-called “multimarker”
technique). Theoretically, multiple markers,
each specific to various pathologic features of
heart disease (ie., fibrosis, ischemia, wall stress,
extracellular matrix remodeling, etc) would offer
more information than any single marker alone.
Multimarker use in veterinary medicine already
is widely used. Take for example a hepatic panel
involving ALT, AST, ALP, GGT, and bile acids:
each one of these markers provides slightly
different information, and the combination of
results typically is more useful than any one
marker alone. Note that the hepatic markers
are not necessarily definitive for any specific
disease, but rather, the results increase the
level of suspicion that various disease states
(ie., inflammation, bile stasis, etc) exist. Markers
also provide the impetus to pursue additional
and more definitive diagnostics (ie., ultrasound,
biopsy, etc). Thus, it is not particularly surprising
that combinations of cardiac markers add
prognostic information to existing risk factors.
For example, in patients undergoing marker
testing for NT-proBNP, C-reactive protein,
cystatin-C, and cardiac troponin-I, the risk
of cardiovascular death increased by 3-, 7-,
and 16-fold depending on whether 2, 3, or all
4 markers were elevated (Zethelius et al.). The
individual markers need not be particularly
complicated or original. In humans, in addition
to NT-proBNP concentration, consideration
of serum glucose and estimated glomerular
filtration rate yielded better prediction of
Challenges in canine medicine.
Another challenge facing the identification of
markers involves the apparently late activation
of neurohormonal axes such as the circulating
renin-angiotensin-aldosterone system in dogs
with MVD (Fujii et al., Häggström et al.); however
another study (Borgarelli et al.) reported
elevated plasma aldosterone in dogs with
advanced asymptomatic MVD. Thus, the exact
timeframe and sequence of compensatory
activity is poorly understood, and biomarker
studies, in addition to their diagnostic and
prognostic potential, can add to our knowledge
about the pathophysiology of disease.
62
4
New opportunities.
To attempt to identify promising candidate
markers for further study, the author has
recently evaluated a panel of 8 novel markers
including markers of platelet adhesion
(E-selectin, ICAM-1), neurohormonal activation
(copeptin, chromogranin A), and hypertrophy,
f i b ro s i s , a n d g ro w t h ( g a l e c t i n - 3 , S T 2 ,
osteopontin, endoglin) in approximately 200
dogs with naturally occurring disease. Pilot
results from these studies will be discussed
during the presentation. Based on these
results, the author believes that certain classes
of markers will be more useful than others,
perhaps due to the unique characteristics of
MVD and volume overload.
References.
Arndt JW et al. J Vet Intern Med 2009;23:1208-13.
Ljungvall I et al.(a). J Vet Intern Med. 2010;24(1):153-9.
Borgarelli et al. ACVIM Forum 2011, Denver CO
Ljungvall I et al.(b). Am J Vet Res. 2011;72(8):1022-8.
Chetboul V et al. J Vet Intern Med 2009 ;23 :984-94.
Moonarmart et al. J Small Anim Pract 2010;51:84-96.
Damman et al. J Am Coll Cardiol 2011;57:29-36.
Nam SJ et al. J Vet Intern Med. 2010;24(6):1383-7
Dell’italia LJ et al. Am J Physiol 1997;273:H961-70.
Oyama et al. ECVIM 2010 Toulouse, France.
Felker et al. Am Heart J 2009;158:422-430.
Rush JE et al. J Vet Intern Med. 2006;20(3):635-9.
Fujii Y et al. Am J Vet Res 2007;68:1045-50.
Serres F et al. J Vet Cardiol 2009;11:103-21.
Häggström et al. Am J Vet Res 1997;58:77-82.
Veloso GF et al. Vet J. 2011;188(3):318-24.
Hezzell MJ et al. J Vet Intern Med. 2011;25 :650.
Zethelius et al. N Engl J Med 2008 ;358 :2107-16
Lee JS et al. J Vet Intern Med. 2009 Jul-Aug;23(4):832-9.
Zheng J et al. Circulation. 2009;119(15):2086-95.
63
Notes
64
4
Notes
65
Rebecca L. Stepien
DVM, MS, DipACVIM (Cardiology)
Clinical Professor of Cardiology
Department of Medical Sciences
University of Wisconsin
School of Veterinary Medicine
Madison, Wisconsin, USA.
Dr. Rebecca L. Stepien graduated from the University of Wisconsin School of
Veterinary Medicine and completed a cardiology residency at the Ohio State
University. She subsequently taught at the Royal Veterinary College in London and
the Virginia-Maryland Regional College of Veterinary Medicine. She is currently a
Clinical Professor at the University of Wisconsin School of Veterinary Medicine,
where she has taught and seen referral patients since 1994. Dr. Stepien holds a
Master’s degree in Clinical Sciences, is board-certified in the specialty of Cardiology
in the American College of Veterinary Internal Medicine and is a past president of
the ACVIM Specialty of Cardiology.
Her academic and clinical interests include diagnosis and therapy of systemic
hypertension, mitral valve disease in whippets, therapy of heart failure and veterinary
ethics. Dr. Stepien is a frequent speaker at international veterinary conferences and
in 2008, was awarded the British Small Animal Veterinary Medical Association
Bourgelat Award for outstanding contribution to the field of small animal practice.
66
4
Cardio-Renal Syndrome, what is behind it?
A RoCk And A HARd PlACe: CARdioRenAl
SyndRome in CliniCAl CAnine VeteRinARy PAtientS
Myxomatous or degenerative valve disease
is the most common type of heart disease
in dogs and typically occurs in middle-aged
to older dogs. Dogs with renal dysfunction
are also typically in the adult to geriatric age
range (Jacob et al. 2003) and the risk of renal
dysfunction may be increased by the presence
of medical therapy for congestive heart failure
(CHF) (Butler et al. 2004; Sayer et al. 2009).
Definition and pathophysiology.
Cardiorenal syndrome has been variously
defined. In clinical medicine, it may be viewed
as “a state in which therapy to relieve heart
failure symptoms is limited by worsening
renal function” (NHLBI Working Group, http://
www.nhlbi.nih.gov/meetings/workshops/
cardiorenal-hf-hd-htm), but this arguably
is a clinical view reflecting a cardiologist’s
concern; a nephrologist may be more likely
to define CRS as “… a normal kidney that is
dysfunctional because of a diseased heart…”
(Ronco et al. 2008). An expansive, multisystem
view is required in order to understand the
complex bidirectional interactions of these
two critical body systems, in which “…each
dysfunctional organ has the ability to initiate
and perpetuate disease in the other organ
through common hemodynamic, neurohormonal, and immunological/biochemical
feedback pathways” (Bock and Gottlieb 2010).
The “low flow” theory of how cardiac
dysfunction leads to renal dysfunction involves
decreased cardiac output leading to decreased
67
renal perfusion, which results in renin release
from the juxtaglomerular cells and pressuresensing baroreceptors. Renin-angiotensinaldosterone system (RAAS) activation causes
retention of sodium, volume retention, afferent
arteriolar constriction that decreases GFR,
and release of profibrotic neurohormones
that lead to ventricular remodeling (Bock and
Gottlieb 2010). However, studies of therapies
to improve cardiac index and decrease
pulmonary capillary wedge pressure (i.e.
effective treatments of cardiac dysfunction)
have shown that these therapies do not predict
improvement in renal function (Weinfeld et al.
1999; Mullens et al. 2008; Mullens et al. 2009)
and therefore, are inadequate to address this
complex issue. A more specific understanding
of the physiologic parameters involved in
maintaining constant blood volume and organ
perfusion promotes better understanding of
their relationships, and perhaps better targets
for therapy. Although understanding of the
physiologic parameters involved in CRS are still
incomplete, there is general recognition that
elevation of intra-abdominal and central venous
pressure, increased sympathetic nervous
system activity, RAAS dysfunction, oxidative
and endothelial dysfunction, renal effects of
arginine vasopressin and adenosine and in
some patients, decreases in erythropoietin
contribute variably to CRS in a given patient
(Bock and Gottlieb 2010).
Cardiorenal syndrome may be divided into 5
types (Ronco et al. 2008).
A RoCk And A HARd PlACe: CARdioRenAl SyndRome in CliniCAl CAnine
VeteRinARy PAtientS
Type of CRS
Description
Type 1 (acute CRS)
Rapid worsening of cardiac function leads to acute kidney
injury
Type 2 (chronic CRS)
Chronic abnormalities in cardiac function lead to progressive
chronic kidney disease
Type 3 (acute
renocardiac syndrome)
Acute, primary worsening of kidney function leads to acute
cardiac dysfunction
Type 4 (chronic
renocardiac syndrome)
Primary chronic kidney disease contributes to decreased
cardiac function, left ventricular hypertrophy, diastolic
dysfunction and increase risk of cardiovascular events
Type 5 (secondary CRS)
Acute or chronic systemic disorders (e.g. diabetes mellitus)
cause combined cardiac and renal dysfunction
Cardiorenal syndrome and its
significance in canine medicine.
Type 2 CRS appears to be of significant clinical
concern in cardiac patients. Approximately
30% of >105,000 people admitted for acute
decompensated heart failure had a history of
renal insufficiency and approximately 21%
of them were azotemic (Adams et al. 2005).
Decreased creatinine clearance is common in
Congestive Heart Failure (CHF) patients, and
affected almost 40% of those human patients
with NYHA Class IV heart failure in one study
(Adams et al. 2005). When worsening renal
function (WRF) is defined as an increase in
serum creatinine of >0.3 mg/dl compared
to baseline, 27% of 1004 human patients
admitted for heart failure developed WRF
in the hospital, and in these patients, WRF
was associated with worse outcomes even
when the increase did not cause creatinine
to exceed normal reference range (Forman
et al. 2004). The sensitivity and specificity of
an increase in creatinine ≥ 0.3 mg/dl with a
final creatinine of ≥ 1.5 mg/dl for prediction
of in-hospital mortality was 73% and 72%
respectively, and this combination was seen
in 29% of acutely decompensated human
cardiac patients (Gottlieb et al. 2002). Higher
creatinine concentrations at admission, as
well as higher doses of loop diuretics and
use of certain vasodilators increases the risk
of worsening renal function in hospitalized
human heart failure patients (Butler et al.
2004). Over a range of increases in creatinine
(≥ 0.1 to ≥ 0.5 mg/dl), renal deterioration
tended to occur within the first 3 days of
hospitalization, regardless of total length of
stay (Gottlieb et al. 2002).
The prevalence of azotemia and decreased
renal function in canine CHF patients is
similarly high. In a report in 2010, 24.1% of
223 dogs with heart disease were azotemic,
although the prevalence of CHF in this cohort
of heart patients was not specified (Ohad
et al. 2010). In an earlier study, Nicolle and
colleagues reported that 62% of small dogs
(<13 kg) with degenerative valve disease were
azotemic either by Blood Urea Nitrogen (BUN)
68
4
or Creat or both. This study included dogs
in all stages of heart failure (NYHA grades
I-IV) and some were treated at the time of
the study. As their NYHA class increased, a
greater percentage of patients were azotemic
and were also more likely to have already been
treated with some combination of angiotensinconverting enzyme inhibitors, furosemide,
spironolactone and digoxin. Older dogs were
also more likely to be azotemic. The severity
of CHF was also linked to renal function;
Class III-IV dogs had 45% decrease in GFR
compared with Class I-II dogs, and 7/9 grade
III-IV dogs had abnormally decreased GFR
(Nicolle et al. 2007).
In human (Butler et al. 2004) and canine
patients, the presence and severity of RAAS
activation and azotemia is affected by therapy,
especially furosemide and vasodilators. In
normal beagles, the combination of a low
sodium diet and “heart failure” doses of
furosemide (2 mg/kg PO q 12 hrs) resulted
in measurably higher renal-angiotensinaldosterone system (RAAS) activation than a
low sodium diet alone (Lovern et al. 2001). In
12 King Charles Spaniels with NYHA Class
III CHF treated with enalapril for 3 weeks,
no change was seen in angiotensin II (ATII)
concentration and aldosterone concentration
decreased, but these findings (suggesting
limitation of RAAS activation) disappeared
with the addition of furosemide to their therapy
(Häggström et al. 1996). After 4 months of
enalapril plus furosemide therapy, both
aldosterone and ATII concentrations were
significantly increased compared to baseline.
The plasma BUN of dogs receiving enalapril
monotherapy for 3 weeks was unchanged
from baseline, but mean BUN of these dogs
69
after furosemide had been added reached
azotemic concentrations at the 6 month
evaluation. Both hydralazine (Häggström et
al. 1996) and amlodipine (Atkins et al. 2007)
administration lead to measurable RAAS
activation.
Anecdotal evidence supports the simultaneous
occurrence of cardiac and renal dysfunction in
clinical canine patients with valvular disease.
Patients may be presented with clinical signs
of CHF and evidence of pre-existing renal
dysfunction diagnosed by detection of azotemia
at the time of presentation. More commonly,
however, renal dysfunction develops over time
in cardiac patients, often increasing subtly but
incrementally over the course of cardiac disease
progression, then increasing more obviously
when cardiac therapy involving furosemide
and some vasodilators begins. In some cases,
inadequate therapy of venous congestion
may contribute to renal dysfunction, resulting
in “congestive kidney failure” (Mullens et al.
2009).
Human and veterinary literature supports
the use of ACEI and aldosterone receptor
antagonists such as spironolactone to limit the
RAAS activation that has been documented
with CHF therapy (CONSENSUS 1987;
RALES 1996; Ettinger et al. 1998; Ovaert et
al. 2009; Bernay et al. 2010), and use of these
modalities has prolonged survival times in
affected patients. The topic of cardiorenal
syndrome is becoming an increasingly
important concern in clinical veterinary
medicine. Avoidance of WRF in dogs before
and during CHF therapy is crucial to maintain
quality of life as survival in dogs with this
common disease increases.
A RoCk And A HARd PlACe: CARdioRenAl SyndRome in CliniCAl CAnine
VeteRinARy PAtientS
Adams, KF, Fonarow, GC, Emerman, CL, LeJemtel, TH,
Costanzo, MR, Abraham, WT, Berkowitz, RL, Galvao, M and
Horton, DP (2005). Characteristics and outcomes of patients
hospitalized for heart failure in the United States: Rationale,
design, and preliminary observations from the first 100,000
cases in the Acute Decompensated Heart Failure National
Registry (ADHERE). Am Heart J 149: 209-216.
Atkins, CE, Rausch, WP, Gardner, SY, DeFrancesco, TC,
Keene, BW and Levine, JF (2007). The effect of amlodipine
and the combination of amlodipine and enalapril ont he
renin-angiotensin-aldosterone system in the dog. J Vet
Pharmacol Therap 30: 394-400.
Bernay, F, Bland, JM, Häggström, J, Baduel, L, Combes, B,
Lopez, A and Kaltsatos, V (2010). Efficacy of spironolactone
in survival in dogs with naturally occurring mitral regurgitation
caused by myxomatous mitral valve disease. J Vet Intern
Med 24(2): 1-11.
Bock, JS and Gottlieb, SS (2010). Cardiorenal syndrome.
New perspectives. Circulation 121: 2592-2600.
Butler, J, Forman, DE, Abraham, WT, Gottlieb, SS, Loh,
E, Massie, BM, O’Connor, CM, Rich, MW, Stevenson, LW,
Wang, Y, Young, JB and Krumholz, HM (2004). Relationship
between heart failure treatment and development of
worsening renal function amoung hospitalized patients. Am
Heart J 147: 331-338.
CONSENSUS, TSG (1987). Effects of enalapril on mortality
in severe congestive heart failure. N Engl J Med 316: 14291435.
Ettinger, SJ, Benitz, AM, Ericsson, GF, Cifelli, S, Jernigan,
AD, Longhofer, SL, Trimboli, W and Hanson, PD (1998).
Effects of enalapril maleate on survival of dogs with
naturally acquired heart failure. The Long-Term Investigation
of Veterinary Enalapril (LIVE) Study Group. J Am Vet Med
Assoc 213: 1573-1577.
Forman, DE, Butler, J, Wang, Y, Abraham, WT, O’Connor, CM,
Gottlieb, SS, Loh, E, Massie, BM, Rich, MW, Stevenson, LW,
Young, JB and Krumholz, HM (2004). Incidence, predictors at
admission, and impact of worsening renal function amoung
patients hospitalized with heart failure. J Am Coll Cardiol
43(1): 61-67.
Gottlieb, SS, Abraham, WT, Butler, J, Forman, DE, Loh, E,
Massie, BM, O’Connor, CM, Rich, MW, Stevenson, LW, Young,
JB and Krumholz, HM (2002). The prognostic importance of
different definitions of worsening renal function in congestive
heart failure. J Cardiac Fail 8(3): 136-141.
Häggström, J, Hansson, K, Karlberg, BE, Kvart, C, Madej,
A and Olsson, K (1996). Effects of long-term treatment with
enalapril or hydralazine on the renin-angiotensin-aldosterone
system and fluid balance in dogs with naturally acquired
mitral valve regurgitation. Am J Vet Res 57(11): 1645-1652.
Jacob, F, Polzin, DJ, Osborne, CA, Neaton, JD,
Lekcharoensuk, C, Allen, TA, Kirk, CA and Swanson, LL
(2003). Association between initial systolic blood pressure
and risk of developing a uremic crisis or of dying in dogs
with chronic renal failure. J Am Vet Med Assoc 222(3): 322329.
Lovern, CS, Swecker, WS, Lee, JC and Moon, ML (2001).
Additive effects of a sodium chloride restricted diet and
furosemide administration in healthy dogs. Am J Vet Res
62(11): 1793-1796.
Mullens, W, Abrahams, Z, Francis, GS, Sokos, G, Taylor, DO,
Starling, RC, Young, JB and Tang, WH (2009). Importance
of venous congestion for worsening renal function in
advanced decompensated heart failure. J Am Coll Cardiol
53: 589-596.
Mullens, W, Abrahams, Z, Skouri, HN, Francis, GS, Taylor,
DO, Starling, RC, Paganini, E and Tang, WHW (2008).
Elevated intra-abdominal pressure in acute decompensated
heart failure. J Am Coll Cardiol 51: 300-306.
Nicolle, AP, Chetboul, V, Allerheiligen, T, Pouchelon,
J-L, Gouni, V, Tessier-Vetzel, D, Sampendrano, CC and
Lefebvre, HP (2007). Azotemia and glomerular filtration rate
in dogs with chronic valvular disease. J Vet Intern Med 21:
943-949.
Ohad, DG, Berkowitz, J and Bdolah-Abram, R (2010).
The prevalence & effects of canine cardio-renal-anemia
syndrome (conference proceedings). 2010 ACVIM Forum,
Anaheim, CA.
Ovaert, P, Elliott, J, Bernay, F, Guillot, E and Bardon, T (2009).
Aldosterone receptor antagonists - how cardiovascular
actions may explain their beneficial effects in heart failure. J
Vet Pharmacol Therap 33: 109-117.
RALES, I (1996). Effectiveness of spironolactone added
to an angiotensin-converting enzyme inhibitor and a loop
diuretic for severe chronic congestive heart failure (The
Randomized Aldactone Evaluation Study [RALES]). Am J
Cardiol 78: 902-907.
Ronco, C, Haapio, M, House, AA, Anavekar, N and Bellomo,
R (2008). Cardiorenal syndrome. J Am Coll Cardiol 52(19):
1527-39.
Sayer, MB, Atkins, CE, Fujii, Y, Adams, AK, DeFrancesco,
TC and Keene, BW (2009). Acute effects of pimobendan and
furosemide on the circulating renin-angiotensin-aldosterone
system in healthy dogs. J Vet Intern Med 23: 1003-1006.
Weinfeld, MS, Chertow, GM and Stevenson, LW (1999).
Aggravated renal dysfunction during intensive therapy for
advanced chronic heart failure. Am Heart J 138: 285-290.
70
4
Notes
71
Professor Claudio Ronco
MD
Director, Department of Nephrology,
Dialysis and Transplantation
International Renal Research Institute
St Bortolo Hospital, Vicenza, Italy.
Professor Claudio Ronco graduated in medicine at the University of Padua, Italy,
in 1976. He specialized in nephrology at the University of Padua in 1979, and in
paediatric nephrology at the University of Naples in 1989.
1977-1998, he was Assistant and Associate professor at the Division of Nephrology
in Vicenza. During the 1999-2001 period, Director of the Renal Laboratory at the
Renal Research Institute and Professor of Medicine at the Albert Einstein College
of Medicine and Beth Israel Medical Centre of New York. Since 2002, Director of
Department of Nephrology at St. Bortolo Hospital, Vicenza, Italy.
Claudio Ronco has co-authored 994 papers, 85 book chapters and 62 books, and
he has delivered more than 650 lectures at international meetings and universities.
He is a council member of several scientific societies and Editor Emeritus of the
International Journal of Artificial Organs. He is also Editor-in-Chief of Blood Purification
and Contributions to Nephrology.
Professor Ronco has received numerous honours and awards including, in 2004,
the Lifetime Achievement Award and honorary membership in the Spanish Society
of Nephrology, the National Kidney Foundation International Medal of Excellence and
in 2009, the ISN Bywaters Award for Acute Renal Failure.
72
4
CaRdio-Renal SyndRomeS:
leSSonS fRom human pathophySiology
Cardiorenal Syndromes in Humans.
Patients admitted to hospital may present
v a r i o u s d e g re e s o f h e a r t a n d k i d n e y
dysfunction. Primary disorders of one of
these two organs often result in secondary
dysfunction or injury to the other. Such
pathophysiological interactions represent
the pathophysiological basis for a clinical
entity often referred to as the Cardio-Renal
Syndrome (CRS).1 Although generally defined
as a condition characterized by the initiation
and/or progression of renal insufficiency
secondary to heart failure, the term CRS is
also used to describe the negative effects
of reduced renal function on the heart (renocardiac syndrome). The absence of a clear
definition and the complexity of heart and
kidney interactions contributed in the past
to lack of clarity with regard to diagnosis and
management. The most recent definition
includes a variety of conditions, either acute
or chronic, where the primary failing organ
can be either the heart or the kidney. “CardioRenal Syndromes” (CRS) are thus disorders
of the heart and kidneys whereby acute or
chronic dysfunction in one organ may induce
acute or chronic dysfunction of the other. The
current definition has been expanded into
five subtypes whose etymology reflects the
primary and secondary pathology, the timeframe and simultaneous cardiac and renal codysfunction secondary to systemic disease
(table 1).2 Such advances in the definition and
classification of CRS allow to characterize the
73
complex organ crosstalk and have proposed
specific prevention strategies and therapeutic
interventions to attenuate end organ injury.3-4-5
A major problem with previous terminology
was that it did not allow to identify the
pathophysiological interactions occurring in
the different types of combined heart/ kidney
disorder.6 A large number of direct and indirect
effects of each organ dysfunction can initiate
and perpetuate the combined disorder of the
two organs through a complex combination
of neuro-humoral feedback mechanisms.
For this reason a subdivision into different
subtypes seems to provide a more concise and
logically correct approach to this condition.
This classification has been the result of a
consensus conference held in Venice in 2008
under the auspices of the Acute Dialysis
Quality Initiative (ADQI). Several experts from
the fields of internal medicine, cardiology,
cardiac surgery, nephrology and intensive
care, debated the topic in a well established
process for consensus. The advantage of this
result is, not only the definition classification
system that represents a great outcome itself,
but also the initiation of a multidisciplinary
collaboration towards new diagnostic,
preventive and therapeutic strategies for
patients suffering from combined disorders
o f t h e h e a r t a n d t h e k i d n e y. S u c h
m u l t i d i s c i p l i n a r y a p p ro a c h re q u i re s a
structured education of young physicians that
should evolve in their careers with an open
mind and an attitude more patient-oriented
CaRdio-Renal SyndRomeS: leSSonS fRom human pathophySiology
rather than organ oriented. The birth of this
new journal may represent the basis for this
innovative trend and for a new era in the
management of cardio-renal patients.
Cardio-renal Syndrome type 2:
a condition close to veterinary
pathophysiology.
Ty p e I I C R S o r c h ro n i c C a rd i o - R e n a l
Syndrome (CCRS) is characterized by
chronic abnormalities in cardiac function
causing progressive chronic kidney disease
(CKD). Worsening renal function (WRF) in the
context of heart failure (HF) is associated with
significantly increased adverse outcomes and
prolonged hospitalizations7. The prevalence
of renal dysfunction in chronic heart failure
(CHF) has been reported to be approximately
25% in humans. Even limited decreases
in estimated GFR of > 9 ml/min appears to
confer a significantly increased mortality risk.
Some researchers have considered WRF a
marker of severity of generalized vascular
disease. Independent predictors of WRF
include: old age, hypertension, diabetes
mellitus and acute coronary syndromes.
Chronic HF is characterized by a relatively
stable long-term situation of probably reduced
renal perfusion, often predisposed by both
micro- and macrovascular disease in the
context of the same vascular risk factors
associated with cardiovascular disease.
No evidence of association between LVEF
and estimated GFR can be consistently
demonstrated.8 Neuro-hormonal abnormalities
are present with excessive production of
vaso-constrictive mediators (epinephrine,
angiotensin, endothelin) and altered sensitivity
and/or release of endogenous vasodilatory
factors (natriuretic peptides, nitric oxide).
Recently, there has been increasing interest in
the pathogenetic role of erythropoietin (EPO)
deficiency and decrease in Vitamin D receptors
activation.3-5 Regardless of the cause, WRF in
the context of heart failure is associated with
increased risk for adverse outcomes. The
proportion of individuals with WRF or CKD
receiving appropriate risk factor modification
and/or interventional strategies is lower than
the general population. 9 Potential reasons
for this therapeutic failure include concerns
about worsening of residual renal function,
and/or therapy-related toxic effects due to low
clearance rates. 10 However, several studies
have shown that when appropriately titrated
and monitored, cardiovascular medications
used in the general population can be safely
administered to those with renal impairment
and with similar benefits.11
Newer approaches to the treatment of cardiac
failure such as cardiac resynchronization
therapy (CRT) have not yet been studied in
terms of their renal functional effects, although
preserved renal function after CRT may predict
a more favorable outcome. 6 Vasopressin
V2-receptor blockers have been reported to
decrease body weight and edema in patients
with CHF 12, but their effects in patients with
CRS have not been systematically studied
and a recent large randomized controlled trial
showed no evidence of a survival benefit with
these agents.13
It has been recognized the difficulty to
distinguish in advanced stages whether
patients belong to type II or type IV CRS. This
however should not be matter of concern
since the classification system describes
clearly that patients may move among
different CRS subtypes along the natural
history of the syndrome.
74
4
Cardiorenal Syndrome (CRS) General Definition:
A complex pathophysiologic disorder of the heart and kidneys whereby acute or chronic dysfunction
in one organ may induce acute or chronic dysfunction in the other organ
CRS Type I (Acute Cardiorenal Syndrome)
Abrupt worsening of cardiac function (e.g. acute cardiogenic shock or acute decompensation of
chronic heart failure) leading to kidney injury
CRS Type II (Chronic Cardiorenal Syndrome)
Chronic abnormalities in cardiac function (e.g. chronic heart failure) causing progressive chronic
kidney disease
CRS Type III (Acute Renocardiac Syndrome)
Abrupt worsening of renal function (e.g. acute kidney failure or glomerulonephritis) causing acute
cardiac disorder (e.g. heart failure, arrhythmia, pulmonary edema)
CRS Type IV (Chronic Renocardiac Syndrome)
Chronic kidney disease (e.g. chronic glomerular disease) contributing to decreased cardiac
function, cardiac hypertrophy and/or increased risk of adverse cardiovascular events
CRS Type V (Secondary Cardiorenal Syndrome)
Systemic condition (e.g. diabetes mellitus, sepsis) causing both cardiac and renal dysfunction
References.
1.
2.
Ronco C, Haapio M, House AA, Anavekar N, Bellomo
R. (2008) Cardiorenal syndrome. J Am Coll Cardiol. Nov
4;52(19):1527-39.
Ronco C, McCullough P, Anker SD, Anand I,
Aspromonte N, Bagshaw SM, Bellomo R, Berl T, Bobek
I, Cruz DN, Daliento L, Davenport A, Haapio M, Hillege
H, House AA, Katz N, Maisel A, Mankad S, Zanco P,
Mebazaa A, Palazzuoli A, Ronco F, Shaw A, Sheinfeld
G, Soni S, Vescovo G, Zamperetti N, Ponikowski P; for
the Acute Dialysis Quality Initiative (ADQI) consensus
group (2009). Cardio-renal syndromes:report from the
consensus conference of the Acute Dialysis Quality
Initiative.
3.
Jie KE, Verhaar MC, Cramer MJ et al. 2006 Erythropoietin
and the cardio-renal syndrome: cellular mechanisms
on the cardio-renal connectors. Am J Physiol Renal
Physiol; 291: F392-44.
4.
Palazzuoli A, Silverberg DS, Iovine F et al. 2007 Effects
of beta-erythropoietin treatment of left ventricular
remodelling, systolic function, and B-type natriuretic
peptide levels in patients with the cardio-renal anemia
syndrome. Am Heart J; 154: e9-15.
5.
Butler J, Forman DE, Abraham WT et al. 2004
Relationship between heart failure treatment and
development of worsening renal function among
hospitalized patients. Am Heart Journal; 147: 331-9.
75
6.
Fung JW, Szeto CC, Cahn JY et al. 2007 Prognostic
value of renal function in patients with cardiac
resynchronization therapy. In J Cardiol; 122: 10-6.
7.
Hillege HL, Nitsch D, Pfeffer MA, et al. 2006 Renal
function as a predictor of outcome in a broad spectrum
of patients with heart failure. Circulation; 113: 671-678.
8.
Bhatia RS, Tu JV, Lee DS et al. 2006 Outcome of heart
failure with preserved ejection fraction in a populationbased study. N Engl J Med; 355: 260-9.
9.
McCullough PA. 2002 Cardiorenal risk: an important
clinical intersection. Rev Cardiovasc Med; 3:71-76.
10. French WJ, Wright RS. 2003; Renal insufficiency and
worsened prognosis with STEMI: a call for action. J
Am Coll Cardiol 42:1544-1546.
11. Ruggenenti P, Perna A, Remuzzi G. 2001 ACE inhibitors
to prevent end-stage renal disease: when to start and
why possibly never to stop: a post hoc analysis of the
REIN trial results. Ramipril Efficacy in Nephropathy. J
Am Soc Nephrol; 12:2832-2837.
12. Gheorghiade M, Niazi I, Ouyang J et al. 2003
Vasorpessin-V-2 receptor blockade with tolvaptan in
patients with chronic heart failure: results of a doubleblind randomized trial. Circulation; 107: 2690-6.
13. Konstan MA, Gheorghiade M, Burnett JC Jr, et al. 2007
Effects of oral tolvaptan in patients hospitalized for
worsening heart failure: the EVEREST outcome trial.
JAMA; 297: 1319-31
Notes
76
4
Notes
77
Frédéric Jaisser
MD, PhD
Research Director - INSERM
(French National Institute of Health and
Medical Research).
Paris, France.
Frédéric Jaisser is Research Director at the Unit 872 of INSERM (Institut National
de la Santé et de la Recherche Médicale), the French public research institution
entirely dedicated to human health. He is Professor at the Faculty of Medicine
of Reims where he coordinates different courses such as « Animal Models and
Pathophysiological Mechanisms ». Since 2010 he is the Scientific coordinator of the
Pathophysiology committee at The National Research Agency.
He is MD, specialist in Nephrology and has a University degree in Biological and
Medical Engineering. He joined INSERM in 1996. His fields of expertise are mainly
renal and cardiovascular pathophysiology, development of transgenic animal models
for pathophysiologic studies or human disease models. He is also the coordinator of
several multicentric projects.
He is an Editorial Board Member of Endocrinology and an expert for several other
peer-review journals such as Circulation or Hypertension. He is currently the President
of ESAC-France (European Section of the Aldosterone Council).
78
4
MineRaloCoRtiCoid ReCeptoR antagoniStS:
new theRapeutiC oppoRtunitieS in ChRoniC
kidney diSeaSeS
Slowing the progression of chronic kidney
diseases needs new efficient treatments.
Blocking the renin-angiotensin-aldosterone
system, especially using angiotensin receptor
blockers, has proven to be effective to
decrease proteinuria in several renal diseases.
Treatment targeting aldosterone and its
receptor, the mineralocorticoid receptor, is
another option that should be considered.
There is a compelling indication for the
use of mineralocorticoid receptor blockers
(MRBs) for patients with heart disease;
prospective randomized controlled trials
have demonstrated reduction in mortality in
patients with severe heart failure1, for those
who develop heart failure following acute
myocardial infarction2 and those with mild
heart failure3. To date, patients with CKD have
not been included in large-scale prospective
outcome studies with MRBs, primarily
because of concerns about hyperkalemia.
The aim of this short review is to consider
the implications of aldosterone, the MR and
MRBs in the progression and treatment of
chronic kidney disease.
New concepts on the
pathophysiological role of aldosterone.
Aldosterone controls sodium reabsorption
and potassium secretion in the distal nephron.
Aldosterone thus plays a major role in volume
and blood pressure homeostasis. The hormone
79
acts in the distal nephron after binding to
the MR, a ligand-dependant transcription
factor which binds to specific hormone
response elements4. Molecular targets whose
expression is modulated by aldosterone in
the distal nephron are numerous 5. MR is
expressed in the distal nephron (convoluted
distal tubule and collecting duct), distal colon
and sweat glands, all sites previously known
as classical targets of aldosterone and the
regulation of renal sodium reabsorption 4, 5.
In the kidney, MR is also expressed in nonepithelial kidney cells such as mesangial cells,
podocytes and renal fibroblasts6. Therefore,
MR is expressed in tissues and cell types
where vectorial sodium transport does not
occur, indicating novel and yet unknown
roles of aldosterone and MR activation in
these targets that do not serve whole body
sodium homeostasis. MR expression is
not fixed, but can be modulated in various
pathophysiological contexts like diabetes7, 8,
chronic kidney disease with heavy proteinuria9,
cardiac failure 10 , myocardial infarction 11 ,
high blood pressure12, vascular aging13. MR
has been reported to be expressed in nonclassical targets like podocytes or mesangial
cells during pathological situations only like
type I diabetes in the rat14 and in spontaneous
hypertensive rats with metabolic syndrome
(SHR/cp rat)15, both conditions in which MR
expression is clearly stimulated in podocytes
in vivo.
MineRaloCoR
MineRaloCoRtiCoid
ReCeptoR antagoniStS: new theRapeutiC
oppoRtunitieS in ChRoniC kidney diSeaSeS
Renal pathophysiological consequences
of MR activation in vivo.
The pathophysiological consequences of MR
activation in the kidney have been described
in experiments done with aldosterone infusion,
with suppression of aldosterone synthesis
after adrenalectomy, and with pharmacological
MR antagonism. Implication of renal MR
activation has been reported in hypertensive
nephropathy, chronic renal disease with
glomerulosclerosis and proteinuria associated
to subtotal nephron reduction and experimental
models of proliferative glomerulopathies,
nephritic syndrome and lupus nephropathy6.
The role of Aldosterone and/or MR activation
in the diabetic nephropathy has also been
demonstrated in experimental models with
type I diabetes (streptozotocin-induced)
or in type II diabetes (db/db mice) 6. Very
recently, aldosterone and/or MR activation
have been proposed as deleterious factors
in Ciclosporine A nephrotoxicity upon kidney
transplantation6.
Mineralocorticoids and kidney
diseases: clinical evidence.
The use of MR antagonists is supported
by aldosterone “breakthrough” reported in
ACE-I and/or ARB-treated patients16, where
aldosterone breakthrough is defined by an
increase in circulating aldosterone levels after
the initiation of a RAAS blockade as compared
to the values before initiation of the treatment,
despite blockade of the effects of angiotensin
II16. Several studies with positive outcomes
have been performed in humans not only in
the diabetic nephropathy and other proteinuric
nephropathies, but also in End Stage Renal
Disease patients and in children. In most of
the clinical studies the primary endpoint was
reduction in proteinuria and/or albuminuria.
The mechanisms underlying these beneficial
effects remain to be explored but could
combine effects on podocyte injury, renal
hemodynamics, reduction of oxidative stress
and inflammatory activation. A more general
effect on the cardiovascular system, with
secondary implications on the progression
of renal injury may also be considered. The
possibility that the beneficial effects of MR
antagonism may not require an effect on
proteinuria per se is raised by studies in anuric
End Stage Renal Disease patients showing
cardiovascular effects of MR antagonists17, 18.
Those performed in anuric patients are
informative on the effects of MR antagonists
that are independent from their action on the
renal epithelium or the glomerulus.
Adverse effects in using
MR antagonists.
The adverse effects in MR antagonists could
be divided in ionic effects (hyperkalemia and
salt depletion related to the diuretic effect)
and anti-androgenic effects (gynecomastia,
disorders of the menstrual cycle, etc., related to
the non-specific androgen receptor blockade).
The use of MR antagonists is classically not
recommended in CKD patients, because of
the concerns about hyperkalemia19, 20 which
often occurs when multiple RAAS blockers
are used. Several authors suggest that the MR
antagonists are not used often enough in heart
failure, based on comparisons to the inclusion
criteria for the RALES1 and EPHESUS2 studies.
They also suggest that the biological follow-up
(monitoring of serum creatinine and potassium)
is not optimal21. Several authors state that the
safety issues related to hyperkalemia may be
overshowed by the potential beneficial effects
of MRBs in patients with CKD. Indeed, the
risks associated with hypokalemia appear
80
4
to be more consequential than the risks
associated with hyperkalemia in patients with
CKD. Controlling hyperkalemia during RAAS
blockade include dietary restriction, increased
colonic secretion of potassium and the use of
adjunctive diuretic therapy16.
6.
Bertocchio JP, Warnock DG, Jaisser F. Mineralocorticoid
receptor activation and blockade: An emerging
paradigm in chronic kidney disease. Kidney Int.
2011;79:1051-1060
7.
Guo C, Ricchiuti V, Lian BQ, Yao TM, Coutinho P, Romero
JR, Li J, Williams GH, Adler GK. Mineralocorticoid
receptor blockade reverses obesity-related changes
in expression of adiponectin, peroxisome proliferatoractivated receptor-gamma, and proinflammatory
adipokines. Circulation. 2008;117:2253-2261
8.
Kosugi T, Heinig M, Nakayama T, Matsuo S, Nakagawa
T. Enos knockout mice with advanced diabetic
nephropathy have less benefit from renin-angiotensin
blockade than from aldosterone receptor antagonists.
Am J Pathol.176:619-629
9.
Quinkler M, Zehnder D, Eardley KS, Lepenies J, Howie
AJ, Hughes SV, Cockwell P, Hewison M, Stewart PM.
Increased expression of mineralocorticoid effector
mechanisms in kidney biopsies of patients with heavy
proteinuria. Circulation. 2005;112:1435-1443
Conclusion.
The pathophysiological implication of aldosterone and the mineralocorticoid receptor
has been demonstrated ex vivo in cell culture
and in vivo in experimental animal models
with kidney damages such as diabetic and
hypertensive kidney nephropathies, chronic
kidney disease and glomerulopathies. The
benefits of pharmacological mineralocorticoid
receptor blockade in this clinical setting have
been demonstrated in human patients and
should stimulate large clinical trial to decipher
benefits and risks of MR antagonisms in
kidney diseases of various origins.
Bibliography.
1.
Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez
A, Palensky J, Wittes J. The effect of spironolactone
on morbidity and mortality in patients with severe
heart failure. Randomized aldactone evaluation study
investigators. N Engl J Med. 1999;341:709-717
2.
Pitt B, Remme W, Zannad F, Neaton J, Martinez F,
Roniker B, Bittman R, Hurley S, Kleiman J, Gatlin M.
Eplerenone, a selective aldosterone blocker, in patients
with left ventricular dysfunction after myocardial
infarction. N Engl J Med. 2003;348:1309-1321
3.
Zannad F, McMurray JJ, Drexler H, Krum H, van
Veldhuisen DJ, Swedberg K, Shi H, Vincent J, Pitt B.
Rationale and design of the eplerenone in mild patients
hospitalization and survival study in heart failure
(emphasis-hf). Eur J Heart Fail. 2010;12:617-622
4.
Farman N, Rafestin-Oblin ME. Multiple aspects of
mineralocorticoid selectivity. Am J Physiol Renal
Physiol. 2001;280:F181-192
5.
Viengchareun S, Le Menuet D, Martinerie L, Munier M,
Pascual-Le Tallec L, Lombes M. The mineralocorticoid
receptor: Insights into its molecular and (patho)
physiological biology. Nucl Recept Signal. 2007;5:e012
81
10. Ohtani T, Ohta M, Yamamoto K, Mano T, Sakata Y, Nishio
M, Takeda Y, Yoshida J, Miwa T, Okamoto M, Masuyama
T, Nonaka Y, Hori M. Elevated cardiac tissue level of
aldosterone and mineralocorticoid receptor in diastolic
heart failure: Beneficial effects of mineralocorticoid
receptor blocker. Am J Physiol Regul Integr Comp
Physiol. 2007;292:R946-954
11. de Resende MM, Kauser K, Mill JG. Regulation of
cardiac and renal mineralocorticoid receptor expression
by captopril following myocardial infarction in rats. Life
Sci. 2006
12. DeLano FA, Schmid-Schonbein GW. Enhancement
of glucocorticoid and mineralocorticoid receptor
density in the microcirculation of the spontaneously
hypertensive rat. Microcirculation. 2004;11:69-78
13. Krug AW, Allenhofer L, Monticone R, Spinetti G, Gekle
M, Wang M, Lakatta EG. Elevated mineralocorticoid
receptor activity in aged rat vascular smooth muscle cells
promotes a proinflammatory phenotype via extracellular
signal-regulated kinase 1/2 mitogen-activated protein
kinase and epidermal growth factor receptor-dependent
pathways. Hypertension.55:1476-1483
14. Lee SH, Yoo TH, Nam BY, Kim DK, Li JJ, Jung DS, Kwak
SJ, Ryu DR, Han SH, Lee JE, Moon SJ, Han DS, Kang SW.
Activation of local aldosterone system within podocytes
is involved in apoptosis under diabetic conditions. Am
J Physiol Renal Physiol. 2009;297:F1381-1390
15. Nagase M, Shibata S, Yoshida S, Nagase T, Gotoda T,
Fujita T. Podocyte injury underlies the glomerulopathy
of dahl salt-hypertensive rats and is reversed by
aldosterone blocker. Hypertension. 2006;47:10841093
MineRaloCoR
MineRaloCoRtiCoid
ReCeptoR antagoniStS: new theRapeutiC
oppoRtunitieS in ChRoniC kidney diSeaSeS
16. Jain G, Campbell RC, Warnock DG. Mineralocorticoid
receptor blockers and chronic kidney disease. Clin J
Am Soc Nephrol. 2009;4:1685-1691
17. Gross E, Rothstein M, Dombek S, Juknis HI. Effect
of spironolactone on blood pressure and the reninangiotensin-aldosterone system in oligo-anuric
hemodialysis patients. Am J Kidney Dis. 2005;46:94-101
18. Vukusich A, Kunstmann S, Varela C, Gainza D, Bravo
S, Sepulveda D, Cavada G, Michea L, Marusic ET. A
randomized, double-blind, placebo-controlled trial
of spironolactone on carotid intima-media thickness
in nondiabetic hemodialysis patients. Clin J Am Soc
Nephrol. 2010
19. Juurlink DN, Mamdani MM, Lee DS, Kopp A, Austin PC,
Laupacis A, Redelmeier DA. Rates of hyperkalemia
after publication of the randomized aldactone
evaluation study. N Engl J Med. 2004;351:543-551
20. Ritz E, Koleganova N. Aldosterone in uremia - beyond
blood pressure. Blood Purif. 2010;29:111-113
21. Ko DT, Juurlink DN, Mamdani MM, You JJ, Wang JT,
Donovan LR, Tu JV. Appropriateness of spironolactone
prescribing in heart failure patients: A populationbased study. J Card Fail. 2006;12:205-210
82
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Notes
83
Notes
84
4

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