PrehyPertension 3 : 1 A. Muruganathan,

Prehypertension
3:1
A. Muruganathan, Tirupur
ABSTRACT
The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and
treatment of High Blood Pressure suggested a new classification for high-normal BP levels-the PreHypertension. Normal blood pressure systolic <120 mmHg and diastolic <80 mmHg Prehypertension
— systolic 120 to 139 mmHg or diastolic 80 to 89 mmHg. Prehypertension is often associated
with multiple additional cardiovascular risk factors, such as obesity, diabetes mellitus, dyslipidemia,
and inflammatory markers, and evidence of organ damage for example, microalbuminuria, retinal
arteriolar narrowing, increased carotid arterial intima-media thickness, left ventricular hypertrophy
and coronary artery disease. Nonpharmacological treatment with lifestyle modifications such as
weight loss, dietary modification and increased physical activity is recommended for all patients with
prehypertension. Where as pharmacological therapy is indicated for some patients with prehypertension
who have specific co-morbidities, including diabetes mellitus, chronic kidney disease and coronary
artery disease. Because of its high prevalence and long-term complications, prehypertension has been
estimated to decrease the average life expectancy by as much as five years. Unfortunately, current
preventive strategies, although admirable from both individual and societal perspectives, are weak.
INTRODUCTION
The term ‘prehypertension’ was coined in 1939 in the context of early studies that linked high blood
pressure recorded for life insurance purposes to subsequent morbidity and mortality . Long-term
follow-up of patients destined to develop essential (primary) hypertension demonstrates that blood
pressure (BP) readings gradually increase over time.
DEFINITION
Prehypertension, defined as the blood-pressure range of 120 to 139 mm Hg systolic or 80 to 89 mm
Hg diastolic, the condition heralds arterial hypertension and thus may be considered a starting point
in the cardiovascular disease continuum. The seventh report of the Joint National Committee (JNC
7) published in 2003 proposed the following classification based upon the average of two or more
properly measured readings at each of two or more visits after an initial screen (Table 1).
The European Society of Hypertension and the European Society of Cardiology (ESH_ESC) guidelines
for the hypertension consider prehypertensive to be categorized into, Normal blood pressure” (systolic
blood pressure SBP,120 to 129 mmHg or diastolic blood pressure DBP, 80 to 84 mmHg) and High
Table 1 : Blood Pressure Classification JNC-7-2003
BP Classification
Normal
SB-P mmHg*
DBP mmHg LSM
Drug Therapy**
<120
And
< 80
Encourage
No
Pre hypertension
120-139
Or
80 – 89
Yes
No
Stage 1 Hypertension
140-159
Or
90-99
Yes
Single agent
Stage 2 Hypertension
> 160
Or
>100
Yes
Combo
*Treatment determined by highest BP category: ** Consider treatment for compelling indications Regardless of BP Normal.
JNC 7 Express. JAMA 2003 Sep 10; 290 (10); 114.
105
Medicine Update 2012  Vol. 22
High-Normal Blood Pressure and CVD Risk:
Framingham Study
Ischemic Heart Disease Mortality Rate
in Each Decade of Age
256
128
128
64
64
32
IHD
mortality 16
(floating
8
absolute risk
and 95% CI) 4
32
2
2
1
1
DBP
Age at risk:
80-89 y
Men
70-79 y
14
12
10
8
6
4
2
0
60-69 y
50-59 y
16
40-49 y
8
4
120 140 160 180
Usual SBP (mm Hg)
High normal 130-139/85-89 mm Hg
Normal 120-129/80-84 mm Hg
Optimal <120/80 mm Hg
Cumulative incidenc (%)
256
SBP
70 80 90 100 110
Usual DBP (mm Hg)
Women
P<.001
0
2
4
6
8
10 12 14
Time (years)
IHD, ischemic heart disease.
Prospective Studies Collaboration. Lancet. 2002;360:1903-1913.
10
8
6
4
2
0
P<.001
0
2
4
6
8
10 12 14
Time (years)
Vasan et al. N Engl J Med. 2001;345:1291-1297.
Fig. 1 : Ischemic heart disease-related mortality rates with blood
pressure in individuals aged 40-89 years. Permission obtained
from Elsevier Ltd lewington, S. et al. Lancet 360, 1903-1913
(2002).
normal blood pressure SBP, 130 to 139mmHg or DBPES to
89 mmHg. In 2007, the ESC Committee decided not to use
the term ‘prehypertension’.
The term pre hypertension is more likely to create anxiety in
a large subset of population and Hence IHG (International
hypertension Guidelines) does not recommend the use of the
term “pre hypertension”.
Despite the fierce opposition the new terminology was adopted
at the strength of scientific research showing that previously
considered normal and high normal blood pressure levels still
contained a significant risk of cardiovascular disease (CVD).
Experts noted that by introducing this new categorization of
hypertension there was progress in bringing prehypertension
to the attention of doctors and the general public for better
hypertension prevention. When we use of the term high
normal blood pressure, the word ‘high’ is often ignored and
‘normal’ is overvalued (Figs. 1 & 2).
Meta-analysis of approximately 1 million individuals from 61
long-term epidemiological studies demonstrated that for each
20 mmHg increase in systolic blood pressure or 10 mmHg
increase in diastolic blood pressure over 115/75 mmHg, there
was a two-fold increase in mortality associated with coronary
artery disease and stroke.
RESONS FOR CREATING A CLASSIFICATION OF
PREHYPERTENSION:
•
Increase awareness of lifetime risk of hypertension.
•
Increased awareness of reduced risk of cardiovascular
complications.
•
Identify individuals in whom early intervention by lifestyle modifications could lower blood pressure.
Fig. 2 : Effect of high-normal blood pressure on risk of cardiovascular disease. Cumulative incidence of cardiovascular events in
a|men and b|women without hypertension according to blood pressure category at baseline examination. Vertical bars indicate 95%
confidence intervals. Optimal blood pressure <120 mmHg and a
diastolic pressure <80 mmHg. Normal blood pressure is a systolic
pressure of 120-129 mmHg or a diastolic pressure of 80-84
mmHg. High-normal blood pressure is a systolic pressure of 130139 mmHg or a diastolic pressure of 85-89 mmHg. If the systolic
and diastolic pressure reading for an individual were in different
categories, the higher of the two categories was used. With permission from Vasan, R. S. et al. N. Engl. J. Med. 345, 1291-1297
(2001) Massachusetts Medical Society. All rights reserved.
•
Decrease the rate of progression to hypertension with
age prevents hypertension entirely.
•
Enable insurance coverage for treatment of prehypertension.
EPIDEMIOLOGY
Data from the 1999 and 2000 National Health and Nutrition
Examination Survey (NHANES III) suggested that the
prevalence of prehypertension among adults in the United States
was approximately 31%. The prevalence was markedly higher
among men than women (39 and 23 percent, respectively).
The prevalence of hypertension and cardiovascular disease
is rapidly increasing in India. A survey conducted in nine
States of India by the National Nutrition Monitoring Bureau
reported the pooled estimate of prehypertension in rural
men to be about 45 %.A few studies from different regions
of India(e.g. Dr. Mohan cures study at Chennai) have also
indicated the prevalence of prehypertension in the range of
40-60%. Ongoing nutrition transition with progressive shift
to a westernized diet may further accentuate the risk. It turns
out that a huge number of people in any given population are
actually people with pre-hypertension. The prevalence of prehypertension is clearly higher than that of high blood pressure
itself. Individuals who are overweight or obese are at risk of
106
45
40
35
30
25
20
15
10
5
0
National Health and Nutrition Examination Survey
31.2
32.8
34.7
31.5
23.1
JNC 7 Class:
N=3488
39.0
28.9
Total
20-39
40-59
Age
≥60
Male
Female
Gender
White
Black Hispanic
Ethnicity
Age
37
26
30
35-64 yrs
65+ yrs
18
16
20
10
5
0
JNC VI Class:
A report from the Framingham Heart Study examined
the incidence of hypertension (defined as blood pressure greater than 140/90 mmHg or use of antihypertensive agent) over a four year period among patients who
initially had optimal (less than 120/80 mmHg), normal
(120-129/80-84 mmHg) or high-normal (130-139/85-89
mmHg) blood pressures . A progressive increase in the
frequency of development of hypertension was observed
in these three groups; 5, 18, and 37 percent, respectively,
under age 65; and 16, 26, and 50 percent, respectively in
older subjects (Fig. 4).
The differential incidence of isolated diastolic hypertension (IDH, blood pressure <140/≥90 mmHg) and isolated systolic hypertension (ISH, blood pressure ≥140/<90
mmHg) was examined in another report from the
Framingham Heart Study with a mean follow-up time
of 10 years. Patients started on antihypertensive therapy
were censored. The following findings were noted:
Among patients who initially had optimal (less than
120/80 mmHg), normal (120-129/80-84 mmHg) or
high-normal (130-139/85-89 mmHg) blood pressures,
the incidence of new onset IDH was 3, 8 and 10 per
1000 person-years at risk, and the incidence of ISH was
6, 23 and 35 per 1000 persons years at risk. The inci-
Normal
120-129/80-84
mm Hg
High Normal
130-139/85-89
mm Hg
Vasan, et al. Lancet 2001;358:1662-86
Fig. 4 :4 Year progression to Hypertension the Framingham Heart
Study
dence of systolic and diastolic hypertension was intermediate.
PROGRESSION TO SUSTAINED HYPERTENSION
As a result of the rise in BP with time, the incidence of
hypertension increases from approximately 10 percent at age
30 to 30 percent at age 60. A rise in BP with aging is relatively
common in normotensive subjects. Predictors — the rate at
which new onset hypertension occurs varies importantly with
the blood pressure at baseline. The magnitude of this effect is
illustrated by the following observations:
Optimal
<120/80
mm Hg
pre-hypertension condition progressing faster to hypertension
stage 1 or stage 2. Also surprisingly yet satisfactorily
explainable, elderly members of society aged above 60 are
less likely to have pre-hypertension. The explanation is that
by this age most of the people would have already developed
hypertension (Figs. 3 & 4).
•
50
40
Fig. 3 : Prevalence of prehypertension
•
Prehypertension
50
23.1
Greenland KJ, et al Arch Intern Med 2004;164:2113-2118.
•
Normal
31.7
Percent
Prevalence (%)
Prehypertension
•
Predictors of IDH were younger age and increased body
weight, and there was a high probability of progression
to systolic and diastolic hypertension at 6.7 years (55
percent, adjusted hazard ratio 23.1), suggesting that IDH
is not a benign condition. Predictors of ISH were older
age and increased body weight. ISH appeared to arise
more commonly from normal and high-normal blood
pressure than from “burned out” diastolic hypertension.
PATHO-PHYSIOLOGY
Prehypertension is one step towards hypertension, hence the
same factors are involved in both.
RISK FACTORS
Elevated concentrations of creative protein, Tumor necrosis
factor – (α) alpha homocysteine, oxidized low – density
lipoprotein, gamma-glutamyl transferase, micoalbuminuria,
and other inflammatory markers are associated with
higher blood pressure. Prehypertension also accelerates
the development of left ventricular (LV) hypertrophy and
diastolic dysfunction.
ATTICA STUDY
Toika et al illustrated evidence of sub clinical atherosclerosis,
by measuring intima-media thickness of the carotid and
brachial arteries in healthy men with borderline hypertension.
prehypertension males and females had 31% higher CRP ,
32% higher TNF α 15% higher oxidized LDL 9% higher
amyloidal, 6% higher homocysteine levels and10% higher
WBC counts compared to normotensives. Thus inflammation
plays a significant role in prehypertension also.
Subject with prehypertension have clinical characteristics of
the insulin resistance. An autonomic imbalance shifting with
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Medicine Update 2012  Vol. 22
augmented sympathetic tone and a significantly impaired
parasympathetic activity is seen in prehypertension. The
increased CV risk with prehypertension is smaller than the
risk associated with having diabetes but is greater than that
associated with smoking.
hypertension stage 2. This is precisely the reason why there are
more people with pre-hypertension than hypertension itself in
many societies. The only way to detect pre-hypertension is to
frequently take blood pressure measurements even at home
using a home blood pressure monitor.
In the cohort of 60,785 women enrolled in the Women’s Health
Initiative (WHI), important cardiovascular risk factorsincluding age, BMI, and prevalence of diabetes mellitus and
Hypercholesterolemia- increased- across rising categories of
blood pressure.
Some reports presents headache and blurred vision amongst
others as symptoms of pre-hypertension. However, these
symptoms and signs may be caused by other things which
are not necessarily high blood pressure. Therefore they are
not reliable signs and symptoms of pre-hypertension.
A study of 36,424 Israelis, of whom 51% of men and 36% of
women had prehypertension, demonstrated that, compared
with normotensive individuals, those with prehypertension
had higher levels of blood glucose, total cholesterol, LDL
cholesterol and triglycerides, higher BMI, and lower levels
of HDL cholesterol. BMI was the strongest predictor of
prehypertension. Prehypertension is also more prevalent in
individuals with diabetes mellitus than in those without. In
a 12 year follow-up study of 2,629 American Indians who
were free from hypertension at baseline examination, the
prevalence of prehypertension was significantly higher in
those who subsequently developed diabetes mellitus than in
those who did not.
NON PHARMACOLOGICAL TREATMENT
SUBCLINICAL DISEASE AND CARDIOVASCULAR
MAKERS
Accordingly, the Rotterdam Study, a prospective, populationbased study with 1,900 participants (≥55 years of age,
including 739 with normal blood pressure and 1,161 with
prehypertension), found that individuals with prehypertension
had significantly smaller arteriolar and venular diameters
and arteriolar-venular ratios than normotensive individuals,
indicating the presence of microvascular damage.
MICROALBUMINURIA
An organ- specific manifestation of generalized endothelial
dysfunction that is associated with increased risk of
cardiovascular disease- is more common in individuals with
prehypertension than in those with normal blood pressure.
There is also an association of serum uric acid levels in
prehypertension as in establish that hypertension.
PSYCHOSOCIAL FACTORS
A study of 2334 middle aged men, in the US with
prehypertension showed that men with high trait anger
scores, revealed a modest association with progression to
hypertension and CHD. The study also showed that long
term psychological stress in persons with prehypertension,
is associated with development of combined CHD and CHD
related deaths.
SYMTOMS
No symptoms at all until high blood pressure advances even to
Lifestyle modification
There is much evidence pointing to the benefits of treating
the condition using lifestyle changes such as dietary
modifications, weight loss and reduction in sodium intake.
The effects of these modifications when put together
produce substantial results. The Dietary Approaches to Stop
Hypertension (DASH) eating plan, which uses a diet rich
in fruits, vegetables, legumes, nuts, and low – fat dietary
products and low saturated fats, induced a significant
lowering of BP, which was reduced even further when dietary
sodium was restricted. It is well recognized that higher salt
intake is associated with higher blood pressure and reduction
in salt intake lowers blood pressure (Table 2).
A follow -up study of the PREMIER trial demonstrated that
multicomponent behavioral interventions with and without
the DASH diet - produced significant reductions in the 10
year risk of coronary heart disease.
The Optimal Macro Nutrient intake trial to prevent Heart
disease (Omni Heart) tested the effects of diets rich in
carbohydrate, protein (half from plant sources) or unsaturated
fat (predominantly monounsaturated fat) for 6 weeks. This
study demonstrates that a variety of healthy diets can
effectively lower cardiovascular risk factors and overall risk
of cardiovascular disease.
In a study by Engelhard et al consumption of tomato extracts,
which contain carotenoids such as lycopene, beta carotene
and vit E led to significant reduction in the levels of systolic
and diastolic BP. Thus natural antioxidants could reduce BP
levels in patient with mild hypertension or prehypertension.
A 10-15 year follow-up of the Trials of Hypertension
Prevention 1 and 2 studies (TOHP and 2) assessed the remote
effects of dietary sodium reduction for 18 months (THOP 1) or
for 36-48 months (TOHP 2) on risk of cardiovascular disease
(myocardial infarction, stroke, coronary revascularization,
or cardiovascular-related death) in middle-aged individuals
with prehypertension. Risk of a cardiovascular event was
25% lower the intervention group than in the placebo group
(Figure 5).
108
a
0.20
Cumulative incidence of CVD
Prehypertension
0.16
Table 2 : Lifestyle intervention for blood pressure reduction
Sodium intervention
Control
Intervention
0.12
Maintain ideal body 5-20 mm Hg per 10 kg
mass index below23 weight loss
kg/cm2
DASH eating plan
Consume diet rich in 8-14 mm Hg
fruits, vegetables ,low
–fat diary products with
reduced content of saturated and total fat
0
Cumulative incidence of CVD
b 0.10
Dietary sodium restric- Reduce dietary sodium 2-8mm Hg
tion
intake to<100 mmol/
day (2.4 g sodium or6 g
sodium chloride )
TOHP II
0.08
0.06
Physical activity
Engage in regular 4-0 mm Hg
aerobic physical activity ,for example ,brisk
walking for at lead 3o
min most days
Alcohol moderation
Men’s < 60ml per day 2-4mmHg
twice a week
Women <60 ml per day
twice week
Tobacco
Total abstinence
0.04
0.02
0
0
2
ed systolic blood pressure reduction
Weight reduction
0.08
0.04
Recommendation
4
6
8
10
Follow-up (years)
12
14
16
Fig. 5 : Incidence of cardiovascular disease (CVD) following
dietary sodium reduction. Cumulative incidence of cardiovascular
disease by sodium intervention group in a| TOHP 1 and b| TOHP
2, adjusted for age, sex, and clinic. Reproduced from BMJ, Cok,
N. R. et. 334, 885 (2007) with permission from BMJ Publishing
Group Ltd.
PHARMACOLOGICAL TREATMENT
Good strategy is to manage the condition with the main aim of
lowering blood pressure to within normal range, preventing a
rise in blood pressure with age, careful monitoring for signs of
end-organ damage and also to prevent blood pressure related
cardiovascular diseases.
TROPHY
In this trial
Participants with prehypertension were
randomly assigned to receive candesartan cilextil or placebo
for 2 years, followed by 2 years of placebo for all participants.
In addition, all participants received instructions for lifestyle
modification. During the first 2 years, the risk of developing
hypertension was reduced by 66.3% in the participants who
received candesartan cilexetil compared with placebo group;
the magnitude of risk of risk reduction decreased to16% by
year 4, but was still statistically different from placebo.
PHARAO TRIAL
Participants with prehypertension were randomly assigned
to receive ramipril or placebo and were followed for 3 years.
The study showed statistically significant 34% reduction in
risk for the ramipril group.
CAMELOT TRIAL
Patients underwent coronary intravascular ultrasound
examination at baseline and after 2 years of amlodipine,
_
enalapril maleate, or placebo therapy. Patients who received
active treatment and who achieved blood pressure values
within the prehypertensive range had no major change(0.9
mm3) in atheroma volume, where as those who became or
remained hypertensive had a 12.0mm3 increase, and who
achieved normal blood pressure values had a decrease in
atheroma volume of 4.6mm3,
Further study is required to determine the role, if any, of
pharmacotherapy in prehypertension among individuals
without other indications for such therapy (e.g., chronic
kidney disease, heart failure).
CONCLUSION
Individuals with prehypertension have an increased risk
of full-blown hypertension, target organ damage and
cardiovascular-related morbidity and mortality. If there
is a future for drug treatment of prehypertension, we need
to learn who should be treated for how many years, and
with which drug and at what dose. There is no convincing
evidence that transient antihypertensive therapy changes the
course of prehypertension or hypertension for now, a healthy
lifestyle is the foundation for all therapies in persons with
prehypertension.
References
1. Prehypertension: epidemiology, consequences and treatment. Reviews Eduardo Pimenta and Suzanne Oparill.
Pimenta, E. and Oparil, S Nat Rev Nephrol 2010;6:2130.
2. Pharmacotherapy for Prehypertension- Mission Ac-
109
Medicine Update 2012  Vol. 22
3.
4.
5.
6.
7.
8.
9.
complished? Heribert Schunkert, M.D. N Engl J Med
2006;354:1742-1744
Prevalence of prehypertension in young military adults
and its association with overweight and dyslipidaemia.
Indian J Med Res 134, August 2011, pp 162-167. Sougat Ray, Bharati Kulkarni* and A. Sreenivas*. Indian J
Med Res 2011;134:162-167.
Prehypertension (PHTN), VG Nadgouda, Medicine Update Volume-20-2010.
Official topic from UpToDate@, the clinical information service, Norman M.Kaplan. Clin J Am Soc Nephro
2009;14:1381,1383,.
Review-High Normal BP and the risk of disease Yoshihiro Kokubo, MD; Kei Kamide, MD. Circ J 2009;73:1381
– 1385.
Feasibility of Treating PREHYPERTENSION with an
ARB. (Trophy Trial) Julius et al; NEJM 2006.
Mancia, G. et al. 2007 Guidelines for the management of
arterial hypertension: The Task Force for the Management of arterial Hypertension of the European Society
of Hypertension (ESH) and of the European Society of
Cardiology (ESC). J Hypertens 2007;25:1105-1187.
Hsia, J. et al. Prehypertension and cardiovascular di-
sease risk in the Women’s Health Initiative. Circulation
2007;115:855-860.
10. Grotto, Grossman, E., Huerta, M. and Sharabi, Y. Prevalence of prehypertension and associated cardiovascular
risk profiles among young Israeli adults. Hypertension
2009;48:254-259.
11. Ikram. M. K. et al. Retinal vessel diameters and risk
of hypertension: the Rotterdam Study. Hypertension
2006;47:189-194.
12. Lee, J. E. et al. Serum uric acid is associated with microalbuminuria in prehypertension. Hypertension
2006;47:962-967.
13. Maruthur, N. M., Wang, N. Y. and Appel, L. J. Lifestyle
interventions reduce coronary heart disease risk: results
from the PREMIER Trial. Circulation 2009;119:20262031.
14. Parikh NI, Pencina MJ, Wang TJ, et al. A risk for predicting near-term incidence of hypertension: the Framingham Heart Study. Ann Intern Med 2008;148:102.
15. National Nutrition Monitoring Bureau (NNMB). Diet
and nutritional status of population and prevalence of
hypertension among adults in rural areas, NNMB Technical Report 24: Hyderabad: NNMB 2006;P.35-7.
110