Prehypertension

3 : 1 A. Muruganathan, Tirupur ABSTRACT The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and treatment of High suggested a new classification for high-normal BP levels-the Pre- . 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, 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 . 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 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 (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 SB-P mmHg* DBP mmHg LSM Drug Therapy** Normal <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.

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Ischemic Heart Disease Mortality Rate High-Normal Blood Pressure and CVD Risk: in Each Decade of Age Framingham Study High normal 130-139/85-89 mm Hg Normal 120-129/80-84 mm Hg SBP DBP Age at risk: Optimal <120/80 mm Hg 256 256 80-89 y 128 128 70-79 y Men Women 64 64 60-69 y 14 32 32 P<.001 IHD 50-59 y 12 mortality 16 16 40-49 y 10 10 (floating 8 8 P<.001 absolute risk 8 8 and 95% CI) 4 4 2 2 6 6 1 1 4 4 2 2 120 140 160 180 70 80 90 100 110 0

Cumulative incidenc (%) 0 Usual SBP (mm Hg) Usual DBP (mm Hg) 0 2 4 6 8 10 12 14 0 2 4 6 8 10 12 14 IHD, ischemic heart disease. Time (years) Time (years) Prospective Studies Collaboration. Lancet. 2002;360:1903-1913. Vasan et al. N Engl J Med. 2001;345:1291-1297. Fig. 1 : Ischemic heart disease-related mortality rates with blood Fig. 2 : Effect of high-normal blood pressure on risk of cardiova- pressure in individuals aged 40-89 years. Permission obtained scular disease. Cumulative incidence of cardiovascular events in from Elsevier Ltd lewington, S. et al. Lancet 360, 1903-1913 a|men and b|women without hypertension according to blood pres- (2002). sure category at baseline examination. Vertical bars indicate 95% normal blood pressure SBP, 130 to 139mmHg or DBPES to confidence intervals. Optimal blood pressure <120 mmHg and a diastolic pressure <80 mmHg. Normal blood pressure is a systolic 89 mmHg. In 2007, the ESC Committee decided not to use pressure of 120-129 mmHg or a diastolic pressure of 80-84 the term ‘prehypertension’. mmHg. High-normal blood pressure is a systolic pressure of 130- The term pre hypertension is more likely to create anxiety in 139 mmHg or a diastolic pressure of 85-89 mmHg. If the systolic a large subset of population and Hence IHG (International and diastolic pressure reading for an individual were in different hypertension Guidelines) does not recommend the use of the categories, the higher of the two categories was used. With per- term “pre hypertension”. mission from Vasan, R. S. et al. N. Engl. J. Med. 345, 1291-1297 (2001) Massachusetts Medical Society. All rights reserved. Despite the fierce opposition the new terminology was adopted at the strength of scientific research showing that previously • Decrease the rate of progression to hypertension with considered normal and high normal blood pressure levels still age prevents hypertension entirely. contained a significant risk of cardiovascular disease (CVD). • Enable insurance coverage for treatment of prehyperten- Experts noted that by introducing this new categorization of sion. hypertension there was progress in bringing prehypertension to the attention of doctors and the general public for better EPIDEMIOLOGY hypertension prevention. When we use of the term high Data from the 1999 and 2000 National Health and Nutrition normal blood pressure, the word ‘high’ is often ignored and Examination Survey (NHANES III) suggested that the ‘normal’ is overvalued (Figs. 1 & 2). prevalence of prehypertension among adults in the United States was approximately 31%. The prevalence was markedly higher Meta-analysis of approximately 1 million individuals from 61 among men than women (39 and 23 percent, respectively). long-term epidemiological studies demonstrated that for each The prevalence of hypertension and cardiovascular disease 20 mmHg increase in systolic blood pressure or 10 mmHg is rapidly increasing in India. A survey conducted in nine increase in diastolic blood pressure over 115/75 mmHg, there States of India by the National Nutrition Monitoring Bureau was a two-fold increase in mortality associated with coronary reported the pooled estimate of prehypertension in rural artery disease and . men to be about 45 %.A few studies from different regions RESONS FOR CREATING A CLASSIFICATION OF of India(e.g. Dr. Mohan cures study at Chennai) have also PREHYPERTENSION: indicated the prevalence of prehypertension in the range of • Increase awareness of lifetime risk of hypertension. 40-60%. Ongoing nutrition transition with progressive shift to a westernized diet may further accentuate the risk. It turns • Increased awareness of reduced risk of cardiovascular out that a huge number of people in any given population are complications. actually people with pre-hypertension. The prevalence of pre- • Identify individuals in whom early intervention by life- hypertension is clearly higher than that of high blood pressure style modifications could lower blood pressure. itself. Individuals who are overweight or obese are at risk of

106 Prehypertension

National Health and Nutrition Examination Survey 45 JNC 7 Class: Normal Prehypertension N=3488 40 39.0 34.7 32.8 35 31.2 31.5 31.7 28.9 50 30 50 25 23.1 23.1 20 40 37 Age 15 Prevalence (%) Prevalence 10 30 26 35-64 yrs 5 18 65+ yrs 0 20 16 Total 20-39 40-59 ≥60 Male Female White Black Hispanic Percent Age Gender Ethnicity 10 5

Greenland KJ, et al Arch Intern Med 2004;164:2113-2118. 0 High Normal Fig. 3 : Prevalence of prehypertension JNC VI Class: Optimal Normal pre-hypertension condition progressing faster to hypertension <120/80 120-129/80-84 130-139/85-89 mm Hg mm Hg mm Hg stage 1 or stage 2. Also surprisingly yet satisfactorily explainable, elderly members of society aged above 60 are Vasan, et al. Lancet 2001;358:1662-86 less likely to have pre-hypertension. The explanation is that Fig. 4 :4 Year progression to Hypertension the Framingham Heart by this age most of the people would have already developed Study hypertension (Figs. 3 & 4). dence of systolic and diastolic hypertension was inter- PROGRESSION TO SUSTAINED HYPERTENSION mediate. As a result of the rise in BP with time, the incidence of • Predictors of IDH were younger age and increased body hypertension increases from approximately 10 percent at age weight, and there was a high probability of progression 30 to 30 percent at age 60. A rise in BP with aging is relatively to systolic and diastolic hypertension at 6.7 years (55 common in normotensive subjects. Predictors — the rate at percent, adjusted hazard ratio 23.1), suggesting that IDH which new onset hypertension occurs varies importantly with is not a benign condition. Predictors of ISH were older the blood pressure at baseline. The magnitude of this effect is age and increased body weight. ISH appeared to arise illustrated by the following observations: more commonly from normal and high-normal blood pressure than from “burned out” diastolic hypertension. • A report from the examined the incidence of hypertension (defined as blood pres- PATHO-PHYSIOLOGY sure greater than 140/90 mmHg or use of antihyperten- Prehypertension is one step towards hypertension, hence the sive agent) over a four year period among patients who same factors are involved in both. initially had optimal (less than 120/80 mmHg), normal (120-129/80-84 mmHg) or high-normal (130-139/85-89 RISK FACTORS mmHg) blood pressures . A progressive increase in the Elevated concentrations of creative protein, Tumor necrosis frequency of development of hypertension was observed factor – (α) alpha homocysteine, oxidized low – density in these three groups; 5, 18, and 37 percent, respectively, lipoprotein, gamma-glutamyl transferase, micoalbuminuria, under age 65; and 16, 26, and 50 percent, respectively in and other inflammatory markers are associated with older subjects (Fig. 4). higher blood pressure. Prehypertension also accelerates • The differential incidence of isolated diastolic hyperten- the development of left ventricular (LV) hypertrophy and sion (IDH, blood pressure <140/≥90 mmHg) and isolat- diastolic dysfunction. ed systolic hypertension (ISH, blood pressure ≥140/<90 ATTICA STUDY mmHg) was examined in another report from the Toika et al illustrated evidence of sub clinical atherosclerosis, Framingham Heart Study with a mean follow-up time by measuring intima-media thickness of the carotid and of 10 years. Patients started on antihypertensive therapy brachial arteries in healthy men with borderline hypertension. were censored. The following findings were noted: prehypertension males and females had 31% higher CRP , • Among patients who initially had optimal (less than 32% higher TNF α 15% higher oxidized LDL 9% higher 120/80 mmHg), normal (120-129/80-84 mmHg) or amyloidal, 6% higher homocysteine levels and10% higher high-normal (130-139/85-89 mmHg) blood pressures, WBC counts compared to normotensives. Thus inflammation the incidence of new onset IDH was 3, 8 and 10 per plays a significant role in prehypertension also. 1000 person-years at risk, and the incidence of ISH was Subject with prehypertension have clinical characteristics of 6, 23 and 35 per 1000 persons years at risk. The inci- the insulin resistance. An autonomic imbalance shifting with

107 Medicine Update 2012  Vol. 22 augmented sympathetic tone and a significantly impaired hypertension stage 2. This is precisely the reason why there are parasympathetic activity is seen in prehypertension. The more people with pre-hypertension than hypertension itself in increased CV risk with prehypertension is smaller than the many societies. The only way to detect pre-hypertension is to risk associated with having diabetes but is greater than that frequently take blood pressure measurements even at home associated with smoking. using a home blood pressure monitor. In the cohort of 60,785 women enrolled in the Women’s Health Some reports presents and blurred vision amongst Initiative (WHI), important cardiovascular risk factors- others as symptoms of pre-hypertension. However, these including age, BMI, and prevalence of diabetes mellitus and symptoms and signs may be caused by other things which Hypercholesterolemia- increased- across rising categories of are not necessarily high blood pressure. Therefore they are blood pressure. not reliable of pre-hypertension. A study of 36,424 Israelis, of whom 51% of men and 36% of NON PHARMACOLOGICAL TREATMENT women had prehypertension, demonstrated that, compared Lifestyle modification with normotensive individuals, those with prehypertension had higher levels of blood glucose, total cholesterol, LDL There is much evidence pointing to the benefits of treating cholesterol and triglycerides, higher BMI, and lower levels the condition using lifestyle changes such as dietary of HDL cholesterol. BMI was the strongest predictor of modifications, weight loss and reduction in sodium intake. prehypertension. Prehypertension is also more prevalent in The effects of these modifications when put together individuals with diabetes mellitus than in those without. In produce substantial results. The Dietary Approaches to Stop a 12 year follow-up study of 2,629 American Indians who Hypertension (DASH) eating plan, which uses a diet rich were free from hypertension at baseline examination, the in fruits, vegetables, legumes, nuts, and low – fat dietary prevalence of prehypertension was significantly higher in products and low saturated fats, induced a significant those who subsequently developed diabetes mellitus than in lowering of BP, which was reduced even further when dietary those who did not. sodium was restricted. It is well recognized that higher salt intake is associated with higher blood pressure and reduction SUBCLINICAL DISEASE AND CARDIOVASCULAR in salt intake lowers blood pressure (Table 2). MAKERS A follow -up study of the PREMIER trial demonstrated that Accordingly, the Rotterdam Study, a prospective, population- multicomponent behavioral interventions with and without based study with 1,900 participants (≥55 years of age, the DASH diet - produced significant reductions in the 10 including 739 with normal blood pressure and 1,161 with year risk of coronary heart disease. prehypertension), found that individuals with prehypertension had significantly smaller arteriolar and venular diameters The Optimal Macro Nutrient intake trial to prevent Heart and arteriolar-venular ratios than normotensive individuals, disease (Omni Heart) tested the effects of diets rich in indicating the presence of microvascular damage. carbohydrate, protein (half from plant sources) or unsaturated fat (predominantly monounsaturated fat) for 6 weeks. This MICROALBUMINURIA study demonstrates that a variety of healthy diets can An organ- specific manifestation of generalized endothelial effectively lower cardiovascular risk factors and overall risk dysfunction that is associated with increased risk of of cardiovascular disease. cardiovascular disease- is more common in individuals with In a study by Engelhard et al consumption of tomato extracts, prehypertension than in those with normal blood pressure. which contain carotenoids such as lycopene, beta carotene There is also an association of serum uric acid levels in and vit E led to significant reduction in the levels of systolic prehypertension as in establish that hypertension. and diastolic BP. Thus natural antioxidants could reduce BP PSYCHOSOCIAL FACTORS levels in patient with mild hypertension or prehypertension. A study of 2334 middle aged men, in the US with A 10-15 year follow-up of the Trials of Hypertension prehypertension showed that men with high trait anger Prevention 1 and 2 studies (TOHP and 2) assessed the remote scores, revealed a modest association with progression to effects of dietary sodium reduction for 18 months (THOP 1) or hypertension and CHD. The study also showed that long for 36-48 months (TOHP 2) on risk of cardiovascular disease term psychological stress in persons with prehypertension, (, stroke, coronary revascularization, is associated with development of combined CHD and CHD or cardiovascular-related death) in middle-aged individuals related deaths. with prehypertension. Risk of a cardiovascular event was SYMTOMS 25% lower the intervention group than in the placebo group (Figure 5). No symptoms at all until high blood pressure advances even to

108 Prehypertension

a 0.20 Sodium intervention Table 2 : Lifestyle intervention for blood pressure reduction Control Intervention Recommendation ed systolic blood pres- 0.16 sure reduction 0.12 Weight reduction Maintain ideal body 5-20 mm Hg per 10 kg mass index below23 weight loss 0.08 kg/cm2 DASH eating plan Consume diet rich in 8-14 mm Hg 0.04 Cumulative incidence of CVD fruits, vegetables ,low –fat diary products with 0 reduced content of satu- rated and total fat

b 0.10 TOHP II Dietary sodium restric- Reduce dietary sodium 2-8mm Hg tion intake to<100 mmol/ 0.08 day (2.4 g sodium or6 g sodium chloride ) 0.06 Physical activity Engage in regular 4-0 mm Hg 0.04 aerobic physical activ- ity ,for example ,brisk 0.02 walking for at lead 3o Cumulative incidence of CVD min most days 0 Alcohol moderation Men’s < 60ml per day 2-4mmHg 0 2 4 6 8 10 12 14 16 twice a week Follow-up (years) Women <60 ml per day Fig. 5 : Incidence of cardiovascular disease (CVD) following twice week dietary sodium reduction. Cumulative incidence of cardiovascular Tobacco Total abstinence _ disease by sodium intervention group in a| TOHP 1 and b| TOHP 2, adjusted for age, sex, and clinic. Reproduced from BMJ, Cok, enalapril maleate, or placebo therapy. Patients who received N. R. et. 334, 885 (2007) with permission from BMJ Publishing active treatment and who achieved blood pressure values Group Ltd. within the prehypertensive range had no major change(0.9 PHARMACOLOGICAL TREATMENT mm3) in atheroma volume, where as those who became or 3 Good strategy is to manage the condition with the main aim of remained hypertensive had a 12.0mm increase, and who lowering blood pressure to within normal range, preventing a achieved normal blood pressure values had a decrease in 3 rise in blood pressure with age, careful monitoring for signs of atheroma volume of 4.6mm , end-organ damage and also to prevent blood pressure related Further study is required to determine the role, if any, of cardiovascular . pharmacotherapy in prehypertension among individuals TROPHY without other indications for such therapy (e.g., chronic kidney disease, ). In this trial Participants with prehypertension were randomly assigned to receive candesartan cilextil or placebo CONCLUSION for 2 years, followed by 2 years of placebo for all participants. Individuals with prehypertension have an increased risk In addition, all participants received instructions for lifestyle of full-blown hypertension, target organ damage and modification. During the first 2 years, the risk of developing cardiovascular-related morbidity and mortality. If there hypertension was reduced by 66.3% in the participants who is a future for drug treatment of prehypertension, we need received candesartan cilexetil compared with placebo group; to learn who should be treated for how many years, and the magnitude of risk of risk reduction decreased to16% by with which drug and at what dose. There is no convincing year 4, but was still statistically different from placebo. evidence that transient antihypertensive therapy changes the PHARAO TRIAL course of prehypertension or hypertension for now, a healthy lifestyle is the foundation for all therapies in persons with Participants with prehypertension were randomly assigned prehypertension. to receive ramipril or placebo and were followed for 3 years. The study showed statistically significant 34% reduction in References risk for the ramipril group. 1. Prehypertension: epidemiology, consequences and treat- ment. Reviews Eduardo Pimenta and Suzanne Oparill. CAMELOT TRIAL Pimenta, E. and Oparil, S Nat Rev Nephrol 2010;6:21- Patients underwent coronary intravascular ultrasound 30. examination at baseline and after 2 years of amlodipine, 2. Pharmacotherapy for Prehypertension- Mission Ac- 109 Medicine Update 2012  Vol. 22

complished? Heribert Schunkert, M.D. N Engl J Med sease risk in the Women’s Health Initiative. Circulation 2006;354:1742-1744 2007;115:855-860. 3. Prevalence of prehypertension in young military adults 10. Grotto, Grossman, E., Huerta, M. and Sharabi, Y. Preva- and its association with overweight and dyslipidaemia. lence of prehypertension and associated cardiovascular Indian J Med Res 134, August 2011, pp 162-167. Sou- risk profiles among young Israeli adults. Hypertension gat Ray, Bharati Kulkarni* and A. Sreenivas*. Indian J 2009;48:254-259. Med Res 2011;134:162-167. 11. Ikram. M. K. et al. Retinal vessel diameters and risk 4. Prehypertension (PHTN), VG Nadgouda, Medicine Up- of hypertension: the Rotterdam Study. Hypertension date Volume-20-2010. 2006;47:189-194. 5. Official topic from UpToDate@, the clinical informati- 12. Lee, J. E. et al. Serum uric acid is associated with mi- on service, Norman M.Kaplan. Clin J Am Soc Nephro croalbuminuria in prehypertension. Hypertension 2009;14:1381,1383,. 2006;47:962-967. 6. Review-High Normal BP and the risk of disease Yoshihi- 13. Maruthur, N. M., Wang, N. Y. and Appel, L. J. Lifestyle ro Kokubo, MD; Kei Kamide, MD. Circ J 2009;73:1381 interventions reduce coronary heart disease risk: results – 1385. from the PREMIER Trial. Circulation 2009;119:2026- 7. Feasibility of Treating PREHYPERTENSION with an 2031. ARB. (Trophy Trial) Julius et al; NEJM 2006. 14. Parikh NI, Pencina MJ, Wang TJ, et al. A risk for predic- 8. Mancia, G. et al. 2007 Guidelines for the management of ting near-term incidence of hypertension: the Framing- arterial hypertension: The Task Force for the Manage- ham Heart Study. Ann Intern Med 2008;148:102. ment of arterial Hypertension of the European Society 15. National Nutrition Monitoring Bureau (NNMB). Diet of Hypertension (ESH) and of the European Society of and nutritional status of population and prevalence of Cardiology (ESC). J Hypertens 2007;25:1105-1187. hypertension among adults in rural areas, NNMB Tech- 9. Hsia, J. et al. Prehypertension and cardiovascular di- nical Report 24: Hyderabad: NNMB 2006;P.35-7.

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