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1 3/23/2016 1

2 This presentation highlights the issues involved in preventing hypertension. Slide notes are included for the majority of slides, containing source materials and references. 2

3 The Framingham, Heart Study is a long-term, ongoing cardiovascular study on the residents of Framingham, Massachusetts, USA, which began in 1948 with 5209 adult subjects, and is now on its third generation of participants. The study provides longterm epidemiologic data on heart disease and stroke. 1 The long-term risk of developing hypertension and the trends associated with this risk over time were explored in 1298 participants in the Framingham Heart Study who were aged years and free of hypertension at baseline ( ). Their lifetime risk of developing hypertension and stage 1 high blood pressure ( 140/90 mmhg regardless of treatment) was 90%. 2 This represents a huge public health burden. The risk for hypertension remained the same over time for women, but was ~60% higher for men in the period compared with References: 1. Accessed February Vasan RS et al. JAMA 2002;287:

4 These figures are taken from The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7), published in Chobanian AV et al. Hypertension 2003;42:

5 This table provides information on blood pressure values for adults. Ranges may be lower for children and teenagers. Those with heart disease, diabetes or chronic kidney disease tend to have higher blood pressure values and need more aggressive treatment to reduce their blood pressure and so prevent life-threatening complications. Accessed February

6 6

7 This study found that a small reduction (average of 2 mmhg) in population distribution of diastolic blood pressure (DBP), such as that potentially achievable by a population-wide lifestyle modification, had a positive impact on the incidence of coronary heart disease and stroke. The study population was white men and women in the United States aged years. This lifestyle DBP change, in addition to medical treatment, could have a great public health impact on the number of coronary heart disease and stroke events prevented. Cook NR et al. Arch Intern Med 1995;155:

8 Many risk factors underlying hypertension have been identified, some of which are non-modifiable, such as age, gender, genetic factors and race. Other factors, such as being overweight, consuming a diet high in sodium and low in potassium, consuming alcohol and having a low level of physical activity are modifiable. Interventions aimed at changing the modifiable factors might decrease blood pressure and may prevent the development of hypertension. Slama M et al. Curr Opin Cardiol 2002;17:

9 Patient-targeted interventions are aimed at individual patients at risk for hypertension, rather than the population as a whole. The first step in this process is to identify those at risk. Slama M et al. Curr Opin Cardiol 2002;17:

10 10

11 Lifestyle modifications are often critically important in controlling hypertension. The six approaches that have been shown to be effective in preventing hypertension are: 1. Moderate physical exercise for example a brisk walk, longer than 30 minutes in duration 2. Maintenance of normal adult body weight, body mass index between 18.5 and 24.9 kg/m 2 3. Alcohol consumption needs to be no more than 1 oz/30 ml ethanol/day for men and no more than 0.5 oz/15 ml of ethanol/day for women and those of lower weight 4. Reduce dietary sodium intake to <100 mmol/day (~2.4 g of sodium or 6 g of sodium chloride) 5. Maintain adequate intake of dietary potassium (>90 mmol [3500 mg]/day) 6. Consume a diet that is rich in fruit, vegetables and low-fat dairy products (reduced content of saturated and total fat) the Dietary Approaches to Stop Hypertension (DASH; details available from accessed February 2016) eating plan. Kaplan NM. J Clin Hypertens 2004;6:

12 12

13 This 4-year, multicentre, randomized, double-blind study investigated whether early pharmacological treatment of those with high-normal blood pressure might prevent or delay the development of clinical hypertension. Untreated subjects were aged years with entry blood pressure readings / 89 or 139/ Participants received either placebo or 16 mg once-daily candesartan cilexetil for 2 years, after which, all subjects took placebo for a further 2 years. The main outcome measure was the development of clinical hypertension, defined as hypertension requiring treatment. Julius S et al. Hypertension 2004;44:

14 This trial was investigator-led, and aimed to find out if treatment of mild blood pressure elevations could prevent or delay the development of hypertension requiring treatment. There were a number of lines of evidence that suggested this might be the case, including the finding, known since the 1970s, that slight elevation of blood pressure is a precursor of future hypertension. As most mortality and morbidity from hypertension occurs with stage 1 hypertension preventing prehypertensives from developing stage 1 hypertension would have a major impact on public health. There seems to be little lasting will amongst the general population to adopt a healthy lifestyle, despite efforts to promote the benefits. In particular, encouraging weight loss, salt restriction, exercise and the DASH diet, all proven to lower blood pressure, have little lasting effect. Julius S et al. Hypertension 2004;44:

15 Julius S et al. Hypertension 2004;44:

16 In this study, 809 subjects were randomized (59% male participants; mean age 49.0±8.1 years) in 71 study centres in the United States. All were instructed to make lifestyle changes to reduce their blood pressure throughout the course of the trial. During the first 2 years, hypertension developed in 154 participants receiving placebo, and in 53 of those receiving candesartan (relative risk reduction 66.3%, P<0.001). After 4 years, hypertension developed in 240 participants receiving placebo, and in 208 of those receiving candesartan (relative risk reduction 15.6%, P<0.007). Stage 1 hypertension developed in nearly two-thirds of subjects without treatment; treatment with candesartan reduced the risk of hypertension during the study period. Julius S et al. N Engl J Med 2006;354:

17 This randomized, double-blind, placebo-controlled trial enrolled those with prehypertension aged years. Subjects received chlorthalidone 12.5 mg plus amiloride 2.5 mg or identical placebo. Subjects were followed for 18 months. Fuchs FD et al. Trials 2011;12:65. 17

18 This study investigated subjects with slightly raised blood pressure, who would not normally be offered blood pressure treatment and compared no treatment with diuretic treatment. Diuretics act on the main mechanism of blood pressure rising with age. Primary outcome measures were the incidence of hypertension, development or worsening of microalbuminuria and of left ventricular hypertrophy. Secondary outcomes were fatal or non-fatal cardiovascular events, such as myocardial infarction, stroke, heart failure, evidence of new subclinical atherosclerosis and sudden death. Fuchs FD et al. Trials 2011;12:65. 18

19 Non-drug treatment to prevent hypertension has had low long-term effectiveness; blood pressure lowering drugs can circumvent such limitation. Diuretics were particularly efficacious in this regard since they act on the main mechanism of blood pressure rising with age. Chlorthalidone with amiloride combines the efficacy of chlorthalidone with the potassium-sparing effect of amiloride, thus preventing electrolyte and metabolic abnormalities induced by chlorthalidone. Fuchs FD et al. Trials 2011;12:65. 19

20 20

21 Most of the numerous manifestations of cardiovascular disease are inheritable. The precise magnitude of the role played by inheritance varies by disease and by other factors, for example, age of disease onset. Angiotensinogen (AGT) was the first gene to show linkage with human essential or primary hypertension. 1 Position 6 of the AGT gene resides in the proximal promoter region, 6 base pairs upstream from the initiation site of transcription 2 and influences the basal rate of transcription of the gene. A study of this functional variant of AGT in 1509 white male and female subjects with diastolic blood pressure between 83 and 89 mmhg, already participating in Phase 2 of the Trial of Hypertension Prevention, found those with the AA genotype had a higher 3-year incidence of hypertension (44.6%) than those with the GG genotype (31.5%), relative risk 1.4 (95% confidence intervals: 0.87, 2.34). 3 References: 1. Hopkins PN and Hunt SC. Nature 2003;5: Inoue I et al. J Clin Invest 1997;99: Hunt SC et al. Hypertension 1998;32:

22 Participants in the AGT study by Hunt et al (previous slide) were randomized to receive sodium retention or weight loss intervention, or a combination of both interventions, or usual care. The incidence of hypertension was significantly lower after intervention to encourage sodium intake reduction for persons with the AA genotype (-2.2 mmhg) compared with those with the GG genotype (+1.1 mmhg) after 36 months. Hunt SC et al. Hypertension 1998;32:

23 Persons with a genetic predisposition to develop hypertension as a result of the AGT locus appear to have the greatest diastolic blood pressure decrease after either sodium reduction or weight loss. Long-term changes in diet and exercise habits may still be needed to control blood pressure. Hunt SC et al. Hypertension 1998;32:

24 This table shows 3-year hypertension incidence (%) of the four study groups by AA, AG and GG angiotensinogen genotypes. Hunt SC et al. Hypertension 1998;32:

25 There is evidence for a genetic influence on blood pressure and, hence, for hypertension running in families. References/Further reading: Goldman L, Ausiello D. Blood pressure: Cecil textbook of Medicine. 22nd edn. An Imprint of Elsevier, Philadelphia; p.346. Feinleib M et al. Am J Epidemiol 1977;106: Longini IM Jr et al. Am J Epidemiol 1984;120: Biron P et al. Can Med Assoc J 1976;115: Padmanabhan S et al. Circ Res 2015;116:

26 Genetic analysis of hypertension has produced complex results, meaning that the identification of genes possibly involved with common forms of hypertension has thus far proved challenging. References/Further reading: Ji W et al. Nat Genet 2008;40: Padmanbhan S et al. Trends Genet 2012;28: Tanira M et al. J Hum Hypertens 2005;19:7 19. Oparil S et al. Ann Intern Med 2003;139:

27 Bartter s syndrome (prevalence of ~1 per million) and Gitelman s syndrome (prevalence of 1 per 40,000) are recessive genetic diseases that change net renal salt absorption, lowering blood pressure. Although the homozygous form often results in neonatal death or salt wasting disease, the heterozygous carriers of the genes causing these blood-pressure-lowering diseases may benefit from their genetic status. Estimates based on the incidence of the homozygous diseases suggest this could be at least 1% of the general adult population. Ji W et al. Nat Genet 2008;40:

28 Genome-wide association studies have successfully identified genetic determinants of blood pressure and hypertension, but missing heritability is still a problem (heritability for blood pressure ranges between 30 and 60%). Future studies in blood pressure genetics need to also look beyond the genome-wide association studies, and may need to involve epigenetic factors in hypertension development. References: Ehret GB et al. Curr Hypertens Rep 2010;12: Levy D et al. Nat Genet 2009;41: Wang X et al. Hypertension 2010;56: Wang X et al. Curr Hypertens Rep 2011;13:

29 Abnormal kidney function has an important role in sodium-induced hypertension. Studies have looked at the effects of renal transplantation on sodium-induced hypertension in Dahl rats. 1 An early study observed that rats from a hypertensionresistant strain (salt-resistant) receiving a kidney from the hypertension-prone (saltsensitive) strain had higher blood pressures compared to controls, while hypertension-prone rats receiving a kidney from a hypertension-resistant strain had lower blood pressures than their respective controls. 2 Another study, using both high and low sodium diets in salt-sensitive and -resistant rats concluded that salt-resistant rats receiving a salt-sensitive kidney developed hypertension during a high sodium diet. The authors of this latter study also found that salt-sensitive rats on a high sodium diet receiving a salt-resistant kidney developed hypertension, leading them to conclude that extrarenal factors also contribute to sodium-induced hypertension in salt-sensitive rats. 3 References: 1. Ni Z and Vaziri D. Am J Hypertens 2001;14: Dahl Lk et al. Exp Biol Med 1972;140: Morgan DA et al. Hypertension 1990;15:

30 There is an escalating pattern of hypertension in sub-saharan African populations. The contribution of salt intake may be particularly important as it has been suggested that this population is more salt sensitive than other ethnic groups. One explanation for this is genetic. References: Opie LH et al. Circulation 2005;112: Weinberger MH. Hypertension 1996;27: Richardson SI et al. J Am Soc Hypertens 2013;7:

31 31

32 Lifestyle changes can be sustained over long periods of time (>3 years) and can have blood-pressure-lowering effects as large as those seen in drug trials. Primary prevention strategies are important in reducing hypertension, and thus reducing the risk of cardiovascular disease. The basic lifestyle changes needed are weight loss in those overweight, increased physical activity, moderation of alcohol intake, and consumption of a diet higher in fruits and vegetables and low-fat dairy products and lower in sodium than the average American diet. Krousel-Wood MA et al. Med Clin North Am 2004;88:

33 The individual lifestyle modifications recommended for blood pressure control are relatively simple, but are more likely to be successful with support. Modern lifestyles are dependent on easy food options, and these are not necessarily those with low sodium levels, or large proportions of fruits and vegetables. Help from the food industry, as well as education to guide choices for the general public are needed to reduce the rate of hypertension and prevent the reductions in health-related quality of life associated with cardiovascular disease. Krousel-Wood MA et al. Med Clin North Am 2004;88:

34 34

35 The US Department of Health and Human Services launched Healthy People 2010 in 2000, with the aim of highlighting specific objectives. One of these was the reduction in the proportion of adults with hypertension from the current rate in 2000 of 28%, down to 16% by Healthy People 2020 was launched in December 2010, with its primary aim to attain high-quality, longer lives, free of preventable disease, disability, injury, and premature death. More information and updates can be obtained from the website. Accessed February

36 The basic lifestyle changes needed are weight loss in those overweight, increased physical activity, moderation of alcohol intake, and consumption of a diet high in fruits and vegetables and low-fat dairy products and low in sodium. 36

37 Although the current national recommendation for sodium intake is <2.4 g daily in the United States, individuals older than 51 years and those of any age (including children) who are African American or have high blood pressure, diabetes, or chronic kidney disease should limit their intake to no more than 1500 g sodium/day. The average daily sodium intake for Americans >2 years old is 3400 g. NHANES. Available at: Accessed February

38 Men and women (n=181) who participated in the Trials of Hypertension Prevention, Phase 1 in Baltimore, USA, aged years and with diastolic blood pressure mmhg and systolic <160 mmhg were randomly assigned to 1 of 2 lifestyle modification interventions, aimed at either weight loss or sodium reduction, or to a usual care control group. After 7 years of follow-up, the incidence of hypertension was 18.9% in the weight loss group, 40.5% in the control group, and 22.4% in the sodium reduction group. Logistic regression analysis found that the odds of hypertension were reduced by 77% (OR 0.23; 95% CI 0.07, 0.76; P=0.02) in the weight loss group and by 35% (OR 0.65; 95% CI 0.25, 1.69; P=0.37) in the sodium reduction group compared with controls. He J et al. Hypertension 2000;35:

39 This meta-analysis comprised 54 randomized controlled trials incorporating 2419 participants. Aerobic exercise was associated with a significant reduction in mean systolic and diastolic blood pressure. Effects were evident in both hypertensive and normotensive persons as well as those overweight and of normal weight. Whelton SP et al. Ann Intern Med 2002;136:

40 This study looked at the role of diet and nutrition in the prevention of hypertension and cardiovascular diseases. Reddy KS and Rolan MB. Public Health Nutr 2004;7:

41 41

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