Obesity, Hypertension, and the Heart

Obesity, Hypertension, and the Heart

Obesity, Hypertension, and the Heart VASHU THAKUR, MD; ROBERT RICHARDS, MD; EFRAIN REISIN, MD ABSTRACT: Hypertension occurs more commonly in obese th...

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Obesity, Hypertension, and the Heart VASHU THAKUR, MD; ROBERT RICHARDS, MD; EFRAIN REISIN, MD

ABSTRACT: Hypertension occurs more commonly in obese than in lean persons at virtually every age. A variety of endocrine, genetic, and metabolic mechanisms have been linked to the development of obesity hypertension. These include insulin resistance and hyperinsulinemia, increased serum aldosterone levels, salt sensitivity and expanded plasma volume in the presence of increased peripheral vascular resistance, a genetic predisposition, and possibly increased leptin levels. Pressure and volume overload are present in obese hypertensives. This leads to a mixed eccentric-concen-

tric form of left ventricular hypertrophy and increases the predisposition to congestive heart failure. Weight loss, even in modest decrements, is effective in reducing obesity-hypertension, possibly by ameliorating several of the proposed pathophysiologic mechanisms. There are currently no specific recommendations concerning pharmacotherapy of obesity-hypertension because each drug group has pros and cons. KEY INDEXING TERMS: Obesity; Hypertension; Left ventricular hypertrophy; Congestive heart failure. [Am J Med Sci 2001;321(4): 242–248.]

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diabetes mellitus, smoking, and increased levels of lipids modify this increased mortality. In fact, obesity in and of itself contributes very little to the increased risk of mortality.10

besity refers to surplus body fat1 and may be defined as weight 20% above ideal body weight. However, because obese persons have an increased fat-free mass compared with lean persons of the same height, the use of an “ideal” body weight to determine obesity may be misleading. Under the current uniform measure for obesity, body mass index (BMI), obesity is defined as having a BMI greater than 27.8 kg/m2 for men and 27.3 kg/m2 for women.2 The incidence of obesity is on the rise; it now affects one third of all Americans.2 There is an established relationship between obesity and hypertension.3–7 However, the literature is divergent on the prevalence of hypertension in the obese. The Second National Health and Nutrition Examination Survey (NHANES II) data offer a possible explanation for this variability.8 Even though overall data showed that obese persons were 3 times as likely as nonobese persons to have hypertension, there were differences among individual groups. For example, obese young adults had a 5.5-fold higher risk than older obese, whereas the risk was only 1.9 times higher in those between the ages of 45 and 75 years. Even though white women had a lower prevalence of obesity, they were at a greater risk for developing obesity-hypertension.9 These differences may be related to close association of hypertension to upper-body rather than lower-body obesity. Not surprisingly, upper-body obesity is associated with increased mortality. The presence of hypertension, From the Sections of Nephrology (VT, ER) and Endocrinology (RR), Louisiana State University School of Medicine, New Orleans, Louisiana. Correspondence: Efrain Reisin, M.D., Section of Nephrology, 1542 Tulane Avenue, New Orleans, LA 70112.

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Pathogenesis of Obesity-Hypertension A series of endocrine, genetic, and metabolic mechanisms have been linked to the development of obesity-hypertension. These include insulin resistance/hyperinsulinemia, overactivity of sympathetic nervous system, the renin-angiotensin-aldosterone system, salt retention, genetic predisposition, and leptin levels. A schematic review of these mechanisms and their probable interaction in causation of obesity hypertension is presented in Figure 1, and each mechanism is discussed below. Insulin Resistance/Hyperinsulinemia. Obesity-hypertension is strongly associated with insulin resistance, which in turn leads to increased insulin levels, especially in those with upper-body obesity. Hyperinsulinemia results from accumulation of lipolytic hyperactive abdominal cells, with release of large amounts of free fatty acids in the portal vein. Excess free fatty acids leads to increased synthesis of triglycerides, which in turn inhibits insulin uptake and causes insulin resistance and hyperinsulinemia.11 Additional evidence that upper-body obesity induces hyperinsulinemia derives from the fact that the percentage of body fat and waist-to-hip ratio strongly correlate with insulin’s action on glucose uptake.12 Therefore, obese-hypertensives have a lower index of insulin action than do nonobese and obese, nonhypertensive persons. It has been well documented in rats that hyperinsulinemia can cause elevated blood pressure.13 AdApril 2001 Volume 321 Number 4

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Figure 1. Schematic of mechanisms of obesity-hypertension and their probable interactions. (Reproduced from Maxwell M, Herber D, Waks AV, et al. Role of insulin and norepinephrine in the hypertension of obesity. Am J Hypertens 1995;7:402– 08. Copyright © 1995 Elsevier Science Inc. Used with permission.)

ministration of insulin in rats leads to increased vascular wall thickness by causing hypertrophy of the tunica media of myocardial vessels.13 Additionally, insulin infused in the renal artery increases sodium absorption in the diluting segment of the distal nephron.14 Accordingly, insulin can raise blood pressure by causing sodium retention and hypervolemia and by increasing peripheral vascular resistance (PVR).13–15 The association between high insulin levels and obesity is not uniform. Maxwell et al failed to demonstrate consistently high insulin levels in the obese.16 It has also been argued that the effect of insulin on blood pressure is short-lived and should not lead to sustained hypertension.17 Despite the controversy, there is a general agreement that insulin plays a causative or contributory role in obesity-hypertension. Renin-Angiotensin-Aldosterone System and Other Endocrine Factors. It has been suggested that the renin-angiotensin-aldosterone system plays an important role in obesity-related hypertension. When measured, however, renin levels are no higher in obese persons than they were in lean subjects. In fact, the renin levels progressively decrease as obesity becomes more severe.18,19 Aldosterone levels, on the other hand, increase in obese persons compared with nonobese persons;20 in obese persons, then, there is an increase in the ratio of plasma aldosterone levels to plasma renin levels. This relative increase in the aldosterone leads to a higher total body salt and water and therefore plays a role in the pathogenesis of hypertension in the obese.19 Other endocrine factors that potentially play a role in the causation of obesity-hypertension relate to corticosteroids and sympathetic nervous system. Cortisol THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES

production and urinary excretion of cortisol are increased in obesity, even though plasma cortisol level is within normal limits.18 Increased sympathetic activity, specifically high norepinephrine levels, is associated with increased incidence of hypertension in the presence of obesity. Ward et al21 demonstrated a 3.5-fold higher prevalence of hypertension in those in the highest terciles of insulin and norepinephrine levels compared with those in the lowest terciles. Salt Sensitivity and Plasma Volume. Obesity promotes salt sensitivity.22 Indeed, increased salt intake seems to play a crucial role in the pathogenesis of obesity-hypertension.23 The mechanisms by which obesity induces salt sensitivity and increased salt intake are not well understood. It has been proposed that insulin resistance and hyperinsulinemia play an important role.20,24 An increase in intracellular calcium concentration by way of decreased Na-K-ATPase may contribute to the generation of obesity hypertension.25,26 Increased intracellular concentration of calcium in the smooth muscle cells can lead to hypertension by causing increased muscle tone and higher PVR.20,27 In lean subjects with hypertension, blood volume has an inverse relationship to blood pressure: the higher the blood pressure, the lower the blood volume.28 Conversely, in obese-hypertensive subjects, total blood volume is increased, which in turn leads to higher cardiac output.29,30 High cardiac output may lead to increased blood pressure. In addition, the normal compensatory response of a decrease in PVR in response to increased blood volume is blunted in the obese. In other words, there is a relative increase in the PVR. Hence, both the increased blood volume with resulting increased car243

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diac output and a relative increase in PVR contribute to obesity-hypertension. Further investigation on the subject has shown that intracellular body water is increased more than interstitial fluid volume and plasma fluid volume.31 The increased intracellular-to-interstitial fluid volume ratio may be related to increased intracellular water or decreased interstitial water or combination of these factors. How or whether it contributes to causation of hypertension remains speculative. Leptin. Leptin is a 167-amino-acid hormone secreted by adipocytes. It decreases caloric intake by interacting with leptin receptors in the hypothalamus.32 It may affect blood pressure by its association with obesity and by its actions on the heart, kidneys, and sympathetic nervous system.33 Studies on animals with obese hypertension have shown low levels of leptin; some animal models exhibited deficient leptin production,34 although others expressed defective leptin receptors.35 However, its role in obesity-hypertension in humans is controversial. Some investigators were able to demonstrate a relationship between obesity-hypertension,36 whereas others found no such association.37 To further confound the issue, administration of leptin can lead to opposing effects on hypertension; although long-term administration may increase sympathetic activity with resultant pressor effects,38 an infusion of leptin in animals’ renal arteries may induce potassium-sparing natriuresis with resultant depressor effect.39 Conflicting studies have also been published concerning the relationship40 of leptin and obesity-hypertension.41 Thus, the role of leptin in causation of obesity-hypertension, if any, is not clear. Genetics. That genetics may be important in causation of obesity-hypertension is derived from the facts that central obesity is caused in part by genetic predisposition42 and that there is clustering of hypertension, diabetes, and obesity in adult male twins.43 Also, high blood pressure is not consistently seen with obesity, and it is likely that the blood pressure response to obesity may be influenced by genetic background.34 Obesity itself has at least some genetic linkage, either at or near the ob locus on chromosome 7.44,45 However, Onions et al46 failed to document association between the ob gene locus and hypertension, at least in African Americans. This is a relatively new area of inquiry and more work is undoubtedly ongoing.

creasing muscle mass, thereby producing thickening of the myocardial wall.48 In addition to the echocardiographic evidence cited above, autopsy study has also documented similar changes.49 In essential hypertension (without obesity), the total PVR is increased, resulting in an accentuated afterload and LV wall tension. Contractile elements are added in parallel, leading to thickening of the chamber wall, which in turn leads to diminished chamber volume.50 As opposed to this concentric hypertrophy seen with essential hypertension, obesity (without hypertension) causes “eccentric” LV hypertrophy. The eccentric hypertrophy is the result of increased LV preload, resulting in chamber dilation and increased wall tension. The LV adapts to it by adding contractile elements in series (as opposed to parallel in the case of nonobese essential hypertension). The result is eccentric LV hypertrophy.51 The coexistence of both obesity and hypertension in the same subject causes a mixed eccentric-concentric LV hypertrophy.30 Other potential factors involved in the pathogenesis of LV hypertrophy include demographics (age, sex, race), exogenous intake (salt and alcohol), and neurohumoral (insulin-like growth factor, angiotensin, sympathetic activity) factors. Diagrammatic representation of these cardiopathies is depicted in Figure 2, and a unifying pathogenetic scheme is shown in Figure 3. LV hypertrophy can increase the hemodynamic burden on the heart and predispose the patient to the development of heart failure. Accordingly, eccentric hypertrophy associated with obesity without hypertension,52,53 concentric hypertrophy associated with essential hypertension without obesity,50 and

Obesity-Hypertension and The Heart Because of the high blood volume in the obese, venous return to the right atrium, preload to the left atrium, left ventricular (LV) filling pressure, LV volume, and cardiac output are all shown to be increased.47 Afterload is also increased because of increased LV wall tension caused by increased LV volume.30 The LV adapts to these changes by in244

Figure 2. Left ventricular cavity size and wall thickness in lean normotensive, obese normotensive, lean hypertensive, and obese hypertensive patients. (Reproduced from Messerli F, Sundgaard -Riise K, Reisin E, et al. Dimorphic cardiac adaptation to obesity and arterial hypertension. Ann Intern Med 1983;99:757– 61. Copyright © 1983 American College of Physicians—American Society of Internal Medicine. Used with permission.)

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Figure 3. Unifying hypothesis concerning the disparate and combined effects of obesity and hypertension on left ventricular morphology. (Reproduced from Reisen E, Frohlich E. Hemodynamics in obesity. In: Zachetti A, Tarazi R, editors. Handbook of hypertension, vol. 7. Amsterdam, The Netherlands: Elsevier Science Publishers; 1986. p. 280 –97. Copyright © 1986 Elsevier Science Publishers. Used with permission.)

the concentric-eccentric hypertrophy associated with the combination of obesity and hypertension50 are all associated with increased risk of developing congestive heart failure. LV hypertrophy affects coronary circulation, causing relative myocardial ischemia during periods of increased demand, and ultimately coronary artery disese.54 LV hypertrophy is also associated with

increased incidence of cardiac arrhythmias.54 Explanation for these arrhythmias derives from autopsy studies on obese subjects. One study documented mononuclear cell infiltration in and around the sinoatrial note and/or its approaches, with marked fat throughout the conduction system;55 the other showed lipomatous hypertrophy of the interatrial septum.56 The high rates of sudden deaths in sub-

Figure 4. Renal alterations associated with obesity-hypertension. (Reproduced from Campese V. Salt sensitivity in hypertension. Renal and cardiovascular implication. Hypertension 1994; 23:531–50. Copyright © 1994 Lippincott Williams & Wilkins. Used with permission.)

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Table 1. Pharmacologic Treatment of Obesity-Hypertension Drug Class

Mechanism

Pros

Cons

Thiazide diuretics

2Intravascular volume 2Cardiac output

Effective

␤-Blockers

2Cardiac output

2Norepinephrine Levels; inexpensive

Centrally acting sympatholytic agents

Inhibition of epinephrine 2Peripheral vascular resistance

Inexpensive; no effect on lipid profile.

Clonidine found not to be effective at a dose of 0.4 mg/day.

␣ 1 blocking agents

2Peripheral vascular resistance

Dihydropyridine calcium channel antagonists

2Peripheral vascular resistance 2Cardiac output Natriuresis 2Peripheral vascular resistance ? Prostaglandin mediated ? Sympathetic blockade

Improved insulin sensitivity and lipid profile Effective; better glucose tolerance and less insulin resistance. Effective in whites and younger patients; improved insulin sensitivity.

Large or long-term studies not available. Expensive; individual responses vary.

Angiotensinconverting enzyme inhibitors

jects with morbid obesity57 are probably the results of coronary artery disease and arrhythmias associated with obesity. Obesity-Hypertension and The Kidneys Hall et al studied dogs with diet-induced obesity.58,59 They demonstrated that sodium retention at the level of loop of Henle that may be caused by insulin resistance and hyperinsulinemia, increased sympathetic activity, activation of renin-angiotensin-aldosterone system, and/or higher renal interstitial fluid hydrostatic pressure. Microscopic examination of the animal kidneys revealed an increase in the interstitial cells and expansion of the extracellular matrix between tubules in the renal medulla. They concluded that obesity-hypertension is associated with a shift of pressure natriuresis toward a higher blood pressure. Similar morphological changes in kidneys of obese humans are described in an autopsy series.60 Based on these observations, Campese24 proposed that the renal alterations seen with obesity are caused by increased filtration fraction and increased intraglomerular pressure. He also implicated salt sensitivity along with increased salt retention, increased sympathetic activity, and insulin resistance and hyperinsulinemia (Figure 4). In both obese and nonobese subjects, increased blood pressure is associated with a higher albumin excretion.61– 63 Because proteinuria may itself accelerate progression of renal failure,64 these subjects are at a higher risk of kidney damage. 246

Higher doses may be needed. Adverse lipid profile ? Efficacy may induce overeating. Adverse lipid profile

Expensive; not effective in blacks and older subjects; limited experience in obesity

Management of Obesity-Hypertension Weight Reduction. It is well documented that reduction of weight is effective in reducing obesityhypertension.65,66 This reduction in blood pressure is seen whether or not salt restriction is instituted at the same time. Modest reduction in weight (5 to 10 kg) was effective in up to 75% of the subjects. In addition to better blood pressure control, weight loss is associated with reduction of insulin levels, sympathetic activity, possibly renin and aldosterone levels, and intracellular sodium levels. Cardiac benefits of weight loss manifest in decrease in the interventricular septal thickness, posterior wall thickness, and total LV mass. However, weight reduction is not always an easy goal to attain, and most weight-loss programs report dropout rates of 50 to 70%. Lifestyle change is recommended and may be more successful. Antihypertensive Medications. Pharmacological therapy should be reserved for those with obesity-hypertension who have moderate to severe hypertension and who are unable/unwilling to lose weight and/or modify lifestyle.67 The goal of treatment is to reduce the cardiovascular risk, and the goal of blood pressure reduction depends on presence of other risk factors as defined by JNC VI.68 Any antihypertensive agent could be used for the treatment of obesityhypertension depending on its efficacy, effect on the metabolic profile, and mechanism of action for lowering blood pressure. Unfortunately, information is sparse concerning the use of antihypertensive medApril 2001 Volume 321 Number 4

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ication in obese-hypertension. Table 1 provides a summary of experience, sometimes limited, with different classes of antihypertensive agents in the treatment of obesity-hypertension. Summary Several epidemiological studies have demonstrated a direct relationship between central obesity and hypertension. A series of endocrine and metabolic mechanisms have been linked to the development of obesity-hypertension. These include insulin resistance, hyperinsulinemia, increased adrenergic activity and aldosterone levels, and increased salt and water retention. Low levels of leptin and genetic predisposition may also be important. Hemodynamically, the cardiac output is increased with relatively little change in PVR. These changes cause eccentricconcentric LV hypertrophy that predisposes to congestive heart failure. The risk of arrhythmias and sudden death is increased in obese persons. Glomerular filtration rate and renal blood flow are increased. Hyperperfusion and hyperfiltration can cause glomerulosclerosis. In addition, changes pertaining to increased salt reabsorption and tubular damage caused by urinary proteins are also observed. Weight loss has a salutary effect on each of these complications of obesity. In the presence of moderate to severe hypertension, and when weight loss is not possible, pharmacological therapy may be instituted; angiotensin-converting enzyme inhibitors, calcium antagonists, and ␤-adrenergic receptor blockers may be used as first-line drugs. References 1. Bray G. Obesity in America. An overview. In: Bray GA, editor. Obesity in America. Bethesda (MD): U.S. Department of Health, Education, and Welfare, Public Health Service; 1979. p. 1–9. 2. Kuczmarski Rr, Flegal K, Cambell S, et al. Increasing prevalence of overweight among US adults. The National Health and Nutrition Examination Surveys (NHANES). JAMA 1994;272:205–11. 3. Hsu P, Mathewson F, Rabkin S. Blood pressure and body mass index pattern: a longitudinal study. J Chronic Dis 1977;30:93–113. 4. Kannel W, Brand N, Skinner J, et al. The relation of adiposity to blood pressure and development of hypertension: the Framingham study. Ann Intern Med 1967;67:48 –9. 5. Stamler R, Stamler J, Riedlinger W, et al. Weight and blood pressure findings in hypertension screening of 1 million Americans. JAMA 1978;240:1607–20. 6. Levi R, White P, Stroud W. Overweight: a prognostic significant in relation to hypertension and cardiovascular renal diseases. JAMA 1946;121:951–3. 7. Hsu PH, Mathewson FA, Rabkin SW. Blood pressure and body mass index patterns-a longitudinal study. J Chronic Dis 1977;30:93–113. 8. Van Itallie T. The problem of obesity: Health implications of overweight and obesity in United States. Ann Intern Med 1985;103:983– 8.

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9. Prineas R, Folsom A, Kaye S. Central obesity and risk of coronary artery disease mortality in older women. Ann Epidemiol 1993;3:35– 41. 10. Menotti A, Descovich GC, Lanti M, et al. Indexes of obesity and all-causes mortality in Italian epidemiological data. Prev Med 1993;22:293–303. 11. Krotkiewski M, Bjorntorp P, Sjostrom L, et al. Impact of obesity on metabolism in men and women: Importance of regional adipose tissue distribution. J Clin Invest 1983;72: 1150 – 62. 12. Istfan W. Plaisted C, Bistrian B, et al. Insulin resistance versus insulin secretion in the hypertension of obesity. Hypertension 1983;19:385–92. 13. Zimlichman R, Zeidel L, Gefel D, et al. Insulin induces medical hypertrophy of myocardial arterioles in rats. Am J Hypertens 1995;8:915–20. 14. DeFronzo R, Cooke R, Andres R, et al. The effect of insulin on renal handling of sodium, potassium, calcium and phosphate in man. J Clin Invest 1975;55:845–55. 15. Feldman R, Hramiak I, Finegood D, et al. Parallel regulation of the local vascular and systemic metabolic effects of insulin. J Clin Endocrinol Metab 1995;80:1556 –9. 16. Maxwell M, Herber D, Waks AV, et al. Role of insulin and norepinephrine in the hypertension of obesity. Am J Hypertens 1995;7:402– 08. 17. Hall J, Brands M, Zapper D, et al. Insulin resistance, hyperinsulinemia, and hypertension: causes, consequences, or merely correlations? Proc Soc Exp Biol Med 1995;208:317–29. 18. Hiramatzu K, Yamada T, Ichikawa K, et al. Changes in endocrine activities relative to obesity in patients with essential hypertension. J Am Geriatr Soc 1981;29:25–30. 19. Messerli F, Christie B, DeCarvalho G, et al. Obesity and essential hypertension, intravascular volume, sodium excretion and plasma renin activity. Arch Intern Med 1981;141:81–5. 20. Rocchini A, Key J, Bondie D, et al. The effect of weight loss on the sensitivity of blood pressure to sodium on obese adolescents. N Engl J Med 1981;321:580 –5. 21. Ward C, Spanow D, Landsberg L, et al. Influence of insulin, sympathetic nervous system and obesity on blood pressure: The normotensive aging study. J Hypertens 1996; 14:301– 8. 22. Rocchini A. The relationship of sodium sensitivity to insulin resistance. Am J Med Sc 1994;307:575– 80. 23. Dahl K, Silver L, Christie R. Role of salt in fall of blood pressure accompanying reduction of obesity. N Engl J Med 1958;258:1186 –92. 24. Campese V. Salt sensitivity in hypertension. Renal and cardiovascular implication. Hypertension 1994;23:531–50. 25. Avenel A, Leeds AR. Sodium intake, inhibition of Na⫹-K⫹ATPase, and obesity. Lancet 1981;1:836. 26. De Luise M, Backburn C, Flier J. Reduced activity of the red-cell sodium-potassium pump in human obesity. N Engl J Med 1980;303:1017–22. 27. Boehringer K, Beretta-Piccoli C, Weidamann P, et al. Pressor factors and cardiovascular responsiveness in lean and overweight normal or hypertensive subjects. Hypertension 1982;4:67–72. 28. Reisen E, Frohlich E. Hemodynamics in obesity. In: Zachetti A, Tarazi R, editors. Handbook of hypertension, vol. 7. Amsterdam, The Netherlands: Elsevier Science Publishers; 1986. p. 280 –97. 29. Alexander J, Dennis E, Smith W, et al. Blood volume, cardiac output, and distribution of systemic blood flow in extreme obesity. Cardiovasc Res Center Bull 1962;1:39 – 44. 30. Messerli F, Sundgaard-Riise K, Reisin E, et al. Dimorphic cardiac adaptation to obesity and arterial hypertension. Ann Intern Med 1983;99:757– 61.

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