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CARDIOVASCULAR EFFECTS OF OBESITY AND HYPERTENSION
1165
hypertension and obesity-are influenced by a common, yet
Occasional
unknown, pathophysiological factor; (4) the
Survey
CARDIOVASCULAR EFFECTS OF OBESITY AND HYPERTENSION FRANZ H. MESSERLI
Department of Internal Medicine, Section on Hypertensive Diseases, Ochsner Medical Institutions, New Orleans, Louisiana, U.S.A.
Although often coexisting in the same patient, obesity and essential hypertension cardiovascular effects. An excess of adipose disparate
Summary exert
tissue augments cardiac output, stroke volume, and left ventricular filling pressure, expands intravascular volume, and lowers total peripheral resistance. In contrast, essential hypertension in a non-obese patient is associated with a contracted intravascular volume, high total peripheral resistance, and normal cardiac output, but increased left ventricular stroke work due to high afterload. Left ventricular adaptation will consist of eccentric hypertrophy in the obese (irrespective of arterial pressure) and concentric hypertrophy in the non-obese hypertensive patient. The combination of obesity and hypertension burdens the heart with high preload and high afterload, thereby greatly enhancing the risk of congestive heart failure. Peripheral resistance and intravascular volume may be normal in mildly hypertensive obese patients because of the mutually antagonising effects of the increase in arterial pressure and the increase in body weight. The fall in arterial pressure associated with weight loss seems to be caused by a decrease in adrenergic activity which leads to a fall in cardiac output without change in vascular resistance. Obesity hypertension may be the result of an inappropriately raised cardiac output in the presence of a relatively restricted arterial capacity due to the low vascularity of adipose tissue. In morbid obesity increased blood viscosity may contribute to the raised arterial pressure. .
INTRODUCTION 1
"Perhaps there is something intrinsically wrong with fat."
THE association between high blood pressure and obesity is well documented.2-9 The evidence linking these clinical entities is based on three different observations: (1) hypertensive patients tend to become obese as the disease progresses;2,3 (2) obese patients are at higher risk of hypertension than non-obese subjects, and weight gain might indicate whether or not borderline hypertension evolves into established hypertension/-13 (3) calorie restriction leading to weight loss is commonly associated with fall in arterial pressure irrespective of whether or not the patient restricts his salt intake.4-7,9,14,15 Despite the clinical and epidemiological evidence, pathogenetic mechanisms of the relation between high blood pressure and obesity remain poorly understood, and whether or not this relation is causal has not been firmly established. The following hypotheses might be considered in this respect: (1) high blood pressure or the drugs used in its treatment stimulate a patient to increase calorie intake inappropriately; (2) obesity and its metabolic changes or a high calorie (and salt) intake with lack of exercise predispose a subject to high blood pressure; (3) both conditions-
common
denominator of high blood pressure and obesity could be the factitious phenomenon of inaccurate blood-pressure recording due to increased arm girth. 16,17 Alexander et al. 18 and Chiang et al. have shown in very careful reviews that the association between body weight and high blood pressure is not due to difficulties in measuring blood pressure in the obese. Also, the fact that weight loss is associated with a decrease in arterial pressure, even when the salt intake is not restricted, argues against excessive dietary sodium intake as the cause of obesity hypertension.7 It seems, therefore, that the two disorders are linked by some distinct common underlying pathophysiological mechanism. The following is a review of some cardiovascular findings that are induced by obesity and high blood pressure or the combination of these disorders.
HEART
Obesity is an increase in body mass produced by an excessive amount of adipose tissue. It increases metabolic demands and hence total body oxygen consumption. Consequently, cardiac output and stroke volume increase to meet the metabolic requirements. Indeed, cardiac output increases in patients with obesity irrespective of the level of arterial pressure. 19-21 Despite the weight gain, heart rate is output is usually unchanged, and the increment in cardiac maintained by an increased stroke volume. 19—23 However, a correction of cardiac output by body surface area (cardiac index) yields values that are normal or even subnormal for non-obese subjects. This type of correction may not be appropriate in overweight patients; the use of another frame of reference such as weight may yield a significantly lower cardiac output per kg of body weight than would be found in similar lean otherwise subjects. Such artificial "normalisation" of cardiac output should not detract from the fact that the heart pumps a higher blood volume per unit of time (i.e., absolute values of cardiac output are raised) and is burdened by a higher workload for obese patients. Since the high cardiac output results usually from increased stroke volume, left ventricular end-diastolic volume and filling pressure will augment in parallel.23,24 High preload sustained over a long period produces predominantly left ventricular hypertrophy and dilatation (eccentric hypertrophy) even in the absence of hypertension.25 Not surprisingly, left ventricular performance and compliance become impaired early in morbid obesity24 and Woodard et al.21 found a 20—55% higher transverse cardiac diameter in obese patients. These findings corroborate previous necropsy studies in obese patients showing increased cardiac weight associated with hypertrophic ventricles.26,27 Like cardiac output, resting cardiac workload increases in proportion to body mass, left ventricular stroke work being 38-40% higher for normotensive patients who were on average 70% overweight than for otherwise similar lean subjects.28 Increase in arterial pressure will also substantially augment left ventricular stroke work. Increased arterial pressure burdens the left ventricle with high afterload and the cardiac adaptation consists of progressive left ventricular hypertrophy which is of the concentric type (i.e., associated with little or no dilatation), since left ventricular end-diastolic volume does not rise. These findings have been confirmed by
echocardiographic studies. 25,29-31
1166
Fig. 2-Cardiovascular effects of obesity and hypertension. Disparate changes in intravascular volume and total peripheral resistance.
adaptation to obesity and hypertension. Obesity produces dilation (and hypertrophy) of the left ventricle, hypertension produces only concentric hypertrophy.
Fig.
1-Cardiac
and
Hence, obesity and high blood pressure synergistically increase left ventricular stroke work (although by different mechanisms), and the combined long-term effect of both evils takes a heavy toll on the heart. The left ventricle has to carry the double burden of high preload (as induced by obesity) and high afterload (as induced by high blood pressure and obesity) (fig. 1). Not surprisingly, obese, hypertensive patients are at particularly high risk of congestive heart failure. Indeed, congestive failure occurs in a high percentage of morbidly obese patients irrespective of arterial pressure.32,33 INTRAVASCULAR VOLUME
Plasma and total blood volumes expand in obese patients in parallel with the amount of adipose tissue.21,22,26,34-36 Conversely, essential hypertension is associated with a contraction of intravascular volume, and the higher the total peripheral resistance, the greater the contraction.37-41 In obese, mildly hypertensive patients the two antagonistic effects will most probably offset each other, so that total blood volume remains normal. However, the higher the arterial pressure (and consequently peripheral resistance) and the leaner the patient, the more intravascular volume will contract; whereas the milder the hypertension and the more obese the subject, the more will intravascular volume expand2(fig. 2). A complicating factor that has to be considered is that intravascular volume is not uniformly distributed throughout the body. In fact, as total body fat increases, the ratio of intravascular volume to body weight falls asymptotically to approximately 45 ml/kg, which suggests that the blood volume of adipose tissue lies somewhat below
this value.34,42 In contrast, in persons who are underweight the ratio ranges from 95 to 100 ml/kg.34,42 These data indicate that, compared with lean tissue, adipose tissue seems to be underperfused. As a consequence, neither body weight nor body height is an ideal frame of reference for expressing volume data for obese patients, with correction for body weight resulting in a volume contraction and correction for body height resulting in volume expansion.22,43 Body surface area is influenced more by height than by weight and its use as a frame of reference could still lead to a slight overestimation of intravascular volume. VASCULAR RESISTANCE
total peripheral resistance is calculated by dividing mean arterial pressure by cardiac output. It depends upon the factors that influence arteriolar diameter and (according to Poiseuille’s law) to a lesser degree upon blood viscosity. Since the arteriolar diameter is controlled by vascular smooth muscle tone on the one hand and structural changes such as wall thickness and atherosclerosis on the other, peripheral resistance is a good indicator of the severity of systemic hypertensive vascular disease.44 Because of the high cardiac output associated with obesity, peripheral resistance will be lower in obese than in lean patients with the same arterial pressure. Essential hypertension, on the other hand, is characterised by raised peripheral resistance (provided that cardiac output remains unchanged). 44,45 Hence, hypertension and obesity have directly opposing effects on total peripheral resistance. As with intravascular volume, the coexistence of marked obesity and hypertension may result in a normal total peripheral resistance22,43 (fig. 2). Whether or not this resistance-lowering effect of increased body weight will ultimately reduce the degree of target-organ disease (i.e., less nephrosclerosis), especially in a patient who is mildly hypertensive only, but distinctly overweight, remains to be seen. Nevertheless, although the haemodynamic effects of obesity should to some extent protect patients with essential hypertension against
Vascular
or
1167
hypertensive vascular disease, they would also place patients at high risk of congestive heart failure.
these
’
The
outlined
arguments
above
support
Volhard’s
suggestion, made more than 50 years ago, that pale hypertension predisposes to nephrosclerosis and vascular disease and red hypertension to congestive heart failure.46 ENDOCRINE FACTORS
No single factor has been identified as being the direct link between hypertension and obesity. However, increased steroid production and alterations in receptors for various pressor substances have been suggested as having a role to play in the association of the two disorders.9 A fall in plasma renin activity and plasma aldosterone values has also been observed in obese subjects who lose considerable weight, whether or not subjects restricted their sodium intake. Similarly, plasma noradrenaline and its reactivity decreases when a low protein diet is taken.48 However, neither the activity of the renin-angiotensin-aldosterone system nor the adrenergic nervous system in obese hypertensive patients differs significantly from those in lean ones with the same blood pressures.30,47,48 Hence, weight reduction may reduce the activity of the renin-angiotensin system in obese patients, but this activity has not been reported to be increased by obesity itself
RESPIRATORY EFFECTS
Cardiopulmonary findings of the classical form of pickwickian syndrome in severe obesity were described more than 25 years ago.49,50 Respiratory complications of obesity with or without hypoventilation include increased demand for ventilation 5 and breathing workload,52,53 respiratory muscle inefficiency,54,55 decreased functional reserve 56 capacity and expiratory reserve volume, and closure of peripheral lung units;57 these often result in a ventilation perfusion mismatch especially when a supine position is adopted. 58 The patients with obesity hypoventilation syndrome (pickwickian) have, in addition, attenuated hypercapnoeic and hypoxic ventilator responsiveness that may antedate or be caused by the obesity; they often have
apnoeic episodes during sleep. 57,59 Chronic hypoxia with cyanosis, hypercapnia, and secondary polycythaemia are common in severe obesity and may directly contribute to the increase in arterial blood pressure. Polycythaemia in particular increases blood viscosity which is already raised in patients with hypertension due to hyperfibrinogenaemia;6o increase in blood viscosity may raise total peripheral resistance 61 and arterial pressure (Gaisbock syndrome).62 Combined effects of hypoxia, hypercapnia, and reflex sympathetic discharge may also produce pulmonary hypertension and possibly accelerate systemic hypertension. In addition, pulmonary hypertension burdens the right ventricle and further perpetuates most other respiratory alterations. This sequence of events is probably of less clinical importance in the pathogenesis of mild obesity hypertension than in that of morbid obesity. WEIGHT REDUCTION
Weight reduction
in the obese
hypertensive patient
is
commonly associated with a fall in arterial pressure,4-7 which
is not related to change in sodium intake.’ Little information is available about the underlying mechanism of bloodpressure-reducing effects of weight reduction.
Total peripheral resistance in any given vessel is directly proportional to blood viscosity, to vessel radius (to the fourth degree), and to vessel length (Poiseuille’s law). Weight reduction by decreasing body mass should also, at least to some extent, reduce total length of the vascular bed and thus total peripheral resistance. Reduction in body mass will also decrease total body oxygen consumption, thus allowing cardiac output to fall. Hence, a weight-reducing diet might be expected to reduce arterial pressure by decreasing both cardiac output and peripheral resistance, but preliminary data indicate that it does so predominantly by decreasing cardiac output, intravascular volume, and circulating . noradrenaline levels, without changing total peripheral resistance (Reisin E., Messerli F. H., Dreslinski G. R. et al., unpublished).
Moreover, weight reduction is accompanied by reduction in adrenergic activity, plasma renin activity levels and, to a lesser extent, levels of aldosterone.47,48 These changes are independent of sodium intake. Calorie restriction in animals and in human beings reduces the activity of the sympathetic nervous system.63-65 Since the sympathetic nervous system directly influences renin release, it seems possible that a decrease in the activity of the renin-angiotensin-aldosterone system reflects diminished sympathetic nervous outflow. Despite the decrease in sympathetic nervous activity reported with weight loss, obese patients do not exhibit symptoms or signs of enhanced adrenergic drives when compared with non-obese subjects with similar blood pressure values.
THE HYPERTENSION-OBESITY CONNECTION
Whyte has suggested that the increased prevalence of high blood pressure associated with obesity results from a discrepancy between raised cardiac output and a relatively normal arterial capacity.66 There is little doubt that cardiac output increases with body mass, probably because of increased metabolic demands; 19-23 but since adipose tissue is less vascular than lean (i.e., muscle) tissue,34,35,42,67 in obese subjects the total vascular bed does not increase to the same extent as cardiac output. The increase in adipose tissue blood flow occurring with is smaller than that in the amount of adipose tissue mass.67 Accordingly, perfusion per unit offat tissue decreases with progressive obesity, reaching 1-3 to 1.5 ml/100 g in patients who are 40% overweight.67 A perfusion value of 1 -5ml/100 g of adipose tissue per minute would correspond to a total adipose blood flow of 0 .525 1/min in patients (such as in subjects in one of our studies) who were 35 kg (71%) overweight.31However, cardiac output was 1-67 1/min higher in these obese subjects than in lean ones with similar (normotensive) arterial pressures. Therefore, the increase in systemic blood flow produced by obesity cannot solely be explained by increased requirements due to adipose tissue perfusion. Although adaptive changes in other organs may further increase metabolic demands, the increment in cardiac output seems to be somewhat inappropriate with regard to the amount of fat tissue.
obesity
in obese patients the following sequence of take place.68 Obesity increases cardiac output, may
Conceivably, events
1168 and intravascular and circulating blood volumes. Such a chronic high cardiac output state with volume expansion may ultimately increase peripheral resistance (and arterial pressure). In excessively obese subjects high blood viscosity may also raise vascular resistance.60 Hence, the hypothesis as originally proposed by Whyte66 that obesity hypertension results from a discrepancy between inappropriately increased cardiac output and a relatively restricted arterial capacity may have some merit. Whatever the mechanism of the connection between
obesity and hypertension, the clinical implications are very clear: despite having disparate cardiovascular effects, the two conditions take a heavy toll on the heart, particularly in combination. I have little query with Caesar’s, "Let me have men about me that are fat", 69 but let’s at least keep their blood pressure down. Correspondence should be addressed to F. H. M., Ochsner Clinic, Jefferson Highway, New Orleans, Louisiana 70121, U.S.A.
1514
REFERENCES 1. 2.
Huxley Aldous After many a summer dies the swan. New York: Harper and Brothers, 1939, p 24. Chiang BN, Perlman LV, Epstein FH. Overweight and hypertension: A review. Circulation 1969; 39: 403-21.
3.
Tyroler HA, Heyden S, Hames CG. Weight and hypertension: Evaris County studies of Blacks and Whites. In: Paul O (ed) Epidemiology and control of hypertension.
New York: Stratton Intercontinental, 1975: 177-201. 4. Brozek J, Chapman CB, Keys A. Drastic food restriction. JAMA 1948; 137: 1569-74. 5. Genuth SM, Castro JH, Vertes V. Weight reduction in obesity by outpatient semistarvation. JAMA 1974; 230: 987-91. 6. Ramsay LE, Ramsay MH, Hettiarachchi J, et al. Weight reduction in a blood pressure clinic Br Med J 1978; ii: 244-45. 7. Reisin E, Abel R, Modan M, Silverberg DS, Eliahon HE, Modan B. Effect of weight loss without salt restriction on the reduction of blood pressure in overweight hypertensive patients. N Engl J Med 1978; 298: 1-6. 8. Johnson AL, Cornoni JC, Cassel JC, Tyroler HA, Heyden S, Hames CG. Influence of race, sex and weight on blood pressure behaviour in young adults. Am J Cardiol 1975; 35: 523-28. 9. Report of the Hypertension Task Force, vol. 9. DHEW Publication No. 79-1631 (NIH) 79-1631. 10. Paffenbarger RS, Rhorna MC, Wing SL. Chronic disease in former college students. VIII. Characteristics in youth predisposing to hypertension in later years. Am J Eptdemiol 1968; 88: 25-30. 11. Taylor HL. Body composition and elevated blood pressure: A comment. In: Stamler J, Stamler R, Pullman TN (eds). The epidemiology of hypertension. New York: Grune & Stratton, 1967: 101. 12. Stamler R, Stamler J, Riedlinger WF, Algera G, Roberts RH. Weight and blood pressure: findings in hypertension screening of 1 million Americans. JAMA 1978; 240: 1607-12. 13. Weiss YA, Safar ME, London GM, Simon AC, Levenson JA, Milliez PM. Repeat hemodynamic determinations in borderline hypertension. Am J Med 1978; 64: 382-87. 14. Kempner W, Newborg BC, Peschel RL, Skyler JS. Treatment of massive obesity with rice/reduction diet program: an analysis of 106 patients with at least 45 kg weight loss. Arch Intern Med 1975; 135: 1575-83. 15. Genuth SM, Castro JH, Vertes V. Weight reduction in obesity by outpatient semistarvation. JAMA 1974; 230: 987-94. 16. Karvonen MJ, Telivuo LJ, Jarvinen EJK. Sphygmomanometer cuff size and the accuracy of individual measurement of blood pressure. Am J Cardiol 1964; 13: 688-95. 17. Nielsen PE, Janniche H. The accuracy of ausculatatory measurement of arm blood pressure in very obese subjects Acta Med Scand 1974; 195; 403-09. 18. Alexander JK, Amad KH, Cole VW. Observations on some clinical features of extreme obesity, with particular reference to cardiorespiratory effects. Am J Med 1962; 32: 512-24. 19. Alexander JK, Peterson KL. Cardiovascular effects of weight reduction Circulation 1972, 45: 310-18. 20. Backman L, Freyschuss U, Hallberg D, et al. Cardiovascular function in extreme obesity. Acta Med Scand 1973; 193: 437-45. 21. Woodard CB, Quinones MA, Alexander JK. Pathogenesis of myocardial dysfunction in extreme obesity. Circulation 1978, 58 (suppl 2) 2: 230-39. 22. Messerli FH, Christie B, de Carvalho JGR, et al. Obesity and essential hypertension: hemodynamics, intravascular volume, sodium excretion, and plasma renin activity. Arch Intern Med 1981; 141: 81-85. 23. Kaltman AJ, Goldring RM. Role of circulatory congestion in the cardiorespiratory failure of obesity. Am J Med 1976; 60: 645-53. 24. Divitis O, Fazio S, Petitto M, Maddalena G, Contaldo F, Mancini M. Obesity and cardiac function Circulation 1981; 64: 477-82. 25. Messerli FH, Sundgaard-Riise K, Reisin E, Dunn F, Dreslinski GR, Frohlich ED. Left ventricular adaptation to obesity. Am J Cardiol 1982; 49: 977. 26. Smith HL. Relation of the weight of the heart to the weight of the body and of the weight of the heart to age. Am Heart J 1928; 4: 79-93.
27. Amad
KA, Brennan JC, Alexander JK. The cardiac pathology of chronic exogenous obesity. Circulation 1965; 32: 740-45. 28. Messerli FH, Ventura HO, Reisin E, et al. Obesity and borderline hypertension: two prehypertensive states with elevated cardiac output. Circulation (in press). 29. Dunn FG, Chandraratna PN, de Carvalho JGR, Basta LL, Frohlich ED. Pathophysiologic assessment of hypertensive heart disease with echocardiography. Am JCardiol 1977; 9: 789-95. 30. Savage DD, Drayes JI, Henry WL, et al. Echocardiographic assessment of cardiac anatomy and function in hypertensive subjects. Circulation 1979; 59: 623-28. 31. Logan AG, Gilbert BW, Haynes RB, Milne BJ, Flanagan PT. Early effects of mild hypertension on the heart. A longitudinal study. Hypertension 1981; 3: suppl II, 187-190. 32. Alexander JK, Pettigrove JR. Obesity and congestive heart failure Geriatrics 1967; 22: 101-06. 33. Gordon T, Kannel WB. Obesity and cardiovascular disease: the Framingham Study. Clin Endocrinol Metabol 1976; 5: 367-74. 34. Feldschuh J, Enson Y. Prediction of the normal blood volume: Relation of blood volume to body habitus. Circulation 1977; 56: 605-12. 35. Alexander JH, Dennis EW, Smith WG, et al. Blood volume, cardiac output and distribution of systemic blood flow in extreme obesity. Cardiovasc Res Cent Bull 1962-1963; 1: 39. 36. Rochester DF, Enson Y. Current concepts in the pathogenesis of the obesityhypoventilation syndrome: Mechanical and circulatory factors. Am J Med 1974; 57: 402-08. 37. Tarazi RC, Frohlich ED, Dustan HP. Plasma volume in man with essential hypertension. N Engl JMed 1968; 278: 762-65. 38. Julius S, Pascual AV, Reilly K, et al. Abnormalities of plasma volume in borderline hypertension. Arch Intern Med 1971; 127: 116-19. 39. Tarazi RC. Hemodynamic role of extracellular fluid in hypertension. Circ Res 1976; 38 (suppl 2): 73-83. 40. Birkenhager WH, van Es LA, Houwing A, et al. Studies on the lability of hypertension in man. Clin Sci Molec Med 1968, 35: 445-56. 41. Messerli FH, de Carvalho JGR, Christie B, et al. Essential hypertension in blacks and whites Hemodynamic findings and fluid volume state. Am J Med 1979; 67: 27-31. 42. Muldowney FP. The relationship of total red cell mass to lean body mass in man Clin
Sci 1957; 16: 163-69. 43. Messerli FH, Reisin E, Suarez DH, Frohlich ED. Obesity and hypertension. In: Worcel M, et al (eds). New trends in arterial hypertension, INSERM symposium no 17. Amsterdam: Elsevier/North Holland Biomedical Press, 1981: 333-37. 44. Freis ED. Hemodynamics of hypertension. Physiol Rev 1960; 40: 27-54. 45. Frohlich ED, Tarazi RC, Dustan HP. Re-examination of the hemodynamics of hypertension. Am J Med Sci 1969; 257: 9-23. 46. Volhard F. Der arterielle Hochdruck. Verh Dtsch Ges Inn Med 1923; 35: 134-84. 47. Tuck ML, Sowers J, Dornfeld D, et al. The effect of weight reduction on blood pressure, plasma renin activity, and plasma aldosterone levels in obese patients. N Engl J Med 1981; 304: 930-33. 48 DeHaven J, Sherwin R, Hendler R, Felig P. Nitrogen and sodium balance and sympathetic-nervous-system activity in obese subjects treated with a low-calorie protein or mixed diet. N Engl J Med 1980; 302: 477-82 49. Siecker HO, Estes EHJ, Kelser GA, et al. A cardiopulmonary syndrome associated with extreme obesity. J Clin Invest 1955; 34: 916-17. 50. Burwell CS, Robin ED, Whaley RD, et al. Extreme obesity associated with alveolar hypoventilation—a pickwickian syndrome. Am J Med 1956, 21: 811-18. 51. Demsey JA, Reddan W, Balke B, et al Work capacity determinants and physiologic cost of weight-supported breathing in obesity. J Appl Physiol 1966; 21: 1815-20. 52. Sharp JT, Henry JP, Sweany SK, et al The total work of breathing in normal and obese men. J Clin Invest 1964; 43: 728-39. 53. Fritts HW, Filler J, Fishman AP, et al. The efficiency of ventilation during voluntary hypercapnea: Studies in normal subjects and in dyspneic patients with either chronic pulmonary emphysema or obesity J Clin Invest 1959; 38: 1339-48. 54. Lourence RV. Diaphragm activity in obesity. J Clin Invest 1969; 48: 1609-14 55. Rochester DF, Enson Y. Current concepts in the pathogenesis of the obesityhypoventilation syndrome. Am J Med 1974; 57: 402-20. 56. Bedell GN, Wilson WR, Seebohm PM. Pulmonary function in obese persons. J Clin Invest 1958, 37: 1049-61. 57. Don HF, Crain DB, Wahbo WM, et al. The measurement of gas trapped in the lungs at functional residual capacity and the effects of posture. Anesthesiology 1971; 35: 582-90. 58. Tucker DH, Sieker HO. The effects of change in body position on lung volumes and intrapulmonary gas mixing in patients with obesity, heart failure and emphysema. J Clin Invest 1960; 39: 787-91. 59. Luce JM. Respiratory complications of obesity. Chest 1980; 78: 626-31. 60. Letcher RL, Chien S, Picketing TG, Sealey JE, Laragh JH. Direct relationship between blood pressure and blood viscosity in normal and hypertensive subjects.
Am J Med 1981; 70: 1195-202. 61. Schloz PM, Karis JH, Gump FE, Kinney JM, Chien S. Correlation of blood rheology with vascular resistance in critically ill patients. J Appl Physiol 1975; 39: 1008-11 62. Gaisbock F. Die Bedeutung der Blutdruckmessung fur die arztliche Praxis. Deutsch Arch Klin Med 1905; 83: 396-409. 63. Landsberg L, Young JB Fasting, feeding and regulation of the sympathetic nervous system. N Engl J Med 1978; 298: 1295-300. 64. Young JB, Mullen D, Landsberg L. Caloric restriction lowers blood pressure in the spontaneously hypertensive rat. Metabolism 1978; 27: 1711-14. 65 Jung RT, Shetty PS, Barrand M, Callingham BA, James WPT. Role of catecholamines in hypotensive response to dieting. Br Med J 1979; i: 12-13. 66. Whyte HM. Blood pressure and obesity. Circulation 1959; 19: 511-18. 67. Lesser GT, Deutsch S. Measurement of adipose tissue blood flow and perfusion in man by uptake of 85-Kr. J Appl Physiol 1967; 23: 621-30. 68. Coleman TG, Granger HJ, Guyton AC. Whole-body circulatory autoregulation and hypertension. Circ Res 1971, Suppl II to Vols. 28 and 29, 76-86. 69. Shakespeare W. Julius Caesar Act I, scene ii:
hypertension and obesity-are influenced by a common, yet
Occasional
unknown, pathophysiological factor; (4) the
Survey
CARDIOVASCULAR EFFECTS OF OBESITY AND HYPERTENSION FRANZ H. MESSERLI
Department of Internal Medicine, Section on Hypertensive Diseases, Ochsner Medical Institutions, New Orleans, Louisiana, U.S.A.
Although often coexisting in the same patient, obesity and essential hypertension cardiovascular effects. An excess of adipose disparate
Summary exert
tissue augments cardiac output, stroke volume, and left ventricular filling pressure, expands intravascular volume, and lowers total peripheral resistance. In contrast, essential hypertension in a non-obese patient is associated with a contracted intravascular volume, high total peripheral resistance, and normal cardiac output, but increased left ventricular stroke work due to high afterload. Left ventricular adaptation will consist of eccentric hypertrophy in the obese (irrespective of arterial pressure) and concentric hypertrophy in the non-obese hypertensive patient. The combination of obesity and hypertension burdens the heart with high preload and high afterload, thereby greatly enhancing the risk of congestive heart failure. Peripheral resistance and intravascular volume may be normal in mildly hypertensive obese patients because of the mutually antagonising effects of the increase in arterial pressure and the increase in body weight. The fall in arterial pressure associated with weight loss seems to be caused by a decrease in adrenergic activity which leads to a fall in cardiac output without change in vascular resistance. Obesity hypertension may be the result of an inappropriately raised cardiac output in the presence of a relatively restricted arterial capacity due to the low vascularity of adipose tissue. In morbid obesity increased blood viscosity may contribute to the raised arterial pressure. .
INTRODUCTION 1
"Perhaps there is something intrinsically wrong with fat."
THE association between high blood pressure and obesity is well documented.2-9 The evidence linking these clinical entities is based on three different observations: (1) hypertensive patients tend to become obese as the disease progresses;2,3 (2) obese patients are at higher risk of hypertension than non-obese subjects, and weight gain might indicate whether or not borderline hypertension evolves into established hypertension/-13 (3) calorie restriction leading to weight loss is commonly associated with fall in arterial pressure irrespective of whether or not the patient restricts his salt intake.4-7,9,14,15 Despite the clinical and epidemiological evidence, pathogenetic mechanisms of the relation between high blood pressure and obesity remain poorly understood, and whether or not this relation is causal has not been firmly established. The following hypotheses might be considered in this respect: (1) high blood pressure or the drugs used in its treatment stimulate a patient to increase calorie intake inappropriately; (2) obesity and its metabolic changes or a high calorie (and salt) intake with lack of exercise predispose a subject to high blood pressure; (3) both conditions-
common
denominator of high blood pressure and obesity could be the factitious phenomenon of inaccurate blood-pressure recording due to increased arm girth. 16,17 Alexander et al. 18 and Chiang et al. have shown in very careful reviews that the association between body weight and high blood pressure is not due to difficulties in measuring blood pressure in the obese. Also, the fact that weight loss is associated with a decrease in arterial pressure, even when the salt intake is not restricted, argues against excessive dietary sodium intake as the cause of obesity hypertension.7 It seems, therefore, that the two disorders are linked by some distinct common underlying pathophysiological mechanism. The following is a review of some cardiovascular findings that are induced by obesity and high blood pressure or the combination of these disorders.
HEART
Obesity is an increase in body mass produced by an excessive amount of adipose tissue. It increases metabolic demands and hence total body oxygen consumption. Consequently, cardiac output and stroke volume increase to meet the metabolic requirements. Indeed, cardiac output increases in patients with obesity irrespective of the level of arterial pressure. 19-21 Despite the weight gain, heart rate is output is usually unchanged, and the increment in cardiac maintained by an increased stroke volume. 19—23 However, a correction of cardiac output by body surface area (cardiac index) yields values that are normal or even subnormal for non-obese subjects. This type of correction may not be appropriate in overweight patients; the use of another frame of reference such as weight may yield a significantly lower cardiac output per kg of body weight than would be found in similar lean otherwise subjects. Such artificial "normalisation" of cardiac output should not detract from the fact that the heart pumps a higher blood volume per unit of time (i.e., absolute values of cardiac output are raised) and is burdened by a higher workload for obese patients. Since the high cardiac output results usually from increased stroke volume, left ventricular end-diastolic volume and filling pressure will augment in parallel.23,24 High preload sustained over a long period produces predominantly left ventricular hypertrophy and dilatation (eccentric hypertrophy) even in the absence of hypertension.25 Not surprisingly, left ventricular performance and compliance become impaired early in morbid obesity24 and Woodard et al.21 found a 20—55% higher transverse cardiac diameter in obese patients. These findings corroborate previous necropsy studies in obese patients showing increased cardiac weight associated with hypertrophic ventricles.26,27 Like cardiac output, resting cardiac workload increases in proportion to body mass, left ventricular stroke work being 38-40% higher for normotensive patients who were on average 70% overweight than for otherwise similar lean subjects.28 Increase in arterial pressure will also substantially augment left ventricular stroke work. Increased arterial pressure burdens the left ventricle with high afterload and the cardiac adaptation consists of progressive left ventricular hypertrophy which is of the concentric type (i.e., associated with little or no dilatation), since left ventricular end-diastolic volume does not rise. These findings have been confirmed by
echocardiographic studies. 25,29-31
1166
Fig. 2-Cardiovascular effects of obesity and hypertension. Disparate changes in intravascular volume and total peripheral resistance.
adaptation to obesity and hypertension. Obesity produces dilation (and hypertrophy) of the left ventricle, hypertension produces only concentric hypertrophy.
Fig.
1-Cardiac
and
Hence, obesity and high blood pressure synergistically increase left ventricular stroke work (although by different mechanisms), and the combined long-term effect of both evils takes a heavy toll on the heart. The left ventricle has to carry the double burden of high preload (as induced by obesity) and high afterload (as induced by high blood pressure and obesity) (fig. 1). Not surprisingly, obese, hypertensive patients are at particularly high risk of congestive heart failure. Indeed, congestive failure occurs in a high percentage of morbidly obese patients irrespective of arterial pressure.32,33 INTRAVASCULAR VOLUME
Plasma and total blood volumes expand in obese patients in parallel with the amount of adipose tissue.21,22,26,34-36 Conversely, essential hypertension is associated with a contraction of intravascular volume, and the higher the total peripheral resistance, the greater the contraction.37-41 In obese, mildly hypertensive patients the two antagonistic effects will most probably offset each other, so that total blood volume remains normal. However, the higher the arterial pressure (and consequently peripheral resistance) and the leaner the patient, the more intravascular volume will contract; whereas the milder the hypertension and the more obese the subject, the more will intravascular volume expand2(fig. 2). A complicating factor that has to be considered is that intravascular volume is not uniformly distributed throughout the body. In fact, as total body fat increases, the ratio of intravascular volume to body weight falls asymptotically to approximately 45 ml/kg, which suggests that the blood volume of adipose tissue lies somewhat below
this value.34,42 In contrast, in persons who are underweight the ratio ranges from 95 to 100 ml/kg.34,42 These data indicate that, compared with lean tissue, adipose tissue seems to be underperfused. As a consequence, neither body weight nor body height is an ideal frame of reference for expressing volume data for obese patients, with correction for body weight resulting in a volume contraction and correction for body height resulting in volume expansion.22,43 Body surface area is influenced more by height than by weight and its use as a frame of reference could still lead to a slight overestimation of intravascular volume. VASCULAR RESISTANCE
total peripheral resistance is calculated by dividing mean arterial pressure by cardiac output. It depends upon the factors that influence arteriolar diameter and (according to Poiseuille’s law) to a lesser degree upon blood viscosity. Since the arteriolar diameter is controlled by vascular smooth muscle tone on the one hand and structural changes such as wall thickness and atherosclerosis on the other, peripheral resistance is a good indicator of the severity of systemic hypertensive vascular disease.44 Because of the high cardiac output associated with obesity, peripheral resistance will be lower in obese than in lean patients with the same arterial pressure. Essential hypertension, on the other hand, is characterised by raised peripheral resistance (provided that cardiac output remains unchanged). 44,45 Hence, hypertension and obesity have directly opposing effects on total peripheral resistance. As with intravascular volume, the coexistence of marked obesity and hypertension may result in a normal total peripheral resistance22,43 (fig. 2). Whether or not this resistance-lowering effect of increased body weight will ultimately reduce the degree of target-organ disease (i.e., less nephrosclerosis), especially in a patient who is mildly hypertensive only, but distinctly overweight, remains to be seen. Nevertheless, although the haemodynamic effects of obesity should to some extent protect patients with essential hypertension against
Vascular
or
1167
hypertensive vascular disease, they would also place patients at high risk of congestive heart failure.
these
’
The
outlined
arguments
above
support
Volhard’s
suggestion, made more than 50 years ago, that pale hypertension predisposes to nephrosclerosis and vascular disease and red hypertension to congestive heart failure.46 ENDOCRINE FACTORS
No single factor has been identified as being the direct link between hypertension and obesity. However, increased steroid production and alterations in receptors for various pressor substances have been suggested as having a role to play in the association of the two disorders.9 A fall in plasma renin activity and plasma aldosterone values has also been observed in obese subjects who lose considerable weight, whether or not subjects restricted their sodium intake. Similarly, plasma noradrenaline and its reactivity decreases when a low protein diet is taken.48 However, neither the activity of the renin-angiotensin-aldosterone system nor the adrenergic nervous system in obese hypertensive patients differs significantly from those in lean ones with the same blood pressures.30,47,48 Hence, weight reduction may reduce the activity of the renin-angiotensin system in obese patients, but this activity has not been reported to be increased by obesity itself
RESPIRATORY EFFECTS
Cardiopulmonary findings of the classical form of pickwickian syndrome in severe obesity were described more than 25 years ago.49,50 Respiratory complications of obesity with or without hypoventilation include increased demand for ventilation 5 and breathing workload,52,53 respiratory muscle inefficiency,54,55 decreased functional reserve 56 capacity and expiratory reserve volume, and closure of peripheral lung units;57 these often result in a ventilation perfusion mismatch especially when a supine position is adopted. 58 The patients with obesity hypoventilation syndrome (pickwickian) have, in addition, attenuated hypercapnoeic and hypoxic ventilator responsiveness that may antedate or be caused by the obesity; they often have
apnoeic episodes during sleep. 57,59 Chronic hypoxia with cyanosis, hypercapnia, and secondary polycythaemia are common in severe obesity and may directly contribute to the increase in arterial blood pressure. Polycythaemia in particular increases blood viscosity which is already raised in patients with hypertension due to hyperfibrinogenaemia;6o increase in blood viscosity may raise total peripheral resistance 61 and arterial pressure (Gaisbock syndrome).62 Combined effects of hypoxia, hypercapnia, and reflex sympathetic discharge may also produce pulmonary hypertension and possibly accelerate systemic hypertension. In addition, pulmonary hypertension burdens the right ventricle and further perpetuates most other respiratory alterations. This sequence of events is probably of less clinical importance in the pathogenesis of mild obesity hypertension than in that of morbid obesity. WEIGHT REDUCTION
Weight reduction
in the obese
hypertensive patient
is
commonly associated with a fall in arterial pressure,4-7 which
is not related to change in sodium intake.’ Little information is available about the underlying mechanism of bloodpressure-reducing effects of weight reduction.
Total peripheral resistance in any given vessel is directly proportional to blood viscosity, to vessel radius (to the fourth degree), and to vessel length (Poiseuille’s law). Weight reduction by decreasing body mass should also, at least to some extent, reduce total length of the vascular bed and thus total peripheral resistance. Reduction in body mass will also decrease total body oxygen consumption, thus allowing cardiac output to fall. Hence, a weight-reducing diet might be expected to reduce arterial pressure by decreasing both cardiac output and peripheral resistance, but preliminary data indicate that it does so predominantly by decreasing cardiac output, intravascular volume, and circulating . noradrenaline levels, without changing total peripheral resistance (Reisin E., Messerli F. H., Dreslinski G. R. et al., unpublished).
Moreover, weight reduction is accompanied by reduction in adrenergic activity, plasma renin activity levels and, to a lesser extent, levels of aldosterone.47,48 These changes are independent of sodium intake. Calorie restriction in animals and in human beings reduces the activity of the sympathetic nervous system.63-65 Since the sympathetic nervous system directly influences renin release, it seems possible that a decrease in the activity of the renin-angiotensin-aldosterone system reflects diminished sympathetic nervous outflow. Despite the decrease in sympathetic nervous activity reported with weight loss, obese patients do not exhibit symptoms or signs of enhanced adrenergic drives when compared with non-obese subjects with similar blood pressure values.
THE HYPERTENSION-OBESITY CONNECTION
Whyte has suggested that the increased prevalence of high blood pressure associated with obesity results from a discrepancy between raised cardiac output and a relatively normal arterial capacity.66 There is little doubt that cardiac output increases with body mass, probably because of increased metabolic demands; 19-23 but since adipose tissue is less vascular than lean (i.e., muscle) tissue,34,35,42,67 in obese subjects the total vascular bed does not increase to the same extent as cardiac output. The increase in adipose tissue blood flow occurring with is smaller than that in the amount of adipose tissue mass.67 Accordingly, perfusion per unit offat tissue decreases with progressive obesity, reaching 1-3 to 1.5 ml/100 g in patients who are 40% overweight.67 A perfusion value of 1 -5ml/100 g of adipose tissue per minute would correspond to a total adipose blood flow of 0 .525 1/min in patients (such as in subjects in one of our studies) who were 35 kg (71%) overweight.31However, cardiac output was 1-67 1/min higher in these obese subjects than in lean ones with similar (normotensive) arterial pressures. Therefore, the increase in systemic blood flow produced by obesity cannot solely be explained by increased requirements due to adipose tissue perfusion. Although adaptive changes in other organs may further increase metabolic demands, the increment in cardiac output seems to be somewhat inappropriate with regard to the amount of fat tissue.
obesity
in obese patients the following sequence of take place.68 Obesity increases cardiac output, may
Conceivably, events
1168 and intravascular and circulating blood volumes. Such a chronic high cardiac output state with volume expansion may ultimately increase peripheral resistance (and arterial pressure). In excessively obese subjects high blood viscosity may also raise vascular resistance.60 Hence, the hypothesis as originally proposed by Whyte66 that obesity hypertension results from a discrepancy between inappropriately increased cardiac output and a relatively restricted arterial capacity may have some merit. Whatever the mechanism of the connection between
obesity and hypertension, the clinical implications are very clear: despite having disparate cardiovascular effects, the two conditions take a heavy toll on the heart, particularly in combination. I have little query with Caesar’s, "Let me have men about me that are fat", 69 but let’s at least keep their blood pressure down. Correspondence should be addressed to F. H. M., Ochsner Clinic, Jefferson Highway, New Orleans, Louisiana 70121, U.S.A.
1514
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