Obesity and Hypertension Hemodynamic
Aspects
Edward D. Frohlich, MD Elevated arterial pressure in patients with obesity-hypertension is associated with an increased cardiac output and total peripheral resistance. The elevated output is related to expanded innavascular volume that increases cardiopulmonary volume, venous return, and left ventricular preload; the ekvated pressure and total peripheral resistance increase afterload. This dual ventricular overload promotes a dimorphic, concentric, and eccentric hypertrophy in response to the volume and pressure overload. Increased myocardial oxygen demand results from the elevated tension in the Left ventricular wall, reflecting its increased diameter and pressure, and provides physiologic rationale for the greater potential of coronary arterial insufficiency and cardiac failure. There are greater renal blood flow and lower renal vascular resistance in patients with obesity-hypertension at any kvel of arterial pressure. This may be offset b an increased renal filtration fraction that may favor protein deposition and glomerulosckrosis, and wedisposition of obese patients for diabetes may aggravate this problem. With weight reduction, these hemodynamic derangements may be reversed: intravascular volume ContracLCts, cardiac output decreases, and arterial pressure falls. Ann
Epidemiol I991 ; 1:287-293 KEY WORDS:
hemodynamics,
Exogenous obesity, essential hypertension, renal hemodynamics,
left ventricular hypertrophy,
systemic
blood volume.
INTRODUCTION
Hypertension and obesity are two independent diseases, yet, over the years, clinical and epidemiologic studies have repeatedly confirmed a more than coincidental association (l-8). Despite this close interrelationship, existence of one disease does not imply the necessary coexistence of the other. When hypertension does coexist with obesity-and this occurs frequently-the mechanisms explaining this association are not completely understood (9-11). Indeed, what is clear is the epidemiologic documentation that attests to an augmented risk for premature cardiovascular morbidity and mortality (2-4, 7). In order to learn why the potential risk is so great, several authors presented evidence for differences in pressor mechanisms (9-14). In this respect, hemodynamic findings have demonstrated important physiologic differences between lean and obese normotensive as well as hypertensive individuals, and that obesity-hypertension is a more severe pathophysiologic state than either state existing independently ( 11-21).
COINCIDENT ESSENTIAL
RISK FACTORS HYPERTENSION
IN PATIENTS
WITH
OBESITY
AND
The term “‘factors of risk” was first introduced by the Framingham Heart Study to delineate identifiable demographic and clinical characteristics that confer special cardiovascular risk to that population (22). These risk factors now include: cigarette
From Alton Ochsner Medical Foundatmn, New Orleans, LA. Address reprint requests to: Edward D. Frohlich, MD, Vice President for Academic Affairs, Alton Ochsner Medical Foundation, 15 16 Jefferson Highway, New Orleans, LA 7012 1. Received August 6, 1990; revised August 30, 1990. 0 1991 Elsevier Science Publishq
Co., Inc.
1047-2797191/$03.50
288
Frohlich OBESITY AND HYPERTENSION:
HEMODYNAMIC
ASPECTS
AEP Vol. 1, No. 4 May 1991: 287-293
smoking, hypertension, left ventricular hypertrophy, exogenous obesity, hyperlipidemia, diabetes mellitus, and hyperuricemia. Other nonmodifiable risk factors are male gender, advancing age (particularly older than 50 years when male and female subjects are of equal risk), and the black race.
MECHANISMS
ASSOCIATED
WITH
EXOGENOUS
OBESITY
In earlier years, particularly with respect to the infectious diseases, it was possible to identify causation of disease in terms of Koch’s postulates. However, in contrast to diseases whose etiology is known, many of the common clinical problems encountered at present are multifactorial in nature; a single cause-effect relationship is not likely (23, 24). The latter have been termed diseases of regulation, explained on the basis of a disregulation of the myraid of physiologic mechanisms that serve to maintain normal body homeostasis. In this respect, no two problems can be better exemplified than those of systemic arterial hypertension and exogenous obesity. It follows, then, that by understanding underlying regulatory factors, it is possible to identify which of the involved mechanisms may go awry. Then, by intervening therapeutically, it may be possible to normalize them and, thus, restore homeostasis. Over the past 30 years it has been possible to identify pressor and depressor mechanisms that operate in patients with essential hypertension, and with the exciting development of new antihypertensive agents, the control of arterial pressure and arrest of the advancing disease has been assured. As a result, it is now evident that the course of hypertensive disease and its complications have been dramatically altered for the better. By this same line of reasoning, exogenous obesity has been the subject of much study; a number of associated mechanisms have been identified. Among those recognized are: altered carbohydrate metabolism; diminished end*organ responsiveness to endogenous insulin; catecholamine excess (or increased adrenergic function); dietary sodium excess; hypervolemia; hormonal alterations including aldosterone, other adrenal steroids, and the thyroid hormone; and altered hemodynamic functions (9, 10, 12-14, 25-35). This discussion concerns the hemodynamic alterations that are associated with obesity and how total body circulatory homeostasis is compromised further when obesity coexists with essential hypertension.
HEMODYNAMIC
ALTERATIONS
Obesity-Normotension Obese normotensive individuals have an increased cardiac output that is in direct proportion to circulating blood volume; this is related to body mass (9, 11, 14-19, 25-27). In these obese patients with an elevated cardiac output, the expanded intravascular volume is the result of increased plasma volume (9, 11, 14-16, 26, 27, 29). The result is an increased venous return to the heart, and an increased volume of blood in the cardiopulmonary circulation. Since height of arterial pressure is directly proportional to the cardiac output and the resistance offered by the small arteries to the forward flow of blood (total peripheral resistance), obese normotensive patients must have a reduced total peripheral resistance. It is conceivable, however, that their arterial pressure might very well be even lower if the obese patient becomes leaner, demonstrating a different response of the peripheral circulation to the expanded intravascular volume and elevated cardiac output.
AEP Vol. 1, No. 4 May 1991: 287-293
Frohlich OBESITYAND HYPERTENSION:HEMODYNAMICASPECTS
289
ObesityeHypertension The hemodynamic alterations associated with both obesity and hypertension represent the combination of factors associated with both diseases (9, 14-20, 25-27, 29). Thus, in patients with essential hypertension, the elevated total peripheral resistance is in direct proportion to the height of arterial pressure (11, 14, 15, 36). Cardiac output remains normal in these patients until the heart can no longer adapt functionally and structurally to the slowly progressing, increased afterload that is imposed on the left ventricle. At that point, left ventricular failure supervenes and is associated with a reduction in cardiac output and in blood flow to the organs. With the coexistence of obesity, and expanded intravascular volume is superimposed on the unrelenting increased pressure overload and the rising total peripheral resistance ( 11). This expanded volume is, in part, translocated from the periphery to the cardiopulmonary area by virtue of the venoconstriction associated with the hypertensive state (11, 14-16, 37). This augmented circulating volume that is redistributed to the cardiopulmonary area increases venous return to the heart and, thus, the cardiac output. With this redistribution, calculated total peripheral resistance tends to be reduced; however, at any level of cardiac output in patients with obesity-hypertension, total peripheral resistance is significantly higher than in normotensive obese patients of the same body mass ( 11, 15, 26, 29). Thus, the state of obesity-hypertension is characterized by a dual hemodynamic left ventricular load: a pressure as well as a volume overload (11).
Cardiac Responses As suggested, any hemodynamic overload imposed on the ventricle evokes a dual response: functional and structural. The functional aspect concerns those intrinsic myocardial responses to stretch produced by volume distention (preload) or by pressure (afterload) overload (24, 37). I n addition, the heart responds structurally; this is dictated, in part, by the stretch of the cardiac myocyte. However, recent evidence has suggested that nonhemodynamic factors also stimulate the left ventricular hypertrophy response (36-40). The nature of this structural response depends on the type of ventricular overload. If the ventricular overload is a volume-preload, the response is a more eccentric configuration; if the overload is a pressure-afterload, the hypertrophy is more concentric (4 1). Under normal circumstances, the former response is more akin to the hypertrophy resulting from isotonic (or dynamic) exercise since this is one of volume overload. By contrast, the ventricular response to a more static form of isometric exercise is mixed; this overload is induced by both pressure and volume. It is not known at present whether there is a difference in the type of myocardial myosin muscle response to these two forms of ventricular overload. At least three myosin isoforms are synthesized by the myocyte; we do not know whether each of these myosins is associated with different functional capabilities. At any rate, in the volume overload of exogenous obesity in the normotensive individual there is an eccentric left ventricular hypertrophy (11, 16-18). But in the more complex obesity-hypertension, the structural response is more dimorphic; that is to say, there is a combination of an eccentric and concentric type of left ventricular hypertrophy (11, 17, 18). This rather simplistic elucidation of the type of hypertrophy that is associated with obesity-hypertension provides a reasonable pathophysiologic understanding of why these patients are more predisposed to congestive heart failure (11, 42-45). It follows, then, that in the setting of hyperlipidemia, diabetes mellitus, or accelerated atherosclerosis (which are associated only with both hypertension and exogenous
290
Frohlich OBESITY AND HYPERTENSION:
HEMODYNAMIC
ASPECTS
AEP Vol. 1, No. 4 May 1991: 287-293
obesity), there is no wonder why these patients have a greater cardiovascular risk. Indeed, this risk includes an increased chance of developing the cardiac complications of coronary arterial insufficiency with or without angina pectoris, myocardial infarction, cardiac dysrhythmias, and sudden death (4, 6, 7, 46).
Renal Hemodynamics With obesity there is not only an increase in cardiac output, but also an increase in its distribution to the renal circulation. Indeed, renal blood flow is increased in obese patients whether or not they have hypertension (20). This is associated with reduced renal vascular resistance. However, renal vascular resistance is higher for any level of renal blood flow if the patient is hypertensive. Because of this lesser intrarenal vasoconstriction associated with obesity (whether or not the patient is hypertensive), there seems to be less renal complication than in patients who are lean (47).
Effects of Weight Reduction In a recent study from our laboratory concerned with weight reduction, we compared two similarly matched groups of obese patients: One lost wieght on a prescribed dietary program, and the other group did not (19). The latter group demonstrated no change in any of the evaluated hemodynamic indices. In contrast, the group that did lose weight demonstrated a decrease in systolic, diastolic, and mean arterial pressure, which was associated with a reduced cardiac output in proportion to the decreased intravascular (plasma) volume (19). Since there was no change in heart rate, the fall in cardiac output was related to a decreased stroke volume. Thus, with the contracted plasma volume achieved with weight reduction, cardiopulmonary volume declined, and was associated with a reduction in venous return and cardiac output. It was of further interest to see that with the reduction in body weight, there was also a decrease in many of the biochemical indices that serve either as pressor mechanisms or as risk factors associated with hypertension, obesity, and cardiovascular disease. These included: serum cholesterol, triglyceride, and uric acid concentrations as well as plasma norepinephrine concentration, plasma renin activity, and 24-hour urinary aldosterone excretion (19). These findings are consistent with others conceming biochemical changes in patients able to reduce their body weight. One study demonstrating reduction in body weight in obese patients also showed decreases in arterial pressure and left ventricular mass index as determined echocardiographically (48). In this study there was no decrease in left ventricular wall thickness associated with the decreased cardiac mass. Whether the decreased cardiac mass was real or merely reflected a decreased diastolic dimension of the left ventricular cavity associated with the decrease in stroke volume that accompanies weight reduction remains to be determined. Other reports seem to leave this issue unresolved at present (11, 17, 43, 49).
COMMENTARY Much can be learned about underlying mechanisms of disease by studying hemodynamic alterations that characterize the disease and its associated mechanisms. Thus, obesity may be characterized hemodynamically as a volume-expanded disease that elevates cardiac output. However, when obesity coexists with essential hypertension, the elevated cardiac output is superimposed on a vasoconstricted circulation. Venoconstriction redistributes the circulating blood to the cardiopulmonary area, thereby increasing
Frohlich OBESITY AND HYPERTENSION: HEMODYNAMIC ASPECTS
AEP Vol. I, No. 4 May 1991: 287-293
291
t
Aging Hyperlipidemia Hyperuricemia Carbohydrate intolerance
1 The inter-relationship between exogenous obesity and hypertension and common risk factors in the hemodynamic progression of cardiovascular morbidity and mortality. CAD = coronary artery disease; LVH = left ventricular hypertrophy; CHF = coronary heart failure.
FIGURE
venous return, left ventricular preload, and cardiac output. Arteriolar constriction increases the arterial pressure, total peripheral resistance, and left ventricular afterload. The net result is a hyperdynamic circulation that provides a dual overload to the left ventricle, which adapts itself structurally by a dimorphic form of cardiac hypertrophy. Conceivably, this cardiac challenge is so great that there are fewer means for further adaptation, particularly in the presence of other risk factors associated with the two diseases: carbohydrate intolerance and diabetes mellitus, accelerated atherosclerosis, hyperlipidemia, and hyperuricemia. Given the clinical experience that these clinical conditions frequently coexist, it is understandable why patients with these problems are at greater risk of greater and premature cardiovascular morbidity and mortality (Figure 1). These data also demonstrate that associated with these hemodynamic changes that characterize the obese state are certain participating pressor mechanisms, including increased circulating levels of plasma norepinephrine, plasma renin activity, adrenergic function, hormonal alterations, and insulin resistance.
REFERENCES 1.
Metropolitan
underweight, 2.
Life Insurance
Metropolitan
Epstein FH. Prevalence
variables in a total community 4.
New York.
Frequency
of overweight
and
Factors in mortality from cardiovascular
dis-
1960;41:4-9.
Life Insurance Company.
ease, Stat Bull Metrop Insur Co. 3.
Company,
Stat Bull Metrop Insur Co.
1960;42:8-10. of chronic
of Tecumseh,
disease and distribution of selected physiological Michigan,
Am J Epidemiol.
Kannel W, Brand N, Skinner J, Dawber T, McNamara
blood pressure and development
of hypertension:
The Framingham
1965;81:307-22.
P. Relation of adiposity to Study, Ann Intern Med.
1967;67:48-59. 5.
Paffenbarger RS Jr, Thome
MC, Wing AL. Chronic
disease in former college stu-
292
Frohlich OBESITY AND HYPERTENSION: HEMODYNAMIC ASPECTS
AEP Vol. I, No. 4 May 1991: 287-293
dents. VIII. Characteristics in youth predisposing to hypertension in later years, Am J Epidemiol. 1968;88:25-32. 6. Chiang BN, Perlman LV, Epstein FH. Overweight and hypertension: A review, Circulation. 1969;9:403-2 1. 7. Stamler R, Stamler J, Riedlinger WE, Algera G, Roberts RH. Weight and blood pressure. Findings in hypertension screening in one million Americans, JAMA. 1978;240:1607-10. 8. Mann GV. The influence of obesity on health, N Engl J Med. 1974;291:178-85. 9. Sims EAH. Mechanisms of hypertension in the overweight, Hypertension. 1982;4(111):43-9. 10. Dustan HP. Mechanisms of hypertension associated with obesity, Ann Intern Med. 1983;98:860-4. 11. Frohlich ED, Messerli FH, Reisin E, Dunn FG. The problem of obesity and hypertension, Hypertension. 1983;5(111):71-8. 12. Frohlich ED. Mechanisms contributing to high blood pressure, Ann Intern Med. 1983;98:709-14. 13. Glass AR. Endocrine aspects of obesity, Med Clin North Am. 1989;73:139-60. 14. Frohlich ED, Reisin E. Hemodynamics in patients with overweight and hypertension. In: Safer, ME, ed. The Heart in Hypertension. Dordrecht, The Netherlands: Kluwer Academic Publishers 1989:117-25. 15. 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;141:81-5. 16. Messerli FH, Ventura HO, Reisin E, et al. Borderline hypertension and obesity: Two prehypertensive states with elevated cardiac output, Circulation. 1982;66:55-60. 17. Messerli FH, Sundgaard-Riise K, Reisin E, Dreslinski GR, Dunn FG, Frohlich ED. Disparate cardiovascular effects of obesity and arterial hypertension, Am J Med. 1983;74:808-12. 18. Messerli FH, Sundgaard-Riise K, Reisin E, et al. Dimorphic cardiac adaptation to obesity and arterial hypertension, Ann Intern Med. 1983;99:757-61. 19. Reisin E, Frohlich ED, Messerli FH, et al. Cardiovascular changes after weight reduction in obesity hypertension, Ann Intern Med. 1983;98:315-9. 20. Reisin E, Messerli FH, Ventura HO, Frohlich ED. Renal haemodynamic studies in obesity hypertension, J Hypertens. 1987;5:397-400. 2 1. Achimastos A., Raison J, Levenson J, Safar M. Adipose tissue cellularity and hemodynamic indexes in obese patients with hypertension, Arch Intern Med. 1984;144:265-8. 22. Kannel WB, Dawber TR, Kagen A, Revotokie N, Stokes J III. Factors of risk in the development of coronary heart disease: Six years’ follow-up experience, Ann Intern Med. 1961;55:33-50. 23. Page IH. Pathogenesis of arterial hypertension, JAMA. 1949;140:451-8. 24. Frohlich ED (State of the Art). The first Irvine H. Page lecture: The mosaic of hypertension: Past, present, and future, J Hypertens. 1988;6(4):2-11. 25. Resin E, Frohlich ED. Hemodynamics in obesity. In: Zanchetti A, Tarazi RE, ed. Pathophysiology of Hypertension-Cardiovascular Aspects. Handbook on Hypertension. v. 7. Amsterdam: Elsevier Science Publishers BV; 1986:280-97. 26. Dustan HP, Tarazi RC, Mujais SK. A comparison of hemodynamic and volume characteristics of obese and non-obese hypertensive patients, Int J Obesity 1981;5(1):19-25. 27. Raison J, Achimastos A, Bouthier J, London G, Safar M. Intravascular volume, extracellular fluid volume, and total body water in obese and nonobese hypertensive patients, Am J Cardiol. 1983;51:165-70. 28. Rocchini AP, Katch V, Kveselis D, et al. Insulin and renal sodium retention in obese adolescents, Hypertension. 1989;14:367-74. 29. Mujais SK, Tarazi RC, Dustan HP, Fouad FM, Bravo EL. Hypertension in obese patients: Hemodynamic and volume studies, Hypertension. 1982;4:84-92.
AEP Vol. I, No. 4 May 1991: 287-293
Frohlich OBESITY AND HYPERTENSION: HEMODYNAMIC ASPECTS
293
30. Crandall DL, DiGirolamo M. Hemodynamic and metabolic correlates in adipose tissue: Pathophysiologic considerations, FASEB J. 1990;4:141-7. 31. Lucas CP, Estigarribia ]A, Darga LL, Reaven GM. Insulin and blood pressure in obesity, Hypertension. 1985;7:702-6. 32. Christlieb AR, Krolewski AS, Warram JH, Soeldner JS. Is insulin the link between hypertension and obesity, Hypertension. 1985;7(11):54-7. 33. Landsberg L, Young JB. Fasting, feeding and regulation of the sympathetic nervous system, N Engl J Med. 1978;298:1295-301. 34. Young JB, Landsberg L. Diet induced changes in sympathetic nervous system activity, possible implications for obesity and hypertension, J Chronic Dis. 1982;35:879-86. 35. Frohlich ED. Hemodynamic factors in the pathogenesis and maintenance of hypertension, Fed Proc. 1982;41:2400-8. 36. Frohlich ED. Hemodynamics and other determinants in development of left ventricular hypertrophy: Conflicting factors in its regression, Fed Proc. 1983;42:2709-15. 37. Frohlich ED (State of the Art). The heart in hypertension: Unresolved conceptual challenges, Hypertension. 1988; 11 (I): 19-24. 38. Frohlich ED, Tarazi RC. Is arterial pressure the sole factor responsible for hypertensive cardiac hypertrophy! Am J Cardiol. 1979;44:959-63. 39. Tarazi RC, Frohlich ED. Is reversal of cardiac hypertrophy a desirable goal of antihypertensive therapy? Circulation. 1987;75(1):113-7. factors associated 40. Frohlich ED. Overview of hemodynamic and non-hemodynamic with LVH, J Mol Cell Cardiol. 1990;21:3-10. 41. Linazbach AJ. Heart failure from the point of view of quantitative anatomy, Am J Cardiol. 1960;5:370-82. 42. Garvaglia GE, Messerli FH, Nunez BD, Schmieder RE, Grossman E. Myocardial contractility and left ventricular function in obese patients with essential hypertension, Am J Cardiol. 1988;62:594-7. 43. Alpert MA, Terry BE, Kelly DL. Effect of weight loss on cardiac chamber size, wall thickness and left ventricular function in morbid obesity, Am J Cardiol. 1985;55:783-6. 44. Quinones MA, Gaasch WH, Alexander JK. Influence of acute changes in preload, afterload, contractile state and heart rate on ejection and isovolumic indices of myocardial contractility in men, Circulation. 1976;53:293-302. 45. DeDivitiis 0, Fazio S, Petitto M, M a dd a Iena G, Contaldo F, Mancini M. Obesity and cardiac function, Circulation. 1981;64:477-82. 46. Gordon T, Kannel WB. Obesity and cardiovascular disease: The Framingham Study, Clin Endocrinol Metab. 1976;5:367-74. 47. Barrett-Connor E, Kow KT. Is hypertension more benign when associated with obesity? Circulation. 1985;72:53-60. 48. MacMahon SW, Wilcken DEL, MacDonald GLJ. The effect of weight reduction on left ventricular mass: A randomized controlled trial in young, overweight, hypertensive patients, N Engl J Med. 1986;314:334-9. 49. Bennett DN, Evans DW. Correlation of left ventricular mass determined by echocardiography with vectorgraphic and electrocardiographic measurements, Br Heart J. 1974;36:981-7.
Aspects
Edward D. Frohlich, MD Elevated arterial pressure in patients with obesity-hypertension is associated with an increased cardiac output and total peripheral resistance. The elevated output is related to expanded innavascular volume that increases cardiopulmonary volume, venous return, and left ventricular preload; the ekvated pressure and total peripheral resistance increase afterload. This dual ventricular overload promotes a dimorphic, concentric, and eccentric hypertrophy in response to the volume and pressure overload. Increased myocardial oxygen demand results from the elevated tension in the Left ventricular wall, reflecting its increased diameter and pressure, and provides physiologic rationale for the greater potential of coronary arterial insufficiency and cardiac failure. There are greater renal blood flow and lower renal vascular resistance in patients with obesity-hypertension at any kvel of arterial pressure. This may be offset b an increased renal filtration fraction that may favor protein deposition and glomerulosckrosis, and wedisposition of obese patients for diabetes may aggravate this problem. With weight reduction, these hemodynamic derangements may be reversed: intravascular volume ContracLCts, cardiac output decreases, and arterial pressure falls. Ann
Epidemiol I991 ; 1:287-293 KEY WORDS:
hemodynamics,
Exogenous obesity, essential hypertension, renal hemodynamics,
left ventricular hypertrophy,
systemic
blood volume.
INTRODUCTION
Hypertension and obesity are two independent diseases, yet, over the years, clinical and epidemiologic studies have repeatedly confirmed a more than coincidental association (l-8). Despite this close interrelationship, existence of one disease does not imply the necessary coexistence of the other. When hypertension does coexist with obesity-and this occurs frequently-the mechanisms explaining this association are not completely understood (9-11). Indeed, what is clear is the epidemiologic documentation that attests to an augmented risk for premature cardiovascular morbidity and mortality (2-4, 7). In order to learn why the potential risk is so great, several authors presented evidence for differences in pressor mechanisms (9-14). In this respect, hemodynamic findings have demonstrated important physiologic differences between lean and obese normotensive as well as hypertensive individuals, and that obesity-hypertension is a more severe pathophysiologic state than either state existing independently ( 11-21).
COINCIDENT ESSENTIAL
RISK FACTORS HYPERTENSION
IN PATIENTS
WITH
OBESITY
AND
The term “‘factors of risk” was first introduced by the Framingham Heart Study to delineate identifiable demographic and clinical characteristics that confer special cardiovascular risk to that population (22). These risk factors now include: cigarette
From Alton Ochsner Medical Foundatmn, New Orleans, LA. Address reprint requests to: Edward D. Frohlich, MD, Vice President for Academic Affairs, Alton Ochsner Medical Foundation, 15 16 Jefferson Highway, New Orleans, LA 7012 1. Received August 6, 1990; revised August 30, 1990. 0 1991 Elsevier Science Publishq
Co., Inc.
1047-2797191/$03.50
288
Frohlich OBESITY AND HYPERTENSION:
HEMODYNAMIC
ASPECTS
AEP Vol. 1, No. 4 May 1991: 287-293
smoking, hypertension, left ventricular hypertrophy, exogenous obesity, hyperlipidemia, diabetes mellitus, and hyperuricemia. Other nonmodifiable risk factors are male gender, advancing age (particularly older than 50 years when male and female subjects are of equal risk), and the black race.
MECHANISMS
ASSOCIATED
WITH
EXOGENOUS
OBESITY
In earlier years, particularly with respect to the infectious diseases, it was possible to identify causation of disease in terms of Koch’s postulates. However, in contrast to diseases whose etiology is known, many of the common clinical problems encountered at present are multifactorial in nature; a single cause-effect relationship is not likely (23, 24). The latter have been termed diseases of regulation, explained on the basis of a disregulation of the myraid of physiologic mechanisms that serve to maintain normal body homeostasis. In this respect, no two problems can be better exemplified than those of systemic arterial hypertension and exogenous obesity. It follows, then, that by understanding underlying regulatory factors, it is possible to identify which of the involved mechanisms may go awry. Then, by intervening therapeutically, it may be possible to normalize them and, thus, restore homeostasis. Over the past 30 years it has been possible to identify pressor and depressor mechanisms that operate in patients with essential hypertension, and with the exciting development of new antihypertensive agents, the control of arterial pressure and arrest of the advancing disease has been assured. As a result, it is now evident that the course of hypertensive disease and its complications have been dramatically altered for the better. By this same line of reasoning, exogenous obesity has been the subject of much study; a number of associated mechanisms have been identified. Among those recognized are: altered carbohydrate metabolism; diminished end*organ responsiveness to endogenous insulin; catecholamine excess (or increased adrenergic function); dietary sodium excess; hypervolemia; hormonal alterations including aldosterone, other adrenal steroids, and the thyroid hormone; and altered hemodynamic functions (9, 10, 12-14, 25-35). This discussion concerns the hemodynamic alterations that are associated with obesity and how total body circulatory homeostasis is compromised further when obesity coexists with essential hypertension.
HEMODYNAMIC
ALTERATIONS
Obesity-Normotension Obese normotensive individuals have an increased cardiac output that is in direct proportion to circulating blood volume; this is related to body mass (9, 11, 14-19, 25-27). In these obese patients with an elevated cardiac output, the expanded intravascular volume is the result of increased plasma volume (9, 11, 14-16, 26, 27, 29). The result is an increased venous return to the heart, and an increased volume of blood in the cardiopulmonary circulation. Since height of arterial pressure is directly proportional to the cardiac output and the resistance offered by the small arteries to the forward flow of blood (total peripheral resistance), obese normotensive patients must have a reduced total peripheral resistance. It is conceivable, however, that their arterial pressure might very well be even lower if the obese patient becomes leaner, demonstrating a different response of the peripheral circulation to the expanded intravascular volume and elevated cardiac output.
AEP Vol. 1, No. 4 May 1991: 287-293
Frohlich OBESITYAND HYPERTENSION:HEMODYNAMICASPECTS
289
ObesityeHypertension The hemodynamic alterations associated with both obesity and hypertension represent the combination of factors associated with both diseases (9, 14-20, 25-27, 29). Thus, in patients with essential hypertension, the elevated total peripheral resistance is in direct proportion to the height of arterial pressure (11, 14, 15, 36). Cardiac output remains normal in these patients until the heart can no longer adapt functionally and structurally to the slowly progressing, increased afterload that is imposed on the left ventricle. At that point, left ventricular failure supervenes and is associated with a reduction in cardiac output and in blood flow to the organs. With the coexistence of obesity, and expanded intravascular volume is superimposed on the unrelenting increased pressure overload and the rising total peripheral resistance ( 11). This expanded volume is, in part, translocated from the periphery to the cardiopulmonary area by virtue of the venoconstriction associated with the hypertensive state (11, 14-16, 37). This augmented circulating volume that is redistributed to the cardiopulmonary area increases venous return to the heart and, thus, the cardiac output. With this redistribution, calculated total peripheral resistance tends to be reduced; however, at any level of cardiac output in patients with obesity-hypertension, total peripheral resistance is significantly higher than in normotensive obese patients of the same body mass ( 11, 15, 26, 29). Thus, the state of obesity-hypertension is characterized by a dual hemodynamic left ventricular load: a pressure as well as a volume overload (11).
Cardiac Responses As suggested, any hemodynamic overload imposed on the ventricle evokes a dual response: functional and structural. The functional aspect concerns those intrinsic myocardial responses to stretch produced by volume distention (preload) or by pressure (afterload) overload (24, 37). I n addition, the heart responds structurally; this is dictated, in part, by the stretch of the cardiac myocyte. However, recent evidence has suggested that nonhemodynamic factors also stimulate the left ventricular hypertrophy response (36-40). The nature of this structural response depends on the type of ventricular overload. If the ventricular overload is a volume-preload, the response is a more eccentric configuration; if the overload is a pressure-afterload, the hypertrophy is more concentric (4 1). Under normal circumstances, the former response is more akin to the hypertrophy resulting from isotonic (or dynamic) exercise since this is one of volume overload. By contrast, the ventricular response to a more static form of isometric exercise is mixed; this overload is induced by both pressure and volume. It is not known at present whether there is a difference in the type of myocardial myosin muscle response to these two forms of ventricular overload. At least three myosin isoforms are synthesized by the myocyte; we do not know whether each of these myosins is associated with different functional capabilities. At any rate, in the volume overload of exogenous obesity in the normotensive individual there is an eccentric left ventricular hypertrophy (11, 16-18). But in the more complex obesity-hypertension, the structural response is more dimorphic; that is to say, there is a combination of an eccentric and concentric type of left ventricular hypertrophy (11, 17, 18). This rather simplistic elucidation of the type of hypertrophy that is associated with obesity-hypertension provides a reasonable pathophysiologic understanding of why these patients are more predisposed to congestive heart failure (11, 42-45). It follows, then, that in the setting of hyperlipidemia, diabetes mellitus, or accelerated atherosclerosis (which are associated only with both hypertension and exogenous
290
Frohlich OBESITY AND HYPERTENSION:
HEMODYNAMIC
ASPECTS
AEP Vol. 1, No. 4 May 1991: 287-293
obesity), there is no wonder why these patients have a greater cardiovascular risk. Indeed, this risk includes an increased chance of developing the cardiac complications of coronary arterial insufficiency with or without angina pectoris, myocardial infarction, cardiac dysrhythmias, and sudden death (4, 6, 7, 46).
Renal Hemodynamics With obesity there is not only an increase in cardiac output, but also an increase in its distribution to the renal circulation. Indeed, renal blood flow is increased in obese patients whether or not they have hypertension (20). This is associated with reduced renal vascular resistance. However, renal vascular resistance is higher for any level of renal blood flow if the patient is hypertensive. Because of this lesser intrarenal vasoconstriction associated with obesity (whether or not the patient is hypertensive), there seems to be less renal complication than in patients who are lean (47).
Effects of Weight Reduction In a recent study from our laboratory concerned with weight reduction, we compared two similarly matched groups of obese patients: One lost wieght on a prescribed dietary program, and the other group did not (19). The latter group demonstrated no change in any of the evaluated hemodynamic indices. In contrast, the group that did lose weight demonstrated a decrease in systolic, diastolic, and mean arterial pressure, which was associated with a reduced cardiac output in proportion to the decreased intravascular (plasma) volume (19). Since there was no change in heart rate, the fall in cardiac output was related to a decreased stroke volume. Thus, with the contracted plasma volume achieved with weight reduction, cardiopulmonary volume declined, and was associated with a reduction in venous return and cardiac output. It was of further interest to see that with the reduction in body weight, there was also a decrease in many of the biochemical indices that serve either as pressor mechanisms or as risk factors associated with hypertension, obesity, and cardiovascular disease. These included: serum cholesterol, triglyceride, and uric acid concentrations as well as plasma norepinephrine concentration, plasma renin activity, and 24-hour urinary aldosterone excretion (19). These findings are consistent with others conceming biochemical changes in patients able to reduce their body weight. One study demonstrating reduction in body weight in obese patients also showed decreases in arterial pressure and left ventricular mass index as determined echocardiographically (48). In this study there was no decrease in left ventricular wall thickness associated with the decreased cardiac mass. Whether the decreased cardiac mass was real or merely reflected a decreased diastolic dimension of the left ventricular cavity associated with the decrease in stroke volume that accompanies weight reduction remains to be determined. Other reports seem to leave this issue unresolved at present (11, 17, 43, 49).
COMMENTARY Much can be learned about underlying mechanisms of disease by studying hemodynamic alterations that characterize the disease and its associated mechanisms. Thus, obesity may be characterized hemodynamically as a volume-expanded disease that elevates cardiac output. However, when obesity coexists with essential hypertension, the elevated cardiac output is superimposed on a vasoconstricted circulation. Venoconstriction redistributes the circulating blood to the cardiopulmonary area, thereby increasing
Frohlich OBESITY AND HYPERTENSION: HEMODYNAMIC ASPECTS
AEP Vol. I, No. 4 May 1991: 287-293
291
t
Aging Hyperlipidemia Hyperuricemia Carbohydrate intolerance
1 The inter-relationship between exogenous obesity and hypertension and common risk factors in the hemodynamic progression of cardiovascular morbidity and mortality. CAD = coronary artery disease; LVH = left ventricular hypertrophy; CHF = coronary heart failure.
FIGURE
venous return, left ventricular preload, and cardiac output. Arteriolar constriction increases the arterial pressure, total peripheral resistance, and left ventricular afterload. The net result is a hyperdynamic circulation that provides a dual overload to the left ventricle, which adapts itself structurally by a dimorphic form of cardiac hypertrophy. Conceivably, this cardiac challenge is so great that there are fewer means for further adaptation, particularly in the presence of other risk factors associated with the two diseases: carbohydrate intolerance and diabetes mellitus, accelerated atherosclerosis, hyperlipidemia, and hyperuricemia. Given the clinical experience that these clinical conditions frequently coexist, it is understandable why patients with these problems are at greater risk of greater and premature cardiovascular morbidity and mortality (Figure 1). These data also demonstrate that associated with these hemodynamic changes that characterize the obese state are certain participating pressor mechanisms, including increased circulating levels of plasma norepinephrine, plasma renin activity, adrenergic function, hormonal alterations, and insulin resistance.
REFERENCES 1.
Metropolitan
underweight, 2.
Life Insurance
Metropolitan
Epstein FH. Prevalence
variables in a total community 4.
New York.
Frequency
of overweight
and
Factors in mortality from cardiovascular
dis-
1960;41:4-9.
Life Insurance Company.
ease, Stat Bull Metrop Insur Co. 3.
Company,
Stat Bull Metrop Insur Co.
1960;42:8-10. of chronic
of Tecumseh,
disease and distribution of selected physiological Michigan,
Am J Epidemiol.
Kannel W, Brand N, Skinner J, Dawber T, McNamara
blood pressure and development
of hypertension:
The Framingham
1965;81:307-22.
P. Relation of adiposity to Study, Ann Intern Med.
1967;67:48-59. 5.
Paffenbarger RS Jr, Thome
MC, Wing AL. Chronic
disease in former college stu-
292
Frohlich OBESITY AND HYPERTENSION: HEMODYNAMIC ASPECTS
AEP Vol. I, No. 4 May 1991: 287-293
dents. VIII. Characteristics in youth predisposing to hypertension in later years, Am J Epidemiol. 1968;88:25-32. 6. Chiang BN, Perlman LV, Epstein FH. Overweight and hypertension: A review, Circulation. 1969;9:403-2 1. 7. Stamler R, Stamler J, Riedlinger WE, Algera G, Roberts RH. Weight and blood pressure. Findings in hypertension screening in one million Americans, JAMA. 1978;240:1607-10. 8. Mann GV. The influence of obesity on health, N Engl J Med. 1974;291:178-85. 9. Sims EAH. Mechanisms of hypertension in the overweight, Hypertension. 1982;4(111):43-9. 10. Dustan HP. Mechanisms of hypertension associated with obesity, Ann Intern Med. 1983;98:860-4. 11. Frohlich ED, Messerli FH, Reisin E, Dunn FG. The problem of obesity and hypertension, Hypertension. 1983;5(111):71-8. 12. Frohlich ED. Mechanisms contributing to high blood pressure, Ann Intern Med. 1983;98:709-14. 13. Glass AR. Endocrine aspects of obesity, Med Clin North Am. 1989;73:139-60. 14. Frohlich ED, Reisin E. Hemodynamics in patients with overweight and hypertension. In: Safer, ME, ed. The Heart in Hypertension. Dordrecht, The Netherlands: Kluwer Academic Publishers 1989:117-25. 15. 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;141:81-5. 16. Messerli FH, Ventura HO, Reisin E, et al. Borderline hypertension and obesity: Two prehypertensive states with elevated cardiac output, Circulation. 1982;66:55-60. 17. Messerli FH, Sundgaard-Riise K, Reisin E, Dreslinski GR, Dunn FG, Frohlich ED. Disparate cardiovascular effects of obesity and arterial hypertension, Am J Med. 1983;74:808-12. 18. Messerli FH, Sundgaard-Riise K, Reisin E, et al. Dimorphic cardiac adaptation to obesity and arterial hypertension, Ann Intern Med. 1983;99:757-61. 19. Reisin E, Frohlich ED, Messerli FH, et al. Cardiovascular changes after weight reduction in obesity hypertension, Ann Intern Med. 1983;98:315-9. 20. Reisin E, Messerli FH, Ventura HO, Frohlich ED. Renal haemodynamic studies in obesity hypertension, J Hypertens. 1987;5:397-400. 2 1. Achimastos A., Raison J, Levenson J, Safar M. Adipose tissue cellularity and hemodynamic indexes in obese patients with hypertension, Arch Intern Med. 1984;144:265-8. 22. Kannel WB, Dawber TR, Kagen A, Revotokie N, Stokes J III. Factors of risk in the development of coronary heart disease: Six years’ follow-up experience, Ann Intern Med. 1961;55:33-50. 23. Page IH. Pathogenesis of arterial hypertension, JAMA. 1949;140:451-8. 24. Frohlich ED (State of the Art). The first Irvine H. Page lecture: The mosaic of hypertension: Past, present, and future, J Hypertens. 1988;6(4):2-11. 25. Resin E, Frohlich ED. Hemodynamics in obesity. In: Zanchetti A, Tarazi RE, ed. Pathophysiology of Hypertension-Cardiovascular Aspects. Handbook on Hypertension. v. 7. Amsterdam: Elsevier Science Publishers BV; 1986:280-97. 26. Dustan HP, Tarazi RC, Mujais SK. A comparison of hemodynamic and volume characteristics of obese and non-obese hypertensive patients, Int J Obesity 1981;5(1):19-25. 27. Raison J, Achimastos A, Bouthier J, London G, Safar M. Intravascular volume, extracellular fluid volume, and total body water in obese and nonobese hypertensive patients, Am J Cardiol. 1983;51:165-70. 28. Rocchini AP, Katch V, Kveselis D, et al. Insulin and renal sodium retention in obese adolescents, Hypertension. 1989;14:367-74. 29. Mujais SK, Tarazi RC, Dustan HP, Fouad FM, Bravo EL. Hypertension in obese patients: Hemodynamic and volume studies, Hypertension. 1982;4:84-92.
AEP Vol. I, No. 4 May 1991: 287-293
Frohlich OBESITY AND HYPERTENSION: HEMODYNAMIC ASPECTS
293
30. Crandall DL, DiGirolamo M. Hemodynamic and metabolic correlates in adipose tissue: Pathophysiologic considerations, FASEB J. 1990;4:141-7. 31. Lucas CP, Estigarribia ]A, Darga LL, Reaven GM. Insulin and blood pressure in obesity, Hypertension. 1985;7:702-6. 32. Christlieb AR, Krolewski AS, Warram JH, Soeldner JS. Is insulin the link between hypertension and obesity, Hypertension. 1985;7(11):54-7. 33. Landsberg L, Young JB. Fasting, feeding and regulation of the sympathetic nervous system, N Engl J Med. 1978;298:1295-301. 34. Young JB, Landsberg L. Diet induced changes in sympathetic nervous system activity, possible implications for obesity and hypertension, J Chronic Dis. 1982;35:879-86. 35. Frohlich ED. Hemodynamic factors in the pathogenesis and maintenance of hypertension, Fed Proc. 1982;41:2400-8. 36. Frohlich ED. Hemodynamics and other determinants in development of left ventricular hypertrophy: Conflicting factors in its regression, Fed Proc. 1983;42:2709-15. 37. Frohlich ED (State of the Art). The heart in hypertension: Unresolved conceptual challenges, Hypertension. 1988; 11 (I): 19-24. 38. Frohlich ED, Tarazi RC. Is arterial pressure the sole factor responsible for hypertensive cardiac hypertrophy! Am J Cardiol. 1979;44:959-63. 39. Tarazi RC, Frohlich ED. Is reversal of cardiac hypertrophy a desirable goal of antihypertensive therapy? Circulation. 1987;75(1):113-7. factors associated 40. Frohlich ED. Overview of hemodynamic and non-hemodynamic with LVH, J Mol Cell Cardiol. 1990;21:3-10. 41. Linazbach AJ. Heart failure from the point of view of quantitative anatomy, Am J Cardiol. 1960;5:370-82. 42. Garvaglia GE, Messerli FH, Nunez BD, Schmieder RE, Grossman E. Myocardial contractility and left ventricular function in obese patients with essential hypertension, Am J Cardiol. 1988;62:594-7. 43. Alpert MA, Terry BE, Kelly DL. Effect of weight loss on cardiac chamber size, wall thickness and left ventricular function in morbid obesity, Am J Cardiol. 1985;55:783-6. 44. Quinones MA, Gaasch WH, Alexander JK. Influence of acute changes in preload, afterload, contractile state and heart rate on ejection and isovolumic indices of myocardial contractility in men, Circulation. 1976;53:293-302. 45. DeDivitiis 0, Fazio S, Petitto M, M a dd a Iena G, Contaldo F, Mancini M. Obesity and cardiac function, Circulation. 1981;64:477-82. 46. Gordon T, Kannel WB. Obesity and cardiovascular disease: The Framingham Study, Clin Endocrinol Metab. 1976;5:367-74. 47. Barrett-Connor E, Kow KT. Is hypertension more benign when associated with obesity? Circulation. 1985;72:53-60. 48. MacMahon SW, Wilcken DEL, MacDonald GLJ. The effect of weight reduction on left ventricular mass: A randomized controlled trial in young, overweight, hypertensive patients, N Engl J Med. 1986;314:334-9. 49. Bennett DN, Evans DW. Correlation of left ventricular mass determined by echocardiography with vectorgraphic and electrocardiographic measurements, Br Heart J. 1974;36:981-7.
