Essential Hypertension in Blacks: Is It a Metabolic Disorder?

Essential Hypertension in Blacks: Is It a Metabolic Disorder? Matthew R. Weir, MD, and Michael L. Tuck, MD

S

UBJECTS with obesity, essential hypertension, and diabetes mellitus have in common underlying metabolic disturbances that contribute to both cardiovascular morbidity and mortality. 1-3 There is a strong association between diabetes mellitus and essential hypertension, as the prevalence of hypertension in patients with noninsulin-dependent diabetes mellitus (NIDDM) is high, with estimates of occurrence in up to 40% to 50% of the subpopulation4 compared with 20% in the general population. A positive family history of hypertension also is common in subjects with diabetes mellitus. Certain indicators of essential hypertension, such as measurements of red blood cell sodium transport pathways, 5 are abnormal in some subjects with diabetes mellitus. Obesity explains, in part, elevated blood pressure in NIDDM patients; 80% are overweight or obese. In addition, more than 50% of essential hypertensive subjects are over ideal body weight. However, obesity can only partially explain the strong association of hypertension in diabetes mellitus. Insulin resistance and hyperinsulinemia are common findings in many industrialized populations determined by multiple genetic and environmental factors. Insulin resistance is a reduction in insulin action for stimulation of glucose uptake in target tissue. Acompensatory response to insulin resistance occurs if pancreatic function is normal, with increased insulin secretion resulting in high circulating levels of insulin. Mechanisms for insulin resistance are multiple, including genetic and environmental influences. 6 Insulin antibodies are a rare cause of insulin resistance in diabetes. Insulin can downregulate its receptors so that conditions with high circulating insulin levels could lead to diminished insulin action. However, most insulin resistance in the From the Division of Nephrology and Clinical Research Unit, Department of Medicine, University of Maryland Hospital, Baltimore, MD; and the Division ofEndocrinology, Veterans Administration Hospital, Sepulveda, CA, and UCLA School of Medicine, Los Angeles, CA . No reprints available. Address correspondence to Matthew R . Weir, MD, Renal Division, University of Maryland Hospital, 22 S Greene St, Baltimore, MD 21201. © 1993 by the National Kidney Foundation, Inc. 0272-6386/93/2104-0111$3.00/0 58

general population is related to cellular abnormalities of the insulin receptor or postreceptor events in cell signaling, such as abnormalities in receptor-linked tyrosine kinase function, in autophosphorylation, and in the glucose transport proteins. 6 In addition to obesity and NIDDM, essential hypertension is accompanied by insulin resistance and hyperinsulinemia. I-3 This observation was first reported by Welborn et aC over 20 years ago. Since then many studies have found a strong correlation between insulin resistance or hyperinsulinemia and higher blood pressure, even after adjustment for other risk factors for hypertension. 8- 13 Modan et al 8 found a strong association between hypertension, glucose intolerance, and insulin levels after correction for age, gender, and body weight in 2,475 Israeli nondiabetic and diabetic subjects. Manicardi et al9 found that overweight subjects who were hypertensive had plasma insulin responses to glucose loading threefold greater than normotensive obese subjects, and there was a positive correlation between blood pressure and insulin. Zavaroni et al J3 showed that 32 hyperinsulinemic subjects had higher systolic and diastolic blood pressures compared with a group of patients with normal insulin levels. Compared with normotensive subjects, insulin levels in essential hypertensive patients are significantly higher after glucose loading. JO Insulin resistance also can be demonstrated in essential hypertensive patients by more precise methods, such as euglycemic insulin clamp or the minimal model computerized technique. Stimulation of whole-body glucose uptake by insulin is decreased up to 40% in some essential hypertensive subjects, but the exact prevalence of this finding in the hypertensive population is uncertain. JO Skeletal muscle appears to be the major site of insulin resistance in essential hypertension involving nonoxidative glucose uptake pathways for glycogen synthesis. The severity of insulin resistance is directly correlated to blood pressure levels in hypertensive subjects, and a causal relation between insulin and blood pressure has been proposed. Pollare et al 12 studied insulin sensitivity in 143 hypertensive subjects (of whom 59% were obese) and in 51 normoten-

American Journal of Kidney Diseases, Vol 21, No 4, Suppl 1 (April), 1993: pp 58-67

HYPERTENSION IN BLACKS: A METABOLIC DISORDER?

sive controls and noted that insulin sensitivity was decreased in obese and normal-weight hypertensive subjects compared with the normotensive controls. There also was a significant negative relationship between insulin sensitivity and systolic blood pressure in the hypertensive subjects. The San Antonio Heart Study3,14 examined metabolic factors in relation to cardiovascular disease in 2,930 subjects from a biethnic population of Mexican Americans and non-Hispanic whites. Hypertension was present in 287 subjects (9.8% prevalence), and five metabolic disorders (including obesity, NIDDM, impaired glucose tolerance [IGT], high serum triglycerides, and high total serum cholesterol) were associated with a higher frequency than expected in hypertensive subjects. A positive correlation of insulin to diastolic blood pressure was found in the hypertensive and normotensive Hispanic population, although the prevalence of hypertension is lower in this population than in non-Hispanic whites. Other reports either have not found a strong association of insulin to blood pressure or have noted no correlation. There may be several reasons for the more recent controversy over the relationship between insulin and blood pressure. For example, such confounding variables as age, gender, body weight, and race may alter this relationship. It now also is apparent that ethnic composition of the study group may markedly effect the association of blood pressure to insulin. The prevalence of hypertension, diabetes, and obesity also varies substantially by ethnicity.15 Most early reports linking insulin to blood pressure were from studies of predominantly white populations. Special groups, such as the Pima Indians, who have a high incidence of obesity, insulin resistance, and hyperinsulinemia, have been shown by Saad et al l5 to have a low prevalence of hypertension compared with the general population. Fasting and postglucose insulin levels are not related to blood pressure in normotensive, nondiabetic Pima Indians, and there is no correlation between insulin sensitivity and mean arterial pressure. 15 These findings are in contrast to a significant negative correlation of insulin sensitivity and mean arterial pressure that was found in the white normotensive nondiabetic group in this study. The relationship between insulin and blood pressure in blacks also has not yet been clearly

59

established. In the study of Saad et al,15 normotensive, nondiabetic black subjects showed no correlation of insulin sensitivity to blood pressure. On the other hand, Falkner et al l6 found that insulin-mediated glucose disposal in borderline hypertensive black men was significantly reduced compared with normotensive blacks. In black children there appears to be little relationship between plasma insulin and blood pressure. 17 In another study of young black subjects (18 to 30 years of age) the correlation coefficient of insulin and blood pressure was quite weak (r = 0.16) and was not found when corrected for other variables, such as body mass index.'s In a study of Chinese men in Taiwan, there was a correlation of insulinemia and blood pressure;19 in a mixed ethnic group comprising AfroCarribeans, Gujerati Indians, and white Europeans, no relationship between plasma insulin levels and blood pressure was found. 20 Alberti et a121 noted that the relationship between plasma insulin and blood pressure was weak, accounting for I %or less of blood pressure variance in four different ethnic or racial groups. Other studies have failed to find a consistent relationship between blood pressure and metabolic parameter. 22 ,23 The reason for interracial and intraracial differences between insulin sensitivity, hyperinsulinemia, and blood pressure remains to be elucidated. Subjects with essential hypertension may have a greater chance of developing diabetes mellitus than normotensive subjects, and diabetic subjects may have a greater occurrence of hypertension than nondiabetics. In retrospective studies ofpatients with NIDDM and hypertension, over 80% of subjects had hypertension prior to developing diabetes mellitus, indicating that there is a greater chance for hypertensive subjects to acquire diabetes mellitus than for normotensive individuals. 24 In longitudinal studies the risk of developing diabetes mellitus in hypertensive women (N = 1,462) compared with normotensive subjects was much greater in those taking diuretic and beta-blocker antihypertensive drugs. 25 Thus, the occurrence rate of diabetes mellitus in hypertensive subjects may be further accentuated by certain antihypertensive therapies. As insulin is linked to hypertension, there has been a recent interest in determining the potential insulin effects on blood pressure control systems

60

that could elevate blood pressure. 26 Insulin has several actions on cardiovascular, neural, and renal tissue that could produce hypertension through effects on ion transport, effects on the sympathetic nervous system, and direct actions of insulin on renal and vascular tissue. Infusion of insulin into normal subjects increases plasma norepinephrine levels27 and increases regional neural outflow,28 suggesting that excess insulin could lead to the development of neurogenic hypertension. Insulin infusion or endogenous insulin excess leads to sodium retention by direct effects on tubular sodium reabsorption so that hyperinsulinemia could initiate volume-dependent hypertension. 1Insulin directly stimulates Na transport pathways, such as the Na-K-ATPase pump and the Na-H antiporter system. Increased activity of these Na transport pathways in the kidney or blood vessels has been proposed to increase blood pressure or vascular tone by sodium retention or by increases in cytosolic calcium, respectively. 1,26 Insulin has several direct effects on arterial tissue, including acceleration of the atherosclerotic plaque formation 29 and structural changes on the vascular wall. In animals, insulin treatment in experimental diabetes is associated more with atherosclerosis than in untreated animals and regression of atherosclerosis is retarded by insulin administration. 29 Insulin is a growth factor for vascular smooth muscle proliferation and it stimulates other growth factors that affect cardiovascular tissue. Cholesterol synthesis in vascular tissue is enhanced by insulin as well as lowdensity lipoprotein receptor activity to enhance cholesterol uptake. Patients with hypertension may have enhanced rates of atherosclerosis that are related not only to elevated blood pressure but also to excess of insulin and other metabolic risks. Insulin levels show a positive correlation to cardiovascular disease. Low-risk populations for heart disease have lower ambient insulin levels, whereas insulin is higher in countries in which ischemic heart disease is high. 30 The Helsinki Po~ liceman Study30 and other large epidemiology trials31 ,32 have confirmed the significant relationship between insulin excess and cardiovascular disease. For example, men in the Helsinki study in the highest quintile for fasting and postglucose insulin had a much higher incidence of coronary heart disease and myocardial infarction. Hyper-

WEIR AND TUCK

insulinemic subjects also have higher levels of other risk factors, such as serum triglycerides and total cholesterol, and lower levels of high-density lipoprotein cholesterol than subjects with normal insulin levels. 32 The finding that hyperinsulinemia and insulin resistance are associated with elevations of blood pressure and other cardiovascular risk factors, which have been studied for the most part by correlative analysis, is powerful but indirect evidence of insulin's role in cardiovascular disease. These studies, however, leave open the question of whether insulin has a direct role in the causation of high blood pressure, renal dysfunction, and atherosclerosis. Insulin and blood pressure may only be indirectly associated to other genetic and environmental factors that directly lead to hypertension and atherosclerosis. These metabolic and hemodynamic relationships also appear to depend heavily on ethnicity. Thus, a predictive role of insulin and glucose in hypertension and cardiovascular disease in blacks is suggested, but the relationships are complex and require further elucidation. HYPERTENSION AND METABOLISM IN RENAL DISEASE

Numerous factors contribute to cardiovascular disease in blacks, and a mixture of biological, psychological, environmental, and sociocultural variables influence the relationship between metabolic factors and hypertension in this population (Fig 1). A combined metabolic and cardiovascular disarray may be the major contributor to the high percentage of black Americans with hypertension, severe cardiovascular disease, and disproportionate target organ damage to the kidney. A genetic predisposition toward enhanced vascular hyperactivity,33 sociocultural stress,34 and obesity34 may trigger events leading to accelerated cardiovascular and renal damage in blacks. Pathology studies of renal histology in moderate to severe hypertensive subjects usually show arteriolar fibrinoid necrosis and glomerular proliferative changes similar to the renal injury of malignant hypertension. 35 However, the dominant histologic feature of renal injury of malignant hypertension in blacks is musculomucoid intimal hyperplasia of small arterioles associated with obsolescence of glomerular tuftS. 36 The ar-

61

HYPERTENSION IN BLACKS: A METABOLIC DISORDER?

Body Fat . - Genetic

t

J..Renal Blood Flow

iNeurohormonal Response

(Glomerular Hyperfiltration)

?

Fig 1. Factors linking metabolic, renal, and cardio-. vascular damage in blacks.

terioles in the kidneys of blacks appear hylanized and thickened with smooth muscle hyperplasia and mucopolysaccharide deposition, as opposed to the classic fibrinoid necrosis of vessel walls of non-blacks with malignant hypertension. There also are differences in the renal hemodynamic adaptation between blacks and whites to the onset of hypertension. Renal blood flow is reduced in hypertensive blacks compared with non-blacks with comparable blood pressure. 3? Frohlich et al 38 compared systemic and renal hemodynamics in white and black hypertensive subjects matched for body habitus, age, and sex. Despite similar mean arterial pressures, heart rates, cardiac indices, and total peripheral resistance, renal blood flow was approximately 25% less in blacks associated with higher renal vascular resistance. These studies suggest that in addition to the effects of age and hypertension on renal perfusion,39,40 there also is a direct influence of race on renal hemodynamics. Reduced renal perfusion in blacks may be due to a generalized vasoconstrictive effect in blacks

b

Insulin

pReSince

• iNA Reabsorption

/

iLipids

Hypertension

1

Excretion" Rest7uring

i Albumin

Insulin

Vascular/Mesangial

•......... .......... ? ~

Glomerulosclerosis that also involves the renal vasculature. Racial differences in vascular cation transport may explain differences in vascular reactivity, as Kurijama et al41 found higher Na turnover rates and increased Na-H antiporter activity in cultured fibroblasts from blacks compared with whites. It has been proposed that high intracellular Na leads to increased cytosolic calcium and increased vascular tone. 42-44 The observations in cultured fibroblasts in blacks mayor may not pertain to reactivity of vascular smooth muscle. Diminished renal perfusion and increased vascular reactivity could predispose the renal microcirculation to dysfunction and damage. Abnormal glomerular hemodynamics (hyperfiltration) and neurohormonal control of renal hemodynamics have a deleterious influence on mesangial cells by promoting mesangial growth, matrix production, and development of glomerulosclerosis. Glomerular capillary hypertension and/or mesangial cell expansion induced in experimental animal models leads to reduced renal function. 45 -48 A pronounced effect of sodium and

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volume changes on renal hemodynamics is found in black hypertensive subjects, as demonstrated in three recent clinical investigations: Campese et al,49 Weir et al,50 and Parmer et a1 51 observed that high sodium intake increased glomerular filtration fraction in black hypertensive subjects, whereas renal hemodynamics in white hypertensives were not effected. The abnormal response to high sodium could accelerate the renal injury in blacks with hypertension leading to elevated filtration fraction and subsequent glomerular damage. Thus, evidence from pathology and clinical studies suggest differences in the renal microcirculation and its adaptation to hypertension in blacks. Stress also may be contributing to metabolic and renal disease in blacks, as several studies have noted an association of psychosocial factors and hypertension in blacks. 52.58 Harberg et a1 52 first identified a positive association between suppressed hostility and blood pressure elevation for both black and white men aged 25 to 60 years. Black men living in high-stress residential areas who hold in their anger when provoked have higher blood pressure levels compared with those able to vent anger. Johnson et al 53 further noted in black female adolescents that inward venting of anger was correlated with higher systolic and diastolic blood pressure, even after controlling for other risk factors for hypertension. Black females in general have lower anger-in scores and higher blood pressures compared with white females, but opposite results for stress also have been found. For example, adult blacks who are unemployed, single, and have a limited education also are at increased risk for health problems if anger was expressed outwardly.57,58 Thus, both inward and outward venting of anger may be associated with hypertension and cardiovascular risk in blacks. James et a1 59 tested the active coping style of blacks to stress, the test instrument being named after the legendary black folk hero, John Henry, whose name is synonymous with hard work and determination to succeed against overwhelming odds. These investigators postulate that blacks with determination may have limited resources to cope successfully, putting them at increased risk for cardiovascular disease. Higher "John Henryism" scores are noted in blacks compared with whites. 59-61 These black hypertensive subjects also could have augmented sym-

WEIR AND TUCK

pathetic nervous system (SNS) activity, which is reflected by higher levels of circulating catecholamines, such as epinephrine and norepinephrine. Stress-induced increases in SNS activity in blacks may lead to cardiovascular disease through vasoconstrictive influences on the systemic and renal blood vessels, through increased renal sodium reabsorption, or by alterations in metabolism and insulin action. 8,62-64 Obesity is the most pervasive diet-related risk factor for cardiovascular disease among black adults,34 occurring with higher frequency in the black community, especially in black females of all ages. 65-67 Black men between the ages of 35 and 54 years also have more obesity when compared with non-blacks.65 There is a strong association of body mass index with blood pressure among black adults, as there is in the general population. In the National Health and Nutrition Examination Survey (NHANES II), the relative risk of hypertension in overweight versus nonoverweight blacks was very high (1.5 black women; 2.0 black men).68 However, hypertension also occurs to a greater extent in normal-weight blacks than in whites,69 suggesting additional factors in the hypertension of blacks. Obesity predisposes to insulin resistance in peripheral tissues and resultant hyperinsulinemia8,64 and increased frequency of type II diabetes. Obesity also is associated with increased SNS activity as reflected by higher plasma norepinephrine levels that correlate with higher blood pressure levels. 7o,71 The high incidence of obesity in blacks along with stress-induced increases in SNS activity and accompanying insulin resistance may explain the increased prevalence of NIDDM in black adults compared with non-blacks. 72 In the NHANES II data, the prevalence of diabetes in black adults is only 3.1 % at the ages of 20 to 44 years, but increased to 12.9%,20.8%, 25.8%, respectively, in the 45 to 54, 55 to 64, and 65 to 74 age groups. The comparable rates for whites in these age groups is much lower (1.6%, 8.1 %, 11.9%, and 16.9%, respectively).73 Among this NHANES II cohort, 55.6% of patients with diabetes mellitus were overweight. 73 Augmented SNS activity in obese blacks and psychosocial stress could cause hypertension through enhanced vascular reactivity and sodium retention. Another mechanism whereby insulin resistance with hyperinsulinemia may contribute

63

HYPERTENSION IN BLACKS: A METABOLIC DISORDER?

to hypertension is through loss of the normal vasodilator effects ofinsulin. 74,75 Diminished tissue sensitivity to the vasodilatory effect of insulin (insulin resistance in blood vessels) could lead to unopposed vasoconstriction with increased vascular reactivity to circulating vasoconstrictors (norepinephrine and angiotensin 11).62,76 Insulinmediated enhancement of renal tubular sodium absorption 77 ,78 would further enhance this hypertensinogenic effect. Vascular smooth muscle restructuring and dyslipidemia as a result of the mitogenic effects ofhyperinsulinemia and insulin resistance also may facilitate vascular damage and further the propagation of hypertension. 79 In the renal microcirculation, higher glomerular capillary pressures, altered glomerular perm selectivity to albumin, and alterations in mesangial cell metabolism may lead to development of musculomucoid intimal hyperplasia of small renal arterioles, progressive glomerulosclerosis, and obsolescence of glomerular tufts. These findings on pathology examination of renal tissue are more commonly found in renal biopsies of blacks with severe hypertension. 36 In a study attempting to correlate renal structural alterations and hypertension in 45 patients with insulin-dependent diabetes mellitus, Mauer et a1 80 reported that no structural glomerular parameter precisely predicted proteinuria. However, mesangial expansion was highly predictive ofhypertension and in these patients filtration was distinctly decreased. Identical renal structural lesions to those found in diabetes have now been reported in markedly obese patients with proteinuria81 ,82 in the absence of diabetes, hypertension, or decreased glomerular filtration rate. Wesson et a1 83 reported a patient with massive obesity, nephrotic range proteinuria, and supranormal creatinine clearance in whom proteinuria remitted following weight loss. Kasiske and Crosson 84 biopsied 17 massively obese patients with marked proteinuria in the absence of apparent systemic disease. Focal glomerulosclerosis was found in nine patients, diabetic nephropathy in five, minimal change disease in two, and mixed focal glomerulosclerosis and diabetic nephropathy in one. These observations suggest that longstanding hyperinsulinemia and insulin resistance in obesity also may culminate in hypertension and glomerulosclerosis, as is the case with diabetes mellitus.

Aging is associated with progressive loss of renal function in humans. In the aged kidney, as in the diabetic kidney, the glomerular basement membrane thickens without affecting glomerular permeability, as has been shown by dextran clearance studies. 85 A progressive increase in the glomerular mesangium accompanied by a reciprocal decrease in the epithelial component results in an effective filtering area that reduces with aging. 86 Moreover, the number of hyalinized glomeruli increases from 1% to 2% during the fifth decade oflife to as high as 30% by the end ofthe seventh decade oflife. 87 These age-related changes resemble findings in diabetic patients and can occur in the elderly in the absence of atherosclerosis, obesity, diabetes, or hypertension. 88 As both basal and postglucose plasma insulin concentrations increase with age as a function of increasing insulin resistance,89 hyperinsulinemia also may be linked to age-related nephrosclerosis. Simultaneous kidney and pancreas transplantation is followed by a reduction of insulin resistance 90 and a reduced probability of recurrent diabetic nephropathy in the renal allograft. 91 Thus, these observations suggest that insulin resistance and hyperinsulinemia are associated with hypertension and glomerulosclerosis, as proposed in Table 1. Whether insulin has a true causal role in the genesis of renal disease in these conditions in blacks awaits further investigation. Hyperinsulinemia and insulin resistance may only be indirectly associated to other genetic and environmental factors that directly lead to hypertension and/or glomerulosclerosis. TREATMENT CONSIDERATIONS

Nonpharmacologic and pharmacologic therapy of hypertension in blacks should control blood pressure in a simple, affordable, and nontoxic fashion that provides a wide therapeutic index. Identification, education, and awareness programs will facilitate finding patients with strong family histories of metabolic and cardiovascular disease who are at increased risk. Educational programs designed to encourage regular exercise, modification of dietary intake of high-fat foods, and modest sodium restriction also will facilitate better control of blood pressure in this population. 34,92 Other dietary interventions, including an increase in potassium and calcium intake, also

64

WEIR ANO TUCK Table 1. Renal, Physiologic, and Morphologic Characteristics of Subjects With Hypertension and Insulin-Resistant States

Insulin resistance Prevalence of hypertension Na, Li countertransport Kidney functiont Mean kidney volume GFR RPF Na excretion Renin Microalbuminuria Microscopic anatomy:j: Mesangial volume Filtration area Glomerulosclerosis

100M

NIOOM

Obesity

Age

Essential Hypertension

++

+++

+++

+

++

20% to 30%

40% to 50%

40% to 50%

t

+1-

45% to 55% nl

100%

t t t t

t t t

t t t

•• •• •

tIN· nl nl

•

•

Nit

Nit

•

++

•• +1-

+1-

t/NIt +

tt

tt

tt

t

t

++

•t

•t

•t

•t

tit

•t

• Countertransport normal in black hypertensive subjects. t In NIOOM: new onset, untreated. :j: In 100M: correlated with hypertension, not glucose control.

may be of importance in reducing cardiovascular risk in blacks, but this approach remains experimental. 93,94 Antihypertensive agents should be selected for hypertensive black subjects based on optimal blood pressure control, protection of the circulation, prevention of metabolic complications, and optimization of renal perfusion. 95 . 97 The propensity for increased renal sodium acquisition in blacks and elevated peripheral vascular resistance indicate that certain classes of antihypertensive agents may be indicated. 95 ,96 Vasodilator agents and thiazide diuretics may be the treatment of choice in this population. Additionally, therapies that attenuate neurohormonal (SNS, angiotensin II) influence on cardiovascular tissue and glomerular capillary hypertension and that have neutral effects on metabolic factors will further benefit the black hypertensive subject. It is well established that lowering blood pressure by any means reduces target organ damage. The fact that hypertensive black subjects have a disproportionately higher risk for hypertensive vascular and renal complications than other populations emphasizes the need for therapeutic agents that go beyond just blood pressure control and that offer protection from the several

other specific complications that accompany hypertension. 96 ,97

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HYPERTENSION IN BLACKS: A METABOLIC DISORDER?

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