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Heredity and hypertension: Impact on metabolic characteristics
Heredity and hypertension: metabolic characteristics
Impact on
This study was performed to evaluate the possible role of heredity in the clinical characteristics of hypertension. Metabolic, endocrine, and renal measurements were compared in subjects with normal blood pressure who had a family history of hypertension (n = 60) with those of subjects with normal blood pressure who did not have a family history of hypertension (n = 48). The groups were matched for age (mean, 44 k 2 years and 45 f 2 years) and blood pressure (127 f l/77 + 1 mm Hg and 127 f 2/77 + 1 mm Hg). The following parameters were higher in the patients with a family history of hypertension than in those without. Plasma insulin concentrations (14.1 f 1.1 vs 10.8 +- 1.0 clU/ml; p < 0.05), insulin-glucose ratio (0.15 + 0.01 vs 0.11 i 0.010; p < 0.05), norepinephrine concentrations (315 * 24 pglml vs 208 -+ 20 pglml; p < O.Ol), plasma renin activity (2.1 ~fr0.2 ng AngllmVhr vs 1.6 + 0.2 ng Angl/ml/hr; p < 0.02), total cholesterol levels (217 i 8 mgldl vs 197 f 0.3 mg/dl; p < 0.05), creatinine clearance (125 + 9 ml/min vs 96 -t 8 mllmin; p < O.Ol), and albumin excretion rate (3.2 f 0.3 pglmin vs 2.6 + 0.3 pglmin; p = 0.1). Moreover, patients with a family history of hypertension had smaller increases in systolic blood pressure during treadmill exercise (55 f 3 mm Hg vs 64 f 3 mm Hg; p < 0.03). There were no differences in echocardiographic left ventricular mass index between the groups. These findings suggest that a family history of hypertension predicts small but significant changes in neuroendocrine, metabolic, and renal values in adults with normal blood pressure. Since age makes future essential hypertension unlikely in these patients, the differences in these measurements may reflect inherited clinical associations of hypertension that are independent of blood pressure. (AM HEART J 1992;124:435.)
Joel M. Neutel, MD, David H. G. Smith, MD, William F. Graettinger, MD, Robert I,. Winer, MD, and Michael A. Weber, MD Long Beach and Irvine, Calif,
Children of persons with hypertension are predisposed to the development of hypertensioql and this hereditary tendency probably involves a polygenetic system.2 However, the pathogenesis of hypertension and the mechanisms that mediate its clinical characteristics are not well understood. It is clear that clinical hypertension comprises more than just high blood pressure3; previous studies have shown that indices of insulin and lipid metabolism,4 renal function,” and left ventricular structure and function6 can be altered very early in the course of hypertension. Indeed, these findings have raised the possibility that measurable metabolic and cardiovascular changes may precede increases in blood pressure. In contrast to earlier studies that have focused on metabolic features of children or young adults,6-g this report
From t.he Hypertension Center, Veterans Affairs Medical Center, Long Beach, and the University of California, Irvine. Received for publication Jan. 6, 1992; accepted Feb. 20, 1992. Reprint requests:Michael A. Weber, MD, Hypertension Center (W130), VA Medical Center, 5901 East Seventh St., Long Beach, CA 90822. 411138089
describes findings in middle-aged adults with normal blood pressure and a family history of hypertension. Specifically, to determine whether the clinical characteristics of the hypertension syndrome might be inherited, we have compared metabolic, renal, and endocrine measurements in subjects with normal blood pressure and a family history of hypertension with those of normal volunteers without a family history of hypertension. METHODS
One hundred and eight volunteers, aged 20 to 73 years (meanage,44years), participated in this study. There were 86 men and 22 women;88 subjectswerewhite, 9 wereblack, and 11 were Hispanic. The meanweight of the participants was 83.2 i 1.4 kg, mean height was 175.0 f 1.0 cm, and mean body massindex was 27.2 + 0.4 m2. Normal blood pressurewas verified in each subject by a mean daytime blood pressure(meanof all diastolic pressuresasmeasured by ambulatory blood pressuremonitoring between6:00AM and 10:00 PM) of less than 85 mm Hg. The group was divided into two subgroupson the basisof presenceof a first-degree family history (father, mother, or sibling) of hypertension (n = 60; 45 men, 15women;48 white, 5 black, and 7 Hispanic subjects) or absenceof a family history of 435
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Fig. 1. Plasma immunoreactive insulin concentrations and the insulin-glucose without a family history of hypertension. Plotted values are means t SEM.
Table
I. Clinical
(Mean
characteristics
5 SEM)
Age (yr) Height (cm) Weight (kg) BMI (kg/m?) Systolic BP (mm Hg) Diastolic BP (mm Hg)
Family histor) of hypertension (n = 60) 44.2 174.4 83.5 27.4 127
k * f i
1.6 1.4 1.8 0.5
i 1 77 t 1
No family histog r)f hypertension in = 48) 44.8 175.3 83.0 26.8 127 77
+ i i -t i i
1.8 1.4 2.2 0.6 2 1
BMI. Body mass index: BP. blood pressure (mean Xhrwri
NEGATNE
ratio in subjects with and
Table II. Blood values in patients ily history of hypertension Parameter
Total cholesterol (mg/dl) Triglycerides (mg/dl) HDL cholesterol (mg/dl) Plasma renin activity (ng Angl/ml/hr) Aldosterone (pg/ml) Glucose (mgidl)
with and without
Fumi1.v hi&or?/ (n = 60)
217 t 136 + 5.1 * 2.1 It
8 13 3 0.2
13 i- 10 95 * n
a fam-
No family h&or>, (n = ‘$8)
197 + 112 !I t59 + 1.6 f
6* 9 3 0.2t
111 +_ 7
97 L 2
Values are expressed as means ? SEM. *p < 0.O.Y +p < 0.0”.
hypertension (n = 48; 41 men, 7 women; 40 white, 4 black, and 4 Hispanic subjects). This information was based on careful questioning of participants; individuals who were uncertain of the presence or absence of hypertension in their first-degree relatives were not included in the study. Subjects with cardiovascular or other chronic illnesses were excluded from the study. All participants provided informed consent by signing a form that was approved by the Human Studies Subcommittee of the Veterans Affairs Medical Center in Long Beach. The patients came into the Hypertension Center at approximately 8~30 AM after a lo-hour fast. Histories were taken, and physical examinations were performed. A heparin lock was inserted into a peripheral vein of the left
forearm of each patient. After a 30-minute rest period in the supine position, blood samples were drawn from the heparin lock for measurements of catecholamines, glucose, insulin, lipids, plasma renin activity, and aldosterone. Two cardiopulmonary exercise treadmill tests, which were separated by an interval of 7 to 14 days, were performed by each patient. The first treadmill test (modified Balke-Ware protocol) was performed to allow patients to familiarize themselves with the procedure of exercise testing and to obtain a measurement of each patient’s maximal oxygen uptake. This measurement was used to individualize the second t.est. The second exercise test was
VOlUme Number
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and hbvpertension
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6
l
P
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T IGATN FAMILY Fig. 2. Plasma norepinephrine and epinephrine pertension. Plotted values are means ? SEM.
HISTORY
levels in subjects with and without
an individualized ramp treadmill stress test.l” After a l-minute warm-up (2.0 mph at O@Ograde), both the rate of change in treadmill speed and the gradient were individualized to yield a work rate of 10 minutes that corresponded to the maximal oxygen uptake, which was determined in the first test. Blood pressures were determined at rest (immediately before exercise with the patient standing on the treadmill) and immediately on termination of the test. All patients were encouraged to exercise to their maximum ability. PaCents whose test results were positive for ischemic heart disease were excluded from the study. M-mode and two-dimensional echocardiography were performed. Left ventricular mass (LVM) was calculated with the formula of Troy”: LVM (gm) = 1.05* ([LVID +- IVS f PWT] ? 3 - [LVID]“), where LVID, IVS, and PWT refer to the end-diastolic dimensions of the left ventricular internal diameter, interventricular septal wall thickness, and posterior wall thickness, respectively. Left ventricular mass was indexed by height. Ambulatory blood pressure monitoring was performed with the SpaceLabs 90207 system (SpaceLabs, Redmond, Wash.). This device measures blood pressure by means of an oscillometric method, which has been demonstrated to
a family history of hy-
provide accurate data.” Blood pressure was automatically measured at 15-minute intervals throughout the monitoring period. Patients were encouraged to carry out their routine daily activities during monitoring. Plasma renin activity and aldosterone13 and insulin levelsi4 were measured by radioimmunoassay, and catecholamines were measured by radioenzyme assay.i” After careful instruction was provided, a urine specimen was collected by each patient during the 24-hour period before the second visit to the clinic for measurements of creatinine and albumin excretion rates. An unpaired Student’s t test was used to compare data from patients with a family history of hypertension with data from those without such a history. Regression analysis by Pearson’s method was used to determine correlations between creatinine clearance and albumin excretion ratio. Values are given as means ? SEM. RESULTS The clinical characteristics of the two groups are presented in Table I. There were no differences in age. body mass index, or blood pressure (i.e., mean
438
Neutel
American
et al.
Table III. Blood values in patients with and without a family history of hypertension Family
history
No family
histoq
(n = 60)
In = 481
Potassium Sodium(mEq/L) (mEq/L) Creatinine (mg/dl)
140.3 4.4 k+ 0.1 0.3 1.1 i 0.2
140.9 4.3 +_ k 0.1 0.3 1.2 ?I 0.3
Uric acid (mg/dl) Hemoglobin (mg/dl) Hematocrit (“c)
5.5 f 0.2 14.2 k 0.2 43.0 + 0.5
5.7 + 0.1 14.5 + 0.3 43.5 i 0.7
Parameter
Values are expressed as means t SEM.
blood pressure between 6:00 AM and 10:00 PM) between the groups. As demonstrated in Fig. 1, the plasma insulin levels were higher (p < 0.05) in the subjects with a family history of hypertension than in those without such a family history. The insulin-glucose ratio was also greater (p < 0.05) in the volunteers with a family history of hypertension. Plasma glucose levels were similar in both groups (Table II). In subjects with a family history of hypertension, plasma norepinephrine levels were greater (p < 0.01) than in subjects without a family history of hypertension (Fig. 2). There were no differences in epinephrine levels between the two groups. As shown in Table II, plasma renin activity was higher (p = 0.02) in the subjects with a family history of hypertension than in those without a family history of hypertension. Aldosterone levels were slightly but not significantly higher in the subjects with a family history of hypertension (Table II). There were also no significant differences in plasma electrolyte or hemoglobin values between the two groups (Table III). Total cholesterol levels, which were measured after an overnight fast, were significantly higher (p < 0.05) in the subjects with a family history of hypertension. Plasma triglyceride levels also tended to be greater (p = 0.1) in these subjects (Table II). There were no differences in high-density lipoprotein cholesterol levels between the groups (Table II). As shown in Fig. 3, creatinine clearance was significantly greater (p < 0.01) in the subjects with a family history of hypertension. Albumin excretion rate (Fig. 3) was slightly but not significantly greater in these subjects. There was a positive relationship (r = 0.383; p < 0.001) between albumin excretion rate and creatinine clearance. The changes in blood pressure that were induced by exercise treadmill testing (during the second test) were compared in the two groups. The increases in systolic blood pressure, which was measured immediately after exercise, were significantly smaller (p < 0.05) in the subjects with a family history of hy-
August 1992 Heart Journal
pertension (preexercise baseline, 138 + 2 mm Hg; mean increase, 55 * 2 mm Hg) than in those without a family history of hypertension (baseline, 134 & 2 mm Hg, mean increase, 64 +- 3 mm Hg). There were no significant differences in the exercise-induced changes in diastolic blood pressures (-4 i- 1 mm Hg and -2 +- 2 mm Hg, respectively) between the two groups. There were no differences in left ventricular mass or left ventricular mass indexed by height (Table II) between the two groups. DISCUSSION
Our findings demonstrate clear differences between subjects with normal blood pressure and a family history of hypertension and subjects with normal blood pressure of similar age and body mass index without a family history of hypertension. Specifically, we have shown differences between the two groups in several endocrine and metabolic factors, in creatinine clearance, and in blood pressure responses to exercise. Previous reports have indicated a tendency for the children of persons with hypertension to develop hypertension themselves. ‘3 l6 These increases in blood pressure are usually not present at birth but develop during young adulthood. The factors that mediate these changes have not been fully defined. However, there is preliminary evidence to suggest that increased activity of the renin-angiotensin systeml’ and the sympathetic nervous system1sl lg and increased insulin levels2* may precede the increases in blood pressure that occur in these patients13 and contribute to the development of clinical hypertension.” A critical feature of the present study, which differentiates it from previous studies, is that the mean
age of our subjects with normal blood pressure (average blood pressure, 127/77 mm Hg) was 44 years. At this age it is unlikely that these subjects are candidates for the development of conventional diastolic hypertension. Thus a family history of hypertension can be predictive of the endocrine and metabolic changes that characterize hypertension, even in the absence of increased blood pressure. This suggests the possibility of an inherited syndrome of abnormalities that, independently of high blood pressure, may predispose these persons to the atheromatous complications that are associated with hypertension. Total cholesterol and triglyceride levels were higher in subjects with a family history of hypertension than in those without such a history. Increased cholesterol levels are an important independent indicator of risk for cardiovascular disease.‘i We also found that plasma insulin levels are higher in subjects with a family history of hypertension. Furthermore,
there
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FAMILY HISTORY Fig. 3. Creatinine clearanceand albumin excretion ratios in subjectswith and without a famiIy history of hypertension. Plott,ed values are means _t SEM.
was reduced insulin sensitivity (insulin-glucose ratio) in subjects with a family history of hypertension. These findings are consistent with earlier reports of hyperinsulinemia in patients with established hypertension and in patients with borderline hypertension.16.22As with abnormal lipid levels, increased insulin concentrations are associated with a heightened risk for the occurrence of cardiovascular events.23 Another interesting observation was the increased creatinine clearance in the subjects with a family history of hypertension. These findings are similar to those that have been report,ed in previous studies and may be secondary to early abnormalities of the renal vasculature that produce hyperfiltration and increased creatinine clearance.” Consistent with this mechanism was the tendency for an increased albumin excretion rate in subjects with a family history of hypertension. The significant correlation between albumin excretion rate and creatinine clearance suggests that these findings may be linked by a common renal mechanism. One explanation may be related to our finding of increased plasma renin activity in subjects with a family history of hypertension. Increased
intrarenal activity of the renin-angiotensin system can cause efferent arteriolar vasoconstriction, which in turn results in glomerular hypertension, hyperfiltration, and increased albumin excretion.24 In contrast to previous reports,25 we found that the subjects with a family history of hypertension had smaller increases in systolic blood pressure during treadmill exercise than subjects without a family history of hypertension. We have previously reported smaller increases in systolic blood pressure during exercise in subjects with normal blood pressure and left ventricular hypertrophy than in subjects with normal blood pressure without left ventricular hypertrophy. These findings suggest a diminished hemodynamic response to exercise in subjects with left ventricular alterations. It is thus possible that the altered hemodynamic responses to exercise in subjects with a family history of hypertension are due to early ventricular changes, which in turn may be secondary to the heightened neuroendocrine activity that was observed in these individuals. There were higher norepinephrine levels in the subjects with a family history of hypertension. These
440
Neutel et al.
findings confirm previous reports of increased norepinephrine levels in patients with labile hypertension and in the children with normal blood pressure of persons with hypertension.18J ig Plasma renin activity and aldosterone levels were also elevated in subjects with a family history of hypertension. Although increased activity of the sympathetic and reninangiotensin systems can increase blood pressure, the normal blood pressures in our subjects with a family history of hypertension suggests that other environmental, behavioral, or dietary factors may be required for clinical expression of high blood pressure. These endocrine findings are potentially important, for there is good evidence to suggest that increases in plasma renin activity are associated with an increased incidence of myocardial infarction27 and that increased levels of norepinephrine and insulin are associated with hypertrophy of cardiovascular smooth muscle.18, 23,28 We have demonstrated metabolic, endocrine, and vascular differences in a group of subjects with normal blood pressure and a family history of hypertension. In such individuals, abnormalities of blood pressure may be a late manifestation of hypertension or may not appear at all. These individuals could be at risk for the development of cardiovascular problems associated with hypertension before they actually have high blood pressure. If we use blood pressure as the sole marker for hypertension, we may overlook individuals who do not have elevated blood pressures but who are nevertheless at risk for the development of cardiovascular abnormalities. These findings suggest that a family history of hypertension justifies a full evaluation for hypertension-related cardiovascular risk factors, even in the absence of high blood pressure. REFERENCES
1. Platt R. Heredity in hypertension. Lancet 1963;1:899-904. 2. Ostfeld AM, Oglesby P. The inheritance of hypertension. Lancet 1963;1:575-9. 3. Weber MA, Smith DHG, Neutel JM, Graettinger WF. The hypertension syndrome: issues beyond blood pressure 1990 (in press). 4. Stout RW. Insulin as a mitogenic factor: role in the pathogenesis of cardiovascular disease. Am J Med 1991;9O(suppl 2A):625-45. I5 Grunfeld B, Perelstein E, Simsolo R, Gimenez M, Romero JC. Renal functional reserve and microalbuminuria in offspring of hypertensive parents. Hypertension 1990;15:257-61. I 6. Celentano A. Galderisis M. Garafalo M. Mureddu GF. Tammaro P, Petitto M, DiSomma S, DeDivitis 0. Blood pressure and cardiac morphology in young children of hypertensive subjects. J Hypertens 1988;6(suppl 4):S107-9. 7. Rauogli A, Trazzi S, Villani A, Mutti E, Cuspidi C, Sampieri L, De Ambroggi L, Parati G, Zanchetti A, Mancia G. Early 24hour blood pressure elevation in normotensive subjects with parental hypertension. Hypertension 1990;16:491-7.
American
August 1992 Heart Journal
B, Hulman S, Tannenbaum J, Kushner H. Insulin re8. Falkner sistance and blood pressure in young black men. Hypertension 1990;16:706-11. 9. Simpson P, McGrath A, Savion S. Myocyte hypertrophy in neonatal rat heart cultures and its regulation by serum and by catecholamines. Circ Res 1982;51:787-95. 10. Myers J, Buchanan N, Walsh D, Kraemer M, McAuley P, Hamilton-Wessller M, Froelicher VF. A comparison of ramp versus standard exercise protocols. J Am Co11 Cardioll991 (in press). 11. Troy BL, Pombo J, Rackley CE. Measurement of left ventricular wall thickness and mass by echocardiography. Circulation 1972;45:602-11. 12. Graettinger WF, Lipson JC, Cheung DG, Weber MA. Validation of portable noninvasive blood pressure monitoring devices: comparisons with intra-arterial and sphygmomanometer measurements. AM HEART J 1988;116:1155-60. 13. Sealey JE, Laragh JH. How to do a plasma renin assay. Cardiovasc Med 1977;2:1079-92. 14. Marschner I. Group experiments on the radioimmunological insulin determination. Horm Metab Res 1974;6:293-6. 15. Durrett LR. Ziegler MG. A sensitive radioenzvmatic assav for catechol drugs. J Neurosci Research 1980;5:5”87-98. ” 16. Julius S, Mejia A, Joneo K, Krause L, Nicholas S, Van de Ven C, Johnson E, Petrin J, Sekkarie MA, Kjeldsen SE, Schmouder R. Guota R. Ferraro J. Nazzaro P. Weissfeld J. “White coat” versus “sustained” borderline hypertension in Tecumseh, Michigan. J Hypertens 1990;16:617-23. 17. Ferraro CM, Gildenberg PL, McCubbin J. Cardiovascular effects of angiotensin mediated by the central nervous system. Circ Res 1972;30:257-62. 18. l’rimarco B, Mcc~arcillll B, LJeLuca N, lJe Simone A, c;uocolo A, Galva MD, Picotti GB, Condorelli M. Participation of endogenous catecholamines in the regulation of left ventricular mass in progeny of hypertensive parents. Circulation 1985; 72:38-45. 19. Falkner B, Hulman S, Tannenbaum J, Kushner H. Insulin resistance and blood pressure in young black men. 3 Hypertens 1990;16:706-11. 20. Ferrari P. Gianchino D, Weidmann P, Keller U, Riesen W, Shaws S. Insulin sensitivity and lipoproteins in hypertension prone man [Abstract]. Kidney Int 1990;38:172. 21. Dewitt S, Goodman MD. The National Cholesterol Education Program: guidelines, status and issues. Am J Med 1991;9O(suppl 2A):325-55. 22. Ferranini E, Buzzigoli G, Giorico MA. Insulin resistance in essential hypertension. N Engl J Med 1987;317:350-7. 23. Stout RW, Bierman C, Ross R. Effects of insulin on the proliferation of cultured primate arterial smooth muscle cells. Circ Res 1975;36:319-27. 24. Lohmeier TE, Cowley W Jr. Hypertensive and renal effects of chronic low level intrarenal angiotensin infusion in the dog. Circ Res 1979;44:154-60. 25. Gottdiener JS, Brown J, Zoltick J, Fletcher RD. Left ventricular hypertrophy in men with normal blood pressure: relation to exaggerated blood pressure response to exercise. Ann Intern Med 1990;112:161-6. 26. Smith DHG, Neutel JM, Graettinger WF, Weber MA. Impaired exercise systolic blood pressure responses in hypertensive patients with left ventricular hypertrophy [Abstract]. Am J Hypertens 1990;4:20A. 27. Alderman MH, Madhavan S, Ooi WL, Cohen H, Sealey JE, Laragh J. Association of the renin-sodium profile with the risk of myocardial infarction in patients with hypertension. N Engl J Med 1991;324:1098-1104. 28. Pfeifle B, Ditschuneit H. Effects of insulin on growth of cultured human arterial smooth muscle cells. Diabetologia 1981;20:155-8.
Impact on
This study was performed to evaluate the possible role of heredity in the clinical characteristics of hypertension. Metabolic, endocrine, and renal measurements were compared in subjects with normal blood pressure who had a family history of hypertension (n = 60) with those of subjects with normal blood pressure who did not have a family history of hypertension (n = 48). The groups were matched for age (mean, 44 k 2 years and 45 f 2 years) and blood pressure (127 f l/77 + 1 mm Hg and 127 f 2/77 + 1 mm Hg). The following parameters were higher in the patients with a family history of hypertension than in those without. Plasma insulin concentrations (14.1 f 1.1 vs 10.8 +- 1.0 clU/ml; p < 0.05), insulin-glucose ratio (0.15 + 0.01 vs 0.11 i 0.010; p < 0.05), norepinephrine concentrations (315 * 24 pglml vs 208 -+ 20 pglml; p < O.Ol), plasma renin activity (2.1 ~fr0.2 ng AngllmVhr vs 1.6 + 0.2 ng Angl/ml/hr; p < 0.02), total cholesterol levels (217 i 8 mgldl vs 197 f 0.3 mg/dl; p < 0.05), creatinine clearance (125 + 9 ml/min vs 96 -t 8 mllmin; p < O.Ol), and albumin excretion rate (3.2 f 0.3 pglmin vs 2.6 + 0.3 pglmin; p = 0.1). Moreover, patients with a family history of hypertension had smaller increases in systolic blood pressure during treadmill exercise (55 f 3 mm Hg vs 64 f 3 mm Hg; p < 0.03). There were no differences in echocardiographic left ventricular mass index between the groups. These findings suggest that a family history of hypertension predicts small but significant changes in neuroendocrine, metabolic, and renal values in adults with normal blood pressure. Since age makes future essential hypertension unlikely in these patients, the differences in these measurements may reflect inherited clinical associations of hypertension that are independent of blood pressure. (AM HEART J 1992;124:435.)
Joel M. Neutel, MD, David H. G. Smith, MD, William F. Graettinger, MD, Robert I,. Winer, MD, and Michael A. Weber, MD Long Beach and Irvine, Calif,
Children of persons with hypertension are predisposed to the development of hypertensioql and this hereditary tendency probably involves a polygenetic system.2 However, the pathogenesis of hypertension and the mechanisms that mediate its clinical characteristics are not well understood. It is clear that clinical hypertension comprises more than just high blood pressure3; previous studies have shown that indices of insulin and lipid metabolism,4 renal function,” and left ventricular structure and function6 can be altered very early in the course of hypertension. Indeed, these findings have raised the possibility that measurable metabolic and cardiovascular changes may precede increases in blood pressure. In contrast to earlier studies that have focused on metabolic features of children or young adults,6-g this report
From t.he Hypertension Center, Veterans Affairs Medical Center, Long Beach, and the University of California, Irvine. Received for publication Jan. 6, 1992; accepted Feb. 20, 1992. Reprint requests:Michael A. Weber, MD, Hypertension Center (W130), VA Medical Center, 5901 East Seventh St., Long Beach, CA 90822. 411138089
describes findings in middle-aged adults with normal blood pressure and a family history of hypertension. Specifically, to determine whether the clinical characteristics of the hypertension syndrome might be inherited, we have compared metabolic, renal, and endocrine measurements in subjects with normal blood pressure and a family history of hypertension with those of normal volunteers without a family history of hypertension. METHODS
One hundred and eight volunteers, aged 20 to 73 years (meanage,44years), participated in this study. There were 86 men and 22 women;88 subjectswerewhite, 9 wereblack, and 11 were Hispanic. The meanweight of the participants was 83.2 i 1.4 kg, mean height was 175.0 f 1.0 cm, and mean body massindex was 27.2 + 0.4 m2. Normal blood pressurewas verified in each subject by a mean daytime blood pressure(meanof all diastolic pressuresasmeasured by ambulatory blood pressuremonitoring between6:00AM and 10:00 PM) of less than 85 mm Hg. The group was divided into two subgroupson the basisof presenceof a first-degree family history (father, mother, or sibling) of hypertension (n = 60; 45 men, 15women;48 white, 5 black, and 7 Hispanic subjects) or absenceof a family history of 435
436
Neutel
et al.
American
August 1992 Heart Journal
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Fig. 1. Plasma immunoreactive insulin concentrations and the insulin-glucose without a family history of hypertension. Plotted values are means t SEM.
Table
I. Clinical
(Mean
characteristics
5 SEM)
Age (yr) Height (cm) Weight (kg) BMI (kg/m?) Systolic BP (mm Hg) Diastolic BP (mm Hg)
Family histor) of hypertension (n = 60) 44.2 174.4 83.5 27.4 127
k * f i
1.6 1.4 1.8 0.5
i 1 77 t 1
No family histog r)f hypertension in = 48) 44.8 175.3 83.0 26.8 127 77
+ i i -t i i
1.8 1.4 2.2 0.6 2 1
BMI. Body mass index: BP. blood pressure (mean Xhrwri
NEGATNE
ratio in subjects with and
Table II. Blood values in patients ily history of hypertension Parameter
Total cholesterol (mg/dl) Triglycerides (mg/dl) HDL cholesterol (mg/dl) Plasma renin activity (ng Angl/ml/hr) Aldosterone (pg/ml) Glucose (mgidl)
with and without
Fumi1.v hi&or?/ (n = 60)
217 t 136 + 5.1 * 2.1 It
8 13 3 0.2
13 i- 10 95 * n
a fam-
No family h&or>, (n = ‘$8)
197 + 112 !I t59 + 1.6 f
6* 9 3 0.2t
111 +_ 7
97 L 2
Values are expressed as means ? SEM. *p < 0.O.Y +p < 0.0”.
hypertension (n = 48; 41 men, 7 women; 40 white, 4 black, and 4 Hispanic subjects). This information was based on careful questioning of participants; individuals who were uncertain of the presence or absence of hypertension in their first-degree relatives were not included in the study. Subjects with cardiovascular or other chronic illnesses were excluded from the study. All participants provided informed consent by signing a form that was approved by the Human Studies Subcommittee of the Veterans Affairs Medical Center in Long Beach. The patients came into the Hypertension Center at approximately 8~30 AM after a lo-hour fast. Histories were taken, and physical examinations were performed. A heparin lock was inserted into a peripheral vein of the left
forearm of each patient. After a 30-minute rest period in the supine position, blood samples were drawn from the heparin lock for measurements of catecholamines, glucose, insulin, lipids, plasma renin activity, and aldosterone. Two cardiopulmonary exercise treadmill tests, which were separated by an interval of 7 to 14 days, were performed by each patient. The first treadmill test (modified Balke-Ware protocol) was performed to allow patients to familiarize themselves with the procedure of exercise testing and to obtain a measurement of each patient’s maximal oxygen uptake. This measurement was used to individualize the second t.est. The second exercise test was
VOlUme Number
124 2
Heredity
and hbvpertension
437
6
l
P
l
T
T IGATN FAMILY Fig. 2. Plasma norepinephrine and epinephrine pertension. Plotted values are means ? SEM.
HISTORY
levels in subjects with and without
an individualized ramp treadmill stress test.l” After a l-minute warm-up (2.0 mph at O@Ograde), both the rate of change in treadmill speed and the gradient were individualized to yield a work rate of 10 minutes that corresponded to the maximal oxygen uptake, which was determined in the first test. Blood pressures were determined at rest (immediately before exercise with the patient standing on the treadmill) and immediately on termination of the test. All patients were encouraged to exercise to their maximum ability. PaCents whose test results were positive for ischemic heart disease were excluded from the study. M-mode and two-dimensional echocardiography were performed. Left ventricular mass (LVM) was calculated with the formula of Troy”: LVM (gm) = 1.05* ([LVID +- IVS f PWT] ? 3 - [LVID]“), where LVID, IVS, and PWT refer to the end-diastolic dimensions of the left ventricular internal diameter, interventricular septal wall thickness, and posterior wall thickness, respectively. Left ventricular mass was indexed by height. Ambulatory blood pressure monitoring was performed with the SpaceLabs 90207 system (SpaceLabs, Redmond, Wash.). This device measures blood pressure by means of an oscillometric method, which has been demonstrated to
a family history of hy-
provide accurate data.” Blood pressure was automatically measured at 15-minute intervals throughout the monitoring period. Patients were encouraged to carry out their routine daily activities during monitoring. Plasma renin activity and aldosterone13 and insulin levelsi4 were measured by radioimmunoassay, and catecholamines were measured by radioenzyme assay.i” After careful instruction was provided, a urine specimen was collected by each patient during the 24-hour period before the second visit to the clinic for measurements of creatinine and albumin excretion rates. An unpaired Student’s t test was used to compare data from patients with a family history of hypertension with data from those without such a history. Regression analysis by Pearson’s method was used to determine correlations between creatinine clearance and albumin excretion ratio. Values are given as means ? SEM. RESULTS The clinical characteristics of the two groups are presented in Table I. There were no differences in age. body mass index, or blood pressure (i.e., mean
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Table III. Blood values in patients with and without a family history of hypertension Family
history
No family
histoq
(n = 60)
In = 481
Potassium Sodium(mEq/L) (mEq/L) Creatinine (mg/dl)
140.3 4.4 k+ 0.1 0.3 1.1 i 0.2
140.9 4.3 +_ k 0.1 0.3 1.2 ?I 0.3
Uric acid (mg/dl) Hemoglobin (mg/dl) Hematocrit (“c)
5.5 f 0.2 14.2 k 0.2 43.0 + 0.5
5.7 + 0.1 14.5 + 0.3 43.5 i 0.7
Parameter
Values are expressed as means t SEM.
blood pressure between 6:00 AM and 10:00 PM) between the groups. As demonstrated in Fig. 1, the plasma insulin levels were higher (p < 0.05) in the subjects with a family history of hypertension than in those without such a family history. The insulin-glucose ratio was also greater (p < 0.05) in the volunteers with a family history of hypertension. Plasma glucose levels were similar in both groups (Table II). In subjects with a family history of hypertension, plasma norepinephrine levels were greater (p < 0.01) than in subjects without a family history of hypertension (Fig. 2). There were no differences in epinephrine levels between the two groups. As shown in Table II, plasma renin activity was higher (p = 0.02) in the subjects with a family history of hypertension than in those without a family history of hypertension. Aldosterone levels were slightly but not significantly higher in the subjects with a family history of hypertension (Table II). There were also no significant differences in plasma electrolyte or hemoglobin values between the two groups (Table III). Total cholesterol levels, which were measured after an overnight fast, were significantly higher (p < 0.05) in the subjects with a family history of hypertension. Plasma triglyceride levels also tended to be greater (p = 0.1) in these subjects (Table II). There were no differences in high-density lipoprotein cholesterol levels between the groups (Table II). As shown in Fig. 3, creatinine clearance was significantly greater (p < 0.01) in the subjects with a family history of hypertension. Albumin excretion rate (Fig. 3) was slightly but not significantly greater in these subjects. There was a positive relationship (r = 0.383; p < 0.001) between albumin excretion rate and creatinine clearance. The changes in blood pressure that were induced by exercise treadmill testing (during the second test) were compared in the two groups. The increases in systolic blood pressure, which was measured immediately after exercise, were significantly smaller (p < 0.05) in the subjects with a family history of hy-
August 1992 Heart Journal
pertension (preexercise baseline, 138 + 2 mm Hg; mean increase, 55 * 2 mm Hg) than in those without a family history of hypertension (baseline, 134 & 2 mm Hg, mean increase, 64 +- 3 mm Hg). There were no significant differences in the exercise-induced changes in diastolic blood pressures (-4 i- 1 mm Hg and -2 +- 2 mm Hg, respectively) between the two groups. There were no differences in left ventricular mass or left ventricular mass indexed by height (Table II) between the two groups. DISCUSSION
Our findings demonstrate clear differences between subjects with normal blood pressure and a family history of hypertension and subjects with normal blood pressure of similar age and body mass index without a family history of hypertension. Specifically, we have shown differences between the two groups in several endocrine and metabolic factors, in creatinine clearance, and in blood pressure responses to exercise. Previous reports have indicated a tendency for the children of persons with hypertension to develop hypertension themselves. ‘3 l6 These increases in blood pressure are usually not present at birth but develop during young adulthood. The factors that mediate these changes have not been fully defined. However, there is preliminary evidence to suggest that increased activity of the renin-angiotensin systeml’ and the sympathetic nervous system1sl lg and increased insulin levels2* may precede the increases in blood pressure that occur in these patients13 and contribute to the development of clinical hypertension.” A critical feature of the present study, which differentiates it from previous studies, is that the mean
age of our subjects with normal blood pressure (average blood pressure, 127/77 mm Hg) was 44 years. At this age it is unlikely that these subjects are candidates for the development of conventional diastolic hypertension. Thus a family history of hypertension can be predictive of the endocrine and metabolic changes that characterize hypertension, even in the absence of increased blood pressure. This suggests the possibility of an inherited syndrome of abnormalities that, independently of high blood pressure, may predispose these persons to the atheromatous complications that are associated with hypertension. Total cholesterol and triglyceride levels were higher in subjects with a family history of hypertension than in those without such a history. Increased cholesterol levels are an important independent indicator of risk for cardiovascular disease.‘i We also found that plasma insulin levels are higher in subjects with a family history of hypertension. Furthermore,
there
Volume124 Number
Heredity
2
and h.ypertension
439
125
3.2~-
120I-
115 E -c E. 110
+ * P
z E 4 ;
3-o-
p
2.6-
E 0 g
2.4 -
z I3 <
2.2 -
5
! 2 < 105 !2 0 LLI 2 100 i= 4 E 95
2.8-
T
2.0
90 ,
t 0c
0: POSITIVE
NEGATIVE
: POSITIVE
NEGATIVE
FAMILY HISTORY Fig. 3. Creatinine clearanceand albumin excretion ratios in subjectswith and without a famiIy history of hypertension. Plott,ed values are means _t SEM.
was reduced insulin sensitivity (insulin-glucose ratio) in subjects with a family history of hypertension. These findings are consistent with earlier reports of hyperinsulinemia in patients with established hypertension and in patients with borderline hypertension.16.22As with abnormal lipid levels, increased insulin concentrations are associated with a heightened risk for the occurrence of cardiovascular events.23 Another interesting observation was the increased creatinine clearance in the subjects with a family history of hypertension. These findings are similar to those that have been report,ed in previous studies and may be secondary to early abnormalities of the renal vasculature that produce hyperfiltration and increased creatinine clearance.” Consistent with this mechanism was the tendency for an increased albumin excretion rate in subjects with a family history of hypertension. The significant correlation between albumin excretion rate and creatinine clearance suggests that these findings may be linked by a common renal mechanism. One explanation may be related to our finding of increased plasma renin activity in subjects with a family history of hypertension. Increased
intrarenal activity of the renin-angiotensin system can cause efferent arteriolar vasoconstriction, which in turn results in glomerular hypertension, hyperfiltration, and increased albumin excretion.24 In contrast to previous reports,25 we found that the subjects with a family history of hypertension had smaller increases in systolic blood pressure during treadmill exercise than subjects without a family history of hypertension. We have previously reported smaller increases in systolic blood pressure during exercise in subjects with normal blood pressure and left ventricular hypertrophy than in subjects with normal blood pressure without left ventricular hypertrophy. These findings suggest a diminished hemodynamic response to exercise in subjects with left ventricular alterations. It is thus possible that the altered hemodynamic responses to exercise in subjects with a family history of hypertension are due to early ventricular changes, which in turn may be secondary to the heightened neuroendocrine activity that was observed in these individuals. There were higher norepinephrine levels in the subjects with a family history of hypertension. These
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findings confirm previous reports of increased norepinephrine levels in patients with labile hypertension and in the children with normal blood pressure of persons with hypertension.18J ig Plasma renin activity and aldosterone levels were also elevated in subjects with a family history of hypertension. Although increased activity of the sympathetic and reninangiotensin systems can increase blood pressure, the normal blood pressures in our subjects with a family history of hypertension suggests that other environmental, behavioral, or dietary factors may be required for clinical expression of high blood pressure. These endocrine findings are potentially important, for there is good evidence to suggest that increases in plasma renin activity are associated with an increased incidence of myocardial infarction27 and that increased levels of norepinephrine and insulin are associated with hypertrophy of cardiovascular smooth muscle.18, 23,28 We have demonstrated metabolic, endocrine, and vascular differences in a group of subjects with normal blood pressure and a family history of hypertension. In such individuals, abnormalities of blood pressure may be a late manifestation of hypertension or may not appear at all. These individuals could be at risk for the development of cardiovascular problems associated with hypertension before they actually have high blood pressure. If we use blood pressure as the sole marker for hypertension, we may overlook individuals who do not have elevated blood pressures but who are nevertheless at risk for the development of cardiovascular abnormalities. These findings suggest that a family history of hypertension justifies a full evaluation for hypertension-related cardiovascular risk factors, even in the absence of high blood pressure. REFERENCES
1. Platt R. Heredity in hypertension. Lancet 1963;1:899-904. 2. Ostfeld AM, Oglesby P. The inheritance of hypertension. Lancet 1963;1:575-9. 3. Weber MA, Smith DHG, Neutel JM, Graettinger WF. The hypertension syndrome: issues beyond blood pressure 1990 (in press). 4. Stout RW. Insulin as a mitogenic factor: role in the pathogenesis of cardiovascular disease. Am J Med 1991;9O(suppl 2A):625-45. I5 Grunfeld B, Perelstein E, Simsolo R, Gimenez M, Romero JC. Renal functional reserve and microalbuminuria in offspring of hypertensive parents. Hypertension 1990;15:257-61. I 6. Celentano A. Galderisis M. Garafalo M. Mureddu GF. Tammaro P, Petitto M, DiSomma S, DeDivitis 0. Blood pressure and cardiac morphology in young children of hypertensive subjects. J Hypertens 1988;6(suppl 4):S107-9. 7. Rauogli A, Trazzi S, Villani A, Mutti E, Cuspidi C, Sampieri L, De Ambroggi L, Parati G, Zanchetti A, Mancia G. Early 24hour blood pressure elevation in normotensive subjects with parental hypertension. Hypertension 1990;16:491-7.
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B, Hulman S, Tannenbaum J, Kushner H. Insulin re8. Falkner sistance and blood pressure in young black men. Hypertension 1990;16:706-11. 9. Simpson P, McGrath A, Savion S. Myocyte hypertrophy in neonatal rat heart cultures and its regulation by serum and by catecholamines. Circ Res 1982;51:787-95. 10. Myers J, Buchanan N, Walsh D, Kraemer M, McAuley P, Hamilton-Wessller M, Froelicher VF. A comparison of ramp versus standard exercise protocols. J Am Co11 Cardioll991 (in press). 11. Troy BL, Pombo J, Rackley CE. Measurement of left ventricular wall thickness and mass by echocardiography. Circulation 1972;45:602-11. 12. Graettinger WF, Lipson JC, Cheung DG, Weber MA. Validation of portable noninvasive blood pressure monitoring devices: comparisons with intra-arterial and sphygmomanometer measurements. AM HEART J 1988;116:1155-60. 13. Sealey JE, Laragh JH. How to do a plasma renin assay. Cardiovasc Med 1977;2:1079-92. 14. Marschner I. Group experiments on the radioimmunological insulin determination. Horm Metab Res 1974;6:293-6. 15. Durrett LR. Ziegler MG. A sensitive radioenzvmatic assav for catechol drugs. J Neurosci Research 1980;5:5”87-98. ” 16. Julius S, Mejia A, Joneo K, Krause L, Nicholas S, Van de Ven C, Johnson E, Petrin J, Sekkarie MA, Kjeldsen SE, Schmouder R. Guota R. Ferraro J. Nazzaro P. Weissfeld J. “White coat” versus “sustained” borderline hypertension in Tecumseh, Michigan. J Hypertens 1990;16:617-23. 17. Ferraro CM, Gildenberg PL, McCubbin J. Cardiovascular effects of angiotensin mediated by the central nervous system. Circ Res 1972;30:257-62. 18. l’rimarco B, Mcc~arcillll B, LJeLuca N, lJe Simone A, c;uocolo A, Galva MD, Picotti GB, Condorelli M. Participation of endogenous catecholamines in the regulation of left ventricular mass in progeny of hypertensive parents. Circulation 1985; 72:38-45. 19. Falkner B, Hulman S, Tannenbaum J, Kushner H. Insulin resistance and blood pressure in young black men. 3 Hypertens 1990;16:706-11. 20. Ferrari P. Gianchino D, Weidmann P, Keller U, Riesen W, Shaws S. Insulin sensitivity and lipoproteins in hypertension prone man [Abstract]. Kidney Int 1990;38:172. 21. Dewitt S, Goodman MD. The National Cholesterol Education Program: guidelines, status and issues. Am J Med 1991;9O(suppl 2A):325-55. 22. Ferranini E, Buzzigoli G, Giorico MA. Insulin resistance in essential hypertension. N Engl J Med 1987;317:350-7. 23. Stout RW, Bierman C, Ross R. Effects of insulin on the proliferation of cultured primate arterial smooth muscle cells. Circ Res 1975;36:319-27. 24. Lohmeier TE, Cowley W Jr. Hypertensive and renal effects of chronic low level intrarenal angiotensin infusion in the dog. Circ Res 1979;44:154-60. 25. Gottdiener JS, Brown J, Zoltick J, Fletcher RD. Left ventricular hypertrophy in men with normal blood pressure: relation to exaggerated blood pressure response to exercise. Ann Intern Med 1990;112:161-6. 26. Smith DHG, Neutel JM, Graettinger WF, Weber MA. Impaired exercise systolic blood pressure responses in hypertensive patients with left ventricular hypertrophy [Abstract]. Am J Hypertens 1990;4:20A. 27. Alderman MH, Madhavan S, Ooi WL, Cohen H, Sealey JE, Laragh J. Association of the renin-sodium profile with the risk of myocardial infarction in patients with hypertension. N Engl J Med 1991;324:1098-1104. 28. Pfeifle B, Ditschuneit H. Effects of insulin on growth of cultured human arterial smooth muscle cells. Diabetologia 1981;20:155-8.