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(Hypertension. 2001;38:761.)
© 2001 American Heart Association, Inc.

Scientific Contributions

Predictors of Target Organ Damage in Hypertensive Blacks and Whites

Areeg H. El-Gharbawy; Jane Morley Kotchen; Clarence E. Grim; Mary Kaldunski; Raymond G. Hoffmann; Zdenka Pausova; Daniel Gaudet; Francis Gossard; Pavel Hamet; Theodore A. Kotchen

From the Departments of Medicine (A.H.El-G., C.E.G., T.A.K.), Epidemiology (J.M.K.), Biostatistics (R.G.H.), and Physiology (M.K.), Medical College of Wisconsin, Milwaukee; and the Centre Hospitalier, University of Montreal (Z.P., D.G., F.G., P.H.), Montreal, Quebec, Canada.

Correspondence to Theodore A. Kotchen, MD, Department of Medicine, Medical College of Wisconsin, 9200 W Wisconsin Ave, Milwaukee, WI 53226. E-mail tkotchen{at}mcw.edu

	Abstract

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Abstract—— The purpose of this study was to evaluate the association of the insulin resistance syndrome with both blood pressure and target organ damage in blacks and whites with essential hypertension. Eighty-two black and 63 white French Canadian patients were studied. None had diabetes, and antihypertensive medications had been discontinued for 1 week. Measurements included 24-hour blood pressure monitoring, fasting plasma lipids, insulin sensitivity determined with the Bergman minimal model, echocardiogram, microalbumin excretion, and inulin and lithium clearances. Compared with the white French Canadians, black patients had an attenuated nighttime reduction in blood pressure (P<0.02), increased cardiac dimensions (P<0.001), greater microalbumin excretion (P<0.05), increased inulin clearance (indicative of glomerular hyperfiltration; P<0.001), and decreased lithium clearance (indicative of increased sodium reabsorption in the proximal tubule; P<0.001). Blood pressure levels were not related to insulin resistance; although in blacks, the nighttime reduction in systolic blood pressure was inversely related to fasting plasma insulin (r=-0.18, P<0.04). In a stepwise multivariate analysis (including blood pressure levels and components of the insulin resistance syndrome as independent variables), race was the strongest predictor of left ventricular mass (r=0.53, P<0.000), relative wall thickness (r=0.49, P<0.000), and both inulin (r=0.53, P<0.000) and lithium (r=0.41, P<0.000) clearances. Nighttime systolic blood pressure was also a significant determinant of concentric left ventricular hypertrophy (r=0.37, P<0.000). In blacks, microalbumin excretion was related to insulin resistance. These observations are consistent with the hypothesis that there is a genetic contribution to cardiac hypertrophy, glomerular hyperfiltration, and sodium retention in blacks with essential hypertension.

Key Words: hypertrophy • glomerular filtration rate • insulin resistance • microalbumin • race • target organ damage

	Introduction

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Resistance to insulin-stimulated glucose uptake is a complex phenotype with both genetic and lifestyle contributory factors. The insulin resistance syndrome includes central obesity, hyperinsulinemia, dyslipidemia, hypertension, hypercoagulability, and an increased potential for developing atherosclerotic disease.¹ The possibility that insulin resistance and hyperinsulinemia may contribute to elevated arterial pressure in patients with essential hypertension has generated considerable interest, and a number of putative mechanisms have been proposed.^2–4 However, results of epidemiological and clinical studies describing the relationship of insulin resistance and/or hyperinsulinemia to hypertension or to the development of hypertension are conflicting.⁵ Some reports suggest that the relationship between insulin resistance and hypertension is less striking in blacks than in whites.⁶

Among hypertensives, both renal disease and cardiac disease have been related to the insulin resistance syndrome. Microalbuminuria is a strong predictor of cardiovascular and renal disease risk.⁷ Several^8–10 but not all^11,12 reports describe an association of plasma insulin concentrations and/or indexes of insulin resistance with microalbuminuria. Glomerular hyperfiltration, a functional renal change that precedes glomerulosclerosis,^13–15 is associated with obesity,¹⁶ and obesity augments the effect of hypertension on albuminuria.¹⁷ Furthermore, in obese hypertensives, higher glomerular filtration rate (GFR) is associated with insulin resistance.¹⁸ Insulin exerts a growth-stimulating effect on cardiac myocytes and increases collagen production in fibroblasts.¹⁹ Several studies suggest that insulin resistance and/or hyperinsulinemia also contribute to concentric left ventricular hypertrophy and diastolic dysfunction in normotensives and hypertensives.^20,21

Blacks are at greater risk for developing hypertension related target organ disease than whites. Hypertensive blacks have a greater rate of decline of renal function over time than do whites,²² and black men have a 4-fold-higher incidence of age-adjusted end-stage renal disease than white men.²³ In addition, left ventricular mass and the prevalence of left ventricular hypertrophy are greater among hypertensive blacks than among whites.^24,25 Hypertensive blacks also have an increased prevalence of concentric remodeling and concentric hypertrophy of the left ventricle.²⁶

The purpose of this study was to evaluate the relationship between the anthropomorphic and metabolic components of the insulin resistance syndrome and both blood pressure and blood pressure-related target organ damage in blacks and in white French Canadians with essential hypertension. These studies were carried out in conjunction with our protocols for studying the genetic determinants of hypertension. Although genetic homogeneity based on race or ethnicity is unlikely, population genetics suggest that there is less genetic heterogeneity within ethnic groups than within the general population. Blacks were selected for study because their prevalence of hypertension is 50% greater than that of white Americans.²⁷ French Canadian patients were selected from a unique population in the Chicoutimi-Saguenay-Lac St Jean region in the province of Quebec. This is the largest genetically isolated population in North America.²⁸

	Methods

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Blacks were studied at the Medical College of Wisconsin in Milwaukee. French Canadians were studied either at Chicoutimi Hospital or at the Research Center of the University of Montreal Health Center in Montreal. Identical protocols were carried out at each site. To ensure standardization of these protocols, periodic exchange visits and teleconferences were held between the investigators at both sites. The protocols were approved by the appropriate Human Research Review Committee at each participating institution. Consenting patients, 18 to 55 years of age, with essential hypertension were potential candidates for study. Exclusion criteria included secondary hypertension, diastolic blood pressure >110 mm Hg on drug therapy, diabetes mellitus, serum creatinine >2.2 mg/dL, body mass index (BMI) >34 kg/m², pregnancy, substance abuse (including alcohol), and myocardial infarction or stroke within 6 months. Lipid-lowering medications were withdrawn for 1 month, and antihypertensive drugs were withdrawn 1 week before study.

At each site, patients were studied on clinical research centers over 2 days and were placed on a weight-maintaining diet containing 150 mEq Na⁺ and 80 mEq K⁺. Baseline anthropometric measurements included BMI, waist circumference, and waist-to-hip ratio. Blood pressures were measured over a 24-hour period with an Accutracker (Suntech Medical Instruments Inc) every 20 minutes during the day (5:00 AM to 11:00 PM) and every 45 minutes during the night (11:00 PM to 5:00 AM). Blood pressure results are presented as the average of these daytime and nighttime measurements. A 24-hour urine sample was collected for measurement of microalbumin excretion.

After an overnight fast, day 1 measurements included plasma concentrations of glucose, insulin, total cholesterol, LDL and HDL cholesterol, triglycerides, apolipoproteins A and B, and serum creatinine. Insulin sensitivity was evaluated by a minimal model method of Steil et al.²⁹ The insulin sensitivity index (Si) represents the increase in net fractional glucose clearance rate per unit change in plasma insulin concentration after the intravenous glucose load. The glucose effectiveness index (Sg) represents the insulin-independent fractional glucose clearance rate.

On protocol day 2, after an overnight fast, inulin and lithium clearances were measured as indexes of GFR and proximal renal tubular sodium reabsorption, respectively, with previously described methods.^30,31 A 2D M-mode echocardiogram (Hewlett Packard Sonos 2500) was obtained during diastole at or just below the tips of the mitral valve leaflets. Measurements of left ventricular internal diameter, interventricular septal thickness, and posterior wall thickness were obtained according to the guidelines of the American Society of Echocardiograpy.³² We previously described our calculations for determination of left ventricular mass index and relative wall thickness.³³

Glucose concentration in plasma samples was measured with a glucose oxidase enzymatic assay.³⁴ Insulin was measured with a double-antibody, equilibrium radioimmunoassay (Linco Corp). Plasma lipids were measured according to procedures outlined elsewhere.³⁵ Plasma cholesterol was measured spectophometrically with the use of an enzymatic procedure.³⁶ HDL cholesterol was measured with the use of the same assay after selective precipitation of the LDL fraction.³⁷ Triglycerides were measured with an enzymatic procedure based on the conversion of triglycerides to glycerol and its subsequent conversion to dihydroxyacetone phosphate and hydrogen peroxide.³⁸ Apolipoprotein A and B concentrations were determined by measuring the ultraviolet absorbance of protein at 340 nm after immunoprecipitation with an anti-apoprotein A or B human antibody.³⁹ Urine microalbumin levels were measured with a radioimmunoassay from Pharmacia-Upjohn. Inulin was measured with a fluorometric assay.⁴⁰ Lithium concentrations in urine and plasma were measured with a Corning flame photometer (model 480, Bayer Corp). All assays were carried out in the same core laboratories.

For statistical analyses, Pearson correlations were used to test the association of the measures of target organ damage with the individual variables. The Spearman rank correlation was used when the variable was skewed. Forward stepwise multiple regression analysis was used to identify the best set of predictors for each cardiac and renal end point. Values are presented as mean±SEM. A value of P<0.05 was considered statistically significant.

	Results

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A total of 145 patients with essential hypertension were studied, including 82 blacks and 63 white French Canadians. Mean ages of the 2 patient groups did not differ. On day 1 of the 2-day protocol, 24-hour urine sodium excretion did not differ significantly in the black and French Canadian patients (184±8 versus 167±8 mEq/24 h); 24-hour potassium excretion was lower (P<0.01) in blacks (43±2 versus 66±3 mEq/24 h). Average day and night systolic and diastolic blood pressures were generally higher in the blacks (Table 1). However, the day-minus-night differences in systolic and diastolic blood pressures were both significantly lower (P<0.001 and P<0.02, respectively) in the blacks than in the French Canadians, indicating an attenuated reduction of nighttime blood pressures in the blacks. The blacks had higher BMI (P<0.0001), waist circumference (P<0.03), and waist-to-hip ratio (P<0.03) than did the French Canadians.

View this table: [in this window] [in a new window]   Table 1. Mean Values of Blood Pressure and Components of the Insulin Resistance Syndrome

Compared with the French Canadians, black patients had lower plasma concentrations of total cholesterol (P<0.02) and triglycerides (P<0.0001) and higher apolipoprotein A (P<0.003). LDL and HDL cholesterol, apolipoprotein B, and fasting plasma insulin concentrations did not differ in the 2 patient groups. Mean Si and Sg also did not differ; however, these variables were not normally distributed, and from a Mann-Whitney analysis, median Si was lower (P<0.02) in the blacks than in French Canadians (1.22 versus 1.91x10^-1 min^-1 · µU^-1 · mL^-1); median Sg was also lower (P<0.04) in the blacks than in the French Canadians (1.8 versus 2.1x10^-2 min^-1). These observations suggest that the blacks were relatively more insulin resistant and had less glucose effectiveness.

Cardiac dimensions (left ventricular mass index, relative wall thickness, posterior wall thickness, and interventricular septal thickness) were all greater (P<0.001 for each) in the blacks than in the French Canadians (Table 2). These differences between patient groups persisted after adjustment for differences in blood pressure and BMI. Twenty-four-hour urine microalbumin excretion was greater (P<0.05) in the blacks. Inulin clearance was greater (P<0.001) and lithium clearance was lower (P<0.001) in blacks.

View this table: [in this window] [in a new window]   Table 2. Mean Values of Cardiac Dimensions and Renal Function

Although antihypertensive agents had been discontinued for only 1 week before study, in both groups of patients, drug class of prior antihypertensive therapy did not influence any of the following phenotypes: plasma lipids, fasting insulin Si, Sg, cardiac dimensions, or inulin clearance. In addition, mean values for these phenotypes did not differ in previously treated and previously untreated patients.

Univariate Correlates in the Combined Group of Black and French Canadian Patients
Overall, Si was inversely related to BMI (r=-0.31, P<0.0001), waist circumference (r=-0.24, P<0.005), waist-to-hip ratio (r=-0.16, P<0.02), fasting plasma insulin (r=-0.32, P<0.0001), and triglycerides (r=-0.18, P<0.03) and positively related to HDL cholesterol (r=0.31, P<0.0002) and apolipoprotein A (r=0.25, P<0.008) concentrations. Sg was inversely related to BMI (r=-0.18, P<0.03) and waist circumference (r=-0.16, P<0.05). There were no significant correlations of daytime or nighttime systolic or diastolic blood pressures with BMI, waist circumference, waist-to-hip ratio, any of the lipid measurements, fasting plasma insulin, Si, or Sg. The nighttime reduction in systolic blood pressure was inversely correlated with BMI (r=-0.16, P<0.05) and fasting plasma insulin (r=-0.18, P<0.04) and positively correlated with Sg (r=0.18, P<0.04).

Table 3 presents correlates of blood pressures and components of the insulin resistance syndrome with markers of target organ damage. Left ventricular mass index and relative wall thickness were related to blood pressure levels, and relative wall thickness was inversely related to awake-minus-asleep blood pressures; ie, increased relative wall thickness was associated with an attenuated nighttime reduction in blood pressure. Inulin and lithium clearances and microalbumin excretion were not significantly related to blood pressures, although there was a suggestive correlation (P<0.07) between day-minus-night systolic blood pressure and microalbumin excretion. Relative wall thickness, microalbumin excretion, and inulin clearance were each significantly correlated with body size and fasting plasma insulin concentrations. Inulin clearance was inversely related to Si, indicating an association of insulin resistance with greater GFR. Lithium clearance was also inversely related to BMI and waist circumference, indicating that renal proximal tubular sodium reabsorption is higher in individuals with a larger body habitus. Sg was not correlated with any of the markers of target organ damage. Unexpectedly, left ventricular mass index was inversely related to plasma concentrations of total cholesterol, LDL cholesterol, and apolipoprotein B.

View this table: [in this window] [in a new window]   Table 3. Univariate Correlates of Blood Pressures and Components of the Insulin Resistance Syndrome With Cardiac and Renal End Points in the Combined Black and French Canadian Patient Group

Multivariate Correlates of Cardiac and Renal End Points
In the multiple regression analysis, when a forward stepwise regression model was used, the independent variables were race, gender, 24-hour blood pressures, adiposity indexes, plasma lipids, apolipoproteins, fasting insulin, Si, and Sg. The dependent variables were measures to evaluate target organ damage. In the combined patient group, race was the most consistent and powerful predictor of left ventricular mass index, relative wall thickness, inulin clearance, and lithium clearance (Table 4). An inverse relationship between LDL cholesterol and left ventricular mass index was again observed in this analysis. Fasting plasma insulin concentration was the only significant predictor of urine microalbumin excretion.

View this table: [in this window] [in a new window]   Table 4. Multivariate Correlates of Cardiac and Renal End Points

The stepwise multiple regression analysis was also performed separately for the black and French Canadian patient groups. As can be seen in Table 4, there were different predictors of cardiac and renal end points in the black and French Canadian patients.

	Discussion

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Our data provide no support for the hypothesis that blood pressure level is related to insulin resistance in patients with essential hypertension. In several prospective cohort studies, fasting plasma insulin levels predict the development of hypertension in both white and black populations.^6,41,42 However cross-sectional studies examining the insulin-blood pressure relationship have yielded conflicting results.^6,43 In our study, using 24-hour blood pressure monitoring under controlled conditions on an inpatient clinical research center, we found no association between level of blood pressure with fasting plasma insulin concentrations, insulin resistance, or insulin-independent glucose utilization in either black or white patients with essential hypertension.

In nonobese patients with essential hypertension consuming a 255-mEq/d-sodium diet for 1 week, Suzuki et al⁴⁴ recently reported an association between insulin resistance (measured as a steady-state plasma glucose with octreotide) and attenuation of a nighttime reduction in blood pressure. In apparent contrast, we did not observe this association. The difference between the 2 studies may be related to different patient groups and/or different techniques for assessing insulin sensitivity. However, in our study, the nighttime reduction in systolic blood pressure was inversely related to fasting plasma insulin concentrations. Furthermore, blacks had a smaller reduction in nighttime blood pressures and tended to be more insulin resistant than the white patients. The relationship between diurnal blood pressure variation and insulin resistance merits further study.

On the basis of a stepwise multivariate analysis (in a model including blood pressure level, body size, and the metabolic components of the insulin resistance syndrome), black race was the most potent and consistent predictor of cardiac size and early indicators of renal disease. Cardiac dimensions were greater in the blacks than in the French Canadians, and based on a partition value of 0.45, the mean relative wall thickness of 0.51 suggests left ventricular concentric remodeling.⁴⁵ GFR was also greater in the black subjects. We have previously demonstrated that the relatively high GFR in blacks is indicative of glomerular hyperfiltration.³⁰ Consistent with this interpretation, microalbumin excretion was greater in blacks. In addition, lithium clearance was lower in blacks, suggesting greater sodium reabsorption in the renal proximal tubule of the blacks than the French Canadians. Conceivably, increased renal tubular reabsorption of sodium may contribute to the greater prevalence of salt-sensitive hypertension in blacks.⁴⁶

Overall, insulin resistance was associated with obesity, dyslipidemia, hyperinsulinemia, and evidence of hypertension-related early target organ damage but not with blood pressure level itself. Results of the univariate and multivariate analyses indicate that target organ damage was related to both the anthropomorphic and metabolic components of the insulin resistance syndrome. In the univariate analysis of the combined patient group, cardiac dimensions, GFR, and microalbumin excretion were related to fasting plasma insulin concentrations and insulin resistance. In the stepwise multivariate analysis, fasting hyperinsulinemia was the strongest single predictor of microalbuminuria. Increased body size, triglyceride concentrations, and insulin resistance also variably predicted microalbumin excretion and GFR. These observations are consistent with the hypothesis that the anthropomorphic and metabolic components of the insulin resistance syndrome, independent of blood pressure level, also contribute to hypertension-related target organ damage.

Whereas Si is a measure of the capacity of the increase in plasma insulin to accelerate the disappearance of glucose from plasma, Sg is a measure of the capacity of glucose to enhance its own disappearance from plasma at basal insulin levels.⁴⁷ Increased Sg has been described in insulin-resistant, normoglycemic relatives of patients with non-insulin-dependent diabetes mellitus, possibly as a compensatory response to insulin resistance.⁴⁸ In the present study, reduced Si and increased Sg are also predictors of inulin clearance in hypertensive blacks.

An effect of endogenous hyperinsulinemia on increasing renal proximal tubular reabsorption of sodium is one of the putative mechanisms of obesity-related hypertension.⁴³ Our data, demonstrating inverse correlations of lithium clearance with BMI, waist circumference, and waist-to-hip ratio, suggest that centripetal obesity is associated with increased proximal tubular sodium reabsorption. However, lithium clearance was not related to either fasting plasma insulin concentrations or insulin resistance, suggesting that obesity-related proximal tubular sodium reabsorption is not specifically related to insulin. Nevertheless, this does not exclude the possibility that insulin may affect renal tubular sodium reabsorption at a site distal to the proximal tubule.⁴⁹

In summary, comparing black and white patients with essential hypertension, black race was a stronger predictor of cardiac size and inulin and lithium clearances than either blood pressure or any of the components of the insulin resistance syndrome. In addition, blood pressure was associated with concentric left ventricular hypertrophy in both patient groups, and in blacks, microalbumin excretion and glomerular hyperfiltration were also related to the insulin resistance syndrome. Our observations are consistent with the hypothesis that there is a genetic contribution to cardiac hypertrophy, glomerular hyperfiltration, and sodium retention in hypertensive blacks. However, we cannot exclude the possibility that environmental factors (eg, diet) may also contribute to these cardiac and renal differences in the 2 patient groups.

	Acknowledgments

 
This study was supported by US Public Health Service grants P50 HL-54998 and 5 M01-RR00058 (General Clinical Research Center).

Received February 2, 2001; first decision March 6, 2001; accepted April 3, 2001.

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