Shanthi Krishnaswami

Hyperaldosteronism and Hypertension. Ethnic Differences

The purpose of this study is to evaluate the relationship between aldosterone and blood pressure in a total of 220 normotensive and 293 essential hypertensive subjects in 2 genetically distinct populations—blacks and white French Canadians. The 24-hour blood pressure monitoring was performed under standardized conditions after discontinuing antihypertensive medications. Plasma renin activity and plasma aldosterone were measured in the supine position and after standing for 10 minutes. Plasma atrial natriuretic factor was also measured. Supine and standing plasma renin activities were lower (P≤0.01), plasma aldosterone was higher (P<0.0001), and the aldosterone/renin ratios were higher (P<0.0001) in the hypertensive subjects. Atrial natriuretic factor was also higher in the hypertensive subjects (P<0.0001). Among blacks, blood pressures did not correlate with plasma renin activity. However, both average daytime and nighttime systolic and diastolic blood pressures were correlated with supine and standing plasma aldosterone and with the aldosterone/renin ratio (P<0.005 or less). In French Canadians, blood pressures tended to be positively correlated with standing plasma renin activity and aldosterone, but not with the aldosterone/renin ratio. Correlations of blood pressure with aldosterone were more consistent and more striking in blacks than in French Canadians. In both ethnic groups, there were inconsistent correlations of blood pressure with atrial natriuretic factor. These observations are consistent with the hypothesis that aldosterone-induced volume expansion is an important contributor to hypertension, especially in blacks.

C-Reactive Protein and Coronary Artery Calcium in Asymptomatic Women With Systemic Lupus Erythematosus or Rheumatoid Arthritis

Patients with systemic lupus erythematosus (SLE) and those with rheumatoid arthritis (RA) have increased risk for atherosclerotic cardiovascular disease. The aims of this study were to compare the presence of coronary artery calcium (CAC) in age- and race-matched women with SLE, those with RA, and healthy controls without diabetes mellitus or history of myocardial infarction, angina pectoris, or stroke and to investigate its relation with traditional risk factors, inflammation, and endothelial activation. Study subjects completed cardiovascular risk factor assessment and electron-beam computed tomography that measured CAC. The 2 patient groups had similar prevalence and extent of CAC as well as significantly increased odds of having any CAC (odds ratio 1.87, 95% confidence interval 1.09 to 3.21) and more extensive CAC (odds ratio 4.04, 95% confidence interval 1.42 to 11.56 for CAC score >100) compared with healthy controls. After controlling for differences in cardiovascular risk factors, including insulin resistance and hypertension, the results remained statistically significant. After adjustment for differences in levels of C-reactive protein and/or soluble intercellular adhesion molecule-1, however, women with chronic inflammatory diseases no longer had significantly increased odds of having any CAC or more extensive CAC compared with controls. In conclusion, asymptomatic and nondiabetic women with chronic inflammatory diseases had significantly increased odds of having CAC and more extensive CAC compared with age- and race-matched healthy controls. The increased odds for CAC may in part result from higher levels of inflammation and endothelial activation in these patients.

Altered relationship of blood pressure to adiposity in hypertension.

BACKGROUND Blood pressure levels and the prevalence of hypertension are related to adiposity. We evaluated the relationship of adiposity to blood pressure in normotensive and untreated hypertensive African Americans-an ethnic group with a high prevalence of hypertension and obesity. METHODS Outpatient measurements were obtained in 1,858 normotensive and 1,998 hypertensive subjects (44% untreated) residing in Milwaukee. The blood pressure-adiposity relationship was also analyzed in non-Hispanic black (n = 908) and non-Hispanic white (n = 2182) National Health and Nutrition Examination Survey (NHANES) participants. RESULTS In Milwaukee subjects, body mass index (BMI), waist/hip ratio, waist/height ratio, and percent body fat were higher in hypertensives (P < 0.0001). Combining normotensive and untreated hypertensive subjects, each of the anthropometric indices was correlated with systolic and diastolic blood pressure (P <0.0001). In separate analyses, correlations of the indices with blood pressure were observed in normotensive subjects (P < 0.0001), but generally not in hypertensive subjects. Further, separating all subjects into quartiles based on systolic blood pressure, indices of adiposity correlated with blood pressure only in subjects in the lowest blood pressure quartile (blood pressure <120/78 mm Hg). Similarly, among NHANES participants, blood pressure correlated with anthropometric indices in normotensive (P < 0.0005), but not in untreated hypertensive blacks or whites. CONCLUSIONS Although indices of adiposity were greater in hypertensive than in normotensive subjects, blood pressures were significantly correlated with measures of adiposity in normotensive, but not in untreated hypertensive subjects. We hypothesize that the blood pressure-adiposity relationship in hypertensives is modulated by a combination of environmental and genetic factors.

Aldosterone Contributes to Blood Pressure Variance and to Likelihood of Hypertension in Normal-Weight and Overweight African Americans

BACKGROUND Hypertension and obesity are highly prevalent among African Americans (AAs). We have previously reported that both plasma aldosterone (PA) and body mass index (BMI) are higher in hypertensive than in normotensive AAs. This study evaluates the relative contributions of adiposity and PA to hypertension in AAs. METHODS A total of 466 AAs (50% hypertensive, 51% women) were evaluated in a Clinical Research Center by stratifying them into three subgroups based on BMI (normal weight, overweight, and obese). Anthropometric measurements, ambulatory blood pressure (BP), fasting glucose, insulin, 24-h urine sodium and potassium, creatinine clearance, standing PA and plasma renin activity (PRA) were measured. Insulin resistance was estimated by the homeostasis model assessment. RESULTS Compared to normotensives, hypertensives had higher BMI, waist circumference (WC), and were more insulin resistant (P < or = 0.01). When stratified by BMI, hypertensives in each BMI strata had higher PA (P < or = 0.05) and lower PRA (P < or = 0.01) compared to normotensives. Compared to normotensives, WC was greater in overweight and obese hypertensives, but not in normal-weight hypertensives. In the overall sample, age, WC, PA, and PRA were the major contributors to BP variance and to hypertension. Among normal-weight subjects, PA and PRA significantly predicted BP and the odds ratio for hypertension, whereas WC had no predictive value. CONCLUSIONS PA, but not WC, is associated with BP and likelihood of hypertension in normal-weight AAs, whereas both WC and PA are predictive of hypertension in overweight and obese individuals. This suggests that aldosterone antagonists may be useful for the treatment of hypertension among AAs, regardless of BMI.

Aldosterone and alterations of hypertension-related vascular function in African Americans.

BACKGROUND African Americans have a high prevalence of hypertension and hypertension-related vascular disease. We previously reported that plasma aldosterone concentrations are relatively high in hypertensive African Americans. This study evaluates the hypothesis that hypertension and hypertension-related alterations of peripheral vascular and renal vascular function are associated with aldosterone. METHODS Twenty four-hour blood pressures, cardiac output, renal blood flow (RBF), plasma renin activity (PRA), and plasma aldosterone were measured in hypertensive and normotensive African Americans. Hemodynamic measurements were repeated in response to graded infusions of norepinephrine (NE). RESULTS Ambulatory blood pressures in hypertensives and normotensives were 142 +/- 1/86 +/- 1 and 117 +/- 1/70 +/- 1 mm Hg, respectively. Cardiac index (CI) was lower (P < 0.01), peripheral vascular resistance was higher (P < 0.0001), arterial compliance was lower (P < 0.0001), RBF was lower (P = 0.04), and renal vascular resistance (RVR) was higher (P < 0.0001) in the hypertensives. Overall, blood pressures were positively correlated with peripheral vascular resistance (P < 0.0001) and inversely correlated with vascular compliance (P < 0.0001). In response to NE, hypertensives had greater increases of systolic blood pressure (P < 0.004) and pulse pressure (P < 0.005). PRA was lower (P < 0.0001) and plasma aldosterone was higher (P < 0.0001) in the hypertensives. Overall, blood pressures and pulse pressure were correlated with aldosterone (P < or = 0.01). Vascular compliance, RVR, and the increment of RVR in response to NE were also correlated with aldosterone (P < or = 0.03). CONCLUSIONS Aldosterone may contribute to hypertension and to hypertension-related alterations of peripheral vascular and renal vascular function in African Americans.

Non-replication study of a genome-wide association study for hypertension and blood pressure in African Americans.

BackgroundA recent genome wide association study in 1017 African Americans identified several single nucleotide polymorphisms that reached genome-wide significance for systolic blood pressure. We attempted to replicate these findings in an independent sample of 2474 unrelated African Americans in the Milwaukee metropolitan area; 53% were women and 47% were hypertensives.MethodsWe evaluated sixteen top associated SNPs from the above genome wide association study for hypertension as a binary trait or blood pressure as a continuous trait. In addition, we evaluated eight single nucleotide polymorphisms located in two genes (STK-39 and CDH-13) found to be associated with systolic and diastolic blood pressures by other genome wide association studies in European and Amish populations. TaqMan MGB-based chemistry with fluorescent probes was used for genotyping. We had an adequate sample size (80% power) to detect an effect size of 1.2-2.0 for all the single nucleotide polymorphisms for hypertension as a binary trait, and 1% variance in blood pressure as a continuous trait. Quantitative trait analyses were performed both by excluding and also by including subjects on anti-hypertensive therapy (after adjustments were made for anti-hypertensive medications).ResultsFor all 24 SNPs, no statistically significant differences were noted in the minor allele frequencies between cases and controls. One SNP (rs2146204) showed borderline association (p = 0.006) with hypertension status using recessive model and systolic blood pressure (p = 0.02), but was not significant after adjusting for multiple comparisons. In quantitative trait analyses, among normotensives only, rs12748299 was associated with SBP (p = 0.002). In addition, several nominally significant associations were noted with SBP and DBP among normotensives but none were statistically significant.ConclusionsThis study highlights the importance of replication to confirm the validity of genome wide association study results.

Hypertension, Insulin Resistance, and Aldosterone: Sex‐Specific Relationships

African Americans, particularly men, have the highest morbidity and mortality rates from hypertension in the United States. The authors studied 527 African Americans in a general clinical research center to determine whether there are sex differences in the relationships between hypertension with insulin resistance (IR) and aldosterone, which are risk factors for cardiovascular disease. Measurements included ambulatory blood pressure (BP), anthropometric measures, plasma renin activity, plasma aldosterone (PA) concentration, and fasting serum lipids, glucose, and insulin. IR was estimated using the Homeostasis Model Assessment (HOMA) model. BP correlated with aldosterone in both sexes. However, both BP and PA correlated with IR in men, but not in women. Compared with men in the lower tertile of HOMA‐IR, men in the upper tertile had higher mean systolic BP, a higher odds ratio of having hypertension, and higher levels of PA. The association of IR with both hypertension and PA in men, but not in women, may contribute to the high prevalence of cardiovascular disease in African American men.

Association between C-reactive protein and depressive symptoms in women with rheumatoid arthritis.

Converging lines of evidence support an association between systemic inflammation and depressive symptoms. Neuroimmune pathways may account for the high prevalence of depression in individuals with inflammatory conditions such as rheumatoid arthritis (RA). However, this relationship is complicated by factors linked to both inflammatory disease activity and mood, such as pain and physical disability. The goal of this cross-sectional study was to examine the relationship between C-reactive protein (CRP) and depressive symptoms among 173 women with RA. Somatic symptoms of depression and circulating CRP were significantly associated in regression analyses adjusted for body mass index (beta=.19, p<.05), but this relationship was attenuated when pain and disability were included as covariates (beta=.09, p=.24). CRP was not significantly associated with negative mood symptoms of depression. Findings suggest that depression in the context of RA may result from the overlap of somatic depressive and RA symptoms rather than neuroimmune pathways.

Cardiovascular correlates of insulin resistance in normotensive and hypertensive African Americans

Insulin resistance (IR) is associated with obesity and predisposes to diabetes mellitus (DM) and cardiovascular disease. The purpose of this study is to determine if IR is related to cardiovascular function independent of DM or hypertension among African Americans (AA). Four hundred sixty-two nondiabetic AA (50% hypertensive and 51% women) were studied on an inpatient General Clinical Research Center. Measurements included anthropometrics and 24-hour blood pressure (BP), heart rate (HR), fasting blood glucose, plasma aldosterone, and insulin. Stroke volume (SV) and cardiac output (CO) were measured by impedance plethysmography; peripheral vascular resistance (PVRI) and vascular compliance indices (VCI) were computed. These measurements were also obtained in response to mental (computerized math testing) and pharmacologic (graded norepinephrine infusion) stress. Insulin resistance was calculated using the homeostasis model assessment (HOMA-IR). SV, CO, and VCI decreased with increasing HOMA-IR, whereas HR and PVRI increased. Overall, BP, HR, and PVRI were positively correlated with HOMA-IR (P < .01); and SV index, cardiac index, and VCI were negatively correlated with HOMA-IR (P < .0001). The correlations persisted after adjustment for BP, age, sex, plasma aldosterone, total cholesterol, or low-density lipoprotein and high-density lipoprotein cholesterol. In addition, multiple linear regression analyses showed that HOMA-IR contributes to the maximum variability of all the hemodynamic variables. Blood pressure responses to math stress and norepinephrine infusion did not correlate with HOMA-IR. Unrelated to DM and BP, IR is associated with increased PVRI and decreased CO in AA. These observations suggest that an exclusive focus on effects of IR on DM or BP may ignore independent pathophysiologic contributions of IR to cardiovascular disease.

Cocaine use in inner city african american research volunteers.

Objectives:To determine the prevalence of cocaine use and associated risk factors in African Americans volunteering as research subjects for a hypertension study. Methods:African Americans recruited from Milwaukees inner city received