Srividya Kidambi

Association of Adrenal Steroids With Hypertension and the Metabolic Syndrome in Blacks

Blacks have a high prevalence of hypertension and adrenal cortical adenomas/hyperplasia. We evaluated the hypothesis that adrenal steroids are associated with hypertension and the metabolic syndrome in blacks. Ambulatory blood pressures, anthropometric measurements, and measurements of plasma renin activity (PRA), aldosterone, fasting lipids, glucose, and insulin were obtained in 397 subjects (46% hypertensive and 50% female) after discontinuing antihypertensive and lipid-lowering medications. Hypertension was defined as average ambulatory blood pressure >130/85 mm Hg. Late-night and early morning salivary cortisol, 24-hour urine-free cortisol, and cortisone excretion were measured in a consecutive subsample of 97 subjects (40% hypertensive and 52% female). Compared with normotensive subjects, hypertensive subjects had greater waist circumference and unfavorable lipid profiles, were more insulin resistant, and had lower PRA and higher plasma aldosterone and both late-night and early morning salivary cortisol concentrations. Twenty-four-hour urine-free cortisol and cortisone did not differ. Overall, ambulatory blood pressure was positively correlated with plasma aldosterone (r=0.22; P<0.0001) and late-night salivary cortisol (r=0.23; P=0.03) and inversely correlated with PRA (r=−0.21; P<0.001). Plasma aldosterone correlated significantly with waist circumference, total cholesterol, triglycerides, insulin, and the insulin-resistance index. Based on Adult Treatment Panel III criteria, 17% of all of the subjects were classified as having the metabolic syndrome. Plasma aldosterone levels, but not PRA, were elevated in subjects with the metabolic syndrome (P=0.0002). The association of aldosterone with blood pressure, waist circumference, and insulin resistance suggests that aldosterone may contribute to obesity-related hypertension in blacks. In addition, we speculate that relatively high aldosterone and low PRA in these hypertensive individuals may reflect a mild variant of primary aldosteronism.

Limitations of nocturnal salivary cortisol and urine free cortisol in the diagnosis of mild Cushing's syndrome

OBJECTIVE Cushings syndrome (CS) is difficult to diagnose due to its nonspecific presentation. Diagnostic tests like 24-h urine free cortisol (UFC) and the overnight 1 mg dexamethasone suppression test (DST) lack sufficient sensitivity and specificity. Measurement of nocturnal salivary cortisol (NSC) is an accurate and reproducible test with a high sensitivity for CS. However, its performance in mild CS has not been reported. We present 11 cases of CS with normal or mildly elevated UFC in whom NSC was helpful in making a diagnosis. DESIGN AND METHODS All patients had at least one collection of 24-h UFC and NSC and eight had an overnight 1 mg DST. The number of NSC measurements per patient was determined by the clinical index of suspicion and the results of initial testing. Imaging studies included magnetic resonance imaging (MRI) of pituitary or computer tomography scan of abdomen. RESULTS Only four out of eleven patients had elevations in UFC and none were >2 times the upper limit of normal. Seven out of eight had an abnormal DST. All patients had some elevated NSCs (14-100%). Out of eleven patients, six had an abnormality in the pituitary gland found by MRI and two out of eleven had adrenal masses. The remaining three had normal pituitary MRI but had inferior petrosal sinus (IPS) sampling indicating Cushings disease. All patients had appropriate surgery, and histopathology of all except one was suggestive of either a cortisol-producing adrenal adenoma or an ACTH-secreting pituitary adenoma. CONCLUSION Neither a normal UFC nor a normal NSC excludes mild CS. Multiple samples (urine/saliva) and DST are needed to make the diagnosis of mild CS.

Sitosterolaemia: pathophysiology, clinical presentation and laboratory diagnosis

Sitosterolaemia is an extremely rare autosomal recessive disease, the key feature of which is the impairment of pathways that normally prevent absorption and retention of non-cholesterol sterols, for example plant sterols and shellfish sterols. The clinical manifestations are akin to familial hypercholesterolaemia (such as presence of tendon xanthomas and premature atherosclerosis), but with “normal to moderately elevated” cholesterol levels. The gene(s) causing sitosterolaemia was mapped to the STSL locus on human chromosome 2p21, and mutations in either of the two genes that comprise this locus, ABCG5 or ABCG8, cause this disease. Exact prevalence is unknown, but there are estimated to be 80–100 cases around the world. This rare disease has shed light into the molecular mechanisms that control sterol trafficking in the enterocyte and hepatocyte; ABCG5 and ABCG8 heterodimerise to form a sterol efflux transporter in the liver and intestine. In this review the pathophysiology, clinical manifestations and approach to clinical and laboratory diagnosis of this disease are described.

Cholesterol and non-cholesterol sterol transporters: ABCG5, ABCG8 and NPC1L1: a review.

1. Whole-body sterol (cholesterol and xenosterol) balance is delicately regulated by the gastrointestinal tract and liver, which control sterol absorption and excretion, respectively, in addition to the contribution to the cholesterol pool by whole-body cholesterol synthesis. In the past ten years enormous strides have been made not only in establishing that specific transporters mediate the entry and exit of sterols and how these may regulate selective sterol access to the body pools, but also in how these pathways operate to integrate these physiological pathways. 2. The entry of sterols from the gastrointestinal and biliary canalicular lumen into the body is mediated by NPC1L1, which was discovered by a novel method, via a genomics–bioinformatics approach. 3. Identification of the genetic basis responsible for causing sitosterolaemia, characterized by plant sterol accumulation, led to the identification of two half-transporters (ABCG5 and ABCG8) that normally efflux plant sterols (and cholesterol) into the intestinal and biliary lumen for faecal excretion. 4. The objective of this review is to provide up-to-date knowledge on genomics, proteomics and function of these two transporter systems.

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.

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.

Epidemiology of Obesity and Pharmacologic Treatment Options

Prevalence of obesity and its related morbidity have increased to alarming levels in adults and children in the United States and globally. Weight loss results in improvement of much of the obesity-related morbidity. Lifestyle changes such as dietary modifications, increased physical activity, and behavioral therapy form the crux of weight management. However, many individuals need additional assistance (pharmacologic or surgical) to initiate or sustain weight loss. Pharmacologic therapy consists of a number of agents that work by decreasing appetite, gastric emptying, or nutrient absorption or by increasing satiety. Five classes of drug are currently approved for adults, including sympathomimetics (with and without an antiepileptic agent topiramate), gastrointestinal lipase inhibitors, serotonin agonists, glucagon-like peptide 1 agonists, and antidepressant/opioid antagonist combination. Pharmacologic options for children with obesity are minimal (lipase inhibitor orlistat is the only approved medication for children aged >12 years); however, all adult medications are approved by the Food and Drug Administration for children aged >16 years old. While side effect profiles of these medications are far superior to older medications, their use is limited by lack of long-term cardiovascular safety data, costs of medications and variable insurance coverages, and the need for continued usage for sustainable benefits. Weight loss medications may induce complacence, on part of both the patient and the provider, regarding lifestyle modifications, without which the drug therapy is almost certain to be of minimal benefit. Several novel drugs are in the pipeline targeting brown fat, energy expenditure, appetite suppression, and satiety.