Unmasking Hormonal Mechanisms of Hypertension in Obesity.

Salt wasting syndrome (hyponatremia, hyperkalemia, dehydration, metabolic acidosis) in early infancy could be caused by either mineralocorticoid deficiency as in congenital adrenal hyperplasia (CAH) and adrenal insufficiency or mineralocorticoid resistance as in pseudohypoaldosteronism (PHA). In salt wasting CAH, serum aldosterone and cortisol levels are expected to be low. Cross reactivity between high levels of adrenal steroid precursors and aldosterone has recently been reported resulting in elevated aldosterone levels in CAH, leading to difficulty in differentiating between CAH and PHA. We report four such cases of salt wasting CAH, where high aldosterone levels and high normal cortisol levels led to initial diagnostic confusion with PHA. Diagnosis of CAH was later established on the basis of significantly elevated adrenocorticotropic hormone (ACTH) stimulated 17-hydroxyprogesterone (17-OHP) values. By reporting these cases we draw attention to the possibility that high levels of adrenal steroid precursors can cross react with aldosterone and cortisol, and underscore the significance of ACTH stimulated 17-OHP values in differentiating CAH and PHA.

Insulin resistance is frequently associated with obesity-related hypertension. Leptin resistance and increased plasma leptin levels are frequent companions in this association. To examine whether in obesity hypertension with insulin resistance, plus hyperleptinemia, the sodium content of erythrocyte (Naie) reflects a positive sodium balance related to the physiological loss of leptin in sodium reabsorption, we studied a group of obese hypertensive patients, and a group of lean normotensive subjects. In obese hypertensives, fasting glucose, insulin and the insulin resistance index were higher as compared to the lean individuals (107.0 ± 4.1 mg/dl, 10.2 ± 1.4 pU/ml and 2.94 ± 0.52, respectively, vs 98.7 ± 4.1 mg/dl, 7.22 ± 1.33 U/ml, and 1.79 ± 0.16, respectively, p < 0.002). Both the leptin/BMI 2 index as well as the Naie were significantly higher in the obese hypertensive group as compared to control group (1.9± 0.21 vs 1.25 ± 0.27, respectively p < 0.01, and 12.5 ± 0.51 vs 10.7 ± 0.5 mEq/ml/cell, respectively p < 0.05). In obese hypertensives the leptin/BMI 2 index was significantly associated with DBP (r= = 0.41, p < 0.04), MBP (r= 0.44, p < 0.03), Naie (r = 0.41, p < 0.05) and age (r = 0.43, p = 0.03). We conclude that in obese hypertensive patients Naie is increased reflecting a state of positive sodium balance. In these patients, the elevated circulating leptin concentrations were one of the main regulators of the content of sodium in erythrocytes.

Hypertension resistant to 2 antihypertensive drugs is more common among obese patients than among lean patients. The case we describe and the observations we report suggest that refractoriness among obese hypertensives is frequently caused by obstructive sleep apnea and/or inappropriately high plasma aldosterone levels. In other words, obese hypertensives may have sleep apnea, obese hypertensives without sleep apnea may have inappropriately elevated levels of plasma aldosterone, and a surprising number of obese patients with sleep apnea also have elevated levels of aldosterone. The mechanisms by which obesity and obstructive sleep apnea increase aldosterone levels and raise blood pressure are not understood, but sympathetic nervous system activation and production of nonclassical adrenal stimuli are two possibilities. Obstructive sleep apnea can be detected with a careful history and various sleep studies. Inappropriately elevated aldosterone levels can be detected by measuring the ratio of plasma aldosterone concentration to plasma renin activity. Successful treatment of these resistant hypertensives often can be achieved by devices that provide positive pressure to the upper airway to correct obstructive sleep apnea and by incorporating an aldosterone antagonist in the therapeutic regimen.

We read with interest the article by Paik et al. [1], who studied nonclassical determinants of parathyroid hormone (PTH) levels in 1,288 women from the Nurses’ Health Study II. Non-smoking, body mass index, low vitamin A intake, and winter season were associated with higher PTH levels. These results are of particular importance when considering the crucial role of PTH for the diagnosis and treatment of bone and mineral disorders [2] and the accumulating data on PTH and cardiovascular risk [3–5]. With our letter we seek to guide attention toward previous data suggesting that the renin–angiotensin–aldosterone system (RAAS) may also have a significant impact on PTH levels [5–9]. Toward this goal, we and others have shown that high aldosterone levels are associated with high PTH levels [5–9]. In experimental studies it has been demonstrated that aldosterone excess increases renal and fecal loss of calcium [8–10]. This in turn results in secondary hyperparathyroidism, which could be effectively treated by mineralocorticoid receptor (MR) blocking therapy in rats [8, 9]. The complex interplay of calcium, PTH, and the RAAS is further underlined by data indicating that both calcium as well as PTH participate in the complex regulation of the RAAS [11–13]. In this context it has been observed that aldosterone levels were elevated and positively correlated with PTH levels in patients with primary hyperparathyroidism [14, 15]. Hence, primary hyperparathyroidism is associated with high aldosterone levels and primary aldosteronism is associated with high PTH levels. Clinical data suggest that treatment of either disease is effective at normalizing the levels of both hormones [6, 8, 9, 14, 15]. We therefore believe that the awareness of an interplay between PTH and aldosterone could, for selected cases, be clinically relevant for diagnostic considerations of patients with elevated levels of either of these two hormones. Apart from this, concomitant elevations of both hormones in states of either hyperparathyroidism or aldosteronism could hypothetically underlie the increased risk of mortality or cardiovascular disease associated with high PTH or high aldosterone levels [2–5, 16]. Whether beneficial effects of treatments of PTH or aldosterone excess are significantly mediated by an impact on both hormones warrants further study. Of note, vitamin D metabolites have already been shown to suppress PTH as well as the RAAS [17, 18]. In conclusion, we hope that our letter can further stimulate interest and research on the relationship of PTH and the RAAS in order to better understand, diagnose, and treat disorders of both hormone systems. The authors have stated that they have no conflict of interest.

The human neonatal period is characterized by renal immaturity with impaired capacity to regulate water and sodium homeostasis, resembling partial aldosterone resistance. Because aldosterone effects are mediated by the mineralocorticoid receptor (MR), we postulated that this hormonal unresponsiveness could be related to low MR expression in the distal nephron. We measured aldosterone and renin levels in umbilical cord blood of healthy newborns. We used quantitative real-time PCR and immunohistochemistry to analyze the expression of MR and key players of the mineralocorticoid signaling pathway during human and mouse renal development. High aldosterone and renin levels were found at birth. MR mRNA was detected in mouse kidney at d 16 postcoitum, peaking at d 18 postcoitum, but its expression was surprisingly very low at birth, rising progressively afterward. Similar biphasic temporal expression was observed during human renal embryogenesis, with a transient expression between 15 and 24 wk of gestation but an undetectable immunoreactive MR in late gestational and neonatal kidneys. This cyclic MR expression was tightly correlated with the evolution of the 11beta-hydroxysteroid dehydrogenase type 2 and the epithelial sodium channel alpha-subunit. In contrast, glucocorticoid and vasopressin receptors and aquaporin 2 followed a progressive and sustained evolution during renal maturation. Our study provides the first evidence for a low renal MR expression level at birth, despite high aldosterone levels, which could account for compromised postnatal sodium handling. Elucidation of regulatory mechanisms governing MR expression should lead to new strategies for the management of sodium waste in preterms and neonates.

Introduction: Obesity is a nutritional disorder and associated with excess fat deposition due to altered balance between energy intake and consumption. Obesity and obesity related hypertension are identified as risk factors in development of diabetes and chronic kidney disease. Obesity alters the hemodynamic functions of organs and is a threat for development of cardiovascular diseases, renal failure and peripheral arterial disease. Objectives: The objective of the present study was to compare the renal profile among healthy individuals, obese individuals, obese with preexisting hypertension and obese individuals without hypertension. Materials and Methods: A prospective cross sectional observational study was conducted at ACSR government medical college and hospital, a tertiary care hospital for a period of two years from October 2014 to September 2016. 120 subjects were divided into 4 groups with 30 in each group, healthy, obese, non obese hypertensive and obese hypertensives. Results: All the measured variables in all the four groups of the study were expressed as mean ± standard deviation. BMI of 32.1 ± 2.1 was observed in obese group whereas 22.1 ± 3.1 was observed in healthy group. Statistically significant correlation was found with BMI, S. urea, S. creatinine, S. uricacid and estimated Glomerular filtration rate (‘p’ value

Obesity is a disorder that develops from the interaction between genotype and environment involving social, behavioral, cultural, and physiological factors. Obesity increases the risk for type 2 diabetes mellitus, hypertension, cardiovascular disease, cancer, musculoskeletal disorders, chronic kidney and pulmonary disease. Although obesity is clearly associated with an increased prevalence of hypertension, many obese individuals may not develop hypertension. Protecting factors may exist and it is important to understand why obesity is not always related to hypertension. The aim of this review is to highlight the knowledge gap for the association between obesity, hypertension, and potential genetic and racial differences or environmental factors that may protect obese patients against the development of hypertension and other co-morbidities. Specific mutations in the leptin and the melaninocortin receptor genes in animal models of obesity without hypertension, the actions of α-melanocyte stimulating hormone, and SNS activity in obesity-related hypertension may promote recognition of protective and promoting factors for hypertension in obesity. Furthermore, gene-environment interactions may have the potential to modify gene expression and epigenetic mechanisms could also contribute to the heritability of obesity-induced hypertension. Finally, differences in nutrition, gut microbiota, exposure to sun light and exercise may play an important role in the presence or absence of hypertension in obesity.

Background.Hypertension is frequently found in obesity, although the mechanisms for obesity related hypertension are still unclear. Several studies showed the role of endothelin-1 in the development of hypertension asso-ciated with obesity. More recent studies showed the possibility for the role of leptin in obesity related hypertension. In vitro study with human umbilical vein endothelial cells (HUVECs) showed correlation between leptin and endothelin-1. The aim of this study was to clarify the relation-ship between leptin, body mass index (BMI), blood pressure (BP) and plasma endothelin-1 in obese hypertensive subjects. Methods.A cross sectional study was performed at National Cardiovas-cular Centre, Harapan Kita Jakarta, which included 80 Indonesian men. The subjects were divided into lean hypertensive and obese hypertensive. The plasma immunoreactive ET-1 and leptin were determined by ELISA method. Results.ET-1 level and leptin level were significantly higher in obese hy-pertensive subjects compared with lean hypertensive subjects. There are significant correlation between endothelin level with BMI (r = 0.32; p < 0.005). There are also significant correlation between leptin level with BMI (r = 0.533; p <0.01), but there are no correlation between plasma leptin and endothelin-1 level in obese hypertensive men. Conclusions.Leptin and ET-1 level were significantly increase in obese hypertensive subjects compared with lean hypertensive subjects. There is no correlation between leptin and ET-1 level in obese hypertensive subjects.

Obesity, impaired glucose tolerance, and diabetes mellitus are associated with a substantially increased prevalence of hypertension, cardiovascular (CVD), and chronic renal disease. The prevalence of hypertension in patients who have type 2 diabetes mellitus is up to 3 times higher than in patients without diabetes mellitus. Further, the coexistence of hypertension in diabetic patients greatly enhances their likelihood of developing CVD and chronic kidney disease.1–4 Indeed, studies conducted in the Framingham population with diabetes mellitus1 indicated that the presence of hypertension in these participants was a resulting risk factor for the presence of CVD. This data and other studies suggest a 2-fold increased risk of CVD events and deaths in diabetic persons with hypertension compared with those with normal blood pressures. The increased association between hypertension and diabetes mellitus can be explained, in part, by the presence of a maladaptive interaction of factors, such as excessive caloric intake/decreased activity and associated insulin resistance (IR), chronic activation of the renin–angiotensin (Ang II)–aldosterone system (RAAS), the sympathetic nervous system, and abnormalities of innate immunity, inflammation, and oxidative stress1–21 (Figure). The epidemic of obesity and sedentary lifestyle, and the aging of populations worldwide have contributed to the current high prevalence of diabetes mellitus and hypertension. Figure. Systemic and metabolic factors that promote coexistent diabetes mellitus, hypertension, cardiovascular, and chronic kidney disease. Hypertension is more common in diabetic patients than in the general population.1–4 In the Strong Heart Study, baseline measurements which independently predicted incident hypertension, included waist circumference, elevations in baseline systolic blood pressure, and left ventricular mass and diabetes mellitus.2 Further, a recent longitudinal Japanese study of 5198 subjects showed that parental hypertension has an age-independent impact on both male and female offspring in elevations in blood pressure, plasma glucose, and triglyceride …

Nocturnal reduction of blood pressure and the antihypertensive response to a diuretic or angiotensin converting enzyme inhibitor in obese hypertensive patients

Purpose of reviewThe prevalence of both obesity and hypertension is increasing in childhood, with considerable overlap in disease and causative factors. Evidence from studies over the past decade suggests both obesity and hypertension have summative effects on both cardiac remodelling in childhood and major adverse cardiovascular events in adulthood.Recent findingsWe highlight recent high-quality evidence reporting epidemiology of obesity, hypertension and hypertension-mediated organ damage (HMOD) in those with obesity-related hypertension. We discuss the early life influences on BP and BMI trajectory and the clustering of cardiovascular risk factors (CVRFs) seen in obesity hypertension. We discuss management options highlighting key contributors to compounding risk for obesity-associated hypertension across the first two decades of life, with potential windows for both individual and population-level intervention.SummaryCurrently, a large and expanding cohort of young people with multiple CVRFs is progressing toward adulthood, where they are likely to experience disproportionate cardiovascular morbidity when compared with age-matched healthy peers. These trends underscore the urgent need for co-ordinated healthcare responses to manage affected children and for robust governmental and public-health interventions to mitigate the environmental and societal drivers of this convergent epidemic.

BackgroundSudden cardiac death is common and accounts largely for the excess mortality of patients on maintenance dialysis. It is unknown whether aldosterone and cortisol increase the incidence of sudden cardiac death in dialysis patients.Methods and resultsWe analysed data from 1255 diabetic haemodialysis patients participating in the German Diabetes and Dialysis Study (4D Study). Categories of aldosterone and cortisol were determined at baseline and patients were followed for a median of 4 years. By Cox regression analyses, hazard ratios (HRs) were determined for the effect of aldosterone, cortisol, and their combination on sudden death and other adjudicated cardiovascular outcomes. The mean age of the patients was 66 ± 8 years (54% male). Median aldosterone was <15 pg/mL (detection limit) and cortisol 16.8 µg/dL. Patients with aldosterone levels >200 pg/mL had a significantly higher risk of sudden death (HR: 1.69; 95% CI: 1.06–2.69) compared with those with an aldosterone <15 pg/mL. The combined presence of high aldosterone (>200 pg/mL) and high cortisol (>21.1 µg/dL) levels increased the risk of sudden death in striking contrast to patients with low aldosterone (<15 pg/mL) and low cortisol (<13.2 µg/dL) levels (HR: 2.86, 95% CI: 1.32–6.21). Furthermore, all-cause mortality was significantly increased in the patients with high levels of both hormones (HR: 1.62, 95% CI: 1.01–2.62).ConclusionsThe joint presence of high aldosterone and high cortisol levels is strongly associated with sudden cardiac death as well as all-cause mortality in haemodialysed type 2 diabetic patients. Whether a blockade of the mineralocorticoid receptor decreases the risk of sudden death in these patients must be examined in future trials.

New guidelines recommend testing for primary aldosteronism (PA) in all people with hypertension. Interpreting population-based results for PA will require understanding the influence of demographic characteristics. 858 adults from across the US meeting traditional guideline criteria for PA testing underwent testing. The influence of demographic factors on test result interpretations was assessed after multivariable adjustment. Mean age was 62±11 years, with 54.6% women, 14% Black, and 22.9% Hispanic. Independent of antihypertensive medications and clinical comorbidities, participants aged ≥70 years had 24% lower aldosterone (P<0.05), 48% lower renin activity (P<0.001), and trended toward higher aldosterone-to-renin ratio (52% higher; P=0.14), compared with those <50 years. Aldosterone levels were higher in women compared with men across the lifespan. Black participants had 81% higher aldosterone-to-renin ratio than White participants (P<0.001), primarily due to lower renin (P<0.005). These demographic factors influenced the ultimate PA testing interpretation: participants ≥70 years old had 19% higher odds of a positive test than those <50 years old (P=0.002), and Black participants had 22% higher odds of a positive test than White participants (P<0.001). In this large, diverse, nationwide sample, older and Black participants had higher aldosterone-to-renin ratio and higher odds of testing positive for PA, and women had higher aldosterone levels than men across the lifespan. With newly expanded indications for PA testing, a greater appreciation of the influence of demographic characteristics on PA test results will be required.

Background: Obesity and hypertension are associated with β2-adrenoceptor polymorphisms accompanying with heightened sympathetic nerve activity. In the present study we compared β2-adrenoceptor protein expression between buffy coats (white blood cells as a representive for whole-body) and abdominal subcutaneous fat to further evaluate the contributions of sympathetic nerve activity and β2-adrenoceptor to obesity and hypertension. Methods: In 17 obese normotensive Caucasian men (BMI≥30.0 kg/m2) and 8 age-matched lean Caucasian men (BMI&lt;25 kg/m2), we measured BMI, blood pressure (BP), whole-body plasma norepinephrine (NE) spillover, NE clearance, plasma leptin, and β2-adrenoceptor protein concentration and leptin receptor protein concentration in buffy coats and in abdominal subcutaneous adipose tissue. The β2-adrenoceptor protein expression and leptin receptor protein expression were analysed by Western blotting. Results: Obese subjects had significantly higher whole-body NE spillover (673±245 ng/mL vs. 431±156, P&lt;0.05), plasma leptin (15.2±4.3 ng/mL vs. 4.8±2.4, P&lt;0.01), and BP levels (P&lt;0.05) compared to lean subjects, but the whole-body NE clearance rate was similar. Obese subjects had significantly greater expression of β2-adrenoceptor protein in buffy coats (P&lt;0.05) compared to lean subjects, while they had significantly less β2-adrenoceptor protein expression in abdominal fat (P&lt;0.05). Leptin receptor protein expression in both buffy coats and abdominal fat were greater in obese subjects compared to lean subjects. Conclusions: Obese subjects had greater β2-adrenoceptor protein expression in buffy coats, but less β2-adrenoceptor protein expression in fat. This may suggest that blunted sympathetic nerve activity in adipose tissue (observed by less β2-adrenoceptor protein expression in fat) might relate to obesity and heightened sympathetic nerve activity in whole-body (observed by greater β2-adrenoceptor protein expression in buffy coats and higher NE spillover) may be linked to hypertension. The findings support the concept of selective leptin resistance. Sympathetic nerve activity and β2-adrenoceptor, not leptin, plays an important role is mechanisms of obesity and obesity-related hypertension.

Analysis of left ventricular hypertrophy in patients with unilateral and bilateral primary aldosteronism