Sex differences in arterial hypertension.

There is strong evidence that sex chromosomes and sex hormones influence blood pressure (BP) regulation, distribution of cardiovascular (CV) risk factors and co-morbidities differentially in females and males with essential arterial hypertension. The risk for CV disease increases at a lower BP level in females than in males, suggesting that sex-specific thresholds for diagnosis of hypertension may be reasonable. However, due to paucity of data, in particularly from specifically designed clinical trials, it is not yet known whether hypertension should be differently managed in females and males, including treatment goals and choice and dosages of antihypertensive drugs. Accordingly, this consensus document was conceived to provide a comprehensive overview of current knowledge on sex differences in essential hypertension including BP development over the life course, development of hypertension, pathophysiologic mechanisms regulating BP, interaction of BP with CV risk factors and co-morbidities, hypertension-mediated organ damage in the heart and the arteries, impact on incident CV disease, and differences in the effect of antihypertensive treatment. The consensus document also highlights areas where focused research is needed to advance sex-specific prevention and management of hypertension

The Kidneys and Aldosterone/Mineralocorticoid Receptor System in Salt-Sensitive Hypertension

Strong evidence supports the ability of the aldosterone/mineralocorticoid receptor (MR) system to dominate long-term blood pressure control. It is also increasingly recognized as an important mediator of cardiovascular and renal diseases, particularly in the presence of excessive salt intake. In a subgroup of individuals with metabolic syndrome, adipocyte-derived aldosterone-releasing factors cause inappropriate secretion of aldosterone in the adrenal glands during salt loading, resulting in the development of salt-induced hypertension and cardiac and renal damage. On the other hand, emerging data reveal that aldosterone is not a sole regulator of MR activity. We have identified the signaling crosstalk between MR and small GTPase Rac1 as a novel pathway to facilitate MR signaling. Such a local control system for MR can also be relevant to the pathogenesis of salt-sensitive hypertension, and future studies will clarify the detailed mechanism for the intricate regulation of the aldosterone/MR cascade

Oxidative damages in tubular epithelial cells in IgA nephropathy: role of crosstalk between angiotensin II and aldosterone

<p>Abstract</p> <p>Background</p> <p>Inhibition of the renin-angiotensin-aldosterone system (RAAS) slows down the progression of chronic renal diseases (CKD) including IgA nephropathy (IgAN). Herein, we studied the pathogenetic roles of aldosterone (Aldo) in IgAN.</p> <p>Methods</p> <p>Human mesangial cells (HMC) was activated with polymeric IgA (pIgA) from IgAN patients and the effects on the expression of RAAS components and TGF-β synthesis examined. To study the roles of RAAS in the glomerulotubular communication, proximal tubular epithelial cells (PTEC) was cultured with conditioned medium from pIgA-activated HMC with eplerenone or PD123319, the associated apoptotic event was measured by the generation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and reactive oxygen species (ROS).</p> <p>Results</p> <p>Polymeric IgA up-regulated the Aldo synthesis and aldosterone synthase expression by HMC. The release of TGF-β by HMC was up-regulated synergistically by AngII and Aldo and this was inhibited by incubation of HMC with losartan plus eplerenone. Cultured PTEC express the mineralocorticoid receptor, but not synthesizing aldosterone. Apoptosis, demonstrated by cleaved PARP expression and caspase 3 activity, was induced in PTEC activated by conditioned medium prepared from HMC cultured with pIgA from IgAN patients. This apoptotic event was associated with increased generation of NADPH oxidase and ROS. Pre-incubation of PTEC with PD123319 and eplerenone achieved complete inhibition of PTEC apoptosis.</p> <p>Conclusions</p> <p>Our data suggest that AngII and Aldo, released by pIgA activated HMC, served as mediators for inducing apoptosis of PTEC in glomerulo-tubular communications. Crosstalk between AngII and Aldo could participate in determining the tubular pathology of IgAN.</p

Effect of eplerenone on parathyroid hormone levels in patients with primary hyperparathyroidism: a randomized, double-blind, placebo-controlled trial

<p>Abstract</p> <p>Background</p> <p>Increasing evidence suggests the bidirectional interplay between parathyroid hormone and aldosterone as an important mechanism behind the increased risk of cardiovascular damage and bone disease observed in primary hyperparathyroidism. Our primary object is to assess the efficacy of the mineralocorticoid receptor-blocker eplerenone to reduce parathyroid hormone secretion in patients with parathyroid hormone excess.</p> <p>Methods/design</p> <p>Overall, 110 adult male and female patients with primary hyperparathyroidism will be randomly assigned to eplerenone (25 mg once daily for 4 weeks and 4 weeks with 50 mg once daily after dose titration] or placebo, over eight weeks. Each participant will undergo detailed clinical assessment, including anthropometric evaluation, 24-h ambulatory arterial blood pressure monitoring, echocardiography, kidney function and detailed laboratory determination of biomarkers of bone metabolism and cardiovascular disease.</p> <p>The study comprises the following exploratory endpoints: mean change from baseline to week eight in (1) parathyroid hormone(1–84) as the primary endpoint and (2) 24-h systolic and diastolic ambulatory blood pressure levels, NT-pro-BNP, biomarkers of bone metabolism, 24-h urinary protein/albumin excretion and echocardiographic parameters reflecting systolic and diastolic function as well as cardiac dimensions, as secondary endpoints.</p> <p>Discussion</p> <p>In view of the reciprocal interaction between aldosterone and parathyroid hormone and the potentially ensuing target organ damage, the EPATH trial is designed to determine whether eplerenone, compared to placebo, will effectively impact on parathyroid hormone secretion and improve cardiovascular, renal and bone health in patients with primary hyperparathyroidism.</p> <p>Trial registration</p> <p>ISRCTN33941607</p

Why are mineralocorticoid receptor antagonists cardioprotective?

Two clinical trials, the Randomized ALdosterone Evaluation Study (RALES) and the EPlerenone HEart failure and SUrvival Study (EPHESUS), have recently shown that mineralocorticoid receptor (MR) antagonists reduce mortality in patients with heart failure on top of ACE inhibition. This effect could not be attributed solely to blockade of the renal MR-mediated effects on blood pressure, and it has therefore been proposed that aldosterone, the endogenous MR agonist, also acts extrarenally, in particular in the heart. Indeed, MR are present in cardiac tissue, and possibly aldosterone synthesis occurs in the heart. This review critically addresses the following questions: (1) is aldosterone synthesized at cardiac tissue sites, (2) what agonist stimulates cardiac MR normally, and (3) what effects are mediated by aldosterone/MR in the heart that could explain the beneficial effects of MR blockade in heart failure? Conclusions are that most, if not all, of cardiac aldosterone originates in the circulation (i.e., is of adrenal origin), and that glucocorticoids, in addition to aldosterone, may serve as the endogenous agonist of cardiac MR. MR-mediated effects in the heart include effects on endothelial function, cardiac fibrosis and hypertrophy, oxidative stress, cardiac inotropy, coronary flow, and arrhythmias. Some of these effects occur via or in synergy with angiotensin II, and involve a non-MR-mediated mechanism. This raises the possibility that aldosterone synthase inhibitors might exert beneficial effects on top of MR blockade

Haemodynamic changes during early bereavement: potential contribution to increased cardiovascular risk.

BACKGROUND: bereavement is associated with increased cardiovascular risk, particularly in surviving spouses and parents, however the mechanism is not well understood due to limited studies. The purpose of this study was to evaluate haemodynamic changes (blood pressure (BP) and heart rate (HR)), that may contribute to increased cardiac risk in early bereavement. METHODS: we enrolled 80 bereaved individuals and 80 non-bereaved as a reference group. Twenty-four hour ambulatory blood pressure monitoring was performed within two weeks (acute assessment) and at six months following bereavement. RESULTS: compared to the non-bereaved, the acutely bereaved had higher 24-hour systolic BP (mean (SE) 130.3 (1.5) vs 127.5 (1.4)mmHg, p=0.03), higher daytime systolic BP (135.6 (1.5) vs 131.6 (1.4)mmHg, p=0.02) and higher daytime systolic load (median % 39.0 vs 29.3, p=0.02). By six months the BP of the bereaved tended to be lower than acute measures. This difference was significant amongst those not taking BP lowering medications for 24-hour systolic BP (126.5 (2.4) vs 129.7 (2.3)mmHg, p=0.04), daytime systolic BP (129.8 (2.1) vs 133.9 (2.0)mmHg, p=0.01) and daytime diastolic pressure (76.7 (1.0) vs 78.9 (0.9)mmHg, p=0.03). Twenty-four hour heart rate was also higher acutely in the bereaved compared with the reference group (74.0 (1.2) vs 71.7 (0.9) b/min, p=0.02); at six months heart rate in the bereaved had fallen to non-bereaved levels (70.4 (0.09), p=0.02). CONCLUSION: early bereavement is associated with increased systolic blood pressure and heart rate. These haemodynamic changes may contribute to a time-limited increase in cardiovascular risk

Placebo-controlled biofeedback blood pressure effect in hypertensive humans

The role of biofeedback in blood pressure control remains ill-defined because of nonspecific (placebo) effects, small study numbers, and the technical limitations of continuous pressure feedback. Clarification of its potential is awaited by those seeking a nonpharmacological approach to blood pressure control. This study examines the capability for, systolic pressure lowering of 5 mm Hg or more using continuous pressure feedback in a statistical sample of untreated, well-characterized, mildly hypertensive individuals. Subjects were randomized in a double-blind study to active or placebo biofeedback. Placebo consisted of a modified contingency approach, using a partial disguise based on a digital high pass filter with 15 elements. Blood pressure-lowering capability was assessed during two laboratory sessions. Continuous visual feedback resulted in 11 of 28 subjects on active treatment and 12 of 28 on placebo treatment lowering their systolic pressure by 5 mm Hg or more (11 ± 5.6 and 12± 8.4 mm Hg, respectively; P=NS). Prestudy pressure was well-matched (153±9/97±4 and 154±8/98±4 mm Hg, respectively). An initial small difference in diurnal profile did not change. These findings indicate that among mildly hypertensive individuals, almost half can lower systolic pressure at will for short periods. This capability is independent of the real or placebo nature of the feedback signal. We conclude that there is no specific short-term biofeedback pressure-lowering capability in hypertensive individuals. Further exploration is needed to determine whether specific components of the placebo effect can be delineated, whether personality characteristics influence the response, and whether further biofeedback training can alter the outcome

Effect of early bereavement on heart rate and heart rate variability.

Early bereavement is associated with increased cardiovascular events. The mechanism, however, has not been well studied. We assessed whether bereavement is associated with an increased heart rate (HR) and decreased heart rate variability that might contribute to increased cardiovascular risk. A total of 78 bereaved spouses and parents (55 women and 23 men; aged 34 to 87 years, mean 65) were studied with 24-hour Holter monitoring within 2 weeks of bereavement (acute) and at 6 months. Their findings were compared to those from a nonbereaved reference group (52 women and 27 men) aged 33 to 91 years (mean 63.6). All participants were in sinus rhythm. We assessed the mean HR, atrial and ventricular arrhythmias, and both time and frequency domain heart rate variability measures. Acute bereavement was associated with increased 24-hour HR (mean ± SE, 75.1 ± 1.1 vs 70.7 ± 1.0; p = 0.004) and reduced heart rate variability, as indicated by lower standard deviation of the NN intervals index (median 45.4 vs 49.9, p = 0.017), total power (7.78 ± 0.10 vs 8.02 ± 0.09, p = 0.03), very low frequency (7.23 ± 0.09 vs 7.44, p = 0.046) and low frequency (5.76 ± 0.12 vs 6.16 ± 0.09, p = 0.01). At 6 months, the bereaved had a significantly lower HR (p = 0.001) and increased standard deviation of the NN intervals index (p = 0.02), square root of the mean square of differences of successive intervals (p = 0.045), number of interval differences of successive NN intervals >50 ms divided by the number of NN intervals (p = 0.039), low-frequency power (p = 0.02), and high frequency (p = 0.002) compared to the initial acute levels. In conclusion, the present study, the first to report 24-hour HR monitoring in the early weeks of bereavement, has demonstrated increased HR and altered autonomic function that might contribute to the increased cardiovascular events in early bereavement