Aldosterone Receptor Blockade Research Articles

Approach to the Patient: Reninoma.

A reninoma is a functional tumor of afferent arteriolar juxtaglomerular cells that secretes the enzyme renin, leading to hyperactivation of the renin-angiotensin-aldosterone system. Reninoma is a potentially curable cause of pathological secondary hyperaldosteronism that results in often severe hypertension and hypokalemia. The lack of suppression of plasma renin contrasts sharply with the much more common primary aldosteronism, but diagnosis is often prompted by screening for that condition. The major differential diagnosis of reninoma is renovascular hypertension. Fewer than 200 cases of reninoma have been described. Reninomas have been reported across a broad demographic but have a 2:1 predilection for women, often of childbearing age. Aldosterone receptor blockade, angiotensin-converting enzyme inhibitors, or angiotensin receptor blockers offer effective medical management but are contraindicated in pregnancy, so surgical curative resection is ideal. The current optimal imaging and biochemical workup of reninoma and management approach (ideally, tumor excision with subtotal renal resection) are described.

NR3C2 genotype is associated with response to spironolactone in diastolic heart failure patients from the Aldo-DHF trial.

This study aimed to determine if variants in NR3C2, which codes the target protein of spironolactone, or CYP11B2, which is involved in aldosterone synthesis, were associated with spironolactone response, focused on the primary end point of diastolic function (E/e'), in Aldosterone Receptor Blockade in Diastolic Heart Failure (Aldo-DHF) participants. Post-hoc genetic analysis. Data and samples were derived from the multi-center, randomized, double-blind, placebo-controlled Aldo-DHF trial. Aldo-DHF participants treated with spironolactone (n=184) or placebo (n=178) were included. Participants were genotyped for NR3C2 rs5522, NR3C2 rs2070951 and CYP11B2 rs1799998 via pyrosequencing. In the placebo and spironolactone arms, separate multivariable linear regression analyses were performed for change in E/e' with each single nucleotide polymorphism (SNP), adjusted for age, sex, and baseline E/e'. To discern potential mechanisms of a genotype effect, associated SNPs were further examined for their association with change in blood pressure, circulating procollagen type III N-terminal peptide (PIIINP), and left atrial area. Carriers of the rs5522 G allele in the placebo arm had a greater increase in E/e' over the 12-month course of the trial compared to noncarriers (β=1.10; 95% confidence interval [CI]: 0.05-2.16; p=0.04). No corresponding E/e' worsening by rs5522 genotype was observed in the spironolactone arm. None of the other genotypes were associated with change in E/e'. Compared to noncarriers, rs5522 G carriers also had a greater increase in left atrial area with placebo (β=0.83; 95% CI: 0.17-1.48; p=0.01) and a greater reduction in diastolic blood pressure with spironolactone (β=-3.56; 95% CI: -6.73 to -0.39; p=0.03). Serum PIIINP levels were similar across rs5522 genotypes. Our results suggest that spironolactone attenuates progression of diastolic dysfunction associated with the NR3C2 rs5522 G allele. Validation of our findings is needed.

Differential restoration of functional hyperemia by antihypertensive drug classes in hypertension-related cerebral small vessel disease.

Dementia resulting from small vessel diseases (SVDs) of the brain is an emerging epidemic for which there is no treatment. Hypertension is the major risk factor for SVDs, but how hypertension damages the brain microcirculation is unclear. Here, we show that chronic hypertension in a mouse model progressively disrupts on-demand delivery of blood to metabolically active areas of the brain (functional hyperemia) through diminished activity of the capillary endothelial cell inward-rectifier potassium channel, Kir2.1. Despite similar efficacy in reducing blood pressure, amlodipine, a voltage-dependent calcium-channel blocker, prevented hypertension-related damage to functional hyperemia whereas losartan, an angiotensin II type 1 receptor blocker, did not. We attribute this drug class effect to losartan-induced aldosterone breakthrough, a phenomenon triggered by pharmacological interruption of the renin-angiotensin pathway leading to elevated plasma aldosterone levels. This hypothesis is supported by the finding that combining losartan with the aldosterone receptor antagonist eplerenone prevented the hypertension-related decline in functional hyperemia. Collectively, these data suggest Kir2.1 as a possible therapeutic target in vascular dementia and indicate that concurrent mineralocorticoid aldosterone receptor blockade may aid in protecting against late-life cognitive decline in hypertensive patients treated with angiotensin II type 1 receptor blockers.

Determinants of renal oxygen metabolism during low Na+ diet: effect of angiotensin II AT1 and aldosterone receptor blockade

Reducing Na+ intake reduces the partial pressure of oxygen in the renal cortex and activates the renin-angiotensin-aldosterone system. In the absence of high blood pressure, these consequences of dietary Na+ reduction may be detrimental for the kidney. In a normotensive animal experimental model, reducing Na+ intake for 2weeks increased renal oxygen consumption, which was normalized by mineralocorticoid receptor blockade. Furthermore, blockade of the angiotensin II AT1 receptor restored cortical partial pressure of oxygen by improving oxygen delivery. This shows that increased activity of the renin-angiotensin-aldosterone system contributes to increased oxygen metabolism in the kidney after 2weeks of a low Na+ diet. The results provide insights into dietary Na+ restriction in the absence of high blood pressure, and its consequences for the kidney. Reduced Na+ intake reduces the (partial pressure of oxygen) in the renal cortex. Upon reduced Na+ intake, reabsorption along the nephron is adjusted with activation of the renin-angiotensin-aldosterone system (RAAS). Thus, we studied the effect of reduced Na+ intake on renal oxygen homeostasis and function in rats, and the impact of intrarenal angiotensin II AT1 receptor blockade using candesartan and mineralocorticoid receptor blockade using canrenoic acid potassium salt (CAP). Male Sprague-Dawley rats were fed standard rat chow containing normal (0.25%) and low (0.025%) Na+ for 2weeks. The animals were anaesthetized (thiobutabarbital 120mgkg-1 ) and surgically prepared for kidney oxygen metabolism and function studies before and after acute intrarenal arterial infusion of candesartan (4.2μgkg-1 ) or intravenous infusion of CAP (20mgkg-1 ). Baseline mean arterial pressure and renal blood flow were similar in both dietary groups. Fractional Na+ excretion and cortical oxygen tension were lower and renal oxygen consumption was higher in low Na+ groups. Neither candesartan nor CAP affected arterial pressure. Renal blood flow and cortical oxygen tension increased in both groups after candesartan in the low Na+ group. Fractional Na+ excretion was increased and oxygen consumption reduced in the low Na+ group after CAP. These results suggest that blockade of angiotensin II AT1 receptors has a major impact upon oxygen delivery during normal and low Na+ conditions, while aldosterone receptors mainly affect oxygen metabolism following 2weeks of a low Na+ diet.

Economic impact of heart failure with preserved ejection fraction: insights from the ALDO-DHF trial.

AimsAlthough heart failure (HF) with preserved ejection fraction (HFpEF) is a leading cause for hospitalization, its overall costs remain unclear.Therefore, we assessed the health care‐related costs of ambulatory HFpEF patients and the effect of spironolactone.Methods and resultsThe aldosterone receptor blockade in diastolic HF trial is a multicentre, prospective, randomized, double‐blind, placebo‐controlled trial conducted between March 2007 and April 2011 at 10 sites in Germany and Austria that included 422 ambulatory patients [mean age: 67 years (standard deviation: 8); 52% women]. All subjects suffered from chronic New York Heart Association (NYHA) class II or III HF and preserved left ventricular ejection fraction of 50% or greater. They also showed evidence of diastolic dysfunction.Patients were randomly assigned to receive 25 mg of spironolactone once daily (n = 213) or matching placebo (n = 209) with 12 months of follow‐up. We used a single‐patient approach to explore the resulting general cost structure and included medication, number of general practitioner and cardiologist visits, and hospitalization in both acute and rehabilitative care facilities.The average annual costs per patient in this cohort came up to €1, 118 (±2,475), and the median costs were €332. We confirmed that the main cost factor was hospitalization and spironolactone did not affect the overall costs. We identified higher HF functional class (NYHA), male patients with low haemoglobin level, with high oxygen uptake (VO2max) and coronary artery disease, hyperlipidaemia, and atrial fibrillation as independent predictors for higher costs.ConclusionsIn this relatively young, oligosymptomatic, and with regard to the protocol without major comorbidities patient cohort, the overall costs are lower than expected compared with the HFrEF population. Further investigation is needed to investigate the impact of, for example, comorbidities and their effect over a longer period of time. Simultaneously, this analysis suggests that prevention of comorbidities are necessary to reduce costs in the health care system.

OPTIMIZATION OF ACUTE MYOCARDITIS TREATMENT

Aim. This paper is aimed at investigating the possibility of preventing an adverse outcome of acute viral myocarditis by means of optimal pharmacotherapy without the use of surgical treatment methods.Results. We describe a clinical case of acute viral myocarditis in a 60-year old female patient. According to the conducted echocardioscopy, the dilatation of the heart cavities and the complete insufficiency of the mitral and tricuspid valves were identified. A cumulative effect of the chosen optimal pharmacotherapy, which included an angiotensin converting enzyme inhibitor, a beta-blocker, a mineralocorticoid receptor antagonist and a loopback diuretic with neurohumoral properties taken in optimal doses, allowed congestion signs to be rapidly eliminated, a reverse remodeling of the heart to be achieved and the heart size to be returned normal values. The double blockade of aldosterone receptors using eplerenone and torasemide prevented both the development of fibrosis in the myocardium and the formation of irreversible dilated cardiomyopathy.Conclusion. The application of antiviral and immunomodulatory therapy, along with the maximum possible doses of drugs used to treat chronic heart failure, allowed the patient’s cardiohemodynamic parameters to be returned to normal values. A timely combination therapy should be used to avoid the formation of dilated cardiomyopathy, thus improving the prognosis of the disease.

Preoperative aldosterone receptor blockade and outcomes of cardiac surgery in patients with chronic kidney disease .

Recent clinical evidence demonstrates that chronic low-dose mineralocorticoid receptor antagonists (MRA), when added to optimal treatment, result in reductions in cardiovascular mortality. However, continuation of MRAs before cardiac surgery in patients with CKD has never been evaluated and its potential benefit or harm in this specific clinical setting is largely unknown. This is an observational study that included adult CKD patients undergoing cardiac surgery. Patients were divided into two groups according to preoperative use of spironolactone (SPL). The studied outcomes were postoperative acute kidney injury (AKI) requiring dialysis, mortality, and major morbidities (cardiovascular, neurologic, and infectious). Data on 698 patients with preoperative CKD stage III and IV were analyzed: 99 received SPL preoperatively and 599 did not. At baseline, patients on SPL had higher EuroScore and had more complicated surgery. No significant differences in the incidence of postoperative AKI, myocardial infarction (MI), cardiovascular accident (CVA), sepsis, and mortality were detected between groups in both univariate and multivariate analyses. However, incidence of postoperative low cardiac output state (p<0.008) was significantly higher in the SPL group. Propensity score matching analyses yielded similar results. Although SPL is usually administered to significantly sicker patients, its use is not associated with increased major postoperative complications. However, the modulating effect of SPL in this clinical study remains to be elucidated in a prospective randomized trial. .

Influence of diuretics with antialdosterone effect on the condition of extracellular matrix and early postinfarction remodeling of the left ventricle in patients with Q-wave myocardial infarction

Objective. Aldosterone receptor blockade regulate activity of matrix metalloproteinase system, increase survival in postinfarction period. Methods and results. In order to study the influence of aldosterone receptor blockade on the serum level of collagen of I and III types, condition of MMP/TIMP system, early postinfarction remodeling of the left ventricle after Q-wave myocardial infarction was studied in 89 patients. The next methods were used: immunoassay analysis of the serum levels of matrix metalloproteinase and its inhibitor, echocardiography. Also systolic and diastolic heart functions were assessed. Conclusion. Under the influence of the treatment it was showed that the intensity of the degradation of connective tissue matrix of the myocardium reduced, and was accompanied by improvement of the left ventricular systolic and diastolic function.

Sodium renders endothelial cells sticky for red blood cells.

Negative charges in the glycocalyx of red blood cells (RBC) and vascular endothelial cells (EC) facilitate frictionless blood flow through blood vessels. Na+ selectively shields these charges controlling surface electronegativity. The question was addressed whether the ambient Na+ concentration controls RBC-EC interaction. Using atomic force microscopy (AFM) adhesion forces between RBC and endothelial glycocalyx were quantified. A single RBC, mounted on an AFM cantilever, was brought in physical contact with the endothelial surface and then pulled off. Adhesion forces were quantified (i) after enzymatic removal of negative charges in the glycocalyx, (ii) under different ambient Na+ and (iii) after applying the intracellular aldosterone receptor antagonist spironolactone. Removal of negative surface charges increases RBC-EC interaction forces. A stepwise increase of ambient Na+ from 133 to 140 mM does not affect them. However, beyond 140 mM Na+ adhesion forces increase sharply (10% increase of adhesion force per 1 mM increase of Na+). Spironolactone prevents this response. It is concluded that negative charges reduce adhesion between RBC and EC. Ambient Na+ concentration determines the availability of free negative charges. Na+ concentrations in the low physiological range (below 140 mM) allow sufficient amounts of vacant negative charges so that adhesion of RBC to the endothelial surface is small. In contrast, Na+ in the high physiological range (beyond 140 mM) saturates the remaining negative surface charges thus increasing adhesion. Aldosterone receptor blockade by spironolactone prevents Na+ induced RBC adhesion to the endothelial glycocalyx. Extrapolation of in vitro experiments to in vivo conditions leads to the hypothesis that high sodium intake is likely to increase the incidence of thrombotic events.

Diastolische Herzinsuffizienz

Heart failure with preserved ejection fraction (i.e. diastolic heart failure) accounts for about half of heart failure cases. The aim of this review is to reflect current knowledge regarding the epidemiology, pathophysiology and treatment. Diastolic heart failure patients are principally elderly and predominantly female. Numerous pathophysiological alterations in this disease have been shown and recent therapeutic recommendations include control of cardiovascular risk factors and symptoms. New therapeutic options, such as inhibition of late sodium current, aldosterone receptor blockade, combined inhibition of AT1 receptor and the enzyme neprilysin, and phosphodiesterase 5 inhibition are discussed in this review and ongoing clinical trials are also briefly presented. Diastolic heart failure remains a cardiac disease which is difficult to treat; however, new study results allow a better definition of a population of patients who could benefit from specific therapies.

Aldosterone and Volume Management in Hypertensive Heart Disease

Aldosterone-receptor antagonists dose-dependently reduce both the epithelial and nonepithelial actions of aldosterone. These compounds are used commonly in the treatment of hypertension, with or without aldosteronism, and in the volume-overload periods of various forms of heart failure, cirrhosis, and renal failure. In this regard, the relevant site of action for these compounds is compartmentalized to the distal nephron. The cardiac benefits of aldosterone-receptor blockade now are sufficiently well established to warrant routine use of these compounds for their survival benefits in moderate to advanced stages of heart failure. Aldosterone-receptor antagonists spironolactone and eplerenone commonly are used in the treatment of resistant forms of hypertension. Spironolactone, but not eplerenone, is a commonly used add-on diuretic that provides incremental benefit for salt-and-water excretion in excess of what may be seen with a loop diuretic given together with a thiazide-type diuretic. The dose-response relationship for natriuresis with spironolactone has not been explored completely as to its combination therapy responses. The quite high doses of spironolactone used in patients with cirrhosis and ascites would infer that the overall treatment effect with this compound exceeds simple receptor blockade and may include a nervous system effect that operationally reduces renal sympathetic nerve traffic. The adverse electrolyte and renal function side effects with aldosterone-receptor antagonists are not uncommon in at-risk patients, such as those with chronic kidney disease, and require that dosing be mindful of the tendency of these drugs to importantly increase serum potassium levels.

Aldosterone inhibition and coronary endothelial function in women without obstructive coronary artery disease: An ancillary study of the National Heart, Lung, and Blood Institute–sponsored Women's Ischemia Syndrome Evaluation

Endothelial dysfunction is highly prevalent and associated with adverse outcomes among patients without obstructive coronary artery disease (CAD). Angiotensin II inhibition may improve endothelial function, but with continued treatment, "aldosterone escape" may occur. Thus, it is unknown if adding aldosterone blockade further improves endothelial function. In a double-blind, parallel-group, repeated-measures study, women with symptoms and signs of ischemia, no significant CAD, and coronary endothelial dysfunction receiving an angiotensin-converting enzyme inhibitor or receptor blocker were randomized to aldosterone blockade or placebo. The primary outcome at 16 weeks was percent change in coronary diameter to acetylcholine, and secondary outcome, coronary flow reserve to adenosine, both adjusted for baseline reactivity. Forty-one women completed the treatment period with repeat coronary reactivity testing. Their mean age was 54 ± 10 years; body mass index, 30 ± 7.4 kg/m2; 12% had diabetes; and 15% had metabolic syndrome. There were no significant differences between treatment groups. At baseline, the percent change in reference vessel coronary diameter to acetylcholine was -5.0% in the aldosterone blockade group and -3.4% in the placebo group and, at 16 weeks, -7.2% in the aldosterone blockade group versus -14.3% in the placebo group (P = .15). At 16 weeks, the change in coronary flow reserve to intracoronary adenosine was -0.13 in the aldosterone blockade group versus -0.25 in the placebo group (P = .66). Adding aldosterone receptor blockade to angiotensin II inhibition did not improve coronary endothelial or microvascular function among women with signs and symptoms of ischemia in the setting of nonobstructive CAD.

Spironolactone Reduces Cardiovascular and Cerebrovascular Morbidity and Mortality in Hemodialysis Patients

This study sought to assess whether spironolactone treatment reduces the high incidence of cardiovascular and cerebrovascular (CCV) morbidity and mortality in hemodialysis (HD) patients. Aldosterone receptor blockers reduce cardiac-related events, but the efficacy of the agents in HD patients is unclear. A 3-year randomized trial involving 5 clinics was performed. Of the 309 oligoanuric HD patients enrolled in the study, 157 patients were randomly assigned to receive 25 mg/day of spironolactone without any restriction on dietary potassium intake (treatment group), and 152 patients were assigned to a control group. The primary outcome was a composite of death from CCV events or hospitalization for CCV events, and the secondary outcome was death from all causes. During the 3-year follow-up, the primary outcome occurred in 5.7% of patients in the treatment group and in 12.5% of patients in the control group. Hazard ratios (HRs) for the primary outcome for treatment were 0.404 (95% confidence interval [CI]: 0.202 to 0.809; p = 0.017) and 0.379 (95% CI: 0.173 to 0.832; p = 0.016) before and after adjustment, respectively. The secondary outcome was significantly reduced in the treatment group compared with the control group (6.4% vs. 19.7%; HRs: 0.355 [95% CI: 0.191 to 0.662; p = 0.002] and 0.335 [95% CI: 0.162 to 0.693; p = 0.003] before and after adjustment, respectively). Gynecomastia or breast pain was reported in 16 patients (10.2%) in the treatment group. Serious hyperkalemia led to treatment discontinuation in 3 patients (1.9%). Aldosterone receptor blockade using spironolactone may substantially reduce the risk of both CCV morbidity and death among HD patients; however, larger-scale studies are recommended to further confirm its efficacy. (Effects of Spironolactone on Cardio- and Cerebrovascular Morbidity and Mortality in Hemodialysis Patients; NCT01687699).

Abstract 67: Anti-aging Gene Klotho Deficiency Causes Hypertension Via Upregulation of CYP11B2 Expression and Aldosterone Synthesis

Background - Klotho (KL) is a recently discovered anti-aging gene. Genetic mutation of KL expedites the aging process and shortens lifespan while overexpression of KL slows down the aging process and extends lifespan. The purpose of this experiment is to assess if KL deficiency affects blood pressure (BP). Methods &amp; Results - KL mutant heterozygeous (+/-) mice showed significant and persistent elevation of BP, demonstrating for the first time that half klotho deficiency causes hypertension. It is noticed that plasma level of aldosterone was elevated and that protein expression of CYP11B2 (key enzyme of aldosterone synthesis) in adrenal cortex was increased in KL(+/-) mice, indicating that KL deficiency upregulates aldosterone synthesis. Blockade of aldosterone receptors by eplerenone (6 mg/kg/day) decreased hypertension of KL(+/-) mice to the control level within one week, suggesting that upregulation of aldosterone levels may play a critical role in KL deficiency-induced hypertension. Indeed, the aldosterone signaling (SGK1, NCC and ATP-β) were increased in kidneys of KL(+/-) mice. In addition, half KL deficiency increased renal inflammation as evidenced by upregulated inflammatory factors (IL-6, TNFα, osteopontin and MCP-1) and increased infiltration of T cells and macrophages in kidneys of KL(+/-) mice. Half KL deficiency led to renal functional impairment (increased plasma creatinine and urea and urine albumin) and structural damage (glomerulus collapse, tubule fibrosis). Blockade of aldosterone receptors attenuated KL deficiency-induced renal inflammation and damage. Conclusions - KL is essential to the maintenance of normal BP. KL deficiency caused hypertension and kidney damage via upregulating aldosterone levels and consequently increasing inflammation and SGK1 and NCC signaling in kidneys.

Effect of Spironolactone on Diastolic Function and Exercise Capacity in Patients With Heart Failure With Preserved Ejection Fraction

Diastolic heart failure (ie, heart failure with preserved ejection fraction) is a common condition without established therapy, and aldosterone stimulation may contribute to its progression. To assess the efficacy and safety of long-term aldosterone receptor blockade in heart failure with preserved ejection fraction. The primary objective was to determine whether spironolactone is superior to placebo in improving diastolic function and maximal exercise capacity in patients with heart failure with preserved ejection fraction. The Aldo-DHF trial, a multicenter, prospective, randomized, double-blind, placebo-controlled trial conducted between March 2007 and April 2012 at 10 sites in Germany and Austria that included 422 ambulatory patients (mean age, 67 [SD, 8] years; 52% female) with chronic New York Heart Association class II or III heart failure, preserved left ventricular ejection fraction of 50% or greater, and evidence of diastolic dysfunction. Patients were randomly assigned to receive 25 mg of spironolactone once daily (n=213) or matching placebo (n=209) with 12 months of follow-up. The equally ranked co-primary end points were changes in diastolic function (E/e') on echocardiography and maximal exercise capacity (peak VO2) on cardiopulmonary exercise testing, both measured at 12 months. Diastolic function (E/e') decreased from 12.7 (SD, 3.6) to 12.1 (SD, 3.7) with spironolactone and increased from 12.8 (SD, 4.4) to 13.6 (SD, 4.3) with placebo (adjusted mean difference, -1.5; 95% CI, -2.0 to -0.9; P < .001). Peak VO2 did not significantly change with spironolactone vs placebo (from 16.3 [SD, 3.6] mL/min/kg to 16.8 [SD, 4.6] mL/min/kg and from 16.4 [SD, 3.5] mL/min/kg to 16.9 [SD, 4.4] mL/min/kg, respectively; adjusted mean difference, +0.1 mL/min/kg; 95% CI, -0.6 to +0.8 mL/min/kg; P = .81). Spironolactone induced reverse remodeling (left ventricular mass index declined; difference, -6 g/m2; 95% CI, -10 to-1 g/m2; P = .009) and improved neuroendocrine activation (N-terminal pro-brain-type natriuretic peptide geometric mean ratio, 0.86; 95% CI, 0.75-0.99; P = .03) but did not improve heart failure symptoms or quality of life and slightly reduced 6-minute walking distance (-15 m; 95% CI, -27 to -2 m; P = .03). Spironolactone also modestly increased serum potassium levels (+0.2 mmol/L; 95% CI, +0.1 to +0.3; P < .001) and decreased estimated glomerular filtration rate (-5 mL/min/1.73 m2; 95% CI, -8 to -3 mL/min/1.73 m2; P < .001) without affecting hospitalizations. In this randomized controlled trial, long-term aldosterone receptor blockade improved left ventricular diastolic function but did not affect maximal exercise capacity, patient symptoms, or quality of life in patients with heart failure with preserved ejection fraction. Whether the improved left ventricular function observed in the Aldo-DHF trial is of clinical significance requires further investigation in larger populations. clinicaltrials.gov Identifier: ISRCTN94726526; Eudra-CT No: 2006-002605-31.

Echocardiographic effects of eplerenone and aldosterone in hypertensive rats

The effects of aldosterone receptor blockade on echocardiography in spontaneously hypertensive rats (SHR) are not fully characterized. In this study, multiple echocardiographic parameters were compared for 42 weeks between SHR versus Wistar-Kyoto rats (WKY) serving as normotensive controls. In addition, echocardiographic parameters were compared for 28 weeks between the SHR versus SHR treated with eplerenone 100 mg/kg/day or spironolactone 50 mg/kg/day. Compared to normotensive WKY rats, SHRs had significantly increased systolic blood pressure, increased cardiac mass, increased isovolumic relaxation time (IVRT), decreased E/A ratio, increased mitral closure opening time interval (MCO) and increased Tei index. Both eplerenone and spironolactone significantly decreased systolic blood pressure compared to the SHR controls. The spironolactone treatment group demonstrated significant increases in heart rate and cardiac output and a decrease in cardiac index compared to SHR controls. Any aldosterone blockade in SHR protected against the increased cardiac mass. Similar to clinical echocardiographic observations, hypertension in rats results in left ventricular hypertrophy (LVH) and diastolic dysfunction and aldosterone receptor blockade reduces LVH in SHR.

Study of Aldosterone Synthase Inhibition as an Add‐On Therapy in Resistant Hypertension

Aldosterone inhibition with mineralcorticoid receptor antagonists (MRAs) is an effective treatment for resistant hypertension. Aldosterone synthase inhibitors (ASIs) are currently being investigated as a new therapeutic strategy to reduce aldosterone secretion from the adrenal gland. In this study, the efficacy and safety of the first-generation ASI LCI699 (0.25 mg twice daily, 1 mg 4 once daily, and 0.5 mg/1 mg twice daily) was compared with placebo and eplerenone (50 mg twice daily), in patients with resistant hypertension. Placebo-adjusted decreases in systolic blood pressure (BP) with LCI699 ranged from 2.6 mm Hg to 4.3 mm Hg at week 8; changes in diastolic BP ranged from +0.3 mm Hg to -1.2 mm Hg. However, reductions were smaller than observed with eplerenone 50 mg twice daily (9.9 mm Hg and 2.9 mm Hg for systolic and diastolic BP, respectively) and not statistically significant vs placebo. LCI699 suppressed plasma aldosterone levels in a dose-related manner with corresponding dose-dependent increases in plasma renin activity and plasma 11-deoxycorticosterone. LCI699 and eplerenone were well tolerated. These data demonstrate that aldosterone synthesis inhibition with LCI699 lowers BP modestly in patients with resistant hypertension. Aldosterone synthesis inhibition might offer an attractive adjunct to aldosterone receptor blockade, although the potential of a combination MRA/ASI has not yet been tested.

ALDO-DHF &amp; PARAMOUNT

[first paragraph of article] Results of the ALDOsterone receptor blockade in Diastolic Heart Failure (ALDO-DHF) were recently presented at the European Society of Cardiology (ESC) meeting in Munich . The multicenter, double-blind randomized, placebo-controlled phase IIb mechanistic study was conducted to test the hypothesis that 12 months treatment with spironolactone would improve cardiac function and structure as well as exercise capacity and quality of life in patients with heart failure with preserved ejection fraction (HFpEF). HFpEF continues to be a challenging form of heart failure – one in which no therapy has yet been proven to improve outcome and with a prevalence that continues to rise at an alarming rate. An extensive review on HFpEF – including various drugs in current use as well as those under trial – was published in the last issue of the journal.

Spironolactone diminishes urinary albumin excretion in patients with type 1 diabetes and microalbuminuria: a randomized placebo‐controlled crossover study

Adding aldosterone receptor blockade to standard renoprotective treatment may provide additional renoprotection in patients with overt nephropathy. We expected an impact of spironolactone in early diabetic nephropathy, and for this hypothesis we studied the effect on markers of glomerular and tubular damage in patients with Type 1 diabetes and persistent microalbuminuria. A double-blind, randomized, placebo-controlled crossover study in 21 patients with Type 1 diabetes and microalbuminuria using spironolactone 25 mg or placebo once daily, for 60 days added to standard antihypertensive treatment. After each treatment period, the primary endpoint were evaluated: urinary(u)-albumin excretion/24 hour(h) and secondary endpoints; 24 h blood pressure, glomerular filtration rate (GFR) and markers of tubular damage: urinary liver-type fatty-acid binding protein (LFABP), neutrophil gelatinase associated lipocalin (NGAL) and kidney injury molecule 1 (KIM1). All patients completed the study. During spironolactone treatment, urinary albumin excretion rate was reduced by 60% (range 21-80%), from 90 mg/24 h to 35 mg/24 h (P=0.01). Blood pressure (24 h) did not change during spironolactone treatment (P>0.2 for all comparisons). The GFR (SD) decreased from 78 (6) mL/min/1.73 m(2) to 72 (6) mL/min/1.73 m(2) (P=0.003). Urinary liver-type fatty-acid binding protein, neutrophil gelatinase-associated lipocalin and kidney injury molecule 1 did not change during treatment (P>0.3 for all comparisons). Treatment was well-tolerated, but two patients had severe hyperkalaemia (plasma potassium = 5.7 mmol/l), which was sufficiently treated with diuretics and dietary intervention. Spironolactone treatment in addition to standard renoprotective treatment lowers urinary albumin excretion in microalbuminuric patients with Type 1 diabetes, and thus may offer additional renoprotection independent of blood pressure.

Abstract 9191: MicroRNA-150 is Essential in the Regulation of Blood Pressure

Background &amp; Hypothesis. Micro RNAs are small noncoding RNAs that regulate protein expression at the post-transcriptional level. The purpose of this study was to determine if microRNA-150 (miR-150) plays a role in the regulation of blood pressure (BP). Methods &amp; Results. We found that knockout of miR-150 resulted in a significant increase in systolic, diastolic and mean BP in mice. Vascular relaxing responses to acetylcholine were decreased significantly in miR-150 knockout (miR150-KO) mice, suggesting impaired endothelial function. Therefore, miR-150 is essential in the maintenance of normal BP and endothelial function. MiR150-KO was accompanied by a significant increase in NADPH oxidase activity and superoxide production in aortas and kidneys. MiR150-KO mice demonstrated vascular and renal remodeling. Interestingly, miR150-KO significantly increased Cyp11β2 protein expression in adrenal cortex, suggesting that miR-150 is a negative regulator of Cyp11β2. Plasma level of aldosterone was elevated in the miR150-KO mice. It was noted that daily treatment with aldosterone receptor blockade eplerenone (EPL) effectively reversed hypertension, endothelial dysfunction, increases in NADPH oxidase activity and superoxide production, and vascular and renal damage in miR150-KO mice. Conclusions. These results suggest that miR150-KO-inudced hypertension may be mediated by the upregulation of Cyp11β2 expression which led to increased biosynthesis of aldosterone. It is concluded that miR-150 is a critical regulator of Cyp11β2 in the control of BP. MiR-150 may be a novel therapeutic target for hypertension. (Supported by NIH R01 HL105362).