Mineralocorticoid Receptor Antagonism Confers Cardioprotection in Heart Failure

Seawell, Michael R.; Darazi, Fahed Al; Farah, Victor; Ramanathan, Kodangudi B.; Newman, Kevin P.; Bhattacharya, Syamal K.; Weber, Karl T.

doi:10.1007/s11897-012-0120-x

Cited by 5 publications

(5 citation statements)

References 103 publications

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“…Recent studies documented a beneficial effect of aldosterone antagonism [50,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98]. In peritoneal dialysis patients, spironolactone treatment showed protective effects on cardiac function [99].…”

Section: Aldosterone and Vascular Calcification In Ckdmentioning

confidence: 99%

Impact of Aldosterone on Osteoinductive Signaling and Vascular Calcification

et al. 2014

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Vascular calcification is frequently found already in early stages of chronic kidney disease (CKD) patients and is associated with high cardiovascular risk. The process of vascular calcification is not considered a passive phenomenon but involves, at least in part, phenotypical transformation of vascular smooth muscle cells (VSMCs). Following exposure to excessive extracellular phosphate concentrations, VSMCs undergo a reprogramming into osteo-/chondroblast-like cells. Such ‘vascular osteoinduction' is characterized by expression of osteogenic transcription factors and triggered by increased phosphate concentrations. A key role in this process is assigned to cellular phosphate transporters, most notably the type III sodium-dependent phosphate transporter Pit1. Pit1 expression is stimulated by mineralocorticoid receptor activation. Therefore, aldosterone participates in the phenotypical transformation of VSMCs. In preclinical models, aldosterone antagonism reduces vascular osteoinduction. Patients with CKD suffer from hyperphosphatemia predisposing to vascular osteogenic transformation, potentially further fostered by concomitant hyperaldosteronism. Clearly, additional research is required to define the role of aldosterone in the regulation of osteogenic signaling and the consecutive vascular calcification in CKD, but more generally also other diseases associated with excessive vascular calcification and even in individuals without overt disease.

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Section: Aldosterone and Vascular Calcification In Ckdmentioning

confidence: 99%

Impact of Aldosterone on Osteoinductive Signaling and Vascular Calcification

et al. 2014

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“…In HF, zinc deficiency may be due to low dietary intake, reduced gastrointestinal absorption, and/or increased excretion as the result of neurohormonal activation [7,[135][136][137]. Metabolic stress may increase cellular uptake of zinc to regulate antioxidant defenses.…”

Section: Zincmentioning

confidence: 99%

“…Metabolic stress may increase cellular uptake of zinc to regulate antioxidant defenses. ACE inhibitors and angiotensin II receptor blockers (ARBs) increase urinary and fecal zinc excretion [137]. Although the prevalence of zinc deficiency in patients with HF is uncertain, serum zinc concentrations have been reported to be lower than those reported as normal values for healthy volunteers (75-140 μg/dl) [44,45,135,138].…”

Section: Zincmentioning

confidence: 99%

Micronutrient deficiencies in heart failure: Mitochondrial dysfunction as a common pathophysiological mechanism?

et al. 2022

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Heart failure is a devastating clinical syndrome, but current therapies are unable to abolish the disease burden. New strategies to treat or prevent heart failure are urgently needed. Over the past decades, a clear relationship has been established between poor cardiac performance and metabolic perturbations, including deficits in substrate uptake and utilization, reduction in mitochondrial oxidative phosphorylation and excessive reactive oxygen species production. Together, these perturbations result in progressive depletion of cardiac adenosine triphosphate (ATP) and cardiac energy deprivation. Increasing the delivery of energy substrates (e.g., fatty acids, glucose, ketones) to the mitochondria will be worthless if the mitochondria are unable to turn these energy substrates into fuel. Micronutrients (including coenzyme Q10, zinc, copper, selenium and iron) are required to efficiently convert macronutrients to ATP. However, up to 50% of patients with heart failure are deficient in one or more micronutrients in cross‐sectional studies. Micronutrient deficiency has a high impact on mitochondrial energy production and should be considered an additional factor in the heart failure equation, moving our view of the failing myocardium away from an “an engine out of fuel” to “a defective engine on a path to self‐destruction.” This summary of evidence suggests that supplementation with micronutrients—preferably as a package rather than singly—might be a potential therapeutic strategy in the treatment of heart failure patients.

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“…In AHF, hypokalemia is more common and is often due to a defect in Na + /K + -ATPase activity and an intracellular potassium shift caused by oxidative stress and neurohormonal activation in combination with loop diuretic use. 25 Spironolactone is rapidly metabolized to several metabolites that produce natriuretic and antikaliuretic effects. 26 While the natriuretic effects decline over a period of 48–72 hours, the antikaliuretic effects may be observed for several days following discontinuation, underscoring the importance of careful monitoring of potassium levels, especially in patients with chronic kidney disease.…”

Section: Risk For Hyperkalemiamentioning

confidence: 99%

Rationale and Design of the ATHENA-HF Trial

Butler

Hernandez

Anstrom

et al. 2016

JACC: Heart Failure

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While therapy with mineralocorticoid receptor antagonists (MRA) is recommended for patients with chronic heart failure (HF) with reduced ejection fraction and in post-infarction HF, it has not been studied well in acute HF (AHF) despite being commonly used in this setting. At high doses, MRA therapy in AHF may relieve congestion through its natriuretic properties and mitigate the effects of adverse neurohormonal activation associated with intravenous loop diuretics. The Aldosterone Targeted Neurohormonal Combined with Natriuresis Therapy in Heart Failure (ATHENA-HF) trial is a randomized, double blind, placebo-controlled study of the safety and efficacy of 100 mg daily spironolactone vs. placebo (or continued low-dose spironolactone use in participants who are already receiving spironolactone at baseline) in 360 patients hospitalized for AHF. Patients are randomized within 24 hours of receiving the first dose of intravenous diuretics. The primary objective is to determine if high-dose spironolactone, when compared to standard care, will lead to greater reductions in N-terminal pro-B-type natriuretic peptide levels from randomization to 96 hours. The secondary endpoints include changes in the clinical congestion score, dyspnea relief, urine output, weight change, loop diuretic dose, and inhospital worsening HF. Index hospital length of stay and 30-day clinical outcomes will be assessed. Safety endpoints Address correspondence to: Javed Butler, MD, MPH, Cardiology Division, Stony Brook University, T-16, Room 080, Stony Brook, NY 11794. Telephone: (631) 444-1066 Fax: (631) 444-1054 javed.butler@stonybrookmedicine.edu. Disclosures: NonePublisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. HHS Public Access Author ManuscriptAuthor Manuscript Author ManuscriptAuthor Manuscript include risk of hyperkalemia and renal function. Differences among patients with reduced versus preserved ejection fraction will be determined. KeywordsHeart failure; acute heart failure; hospitalization; mineralocorticoid receptor antagonist; aldosterone; natriuretic peptides Heart failure (HF) accounts for over a million hospitalizations in the United States annually. 1, 2 Hospitalizations for HF are associated with a significantly elevated risk for post-discharge mortality and recurrent hospitalizations. Mortality or readmission risk at 60-days post discharge is ~30% and may be as high as 50% by 6 months in these patients. [3][4][5][6][7] While therapy for chronic HF with reduced ejection fraction has evolved over time favorably impacting survival, outcomes for patients with acute heart failure ...

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Mineralocorticoid Receptor Antagonism Confers Cardioprotection in Heart Failure

Cited by 5 publications

References 103 publications

Impact of Aldosterone on Osteoinductive Signaling and Vascular Calcification

Impact of Aldosterone on Osteoinductive Signaling and Vascular Calcification

Micronutrient deficiencies in heart failure: Mitochondrial dysfunction as a common pathophysiological mechanism?

Rationale and Design of the ATHENA-HF Trial

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