The role of mineralocorticoid receptor antagonists (MRAs) in very old patients with heart failure

Abstract

Mineralocorticoid receptor antagonists (MRAs) have been effective in reducing total mortality in patients with heart failure (HF) and a reduced left ventricular ejection fraction. Due to the finding that aldosterone levels decrease with age, one might question the effectiveness of MRAs in very old patients (≥80 years of age), those at the greatest risk for developing HF with a preserved left ventricular ejection fraction (PEF). However, while aldosterone levels decrease with age, there is also a decrease in the enzyme 11 beta HSD2 levels with age, thereby allowing cortisol to stimulate the mineralocorticoid receptor (MR), which in younger patients with higher levels of 11 beta HSD 2 levels is converted to cortisone which cannot activate the MR. There is also an increase in the expression of the MR in the vascular wall with age. Thus, there is reason to believe that MRAs might be effective in reducing cardiovascular mortality and the incidence of hospitalizations for HF in very old patients with HFPEF. There is also reason to believe that MRAs might favorably affect many of the comorbid conditions associated with HFPEF in very old patients. The safety and efficacy of this hypothesis is currently under investigation in the NHLBI sponsored TOPCAT trial.

Emerging Roles of the Mineralocorticoid Receptor in Pathology: Toward New Paradigms in Clinical Pharmacology

“…Glucocorticoid-mediated MR activation occurring in aging persons should be considered in light of the risks for development of heart failure and aging-associated pathologies (Pitt, 2012). Although plasma aldosterone concentration declines with age, cortisol concentration, and the cortisol/cortisone ratio (an indicator of reduced 11HSD2 activity) increases (Henschkowski et al, 2008;Pitt, 2012).…”

“…Although plasma aldosterone concentration declines with age, cortisol concentration, and the cortisol/cortisone ratio (an indicator of reduced 11HSD2 activity) increases (Henschkowski et al, 2008;Pitt, 2012). A cross sectional study of normotensive subjects indicated that 11HSD2 activity declines after the 4th decade of life, favoring cortisol activation of MR and onset of hypertension (Campino et al, 2013).…”

Baseline Characteristics of Patients in the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial

“…19 Prior studies have demonstrated that MRAs improve clinical outcomes in patients with symptomatic HFrEF 2021 and those with HF or left ventricular (LV) systolic dysfunction complicating myocardial infarction. 22 …”

“…23-26 Despite these promising preliminary data, 19 no prior large randomized trials have specifically evaluated the effect of an MRA on clinical outcomes in patients with HFpEF. Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) Study is the first large randomized controlled trial of spironolactone versus placebo for HFpEF adequately powered to examine clinical outcomes.…”

Role of Aldosterone and Mineralocorticoid Receptor in Cardiovascular Aging

“…In light of the significant cardiovascular benefits of MR antagonism in the aging population, their use in clinical setting is limited by the adverse effects induced by MR blockade on the kidney, such as hyperkalemia, particularly in older patients with reduced renal function and by their anti-androgenic properties (particularly exhibited by spironolactone) which can induce gynecomastia and erectile dysfunction in men (129, 130). Therefore, the current use of MR antagonists is restricted to patients with an estimated glomerular filtration rate >45 mL/min and a plasma potassium concentration of <4.5 mmol/L, in order to avoid the risk of hyperkalaemia (127).…”