Elsevier

Heart Failure Clinics

Volume 14, Issue 4, October 2018, Pages 525-535
Heart Failure Clinics

Aldosterone Receptor Blockade in Heart Failure with Preserved Ejection Fraction

https://doi.org/10.1016/j.hfc.2018.06.002Get rights and content

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Key points

  • Heart failure with preserved ejection fraction (HFpEF) is a complex disorder with variable clinical phenotypes.

  • Clinical trials in HFpEF have failed to show an effective therapy that has provided mortality benefit.

  • Aldosterone is key mediator of myocardial fibrosis and has shown efficacy in reducing collagen turnover and in potentially improving structure and diastolic function in HFpEF.

  • Although the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT)

Pathophysiologic basis of heart failure with preserved ejection fraction

HFpEF is now defined in the American Heart Association (AHA)/American College of Cardiology (ACC) HF guidelines as clinical symptoms and signs of HF with a left ventricular ejection fraction (LVEF) greater than or equal to 50%,2 although several clinical trials have used an LVEF of greater than or equal to 45%, and a few trials have used LVEF greater than or equal to 50%. HFpEF may also be characterized by diastolic dysfunction on echocardiography, although this parameter is not present in all

The renin-angiotensin-aldosterone system in heart failure

HF and hypertension are associated with activation of the renin-angiotensin-aldosterone system (RAAS). Chronic RAAS activation leads to increases in aldosterone level, which can promote an increase in extracellular matrix collagen and endothelial dysfunction. This condition can subsequently lead to LV hypertrophy, decreased ventricular and vascular compliance, and LV systolic and diastolic dysfunction (Fig. 1).16 Inhibition of RAAS can reverse this process and may improve diastolic function.

Aldosterone receptor antagonists in heart failure with reduced ejection fraction

Patients with HF with reduced ejection fraction (HFrEF) frequently had aldosterone breakthrough despite treatment with ACEI or ARBs caused by renin-angiotensin system (RAS)–mediated and non–RAS-mediated aldosterone secretion.17 The addition of aldosterone antagonists to standard HFrEF therapy was hence validated in 3 large clinical trials.21, 22, 23 These trials have shown the efficacy of aldosterone receptor blockade in significantly reducing mortality and morbidity caused by HF and

Renin-angiotensin system inhibition in heart failure with preserved ejection fraction

Treatment with ACEIs or ARBs is fundamental in the treatment of HFrEF,24 and the benefits of aldosterone inhibitors were evaluated on background therapy with ACEIs or ARBs. However, the benefits of these drugs cannot be extended to patients with HFpEF based on the results of several large trials that have not shown any significant benefit in mortality with ACEIs or ARBs in HFpEF. Although there was a signal for reduction in HF hospitalizations in some trials, this was not consistently seen

Aldosterone receptor antagonist in heart failure with preserved ejection fraction: structure and diastology

In the Randomized Aldactone Evaluation Study (RALES) trial, excessive turnover of the extracellular matrix was associated with advanced cardiac remodeling and poor clinical outcomes, and the clinical benefit from the aldosterone antagonism was most pronounced if this turnover was reduced.28 Fibrosis and expansion of the extracellular matrix is a key pathologic process in HFpEF, and aldosterone antagonism has been a focal point in therapeutic strategies. In patients with HFpEF, aldosterone

Aldosterone receptor antagonists in heart failure with preserved ejection fraction: clinical outcomes

The TOPCAT trial evaluated the efficacy of spironolactone in preventing major clinical end points in patients with HFpEF.37 The study randomized 3445 with symptomatic HF and an LVEF of 45% or greater to spironolactone (15 mg–45 mg) or placebo. Eligible patients either had a history of hospitalization within the previous 12 months, with HF management as a major component of care, or increased natriuretic peptide levels within 60 days before enrollment (BNP ≥100 pg/mL or NT-proBNP ≥360 pg/mL).

Recommendations for aldosterone inhibition in heart failure

Given the notable geographic disparities in the TOPCAT trial, it seems prudent to treat patients with HFpEF who resemble those enrolled in North and South America with aldosterone antagonists. However, their use across all patients with HFpEF cannot be advocated, given the lack of clear benefit on mortality, hospitalization, or symptoms and the potential for harm in patients with renal dysfunction or prone to hyperkalemia. In the large clinical trials discussed earlier, patients were excluded

Summary

Given the expanding public burden of HFpEF, effective therapy is of critical importance. The β-blockers, such as nebivolol, may have potential benefit in reducing hospitalizations for HFpEF,50 although there have been no large-scale studies evaluating mortality benefit or clinical outcomes only in patients with HFpEF. Phosphodiesterase-5 inhibition failed to improve exercise capacity or clinical status.51 ARBs were shown to have a trend toward modest reduction in HF hospitalizations in only 1

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      Although the mechanism for this discrepancy in clinical response is unknown, a possible explanation is an increased preload sensitivity with a need to re-equilibrate intravascular volume in patients with acute decompensated HFpEF.43 Mineralocorticoid receptor antagonists have been of particular interest in HFpEF owing to their positive effects on interstitial fibrosis, endothelial dysfunction, extracellular matrix collagen, and myocardial stiffness, which are key components in the pathogenesis of HFpEF.44 In the Aldo-DHF trial, spironolactone was shown to improve diastolic function and reverse remodeling.45

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      This approach would be common in adults with heart failure but has to be balanced against the high incidence of side effects such as metabolic bone disease, deceleration in growth velocity and electrolyte disturbances [49]. Spironolactone, an aldosterone receptor antagonist, does not have an appreciable diuretic effect but helps reducing mortality in adults with diastolic heart failure [50]. There is growing evidence that preterm birth is a risk factor for early heart failure later in life caused by abnormal cardiac development during a critical period of growth and development, and further studies are needed to review if spironolactone can help prevent cardiac remodeling due to PDA volume load [51].

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    Disclosure: The authors have nothing to disclose.

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