Effect of Aldosterone Antagonism on Exercise Tolerance in Heart Failure With Preserved Ejection Fraction

^aCardiology Department, Wroclaw Medical University, Wroclaw, Poland
^bMenzies Institute for Medical Research, University of Tasmania, Hobart, Australia
^cBaker IDI Heart and Diabetes Institute, Melbourne, Australia

↵∗Reprint requests and correspondence:
Dr. Thomas H. Marwick, Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia and Baker IDI Heart and Diabetes Institute, Baker IDI Heart and Diabetes Institute, 75 Commercial Road, P.O. Box 6492, Melbourne, Victoria 3004, Australia.

Central Illustration

Abstract

Background Impaired functional capacity is a hallmark of patients with heart failure with preserved ejection fraction (HFpEF). Despite the association of HFpEF with reduced myocardial compliance attributed to fibrosis, spironolactone has not been shown to alter outcomes—perhaps reflecting the heterogeneity of underlying pathological mechanisms.

Objectives The authors sought to identify improvement in exercise capacity with spironolactone in the subset of patients with HFpEF with exercise-induced increase in ratio between early mitral inflow velocity and mitral annular early diastolic velocity (E/e′) reflecting elevation of left ventricular (LV) filling pressure.

Methods In this randomized, blinded, parallel-group, placebo-controlled trial, 150 subjects (age 67 ± 9 years) with exertional dyspnea (New York Heart Association functional class II to III, left ventricular ejection fraction >50%, diastolic dysfunction, and exertional E/e′ >13), excluding those with ischemic heart disease, were recruited in a tertiary cardiology center. Patients were randomized to 6 months of oral spironolactone 25 mg/day or matching placebo. Primary outcomes were improvements in peak oxygen uptake (VO₂) and exertional E/e′ ratio, and secondary outcomes were improvements in exercise blood pressure response and global LV longitudinal strain.

Results At follow-up, 131 patients completed therapy—64 taking spironolactone and 67 placebo. At baseline, subjects had substantial exercise limitation (peak VO₂ 64 ± 17% predicted). The spironolactone group showed improvement in exercise capacity (increment in peak VO₂ [2.9 ml/min/kg (95% confidence interval [CI]: 1.9 to 3.9 ml/min/kg) vs. 0.3 ml/min/kg (95% CI: −0.5 to 1.1 ml/min/kg); p < 0.001], anaerobic threshold [2.0 ml/min/kg (95% CI: 0.9 to 3.2 ml/min/kg) vs. −0.9 ml/min/kg (95% CI: −3.4 to 1.6 ml/min/kg); p = 0.03], and O₂ uptake efficiency [0.19 (95% CI: 0.06 to 0.31) vs. −0.07 (95% CI: −0.17 to 0.04); p = 0.002]), with reduction in exercise-induced increase in E/e′ (−3.0 [95% CI: −3.9 to −2.0] vs. 0.5 [95% CI: −0.6 to 1.6]; p < 0.001). There was a significant interaction of spironolactone and change in E/e′ on VO₂ (p = 0.039).

Conclusions In patients with HFpEF and abnormal diastolic response to exertion, improvement in exercise E/e′ mediates the beneficial effect of spironolactone on exercise capacity. Identification of exercise-induced increase in LV filling pressure in patients with HFpEF may define a subgroup with warranting trial of spironolactone.

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Footnotes

This study was funded by grants ST-678 from Wroclaw Medical University and 13-024 from the Royal Hobart Hospital Foundation. The authors have reported that they have no relationships relevant to the contents of this paper to disclose. Bertram Pitt, MD, served as Guest Editor for this paper.
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