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.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.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.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).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.