LAUSR

Despite compelling evidence to the contrary, we in the cardiovascular community have maintained an unbridled sense of optimism that phosphodiesterase 5 inhibitors (PDE5i) such as sildenafil might still be effective to help our patients suffering with heart failure (HF) with preserved ejection fraction (HFpEF). This optimism comes from groundbreaking studies showing that PDE5i can prevent and reverse left ventricular (LV) hypertrophy,1 reduce pulmonary artery (PA) pressures,2 improve lung gas exchange, and enhance right ventricular–PA coupling.3 This extensive body of data formed the basis for the multicentre RELAX trial, which unfortunately but convincingly showed that sildenafil did not improve exercise capacity, quality of life, neurohormone levels, or any measure of clinical status in people with HFpEF.4 The RELAX trial curbed but did not extinguish our optimism for PDE5i in HFpEF. The strategy of reducing high PA pressures in people with HFpEF was shown to decrease hospitalizations resulting from HF,5,6 and the RELAX inclusion criteria did not require that subjects display objective evidence of pulmonary hypertension (PH) for eligibility.4 Thus practice habits did not change much following RELAX, and physicians continued to prescribe sildenafil to patients with HFpEF. This is because PDE5i were known to be efficacious in patients with non-HF related PH,2 and it seemed plausible that these drugs might still be effective, provided that patients had PH with HFpEF. This motivated Hoendermis and colleagues7 to design and conduct another trial testing sildenafil in subjects with HFpEF, this time requiring patients to display invasively-proven PH to be eligible. Unfortunately, as in RELAX, the authors observed no clinically relevant improvements with sildenafil, with no reduction in PA pressure and no improvement in exercise capacity.7 In this issue of the European Journal of Heart failure, Liu et al.8 report intriguing new data from this trial on the effects of sildenafil on ventricular