## 4 Discussion
Previous studies have investigated the effects of PDE5i on cardiac function, reporting controversial results. In 44 patients with stable systolic heart failure randomly assigned to placebo or sildenafil, [PERSON] et al. demonstrated that PDE5 inhibition with sildenafil significantly improves left ventricular diastolic function properties [22]. In contrast, in the subsequent Relax trial by [PERSON] et al., including 216 patients with heart failure with preserved ejection fraction, sildenafil showed no beneficial effects on exercise capacity and left ventricular diastolic function [23]. Similarly, [PERSON] et al. reported that sildenafil treatment for 9 weeks did not show any significant improvements in the predetermined primary endpoints (LV filling pressure at rest or during exercise) in 70 patients with diastolic dysfunction and preserved ejection fraction after acute myocardial infarction. In addition, [PERSON] and coworkers did not detect any significant improvement in diastolic function, as assessed by Doppler echocardiography, following the treatment with sildenafil [24]. Differently, in a 12-week, randomized, double-blind, placebo-controlled trial, [PERSON] et al. reported that PDE 5 inhibition with udenafil ameliorates systolic and diastolic function of the left ventricle along with exercise capacity in patients with chronic heart failure with reduced ejection fraction [25]. A subsequent meta-analysis performed by [PERSON] et al. found that PDE5 inhibitors improved clinical outcomes, exercise capacity, and pulmonary hemodynamics in the RCTs of patients (\(n=555\)) with heart failure and reduced left ventricular ejection fraction [26]. In contrast, in the RCTs of patients with heart failure with preserved left ventricular ejection fraction (\(n=373\)), no benefit was shown from PDE5i use regarding all of the investigated endpoints. Again, in a randomized placebo-controlled study, [PERSON] et al. found that treatment with sildenafil for 12 weeks in 52 patients with heart failure with preserved ejection fraction and predominantly isolated post-capillary pulmonary hypertension did not affect the cardiac structure, cardiac function, exercise response, or quality of life [27]. More recently, [PERSON] et al. investigated 50 patients with heart failure with preserved ejection fraction and combined pre- and post-capillary pulmonary hypertension [28]. In the 30 patients treated with sildenafil for 6 months, the authors observed improvements in exercise capacity, pulmonary hemodynamic parameters, and right ventricular function. No changes occurred in the control group [29]. One explanation for the seemingly contradictory findings in the above studies may be due to the differences in the assessment methods of the effects of the drugs. It is also possible that a lack of homogeneity in the characteristics of the study populations in terms of etiology, comorbidities, and therapies associated with PDE5 inhibitors may have contributed. The efficacy of PDE5 inhibitors might differ according to the pathological process under study. A single class of drugs cannot prove effective in all clinical scenarios. PDE5 inhibitors demonstrated clinical benefit in patients with heart failure with reduced ejection fraction. In the preserved ejection fraction setting, PDE5 inhibitors may only benefit select patients with reversible pulmonary hypertension and right ventricular systolic dysfunction. Additionally, further differences in cardiovascular response to treatment could be found in the different genetic backgrounds. Indeed, [PERSON] et al. demonstrated that the impact of heart failure treatment on the right heart chamber could be influenced by different genetic backgrounds,determining heterogenic results [30]. Given the small numbers of patients enrolled in the various studies, we cannot exclude a play of chance.