PDE5 Inhibition With Sildenafil Improves Left Ventricular Diastolic Function, Cardiac Geometry, and Clinical Status in Patients With Stable Systolic Heart Failure

Abstract

Background— In heart failure (HF), a defective nitric oxide signaling is involved in left ventricular (LV) diastolic abnormalities and remodeling. PDE5 inhibition, by blocking degradation of nitric oxide second-messenger cyclic guanosine monophosphate, might be beneficial. In a cohort of systolic HF patients, we tested the effects of PDE5 inhibition (sildenafil) on LV ejection fraction, diastolic function, cardiac geometry, and clinical status. Methods and Results— Forty-five HF patients (New York Heart Association class II-III) were randomly assigned to placebo or sildenafil (50 mg three times per day) for 1 year, with assessment (6 months and 1 year) of LV ejection fraction, diastolic function, geometry, cardiopulmonary exercise performance, and quality of life. In the sildenafil group only, at 6 months and 1 year, LV ejection fraction, early diastolic tissue Doppler velocities (E′) at the mitral lateral (from 4.62 to 5.20 and 5.19 m/s) and septal (from 4.71 to 5.23 and 5.24 m/s) annuli significantly increased, whereas the ratio of early transmitral (E) to E′ lateral decreased (from 13.1 to 9.8 to 9.4) ( P <0.01). Changes were accompanied by a reverse remodeling of left atrial volume index (from 32.0 to 29.0 and 29.1 mL/m 2 ; P <0.01) and LV mass index (from 148.0 to 130.0 and 128.0 g/m 2 ; P <0.01). Furthermore, sildenafil improved exercise performance (peak V o 2 ), ventilation efficiency (ventilation to CO 2 production slope), and quality of life ( P <0.01). Minor adverse effects were noted: flushing in 4 and headache in 2 treated patients. Conclusions— Findings confirm that in HF, sildenafil improves functional capacity and clinical status and provide the first human evidence that LV diastolic function and cardiac geometry are additional targets of benefits related to chronic PDE5 inhibition. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00975494.