Effects of phosphodiesterase V inhibition alone and in combination with BNP on cardiovascular and renal response to volume load in human preclinical diastolic dysfunction

Siu-Hin Wan, Paul M McKie, Joshua P Slusser, John C Burnett Jr, David O Hodge, Horng H Chen, Siu-Hin Wan, Paul M McKie, Joshua P Slusser, John C Burnett Jr, David O Hodge, Horng H Chen

Abstract

Preclinical diastolic dysfunction (PDD) results in impaired cardiorenal response to volume load (VL) which may contribute to the progression to clinical heart failure with preserved ejection fraction (HFpEF). The objective was to evaluate if phosphodiesterase V inhibition (PDEVI) alone or combination PDEVI plus B-type natriuretic peptide (BNP) administration will correct the impaired cardiorenal response to VL in PDD. A randomized double-blinded placebo-controlled cross-over study was conducted in 20 subjects with PDD, defined as left ventricular ejection fraction (LVEF) >50% with moderate or severe diastolic dysfunction by Doppler echocardiography and without HF diagnosis or symptoms. Effects of PDEVI with oral tadalafil alone and tadalafil plus subcutaneous (SC) BNP, administered prior to acute volume loading, were assessed. Tadalafil alone did not result in improvement in cardiac response to VL, as measured by LVEF, LV end diastolic volume, left atrial volume (LAV), or right ventricular systolic pressure (RVSP). Tadalafil plus SC BNP resulted in improved cardiac response to VL, with increased LVEF (4.1 vs. 1.8%, p = 0.08) and heart rate (4.3 vs. 1.6 bpm, p = 0.08), and reductions in both LAV (-4.3 ± 10.4 vs. 2.8 ± 6.6 ml, p = 0.03) and RVSP (-4.0 ± 3.0 vs. 2.1 ± 6.0 mmHg, p < 0.01) versus tadalafil alone. Plasma and urinary cyclic guanosine monophosphate (cGMP) excretion levels were higher (11.3 ± 12.3 vs. 1.7 ± 3.8 pmol/ml, 1851.0 ± 1386.4 vs. 173.4 ± 517.9 pmol/min, p < 0.01) with tadalafil plus SC BNP versus tadalafil alone. There was no improvement in renal response as measured by GFR, renal plasma flow, sodium excretion, and urine flow with tadalafil plus SC BNP compared to tadalafil alone. In subjects with PDD, tadalafil alone resulted in no improvement in cardiac adaptation, while tadalafil and SC BNP resulted in enhanced cardiac adaptation to VL. TRIAL REGISTRATION: ClinicalTrials.gov NCT01544998.

Conflict of interest statement

Dr. Chen and Dr. Burnett have patented and licensed designer natriuretic peptides.

The authors have no conflict of interest to report.

© 2021 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.

Figures

FIGURE 1
FIGURE 1
Study design. BNP, B type natriuretic peptide; Echo, echocardiogram; SC, subcutaneous
FIGURE 2
FIGURE 2
Echocardiographic Parameters and Response to VL in tadalafil and SC placebo versus tadalafil and SC BNP. SC BNP: received tadalafil plus SC BNP. Placebo: received tadalafil plus placebo. EF, ejection fraction; LAV, left atrial volume; RVSP, right ventricular systolic pressure
FIGURE 3
FIGURE 3
Neurohumoral Parameters and Response to VL in tadalafil and SC placebo versus tadalafil and SC BNP. (a) Urinary cGMP excretion. SC BNP: received tadalafil plus SC BNP. Placebo: received tadalafil plus placebo. (b) Plasma BNP. SC BNP: received tadalafil plus SC BNP. Placebo: received tadalafil plus placebo. (c) Plasma cGMP. SC BNP: received tadalafil plus SC BNP. Placebo: received tadalafil plus placebo. cGMP, cyclic guanosine monophosphate

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