Abstract
BACKGROUND: Phosphodiesterases degrade cyclic GMP (cGMP), the second messenger that mediates the cardioprotective effects of natriuretic peptides. High natriuretic peptide/cGMP ratio may reflect, in part, phosphodiesterase activity. Correlates of natriuretic peptide/cGMP in patients with heart failure with preserved ejection fraction are not well understood. Among patients with heart failure with preserved ejection fraction in the RELAX (Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure With Preserved Ejection Fraction) trial, we examined (1) cross-sectional correlates of circulating NT-proBNP (N-terminal pro-B-type natriuretic peptide)/cGMP ratio, (2) whether selective phosphodiesterase-5 inhibition by sildenafil changed the ratio, and (3) whether the effect of sildenafil on 24-week outcomes varied by baseline ratio. METHODS AND RESULTS: In 212 subjects, NT-proBNP/cGMP ratio was calculated at randomization and 24 weeks. Correlates of the ratio and its change were examined in multivariable proportional odds models. Whether baseline ratio modified the sildenafil effect on outcomes was examined by interaction terms. Higher NT-proBNP/cGMP ratio was associated with greater left ventricular mass and troponin, the presence of atrial fibrillation, and lower estimated glomerular filtration rate and peak oxygen consumption. Compared with placebo, sildenafil did not alter the ratio from baseline to 24 weeks (P=0.17). The effect of sildenafil on 24-week change in peak oxygen consumption, left ventricular mass, or clinical composite outcome was not modified by baseline NT-proBNP/cGMP ratio (P-interaction >0.30 for all). CONCLUSIONS: Among patients with heart failure with preserved ejection fraction, higher NT-proBNP/cGMP ratio associated with an adverse cardiorenal phenotype, which was not improved by selective phosphodiesterase-5 inhibition. Other phosphodiesterases may be greater contributors than phosphodiesterase-5 to the adverse phenotype associated with a high natriuretic peptide/cGMP ratio in HFpEF. REGISTRATION INFORMATION: clinicaltrials.gov. Identifier: NCT00763867.
| Original language | English (US) |
|---|---|
| Article number | e031796 |
| Journal | Journal of the American Heart Association |
| Volume | 13 |
| Issue number | 7 |
| DOIs | |
| State | Published - Apr 2 2024 |
Funding
The RELAX trial was funded by the National Institutes of Health grants U10HL 084904 (for the data coordinating center), and U10HL084861, U10HL084875, U10HL084877, U10HL084889, U10HL084890, U10HL084891, U10HL084899, U10HL084907, and U10HL084931 (for the clinical centers) from the National Heart, Lung, and Blood Institute. The RELAX trial was also supported by grant UL1TR000454 from the National Center for Advancing Translational Sciences and grant 8 U54 MD007588 from the National Institute on Minority Health and Health Disparities. Pfizer provided the study drug (sildenafil and matched placebo). Drs Gupta, Collins, Hemnes, and Lindenfeld received research support from Imara. Drs Gupta and Stevenson received research support from the National Institutes of Health (R01 HL145293). Drs Hill, Shah, and Wang were consultants to Imara. The remaining authors have no disclosures to report.
Keywords
- cyclic GMP
- heart failure
- natriuretic peptide
- phosphodiesterase
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine
