Correlates of Plasma Nt-probnp to Cyclic Gmp Ratio in Heart Failure with Preserved Ejection Fraction: an Analysis of the Relax Trial

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.