Abstract 3706: NO Independent Activation of Soluble Guanylyl Cyclase Provides Additional Benefit to ACE Inhibition on Cardiac Remodeling Postinfarction
Background: Impairment of nitric oxide (NO) signaling contributes to progression of heart failure. Activation of soluble guanylyl cyclase (sGC) by NO is the key event in NO/sGC/cyclicGMP signaling. We investigated the effects of the NO independent sGC activator HMR1766 (Sanofi-Aventis) alone and in combination with the angiotensin-converting enzyme (ACE) inhibitor ramipril, on hemodynamics and cardiac remodeling in rats after extensive myocardial infarction (MI).
Methods and Results: Starting 7 days after MI, rats were treated with placebo, HMR1766 (10mg/kg, twice daily), ramipril (1 mg/kg/day), or a combination of both, administered by gavage for 9 weeks. HMR1766 monotherapy, like ACE inhibition, improved left ventricular (LV) function, attenuated the rise in LV filling pressure (LVEDP), and LV volumes compared to placebo. Combination therapy with ramipril more effectively improved LV function and LV ejection fraction, and led to a substantial further leftward shift of the LV pressure-volume curve and reduction in LVEDP and LV volumes. In addition, LV pressure isovolumic decay, LV dP/dtmax divided by instantaneous pressure, and pulmonary fluid accumulation were significantly improved by HMR1766 and further ameliorated by HMR1766/ramipril. Interstitial fibrosis and myocyte cross-sectional area were markedly increased in placebo rats, significantly decreased by HMR1766 and further reduced by HMR1766/ramipril. Moreover, the addition of HMR1766 to ACE inhibition enhanced the ratio of capillaries to cardiomyocytes, and reduced the increased mitochondrial superoxide anion formation in the failing LV myocardium more effectively than either monotherapy. Microarray analysis revealed 69, 68 and 69 independently regulated transcripts by HMR1766, ramipril and HMR1766/ramipril respectively (p<0.05, fold change >1.5).
Conclusions: Long-term treatment with the NO independent sGC activator HMR1766 improved LV dysfunction and remodeling postinfarction to a similar extent as ACE inhibition. Combination of HMR1766 with an ACE inhibitor substantially potentiates this effect by a complementary prevention of LV fibrosis, cardiac hypertrophy, oxidative stress, as well as molecular alterations.