QGC606: A Best-in-Class Orally Active Centrally Acting Aminopeptidase A Inhibitor Prodrug for Treating Heart Failure Following Myocardial Infarction.

BACKGROUND: Blockade of brain renin-angiotensin system (RAS) overactivity by firibastat, the first centrally acting aminopeptidase A (APA) inhibitor prodrug, has already demonstrated its effectiveness in improving cardiac function after myocardial infarction (MI). We developed QGC606, a more potent and more selective APA inhibitor prodrug and studied its effects after long-term oral administration in mice post-MI. METHODS: Two days after MI induced by the left anterior descending artery ligation, adult male mice were randomized into 4 groups to receive oral treatment during 4 weeks with vehicle; QGC606; firibastat; or the angiotensin-I converting enzyme inhibitor ramipril, used as positive control. RESULTS: Four weeks post-MI, brain APA was overactivated in vehicle-treated MI mice. QGC606 treatment normalized brain APA hyperactivity to control values measured in sham-operated mice. Four weeks post-MI, QGC606-treated mice had higher left ventricular (LV) ejection fractions, significantly smaller LV end-systolic diameter and volume, significantly lower HF biomarkers mRNA expression (Myh7 and Anf) and plasma N-terminal pro B-type natriuretic peptide (NT-pro-BNP) and noradrenaline levels than saline-treated mice. QGC606 treatment significantly improved the dP/dt max and min, LV end-diastolic pressure without affecting blood pressure (BP), whereas we observed a decrease in BP in ramipril-treated mice. We observed also a reduction of cardiac fibrosis, highlighted by lower connective tissue growth factor mRNA levels and a reduction of both the fibrotic area and MI size in QGC606-treated mice. CONCLUSIONS: Chronic oral QGC606 administration in post-MI mice showed beneficial effects in improving cardiac function and reducing cardiac remodeling and fibrosis but, unlike ramipril, without lowering BP.

Metabolic Therapy of Heart Failure: Is There a Future for B Vitamins?

Heart failure (HF) is a plague of the aging population in industrialized countries that continues to cause many deaths despite intensive research into more effective treatments. Although the therapeutic arsenal to face heart failure has been expanding, the relatively short life expectancy of HF patients is pushing towards novel therapeutic strategies. Heart failure is associated with drastic metabolic disorders, including severe myocardial mitochondrial dysfunction and systemic nutrient deprivation secondary to severe cardiac dysfunction. To date, no effective therapy has been developed to restore the cardiac energy metabolism of the failing myocardium, mainly due to the metabolic complexity and intertwining of the involved processes. Recent years have witnessed a growing scientific interest in natural molecules that play a pivotal role in energy metabolism with promising therapeutic effects against heart failure. Among these molecules, B vitamins are a class of water soluble vitamins that are directly involved in energy metabolism and are of particular interest since they are intimately linked to energy metabolism and HF patients are often B vitamin deficient. This review aims at assessing the value of B vitamin supplementation in the treatment of heart failure.