Sacubitril/Valsartan Averts Adverse Post-Infarction Ventricular Remodeling and Preserves Systolic Function in Rabbits

• Published in: Journal of the American College of Cardiology 2018-11, Vol.72 (19), p.2342-2356
• Main Authors: Torrado, Juan, Cain, Chad, Mauro, Adolfo G., Romeo, Francisco, Ockaili, Ramzi, Chau, Vinh Q., Nestler, John A., Devarakonda, Teja, Ghosh, Siddhartha, Das, Anindita, Salloum, Fadi N.
• Format: Article
• Language: English
• Subjects: adverse cardiac remodeling; Aminobutyrates - pharmacology; Aminobutyrates - therapeutic use; Angiotensin Receptor Antagonists - pharmacology; Angiotensin Receptor Antagonists - therapeutic use; Animals; Balloon treatment; Calcium-binding protein; Cardiology; Cardiovascular disease; Clinical outcomes; Drug Combinations; Drug dosages; Echocardiography; FDA approval; Health care; Heart; Heart attacks; Heart diseases; Heart failure; infarct scar size; Ischemia; Laboratory animals; left ventricular ejection fraction; Male; Mortality; Myocardial infarction; Myocardial Infarction - diagnostic imaging; Myocardial Infarction - drug therapy; Myocardial Infarction - physiopathology; Ostomy; Peptides; Prevention; Rabbits; Random Allocation; Reduction; Reperfusion; Rodents; sacubitril/valsartan; Staining; Stroke Volume - drug effects; Stroke Volume - physiology; Studies; Systole - drug effects; Systole - physiology; Tetrazoles - pharmacology; Tetrazoles - therapeutic use; Troponin; Ventricle; Ventricular Remodeling - drug effects; Ventricular Remodeling - physiology
• ISSN: 0735-1097; 1558-3597
• DOI: 10.1016/j.jacc.2018.07.102

Sacubitril/valsartan (SAC/VAL) is approved by the U.S. Food and Drug Administration for heart failure with reduced ejection fraction (HFrEF). This study investigated the effects of SAC/VAL on acute myocardial infarction (MI) and cardiac remodeling in a translational rabbit model of MI. New Zealand White rabbits were sedated and underwent conscious MI (45-min ischemia) by balloon inflation (previously implanted surgically) followed by 72 h (acute protocol) or 10 weeks (chronic protocols) of reperfusion. “Infarct-sparing” protocol: SAC/VAL, VAL, or placebo were randomly allocated and administered at reperfusion. “HFrEF-treatment” protocol: rabbits were randomized, and treatment commenced after echocardiography-confirmed left ventricular ejection fraction (LVEF) ≤40%. “HFrEF-prevention” protocol: treatment started at reperfusion and continued daily throughout the study. Compared with placebo, SAC/VAL and VAL significantly reduced infarct size (TTC staining) and plasma troponin levels; however, only SAC/VAL preserved LVEF at 72 h post-MI. In the HFrEF-treatment protocol, LVEF improvement was observed with SAC/VAL compared with both placebo and VAL starting 2 weeks post-treatment, a benefit that persisted throughout study duration. In the HFrEF-prevention protocol, SAC/VAL and VAL attenuated the decline in LVEF post-MI, although SAC/VAL offered better functional protection. The functional improvement observed in both treatment protocols was paralleled by significant reduction in left ventricular (LV) scar size (Picrosirius red staining) in the SAC/VAL groups. Reperfusion therapy with SAC/VAL or VAL offers robust acute infarct-sparing benefits; however, SAC/VAL treatment offered superior short-term and long-term benefits in preventing MI-induced LV dysfunction compared with VAL. SAC/VAL also significantly attenuated LV scar size following MI compared with placebo, whereas VAL did not reach statistical significance in scar reduction. [Display omitted]