Abstract 15822: Cardiac Effects of EDG-7500, a Novel Cardiac Sarcomere Regulator: In vitro and in vivo Evidence for Slowing Isovolumic Contraction and Improved Ventricular Compliance

Abstract

Background: Hypertrophic Cardiomyopathy (HCM) is a disease where excess acto-myosin crossbridge formation results in hyperdynamic contraction, LV hypertrophy, and diastolic dysfunction due to increased myocardial stiffness. Conventional negative inotropes alleviate, to some degree, the systolic alteration in HCM, but do not improve LV filling. EDG-7500 is a small molecule that preferentially decreases diastolic tension and slows the velocity of myocardial force generation by regulating, but not inhibiting, cardiac myosin. This study assessed pharmacodynamic responses to EDG-7500. Methods: Myofilament biomechanics and sarcomere structure were evaluated on LV permeabilized pig fibers. In vivo, dogs were instrumented for arterial pressure and LV pressure-volume recordings. Data were obtained with vehicle, EDG-7500 (n = 5; 0.3 mg/kg IV), or metoprolol (2-4 mg/kg IV, n = 3); systemic and LV hemodynamics and load-independent function were examined. *:P<0.05 for EDG-7500 vs. vehicle Results: X-ray diffraction studies showed EDG-7500 preserved the myosin head population competent to form crossbridges as well as the recruitment of reserve myosin-heads during calcium activation. EDG-7500 (1μM) slowed crossbridge formation, with a limited reduction in maximal force (-6±2%) and decreased diastolic tension. At 0.3 mg/kg, EDG-7500 slowed early contraction (PEP: +10±1%*) and reduced the peak rate of LV pressure development (+dP/dtmax: -8 ± 1%*) with minimal reductions in peak end systolic elastance (Emax: -4±1%*). Systemic mean arterial pressure and cardiac output were unchanged. EDG-7500 increased LV end-diastolic volume (+5 ± 1%*) and preserved LV end-diastolic pressure (EDP: -8 ± 3%, 9 ± 1 to 8 ± 1 mmHg). A downward and rightward shift of the pressure-volume relationship indicated improved LV compliance. β-AR blockade did not elicit this pro-compliant effect (EDP: +26 ± 12%). Conclusions: Cardiac sarcomere regulation with EDG-7500 has a unique cardiovascular profile characterized by the overall preservation of the myosin motor-head population and a slowing of early cardiac contraction and improved LV distensibility. This cardiovascular profile could have salutary effects in patients with HCM or patients with impaired diastolic function.