Abstract 3911: A Novel Small Molecule Approach for Treating Mechano-electrical Dysfunction in Heart Failure
Mechano-electrical remodeling is a major cause of mortality in patients with heart failure. Most pharmacological treatments for improving contractility enhance calcium entry into the cell. Unfortunately, these strategies increase mortality by promoting arrhythmias, secondary to chronic activation of PKA mediated pathways. Here, we test a novel pharmacological approach for improving contractility using a class of small molecules that are allosteric modulators of the sarcoplasmic reticulum calcium pump (SERCA2a).
Methods & Results: Using a high-throughput FRET based assay, we identified, from a library of 20,000 compounds, a class of 43 small molecules that activated SERCA2a in a dose- and calcium- dependent manner (CDN). Blinded measurements of cellular contractility, indexed by changes in sarcomere shortening of isolated rat cardiomyocytes, guided the design of 2nd & 3rd generation classes of CDN with improved solubility and pharmacokinetic features based on structure-activity relationship analyses. Several CDN compounds (10μM) effectively enhanced contractility (by 15– 40%, p<0.05) and hastened the rate of sarcomere relaxation and calcium transient decay in myocytes from normal and failing hearts. Importantly, the increase in myocyte contractility was inversely related to the basal level of contraction, which was modulated by altering extracellular calcium (0.4 –1.0mM). To determine if improved contractility was associated with electrical remodeling, we measured action potential properties in ex vivo perfused guinea pig hearts for a subset of compounds using high resolution optical imaging. Neither conduction nor repolarization gradients were altered by CDN perfusion. Burst pacing, which promoted VF in isoproterenol (50nM) treated hearts, failed to elicit arrhythmias during CDN perfusion. Finally, IV bolus infusions (4mg/kg) of CDN produced transient increases in stroke volume in mice and rats in vivo. In stark contrast to isoproterenol, CDN decreased heart rate by ~20%.
Conclusion: We have identified a class of small molecules that activate SERCA2a in a dose and calcium dependent manner. These compounds modulate contractility in small animals without promoting the incidence of arrhythmias ex vivo or elevating heart rate in vivo.