Sodium-glucose co-transporter 2 Inhibitors Act Independently of SGLT2 to Confer Benefit for Heart Failure with Reduced Ejection Fraction in Mice.

Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are novel, potent heart failure medications with an unknown mechanism of action. We sought to determine if the beneficial actions of SGLT2i in heart failure were on- or off-target, and related to metabolic reprogramming, including increased lipolysis and ketogenesis. The phenotype of mice treated with empagliflozin and genetically engineered mice constitutively lacking SGLT2 mirrored metabolic changes seen in human clinical trials (including reduced blood glucose, increased ketogenesis, and profound glucosuria). In a mouse heart failure model, SGLT2i treatment, but not generalized SGLT2 knockout, resulted in improved systolic function and reduced pathologic cardiac remodeling. SGLT2i treatment of the SGLT2 knockout mice sustained the cardiac benefits, demonstrating an off-target role for these drugs. This benefit is independent of metabolic changes, including ketosis. The mechanism of action and target of SGLT2i in HF remain elusive.

Titin-truncating variants in hiPSC cardiomyocytes induce pathogenic proteinopathy and sarcomere defects with preserved core contractile machinery.

Titin-truncating variants (TTNtv) are the single largest genetic cause of dilated cardiomyopathy (DCM). In this study we modeled disease phenotypes of A-band TTNtv-induced DCM in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) using genome editing and tissue engineering technologies. Transcriptomic, cellular, and micro-tissue studies revealed that A-band TTNtv hiPSC-CMs exhibit pathogenic proteinopathy, sarcomere defects, aberrant Na+ channel activities, and contractile dysfunction. These phenotypes establish a dual mechanism of poison peptide effect and haploinsufficiency that collectively contribute to DCM pathogenesis. However, TTNtv cellular defects did not interfere with the function of the core contractile machinery, the actin-myosin-troponin-Ca2+ complex, and preserved the therapeutic mechanism of sarcomere modulators. Treatment of TTNtv cardiac micro-tissues with investigational sarcomere modulators augmented contractility and resulted in sustained transcriptomic changes that promote reversal of DCM disease signatures. Together, our findings elucidate the underlying pathogenic mechanisms of A-band TTNtv-induced DCM and demonstrate the validity of sarcomere modulators as potential therapeutics.

Structural and Thermodynamic Model for the Activation of Cardiac Troponin.

Cardiac troponin is a regulatory protein complex located on the sarcomere that regulates the engagement of myosin on actin filaments. Low-molecular weight modulators of troponin that bind allosterically with the calcium ion have the potential to improve cardiac contractility in patients with reduced cardiac function. Here we propose an approach to the rational design of troponin modulators through the combined use of solution nuclear magnetic resonance and isothermal titration calorimetry methods. In contrast to traditional approaches limited to calcium and activator-bound troponin structures, here we analyzed the structural and thermodynamic impact of an activator in the context of the troponin functional cycle. This led us to propose a rationale for developing an efficacious troponin activator.