Abstract 231: Bendavia, a Novel Mitochondria-Targeting Peptide, Improves Contraction and Relaxation of Failing Cardiomyocytes Isolated From Dogs With Chronic Heart Failure

Abstract

Background: Mitochondria (MITO) of humans and dogs with heart failure (HF) manifest functional abnormalities characterized by poor respiration, reduced rate of ATP synthesis and increased production of reactive oxygen species (ROS) that adversely impact LV systolic and diastolic function. We previously showed that chronic therapy with Bendavia (BEN, MTP-131), a novel mitochondria-targeting peptide, improves global LV function in dogs with HF without affecting heart rate or blood pressure. This improvement was associated with a reversal of MITO abnormalities and normalization of rate of ATP synthesis. This study tested the hypothesis that the improvement in global LV function seen in dogs with HF during treatment with BEN results primarily from enhanced function of constituent LV cardiomyocytes. Methods: Cardiomyocytes were isolated from the LV free wall of 8 untreated dogs with coronary microembolization-induced HF (LV ejection fraction <30%). A collagenase-based enzymatic process was used for the isolation and yielded ~70% viable rod-shaped cardiomyocytes that excluded trypan blue. Extent of cardiomyocytes shortening, shortening velocity and lengthening velocity were assessed during 1.0 Hz electrical field stimulation delivered via a MyoPacer (ION Optix). Measurements were made at baseline and were repeated after one hour of gradual exposure of the same cardiomyocytes to BEN at a concentration of 0.1 μM. Results: At baseline, the extent of cardiomyocyte shortening was 3.7 ± 0.8 μm, shortening velocity was 62.8 ± 16.9 μm /sec and lengthening velocity was -53.8 ± 16.5 μm/sec. Exposure of cardiomyocyte to BEN significantly increased the extent of cardiomyocyte shortening to 5.4 ± 1.1 μm (p<0.012), shortening velocity to 94.5 ± 21.9 μm/sec (p<0.020) and lengthening velocity to -96.8 ± 21.1 μm/sec (p<0.016) compared to baseline. Conclusions: Exposure of failing isolated cardiomyocytes to BEN elicits improvements in the rate of cardiomyocyte shortening and re-lengthening indicative of improved cell contractility and relaxation. This improvement is likely mediated by increased availability of ATP along with reduced ROS production both secondary to improved mitochondrial function elicited by treatment with BEN.