Abstract 12713: Increased Calcium Sensitivity in Hypoplastic Left Heart Syndrome Hearts With Systolic Failure

Abstract

Introduction: Systolic failure of the systemic right ventricle (RV) in children with hypoplastic left heart syndrome (HLHS) is a significant cause of death and a growing indication for heart transplantation. However, the underlying etiology of RV systolic failure in this population remains ill-defined. Hypothesis: We hypothesize that cardiomyocyte autonomous defects in contractility, characterized by increased calcium sensitivity, may contribute to systolic failure in HLHS. Methods: Explanted RV tissue was collected and flash frozen at the time of heart transplant in pediatric subjects with HLHS. HLHS subjects were classified by their primary indication for transplant: HLHS subjects with normal systolic function (HLHS-NF, N=2) were transplanted secondary to refractory protein losing enteropathy, and HLHS-F subjects (N=9) had end-stage heart failure due to decreased systolic function. Cardiomyocytes were isolated from frozen RV tissue, permeabilized, and glued to a force transducer and length controller. Force generated by the cardiomyocyte at different calcium concentrations was measured and force-calcium dose response curves were generated (modified Hill equation). pCa50 denotes the negative log of calcium concentration required to generate 50% maximal tension. Results: Less calcium is required to generate 50% maximal tension in HLHS-F cardiomyocytes (n=33 cardiomyocytes) when compared to HLHS-NF (n=5 cardiomyocytes), demonstrated by a higher pCa50 (5.62 vs. 5.46, p=0.027). Maximal force generation is similar between HLHS-NF and HLHS-F cardiomyocytes (55.5 mN/mm2 vs. 54.8 mN/mm2, p=0.96). Conclusions: Cardiomyocytes isolated from HLHS-F demonstrate increased calcium sensitivity when compared to those from HLHS-NF. Although future studies are needed, the presence of intrinsic alterations in sarcomeric properties in HLHS-F supports the hypothesis that cardiomyocyte autonomous defects may contribute to systolic failure in HLHS.