Abstract 9821: Calcium-Dependent Changes in Myocardial Sheet Mechanics Reveal Reversible Diastolic Dysfunction in Aged Duchenne Muscular Dystrophy ( mdx ) Mice

Abstract

INTRODUCTION: The relationship between abnormal sarcoplasmic Ca 2+ handling and cardiac structural mechanics in mdx mice has not been defined. Diffusion tensor MRI (DTI) has been used to quantify the contribution of myocardial sheet architecture in ventricular wall thickening mechanics. In this study, DTI was employed to assess altered sheet mechanics due to impaired intracellular calcium homeostasis. METHODS: Sixteen-month old mdx (n = 10) and age matched wildtype (WT, n = 10) mice were used. Hearts were excised and prepared for Langendorff retrograde perfusion to be sequentially arrested in diastole and systole for DTI. The first group was perfused with regular St. Thomas’ cardioplegic solution containing normal [Ca 2+ ] (1.2 mM) to arrest hearts in diastole. To assess the regulatory effect of [Ca 2+ ] on diastolic sheet mechanics, the second group was perfused with modified cardioplegic solution containing low [Ca 2+ ] (0.078 mM). All hearts were then reperfused with Krebs buffer to resume beating followed by 2.5mM barium-induced systolic arrest for DTI. Magnitude of sheet angle, |β|, of each heart was calculated from the diffusion tensors. MANOVA was used for statistical analysis. RESULTS: In diastole, mdx hearts exhibited lower |β| in midventricle than WT (Fig. A). Reducing [Ca 2+ ] in cardioplegic solution restored diastolic |β| in mdx hearts to normal level but had no detectable effect on WT hearts. No significant difference of systolic |β| was observed between mdx and WT hearts (Fig. B). CONCLUSION: The observed lower diastolic |β| in mdx hearts indicated mdx cardiomyocytes failed to fully relax at resting state. The regulatory effect of [Ca 2+ ] on diastolic |β| of mdx hearts suggested sheet structural abnormality is reversible despite the advance age of mdx mice. Thus, the disturbed sheet mechanics may reflect functional consequences of abnormal Ca 2+ handling in vivo, which may correlate with membrane calcium channel dysfunction preceding eventual cardiac failure.