Abstract 17560: Myocardial Sheet Dysfunction and Abnormal Calcium Transient Duration Manifest Reversible Regional Heterogeneity in Aged Duchenne Muscular Dystrophy (mdx) Mouse Hearts Despite the Ubiquitous Deficiency of Dystrophin_Using Diffusion Tensor MRI (DTI) and Calcium Optical Mapping (COM)
Introduction: Ca2+-mishandling has been demonstrated in isolated myocytes from mdx mice to be a critical feature of heart failure. However, how dysfunctional Ca kinetics affects myocardial fiber and sheet function throughout the whole heart has not been defined. In addition, whether regional defects exist in these indexes despite global penetration of the genetic defect in dystrophin is not known. In this study, DTI & COM were employed to map myocardial sheet dysfunction and Ca-mishandling in intact mdx mouse hearts.
Methods: 16-mo old mdx (n = 10) & wildtype (WT, n = 10) mice were used in DTI. Langendorff perfusion was used to arrest hearts in diastole for motion artifact-free DTI (11.7 T, 12 directions). The first group was perfused with normal [Ca2+] cardioplegic solution (1.2 mM, denoted as NC in Fig A). The second group was perfused with low [Ca2+] cardioplegic solution (0.078 mM, denoted as LC). Magnitude of sheet angle, |β|, was calculated from the diffusion tensors. COM was performed on another set of paced Langendorff hearts (3 WT & 4 mdx) under unloaded (0 mmHg) and stretched (80 mmHg) conditions; then, Ca transient duration at 80% relaxation (CaD80) was determined.
Results: In diastole, mdx hearts exhibited lower |β| than did WT in the base but not apex (Fig. A). By reducing [Ca2+] in the cardioplegic solution, diastolic |β| was restored to normal levels in mdx hearts but no effect was seen in WT. Significant prolongation of CaD80 was observed predominantly at the base of the stretched mdx hearts (Fig. B), but not in the apex or in WT.
Conclusion: The observed lower |β| in mdx hearts reflects mdx cardiomyocytes failed to fully relax in resting state through a calcium dependent mechanism. Strikingly, diastolic sheet function & calcium kinetics manifest this reversible abnormality primarily at the base but not apex, indicating that local mechanical properties likely modulate the phenotypic expression of the cardiomyopathy despite the global lack of dystrophin in mdx mice. .
- © 2012 by American Heart Association, Inc.