Molecular and cellular mechanisms associated with cardiac hypertrophy following myocardial infarction in rats, studies on ion channels and intracellular calcium

grantor: University of TorontoProlongation of the cardiac action potential duration (APD) is a hallmark feature of cardiac hypertrophy. In my studies, I examined the molecular and ionic basis of this electrical phenotype in different anatomical regions of the heart and examined its functional consequence on calcium handling in rats 8 weeks following ligation of the left anterior descending (LAD) coronary artery. LAD ligation resulted in approximately 40% infarction of the left ventricle, a decrease in left ventricular developed pressure, an increase in left ventricular end-diastolic pressure with no evidence of pulmonary congestion, increased wet heart weight to body weight ratios and elevated cellular capacitance. Following myocardial infarction (MI), the density of the transient outward K+ current (Ito) was reduced by about 2 fold in right ventricular myocytes but not septal myocytes. Kv4.2 mRNA and protein and Kv4.3 mRNA were markedly reduced in the right ventricular myocytes but not in septal myocytes, suggesting that reductions in Kv4.2 and Kv4.3 are responsible for the reduced Ito. The recovery from inactivation of Ito was slowed and was associated with an elevation in Kv1.4 mRNA and protein in right ventricular myocytes, but not septal myocytes. Consistent with the changes in I'to' density, changes in APD and Ca 2+ transients following MI varied between the right ventricle and septum. Moreover, the elevations in [Ca2+]i were directly linked to prolongation of action potential duration and were not related to changes in L-type Ca2+ currents or altered calcium handling in post-MI myocytes. Treatment with the thyroid hormone analog, DITPA, for five weeks restored Ito density by reversing Kv4.2 and Kv1.4 expression and abbreviating action potential duration to levels observed in sham-operated controls. Our findings demonstrate that LAD ligation in rats is associated with electrical, ionic and genetic changes that can be reversed by thyroid hormone administration.Ph.D