Role of T-type calcium channel subunits in post-myocardial infarction remodelling probed with genetically engineered mice

Abstract

Aims Previous studies suggested that T-type Ca 2+-current (I CaT)-blockers improve cardiac remodelling, but all available I CaT-blockers have non-specific actions on other currents and/or functions. To clarify the role of I CaT in cardiac remodelling, we studied mice with either of the principal cardiac I CaT-subunits (Cav3.1 or Cav3.2) knocked out. Methods and results Adult male Cav3.1- or Cav3.2-knockout (Cav3.1 -/-, Cav3.2 -/-) mice and respective wild-type (WT) littermate controls were subjected to left anterior descending coronary artery ligation to create myocardial infarction (MI). Echocardiography and programmed electrical stimulation were performed at baseline and 4 weeks post-MI. At baseline, Cav3.1 -/- mice had slowed heart rates and longer PR intervals vs. WT, but no other electrophysiological and no haemodynamic differences. Cav3.2 -/- showed no differences vs. WT. Contractile indices (left ventricular fractional shortening and ejection fraction) decreased more post-MI in Cav3.1 -/- mice than in Cav3.1 +/+ (e.g. by 34 and 29 for WT; 50 and 45 for Cav3.1 -/-, respectively; P < 0.05 for each). Cav3.1 -/- mice had increased ventricular tachycardia (VT) inducibility post-MI (9 of 11, 82) vs. WT (3 of 10, 30; P < 0.05). Cav3.2 -/- mice were not different in cardiac function or VT inducibility vs. WT. Quantitative polymerase chain reaction showed that Cav3.1 is the major I CaT-subunit and that no compensatory Cav3.2 up-regulation occurs in Cav3.1 -/- mice. Cav3.1 -/- and Cav3.2 -/- mice had no mRNA expression for the knocked-out gene, at baseline or post-MI. Conclusion Our findings suggest that, contrary to suggestions from previous studies with (imperfectly selective) pharmacological agents having T-type Ca 2+-channel-blocking actions, elimination of Cav3.1 expression leads to impaired cardiac function and enhanced arrhythmia vulnerability post-MI, whereas Cav3.2 elimination has no effect. © The Author 2011.