Increasing cardiac contractility after myocardial infarction exacerbates cardiac injury and pump dysfunction.

Abstract

Myocardial infarction (MI) leads to heart failure (HF) and premature death. The respective roles of myocyte death and depressed myocyte contractility in the induction of HF after MI have not been clearly defined and are the focus of this study. We developed a mouse model in which we could prevent depressed myocyte contractility after MI and used it to test the idea that preventing depression of myocyte Ca(2+)-handling defects could avert post-MI cardiac pump dysfunction. MI was produced in mice with inducible, cardiac-specific expression of the β2a subunit of the L-type Ca(2+) channel. Myocyte and cardiac function were compared in control and β2a animals before and after MI. β2a myocytes had increased Ca(2+) current; sarcoplasmic reticulum Ca(2+) load, contraction and Ca(2+) transients (versus controls), and β2a hearts had increased performance before MI. After MI, cardiac function decreased. However, ventricular dilation, myocyte hypertrophy and death, and depressed cardiac pump function were greater in β2a versus control hearts after MI. β2a animals also had poorer survival after MI. Myocytes isolated from β2a hearts after MI did not develop depressed Ca(2+) handling, and Ca(2+) current, contractions, and Ca(2+) transients were still above control levels (before MI). Maintaining myocyte contractility after MI, by increasing Ca(2+) influx, depresses rather than improves cardiac pump function after MI by reducing myocyte number.