Fiber Contractility In An In Vivo Model Of Myocardial Ischemia - Reperfusion

Abstract

Altered blood flow to the heart, either transient or chronic, underscores the progression towards heart failure. Multiple models have suggested that alterations in Ca2+ handling and reduced energy reserves contribute to the reduction in cardiac muscle contractility. However, we have hypothesized that altered blood flow is also responsible for reversible, post-translational modifications to proteins of the contractile filaments, in turn limiting muscle contractility independent of available Ca2+ or ATP. Using an in vivo rat model, three experimental groups (perfused, ischemic, and reperfused) were established by limiting and re-establishing blood flow through the left anterior descending artery. Thin strips of the anterolateral papillary muscle were recovered and permeabilized with Triton-X100 to measure various contractile parameters. The maximum force and stiffness per cross-section (Fmax and Smax) of fibers from the three conditions were measured in pCa4 solution. The Fmax and Smax were significantly reduced in ischemic fibers (79% and 74% of perfused fibers), but restored to some extent in reperfused fibers (90% and 75% of perfused fibers). However, the Ca2+ sensitivity of contraction (EC50) was significantly shifted rightward only in ischemic fibers, with complete recovery in reperfused fibers. The reversible nature of the force decline and change in EC50 during ischemia suggests that the underlying changes in the contractile proteins were reversible, and most likely post-translational in nature. Additional experiments characterizing the altered contractility of ischemic fibers will be presented. Supported by NIH grant HL78845.