Impaired Cross Bridge Formation Contributes to Reduced Cardiac Contraction in the Infarct Border Zone

Abstract

After myocardial infarction, adjacent to the infarct there is a poorly contracting non-ischemic border zone. The mechanism of border zone dysfunction is unclear. We found that border zone dysfunction does not involve myocardial fibrosis, or a decreased content of either myofibrils or myosin, suggesting there is a defect in the contractile mechanism. Goal: Determine the mechanism for border zone dysfunction. Methods: We used sheep hearts 2 weeks after apical infarction. Cardiac muscle strips were dissected from the border zone adjacent to the infarct and from a zone remote from the infarct. Myofilament contraction was assessed using in-vitro isometric and isotonic contractions of demembranated cardiac muscle strips bathed in activating solutions. To assess strongly bound cross-bridge formation, we measured muscle stiffness using high frequency, low amplitude oscillations of muscle length in the absence of ATP (in this rigor state, cross bridge formation should be maximal). Results: In border zone myocardium, maximal force development (Fmax) was reduced by 31±2% (n=6, P<0.01) compared to Fmax of remote zone myocardium (85±1 mN/mm2). The stiffness in the rigor state was reduced by 34±6% (n=5, P<0.05) in border zone myocardium versus remote zone myocardium, suggesting impaired cross bridge formation in the border zone. There was no difference between border zone and remote zone myocardium in the maximum velocity of muscle shortening (∼0.35 muscle lengths/s), or in the rate constant of force redevelopment (Ktr, ∼2.5 s−1) after briefly mechanically disrupting cross bridges with a rapid perturbation of muscle length. Conclusions: Impaired contraction of border zone myocardium involves a reduction in cross bridge formation, without effects on cross bridge kinetics. Preliminary studies suggest proteolytic cleavage of contractile proteins may play a role.