Milburn, G. N.; Roth, C. I.; Bell, J.; Wellette-Hunsucker, A.; Pakbaz, M.; Lewalle, A.; Niederer, S. A.; Campbell, K. S.

Background Ischemic heart failure (IHF) has been shown to impair contractility and disrupt sarcomere function in the left ventricle. Left ventricular failure can cause left atrial dysfunction, which is associated with a greater risk of patient mortality. Despite this, the biochemical and biomechanical characteristics of the left atrium in IHF remain obscure. Methods Myocardial mechanical properties were measured using permeabilized muscle isolated from the left ventricle (LV) and left atrium (LA) of donors and patients with IHF. Tissue homogenates from these samples were used to measure titin and myosin isoforms as well as the phosphorylation of sarcomeric regulatory proteins. Histology was used to quantify fibrosis in the patients' left ventricle and left atrium. Results Length-dependent changes in Ca2+-sensitivity were blunted in LV myocardium from patients with IHF. LA myocardium did not show robust length-dependence of Ca2+-dependent force. The calcium sensitivity of both LA and LV myocardium was increased in IHF. The maximum force generated by LV but not LA myocardium was decreased in IHF. LA myocardial samples exhibited faster contractile kinetics than LV samples, irrespective of disease. Troponin I phosphorylation decreased in both chambers with IHF. Conclusions Left atrial IHF myocardium maintained contractile force and displayed increases in calcium sensitivity, which may allow for increased LA contraction under pathological conditions. The increases in calcium sensitivity observed in ischemic myocardium of both chambers are likely driven by decreased phosphorylation of troponin I, which alters thin filament regulation. Conversely, thick filament properties of the left ventricle, such as thick filament protein isoforms and phosphorylation of myosin binding protein-C, displayed chamber-specific differences independent of disease state. These biochemical changes may explain the chamber-specific differences in kinetics and length-dependent properties. Collectively, these biophysical and biochemical data suggest LA remodeling in IHF may assist in increasing LV end-diastolic volume to maintain adequate cardiac output.