LAUSR

Heart failure contributes to 1 in 9 deaths in the United States. Contractile deficits at the myofilament level may contribute to the heart inadequately pumping blood throughout the body. Yet, few studies have investigated force production and cross-bridge kinetics at physiological temperature in human myocardium from non-failing and failing hearts. Using skinned myocardial strips from the left ventricle free wall, we found that maximal Ca2+-activated, isometric force was ∼35% greater in non-failing vs. failing tissue at both 17 and 37°C (p<0.001 for condition effect at pCa 4.8 and 2.3 µm sarcomere length). Moreover, increasing temperature from 17 to 37°C increased maximal force by roughly 30% and 40% in non-failing and failing myocardial strips, respectively (p<0.001 for temperature effect). Ca2+-sensitivity of the force-pCa relationship was reduced for non-failing vs. failing myocardial strips (p=0.03 for condition effect), with differences in pCa50 being greatest at 17°C between non-failing and failing samples. These decreases in maximal force and increases in Ca2+-sensitivity of the force-pCa relationship that occurred with heart failure were not driven via differences in cross-bridge attachment or detachment kinetics, as kinetics measures were largely consistent among non-failing and failing samples at each temperature. However, cross-bridge kinetics were 12-13 times faster at physiological temperature vs. 17°C in both non-failing and failing samples (p<0.001 for temperature effect), thereby representing a Q10 of ∼3.5 for cross-bridge attachment and detachment rates in human myocardial strips. Thus, faster cross-bridge cycling rates accompanied greater force production at physiological temperature in both non-failing and failing samples. In addition, these data suggest that heart failure compromises force production without significantly altering cross-bridge kinetics, both at sub-physiological and physiological temperatures in human myocardium.