Sarcomere length affects Ca2+ sensitivity of contraction in ischemic but not non-ischemic myocardium

Abstract

In healthy hearts, myofilaments become more sensitive to Ca2+ as the myocardium is stretched. This effect is known as length-dependent activation and is an important cellular-level component of the Frank–Starling mechanism. Few studies have measured length-dependent activation in the myocardium from failing human hearts. We investigated whether ischemic and non-ischemic heart failure results in different length-dependent activation responses at physiological temperature (37°C). Myocardial strips from the left ventricular free wall were chemically permeabilized and Ca2+-activated at sarcomere lengths (SLs) of 1.9 and 2.3 µm. Data were acquired from 12 hearts that were explanted from patients receiving cardiac transplants; 6 had ischemic heart failure and 6 had non-ischemic heart failure. Another 6 hearts were obtained from organ donors. Maximal Ca2+-activated force increased at longer SL for all groups. Ca2+ sensitivity increased with SL in samples from donors (P < 0.001) and patients with ischemic heart failure (P = 0.003) but did not change with SL in samples from patients with non-ischemic heart failure. Compared with donors, troponin I phosphorylation decreased in ischemic samples and even more so in non-ischemic samples; cardiac myosin binding protein-C (cMyBP-C) phosphorylation also decreased with heart failure. These findings support the idea that troponin I and cMyBP-C phosphorylation promote length-dependent activation and show that length-dependent activation of contraction is blunted, yet extant, in the myocardium from patients with ischemic heart failure and further reduced in the myocardium from patients with non-ischemic heart failure. Patients who have a non-ischemic disease may exhibit a diminished contractile response to increased ventricular filling.

Discovery of novel cardiac troponin activators using fluorescence polarization-based high throughput screening assays

“…S5), suggesting that the compound did not affect the length-dependent activation response of human donor myocardium. Moreover, we have tested for the functional effects of NS5806 in non-ischemic heart failure tissue with very low cardiac troponin I and myosin binding protein-C phosphorylation levels 36 . Intriguingly, although NS5806 did increase the calcium sensitivity of the failing human tissue, it had no effect its maximal isometric force.…”