Incomplete Recovery of Myocyte Contractile Function Despite Improvement of Myocardial Architecture With Left Ventricular Assist Device Support

Abstract

Background Unloading a failing heart with a left ventricular assist device (LVAD) can improve ejection fraction (EF) and left ventricular (LV) size; however, recovery with LVAD explantation is rare. We hypothesized that evaluation of myocyte contractility and biochemistry at the sarcomere level before and after LVAD may explain organ level changes. Methods and Results Paired LV tissue samples were frozen from 8 patients with nonischemic cardiomyopathy at LVAD implantation (Before LVAD) and prior to transplant (After LVAD). These were compared to 8 nonfailing hearts. Isolated skinned myocytes were purified, attached to a force transducer, and dimensions, maximal calcium saturated force (Fmax), calcium sensitivity, and myofilament cooperativity were assessed. Relative isoform abundance and phosphorylation levels of sarcomeric contractile proteins were measured. With LVAD support, the unloaded EF improved (10.0±1.0 to 25.6±11.0%, p=0.007), LV size decreased (LVIDd 7.6±1.2 to 4.9±1.4cm, p<0.001), and myocyte dimensions decreased (cross-sectional area 1247±346 to 638±254μm2, p=0.001). Fmax improved after LVAD (3.6±0.9 to 7.3±1.8mN/mm2, p<0.001), but was still lower than nonfailing (7.3±1.8 vs. 17.6±1.8mN/mm2, p<0.001). An increase in troponin I (TnI) phosphorylation after LVAD was noted, but protein kinase C phosphorylation of TnI decreased. Biochemical changes of other sarcomeric proteins were not observed after LVAD. Conclusions There is significant improvement in LV and myocyte size with LVAD, but there is only partial recovery of EF and myocyte contractility. LVAD support was only associated with biochemical changes in TnI. This suggests that alternate mechanisms might contribute to contractile changes after LVAD and that additional interventions may be needed to alter biochemical remodeling of the sarcomere to further enhance myofilament and organ level recovery.

Cardiac resynchronization sensitizes the sarcomere to calcium by reactivating GSK-3β

“…Similar results have appeared in several prior studies, though they were not specifically highlighted. For example, in HF patients treated with LV assist devices (LVAD), F max (normalized to cell area) was one-fourth that of healthy control levels prior to LVAD insertion and doubled after LVAD insertion (46). However, myocyte size was 4 times greater than normal before LVAD insertion and fell by 50% after LVAD insertion (cells got smaller).…”

Imaging for Ventricular Function and Myocardial Recovery on Nonpulsatile Ventricular Assist Devices

“…5,7,11 The clinical observation regarding the decrease in LV volumes with persistent compromise in LV systolic dysfunction mirrors the observation at the myocyte level. 17 When imaging is used to evaluate myocardial recovery in patients supported with continuous-flow LVADs, underlying LV size and function are best assessed when the LVAD support (flow speed) is turned down. Interestingly, during continuous-flow LVAD support, most patients report significant symptomatic improvement irrespective of LV size and systolic performance.…”

Transmural Heterogeneity of Cellular Level Power Output Is Reduced in Human Heart Failure

“…Another study [11] documents no change. Again, similar to the previous discussion relating to isometric force generation, it is difficult to interpret these data without more information about the transmural source of the sample [11,19,20].…”

“…However, a few studies have measured the effect of heart failure on isometric force generation, with potentially conflicting results. For example, separate studies using epicardial biopsies [10] and samples from unspecified regions of the heart [11] have shown that isometric force is reduced by ~80% in patients with heart failure. Other works, using samples from unspecified regions of the left ventricle, suggests that there is no significant effect of heart failure on maximum isometric force [12][13][14].…”