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Ambardekar Lab

Heart failure (HF) affects nearly 5 million Americans, and despite two decades of advancements that have improved outcomes, a significant number of patients progress to end-stage HF, with nearly 250,000 deaths annually. Treatment options for end-stage HF are largely limited to cardiac transplantation and mechanical circulatory support devices such as the left ventricular assist device (LVAD). The mechanical unloading of the left ventricle (LV) with a LVAD and the subsequent restoration of cardiac output results in improvements in HF symptoms, functional status, quality of life, and end-organ perfusion. In addition to these systemic effects, some patients undergoing LVAD support have demonstrated clinical evidence of improvement in function of the native LV, termed reverse remodeling. Such organ level improvements include decreased LV chamber size, decreased LV mass, and improved LV ejection fraction (EF). Tissues studies from before and after LVAD placement have shown that a variety of pathologic markers tend to improve or normalize during LVAD support, and two single centers have reported sufficient recovery of LV function during LVAD support to allow for LVAD explantation, raising the concept of LVADs as a bridge to recovery. Unfortunately, larger multi-institutional studies have failed to replicate such promising results, and very few LVADs are successfully explanted in clinical practice.

There is currently a gap between known clinical markers of reverse remodeling with LVAD support and the cellular and molecular mechanisms behind these improvements. The long-term focus of our research has been the evaluation of myocyte contractility and biochemistry at the most fundamental contractile level of the heart – the sarcomere. Force development in muscle is ultimately the result of actin and myosin interactions and cross-bridge cycling within the sarcomere. These processes are, at least in part, regulated by modifications of the sarcomeric contractile proteins of troponin I (TnI), myosin binding protein C (MyBPC), and regulatory myosin light chain (MLC-2).

We have previously assessed sarcomeric contractility by measuring direct isometric force of skinned muscle preparations before and after LVAD placement. We have found that contractile dysfunction at the level of the sarcomere is present in failing hearts and parallels organ level contractile dysfunction as assessed by circumferential strain and strain-rate, longitudinal strain and strain-rate, and EF. We have also shown that there is partial recovery in maximum developed sarcomeric force with LVAD, but that LVAD supported myocyte forces were still half of that seen in nonfailing hearts. The persistence of sarcomeric contractile dysfunction may be one of the reasons most LVADs are unable to be successfully explanted in clinical practice. In assessing sarcomeric biochemical alterations after LVAD support, we have found changes in TnI phosphorylation that may account for some of the partial improvement in sarcomeric force. Other sarcomeric contractile proteins revealed minimal changes in biochemistry. This would suggest that additional interventions (in addition to mechanical unloading with LVAD) may be needed to optimize TnI phosphorylation and/or modify other sarcomeric protein biochemistry to further enhance sarcomeric and organ level recovery. The over-arching goal of our current research is to define whether prolonged unloading with a LVAD has deleterious effects on sarcomeric (and subsequently myocardial) contractile function and to test whether the additional intervention of pharmacologic α/β-blocker medical therapy during LVAD support is a potential strategy that may be employed in the future to enhance LV recovery during LVAD support.