Antiarrhythmic Engineering of Skeletal Myoblasts for Cardiac Transplantation

Abstract

Abstract-Skeletal myoblasts are an attractive cell type for transplantation because they are autologous and resistant to ischemia. However, clinical trials of myoblast transplantation in heart failure have been plagued by ventricular tachyarrhythmias and sudden cardiac death. The pathogenesis of these arrhythmias is poorly understood, but may be related to the fact that skeletal muscle cells, unlike heart cells, are electrically isolated by the absence of gap junctions. Using a novel in vitro model of myoblast transplantation in cardiomyocyte monolayers, we investigated the mechanisms of transplant-associated arrhythmias. Cocultures of human skeletal myoblasts and rat cardiomyocytes resulted in reentrant arrhythmias (spiral waves) that reproduce the features of ventricular tachycardia seen in patients receiving myoblast transplants. These arrhythmias could be terminated by nitrendipine, an L-type calcium channel blocker, but not by the Na channel blocker lidocaine. Genetic modification of myoblasts to express the gap junction protein connexin43 decreased arrhythmogenicity in cocultures, suggesting a specific means for increasing the safety (and perhaps the efficacy) of myoblast transplantation in patients.

A possible mechanism of halocarbon-induced cardiac sensitization arrhythmias

“…Previously, the FPs have been shown to correlate well with the underlying cellular electrophysiology [8], and this arrangement allowed for evaluation of changes in the dominant pacemaker, a surrogate for ectopic activity, and of conduction velocity [9,10]. Mapping of two-dimensional cardiomyocytes cultures has proven an efficient methodology for exploring arrhythmic risk [9][10][11][12][13][14][15][16].…”

C2C12 skeletal muscle cells adopt cardiac-like sodium current properties in a cardiac cell environment

“…Importantly, a paracrine role for the heart recently was suggested, also in vivo (3), by which stem cell differentiation into cardiomyocytes is driven. Moreover, Abraham et al (1) proposed a paracrine effect of skeletal myoblasts on cardiomyocytes. Medium preconditioned by skeletal myoblasts prolonged AP duration in cardiomyocytes.…”

Cell cultures as models of cardiac mechanoelectric feedback

“…This intermediate level of complexity between cell and tissue provides a quantitative biophysical model that is experimentally accessible to reproducible conditions such as different forms of mechanical perturbations. Unlike conventional tissue preparations, the two dimensional (2-D) monolayer structure can be controlled using methods of tissue engineering to direct the pattern of cell growth (via engineered surfaces and substrates) (Rohr et al, 1991;Bursac et al, 2002) and the composition of cell types (Abraham et al, 2005;Chang et al, 2006), so that potentially, the mechanosensitivity of different cell types or mixtures can be characterized. Because the 2-D cell culture allows rapid superfusion and control of the extracellular environment, they are well suited for detailed biophysical experiments, especially when applying different drugs or molecular interventions to identify signaling pathways of interest in MEF.…”