The arrhythmic substrate of ventricular tachycardias in many structural heart diseases is located in the epicardium, often resulting in poor outcomes with currently available therapies. Cardiosphere-derived cells (CDCs) have been shown to modify myocardial scarring. A total of 19 Large White pigs were infarcted by occlusion of the mid-left anterior descending coronary artery for 150 min. Baseline cardiac magnetic resonance (CMR) imaging with late gadolinium enhancement sequences was obtained 4 weeks post-infarction and pigs were randomized to a treatment group (intrapericardial administration of 300,000 allogeneic CDCs/kg), (n = 10) and to a control group (n = 9). A second CMR and high-density endocardial electroanatomical mapping were performed at 16 weeks post-infarction. After the electrophysiological study, pigs were sacrificed and epicardial optical mapping and histological studies of the heterogeneous tissue of the endocardial and epicardial scars were performed. In comparison with control conditions, intrapericardial CDCs reduced the growth of epicardial dense scar and epicardial electrical heterogeneity. The relative differences in conduction velocity and action potential duration between healthy myocardium and heterogeneous tissue were significantly smaller in the CDC-treated group than in the control group. The lower electrical heterogeneity coincides with heterogeneous tissue with less fibrosis, better cardiomyocyte viability, and a greater quantity and better polarity of connexin 43. At the endocardial level, no differences were detected between groups. Intrapericardial CDCs produce anatomical and functional changes in the epicardial arrhythmic substrate, which could have an anti-arrhythmic effect.
Clinical data suggest that cardiosphere-derived cells (CDCs) could modify post-infarction scar and ventricular remodeling and reduce the incidence of ventricular tachycardia (VT). This paper assesses the effect of CDCs on VT substrate in a pig model of postinfarction monomorphic VT. We studied the effect of CDCs on the electrophysiological properties and histological structure of dense scar and heterogeneous tissue (HT). Optical mapping and histological evaluation were performed 16 weeks after the induction of a myocardial infarction by transient occlusion of the left anterior descending (LAD) artery in 21 pigs. Four weeks after LAD occlusion, pigs were randomized to receive intracoronary plus trans-myocardial CDCs (IC+TM group, n:10) or to a control group. Optical mapping (OM) showed an action potential duration (APD) gradient between HT and normal tissue in both groups. CDCs increased conduction velocity (53 ± 5 vs. 45 ± 6 cm/s, p < 0.01), prolonged APD (280 ± 30 ms vs. 220 ± 40 ms, p < 0.01) and decreased APD dispersion in the HT. During OM, a VT was induced in one and seven of the IC+TM and control hearts (p = 0.03), respectively; five of these VTs had their critical isthmus located in intra-scar HT found adjacent to the coronary arteries. Histological evaluation of HT revealed less fibrosis (p < 0.01), lower density of myofibroblasts (p = 0.001), and higher density of connexin-43 in the IC+TM group. Scar and left ventricular volumes did not show differences between groups. Allogeneic CDCs early after myocardial infarction can modify the structure and electrophysiology of post-infarction scar. These findings pave the way for novel therapeutic properties of CDCs.
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