Assessment of myocardial fibrosis by endoventricular electromechanical mapping in experimental nonischemic cardiomyopathy

Abstract

Cardiac fibrosis plays an important prognostic role in nonischemic cardiomyopathy (NICM), making it a potential therapeutic target. Although electromechanical mapping has been used to identify myocardial scar and facilitate intramyocardial intervention in the setting of ischemic heart disease, its application has not been described in NICM. We assessed the detection of myocardial fibrosis by endoventricular electromechanical mapping in an experimental model of NICM. The NOGA® XP system was used to perform left ventricular mapping in twelve sheep that had undergone intracoronary doxorubicin dosing to induce NICM and in six healthy control animals. Results for endocardial voltage and mechanical shortening were evaluated against myocardial fibrosis burden, as determined by delayed-enhancement cardiac magnetic resonance and quantitative histomorphometry. Doxorubicin treatment resulted in dilated cardiomyopathy with moderate-severe impairment of left ventricular ejection fraction. Late gadolinium uptake was present in 9/12 doxorubicin animals, while histological fibrosis was approximately doubled compared to controls and was distributed multisegmentally throughout the left ventricle. Cardiomyopathy was associated with widespread reductions in unipolar and bipolar voltage amplitude and endocardial shortening. Each parameter showed an inverse relationship with the burden of fibrosis. Moreover, unipolar voltage and linear local shortening ratio displayed moderate accuracy for identifying myocardial segments with delayed contrast enhancement or increased fibrosis content, with optimal discriminatory thresholds of 7.5 mV and 11.5%, respectively. In this model of NICM, electromechanical mapping shows potential for delineating segmental differences in fibrosis. Pending clinical evaluation, it may therefore have applicability for directing targeted intramyocardial interventions in nonischemic heart disease.

Reparative Effects of Allogeneic Mesenchymal Precursor Cells Delivered Transendocardially in Experimental Nonischemic Cardiomyopathy

“…However, all interventions were associated with elevations in serum troponin-T, indicating that early myocardial injury may have been caused by the injection process itself or by the cryopreservant agent that was common to both groups. Although the long-term consequences of injection site injury/inflammation are difficult to ascertain, the burden of fibrosis in placebo-injected animals was consistent with the level that we have previously noted in other doxorubicin NICM sheep (21). Effects of MPC in experimental NICM.…”

“…However, corresponding results in large animal or clinical studies have thus far been lacking. Therefore, in the present study, we evaluated MPC therapy in an ovine model of anthracycline-induced cardiomyopathy that consists of reproducible, moderate-severe LV dysfunction, with extensive cardiomyocyte, small-vessel and Purkinje fiber injury and increased myocardial fibrosis (19,21). Transendocardial cell delivery.…”

“…For these reasons, we administered cells by direct, intramyocardial injection, adopting a catheter-based, transendocardial approach, due to it being less invasive and more clinically relevant than open, transepicardial injection. We used 3-dimensional electromechanical navigation to target unhealthy myocardium (21) and achieve multisegmental distribution of injections to enhance the prospects of achieving global LV repair.…”

“…1A and 1B). These threshold values had been determined in a previous validation study (21). The apex and posterior wall were injected less frequently to avoid cardiac perforation and due to difficulty in establishing catheter tip stability near the papillary muscles.…”

Comparison of Transendocardial and Intracoronary CD34 + Cell Transplantation in Patients With Nonischemic Dilated Cardiomyopathy

“…14 Consistent with the findings of preclinical studies, 15 we found significant heterogeneity of myocardial viability and contractile dysfunction in patients with DCM. In our study, we chose the viable regions with the greatest perfusion defect or greatest decrease in linear shortening to target the region of interest, theoretically maximizing the response to stem cell therapy.…”