Faculty Bibliography

The cardiac transplantation program at Cleveland Clinic has performed 1,627 adult orthotopic heart transplants, with a current 1-year survival of 96% and a 3-year survival of 82%. The change in the heart allocation system in 2006 has affected our Center by both reducing the number of transplants we perform annually and increasing the percentage of recipients on MCS at the time of transplant. Despite the increased utilization of left ventricular assist devices (LVADs) as a bridge to transplant, we continue to maintain excellent outcomes. The major clinical advances in LVAD technology have allowed us to expand this therapy to ineligible transplant patients, with outcomes that are continually improving. Nevertheless, the field of MCS as permanent therapy is still in its infancy. The number of patients who can benefit from this technology in the U.S. alone is in the thousands, but refinements in patient selection and management are needed to further advance this lifesaving therapy.

BACKGROUND: Several arrhythmogenic mechanisms have been inferred from animal heart failure models. However, the translation of these hypotheses is difficult because of the lack of functional human data. We aimed to investigate the electrophysiological substrate for arrhythmia in human end-stage nonischemic cardiomyopathy. METHODS AND RESULTS: We optically mapped the coronary-perfused left ventricular wedge preparations from human hearts with end-stage nonischemic cardiomyopathy (heart failure, n=10) and nonfailing hearts (NF, n=10). Molecular remodeling was studied with immunostaining, Western blotting, and histological analyses. Heart failure produced heterogeneous prolongation of action potential duration resulting in the decrease of transmural action potential duration dispersion (64 +/- 12 ms versus 129 +/- 15 ms in NF, P<0.005). In the failing hearts, transmural activation was significantly slowed from the endocardium (39 +/- 3 cm/s versus 49 +/- 2 cm/s in NF, P=0.008) to the epicardium (28 +/- 3 cm/s versus 40 +/- 2 cm/s in NF, P=0.008). Conduction slowing was likely due to connexin 43 (Cx43) downregulation, decreased colocalization of Cx43 with N-cadherin (40 +/- 2% versus 52 +/- 5% in NF, P=0.02), and an altered distribution of phosphorylated Cx43 isoforms by the upregulation of the dephosphorylated Cx43 in both the subendocardium and subepicardium layers. Failing hearts further demonstrated spatially discordant conduction velocity alternans which resulted in nonuniform propagation discontinuities and wave breaks conditioned by strands of increased interstitial fibrosis (fibrous tissue content in heart failure 16.4 +/- 7.7 versus 9.9 +/- 1.4% in NF, P=0.02). CONCLUSIONS: Conduction disorder resulting from the anisotropic downregulation of Cx43 expression, the reduction of Cx43 phosphorylation, and increased fibrosis is likely to be a critical component of arrhythmogenic substrate in patients with nonischemic cardiomyopathy.