Faculty Bibliography

The development of ventricular assist devices (VADs) over the past 5 decades as therapy for advanced heart failure (HF) has been extraordinary. Since the original VAD design by Michael DeBakey in the early 1960s, numerous devices for mechanical circulatory support have been engineered, assessed in preclinical studies, applied to human patients in large multicenter clinical trials, and now, select devices are Food and Drug Administration-approved therapy for advanced HF patients. This review highlights select examples of durable VADs from the engineering aspect of design and conception to experimental studies and clinical application underscoring the remarkable progression of such technology to now becoming the standard of care for many advanced HF patients.

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.