Transmural Dispersion of Repolarization in Failing and Nonfailing Human Ventricle

Abstract

Rationale: Transmural dispersion of repolarization has been shown to play a role in the genesis of ventricular tachycardia and fibrillation in different animal models of heart failure (HF). Heterogeneous changes of repolarization within the midmyocardial population of ventricular cells have been considered an important contributor to the HF phenotype. However, there is limited electrophysiological data from the human heart. Objective: To study electrophysiological remodeling of transmural repolarization in the failing and nonfailing human hearts. Methods and Results: We optically mapped the action potential duration (APD) in the coronary-perfused scar-free posterior-lateral left ventricular free wall wedge preparations from failing (n‫)5؍‬ and nonfailing (n‫)5؍‬ human hearts. During slow pacing (S1S1‫0002؍‬ ms), in the nonfailing hearts we observed significant transmural APD gradient: subepicardial, midmyocardial, and subendocardial APD80 were 383؎21, 455؎20, and 494؎22 ms, respectively. In 60% of nonfailing hearts (3 of 5), we found midmyocardial islands of cells that presented a distinctly long APD (537؎40 ms) and a steep local APD gradient (27؎7 ms/mm) compared with the neighboring myocardium. HF resulted in prolongation of APD80: 477؎22 ms, 495؎29 ms, and 506؎35 ms for the subepi-, mid-, and subendocardium, respectively, while reducing transmural APD80 difference from 111؎13 to 29؎6 ms (P<0.005) and presence of any prominent local APD gradient. In HF, immunostaining revealed a significant reduction of connexin43 expression on the subepicardium. Conclusions: We present for the first time direct experimental evidence of a transmural APD gradient in the human heart. HF results in the heterogeneous prolongation of APD, which significantly reduces the transmural and local APD gradients. (Circ Res. 2010;106:981-991.)Key Words: heart failure Ⅲ repolarization Ⅲ transmural gradient Ⅲ optical mapping Ⅲ connexin43 H eart failure (HF) claims more than 200 000 lives annually in the US alone. 1,2 Approximately a half of these deaths are sudden and presumably caused by ventricular tachyarrhythmias. Pathophysiological remodeling of cardiac function occurs at multiple levels and includes the alterations in a host of ion channels, Ca 2ϩ -handling proteins, and proteins mediating cell-cell coupling, predisposing to arrhythmias and sudden death. 3 Numerous animal models have shown the importance of such electrophysiological (EP) remodeling in the mechanisms of HF-related arrhythmogenesis. 4 Prolongation of the repolarization is a hallmark of cells and tissues isolated from failing hearts independent of the cause, which has been observed in isolated myocytes 5 and intact ventricular preparations. 4,6 This fundamental change in myocyte biology underlies QT-interval prolongation of the surface ECG in patients with HF. The action potential (AP) prolongation is heterogeneous, resulting in exaggeration of the physiological heterogeneity of electric properties in the failing heart. 1,4 These cellular EP changes were linked to down...

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