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...

Background Several arrhythmogenic mechanisms have been inferred from animal heart failure (HF) models. However, the translation of these hypotheses is difficult due to lack of functional human data. We aimed to investigate the electrophysiological substrate for arrhythmia in human end-stage non-ischemic cardiomyopathy. Methods and Results We optically mapped the coronary-perfused left ventricular wedge preparations from human hearts with end-stage non-ischemic cardiomyopathy (HF, n=10) and non-failing hearts (NF, n=10). Molecular remodeling was studied with immunostaining, Western blotting, and histological analyses. HF produced heterogeneous prolongation of action potential duration (APD) resulting in the decrease of transmural APD dispersion (64±12 ms vs 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 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 wavebreaks conditioned by strands of increased interstitial fibrosis (fibrous tissue content in HF 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 non-ischemic cardiomyopathy.

No abstract