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Effects of Endothelin-1 Chronic Stimulation on Electrical Restitution, Beat-to-beat Variability of Repolarization, and Ventricular Arrhythmogenesis

Liu, Tao MD*,†; Qin, Mu MD*,†,‡; Shi, Shao Bo MD*,†; Chen, Zhen MMSc§; Wang, Teng MMSc; Huang, Cong-Xin MD, PhD*,†

Journal of Cardiovascular Pharmacology: December 2013 - Volume 62 - Issue 6 - p 549–558
doi: 10.1097/FJC.0000000000000015
Original Article

Abstract: Chronically elevated levels of endothelin-1 (ET-1) have been detected in several cardiovascular diseases. In this study, we investigated the chronic effects of ET-1 on the electrophysiological characteristics expected to influence the genesis and maintenance of ventricular arrhythmia (VA). Rabbits were randomized to ET-1 (ET-1 group) or 0.9% saline (control group) for 2 weeks. The S1–S2 protocol and S1–S1 dynamic pacing were performed to assess the action potential duration restitution (APDR) and to induce APD alternans or VA in 4 sites of Langendorff-perfused rabbit hearts. The beat-to-beat variability of repolarization was quantified as short-term variability and long-term variability. Compared with the control group, chronic ET-1 administration significantly prolonged QT intervals, APD at 90% repolarization (APD90), and effective refractory period (ERP), steepened the maximum slopes of the APDR curve, decreased the ERP/APD90 ratio, and increased the spatial dispersions of APD90, ERP, and maximum slopes (P < 0.05 for all). Moreover, chronic ET-1 administration markedly increased the short-term variability and long-term variability (P < 0.01 for all). APD alternans occurred in both groups, but the threshold of APD alternans was decreased at all sites in the ET-1 group (P < 0.01 for all). We also observed that chronic ET-1 stimulation significantly increased the incidence and duration of the VA episodes. These results suggest that chronic stimulation with ET-1 facilitated VA by steepening the APDR curve and increasing the spatial dispersion of APDR and beat-to-beat variability of repolarization.

*Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China;

Cardiovascular Research Institute, Wuhan University, Wuhan, China;

Department of Cardiology, The First Clinical Medical College of Three Gorges University, Yichang, China; and

§Department of Emergency, Central Hospital of Wuhan, Wuhan, China.

Reprints: Cong Xin Huang, MD, PhD, Department of Cardiology, Renmin Hospital of Wuhan University, No. 238 Jiefang Road, Wuchang District, Wuhan 430060, Hubei Province, China (e-mail:

Supported by the National Key Basic Research Development Program of China (The “973” Program) (No. 2012CB518604) and the Fundamental Research Funds for the Central Universities of China (No. 201130202020023).

The authors report no conflicts of interest.

T. Liu and M. Qin have contributed equally.

Received June 06, 2013

Accepted August 19, 2013

© 2013 by Lippincott Williams & Wilkins.