Evidence of a Pro-Arrhythmic Substrate in the Failing Right Ventricle of Pulmonary Hypertensive Rats

Abstract

Arrhythmic risk is increased in patients with heart failure. We have investigated the arrhythmic state of the failing right ventricle in a model of pulmonary hypertension (PAH).Wistar rats were injected intraperitoneally with monocrotaline (MCT, 60 mg/kg) to induce PAH and right ventricular failure within 3-4 weeks and compared to age-matched saline-injected animals (CON).In vivo measurement of ECG parameters using radiotelemetry indicated modification of T wave-parameters in MCT treated animals e.g. a prolonged QT interval (CON 49.7±2.0 vs. MCT 76.2±2.5 ms, P<0.001) and time from the peak to the end of the T-wave (Tpe, CON 25±1.8 vs. MCT 33.1±1.7 ms, P = 0.007) (CON n = 6, MCT n = 7).Animals were humanely killed upon showing clinical symptoms of HF. Monophasic action potentials (MAPs) were recorded at the right ventricular epicardial surface of isolated hearts and a S1-S2 protocol used to construct standard APD restitution curves. MAP duration was significantly prolonged in failing hearts (MAP90, 39.9±1.9 ms in CON vs. 80.7±3.5 ms in MCT, P<0.001) and standard restitution slopes were steeper (mean maximum slope was 0.18±0.02 CON vs. 0.73±0.28 MCT, P<0.001).Optical action potentials were recorded at stimulation frequencies between 5-12 Hz using the voltage-sensitive dye di-4-ANEPPS and dynamic APD and conduction velocity restitution curves measured. The failing right ventricle exhibited steeper restitution and conduction velocity restitution curves (mean maximum slope for conduction velocity was 0.013±0.004 MCT vs. 0.002±0.001 CON, P<0.001). At high pacing frequencies, arrhythmias were induced in failing but not in control hearts.T-wave modification, APD prolongation, steeper APD and conduction velocity restitution curves are typically associated with a pro-arrhythmic state. We conclude that the failing right ventricle of pulmonary hypertensive rats have an elevated risk of developing arrhythmias. The underlying mechanisms are under investigation.