David Benoist, Olivier Bernus*, Ed White
Multidisciplinary Cardiovascular Research Centre,
*o.bernus@leeds.ac.uk
Arrhythmias are a major cause of death in patients with heart failure (HF). The arrhythmic risk of a failing heart can be estimated from parameters including action potential duration (APD) restitution curves. The aim of this work was to evaluate restitution curves in the rat model of pulmonary artery hypertension (PAH) and right ventricular failure, induced by monocrotaline (MCT).
Male Wistar rats (200g) were injected with MCT (60 mg/kg) to induce PAH and right ventricular failure (HF) or with saline (CON). Isolated hearts were mounted on a Langendorff apparatus and perfused at 37°C. Standard APD restitution curves were constructed by recording monophasic action potentials (MAPs) at the right ventricular epicardial surface with a S1-S2 pacing protocol. Alternatively a voltage-sensitive dye di-4-ANEPPS was used to record optical action potentials at pacing frequencies between 5-12Hz, to construct dynamic APD and conduction velocity restitution curves.
MAP duration in HF was significantly prolonged at 90% repolarisation (HF, 80.7±3.5 ms, CON 39.9±1.9 ms n= 14-17 hearts) and optical action potentials showed the same trend. HF standard and dynamic APD restitution curves had steeper slopes than CON (e.g. for standard restitution curves, mean maximal slope was 0.73±0.28 in HF and 0.18±0.02 in CON). Moreover, the standard APD restitution curve highlighted a prolonged refractory period in failing hearts (+115% vs. control). Conduction velocity restitution curves also had steeper slopes in HF (0.013±0.004 vs. 0.002±0.001). When pacing above 10Hz, arrhythmias were induced in HF but not in CON.
APD prolongation, steeper APD and conduction velocity restitution curves are typically associated with a pro-arrhythmic state (Tomaselli et al. 1999, Wilson et al. 2007). We therefore conclude that the failing right ventricle is more susceptible to develop arrhythmias in this model.
References
Tomaselli GF, Marbán
E. Electrophysiological remodelling in hypertrophy and heart failure. Cardiovasc. Res. 42: 270-283, 1999.