Electrophysiologic Remodeling of the Left Ventricle in Pressure Overload-Induced Right Ventricular Failure

Objectives The purpose of this study was to analyze the electrophysiologic remodeling of the atrophic left ventricle (LV) in right ventricular (RV) failure (RVF) after RV pressure overload. Background The LV in pressure-induced RVF develops dysfunction, reduction in mass, and altered gene expression, due to atrophic remodeling. LV atrophy is associated with electrophysiologic remodeling. Methods We conducted epicardial mapping in Langendorff-perfused hearts, patch-clamp studies, gene expression studies, and protein level studies of the LV in rats with pressure-induced RVF (monocrotaline [MCT] injection, n = 25; controls with saline injection, n = 18). We also performed epicardial mapping of the LV in patients with RVF after chronic thromboembolic pulmonary hypertension (CTEPH) (RVF, n = 10; no RVF, n = 16). Results The LV of rats with MCT-induced RVF exhibited electrophysiologic remodeling: longer action potentials (APs) at 90% repolarization and effective refractory periods (ERPs) (60 +/- 1 ms vs. 44 +/- 1 ms; p < 0.001), and slower longitudinal conduction velocity (62 +/- 2 cm/s vs. 70 +/- 1 cm/s; p = 0.003). AP/ERP prolongation agreed with reduced Kcnip2 expression, which encodes the repolarizing potassium channel subunit KChIP2 (0.07 +/- 0.01 vs. 0.11 +/- 0.02; p < 0.05). Conduction slowing was not explained by impaired impulse formation, as AP maximum upstroke velocity, whole-cell sodium current magnitude/properties, and mRNA levels of Scn5a were unaltered. Instead, impulse transmission in RVF was hampered by reduction in cell length (111.6 +/- 0.7 mu m vs. 122.0 +/- 0.4 mu m; p = 0.02) and width (21.9 +/- 0.2 mu m vs. 25.3 +/- 0.3 mu m; p = 0.002), and impaired cell-to-cell impulse transmission (24% reduction in Connexin-43 levels). The LV of patients with CTEPH with RVF also exhibited ERP prolongation (306 +/- 8 ms vs. 268 +/- 5 ms; p = 0.001) and conduction slowing (53 +/- 3 cm/s vs. 64 +/- 3 cm/s; p = 0.005). Conclusions Pressure-induced RVF is associated with electrophysiologic remodeling of the atrophic LV. (J Am Coll Cardiol 2012;59:2193-202) (C) 2012 by the American College of Cardiology Foundation