Heart rate reduction improves biventricular function and interactions in experimental pulmonary hypertension

Abstract

The objective of the present study was to investigate mechanisms of heart rate (HR) reduction on biventricular function and interactions in experimental pulmonary arterial hypertension (PAH). We compared cardiac cycle mechanics and interventricular interactions in 15 sham, 8 monocrotaline-PAH, 9 PAH + carvedilol, and 8 PAH + ivabradine rats. We used echocardiography to assess biventricular function, timing of cardiac cycle events, and septal position in PAH rats and related HR reduction effects on biventricular function measured by echocardiography and conductance catheter. HR was 302 beats/min in PAH + carvedilol rats and 303 beats/min in PAH + ivabradine rats versus 359 beats/min in PAH rats (P < 0.01). Sham rats showed temporal alignment between right ventricular (RV) and left ventricular (LV) events, whereas PAH rats showed increased biventricular isovolumic contraction times (ICTs), delayed RV peak radial motion, and impaired early relaxation. Temporal malalignment was associated with decreased tricuspid and mitral diastolic annular peak velocities (3.7 vs. 6.4 and 3.4 vs. 5.3 cm/s, respectively, P < 0.001), delayed and shortened biventricular filling, and reduced early diastolic LV filling velocity (0.56 vs. 0.81 cm/s, P < 0.01). LV eccentricity index was increased at systole (2.0 vs. 1.2, P < 0.001), early diastole (2.1 vs. 1.1, P < 0.001), and end diastole (1.6 vs. 1.1, P < 0.001) in PAH versus sham rats. HR reduction with carvedilol and ivabradine shortened biventricular ICTs and the time to biventricular peak radial motion, improved RV relaxation, and increased early diastolic LV filling through reduced interventricular interaction and improved timing. These improvements corresponded with enhanced hemodynamics (increased cardiac output, RV contractility, and diastolic relaxation). In conclusion, HR reduction by carvedilol and ivabradine improves biventricular filling and hemodynamics in experimental PAH through realignment of RV-LV cardiac cycle events and improved interventricular interactions.