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

Objectives: To investigate mechanisms of heart rate (HR) reduction on biventricular function and interactions in experimental pulmonary arterial hypertension (PAH). Methods: 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 effect on biventricular function measured by echocardiography and conductance catheter. Results: HR was 302 in PAH+carvedilol , 303 in PAH+ivabradine vs. 359 bpm in PAH (p<0.01, respectively). Shams showed temporal alignment between right (RV) and left ventricular (LV) events; while PAH-rats showed increased biventricular isovolumic contraction times (ICT), delayed RV peak-radial motion and impaired early relaxation. Temporal malalignment was associated with decreased tricuspid and mitral diastolic annular peak velocities (E9) (3.7 vs. 6.4 and 3.4 vs. 5.3, p<0.001 respectively), delayed and shortened biventricular filling and reduced early-diastolic LV- filling (E) velocity (0.56 vs. 0.81, p<0.01). LV eccentricity index was increased in 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 vs. shams. HR reduction with carvedilol and ivabradine shortened biventricular ICT, time-to biventricular peak-radial motion, improved RV relaxation and increased early-diastolic LV filling through reduced inter-ventricular interaction and improved timing. These improvements corresponded with enhanced hemodynamics (increased cardiac-output, RV contractility and diastolic relaxation). Conclusions: HR reduction by carvedilol and ivabradine improve biventricular filling and hemodynamics in experimental PAH through re-alignment of RV-LV cardiac-cycle events and improved interventricular interactions.