Abstract 15271: Right Ventricular Hemodynamic and Cellular Changes in a Mouse Model of Severe Pulmonary Arterial Hypertension
Introduction: Pulmonary arterial hypertension (PAH) is the most severe form of pulmonary hypertension due to its rapid progression to right ventricular (RV) failure. However, the mechanisms of RV failure in PAH are largely unknown. Here, we investigated RV dysfunction during PAH progression using a mouse model. We hypothesized that chronic pressure overload leads to progressive changes in RV structure and function and eventual RV dysfunction.
Methods: Progressively more severe PAH was induced in C57BL6 mice by exposing animals to weekly treatments of SUGEN (SU5416) combined with hypoxia for 14, 28 and 56 days. Age-matched untreated mice were used as controls. In vivo RV pressure-volume loops were obtained and analyzed using a previously established method. In additional groups of mice treated identically, skinned RV trabeculae were used to examine the effect of PAH on sarcomere length (SL)-dependent changes in mechanical properties.
Results: With PAH progression, RV afterload increased while RV ejection fraction decreased monotonically (p<0.05). Cardiac output remained constant. RV hypertrophy occurred early in PAH progression (14-day) and then plateaued (p<0.05). RV contractility increased initially but then remained at control levels in later, severe PAH (56-day). These changes led to a preserved ventricular-vascular coupling efficiency (Ees/Ea) early in PAH but a decreased Ees/Ea in severe PAH (p<0.05). In skinned RV trabeculae, the Ca2+ sensitivity of force (pCa50) initially increased (p<0.05) but then remained at control levels as PAH progressed; passive force and maximum Ca2+ activated force were elevated and remained elevated as PAH progressed (p<0.05); and SL-dependent changes in mechanical properties did not change dramatically with PAH.
Conclusions: In the presence of severe pulmonary arterial pressure elevation and RV hypertrophy, we observed impaired RV function at both the whole-organ and cellular levels. The unchanged SL-dependent mechanical properties of RV trabeculae imply a preserved Frank-Starling mechanism even with RV dysfunction. Our results suggest RV remodeling leads to RV dysfunction with increasing duration of SUGEN+hypoxia exposure, which mimics changes in RV function with PAH progression found clinically.
- © 2013 by American Heart Association, Inc.