Pulmonary Hypertension Increases Left Ventricular Chamber Stiffness Through Ventricular Interdependence and Is Attenuated by Pulmonary-Targeted SERCA2a Gene Therapy

Background: Prognosis in patients with left ventricular (LV) failure is significantly worse when accompanied by pulmonary hypertension (PH). We hypothesized that right ventricular (RV) pressure overload negatively influences LV function through ventricular interdependence, and that attenuation of PH would attenuate this adverse interaction. Methods: Chronic post-capillary PH was induced by partial pulmonary vein banding in Yorkshire pigs. Animals underwent echocardiography and invasive LV pressure-volume relationship studies 2 months after intra-airway delivery of adeno-associated virus (AAV)-1 carrying the Sarco/endoplasmic reticulum Ca2+ ATPase (SERCA2a) gene or saline. LV function and morphology were compared among PH treated with saline (PH+Saline, n=5), AAV1.SERCA2a (PH+SERCA group: n=7), and naïve (n=8) animals. Results: PH+Saline pigs had elevated mean pulmonary artery pressure, lower cardiac output, and increased RV mass, but these changes were attenuate in the PH+SERCA group. The RV-to-LV diameter ratio was significantly larger in the PH+Saline group than in both the naïve and PH+SERCA groups (p=0.006), with smaller LV eccentricity index (p=0.01). LV systolic parameters as well as relaxation parameters (dP/dt minimum and tau) were not different among the groups. Meanwhile, LV pressure-volume relationship during the preload reduction revealed significantly increased LV chamber stiffness in the PH+Saline group compared to sham group, whereas the change in relationship was attenuated in the PH+SERCA group (β coefficient: PH+Saline 0.094±0.027, PH+SERCA2a 0.058±0.018, naïve 0.043±0.017; P=0.002). Conclusion: RV pressure overload associated with PH increases LV chamber stiffness. Attenuation of PH with SERCA2a gene therapy attenuated the increase in LV chamber stiffness in a pig model of chronic post-capillary PH.