(H-304) Right Ventricular Architecture Determines Functional Adaptation in Pulmonary Hypertension

Introduction:: Right ventricle (RV) pressure overload in patients with pulmonary hypertension (PH) initiates progressive RV remodeling including alteration of the myofiber architecture, hypertrophy, and RV free wall (RVFW) stiffening. Studies suggest RV functional outcome is not dependent on the severity of pressure overload but rather by the adaptive response of the RV to increased pressure. While global indices of RV function such as ejection fraction, RV-pulmonary artery (RV-PA) coupling, and ventricular strains have been used to assess prognosis in PH, there remains a need for novel structurally-informed functional metrics that may provide insight into the transition from adaptive to maladaptive RV remodeling. In this work, we use of two rodent models of PH, each with unique adaptive responses to PH, and diffusion-weighted cardiac magnetic resonance imaging (DWI) to investigate the effect of RV architectural remodeling on RV function and RV-PA coupling.


Materials and Methods:: PH was induced in 24 rodent subjects by SU5416 injection (20 mg/kg sq.) followed by 3 weeks of hypoxia (10% FiO₂) and 1-4 weeks of normoxia. Two rodent strains were used: Sprague-Dawley (SD, n=12) and Fischer (CDF, n=12). Half of the animals were used as control. Control animals were injected with an equal volume of diluent and housed at normoxia for 4 weeks. Echocardiography and hemodynamic measurements characterizing RV function were obtained. DWI scans were performed on excised hearts and reconstruction of regional myocardial architecture was obtained. Transmural helix angle distribution was assessed in the entire RVFW region (Fig. 1).

Results, Conclusions, and Discussions:: Key differences in hemodynamic and coupling measurements were noted between the two PH rat models. RV stroke volume (SV) was significantly decreased in CDF-PH rats. In comparison to SD-PH rats, CDF-PH rats showed a greater reduction in TAPSE/RVSP (a measure of RV-PA coupling) and a higher RV systolic pressure (Fig. 1A-B). These results indicate the CDF-PH model has a more severe hemodynamic profile in comparison to the SD-PH model. In contrast to the PH rats with severe RV maladaptation, PH rats with mild RV maladaptation showed a decrease in helical range of fiber orientation in the RVFW (Fig. 1C-D), preserved global circumferential strain, and exhibited less reduction in RV-PA coupling (Fig. 1B). Helical range correlated positively with coupling and stroke volume index (Fig. 2B-C). Our findings suggest that architectural remodeling in the RVFW is a key structural change behind the adaptations of RVFW contractile patterns in PH at the tissue-level that could translate to the curtailment or advancement of RV-PA uncoupling at the organ-level. Preclinical data analysis suggest that adaptive RV architectural remodeling could improve RV function in PH. Our findings highlight the need to assess RV architecture within routine screenings of PH patients to improve our understanding of its prognostic and therapeutic significance in PH.



Acknowledgements: : Dr. Avazmohammadi was funded by National Institutes of Health grant R00HL138288. Dr. Choudhary was funded by National Heart, Lung, and Blood Institute grants R01HL128661 and R01HL148727 and Veterans Affairs Clinical Science Research and Development grant I01CX001892.