(B-46) Integrated right ventricular-pulmonary artery biomechanics in pulmonary hypertension

Introduction:: Pulmonary hypertension (PH) is defined as an elevation in mean pulmonary arterial pressure and is believed to affect 1% of the world population [1]. PH leads to the remodeling of the pulmonary artery (PA) and pulmonary vasculature following the increased resistance in the downstream capillary bed, requiring a larger RV afterload to maintain the flow rate at the capillaries. The RV contracts harder to achieve this increased pressure head leading to RV stiffening and remodeling. Despite significant advances in studying RV and PA remodeling, the correlation between RV and PA remodeling remains understudied. Our objectives in this study were to i) investigate the correlation between RV and proximal PA stiffening events and ii) deconvolute the effects of stiffening and narrowing in the pulmonary vasculature on the stress experienced by the RV free wall (RVFW).


Materials and Methods:: A mild model of PH was developed by placing Sprague Dawley (SD) rats (n=6) in a hypoxia (Hx) chamber (10% O2) for 3 weeks. A severe model of PH was developed by injecting SU5416 (20 mg/kg sc) into Fischer (CDF) (n=6) and placing them in a hypoxia chamber for 3 weeks, followed by 1 week of normoxia (SuHx). The respective controls (N=6 SD and N=6 CDF) were placed in normoxia and the CDF controls were injected with vehicle instead of Sugen5416. RVFW and proximal PA tissues were harvested and subjected to biaxial and uniaxial loading, respectively. To analyze the PA remodeling, the pulmonary vasculature was reconstructed from µCT imaging (Fig. 2A). A 1-D fluid-structure interaction (FSI) model, originally developed by Colebank et al. [3], was extended to include nonlinear vessel elasticity. The pressure at the inlet of the pulmonary vasculature was translated into the stress on the RVFW via our integrated RV-PA model. The stiffness and resistance of the PA vasculature were altered to determine the contributions of narrowing and stiffening of the pulmonary vasculature on RVFW stress.


Results, Conclusions, and Discussions:: Results and Discussion: RVFW stiffness increased in both mild and severe PH, but the increase observed in the case of SuHx was more substantial (SuHx - 264.16±58.86 vs 1070.05±248.23 kPa; Hx - 231.29±67.06 vs 422.26±82.06 kPa). There was a strong correlation between the change in RVFW stiffness and the alteration in RV-PA coupling (Fig. 1). These results indicate a strong relationship between RVFW remodeling and RV-PA uncoupling, which is the hallmark of RV maladaptation and triggers RV failure. The uniaxial testing of the PA specimen revealed that the PA stiffness increased significantly in the circumferential direction for the SuHx rats, but mildly decreased in the Hx rats (SuHx - 280.13±215.79 vs 876.95±437.27 kPa; Hx - 296.23±121.36 vs 163.40±54.20 kPa). Based on the results from 1-D FSI simulations (Fig. 2B), the combined effect of the remodeling events (10x vascular resistance and 3x vascular stiffness) triples the RV afterload, with vessel stiffening being an important contributor. Our results suggest that stiffening of the pulmonary vasculature contributes significantly more to the increase of RV afterload compared to increased vascular resistance.

Conclusions: Results from the study indicate that both the RVFW and pulmonary vasculature undergo significant remodeling due to PH. Distinguishing the contributions of various vascular remodeling events on the function of the RV can provide new insights into risk-stratification markers and aid in identifying optimal therapeutic targets.




Acknowledgements (Optional): : Acknowledgments: RA was supported by the NIH, under grant No. R00HL138288.


References (Optional): : References: [1] Hoeper, M. M. et al. Deutsches Arzteblatt international 114, 73-84 2017.[2] Knutsen, R. H., et al. J. Vis. Exp. (160), e61242, 2020. [3] Colebank, M. J. et al. J. The Royal Soc. Interface 16, 20190284 2019