Abstract Body: Introduction: Pulmonary hypertension (PH) is characterized by increased right ventricular (RV) afterload and is frequently accompanied by significant RV remodeling and dysfunction. Mechanistic contributors to RV remodeling, such as alterations in active force generation, have been independently linked to poor survival outcomes. However, the relationship between passive forces and impaired contractility, as well as the underlying transition from adaptive to maladaptive remodeling in PH, remains unclear. In this study, we hypothesize that a combined index of passive stress and active contractility is a key indicator of maladaptive RV remodeling in PH.
Methods: PH was induced in Sprague-Dawley rats (PH; n =4) by an injection of SU5416, followed by 3 weeks of hypoxia and 1 week of normoxia. Wild-type rats receiving a vehicle and maintained normoxia were used as controls (CTL; n = 4). Mechanical testing of the RV free wall (RVFW) was used to assess active force generation and contractility. RVFW samples were chemically skinned in 12.5% Triton X-100 and stored overnight. Isometric testing: The passive RVFW was stretched to 20% of its initial length, immersed in an activation solution and activated at pCa 4.5. Isotonic testing: Contractility was assessed using 1-mm-thick RVFW strips, mounted with one end fixed and the other free to contract in the activation solution.
Results: PH rats exhibited enhanced passive stiffening compared to CTL (Fig. 1A). Contractility, measured as maximal shortening of the RVFW strips between relaxed and contracted states (Fig. 1B), showed a trend toward reduced shortening in PH rats versus CTL, but this difference was not statistically significant (Fig. 1C). Notably, the combined stress-contractility ratio (SCR) was significantly decreased in PH rats, with narrower confidence intervals than those of peak stress or contractility measured individually (Fig. 1D).
Conclusion: The measurement of SCR as a mechanistic marker highlights the competing contributions of active contractility and passive stiffening to overall RV remodeling. Identifying the role and relative contribution of individual remodeling events is highly significant for optimizing treatment strategies in PH patients, potentially targeting wall stiffening and/or improving contractility.