Characterization of a Pulmonary Hypertension Model Caused by Left Heart Disease in Mouse

Objectives: Pulmonary hypertension (PH) due to left heart disease (Group 2) is the most prevalent type of PH as it covers approximately 60 to 80% of patients. The disease is characterized by an elevated mean pulmonary arterial pressure (mPAP) of ≥25 mm Hg and reduced survival. The underlying molecular mechanisms are still largely unknown and there is no specific medication for this type of PH. To explore the pathophysiology of the disease in detail and to unravel new therapeutic targets, we created a mouse model that mimics type 2 PH.

Methods: For this purpose, transverse aortic constriction (TAC) was performed in 10-week-old C57BL/6 mice. A standardized diameter of constriction was generated by ligating the aorta between the brachiocephalic artery and the left carotid artery using a 26-G needle. Echocardiography and right and left heart catheter measurements (RHC, LHC; 1F pressure catheter, Millar) were applied to determine functional changes after 3 and 8 weeks. Mice were killed, hearts and lungs were harvested, and histological analysis was performed.

Results: After TAC hearts showed hypertrophy verified by measurement of the ratio of heart weight/tibia length. Cross-sectional areas of single cardiomyocytes from the left ventricle (LV) were significantly increased after 3 and 8 weeks also in the RV (LV: 245 ± 7 μm², n = 5 (sham) vs. 448.5 ± 23 μm², n = 7 (TAC), p < 0.001; RV: 184.2 ± 11 μm², n = 5 (sham) vs. 251 ± 13 μm², n = 7 (TAC), p < 0.01). Wall thickness of pulmonary arteries (24.5 ± 1.3%, n = 5 (sham) vs 32 ± 1.3%, n = 7 (TAC), p < 0.01) and interstitial collagen deposition (26.4 ± 0.7%, n = 5 (sham) vs. 59 ± 1.5%, n = 7 (TAC), p < 0.001) also significantly increased after 8 weeks. Echocardiography revealed significant LV wall thickening and impairment of LV function over time, indicators of enhanced cardiac remodeling. Invasive pressure measurements showed significant increased LV pressures at 3 (85.9 ± 3.7 mm Hg, n = 6 (sham) vs. 108.3 ± 5.7 mm Hg, n = 6 (TAC), p < 0.01) and 8 weeks following TAC (87.8 ± 3.1 mm Hg, n = 6 (sham) vs. 123.4 ± 2.2 mm Hg, n = 7 (TAC), p < 0.001). RV pressures were increased after 8 weeks of TAC compared to sham operated mice (22.8 ± 1.4 mm Hg, n = 4 (sham) vs. 26.3 ± 0.6 mm Hg, n = 5 (TAC), p < 0.05).

Conclusion: In summary, the chronic TAC model is able to mimic PH Group 2. We found time-dependent LV and RV hypertrophy, adverse cardiac remodeling, and structural changes of the lung tissue due to the changed hemodynamics. Future experiments will focus on direct and indirect signs of PH and therapeutic approaches.