Macrophages Infiltration is Associated with Maladaptive Remodeling of the Right Ventricle in an Experimental Model of Pulmonary Hypertension

Objectives: Macrophages play a central role in the development of pulmonary vascular damages in pulmonary hypertension (PH). The involvement of macrophages in right ventricular (RV) remodeling related to chronic pressure overload has been poorly examined.

Methods: Experimental PH was induced in 7 athymic rats (PH group) by single injection of the vascular endothelial growth factor receptor blocker sumatinib (40 mg/kg). A control group including 6 athymic rats only received an injection of the sumatinib vehicle. The right ventricular fractional area change (RVFAC) and the RV end-diastolic diameter (RVEDD) were followed using echocardiography. At 4 weeks, the RV systolic pressure (RVSP) was recorded and the density of CD68 in the RV assessed histologically.

Results: Sumatinib injection induced a significant increase in RVSP at 4 weeks compared with controls (66 ± 9 vs. 24 ± 6 mm Hg, p < 0.01). RV pressure overload was associated with a lower RVFAC (0.27 ± 0.04 vs. 0.57 ± 0.08, p < 0.01) and with a higher RVEDD (5.6 ± 0.5 vs. 2.3 ± 0.2, p < 0.01). The average RV macrophages infiltration was significantly higher in the PH group (15.2 ± 5.2% vs. 2.6 ± 1.5%, p < 0.01) and was strongly associated with RVFAC through an inverse linear relationship (R²=0.74, p < 0.01). The elevated rate of macrophages in the myocardium was also associated with a higher degree of RV enlargement (R²=0.68, p < 0.01).

Conclusion: We show that myocardial infiltration by macrophages was strongly associated with RV systolic dysfunction and enlargement in a rat model of PH. Although the precise mechanism remains elusive, our results support the notion of an innate immunity-driven process in the development of PH.