CCR2-Dependent Myeloid Cell Recruitment Links Post-MI Heart Failure to Pulmonary Hypertension

Pulmonary hypertension due to left heart disease (PH-LHD) is a common complication of myocardial infarction (MI) and heart failure (HF). Myeloid inflammation is a major hallmark of both the local cardiac and systemic post-MI response, with resident and recruited monocyte-derived macrophages orchestrating each step of the ensuing inflammatory cascade, from clearance of dead cardiomyocytes to scar tissue formation. Similarly, myeloid inflammation is a key feature of the PH lung, driving remodeling of small pulmonary vessels. We thus hypothesized that MI-induced systemic myeloid inflammation contributes directly to the development of PH-LHD.

We assessed expression of inflammatory adhesion molecules, as markers of vascular inflammatory activation and myeloid cell recruitment pathways, in patients with pulmonary arterial hypertension, PH-LHD, as well as in a PH-LHD rat model. We then induced MI and subsequent HF in 8- to 10-week-old female C57BL/6J mice via permanent ligation of the left anterior descending coronary artery. HF mice were then treated with a CCR2 (C-C chemokine receptor 2) antagonist to block monocyte recruitment and the development of PH-LHD was assessed at 6 weeks post-MI by a combination of invasive hemodynamics, flow cytometry, echocardiography, and lung histology.

Expression of key inflammatory adhesion molecules, including VCAM1 and SELE, was increased in PH-LHD lungs from humans and rats. Following early post-MI development of HF with reduced ejection fraction, mice exhibited increased numbers of circulating monocytes, lung monocytes, and lung interstitial macrophages, as well as PH-LHD by 6 weeks, characterized by right ventricular hypertrophy, elevated right ventricular pressures, and lung vascular remodeling of small-to-medium-sized pulmonary vessels. Administration of the selective CCR2 antagonist RS102895 from day 10 post-MI to reduce monocyte tissue recruitment attenuated lung vascular remodeling, right ventricular systolic and diastolic pressures, right ventricular hypertrophy, and lung adhesion molecule expression at 6 weeks, compared with vehicle-treated controls, without improving the underlying left-sided HF.

This proof-of-concept study demonstrates a causal role for CCR2-dependent myeloid cell recruitment in the progression from MI-induced HF to secondary pulmonary vascular disease.