Key result
CCR2 antagonist RS102895 attenuates pulmonary vascular remodeling and right ventricular hypertrophy in post-MI heart failure.
Why the study?
Pulmonary hypertension due to left heart disease (PH-LHD) is a common complication of MI and HF, and myeloid inflammation is a feature of both the post-MI response and the PH lung. Whether MI-induced systemic myeloid inflammation contributes directly to the development of PH-LHD required investigation.
Does the selective CCR2 antagonist RS102895 attenuate the development of pulmonary hypertension due to left heart disease in mice with post-MI heart failure?
Does the selective CCR2 antagonist RS102895 attenuate the development of pulmonary hypertension due to left heart disease in mice with post-MI heart failure?
This preclinical proof-of-concept study demonstrates that blocking CCR2-dependent myeloid cell recruitment attenuates the progression from post-MI heart failure to secondary pulmonary hypertension without altering underlying left-sided heart failure.
CCR2 blockade attenuates secondary PH in post-MI HF mice without altering left HF; leaves open translation to human left heart disease.
BACKGROUND: 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. METHODS: 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. 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. CONCLUSIONS: 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.
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Gillan et al. (2026) studied Pulmonary hypertension due to left heart disease (PH-LHD) post-myocardial infarction. Selective CCR2 antagonist RS102895 vs. Vehicle-treated controls was evaluated on Development of PH-LHD (lung vascular remodeling, right ventricular systolic and diastolic pressures, and right ventricular hypertrophy) at 6 weeks post-MI. CCR2 antagonist RS102895 from day 10 post-MI attenuated lung vascular remodeling, right ventricular pressures, and hypertrophy at 6 weeks vs vehicle in HF mice.
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