CCR2+ MONOCYTE-DERIVED MACROPHAGES DRIVE CARDIAC HYPERTROPHY IN EARLY HFPEF.

Abstract

Heart Failure with Preserved Ejection Fraction is a chronic syndrome driven by systemic inflammation. Resident and monocyte-derived macrophages play opposing roles in several heart diseases. Though general ablation of macrophages has previously been studied in HFpEF, the individual contribution of these subsets to HFpEF development is unknown. We induced preclinical HFpEF in mice using a model consisting of high-fat diet, chronic low-dose angiotensin II administration, and salt supplemented drinking water. Our model was marked by circulating Ly6C^hi monocytosis and elevated pro-inflammatory CCR2⁺ macrophage infiltration at the expense of the cardioprotective TIMD4⁺ resident macrophage subset. Beyond an inflammatory signature typical of HFpEF, the mouse model also faithfully recreates cardiac fibrosis, hypertrophy, and functional changes in the heart as measured by echocardiography and pressure-volume loops. The experimental mice also show exercise intolerance. Using a loss-of-function genetic model, we found that CCR2 ablation prevented classical macrophage infiltration and improved the resident TIMD4⁺ macrophage representation early in HFpEF development. CCR2^-/- mice showed a higher accumulation of dysfunctional mitochondria in the heart with diffusely organized cristae without worsened mitochondrial fusion (Mitofusin2) or functioning in general (TOM20). Loss of CCR2 did prevent LV hypertrophy in our preclinical model but it did not resolve the cardiac fibrosis or diastolic dysfunction. Mitochondrial damage has been suggested to drive hypertrophy, however, we found that preventing classical macrophage recruitment increased the presence of damaged mitochondria, even though hypertrophy is resolved. In the future, our results can contribute to successful therapeutic immunomodulation to tackle HFpEF, if combined with anti-fibrotic treatment.