Early Changes in Cardiac Macrophage Subsets in Heart Failure with Preserved Ejection Fraction

Heart failure with preserved ejection fraction (HFpEF) is a complex syndrome characterized by left ventricular diastolic dysfunction, exercise intolerance, low-grade chronic inflammation, and comorbidities such as hypertension, obesity, and glucose intolerance. Myocardial infiltration by activated macrophages has been proposed as a mechanism linking low-grade inflammation to increased diastolic LV stiffness in HFpEF. Changes in the relative abundance of cardiac macrophage populations may precede and promote the development of HFpEF in the aged heart. This study aimed to characterize the cardiac macrophage subsets that predominate during progression from experimental preclinical to established HFpEF. To generate the model, wild-type male C57BL/6N mice were randomized to control chow or a combination of high-fat diet plus L-NAME in drinking water for 5 weeks (asymptomatic pre-HFpEF) or 15 weeks (established HFpEF). At the end of each period, we measured body weight, running distance, metabolic biomarkers, systolic and diastolic blood pressure, myocardial function and morphology, cardiac remodeling by hypertrophic markers, morphometric analyses, fibrosis, cytokines TNF-α and IL-10, cardiac macrophage phenotype profiles (CCR2⁺ and CCR2^-), and AMP-Activated Protein Kinase (AMPK)activity.Significant changes in myocardial macrophage populations were observed at 5 weeks (pre-HFpEF), specifically a decrease in resident reparative CCR2^-MHCII^- and increase in proinflammatory CCR2⁺MHCII⁺ macrophages. These early changes were associated with higher circulating TNF-α, decreased myocardial AMPK activation, and more severe myocardial fibrosis. At 15 weeks (established HFpEF), proinflammatory CCR2⁺MHCII⁺ macrophage levels remained elevated in the myocardium; whereas the initial number of resident reparative CCR2^-MHCII^- levels was reduced, it subsequently returned to baseline. In this model of HFpEF induced by a high-fat diet and L-NAME, which produced obesity, glucose intolerance, and hypertension, myocardial resident reparative CCR2^-MHCII^- macrophages decreased and proinflammatory CCR2⁺MHCII⁺ macrophages increased during preclinical stages. These early changes in cardiac macrophage profile were associated with low-grade inflammation and myocardial remodeling and preceded the onset of HFpEF.