Macrophage‐Dependent Intercellular Crosstalk in Multiphenotypic Heart Failure With Preserved Ejection Fraction

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  Figure 1. Macrophage in multiphenotypic HFpEF. This review highlights the central role of macrophage‐driven intercellular crosstalk in the pathogenesis of multiphenotypic HFpEF. HFpEF is a heterogeneous metabolic syndrome driven by inflammation and metabolic dysregulation. Cardiac macrophages undergo distinct phenotypic and functional reprogramming across age‐associated, cardiometabolic, and hypertension‐related HFpEF subtypes. These reprogrammed macrophages promote disease progression by exacerbating inflammation, fibrosis, and endothelial dysfunction through complex interactions with cardiomyocytes, fibroblasts, and other cardiac cells. Targeting specific macrophage subsets and their effector mechanisms represents a promising therapeutic strategy to break this vicious cycle and mitigate the burden of HFpEF. HFpEF indicates heart failure with preserved ejection fraction.

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  Figure 2. Macrophages in the heart. Cardiac macrophages constitute 6% to 8% of myocardial cells and are primarily classified into 2 main populations based on origin and function. Resident cardiac macrophages (CCR2−) are characterized by expression of markers, including CD163, LYVE1, FOLR2, F13A1, TIMD4, and CD169. Monocyte‐derived macrophages (CCR2+) originate from circulating monocytes, express CCR2, and accumulate in the heart under stress conditions. Beyond the traditional M1/M2 polarization framework, cardiac macrophages exhibit a broad spectrum of functions essential for both homeostasis and disease: secretion of both proinflammatory (eg, TNF‐α and IL‐6) and anti‐inflammatory (eg, IL‐10 and TGF‐β) cytokines, promotion of fibrosis (via TGF‐β), and regulation of extracellular matrix dynamics and clearance of dysfunctional mitochondria (efferocytosis/heterophagy) from cardiomyocytes to maintain metabolic homeostasis. And there exists cellular crosstalk: modulating fibroblast activity and differentiation into myofibroblasts, facilitating electrical conduction with cardiomyocytes, presenting antigens to T cells, linking innate and adaptive immunity and regulating angiogenesis and vascular…

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  Figure 3. Changes in macrophages during HFpEF. Macrophages exhibit distinct phenotypic and functional alterations across HFpEF subtypes, contributing to disease pathogenesis through inflammatory modulation, metabolic reprogramming, and fibrotic responses. In age‐associated HFpEF, macrophages display reduced MHC‐II expression accompanied by mitochondrial dysfunction, impaired autophagy, and a skewed cytokine profile featuring elevated IL‐6, CXCL8, MMP‐9, TGF‐β, galectin‐3, and NOX2, alongside decreased lipoxygenase activity. Cardiometabolic HFpEF, driven by obesity and diabetes, promotes glycolytic reprogramming in macrophages, leading to expanded both proinflammatory (CD11b+F4/80+CD86+CCR2+Timd4−) and anti‐inflammatory (CD11b+F4/80+CD206+CCR2−Timd4+) subsets, impaired mitochondrial transfer, and elevated IL‐1β, Plin2, TNF‐α, and IL‐6 with reduced TGF‐β. In hypertension‐associated HFpEF, CCR2+ monocyte infiltration is prominent, causing macrophages with low MHC‐II, elevated CXCR4 (with reduced PPARγ), TREM2/sTREM2 upregulation, suppressed cGAS‐STING signaling, and increased OPN, TGF‐β, IL‐1β, IL‐6, and TNF‐α. Resident macrophages (CCR2−): green. Monocyte‐derived macrophages (CCR2+): orange.…

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  Figure 4. Differential effects of cardiac macrophage populations on HFpEF phenotypes. Cardiac macrophages play distinct roles in various HFpEF subtypes through phenotype‐specific mechanisms. Age‐associated HFpEF: characterized by collagen deposition, driven by IL‐1β and CCL2, promoting a proinflammatory state. Features cardiac inflammatory infiltration with upregulated CCR2, Spp1, TNF‐α, and CXCL3, facilitating macrophage‐fibroblast crosstalk. Monocyte infiltration and TGF‐β activation enhance CXCL9/10/11 signaling, reinforcing immune cell recruitment. Cardiometabolic HFpEF: driven by EAT‐derived inflammatory signals (eg, IL‐1β/TNF‐α), activating fibrotic pathways, like TGF‐β and MMP‐2/9. TIMP‐1/LOX upregulation further promotes collagen stabilization and myocardial stiffness. Monocytes exhibit enhanced OXPHOS and glycolytic shift, leading to cardiomyocyte dysfunction, apoptosis, and diffuse collagen accumulation. Hypertension‐associated HFpEF: dominated by fibroblast‐to‐myofibroblast transition and extracellular matrix remodeling. Hypoxia and elevated succinate levels contribute to metabolic dysregulation, whereas reduced activation of protective pathways exacerbates dysfunction.…