Cardio-Immunology: Reframing the Pathogenesis of Cardiovascular Disease

Abstract

For decades, cardiovascular disease was understood primarily through metabolic, hemodynamic, and structural models that linked hypercholesterolemia and hypertension to vascular disease, atherosclerotic plaque formation, ischemic injury, cardiac hypertrophy, and ultimately to the development of heart failure. Over the past 15 years, our understanding of cardiovascular disease pathogenesis has undergone a major conceptual shift, with dysregulated innate and adaptive immune responses now recognized as central features of major cardiovascular disorders, including atherosclerotic coronary artery disease, vascular disease, hypertension, and heart failure (Figure 1). The Cardio-Immunology compendium in this issue of Immunological Reviews brings together sixteen comprehensive reviews, written by experts and pioneers in their fields that collectively map the immune mechanisms that maintain cardiovascular homeostasis and drive cardiovascular disease, laying the groundwork for precision immune-targeted therapeutics that have the potential to transform cardiovascular care.

A deeper understanding of the role of inflammation in the heart begins with its evolutionary role in preserving tissue homeostasis. In the opening contribution, Mann reframes the relationship between phylogenetically ancient immune responses and myocardial injury through the lens of disease tolerance: A cell-autonomous stress-response program that coordinates cytoprotective signaling in cardiac myocytes with tightly regulated, self-limited inflammatory responses after tissue injury, mediated in part by trained innate immunity [1]. A central insight highlighted in this article, and a recurrent theme throughout the compendium, is that inflammation is not inherently pathological; rather, its salutary effects become maladaptive when inflammatory responses are dysregulated, excessive, or sustained.

Aging has long been recognized as the strongest risk factor for developing cardiovascular disease; however, therapies that directly target cardiovascular aging remain limited. Zanders, Dimmeler, and colleagues synthesize evidence implicating cellular senescence and the senescence-associated secretory phenotype (SASP) as drivers of inflammaging, chronic low-grade inflammation coupled to vascular and cardiac remodeling [2]. Senescent cells accumulate in aging cardiovascular tissue, secrete pro-inflammatory mediators, including IL-6, IL-8, TNF, and MMP-3, activate immune cells, and impair tissue repair. Senolytics, SASP modulators, anti-inflammatory agents, and metabolic interventions such as metformin show promise, but translating senescence biology into therapies that improve cardiovascular outcomes in older adults remains an unmet need. Studying immune niches within the myocardium offers another framework for understanding aging-related cardiac dysfunction. Perez-Shibayana, Ludewig, and colleagues describe how immune cells cooperate with fibroblast and endothelial stromal cells to maintain cardiac myocyte function, contractility, and metabolic balance [3]. They describe how inflammatory signals disrupt these homeostatic interactions by activating local stromal and immune circuits. Defining how aging alters immune-stromal crosstalk may reveal strategies to preserve niche function and prevent age-related cardiac dysfunction.

The reframing of atherosclerosis from a lipid storage disorder to a chronic inflammatory disease has gained broad clinical acceptance, yet the immunological heterogeneity of atherosclerosis remains incompletely appreciated [4]. Spindler, Libby, and Ridker review key inflammatory pathways, emphasizing the central roles of IL-1β, IL-6, and IL-18, and discussing the data that demonstrate that residual inflammatory risk, measured by high-sensitivity C-reactive protein, predicts cardiovascular events independently of cholesterol burden. The variable efficacy of IL-1β inhibition, colchicine, IL-6 blockade, and NLRP3 inflammasome inhibition further underscores the need for biomarker-guided patient selection. Boden, Chai, Choudhury, and colleagues extend this framework by discussing the role of trained innate immunity induced by metabolic stress, infection, chronic stress, and inflammatory disease [5]. By epigenetically and metabolically reprogramming innate immune cells, trained immunity provides a mechanistic bridge between cardiovascular risk factors and sustained vascular inflammation. Lems, Mazzei, Folks, and McNamara further illustrate disease complexity by reviewing B cell heterogeneity in atherosclerosis [6]. Atheroprotective innate B cells producing IgM against oxidation-specific epitopes coexist with atherogenic age-associated B cells and conventional antibody-producing B cells, suggesting that therapy should enhance protective immune functions rather than broadly suppress immunity. Finally, Amend, Moore, and colleagues highlight the bidirectional relationship between atherosclerotic cardiovascular disease and cancer. Along the forward axis, cancer therapies, including chemotherapy, radiation, and immune checkpoint inhibitors promote cardiovascular injury; along the reverse axis, myocardial infarction and heart failure promote tumor initiation and progression through hematopoietic remodeling of the bone marrow niche leading to an immunosuppressive myeloid bias that enables tumors to escape immune detection. Shared metabolic risk factors, aging, and clonal hematopoiesis of indeterminate potential create a chronic inflammatory milieu, amplified by cytokines such as IL-1β, IL-6, and TNF, which reprogram myeloid and lymphoid compartments across both diseases. They conclude that immune-based stratification and targeted modulation of inflammation may enable more precise management of patients at the intersection of cardiovascular disease and cancer [7].

Hypertension, long viewed through a hemodynamic lens, is increasingly recognized as an immune-mediated disease [8]. Hunter and Harrison review evidence that T cells, dendritic cells, and macrophages infiltrate hypertensive target organs, where they release cytokines, reactive oxygen species, and metalloproteinases. A key mechanistic advance is the identification of isolevuglandin-adducted neoantigens, oxidative stress–modified self-proteins that activate CD8+ T cells and sustain hypertensive inflammation. Endothelial cells also emerge as non-professional antigen-presenting cells that coordinate immune responses under mechanical and oxidative stress. Together, these findings recast hypertension as an immunological disorder and suggest new therapeutic opportunities through antigen-specific immunotherapy or neuroimmune modulation.

Heart failure reflects the convergence of distinct immune mechanisms that can lead to sustained inflammation and adverse cardiac remodeling. Xiao, MacDonald, Epelman, and Lavine discuss single-cell and lineage-tracing studies showing that macrophage ontogeny, recruitment kinetics, and reparative programs are highly time- and context-dependent [9]. Embryonically derived tissue-resident macrophages and recruited monocyte-derived macrophages and their interactions with fibroblasts, neutrophils, and T cells help determine whether cardiac repair resolves successfully or progresses to maladaptive remodeling. Efferocytotic clearance of cellular and mitochondrial debris is central to repair; when impaired, inflammation and fibrosis persist. These findings support strategies targeting chemokine pathways and specialized pro-resolving mediators, although benefit will likely require temporal staging and stratification by macrophage phenotype and imaging biomarkers. T cell responses in heart failure reflect both cardiac autoimmunity and systemic immune dysregulation. Manandhar, Yan, Moslehi, and colleagues propose that cardiac injury generates antigen-specific T cells, particularly against alpha-myosin heavy chain (α-MyHC), that acquire tissue-resident memory (Trm) phenotypes within the myocardium [10]. These Trm cells can persist after injury and reactivate locally, linking acute immune activation to chronic relapsing inflammation. This framework is particularly relevant to immune checkpoint inhibitor-associated myocarditis, where α-MyHC-reactive Trm may trigger disease after checkpoint blockade, and suggests that targeting pathogenic Trm or enhancing local regulatory circuits could interrupt chronic cardiac inflammation while preserving systemic immunity. Metabolic stress is also emerging as a major driver of immune activation, particularly in heart failure with a preserved ejection fraction. Pereira, Thorp, and colleagues show that systemic and cellular metabolic imbalance activates immune cells through mTORC1, glycolytic flux, lipid metabolism, and epigenetic remodeling, sustaining low-grade inflammation and tissue remodeling [11]. Heart failure with a preserved ejection fraction is therefore increasingly viewed as a metabolic-inflammatory disease that differs mechanistically from ischemic-induced heart failure, despite shared downstream immune activation, and may require immune-metabolic therapeutic strategies. Erebholo and Karlstaedt further this discussion by examining how the molecules involved in intermediary metabolism operate as a signaling interface between cardiac myocytes and immune cells [12]. They describe how Krebs cycle intermediates and glycolytic end products that accumulate during ischemic and non-ischemic injury, including succinate, itaconate, and lactate, act as metabolite signals that shape macrophage and T cell effector programs through allosteric enzyme inhibition, HIF-1α stabilization, and metabolite-driven epigenetic remodeling, thereby coupling substrate availability to the magnitude and duration of the inflammatory response. The recognition that these metabolic signatures are shared across the cellular constituents of the failing myocardium raises the possibility that interventions that modify systemic and cellular metabolism, including SGLT2 inhibitors and dietary strategies, act in part through immunometabolic mechanisms. Clonal hematopoiesis (CH), the expansion of somatically mutated hematopoietic clones, has emerged as an unexpected driver of heart failure [13]. Evans and Walsh discuss their pioneering studies which show that CH driver mutations, including DNMT3A, TET2, TP53, and JAK2, promote pro-inflammatory immune phenotypes that contribute to cardiac injury, remodeling, and adverse outcomes. In contrast, loss of the Y chromosome shifts macrophages toward a fibrotic rather than pro-inflammatory phenotype, illustrating that somatic immune alterations can produce divergent effects. Because CH increases with age and spans both heart failure with a preserved and reduced ejection fraction, it links aging, immune dysregulation, and heart failure while raising the possibility of CH-guided intervention.

Myocarditis was the first cardiomyopathy recognized as an immunological disorder, initially linked to infection and autoimmune activation and, more recently, to immune checkpoint inhibitor therapy. Jo, Sun, and Cihakova integrate human studies with mechanistic models to define convergent pathways involving pattern-recognition signaling, antigen presentation, T and B cell responses, and monocyte–macrophage networks in coxsackievirus B3 infection, experimental autoimmune myocarditis, and checkpoint-associated myocarditis [14]. Across these contexts, α-MyHC-reactive T cells emerge as key effectors. The authors propose a unifying model in which cardiac myosin-specific Trms persist in health as part of immune surveillance but promote disease when tolerance is breached by infection, injury, or checkpoint blockade. This framework helps explain heterogeneous outcomes in viral myocarditis through differences in T cell clonal dynamics, Trm burden, and local regulatory capacity. The review emphasizes biomarker-guided stratification to distinguish viral, autoimmune, and checkpoint-associated etiologies using TCR sequencing, imaging-omics integration, and targeted immunomodulation strategies that limit disease progression while preserving protective tissue immunity. Richter, Dias-Ferreira, Campos-Ramos, and Ashour expand upon this theme by presenting a first-in-class adaptive immune receptor database across cardiovascular disease, the CVD-TCR database, showing that clonal T cell expansions occur in atherosclerosis, myocardial infarction, heart failure, and myocarditis [15]. Shared clonotypes and TCR motifs across these conditions suggest conserved antigenic targets and mechanistic convergence, providing a resource to distinguish disease-driving from bystander T cell clones and prioritize antigen-specific immunotherapy targets. Finally, Peretto, Villatore, and Cooper extend this discussion by reviewing the immunogenetic basis of inflammatory cardiomyopathies and myocarditis, emphasizing how variants that predispose to autoimmunity or impair cardiac function interact with immune activation to shape disease risk and severity [16].

Although clinicians have recognized the pathophysiological importance of inflammatory mediators in the heart as early as 1669 [17], the formal recognition that inflammation contributes to heart disease did not emerge for another three centuries. The reviews in this compendium highlight how cardiovascular medicine has moved from describing immune dysregulation in cardiovascular disease to demonstrating that immunology is central to its pathogenesis. This conceptual reframing has important therapeutic implications, highlighted by the recent Food and Drug Administration approval of low dose oral colchicine (Lodoco) as the first anti-inflammatory therapy to reduce cardiovascular events, marking a major translational milestone for cardio-immunology [18]. Progress over the next decade will require rigorous attention to the temporal dynamics and interactions of bone marrow derived and tissue-resident immune cells with cardiac stromal cells, biomarker-guided patient stratification for clinical studies, as well as a deeper understanding of the heterogeneity of immune responses in cardiovascular disease. Together, the contributions in this compendium provide the conceptual foundation and clinical context for translating immunological insights into improved cardiovascular outcomes.

The author declares no conflicts of interest.

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