Background: Autoimmunity is increasingly recognized as a key contributing factor in heart muscle diseases. The functional features of cardiac autoimmunity in humans remain undefined because of the challenge of studying immune responses in situ. We previously described a subset of c-mesenchymal epithelial transition factor (c-Met)–expressing (c-Met ⁺ ) memory T lymphocytes that preferentially migrate to cardiac tissue in mice and humans. Methods: In-depth phenotyping of peripheral blood T cells, including c-Met ⁺ T cells, was undertaken in groups of patients with inflammatory and noninflammatory cardiomyopathies, patients with noncardiac autoimmunity, and healthy controls. Validation studies were carried out using human cardiac tissue and in an experimental model of cardiac inflammation. Results: We show that c-Met ⁺ T cells are selectively increased in the circulation and in the myocardium of patients with inflammatory cardiomyopathies. The phenotype and function of c-Met ⁺ T cells are distinct from those of c-Met–negative (c-Met ⁻ ) T cells, including preferential proliferation to cardiac myosin and coproduction of multiple cytokines (interleukin-4, interleukin-17, and interleukin-22). Furthermore, circulating c-Met ⁺ T cell subpopulations in different heart muscle diseases identify distinct and overlapping mechanisms of heart inflammation. In experimental autoimmune myocarditis, elevations in autoantigen-specific c-Met ⁺ T cells in peripheral blood mark the loss of immune tolerance to the heart. Disease development can be halted by pharmacologic c-Met inhibition, indicating a causative role for c-Met ⁺ T cells. Conclusions: Our study demonstrates that the detection of circulating c-Met ⁺ T cells may have use in the diagnosis and monitoring of adaptive cardiac inflammation and definition of new targets for therapeutic intervention when cardiac autoimmunity causes or contributes to progressive cardiac injury.

Clonal hematopoiesis of indeterminate potential (CHIP) is a common bone marrow abnormality induced by age‐related DNA mutations, which give rise to proinflammatory immune cells. These immune cells exacerbate atherosclerotic cardiovascular disease and may induce or accelerate heart failure. The mechanisms involved are complex but point toward a central role for proinflammatory macrophages and an inflammasome‐dependent immune response (IL‐1 [interleukin‐1] and IL‐6 [interleukin‐6]) in the atherosclerotic plaque or directly in the myocardium. Intracardiac inflammation may decrease cardiac function and induce cardiac fibrosis, even in the absence of atherosclerotic cardiovascular disease. The pathophysiology and consequences of CHIP may differ among implicated genes as well as subgroups of patients with heart failure, based on cause (ischemic versus nonischemic) and ejection fraction (reduced ejection fraction versus preserved ejection fraction). Evidence is accumulating that CHIP is associated with cardiovascular mortality in ischemic and nonischemic heart failure with reduced ejection fraction and involved in the development of heart failure with preserved ejection fraction. CHIP and corresponding inflammatory pathways provide a highly potent therapeutic target. Randomized controlled trials in patients with well‐phenotyped heart failure, where readily available anti‐inflammatory therapies are used to intervene with clonal hematopoiesis, may pave the way for a new area of heart failure treatment. The first clinical trials that target CHIP are already registered.

• Myocardial fibrosis represents an unmet medical need, and its regulation by immunological mechanisms is increasingly evident. • Emerging immunotherapies ameliorate myocardial fibrosis either by targeting cardiac fibroblast directly or via the immune system. • Targeted immunotherapeutic approaches may reduce the risk of heart failure while mitigating potential safety concerns.

Hypertrophic cardiomyopathy (HCM) is the most prevalent inherited cardiac disease. The impact of HCM on quality of life (QoL) and societal costs remains poorly understood. This prospective multi-centre burden of disease study estimated QoL and societal costs of genotyped HCM patients and genotype-positive phenotype-negative (G+/P-) subjects. Participants were categorized into three groups based on genotype and phenotype: 1) G+/P- (left ventricular (LV) wall thickness <13 mm), 2) non-obstructive HCM (nHCM, LV outflow tract (LVOT) gradient <30 mmHg), and 3) obstructive HCM (oHCM, LVOT gradient ≥30 mmHg). We assessed QoL with EQ-5D-5L and Kansas City Cardiomyopathy Questionnaires (KCCQ). Societal costs were measured using medical consumption (iMCQ) and productivity cost (iPCQ) questionnaires. We performed subanalyses within three age groups: <40, 40-59, and ≥60 years. From three Dutch hospitals, 506 subjects were enrolled (84 G+/P-, 313 nHCM, 109 oHCM; median age 59 years, 39% female). HCM (both nHCM and oHCM) patients reported reduced QoL vs G+/P- subjects (KCCQ: 88 vs 98, EQ-5D-5L: 0.88 vs 0.96; both p<0.001). oHCM patients reported lower KCCQ scores than nHCM patients (83 vs 89, p=0.036). Societal costs were significantly higher in HCM patients (€19,035/year vs €7,385/year) compared to G+/P- controls, mainly explained by higher healthcare costs and productivity losses. Being symptomatic and of younger age (<60 years) particularly led to decreased QoL and increased costs. HCM is associated with decreased QoL and increased societal costs, especially in younger and symptomatic patients. oHCM patients were more frequently symptomatic than nHCM patients. This study highlights the substantial disease burden of HCM and can aid in assessing new therapy cost-effectiveness for HCM in the future.

Dilated cardiomyopathy (DCM) has a genetic cause in up to 40% of cases, with differences in disease penetrance and clinical presentation, due to different exogeneous triggers and implicated genes. Cardiac inflammation can be the consequence of an exogeneous trigger, subsequently unveiling a phenotype. The study aimed to determine cardiac inflammation in a cohort of genetic DCM patients and investigate whether it associated with a younger disease onset. The study included 113 DCM patients with a genetic etiology, of which 17 had cardiac inflammation as diagnosed in an endomyocardial biopsy. They had a significant increased cardiac infiltration of white blood, cytotoxic T, and T-helper cells (p < 0.05). Disease expression was at a younger age in those patients with cardiac inflammation, compared to those without inflammation (p = 0.015; 50 years (interquartile range (IQR) 42–53) versus 53 years (IQR 46–61). However, cardiac inflammation was not associated with a higher incidence of all-cause mortality, heart failure hospitalization, or life-threatening arrhythmias (hazard ratio 0.85 [0.35–2.07], p = 0.74). Cardiac inflammation is associated with an earlier disease onset in patients with genetic DCM. This might indicate that myocarditis is an exogeneous trigger unveiling a phenotype at a younger age in patients with a genetic susceptibility, or that cardiac inflammation resembles a ‘hot-phase’ of early-onset disease.