Circulating c-Met-Expressing Memory T Cells Define Cardiac Autoimmunity

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

Immunomodulation of Myocardial Fibrosis

Immunotherapy is a potential cornerstone in the treatment of myocardial fibrosis. During a myocardial insult or heart failure, danger signals stimulate innate immune cells to produce chemokines and profibrotic cytokines, which initiate self-escalating inflammatory processes by attracting and stimulating adaptive immune cells. Stimulation of fibroblasts by inflammatory processes and the need to replace damaged cardiomyocytes fosters reshaping of the cardiac fibroblast landscape. In this review, we discuss new immunomodulatory strategies that manipulate and direct cardiac fibroblast activation and differentiation. In particular, we highlight immunomodulatory strategies that target fibroblasts such as chimeric antigen receptor T cells, interleukin-11, and invariant natural killer T-cells. Moreover, we discuss the potential of manipulating both innate and adaptive immune system components for the translation into clinical validation. Clearly, multiple pathways should be considered to develop innovative approaches to ameliorate myocardial fibrosis and hence to reduce the risk of heart failure

Quality of life and societal costs in patients with dilated cardiomyopathy

AIMS: Dilated cardiomyopathy (DCM) is a major cause of heart failure impairing patient wellbeing and imposing a substantial economic burden on society, but respective data is missing. This study aims to measure the quality of life (QoL) and societal costs of DCM patients. METHODS AND RESULTS: A cross-sectional evaluation of QoL and societal costs of DCM patients was performed through the 5-level EuroQol (EQ-5D-5 L) and the Medical Consumption Questionnaire (iMCQ) and Productivity Cost Questionnaire (iPCQ), respectively. QoL was translated into numerical values (i.e. utilities). Costs were measured from a Dutch societal perspective. Final costs were extrapolated to one year, reported in 2022 Euros, and compared between DCM severity according to NYHA classes. A total of 550 DCM patients from the Maastricht cardiomyopathy registry (mCMP-registry) were included. Mean age was 61 years, and 34% were women. Overall utility was slightly lower for DCM patients than the population mean (0.840 vs. 0.869, p = 0.225). Among EQ-5D dimensions, DCM patients scored lowest in 'usual activities'. Total societal DCM costs were €14 843 per patient per year. Cost drivers were productivity losses (€7 037) and medical costs (€4 621). Patients with more symptomatic DCM (i.e. NYHA class III or IV) had significantly higher average DCM costs per year compared to less symptomatic DCM (€31,099 vs. €11 446, p < 0.001) and significantly lower utilities (0.631 vs. 0.883, p < 0.001). CONCLUSION: DCM is associated with high societal costs and reduced QoL, in particular with high DCM severity

Clonal Hematopoiesis of Indeterminate Potential From a Heart Failure Specialist's Point of View

ABSTRACT 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

Inflammation and Syndecan-4 Shedding from Cardiac Cells in Ischemic and Non-Ischemic Heart Disease

Circulating biomarkers reflecting cardiac inflammation are needed to improve the diagnostics and guide the treatment of heart failure patients. The cardiac production and shedding of the transmembrane proteoglycan syndecan-4 is upregulated by innate immunity signaling pathways. Here, we investigated the potential of syndecan-4 as a blood biomarker of cardiac inflammation. Serum syndecan-4 was measured in patients with (i) non-ischemic, non-valvular dilated cardiomyopathy (DCM), with (n = 71) or without (n = 318) chronic inflammation; (ii) acute myocarditis (n = 15), acute pericarditis (n = 3) or acute perimyocarditis (23) and (iii) acute myocardial infarction (MI) at day 0, 3 and 30 (n = 119). Syndecan-4 was investigated in cultured cardiac myocytes and fibroblasts (n = 6–12) treated with the pro-inflammatory cytokines interleukin (IL)-1β and its inhibitor IL-1 receptor antagonist (IL-1Ra), or tumor necrosis factor (TNF)α and its specific inhibitor infliximab, an antibody used in treatment of autoimmune diseases. The levels of serum syndecan-4 were comparable in all subgroups of patients with chronic or acute cardiomyopathy, independent of inflammation. Post-MI, syndecan-4 levels were increased at day 3 and 30 vs. day 0. IL-1Ra attenuated IL-1β-induced syndecan-4 production and shedding in vitro, while infliximab had no effect. In conclusion, syndecan-4 shedding from cardiac myocytes and fibroblasts was attenuated by immunomodulatory therapy. Although its circulating levels were increased post-MI, syndecan-4 did not reflect cardiac inflammatory status in patients with heart disease

Cardiac Inflammation in Adult-Onset Genetic Dilated Cardiomyopathy

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 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

Clonal Hematopoiesis has Prognostic Value in Dilated Cardiomyopathy independent of Age and Clone Size

BACKGROUND: Clonal hematopoiesis (CH) gives rise to mutated leukocyte clones that induce cardiovascular inflammation, and thereby impact the disease course in atherosclerosis and ischemic heart failure. Clonal hematopoiesis of indeterminate potential (CHIP) refers to a variant allele frequency (VAF; a marker for clone size) in blood of =2%. The impact of CH clones -including small clone sizes (VAF<0.5%)- in non-ischemic dilated cardiomyopathy (DCM) remains largely undetermined. OBJECTIVES: To establish the prognostic impact of CH in DCM including small clones. METHODS: CH is determined using an ultrasensitive single-molecule Molecular Inversion Probe technique that allows detection of clones down to a VAF of 0.01%. Cardiac death and all-cause mortality were analyzed using receiver operating characteristic curve-optimized VAF cut-off values. RESULTS: Five hundred twenty DCM patients have been included. One hundred and nine patients (21%) had CH driver mutations, of which 45 had a VAF of =2% and 31 <0.5%. The median follow-up duration is 6.5 years [interquartile range 4.7-9.7]. DCM patients with CH have a higher risk of cardiac death (HR 2.33 using a VAF cut-off of 0.36%, 95% confidence interval 1.24-4.40) and all-cause mortality (HR 1.72 using a VAF cut-off of 0.06%, 95% confidence interval 1.10-2.69), independent of age, sex, left ventricle ejection fraction and New York Heart Association classification. CONCLUSION: CH predicts cardiac death and all-cause mortality in DCM patients with an optimal threshold for clone size of 0.36% and 0.06%, respectively. Therefore, CH is prognostically relevant independent of clone size in patients with DCM