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.

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.

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.

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

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)-1ß 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-1ß-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 < 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.

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. CH of indeterminate potential 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 nonischemic dilated cardiomyopathy (DCM) remains largely undetermined. OBJECTIVES: The authors sought 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 cutoff values. RESULTS: A total of 520 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 was 6.5 years [IQR: 4.7-9.7 years]. DCM patients with CH have a higher risk of cardiac death (HR: 2.33 using a VAF cutoff of 0.36%, 95% CI: 1.24-4.40) and all-cause mortality (HR: 1.72 using a VAF cutoff of 0.06%, 95% CI: 1.10-2.69), independent of age, sex, left ventricular ejection fraction, and New York Heart Association classification. CONCLUSIONS: CH predicts cardiac death and all-cause mortality in DCM patients with optimal thresholds for clone size of 0.36% and 0.06%, respectively. Therefore, CH is prognostically relevant, independent of clone size in patients with DCM.

Clustering of Cardiac Transcriptome Profiles Reveals Unique: Subgroups of Dilated Cardiomyopathy Patients.

Dilated cardiomyopathy is a heterogeneous disease characterized by multiple genetic and environmental etiologies. The majority of patients are treated the same despite these differences. The cardiac transcriptome provides information on the patient's pathophysiology, which allows targeted therapy. Using clustering techniques on data from the genotype, phenotype, and cardiac transcriptome of patients with early- and end-stage dilated cardiomyopathy, more homogeneous patient subgroups are identified based on shared underlying pathophysiology. Distinct patient subgroups are identified based on differences in protein quality control, cardiac metabolism, cardiomyocyte function, and inflammatory pathways. The identified pathways have the potential to guide future treatment and individualize patient care.

Diagnostic and prognostic relevance of using large gene panels in the genetic testing of patients with dilated cardiomyopathy.

It was previously suggested that increasing the number of genes on diagnostic gene panels could increase the genetic yield in patient with dilated cardiomyopathy (DCM). We explored the diagnostic and prognostic relevance of testing DCM patients with an expanded gene panel. The current study included 225 consecutive DCM patients who had no genetic diagnosis after a 48-gene cardiomyopathy-panel. These were then evaluated using an expanded gene panel of 299 cardiac-associated genes. A likely pathogenic/pathogenic (P/LP) variant was detected in 13 patients. Five variants were reclassifications of variants found in genes which were already detected using the 48 gene panel. Only one of the other eight variants could explain the phenotype of the patient (KCNJ2). The panel detected 186 VUSs in 127 patients (of which 6 also had a P/LP variant). The presence of a VUS was significantly associated with the combined end-point of mortality, heart failure hospitalization, heart transplantation or life-threatening arrhythmias(HR, 2.04 [95% CI, 1.15 to 3.65]; p = 0.02). The association of a VUS with prognosis remained when we only included VUSs in robust DCM-associated genes (high suspicious VUSs), but disappeared when we only included VUSs in non-robust DCM-associated genes (low suspicious VUSs), highlighting the importance of weighing of VUSs. Overall, the use of large gene panels for genetic testing in DCM does not increase the diagnostic yield, although a VUS in a robust DCM-associated gene is associated with an adverse prognosis. Altogether, current diagnostic gene panels should be limited to the robust DCM-associated genes.

Prevalence and Clinical Consequences of Multiple Pathogenic Variants in Dilated Cardiomyopathy.

BACKGROUND: Dilated cardiomyopathy (DCM) was considered a monogenetic disease that can be caused by over 60 genes. Evidence suggests that the combination of multiple pathogenic variants leads to greater disease severity and earlier onset. So far, not much is known about the prevalence and disease course of multiple pathogenic variants in patients with DCM. To gain insight into these knowledge gaps, we (1) systematically collected clinical information from a well-characterized DCM cohort and (2) created a mouse model. METHODS: Complete cardiac phenotyping and genotyping was performed in 685 patients with consecutive DCM. Compound heterozygous digenic (LMNA [lamin]/titin deletion A-band) with monogenic (LMNA/wild-type) and wild-type/wild-type mice were created and phenotypically followed over time. RESULTS: One hundred thirty-one likely pathogenic/pathogenic (LP/P) variants in robust DCM-associated genes were found in 685 patients with DCM (19.1%) genotyped for the robust genes. Three of the 131 patients had a second LP/P variant (2.3%). These 3 patients had a comparable disease onset, disease severity, and clinical course to patients with DCM with one LP/P. The LMNA/Titin deletion A-band mice had no functional differences compared with the LMNA/wild-type mice after 40 weeks of follow-up, although RNA-sequencing suggests increased cardiac stress and sarcomere insufficiency in the LMNA/Titin deletion A-band mice. CONCLUSIONS: In this study population, 2.3% of patients with DCM with one LP/P also have a second LP/P in a different gene. Although the second LP/P does not seem to influence the disease course of DCM in patients and mice, the finding of a second LP/P can be of importance to their relatives.

Interatrial Block Predicts Life-Threatening Arrhythmias in Dilated Cardiomyopathy.

Background Interatrial block (IAB) has been associated with supraventricular arrhythmias and stroke, and even with sudden cardiac death in the general population. Whether IAB is associated with life-threatening arrhythmias (LTA) and sudden cardiac death in dilated cardiomyopathy (DCM) remains unknown. This study aimed to determine the association between IAB and LTA in ambulant patients with DCM. Methods and Results A derivation cohort (Maastricht Dilated Cardiomyopathy Registry; N=469) and an external validation cohort (Utrecht Cardiomyopathy Cohort; N=321) were used for this study. The presence of IAB (P-wave duration>120 milliseconds) or atrial fibrillation (AF) was determined using digital calipers by physicians blinded to the study data. In the derivation cohort, IAB and AF were present in 291 (62%) and 70 (15%) patients with DCM, respectively. LTA (defined as sudden cardiac death, justified shock from implantable cardioverter-defibrillator or anti-tachypacing, or hemodynamic unstable ventricular fibrillation/tachycardia) occurred in 49 patients (3 with no IAB, 35 with IAB, and 11 patients with AF, respectively; median follow-up, 4.4 years [2.1; 7.4]). The LTA-free survival distribution significantly differed between IAB or AF versus no IAB (both P<0.01), but not between IAB versus AF (P=0.999). This association remained statistically significant in the multivariable model (IAB: HR, 4.8 (1.4-16.1), P=0.013; AF: HR, 6.4 (1.7-24.0), P=0.007). In the external validation cohort, the survival distribution was also significantly worse for IAB or AF versus no IAB (P=0.037; P=0.005), but not for IAB versus AF (P=0.836). Conclusions IAB is an easy to assess, widely applicable marker associated with LTA in DCM. IAB and AF seem to confer similar risk of LTA. Further research on IAB in DCM, and on the management of IAB in DCM is warranted.

Improving diagnosis and risk stratification across the ejection fraction spectrum: the Maastricht Cardiomyopathy registry.

AIMS: Heart failure (HF) represents a clinical syndrome resulting from different aetiologies and degrees of heart diseases. Among these, a key role is played by primary heart muscle disease (cardiomyopathies), which are the combination of multifactorial environmental insults in the presence or absence of a known genetic predisposition. The aim of the Maastricht Cardiomyopathy registry (mCMP-registry; NCT04976348) is to improve (early) diagnosis, risk stratification, and management of cardiomyopathy phenotypes beyond the limits of left ventricular ejection fraction (LVEF). METHODS AND RESULTS: The mCMP-registry is an investigator-initiated prospective registry including patient characteristics, diagnostic measurements performed as part of routine clinical care, treatment information, sequential biobanking, quality of life and economic impact assessment, and regular follow-up. All subjects aged ≥16 years referred to the cardiology department of the Maastricht University Medical Center (MUMC+) for HF-like symptoms or cardiac screening for cardiomyopathies are eligible for inclusion, irrespective of phenotype or underlying causes. Informed consented subjects will be followed up for 15 years. Two central approaches will be used to answer the research questions related to the aims of this registry: (i) a data-driven approach to predict clinical outcome and response to therapy and to identify clusters of patients who share underlying pathophysiological processes; and (ii) a hypothesis-driven approach in which clinical parameters are tested for their (incremental) diagnostic, prognostic, or therapeutic value. The study allows other centres to easily join this initiative, which will further boost research within this field. CONCLUSIONS: The broad inclusion criteria, systematic routine clinical care data-collection, extensive study-related data-collection, sequential biobanking, and multi-disciplinary approach gives the mCMP-registry a unique opportunity to improve diagnosis, risk stratification, and management of HF and (early) cardiomyopathy phenotypes beyond the LVEF limits.