Imaging for the diagnosis of acute myocarditis: can artificial intelligence improve diagnostic performance?

Myocarditis is a cardiovascular disease characterised by inflammation of the heart muscle which can lead to heart failure. There is heterogeneity in the mode of presentation, underlying aetiologies, and clinical outcome with impact on a wide range of age groups which lead to diagnostic challenges. Cardiovascular magnetic resonance (CMR) is the preferred imaging modality in the diagnostic work-up of those with acute myocarditis. There is a need for systematic analytical approaches to improve diagnosis. Artificial intelligence (AI) and machine learning (ML) are increasingly used in CMR and has been shown to match human diagnostic performance in multiple disease categories. In this review article, we will describe the role of CMR in the diagnosis of acute myocarditis followed by a literature review on the applications of AI and ML to diagnose acute myocarditis. Only a few papers were identified with limitations in cases and control size and a lack of detail regarding cohort characteristics in addition to the absence of relevant cardiovascular disease controls. Furthermore, often CMR datasets did not include contemporary tissue characterisation parameters such as T1 and T2 mapping techniques, which are central to the diagnosis of acute myocarditis. Future work may include the use of explainability tools to enhance our confidence and understanding of the machine learning models with large, better characterised cohorts and clinical context improving the diagnosis of acute myocarditis.

Management of acute myocarditis: a systematic review of clinical practice guidelines and recommendations.

The management of acute myocarditis (AM) is addressed in multiple clinical guidelines. We systematically reviewed current guidelines developed by national and international medical organizations on the management of AM to aid clinical practice. Publications in MEDLINE, EMBASE and Cochrane were identified between 1 January 2013 and 12 April 2024. Additionally, the websites of relevant organizations and the Guidelines International Network, Guideline Central, and NHS knowledge and library hub were reviewed. Two reviewers independently screened titles and abstracts, two reviewers assessed the rigour of guideline development, and one reviewer extracted the recommendations. Two of the three guidelines identified showed good rigour of development. Those rigorously developed agreed on the definition of AM, sampling serum troponin as part of the workflow for AM, testing for B-type natriuretic peptides in heart failure, key diagnostic imaging in the form of cardiovascular magnetic resonance, coronary angiography to exclude significant coronary disease, indications for endomyocardial biopsy (EMB), and indications for immunosuppression and advanced treatment options. Discrepancies exist in sampling creatine kinase-myocardial bound as a marker of myocardial injury, indications for EMB, and indications for immunosuppression and treatment of uncomplicated AM. Evidence is lacking for the use of 18F-Fluorodeoxyglucose Positron Emission Tomography for myocardial imaging, exercise restriction, follow-up measures and genetic testing, and there are few high-quality randomized trials to support treatment recommendations. Recommendations for management of AM in the guidelines have largely been developed from expert opinion rather than trial data.

The arrhythmic substrate of hypertrophic cardiomyopathy using ECG imaging.

Introduction: Patients with hypertrophic cardiomyopathy (HCM) are at risk for lethal ventricular arrhythmia, but the electrophysiological substrate behind this is not well-understood. We used non-invasive electrocardiographic imaging to characterize patients with HCM, including cardiac arrest survivors. Methods: HCM patients surviving ventricular fibrillation or hemodynamically unstable ventricular tachycardia (n = 17) were compared to HCM patients without a personal history of potentially lethal arrhythmia (n = 20) and a pooled control group with structurally normal hearts. Subjects underwent exercise testing by non-invasive electrocardiographic imaging to estimate epicardial electrophysiology. Results: Visual inspection of reconstructed epicardial HCM maps revealed isolated patches of late activation time (AT), prolonged activation-recovery intervals (ARIs), as well as reversal of apico-basal trends in T-wave inversion and ARI compared to controls (p < 0.005 for all). AT and ARI were compared between groups. The pooled HCM group had longer mean AT (60.1 ms vs. 52.2 ms, p < 0.001), activation dispersion (55.2 ms vs. 48.6 ms, p = 0.026), and mean ARI (227 ms vs. 217 ms, p = 0.016) than structurally normal heart controls. HCM ventricular arrhythmia survivors could be differentiated from HCM patients without a personal history of life-threatening arrhythmia by longer mean AT (63.2 ms vs. 57.4 ms, p = 0.007), steeper activation gradients (0.45 ms/mm vs. 0.36 ms/mm, p = 0.011), and longer mean ARI (234.0 ms vs. 221.4 ms, p = 0.026). A logistic regression model including whole heart mean activation time and activation recovery interval could identify ventricular arrhythmia survivors from the HCM cohort, producing a C statistic of 0.76 (95% confidence interval 0.72-0.81), with an optimal sensitivity of 78.6% and a specificity of 79.8%. Discussion: The HCM epicardial electrotype is characterized by delayed, dispersed conduction and prolonged, dispersed activation-recovery intervals. Combination of electrophysiologic measures with logistic regression can improve differentiation over single variables. Future studies could test such models prospectively for risk stratification of sudden death due to HCM.

Distal Ventricular Pacing for Drug-Refractory Mid-Cavity Obstructive Hypertrophic Cardiomyopathy: A Randomized, Placebo-Controlled Trial of Personalized Pacing.

BACKGROUND: Patients with refractory, symptomatic left ventricular (LV) mid-cavity obstructive (LVMCO) hypertrophic cardiomyopathy have few therapeutic options. Right ventricular pacing is associated with modest hemodynamic and symptomatic improvement, and LV pacing pilot data suggest therapeutic potential. We hypothesized that site-specific pacing would reduce LVMCO gradients and improve symptoms. METHODS: Patients with symptomatic-drug-refractory LVMCO were recruited for a randomized, blinded trial of personalized prescription of pacing (PPoP). Multiple LV and apical right ventricular pacing sites were assessed during an invasive hemodynamic study of multisite pacing. Patient-specific pacing-site and atrioventricular delays, defining PPoP, were selected on the basis of LVMCO gradient reduction and acceptable pacing parameters. Patients were randomized to 6 months of active PPoP or backup pacing in a crossover design. The primary outcome examined invasive gradient change with best-site pacing. Secondary outcomes assessed quality of life and exercise following randomization to PPoP. RESULTS: A total of 17 patients were recruited; 16 of whom met primary end points. Baseline New York Heart Association was 3±0.6, despite optimal medical therapy. Hemodynamic effects were assessed during pacing at the right ventricular apex and at a mean of 8 LV sites. The gradients in all 16 patients fell with pacing, with maximum gradient reduction achieved via LV pacing in 14 (88%) patients and right ventricular apex in 2. The mean baseline gradient of 80±29 mm Hg fell to 31±21 mm Hg with best-site pacing, a 60% reduction (P<0.0001). One cardiac vein perforation occurred in 1 case, and 15 subjects entered crossover; 2 withdrawals occurred during crossover. Of the 13 completing crossover, 9 (69%) chose active pacing in PPoP configuration as preferred setting. PPoP was associated with improved 6-minute walking test performance (328.5±99.9 versus 285.8±105.5 m; P=0.018); other outcome measures also indicated benefit with PPoP. CONCLUSIONS: In a randomized placebo-controlled trial, PPoP reduces obstruction and improves exercise performance in severely symptomatic patients with LVMCO. REGISTRATION: URL: https://clinicaltrials.gov/study; Unique Identifier: NCT03450252.

Innate and adaptive immunity in acute myocarditis.

Acute myocarditis is an acute inflammatory cardiomyopathy associated with cardiac damage triggered by a virus or a pathological immune activation. It may present with a wide range of clinical presentations, ranging from mild symptoms to severe forms like fulminant myocarditis, characterized by hemodynamic compromise and cardiogenic shock. The immune system plays a central role in the pathogenesis of myocarditis. In fact, while its function is primarily protective, aberrant responses can be detrimental. In this context, both innate and adaptive immunity play pivotal roles; notably, the innate system offers a non-specific and immediate defense, while the adaptive provides specialized protection with immunological memory. However, dysregulation in these systems can misidentify cardiac tissue, triggering autoimmune reactions and possibly leading to significant cardiac tissue damage. This review highlights the importance of innate and adaptive immune responses in the progression and treatment of acute myocarditis.

The atrial and ventricular myocardial proteome of end-stage lamin heart disease.

Lamins A/C (encoded by LMNA gene) can lead to dilated cardiomyopathy (DCM). This pilot study sought to explore the postgenomic phenotype of end-stage lamin heart disease. Consecutive patients with end-stage lamin heart disease (LMNA-group, n = 7) and ischaemic DCM (ICM-group, n = 7) undergoing heart transplantation were prospectively enrolled. Samples were obtained from left atrium (LA), left ventricle (LV), right atrium (RA), right ventricle (RV) and interventricular septum (IVS), avoiding the infarcted myocardial segments in the ICM-group. Samples were analysed using a discovery 'shotgun' proteomics approach. We found that 990 proteins were differentially abundant between LMNA and ICM samples with the LA being most perturbed (16-fold more than the LV). Abundance of lamin A/C protein was reduced, but lamin B increased in LMNA LA/RA tissue compared to ICM, but not in LV/RV. Carbonic anhydrase 3 (CA3) was over-abundant across all LMNA tissue samples (LA, LV, RA, RV, and IVS) when compared to ICM. Transthyretin was more abundant in the LV/RV of LMNA compared to ICM, while sarcomeric proteins such as titin and cardiac alpha-cardiac myosin heavy chain were generally less abundant in RA/LA of LMNA. Protein expression profiling and enrichment analysis pointed towards sarcopenia, extracellular matrix remodeling, deficient myocardial energetics, redox imbalances, and abnormal calcium handling in LMNA samples. Compared to ICM, end-stage lamin heart disease is a biventricular but especially a biatrial disease appearing to have an abundance of lamin B, CA3 and transthyretin, potentially hinting to compensatory responses.

Cardiovascular involvement in later-onset malonyl-CoA decarboxylase deficiency: Case studies and literature review.

BACKGROUND: Malonyl-CoA decarboxylase deficiency (MLYCDD) is an ultra-rare inherited metabolic disorder, characterized by multi-organ involvement manifesting during the first few months of life. Our aim was to describe the clinical, biochemical, and genetic characteristics of patients with later-onset MLYCDD. METHODS: Clinical and biochemical characteristics of two patients aged 48 and 29 years with a confirmed molecular diagnosis of MLYCDD were examined. A systematic review of published studies describing the characteristics of cardiovascular involvement of patients with MLYCDD was performed. RESULTS: Two patients diagnosed with MLYCDD during adulthood were identified. The first presented with hypertrophic cardiomyopathy and ventricular pre-excitation and the second with dilated cardiomyopathy (DCM) and mild-to-moderate left ventricular (LV) systolic dysfunction. No other clinical manifestation typical of MLYCDD was observed. Both patients showed slight increase in malonylcarnitine in their plasma acylcarnitine profile, and a reduction in malonyl-CoA decarboxylase activity. During follow-up, no deterioration of LV systolic function was observed. The systematic review identified 33 individuals with a genetic diagnosis of MLYCDD (median age 6 months [IQR 1-12], 22 males [67%]). Cardiovascular involvement was observed in 64% of cases, with DCM the most common phenotype. A modified diet combined with levocarnitine supplementation resulted in the improvement of LV systolic function in most cases. After a median follow-up of 8 months, 3 patients died (two heart failure-related and one arrhythmic death). CONCLUSIONS: For the first time this study describes a later-onset phenotype of MLYCDD patients, characterized by single-organ involvement, mildly reduced enzyme activity, and a benign clinical course.

Improved Diagnostic Criteria for Apical Hypertrophic Cardiomyopathy.

BACKGROUND: There is no acceptable maximum wall thickness (MWT) threshold for diagnosing apical hypertrophic cardiomyopathy (ApHCM), with guidelines referring to ≥15 mm MWT for all hypertrophic cardiomyopathy subtypes. A normal myocardium naturally tapers apically; a fixed diagnostic threshold fails to account for this. Using cardiac magnetic resonance, "relative" ApHCM has been described with typical electrocardiographic features, loss of apical tapering, and cavity obliteration but also with MWT <15 mm. OBJECTIVES: The authors aimed to define normal apical wall thickness thresholds in healthy subjects and use these to accurately identify ApHCM. METHODS: The following healthy subjects were recruited: healthy UK Biobank imaging substudy subjects (n = 4,112) and an independent healthy volunteer group (n = 489). A clinically defined disease population of 104 ApHCM subjects was enrolled, with 72 overt (MWT ≥15 mm) and 32 relative (MWT <15 mm but typical electrocardiographic/imaging findings) ApHCM subjects. Cardiac magnetic resonance-derived MWT was measured in 16 segments using a published clinically validated machine learning algorithm. Segmental normal reference ranges were created and indexed (for age, sex, and body surface area), and diagnostic performance was assessed. RESULTS: In healthy cohorts, there was no clinically significant age-related difference for apical wall thickness. There were sex-related differences, but these were not clinically significant after indexing to body surface area. Therefore, segmental reference ranges for apical hypertrophy required indexing to body surface area only (not age or sex). The upper limit of normal (the largest of the 4 apical segments measured) corresponded to a maximum apical MWT in healthy subjects of 5.2 to 5.6 mm/m2 with an accuracy of 0.94 (the unindexed equivalent being 11 mm). This threshold was categorized as abnormal in 99% (71/72) of overt ApHCM patients, 78% (25/32) of relative ApHCM patients, 3% (122/4,112) of UK Biobank subjects, and 3% (13/489) of healthy volunteers. CONCLUSIONS: Per-segment indexed apical wall thickness thresholds are highly accurate for detecting apical hypertrophy, providing confidence to the reader to diagnose ApHCM in those not reaching current internationally recognized criteria.

Microstructural and Microvascular Phenotype of Sarcomere Mutation Carriers and Overt Hypertrophic Cardiomyopathy.

BACKGROUND: In hypertrophic cardiomyopathy (HCM), myocyte disarray and microvascular disease (MVD) have been implicated in adverse events, and recent evidence suggests that these may occur early. As novel therapy provides promise for disease modification, detection of phenotype development is an emerging priority. To evaluate their utility as early and disease-specific biomarkers, we measured myocardial microstructure and MVD in 3 HCM groups-overt, either genotype-positive (G+LVH+) or genotype-negative (G-LVH+), and subclinical (G+LVH-) HCM-exploring relationships with electrical changes and genetic substrate. METHODS: This was a multicenter collaboration to study 206 subjects: 101 patients with overt HCM (51 G+LVH+ and 50 G-LVH+), 77 patients with G+LVH-, and 28 matched healthy volunteers. All underwent 12-lead ECG, quantitative perfusion cardiac magnetic resonance imaging (measuring myocardial blood flow, myocardial perfusion reserve, and perfusion defects), and cardiac diffusion tensor imaging measuring fractional anisotropy (lower values expected with more disarray), mean diffusivity (reflecting myocyte packing/interstitial expansion), and second eigenvector angle (measuring sheetlet orientation). RESULTS: Compared with healthy volunteers, patients with overt HCM had evidence of altered microstructure (lower fractional anisotropy, higher mean diffusivity, and higher second eigenvector angle; all P<0.001) and MVD (lower stress myocardial blood flow and myocardial perfusion reserve; both P<0.001). Patients with G-LVH+ were similar to those with G+LVH+ but had elevated second eigenvector angle (P<0.001 after adjustment for left ventricular hypertrophy and fibrosis). In overt disease, perfusion defects were found in all G+ but not all G- patients (100% [51/51] versus 82% [41/50]; P=0.001). Patients with G+LVH- compared with healthy volunteers similarly had altered microstructure, although to a lesser extent (all diffusion tensor imaging parameters; P<0.001), and MVD (reduced stress myocardial blood flow [P=0.015] with perfusion defects in 28% versus 0 healthy volunteers [P=0.002]). Disarray and MVD were independently associated with pathological electrocardiographic abnormalities in both overt and subclinical disease after adjustment for fibrosis and left ventricular hypertrophy (overt: fractional anisotropy: odds ratio for an abnormal ECG, 3.3, P=0.01; stress myocardial blood flow: odds ratio, 2.8, P=0.015; subclinical: fractional anisotropy odds ratio, 4.0, P=0.001; myocardial perfusion reserve odds ratio, 2.2, P=0.049). CONCLUSIONS: Microstructural alteration and MVD occur in overt HCM and are different in G+ and G- patients. Both also occur in the absence of hypertrophy in sarcomeric mutation carriers, in whom changes are associated with electrocardiographic abnormalities. Measurable changes in myocardial microstructure and microvascular function are early-phenotype biomarkers in the emerging era of disease-modifying therapy.

The mitral valve in hypertrophic cardiomyopathy.

PURPOSE OF REVIEW: Whilst abnormally increased left ventricular wall thickness is the hallmark feature of hypertrophic cardiomyopathy (HCM), anomalies of the mitral valve and supporting apparatus are well documented. This review addresses the clinical importance of mitral valve abnormalities in HCM, their mechanistic associations with symptoms, and therapeutic strategies targeting mitral valve and apparatus abnormalities. RECENT FINDINGS: The normal mitral valve possesses anatomical features facilitating unrestricted blood flow during LV filling, preventing regurgitation during LV systole, and avoiding obstruction of LV ejection. In HCM, a variety of structural and functional abnormalities can conspire to cause deranged mitral valve function, with implications for management strategy. Identification and characterization of these abnormalities is facilitated by multimodality imaging. Alcohol septal ablation (ASA) cannot address primary mitral valve abnormalities, and so is not preferred to surgical intervention if mitral valve abnormalities are present and are judged to make dominant contributions to LV outflow tract obstruction (LVOTO). Two broadly opposing surgical intervention strategies exist, one advocating isolated septal myectomy and the other including adjuvant mitral apparatus modification. Newer, less invasive surgical and transcatheter techniques will expand interventional options. SUMMARY: Mitral valve abnormalities are a central pathological feature of HCM. Multimodality imaging is crucial for their identification and characterization prior to therapeutic intervention.

Characterizing the hypertensive cardiovascular phenotype in the UK Biobank.

AIMS: To describe hypertension-related cardiovascular magnetic resonance (CMR) phenotypes in the UK Biobank considering variations across patient populations. METHODS AND RESULTS: We studied 39 095 (51.5% women, mean age: 63.9 ± 7.7 years, 38.6% hypertensive) participants with CMR data available. Hypertension status was ascertained through health record linkage. Associations between hypertension and CMR metrics were estimated using multivariable linear regression adjusting for major vascular risk factors. Stratified analyses were performed by sex, ethnicity, time since hypertension diagnosis, and blood pressure (BP) control. Results are standardized beta coefficients, 95% confidence intervals, and P-values corrected for multiple testing. Hypertension was associated with concentric left ventricular (LV) hypertrophy (increased LV mass, wall thickness, concentricity index), poorer LV function (lower global function index, worse global longitudinal strain), larger left atrial (LA) volumes, lower LA ejection fraction, and lower aortic distensibility. Hypertension was linked to significantly lower myocardial native T1 and increased LV ejection fraction. Women had greater hypertension-related reduction in aortic compliance than men. The degree of hypertension-related LV hypertrophy was greatest in Black ethnicities. Increasing time since diagnosis of hypertension was linked to adverse remodelling. Hypertension-related remodelling was substantially attenuated in hypertensives with good BP control. CONCLUSION: Hypertension was associated with concentric LV hypertrophy, reduced LV function, dilated poorer functioning LA, and reduced aortic compliance. Whilst the overall pattern of remodelling was consistent across populations, women had greater hypertension-related reduction in aortic compliance and Black ethnicities showed the greatest LV mass increase. Importantly, adverse cardiovascular remodelling was markedly attenuated in hypertensives with good BP control.

Apical Ischemia Is a Universal Feature of Apical Hypertrophic Cardiomyopathy.

BACKGROUND: Apical hypertrophic cardiomyopathy (ApHCM) accounts for ≈10% of hypertrophic cardiomyopathy cases and is characterized by apical hypertrophy, apical cavity obliteration, and tall ECG R waves with ischemic-looking deep T-wave inversion. These may be present even with <15 mm apical hypertrophy (relative ApHCM). Microvascular dysfunction is well described in hypertrophic cardiomyopathy. We hypothesized that apical perfusion defects would be common in ApHCM. METHODS: A 2-center study using cardiovascular magnetic resonance short- and long-axis quantitative adenosine vasodilator stress perfusion mapping. One hundred patients with ApHCM (68 overt hypertrophy [≥15 mm] and 32 relative ApHCM) were compared with 50 patients with asymmetrical septal hypertrophy hypertrophic cardiomyopathy and 40 healthy volunteer controls. Perfusion was assessed visually and quantitatively as myocardial blood flow and myocardial perfusion reserve. RESULTS: Apical perfusion defects were present in all overt ApHCM patients (100%), all relative ApHCM patients (100%), 36% of asymmetrical septal hypertrophy hypertrophic cardiomyopathy, and 0% of healthy volunteers (P<0.001). In 10% of patients with ApHCM, perfusion defects were sufficiently apical that conventional short-axis views missed them. In 29%, stress myocardial blood flow fell below rest values. Stress myocardial blood flow was most impaired subendocardially, with greater hypertrophy or scar, and with apical aneurysms. Impaired apical myocardial blood flow was most strongly predicted by thicker apical segments (ß-coefficient, -0.031 mL/g per min [CI, -0.06 to -0.01]; P=0.013), higher ejection fraction (-0.025 mL/g per min [CI, -0.04 to -0.01]; P<0.005), and ECG maximum R-wave height (-0.023 mL/g per min [CI, -0.04 to -0.01]; P<0.005). CONCLUSIONS: Apical perfusion defects are universally present in ApHCM at all stages. Its ubiquitous presence along with characteristic ECG suggests ischemia may play a disease-defining role in ApHCM.

Excessive Trabeculation of the Left Ventricle: JACC: Cardiovascular Imaging Expert Panel Paper.

Excessive trabeculation, often referred to as "noncompacted" myocardium, has been described at all ages, from the fetus to the adult. Current evidence for myocardial development, however, does not support the formation of compact myocardium from noncompacted myocardium, nor the arrest of this process to result in so-called noncompaction. Excessive trabeculation is frequently observed by imaging studies in healthy individuals, as well as in association with pregnancy, athletic activity, and with cardiac diseases of inherited, acquired, developmental, or congenital origins. Adults with incidentally noted excessive trabeculation frequently require no further follow-up based on trabecular pattern alone. Patients with cardiomyopathy and excessive trabeculation are managed by cardiovascular symptoms rather than the trabecular pattern. To date, the prognostic role of excessive trabeculation in adults has not been shown to be independent of other myocardial disease. In neonates and children with excessive trabeculation and normal or abnormal function, clinical caution seems warranted because of the reported association with genetic and neuromuscular disorders. This report summarizes the evidence concerning the etiology, pathophysiology, and clinical relevance of excessive trabeculation. Gaps in current knowledge of the clinical relevance of excessive trabeculation are indicated, with priorities suggested for future research and improved diagnosis in adults and children.

Dilated cardiomyopathy and chronic cardiac inflammation: Pathogenesis, diagnosis and therapy.

Dilated cardiomyopathy (DCM) is typically defined by left ventricular dilation and systolic dysfunction in the absence of a clear precipitant. Idiopathic disease is common; up to 50% of patients with DCM have no cause found despite imaging, genetic and biopsy assessments. Treatment remains focused on managing symptoms, reducing the risk of sudden cardiac death and ameliorating the structural and electrical complications of disease progression. In the absence of aetiology-specific treatments, the condition remains associated with a poor prognosis; mortality is approximately 40% at 10 years. The role of immune-mediated inflammatory injury in the development and progression of DCM was first proposed over 30 years ago. Despite the subsequent failures of three large clinical trials of immunosuppressive treatment (ATTACH, RENEWAL and the Myocarditis Treatment Trial), evidence for an abnormal adaptive immune response in DCM remains significant. In this review, we summarise and discuss available evidence supporting immune dysfunction in DCM, with a specific focus on cellular immunity. We also highlight current clinical and experimental treatments. We propose that the success of future immunosuppressive treatment trials in DCM will be dependent on the deep immunophenotyping of patients, to identify those with active inflammation and/or an abnormal immune response who are most likely to respond to therapy.

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.

Acute Myocarditis Associated With Desmosomal Gene Variants.

BACKGROUND: The risk of adverse cardiovascular events in patients with acute myocarditis (AM) and desmosomal gene variants (DGV) remains unknown. OBJECTIVES: The purpose of this study was to ascertain the risk of death, ventricular arrhythmias, recurrent myocarditis, and heart failure (main endpoint) in patients with AM and pathogenic or likely pathogenetic DGV. METHODS: In a retrospective international study from 23 hospitals, 97 patients were included: 36 with AM and DGV (DGV[+]), 25 with AM and negative gene testing (DGV[-]), and 36 with AM without genetics testing. All patients had troponin elevation plus findings consistent with AM on histology or at cardiac magnetic resonance (CMR). In 86 patients, CMR changes in function and structure were re-assessed at follow-up. RESULTS: In the DGV(+) AM group (88.9% DSP variants), median age was 24 years, 91.7% presented with chest pain, and median left ventricular ejection fraction (LVEF) was 56% on CMR (P = NS vs the other 2 groups). Kaplan-Meier curves demonstrated a higher risk of the main endpoint in DGV(+) AM compared with DGV(-) and without genetics testing patients (62.3% vs 17.5% vs 5.3% at 5 years, respectively; P < 0.0001), driven by myocarditis recurrence and ventricular arrhythmias. At follow-up CMR, a higher number of late gadolinium enhanced segments was found in DGV(+) AM. CONCLUSIONS: Patients with AM and evidence of DGV have a higher incidence of adverse cardiovascular events compared with patients with AM without DGV. Further prospective studies are needed to ascertain if genetic testing might improve risk stratification of patients with AM who are considered at low risk.