Cooper, Leslie T.

Introduction: Studying the clinical nature of myocarditis on a broad scale across age and sex groups is required to investigate risk factors and patterns of disease. This study aimed to examine patient- and hospital-centered characteristics of patients being hospitalized for myocarditis. Hypothesis: Sex differences in myocarditis prevalence are dependent on age. Methods and Results: We included all patients being hospitalized in three tertiary care centers between 1999 and 2021 with a diagnosis of acute or chronic myocarditis. We utilized Chi-square, T-test, Fisher exact or Wilcoxon-Mann-Whitney U tests. 7,031 patients with acute or chronic myocarditis were included in total. 231 (3.3%) were of pre-pubescent age (<13 years if male, <11 years if female), 410 (5.8%) were adolescent patients (<18 years), 2,089 (29.7%) young adults (18-35 years), 2,535 (36.1%) middle-aged adults (35-54 years) and 1,766 (25.1%) patients were over 54 years (post-menopausal age). The diagnosis of myocarditis was confirmed by endomyocardial biopsy in 1,337 patients (19%), while it was based on clinical parameters and/or magnetic resonance imaging in the remaining patients. Adolescent patients had the highest levels of procalcitonin (6.98 ±44.6 μg/l), troponin T (450 ±1,550 ng/l) and creatine kinase (360 ±677U/l), while pre-pubescent patients had the highest levels of anti-streptolysin antibody (320 ±470 kU/l) and NT-proBNP (14,000 ±20,800ng/l) compared to all other age groups. Left-ventricular ejection fraction decreased over age groups from 60 ±4% in adolescent patients to 44.0 ±16% in senior patients. The strongest sex difference in myocarditis frequency was observed in young (608 female vs. 1,481 male; P<0.001) and middle-aged adults (1,025 female vs. 1,510 male; P<0.001) (see Figure 1). Conclusion: Strong sex differences in myocarditis prevalence were particularly observed in young and middle-aged patients. Sex hormones may determine the risk of developing myocarditis.

Background: Myocarditis may predispose to dilated cardiomyopathy (DCM) and sudden cardiac death (SCD). Familial data indicate a potential genetic susceptibility shared with arrhythmogenic cardiomyopathy (ACM). We present the first large-scale genotype-phenotype study of adults with acute myocarditis. Methods: A cohort comprising 336 consecutive patients with acute myocarditis was enrolled in London and Maastricht. All participants underwent targeted DNA sequencing for well-characterised cardiomyopathy-associated genes. The burden of rare protein altering variants (PAV) in ACM genes, DCM genes, and TTN specifically, were compared with local healthy controls sequenced on the same platform (n=1053). Case ascertainment was assessed against national hospital admission data. Results: We identified rare protein-altering variants in 23% of cases compared to 16% in controls (Δ+6.8%; p=0.021), with rare truncating variants (tv) in 6% of cases compared to <1% of controls ((Δ+5%; p=0.0097). In London (n=230; median left ventricular ejection fraction (LVEF) 63%), which was representative of national myocarditis admissions, 4.8% of cases carried rare tv, particularly within ACM genes (3% cases vs 0% controls; odds ratio 8.2; p=0.001). This was predominantly driven by desmoplakin (DSP)-tv in patients with normal LVEF. In Maastricht (n=106; median LVEF 30%), rare tv in DCM genes were enriched, particularly TTN-tv found in 7% (all with LVEF<50%) compared to 1% in controls (OR 3.6; p=0.0116). During a median follow-up of 1.9 years, all-cause mortality was greatest in those with a DCM variant (18% vs 4% with no variant; OR 5.0; p=0.004). Conclusion: We identified enrichment of cardiomyopathy gene variants in acute myocarditis patients, dominated by DSP-tv in those with normal LVEF and TTN-tv in those with reduced LVEF. Incorporation of genetic testing may be beneficial to identify such high-risk individuals and guide family screening in acute myocarditis patients.

Arrhythmogenic cardiomyopathy (ACM) is a primary disease of the myocardium, predominantly caused by genetic defects in proteins of the cardiac intercalated disc, particularly, desmosomes. Transmission is mostly autosomal dominant with incomplete penetrance. ACM also has wide phenotype variability, ranging from premature ventricular contractions to sudden cardiac death and heart failure. Among other drivers and modulators of phenotype, inflammation in response to viral infection and immune triggers have been postulated to be an aggravator of cardiac myocyte damage and necrosis. This theory is supported by multiple pieces of evidence, including the presence of inflammatory infiltrates in more than two-thirds of ACM hearts, detection of different cardiotropic viruses in sporadic cases of ACM, the fact that patients with ACM often fulfill the histological criteria of active myocarditis, and the abundance of anti–desmoglein-2, antiheart, and anti-intercalated disk autoantibodies in patients with arrhythmogenic right ventricular cardiomyopathy. In keeping with the frequent familial occurrence of ACM, it has been proposed that, in addition to genetic predisposition to progressive myocardial damage, a heritable susceptibility to viral infections and immune reactions may explain familial clustering of ACM. Moreover, considerable in vitro and in vivo evidence implicates activated inflammatory signaling in ACM. Although the role of inflammation/immune response in ACM is not entirely clear, inflammation as a driver of phenotype and a potential target for mechanism-based therapy warrants further research. This review discusses the present evidence supporting the role of inflammatory and immune responses in ACM pathogenesis and proposes opportunities for translational and clinical investigation.

Introduction : The incidence of spontaneous clinical improvement in acute cardiomyopathy (ACM) patients treated with evidence based medical therapy is unknown. We hypothesized that pts without LV dilatation at presentation would have the greatest potential for recovery of ejection fraction (EF). Methods: A multi-center NHLBI sponsored trial, Intervention in Myocarditis and Acute Cardiomyopathy II (IMAC 2) was designed to study the clinical course of ACM and the mechanisms associated with outcomes. A clinical, echocardiography, and genetics core lab are established. Results: 15 centers have enrolled 215 pts, mean age 45 ± 14 yrs, 34% female, NYHA class I–IV% 18/54/21/7, baseline EF 0.25 ± 0.09. Therapy included 80% beta blockers and 92% ACE or ARB treated. All patients enrolled had symptoms for ≤ 6 mos and were diagnosed with acute, idiopathic cardiomyopathy or myocarditis. Baseline and 6 mo echoes in 140 pts reviewed by the core lab demonstrated increased ejection fraction (EF): 0.25 ± 0.09 to 0.40 ± 0.11 p<0.001; mean increase 0.15 ± 0.10. Recovery in EF from baseline to 6 mos was related to LVEDD at baseline as shown in the Figure . Kaplan Meier survival n=207 at 1 and 2 years 96% and 94% and transplant free survival at 1 and 2 yrs 92% and 91%. Conclusions: Results of IMAC 2 reveal a marked spontaneous improvement in EF over 6 months, greatest in those with non-dilated LVEDD at baseline, and excellent overall survival in ACM pts treated with evidence based therapies.

Dilated cardiomyopathy (DCM) is characterized by dilatation of the left ventricle and impaired systolic function and is the second most common cause of heart failure after coronary heart disease. The etiology of DCM is diverse including genetic pathogenic variants, infection, inflammation, autoimmune diseases, exposure to chemicals/toxins as well as endocrine and neuromuscular causes. DCM is inherited in 20–50% of cases where more than 30 genes have been implicated in the development of DCM with pathogenic variants in TTN (Titin) most frequently associated with disease. Even though male sex is a risk factor for heart failure, few studies have examined sex differences in the pathogenesis of DCM. We searched the literature for studies examining idiopathic or familial/genetic DCM that reported data by sex in order to determine the sex ratio of disease. We found 31 studies that reported data by sex for non-genetic DCM with an average overall sex ratio of 2.5:1 male to female and 7 studies for familial/genetic DCM with an overall average sex ratio of 1.7:1 male to female. No manuscripts that we found had more females than males in their studies. We describe basic and clinical research findings that may explain the increase in DCM in males over females based on sex differences in basic physiology and the immune and fibrotic response to damage caused by mutations, infections, chemotherapy agents and autoimmune responses.

Abstract Endomyocardial biopsy (EMB) is an invasive procedure, globally most often used for the monitoring of heart transplant (HTx) rejection. In addition, EMB can have an important complementary role to the clinical assessment in establishing the diagnosis of diverse cardiac disorders, including myocarditis, cardiomyopathies, drug-related cardiotoxicity, amyloidosis, other infiltrative and storage disorders, and cardiac tumours. Improvements in EMB equipment and the development of new techniques for the analysis of EMB samples have significantly improved diagnostic precision of EMB. The present document is the result of the Trilateral Cooperation Project between the Heart Failure Association of the European Society of Cardiology, the Heart Failure Society of America, and the Japanese Heart Failure Society. It represents an expert consensus aiming to provide a comprehensive, up-to-date perspective on EMB, with a focus on the following main issues: (i) an overview of the practical approach to EMB, (ii) an update on indications for EMB, (iii) a revised plan for HTx rejection surveillance, (iv) the impact of multimodality imaging on EMB, and (v) the current clinical practice in the worldwide use of EMB.