Loss-of-function desmoplakin I and II mutations underlie dominant arrhythmogenic cardiomyopathy with a hair and skin phenotype.

BACKGROUND: Arrhythmogenic cardiomyopathy (AC) is an inherited, frequently underdiagnosed disorder, which can predispose individuals to sudden cardiac death. Rare, recessive forms of AC can be associated with woolly hair and palmoplantar keratoderma, but most autosomal dominant AC forms have been reported to be cardiac specific. Causative mutations frequently occur in desmosomal genes including desmoplakin (DSP). OBJECTIVES: In this study, we systematically investigated the presence of a skin and hair phenotype in heterozygous DSP mutation carriers with AC. METHODS: Six AC pedigrees with 38 carriers of a dominant loss-of-function (nonsense or frameshift) mutation in DSP were evaluated by detailed clinical examination (cardiac, hair and skin) and molecular phenotyping. RESULTS: All carriers with mutations affecting both major DSP isoforms (DSPI and II) were observed to have curly or wavy hair in the pedigrees examined, except for members of Family 6, where the position of the mutation only affected the cardiac-specific isoform DSPI. A mild palmoplantar keratoderma was also present in many carriers. Sanger sequencing of cDNA from nonlesional carrier skin suggested degradation of the mutant allele. Immunohistochemistry of patient skin demonstrated mislocalization of DSP and other junctional proteins (plakoglobin, connexin 43) in the basal epidermis. However, in Family 6, DSP localization was comparable with control skin. CONCLUSIONS: This study identifies a highly recognizable cutaneous phenotype associated with dominant loss-of-function DSPI/II mutations underlying AC. Increased awareness of this phenotype among healthcare workers could facilitate a timely diagnosis of AC in the absence of overt cardiac features.

Use of high-throughput targeted exome-sequencing to screen for copy number variation in hypertrophic cardiomyopathy.

INTRODUCTION: The role of copy-number variants (CNV) as a cause of hypertrophic cardiomyopathy (HCM) is poorly studied. The aim of this study was to use high-throughput sequence (HTS) data combined with a read-depth strategy, to screen for CNV in cardiomyopathy-associated genes in a large consecutive cohort of HCM patients. METHODS: Five-hundred-and-five unrelated HCM patients were genotyped using a HTS approach for 41 cardiovascular genes. We used a previously validated read-depth strategy (ExomeDepth) to call CNVs from the short-read sequence data. Detected CNVs in 19 cardiomyopathy-associated genes were then validated by comparative genomic hybridization array. RESULTS: Twelve CNVs were identified. Four CNVs in 4 patients (0.8% of the cohort) were validated: one large deletion in MYBPC3, one large deletion in PDLIM3, one duplication of the entire TNNT2 gene and one large duplication in LMNA. CONCLUSIONS: Our data suggest that the proportion of HCM cases with pathogenic CNVs is small (<1%). For the small subset of patients with clearly interpretable CNVs, our findings have direct clinical implications. Short read sequence data can be used for CNV calling, but the high false positive rate requires a validation step. The two-step strategy described here is effective at identifying novel genetic causes of HCM and similar techniques should be applied whenever possible.

Myocarditis and the military patient.

Myocarditis, simply defined as inflammation of the heart muscle, is a commonly encountered cardiac disease in primary and secondary care, both in the UK and on Operational deployments. In the UK Armed Forces, myocarditis results in deaths as well as the premature termination of military careers on medical grounds. The aetiology is usually the result of a number of infectious aetiologies with viruses being the most common pathogens in the vast majority of cases. However, it may also be the result of autoimmune activation, chemical or pharmacological toxins, environmental insult or hypersensitivity reactions. Particular aetiologies that are more likely to be seen in a military population are discussed and include certain infections, smallpox vaccine, and hyperthermia and hypothermia. The clinical features can be highly variable ranging from an asymptomatic infection to fulminant heart failure. Features pertinent to the military doctor, including the natural history, investigative modalities and management strategies, with a particular emphasis on the occupational impact of myocarditis in the UK Armed Forces are reviewed.

The natural history of a genetic subtype of arrhythmogenic right ventricular cardiomyopathy caused by a p.S358L mutation in TMEM43.

To determine the phenotype and natural history of a founder genetic subtype of autosomal dominant arrhythmogenic right ventricular cardiomyopathy (ARVC) caused by a p.S358L mutation in TMEM43. The age of onset of cardiac symptoms, clinical events and test abnormalities were studied in 412 subjects (258 affected and 154 unaffected), all of which occurred in affected males significantly earlier and more often than unaffected males. Affected males were hospitalized four times more often than affected females (p ≤ 0.0001) and died younger (p ≤ 0.001). The temporal sequence from symptoms onset to death was prolonged in affected females by 1-2 decades. The most prevalent electrocardiogram (ECG) manifestation was poor R wave progression (PRWP), with affected males twice as likely to develop PRWP as affected females (p ≤ 0.05). Left ventricular enlargement (LVE) occurred in 43% of affected subjects, with 11% fulfilling criteria for dilated cardiomyopathy. Ventricular ectopy on Holter monitor was common and occurred early: the most diagnostically useful clinical test. No symptom or test could rule out diagnosis. This ARVC subtype is a sex-influenced lethal arrhythmogenic cardiomyopathy, with a unique ECG finding, LV dilatation, heart failure and early death, where molecular pre-symptomatic diagnosis has the greatest clinical utility.

Cardiomyopathy mutations reveal variable region of myosin converter as major element of cross-bridge compliance.

The ability of myosin to generate motile forces is based on elastic distortion of a structural element of the actomyosin complex (cross-bridge) that allows strain to develop before filament sliding. Addressing the question, which part of the actomyosin complex experiences main elastic distortion, we suggested previously that the converter domain might be the most compliant region of the myosin head domain. Here we test this proposal by studying functional effects of naturally occurring missense mutations in the beta-myosin heavy chain, 723Arg --> Gly (R723G) and 736Ile --> Thr (I736T), in comparison to 719Arg --> Trp (R719W). All three mutations are associated with hypertrophic cardiomyopathy and are located in the converter region of the myosin head domain. We determined several mechanical parameters of single skinned slow fibers isolated from Musculus soleus biopsies of hypertrophic cardiomyopathy patients and healthy controls. Major findings of this study for mutation R723G were i), a >40% increase in fiber stiffness in rigor with a 2.9-fold increase in stiffness per myosin head (S( *)(rigor R723G) = 0.84 pN/nm S( *)(rigor WT) = 0.29 pN/nm); and ii), a significant increase in force per head (F( *)(10 degrees C), 1.99 pN vs. 1.49 pN = 1.3-fold increase; F( *)(20 degrees C), 2.56 pN vs. 1.92 pN = 1.3-fold increase) as well as stiffness per head during isometric steady-state contraction (S( *)(active10 degrees C), 0.52 pN/nm vs. 0.28 pN/nm = 1.9-fold increase). Similar changes were found for mutation R719W (2.6-fold increase in S( *)(rigor); 1.8-fold increase in F( *)(10 degrees C), 1.6-fold in F( *)(20 degrees C); twofold increase in S( *)(active10 degrees C)). Changes in active cross-bridge cycling kinetics could not account for the increase in force and active stiffness. For the above estimates the previously determined fraction of mutated myosin in the biopsies was taken into account. Data for wild-type myosin of slow soleus muscle fibers support previous findings that for the slow myosin isoform S( *) and F( *) are significantly lower than for fast myosin e.g., of rabbit psoas muscle. The data indicate that two mutations, R723G and R719W, are associated with an increase in resistance to elastic distortion of the individual mutated myosin heads whereas mutation I736T has essentially no effect. The data strongly support the notion that major elastic distortion occurs within the converter itself. Apparently, the compliance depends on specific residues, e.g., R719 and R723, presumably located at strategic positions near the long alpha-helix of the light chain binding domain. Because amino acids 719 and 723 are nonconserved residues, cross-bridge stiffness may well be specifically tuned for different myosins.

High-density substrate mapping in Brugada syndrome: combined role of conduction and repolarization heterogeneities in arrhythmogenesis.

BACKGROUND: Two principal mechanisms are thought to be responsible for Brugada syndrome (BS): (1) right ventricular (RV) conduction delay and (2) RV subepicardial action potential shortening. This in vivo high-density mapping study evaluated the conduction and repolarization properties of the RV in BS subjects. METHODS AND RESULTS: A noncontact mapping array was positioned in the RV of 18 BS patients and 20 controls. Using a standard S(1)-S(2) protocol, restitution curves of local activation time and activation recovery interval were constructed to determine local maximal restitution slopes. Significant regional conduction delays in the anterolateral free wall of the RV outflow tract of BS patients were identified. The mean increase in delay was 3-fold greater in this region than in control (P=0<0.001). Local activation gradient was also maximally reduced in this area: 0.33+/-0.1 (mean+/-SD) mm/ms in BS patients versus 0.51+/-0.15 mm/ms in controls (P<0.0005). The uniformity of wavefront propagation as measured by the square of the correlation coefficient, r(2), was greater in BS patients versus controls (0.94+/-0.04 versus 0.89+/-0.09 [mean+/-SD]; P<0.05). The odds ratio of BS hearts having any RV segment with maximal restitution slope >1 was 3.86 versus controls. Five episodes of provoked ventricular tachycardia arose from wave breaks originating from RV outflow tract slow-conduction zones in 5 BS patients. CONCLUSIONS: Marked regional endocardial conduction delay and heterogeneities in repolarization exist in BS. Wave break in areas of maximal conduction delay appears to be critical in the initiation and maintenance of ventricular tachycardia. These data indicate that further studies of mapping BS to identify slow-conduction zones should be considered to determine their role in spontaneous ventricular arrhythmias.

Homozygous mutation of desmocollin-2 in arrhythmogenic right ventricular cardiomyopathy with mild palmoplantar keratoderma and woolly hair.

OBJECTIVES: The phenotypic triad of arrhythmogenic right ventricular cardiomyopathy (ARVC) associated with palmoplantar keratoderma and woolly hair has been previously associated with homozygous mutations in both plakoglobin and desmoplakin, which are both critical components of the desmosome. We present here a clinical and genetic study of a consanguineous pedigree in which 2 siblings present with ARVC with left ventricular involvement and associated mild palmoplantar keratoderma and woolly hair. METHODS: Clinical evaluation of the 2 patients and their family members was undertaken along with a homozygosity-mapping approach to identify the relevant gene and sequencing analysis to identify the causative mutation. RESULTS: The homozygosity-mapping approach excluded the involvement of both plakoglobin and desmoplakin in this pedigree. However, an extended region of homozygosity in both affected cases was revealed at the chromosome 18 desmocollin/desmoglein cluster, genes which encode components of the desmosome. Sequence analysis of the democollin-2 gene, located within this cluster, revealed a homozygous single-base deletion in exon 12 (1841delG). This mutation is predicted to lead to a frame shift and a premature termination codon at position 625 (S614fsX625). CONCLUSIONS: This is the first reported case of a mutation in desmocollin-2 associated with autosomal recessive ARVC.

Episodic syncope in hypertrophic cardiomyopathy: evidence for inappropriate vasodilation.

Symptoms of impaired consciousness (syncope and pre-syncope) occur in 15-25% of patients with hypertrophic cardiomyopathy (HCM).1 In young patients a history of recurrent syncope is associated with an increased risk of sudden death.2(-)5 Syncope usually occurs without warning or symptoms suggestive of the cause. Detailed investigations identify a probable mechanism in a minority, usually paroxysmal atrial fibrillation or ventricular tachycardia. In the majority however no likely mechanism is found despite repeated 24-hour ambulatory echocardiography (ECG) or patient-activated monitoring, exercise testing and invasive electrophysiological studies.1 6 Empirical treatment with amiodarone, a pacemaker or an implantable cardioverter-defibrillator is commonly employed, but is often unsuccessful in relieving the symptoms. We have previously observed that approximately 30% of patients with HCM have abnormal blood pressure response during maximal upright exercise.7 8 This was due in the majority of patients to an exaggerated fall in systemic vascular resistance, possibly arising from abnormal activation of stretch-sensitive left ventricular mechanoreceptors,9 10 by a mechanism similar to that described in aortic stenosis.11 However, in some patients an inadequate cardiac output response to exercise may be responsible.12 We hypothesised that abnormal vasodepressor-mediated hypotension may also occur during daily life in patients with HCM, and that this may be an important mechanism of syncope when conventional investigations fail to reveal a cause.

Idiopathic restrictive cardiomyopathy in children is caused by mutations in cardiac sarcomere protein genes.

BACKGROUND: Restrictive cardiomyopathy (RCM) is rare in childhood, but has a grave prognosis. The cause of disease in most cases is unknown. OBJECTIVE: To determine the prevalence of sarcomere protein gene mutations in children with idiopathic RCM. METHODS: Twelve patients (9 female, mean age 5.1 years) with idiopathic RCM referred between 1991 and August 2006 underwent detailed clinical and genetic evaluation. Nine had received cardiac transplants at the time of the study. The entire coding sequences of the genes encoding eight cardiac sarcomere proteins and desmin were screened for mutations. Familial evaluation was performed on first-degree relatives. RESULTS: Four patients (33%) had a family history of cardiomyopathy: RCM (n = 2); dilated cardiomyopathy (n = 1) and left ventricular non-compaction (n = 1). Sarcomere protein gene mutations were identified in four patients (33%): 2 in the cardiac troponin I gene (TNNI3) and 1 each in the troponin T (TNNT2) and alpha-cardiac actin (ACTC) genes. Two were de novo mutations and 3 were new mutations. All mutations occurred in functionally important and conserved regions of the genes. CONCLUSIONS: Sarcomere protein gene mutations are an important cause of idiopathic RCM in childhood. We describe the first mutation in ACTC in familial RCM. The identification of RCM in a child should prompt consideration of sarcomere protein disease as a possible cause and warrants clinical evaluation of the family.

B-type natriuretic peptide predicts disease severity in children with hypertrophic cardiomyopathy.

BACKGROUND: In adults with hypertrophic cardiomyopathy (HCM), plasma B-type natriuretic peptide (BNP) levels correlate with dyspnoea class and other markers of disease severity. In children with HCM, symptoms are a poor guide to disease severity and no studies have evaluated the clinical utility of BNP testing. OBJECTIVE: To assess the relation of BNP levels to symptoms and markers of disease severity in children with HCM. METHODS: Forty-four consecutive patients with HCM (27 male, age 10 (area under the receiver operator characteristic curve = 0.875 (p<0.001)). CONCLUSIONS: BNP levels correlate with non-invasive parameters of disease severity in children with HCM, including measures of raised LV filling pressures. For patients in whom evaluation of symptoms is difficult, BNP may be a useful additional tool in the assessment of disease severity.

Prevalence of exercise-induced left ventricular outflow tract obstruction in symptomatic patients with non-obstructive hypertrophic cardiomyopathy.

BACKGROUND: Resting left ventricular outflow tract obstruction (LVOTO) occurs in 25% of patients with hypertrophic cardiomyopathy (HCM) and is an important cause of symptoms and disease progression. The prevalence and clinical significance of exercise induced LVOTO in patients with symptomatic non-obstructive HCM is uncertain. METHODS AND RESULTS: 87 symptomatic patients (43.3 (13.7) years, 67.8% males) with HCM and no previously documented LVOTO (defined as a gradient >or=30 mm Hg) underwent echocardiography during upright cardiopulmonary exercise testing: 54 patients (62.1%; 95% CI 51.5 to 71.6) developed LVOTO during exercise (latent LVOTO); 33 (37.9%; 95% CI 28.4 to 48.5) had neither resting nor exercise LVOTO (non-obstructive). Patients with latent LVOTO were more likely to have systolic anterior motion of the mitral valve (SAM) at rest (relative risk 2.1, 95% CI 1.2 to 3.8; p = 0.01), and higher peak oxygen consumption (mean difference: 10.3%, 95% CI 2.1 to 18.5; p = 0.02) than patients with non-obstructive HCM. The only independent predictors of Delta gradient during exercise were a history of presyncope/syncope, incomplete/complete SAM at rest and Wigle score (all p<0.05). Subsequent invasive reduction of LVOTO in 10 patients with latent obstruction and drug refractory symptoms resulted in improved functional class and less syncope/presyncope (all p<0.05). CONCLUSIONS: Approximately two-thirds of patients with symptomatic non-obstructive HCM have latent LVOTO. This study suggests that all patients with symptomatic non-obstructive HCM should have exercise stress echocardiography.

Sudden arrhythmic death syndrome: a national survey of sudden unexplained cardiac death.

OBJECTIVE: To describe the characteristics of sudden arrhythmic death syndrome (SADS) and compare its incidence with official national mortality statistics for unascertained deaths. DESIGN AND SETTING: Sudden unexplained deaths were prospectively surveyed through 117 coroners' jurisdictions in England. Consecutive cases meeting the following criteria were included: white Caucasian, aged 4-64 years, no history of cardiac disease, last seen alive within 12 h of death, normal coroner's autopsy, cardiac pathologist's confirmation of a normal heart and negative toxicology. MAIN OUTCOME MEASURES: The estimated mortality from SADS was calculated and the official mortality statistics for unascertained causes of deaths in 4-64-year-olds was identified for the same time period. RESULTS: 115 coroner's cases were reported and 56 (49%) SADS victims were identified: mean age 32 years, range 7-64 years and 35 (63%) male. 7 of 39 cases (18%) had a family history of other premature sudden deaths (<45). The estimated mortality from SADS was 0.16/100 000 per annum (95% CI 0.12 to 0.21), compared with an official mortality of 0.10/100 000 per annum for International Classification of Diseases 798.1 (sudden death, cause unknown-instantaneous death) or 1.34/100 000 per annum for unascertained causes of death. CONCLUSIONS: Deaths from SADS occur predominantly in young males. When compared with official mortality, the incidence of SADS may be up to eight times higher than estimated: more than 500 potential SADS cases per annum in England. Families with SADS carry genetic cardiac disease, placing them at risk of further sudden deaths. SADS should therefore be a certifiable cause of death prompting specialised cardiological evaluation of families.

Arrhythmogenic right ventricular dysplasia, a cell adhesion cardiomyopathy: insights into disease pathogenesis from preliminary genotype--phenotype assessment.

Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC) is a genetically determined heart muscle disorder presenting clinically with even lethal ventricular arrhythmias, particularly in the young and athletes. It is reported familial with recessive and most commonly dominant inheritance. Disease-causing genes are increasingly recognised among desmosomal proteins plakoglobin, desmoplakin, plakophilin2, and desmoglein2 displaying phenotypic heterogeneity. Mutations in the plakoglobin and desmoplakin genes have been identified to underlie recessive ARVC associated with woolly hair and palmoplantar keratoderma (Naxos disease), while mutations in plakophilin2, desmoglein2 as well as desmoplakin have been identified to underlie the dominant non-syndromic form. Preliminary genotype-phenotype assessment indicates that mutations affecting the outer dense plaque of desmosome (desmoglein2, plakoglobin, plakophilin2 and the N-terminal of desmoplakin) result in ARVC with the ordinary described phenotype. However, mutations at the inner dense plaque, particularly affecting the desmin-binding site of desmoplakin, may result in ARVC with predominantly left ventricular involvement and clinical overlapping with dilated cardiomyopathy. The interesting finding of abnormal distribution of plakoglobin, independently of the primarily affected protein, might suggest a common pathway for plakoglobin in ARVC pathogenesis.

High-efficiency multiplex capillary electrophoresis single strand conformation polymorphism (multi-CE-SSCP) mutation screening of SCN5A: a rapid genetic approach to cardiac arrhythmia.

Mutations in the SCN5A gene coding for the alpha-subunit of the cardiac Na(+) ion channel cause long QT syndrome, Brugada syndrome, idiopathic ventricular fibrillation, sick sinus node syndrome, progressive conduction disease, dilated cardiomyopathy and atrial standstill. These diseases exhibit variable expressivity, and identification of gene carriers is clinically important, particularly in sudden infant and adult death syndromes. The SCN5A gene comprises 28 exons distributed over 100 kbp of genomic sequence at chromosome 3p21. Disease-causing mutations are private and scattered over the DNA sequence, making it difficult to screen for specific mutations. We developed a multiplex capillary-electrophoresis single-strand conformation polymorphism (Multi-CE-SSCP) mutation screening protocol on the ABI 3100 platform and applied it to 10 previously slab-gel SSCP identified mutations and SNPs and used it to identify one novel deletion. The method is highly efficient, with a turnover of 23 patients per 24 h and a false positive rate of 0.5% of the analyzed amplicons. Each variant has a particular elution pattern, and all 20 carriers of the H558R polymorphism out of 57 persons were correctly identified. We suggest that the method could become part of routine work-up of patients with suspicious syncope and of members of families with sudden unexplained death.

Coronary microvascular dysfunction in male patients with Anderson-Fabry disease and the effect of treatment with alpha galactosidase A.

OBJECTIVE: To measure coronary flow reserve (CFR), an index of microvascular function, in Anderson-Fabry disease (AFD) at baseline and after enzyme replacement therapy (ERT). METHODS AND RESULTS: Mean (SD) myocardial blood flow (MBF) at rest and during hyperaemia (adenosine 140 microg/kg/min) was measured in 10 male, non-smoking patients (53.8 (10.9) years, cholesterol 5.5 (1.3) mmol/l) and in 24 age matched male, non-smoking controls (52.0 (7.6) years, cholesterol 4.5 (0.6) mmol/l) by positron emission tomography (PET). Resting and hyperaemic MBF and CFR (hyperaemic/resting MBF) were reduced in patients compared with controls (0.99 (0.17) v 1.17 (0.25) ml/g/min, p < 0.05; 1.37 (0.32) v 3.44 (0.78) ml/g/min, p < 0.0001; and 1.41 (0.39) v 3.03 (0.85), p < 0.0001, respectively). This coronary microvascular dysfunction was independent of cholesterol concentrations. PET was repeated in five patients after 10.1 (2.3) months of ERT; resting and hyperaemic MBF and CFR were unchanged after ERT (0.99 (0.16) v 0.99 (0.16) ml/g/min; 1.56 (0.29) v 1.71 (0.3) ml/g/min; and 1.6 (0.37) v 1.74 (0.28), respectively; all not significant). CONCLUSIONS: The results of the present study show that patients with AFD have very abnormal coronary microvascular function. These preliminary data suggest that ERT has no effect on coronary microvascular dysfunction. Further work is necessary to determine whether treatment at an earlier stage in the course of the disease may improve coronary microvascular function in patients with AFD.

Historical trends in reported survival rates in patients with hypertrophic cardiomyopathy.

OBJECTIVE: To determine the range of survival rates of patients with hypertrophic cardiomyopathy (HCM) by comparing and contrasting the natural history of a cohort of patients seen between 1988 and 2002 with that of other published series. METHODS: 956 adult (> or = 16 years old) patients with HCM (572 men, mean (SD) age 42 (15) years, range 16-88) were evaluated by ECG, Holter, exercise testing, and echocardiography. Patient characteristics and survival data were compared with those in natural history studies from referral and non-referral centres published between 1960 and January 2003. RESULTS: The duration of follow up was 69 (45) months. 120 (12.6%) patients died or underwent cardiac transplantation. Sudden cardiac death (n = 48) was the most common mode of death. The annual rate of sudden death or implantable cardioverter-defibrillator discharge was 1.02 (95% confidence interval (CI) 0.76 to 1.26). Annual rates for heart failure death or transplantation and stroke related death were 0.55% (95% CI 0.37% to 0.78%) and 0.07% (95% CI 0.02% to 0.19%), respectively. When studies published within the last 10 years of the study period were compared with earlier reports, the size of individual study cohorts was larger (309 (240.6) v 136.5 (98.8), p = 0.058) and the proportion with severe functional limitation NYHA class III/IV lower (12.4% v 24.8%, p < 0.0001), and fewer patients underwent septal myotomy-myectomy (5.2% v 18.7%, p < 0.0001). Published sudden death rates over the last 10 years were lower than previously published figures (median 1.0% (range 0.1-1.7) v 2.0% (0-3.5)). CONCLUSION: Published survival rates in HCM cohorts have improved progressively over the past 40 years. In the modern era the prevalence of disease related complications is similar in all reporting centres.

Clinical implications of anti-cardiac immunity in dilated cardiomyopathy.

Criteria of organ-specific autoimmunity are fulfilled in a subset of patients with myocarditis/dilated cardiomyopathy (DCM). In particular, circulating heart-reactive autoantibodies are found in such patients and symptom-free relatives. These autoantibodies are directed against multiple antigens, some of which are expressed in the heart (organ-specific), others in heart and some skeletal muscle fibres (partially heart-specific) or in heart and skeletal muscle (muscle-specific). Distinct autoantibodies have different frequency in disease and normal controls. Different techniques detect one or more antibodies, thus they cannot be used interchangeably for screening. It is unknown whether the same patients produce more antibodies or different patient groups develop autoimmunity to distinct antigens. IgG antibodies, shown to be cardiac- and disease-specific for myocarditis/DCM, can be used as autoimmune markers for relatives at risk as well as for identifying patients in whom immunosuppression may be beneficial. Some autoantibodies may also have a functional role, but further work is needed.