Nonfamilial Dilated Cardiomyopathy Research Articles

Implications of Genetic Testing in Dilated Cardiomyopathy.

Genetic analysis is a first-tier test in dilated cardiomyopathy (DCM). Electrical phenotypes are common in genetic DCM, but their exact contribution to the clinical course and outcome is unknown. We determined the prevalence of pathogenic gene variants in a large unselected DCM population and determined the role of electrical phenotypes in association with outcome. This study included 689 patients with DCM from the Maastricht Cardiomyopathy Registry, undergoing genetic evaluation using a 48 cardiomyopathy-associated gene-panel, echocardiography, endomyocardial biopsies, and Holter monitoring. Upon detection of a pathogenic variant in a patient with DCM, familial segregation was performed. Outcome was defined as cardiovascular death, heart transplantation, heart failure hospitalization, and/or occurrence of life-threatening arrhythmias. A (likely) pathogenic gene variant was found in 19% of patients, varying from 36% in familial to 13% in nonfamilial DCM. Family segregation analysis showed familial disease in 46% of patients with DCM who were initially deemed nonfamilial by history. Overall, 18% of patients with a nongenetic risk factor had a pathogenic gene variant. Almost all pathogenic gene variants occurred in just 12 genes previously shown to have robust disease association with DCM. Genetic DCM was independently associated with electrical phenotypes such as atrial fibrillation, nonsustained ventricular tachycardia, and atrioventricular block and inversely correlated with the presence of a left bundle branch block (P<0.01). After a median follow-up of 4 years, event-free survival was reduced in genetic versus patients with nongenetic DCM (P=0.01). This effect on outcome was mediated by the associated electrical phenotypes of genetic DCM (P<0.001). One in 5 patients with an established nongenetic risk factor or a nonfamilial disease still carries a pathogenic gene variant. Genetic DCM is characterized by a profile of electrical phenotypes (atrial fibrillation, nonsustained ventricular tachycardia, and atrioventricular block), which carries increased risk for adverse outcomes. Based on these findings, we envisage a broader role for genetic testing in DCM.

A novel heterozygous variant p.(Trp538Arg) of SYNM is identified by whole‐exome sequencing in a Chinese family with dilated cardiomyopathy

Dilated cardiomyopathy (DCM) is a relatively frequent myocardial disease that may lead to heart failure, syncope, and sudden cardiac death. Genetic factors play important roles in the etiology of the disease. To date, at least 50 genes have been identified in patients with DCM, among them, only three mutations have been reported in Synemin (SYNM) gene. In this study, we investigate a Chinese family of three generations with four patients with DCM. Employing whole-exome sequencing (WES) and bioinformatics strategies, a novel heterozygous missense mutation p.(Trp538Arg) of SYNM was identified and cosegregated with the affected family members. The missense mutation locates in the C-terminal domain of SYNM and leads to a substitution of tryptophan by arginine and may cause the structure change of synemin protein. In conclusion, we employed WES to detect the mutations of DCM patients and identified a novel likely pathogenic mutation in SYNM gene. Our study not only expands the spectrum of SYNM mutations, it further confirms that mutations in SYMN may underlie nonfamilial DCM, and offers genetic testing information to additional DCM patients.

Myocardial expression profiles of candidate molecules in patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia compared to those with dilated cardiomyopathy and healthy controls

Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is mainly an autosomal dominant disease characterized by fibrofatty infiltration of the right ventricle, leading to ventricular arrhythmias. Mutations in desmosomal proteins can be identified in about half of the patients. The pathogenic mechanisms leading to disease expression remain unclear. The purpose of this study was to investigate myocardial expression profiles of candidate molecules involved in the pathogenesis of ARVC/D. Myocardial messenger RNA (mRNA) expression of 62 junctional molecules, 5 cardiac ion channel molecules, 8 structural molecules, 4 apoptotic molecules, and 6 adipogenic molecules was studied. The averaged expression of candidate mRNAs was compared between ARVC/D samples (n = 10), nonfamilial dilated cardiomyopathy (DCM) samples (n = 10), and healthy control samples (n = 8). Immunohistochemistry and quantitative protein expression analysis were performed. Genetic analysis using next generation sequencing was performed in all patients with ARVC/D. Following mRNA levels were significantly increased in patients with ARVC/D compared to those with DCM and healthy controls: phospholamban (P ≤ .001 vs DCM; P ≤ .001 vs controls), healthy tumor protein 53 apoptosis effector (P = .001 vs DCM; P ≤ .001 vs controls), and carnitine palmitoyltransferase 1β (P ≤ .001 vs DCM; P = 0.008 vs controls). Plakophillin-2 (PKP-2) mRNA was downregulated in patients with ARVC/D with PKP-2 mutations compared with patients with ARVC/D without PKP-2 mutations (P = .04). Immunohistochemistry revealed significantly increased protein expression of phospholamban, tumor protein 53 apoptosis effector, and carnitine palmitoyltransferase 1β in patients with ARVC/D and decreased PKP-2 expression in patients with ARVC/D carrying a PKP-2 mutation. Changes in the expression profiles of sarcolemmal calcium channel regulation, apoptosis, and adipogenesis suggest that these molecular pathways may play a critical role in the pathogenesis of ARVC/D, independent of the underlying genetic mutations.

GW26-e4548 Significance of sarcomere gene mutation in patients with dilated cardiomyopathy

Dilated cardiomyopathy (DCM) is a myocardial disease with a high mortality rate. Approximately 40 genes have been found to be associated with DCM to date. Non-familial DCM can also be caused by gene mutations, suggesting that genetic factors were involved in the pathogenesis of DCM; therefore

Prognostic Relevance of Gene-Environment Interactions in Patients With Dilated Cardiomyopathy: Applying the MOGE(S) Classification

BackgroundThe multifactorial pathogenesis leading to dilated cardiomyopathy (DCM) makes stratification difficult. The recent MOGE(S) (morphofunctional, organ involvement, genetic or familial, etiology, stage) classification addresses this issue. ObjectivesThe purpose of this study was to investigate the applicability and prognostic relevance of the MOGE(S) classification in patients with DCM. MethodsThis study used patients from the Maastricht Cardiomyopathy Registry in the Netherlands and excluded patients with ischemic, valvular, hypertensive, and congenital heart disease. All other patients underwent a complete diagnostic work-up, including genetic evaluation and endomyocardial biopsy. ResultsA total of 213 consecutive patients with DCM were included: organ involvement was demonstrated in 35 (16%) and genetic or familial DCM in 70 (33%) patients, including 16 (8%) patients with a pathogenic mutation. At least 1 cause was found in 155 (73%) patients, of whom 48 (23%) had more than 1 possible cause. Left ventricular reverse remodeling was more common in patients with nongenetic or nonfamilial DCM than in patients with genetic or familial DCM (40% vs. 25%; p = 0.04). After a median follow-up of 47 months, organ involvement and higher New York Heart Association functional class were associated with adverse outcome (p < 0.001 and p = 0.02, respectively). Genetic or familial DCM per se was of no prognostic significance, but when it was accompanied by additional etiologic-environmental factors such as significant viral load, immune-mediated factors, rhythm disturbances, or toxic triggers, a worse outcome was revealed (p = 0.03). A higher presence of MOGE(S) attributes (≥2 vs. ≤1 attributes) showed an adverse outcome (p = 0.007). ConclusionsThe MOGE(S) classification in DCM is applicable, and each attribute or the gene-environment interaction is associated with outcome. Importantly, the presence of multiple attributes was a strong predictor of adverse outcome. Finally, adaptation of the MOGE(S) involving multiple possible etiologies is recommended.

Significance of sarcomere gene mutation in patients with dilated cardiomyopathy.

Dilated cardiomyopathy (DCM) is a myocardial disease with a high mortality rate. Approximately 40 genes have been found to be associated with DCM to date. Non-familial DCM can also be caused by gene mutations, suggesting that genetic factors were involved in the pathogenesis of DCM; therefore genetic testing is beneficial for the early diagnosis of DCM, which can facilitate the implementation of preventive measures by and within patient's families. Here, we investigated the underlying genetic mutations involved in the cause of patients with DCM. This prospective study included 240 patients with idiopathic DCM and 240 healthy volunteers. Subject clinical data were collected and polymerase chain reaction amplification was carried out on subject DNA for three candidate genes tropomyosin (TPM1), cardiac troponin T type-2 (TNNT2), and nuclear lamina protein A/C. Single nucleotide polymorphism (SNP) loci were detected in the TPM1 (rs1071646) and TNNT2 (rs3729547) genes, respectively. The genotype distributions and allele frequencies were found to satisfy Hardy-Weinberg equilibrium, which indicated that the group was representative. Statistically significant differences were found between the variant frequencies in the two SNP loci between the Kazakh patients with idiopathic DCM (IDCM) and healthy volunteers. A significant difference in the genotype distributions (P = 0.000) and allele frequencies (P = 0.000) of SNP rs1071646, and another significant difference in the genotype distributions (P = 0.000) and allele frequencies (P = 0.039) of SNP rs3729547 between Kazakhs with IDCM and Kazakh controls. These results suggest that the TPM1 (rs1071646) and TNNT2 (rs3729547) gene variants might represent risk factors for patients with DCM in the Kazakh population.

The Genetics of Dilated Cardiomyopathy: A Prioritized Candidate Gene Study of LMNA, TNNT2, TCAP, and PLN

Dilated cardiomyopathy (DCM), which is characterized by left ventricular enlargement and systolic dysfunction, is divided into cases with a clear predisposing condition (eg, hypothyroidism, chemotherapeutic agents, alcoholism, ischemia) and those of unknown cause (idiopathic DCM). Many cases (20%-35%) of DCM are familial, implicating a genetic contribution to the etiology. More than 30 genes have been identified, many involving "private" mutations not shared among families. Evidence suggests that nonfamilial cases also have a genetic predisposition, again involving many genes. The goal of this study was to identify mutations in genes associated with DCM in a Québec study sample including familial and nonfamilial DCM cases. A prioritized gene study conducted within a framework for the classification of identified genetic variants could yield etiological information even in the absence of family data. We sequenced 4 previously identified genes: lamin A/C (LMNA), cardiac troponin T type 2 (TNNT2), titin-cap (TCAP), and phospholamban (PLN). We discovered a nonsense mutation in the LMNA gene and a frameshift mutation in the TNNT2 gene, as well as other clinically significant variants that were not observed in publicly available databases or in Québec-based controls. PLN was sequenced to investigate a previously published promoter variant. However, our data confirm that this variant does not have a causal role in DCM. Despite high locus and allele heterogeneity, we demonstrate that a prioritized gene study, combined with next-generation exome-sequencing data, can be fruitful for the identification of DCM mutations.

Can Serum Tenascin-C Be Used as a Marker of Inflammation in Patients with Dilated Cardiomyopathy?

Background. Tenascin-C (TN-C) is an extracellular matrix glycoprotein that appears at sites of inflammation in cardiac pathologies. Aim of the Work. To evaluate the role of TN-C as a marker for active inflammation in children with dilated cardiomyopathy (DCM). Subjects and Methods. 24 consecutive patients with primary nonfamilial DCM aged 6–72 months (mean 45.19 ± 11.03) were divided into group I, twelve patients with acute onset DCM (<6 months duration), and group II, twelve patients with chronic DCM (>6 months duration), and compared to 20 healthy age- and sex-matched controls. Investigations included estimation of serum TN-C and echocardiographic evaluation using M-mode and 2D speckle tracking echocardiography (STE). Results. Serum TN-C showed a higher significant statistical elevation among patients than controls (P < 0.001) and in group I than group II (P < 0.001). EF was significantly decreased, and LVEDD and EDV increased in patients than controls and in GI than GII. STE showed a statistically significant difference in global peak strain longitudinal (GPSL) average in patients than controls (P < 0.05) and between GI and GII (P < 0.001). STE wall motion scoring showed normokinesia (33.5%), hypokinesia (8.33%), and akinesia (50%) in GI and hypokinesia (100%) in GII. There was a statistically significant positive correlation between serum TN-C and GPSL average. Conclusions. Increased serum TN-C can be used as a marker of inflammation in DCM and is associated with the severity of heart failure and LV dysfunction as detected by STE.

A new duplication in the mitochondrially encoded tRNA proline gene in a patient with dilated cardiomyopathy

Mitochondria provide an environment conducive to mutations in DNA molecules (mtDNA). Analyses of mtDNA have shown mutations potentially leading to many cardiovascular traits. Here, we describe a patient with dilated cardiomyopathy and new mtDNA duplication. The patient presented symptoms of heart failure New York Heart Association functional class III and was diagnosed with non-familial dilated cardiomyopathy with important left ventricular systolic dysfunction. Sequencing of mtDNA control region was done, and a 15 bp duplication was observed between nucleotides 16,018 and 16,032. Part of this duplication is localized within the tRNA proline gene (tRNAPro) that has an important role in cell protection against oxidative stress and is considered an important regulatory factor for cellular reactive oxygen species balance. This duplication could alter the stability or secondary structure of tRNAPro, affecting mt-protein synthesis. In turn, the presence of duplication in tRNAPro could cause some oxidative stress imbalance and, so, mitochondrial dysfunction could result in the pathogenicity.

Abstract 9208: Association of Polymorphism in Glutamate-Cysteine Ligase Modifier Subunit Gene with Idiopathic Dilated Cardiomyopathy

Myocardial mitochondrial dysfunction due to oxidative stress contributes to the pathogenesis of cardiomyopathy. Reduced glutathione (GSH) plays a crucial role in antioxidant defense mechanisms, and it is synthesized by glutamate-cysteine ligase (GCL) which is composed of catalytic (GCLC) and modifier (GCLM) subunits. We have found a polymorphism (-588C/T) in the 5’-flanking region of the GCLM gene in which the T allele showed lower promoter activity (40% of C allele) in response to oxidants and is associated with lower plasma GSH levels. This study examined the hypothesis that this polymorphism of GCLM gene may be associated with dilated cardiomyopathy (DCM). And, we studied potential role of GCLM in myocardial mitochondrial function using GCLM deficient (GCLM -/- ) mice. Methods and Results: The frequency of the polymorphism (-588C/T) of the GCLM gene was determined in 205 consecutive patients with non-familial idiopathic DCM and age- and sex-matched 253 normal healthy subjects. The T allele was highly frequent in patients with DCM, compared with control subjects (CT and TT genotypes: 36.2% in DCM vs. 18.6% in controls; P &lt; 0.0001), and it was a significant risk factor for DCM, that was independent of hypertension, diabetes, smoking and BMI (OR 3.13, 95% CI 2.28 to 4.44; P &lt; 0.0001). The mitochondrial GSH levels in myocardium were lower in GCLM -/- mice (39% of baseline GCLM +/+ ). Mitochondrial respiratory function in the myocardium of GCLM -/- mice had a reduction in the ADP-stimulated state 3 activity (60% of GCLM +/+ ). Hypoxia re-oxygenation induced greater mitochondrial damages in cultured GCLM -/- cardiomyocytes than GCLM +/+ cardiomyocytes, as evidenced by reduced membrane potential, increased protein carbonyl content, and increased GSSG/GSH rate in the isolated mitochondria. After myocardial ischemia-reperfusion, GCLM -/- mice had a greater dilation and systolic dysfunction of left ventricle (LV) than GCLM +/+ mice. Conclusions: The -588T polymorphism of the GCLM gene is associated with non-familial idiopathic DCM. This association is supported by the animal study that GCLM deletion increased susceptibility of myocardial mitochondria to oxidative damage through mitochondrial GSH reduction, which may potentially contribute to LV dysfunction.

Effects of protein A immunoadsorption in patients with chronic dilated cardiomyopathy

The objective of this study was to investigate functional effects of immunoadsorption (IA) in patients with chronic nonfamilial dilated cardiomyopathy (DCM) regarding clinical and humoral markers of heart failure. IA has been shown to induce early hemodynamic improvement in patients with nonfamilial dilated cardiomyopathy (DCM). We performed IA using protein A agarose columns on five consecutive days in 51 patients with chronic DCM, congestive heart failure of NYHA class ≥ II, left ventricular ejection fraction ≤50%, and mean time since initial diagnosis of 5.0 ± 5.8 years. Immediately after IA, immunoglobulin G (IgG) decreased by 89.4% and IgG3 by 66.7% (both P < 0.0001). Median NT-pro BNP was reduced from 1230.0 ng L(-1) at baseline to 829.0 ng L(-1) after 6 months (P < 0.0001). Also mean left ventricular ejection fraction (LVEF) was significantly improved (26.3% ± 9.4% to 28.7% ± 11.4% after 6 months, P = 0.016) and LVEF improved ≥5% (absolute) in 21 of 51 (41.2%) patients. After 6 months, bicycle spiroergometry showed a significant increase in exercise capacity from 82.0 ± 30.8 Watts to 93.1 ± 34.3 Watts (P = 0.008) while VO2max rose from 15.0 ± 4.1 to 16.4 ± 4.8 mL min(-1) kg(-1) (P = 0.01). In this study, on heart failure patients with nonfamilial DCM, IA therapy significantly improved clinical and humoral markers of heart failure severity. These promising results may be due to the selected study population, with a shorter disease duration and the higher amount of IgG 3 reduction. Future blinded prospective multicenter studies are necessary to identify those patients that benefit most.

SPOC: A Functional Assay of Failing and Non-Failing Human Cardiomyocytes

SPontaneous Oscillatory Contractions, known as SPOCs, are well characterized for skeletal muscle fibers but less so for cardiac muscle. A survey of SPOCs on mammalian hearts from rat to cow showed that, like myosin ATPase activity, SPOC contractions exhibit a linear relationship relative to body size. SPOCs exhibit slow, travelling waves of relaxations that can be induced under precise solvent conditions. These are observed by light microscopy and the time-resolved images are analysed with high spatial and temporal resolution for up to 1 h. Here we examine the functional performance of failing and non-failing human heart samples snap frozen at -200°C (liquid nitrogen) within minutes of clamping the coronary arteries. Thus, it is possible to study the contraction and relaxation of cardiomyocytes from hearts that were also used in transcriptomics studies. With our large bank of frozen human heart tissue we can study the effects of: (1) end-stage heart failure on multiple heart samples from a wide range of patients; and (2) aging on contractile performance using multiple samples of non-failing hearts. We will report preliminary findings from end-stage heart failure patients with familial and non-familial dilated cardiomyopathy, and from un-used donor hearts aged 9-65 years.

Effects of protein A immunoadsorption in patients with advanced chronic dilated cardiomyopathy

The objective of this study was to investigate functional effects of immunoadsorption (IA) in severely limited study patients with chronic nonfamilial dilated cardiomyopathy (DCM), and to analyze the prevalence of Troponin I (TNI) autoantibodies. Immunoadsorption (IA) has been shown to induce early hemodynamic improvement in patients with nonfamilial DCM. We performed IA using Immunosorba columns on five consecutive days in 27 patients with chronic DCM, congestive heart failure of NYHA class >or=II, left ventricular ejection fraction below 40%, and mean time since initial diagnosis of 7.2 +/- 6.8 years. Immediately after IA, IgG decreased by 87.7% and IgG3 by 58.5%. Median NT-pro BNP was reduced from 1740.0 ng/L at baseline to 1504.0 ng/L after 6 months (P = 0.004). Mean left ventricular ejection fraction (LVEF) was not significantly improved overall (24.1 +/- 7.8% to 25.4 +/- 10.4% after 6 months, P = 0.38), but LVEF improved >or=5% (absolute) in 9 of 27 (33%) patients. Bicycle spiroergometry showed a significant increase in exercise capacity from 73.7 +/- 29.4 Watts to 88.8 +/- 31.1 Watts (P = 0.003) after 6 months while VO2max rose from 13.7 +/- 3.8 to 14.9 +/- 3.0 mL/min kg after 6 months (P = 0.09). Subgroup analysis revealed a higher NT-pro BNP reduction in patients with shorter disease duration (P = 0.03) and without TNI autoantibodies at baseline (P = 0.05). All 9 patients with an absolute increase of LVEF of >or=5.0% were diabetic (P = 0.0001). In this study, on severely limited heart failure patients with nonfamilial DCM, IA therapy moderately improved markers of heart failure severity in a limited subgroup of patients. This may be due to the selected study population with end-stage heart failure patients and the lower reduction of IgG3 compared to previous studies. Future blinded multicenter studies are necessary to identify those patients that benefit most.

Coronary Sinus Focus Acting as a Trigger for Atrial Fibrillation in a Patient with Orthotopic Heart Transplantation

Coronary Sinus Focus Acting as a Trigger for Atrial Fibrillation. We report the case of a 46-year-old man who presented for evaluation and ablation of paroxysmal atrial fibrillation, which he developed one year prior to presentation and that was refractory to antiarrhythmic drugs. His past medical and surgical history was significant for orthotopic heart transplantation (OHTX) and idiopathic nonfamilial dilated cardiomyopathy. We present the first case of post OHTX where the coronary sinus was acting as a trigger and driver for atrial fibrillation. This illustrates an unusual role of nonpulmonary vein foci in the etiology of atrial fibrillation in patients status post OHTX.

Abstract 2911: T-182C Polymorphism in the Norepinephrine Transporter Gene (SLC6A2) and Risk of Cardiovascular Events in Patients with Dilated Cardiomyopathy: Association of the T allele with a Reduced Risk for Cardiovascular Events

Backgrounds: The increase in sympathetic activity is one of the hallmarks of the chronic heart failure and has been shown to have an important impact on survival in patients with dilated cardiomyopathy (DCM). Norepinephrine transporter (NET) recaptures as much as 90% of released norepinephrine in the heart, making it a critical mediator of norepinephrine inactivation and presynaptic catecholamine homeostasis. Recently, the polymorphism of NET T-182C was reported to be associated with the improvement of left ventricular systolic function by beta-blockers in patients with DCM. However, the association between the incidence of cardiovascular events and the NET polymorphism in patients DCM has not been understood. The purpose of this study was to evaluate the effect of this polymorphism on the incidence of cardiovascular events in patients with DCM. Methods: Eighty-three genetically unrelated patients with nonfamilial DCM (64 males, mean age at initial clinical evaluation 59 ± 14 years) were enrolled in this study. An adverse cardiovascular event was defined as cardiac death or hospitalization for cardiac reasons. The time to the first adverse cardiovascular event was analyzed by the Kaplan-Meier method. The TaqMan polymerase chain reaction method was used for the determination of genotypes of the NET T-182C gene (SLC6A2) (rs#2242446). Results: The distribution of the NET T-182C genotypes (T/T, T/C, and C/C) was 43%, 45%, and 12%, respectively. The NET T-182C T allele frequency was 0.63. During a mean follow-up period of 45 months, 20 cardiovascular events had occurred. Eight patients died from cardiac cause (1 from pump failure and 7 from sudden cardiac death) and there were 12 hospitalizations for new onset or worsening of heart failure symptoms. The cardiovascular event rate of the patients carrying the T allele (T/T and T/C genotype, n = 73) was significantly lower than that of the patients not carrying the T allele (C/C genotype, n = 10) (p = 0.03). Conclusion: Our data suggested that the T allele of the NET T-182C gene may be a protective factor against cardiovascular events in patients with DCM.

Association of a G994-->T missense mutation in the plasma platelet-activating factor acetylhydrolase gene with genetic susceptibility to nonfamilial dilated cardiomyopathy in Japanese.

Although several genes or genetic loci that are responsible for or confer susceptibility to familial dilated cardiomyopathy (DCM) have been identified, genetic defects that underlie nonfamilial DCM remain to be characterized. Mice lacking manganese superoxide dismutase exhibit DCM, suggesting that impairment of the defense mechanisms against oxidative stress is an important susceptibility factor for DCM. Plasma platelet-activating factor (PAF) acetylhydrolase also acts as a key defense against oxidative stress by hydrolyzing PAF and oxidized phospholipids. Thus, abnormalities in the activity of this enzyme may result in predisposition to myocardial damage. The possible association of a G994 (M allele)-->T (m allele) missense mutation in the plasma PAF acetylhydrolase gene with genetic susceptibility to nonfamilial DCM has now been investigated in 122 Japanese individuals with this condition and 226 healthy control subjects. PAF acetylhydrolase activity in plasma was significantly associated with plasma PAF acetylhydrolase genotype in both DCM patients and healthy control subjects. The frequency of the mutant m allele was significantly higher in DCM patients than in control subjects. Left ventricular mass (LVM) and the LVM index in DCM patients with Mm or mm genotypes were significantly greater than those in patients with the MM genotype. The G994-->T mutation in the plasma PAF acetylhydrolase gene is associated with nonfamilial DCM in Japanese subjects. Although the mutation is unlikely to be a causative factor, it may contribute to genetic susceptibility to or progression of nonfamilial DCM.

Idiopathic dilated cardiomyopathy: familial prevalence and HLA distribution.

OBJECTIVES: To compare HLA distribution in familial and non-familial dilated cardiomyopathy, because a serum marker that could identify families at risk of developing dilated cardiomyopathy should be of use in...

Increased frequency of organ-specific cardiac antibodies in healthy relatives of patients with dilated cardiomyopathy: evidence for autoimmunity in Polish families.

Autoantibodies represent markers of autoimmune involvement and are found with increased frequency in patients and their symptom-free relatives at risk compared with normal controls. Cardiac-specific autoantibodies, detected by immunofluorescence, were found in 20% of symptom-free relative of patients with dilated cardiomyopathy (DCM) from England and Italy. The role of autoimmunity may vary in DCM patients from Poland due to ethnic differences in genetic susceptibility to autoimmune disease. We assessed the frequency of the organ-specific cardiac autoantibodies in 162 symptom-free relatives of DCM patients [85 male, mean (SD) age 27 (18) years] and 80 control subjects from Poland. Familial DCM (> 1 affected member) was present in 4 families, nonfamilial DCM in the remaining 24 pedigrees. We performed antibody screening and noninvasive cardiological assessment in the whole group. The frequency of cardiac-specific autoantibodies was higher among patients with documented DCM (probands and relatives) (50%) and their symptom-free relatives (38%) than in unrelated normal subjects (10%; p = 0.0001). In 24 (86%) of the pedigrees studied, autoantibodies were found in the proband and/or in at least one family member and tended to be more common in familial than in nonfamilial DCM (50 vs. 35%, p = NS). Echocardiographic indices of left ventricular size and function were similar in relatives with and without detectable antibodies. The presence of cardiac-specific autoantibodies in symptom-free relatives of DCM patients provides evidence for autoimmunity in the majority (86%) of our pedigrees, including both familial and nonfamilial forms of DCM.

Evidence for autoimmunity to myosin and other heart-specific autoantigens in patients with dilated cardiomyopathy and their relatives

Autoimmune disease is characterised by the presence of circulating autoantibodies in the affected patients and in a proportion of their relatives. These antibodies are generally not pathogenic but are reliable markers of immune-mediated tissue damage. In organ-specific autoimmune disease, the destruction process is largely restricted to one organ within the body and the autoantibodies react with autoantigens which are unique to the diseased target organ. At least in a patient subset, myocarditis and dilated cardiomyopathy (DCM) may represent the acute and chronic stages of a progressive organ-specific autoimmune disease of the myocardium. Autoimmune features in patients with myocarditis/DCM include: familial aggregation, a weak association with HLA-DR4, abnormal expression of HLA class II on cardiac endothelium on endomyocardial biopsy, and detection of organ- and disease-specific cardiac autoantibodies, by immunofluorescence and absorption techniques, in the affected patients and in a proportion of their symptom-free relatives from both familial and non-familial DCM pedigrees. The organ-specific cardiac autoantibodies detected by immunofluorescence are directed against multiple antigens. One of these, first identified using immunoblotting and confirmed by ELISA, is the cardiac-specific α-myosin isoform. Myosin fulfils the expected criteria for organ-specific autoimmunity, in that immunisation with cardiac but not skeletal myosin reproduces, in susceptible mouse strains, the human disease phenotype of DCM; in addition, α-myosin is entirely cardiac-specific and is only expressed in the myocardium. Using ELISA, high titer organ- and disease-specific anti α-myosin antibodies have been found in 16% of the symptom-free relatives of DCM patients and in 38% of the pedigrees of the same cohort of relatives studied by immunofluorescence. The ELISA results provide additional evidence for autoimmunity in a subset of DCM families, and emphasise the importance of α-myosin as a target antigen.

Organ-specific cardiac autoantibodies in dilated cardiomyopathy--an update.

Autoimmune disease is characterized by the presence of organ- and disease-specific autoantibodies in patients and first degree relatives; antibody detection may precede disease onset by several years. We investigated potential involvement of organ-specific autoimmunity in dilated cardiomyopathy (DCM). Using indirect immunofluorescence and absorption studies, organ- and disease-specific IgG cardiac antibodies were found in one-third of DCM patients. Antibody status at diagnosis was associated with better exercise capacity; at 1-year follow-up two-thirds of antibody-positive patients became negative. These findings suggest that antibodies are early markers; their absence in the majority of patients at diagnosis may relate to long-standing pre-clinical DCM. Antibody screening was performed in asymptomatic DCM relatives, 177 from 33 families with > 1 affected individual (familial DCM) and 165 from 31 pedigrees with non-familial DCM. Antibodies were detected in 37 (58%) pedigrees and were more common among relatives than in normals (20% vs 3.5%, P = 0.0001). Antibody-positive relatives were younger, had larger left ventricular end-systolic dimension and reduced % fractional shortening compared to antibody-negative relatives. These findings provide evidence for autoimmunity in a subset (58%) including both familial and non-familial DCM; cardiac-specific antibodies may identify relatives at risk of developing DCM.