Pathogenesis Of Idiopathic Dilated Cardiomyopathy Research Articles

The abnormal distribution of peripheral B1 cells and transition B cells in patients with idiopathic dilated cardiomyopathy: a pilot study

BackgroundThe aberrant distribution of peripheral B cell subsets is associated with the pathogenesis of a variety of inflammatory and autoimmune diseases. However, the distribution of peripheral B cell subsets in patients with idiopathic dilated cardiomyopathy (DCM) remains to be elucidated.MethodsTwenty-seven patients with idiopathic DCM (DCM group), 18 control patients with heart failure (HF group) and 21 healthy individuals (HC group) were included in this study. Peripheral B cell subsets were analysed using multicolour flow cytometry. The plasma β1 adrenergic receptor (β1-AR) autoantibody titre was determined using ELISA. Additionally, clinical features were also collected.ResultsCompared with the HF and HC groups, the percentage of B1 cells was significantly decreased, whereas the percentage of transitional B cells (Tr) was significantly increased in the DCM group. Notably, the percentage of B1 cells was significantly lower in patients with β1-AR autoantibody-positive DCM than in β1-AR autoantibody-negative patients. The correlation analysis showed that the percentage of B1 cells was negatively correlated with N-terminal pro-brain natriuretic peptide (NT-proBNP) levels and positively correlated with the left ventricular ejection fraction in patients with DCM.ConclusionAs shown in the present study, the percentage of B1 cells in the peripheral blood of patients with idiopathic DCM is abnormally decreased, especially in β1-AR autoantibody-positive patients, while the percentage of Tr cells is significantly increased, indicating that B1 cells and Tr cells may be implicated in the pathogenesis of idiopathic DCM. The decrease in the percentage of B1 cells is directly related to the severity of DCM.

Molecular Mechanisms behind Persistent Presence of Parvovirus B19 in Human Dilated Myocardium.

The role of parvovirus B19 (PVB19) in the pathogenesis of idiopathic dilated cardiomyopathy (DCM) remains poorly understood. Therefore, we have measured the levels of inflammation, fibrosis, apoptosis, and necrosis in endomyocardial biopsies (EMBs) and sera of nonischemic PVB19-positive (n=14) and PVB19-negative (n=18) DCM patients. Chronic persistence of PVB19 in myocardium did not induce significant infiltration of T cells (CD3 and CD45Ro) and macrophages (CD68), and did not secrete TNFα, IL-6, and CRB. The fibrosis in PVB19-positive EMBs was also lower compared to the virus-negative ones, while ECM degrading matrix metalloproteinase MMP1 and gelatinase MMP2 were significantly (by twofold) upregulated. In addition, there was no activation of neither apoptotic nor necrotic pathways. However, levels of antiapoptotic mitochondrial Bcl-2 and heat shock protein 60 (Hsp60) in PVB19-positive biopsies were almost threefold lower than in PVB19-negative ones revealing impairment of mitochondria. Altogether, data indicate that persistence of PVB19 in myocardiums of nonischemic DCM patients can cause myocardial ECM remodeling through the MMPs, such as MMP1 and MMP2, and mitochondrial impairment. The correlative analysis of measured biomarkers suggested likely further activation of apoptotic cell death pathways rather than fibrosis. Data also suggest that antiviral therapy could be beneficial for PVB19-positive DCM patients by managing further pathological myocardial remodeling.

The expression of NKT like cells and NK cells in the peripheral blood among patients with idiopathic dilated cardiomyopathy (IDCM)

Abstract Introduction Dilated cardiomyopathy is associated with various immunological abnormalities, such as decreases in the activity and subsets of suppressor T cells and in the activity of natural killer cells, suggesting the involvement of immunological mechanisms in the pathogenesis of this disease. However, the role of NKT like cells and NK cells in the pathogenesis of idiopathic dilated cardiomyopathy remains still uncertain. The aim of the study was to compare the frequencies of peripheral NKT like cells and NK cells among patients with IDCM to healthy controls. Methods The frequencies of NKT like cells and NK cells were measured by flow of cytometry among 50 patients with IDCM from Cardiology Clinic in Lublin. The control group consisted of 50 healthy sex- and age- matched volunteers. The diagnosis of IDCM was based on the common known ESC Guidenlines 2018 criteria. Statistical analysis of the results was conducted using IBM program. A value of p less than 0.05 was considered statistically significant. Results The frequency (%) (mean ± SD) of NK cells (CD3+/CD16+CD56+) was significantly lower (p≤0.001) in IDCM group (12.0±4.5) when compared to control group (15.6±3.4). The frequency (%) (mean ± SD) of NK T like cells (CD3+/CD16+CD56+) was significantly elevated (p≤0,04) in IDCM group (4,66±3,4) in comparison to the control group (3,23±1,7). Conclusions Our findings of the abnormalities in immune cells distribution in peripheral blood of IDCM patients suggest that IDCM development and progression is related to the dysregulation of the immune system. The decreases in the activity in the NK cells among patients with IDCM might indicate chronic myocarditis and lymphocyte infiltration in the myocardium. Moreover, the elevation of NKT like cells could be a result of prolonged exposure to pathogen in which TCD3+ cells become involved more than less mature NK cells in engaging specific immunity response. Funding Acknowledgement Type of funding source: Private hospital(s). Main funding source(s): Medical University in Lublin, Grant for Young Reserchers

Variants of resistin gene and the risk of idiopathic dilated cardiomyopathy in Pakistan

BackgroundIn cardiovascular disease phenotypes, a genetic factor is an important determinant of both familial and non-familial dilated cardiomyopathies. Resistin is a novel adipocyte derived peptide, associated with inflammation and suggested to be involved in contractile abnormalities of cardiomyocytes. MethodsIn this study, we examined the association of the RETN SNPs in −420 and +299 in patients with idiopathic dilated cardiomyopathy (IDCM). Patients with IDCM (n=250) and healthy controls (n=250) were enrolled in this study. RETN genotyping was performed by using PCR-RFLP method. ResultsRETN −420C>G and +299G>A polymorphisms were significantly more prevalent in patient group vs. controls (P<0.0001 and P=0.0007, respectively). GG genotype at −420 and AA genotype at +299 were higher in the patient group compared with healthy controls (OR=11.4, P<0.0001, and OR=2.3, P=0.030, respectively). We found that the −420G allele increased the risk of developing IDCM in patients (P<0.0001). Moreover, there was a significant difference between G and A alleles at RETN +299 from IDCM cases and controls (P=0.0032). The RETN −420G and +299A haplotypes were more prevalent in the patient vs. control group (P<0.0001). ConclusionThe results suggest that the RETN −420C>G and +299G>A polymorphisms may have a role in the pathogenesis of IDCM.

Prevalence and spectrum of LRRC10 mutations associated with idiopathic dilated cardiomyopathy.

Dilated cardiomyopathy (DCM) is the most common form of primary myocardial disease. It is the most common cause of chronic congestive heart failure and the most frequent reason for heart transplantation in young adults. There is increasing evidence demonstrating that genetic defects are involved in the pathogenesis of idiopathic DCM. Recent studies have shown that genetically defective LRRC10 predisposes animals to DCM. However, the association of LRRC10 with DCM in humans has not been reported. In the current study, the whole coding region and flanking splice junction sites of the LRRC10 gene were sequenced in 220 unrelated patients with idiopathic DCM. The available relatives of the index patients harboring identified mutations and 200 unrelated ethnically matched healthy individuals used as controls were also genotyped for LRRC10. The functional effect of the LRRC10 mutations was analyzed in silico. As a result, two novel heterozygous LRRC10 mutations, p.L41V and p.L163I, were identified in two families with DCM, respectively, with a mutational prevalence of ~0.91%. Genetic analyses of the pedigrees showed that in each family, the mutation co-segregated with DCM was transmitted as an autosomal dominant trait with complete penetrance. The missense mutations were absent in 400 control chromosomes and the altered amino acids were completely conserved evolutionarily across various species. Functional analysis in silico indicated that the LRRC10 mutations were causative. This study firstly reports the association of LRRC10 mutations with enhanced susceptibility to DCM in humans, which provides novel insight into the molecular mechanism underpinning DCM, and contributes to the development of novel prophylactic and therapeutic strategies for DCM.

Abstract 11977: Tranilast, Transient Receptor Potential Vanilloid 2 Antagonist, Ameliorates End-Stage Heart Failure of Mice With Dilated Cardiomyopathy

Introduction: Abnormal intracellular Ca2+ handling seems to be involved in the pathogenesis of idiopathic dilated cardiomyopathy (DCM). We have found up-regulation of the expression of transient receptor potential vanilloid 2 (TRPV2), a calcium-permeable cation channel, in the sarcolemma of myocardium of animal and human DCM. Hypothesis: We hypothesized an orally active TRPV2 antagonist, tranilast, ameliorated heart failure symptoms of DCM mice. Methods: We used 4C30 mice (created by National Institute of Biomedical Innovation, Japan), which has abnormal myocardial calcium handling, as a model of DCM. Sixteen 4C30 mice of 25 weeks old with end-stage heart failure were given no drug (control) or 20 mg/kg/day of carvediol (group C) or 400 mg/kg/day of tranilast (group T) or both of them (group B) for 2 weeks. Results: Blood pressure and heart rate were similar among the 4 groups. Echocardiography demonstrated tranilast improved fractional shortening (in %). Control: 6.2±2.5; Group C: 14.2±5.6, NS; Group T: 16.6±2.3, p&lt;0.05; Group B: 17.2±3.2, p&lt;0.05. Tranilast also improved cardiac hypertrophy measured with heart-to-body weight ratio (HW/BW in mg/g). Control: 12.4±2.5; Group C: 11.5±3.4, NS; Group T: 8.6±0.9, p&lt;0.05; Group B: 5.9±1.1, p&lt;0.01. Sarcolemmal expression of TRPV2 measured with immunostaining in 4C30 mice increased twice as much as syngeneic C57BL/6J. Tranilast, not carvedilol, halved the expression of TRPV2, corresponding to reduction in [Ca2+]i of isolated cardiomyocytes. Consistent with those changes, CaMKII phosphorylation reduced in the 4C30 mice after treatment of tranilast. Conclusions: Tranilast ameliorated heart failure symptoms of 4C30 mice, possibly due to the inhibition of Ca2+ influx through TRPV2.

Polymorphisms of tumor necrosis factor-alpha and interleukin-6 gene and C-reactive protein profiles in patients with idiopathic dilated cardiomyopathy.

BACKGROUND AND OBJECTIVESThe tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-6 gene polymorphism has a controversial role in the pathogenesis of cardiovascular disease among different populations. The effect of the cytokine’s gene polymorphism on idiopathic dilated cardiomyopathy (IDCM) is still unresolved. The current study aimed to evaluate the association of the TNF-α −308 G/A and IL-6 −174 G/C polymorphism with IDCM in a Pakistani population.DESIGN AND SETTINGSBlood samples for this case-control study were collected from the cardiology outpatient department of multiple cardiology centers of Rawalpindi/Islamabad, Pakistan, between July 2012 and December 2012.PATIENTS AND METHODSIDCM cases (number [n]=250) and healthy controls (n=300) were genotyped using polymerase chain reaction and restriction fragment length polymorphism.RESULTSThe TNF-α −308 variant genotypes GA and AA were more prevalent in patients compared with the control group (P<.0001). Similarly, the IL-6 −174 variant genotypes GC and CC showed a high prevalence in patients with IDCM compared with healthy controls (P=.0019). IDCM cases had a higher prevalence of the TNF-α–308A (P<.0001) and the IL-6 −174C (P=.0008) mutant alleles than did the control group. The IDCM cases bearing the TNF-α−308 and IL-6 variant genotypes revealed elevated levels of high-sensitivity C-reactive protein (hs-CRP) when compared with the corresponding controls (P<.05).CONCLUSIONThe TNF-α −308 G/A and IL-6 −174 G/C gene polymorphisms and high levels of hs-CRP may be associated with the pathogenesis of IDCM in the study population.

A novel GATA4 loss-of-function mutation responsible for familial dilated cardiomyopathy

Dilated cardiomyopathy (DCM) is the most common form of primary myocardial disorder and is associated with substantial morbidity and mortality. Increasing evidence suggests that genetic risk factors play an important role in the pathogenesis of idiopathic DCM. However, DCM is a genetically heterogeneous disease, and the genetic defects responsible for DCM in an overwhelming majority of cases remain to be identified. In the present study, the entire coding region and the splice junction sites of the GATA4 gene, which encodes a cardiac transcription factor essential for cardiogenesis, were sequenced in 150 unrelated patients with idiopathic DCM. The available relatives of the index patient harboring an identified mutation and 200 unrelated ethnically matched healthy individuals used as controls were genotyped. The functional characteristics of the mutant GATA4 were delineated in contrast to its wild-type counterpart using a luciferase reporter assay system. As a result, a novel heterozygous GATA4 mutation, p.V291L, was identified in a family with DCM inherited in an autosomal dominant pattern, which co-segregated with DCM in the family with complete penetrance. The missense mutation was absent in 400 control chromosomes, and the altered amino acid was completely conserved evolutionarily among species. Functional analysis revealed that the GATA4 mutant was associated with significantly diminished transcriptional activity. The findings expand the mutational spectrum of GATA4 linked to DCM and provide novel insight into the molecular etiology involved in DCM, suggesting the potential implications in the early prophylaxis and allele-specific treatment for this common type of cardiomyopathy.

A genome-wide association study identifies 6p21 as novel risk locus for dilated cardiomyopathy

Dilated cardiomyopathy (DCM) is one of the leading causes for cardiac transplantations and accounts for up to one-third of all heart failure cases. Since extrinsic and monogenic causes explain only a fraction of all cases, common genetic variants are suspected to contribute to the pathogenesis of DCM, its age of onset, and clinical progression. By a large-scale case-control genome-wide association study we aimed here to identify novel genetic risk loci for DCM. Applying a three-staged study design, we analysed more than 4100 DCM cases and 7600 controls. We identified and successfully replicated multiple single nucleotide polymorphism on chromosome 6p21. In the combined analysis, the most significant association signal was obtained for rs9262636 (P = 4.90 × 10(-9)) located in HCG22, which could again be replicated in an independent cohort. Taking advantage of expression quantitative trait loci (eQTL) as molecular phenotypes, we identified rs9262636 as an eQTL for several closely located genes encoding class I and class II major histocompatibility complex heavy chain receptors. The present study reveals a novel genetic susceptibility locus that clearly underlines the role of genetically driven, inflammatory processes in the pathogenesis of idiopathic DCM.

Virus Detection and Semiquantitation in Explanted Heart Tissues of Idiopathic Dilated Cardiomyopathy Adult Patients by Use of PCR Coupled with Mass Spectrometry Analysis

Viral detection in heart tissues has become a central issue for the diagnosis and exploration of the pathogenesis of idiopathic dilated cardiomyopathy (IDCM). In the present study, common cardiotropic viruses in 67 explanted heart samples of 31 IDCM adult patients were detected and semiquantified by using for the first time a new technology based on PCR assay coupled to electrospray ionization-time of flight mass spectrometry analysis (PCR-MS), with comparison to reference quantitative real-time PCR (RT-qPCR) assay. PCR-MS identified single or mixed enterovirus (EV) and parvovirus B19 (PVB19) infections in 27 (40.2%) of 67 samples, corresponding to 15 (48.3%) of the 31 patients, whereas RT-qPCR identified viral infections in 26 (38.8%) samples, corresponding to 16 (51.6%) of the patients. The PCR-MS results correlated well with EV and PVB19 detection by RT-qPCR (kappa = 0.85 [95% confidence interval {CI}, 0.72 to 1.00] and kappa = 0.82 [95% CI, 0.66 to 0.99], respectively). The levels of EV RNA (median, 550 [range, 178 to 3,200] copies/μg of total extracted nucleic acids) and of PVB19 DNA (median, 486 [range, 80 to 1,157] copies/μg of total extracted nucleic acids) were measured using PCR-MS and correlated with those obtained by RT-qPCR (r(2) = 0.57, P = 0.002 and r(2) = 0.64, P < 0.001 for EV and PVB19, respectively). No viruses other than EV and PVB19 strains were detected using the new PCR-MS technology, which is capable of simultaneously identifying 84 known human viruses in one assay. In conclusion, we identified single or mixed EV and PVB19 cardiac infections as potential causes of IDCM. The PCR-MS analysis appeared to be a valuable tool to rapidly detect and semiquantify common viruses in cardiac tissues and may be of major interest to better understand the role of viruses in unexplained cardiomyopathies.

Association of nucleotide-binding oligomerization domain-like receptor 3 inflammasome and adverse clinical outcomes in patients with idiopathic dilated cardiomyopathy

The nucleotide-binding oligomerization domain-like receptor 3 (NLRP3) inflammasome is a multiprotein complex consisting of NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) and caspase-1. In peripheral blood mononuclear cells (PBMCs), NLRP3 can activate interleukin-1β (IL-1β), important in the chronic inflammatory process of idiopathic dilated cardiomyopathy (IDCM). Therefore, the NLRP3 inflammasome in PBMCs may be involved in the pathogenesis of IDCM. We evaluated the association of circulating levels of NLRP3 inflammasome and cardiac function in patients with IDCM and 6-month rehospitalization. We enrolled 54 patients with IDCM and 20 healthy volunteers and analyzed left ventricle ejection fraction (LVEF), electrocardiography findings and circulating levels of NLRP3, ASC, caspase-1, IL-1β, N terminal-pro type B natriuretic peptide (NT-pro BNP) and blood values. Patients were followed up for 6 months. On admission and discharge, the circulating levels of NLRP3, ASC, caspase-1 and IL-1β were higher in IDCM patients than healthy controls (all p<0.05). In patients, NLRP3 mRNA level was associated with LVEF, NT-pro BNP level and monocyte count (all p<0.05). LVEF at admission and mRNA levels of NLRP3 and IL-1β at discharge were independent risk factors of 6-month rehospitalization for patients. High NLRP3 mRNA level was associated with cumulative rehospitalization rate (p<0.05). NLRP3 level in PBMCs may be associated with cardiac function and rehospitalization in IDCM patients.

Differences in Virus Prevalence and Load in the Hearts of Patients with Idiopathic Dilated Cardiomyopathy with and without Immune-Mediated Inflammatory Diseases

Infections with cardiotrophic viruses and immune-mediated responses against the heart have been suggested to play a dominant role in the pathogenesis of idiopathic dilated cardiomyopathy (DCM). Furthermore, immune-mediated inflammatory diseases (IMIDs) may result in DCM. It has not previously been assessed whether DCM patients with and without an IMID have different prevalences and quantities of cardiotrophic viruses in the heart. Therefore, we compared the profiles of cardiotrophic viruses in heart tissue of DCM patients with and without an IMID. Serum and myocardial tissue samples were obtained from 159 consecutive patients with DCM and 20 controls. Patients were subdivided into three groups, the first two based on the presence (n = 34) or absence (n = 125) of an IMID and the third being a control group. The parvovirus B19 virus genome was detected in equal quantities in the non-IMID DCM patients (100/125) and the control group (15/20) but in lower quantities in the IMID patients (21/34, P = 0.02). Both the non-IMID and IMID DCM patients demonstrated increased myocardial inflammation compared to controls: 12.5 ± 1.8 and 14.0 ± 3.2 CD45-positive inflammatory cells, respectively, versus 5.1 ± 0.7 for the controls (P < 0.05 for both). Importantly, significantly higher parvovirus B19 copy numbers could be amplified in non-IMID than in IMID patients (561 ± 97 versus 191 ± 92 copies/μg DNA, P < 0.001) and control subjects (103 ± 47 copies/μg DNA, P < 0.001). The present study shows decreased parvovirus B19 prevalence and copy numbers in hearts of DCM patients with an IMID compared to those without an IMID. These findings may suggest that DCM patients with an IMID have a different pathophysiologic mechanism from that which is present in the virus-induced form of DCM.

Arrhythmogenic autoantibodies against calcium channel lead to sudden death in idiopathic dilated cardiomyopathy

Calcium channel plays an important role in the autoimmune pathogenesis of idiopathic dilated cardiomyopathy (DCM). Autoantibodies have emerged as a new upstream target of sudden death in DCM. We sought to validate the hypothesis that autoantibodies against l-type calcium channel (CC-AAbs) are arrhythmogenic and lead to sudden death in patients with DCM. We investigated sudden death and ventricular arrhythmias in 80 patients with DCM in a prospective, case follow-up survey. During a follow-up of 32 (SD 8) months, CC-AAbs-positive patients not only had a higher incidence of ventricular tachycardia (VT) but also a higher incidence of sudden death than CC-AAbs-negative patients (for VT: 59.0 vs. 24.4%, P = 0.002 and for sudden death: 20.5 vs. 4.9%, P = 0.045). Further univariate and multivariate analyses showed that the occurrence of CC-AAbs was the strongest independent predictor for sudden death (odds ratio: 10.20, 95% confidence interval: 2.43-36.78, P = 0.0027). Experimental studies in ex vivo systems using affinity-purified CC-AAbs from patients demonstrated that CC-AAbs were able to induce VT by prolongation of action potential duration (APD) and triggered activity by early afterdepolarization (EAD). Our results demonstrate for the first time to our knowledge that there is a high incidence of sudden death and VT in CC-AAbs-positive patients with DCM. Furthermore, experimental data from ex vivo systems suggest that CC-AAbs might induce VT by prolongation of APD and triggered activity by EAD.

Low level myocardial parvovirus B19 persistence is a frequent finding in patients with heart disease but unrelated to ongoing myocardial injury

While myocardial parvovirus B19 (B19V), aside from enteroviruses (EV) and adenoviruses (ADV), has recently been found often in patients with myocarditis and idiopathic dilated cardiomyopathy (IDC), the pathogenetic significance of B19V genomes in those patients has not yet been sufficiently elucidated. In the present study, left ventricular endomyocardial biopsies from 24 patients with left ventricular ejection fraction (LVEF) below 55% due to IDC, and tissue from the right atrial appendage of 10 control patients undergoing bypass surgery with normal LVEF (>55%) were investigated for B19V, ADV, and EV genomes by specific nested polymerase chain reaction (PCR), by real time PCR or by reverse-transcription PCR, respectively. The myocardial tissue samples from the 10 controls were analyzed each in three different virological laboratories for B19V. In the IDC group, the frequency of the myocardial virus genomes found in 54% (13/24) of the patients was as follows: B19V: 50% (12/24), EV: 8% (2/24), including one patient with B19V and EV, and ADV: 0% (0/24). For comparison, the prevalence of B19V genomes was between 30% and 60% in the control group as detected in three different laboratories, but all these control subjects were EV- and ADV-negative. The number of B19V gene copies, however, was very low and similar both in the IDC and control group. In the majority of patients myocardial B19V persistence was associated with a low virus load irrespective of the underlying heart disease so that it may be of no importance in the pathogenesis of IDC.

P-18 Matrix Metalloproteinases and Late Gadolinium-Enhancement with Cardiovascular Magnetic Resonance in Patients with Dilated Cardiomyopathy

Enteroviruses have been implicated in the pathogenesis of idiopathic dilated cardiomyopathy (IDC). Recently, adenovirus and parvovirus have been proposed as etiological agents of IDC. Viral Infection in the myocardium of patients with end-stage IDC was evaluated. Myocardial specimens from 30 American IDC patients, obtained during heart transplants, and from 47 Japanese IDC patients, obtained during partial left ventriculectomy, were analyzed for the presence of viruses. Established RT-PCR or PCR was used to detect genomic sequences of enterovirus, influenza virus, mumps virus, adenovirus, herpes simplex virus, varicellazoster virus, and Epstein-Barr virus. Enteroviral RNA was detected in 7 (23%) of the 30 American patients and in 15 (32%) of the 47 Japanese patients. Sequence analysis revealed that the viruses detected were coxsackieviruses, such as coxsackievirus B3. No genomic sequences of other viruses were detected in the myocardium. A highly sensitive real-time LightCycler PCR assay was developed for the quantification of coxsackieviral genome in the myocardium. The linear dynamic range, spanning from 10 to 1010 copies, can detect viral genome in the myocardium of patients at all stages of the disease process. Low copy number of coxsackieviral RNA was detected in the myocardium of both American and Japanese patients. Conclusion: Low level of coxsackieviral RNA in the myocardium was demonstrated in a significant proportion of patients with end-stage IDC. There was no evidence of infection by other viruses in the myocardium of IDC patients.

Etiology and Quantitative Evaluation of Viral Infection in the Myocardium of Patients With End-stage Idiopathic Dilated Cardiomyopathy

Enteroviruses have been implicated in the pathogenesis of idiopathic dilated cardiomyopathy (IDC). Recently, adenovirus and parvovirus have been proposed as etiological agents of IDC. Viral Infection in the myocardium of patients with end-stage IDC was evaluated. Myocardial specimens from 30 American IDC patients, obtained during heart transplants, and from 47 Japanese IDC patients, obtained during partial left ventriculectomy, were analyzed for the presence of cardiotropic viruses. Established RT-PCR or PCR was used to detect genomic sequences of enterovirus, influenza virus, mumps virus, adenovirus, herpes simplex virus, varicella-zoster virus, and Epstein-Barr virus.

Genetics of dilated cardiomyopathy

Dilated cardiomyopathy (DCM) is a myocardial disease characterized by dilatation and impaired systolic function of the left or both ventricles. The etiology of DCM is multifactorial, and many different clinical conditions can lead to the phenotype of DCM. During recent years it has become evident that genetic factors play an important role in the etiology and pathogenesis of idiopathic DCM. The genetics of DCM have been under intensive investigation lately, and thereby the knowledge on the genetic basis of DCM has increased rapidly. The genetic background of the disease seems to be relatively heterogeneous, and the disease‐associated mutations concern mostly single families and only few affected patients. Disease‐associated mutations have been detected e.g. in genes encoding sarcomere, cytoskeletal, and nuclear proteins, as well as proteins involved with regulation of Ca2+ metabolism. The mechanisms, by which mutations eventually result in clinical heart failure, are complex and not yet totally resolved. DCM causes considerable morbidity and mortality. Better knowledge of the genetic background and disease‐causing mechanisms would probably help us in focusing early treatment on right subjects and potentially also developing new treatment modalities and improving cardiac outcome in the affected patients. This review deals with DCM of genetic origin.

Specific removal of β1-adrenoceptor autoantibodies by immunoabsorption in rabbits with autoimmune cardiomyopathy improved cardiac structure and function

Objective. Growing evidence suggests that the β1-adrenoceptor-directed autoimmune mechanism may play an important role in the pathogenesis of idiopathic dilated cardiomyopathy. The aim of this study is to further study the effect of specific immunoabsorption of anti-β1-adrenoceptor autoantibodies on cardiac structure and function in autoimmune cardiomyopathy in rabbits. Methods and results. Twenty-four male rabbits were divided into 2 groups: (1) one immunized with β1-adrenoceptor peptide (β1 group, n = 16), and (2) the other receiving saline injection as a control (control group, n = 8). Immunization was performed once a month for 8 months. A high concentration of anti-β1-adrenoceptor autoantibodies was exhibited throughout the immunization period. Rabbits in the β1 group showed increased left ventricular end-diastolic diameter (LVDd), decreased left ventricular ejection fraction (LVEF) and increased LV mass/body weight ratio after the 8th month. Immunoabsorption with β1-adrenoceptor peptide column was able to remove up to 35% of anti-β1-adrenoceptor autoantibodies in 2 h, resulting in decreased LVDd and increased LVEF 3 months after. Conclusions. Specific removal of anti-β1-adrenoceptor autoantibodies improved cardiac structure and function in experimental autoimmune cardiomyopathy. These results suggest that anti-β1-adrenoceptor autoantibodies are of pathogenic importance in the induction of cardiomyopathy, and that specific immunoabsorption as an emerging therapy may be considered when anti-β1-adrenoceptor autoantibodies are pathophysiologically involved.

Evidence of viral infection in the myocardium of American and Japanese patients with idiopathic dilated cardiomyopathy

Enteroviruses have been implicated in the pathogenesis of idiopathic dilated cardiomyopathy (IDC). Recently, the association of adenovirus or parvovirus with IDC has been reported. Viral infection in the myocardium of American and Japanese patients with end-stage IDC was evaluated. Myocardial specimens from 30 American patients with IDC and 47 Japanese patients with IDC were analyzed for the presence of cardiotropic viruses. The strand-specific detection of enteroviral ribonucleic acid (RNA) was performed to determine viral activity in hearts with IDC. Established reverse transcription-polymerase chain reaction (PCR) or PCR techniques were used to detect genomic sequences of influenza viruses, mumps virus, adenovirus, parvovirus, herpes simplex viruses, varicella-zoster virus, and Epstein-Barr virus. Enteroviral RNA was detected in 7 of the 30 American patients (23%) and in 15 of the 47 Japanese patients (32%). Minus-strand enteroviral RNA, an indicator of active enteroviral RNA replication, was demonstrated in 5 of 7 plus-strand-positive American patients (71%) and in 12 of 15 plus-strand-positive Japanese patients (80%). Sequence analysis revealed that the viruses detected were Coxsackie B viruses. No genomic sequences of other viruses were detected in the myocardium of either American or Japanese patients with IDC. Therefore, active group B Coxsackie virus RNA replication in the myocardium was demonstrated in a significant proportion of American and Japanese patients with end-stage IDC. There was no evidence of persistent infection by other viruses in hearts with IDC. Specific therapy should be designed for Coxsackie virus positive patients with IDC.

Immunoglobulin G3 cardiac myosin autoantibodies correlate with left ventricular dysfunction in patients with dilated cardiomyopathy: Immunoglobulin G3 and clinical correlates

Background Effector functions of an aberrant immune response have been implicated in the pathogenesis of idiopathic dilated cardiomyopathy (DCM). The immunologic determinants of myocardial dysfunction, however, remain poorly understood. This study sought to determine the relation of different immunologic responses to hemodynamic dysfunction in DCM. Methods Immunoglobulin (Ig) G class/subclass response ELISA (enzyme-linked immunosorbent assay) against cardiac myosin heavy chain, histologic characteristics (DALLAS criteria), immunohistochemistry, plasma interleukin-4 and plasma interferon gamma (IFN-γ) were determined in patients (n = 76) with clinically suspected myocarditis or DCM. Patients were prospectively evaluated, both clinically and hemodynamically, on admission (baseline) and at 6-month follow-up. Results Indices of hemodynamic dysfunction (by cardiac catheterization and transthoracic echocardiography) correlated significantly with an Ig subclass response. IgG3 levels correlated with left ventricular ejection fraction (P =.02), pulmonary capillary wedge pressure (P <.0001), left ventricular end-systolic volume index (P =.002), left ventricular end-diastolic volume index (P =.033), left ventricular end-diastolic pressure (P =.04), right ventricular end-diastolic pressure (P =.039), and left ventricular end-systolic dimension and left ventricular end-diastolic dimension (P <.05). Patients positive for IgG3 (predominantly male, P =.01) had depressed left ventricular ejection fraction (≤45%, relative risk 3.0, 95% CI 1.5-5.7, P =.005) at baseline and 6 months. Mitral-septal separation at follow-up improved in patients negative for IgG3 (P =.018), and the number of patients on conventional therapy in this group declined at 6-month follow-up (P <.05). Lymphocyte counts/high-power field; CD2, CD3, CD4, and CD8 (independent of IgG class/subclass response and left ventricular dysfunction) were significantly higher in patients positive for IFN-γ (25%). A positive IFN-γ response was higher in patients positive for IgG3. These patients, positive for IgG3 and IFN-γ (10%), had significantly shorter duration of clinical symptoms: 0.17 years (0.12-2.36 y) versus 1.01 years (0.49-5.35 y, P =.04). Conclusion IgG3 reactivity correlated with depressed myocardial dysfunction. This may render this subclass Ig a surrogate target for therapeutic intervention in DCM. With IFN-γ, IgG3 may reflect a more aggressive disease. (Am Heart J 2002;143:1076-84.)