Cytotoxic T lymphocyte associated antigen-4 gene exon 1A49→G polymorphisms confer susceptibility to idiopathic dilated cardiomyopathy

Autoimmune mechanisms, including cellular and humoral immune, are likely to participate in the pathogenesis of at least a subgroup of idiopathic dilated cardiomyopathy （IDC）, in which cellular immune-mediation plays a more important role. Cytotoxic T lymphocyte associated antigen-4 （CTLA-4） is the major negative regulatory factor of cellular immunity. This study was conducted to investigate the association of CTIA-4 gene exon 1 A49→G polymorphism with susceptibility to IDC in Han Chinese and its influences on serum soluble CTIA-4 （sCrLA-4） and Th1/Th2 cytokine bias. Polymerase chain reaction-restriction fragment length polymorphism （PCR-RFLP） techniques were used to analyze the dimorphism of CTL4-4 exon 1 in the unrelated Han ethnic population in Heilongjiang Province （ including 48 IDC patients and 50 normal controls）. Serum sCTLA-4, IFN-γ and IL-4 were evaluated by ELISA, with the ratio of IFN-γ/IL-4 as indicator for Th1/Th2 bias. Compared with controls, the frequencies of GG genotype （0.6042 and 0.3600, P = 0.012） and the G allele （0.7396 and 0.5600, P = 0.008） were significantly increased in IDC patients. Increased serum sCTIA-4 was found in the 1DC group compared with the controls [ （ 1.87 ± 1.06） μg/L vs. （0.54 ± 0.19） 〉g/L, P 〈 0.05 ~. 1FN-7 was much lower in IDC patients than that of the controls [ （ 16.38 ± 6.25） ng/L vs. （29.81 ± 10.66） ng/L （P 〈 0.05）~., whereas no statistical difference of IL-4 was found between the two groups I （12.85 ± 1.86） ng/L vs. （12.11 ± 2.76） ng/L], so the ratio of IFN-γ/IL-4 declined significantly （ 1.63 ± 0.50 vs. 3.01 ± 0.89, P 〈 0.05）. Linear regression analysis manifested a significant interrelationship between the GG genotype, G allele frequencies and serum sCTLA-4, IFN-γ/IL-4 in the IDC group （ r = 0.57, P = 0. 021 and r = 0.32, P = 0. 036）. CTLA-4 gene A49→G substitution was associated with an increased IDC risk, which implicated that the CTLA-4 gene exon 1 may have a considerable role in autoimmune cardiac damage, possibly via a Thr→Ala change in signal peptide, which influences the protein synthesis and modification processes, with a result of functional alteration of sCTLA-4. The bias of Th1/Th2 paradigm was associated with the increased sCTIA-4 under certain background of immunogenetics.

HLA-DQA1 Polymorphism in Idiopathic Dilated Cardiomyopathy

To determine whether the possession of certain HLA-DQA1 alleles was associated with the risk of developing idiopathic dilated cardiomyopathy (IDC) and to substantiate the role of an autoimmunologic pathogenesis in IDC. Type the alleles of HLA-DQA1 by polymerase chain reaction with sequence-specific primers (PCR-SSP) technique in 38 patients of idiopathic dilated cardiomyopathy (7 women and 31 men), aged from 17 to 56 years old with diagnosis being according to World Health Organization criteria (IDC group), in 50 patients of end-stage heart failure of known etiology (18 women and 32 men), with ages ranging from 34 to 72(HF group), and in the control group consisting of presumably 100 healthy subjects (39 women and 61 men) from the health survey, aged from 30 to 59 years old. The frequency of HLA-DQA1*0501 in the DCM patients was significantly elevated than that in the HF and the control group. Molecular analysis of the DQA1 gene polymorphism performed in the three subgroups shows an increased frequency of DQA1*0501 among patients with less EF. The HF group carries a high frequency of HLA-DQA1*0301. An increased frequency of DQA1*0201 and DQA1*0103 was found in the control group. HLA-DQA1*0501 is an associated gene of idiopathic dilated cardiomyopathy and the possession of DQA1*0301 may be indicative of the known etiologic heart failure, suggesting that the mechanisms involved in the pathogenesis of IDC and otherwise heart failure are different. Immunologic abnormalities may be a major contributor to the susceptibility of developing of IDC.

Prognostic Significance of Frontal QRS-T Angle in Patients with Idiopathic Dilated Cardiomyopathy

Background： Current risk stratification of idiopathic dilated cardiomyopathy （IDC） lacks sufficient sensitivity and specificity. The objective of this study was to investigate the predictive role of frontal QRS-T angles in IDC. Methods： A prospective study with 509 IDC patients was performed from February 2008 to December 2013 in the Affiliated Drum Tower Hospital, Nanjing University School of Medicine. Baseline values and changes in QRS-T angles were recorded. Follow-up was conducted every 6 months. Analyses by Cox Proportional Hazards model were performed to evaluate the association between QRS-T angle and outcomes. The primary outcome of interest was all-cause mortality. Results： During a median follow-up of 34 months, 90 of 316 patients with QRS-T angles 〉90° died compared to 31 of 193 patients with QRS-T angles ≤90° （hazard ratio [HR] 2.4, P 〈 0.001）. Cardiac death was more prevalent in patients with a wide QRS-T angle （HR 2.4, P 〈 0.001）, similar to heart failure rehospitalization （HR = 2.5, P 〈 0.001）. After adjustment for potential prognostic factors, the QRS-T angle was independently associated with all-cause mortality （HR - 2.5, P 〈 0.05）, cardiac mortality （HR = 1.9, P 〈 0. 05）, and heart failure rehospitalization （HR = 2.3, P 〈 0.01）. Optimized therapy significantly narrowed the frontal QRS-T angle （100.9 ±53.4° vs. 107.2 ± 54.4°, P 〈 0.001 ）. The frontal QRS-T angle correlated well with established risk factors, such as left ventricular ejection fraction, brain natriuretic peptide, and New York Heart Association functional class. Conclusions; The frontal QRS-T angle is a powerful predictor of all-cause mortality, cardiac mortality, and worsening heart failure in IDC patients, independent of well-established prognostic factors. Optimized therapy significantly narrows the QRS-T angle, which might be an indicator of medication compliance, but this requires further investigation.

Relationship between HLA-DQA1 polymorphism and genetic susceptibility to idiopathic dilated cardiomyopathy

Background Autoimmune mechanisms are likely to participate in the pathogenesis of subgroup of idiopathic dilated cardiomyopathy (IDC), and components of the major histocompatibility complex may serve as markers for the propensity to develop immune-mediated myocardial damage. Human leukocyte antigen (HLA) class Ⅱ genes, especially highly polymorphic HLA-DQ genes, play an important role in the activation of immune responses, and thus control the predisposition for or protect from IDC. This study was conducted to investigate the HLA-DQA1 allele polymorphisms in IDC patients and to explore the underlying immunological mechanism and the hereditary susceptibility to IDC.Methods The polymerase chain reaction sequence-specific primers (PCR-SSP) technique was used to analyze the polymorphisms in the second exon of DQA1 in three groups: 72 IDC patients diagnosed according to the criteria of World Health Organization (IDC group); 100 end-stage heart failure patients suffering from a disease of known etiology (HF group); and 100 healthy subjects enrolled for the study during a routine health survey (control group). Patients in the IDC group were stratified according to ejection fraction (EF). Those with EF values were higher than 35% were placed into subgroup 1; subgroup 2 included patients with an EF value of 15%-35%; and subgroup 3 consisted of those whose EF values less than 15%. Results The frequency of HLA-DQA1*0501 alleles was significantly higher in the IDC group (0.39) than that in the HF group (0.12) and the control group (0.09) (both P<0.05). Further analysis of the three IDC subgroups showed a higher frequency of DQA1*0501 among patients with lower EF values (both P<0.05, compared with subgroups 1 and 2). The frequency of DQA1*0201 was higher in the control group than that in the IDC group (P<0.05).Conclusions The HLA-DQA1*0501 allele confers susceptibility to IDC, while the DQA1*0201 allele confers protection against it, which indicates that genetic background involved in IDC and heart failure is different. HLA-DQA1 genes are involved in the regulation of specific immune responses by auto- or foreign anti-myocardium antibody.

Impact of LDB3 gene polymorphisms on clinical presentation and implantable cardioverter defibrillator(ICD) implantation in Chinese patients with idiopathic dilated cardiomyopathy

Objective:Mutations in LIM domain binding 3(LDB3)gene cause idiopathic dilated cardiomyopathy(IDCM),a structural heart disease with a complicated genetic background.However,the association of polymorphisms in the LDB3 gene with susceptibility to IDCM in Chinese populations remains unexplored as dose the impact on clinical presentation.Methods:We sequenced all exons and the adjacent part of introns of the LDB3 gene in 159 Chinese Han IDCM patients and 247 healthy controls.Then we detected the distribution of polymorphisms in the LDB3 gene in all participants and assessed their associations with risk of IDCM.Additionally,we conducted a stratified genotype–phenotype correlation analysis.Results:The A allele of rs4468255 was significantly associated with IDCM(P<0.01).The rs4468255,rs11812601,rs56165849,and rs3740346 were also associated with diastolic blood pressure(DBP)and left ventricular ejection fraction(LVEF)(P<0.05).Notably,a higher frequency of rs4468255 polymorphism was observed in implantable cardioverter defibrillator(ICD)recipients under a recessive model(P<0.01),whereas the significant association disappeared after adjusting for potential confounders.However,in the dominant model,notable correlations could only be observed after adjusting for multi parameters.Conclusions:The rs4468255 was significantly correlated with IDCM of Chinese Han population.A allele of rs4468255 is higher in IDCM patients with ICD implantation,suggesting the influence of genetic background in the generation of this response.In addition,rs11812601,rs56165849,and rs3740346 in LDB3 show association with brain natriuretic peptide,DBP,and LVEF levels in patients with IDCM but did not show any association with IDCM susceptibility.

Polymorphism of the second exon of human leukocyte antigen-DQA1, -DQB1 gene and genetic susceptibility to idiopathic dilated cardiomyopathy in people of the Han nationality in northern China

Idiopathic dilated cardiomyopathy ( IDC) is characterized by dilation andimpaired contraction of the left ventricle or both, and it is a relevant cause of heart failure anda common indication for heart transplantation. The major pathogenetic hypothesis in IDC involvesautoimmune mediated damage to myocytes. The development of autoimmune inflammatory damage occursonly in patients with a predisposing genetic background. Changes in the immune system concerningcell-mediated and humoral immunity have been detected. The immune system is strictly related tohuman leukocyte antigen (HLA), which is located on the surface of antigen presenting cells. Itsprimary function is to restrict T-cell receptors in the process of recognizing auto- or exteriorantigen, and thus participates in or mediates immunological recognition, immunological response andimmune regulation at various levels. HLA is a genetic marker of susceptibility to autoimmunemyocardial damage. In the present study, the HLA-DQA1 and -DQB1 alleles in IDC patients weredetected with the techniques of polymerase chain reaction-sequence specific primers ( PCR-SSP) toexplore the immunogenetic mechanisms involved in the pathogenesis of IDC.

Association of HLA-DQ with Idiopathic Dilated Cardiomyopathy in a Northern Chinese Han Population

Autoimmune mechanisms are likely involved in the pathogenesis of idiopathic dilated cardiomyopathy (IDC) and components of MHC may serve as markers for the propensity to develop immune-mediated myocardial damage.This study was conducted to investigate the possible association between HLA-DQA1,-DQB1 alleles and IDC in Han population from northern China by using PCR-based sequence-specific primer (PCR-SSP) technique for HLA genotyping.Among 68 unrelated IDC patients,4 probands of IDC pedigrees and 100 healthy controls,we found that the alleles of HLA-DQA1*0501 and HLA-DQB1*0303 conferred susceptibility to IDC while HLA-DQA1*0201 and HLA-DQB1*0502,*0504 alleles were in negative association with IDC.The serine at position 57 (SER^(57)) in the exon of HLA-DQB1*0502 and *0504 was confirmed in our experiment as a marker for resistance to IDC.The results suggest that HLA-DQ polymorphism may be involved in the pathogenesis of IDC.Cellular & Molecular Immunology.2004;1 (4):311-314.

PRVALENCE OF ARRHYTHMIAS IN PATIENTS WITH IDIOPATHIC DILATED CARDIOMYOPATHY

A total of 105 patients with idiopathic dilated cardiomyopathy （IDCM） underwent Holter monitoring. The prevalence of arrhythmias was as follows: ventricular premature beats （VPB） 100%, including complex VPB 58.1%, short runs of ventricular tachycardia （VT） 25.7%, A-VB or BBB 46.7%, atrial arrhythmias 38.1%, sinus node dysfunction 6.6％, ST-T change 38.1%. The incidence of ventricular arrhythmia （VA） was not related to severity of cardiac dysfunction （NYHA）, duration of illness and sex. The most common arrhythmia was VA, the second one was heart block and atrial arrhythmia. Serum norepinephrine and epinephrine levels were 743.4± 252.5 and 688.0± 452.4 pg/ml, respectively, which were higher than those in control group （P<0.01）. Isoproterenol sensitivity test （ICD5） 8.43± 11.21 μg, was also much higher than that in control group （P<0.01）.Average H-V interval was 69.4±13.3 msec in HBE. Eight patients died.Two died of congestive heart failure （class Ⅱ-Ⅳ）,and six cases were diagnosed as sudden cardiac

Clinical outcome of cardiac resynchronization therapy in dilated-phase hypertrophic cardiomyopathy

Backgrounds Clinical trials have demonstrated that cardiac resynchronization therapy （CRT） is effective in patients with ＂non-is- chemic cardiomyopathy＂. However, patients with dilated-phase hypertrophic cardiomyopathy （DHCM） have been generally excluded from such trials. We aimed to compare the clinical outcome of CRT in patients with DHCM, idiopathic dilated cardiomyopathy （IDCM）, or ischemic cardiomyopathy （ICM）. Methods A total of 312 consecutive patients （DHCM： n = 16; IDCM： n = 231; ICM： n = 65） undergoing CRT in Fuwai hospital were studied respectively. Response to CRT was defmed as reduction in left ventricular end-systolic volume （LVESV） _〉 15% at 6-month follow-up. Results Compared with DHCM, IDCM was associated with a lower total mortality （HR： 0.35, 95% CI： 0.13-0.90）, cardiac mortality （HR： 0.29; 95% CI： 0.11-0.77）, and total mortality or heart failure （HF） hospitalizations （HR： 0.34, 95% CI： 0.17-0.69）, independent of known confounders. Compared with DHCM, the total mortality, cardiac mortality and total mortality or HF hospitalizations favored ICM but were not statistically significant （HR： 0.59, 95% CI： 0.22-1.61; HR： 0.59, 95% CI： 0.21-1.63; HR： 0.54, 95% CI： 0.26-1.15; respectively）. Response rate to CRT was lower in the DHCM group than the other two groups although the differences didn＇t reach statistical significance. Conclusions Compared with IDCM, DHCM was associated with a worse outcome after CRT. The clinical outcome of DHCM patients receiving CRT was similar to or even worse than that of ICM patients. These indicate that DHCM behaves very differently after CRT.

Plasma Lysophosphatidylcholine and Phospholipase A2 Activity in Chagas Disease Patients: A Comparative Analysis

Chagas disease (CD) affects 21 countries in the Americas and is caused by the parasite Trypanosoma cruzi. A key molecule involved in CD is lysophosphatidylcholine (LPC), which has been studied in various contexts: in the saliva of insect vectors, during the establishment of infection in the vertebrate host, and for the parasite itself. This lipid can be produced by the action of phospholipases A2 (PLA2), enzymes that catalyze the hydrolysis of phospholipids releasing fatty acids and lysophospholipids, such as LPC. This study investigates LPC levels and PLA2 activities in the plasma of CD patients and compares these levels with those in healthy individuals and patients with idiopathic dilated cardiomyopathy (IDCM). Plasma from 64 CD patients, 54 healthy individuals, and 16 IDCM patients were analyzed. LPC levels and the activity of two types of phospholipase A2: secreted (sPLA2) and lipoprotein-associated (Lp-PLA2) were measured. LPC levels and sPLA2 activity were similar between CD patients and the control groups. However, there were notable differences in LPC levels and sPLA2 activity between subgroups of CD patients and IDCM patients. This study is the first to identify LPC in patients with CD across various stages of the disease. It also offers new insights into the biochemical changes observed in the plasma of patients with IDCM.