Risk Of Idiopathic Dilated Cardiomyopathy Research Articles

A genetic association study of heart failure: more evidence for the role of BAG3 in idiopathic dilated cardiomyopathy.

AimsFew investigations have been conducted to identify genetic determinants of common, polygenetic forms of heart failure (HF), and only a limited number of these genetic associations have been validated by multiple groups.Methods and resultsWe performed a case–control study to further investigate the potential impact of 14 previously reported candidate genes on the risk of HF and specific HF sub‐types. We also performed an exploratory genome‐wide study. We included 799 patients with HF and 1529 controls. After adjusting for age, sex, and genetic ancestry, we found that the C allele of rs2234962 in BAG3 was associated with a decreased risk of idiopathic dilated cardiomyopathy (odds ratio 0.42, 95% confidence interval 0.25–0.68, P = 0.0005), consistent with a previous report. No association for the other primary variants or exploratory genome‐wide study was found.ConclusionsOur findings provide independent replication for the association between a common coding variant (rs2234962) in BAG3 and the risk of idiopathic dilated cardiomyopathy.

Novel polymorphisms in PDLIM3 and PDLIM5 gene encoding Z-line proteins increase risk of idiopathic dilated cardiomyopathy.

Idiopathic dilated cardiomyopathy (IDCM), characterized by ventricular dilation and impaired systolic function, is a primary cardiomyopathy resulting in heart failure. During heart contraction, the Z‐line is responsible for transmitting force between sarcomeres and is also a hot spot for muscle cell signalling. Mutations in Z‐line proteins have been linked to cardiomyopathies in both humans and mice. Actinin‐associated LIM protein (ALP) and enigma homolog protein (ENH), encoded by PDLIM3 and PDLIM5, are components of the muscle cytoskeleton and localize to the Z‐line. A PDLIM3 or PDLIM5 deficiency in mice leads to dilated cardiomyopathy. Since PDLIM3 and PDLIM5 are candidate IDCM susceptibility genes, the current study aims to investigate whether polymorphisms within PDLIM3 and PDLIM5 could be correlated with IDCM. We designed a case‐control study, and exons of the PDLIM3 and PDLIM5 were amplified by polymerase chain reactions in 111 IDCM patients and 137 healthy controls. We found that five synonymous polymorphisms had statistical distribution differences between IDCM patients and controls, including rs4861669, rs4862543, c.731 + 131 T > G, c.1789‐3 C > T and rs7690296, according to genotype and allele distribution. Haplotype G‐C‐C‐C and A‐T‐C‐T (rs2306705, rs10866276, rs12644280 and rs4635850 synthesized) were regarded as risk factors for IDCM patients when compared with carriers of other haplotypes (all P < .05). Furthermore, IDCM patients with two novel polymorphisms (c.731 + 131 T > G and c.1789‐3 C > T) had lower systolic blood pressure. In conclusion, these five synonymous polymorphisms might constitute a genetic background that increases the risk of the development of IDCM in the Chinese Han population.

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

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. 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. 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. 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.

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.

HLA-DR3 antigen in the resistance to idiopathic dilated cardiomyopathy.

Idiopathic dilated cardiomyopathy (IDC) has been hypothesized as a multifactorial disorder initiated by an environment trigger in individuals with predisposing human leukocyte antigen (HLA) alleles. Published data on the association between HLA-DR3 antigen and IDC risk are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. Studies were identified by searching the PUBMED and Embase database (starting from June 2015). A total of 19 case-control studies including 1378 cases and 10383 controls provided data on the association between HLA-DR3 antigen and genetic susceptibility to IDC. Overall, significantly decreased frequency of HLA-DR3 allele (OR=0.72; 95%CI=0.58-0.90; P=0.004) was found in patients with IDC compared with controls. When stratified by myocardial biopsy or non-biopsy cases, statistically decreased risk was found for IDC in myocardial biopsy cases (OR=0.69; 95%CI=0.57-0.84; P=0.0003). In the subgroup analysis by ethnicity, borderline statistically significantly decreased risk was found among Europeans from 12 case-control studies (OR=0.76; 95%CI=0.58-1.00; P=0.05). In conclusion, our results suggest that individuals with HLA-DR3 antigen may have a protective effect against IDC.

The tumor necrosis factor-α -238G/A and IL-6 -572G/C gene polymorphisms and the risk of idiopathic dilated cardiomyopathy: a meta-analysis of 25 studies including 9493 cases and 13,971 controls.

Inflammation plays an imperative role in the etiology of cardiovascular diseases (CVD). The role of cytokines in the development and progression of idiopathic dilated cardiomyopathy (IDCM) is still uncertain. The current study was conducted to evaluate the association of tumor necrosis factor-α (TNF-α) -238G/A and IL-6 -572G/C gene polymorphism with IDCM in a Pakistani population. IDCM cases (n=250) and healthy controls (n=300) were genotyped using PCR-RFLP. The variant genotypes of both the loci showed significant differences between patients and controls (p<0.05). However, -238G/A polymorphism did not show association with the disease in the presence of covariates. We also conducted a meta-analysis of both the loci with regards to CVD in accordance with the Prisma checklist. No significant relation of the TNF-α -238G/A polymorphism with CVD was found; however, this single nucleotide polymorphism (SNP) showed an association with the disease in the Asian population after subgroup analysis (p=0.01). Whereas, the IL-6 -572G/C polymorphism showed that the variant genotype (GC+CC) was associated with higher risk of CVD in contrast to the GG genotype. Furthermore, subgroup meta-analysis demonstrated a significant association of the -572 polymorphism with CVD in Asians, but no association was observed among Western populations with this SNP. Our findings support an association between the IL-6 -572G/C polymorphism and IDCM risk. The role of the TNF-α -238G/A polymorphism in IDCM is still unclear. Further studies are warranted to determine the serum cytokine levels in relation to the cytokines' SNP in diverse ethnic groups to ascertain the molecular basis of the disease pathology.

A meta-analysis of HLA-DR polymorphism and genetic susceptibility to idiopathic dilated cardiomyopathy

Idiopathic dilated cardiomyopathy (IDC) has been hypothesized as a multifactorial disorder initiated by an environment trigger in individuals with predisposing human leukocyte antigen (HLA) alleles. Published data on the association between HLA-DR polymorphism and IDC risk are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. A total of 19 case-control studies including 1,378 cases and 10,383 controls provided data on the association between HLA-DR polymorphism and genetic susceptibility to IDC. Overall, statistically elevated frequencies of HLA-DR4 (OR 1.58; 95% CI 1.21-2.07; P=0.0009) and HLA-DR5 (OR 1.35; 95% CI 1.05-1.73; P=0.02) alleles were found in patients with IDC compared with controls. Individuals with HLA-DR3 antigen have a protective effect against IDC (OR 0.72; 95% CI 0.58-0.90; P=0.004). In summary, this meta-analysis indicated that certain HLA-DR alleles may be genetic markers for susceptibility and resistance to IDC.

HLA-DR4 antigen and idiopathic dilated cardiomyopathy susceptibility: a meta-analysis involving 11,761 subjects

Idiopathic dilated cardiomyopathy (IDC) has been hypothesized as a multifactorial disorder initiated by an environment trigger in individuals with predisposing human leukocyte antigen (HLA) alleles. Published data on the association between HLA-DR4 antigen and IDC risk are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. Studies in English-language articles were identified by a search of PubMed and Embase database (inception to June 2010). A total of 19 case-control studies including 1378 cases and 10,383 controls provided data on the association between HLA-DR4 antigen and genetic susceptibility to IDC. Overall, statistically elevated frequency of HLA-DR4 allele [OR (odds ratio), 1.58; 95% CI (confidence interval), 1.21-2.07; P = 0.0009] was found in patients with IDC compared with controls. When stratified by myocardial biopsy or non-biopsy cases, statistically increased risks were found for IDC in both subgroups. In the subgroup analysis by ethnicity, significantly increased risk was found among Europeans from 12 case-control studies (OR, 1.54; 95% CI, 1.11-2.12; P = 0.009). In conclusion, our results suggest that HLA-DR4 antigen is a low-penetrant risk factor for developing IDC in Europeans.

Matrix metalloproteinase-1, -3, and -9 gene polymorphisms and the risk of idiopathic dilated cardiomyopathy in a Chinese Han population

Objectives: To investigate the association between matrix metalloproteinase (MMP)-1(− 1607 1G/2G), MMP-3(− 1171 5A/6A), and MMP-9(− 1562 C/T) polymorphism and susceptibility to idiopathic dilated cardiomyopathy (IDCM). Design and methods: MMP-1, -3, -9 genotypes were determined by PCR-RFLP analysis. Results: Genotype frequency of MMP-3, but not MMP-1 and MMP-9 in IDCM patients, was significantly different from that in healthy controls. Conclusions: Our data suggested that MMP-3 5A/6A polymorphism could be a risk factor for the susceptibility to IDCM.

Environmental Factors and Risk of Idiopathic Dilated Cardiomyopathy-A Multi-Hospital Case-Control Study in Japan-

Detailed epidemiological investigations on the relationship of environmental factors, especially occupational and microbiological factors, to the development of idiopathic dilated cardiomyopathy (IDC) are scarce. A multi-hospital case-control study was conducted in 38 hospitals throughout Japan in order to survey IDC cases and age, sex-matched outpatient controls at each hospital. Crude and adjusted odds ratios (ORs) by various environmental factors were calculated in 135 pairs of cases and controls. Univariate analyses revealed significantly increased ORs for lower education, passive smoking in the workplace, cold and/or hot workplace, symptoms of fatigue and history of bacterial infection; in contrast, decreased ORs were associated with a history of rubella and gastroduodenal diseases. Based on multivariate adjusted analyses, lower education (OR 1.96, 95% confidence interval (CI) 1.13-3.40), cold or hot workplace (OR 1.84, 95%CI 1.08-3.12) and history of measles (OR 1.78, 95%CI 1.01-3.08) exhibited a significant positive relationship with IDC risk. History of rubella (OR 0.17, 95%CI 0.06-0.52) and gastroduodenal diseases (OR 0.14, 95%CI 0.07-0.29) were inversely related to the risk. Some occupational and microbiological factors appear to relate independently to the development of IDC and further investigation is required to establish their respective mechanisms.

Viral infection, inflammation, and the risk of idiopathic dilated cardiomyopathy: can the fire be extinguished?

Idiopathic dilated cardiomyopathy (IDC) remains an enigmatic disease (or group of diseases) in which the clinical phenotype is an impairment of left ventricular systolic function. The last 2 decades have witnessed advances in pharmacologic therapy and an improved understanding of the natural history, added to the recent exciting development of serum biomarkers that may provide further insight into prognosis and response to therapy. Nonetheless, the etiology or etiologies continue to elude us despite intriguing recent studies identifying a genetic substrate in some families with IDC. A common thread of investigation has centered on a viral-mediated insult leading to the final common pathway of IDC (Figure 1). This commentary reviews recent advances in myocarditis research, suggests investigative goals for the near future, and identifies the obstacles that must be overcome to reach these targets.

Epidemiology of idiopathic dilated cardiomyopathy in the elderly: pooled results from two case-control studies.

Although idiopathic dilated cardiomyopathy is often viewed as an affliction of young of middle-aged adults, morbidity and mortality rates from idiopathic dilated cardiomyopathy rise sharply with age and are the highest in the elderly. To learn more about the determinants of this increasingly important cause of heart failure in the elderly, the authors conducted a pooled analysis of data from two case-control studies of idiopathic dilated cardiomyopathy carried out in Baltimore, Maryland (1984-1986), and in Washington, DC (1990-1992). Identical diagnostic criteria and interviewing procedures had been used in both studies. All of the cases of idiopathic dilated cardiomyopathy had evidence of ventricular dilation and hypokinesis, with a left ventricular ejection fraction of < 40%. Cases with a history of coronary artery disease were excluded along with those with known secondary forms of cardiomyopathy, Up to two neighborhood controls of the same sex and appropriate age (+/- 5 years) were selected for each case using a random digit dialing technique. The subjects or a suitable surrogate was interviewed by telephone to obtain medical history information. The present analysis was limited to 94 cases and 152 matched controls who were at least 60 years of age. Conditional logistic regression methods were used in the analysis. Significant associations were observed with lower educational attainment and a history of hypertension (P < 0.05). The association with hypertension (relative odds = 2.2, 95% confidence interval 1.1-4.6) persisted after adjustment for race, education, and diabetes and was not accounted for by coronary angiography utilization patterns. The association with diabetes was of borderline significance (p < 0.10). The pattern of risk factors identified in this analysis may allow for the early identification of elderly persons who are at increased risk of idiopathic dilated cardiomyopathy.

Diabetes mellitus and risk of idiopathic dilated cardiomyopathy the Washington, DC dilated cardiomyopathy study

An epidemiologic study was carried out to examine the possible role of diabetes mellitus and other factors in the development of idiopathic dilated cardiomyopathy. Possible associations with diabetes and other factors were examined by comparing newly diagnosed case patients (n = 129) ascertained from five Washington, DC area hospitals with neighborhood control subjects (n = 258) identified using a random-digit dialing technique. The case patients and control subjects were matched by sex and 5-year age intervals and were compared in the analysis using conditional logistic regression methods. A statistically significant association was observed between idiopathic dilated cardiomyopathy and history of diabetes (relative odds = 2.2; 95% confidence interval: 1.5 to 3.3). The association with diabetes was not explained by race, income, cigarette usage, or hypertension. A total of 28.7% (37/129) of the case patients had a reported history of diabetes, as compared with 13.6% (35/258) of the control subjects (P < 0.05). A possible interactive effect was also observed between diabetes and history of hypertension (P > 0.05). These findings support the view that diabetics, particularly those with a history of hypertension, may be at increased risk of idiopathic dilated cardiomyopathy.

Black-white differences in idiopathic dilated cardiomyopathy: the Washington DC dilated Cardiomyopathy Study.

We conducted an epidemiologic study to examine the extent to which differences in purported risk factors account for black-white differences in risk of idiopathic dilated cardiomyopathy. We examined associations with race and other factors by comparing newly diagnosed cases (N = 122), ascertained from five Washington DC area hospitals, with neighborhood controls (N = 234) identified using a random digit dialing technique. We matched the cases and controls on sex and 5-year age intervals and analyzed the data using conditional logistic regression methods. We found that blacks were at increased risk for idiopathic dilated cardiomyopathy (relative odds = 2.6, 95% confidence interval = 1.6-4.3). The increased risk for blacks could not be explained by income, educational attainment, alcohol consumption, cigarette smoking, or history of hypertension, obesity, diabetes, or asthma. We also observed a possible interactive effect between black race and hypertension.