TNF gene polymorphisms are associated with reduced survival in severe Chagas' disease cardiomyopathy patients

Chronic Chagas' disease cardiomyopathy (CCC) is the most important clinical outcome of infection by the parasite Trypanosoma cruzi, affecting 18 million individuals in Latin America. One-third of CCC patients develop heart failure due to end-stage dilated cardiomyopathy, and their survival is reduced by 50% compared to patients with other cardiomyopathies. Genetic susceptibility may play a role in the differential survival of severe CCC patients. Given the role of TNF-alpha in the progression of heart failure, and the increased TNF-alpha plasma and heart tissue levels observed in these patients, we chose TNF as a candidate gene for increased mortality in severe CCC patients. We typed the TNFa microsatellite and the -308 TNF promoter polymorphism and then analyzed the survival curves of 42 patients with severe ventricular dysfunction (left ventricular ejection fraction相似文献   

Multiple Loci are associated with dilated cardiomyopathy in Irish wolfhounds

Dilated cardiomyopathy (DCM) is a highly prevalent and often lethal disease in Irish wolfhounds. Complex segregation analysis indicated different loci involved in pathogenesis. Linear fixed and mixed models were used for the genome-wide association study. Using 106 DCM cases and 84 controls we identified one SNP significantly associated with DCM on CFA37 and five SNPs suggestively associated with DCM on CFA1, 10, 15, 21 and 17. On CFA37 MOGAT1 and ACSL3 two enzymes of the lipid metabolism were located near the identified SNP.     

Inter-simple-sequence-repeat (ISSR) polymorphisms are useful for finding markers associated with disease resistance gene clusters

 We describe a simple and new approach, based on inter-simple sequence repeats (ISSRs), for finding markers linked to clusters of disease resistance genes. In this approach, simple sequence repeats (SSR) are used directly in PCR reactions, and markers found to be linked to disease resistance genes provide important information for the selection of other sequences which can be used with PCR to find other linked markers. Based on an ISSR marker linked to a gene of interest, many new markers can be identified in the same region. We previously demonstrated that ISSR markers are useful in gene tagging and identified a marker, UBC-855₅₀₀, linked to the gene for resistance to fusarium wilt race 4 in chickpea. This ISSR marker provided the information used in the present study for selecting other primers which amplified a region linked to the gene for resistance to fusarium wilt race 4. The primers were based on homology with the (AC)_n sequence and were used for PCR amplifications. Changes in the sequence were at the anchor region of the primers. The repeat (AC)₈T amplified a marker, UBC-825₁₂₀₀, which was located 5.0 cM from the gene for resistance to fusarium wilt race 4 and was closer than other markers. These results indicated that ISSR markers can provide important information for the design of other primers and that by making changes at the 3′ and 5′ anchors close linkage to the desired gene can be found. The approach allows rapid scanning of the targeted region and may provide important information for genome analysis of plant species. Received: 20 January 1998 / Accepted: 19 March 1998     

Polymorphisms in the SOD2 and HLA-DRB1 genes are associated with nonfamilial idiopathic dilated cardiomyopathy in Japanese.

To reveal genetic risk factors of nonfamilial idiopathic cardiomyopathy (IDC) in Japanese, polymorphisms in the SOD2 and HLA-DRB1 genes were investigated in 86 patients and 380 healthy controls. There was a significant excess of homozygotes for the V allele [Val versus Ala (A allele), a polymorphism in the leader peptide of manganese superoxide dismutase at position 16] of the SOD2 gene in the patients compared with the controls (87.2% versus 74.7%, odds ratio = 2.30, p = 0.013, pc < 0.03), and a significant increase in the frequency of HLA-DRB1*1401 in the patients was confirmed (14.0% vs 4.5%, odds ratio = 3.46, p = 0.001, pc < 0.03). A two-locus analysis suggested that these two genetic markers (SOD2-VV genotype and DRB1*1401) may play a synergistic role in controlling the susceptibility to nonfamilial IDC. In addition, processing efficiency of Val-type SOD2 leader peptide in the presence of mitochondria was siginificantly lower than that of the Ala-type by 11 +/- 4%, suggesting that this lower processing efficiency was in part an underlying mechanism of the association between the SOD2-VV genotype and nonfamilial IDC.     

Cytokine gene polymorphisms are associated with risk of urinary bladder cancer and recurrence after BCG immunotherapy

The association of interleukin-1β (IL-1B) -511C?>?T and IL-1 receptor antagonist (IL-1RN) VNTR, transforming growth factor-β (TGF-B1) +28C?>?T and interferon-γ (IFN-G)?+?874T>A polymorphisms with bladder cancer (CaB) susceptibility and risk of recurrence in Bacillus Calmette–Guérin (BCG)-treated patients was analyzed in 287 controls and 213 CaB patients (73 BCG treated). Increased risk was observed with the IL-1RN*2 allele (odds ratio (OR) 5.01) and the IFN-G +874 A allele (OR 1.78). TGF-B TT and IFN-G +874 A carriers were associated with reduced (hazard ratio (HR) 0.37) and enhanced (HR 2.24) risk of recurrence after BCG immunotherapy, respectively. The study suggests that cytokine gene variants may modulate CaB susceptibility and risk of recurrence after BCG immunotherapy.     

Aromatase gene polymorphisms are associated with survival among patients with cardiovascular disease in a sex-specific manner

Introduction

CYP19A1 encodes aromatase, the enzyme responsible for the conversion of androgens to estrogens, and may play a role in variation in outcomes among men and women with cardiovascular disease. We sought to examine genetic variation in CYP19A1 for its potential role in sex differences in cardiovascular disease outcomes.

Methods

Caucasian individuals from two independent populations were assessed: 1) a prospective cohort of patients with acute coronary syndromes with 3-year mortality follow-up (n = 568) and 2) a nested case-control study from a randomized, controlled trial of hypertension patients with stable coronary disease in which the primary outcome was death, nonfatal myocardial infarction (MI) or nonfatal stroke (n = 619). Six CYP19A1 SNPs were genotyped (-81371 C>T, -45965 G>C, M201T, R264C, 80 A>G, and +32226 G>A). The sex*genotype interaction term was assessed for the primary outcome and compared by genotype in men and women when a significant interaction term was identified.

Results

We identified a significant interaction between -81371 C>T and sex (p = 0.025) in the ACS population. The variant allele was associated with a 78% increase in mortality in men (HR 1.78, 95% confidence interval [CI] 1.08-2.94) and a nonsignificant 42% decrease in mortality among women (HR 0.58, 95% CI 0.22-1.54). We identified a similar association in the hypertensive CAD group, the -81371 C>T*sex interaction term was p<0.0001, with an associated 65% increase in death, MI, or stroke (HR 1.65, 95% CI 1.00-2.73) in men and a 69% decrease (HR 0.31, 95% CI 0.16-0.6) in women.

Conclusions

Using two independent populations, this study is the first to document a significant interaction between CYP19A1 genotype and sex on cardiovascular outcomes. These findings could illuminate potential mechanisms of sex differences in cardiovascular disease outcomes.     

Manganese superoxide dismutase dimorphism relationship with severity and prognosis in cardiogenic shock due to dilated cardiomyopathy

The aim was to determine (a) Ala-16Val-SOD2 dimorphisms; (b) allelic frequency and phenotype of a common Pro-Leu polymorphism in GPx1, in a cohort of patients with a cardiogenic shock (CS) due to dilated cardiomyopathy without acute coronary syndrome. Consecutive patients with de novo CS that worsened a dilated (DCM) or ischemic (ICM) cardiomyopathy. Congenital heart disease, pacemaker and other shock aetiologies were excluded. To determine oxidative stress (OS), this study evaluated lipid peroxidation, protein oxidation and erythrocyte GPx, SOD and catalase activities. Ala16Val-SOD2 (dbSNP: rs4880) and Pro198Leu-GPx1 (dbSNP: rs1050450) polymorphisms were studied by allelic discrimination using fluorogenic probes and the 5'nuclease (TaqMan) assay. Twenty-four patients (with ICM (n = 8) or DCM (n = 16), age = 57.5 ± 10.7 years, LVEF = 25.3 ± 8.5%, NT-proBNP levels = 8540 ± 1703 ng/L) were included during a 15 month follow-up. OS parameters were significantly higher in patients than in controls. Distribution of MnSOD genotypes was 47% Val/Val-variant, 29.5% Ala/Val and 23.5% Ala/Ala-variants. Severity of CS was more important in patients with Val/Val-variant and can be put in parallel with NT-proBNP levels (Val/Val-variant: 11 310 ± 3875 ng/L vs Ala/Ala-variant: 6486 ± 1375 ng/L and Ala/Val-variant: 6004 ± 2228 ng/L; p < 0.05) and hemodynamic support duration (144.6 vs Ala/Val-variant: 108.8 h and Ala/Ala-variant: 52.5 h; p < 0.05) with a positive correlation (Spearman rho = 0.72, p < 0.05). Moreover, Val/Val-variant significantly influenced the mortality (Spearman rho = 0.67, p < 0.05), but not the morbidity (p = 0.3). Distribution of GPx genotypes was 64% Pro/Pro, 18% Pro/Leu and 18% Leu/Leu. GPx-variants influenced neither GPx activities nor cardiac events. In conclusion, CS was associated with markers of increased OS. GPx polymorphism did not influence the GPx activity. Only the Val-encoding MnSOD allele was significantly correlated with the severity and prognosis of CS.     

Long-term follow-up of patients with myocarditis and idiopathic dilated cardiomyopathy after immunomodulatory therapy

Abstract The randomized clinical trial with interferon-α (IFN) or thymic hormones versus conventional therapy was conducted in patients with myocarditis and idiopathic dilated cardiomyopathy (IDC). We enrolled 180 patients to receive IFN (3–5 million units per day) for 3 months, thymomodulin (10 mg three times per week) for 2 months, or conventional therapy alone. Patients were followed-up for 7 years after the end of treatment. Left ventricular function, exercise tolerance and survival rate were significantly better at long-term follow-up in patients treated with IFN or thymomodulin, than in conventionally treated patients. These results implicate that immune modulating therapy might represent important contribution in the treatment of myocarditis and IDC.     

Coordinate changes in Myosin heavy chain isoform gene expression are selectively associated with alterations in dilated cardiomyopathy phenotype

BACKGROUND: The most common cause of chronic heart failure in the US is secondary or primary dilated cardiomyopathy (DCM). The DCM phenotype exhibits changes in the expression of genes that regulate contractile function and pathologic hypertrophy. However, it is unclear if any of these alterations in gene expression are disease producing or modifying. MATERIALS AND METHODS: One approach to providing evidence for cause-effect of a disease-influencing gene is to quantitatively compare changes in phenotype to changes in gene expression by employing serial measurements in a longitudinal experimental design. We investigated the quantitative relationships between changes in gene expression and phenotype n 47 patients with idiopathic DCM. In endomyocardial biopsies at baseline and 6 months later, we measured mRNA expression of genes regulating contractile function (beta-adrenergic receptors, sarcoplasmic reticulum Ca(2) + ATPase, and alpha- and beta-myosin heavy chain isoforms) or associated with pathologic hypertrophy (beta-myosin heavy chain and atrial natriuretic peptide), plus beta-adrenergic receptor protein expression. Left ventricular phenotype was assessed by radionuclide ejection fraction. RESULTS: Improvement in DCM phenotype was directly related to a coordinate increase in alpha- and a decrease in beta-myosin heavy chain mRNA expression. In contrast, modification of phenotype was unrelated to changes in the expression of beta(1)- or beta(2)-adrenergic receptor mRNA or protein, or to the mRNA expression of sarcoplasmic reticulum Ca(2) + ATPase and atrial natriuretic peptide. CONCLUSION: We conclude that in human DCM, phenotypic modification is selectively associated with myosin heavy chain isoform changes. These data support the hypothesis that myosin heavy chain isoform changes contribute to disease progression in human DCM.     

An analytical comparison of cobalt cardiomyopathy and idiopathic dilated cardiomyopathy

Toxic cardiomyopathy (TC) has a rapid clinical course and morphologically resembles idiopathic dilated cardiomyopathy (IDC). To further characterize TC, we used light microscopy to compare lesions caused by cobalt (Co) to those of IDC. Cobalt levels were also measured as a chemical marker to differentiate TC from IDC. We reviewed cases with TC and IDC and excluded all cases with chemotherapy-induced myopathy and catecholamine toxicity as well as cases with possible infectious, ischemic, or hypersensitivity-induced myopathies. We compared the light microscopic findings of 12 TC cases to 12 cases of IDC, and measured trace Co levels on digested heart tissue samples. The TC cases had prominent myofibrillar loss and atrophy; no cases had neutrophil infiltration or frank myocyte necrosis. In contrast, IDC had minimal myofibril loss and atrophy. Cobalt levels in the range of 0.6 to 5.45 μg/g of dry tissue were obtained for the TC cases, while IDC demonstrated Co levels of 0.01–0.2 μg/g. Distinction between TC and IDC is predominantly a function of myocyte change, with TC showing myofibrillar loss and atrophy in the absence of inflammatory infiltrates and fibrosis; IDC is predominantly associated with myocyte hypertrophy, atrophy, and fibrosis. The opinions or assertions expressed herein are the private views of the authors and are not to be construed as official or as representing the views of the Armed Forces Institute of Pathology, the Department of the Army or the Department of Defense.     

Characterization of the human nebulette gene: a polymorphism in an actin-binding motif is associated with nonfamilial idiopathic dilated cardiomyopathy

Idiopathic dilated cardiomyopathy (IDC) is characterized by a thin-walled heart with systolic dysfunction of unknown etiology. Because abnormalities in genes for cytoskeletal proteins related to Z-disc function have recently been reported to cause IDC, genomic organization of the gene for nebulette, a novel actin-binding Z-disc protein, was determined and its sequence variations were searched for in Japanese patients with IDC and healthy controls. The nebulette gene consists of 28 exons, and four sequence variations leading to amino acid replacement (Gln187His, Met351Val, Asn654Lys, and Thr728Ala) were identified in the patients. These variations were also found in the healthy controls and hence they were polymorphisms and not disease-specific mutations. Frequencies of Gln187His, Met351Val, and Thr728Ala variants were similar in the patients and controls. However, the frequency of homozygotes for Lys at codon 654, a variant at a relatively conserved residue in an actinbinding motif, was significantly increased in nonfamilial IDC patients (n=106) as compared with healthy control subjects (n=331) (7.54% vs 1.21%, OR=6.25, P=0.002, 95% CI=1.92-20.29), while this association was not found in familial IDC patients (n=24). These observations suggest that the nebulette polymorphism in the actin-binding motif was a novel genetic marker of susceptibility to nonfamilial IDC.     

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.     

Plasma microRNA profiling of children with idiopathic dilated cardiomyopathy

Context: Dilated cardiomyopathy (DCM) is the most common cardiomyopathy in children. MicroRNAs (miRNA) are small RNAs which have regulatory functions in many biological processes.

Objective: We aimed to determine miRNA expression levels in plasma of children with DCM.

Materials and methods: Plasma expression levels of 379 miRNAs were compared between 23 DCM and 26 healthy children.

Results: The expression levels of miR-618, miR-875-3p, miR-205, miR-194, miR-302a, miR-147, and miR-544 were found decreased. The expression levels of miR-518f and miR-454 were found increased in DCM patients.

Discussion: miRNA level differences may provide the chance of using these miRNAs as new biomarkers.     

Reduced regional myocardial perfusion reserve is associated with impaired contractile performance in idiopathic dilated cardiomyopathy

Background. In idiopathic dilated cardiomyopathy (IDC) an imbalance between myocardial oxygen consumption and supply has been postulated. Subclinical myocardial ischaemia may contribute to progressive deterioration of left ventricular function. The relation between regional myocardial perfusion reserve (MPR) and contractile performance was investigated. Methods. Patients with newly diagnosed IDC underwent positron emission tomography (PET) scanning using both ¹³N-ammonia as a perfusion tracer (baseline and dypiridamole stress), and ¹⁸F-fluorodeoxyglucose viability tracer and a dobutamine stress MRI. MPR (assessed by PET) as well as wall motion score (WMS, assessed by MRI) were evaluated in a 17-segment model. Results. Twenty-two patients were included (age 49±11 years; 15 males, LVEF 33±10%). With MRI, a total of 305 segments could be analysed. Wall motion abnormalities at rest were present in 127 (35.5%) segments and in 103 (29.9%) during dobutamine stress. Twenty-one segments deteriorated during stress and 43 improved. MPR was significantly higher in those segments that improved, compared with those that did not change or were impaired during stress (1.87±0.04 vs. 1.56± 0.07 p<0.01.) Conclusion. Signs of regional ischaemia were clearly present in IDC patients. Ischaemic regions displayed impaired contractility during stress. This suggests that impaired oxygen supply contributes to cardiac dysfunction in IDC. (Neth Heart J 2009;17:470–4.)     

Measurement of multiple cytokines for discrimination and risk stratification in patients with Chagas’ disease and idiopathic dilated cardiomyopathy

Chagas’ disease (CD), caused by the hemoflagellate protozoan, Trypanosoma cruzi, is endemic in most countries of Latin America. Heart failure (HF) is often a late manifestation of chronic CD, and is associated with high morbidity and mortality. Inflammatory processes mediated by cytokines play a key role in the pathogenesis and progression of CD. Keeping in view the inflammatory nature of CD, this study investigated the possible role of 21 different inflammatory cytokines as biomarkers for prediction and prognosis of CD. The plasma concentration of these cytokines was measured in a group of patients with CD (n = 94), and then compared with those measured in patients with dilated cardiomyopathy (DCM) from idiopathic causes (n = 48), and with control subjects (n = 25). Monovariately, plasma levels of cytokines such as stem cell growth factor beta (SCGF beta), hepatocyte growth factor (HGF), monokine induced by interferon gamma (CXCL9), and macrophage inhibitory factor (MIF) were significantly increased in CD patients with advanced HF compared to control group. None of the cytokines could demonstrate any prognostic potency in CD patients, and only MIF and stromal derived factor-1 alpha (CXCL12) showed significance in predicting mortality and necessity for heart transplant in DCM patients. However, multivariate analysis prognosticated a large proportion of CD and DCM patients. In CD patients, HGF and Interleukin-12p40 (IL-12p40) together separated 81.9% of 3-year survivors from the deceased, while in DCM patients, CXCL12, stem cell factor (SCF), and CXCL9 together discriminated 77.1% of survivors from the deceased. The significant increase in plasma concentrations of cytokines such as HGF and CXCL9 in CD patients, and the ability of these cytokines to prognosticate a large proportion of CD and DCM patients multivariately, encourages further studies to clarify the diagnostic and prognostic potential of cytokines in such patients.     

Sera from patients with idiopathic dilated cardiomyopathy decrease ICa in cardiomyocytes isolated from rabbits

Autoantibodies against muscarinic and adrenergic receptors have been found in the sera of patients with idiopathic dilated cardiomyopathy (IDC) and Chagas disease, but it is still unclear whether they can functionally interact with their respective receptors to modulate cardiac functions. In this study, our goal was to detect the presence of those antibodies in the sera of patients with IDC and characterize their electrophysiological effects on cardiomyocytes from rabbits. By using ELISA immunoassays, we detected high titers of antibodies against muscarinic M2 receptors in the sera of all IDC patients, whereas the detection of antibodies against the beta1-receptor occurred in 50% of them. Electrophysiological experiments using the whole cell configuration of the patch-clamp technique showed that sera from 43% of IDC patients induced a significant decrease (approximately 26%) in isoproterenol-stimulated L-type Ca2+ currents in rabbit ventricular myocytes, whereas the sera from healthy blood donors failed to do so. As expected, IDC sera also decreased the action potential duration (by 10.5%) due to a shortening of the plateau phase. Sera that reduced isoproterenol-stimulated L-type Ca2+ currents did not cause any effect on K+ currents. We conclude that sera from IDC patients have autoantibodies, which interact with muscarinic M2 receptors of rabbit cardiomyocytes, acting in an agonist-like fashion. This action results in changes in electrogenesis, which, as often observed in patients with IDC, could initiate ventricular arrhythmias that lead to sudden death.     

Concentations of copper, Zinc, and magnesium in sera from patients with idiopathic dilated cardiomyopathy

Trace elements are known to have a key role in myocardial metabolism. The accumulation (cobalt, arsenic, copper) or deficiency (selenium, zinc) of trace elements may be responsible for idiopathic dilated cardiomyopathy. We investigated the trace element concentrations (Cu, Zn, Mg) in sera from patients with dilated cardiomyopathy by atomic absorption spectrophotometry. We observed that patients with dilated cardiomyopathies have higher copper and lower zinc concentrations in serum than healthy controls. The magnesium concentrations of patients did not differ significantly from that of control subjects.