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Biomedical subjects

M Komajda

Publications and source records attributed to M Komajda.

At least 55 records · Page 3Linked to original sources
PubMed2000

Lack of association between polymorphisms of eight candidate genes and idiopathic dilated cardiomyopathy: the CARDIGENE study.

OBJECTIVES: The study investigated the potential role of eight candidate genes in the susceptibility to idiopathic dilated cardiomyopathy (IDC). BACKGROUND: Idiopathic dilated cardiomyopathy has a familial origin in 20% to 25% of cases, and several genetic loci have been identified in rare monogenic forms of the disease. These findings led to the hypothesis that genetic factors might also be involved in sporadic forms of the disease. In complex diseases that do not exhibit a clear pattern of familial aggregation, the candidate gene approach is a strategy widely used to identify susceptibility genes. All genes coding for proteins involved in biochemical or physiological abnormalities of cardiac function are potential candidates for IDC. METHODS: We studied 433 patients with IDC and 401 gender- and age-matched controls. Polymorphisms investigated were the I/D polymorphism of the angiotensin I-converting enzyme (ACE) gene, the T174M and M235T polymorphisms of the angiotensinogen (AGT) gene, the A-153G and A+39C polymorphisms of the angiotensin-II type 1 receptor (AGTR1) gene, the T-344C polymorphism of the aldosterone synthase (CYP11B2) gene, the G-308A polymorphism of the tumor necrosis factor-alpha (TNF) gene, the R25P polymorphism of the transforming growth factor beta1 (TGFB1) gene, the G+11/in23T polymorphism of the endothelial nitric oxide synthase (NOS3) gene and the C-1563T polymorphism of the brain natriuretic peptide (BNP) gene. RESULTS: None of the polymorphisms were significantly associated with the risk or the severity of the disease. CONCLUSIONS: We did not find evidence for an involvement of any of the 10 investigated polymorphisms in the susceptibility to IDC.

Adolescent↗
PubMed2000

Implantable left ventricular assist systems (LVAS): recent results. A report from a series of meetings sponsored by the Study Group on Advanced Heart Failure of the Working Group on Heart Failure.

Implantable left ventricular assist systems (LVAS) consist of implantable pumps with small control consoles and power sources that can be worn externally. These systems provide far greater patient mobility and independence than external pumps with bulky control consoles. Patients with implantable LVAS can be discharged from hospital and are able to return to work and resume active sports. Most patients have received these systems as a bridge to heart transplantation. Clinical status and quality of life improve dramatically after device implantation and survival on support (60-70% after approx. 100 days of support) is acceptable compared with transplant candidates on medical therapy. Patient selection and adverse events, primarily bleeding, thromboembolism and infection, are important issues with LVAS. In the future, long-term support and bridging to myocardial recovery may become important indications for LVAS.

Adolescent↗
PubMed2000

Plasma adrenomedullin, a new independent predictor of prognosis in patients with chronic heart failure.

BACKGROUND: Adrenomedullin, a potent endogenous vasodilating and natriuretic peptide, may play an important role in the pathophysiology of chronic heart failure. Plasma levels of immunoreactive adrenomedullin were examined for prediction of prognosis in chronic heart failure. METHODS AND RESULTS: Plasma levels of immunoreactive-ADM (ir-ADM) were measured by radioimmunoassay in 117 chronic heart failure patients with idiopathic or ischaemic cardiomyopathy (mean ejection fraction: 28 +/- 10%, in the NYHA functional class I/II/III/IV:8/73/29/7, and treated with ACE inhibitors and diuretics. Plasma levels of immunoreactive adrenomedullin were significantly increased in chronic heart failure patients by comparison to controls (618 +/- 293 pg x ml(-1) vs 480 +/- 135 pg x ml(-1), P=0.01). During the follow-up period (237 +/- 137 days) 14 cardiovascular deaths and four urgent cardiac transplantations occurred. In the univariate Cox model, immunoreactive adrenomedullin plasma levels were related to prognosis (P=0.004). A multivariate analysis including heart rate, systolic blood pressure, NYHA class, left ventricular ejection fraction, left ventricular echocardiographic end-diastolic diameter, plasma levels of immunoreactive adrenomedullin, endothelin-1, norepinephrine and atrial natriuretic peptide was performed: plasma levels of immunoreactive adrenomedullin (P=0.03), of endothelin-1 (P=0.0001), and systolic blood pressure (P=0.003) were significantly associated with outcome. CONCLUSION: Our results suggest that elevated plasma levels of immunoreactive adrenomedullin are an independent predictor of prognosis in predominantly mild to moderate chronic heart failure treated by conventional therapy and provide additional prognostic information.

Adrenomedullin↗
PubMed2000

Epidemiology of desmin and cardiac actin gene mutations in a european population of dilated cardiomyopathy.

AIMS: Although dilated cardiomyopathy is the most frequent form of cardiomyopathy, its aetiology is still poorly understood. In about 20-30% of cases the disease is familial with a large predominance of autosomal dominant transmission. Ten different chromosomal loci have been described for autosomal dominant forms of dilated cardiomyopathy. Only two genes have been associated with pure forms (without myopathy and/or conduction disorders) of the disease, the cardiac actin and the desmin genes. Our aim was to determine the proportion of dilated cardiomyopathy affected individuals carrying a mutation in one of these two genes. METHODS AND RESULTS: We performed (1) a systematic polymerase chain reaction-SSCP-sequencing screening of the coding sequences of cardiac actin on DNA samples from 43 probands of dilated cardiomyopathy families and 43 sporadic cases; (2) a systematic polymerase chain reaction-SSCP-sequencing screening of the coding sequences of desmin combined with a search for the described missense mutation (Ile451Met) by restriction fragment length polymorphism analysis on DNA samples from 41 probands of dilated cardiomyopathy families and 22 sporadic cases. CONCLUSION: None of the patients presents a mutation in any of these two genes. Consequently, the proportion of European dilated cardiomyopathy affected individuals bearing a mutation in (1) the cardiac actin gene is less than 1.2%, (2) the desmin gene is less than 1.6%.

Actins↗
PubMed2000

Effects of prolonged propranolol treatment on left ventricular remodeling and oxidative stress after myocardial infarction in rats.

Mechanisms determining the benefit of beta blockade in patients with heart failure remain incompletely understood but are assumed consequent to prevention of deleterious effects of catecholamines. Recent studies have demonstrated that oxidative stress in congestive heart failure may be related to increased catecholamine levels. The aim of this study was to examine effects of long-term treatment with propranolol on progression of left ventricular (LV) dysfunction, remodeling and oxidative stress on an experimental model of chronic heart failure. Six weeks after myocardial infarction by coronary ligation, Wistar rats were randomized to two groups: 10 weeks of therapy with propranolol (50 mg/kg/day in drinking water) and no treatment (infarcted controls). A third group was sham-operated rats without treatment. Animals were anesthetized for hemodynamic measurements, and hearts were then removed for histologic analysis, papillary muscle contractility study, and oxidative stress measurements using thiobarbituric acid reactive substance (TBARS) determination. Control infarcted rats demonstrated significant alterations of hemodynamic parameters and remodeling with increase of heart weight/body weight, of right ventricular lateral wall thickness, of LV circumference, LV septal area/body weight, and LV papillary muscle weight/body weight as compared with sham. In propranolol-treated rats, hypertrophy of the LV septum, papillary muscle, and right ventricle were similar to those of the infarcted control. Myocardial oxidative stress was significantly increased in control infarcted rats compared with sham, and propranolol prevented such oxidative stress increase. Papillary muscle isometric tension parameters were not significantly different among groups. Propranolol treatment prevented isoprenaline-induced spontaneous papillary muscle activity in vitro. Oxidative stress is increased in the rat model of heart failure secondary to coronary ligation. Long-term treatment with propranolol in vivo does not modify the compensatory process of hypertrophy but completely abolishes the oxidative stress increase and reduces the increased cardiac sensitivity to catecholamine-induced arrhythmias observed in this experimental model of heart failure.

Animals↗
PubMed2000

First description of germline mosaicism in familial hypertrophic cardiomyopathy.

Familial hypertrophic cardiomyopathy is a genetically and phenotypically heterogeneous disease caused by mutations in seven sarcomeric protein genes. It is known to be transmitted as an autosomal dominant trait with rare de novo mutations.A French family in which two members are affected by hypertrophic cardiomyopathy was clinically screened with electrocardiography and echocardiography. Genetic analyses were performed on leucocyte DNA by haplotype analysis with microsatellite markers at the MYH7 locus and mutation screening by single strand conformation polymorphism analysis. Two subjects exhibited severe hypertrophic cardiomyopathy. A mutation in the MYH7 gene was found in exon 14 (Arg453Cys). The two affected patients were carriers of the mutation, which was not found in the circulating lymphocytes of their parents. Haplotype analysis at the MYH7 locus with two intragenic microsatellite markers (MYOI and MYOII) and the absence of the mutation in the father's sperm DNA suggested that the mutation had been inherited from the mother. However, it was not found in either her fibroblasts or hair. This is the first description of germline mosaicism shown by molecular genetic analysis in an autosomal dominant disorder and more especially in hypertrophic cardiomyopathy. This mosaicism had been inherited from the mother but did not affect her somatic cells. Such a phenomenon might account for some de novo mutations in familial hypertrophic cardiomyopathy.

Adolescent↗
PubMed2000

[Cardiac insufficiency: what treatment? what dose? For which patients? Converting enzyme inhibitors and diuretics].

Diuretics were the first family of drugs to be used in cardiac failure. They improve symptoms but no randomised control trials show their efficacy in prolonging survival. The results of the recent RALES trial, however, provides evidence in favour of antialdosterone diuretics on survival in association with a loop diuretic and an angiotensin converting enzyme inhibitor. At present, the legal requirements in France state that "the association of spironolactone and converting enzyme inhibitors is possible with low doses of angiotensin converting enzyme inhibitors and diuretic hypokalaemiant; kalaemia and creatinine have to be monitored". "The association of hypokalaemia-inducing diuretics (loop diuretics, thiazides and similar: the association with this type of diuretic, rational and useful in certain patients, does not exclude the risk of hypo- or even hyperkalaemia, especially in renal failure and diabetes; it also imposes the monitoring of serum potassium and eventually of the electrocardiogram and, if necessary, to reconsider the treatment". Many points remain unclear concerning the value and harmlessness of the prescription of diuretics in asymptomatic left ventricular failure. In cases of diuretic resistance, the use of intravenous administration, the fragmentation of doses or the association of diuretics, may induce a diuretic response. Angiotensin converting enzyme inhibitors are the first line treatment of moderate and severe cardiac failure and in post-infarction left ventricular dysfunction. On the other hand, the value of this family of drugs in left ventricular failure and normal systolic function has not been demonstrated. Analysis of clinical practice shows an underprescription of angiotensin converting enzyme inhibitors, both in number of patients and in dosage. The results of the recent ATLAS trial suggest that high doses of lisinopril improve morbidity related to cardiac failure and the combined morbi-mortality criterion. The results of this study incite the prescription of high rather than low doses of angiotensin converting enzyme inhibitor.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2000

[Paralysing hypokalemic thyrotoxicosis].

Thyrotoxicosis is a rare cause of hypokalaemia. The clinical presentation associates signs of thyrotoxicosis which may be discrete, with severe hypokalaemia and peripheral muscular weakness with paralysis of the lower limbs. It is important not to miss this diagnosis because of the therapeutic implications. Treatment of this form of hypokalaemia is that of hyperthyroidism.

Adult↗
PubMed1999

Characterization of a unique genetic variant in the beta1-adrenoceptor gene and evaluation of its role in idiopathic dilated cardiomyopathy. CARDIGENE Group.

The genetic factors that underlie idiopathic dilated cardiomyopathy (IDCM) have not yet been elucidated. Since beta1-adrenoceptors are downregulated in patients with IDCM, and since beta-blocker therapy is consistently beneficial in this setting, we hypothesized that genetic variation in the beta1-adrenoceptor might affect susceptibility to and/or severity of IDCM. As no intragenic polymorphism was available, a systematic screening of the gene was first performed. The organization and sequence of the human beta1-adrenoceptor gene were established using polymerase chain reaction, single-strand conformation polymorphism analysis and sequencing. The gene comprises 1434 bp and no intron was observed. We found a unique and frequent polymorphism (C1165G) which predicts an Arg389Gly substitution. The association of this polymorphism with IDCM was then analysed using the PCR-restriction fragment length polymorphism method in the CARDIGENE population, a clinically well-characterized population of IDCM. Genotypic distribution was in agreement with Hardy-Weinberg equilibrium. There were no differences in the beta1-adrenoceptor allele frequencies between IDCM (n=426; C/G=0.76/0.24) and age- and sex-matched control subjects (n=395; C/G=0.78/0.22). Within the patient group, no association was observed with the severity of the disease. In conclusion, the genomic organization of beta1-adrenoceptor is described here for the first time. We found a unique and frequent polymorphism in the coding sequence of the gene. No association was observed between IDCM and the genetic variant. Its possible involvement in other cardiac diseases related to the beta1-adrenoceptor remains to be analysed.

Adult↗
PubMed1999

Genetic aspects of heart failure.

Heart failure is a major health problem and is associated with a high mortality and morbidity. Recently, the role of the genetic background in the onset and the development of the disease has been evidenced in both heart failure with and without systolic dysfunction and in familial and non-familial forms of this condition. Preliminary studies suggest that the I/D polymorphism of the Angiotensin Converting Enzyme gene influence the development of left ventricular hypertrophy, a major determinant of heart failure. Familial hypertrophic cardiomyopathy (FHC) is a highly heterogenous autosomal dominant disease. Seven genes have been identified which all encode proteins of the sarcomere or proteins involved in the regulation of contraction. More than one hundred mutations have been evidenced. Modifier genes such as the I/D polymorphism seem to play a role in the expression of the disease. Susceptibility genes have been searched for in sporadic forms of dilated cardiomyopathy and conflicting results have been published with regard to the I/D polymorphism. Finally, familial forms of dilated cardiomyopathy (FDC) are frequent. Various modes of inheritance and phenotypes have been reported and this condition appears genetically highly heterogenous. It has been postulated that the molecular defect involved in FDC is an abnormality in the transmission of contractile force. The analysis of genetic factors that predispose to heart failure looks promising: it should allow better understanding of the underlying mechanisms that promote the progression of the disease, to identify subjects at risk of the disease who would benefit from early medical management and promote the development of pharmacogenetics.

Cardiomyopathy, Hypertrophic↗
PubMed1999

Familial dilated cardiomyopathy: clinical features in French families.

UNLABELLED: The aims of the study were to analyze the clinical features, the penetrance and the mode of inheritance of 13 French families with dilated cardiomyopathy using diagnostic criteria recently established by a European collaboration. METHODS: Screening consisted of physical examination, ECG and Echo of all the probands first degree relatives (n = 118). Using major Echo criteria [ejection fraction (EF) < 45% or FS < 25% and left ventricular diameter (LVD) > 117% of the predictive value], or combined minor Echo/ECG criteria, relatives were classified as affected, unknown or healthy. RESULTS: (1) Adult affected relatives (n = 31) were identified with major Echo criteria in 74% of cases, and with combined minor Echo/ECG criteria in 26% of cases. (2) In the unknown relatives (n = 21), the most common abnormality was an isolated left ventricular dilation (67%). (3) Mode of inheritance was autosomal dominant (AD) in 11 families and possibly autosomal recessive in two. (4) In AD families, the penetrance was incomplete in adults (72%), age-related (O.R.: 1.3 per 10 years; 95% CI 1.03-1.56) and sex-related [greater in men (87%) than in women (61%), actuarial survival curve: P<0.002]. (5) Mortality related to end stage heart failure was 2.2 times as high as mortality related to sudden death (11% vs. 5%). CONCLUSIONS: (1) In the absence of a specific phenotype of FDC, the characterization of relatives appears more accurate when minor criteria were added. (2) Since high mortality (16%) and incomplete penetrance frequently give rise to small nuclei of clinically affected and alive relatives per family, the accurate model of penetrance that we proposed might be helpful in the future to enhance the statistical power of linkage analysis in this disease.

Adult↗
PubMed1999

Identification of a genetic risk factor for idiopathic dilated cardiomyopathy. Involvement of a polymorphism in the endothelin receptor type A gene. CARDIGENE group.

BACKGROUND: Idiopathic dilated cardiomyopathy is a frequent cause of heart failure, a major concern of public health. Although idiopathic dilated cardiomyopathy may be familial, most cases are sporadic and the disease is considered to be multifactorial, for which genetic factors may account for a significant part. METHODS AND RESULTS: We hypothesized that genetic abnormalities of the endothelin pathway may be involved in idiopathic dilated cardiomyopathy pathophysiology and therefore examined the possible association between idiopathic dilated cardiomyopathy and polymorphisms in genes encoding endothelin 1, endothelin type A and type B receptors, in a case-control study (433 patients and 400 age- and sex-matched control subjects). Analysis of the Exon 8 C/T polymorphism in the endothelin receptor type A gene indicated that individuals who are homozygote for the T allele were at significantly increased risk for the disease (odds ratio: 1.9; 95% confidence interval: 1.2 to 3. 01;P<0.006). Analysis of the other polymorphisms indicated that no significant difference was observed in genotype or allele frequencies between cases and controls. CONCLUSIONS: The variant in the Exon 8 of the endothelin receptor type A gene appears as a genetic risk factor for idiopathic forms of heart failure. These results provide a new approach to the pathophysiology of idiopathic dilated cardiomyopathy.

Adult↗
PubMed1999

Double heterozygosity for mutations in the beta-myosin heavy chain and in the cardiac myosin binding protein C genes in a family with hypertrophic cardiomyopathy.

Familial hypertrophic cardiomyopathy is a genetically heterogeneous autosomal dominant disease, caused by mutations in several sarcomeric protein genes. So far, seven genes have been shown to be associated with the disease with the beta-myosin heavy chain (MYH7) and the cardiac myosin binding protein C (MYBPC3) genes being the most frequently involved. We performed electrocardiography (ECG) and echocardiography in 15 subjects with hypertrophic cardiomyopathy from a French Caribbean family. Genetic analyses were performed on genomic DNA by haplotype analysis with microsatellite markers at each locus involved and mutation screening by single strand conformation polymorphism analysis. Based on ECG and echocardiography, eight subjects were affected and presented a classical phenotype of hypertrophic cardiomyopathy. Two new mutations cosegregating with the disease were found, one located in the MYH7 gene exon 15 (Glu483Lys) and the other in the MYBPC3 gene exon 30 (Glu1096 termination codon). Four affected subjects carried the MYH7 gene mutation, two the MYBPC3 gene mutation, and two were doubly heterozygous for the two mutations. The doubly heterozygous patients exhibited marked left ventricular hypertrophy, which was significantly greater than in the other affected subjects. We report for the first time the simultaneous presence of two pathological mutations in two different genes in the context of familial hypertrophic cardiomyopathy. This double heterozygosity is not lethal but is associated with a more severe phenotype.

Adult↗