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M Desnos

Publications and source records attributed to M Desnos.

At least 55 records · Page 3Linked to original sources
PubMed1999

Predicting sudden death in the population: the Paris Prospective Study I.

BACKGROUND: Sudden death was found to share the same set of usual risk factors as coronary events and therefore could not be specifically predicted in the population. It appears, however, that parental history of sudden death has not been investigated yet as a risk factor for sudden death. Therefore, we assessed risk factors, including parental sudden death, associated with the occurrence of sudden death in a long-term cohort study. METHODS AND RESULTS: We included 7746 men employed by the city of Paris who were 43 to 52 years of age in 1967 to 1972 in the Paris Prospective Study I. Each subject underwent a physical examination and an ECG, provided blood for laboratory tests, and answered questionnaires administered by trained interviewers who paid particular attention to family medical history. Men with known ischemic cardiac disease were further excluded from analysis. For 95.5% of the men, vital status was obtained from specific inquiries until retirement, then by death certificates. Resting heart rate, systolic or diastolic blood pressure, tobacco consumption, body mass index, diabetes status, serum cholesterol, and parental history of sudden death were independent factors associated with sudden death during follow-up (23 years on average). When adjusted for confounding variables, including parental history of myocardial infarction, relative risk of sudden death associated with parental sudden death was 1.80 (95% CI, 1.11 to 2.88). CONCLUSIONS: Parental sudden death is an independent risk factor for sudden death in middle-aged men. The existence of familial risk factors for sudden death may help provide better identification of subjects at high risk of and early prevention of sudden death.

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

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

Idiopathic atrial fibrillation as a risk factor for mortality. The Paris Prospective Study I.

AIMS: Idiopathic atrial fibrillation describes atrial fibrillation of unknown origin occurring without heart disease. Mortality is considered unaffected by idiopathic atrial fibrillation. We used the long follow-up period (23 years on average) of the Paris Prospective Study I to assess the mortality of idiopathic atrial fibrillation subjects in middle-aged men. METHODS: 7746 working Frenchmen, aged 43-52 in 1967-72, underwent a physical examination plus ECG, answered questionnaires, and provided blood samples. Strict exclusion criteria were used to select idiopathic atrial fibrillation only, and men with known cardiac disease were further excluded from analysis. At 1 January 1994, vital status was unknown for 4.6% of the subjects. The analysis was conducted on the 6722 remaining subjects. RESULTS: Twenty-five subjects had idiopathic atrial fibrillation at inclusion. The relative risk (and 95% confidence interval) associated with idiopathic atrial fibrillation was 4.22 [2.10-8.47] for cardiovascular mortality (P=0.0001) and 1. 97 [1.14-3.40] for total mortality (P=0.01). When age, systolic blood pressure, cholesterol, body mass index and tobacco consumption were entered into a Cox model, idiopathic atrial fibrillation remained an independent risk factor for cardiovascular (P=0.0008) and total death (P=0.04). CONCLUSION: With a long follow-up period, idiopathic atrial fibrillation was associated with higher mortality in middle aged Frenchmen.

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

[Evaluation of a specific French scale of activity in chronic heart failure. A national multicenter study. Group for Cardiac Insufficiency and Cardiomyopathy of the French Society of Cardiology].

Many systems have been proposed to evaluate the functional incapacity caused by chronic cardiac failure. The classification of the New York Heart Association (NYHA) is the best known. It is subjective, poorly reproducible and has a poor predictive value on effort. The authors propose a Specific French Scale of Activity with the object of a more accurate functional evaluation of cardiac failure, easier to use by the doctor and more specific to French patients and their life styles. A French multicentre study was set up in hospital departments by the French Society of Cardiology working group on Cardiomyopathy and Cardiac Failure to assess this new classification with respect to the NYHA classification and peak VO2 (Weber's classification). Eight centres participated in the study. A total of 124 patients with chronic cardiac failure and a mean age of 61 years (102 men) were included. Cardiac failure was due to ischaemic heart disease in 72 cases, hypertension in 10 cases, dilated cardiomyopathy in 40 cases and aortic regurgitation in 2 cases. Eighty-two patients underwent a double evaluation using the French Scale: 40 patients by 2 physicians and 42 patients by a physician and a nurse. Good reproducibility was found between the assessment by the 2 physicians in 35 cases (87%) and between the physician and nurse in 30 cases (71%). When compared with peak VO2, the classification was concordant in 47% of cases using the NYHA and in 61% of cases using the French Scale, with variation of one class in 40% of cases with the NYHA and 35% of cases with the French Scale. These results show good reproducibility and correspondence of classification with the exercise test which was better using the French Scale than the NYHA classification.

Aged↗
PubMed1998

Clinical features and prognostic implications of familial hypertrophic cardiomyopathy related to the cardiac myosin-binding protein C gene.

BACKGROUND: Little information is available on phenotype-genotype correlations in familial hypertrophic cardiomyopathy that are related to the cardiac myosin binding protein C (MYBPC3) gene. The aim of this study was to perform this type of analysis. METHODS AND RESULTS: We studied 76 genetically affected subjects from nine families with seven recently identified mutations (SASint20, SDSint7, SDSint23, branch point int23, Glu542Gln, a deletion in exon 25, and a duplication/deletion in exon 33) in the MYBPC3 gene. Detailed clinical, ECG, and echocardiographic parameters were analyzed. An intergene analysis was performed by comparing the MYBPC3 group to seven mutations in the beta-myosin heavy-chain gene (beta-MHC) group (n=52). There was no significant phenotypic difference among the different mutations in the MYBPC3 gene. However, in the MYBPC3 group compared with the beta-MHC group, (1) prognosis was significantly better (P<0.0001), and no deaths occurred before the age of 40 years; (2) the age at onset of symptoms was delayed (41+/-19 versus 35+/-17 years, P<0.002); and (3) before 30 years of age, the phenotype was particularly mild because penetrance was low (41% versus 62%), maximal wall thicknesses lower (12+/-4 versus 16+/-7 mm, P<0.03), and abnormal T waves less frequent (9% versus 45%, P<0.02). CONCLUSIONS: These results are consistent with specific clinical features related to the MYBPC3 gene: onset of the disease appears delayed and the prognosis is better than that associated with the beta-MHC gene. These findings could be particularly important for the purpose of clinical management and genetic counseling in familial hypertrophic cardiomyopathy.

Adolescent↗
PubMed1998

Genotype-phenotype analysis in four families with mutations in beta-myosin heavy chain gene responsible for familial hypertrophic cardiomyopathy.

Familial hypertrophic cardiomyopathy is a genetically heterogeneous disease in which one of the most frequently implicated gene is the gene encoding the beta-myosin heavy chain. To date, more than 40 distinct mutations have been found within this gene. In order to progress on the determination of genotype-phenotype relationship, we have screened the beta-myosin heavy chain gene for mutations in 18 probands from unrelated families. We identified the mutation implicated in the disease in four families. Two of them, the Glu930 codon deletion and the Ile263Thr mutation, are reported here for the first time. The two other mutations are the Arg723Cys mutation, that was previously described in a proband as a de novo mutation, and the Arg719Trp mutation. A poor prognosis was associated with the Glu930codon deletion (mean maximal wall thickness (MWT) = 19.5 mm +/- 5) and the Arg719Trp mutation (mean MWT = 15.3 mm +/- 7), whereas a good prognosis was associated with the Arg723Cys mutation (mean MWT = 20.1 mm +/- 7). The combination of clinical and genetic characteristics of each family member suggests that prognosis is related neither to the degree of left ventricular wall thickness nor to a change in the net electrical charge of the protein. Additional family studies are needed to confirm these findings and to contribute to stratify the prognosis according to the mutation involved.

Adolescent↗
PubMed1998

Identification of two novel mutations in the ventricular regulatory myosin light chain gene (MYL2) associated with familial and classical forms of hypertrophic cardiomyopathy.

Five disease genes encoding sarcomeric proteins and associated with familial and classical forms of hypertrophic cardiomyopathy have been determined since 1989. In 1996 two other genes encoding ventricular regulatory and essential myosin light chains were shown to be associated with a particular phenotype of the disease characterized by mid left ventricular obstruction. The aim of the present study was to search for mutations in the ventricular regulatory myosin light chain gene (MYL2), located on chromosome 12q23q24.3, in a panel of 42 probands presenting a classical phenotype of familial hypertrophic cardiomyopathy. Single-strand conformation polymorphism analysis was used to search for mutations in the coding segments of the MYL2 gene, and the abnormal products were sequenced. Two novel missense mutations, Phe18Leu in exon 2 and Arg58Gln in exon 4 were identified in three unrelated families. None of the affected patients had hypertrophy localized only at the level of the papillary muscle with mid left ventricular obstruction. By analysis of genetic recombinations, one of these mutations identified in a large family allowed us to refine the localization of the MYL2 gene on the genetic map, in an interval of 6 cM containing six informative microsatellite markers. In conclusion, we show that mutations in the MYL2 gene may be involved in familial and classical forms of hypertrophic cardiomyopathy, and we provide new tools for the genetic analysis of patients with familial hypertrophic cardiomyopathy.

Adolescent↗
PubMed1998

Genotype-phenotype correlations in familial hypertrophic cardiomyopathy. A comparison between mutations in the cardiac protein-C and the beta-myosin heavy chain genes.

BACKGROUND: The gene involved in familial hypertrophic cardiomyopathy on chromosome 11 was recently identified as the cardiac myosin binding protein-C (MyBP-C) gene. The phenotype of two families associated with mutation in this gene is described here and compared to that of five families with mutations in the beta-myosin heavy chain gene. METHODS AND RESULTS: In adults (n = 33) bearing a splice acceptor site mutation in the MyBP-C gene, penetrance of familial hypertrophic cardiomyopathy was incomplete (69%) and ventricular hypertrophy mild. Among 37 clinical, electrocardiographic and echocardiographic parameters analysed, the only difference with the beta-MHC group (n = 35) was a shorter acceleration time of systolic flow in the pulmonary artery (P < 0.05). Sensitivity and specificity of diagnostic criteria were similar for the two genes. Cumulative survival rate for the splice acceptor site mutation (90% at 50 years old) was mid-way between that observed with a malignant (Arg403Leu: 42%) and a benign mutation (Arg403Trp: 100%) in the beta myosin heavy chain gene (P = 0.002). CONCLUSIONS: The detailed phenotype associated with a mutation in the MyBP-C gene was no different from that associated with mutations in the beta myosin heavy chain gene, except for prognosis which appeared more benign. These preliminary results suggest that there is no locus-specific genotype-phenotype correlation for the two genes analysed.

Adult↗
PubMed1998

Familial hypertrophic cardiomyopathy. Cardiac ultrasonic abnormalities in genetically affected subjects without echocardiographic evidence of left ventricular hypertrophy.

AIMS: It is not known whether the apparent normality of echocardiographic examination results, in subjects bearing a mutation for hypertrophic cardiomyopathy but without ultrasonic left ventricular hypertrophy, is due to incomplete phenotypic expression, or inaccurate echocardiographic criteria. The aim of this study was to search for echocardiographic abnormalities in these patients. METHODS AND RESULTS: Echocardiography was performed in 100 subjects from two families with a mutation in the beta-MHC (720) or My-BPC (714) genes. We compared genetically affected subjects with an apparently normal left ventricle (thickness < 13 mm) (20 patients), and nonaffected first-degree relatives (61 normal subjects). (1) Patients had a thicker left ventricular wall (9.7 +/- 1.4 vs 8.9 +/- 1.4 mm, P = 0.03), a greater indexed mass (107 +/- 18 vs 97 +/- 17 g. m-2, P = 0.03), a larger left atrium (27 +/- 9 vs 23 +/- 10 mm3, P = 0.09) and lower wall stress (78 +/- 11 vs 89 +/- 15 10(3) dynes. cm-2, P = 0.002); these differences were highly significant after adjustment for height, age and systolic blood pressure either for wall thickness (P = 0.000003), mass (P = 0.005) or atrial volume (P = 0.001), and the ventricular systolic dimension appeared smaller (P = 0.01); (2) results remained significant (P < 0.01) when a lower cut-off value (< or = 11 mm) or only adults (> or = 18 years) were considered; (3) a subanalysis of Family 714 (13 patients, 25 normals matched for sex, age and height) showed the same trends. CONCLUSION: In familial hypertrophic cardiomyopathy, genetically affected subjects with an apparently normal heart by echocardiography show slight ultrasonic structural and functional left ventricular modifications, suggesting that the phenotype of the disease is a continuous spectrum from normal structure to typical hypertrophy.

Adolescent↗
PubMed1998

Diagnostic value of electrocardiography and echocardiography for familial hypertrophic cardiomyopathy in genotyped children.

AIM: The aim of the study was to evaluate electrocardiography and echocardiography in the diagnosis of familial hypertrophic cardiomyopathy in children, using the genetic status as the criterion of reference. METHODS AND RESULTS: We analysed 35 children (<18 years) from 13 families with identified mutations: 16 were genetically affected (11.2 +/- 3 years), 19 unaffected (13.1 +/- 2.8 years). Conventional major diagnostic criteria were: left ventricular wall thickness >95% confidence interval on the echocardiogram; abnormal Q waves, left ventricular hypertrophy (voltage >95th percentile), or marked ST-T changes on the electrocardiogram. Twenty-two minor electrocardiographic and echocardiographic criteria were also analysed. Using major criteria, the specificity of the electrocardiogram and echocardiogram was excellent (100% for both) but sensitivity was particularly low (38% and 50% respectively). However, when four relevant additional criteria (QRS axis, left atrium dimension, intraventricular septum/posterior wall ratio, E/A wave ratio) were taken into account, sensitivity increased to 88% and specificity remained high (95%). CONCLUSIONS: (1) Familial hypertrophic cardiomyopathy was diagnosed in only approximately 50% of genetically affected children by conventional electrocardiographic and/or echocardiographic criteria. (2) Relevant additional diagnostic criteria were selected so that nearly all children considered as healthy carriers of a mutation (based on conventional criteria) could be identified with excellent specificity.

Adolescent↗
PubMed1997

Diagnostic value of electrocardiography and echocardiography for familial hypertrophic cardiomyopathy in a genotyped adult population.

BACKGROUND: The diagnostic value of ECG and echocardiography for familial hypertrophic cardiomyopathy (FHC) has not been reassessed since the development of molecular genetics. The aim of the study was to evaluate it in adults, with the genetic status used as the criterion of reference. METHODS AND RESULTS: Ten families with previously identified mutations were studied (9 mutations in 3 genes). ECG and echocardiography were analyzed in 155 adults, of whom 77 were genetically affected and 78 unaffected. The major diagnostic criteria were, for echocardiography, a left ventricular wall thickness > 13 mm and, for ECG, abnormal Q waves, left ventricular hypertrophy, and marked ST-T changes. Minor ECG and echographic abnormalities were also analyzed. (1) Sensitivity and specificity of major criteria were 61% and 97% for ECG and 62% and 100% for echocardiography. (2) Sensitivity but not specificity was age related (from 50% at < 30 years to 94% at > 50 years old, P < .01) and sex related (83% in men versus 57% in women, P = .01). (3) Sensitivity was improved by the addition of minor criteria and by the association of ECG and echocardiography. The negative predictive value was therefore very good (95%) at > 30 years of age. (4) Healthy carriers without any ECG or echocardiographic abnormality represented 17% of genetically affected adults. CONCLUSIONS: ECG and echocardiography have similar diagnostic values for FHC in adults, with an excellent specificity and a lower sensitivity. The association of the two techniques allows a better evaluation of the risk of being genetically affected in families with hypertrophic cardiomyopathy.

Adult↗
PubMed1997

Experience from clinical genetics in hypertrophic cardiomyopathy: proposal for new diagnostic criteria in adult members of affected families.

The diagnosis of hypertrophic cardiomyopathy has relied on echocardiographic demonstration of unexplained left ventricular hypertrophy. The prevalence of hypertrophic cardiomyopathy defined in this way has been estimated to be 1:500 and experience indicates that these criteria are relatively specific when other causes of left ventricular hypertrophy are absent. In recent years, however, the systematic evaluation of pedigrees performed in the context of molecular genetic studies revealed that in some families with hypertrophic cardiomyopathy up to 20% of adults who carry a disease causing gene defect do not fulfil conventional echocardiographic criteria. None the less, most of these individuals show symptoms, electrocardiographic alterations, and/or minor echocardiographic abnormalities. Revised diagnostic criteria in members of families with hypertrophic cardiomyopathy are proposed, including major and minor criteria based on symptoms, and electrocardiographic and echocardiographic abnormalities. Given that the chance of inheriting the gene defect is 1:2, the likelihood that symptoms plus electrocardiographic or echocardiographic abnormalities are the expression of a disease causing gene is high.

Adult↗