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M Komajda

Publications and source records attributed to M Komajda.

At least 109 records · Page 6Linked to original sources
PubMed1995

[Hypertrophic cardiomyopathy: practical application of genetic research].

Hypertrophic cardiomyopathy is usually familial with an autosomal dominant mode of transmission. The condition is genetically heterogeneous. The first defective gene to be described was that of the beta heavy chain of cardiac myosin (beta-MHC, chromosome 14 q11-q12) where over 20 different localised false sense mutations and a hot point of mutation in exon 13 have been reported. This locus seems to be implicated in 30% of families studied. Systematic screening of the genome has led to the detection of new sites on chromosomes 1, 11 and 15. No gene has yet been identified in these three new loci. For all new families, present strategy consists in determining the locus responsible for the disease by linkage analysis. For beta-MHC locus a panel of several markers (the two MYO I and MYO II microsatellites of the beta-MHC gene and two new AFN microsatellites) has been established which allows accurate detection of whether the haplotype cosegregates with the disease, even in relatively small families. It is then necessary to define the mutation by PCR amplification of the exons followed by electrophoresis on Hydrolink-MDE gels and sequencing of the mutant exons. Some subjects are genotypically affected but phenotypically normal and it seems the penetrance varies with the type of mutation. Analysis of the genotype/phenotype relationship should be continued in order to improve our knowledge of the consequences of each mutation. The genotype diagnosis is therefore complex and cannot be undertaken at present of the examination of the propositus. Whole families must be sampled.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiomyopathy, Hypertrophic↗
PubMed1995

[Treatment of chronic heart failure: current views].

New agents for treating chronic heart failure include angiotensin converting enzyme (ACE) inhibitors, betablockers and phosphodiesterase inhibitors. The ACE inhibitors represent the major therapeutic advance of the 1980-1990 decade. This is the most effective class of drugs on survival, whatever the stage of heart failure and it shows the evolution towards symptoms in asymptomatic patients. Studies currently under way are evaluating the dose-effect relationship of ACE inhibitors. Betablockers improve the quality of life and physical performance but a benefit on mortality has not been shown in two recent trials. Phosphodiesterase inhibitors improve quality of life and physical performance at the price of an increase in mortality. Therefore, they are not indicated in the treatment of heart failure. However, new molecules such as vesnarininone or pimobendan are under trial. Finally, in the next few years, the introduction of antagonists to Angiotensin II receptors is eagerly awaited.

Adrenergic beta-Antagonists↗
PubMed1994

Identification of a mutation near a functional site of the beta cardiac myosin heavy chain gene in a family with hypertrophic cardiomyopathy.

Several mutations within the gene coding for the cardiac beta myosin heavy chain (designed MYH7) have been shown to be responsible for Familial Hypertrophic Cardiomyopathy (FHC) in several families, and evidence of genetic heterogeneity has been reported. To investigate the MYH7 gene as the cause of the disease in a small family with FHC, inheritance of the disease and chromosome 14 q11-q12 markers haplotype were studied, exons coding for the head domain of the cardiac beta myosin heavy chain (beta MHC) were analysed for mutations by MDE gel electrophoresis, and sequenced. We report a mutation within exon eight of the MYH7 gene at a very conserved amino acid at position 232, which results in the conversion of an asparagine to serine. This residue Asn-232 is located in a MHC area that has been recently identified as a critical site for ATPase activity. According to recent results on the three-dimensional structure of the myosin head or subfragment-1 (S1), Asn-232 is located in an alpha-helix which forms part of the nucleotide binding pocket. Although this mutation affects an active site, it seems to be associated with a favourable prognosis and a weak penetrance in this family.

Adult↗
PubMed1994

[Physiopathology of mitral mechanics in hypertrophic cardiomyopathy. Groupe de travail "Cardiomyopathies et insuffisance cardiaque" de la Société Française de Cardiologie].

Ventricular hypertrophy, the only indisputable phenotypical marker of hypertrophic cardiomyopathy, is the basis of the physiopathology and treatment of the disease. Mitral valve abnormalities are usually considered to be secondary to the hypertrophy but the genesis of systolic anterior motion by the Venturi effect has been questioned by many clinical and experimental observations. Abnormalities of the mitral valve apparatus may in themselves (elongation of the valves, antero-internal malposition of the mitral papillary muscles and/or hyperlaxicity of antero-internal corhdae tendinae) create systolic anterior motion or subaortic obstruction in the absence of septal hypertrophy and/or increased subaortic flow velocities. Anatomo-clinical studies have confirmed this hypothesis: a high prevalence of mitral valve disease (increased valvular surface and length) has been found in hypertrophic cardiomyopathy. The recognition of these abnormalities is of value from the therapeutic (mitral valvuloplasty) diagnostic (in borderline cases) and genetic (when the primary nature of the abnormalities is confirmed) points of view.

Animals↗
PubMed1994

[The ATLAS study (Assessment of Treatment with Lisinopril and Survival); justification and objectives].

Treatment with ACE inhibitors has improved the prognosis of cardiac failure (CF). The results of CONSENSUS I, SOLVD and V HEFT II show clinical improvement and longer survival with this therapeutic class of drugs. However, the search for the optimal dosage was not undertaken in these trials (a standard dose was fixed at the onset, average dose of enalapril from 15 to 20 mg/day). In clinical practice, patients are prescribed lower doses of ACE inhibitors (enalapril: 7.5 mg/day) than the averages used in large scale trials. In order to optimise the use of ACE inhibitors, the ATLAS study (Assessment of Treatment with Lisinopril and Survival) was undertaken with the precise objective of comparing two dosages (2.5 to 5 mg/day vs 32.5 to 35 mg/day) of lisinopril on the morbidity and mortality of patients with CF. This international, multicenter, randomised, double-blind parallel group trial aims to include 3,000 patients over 18 years of age with NYHA Classes II, III and IV, and an ejection fraction < or = 30% and to follow them up for 3 to 4.5 years. Nearly 30 French centres will participate in this trial. After an initial, open period of evaluation of tolerance (5 mg to 15 mg/day of lisinopril in France), the patients will be randomised to two groups. After randomisation, all patients will receive 5 mg per day of lisinopril. The "high dose" group will receive 20 mg/day for two weeks, then 30 mg/day in addition to the "open dosage". In cases of intolerance, the dosage may be reduced to 20 mg/day or 10 mg/day, or the drug may be withdrawn.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical Protocols↗
PubMed1993

Variations in plasma endothelin concentrations during coronary spasm.

A provocation test using methylergometrine was carried out in patients with a normal coronary angiogram. Patients exhibiting spasm (Group 1, n = 6) were compared with non-spasm patients (Group II, n = 6). The endothelin concentration was determined in all cases at 0800, 1100, 1400, 1600, 1900, 2100, 2300 and 0100 h. The provocation test was carried out at 1700 h and an additional determination was made during spasm if the test was positive. The two groups had similar clinical characteristics and did not differ in terms of risk factors. Apart from the value recorded during spasm, the endothelin plasma level was significantly higher in Group I. A time x measurement interaction was noted in both groups, with a higher endothelin level in the morning. The endothelin level increased significantly during spasm in Group I patients. The plasma concentration of endothelin appeared to be higher in the basal state and during spasm in patients exhibiting spastic angina.

Adult↗
PubMed1993

Glomerular atrial natriuretic factor receptors in experimental congestive heart failure.

Heart failure is usually characterized by a relative insensitivity to atrial natriuretic factor (ANF). Downregulation of ANF receptors has been reported but remains controversial. Renal response to ANF infusion, glomerular ANF receptors, and guanosine 3',5'-cyclic monophosphate (cGMP) production have been studied in rabbits with congestive heart failure (CHF) after traumatic aortic regurgitation and abdominal aortic stenosis. Diuresis and natriuresis induced by ANF infusions were significantly decreased in CHF animals. Plasma cGMP was higher in CHF rabbits before ANF administration than in controls (37.6 +/- 7.2 vs. 17.1 +/- 3.9 pmol/ml, P < 0.02) and increased to a same level after ANF in both groups (48.8 +/- 4.2 vs. 52.5 +/- 2.8 pmol/ml, NS). No difference was found in glomerular ANF receptor density (436 +/- 54 vs. 425 +/- 57 fmol/mg protein, NS) nor in affinity between the two groups (dissociation constant; 240 +/- 24 vs. 347 +/- 49 pM, NS). Moreover, in vitro glomerular cGMP production in response to exogenous ANF was preserved. In conclusion, despite a blunted renal response to ANF in vivo, glomerular ANF receptors were unchanged in this model, and no defect in cGMP production in response to ANF was found. This suggests the existence of an intracellular defect beyond the second messenger.

Animals↗
PubMed1993

Familial hypertrophic cardiomyopathy. Microsatellite haplotyping and identification of a hot spot for mutations in the beta-myosin heavy chain gene.

Familial hypertrophic cardiomyopathy (FHC) is a clinically and genetically heterogeneous disease. The first identified disease gene, located on chromosome 14q11-q12, encodes the beta-myosin heavy chain. We have performed linkage analysis of two French FHC pedigrees, 720 and 730, with two microsatellite markers located in the beta-myosin heavy chain gene (MYO I and MYO II) and with four highly informative markers, recently mapped to chromosome 14q11-q12. Significant linkage was found with MYO I and MYO II in pedigree 720, but results were not conclusive for pedigree 730. Haplotype analysis of the six markers allowed identification of affected individuals and of some unaffected subjects carrying the disease gene. Two novel missense mutations were identified in exon 13 by direct sequencing, 403Arg-->Leu and 403Arg-->Trp in families 720 and 730, respectively. The 403Arg-->Leu mutation was associated with incomplete penetrance, a high incidence of sudden deaths and severe cardiac events, whereas the consequences of the 403Arg-->Trp mutation appeared less severe. Haplotyping of polymorphic markers in close linkage to the beta-myosin heavy chain gene can, thus, provide rapid analysis of non informative pedigrees and rapid detection of carrier status. Our results also indicate that codon 403 of the beta-myosin heavy chain gene is a hot spot for mutations causing FHC.

Adolescent↗
PubMed1993

[French familial multicenter survey of hypertrophic cardiomyopathy. Initial Doppler echocardiographic results].

A French multicentre study of hypertrophic cardiomyopathy has recruited 260 subjects belonging to 18 families. At least 3 persons from each family included had a hypertrophic cardiomyopathy. A Doppler echocardiographic examination was performed in all members of these 18 families. The diagnosis of hypertrophic cardiomyopathy was based on M mode and/or 2D observations of parietal hypertrophy: wall thickness over 13 mm. Asymmetrical forms were distinguished from symmetrical forms by a septum/posterior wall ratio of over 1.3 in M mode or 2D study. The patients had an average age of 40 +/- 18 years, 127 were men and 133 women. One hundred and sixty eight were considered to be normal, 87 had hypertrophic cardiomyopathy and 5 were border line. The maximal diastolic wall thickness on M mode recording of pathological cases was 19.2 +/- 4.8 mm compared with 9.5 +/- 1.9 mm in healthy subjects (p < 0.001). The septum/posterior wall ratio was 1.8 +/- 0.62 in pathological cases and 1.1 +/- 0.8 in normal ones (p < 0.001). Eighty five per cent of the cardiomyopathic cases were asymmetrical (74/87) and only 15% were considered to be symmetrical (13/87) on M mode study whereas 5% were concentric on 2D echocardiography. By Maron's classification, type I hypertrophy was observed in 6% of cases (4/64), type II in 30% (19/64), type III in 58% (37/64), and type IV in 6% (4/64). Signs of obstruction were looked for and systolic anterior motion of the mitral valve was observed in 52% of pathological cases (45/86) and mid-systolic aortic valve closure in 30% (25/83).(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiomyopathy, Hypertrophic↗
PubMed1993

Exclusion of genes coding for proteins of the cytoskeleton and the extracellular matrix in familial hypertrophic cardiomyopathy using a candidate gene approach.

Familial hypertrophic cardiomyopathy (FHC), a primary cardiac pathology, is a genetically heterogeneous disease, with autosomal dominant inheritance. The first gene identified as responsible for FHC codes for beta-myosin heavy chain (beta-MHC). To find a second locus, a candidate gene approach was applied on two families for which the beta-MHC locus was excluded. Selection of candidate genes is based on the observation of tissular and cellular disorganisation in FHC, and included genes coding for proteins involved in human myocardium architecture: the extracellular matrix components and cytoskeleton proteins. Chromosomal areas containing the candidate genes were examined by linkage analysis with microsatellite markers. The genes coding for different types of collagens, laminins, fibronectin, fibrillins, desmin, titin, alpha-actinin, vinculin, cardiac and skeletal alpha-actins, ankyrin and spectrin were excluded as responsible for FHC.

Cardiomyopathy, Hypertrophic↗
PubMed1992

[Converting enzyme inhibitors and aims of the objectives of the treatment of cardiac failure].

Angiotensin-converting enzyme (ACE) inhibitors were introduced in the treatment of heart failure in 1982. They improve the life comfort of the patients and their capacity for exercise in both moderate and severe heart failure. In moderate heart failure, their effectiveness on exercise performance is about the same as that of digitalis compounds and classical vasodilators, and superior to that of diuretics. The superiority of ACE inhibitors lies in that they improve the prognosis of heart failure, as has been demonstrated in the severe and moderate forms of the disease and, quite recently, in asymptomatic left ventricular dysfunction following myocardial infarction. Their beneficial effects on mortality undoubtedly result from their favourable action on the neurohormonal systems which are activated early in the course of heart failure. Extending the indications of these drugs to asymptomatic patients raises questions concerning optimal dosage, date of initiation and duration of treatment and possible class effect.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1992

[Atrial natriuretic factor in heart insufficiency].

The atrial natriuretic factor is a peptide with vasodilator and natriuretic properties which is synthesized and released by atrial myocytes. In patients with chronic heart failure the ventricles contribute to the synthesis of this peptide, so that its plasma concentration rises in proportion to the heart filling pressure. The atrial natriuretic factor, therefore, seems to be a good biological marker of functional and haemodynamic severity of heart failure. However, the weight of this factor in the neuro-hormonal balance has not yet been fully evaluated, owing to the usual attenuation of its biological effects. This, and the necessity of continuous parenteral administration limits, for the moment, its therapeutic applications. Inhibitors of the enzyme involved in its metabolism are being tested, but only preliminary results are available in humans.

Atrial Natriuretic Factor↗
PubMed1992

Detection of enteroviruses in endomyocardial biopsy by molecular approach.

Enteroviruses are considered to be the most common agents implicated in myocarditis and cardiomyopathy. Recent studies have suggested persistent enterovirus infection in chronic disease showing the presence of enteroviral RNA in the myocardium. We used gene amplification by PCR which can demonstrate directly the presence of enteroviral sequences in endomyocardial biopsies. The primers were chosen in the 5' non-coding region of the genome representing highly conserved sequences among enteroviruses and therefore allowed the amplification of the majority of enteroviruses. The hybridization of the amplified products was effected with specific general riboprobe derived from 5' non-coding sequences internal of the amplified fragments. The results include 105 patients distributed in 6 groups: 45 idiopathic dilated cardiomyopathies with 66.7%, 17 alcoholic cardiomyopathies with 52.9%, 10 myocarditis with 30%, 5 multifactorial cardiomyopathies with 40%, 5 patients with immunosuppressive therapy with 100%, and 23 control group without viral etiology with 39.1% positive samples. The study suggested a positive link between viral infection and cardiomyopathies, but did not allow a direct relation between enterovirus infection and idiopathic dilated cardiomyopathy to be established.

Adolescent↗