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Biomedical subjects

M Komajda

Publications and source records attributed to M Komajda.

At least 91 records · Page 5Linked to original sources
PubMed1997

Hemodynamic and neurohormonal effects of flosequinan in patients with heart failure.

In a double-blind, placebo-controlled study, the central and peripheral hemodynamic effects of 100 mg oral flosequinan and the impact of this drug on neurohormonal activation were noninvasively evaluated in 18 patients with congestive heart failure, after the first administration and after 10 days of treatment. No significant hemodynamic and neurohormonal changes were observed after acute administration. After 10 days, flosequinan produced central and peripheral hemodynamic improvement characterized by an increase in left ventricular circumferential fiber shortening velocity (+12%), a decrease in total systemic resistance (-36%), and an increase in leg blood flow (+37%). No significant changes were observed in heart rate and arterial pressure in patients receiving flosequinan, though a slight increase in heart rate (+17%) was recorded. Despite these favorable hemodynamic effects, flosequinan significantly increased plasma norepinephrine (+38%) and plasma renin activity (+13%) after 10 days of treatment. Thus, the beneficial central and peripheral hemodynamic effects of flosequinan are accompanied by activation of the sympathetic and reninangiotensin systems. This might be related to the unfavorable effects of the drug on survival in patients with heart failure.

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↗
PubMed1997

Organization and sequence of human cardiac myosin binding protein C gene (MYBPC3) and identification of mutations predicted to produce truncated proteins in familial hypertrophic cardiomyopathy.

Cardiac myosin binding protein C (MyBP-C) is a sarcomeric protein belonging to the intracellular immunoglobulin superfamily. Its function is uncertain, but for a decade evidence has existed for both structural and regulatory roles. The gene encoding cardiac MyBP-C (MYBPC3) in humans is located on chromosome 11p11.2, and mutations have been identified in this gene in unrelated families with familial hypertrophic cardiomyopathy (FHC). Detailed characterization of the MYBPC3 gene is essential for studies on gene regulation, analysis of the role of MyBP-C in cardiac contraction through the use of recombinant DNA technology, and mutational analyses of FHC. The organization of human MYBPC3 and screening for mutations in a panel of French families with FHC were established using polymerase chain reaction, single-strand conformation polymorphism, and sequencing. The MYBPC3 gene comprises > 21,000 base pairs and contains 35 exons. Two exons are unusually small in size, 3 bp each. We found six new mutations associated with FHC in seven unrelated French families. Four of these mutations are predicted to produce truncated cardiac MyBP-C polypeptides. The two others should each produce two aberrant proteins, one truncated and one mutated. The present study provides the first organization and sequence for an MyBP-C gene. The mutations reported here and previously in MYBPC3 result in aberrant transcripts that are predicted to encode significantly truncated cardiac MyBP-C polypeptides. This spectrum of mutations differs from the ones previously observed in other disease genes causing FHC. Our data strengthen the functional importance of MyBP-C in the regulation of cardiac work and provide the basis for further studies.

Base Sequence↗
PubMed1997

Penetrance of familial hypertrophic cardiomyopathy.

Familial hypertrophic cardiomyopathy (FHC) is an autosomal dominant cardiac disease for which the penetrance remains a much-debated issue. Since the recent identification of the genes involved in the disease, the penetrance of FHC has not been reassessed in a large genotyped population. The aim of our study was therefore to evaluate it, according to age and sex, in ten families with previously identified mutations. Among 178 individuals we studied, 90 were genetically affected (9 different mutations in 3 genes). We found that penetrance, assessed by classical echocardiographic and electrocardiographic criteria, was (1) incomplete: 69%; (2) age-related: 55% between 10 and 29 years old, 75% between 30 and 49 y. and 95% over 50 y.; (3) greater in males than in females: 77% vs 58%, age-adjusted odds ratio: 3.98, CI 95%: 1.34 to 11,48; (4) similar for the genes analyzed. The consequences of these results for genetic counseling and linkage analyses are discussed.

Adolescent↗
PubMed1996

Codon 102 of the cardiac troponin T gene is a putative hot spot for mutations in familial hypertrophic cardiomyopathy.

BACKGROUND: Familial hypertrophic cardiomyopathy is a phenotypically and genetically heterogeneous disease. In some families, the disease is linked to the CMH2 locus on chromosome 1q3, in which the cardiac troponin T gene (TNNT2) has been identified as the disease gene. The mutations found in this gene appear to be associated with incomplete penetrance and poor prognosis. Because mutational hot spots offer unique possibilities for analysis of genotype-phenotype correlations, new missense mutations that could define such hot spots in TNNT2 were looked for in unrelated French families with familial hypertrophic cardiomyopathy. METHODS AND RESULTS: Family members were genotyped with microsatellite markers to detect linkage to the four known disease loci. In family 715, analyses showed linkage to CMH2 only. To accurately position potential mutations on TNNT2, its partial genomic organization was established. Screening for mutations was performed by single-strand conformation polymorphism analysis and sequencing. A new missense mutation, Arg102Leu, was identified in affected members of family 715 because of a G-->T transversion located in the 10th exon of the gene. Penetrance of this new mutation is complete; echocardiographic data show a wide range of hypertrophy; and there was no sudden cardiac death in this family. CONCLUSIONS: The codon 102 of the TNNT2 gene is a putative mutational hot spot in familial hypertrophic cardiomyopathy and is associated with phenotypic variability. Analysis of more pedigrees carrying mutations in this codon is necessary to better characterize the clinical and prognostic implications of TNNT2 mutations.

Adult↗
PubMed1996

[Current treatments of congestive heart failure].

Mortality in patients with congestive heart failure has been assessed in several large scale multicentric studies, confirming the therapeutic effect of certain treatments and raising questions as to the efficacy of other, sometimes new propositions. Conversion enzyme inhibitors are currently considered to be the first line treatment for heart failure because of their beneficial effect on mortality figures and their capacity to prevent aggravation. These drugs should always be prescribed for patients without contraindications, together with diuretics when signs of congestion develop, and digitalis in case of non-response, then finally nitroglycerin. Debate is still open on the effect of beta-blockers and amiodarone which should be reserved for use by specialists since it has not been definitely proven that they can lengthen survival time. Certain other drugs have given disappointing results compared with early expectations: direct vasodilators, positive inotrops (with the possible exception of vesnarinone), and class Ic antiarrhythmics. Finally several drugs in the development or research stage may prove to be effective in improving heart function, intermediary criteria and, most importantly, survival.

Adrenergic beta-Antagonists↗
PubMed1996

Parasympathetic activity in Friedrich's ataxia.

We compared 19 patients with Friedreich's ataxia, a progressive hereditary neuromuscular disorder, with 19 healthy age-matched subjects. During nighttime, patients had shorter mean RR and decreased heart rate variability parameters related to parasympathetic activity than healthy subjects, whereas no difference occurred during daytime.

Adult↗
PubMed1996

Captopril does not acutely modulate plasma endothelin-1 concentration in human congestive heart failure.

Congestive heart failure (CHF) is a syndrome characterized by increased levels of angiotensin II (Ang II) and endothelin-1 (ET-1). In vitro, Ang II stimulates ET-1 release. The purpose of the study was to assess the effect of a single dose of an angiotensin-converting enzyme inhibitor (ACEI) captopril versus placebo on plasma endothelin concentration in human congestive heart failure. Captopril (25 mg, given orally) was compared with placebo in a group of 20 patients with systolic dysfunction in a double-blind randomized study. Plasma irET concentration was significantly increased in CHF patients compared with normal subjects (5.59 pg/ml +/- 0.35 vs. 3.58 pg/ml +/- 0.99, p < 0.0002). Despite the decrease in systolic blood pressure and the increase in plasma renin activity, suggesting a significant blockade of the renin-angiotensin system, no difference in plasma irET-1 was observed between captopril and placebo. Our results suggest that captopril does not acutely influence irET-1 plasma concentration in human CHF. These data do not support the hypothesis that the acute vasodilator effect of a single dose of 25 mg of captopril given daily orally involves modulation of the increased plasma concentration of endothelin observed in CHF.

Adult↗
PubMed1996

Muscular blood flow response to submaximal leg exercise in normal subjects and in patients with heart failure.

Blood flow to working skeletal muscle is usually reduced during exercise in patients with congestive heart failure. An intrinsic impairment of skeletal muscle vasodilatory capacity has been suspected as a mechanism of this muscle underperfusion during maximal exercise, but its role during submaximal exercise remains unclear. Therefore, we studied by transcutaneous Doppler ultrasonography the arterial blood flow in the common femoral artery at rest and during a submaximal bicycle exercise in 12 normal subjects and in 30 patients with heart failure. Leg blood flow was lower in patients than in control subjects at rest [0.29 +/- 0.14 (SD) vs. 0.45 +/- 0.14 l/min, P < 0.01], at absolute powers and at the same relative power (2.17 +/- 1.06 vs. 4.39 +/- 1.4 l/min, P < 0.001). Because mean arterial pressure was maintained, leg vascular resistance was higher in patients than in control subjects at rest (407 +/- 187 vs. 247 +/- 71 mmHg.l-1.min, P < 0.01) and at the same relative power (73 +/- 49 vs. 31 +/- 13 mmHg.l-1.min, P < 0.01) but not at absolute powers. Although the magnitude of increase in leg blood flow corrected for power was similar in both groups (31 +/- 10 vs. 34 +/- 10 ml.min-1.W-1), the magnitude of decrease of leg vascular resistance corrected for power was higher in patients than in control subjects (5.9 +/- 3.3 vs. 1.9 +/- 0.94 mmHg.l-1.min.W-1, P < 0.001). These results suggest that the ability of skeletal muscle vascular resistance to decrease is not impaired and that intrinsic vascular abnormalities do not limit vasodilator response to submaximal exercise in patients with heart failure.

Adult↗
PubMed1996

Plasma levels and molecular forms of proatrial natriuretic peptides in healthy subjects and in patients with congestive heart failure.

A specific and sensitive radioimmunoassay (RIA) for the N-terminal fragment of proatrial natriuretic peptide (NproANP) was developed. Antiserum raised in rabbits against a mixture enriched with prohormone was 100% cross-reactive with human proANP(1-30). Plasma concentrations of proANP(1-30) and ANP immunoreactivities (ir-) were simultaneously measured in healthy subjects and patients with congestive heart failure (CHF; 26 dilated cardiomyopathy and 5 ischemic heart disease). High plasma levels of both ir-proANP(1-30) and ir-ANP were detected in CHF patients. Circulating ir-ANP levels were elevated in New York Heart Association functional Classes II and III patients but not in Class I patients. However, plasma levels of ir-proANP(1-30) were higher in asymptomatic patients than in healthy subjects, and markedly increased in patients of Classes II and III. Analysis of ir-proANP(1-30) by gel filtration chromatography or reverse-phase high pressure liquid chromatography revealed a 10 kDa peptide circulating as a distinct entity. These findings indicate that: (i) the most probable form of NproANP in human plasma is a 10 kDa peptide and (ii) in CHF patients the rise in plasma ir-proANP(1-30) levels is more pronounced than the variation in plasma ir-ANP. Thus, NproANP plasma levels may prove to be a more sensitive marker of left ventricular dysfunction than ANP.

Adult↗
PubMed1996

[Genetics of hypertrophic cardiomyopathies: what are the clinical perspectives?].

Considerable progress has been accomplished in the understanding of the genetics of familial hypertrophic cardiomyopathy over the last five years. This is a monogenic autosomal dominant condition with much inter- and intragenic variability. Four morbid genes coding for the contractile proteins have been identified: the heavy beta chain of cardiac myosin (14q11), cardiac troponin T (1q3), alpha tropomyosin (15q2), and myosin binding cardiac C protein (11p13-q-13). In addition, other genetic localisations not yet identified are certain. Moreover, many mutations have been reported in the already identified genes. The principal clinical perspectives ot this research lie in the analysis of the relationships between phenotype (clinical expression) and genotype with respect to prognosis, the severity and morphology of the hypertrophic process, the reevaluation of our diagnostic criteria and the long-term follow-up of the many healthy carriers in the identified families. The genetic heterogeneity of the disease is a limiting factor in genetic counselling and there are ethical problems related to the absence of effective treatment.

Cardiomyopathy, Hypertrophic↗
PubMed1996

[Epidemiology of cardiac failure and current prognosis of the most seriously ill patients].

The lack of consensus concerning the diagnostic criteria of cardiac failure explains the relative paucity of epidermiological data. Most of the available information comes from American health registers and the Framingham study: in the United States, there are more than 3 million people with cardiac failure (over 1% of the population) and over 400,000 new patients each year. Cardiac failure is the main cause of death in 40,000 deaths and an associated cause in a further 250,000 deaths. In the Framingham study (1948-1988) the mean survival time after diagnosis is 1.7 year in men and 3.2 years in women, corresponding to 1 and 5 year survival rates of 57% and 25% in men and 64% and 38% in women. These figures are worse than those of the large scale therapeutic trials of the last 10 years and represent survival of the most severe cases. Although not strictly epidemiological data, analysis of the large scale trials allows evaluation of the clinical features and survival of patients under optimal medical treatment (ACE inhibitors associated with other treatments): these results are important to bear in mind when considering alternative therapies (transplantation, mechanical assist devices), the accessibility of which may be limited for reasons of availability or cost. In terms of public health, it is important that accurate epidemiological data concerning cardiac failure. In particular severe cardiac failure, is made available in France.

Adolescent↗
PubMed1995

Cardiac myosin binding protein-C gene splice acceptor site mutation is associated with familial hypertrophic cardiomyopathy.

Familial hypertrophic cardiomyopathy (FHC) is an autosomal dominant disease characterized by a ventricular hypertrophy predominantly affecting the interventricular septum and associated with a large extent of myocardial and myofibrillar disarray. It is the most common cause of sudden death in the young. In the four disease loci found, three genes have been identified which code for beta-myosin heavy chain, cardiac troponin T and alpha-tropomyosin. Recently the human cardiac myosin binding protein-C (MyBP-C) gene was mapped to chromosome 11p11.2 (ref. 8), making this gene a good candidate for the fourth locus, CMH4 (ref. 5). Indeed, MyBP-C is a substantial component of the myofibrils that interacts with several proteins of the thick filament of the sarcomere. In two unrelated French families linked to CMH4, we found a mutation in a splice acceptor site of the MyBP-C gene, which causes the skipping of the associated exon and could produce truncated cardiac MyBP-Cs. Mutations in the cardiac MyBP-C gene likely cause chromosome 11-linked hypertrophic cardiomyopathy, further supporting the hypothesis that hypertrophic cardiomyopathy results from mutations in genes encoding contractile proteins.

Amino Acid Sequence↗