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Biomedical subjects

P Coumel

Publications and source records attributed to P Coumel.

At least 55 records · Page 3Linked to original sources
PubMed1997

KVLQT1 C-terminal missense mutation causes a forme fruste long-QT syndrome.

BACKGROUND: KVLQT1, the gene encoding the alpha-subunit of a cardiac potassium channel, is the most common cause of the dominant form of long-QT syndrome (LQT1-type), the Romano-Ward syndrome (RWS). The overall phenotype of RWS is characterized by a prolonged QT interval on the ECG and cardiac ventricular arrhythmias leading to recurrent syncopes and sudden death. However, there is considerable variability in the clinical presentation, and potential severity is often difficult to evaluate. To analyze the relationship between phenotypes and underlying defects in KVLQT1, we investigated mutations in this gene in 20 RWS families originating from France. METHODS AND RESULTS: By PCR-SSCP analysis, 16 missense mutations were identified in KVLQT1, 11 of them being novel. Fifteen mutations, localized in the transmembrane domains S2-S3, S4-S5, P, and S6, were associated with a high percentage of symptomatic carriers (55 of 95, or 58%) and sudden deaths (23 of 95, or 24%). In contrast, a missense mutation, Arg555Cys, identified in the C-terminal domain in 3 families, was associated with a significantly less pronounced QT prolongation (459+/-33 ms, n=41, versus 480+/-32 ms, n=70, P=.0012), and significantly lower percentages of symptomatic carriers (7 of 44, or 16%, P<.001) and sudden deaths (2 of 44, or 5%, P<.01). Most of the cardiac events occurring in these 3 families were triggered by drugs known to affect ventricular repolarization. CONCLUSIONS: Our data show a wide KVLQT1 allelic heterogeneity among 20 families in which KVLQT1 causes RWS. We describe the first missense mutation in the C-terminal domain of KVLQT1, which is clearly associated with a fruste phenotype, which could be a favoring factor of acquired LQT syndrome.

Adult↗
PubMed1997

Direct-current cardioversion of atrial tachyarrhythmias under oral flecainide therapy.

Results of direct-current cardioversion of 48 patients with atrial arrhythmia taking oral flecainide were compared with those of 96 control-matched patients. After completion of 3 shocks, 98% of flecainide patients were converted versus 78% of control patients (p <0.01). Thus, despite an experimental increase in defibrillation threshold, flecainide given before cardioversion seems to have a beneficial effect.

Administration, Oral↗
PubMed1997

Time- and rate-dependent alterations of the QT interval precede the onset of torsade de pointes in patients with acquired QT prolongation.

OBJECTIVES: The purpose of this study was to determine whether the QT interval dynamics that precede torsade de pointes are consistent with the initiation of this arrhythmia by early afterdepolarization-induced triggered activity. BACKGROUND: Early afterdepolarization-induced triggered activity has been suggested as an electrophysiologic mechanism for torsade de pointes. Consequently, the initiation of torsade de pointes should involve time- and rate-dependent alterations of ventricular repolarization similar to those known to modulate the development of early afterdepolarizations. METHODS: RR and QT intervals were measured in digitized 24-h ambulatory electrocardiographic recordings obtained from seven patients with acquired prolongation of ventricular repolarization. Each patient had one or more episodes of torsade de pointes. The relation between RR and QT intervals was determined before, during and after multiple episodes of torsade de pointes. RESULTS: In patients with multiple episodes of ventricular arrhythmias, the onset of the arrhythmias was associated with a critical prolongation of the QT interval. In some episodes, prolongation of the QT interval was associated with sudden prolongation of the sinus cycle length, whereas in other episodes, the QT interval prolonged progressively at a constant cycle length. CONCLUSIONS: The association between a critically prolonged QT interval and the onset of ventricular arrhythmias suggests that the initial complex of torsade de pointes is an early afterdepolarization-induced triggered response. However, prolongation of the QT interval itself was not sufficient to account for the initiation of torsade de pointes, suggesting that other, as yet unidentified factors are required.

Aged↗
PubMed1997

A novel mutation in the potassium channel gene KVLQT1 causes the Jervell and Lange-Nielsen cardioauditory syndrome.

The Jervell and Lange-Nielsen (JLN) syndrome (MIM 220400) is an inherited autosomal recessive disease characterized by a congenital bilateral deafness associated with a QT prolongation on the electrocardiogram, syncopal attacks due to ventricular arrhythmias and a high risk of sudden death. JLN syndrome is a rare disease, which seems to affect less than one percent of all deaf children. Linkage to chromosome 11p15.5 markers was found by analysing four consanguinous families. Recombinants allowed us to map the JLN gene between D11S922 and D11S4146, to a 6-cM interval where KVLQT1, a potassium channel gene causing Romano-Ward (RW) syndrome, the dominant form of long QT syndrome, has been previously localized. An homozygous deletion-insertion event (1244, -7 +8) in the C-terminal domain of this gene was detected in three affected children of two families. We found that KVLQT1 is expressed in the stria vascularis of mouse inner ear by in situ hybridization. Taken together, our data indicate that KVLQT1 is responsible for both JLN and RW syndromes and has a key role not only in the ventricular repolarization but also in normal hearing, probably via the control of endolymph homeostasis.

Adult↗
PubMed1997

Polymorphous ventricular tachyarrhythmias in the absence of structural heart disease.

Polymorphous ventricular tachyarrhythmias (PVTA) in the absence of structural heart disease form a particularly important target for comprehensive research. They occur in young, healthy children and young adults and most probably cover several underlying electrophysiological abnormalities. We individualized two syndromes, namely catecholaminergic ventricular tachyarrhythmias, and torsade de pointes (TDP) with a short coupling interval, but these two entities certainly represent only a part of the problem of idiopathic ventricular fibrillation. Having the implanted defibrillator as a therapeutic umbrella for those patients who were fortunate enough to escape from sudden death is not sufficient. Too often in modern cardiology the therapeutic achievements tend to precede the process of diagnosis and comprehension. At least, the former should not preclude the latter, a situation that can be observed, for instance, when the favorable effect of a drug is evidenced before its mode of action was understood. At best, both progress together, provided we pay attention to adequately exploit the resources of modern technology.

Adrenergic Fibers↗
PubMed1997

Changes in repolarization dynamicity and the assessment of the arrhythmic risk.

At the present time, the assessment of the arrhythmic risk from surface ECG recordings is built on time-domain and frequent-domain analysis of high resolution ECG acquisition together with interlead variability of QT interval duration (QT dispersion). The corresponding raw ECG tracings are obtained in resting conditions. However, the dynamic aspects of the ECG signal is a rapidly evolving matter of interest. In addition to the beat-to-beat oscillations of the ventricular repolarization amplitude (QT alternans), there is growing evidence that the patterns of QT interval shortening with increasing heart rate are linked to susceptibility to ventricular arrhythmias. In this report, we will mainly address the association between QT dynamicity and the risk of developing torsades de pointes.

Anti-Arrhythmia Agents↗
PubMed1997

[Pharmacological treatment of atrial fibrillation].

Atrial fibrillation is not a single entity. Many factors play a role in its genesis, its maintenance and termination. The presence of underlying cardiac disease and left ventricular dysfunction is a major factor due to the electrophysiological and haemodynamic consequences, the effect on autonomic nervous system and on the effect of antiarrhythmic drugs themselves. It is therefore essential to take this into account before deciding on a therapeutic approach. This also emphasises the difficulty of interpreting clinical trials comparing pharmacological treatments when the study population is poorly defined. In general, one molecule is not more or less effective than another, it is more or less adapted to the patient under treatment.

Adrenergic beta-Antagonists↗
PubMed1997

[Sustained ventricular tachycardia in older children. Spontaneous regression in 3 cases].

Extensively described since Gallvardin's reports, the electrical features of salves of ventricular tachycardia in an apparently healthy heart are now well known. The usual benign nature of this arrhythmia is acknowledged, seldom contradicted by isolated clinical cases. Although chronicity is the rule in young adults, there have been a few publications concerning the natural history of these tachycardias in the paediatric age group. The authors report three cases of episodic sustained ventricular tachycardia in older children, presenting at an average of 7 years of age (range 5 to 9 years) and followed up for an average of 7 years (range: 5.5 to 9 years). These three children were treated for an average of 4.5 years (range: 3 to 5.5 years). All treatment was finally withdrawn when stable permanent sinus rhythm without ventricular extrasystoles was restored and confirmed over an average period of 2 years (range 10 months to 3.5 years), an average of 4 (range 3 to 7) successive normal Holter recordings at several months' interval. The outcome in children to spontaneous regression after several years would seem to make radiofrequency ablation more dangerous than useful given the benign nature of the arrhythmia and its good response to pharmacological intervention.

Adult↗
PubMed1997

[Analysis of frequency-dependence of ventricular repolarisation by the Holter method in young adults. Influence of the autonomic nervous system on the rate-dependence of QT].

UNLABELLED: Adaptation of ventricular repolarization duration to heart rate provides additional information to the static duration of QT interval. METHODS: QT/RR relation and his slope were determined using 24-hour ECG recordings from 17 young male normal volunteers (mean age: 22 +/- 3 years). In order to determine the influence of the autonomic nervous system on the rate-dependence of QT, the authors compared the slopes obtained from recordings during the day and the night. Then, the respective rate-dependences of the entire QT interval (QTe) and its initial subdivision (QTa) and their correlations with parameters of heart rate variability were studied. RESULTS: the QTa/RR and QTe/RR relations were constantly linear, with very significant regression coefficients. The daytime QTa/RR and QTe/RR slopes were significantly steeper than the nighttime ones (0.138 +/- 0.035 vs 0.108 +/- 0.040, p < 0.05 for QTe/RR, 0.160 +/- 0.069 vs 0. 108 +/- 0.055, p < 0.01 for QTa/RR). The early part of QT showed a stronger rate-dependence than the global QT, but only at daytime (0.160 +/- 0.069 vs 0.138 +/- 0.035, p < 0.05). No correlation was found between rate dependences and heart rate variability parameters. CONCLUSION: the authors demonstrate, from ambulatory ECG recordings, the influence of the autonomic nervous system on the rate-dependence of ventricular repolarization in normal young adults, and a difference in rate-dependence between the entire QT interval and its initial part QTa, due to differences in autonomic nervous system tone. This heterogeneity should be taken to account in the study of pathological changes or drugs effects on ventricular repolarization.

Adolescent↗
PubMed1996

Drug therapy for prevention of atrial fibrillation.

Atrial fibrillation is not a homogeneous entity, and many factors are responsible for a number of different behaviors, clinical consequences, and reactions to therapy. Therefore, the conventional evaluation of preventive treatments is not really adapted to provide the correct answers to difficult problems of therapeutic indications, as the 2 components of the benefit-risk ratio are not really known. Like ventricular fibrillation, atrial fibrillation may be primary or secondary to organized tachyarrhythmias, and reentrant flutter or automatic atrial tachycardia may well form the actual target for treatment. The automatic nervous system is never absent as a determinant of the onset of arrhythmia, and the vagal as well as the sympathetic action may predominate and explain why a treatment may or may not be effective in situations that are identical only in appearance. The electrophysiologic milieu formed by the atrial tissue probably accounts for the perpetuation of the process of atrial fibrillation or its self-termination, and drugs themselves may contribute to modify the milieu in a way that in the end may be favorable or not. Finally, the presence or the absence of heart disease and heart failure largely contributes to the state of the vagosympathetic balance, to the hemodynamic consequences of atrial fibrillation, and ultimately to the proper toxic effects of drugs. The overall consequence of these complex situations is that any precise therapeutic decision algorithm for atrial fibrillation is always simplistic and that any global evaluation of drug efficacy or toxicity is not really meaningful as long as the category of patients treated is not precisely determined: no drug appears better or worse than others, but simply more or less adapted to various situations.

Anti-Arrhythmia Agents↗
PubMed1996

Prospective comparison of flecainide versus quinidine for the treatment of paroxysmal atrial fibrillation/flutter. The Flecainide Multicenter Atrial Fibrillation Study Group.

In order to compare the efficacy and long-term tolerability of flecainide acetate versus quinidine, 239 patients with paroxysmal atrial fibrillation were prospectively treated with flecainide (n = 122) or quinidine (n = 117) in an open-label, randomized trial. All patients were followed for 1 year after initiation of therapy unless their antiarrhythmic drug was discontinued due to an inadequate therapeutic response or intolerable side effects. Although both drugs were equally effective in adequately controlling recurrences of atrial fibrillation (difference, p = 0.282; not significant), fewer flecainide patients had to have their therapy discontinued due to adverse experiences (p = 0.012). Based on both endpoints (efficacy and tolerability), an estimated 70.5% of flecainide versus 55.4% of quinidine patients would remain effectively treated at the end of 1 year on therapy (p < or = 0.007). The findings of this prospective study suggest that in the treatment of paroxysmal atrial fibrillation (1) flecainide and quinidine are equally effective in the acceptable suppression of symptomatic paroxysmal atrial fibrillation; (2) flecainide is better tolerated than quinidine and is less likely to be discontinued due to adverse effects; and (3) given the overall endpoint of efficacy and tolerability, more patients are likely to continue long-term therapy with flecainide than with quinidine.

Administration, Oral↗
PubMed1996

A randomized comparison of flecainide versus verapamil in paroxysmal supraventricular tachycardia. The Flecainide Multicenter Investigators Group.

Reentrant paroxysmal supraventricular tachycardia (PSVT) are frequently encountered in clinical practice. Verapamil and flecainide have both been successfully used as chronic oral therapy to prevent PSVT recurrences. This open-label, randomized, multicenter study was designed to compare the efficacy and adverse effects of verapamil (median dose, 240 mg/day) versus flecainide (median dose, 200 mg/day) in patients with frequent and symptomatic attacks of PSVT (other than atrial fibrillation or flutter). A total of 121 patients receiving flecainide (n = 63) or verapamil (n = 58) were followed for 8.1 +/- 5.1 and 7.5 +/- 5.4 months, respectively. Response was judged clinically as effective or not by the treating physician. By life table analysis, 11% discontinued flecainide and 19% discontinued verapamil for inefficacy at 1 year (difference not significant). Both groups showed a marked reduction in the frequency of attacks of PSVT. Before therapy, 71% of flecainide patients and 73% of verapamil patients had > or = 2 attacks per month. During therapy, 86% of all flecainide patient-months and 73% of all verapamil patient-months occurred with 0 or 1 attack; 19 (30%) patients on flecainide completed the trial ( > 270 days) without symptomatic attacks versus 7 (13%) of the patients on verapamil (p = 0.026). Both drugs were well tolerated; 19% of the flecainide group discontinued primarily because of adverse effects, compared with 24% discontinuing verapamil for this reason (difference not significant). Both flecainide and verapamil are effective and well tolerated for the prevention of recurrences of PSVT. For patients in whom radiofrequency ablation procedures cannot be performed or are not indicated, either therapy is a reasonable choice for long-term prophylaxis.

Administration, Oral↗
PubMed1996

Electrophysiological effects of catheter ablation of inferior vena cava-tricuspid annulus isthmus in common atrial flutter.

BACKGROUND: The electrophysiological mechanisms for successful catheter ablation of atrial flutter (AFI) targeting the inferior vena cava-tricuspid annulus (IVC-TA) isthmus have not been determined. METHODS AND RESULTS: Twenty patients with common AFI were studied. All had inducible common AFI, and 8 of them had both common and reverse AFI. Right atrial (RA) activation sequences were investigated during pacing from sites proximal (low lateral RA) and distal (proximal coronary sinus) to the IVC-TA isthmus both during entrainment of common or reverse AFI and during pacing in sinus rhythm. This was repeated after ablation. During pacing in sinus rhythm from the low lateral RA, the septum was activated by caudocranial and craniocaudal wave fronts. Similarly, during pacing from the proximal coronary sinus, the lateral RA was activated by two wave fronts. Catheter ablation of the IVC-TA isthmus induced dramatic changes in mapping due to the loss of caudocranial wave front in all but 1 patient. The septum and the lateral RA were activated by a single craniocaudal front as during entrainment of reverse or common AFI, respectively. After a follow-up of 8 +/- 2 months, common or reverse AFI occurred in 4 patients. Two had no or only unidirectional changes in the isthmus conduction induced by ablation. The other 2 had a late recovery of conduction. CONCLUSIONS: The present study provides evidence that the mechanism of successful AFI ablation targeting the IVC-TA isthmus is local bidirectional conduction block. This change can be used as a new and complementary electrophysiological end point for the procedure. AFI recurrences are associated with failure to achieve a permanent block.

Aged↗
PubMed1996

A mutation in HERG associated with notched T waves in long QT syndrome.

Long QT syndrome (LQT) is a genetically heterogeneous inherited disorder that causes sudden death from cardiac arrhythmia. Four loci have been mapped to chromosomes 3, 4, 7 and 11 and three specific mutated genes for LQT syndrome have been identified. LQT2 results from mutations in the human ether-a-gogo-related gene, HERG, a cardiac potassium channel, whose protein product likely underlies Ikd the rapidly activating delayed rectifier current. By SSCP analysis and direct sequencing, we determined a new missense mutation in the HERG coding sequence, a G to A transition at position 1681 resulting in the substitution of threonine for a highly conserved alanine at codon 561. This mutation, Ala561Thr, in the coding sequence of the fifth membrane-spanning domain (S5) of the HERG protein seems to convey a risk of cardiac events in affected family members. In addition to a prolonged T wave of low amplitude on the surface ECG, a distinctive biphasic T-wave pattern was found in the left precordial leads of all affected subjects with the Ala561Thr mutation regardless of age, gender and beta blocking therapy.

Adolescent↗
PubMed1996

Exclusion of KCNE1 (IsK) as a candidate gene for Jervell and Lange-Nielsen syndrome.

The KCNE1 gene encodes a small protein, IsK, of 14.4 kDa, with a single transmembrane domain, and is part of a potassium channel expressed in the heart. This channel is thought to underly the very slow component of the cardiac delayed rectifying current which controls the duration and the degree of ventricular repolarization. This suggested that KCNE1 could be the morbid gene responsible for an autosomal recessive cardio-auditory disease, the Jervell and Lange-Nielsen syndrome, characterized by ventricular repolarization abnormalities and recurrent syncopes leading eventually to sudden death associated with a bilateral congenital deafness. By linkage analysis in four consmanguinous families, using microsatellite markers of chromosome 21 as well as KCNE1 intragenic polymorphisms, we excluded KCNE1 as a candidate gene for Jervell and Lange-Nielsen syndrome. In addition, we described a new polymorphism, a G-to-A substitution at position 253, in the KCNE1 coding sequence detectable by SSCP analysis or RFLP.

Female↗