Biomedical subjects

I Denjoy

Publications and source records attributed to I Denjoy.

At least 37 records · Page 2Linked to original sources

PubMed2001

Notched T waves on Holter recordings enhance detection of patients with LQt2 (HERG) mutations.

BACKGROUND: The 2 genes KCNQ1 (LQT1) and HERG (LQT2), encoding cardiac potassium channels, are the most common cause of the dominant long-QT syndrome (LQTS). In addition to QT-interval prolongation, notched T waves have been proposed as a phenotypic marker of LQTS patients. METHODS AND RESULTS: The T-wave morphology of carriers of mutations in KCNQ1 (n=133) or HERG (n=57) and of 100 control subjects was analyzed from Holter ECG recordings. Averaged T-wave templates were obtained at different cycle lengths, and potential notched T waves were classified as grade 1 (G1) in case of a bulge at or below the horizontal, whatever the amplitude, and as grade 2 (G2) in case of a protuberance above the horizontal. The highest grade obtained from a template defined the notch category of the subject. T-wave morphology was normal in the majority of LQT1 and control subjects compared with LQT2 (92%, 96%, and 19%, respectively, P:<0.001). G1 notches were relatively more frequent in LQT2 (18% versus 8% [LQT1] and 4% [control], P:<0.01), and G2 notches were seen exclusively in LQT2 (63%). Predictors for G2 were young age, missense mutations, and core domain mutations in HERG. CONCLUSIONS: This study provides novel evidence that Holter recording analysis is superior to the 12-lead ECG in detecting G1 and G2 T-wave notches. These repolarization abnormalities are more indicative of LQT2 versus LQT1, with G2 notches being most specific and often reflecting HERG core domain missense mutations.

Adult↗

PubMed2001

Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for life-threatening arrhythmias.

BACKGROUND: The congenital long-QT syndrome (LQTS) is caused by mutations on several genes, all of which encode cardiac ion channels. The progressive understanding of the electrophysiological consequences of these mutations opens unforeseen possibilities for genotype-phenotype correlation studies. Preliminary observations suggested that the conditions ("triggers") associated with cardiac events may in large part be gene specific. METHODS AND RESULTS: We identified 670 LQTS patients of known genotype (LQT1, n=371; LQT2, n=234; LQT3, n=65) who had symptoms (syncope, cardiac arrest, sudden death) and examined whether 3 specific triggers (exercise, emotion, and sleep/rest without arousal) differed according to genotype. LQT1 patients experienced the majority of their events (62%) during exercise, and only 3% occurred during rest/sleep. These percentages were almost reversed among LQT2 and LQT3 patients, who were less likely to have events during exercise (13%) and more likely to have events during rest/sleep (29% and 39%). Lethal and nonlethal events followed the same pattern. Corrected QT interval did not differ among LQT1, LQT2, and LQT3 patients (498, 497, and 506 ms, respectively). The percent of patients who were free of recurrence with ss-blocker therapy was higher and the death rate was lower among LQT1 patients (81% and 4%, respectively) than among LQT2 (59% and 4%, respectively) and LQT3 (50% and 17%, respectively) patients. CONCLUSIONS: Life-threatening arrhythmias in LQTS patients tend to occur under specific circumstances in a gene-specific manner. These data allow new insights into the mechanisms that relate the electrophysiological consequences of mutations on specific genes to clinical manifestations and offer the possibility of complementing traditional therapy with gene-specific approaches.

Adrenergic beta-Antagonists↗

PubMed2001

[Congenital long QT syndrome].

Long QT syndrome (LQTS) is a clinically and genetically heterogenous syndrome characterized by a lengthening of the QT interval on the surface ECG and a propensity to severe ventricular arrhythmias such as torsades de pointes and ventricular fibrillation, leading eventually to syncope and sudden death. This rare syndrome with a mendelian inheritance occurs in subjects with otherwise normal cardiac morphological examination. The potentially severe prognosis justifies a presymptomatic diagnosis. The genetic nature of the disease has been confirmed with the identification of at least six loci and five genes. This syndrome is a perfect illustration of an adrenergic-induced ventricular arrhythmia. The first-line treatment is a beta-blocking agent for all symptomatic patients. In addition, a number of drugs known to lengthen ventricular repolarization must be prohibited. In case of suspicion of LQTS, all family members should be tested both clinically with a surface ECG and genetically in order to diagnose presymptomatic patients.

Adrenergic beta-Antagonists↗

PubMed2001

[New markers for the risk of sudden death: analysis of ventricular repolarization].

The identification of patients at high risk of sudden cardiac death is one of the greatest challenges for cardiologists. Non-invasive methods have, characteristically, low predictive sensitivities and specificities. The role of abnormalities of ventricular repolarisation (QT interval) in the genesis of ventricular arrhythmias has been well established by experimental data. For this reason, parameters of ventricular repolarisation on the surface electrocardiogram have been proposed. However, taken in isolation, these markers are limited in terms of arrhythmic risk stratification. This report analyses the value of the different parameters of ventricular repolarisation in the identification of high risk: QT dispersion, QT dynamics and T wave alternans. The dispersion of the QT interval is a marker of unhomogenous ventricular depolarisation. This concept must be applied differently in such pathologically dissimilar diseases such as myocardial infarction, cardiomyopathy or the long QT syndrome. Moreover, methodological problems make the interpretation of many experimental studies very delicate. Frequency dependence of the QT helps select high risk patients after myocardial infarction or with dilated cardiomyopathy. A common feature of pathological ventricular myocardium is the more pronounced frequency-dependency of the QT interval. The predictive value of this new index should be evaluated and compared with other non-invasive risk factors in prospective trials. Studies of T wave alternans in selected high risk populations, essentially patients with coronary artery disease and dilated cardiomyopathy, have shown this parameter to be predictive of arrhythmia. The predictive value requires confirmation in much larger populations at lower levels of risk of arrhythmia and sudden death in prospective trials. A new field of research has opened up in the study of ventricular repolarisation. Many studies have been undertaken on the duration of the QT interval, the morphology of the QT (including T wave alternans and post-pause changes) and, finally, the dynamics of the QT interval. By regrouping, analysing and using these data correctly, we should be able to identify new markers of high arrhythmic risk.

Death, Sudden, Cardiac↗

PubMed2001

[T wave abnormalities on Holter monitoring of congenital long QT syndrome: phenotypic marker of a mutation of LQT2 (HERG)].

The two genes which code for the potassium channels, KCNQ1 and HERG, are responsible for the most common forms of the long QT syndrome, LQT1 and LQT2. Abnormalities of duration and morphology of the ventricular repolarisation are amongst the diagnostic criteria of this syndrome. The morphology of the T waves was studied by 24 hour Holter monitoring in 190 subjects with a long QT syndrome due to KCNQ1 (LQT1) [N = 133] or HERG (N = 57) and in 100 controls, and it was compared with the ECG T wave. The T wave was characterised according to 3 morphological features: grade 0 (G0) = normal, grade 1 (G&) = slight ST depression and grade 2 (G2) = presence of ST elevation of the descending phase of the T wave. The T wave morphology on Holter ECG was normal for most LQT1 and control subjects compared with LQT2 (92%, 96% and 19% respectively, p < 0.01). Grade 1 appearances were observed more often in LQT2 (18 vs 8% for LQT1 and 4% for controls, p < 0.01). Grade 2 appearances were only observed in the cases of LQT2 (63%). The predictive factors of G2 were young age and an anti-sense mutation of the transmembrane domaines of HERG. The authors conclude that Holter monitoring improves detection of T wave changes compared with the ECG. Grade 2 changes seem to be a phenotype marker for a HERG mutation, especially those situated in the transmembrane domaines.

Adolescent↗

PubMed2001

[Cardiac consequences of adolescent anorexia nervosa].

Cardiac complications are common in adolescent anorexia nervosa and are the cause of a third of deaths. Some workers have reported prolongation of the QT interval and cases of sudden death in these patients. The aim of this study was two-fold: to assess the cardiac complications of anorexic adolescents and to determine the outcome after renutrition in the hospital setting. This was a prospective study of 48 consecutive cases (45 girls) with an average age of 14 +/- 2 years, admitted to the paedopsychiatric unit and fulfilling the DSM-IV criteria of anorexia nervosa. The digitised ECG, Holter ECG and echocardiography were recorded before and after renutrition. Anorexia nervosa was severe with a body mass index < 14 in 2/3 of cases. Over 2/3 of patients had bradycardia with a heart rate < 50/min in half the cases but normal chronotropic function on Holter monitoring. Prolongation of the QTc interval was demonstrated (QTc > 440 ms in 11/44 cases). Echocardiographic abnormalities, in particular left ventricular dysfunction (24/46) and pericardial effusion (12/46) were reversible after renutrition. There were no clinical or biological predictive factors for the occurrence of cardiac complications on admission. The authors confirm that cardiac complications of anorexia nervosa are common, usually benign and always reversible after renutrition in hospital. Therefore, most electrical abnormalities normalise with the heart rate and echocardiographic abnormalities with improvement of conditions of load.

Adolescent↗

PubMed2001

[Antenatal atrial tachycardia. Two case reports].

The authors report two cases of foetal supraventricular tachycardia in healthy hearts with 1/1 atrioventricular conduction which turned out to be atrial tachycardias in the postnatal period. The first foetus had permanent tachycardia at 190/minute at 34 weeks' amenorrhea with left ventricular dysfunction at 36 weeks. In the postnatal period, treatment with digoxine and amiodarone restored sinus rhythm and normal left ventricular function. Permanent foetal tachycardia, even at a rate of less than 200 beats/minute, should suggest an arrhythmia and may lead to left ventricular dysfunction in utero. The other foetus had an aneurysm of the foramen ovale with paroxysmal tachycardias at 220/minute without cardiac dysfunction. A Holter at 1 month showed paroxysmalatrial tachycardia. Postnatal rhythm monitoring is necessary in paroxysmal foetus tachycardia, especially with prenatal aneurysm of the foramen ovale.

Adult↗

PubMed2000

Electrophysiological characterization of SCN5A mutations causing long QT (E1784K) and Brugada (R1512W and R1432G) syndromes.

UNLABELLED: Familial long QT syndrome (LQTS) and Brugada syndrome are two distinct human hereditary cardiac diseases known to cause ventricular tachyarrhythmias (torsade de pointes) and idiopathic ventricular fibrillation, respectively, which can both lead to sudden death. OBJECTIVE: In this study we have identified and electrophysiologically characterized, in patients having either LQTS or Brugada syndrome, three mutations in SCN5A (a cardiac sodium channel gene). METHOD: The mutant channels were expressed in a mammalian expression system and studied by means of the patch clamp technique. RESULTS: The R1512W mutation found in our first patient diagnosed with Brugada syndrome produced a slowing of both inactivation and recovery from inactivation. The R4132G mutation found in our second patient who also presented Brugada syndrome, resulted in no measurable sodium currents. Both Brugada syndrome patients showed ST segment elevation and right bundle-branch block, and had experienced syncopes. The E1784K mutation found in the LQTS showed a persistent inward sodium current, a hyperpolarized shift of the steady-sate inactivation and a faster recovery from inactivation. CONCLUSION: The different clinical manifestations of these three mutations most probably originate from the distinct electrophysiological abnormalities of the mutant cardiac sodium channels reported in this study.

Adult↗

PubMed2000

Novel mutations in KvLQT1 that affect Iks activation through interactions with Isk.

OBJECTIVES: We report the functional expression of four KCNQ1 mutations affecting arginine residues and resulting in Romano-Ward (RW) and the Jervell and Lange-Nielsen (JLN) congenital long QT syndromes. RESULTS: The R539W and R190Q mutations were found in typical RW families with an autosomal dominant transmission. The R243H mutation was found in a compound heterozygous JLN patient who presents with deafness and cardiac symptoms. The fourth mutation, R533W, was a new case of recessive form of the RW syndrome since homozygous carriers experienced syncopes but showed no deafness, whereas the heterozygous carriers were asymptomatic. The R190Q mutation failed to produce functional homomeric channels. The R243H, R533W and R539W mutations induced a positive voltage shift of the channel activation but only when co-expressed with IsK, pointing out the critical role of these positively charged residues in the modulation of the gating properties of KvLQT1 by IsK. The positive shift induced by R533W was merely 15%. This small effect was compatible with the recessive character of the RW phenotype transmission. The average QTc was significantly longer (P < 0.01) in patients carrying mutations inducing a total loss of channel function and those patients were also prone to cardiac adverse symptoms (whether syncopes or sudden death) to a greater extent (62 vs. 21%, P < 0.001). CONCLUSIONS: Novel mutations are described that induce a voltage shift of the channel activation only in the presence of IsK. They appear associated with a milder cardiac phenotype.

Action Potentials↗

PubMed2000

Paroxysmal vagal overactivity, apparent life-threatening event and sudden infant death.

The possibility of reversible cardiac asystoly due to paroxysmal vagal overactivity (VO) has been well studied, first in adults, then in children, and finally in breath-holding spells. Few studies deal with infants and the incidence of VO among preterm, apparent life-threatening event (ALTE) and sudden infant death syndrome (SIDS). In this review, we summarize data acquired during the past 20 years leading to the diagnosis of VO in infants. We describe the clinical aspects of VO in infants and young children such as Holter-ECG and oculocardiac reflex criteria. The familial aspect of VO and its possible link with SIDS (a new risk factor?) are discussed. Finally, whether or not to treat infants with symptomatic VO is discussed.

Child, Preschool↗

PubMed2000

[Present concepts of congenital long QT syndrome].

The congenital long QT syndrome is characterised by the presence of syncopes due to torsades de pointe which may degenerate to ventricular fibrillation and cause sudden death. These syncopes occur in young subjects with electrocardiographic abnormalities and prolongation of the QT interval. Patients with the autosomally dominant transmitted Romano-Ward syndrome with normal audition are classically opposed to those with the Jervell and Lange-Nielsen autosomally recessive syndrome who have bilateral total deafness. Our understanding of the congenital long QT syndrome has improved in recent years with respect to the physiopathology, diagnosis and treatment, due to research in the fields of genetics, electrocardiography and electrophysiology. The diagnosis is based on analysis of the phenotype and genotypes. A family enquiry is always necessary to detect unrecognised forms. Five culprit genes have been identified for the Romano-Ward syndrome. All code for subunits of sodium or potassium channels: two a subunits of the potassium channels (QVLQT1 for LQT1, HERG for LQT2), the a subunit of the sodium channel INa (SCN5A for LQT3), and two regulatory subunits of potassium channels (KCNE1 for LQT5 regulating the KvLQT1 channel and MiRP1 regulating HERG). The concept of genetic heterogeneity of the congenital long QT syndrome may thus be understood: different genes may be responsible for the same phenotype. Except for specific cases, the usual treatment is life-long betablocker therapy and the avoidance of a large number of drugs, the list of which is continually updated. A multicentre trial is underway to validate betablocker therapy for the prevention of cardiac events in a LQT1 genotype population. Prospective studies will be necessary to assess gene-specific treatments.

Adrenergic beta-Antagonists↗

PubMed2000

[Bundle of His tachycardia and chronic reciprocating rhythm: rare forms of prenatal tachycardia].

In cases of permanent tachycardia, ante-natal diagnosis of chronic reciprocating rhythms with long RP' intervals or His bundle tachycardias is difficult. The authors report two cases of permanent foetal tachycardia with 1/1 atrioventricular conduction. In one case, the tachycardia rate was 170/min with anasarca treated by amiodarone in view of a family history of His bundle tachycardia. In the other case, the tachycardia rate was 200/min but with no signs of cardiac failure and was, therefore, not treated. The ECG at birth confirmed the diagnosis of His bundle tachycardia in the first case and identified a chronic reciprocating rhythm in the other.

Adult↗

PubMed1999

Splicing mutations in KCNQ1: a mutation hot spot at codon 344 that produces in frame transcripts.

BACKGROUND: Long-QT syndrome is a monogenic disorder that produces cardiac arrhythmias and can lead to sudden death. At least 5 loci and 4 known genes exist in which mutations have been shown to be responsible for the disease. The potassium channel gene KCNQ1, previously named KVLQT1, on chromosome 11p15.5 is one of these. METHODS AND RESULTS: We initially analyzed one family using microsatellite markers and found linkage to KCNQ1. Mutation detection showed a G to C change in the last base of exon 6 (1032 G-->C) that does not alter the coded alanine. Restriction digest analysis in the family showed that only affected individuals carried the mutation. A previous report suggested that a G to A substitution at the same position may act as a splice mutation in KCNQ1, but no data was given to support this hypothesis nor was the transcription product identified. We have shown by reverse-transcription polymerase chain reaction that 2 smaller bands were produced for the KCNQ1 gene transcripts in addition to the normal-sized transcripts when lymphocytes of affected individuals were analyzed. Sequencing these transcripts showed a loss of exon 7 in one and exons 6 and 7 in the other, but an in-frame transcript was left in each instance. We examined other families in whom long-QT syndrome was diagnosed and found another unreported splice-site mutation, 922-1 G-->C, in the acceptor site of intron 5, and 2 of the previously reported 1032 G-->A mutations. All these showed a loss of exons 6 and 7 in the mutant transcripts, validating the proposal that a consensus sequence is affected in the exonic mutations and that the integrity of the base at position 1032 is essential for correct processing of the transcript. CONCLUSIONS: The 6 cases already reported in the literature with the 1032 G-->A transition, the novel 1032 G-->C transversion, and a recent G-->T transversion at the same base show that codon 344 is the second most frequently mutated after codon 341, suggesting at least two hotspots for mutations in KCNQ1.

Child, Preschool↗

PubMed1999

C-terminal HERG mutations: the role of hypokalemia and a KCNQ1-associated mutation in cardiac event occurrence.

BACKGROUND: The long-QT syndrome (LQTS) is a genetically heterogeneous disease in which 4 genes encoding ion-channel subunits have been identified. Most of the mutations have been determined in the transmembrane domains of the cardiac potassium channel genes KCNQ1 and HERG. In this study, we investigated the 3' part of HERG for mutations. METHODS AND RESULTS: New specific primers allowed the amplification of the 3' part of HERG, the identification of 2 missense mutations, S818L and V822 M, in the putative cyclic nucleotide binding domain, and a 1-bp insertion, 3108+1G. Hypokalemia was a triggering factor for torsade de pointes in 2 of the probands of these families. Lastly, in a large family, a maternally inherited G to A transition was found in the splicing donor consensus site of HERG, 2592+1G-A, and a paternally inherited mutation, A341E, was identified in KCNQ1. The 2 more severely affected sisters bore both mutations. CONCLUSIONS: The discovery of mutations in the C-terminal part of HERG emphasizes that this region plays a significant role in cardiac repolarization. Clinical data suggests that these mutations may be less malignant than mutations occurring in the pore region, but they can become clinically significant in cases of hypokalemia. The first description of 2 patients with double heterozygosity associated with a dramatic malignant phenotype implies that genetic analysis of severely affected young patients should include an investigation for >1 mutation in the LQT genes.

Adolescent↗

PubMed1999

Genomic organization of the KCNQ1 K+ channel gene and identification of C-terminal mutations in the long-QT syndrome.

The voltage-gated K+ channel KVLQT1 is essential for the repolarization phase of the cardiac action potential and for K+ homeostasis in the inner ear. Mutations in the human KCNQ1 gene encoding the alpha subunit of the KVLQT1 channel cause the long-QT syndrome (LQTS). The autosomal dominant form of this cardiac disease, the Romano-Ward syndrome, is characterized by a prolongation of the QT interval, ventricular arrhythmias, and sudden death. The autosomal recessive form, the Jervell and Lange-Nielsen syndrome, also includes bilateral deafness. In the present study, we report the entire genomic structure of KCNQ1, which consists of 19 exons spanning 400 kb on chromosome 11p15.5. We describe the sequences of exon-intron boundaries and oligonucleotide primers that allow polymerase chain reaction (PCR) amplification of exons from genomic DNA. Two new (CA)n repeat microsatellites were found in introns 10 and 14. The present study provides helpful tools for the linkage analysis and mutation screening of the complete KCNQ1 gene. By use of these tools, five novel mutations were identified in LQTS patients by PCR-single-strand conformational polymorphism (SSCP) analysis in the C-terminal part of KCNQ1: two missense mutations, a 20-bp and 1-bp deletions, and a 1-bp insertion. Such mutations in the C-terminal domain of the gene may be more frequent than previously expected, because this region has not been analyzed so far. This could explain the low percentage of mutations found in large LQTS cohorts.

Base Sequence↗

PubMed1999

Prenatal diagnosis of a familial form of junctional ectopic tachycardia.

Junctional ectopic tachycardia (JET) is a rare cardiac arrhythmia characterized by atrio-ventricular dissociation, a high rate junctional escape rhythm and poor clinical tolerance in neonates and infants. Sudden infant death has been reported. The intra-uterine presentation of this arrhythmia is unknown. We report a familial form of JET with antenatal diagnosis. A sustained tachycardia at a rate of 170 beats/min with a 1:1 conduction was diagnosed in a hydropic fetus at a gestational age of 32 weeks. The older brother had presented with prenatal hydrops and junctional ectopic tachycardia was diagnosed at birth. Assuming that this arrhythmia was a JET, amiodarone was given to the mother in order to control the fetal tachycardia. The arrhythmia persisted with a 1/1 pattern but at a slower ventricular rate (140 beats/min). The ECG performed at birth revealed a narrow QRS tachycardia with a ventricular rate of 180 beats/min and a 1/1 retrograde conduction. Amiodarone therapy was continued with the addition of propanolol. Postnatal echocardiography revealed normal chambers and left ventricular dysfunction with a left ventricular shortening fraction of 17 per cent. Subsequent ECGs and Holter monitoring demonstrated typical electrocardiographic features of JET. Both parents had a normal ECG and Holter monitoring. A fetal tachycardia of moderately high rate with a 1/1 retrograde conduction and poor cardiac tolerance can be due to JET. In such cases, the use of amiodarone can be considered as a first line drug.

Adult↗

PubMed1999

[Mechanism of spontaneous occurrence of tachycardia].

Tachycardias arise from an arrhythmogenic substrate and a trigger factor, an extrasystole, the two factors being under the influence of the autonomic nervous system. The study of the mechanisms of spontaneous initiation of arrhythmias must, therefore, take these three factors and their interactions into account. The frequency dependency of an arrhythmia and the sensitivity of the substrate to the adrenergic system varies with time in a given subject and from one patient to another according to the presence and type of cardiac disease. The mode of initiation of most ventricular tachycardias and the therapeutic consequences may be understood: in some forms of cardiac disease, such as arrhythmogenic right ventricular dysplasia, the increase in heart rate which usually precedes sustained ventricular arrhythmias is only perceptible in mild or recent forms, unlike the more chronic dysplasias. This suggests that the arrhythmogenic substrate becomes more sensitive to catecholamines with time, and therefore requires smaller changes in sympathetic tone in order to be expressed (adrenergic paradox). Heart rate changes accompany modifications of sinus variability. Holter monitoring has shown, and this has been confirmed by recordings obtained from patients with implanted automatic defibrillators, that global sinus variability decreases before the initiation of a ventricular arrhythmia. Studies of the dynamics of ventricular repolarisation should also confirm the changes of QT frequency-dependency. The analysis of the initiation of arrhythmias would only have an academic interest if this was limited to a purely descriptive exercise. It is one of the best means of understanding arrhythmias and their therapeutic implications. The development of computerised methods of analysis of Holter monitoring should lead to further progress in this field.

Cardiomegaly↗

PubMed1999

[Congenital long QT syndrome. The value of genetics in prognostic evaluation].

The congenital long QT syndrome (QTL) is a heterogenic clinical and genetic entity characterised by prolongation of the QT interval which may be complicated by syncope and sudden death. Four genes have been identified for the cardiac potassium (KCNQ1, HERG and KCNE1) and sodium (SCN5A). The aim of this study was to assess the prognosis of the disease by the site of mutation identified on the morbid gene. Thirty-two genotyped families participated to this study. Each subject gave a clinical history, an ECG and a search for genetic mutation. Eighteen mutations in the transmembrane domains of KCNQ1 were identified in 25 families and 2 mutations in the C-terminal part were found in 4 families. The phenotype was less severe in C-terminal part mutations: less syncopes and sudden deaths (22 vs 55%, p < 0.001) and a shorter QTc (458 +/- 31 ms vs 479 +/- 31 ms, p = 0.0003). Three mutations were detected in the C-terminal part of HERG in 3 different families. Their phenotype was less severe with syncoped related to hypokalemia. The authors also report the case of a family in which two subjects who were the most severely affected had two mutations, one in HERG and the other in KCNQ1. This study confirms the value of a genetic research in assessing the severity of the congenital long QT syndrome.

Adolescent↗