Philippe Coumel

Ambulatory sudden cardiac death: Mechanisms of production of fatal arrhythmia on the basis of data from 157 cases

The study of the tapes of ambulatory patients who died while wearing Holter devices allows us to know the terminal electrical events of death in these cases and which are the electrical triggering mechanisms leading to the terminal event. From the evaluation of seven published series with 10 or more cases, we can see that the most frequent causes of sudden death are ventricular tachyarrhythmias (84% of cases) and bradyarrhythmias (16%). VF was the most frequent ventricular tachyarrhythmia, usually secondary to VT. The rest were due to torsades de pointes in patients often without heart disease but who were taking antiarrhythmic drugs. The VT leading to VF was often preceded by sinus tachycardia or new atrial tachyarrhythmia. Only a small percentage of patients presented ischemic ST changes. In patients who died due to bradyarrhythmias, this was more often due to sinus depression than to atrioventricular block.

Characterization of Different Subsets of Atrial Fibrillation in General Practice in France The ALFA Study

BACKGROUND The clinical presentation and causes of atrial fibrillation (AF) in the 1990s may differ from AF seen 2 to 3 decades ago. It was the objective of this prospective study to characterize various clinical presentations and underlying conditions of patients with AF observed in general practice in France. METHODS AND RESULTS The study population comprised 756 patients (19 to 95 years of age) with electrocardiographically documented AF subdivided into paroxysmal (<7 days), chronic (last episode >1 month) and recent onset AF(persistent >7 days and<1 month). Symptoms were present in 670 patients (88.6%). The relative prevalences of paroxysmal, chronic, and recent onset AF were 22.1%, 51.4%, and 26.4%, respectively. Cardiac disorders, present in 534 patients (70.6%), included hypertension (39.4%), coronary artery disease (16.6%), and myocardial diseases (15.3%) as the most common. Rheumatic valvular disease represented a common cause in women (25. 0%) but not in men (8.0%). The paroxysmal group differed by a high percentage of palpitations (79.0%) and a low percentage of underlying heart disease (53.9%). With a mean follow-up of 8.6+/-3.7 months, 28 patients (3.7%) died, including 6 fatal cerebrovascular accidents. Among the 728 patients who survived, congestive heart failure occurred in 30 patients (4.1%), and embolic complications occurred in 13 patients (1.8%). In the paroxysmal AF group, 13 patients (8.0%) developed chronic AF and 51 (31.3%) had AF recurrences. At the time of follow-up, 53 patients (14.3%) from the chronic AF group and 108 patients (55.7%) from the recent onset AF group were in sinus rhythm. CONCLUSIONS This large-scale study establishes the current demographic profile of out-of-hospital patients with AF and highlights some of the changes that have occurred in the past decades, including a particular shift in cardiac causes toward nonrheumatic AF. This study also demonstrates significant differences between various subsets of AF.

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.

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.

Failure in the rate adaptation of the atrial refractory period: its relationship to vulnerability.

We evaluated the relationship of rate-dependent changes in atrial refractoriness to atrial vulnerability in 39 patients. Vulnerability was considered present when sustained atrial tachyarrhythmias, lasting longer than 1 minute, could be provoked with one to three extra stimuli. Adaptation of atrial refractory period duration to rate was defined as: normal: steep rate reduction with a linear correlation slope value of 0.08 or more; non-adaptation: absence of rate reduction, the slope value being 0 to 0.01; poor adaptation: slight reduction with rate, the slope having values of 0.02 to 0.07. Increased vulnerability was demonstrable in 16 of 17 patients with non-adaptation of the effective refractory period (ERP), and in 10 of 10 with a similar defect of the functional refractory period (FRP); in the intermediate category (poor adaptation) the results for ERP and FRP were 7/11 and 5/6. By way of contrast when both measurements showed normal adaptation, vulnerability was elicited in 2/9 patients. The significance between these groups showed P less than 0.005. Of 17 patients with atrial arrhythmia by Holter, 14 showed poor or non-adaptation of the ERP. It is suggested that poor or absent rate adaptation of the atrial refractory period, and a propensity to atrial fibrillation or flutter, constitute a clinical entity not previously described.

Long‐term Prevention of Vagal Atrial Arrhythmias by Atrial Pacing at 90/Minute: Experience with 6 Cases

Six patients (5 men, 1 woman) with a history ranging from 3–16 years of resistant vagal atrial arrhythmias were treated by atrial pacing at a rate of 90Jmin. These patients have been followed up for an average of 5.5 years (range 2–11 years) with favorable resutls. The arrhythmias were charactemed by daily or weekly attacks of rypical alrial flutter and atrial fibrillalion occurring mainly or exclusively at night, at rest, or in the digestive periods in otherwise normal hearts of middle‐aged palients (first attack between 25 and 54, mean 40). The arrhythmias werc resistant to quinidinc, and were usually aggravated by digitalis, beta‐blockers and verapamil. Amiodaroneisusually the only effective drug in this syndrome, but was not used before pacing in the 2 first cases, and was in effective in the other 4 cases. Electrophysiologic studies confirmed the absence of sick sinus syndrome, and the close relationship betwecn a relative bradycardia and the onset of the arrhythmia. Atrial pacing alone totally controiled the arrhythmia in 1 palient; amiodarone was used in conjunction with pacing in 3 palients. In 1 patient the improvement was clear but incomplete, and in 1 patient permanent alrial fibrillation occurred shortly afler pacemaker implantalion.

Dispersion of Ventricular Repolarization Reality? Illusion? Significance?

The QT interval is considered to be a surrogate of cellular action potential duration. However, it yields a limited view of the complex electrogenesis of the ventricular repolarization (VR). Evidence of T-wave end inequality among surface ECG traces back to Wilson et al,1 and it was recently revived by the concept of dispersion.2 Because of its apparent simplicity, QT dispersion became fashionable, and a growing literature is now devoted to its potential prognostic interest. The study by Zabel et al3 seems timely to temper the enthusiasm. In a prospectively collected cohort of patients, it offers evidence that avoiding technical biases of measurement, QT dispersion is not a prognostic marker. This contrasts with the confirmation that ejection fraction, heart rate variability, and simply heart rate are indeed good predictors of events. It suggests some reflections about the correct and comprehensive use of a concept that still needs to be validated. ### Measurement of QT Duration QT interval can be measured manually or with dedicated algorithms. The performances of the 2 approaches were compared in a remarkable study conducted by the late Jos Willems.4 The aim was to assess the diagnostic performances of computerized systems.5 In view of the interobserver and intraobserver variability in determining wave recognition points, an elaborate reviewing scheme was devised to obtain a group estimate that should define the “truth,” ultimately serving as a standard for computer measurement. Five experts defined individually the P- and QRS-wave onset and offset and the T-wave offset. The database was formed of 250 digitized (500 Hz) 12 standard leads and Frank XYZ leads, including a 25% proportion of normal hearts and a variety of ventricular hypertrophies and infarctions but no bundle-branch block or long-QT syndrome. The interexpert variation was expressed as 2 SD of the difference between the median and the individual …

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.

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.

Circadian modulation of QT rate dependence in healthy volunteers: Gender and age differences

QT rate dependence is known to be linked with both circadian variations of the autonomic tone and gender. However, age and heart rate variability (HRV) influences are not well established. The QT/RR relationship was evaluated, separately during the day and at night, on 24-hour electrocardiogram in 60 healthy subjects (30 men) divided into three homogeneous groups (group 1, 20-29; group 2 30-39; group 3, 40-50 years). QT rate dependence was larger during the day in both genders. Women showed stronger QT rate dependence (0.195 during the day vs. 0.154 in men P< .0001). The circadian modulation decreased with increasing age (day/night slope differences: group 1, 0.038; group 2, 0.031; group 3, 0.001; analysis of variance P<.05). In addition, QT rate dependence increased as mean RR decreased (r = -0.58, P<.0001) and decreased as HRV parameters increased. Multiple influences on QT rate dependence can be found: not only circadian and gender modulation, but also age, heart rate, and HRV interventions.