[From provocation tests to clinical practice: invasive and non-invasive electrophysiology]. / Des tests de déclenchement à la clinique: électrophysiologie invasive et non invasive.

There are always three main ingredients required for the production of a clinical arrhythmia: the arrhythmogenic substrate, the trigger factor and the modulation factors of which the most common is the autonomic nervous system. These different components may be appreciated by invasive and non-invasive electrophysiological methods, the values of which are extremely variable according to the way they are used and to the particular arrhythmia being investigated. For example, programmed electrical stimulation is extremely valuable whenever a reentry mechanism is suspected and may even provide access to treatment of the underlying arrhythmogenic substrate. On the other hand, it is of little use when the arrhythmia is not caused by an inducible mechanism and anatomically very localised. In this situation, pharmacological adrenergic stimulation or exercise stress testing may be more appropriate given their effects on the autonomic nervous system and their influence on the substrate or the occasional trigger factor, thereby making analysis of the results more difficult. The role of the autonomic nervous system is best assessed by the data provided from Holter recordings, a true electrophysiological investigation, rather than a simple tool for picking up spontaneous arrhythmias. Finally, present day computer techniques have completely revised conventional electrocardiography. For example, the search for the arrhythmogenic substrate by the demonstration of late ventricular potentials on signal-averaged ECG. Even more valuable is the analysis of ventricular repolarisation and its variations as it reflects arrhythmogenic electrophysiological conditions at cellular level.

[Indications for implantable automatic defibrillators: critical analysis]. / Les indications du défibrillateur automatique implantable: analyse critique.

The implantable automatic defibrillator (IAD), invented in 1980, has revolutionised the management of patients with malignant ventricular arrhythmias resistant to medical treatment or ablation procedures. The number of devices implanted continues to increase in the industrialised countries and, based on the results of clinical trials, the indications for IAD are now well codified and increase as new clinical studies are published. However, the absolute number of implantations in France remains low (about 1200 to 2000, about 20 per million population) for a number of reasons: cost of IAD, absence of reimbursement by the health service which has restrained the implantation to public hospitals, and information of cardiologists for whom IAD may seem to be reserved for a few exceptional cases. Several factors suggest that the number of implantations will increase in the near future. First of all, the procedures of implantation have become much more simple due mainly to technical improvements. Then, the results of recent studies have validated prophylactic implantations of these devices in primary prevention in the post-infarction period (MADIT, MUSTT, MADIT II studies) and have demonstrated the superiority of IAD over antiarrhythmic drug therapy in terms of global survival in patients with severe ventricular arrhythmias (AVID, CIDS, CASH studies).

Safety of a controlled-release flecainide acetate formulation in the prevention of paroxysmal atrial fibrillation in outpatients.

OBJECTIVES: The cardiac safety of a once-a-day 200 mg controlled-release formulation of flecainide acetate in the prevention of paroxysmal atrial fibrillation (PAF) was assessed in outpatients. MATERIAL AND METHODS: The drug was administered for 24 weeks to 227 patients diagnosed with recurrent Paf episodes. Cardiac safety was assessed primarily by the maximum change from baseline in QRS duration. Changes in left ventricular function at echocardiography, incidence of proarrhythmic effects determined from ECG and Holter recordings and cardiovascular adverse events were also taken into account to assess cardiac safety. Efficacy was documented by actuarial methods. RESULTS: Mean maximum QRS increase from baseline was 11.4% (n = 181); QRS increase was < 15% in 71.8% of the patients and > or = 25% in 18.8%. Only 4 patients had maximum QRS value > 100 ms under treatment. Left ventricular ejection fraction remained within +/- 20% of baseline for 90% of the patients, increased above 20% for 8.6% and decrease below 30% for 1.4% (n = 139). Bradycardia (13.2%; n = 129) and ventricular extrasystoles (10.6%; n = 104) were the most frequently identified proarrhythmic effects. Atrio-ventricular block (4.0%), supra-ventricular tachycardia (2.2%), bundle branch block (1.8%) and atrial fibrillation (1.3%) were the most frequent drug-related cardiac adverse events. Estimated treatment success rate was 74% (95% CI: [68%; 80%]) and the incidence of Paf episodes decreased from baseline 28.6% to 11.0% (P < 0.0001). CONCLUSIONS: We provided evidence for a good cardiac safety profile of the controlled-release formulation of flecainide acetate and confirmed the effectiveness of the drug in the prevention of PAF recurrences.

Influence of atenolol on the kinetics of RT interval rate adaptation in conscious dogs.

The objective was to test an effect of atenolol independent of heart rate on electrocardiographic RT rate adaptation by investigating RT adaptation during spontaneous rate and after an abrupt change of atrial rate (study of RT delay). Digital electrocardiograms were recorded from eight conscious dogs. Analysis of RT interval (measured from QRS apex to end of T) was performed on a beat-to-beat basis. The protocol was repeated in the control state and after atenolol administration (2 mg/kg). Regarding spontaneous heart rate, an increased or decreased RR duration did not modify the beat-to-beat relative adaptation of RT to a change of RR (2.15 +/- 1% during control). Atenolol increased mean RR (p < 0.001) and decreased relative adaptation of RT (0.22 +/- 0.18%, p < 0.001). The inverse correlation between mean RR and the relative RT adaptation (r = -0.76, p < 0.05) disappeared after atenolol administration. Regarding RT delay, complete adaptation of RT required 3 min; 48 +/- 16% of this adaptation was observed after the first beat and 60 +/- 11% was observed after the 20th. Atenolol attenuated this adaptation during the first six beats following the abrupt cycle length change (p < 0.05). We concluded that the attenuation of RT rate adaptation after atenolol is related to heart rate modulation and to the time delay in RT rate adaptation.

[T wave abnormalities on Holter monitoring of congenital long QT syndrome: phenotypic marker of a mutation of LQT2 (HERG)]. / Anomalies de l'onde T au Holter dans le syndrome du QT long congénital: marqueur phénotypique d'une mutation dans 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.

[Congenital long QT syndrome]. / Syndrome du QT long congénital.

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.

[New markers for the risk of sudden death: analysis of ventricular repolarization]. / Nouveaux marqueurs de risque de mort subite: apport de l'analyse de la repolarisation ventriculaire.

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.

Autonomic influences on ventricular repolarization in congestive heart failure.

We studied the QT interval rate-dependence in patients with congestive heart failure (CHF). The long-term autonomic nervous function was investigated by separate analysis of diurnal and nocturnal periods. For this purpose, QTm rate-dependence was determined from Holter recordings. Twelve patients with stable CHF (mean age 63 +/- 2 years) and 15 healthy subjects (mean age 59 +/- 4 years) were included in the study. CHF patients showed an increased nocturnal QTm rate-dependence when compared to normal subjects (0.150 [95% confidence interval (CI) 0.114 to 0.186] versus 0.106 [95% CI 0.080 to 0.133], P < .05). In contrast, QTm rate-dependence was not significantly different between the 2 groups during the day (0.177 [95% CI 0.149 to 0.210] in the CHF group versus 0.194 [95% CI 0.158 to 0.231] in the control group). It was also not significantly different between day and night for the CHF group, thus showing a loss of the circadian modulation in these patients. Thus, ventricular myocardial properties are altered by changes in the autonomic nervous system in CHF, as observed at the atrial level. These modifications may be related to the increased susceptibility to ventricular arrhythmias.

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.

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.

Association between heart rate-corrected QT interval and coronary risk factors in 2,894 healthy subjects (the DESIR Study). Data from an Epidemiological Study on the Insulin Resistance syndrome.

In the prospective Data from an Epidemiological Study on the Insulin Resistance Syndrome, 2,894 healthy subjects aged 30 to 64 years had determinations of fasting glucose, insulin, serum lipid and fibrinogen concentrations, blood pressures, body mass index, and waist-hip ratio, as well as tobacco and alcohol consumptions and physical activity. A 12-lead electrocardiogram with automatic measurement of the QT interval was recorded and the formula used for heart rate correction was based on the best-fit regression between QT and heart rate. The QT duration was influenced by glucose homeostasis in both sexes, and increased in men with physical activity; there was a dose-effect relation for men who smoked.

Frequency-domain heart rate variability in 24-hour Holter recordings: role of spectral method to assess circadian patterns and pharmacological autonomic modulation.

Different spectral methodologies for heart rate variability were recently shown to provide the same qualitative results in the context of passive tilt test. However, the impact of the method and the use of normalized power units in long-term ECG monitoring is still debated. Autoregressive and Fast Fourier transform (FFT) spectral approaches were applied to assess circadian modulation and the effect of beta-blocker administration in mild hypertensive patients who underwent continuous ambulatory ECG recording (n = 44, 51 +/- 12 years, 30 men). Spectral analysis was applied to 5-minute sequences and spectral parameters representative of each circadian period (24 hour, day, night) were calculated. In baseline recordings, FFT spectral method provided a smaller estimate of total and very low frequency powers. On the contrary, low- and high-frequency components were systematically larger with FFT. Circadian variations were in favor of an increased overall nocturnal variability but of a reduced low frequency normalized power with both spectral methods. Chronic oral administration of beta-blocker induced an increase of all spectral components except for an unchanged low-frequency normalized power, independently from the spectral approach. In spite of quantitative differences, the qualitative assessment of circadian patterns and beta-blockade effect by autoregressive- and FFT-based spectral analyses is equivalent. The low-frequency component of heart rate variability cannot be considered a reliable direct marker of sympathetic activity in long-term ambulatory ECG recording.

[Present concepts of congenital long QT syndrome]. / Données actuelles sur le syndrome du QT long congénital.

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.

[Ventricular repolarization and Holter monitoring. Effect of sympathetic blockage on the QT/RR ratio]. / Repolarisation ventriculaire et enregistrement Holter. Rôle du blocage sympathique sur la physiologie de la relation QT/RR.

Circadian variations of the QT interval and its heart rate dependency have been established. However, the respective roles of the sympathetic and parasympathetic nervous systems in their regulation are still undetermined. Eighteen healthy volunteers (average age 39 +/- 7 years, 10 men) were recruited and selected randomly to receive either placebo or atenolol (100 mg/day). The treatments were crossed after 7 days. The rate dependency of the QT was assessed by day and by night by 24 hour Holter ECG monitoring. The effects of atenolol on the rate dependency of the QT interval depend on the time of day. During the daytime, the QT rate dependency was reduced by atenolol (0.180 (0.162:0.198) versus 0.216 (0.195:0.236) with placebo, p < 0.01) whereas during the night, the QT rate dependency was the same in both groups. Therefore, the betablocker is associated with an inversion of the daily modulation of the QT rate dependency. The daytime rate-dependency of the QT interval in decreased with betablocker therapy. This result suggests a direct or indirect influence of the sympathetic nervous system on the rate dependency of ventricular repolarisation.

[Electrocardiographic changes and rhythm problems in the diabetic]. / Modulation de l'électrocardiogramme et troubles du rythme chez le diabétique.

Diabetes is a cause of serious myocardial disease related to an increased incidence of coronary artery disease, probably aggravated by cardiac autonomic neuropathy (CAN). In its incipient form, CAN hardly changes the sinus rhythm with an increase in nocturnal heart rate but without an appreciable effect on the indices of variability. In more advanced forms, "CAN+", there are not only changes in the heart rate variability but also in ventricular repolarisation. It is classical to underline the value of the corrected QT interval but this index has little real value. The "QT dispersion", comparing the duration of ventricular repolarisation on the surface leads, is no better a marker from the theoretical point of view. The dynamics of ventricular repolarisation on the other hand seem to be much more indicative of ventricular myocardial disease. They are studied by evaluating the QT-heart rate relationship and its increase distinguishes clearly CAN diabetics from CAN+ diabetics. In addition, in the latter subjects, diurnal physiological increase in the heart rate dependency of the QT interval (QT/RR slope) disappears or even inverse. It is probably this phenomenon which is responsible for the traditionally increased risk of ventricular arrhythmias and particularly sudden death in diabetics with autonomic neuropathy.