High prevalence of ventricular repolarization abnormalities in people carrying TGFßR2 mutations.

Mutations in the TGFßR2 gene have been associated with a life threatening risk of aortic dissection but no arrhythmic death has been previously reported. Two young females carrying a TGFßR2 mutation, initially diagnosed as Marfan syndrome or Loeys Dietz syndrome, presented sudden death with autopsy ruling out dissection. The ECGs of the 2 Sudden Cardiac Deaths revealed profound ventricular repolarization abnormalities with a sinusoidal T-U morphology associated with normal left ventricular ejection fraction. These data strongly suggest sudden cardiac arrhythmic deaths and prompted us to systematically study the repolarization pattern in the patients with TGFßR2 mutations. ECG findings from 58 mutation carriers patients (TGFßR2 group) were compared with those of 46 non-affected first degree relatives (control group). TGFßR2 mutation was associated with ventricular repolarization abnormalities in 47% of patients (p < 0.001 vs. controls), including a 19.6 ms (95%CI 8.7; 30.5) QTc interval prolongation compared to the non-affected first degree relatives (p < 0.001), higher prevalence of abnormal U waves (16% vs. 2%), and sinusoidal T-U morphology (10% vs. 0%). TGFßR2 mutations can be associated with abnormal ventricular repolarization pattern, longer QT interval than non-carrier relatives and an increased risk for sudden death.

Influence of blood glucose on heart rate and cardiac autonomic function. The DESIR study.

OBJECTIVES: To evaluate in a general population, the relationships between dysglycaemia, insulin resistance and metabolic variables, and heart rate, heart rate recovery and heart rate variability. METHODS: Four hundred and forty-seven participants in the Data from an Epidemiological Study on the Insulin Resistance syndrome (DESIR) study were classified according to glycaemic status over the preceding 9 years. All were free of self-reported cardiac antecedents and were not taking drugs which alter heart rate. During five consecutive periods: rest, deep breathing, recovery, rest and lying to standing, heart rate and heart rate varability were evaluated and compared by ANCOVA and trend tests across glycaemic classes. Spearman correlation coefficients quantified the relations between cardio-metabolic risk factors, heart rate and heart rate varability. RESULTS: Heart rate differed between glycaemic groups, except during deep breathing. Between rest and deep-breathing periods, patients with diabetes had a lower increase in heart rate than others (P(trend) < 0.01); between deep breathing and recovery, the heart rate of patients with diabetes continued to increase, for others, heart rate decreased (P(trend) < 0.009). Heart rate was correlated with capillary glucose and triglycerides during the five test periods. Heart rate variability differed according to glycaemic status, especially during the recovery period. After age, sex and BMI adjustment, heart rate variability was correlated with triglycerides at two test periods. Change in heart rate between recovery and deep breathing was negatively correlated with heart rate variability at rest, (r=-0.113, P < 0.05): lower resting heart rate variability was associated with heart rate acceleration. CONCLUSIONS: Heart rate, but not heart rate variability, was associated with glycaemic status and capillary glucose. After deep breathing, heart rate recovery was altered in patients with known diabetes and was associated with reduced heart rate variability. Being overweight was a major correlate of heart rate variability.

[Primary anomalies of ventricular repolarisation]. / Anomalies primaires de la repolarisation ventriculaire. Conséquences electrophysiologiques.

The duration of repolarisation is the main determinant of the refractory period and therefore plays a major electrophysiological role. Ventricular repolarisation can be influenced or modified by very many extrinsic factors responsible for so-called secondary changes or anomalies. On the contrary, primary anomalies of ventricular repolarisation correspond to intrinsic anomalies of ionic conduction which in turn affect repolarisation. Primary anomalies of ventricular repolarisation are the consequences of vascular disease, which is the origin of both electrocardiographic anomalies and rhythm disorders, and which can result in sudden death from ventricular fibrillation. Three clinical syndromes correspond with these definitions: long QT syndrome, short QT syndrome, and Brugada syndrome. Much of the experimental work seems to show that arrhythmogenic action results mostly from an increase in the heterogeneity of the refractory periods, whether this involves a prolonged, short or even normal repolarisation time. The various experimental models also give a better understanding of the repolarisation changes observed on the electrocardiogram. Knowledge of the mechanisms responsible for arrhythmias due to primary anomalies of ventricular repolarisation could provide a model for secondary anomalies.

[Recent concepts of the Brugada syndrome, the long QT syndrome and adrenergic ventricular tachycardias]. / Aspects récents dans le syndrome de Brugada, le syndrome du QT long et les TV catécholergiques.

The clinical syndromes responsible for sudden death have benefited from spectacular advances in recent years. The authors propose a brief review of the genetic, electrophysiological, physiopathological and clinical characteristics of the long QT syndrome, Brugada's syndrome, adrenergic ventricular tachycardias and the short QT syndrome. The initial concept of one gene responsible for one pathology has uncovered new zones of complexity within diseases considered to be monogenetic in origin. These new findings have impacted on diagnostic and therapeutic strategies of these conditions. However, the assessment of the arrhythmic risk and the choice of treatment in individual cases still remain almost exclusively the domain of clinical judgement. Similarly, the better understanding of the mechanisms of the arrhythmias in these syndromes has opened up new specific therapeutic approaches which require validation by clinical trial.

[Role of antiarrhythmics in the treatment of paroxysmal atrial fibrillation]. / Place des antiarythmiques dans le traitement de la fibrillation auriculaire paroxystique.

Atrial fibrillation is not a homogenous entity. Numerous parameters affect its cause, its continuation, and the arrest of an attack. The presence or absence of cardiopathy and left ventricular dysfunction play a major role via the electrophysiological and haemodynamic consequences and the repercussions on the state of the autonomic nervous system, and finally on the effect of anti-arrhythmics themselves. This shows the importance of taking into account all of these parameters together in order to adapt the therapeutic approach. Equally, this underlines the difficulty in interpreting clinical studies comparing pharmacological treatments when the populations treated are poorly defined or very heterogenous. Most often, one drug is not more or less effective than another, it is more or less suited to the patients treated. The frequency of recurrences of AF despite anti-arrhythmic treatment (on average 50% to 60% at one year) means that in paroxysmal AF the goal of anti-arrhythmic treatment is relatively modest: essentially reducing the frequency, duration and severity of AF attacks, allowing an improvement in the quality of life. The consequences in daily practice are clear: one must ensure good patient compliance and minimise the risks of treatment: side effects of and pro-arrhythmic effects of anti-arrhythmics.

A neural network approach for predicting and modelling the dynamical behaviour of cardiac ventricular repolarisation.

Physiological signals are usually patient specific, and they are difficult to predict, especially for the cardiovascular system. New methods capable to be adapted to each case and to learn the singular behavior of heart functions should be developed to support physicians in their decision-making. One of the most widely studied relations is the QT-RR one, between the total duration of the ventricle activation and inactivation, and the heart rate. In the past, different studies were made to approach this relation in the steady state. In this paper, a new method for modeling and predicting the transient dynamic behaviour of QT interval in relation to changing RR intervals is presented using artificial neural networks.

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.

[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.

Parasympathetic activity during parabolic flight, effect of LBNP during microgravity.

BACKGROUND/HYPOTHESIS: During parabolic flight, in the standing position, changes are partly due to an acute shift in fluid between the lower extremities, the head and the thorax (Vaïda P, et al. J Appl Physiol 1997; 82:1091-7; and Bailliart O, et al. J Appl Physiol 1998; 85:2100-5). We hypothesized that modifications of parasympathetic activity associated with changes in hydrostatic pressure gradients induced by changes in gravity could be detected by analysis of short time periods. METHODS: We assessed heart rate variability (HRV) in 11 healthy volunteers by indices of temporal analysis (NN, SDNN, RMSSD) and normalized indices such as coefficients of variation CV-SDNN and CV-RMSSD and ratio SDNN/RMSSD. A lower body negative pressure (LBNP) at -50 mm Hg was randomly applied during the microgravity phase (0 Gz) to counteract the lack of hydrostatic pressure in the lower part of the body. RESULTS: NN, CV-SDNN and CV-RMSSD decreased during hypergravity phases and increased during microgravity and during early normogravity (1 Gz) period at the end of parabolas. With LBNP changes are less pronounced at 0 Gz and in the 1 Gz post parabolic period. CONCLUSION: We concluded that parasympathetic nervous activity is recordable by temporal analysis of HRV during short periods of time. LBNP applied during 0 Gz phase reduced the parasympathetic activation at 0 Gz and post parabolic 1 Gz.

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.

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.

Influence of sympathetic heart rate modulation on RT interval rate adaptation in conscious dogs.

The objective was to test if changes in autonomic tone still influenced the RT-RR relationship when full RT adaptation is completed, when heart rate is controlled, and when beat-to-beat variability is abolished by atrial pacing. Eight dogs (8-11 kg) were chronically instrumented with atrial pacing electrodes. Digital ECG (1,000 Hz, 12 bits) were recorded from healthy conscious dogs during spontaneous sinus rhythm and during atrial pacing. The protocol was repeated before and after atenolol (2 mg/kg), prazosin (0.5 mg/kg), or atenolol + prazosin. A vocal incitation was used as sympathetic stimulation. Beat-to-beat quantitative analysis of the RT interval (from QRS apex to end of T wave) was correlated with the preceding RR by linear regression. In spontaneous rhythm, atenolol increased RR (P < 0.001), RT (P < 0.001), and short-term heart rate variability (P < 0.01) and decreased RT-RR slopes (P < 0.001). Prazosin did not significantly modify any parameter. Sympathetic stimulation decreased RR (P < 0.001), RT (P < 0.05), and short-term heart rate variability (P < 0.01) and increased RT-RR slopes (P < 0.001). In atrial pacing, the RT-RR slopes were steeper during pacing than during spontaneous rhythm but were not modified by pharmacological manipulation of the autonomic nervous system. During sinus rhythm the RT-RR relationship is increased by sympathetic stimulation and decreased by beta-blockade. When heart rate modulation and the effects of the time delay in RT rate adaptation are abolished by atrial pacing, the influence of autonomic tone on RT rate adaptation disappears.

[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.

QT interval analysis on ambulatory electrocardiogram recordings: a selective beat averaging approach.

A computerised method for the analysis of QT intervals in ambulatory ECG recordings is presented. This approach is based on selective beat averaging which allows one to process P-QRS-T complexes together with the environment that characterises them. Long-term autonomic nervous system influences are accounted for by separating the analysis over different circadian periods. Effects of QT recovery time are taken into account by requiring a stable heart rate preceding each beat to be averaged. Before averaging, beats are resampled and realigned with respect to the R-wave peak estimated by parabolic interpolation. Averaged ECG templates are then analysed with an algorithm which automatically detects QRS complex and T-wave features. Repolarisation analysis is based on first and second derivatives of lowpass filtered ECG (recursive Butterworth filter). The QT/RR relationship and the circadian QT variation at identical heart rate were analysed in 14 normal individuals. When performed at stable heart rate conditions and when confined to well-defined circadian periods, the QT/RR relationship was strongly linear (r = 0.95 +/- 0.06); in addition, the slope of this relation changed between day and night (respectively, 0.197 +/- 0.07 and 0.139 +/- 0.03, p < 0.01). The range of circadian QT variation at identical heart rate was approximately 20 ms for both males and females.

[Mechanism of spontaneous occurrence of tachycardia]. / Mécanismes de démarrage spontané des tachycardies.

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.

QT interval and arrhythmic risk assessment after myocardial infarction.

To assess ventricular repolarization features as predictors of ventricular tachyarrhythmias (VT) in patients with previous myocardial infarction, we performed a dynamic study of QT interval from 24-hour electrocardiographic data. QT rate dependence was enhanced in patients with VT when compared with patients without VT.