Faculty Bibliography

BACKGROUND: QT interval dispersion, measured as interlead variability of QT, is a marker of dispersion of ventricular repolarization and, hence, of cardiac electrical instability. We tested the hypothesis that dispersion of ventricular repolarization may be differently affected by interventions destined to provide complete or incomplete protection against malignant arrhythmias in patients with long QT syndrome (LQTS). Twenty-eight patients affected by the Romano Ward form of LQTS entered the study and were divided into three groups: LQTS patients before institution of therapy, patients who did respond to beta-blocker therapy, and patients who continued to have syncope and cardiac arrest despite beta-blockade and who underwent left cardiac sympathetic denervation. A group of 15 healthy volunteers served as control subjects. METHODS AND RESULTS: Dispersion of QT and QTc were calculated using two indexes: the difference between the longest and the shortest value measured in each of the 12 ECG leads (QTmax-QTmin, QTcmax-QTcmin) and the relative dispersion of QT and QTc (standard deviation of QT/QT average x100, standard deviation of QTc/QTc average x100). Both indexes of dispersion of repolarization were higher in the LQTS patients than in control subjects; also, patients not responding to beta-blockers had a significantly higher dispersion of repolarization than responders. A cutoff value of 100 milliseconds for QTmax-QTmin had an 80% sensitivity and 82% specificity in discriminating between responders and nonresponders. A cutoff value of 6 for QT relative dispersion yielded similar results. The LQTS patients who did not respond to beta-blockade underwent left cardiac sympathetic denervation and thereafter remained asymptomatic (mean follow-up, 5 +/- 4 years). In this group, dispersion of repolarization was significantly reduced by the surgical denervation to values similar to that of the responders to beta-blockade. CONCLUSIONS: These data indicate that QT dispersion is a useful clinical tool to predict efficacy of antiadrenergic therapy in LQTS patients

Torsade de pointes is a polymorphic ventricular tachycardia showing a peculiar electrocardiographic pattern characterised by a continuous twisting in QRS axis around an imaginary baseline. An abnormally prolonged QT interval is actually associated with torsade de pointes and it is constantly observed in the sinus beats preceding the onset of the arrhythmic event. Prolongation of ventricular repolarisation associated with the development of torsade de pointes can be observed in many clinical conditions, commonly referred to as prolonged QT syndromes, which can be divided into two major groups: (a) idiopathic long QT syndrome (LQTS), which include the Jervell-Lange-Nielsen and the Romano-Ward syndromes; and (b) acquired prolonged QT syndromes, which are largely iatrogenic and may follow treatment with antiarrhythmic drugs, tricyclic antidepressants, phenothiazines or macrolide antibiotics, and may be associated with metabolic disturbances (hypokalaemia, hypocalcaemia and hypomagnesaemia). Clinical studies have provided criteria for the definition and guidelines for the management of torsade de pointes, while the electrophysiological mechanisms responsible for its onset are still unclear. Two pathogenetic hypotheses have been proposed to account for the electrophysiological mechanisms underlying the condition: (a) re-entry due to a dispersion of refractory periods; and (b) triggered activity initiated by either early or delayed after-depolarisations. Both mechanisms are supported by clinical and experimental observations but a conclusive answer is not yet available

New evidence has been accumulated allowing a better understanding of the physiology and pathophysiology of receptors in the heart. Three major receptor systems influence electrophysiological characteristics of myocardial cells and are critical in the development and prevention of cardiac arrhythmias: the adrenergic, the muscarinic and the adenosine systems. Although it has long been recognized that beta adrenergic stimulation is arrhythmogenic, only recently have the mechanisms of this arrhythmogenic effect been clarified. In addition, the contribution to arrhythmogenesis of alpha receptor stimulation, which has been overlooked for many years, has been recognized as an important accompaniment to the beta component, especially during hypoxia-ischaemia. On the other hand, it has been demonstrated that although direct electrophysiological effects of acetylcholine on the ventricle remain controversial, the antagonism of sympathetic activation by cholinergic stimulation may be important in preventing arrhythmias induced by a high sympathetic tone in the presence of myocardial ischaemia. More recently, the importance of the adenosine system has been better appreciated. Experimental studies have shown that adenosine receptor activation inhibits the adenylyl cyclase system by activating the Gi regulatory proteins. Activation of this pathway inhibits the development of adrenergic-dependent triggered activity in isolated cells and these have also been confirmed in man. It is likely that this effect is specific against triggered rhythms induced by adrenergic activation. Even though further research is needed to clarify fully the interaction of these three systems at the subcellular level, the pharmacological modulation of these cardiac receptors appears as a rational approach for refining the treatment of arrhythmias

Torsades de pointes (TDP) is a polymorphic ventricular tachycardia with a peculiar electrocardiographic pattern of continuously changing morphology of the QRS complex twisting around an imaginary baseline. The clinical setting under which TDP develops covers many clinico-pathologic conditions, including the long QT syndrome (LQTS). In the present review, we analyze the evolution of the hypotheses for the mechanisms underlying TDP and we discuss some of the experimental models used and their related clinico-pathologic counterparts. Together with the hypothesis that TDP represents a form of reentrant arrhythmia, recent evidence has suggested the possibility that triggered activity may indeed be responsible for TDP. Data collected in vitro are presented that demonstrate a role for catecholamines in the development of afterpotentials in ventricular tissue. Whether adrenergic-mediated afterdepolarizations are the mechanism responsible for TDP in the clinical setting of LQTS has not yet been proven and remains an important area of investigation

Recent studies in vitro have shown that afterdepolarizations may develop during reperfusion after hypoxia, thus suggesting that these afterdepolarizations may contribute to the genesis of reperfusion arrhythmias. We recorded monophasic action potentials (MAPs) during myocardial ischemia and reperfusion to investigate whether afterdepolarizations develop in vivo when reperfusion arrhythmias occur. In 15 anesthetized cats, 24 trials of 10 minutes of occlusion of the left anterior descending coronary artery were followed by reperfusion. In 13 of 24 (54%) trials, afterdepolarizations developed at the moment of reperfusion, with a mean amplitude of 2.4 +/- 1.1 mV (13 +/- 8% of MAP amplitude). When cycle length was either increased by vagal stimulation or decreased by atrial pacing, early afterdepolarization (EAD) amplitude was modified, according to what has been described for EAD in vitro, with a positive linear correlation between cycle length and EAD amplitude (r = 0.91, p less than 0.0001). The occurrence of EAD was not related to rapid changes in left ventricular pressure. In the eight of 13 (62%) cases in which EAD development was associated with reperfusion arrhythmias, the coupling interval of the EAD and of premature ventricular contractions showed a significant correlation (r = 0.86, p less than 0.0001). However, in five of 13 (38%) cases, occurrence of reperfusion arrhythmias was not accompanied by the presence of EAD on the MAP recording. In two animals, a 2:1 block of EAD conduction was observed, and this was reflected on the intracavitary electrocardiogram as T wave alternans. Thus, EADs occur frequently after reperfusion in vivo, with a time course that parallels the onset of reperfusion arrhythmias. This finding further supports the role of triggered activity in the genesis of reperfusion arrhythmias in vivo