LMU München, Klinikum Großhadern, Department of Medicine I, 81366 Munich, Germany
* Corresponding author. Tel.: +49-89-7095-3049; Fax: +49-89-7095-6076
E-mail address: skaab{at}helios.med.uni-muenchen.de
accepted 16 October 2002
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Methods Twenty consecutive patients who had experienced torsades de pointes in association with QT-prolonging drugs were tested with i.v. D,L-sotalol (2mg/kg) with 24-h intensive care monitoring to evaluate the repolarization process by determining QT- and QTc-prolongations. Results were compared to age and sex matched controls.
Results At baseline, no differences between control and study population with regard to QT and QTc were detected. After sotalol infusion, QTc increased from 422±17 to 450±22ms in controls and from 434±20 to 541±37ms in the study population. Torsades de pointes occurred in three out of 20 patients (15%) in the study population but in none of the control patients following i.v. sotalol testing.
Conclusions Controlled exposure to sotalol successfully identifies patients with normal QTc intervals but altered myocardial repolarization. This may be useful for clarifying diagnosis and pathogenesis of acquired Long-QT-Syndrome.
Key Words: Long-QT syndrome Repolarization Torsades de pointes Risk factors D,L-sotalol
![]() |
1. Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Current understanding postulates extrinsicfactors to destabilize repolarization, while anunknown number of intrinsic myocardial variables may predispose to an increased lability of therepolarization process.3 Evidence for an increased susceptibility to QT-prolongation upon challengeof repolarization led to the concept of altered repolarization reserve as a proarrhythmic substrate.6 Disproportionate QT-prolongation during therapy with class I or III antiarrhythmic agents followed by arrhythmias of the torsades de pointes type have long been described as unpredictable for an individual patient.7 More recently, increasing awareness of drug induced arrhythmias has pointed to the QT-prolonging and arrhythmogenic potential of a wide variety of non-antiarrhythmic drugs,expanding the population at risk and demonstrating the need for understanding factors determining susceptibility for drug induced Long-QT-Syndrome in the individual patient.8
Experimental evidence demonstrates that QT-prolongation by class III antiarrhythmic agents as well as by non-antiarrhythmic drugs is primarily due to block of the rapidly activating component of the delayed rectifier potassium current, IKr.3,6,810 In this context, hypokalemia may increase labilerepolarization both by reducing intrinsic potassium outward current (IKr) and by increasing drug binding to the channel, resulting in excessive prolongation of repolarization.1012
Attempts to explain the individual predisposition to acquired Long-QT-Syndrome by mutations in HERG and MiRP, the alpha and beta subunits presumably encoding the human IKr, or by mutationsin other genes known to cause congenital Long-QT-Syndrome, so far revealed apparent genetic predisposition only in a small fraction of patients.1315 Clinical and experimental evidence led to the hypothesis of a variable impact of a number of modifier genes that affect both susceptibility and severity of acquired Long-QT-Syndrome.3,16,17 In addition, altered drugmetabolism due to renal or hepatic insufficiency, cytochrome P-450 polymorphism, or drugdruginteractions with an unpredictable increase of the plasma concentration of QT-prolonging drugs have been implicated to be crucial for the occurrence of acquired Long-QT-Syndrome.4
Among the many risk factors for drug induced torsades de pointes, none has been rigorouslyvalidated with respect to its actual role for the predisposition to acquired Long-QT-Syndrome.1 The preponderance of, e.g. female gender18,19 and heart failure20 in patients with acquired Long-QT-Syndrome suggests that intrinsic electrophysiological properties of the myocardium (genetically determined or acquired) may be of major importance. Additional factors such as hypokalemia and exposure to QT-prolonging drugs may cause disproportionate QT-prolongation and torsades de pointes arrhythmias primarily in patients with intrinsic myocardial predisposition, manifested by reduced repolarization reserve.
The present study aimed to establish a clinical test to assess the stability of the myocardialrepolarization process to substantiate themechanisms and the diagnosis of acquired Long-QT-Syndrome and to potentially offer a novel toolfor risk stratification for selected patients in the future.
![]() |
2. Patients and methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
2.2. ECG analysis
The ECG readings were analyzed manually by a single observer blinded to patient data and diagnosis, and were confirmed by a second observer in a blinded manner. The QT-interval was measured in each of the 12 leads from the onset of the QRS complex to the end of the T wave (a tangent from the downstroke of the T wave crossing the isoelectric line).21 QTc was calculated using Bazett's formula .22 The longest QT-interval in any of the 12 leads at baseline and 510min after completion of sotalol infusion was selected for data analysis.
2.3. Statistical analysis
Statistical analysis was performed by MannWhitney Rank Sum Test and Wilcoxon Signed Rank Test as appropriate. All hypotheses were two-tailed, and a value of was considered to be significant. Data are presented as mean±SD if not stated otherwise.
![]() |
3. Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
3.2. Sotalol test
At baseline, there were no differences between control and study population with regard to ECG parameters (regular sinus rhythm in all), in particular QT and QTc (Table 3). After sotalol infusion, QT and QTc increased from 406±27 to 470±31ms (QT) and 422±17 to 450±22ms (QTc) in controls and from 404±39 to 561±68ms (QT) and 434±21 to 541±37ms (QTc) in the study population. QT-prolongation was more pronounced in every patient of the study population as comparedto its matched control(Fig. 1;comptd;;center;stack;;;;;6;;;;;width> ). QT- and QTc-intervals as well as relative QT- and QTc-changes after sotalol were significantly longer in the study population as compared to control patients (Figs. 1 and 2;comptd;;center;stack;;;;;6;;;;;width> , Table 3).
|
|
|
3.3. Adverse events
Two patients of the study population developed short episodes of asymptomatic non-sustainedtorsades de pointes arrhythmias after the end of sotalol infusion (10 and 45min after completionof infusion). Both patients received magnesium (500mg) and potassium (40mmol/l over a 2-hperiod) supplementation intravenously, whichresulted in prompt and sustained suppression of the short episodes of torsades de pointes arrhythmias. One patient of the study population developed a prolonged episode of torsades de pointes (5min after completion of sotalol infusion) that required one time defibrillation in addition to magnesium and potassium supplementation. In the control group no adverse events were observed.
3.4. Follow-up
All medications potentially prolonging repolarization were stopped in patients with acquired Long-QT-Syndrome. Additionally, these patients were advised to avoid hypokalemic states. At a mean follow-up of 18±7 months there were no deaths or documented arrhythmic events neither in the study nor in the control population. Sotalol was continued as oral medication in control patients on average for 12±7 months.
![]() |
4. Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Given the poor correlation between genotype and clinical presentation, provocative drug testing for repolarization stability may also prove to be a useful tool in identifying the risk of arrhythmic events both in selected asymptomatic and symptomatic patients with congenital Long-QT-Syndrome in the future.
4.1. Patient selection
With the primary goal to proof the principle of altered myocardial repolarization in patients with acquired Long-QT-Syndrome and to potentiallyestablish a test to identify patients with a predisposition to acquired Long-QT-Syndrome, for this pilot study we chose patients with documented torsades de pointes tachycardia that, from thepatient's history, were likely to be associated with QT-prolonging drugs. To clarify whether the predisposition to acquired Long-QT-Syndrome isrelated to altered myocardial electrophysiological properties rather than to abnormal drug metabolism or accumulation, or additional variables such as serum electrolyte concentrations and female gender18,19 these factors that might influencerepolarization stability were taken into account and controlled. We used a sex matched control group, excluded hepatic and renal impairment, and closely controlled serum potassium levels in all individuals tested.
As a control group, age and sex matched patients were selected who had to be started on sotalol medication for prevention of atrial fibrillation or atrial flutter. Since all patients of the studypopulation had a history of atrial fibrillation or flutter, it seemed appropriate to select a control group of patients with a similar clinical history.
4.2. Repolarization reserve
Instability and prolongation of repolarization has long been linked to ventricular arrhythmogenesis and torsades de pointes in a number of experimental models.2325 In congenital Long-QT-Syndrome, altered repolarization caused by abnormal ion channel function has been shown to be closely linked to arrhythmogenesis.24 Similarly, arrhythmogenesis and sudden cardiac death in case of heart failure may also be promoted by an acquired repolarization abnormality due to downregulation of repolarizing potassium currents.26,27 In a small clinical study, Choy et al.28 showed that increasing serum potassium concentrations, an intervention known to increase repolarizing K+-currents, could partially reverse altered repolarization due toeither heart failure or quinidine. In an attempt to identify risk factors for drug induced torsades de pointes, Houltz et al.29 investigated the effect of almokalant infusion (IKrblock) in patients with chronic atrial fibrillation or atrial flutter in an uncontrolled fashion. Although QT-analysis was hampered by the presence of atrial fibrillation, six patients developing torsades de pointes showed more pronounced QT-prolongation and T-wave changes after IKrblock with almokalant thanpatients without arrhythmic event. In a retrospective analysis of 1288 patients receiving sotalol (85% of patients for control of ventricular arrhythmias), QTc after initiation of sotalol therapy was significantly longer in those patients who later developed serious proarrhythmias as compared to patients with no proarrhythmic events.30
4.3. Sotalol for testing repolarization reserve
Sotalol is frequently used for treatment of ventricular and supraventricular arrhythmias. Its QT-prolonging potential is well studied and mediated predominantly by block of IKrwhich appears to be the target of most antiarrhythmic and non-antiarrhythmic drugs with QT-prolonging potential.10 Hepatic biotransformation of sotalol is limited, and no pharmacologically active metabolites have been identified. Elimination occurs via the renal route, with 7590% of an oral or intravenous dose being recovered in the urine within 48h of administration. The plasma elimination half-life of sotalol is 615h on acute administration. Obesity or hepatic impairment does not significantly modify the pharmacokinetic properties of sotalol, while renal insufficiency accounts for major sotalol accumulation. In patients withnormal renal function, D,L-sotalol seemed the most suitable drug to challenge repolarization stability by blocking IKrin a controlled way. The betablocking effects of D,L-sotalol did not appear to interfere with analysis since comparable results were obtained using absolute and frequencycorrected QT-intervals.
4.4. Quantification of repolarization reserve
Disorders of repolarization are currently bestdescribed by ECG parameters such as QT- and QTc-intervals, and QT-dispersion. The value of any of the QT-parameters to assess the risk of potentially lethal ventricular arrhythmias in patients after myocardial infarction, with ischemic or dilatedcardiomyopathy, as well as in patients withcongenital Long-QT-Syndrome, still is notconvincing.31
Provocative drug testing challenging repolarization in a controlled way (e.g. block of IKrby sotalol) in our study proved to be a conclusivetest to differentiate patients with heterogeneous factors predisposing to acquired Long-QT-Syndrome from a group of age and sex matched controls. None of the patients in the control group had an increase in QTc>480ms while all study patients had anincrease in QTc>480ms after sotalol infusion, indicating 480ms as a potential cut off for future studies (Figs. 1 and 2).
For calculation of heart rate corrected QT-interval, we used Bazett's formula22 because it is well established and has been evaluated in large studies. Calculation of QTc using formulas by Fridericia,32 Hodges33 and the Framingham Study34 revealed the same qualitative differences between study and control groups and would not haveaffected our findings.
4.5. Study limitations
All patients of the study had a history of paroxysmal atrial fibrillation or atrial flutter. Effects ofparoxysmal atrial fibrillation on ventricularrepolarization reserve and the predisposition to acquired Long-QT-Syndrome cannot be excluded, but seem unlikely and would have affected both groups in a similar way. The history of atrialfibrillation or flutter in all patients of our study accounts for the dominance of sotalol as themedication that presumably had triggered thearrhythmic event (15/20).
As an alternate source for altered myocardial electrical properties and altered repolarizationreserve we cannot fully rule out incomplete recovery from resuscitation/defibrillation in our study population (average time between defibrillation (17 patients) and sotalol test was 20±13 days (range 440 days). Yet QT-prolongation did not correlate with time after resuscitation/defibrillation or number/energy of defibrillation or CK-levels post resuscitation/defibrillation.
Given the high rate of induced torsades de pointes in patients predisposed to acquired Long-QT-Syndrome (15%) and the intensity of clinical monitoring in an ICU for 24h required for patient safety, sotalol challenge as a clinical test willbe reserved for selected patients in specialized centers.
On the other hand, careful selection of patients and matched pairs allowed to define and proof a pathophysiological and diagnostic principle and may mark a starting point for future trials that are needed to establish the validity of sotalol testing for risk assessment for the development of torsades de pointes arrhythmias including a wider spectrum of QT-prolonging drugs.
4.6. Clinical implications
We started to establish a novel test to identify patients with an intrinsic predisposition to torsades de pointes arrhythmias. Our pilot study suggests that this predisposition to acquired Long-QT-Syndrome is primarily due to specific myocardial electrical properties rather than to conditionssuch as altered drug metabolism or electrolyte imbalance. Provocative drug testing to unmasklatent abnormalities in myocardial repolarization may allow to substantiate the diagnosis of acquired Long-QT-Syndrome and help to identify selected patients at risk for developing torsades de pointes. A larger trial may be necessary to validate our findings.
![]() |
Acknowledgments |
---|
This study was supported in part by the Friedrich-Baur-Stiftung and BMBF-Grant 01GS0109.
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|