Sotalol testing unmasks altered repolarization in patients with suspected acquired long-QT-syndrome—a case-control pilot study using i.v. sotalol

Stefan Kääb*, Martin Hinterseer, Michael Näbauer and Gerhard Steinbeck

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
 Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
 References
 
Aims The aim of this pilot study was to evaluate provocative sotalol testing to unmask abnormal repolarization due to altered myocardial electrical properties as the key feature in acquired Long-QT-Syndrome. Reliable diagnosis and risk stratification for the individual patient are complicated by the multitude of mechanisms involved in acquired QT-prolongation. The combined influence of all components determines susceptibility to arrhythmias related to QT-prolongation.

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
 Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
 References
 
The occurrence of torsades de pointes arrhythmias with potentially lethal outcome has been identified as a major risk of antiarrhythmic as well as ofsome non-antiarrhythmic drugs. Despite the rapidlyexpanding knowledge of genetic and molecularaspects of the pathophysiology of congenital Long-QT-Syndrome, predisposing factors and strategies for identifying patients at risk for acquired Long-QT-Syndrome remain obscure.1–5

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.3,6,8–10 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.10–12

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.13–15 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 drug–druginteractions 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
 Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
 References
 
Twenty consecutive patients who had experienced torsades de pointes tachycardia in association with QT-prolonging drugs were tested with sotalol to evaluate repolarization reserve. Data were compared to QT- and QTc-changes in an age and sex matched control group. The control population was selected from a total of 24 patients who were started on sotalol for prevention of paroxysmalAF and had given informed consent to receivetheir first dose, closely monitored intraveneously, according to the study protocol. Twenty-sevenpatients were screened and i.v. sotalol tests were performed in 24 patients to obtain 20 matched controls (Table 1). All patients in both groups had a history of paroxysmal atrial fibrillation or atrial flutter. Concomitant medication for hypertension or mild congestive heart failure in control andstudy groups were diuretics (2/6), ACE inhibitors (7/7), and digoxin (0/2), respectively. Two patients in each group were on glibenclamide for type II diabetes. No beta-adrenoceptor blocking agents or antiarrhythmic medication were taken, at least five plasma half-lives of the respective drug, before testing. Patients with impaired renal function or impaired hepatic function were excluded. Serum creatinine, creatinine clearance, transaminaselevels, serum albumine, and INR were all within reference limits. At the time of testing, all patients were in good and stable clinical condition. Electrolyte levels and thyroid hormones were within reference limits 3 days prior to and at the time of testing. The study was approved by the local ethics committee of the university, and all patients provided written informed consent. The procedures followed were in accordance with institutional guidelines.


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Table 1 Patient characteristics of the control group

 
2.1. Protocol
After obtaining venous access via a large vein, subjects rested in a supine position for 60–90min prior to testing. For safety reasons, testing was performed in the ICU with all patients (control and study population) continuously monitored (rhythm, non-invasive blood pressure) from 1h before to 24h after testing. All patients had fasted at least 6–8h prior to testing and 2h following sotalol exposure. Tests were performed during morning hours between 9 a.m. and 1 p.m. For treatment of potentially induced torsades de pointes arrhythmias, infusions containing 500mg magnesium in 100ml of 0.9% saline and 40mEq/l potassiumin 500ml of 0.9% of saline were prepared. Surface 12-lead ECGs (Mortara Instr., Milwaukee, WI, USA) were repeatedly recorded with the patient resting supine: at baseline, in 5-min intervals during sotalol infusion and a 20-min steady state phase, and on the next day. Venous blood samples were taken at baseline for serum sodium, potassium, magnesium, calcium, creatinine, and thyroid hormone measurement. D,L-sotalol was given intravenously at a constant rate over a 20-min interval at a dose of 2mg/kg in 50ml of 0.9% saline solution. At the time of sotalol testing all patients were in stable regular sinus rhythm.

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 5–10min after completion of sotalol infusion was selected for data analysis.

2.3. Statistical analysis
Statistical analysis was performed by Mann–Whitney 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
 Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
 References
 
3.1. Control and study population
The study and the control group each consisted of 14 females and six males. Mean age was 57±13 and 60±13 years in the control and the study groups, respectively. In the study population, the index arrhythmic event was syncope in three patients, and required repetitive defibrillation and mechanical resuscitation in the other 17 patients. In all patients, torsades de pointes arrhythmias occurred during sinus rhythm. Time from arrhythmic event to sotalol test was 20±13 days (range 4–40 days). Medication was most likely responsible for triggering the arrhythmic event in the 20 patients which is shown in Table 2. In addition, hypokalemia was documented in five patients close to the arrhythmic episode (Table 2). Average time on medication likely to have caused the arrhythmia was 3±1 days. Three patients in the control group had stable coronary heart disease compared to six patients in the study population. Mild heart failure (NYHA II) was present in two patients of the study population and in none of the control group. Echocardiography was performed in all patients and revealed no significant differences between control and study population with respect to structure (left ventricular enddiastolic diameter 51±4 vs. 50±4mm), wall thickness (enddiastolic diameter septum 10±1.9 vs. 11±3.0mm; enddiastolic diameter posterior wall 10.8±1.6 vs. 11.2±2.8mm) and myocardial function (fractional shortening 37±7 vs. 36±7%).


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Table 2 Patient characteristics of the study group

 
Electrophysiological study was performed in all patients of the study population. Sustained ventricular tachyarrhythmias could not be induced in any of the subjects by programmed ventricular stimulation using a standard protocol with two premature stimuli. Baseline potassium levels were not different between control and study population at the time of testing (4.4±0.3 vs. 4.5±0.3mmol/l).

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).


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Table 3 Summarized ECG parameters in control and study groups

 


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Fig. 1 Individual QTc-intervals in control and study groups before and after sotalol. The dotted line indicates a cut off value of 480ms that distinguished best between study population and control group.

 


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Fig. 2 Averaged QTc-intervals in control and study groups before and after sotalol. Box plots indicating the median and the 25th to 95th percentile. Error bars indicate 5 and 95% confidence interval. The dotted line indicates a cut off value of 480ms that distinguished best between study population and control group.

 
Cycle lengths were similar at baseline (952±137 vs. 891±145ms) and after sotalol challenge (1116±145 vs. 1079±173ms) both in the control and the study population.

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
 Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
 References
 
Labile repolarization is likely to be the key substrate for arrhythmogenesis in acquired Long-QT-Syndrome. In order to assess lability of repolarization in the absence of QT-prolongation and to reliably identify patients with suspected acquired Long-QT-Syndrome, a novel method to evaluate repolarization stability was applied using provocative testing with sotalol. The present study reveals that in patients with a previous episode of symptomatic acquired Long-QT-Syndrome, sotalol disproportionally prolonged QTc-interval as compared to an age and sex matched control group. By excluding patients with impaired renal or hepatic function and selecting i.v. sotalol for challenging repolarization stability the pathophysiologic focus for altered repolarization is on intrinsic electrophysiological properties of the heart causing a decrease of myocardial repolarization reserve rather than dose–response effects due to altered drug metabolism. Moreover, provocative testing with sotalol under stable clinical conditions and close monitoring in specialized centers may be capable of identifying patients with this intrinsic predisposition to acquiredLong-QT-Syndrome.

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.23–25 In congenital Long-QT-Syndrome, altered repolarization caused by abnormal ion channel function has been shown to be closely linked to arrhythmogenesis.2–4 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 75–90% of an oral or intravenous dose being recovered in the urine within 48h of administration. The plasma elimination half-life of sotalol is 6–15h 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 4–40 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
 
The authors wish to thank Dr Dirschedl (Department of Medical Informatics, Biometry and Epidemiology) for his expert advice in planning and analyzing this study.

This study was supported in part by the Friedrich-Baur-Stiftung and BMBF-Grant 01GS0109.


    References
 Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
 References
 

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