Journal of Electrocardiology
Volume 42, Issue 6 , Pages 505-510, November 2009

Intracardiac QT variability in patients with structural heart disease on class III antiarrhythmic drugs

  • Larisa G. Tereshchenko, MD, PhD

      Affiliations

    • The Division of Cardiology, Department of Medicine, Johns Hopkins Hospital, Baltimore, MD, USA
    • Cardiovascular Division, Washington University School of Medicine, St. Louis, MO, USA
    • Corresponding Author InformationCorresponding author. The Division of Cardiology, Department of Medicine, Johns Hopkins Hospital, Carnegie 592, 600 N. Wolfe St., Baltimore, MD 21287, USA.
    • ,
  • Barry J. Fetics, MS

      Affiliations

    • The Division of Cardiology, Department of Medicine, Johns Hopkins Hospital, Baltimore, MD, USA
    • ,
  • Ronald D. Berger, MD, PhD

      Affiliations

    • The Division of Cardiology, Department of Medicine, Johns Hopkins Hospital, Baltimore, MD, USA

Received 23 April 2009 published online 24 August 2009.

Article Outline

Abstract 

We previously showed that increased intracardiac repolarization lability predicts life-threatening ventricular arrhythmias in patients with structural heart disease. Patients with structural heart disease frequently take antiarrhythmic drugs (AADs), which directly affect repolarization. The effect of AADs on the predictive value of repolarization lability is unknown. We hypothesized that increased intracardiac beat-to-beat QT variability predicts sustained ventricular tachyarrhythmias in structural heart disease patients on class III AADs. Intracardiac electrograms and surface electrocardiogram were simultaneously recorded at rest for 5 minutes in 500 patients (mean ± SD age, 61 ± 14 years; 368 male [74%]) with implanted implantable cardioverter-defibrillator for primary (295 patients, or 79%) or secondary prevention of sudden cardiac death. Mean (SD) follow-up currently reached 24.8 (11.7) months. Intracardiac QT variability index was an independent predictor of ventricular tachycardia/ventricular fibrillation events and fast ventricular arrhythmias with cycle length of 240 ms or less in the multivariate Cox model. Intracardiac QT variability was higher in patients on class III AADs than in those not taking these drugs. Increased intracardiac QT variability after adjustment for class III AADs use carried independent risk of life-threatening ventricular tachyarrhythmias.

Keywords: Ventricular tachyarrhythmias, QT variability, Intracardiac electrograms, Class III antiarrhythmic drugs

 

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Introduction 

Cardiovascular diseases remain the main cause of death in the world,1 with sudden cardiac death (SCD) due to fast ventricular arrhythmias (FVAs) as the most frequent and the most dramatic. Remarkable success in prevention and treatment of SCD was achieved after invention of implantable cardioverters-defibrillators (ICDs). However, stratification of patients at risk for life-threatening ventricular tachyarrhythmias remains a difficult goal and a moving target.

Use of ICD for primary and secondary prevention of SCD opened a new era in cardiology. Monitoring and analysis of intracardiac electrograms (EGMs) in ICD patients help to study ventricular tachycardia (VT)/ventricular fibrillation (VF) mechanisms, to test both long-term (months and years) and short-term (minutes and seconds) predictors of VT/VF and ultimately to develop novel interventions that may prevent VT/VF onset. A few previous studies showed feasibility of intracardiac EGM analysis.2, 3 Intracardiac near-field (NF) right ventricular (RV) EGM T-wave alternans has shown significance for prediction of ventricular tachyarrhythmias in ICD patients.4 Our results5 showed that increased intracardiac QT variability predicts VT/VF events in patients with structural heart disease.

Widely used cardiovascular and noncardiovascular medications may affect the cardiac repolarization. It is well known that use of class I and III antiarrhythmic drugs (AADs) could change action potential duration (APD) and QT interval. In experiments, chronic and acute use of amiodarone and sotalol was associated with prolongation of QT interval and duration of the ventricular action potential, and increased beat-to-beat variability of APD.6 However, it is unknown how AADs modify the predictive value of intracardiac repolarization measures. We hypothesized that increased intracardiac beat-to-beat QT variability predicts sustained ventricular tachyarrhythmias in patients with structural heart disease, including those on class III AADs.

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Methods 

The ICD EGMs study protocol was approved by the Johns Hopkins University and the Washington University Human Studies Committees, and all patients gave written informed consent before entering the study.

Study population 

Adult patients with structural heart disease were eligible for the study if they had an ICD implanted for primary or secondary prevention of SCD. Patients who were pregnant, inherited channelopathies, and had concomitant conditions other than cardiac diseases with a high likelihood of death during 1 year after enrollment were excluded from the study.

Intracardiac EGMs recording 

Baseline recordings of NF RV intracardiac EGMs at rest during 5 to 15 minutes simultaneously with 1-lead (lead II) surface electrocardiogram were obtained via Medtronic programmer 2090 using the NI USB-9215A portable data acquisition system, with customized LabVIEW (National Instruments, Austin, TX) software application. Bipolar endocardial NF RV EGM was recorded as difference of potentials between the tip and the ring of the dedicated bipolar ICD lead implanted in the apex of RV.

Intracardiac beat-to-beat QT variability analysis 

Intracardiac beat-to-beat QT variability was measured as previously described.5, 7 Near-field RV EGM was used for automated R-wave peak detection. Template QT interval on NF EGM was defined by selecting the beginning and the end of QRS complex, and the end of the T wave. The algorithm then found the QT interval of all other beats by determining how much the ST segment and T wave of each beat must be stretched or compressed in time to best match the template. The heart rate mean and variance and QT interval mean and variance were computed from the 3- to 5-minute time series. A normalized QTVI was calculated according to equation: QTVI = log10 [(QTv/QTm2)/(HRv/HRm2)], where QTV is the QT interval variance, QTm is the QT interval mean, HRv is the heart rate variance, and HRm is the heart rate mean. Custom software was written in MATLAB (MathWorks, Inc, Natick, MA). Recordings with more than 15% of ectopic, paced, or noise-distorted beats were excluded from analysis; only normal sinus beats were analyzed. Sinus rhythm was confirmed by simultaneously recorded lead II surface electrocardiogram.

End points 

Sustained VT/VF that required appropriate ICD therapies (both shocks and antitachycardia pacing) was the primary end point for analysis. Fast ventricular arrhythmia was defined as VT/VF with the cycle length of 240 ms or less. Programming of the ICD device was based on the discretion of the attending electrophysiologist. Patients were followed-up in Washington University Arrhythmia Clinic and remotely via the Internet-based CareLink remote monitoring system. All events were reviewed by an ICD end point committee (attending electrophysiologist and 2 of the investigators [L.G.T. and R.D.B.]), who adjudicated each ICD event.

Use of AADs 

Information regarding indications, onset and duration of AADs use, and dose of AAD was collected at enrollment.

Statistical analysis 

Results are presented as mean ± SD for normally distributed variables and as median and interquartile range for nonnormally distributed variables. The independent samples t test was used to compare continuous variables if normally distributed and the Wilcoxon rank sum test if skewed. The Pearson χ2 test was used to compare categorical variables. A P value less than .05 was considered significant. Kaplan-Meier survival analysis was used to compare survival time. A univariate and multivariate Cox proportional hazards analysis was performed. STATA 10 (StatCorp LP, College Station, TX) software package was used for calculations.

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Results 

Among 298 eligible patients for repolarization analysis study, 216 were men (72.5%) and 82 were women (27.5%) who underwent ICD implantation for primary (231 patients, or 77.5%) or secondary (67 patients, or 22.5%) prevention of SCD. The mean (SD) age was 58.5 (14.1) years (range, 18-93 years). Ischemic cardiomyopathy with myocardial infarction history was diagnosed in 181 (60.7%) patients. A single-chamber Medtronic ICD was implanted in 221 (74.2%) patients and dual-chamber ICD in 77 (25.8%) patients. The patients were enrolled in the study in median time of 9.4 months after ICD implantation (range, 6 days to 8 years). During the mean (SD) follow-up of 24.8 (11.7) months, 61 patients sustained VT/VF (20.5% or 10.2% per person-year of follow-up) and received appropriate ICD therapies, and 22 of them sustained FVA with a cycle length of 240 ms or less (7.4%, or 3.7% per person-year of follow-up) with successful rescue ICD shocks. Clinical characteristics of patients are presented in Table 1.

Table 1. Clinical characteristics of patients with and without subsequent appropriate ICD therapy for VT/VF
No VT/VF events (n = 237)VT/VF events at follow-up (n = 61)P
Age, mean ± SD, y58.9 ± 13.859.8 ± 13.9.868
Females, n (%)62 (26)11 (18).189
African American, n (%)46 (19)7 (12).159
CHF NYHA class III, n (%)33 (14)9 (15).961
Ischemic CM with MI history, n (%)149 (63)42 (69).400
Primary prevention of SCD, n (%)191 (81)42 (69).055
Single-chamber ICD, n (%)171 (72)42 (69).633
LVEF, mean ± SD, %32.9 ± 12.632.5 ± 11.4.406
Diabetes mellitus, n (%)84 (36)28 (46).146
Hypertension, n (%)180 (76)47 (77).910
CABG, n (%)87 (37)22 (36).945
PTCA, n (%)78 (33)24 (39).350
β-Blockers, n (%)196 (83)55 (90).166
Aldosterone antagonists, n (%)84 (36)25 (41).440
Class 1 antiarrhythmic medication, n (%)1 (0.5)5 (8.2).01
Class III antiarrhythmic medication, n (%)48 (20)28 (46)<.0001

CHF indicates chronic heart failure; NYHA, New York Heart Association; CM, cardiomyopathy; MI, myocardial infarction; CABG, history of coronary artery bypass graft surgery; PTCA, history of percutaneous transluminal coronary angioplasty.

Intracardiac QT variability analysis 

Intracardiac QTVI measured from NF EGM was significantly higher in the patients with subsequent sustained VT/VF (Table 2).

Table 2. Comparison of studied repolarization lability parameters in patients with and without subsequent appropriate ICD therapy for all VT/VF
No VT/VF events (n = 237)VT/VF at follow-up (n = 61)P
Heart rate, mean ± SD, beats/min74 ± 1675 ± 15.98
Heart rate variance, median (interquartile range), beats/min231.8 (4.8-72.7)16.7 (3.6-69.2).728
NF EGM, mean QT ± SD, ms491 ± 83504 ± 78.321
NF EGM QT variance, median (interquartile range), ms2419.8 (90.5-1051.3)846.4 (141.5-1449.9).109
NF EGM QTVI, mean ± SD−0.385 ± 0.519−0.226 ± 0.597.048

Use of AADs 

Patients who sustained VT/VF events were more likely on class I and III AADs at the moment of baseline EGM recording (Table 1). QT variability was not different in patients on class I AADs (mexiletine and propafenone). However, NF RV EGM QTVI was significantly higher, NF EGM QT interval duration was significantly longer, mean heart rate was significantly lower, and heart rate variance was significantly less in patients on class III AADs (Table 3). There were no correlations between the dose of AAD and studied EGM parameters. Amiodarone was taken by 50 patients (17%) and sotalol by 24 (8%) patients at least during the month before the baseline EGM recording. Indications for class III AADs included rhythm control of paroxysmal atrial fibrillation in 28 patients and control of VT in 46 patients. Mean dose of sotalol was not different between patients who took it for VT control (15 patients) compared with atrial fibrillation control (9 patients; 120 ± 62 vs 102 ± 54 mg twice a day, P = .346). However, mean dose of amiodarone was significantly higher in 30 patients who took it for VT control indications, compared with 20 patients who was on amiodarone for atrial fibrillation (266 ± 101 vs 210 ± 62 mg/d, P = .005). All patients on class III AADs for VT had a history of multiple treated VT events (mean, 4; range, 2-104), and 9 patients survived electrical storm, defined as 3 or more sustained appropriately treated VT/VF events for 24 hours.

Table 3. Comparison of QT variability and clinical characteristics of patients with and without class III antiarrhythmic medication therapy
Off class III AAD (n = 224)On class III AAD (n = 74)P
Heart rate, mean ± SD, beats/min76 ± 1669 ± 14.006
Heart rate variance, median (interquartile range), beats/min234.0 (5.4-76.1)15.3 (2.4-55.4).029
NF EGM, mean QT ± SD, ms482 ± 84527 ± 90.001
NF EGM QT variance, median (interquartile range), ms2540 (96-1344)938 (588-1679).643
NF EGM QTVI, mean ± SD−0.315 ± 0.489−0.151 ± 0.541.020

Survival analysis 

The highest QTVI quartile from NF RV EGM predicted all VT/VF events and, in particular, FVA in patients off AADs (Fig. 1) and in patients on class III AAD for atrial fibrillation (Fig. 2). QTVI was not significant predictor of VT/VF in the subgroup of patients who had history of multiple VT/VF, taking class III AADs for VT control (Fig. 3). The hazard of VT/VF events in patients not on AADs with baseline highest intracardiac QTVI quartile was approximately 2 times that of the patients with the 3 lower QTVI quartiles (Table 4). The hazard of VT/VF in patients with baseline highest intracardiac QTVI quartile on class III AADs was approximately 3-fold. In the multivariate Cox regression analysis, the highest NF RV EGM QTVI quartile was a significant predictor of VT/VF events after adjustment for age, sex, indication for ICD implantation (primary or secondary prevention), and indications for class III AAD (hazard ratio, 1.78 ; 95% confidence interval [CI], 1.02-3.11; P = .041).

  • View full-size image.
  • Fig. 1. 

    Kaplan-Meier curves for freedom from all VT/VF events (A) and FVA (B) in patients not on class III AADs, with the highest QTVI quartile (QTVI ≥ 0.1) and those with the lower 3 QTVI quartiles on NF RV EGM (QTVI < 0.1).

  • View full-size image.
  • Fig. 2. 

    Kaplan-Meier curves for freedom from all VT/VF events (A) and FVA (B) in patients on class III AADs for atrial fibrillation control, with the highest QTVI quartile (QTVI ≥ 0.1) and those with the lower 3 QTVI quartiles on NF RV EGM (QTVI < 0.1).

  • View full-size image.
  • Fig. 3. 

    Kaplan-Meier curves for freedom from all VT/VF events (A) and FVA (B) in patients on class III AADs for VT control, with the highest QTVI quartile (QTVI ≥ 0.1) and those with the lower 3 QTVI quartiles on NF.

Table 4. Unadjusted hazard ratios of the highest QTVI quartile on NF RV EGM
Subgroup of patientsHazard ratio (95% CI), and P value
Not on class III AAD, hazard ratio for all VT/VF1.94 (1.15-3.27), P = .013
On class III AAD, hazard ratio for all VT/VF2.81 (1.10-7.15), P = .031
Not on class III AAD, hazard ratio for FVA2.45 (1.06-5.67), P = .036
On class III AAD, hazard ratio for FVA5.34 (1.69-18.14), P = .005

Univariate Cox regression analysis showed that the risk of FVA in patients on class III AADs with highest intracardiac QTVI quartile was 5-fold higher, whereas the risk for patients not on class III AAD was 2.5-fold higher compared with patients with the 3 lower QTVI quartiles (Table 4). In the multivariate Cox regression analysis (adjusted for the history of VT/VF and class III AAD indications), highest NF RV EGM QTVI quartile significantly predicted FVA (hazard ratio, 2.82; 95% CI, 1.11-7.16; P = .029).

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Discussion 

Our study showed that increased intracardiac beat-to-beat QT variability predicts sustained ventricular tachyarrhythmias and, in particular, FVAs in patients with structural heart disease on and off class III AADs, except patients with history of multiple prior VT/VF events on class III AADs.

Prediction of VT/VF in patients on class III AADs 

Class III AADs are frequently used in patients with structural heart disease for rhythm control of paroxysmal atrial fibrillation. Ventricular tachycardia/ventricular fibrillation risk stratification in such patients is difficult, and frequently, these patients are excluded from repolarization lability studies. We excluded patients on class III AADs from intracardiac repolarization lability analysis in our previous report 5 to demonstrate predictive value of intracardiac QT variability. However, extended follow-up allowed us to show significant predictive value of QTVI in multivariate analysis after adjustment for history of VT/VF and indications for class III AADs.

Effect of class III AADs on cardiac repolarization lability was previously described. In experiments,6 amiodarone demonstrated concentration-dependent biphasic effect: initial increase, with subsequent decrease of beat-to-beat APD variability. We showed increased QT variability in patients on class III AAD as well.

Importantly, we showed that QT variability is highly predictive of subsequent VT/VF events in patients without history of multiple VT/VF events, including patients with paroxysmal atrial fibrillation on class III AADs. Our findings justify inclusion of patients on class III AADs in repolarization lability analysis for VT/VF risk stratification.

Cellular and tissue level basis of repolarization lability on and off AAD 

Several mechanisms on cellular and myocardial tissue levels could result in repolarization lability. A combination of instabilities in APD restitution8, 9 and intracellular calcium dynamics10 may produce both alternating11 and nonalternating12 repolarization lability. Instability in potassium ion channels kinetics may result in the temporal variability of the action potential.13 Autonomic fluctuations may modify repolarization on a beat-to-beat basis.

QT interval measured on NF RV EGM corresponds to the APD.14, 15 Filtering of NF RV EGM signal does not allow us to measure an absolute value of APD, but we could assess variance of APD. Stochastic APD prolongation may be an important mechanism of VT/VF16 and may be detected on NF RV EGM by means of intracardiac QT variability analysis.

Mechanisms of action of class III AADs are complex. Amiodarone blocks rapidly and slowly activating delayed rectifier K+ currents (IKr and IKs), Na+ current (INa), L-type Ca2+ current (ICaL), and adrenergic receptors.17, 18 Sotalol is both a β-blocker and Ikr channel blocker. Summation of several factors may lead to increased QT variability in structural heart disease patients on class III AADs. First, β-blocking effect of class III AAD decreases heart rate variability and therefore increases QTVI. Heart rate and heart rate variance were significantly lower in our study patients on class III AADs. Second, structural heart disease may diminish19, 20 the repolarization reserve21, 22 of the myocardium. Amiodarone-induced torsades de pointes seems to be more common in subjects with structural heart diseases.23, 24 In our study, QT variability did not predict VT/VF in a highly selected subgroup of patients with history of multiple treated VT/VF events and electrical storms. Preexisting repolarization heterogeneity in these patients may be exaggerated by the use of class III AADs. Third, response to class III AADs vary among individuals.25 Underlying structural heart disease and DNA polymorphism are recognized to be modulators of the ventricular repolarization process. Adjustment of QT variability for individual ion-channel genes expression map in the future may allow more precise prediction of VT/VF in structural heart disease patients on class III AADs.

Limitations 

This study was not designed to investigate effect of AADs. Concentration of AADs was not monitored.

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Conclusions 

Increased intracardiac repolarization lability predicts ventricular tachyarrhythmias and, in particular, FVAs in patients with structural heart disease on and off class III AADs, except patients with history of multiple VT/VF on class III AADs.

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PII: S0022-0736(09)00323-9

doi:10.1016/j.jelectrocard.2009.07.011

Journal of Electrocardiology
Volume 42, Issue 6 , Pages 505-510, November 2009

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