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The Canadian Journal of Cardiology logoLink to The Canadian Journal of Cardiology
. 2010 Apr;26(4):208–212. doi: 10.1016/s0828-282x(10)70369-x

Torsades de pointes during complete atrioventricular block: Genetic factors and electrocardiogram correlates

Rajesh N Subbiah 1, Michael H Gollob 2, Lorne J Gula 1, Robert W Davies 2, Peter Leong-Sit 1, Allan C Skanes 1, Raymond Yee 1, George J Klein 1, Andrew D Krahn 1,✉
PMCID: PMC2886542  PMID: 20386770

Abstract

INTRODUCTION:

Atrioventricular (AV) block is infrequently associated with QT prolongation and torsades de pointes (TdP). It was hypothesized that patients with AV block-mediated QT-related arrhythmia may have latent congenital long QT syndrome or a vulnerable genetic polymorphism.

METHODS:

Eleven patients with complete AV block and TdP were prospectively identified. Patients underwent assessment, resting electrocardiography and telemetry at baseline, during AV block and pre-TdP. Genetic testing of KCNH2, KCNQ1, KCNE1, KCNE2 and SCN5A was performed. Thirty-three patients with AV block without TdP were included for comparison.

RESULTS:

Genetic variants were identified in 36% of patients with AV block and TdP. Patients with AV block who developed TdP had significantly longer mean (± SD) corrected QT intervals (440±93 ms versus 376±40 ms, P=0.048) and Tpeak to Tend (Tp-Te) intervals (147±25 ms versus 94±25 ms, P=0.0001) than patients with AV block alone. In patients with a genetic variant, there was a significant increase in Tp-Te intervals at baseline, in AV block and pre-TdP compared with those who were genotype negative. A personal or family history of syncope or sudden death was more likely observed in patients with a genetic variant.

CONCLUSIONS:

TdP in the setting of AV block may be a marker of an underlying genetic predisposition to reduced repolarization reserve. The Tp-Te interval at baseline, in AV block and pre-TdP may predict a genetic mutation or polymorphism compromising repolarization reserve. Patients with TdP in the setting of AV block represent a phenotypic manifestation of latent congenital long QT syndrome.

Keywords: AV block, Bradycardia, Genetics, QT interval, Torsades de pointes

Ventricular arrhythmias have been reported in the setting of complete atrioventricular (AV) block since 1918 (1). In 1966, Dessertenne (2) described such an arrhythmia as torsades de pointes (TdP), a polymorphic ventricular tachycardia preceded by QT interval prolongation, now known to be caused by congenital or acquired long QT syndrome (LQTS) (3).

Bradyarrhythmias caused by high-grade AV block are common. It is, however, infrequent that bradyarrhythmias are associated with QT interval prolongation and TdP phenomena (4–6). In patients with bradycardia-induced TdP, a number of electrocardiogram (ECG) parameters during bradycardia correlate with increased risk of TdP, including the QT interval (4–6), T wave morphology and Tpeak to Tend (Tp-Te) (6). Although ECG parameters can be reasonable predictors of TdP in bradyarrhythmias (4–6), there are limited data on cellular or genetic mechanisms of bradycardia-induced TdP (7,8).

We hypothesized that patients with bradycardia-mediated QT arrhythmia may have latent congenital LQTS or a vulnerable genetic polymorphism. In the setting of AV block, reduced repolarization reserve may be ‘unmasked’ in patients, manifesting as QT interval prolongation and TdP. Such an occult form of LQTS has previously been reported among patients with undiagnosed congenital LQTS who develop marked QT interval prolongation and TdP when exposed to QT-prolonging drugs (9,10). Moreover, the development of TdP in the setting of AV block may identify ion channel mutations that have a propensity to cause TdP and sudden cardiac death.

Methods

Patients

A total of 11 patients referred to the Arrhythmia Service at London Health Sciences Centre in London, Ontario, with complete AV block and TdP were prospectively identified. TdP was defined as 10 or more beats of polymorphic ventricular tachycardia (rate of more than 150 beats/min) preceded by QT interval prolongation (corrected QT [QTc] interval of greater than 440 ms [men] or 460 ms [women]). Inclusion criteria were TdP in the setting of complete AV block, without a history of TdP, or known congenital or acquired LQTS. Patients with bradycardia or AV block and TdP in the setting of acute myocardial infarction, or exposure to known QT-prolonging drugs were excluded. Patients underwent clinical assessment including history, physical examination, drug review and ECG analysis. ECGs before AV block were examined for comparison of baseline characteristics. Blood analysis was performed to rule out electrolyte or metabolic abnormalities. All patients received a permanent pacemaker or implantable cardioverter defibrillator, with follow-up in the Arrhythmia Service at London Health Sciences Centre.

ECG acquisition

All ECGs recorded during hospitalization and clinic visits were reviewed. ECGs were obtained using standard gain (10 mV/mm) and paper speed (25 mm/s, GE Marquette MUSE system, GE Healthcare, USA). A 1:3 case control model was chosen; controls were patients with complete AV block but without TdP. ECGs were analyzed for rate, rhythm, QRS duration, QT and QTc intervals, Tp-Te interval, T wave morphology and RR interval at three time points – at baseline, during complete AV block and immediately preceding TdP. The QT interval was defined as the onset of QRS to the point of return of the T wave to the isoelectric line using the maximum slope technique. The QT interval was measured in all leads where the terminal segment of the T wave was clearly demarcated (11), with the longest interval in any lead used as the representative QT interval. The RR interval was calculated from the preceding two consecutive R waves. The QT interval was then corrected (QTc) for rate using Bazett’s formula (12): QTc interval = QT/square root of RR interval in seconds. The Tp-Te was the interval from the apex of the T wave to the end of the QT interval.

Genetic testing

Written informed consent was obtained before genetic testing. Blood for DNA analysis was sent to the Ottawa Heart Institute (Ottawa, Ontario). Genetic testing of KCNH2, KCNQ1, KCNE1, KCNE2 and SCN5A was performed. Genomic DNA isolated from blood lymphocytes was screened using temperature-gradient capillary electrophoresis and/or direct DNA sequencing. In temperature-gradient capillary electrophoresis analysis (SpectruMedix, USA), polymerase chain reaction-amplified DNA samples were separated by capillary electrophoresis under two temperature gradient conditions (50°C to 58°C and 55°C to 63°C). Samples containing mutations were identified on the basis of altered electrophoretic patterns of heteroduplexes caused by their different melting equilibria and electrophoretic mobilities. Samples containing heteroduplexes then underwent direct DNA sequencing.

Statistics

Univariate analyses were conducted by using the two-tailed Student’s t test for continuous variables and the χ2 test for categorical variables. Statistical analysis was performed using SAS software version 9.1 (SAS Institute, USA). P<0.05 was considered significant. All results are expressed as mean ± SD.

RESULTS

Genetic screening in patients with complete AV block and TdP identified DNA variants in four of 11 patients (36%). The SCN5A Glu161Lys mutation has been reported to cause disease (13). The KCNH2 Pro1075Leu mutation, recently reported to cause LQTS (14), is in a region of the gene known to be a ‘hot spot’ for disease-causing mutations. Two additional sequence variations were identified as genetic polymorphisms (Table 1).

TABLE 1.

Genotypes of patients with complete atrioventricular (AV) block and torsades de pointes (TdP)

AV block + TdP Gene Ion channel Mutation
Patient 1* SCN5A INa Exon 4 – Glu161Lys
Patient 2 SCN5A INa Exon 12 – His558Arg
Patient 3 KCNH2 IKr Exon 14 – Pro1075Leu
Patient 4† KCNH2 IKr Exon 11 – Lys897Thr
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*

Recurrent TdP after device implantation requiring a rate increase from 60 beats/min to 80 beats/min;

†

Recurrent episodes of TdP requiring electrical cardioversion, not responsive to isoproterenol, with continued episodes of TdP despite pacing at 80 beats/min, requiring bisoprolol. IKr Rapid delayed rectifier K+ current; INa Inward Na+ current

Individual ECG characteristics of the four patients with genetic mutations or polymorphisms are listed in Table 2. The ECGs of patient 1 are shown in Figure 1. At baseline, all four patients had normal QTc intervals. In the setting of complete AV block, patient 1 and patient 4 had significantly prolonged QTc intervals. All four patients had marked QTc interval prolongation pre-TdP. Similarly, the Tp-Te interval increased from baseline, in complete AV block and pre-TdP (Table 2). Of note, there were no differences in PR interval, QRS duration or ST-T segments at baseline.

TABLE 2.

Electrocardiogram parameters of patients with a genetic mutation or polymorphism

Parameter, ms Patient 1 Patient 2 Patient 3 Patient 4
QTc at baseline 429 430 439 436
QTc in complete AV block 516 439 446 527
QTc pre-TdP 665 531 581 613
Tp-T e baseline 100 120 80 100
Tp-T e in complete AV block 170 160 170 200
Tp-T e pre-TdP 180 200 200 220
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AV Atrioventricular; QTc Corrected QT interval; TdP Torsades de pointes; Tp-Te Tpeak to Tend interval

Figure 1).

Figure 1)

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Representative electrocardiograms (ECGs) from patient 1 with a Glu161Lys mutation involving SCN5A. Although this mutation has previously been associated with a Brugada-type ECG and conduction abnormalities, this patient clearly developed dramatic bradycardia-related QT prolongation and polymorphic ventricular tachycardia, with a relatively normal-appearing reference ECG before the development of complete atrio-ventricular block

Patients were divided into three groups (Tables 3 and 4). Group 1 included patients with complete AV block and TdP who had a genetic mutation or polymorphism. Group 2 included patients with complete AV block and TdP in whom a genetic abnormality was not identified. Group 3 included patients with complete AV block but no TdP. When patients with and without TdP were compared (groups 1 and 2 compared with group 3), those with complete AV block who developed TdP had significantly longer QTc intervals (440±93 ms versus 376±40 ms, P=0.048; Table 4). This difference was almost entirely explained by the dramatic difference in the Tp-Te intervals, which were significantly longer in patients with complete AV block and TdP (groups 1 and 2) compared with those without TdP (group 3) (147±25 ms versus 94±25 ms, P=0.0001, Table 4). Chart and serum electrolyte review did not identify specific triggers for complete AV block or TdP.

TABLE 3.

Electrocardiogram and clinical characteristics of patients with complete atrioventricular (AV) block and torsades de pointes (TdP)

Characteristic Group 1 (n=4) Group 2 (n=7) P
Age, years, mean ± SD 74±14 70±10 0.66
Women 3 (75) 6 (86) 0.66
Cardiomyopathy with ejection fraction <40% 0 2 (29) 0.24
History of atrial fibrillation 0 3 (43) 0.13
Family history of SCD 2 (50) 0 0.039
Family history of syncope 4 (100) 2 (29) 0.022
History of syncope (>12 months before presentation in complete AV block) 2 (50) 0 0.039
Recurrent TdP despite treatment 2 (50) 0 0.039
T wave abnormalities 1 (25) 2 (29) 0.90
QTc baseline, ms, mean ± SD 434±5 413±25 0.067
QTc in complete AV block, ms, mean ± SD 482±46 416±108 0.29
QTc pre-TdP, ms, mean ± SD 597±56 564±78 0.48
Tp-T e baseline, ms, mean ± SD 100±9 71±4 0.016
Tp-T e in complete AV block, ms, mean ± SD 175±17 131±9 0.0072
Tp-T e pre-TdP, ms, mean ± SD 200±16 141±22 0.0013
RR interval pre-TdP, ms, mean ± SD 1.2±0.3 1.2±0.2 0.70
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Data presented as n (%) unless otherwise indicated. Group 1 represents patients with complete AV block and TdP who are mutation positive. Group 2 represents patients with complete AV block and TdP who are mutation negative. QTc Corrected QT interval; SCD Sudden cardiac death; Tp-Te Tpeak to Tend interval

TABLE 4.

Electrocardiogram and clinical characteristics of patients with complete atrioventricular (AV) block and torsades de pointes (TdP) compared with complete AV block controls

Characteristic Complete AV block
 P
With TdP (n=11) No TdP (n=33)
Women, n (%) 9 (82) 18 (55) 0.11
QTc in complete AV block, ms, mean ± SD 440±93 376±40 0.048*
Tp-T e in complete AV block, ms, mean ± SD 147±25 94±25 <0.0001*
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*

P<0.05. QTc Corrected QT interval; Tp-Te Tpeak to Tend interval

Comparing groups 1 and 2, there was a striking difference in Tp-Te intervals at baseline, in complete AV block and pre-TdP but no differences in QTc intervals at baseline, in complete AV block or pre-TdP (Figure 2 and Table 3).

Figure 2).

Figure 2)

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Tpeak to Tend (Tp-Te) intervals for patients at baseline, in complete atrioventricular (AV) block and pre-torsades de pointes (TdP). There was a clear difference among patients who had a genetic mutation or polymorphism identified (closed squares) compared with those who did not have a genetic mutation or polymorphism (open circles) at baseline, in complete AV block and pre-TdP

Recurrent TdP in AV block was more likely in patients with an underlying genetic mutation or polymorphism (P=0.039; Table 3). Two patients had recurrent TdP; both had an underlying genetic mutation or polymorphism. Patient 1 had recurrent TdP after pacemaker implantation with initial programming at a lower rate of 60 beats/min (Table 1). The pacemaker was reprogrammed to a pacing rate of 80 beats/min and no further TdP occurred. Patient 4 had multiple episodes of TdP at presentation that required electrical cardioversion. After device implantation, the patient continued to have high ventricular rate episodes with documented TdP, despite a minimum pacing rate of 80 beats/min. Bisoprolol 10 mg orally daily was started and the patient remained free of symptoms in follow-up for eight months.

Clinical history provided important correlates. Patients with a family history of sudden cardiac death (P=0.039) or syncope (P=0.022), and those with a personal history of syncope (P=0.039) were more likely to have an underlying genetic mutation or polymorphism than genotype-negative patients with complete AV block and TdP (Table 3).

DISCUSSION

The findings of the current study suggest that bradycardia alters the repolarization milieu and may unmask a propensity to life-threatening tachyarrhythmias based on genetic and clinical factors. The results of the present study demonstrated the feasibility of genetic screening of patients with TdP in the context of high-grade AV block.

Mechanism of TdP in complete AV block

Mechanistically, it has been reported that during bradyarrhythmias, downregulation of the repolarizing currents – rapid and slow delayed rectifier K+ currents (IKr and IKs, respectively) – results in QT interval prolongation and TdP (15–18). These findings were based on canine and rabbit models of chronic complete AV block that showed reduction in IKr and IKs, and altered L-type Ca2+ current, with other currents (inward Na+ current, transient outward K+ current and inward rectifier K+ current) remaining normal (15,16,18). The antiarrhythmic drugs, dofetilide and azimilide, produced similar electrophysiological and proarrhythmic effects on canine hearts (19). Thus, evidence suggests that over four or more weeks, downregulation of repolarizing currents in the setting of chronic complete AV block may reduce repolarization reserve. In addition, AV block was associated with the development of biventricular hypertrophy in the canine model, which may have played a contributory role (17,20).

In humans with high-grade AV block and TdP, the clinical course is far more rapid from admission for bradycardia to the onset of TdP (6). Also, patients can continue to have recurrence of TdP after implantation of a pacemaker, if the lower rate of the device is programmed in the ‘nominal’ range at 60 beats/min (6). If the observed QT interval prolongation and TdP were purely due to bradycardia-mediated downregulation of IKr and IKs, one would expect pacing at a rate of 60 beats/min to prevent recurrence of TdP. Taken together, these observations suggest that there are other factors present that may influence repolarization reserve in patients with bradycardia-mediated TdP.

Genetic mutations and polymorphisms may influence repolarization reserve

There is mounting evidence that acquired LQTS is a manifestation of reduced repolarization reserve, which is unmasked by physiological or pharmacological stressors (8–10). Bradycardia-induced TdP may be further proof of this phenomenon. Chevalier et al (8) recently described a series of patients with pacemakers who had preimplant QT intervals of greater than 600 ms and complete AV block. These patients underwent genetic screening for mutations in ion channels known to cause congenital LQTS. Five of 29 patients had mutations in KCNH2 (8). The study only included patients with profound QT interval prolongation and only identified one patient with TdP, who also had hypokalemia. The Tp-Te interval was not measured and no ECGs before the development of AV block were obtained (8). Our study provided novel data on baseline (before the development of AV block), during AV block and pre-TdP ECG parameters, as well as probable genetic correlates of TdP in complete AV block.

Although genetic abnormalities found in the general population at a frequency of greater than 1% are classified as polymorphisms, physiological or pharmacological stress may unmask repolarization vulnerabilities. For instance, the KCNQ1 G643S polymorphism predisposes to marked QT interval prolongation with class IA antiarrhythmic drugs (21), and the SCN5A S1102Y polymorphism increases the likelihood of drug-induced QT interval prolongation and TdP (22,23). It is, therefore, conceivable that the presence of a genetic polymorphism in the setting of AV block may predispose to QT interval prolongation and TdP. Further genetic correlation studies are required to explore this hypothesis.

Predictors of TdP, and an underlying genetic mutation or polymorphism in AV block

Our study demonstrated that 36% of patients with complete AV block and TdP had an underlying genetic mutation or polymorphism. Moreover, we identified the QTc interval and, in particular, the Tp-Te interval as significant predictors of TdP in AV block. We also determined that the Tp-Te interval was more likely to be prolonged in patients with a genetic mutation or polymorphism at baseline, in AV block and pre-TdP (Figure 1 and Table 3). The present study was the first to specifically include ECG parameters at baseline, before the development of AV block. The Tp-Te is an ECG correlate of the transmural dispersion of repolarization (24,25). This measure reflects the heterogeneity of repolarization, an intrinsic property of the cells that populate the endocardium, midmyocardium and epicardium. Prolongation of the transmural dispersion of repolarization may predispose to TdP (24,25). In our study, the Tp-Te interval appears to identify a subgroup of patients with an underlying genetic mutation or polymorphism, and subsequent propensity to TdP in the setting of AV block. A larger study will be required to explore this further.

The Glu161Lys mutation involving SCN5A, identified in patient 1, has been associated with a Brugada-type ECG and conduction abnormalities (13). In our patient, the phenotype appears to be more consistent with LQTS and conduction disease. SCN5A has been shown to have considerable phenotypic variability, with reports of both Brugada and LQT3 phenotypes with a single genotype (26–31). The underlying electrophysiological explanation for this may involve differential effects on the fast and slow components of sodium channel inactivation (31). Further cellular expression studies are necessary to provide insight into the underlying mechanism; nonetheless, it is a known disease-causing mutation. Moreover, extensive analysis of our patient with the Glu161Lys mutation, including all previous ECGs and drug challenge with class IA antiarrhythmic agents, did not reveal evidence of Brugada syndrome, which suggests that this is the first report of Glu161Lys mutation associated with LQTS.

Patient 3 had a Pro1075Leu mutation involving KCNH2, identified on genetic screening. This mutation was recently reported to cause LQTS (14). The mutation is located at the C-terminus of KCNH2, which is believed to be a mutation ‘hot spot’ because there are reports of mutations involving nearby residues also causing congenital LQTS (9,32). Patient 3 had a normal QTc interval at baseline with marked QT interval prolongation pre-TdP (439 ms versus 581 ms, Table 2). Complete AV block appears to have unmasked a genetic predisposition to reduced repolarization reserve. Characterization of the Pro1075Leu mutation at a cellular level may provide further insight into the mechanism of the observed phenotype.

Two of our patients had known genetic polymorphisms. Both patients had clinical characteristics and ECG features similar to patients with a clear-cut disease-causing mutation. In addition, both patient 1 and patient 4 had recurrent episodes of TdP. The KCNH2 Lys897Thr polymorphism in patient 4 has a population frequency of 6% to 30% (33). When expressed in human embryonic kidney-293 cells, Lys897Thr channels have reduced current density caused by reduced channel expression (34). When patients with the KCNH2 Lys897Thr polymorphism underwent stress testing, their QTc intervals were longer than those of controls (34). Similar observations were made in a study of Finnish women with the KCNH2 Lys897Thr polymorphism (35). Taken together, these data suggest that the KCNH2 Lys897Thr polymorphism reduces repolarization reserve, which may be ‘unmasked’ in the setting of physiological stress.

The SCN5A H588R polymorphism in patient 2 has an estimated population frequency of 15% to 30% (36). The SCN5A H588R polymorphism has been shown to significantly modify the phenotype of some mutations and, as such, is known as an internal disease gene modifier (37,38). At slower heart rates caused by complete AV block, this polymorphism may modulate the Nav1.5 current. So far, QT interval prolongation and TdP have not been associated with this polymorphism. However, in the absence of electrophysiological data, the manifestation of QT interval prolongation and TdP in patient 2 may not be explained by the presence of this polymorphism alone.

History of syncope and likelihood of an underlying genetic mutation or polymorphism

A personal or family history of syncope or a family history of sudden cardiac death was more likely in patients with a genetic mutation or polymorphism (Table 3). This emphasizes the importance of a thorough clinical history in patients presenting with TdP and complete AV block. Without symptom-rhythm correlates, it is difficult to be certain about the etiology of the syncope and whether the genetic mutation or polymorphism could be causally implicated. Regardless of etiology, however, a family history of syncope should alert the clinician to consider an underlying genetic mutation or polymorphism in patients with AV block and TdP.

Clinical implications

In principle, there may be no real distinction between congenital and acquired LQTS. A genetic repolarization complement is present in any given individual, influenced by autonomic tone including heart rate, electrolytes, QT-prolonging drugs, ischemia and a range of other factors, which we simplistically measure with a surface QT interval. Further assessment of other repolarization genes, as well as measures of gene expression and gene-gene interaction will undoubtedly provide further insight into the concept of repolarization reserve.

The present study is novel because ECG correlates were provided at baseline as well as in AV block and pre-TdP. In addition, patients with AV block and TdP, rather than just profound QT interval prolongation, were included in the analysis (8). The current study suggests that AV block is another QT ‘stressor’ in a genetically susceptible population. In this context, genetic assessment of the proband, as well as clinical and genetic assessment of first-degree relatives, should be considered. Moreover, patients who are found to have a mutation or vulnerable polymorphism should be treated with the same precautions as patients with congenital LQTS, and genetic screening should be offered to their families. Further studies are needed to assess implications to patient care. However, there is little doubt that some patients have a genetic predisposition to arrhythmia. We anticipate that genetic screening will become more accessible and be used to guide therapy in susceptible individuals. There are major implications pertaining to the future use of potentially proarrhythmic drugs, family screening for arrhythmia risk and tailoring treatment to genotype.

Limitations

The present study prospectively evaluated a modest number of patients with complete AV block and TdP for underlying genetic mutations or polymorphisms. A larger sample of patients to establish the range of causative mutations and polymorphisms is needed. Genetic screening was targeted specifically at the known ion channel genes involved in LQTS. Regulatory proteins, effects of gene expression and the involvement of other ion channels may have had a contributory role. We did not perform cellular expression studies on the identified genetic mutations or polymorphisms. However, all except the Pro1075Leu mutation were previously characterized at a cellular level. The 33 patients whose ECGs were used for comparison did not undergo genetic testing because the general population frequency is known for the described genetic mutations.

CONCLUSION

TdP in the setting of AV block may be a marker of an underlying genetic predisposition to reduced repolarization reserve. A personal or family history of syncope or sudden death, as well as the Tp-Te interval at baseline, in AV block and pre-TdP may predict a genetic mutation or polymorphism compromising repolarization reserve. Patients with TdP in the setting of AV block, previously considered an ‘acquired’ form of LQTS, may represent a phenotypic manifestation of a genetic vulnerability.

Footnotes

FUNDING: The present study was supported by Grant NA3397 from the Heart and Stroke Foundation of Ontario.

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