Ventricular arrhythmia in repaired Tetralogy of Fallot-role of repolarization heterogeneity
Date Issued
2011
Date
2011
Author(s)
Chiu, Shuenn-Nan
Abstract
Background With advances in operative techniques and perioperative support, surgical outcome of Tetralogy of Fallot (TOF) has been greatly improved in recent three decades. However, patients are still at risk of cardiac death late after total repair. Sudden cardiac death (SCD), mostly due to ventricular tachyarrhythmia, are the major causes of late death. From previous reports, risk factors for ventricular arrhythmia include hemodynamic factors such as severe pulmonary regurgitation (PR), right ventricular dilatation, and increased left ventricle end-diastolic pressure, and electrophysiologic factors such as prolonged QRS duration and QTc interval. Gatzoulis et al had proposed mechanoelectrical interaction as the mechanism for the ventricular arrhythmia in repaired TOF. They proposed that the hemodynamic factors, including pulmonary regurgitation and peripheral pulmonary stenosis, caused right ventricle dilatation especially the outflow tract. Such ventricular dilatation and right ventricular outflow tract surgical scar would then provide the substrate of ventricular arrhythmia and increase susceptibility to monomorphic ventricular tachycardia (VT).
In repaired TOF, not only the monomorphic VT, but also the polymorphic VT is important cause of cardiac death. In the electrophysiological studies of repaired TOF patients, Khairy et al found that those with inducible polymorphic VT has highest risk developing clinical VT or SCD at follow-up (odds ratio of 12.9), followed by those with inducible monomorphic VT (odds ratio 5.0). As polymorphic VT often associates with repolarization heterogeneity, the role played by repolarization heterogeneity in the genesis of ventricular arrhythmia in repaired TOF patients is crucial. In addition, repolarization heterogeneity is also an important substrate for monomorphic VT. In the previous animal studies using optical mapping method, for the myocardium with structural barrier, electrical stimulation often induces monomorphic VT in the presence of repolarization heterogeneity. Therefore, repolarization heterogeneity may be in the central pivot of the pathogenesis of ventricular arrhythmia in these repaired TOF patients.
The indicators of repolarization heterogeneity include QTc interval or QT dispersion detected by surface EKG. However, the sensitivity and specificity were both low. Microvolt T wave alternans (MTWA), had recently been recognized as a new indicator of repolarization heterogeneity. It can be analyzed either by spectral method or time domain analysis. The method used in time domain analysis is modified moving average beat analysis (MMA), which averaged the morphologies of odd and even beats of continuing heart beats and subtracted the amplitude of them. MTWA value was then defined as the maximal difference in twelve leads. In several large-scale long-term follow up studies and meta-analysis, MTWA by either spectral or MMA methods has been documented as a useful predictor for mortality and SCD in patients with ischemic heart disease and dilated cardiomyopathy. However, the data of MTWA in repaired TOF patients is still limited.
Congenital long QT syndrome (LQTS) is a familial disorder characterized by prolonged QT interval in surface EKG and sudden cardiac death. The exact pathogenesis of congenital LQTS is mutation of ion channel genes which induces repolarization prolongation and repolarization heterogeneity. In addition to congenital LQTS, QT prolongation and life threatening events can be acquired after exposure to drugs or electrolyte imbalance in those with genetic susceptibility i.e., patients with long QT gene polymorphisms. They are categorized as acquired LQTS. Whether the long QT genes mutations or polymorphisms will further aggravate the repolarization heterogeneity caused by surgery, hemodynamic and electrophysiological factors in repaired TOF patients and increase the risk of sudden death, it has never been studied.
Thesis We hypothesized that (1) repolarization heterogeneity plays a central role in the genesis of ventricular arrhythmia in repaired TOF patients; (2) The interactions between mechanical and electrical factors are two-way: the hemodynamic factors may accentuate the repolarization heterogeneity, and the electrophysiologic factors may cause progression of ventricular dilatation; (3) long QT gene mutation/polymorphisms may have additive effects on the repolarization heterogeneity in repaired TOF patients and thereby increase the risk of ventricular arrhythmia and life threatening events.
Methods and Results
Epidemiology study
The patient cohort constituted consecutive 819 TOF patients who received total repair in our hospital from 1970 to 2002. The survival status was confirmed by data check using National Health Bureau death records. After 13,808 patient-years follow-up, the 30 year survival rate was 90.5%. The mortality rate increased significantly at late follow-up period and the annual mortality increased from 0.123% in the first 15 years to 0.395% after 15 years follow-up. Cardiac cause of deaths accounted for 51.7% of the total death in our patient cohorts. Besides, we also noticed a relatively high unnatural death rate (accident and suicide joining, 27.6%) in our patient cohort. Such observation suggested that integrated care of medical and psychosocial support for these patients is still inadequate in our country.
Animal model creation and finding
We created an animal model to assure the effects and the interaction of mechanical and electrophysiological factors on the genesis of ventricular arrhythmia. We performed surgical right ventricular outflow tract (RVOT) transannular patch plus pulmonary valve destruction to simulate mechanical factors of repaired TOF patients. We performed right bundle branch (RBB) ablation and sham operation to simulate electrophysiological factors. Among the three groups of dogs, mechanical factors, electrophysiological factors, and combined mechanical and electrophysiological factors groups, we found (1) progressive RVOT dilatation was found in both mechanical factors group and combined group, but it was most significant in combined group, (2) the increments of QRS duration, QTc interval, JTc interval, and QT dispersion between 1 month and 1 year were all greatest in combined group, and (3) ventricular arrhythmia events recorded by implanted loop recorders were also most frequent in combined group (median 3.3/month in combined group and 1/month in the other two groups). Based on these results, we suggest that the electrophysiological factors and its interaction with mechanical factors are important determinants of the repolarization heterogeneity and genesis of ventricular arrhythmia in repaired TOF. Besides, electrophysiological factors may contribute to the progression of right ventricular dilatation via the mechanism of right ventricle dyssynchrony.
Clinical repolarization heterogeneity significance
We analyzed the microvolt T wave alternans (MTWA) through Treadmill EKG examination on the repaired TOF patients. By comparison of 101 repaired TOF patients to 103 age- and sex-matched controls, we found higher MTWA values in the repaired TOF patients (25.1±14.0 versus 17.6±9.2 μV, p<0.001). The MTWA values are also higher in those with high risk patients including longer QRS duration, severe degree of pulmonary regurgitation, and those receiving transannular RVOT patch repair. In addition, for those with previous ventricular arrhythmia events, their MTWA values are even higher (34.0±16.5 vs. 24.2±13.5 μV, p=0.053). However, the predictive value of MTWA was less than QRS duration alone. Nevertheless, these results showed that the repolarization heterogeneity is common in repaired TOF patients and aggravated by pulmonary regurgitation and longer QRS duration. It also supported the importance of repolarization heterogeneity on ventricular arrhythmia in repaired TOF patients.
Genetic study of LQT gene
Finally, we investigated the effects of long QT syndrome (LQTS) gene mutations/polymorphisms on the aggravation of the repolarization heterogeneity in repaired TOF patients. We checked the three common LQTS gene (KVLQT1, hERG, SCN5A) on the 84 repaired TOF patients. Five of them had life-threatening events and received implantable cardioverter defibrillator implantation. We found the life-threatening events were more often found in those with genetic variants (5/5 vs. 35/79, p=0.021), particularly the presence of hERG or SCN5A gene. Presence of compound long QT gene variants further increased the risk of life-threatening events (3/13 vs. 2/71, p=0.025). Therefore, multiple hits from LQTS gene mutation/polymorphisms and repolarization heterogeneity after cardiac repair increase the risk of ventricular arrhythmia in repaired TOF.
Conclusion From animal study, we addressed the importance of interaction of electrophysiological factors with mechanical factors on the repolarization heterogeneity and ventricular arrhythmia. From the clinical study of MTWA in repaired TOF patients, we found the repolarization heterogeneity is common and is highly associated with the risk of ventricular arrhythmia in these patients. The presence of LQT gene mutation/polymorphisms may further aggravate the repolarization heterogeneity and therefore increased the risk of ventricular arrhythmia in repaired TOF patients.
Subjects
Tetralogy of Fallot
ventricular arrhythmia
sudden cardiac death
repolarization heterogeneity
pulmonary regurgitation
right bundle branch block
microvolt T wave alternans
long QT syndrome gene
variants or polymorphisms
SDGs
Type
thesis
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