The role of mechanical-electrical interaction in ventricular arrhythmia: evidence from a novel animal model for repaired tetralogy of Fallot.

Department of Pediatrics, National Taiwan University Hospital and Medical College, National Taiwan University, Taipei 100, Taiwan, Republic of China.
Pediatric Research (Impact Factor: 2.67). 05/2011; 70(3):247-52. DOI: 10.1203/PDR.0b013e318225fd8b
Source: PubMed

ABSTRACT Pulmonary regurgitation and prolonged QRS duration of right bundle branch (RBB) block are common in repaired tetralogy of Fallot (TOF) and increase the risk of sudden death. We sought to establish an animal model to reflect both abnormalities. Twenty-one canines: group I (n = 7) received a surgical right ventricular outflow tract (RVOT) transannular patch plus pulmonary valve destruction; group II (n = 5) received RBB ablation and sham operation; and group III (n = 9) received combined interventions. Serial electrophysiological data were obtained up to 1 y. Procedure mortality was 27.6%. At 1 y, although severe pulmonary regurgitation was documented in most dogs in groups I (71%) and III (100%), progressive RVOT dilatation was noted in group III. RBB block was present in all dogs in groups II and III. However, the increments of QRS duration, QTc, JTc, and QT dispersion progression between 1 mo and 1 y were all greatest in group III. Ventricular arrhythmia events were frequent in group III (median 3.3/mo) but uncommon in groups I and II (median 1/mo). We have created a novel animal model that adequately reflects both the hemodynamic and electrophysiological characteristics of repaired TOF patients and can be applied to examine the risk of ventricular arrhythmias.

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    ABSTRACT: Coexisting long QT gene mutations/polymorphisms in Tetralogy of Fallot (TOF) patients may aggravate the repolarization abnormality from cardiac repair. We investigated the impact of these genes on the risk of life-threatening events. Genetic variants of the three common long QT genes were identified from patients with repaired TOF. Life-threatening events were defined as sudden cardiac death and hemodynamic unstable ventricular arrhythmia. Biophysical characterization of the alleles of the genetic variants was performed using a whole-cell voltage clamp with expression in Xenopus oocytes. A total of 84 patients (56.0 % male with 1,215 patients-year follow-up) were enrolled. Six rare variants and six non-synonymous single nucleotide polymorphisms (SNPs) were found in 40 (47.6 %) patients. Life-threatening events occurred in five patients; four received implantable cardioverter defibrillator and one died of sudden cardiac death. Life-threatening events occurred more often in those with genetic variants than those without (5/40 vs. 0/44, P = 0.021); particularly, the hERG or SCN5A gene mutations/polymorphisms (2/5 vs. 3/79, P = 0.027 and 5/27 vs. 0/57, P = 0.003, respectively). Among the five patients with life-threatening events, three had compound variants (hERG p.M645R/SCN5A p.R1193Q, hERG p.K897T/SCN5A p.H558R, and KVLQT1 p.G645S/SCN5A p.P1090L), that also increased the risk of events. Their QTc and JTc were all prolonged. Functional study of the novel variant (hERG gene p.M645R) from patients with life-threatening events revealed a dominant negative effect. In conclusion, in repaired TOF patients, coexisting long QT mutations/polymorphisms might have additive effects on the repolarization abnormality from surgery and thereby increase the risks of life-threatening events.
    Human Genetics 03/2012; 131(8):1295-304. · 4.63 Impact Factor
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    ABSTRACT: BACKGROUND: Fragmented QRS complexes (fQRS) correlate with myocardial scar, and may predict arrhythmias in patients with repaired tetralogy of Fallot (TOF). We investigated the relationship between fQRS in operated TOF patients with right ventricular (RV) dysfunction and RV outflow tract (RVOT) aneurysm. METHODS: We studied 56 operated TOF patients with moderate/severe pulmonary regurgitation, referred for cardiac magnetic resonance imaging (MRI) over a 4.5year period. The presence of fQRS (additional notches in the R/S wave in ≥2 contiguous leads on the ECG) was correlated with MRI findings. RESULTS: fQRS was observed in 44 (78.6%) patients. Patients with fQRS had significantly larger RV end diastolic volume index (RVEDVi; 162ml vs 141ml, p=0.028) and RV end systolic volume index (RVESVi; 88ml vs 70ml, p=0.031). Increasing number of leads with fragmentation was independently associated with increasingly lower RV ejection fraction (adjusted co-efficient -0.97, 95%CI -1.83 to -0.12, p=0.026), greater pulmonary regurgitation fraction (1.65, 0.28 to 3.01, p=0.019), larger RVEDVi (6.78, 2.00 to 11.56, p=0.006) and RVESVi (5.41, 1.66 to 9.15, p=0.005). Anterior fragmentation correlated most significantly with RV dysfunction (p<0.05). fQRS had no significant association with LV dysfunction. Presence of any fQRS (OR 17.5, 95%CI 2.1-147.8, p=0.009) and inferior fQRS (OR 9.0, 95%CI 2.7-30.1, p<0.001) were found to be significant predictors for RVOT aneurysm. CONCLUSIONS: The presence of fQRS on the ECG is significantly associated with RV dysfunction and RVOT aneurysms in repaired TOF patients. Increasing burden of fragmentation, especially in the anterior leads, is associated with increasing RV dysfunction.
    International journal of cardiology 04/2012; · 6.18 Impact Factor

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