Coexisting mutations/polymorphisms of the long QT syndrome genes in patients with repaired Tetralogy of Fallot are associated with the risks of life-threatening events

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.

Primary ventricular tachycardia in paediatric population in a tertiary centre

“…The mechanisms underlying VT development in patients with repaired TOF include repolarisation heterogeneity and surgical scar-related re-entry lesions 26 29 30. In addition, for some patients with repaired TOF, coexisting long QT mutations or polymorphisms might have additive effects on the repolarisation abnormality 31. Because of these complex mechanisms, catheter ablation can be difficult and recurrences frequent.…”

Eligibility and Disqualification Recommendations for Competitive Athletes With Cardiovascular Abnormalities: Task Force 4: Congenital Heart Disease

“…Clinical evaluation of patients before participation in competitive sports should include assessment of pulmonary valve function and assessment of factors associated with increased risk of sudden death in this population. 15,[19][20][21] In particular, attention should be paid to careful assessment of LV function. 13,22 Exercise testing is recommended to evaluate ability to augment cardiovascular function during increasing exercise intensity and for evidence of exercise-related ECG changes suggestive of arrhythmia or ischemia.…”

Repolarization Alternans and Ventricular Arrhythmia in a Repaired Tetralogy of Fallot Animal Model

“…These findings are similar to those in left heart failure. For the mechanism of ventricular arrhythmia in rTOF, the role of repolarization abnormality on the genesis of ventricular arrhythmia in rTOF patients is increasingly recognized recently . Khairy et al.…”

“…Hemodynamic factors, including residual pulmonary regurgitation and resulting right ventricular outflow tract (RVOT) dilatation and right heart failure, could prolong QRS duration and result in ventricular arrhythmia in these rTOF patients. This mechano‐electrical interaction is considered as the possible mechanism of ventricular arrhythmia in these patients . It is regarded as the model of ventricular arrhythmia in repaired congenital heart disease.…”