Contemporary predictors of death and sustained ventricular tachycardia in patients with repaired tetralogy of Fallot enrolled in the INDICATOR cohort

Objective: Patients with repaired tetralogy of Fallot (TOF) experience increased rates of mortality and morbidity in adulthood. This study was designed to identify risk factors for death and ventricular tachycardia (VT) in a large contemporary cohort of patients with repaired TOF. Methods: Subjects with repaired TOF from four large congenital heart centres in the USA, Canada and Europe were enrolled. Clinical, ECG, exercise, cardiac magnetic resonance (CMR) and outcome data were analysed. Results: Of the 873 patients (median age 24.4 years), 32 (3.7%) reached the primary outcome (28 deaths, 4 sustained VT; median age at outcome 38 years; median time from CMR to outcome 1.9 years). Cox proportional-hazards regression identified RV mass-to-volume ratio ≥0.3 g/mL (HR, 5.04; 95% CI 2.3 to 11.0; p<0.001), LV EF z score<−2.0 (HR, 3.34; 95% CI 1.59 to 7.01; p=0.001), and history of atrial tachyarrhythmia (HR, 3.65; 95% CI 1.75 to 7.62; p=0.001) as outcome predictors. RV dysfunction was predictive of the outcome similar to LV dysfunction. In subgroup analysis of 315 subjects with echocardiographic assessment of RV systolic pressure, higher pressure (HR 1.39; 95% CI 1.19 to 1.62; p<0.001) was associated with death and sustained VT independent of RV hypertrophy and LV dysfunction. Conclusions: RV hypertrophy, ventricular dysfunction and atrial tachyarrhythmias are predictive of death and sustained VT in adults with repaired TOF. These findings may inform risk stratification and the design of future therapeutic trials

Genetic Variation in VEGF Does Not Contribute Significantly to the Risk of Congenital Cardiovascular Malformation

Several previous studies have investigated the role of common promoter variants in the vascular endothelial growth factor (VEGF) gene in causing congenital cardiovascular malformation (CVM). However, results have been discrepant between studies and no study to date has comprehensively characterised variation throughout the gene. We genotyped 771 CVM cases, of whom 595 had the outflow tract malformation Tetralogy of Fallot (TOF), and carried out TDT and case-control analyses using haplotype-tagging SNPs in VEGF. We carried out a meta-analysis of previous case-control or family-based studies that had typed VEGF promoter SNPs, which included an additional 570 CVM cases. To identify rare variants potentially causative of CVM, we carried out mutation screening in all VEGF exons and splice sites in 93 TOF cases. There was no significant effect of any VEGF haplotype-tagging SNP on the risk of CVM in our analyses of 771 probands. When the results of this and all previous studies were combined, there was no significant effect of the VEGF promoter SNPs rs699947 (OR 1.05 [95% CI 0.95–1.17]); rs1570360 (OR 1.17 [95% CI 0.99–1.26]); and rs2010963 (OR 1.04 [95% CI 0.93–1.16]) on the risk of CVM in 1341 cases. Mutation screening of 93 TOF cases revealed no VEGF coding sequence variants and no changes at splice consensus sequences. Genetic variation in VEGF appears to play a small role, if any, in outflow tract CVM susceptibility

Magnetic resonance imaging phantoms for quality-control of myocardial T1 and ECV mapping: specific formulation, long-term stability and variation with heart rate and temperature

Background: Magnetic resonance imaging (MRI) phantoms are routinely used for quality assurance in MRI centres; however their long term stability for verification of myocardial T1/ extracellular volume fraction (ECV) mapping has never been investigated. Methods: Nickel-chloride agarose gel phantoms were formulated in a reproducible laboratory procedure to mimic blood and myocardial T1 and T2 values, native and late after Gadolinium administration as used in T1/ECV mapping. The phantoms were imaged weekly with an 11 heart beat MOLLI sequence for T1 and long TR spin-echo sequences for T2, in a carefully controlled reproducible manner for 12 months. Results: There were only small relative changes seen in all the native and post gadolinium T1 values (up to 9.0 % maximal relative change in T1 values) or phantom ECV (up to 8.3 % maximal relative change of ECV, up to 2.2 % maximal absolute change in ECV) during this period. All native and post gadolinium T2 values remained stable over time with <2 % change. Temperature sensitivity testing showed MOLLI T1 values in the long T1 phantoms increasing by 23.9 ms per degree increase and short T1 phantoms increasing by 0.3 ms per degree increase. There was a small absolute increase in ECV of 0.069 % (~0.22 % relative increase in ECV) per degree increase. Variation in heart rate testing showed a 0.13 % absolute increase in ECV (~0.45 % relative increase in ECV) per 10 heart rate increase. Conclusions: These are the first phantoms reported in the literature modeling T1 and T2 values for blood and myocardium specifically for the T1mapping/ECV mapping application, with stability tested rigorously over a 12 month period. This work has significant implications for the utility of such phantoms in improving the accuracy of serial scans for myocardial tissue characterisation by T1 mapping methods and in multicentre work