A New Score for Life-threatening Ventricular Arrhythmias and Sudden Cardiac Death in Adults with Transposition of the Great Arteries and a System Right Ventricle.

A New Score for Life-threatening Ventricular Arrhythmias and Sudden Cardiac Death in Adults with Transposition of the Great Arteries and a System Right Ventricle.

Ladouceur M et al, Eur Heart J. 2022 Jul 21;43(28):2685-2694. doi: 10.1093/eurheartj/ehac288. PMID: 35673927


Take-home points:

1) Ventricular arrhythmic sudden death remains a concerning long-term risk in patients with D- or L-TGA with systemic right ventricles, though event rates remain proportionately low in comparison to other conventional cardiovascular substrates in adult patients, making risk stratification challenging

2) Risk factors can be identified and combined to help predict higher or lower risk of arrhythmic death among TGA/systemic RV patients

3) Determining candidates that will benefit most from primary prevention ICD implantation in TGA/systemic RV remains challenging despite identification of contributing risk factors, with most primary prevention ICD recipients not receiving appropriate shocks





Commentary by Dr. Philip Chang (Gainesville, FL, USA) Congenital and Pediatric Cardiac EP section editor:  

Sudden cardiac death remains a challenging and devastating end point for older patients surviving with congenital heart disease.  Factors that contribute to risk of sudden death have been identified, though stratification schemes and prediction of who may carry higher/highest risk (and therefore benefit from primary prevention ICD implantation) remain limited given the significant heterogeneity between CHD substrates, intra-substrate variability, and proportionately low event rates overall.  A subpopulation that particularly highlights all of these is the CHD subgroup of patients with TGA and systemic RV.

Ladouceur et al performed a multi-center retrospective study including all patients >16 years old with TGA substrates and systemic RV followed over time across several European ACHD programs, specifically looking at incidence of Major Adverse ventricular arrhythmias and Related Events (MAREs).  Patients encountered between 2000-2018 with at least 2 years of follow-up were included.  Demographic and clinical data were gathered to identify risk factors for MAREs and then used to derive a risk calculator and scoring system to facilitate the identification and categorization of patients at lower vs. higher risk.

A total of 1184 patients were identified and met inclusion criteria (median age 27.1 years, 59% male, 70% D-TGA).  Among D-TGA patients, there were nearly twice as many Mustard atrial switch procedures performed compared to Senning operations.  Over a median follow-up duration of 9.4 years, 59 patients (5%) experienced MAREs yielding an overall incidence of 6.3 per 1000 patient-years.  There were 79 patient deaths (6.7%), of which MAREs accounted for 13.  Nearly a quarter of patients during the study period experienced new cardiovascular events including atrial arrhythmias (12%), symptomatic heart failure (10%), and pacemaker implant (9%).

While multiple risk factors were identified and considered significant based on univariate analysis, increasing age, history of heart failure, syncope, wider QRS duration, severe systemic RV dysfunction, and at least moderate subpulmonary LV outflow obstruction were significant risk factors by multivariate analysis.

Among patients with ICDs during the study period, 121 had an ICD for primary prevention, with recipients being older and more likely to have L-TGA.  Nearly 12% experienced inappropriate shocks and appropriate shocks occurred in only 8/121 patient.

The MAREs risk calculator was derived from the 6 risk factors identified as significant by multivariate analysis.  Each risk factor was weighted and integrated into a prognostic index value that was then incorporated into an equation to calculate a score for risk of MAREs over 5 years.  The authors then applied the model to the study population for basic validation, noting the comparison between prediction of MAREs risk by the calculator and the observed MAREs incidence.  Using cutoffs of <5%, 5 to <10%, and >10% for risk of MAREs over 5 years of follow-up, the authors were able to determine a percentage of patients who would have qualified for primary prevention ICDs by risk calculation and how many would receive appropriate ICD therapies based on the incidence of events over the study period.  From these calculations, they determined that 1 patient could potentially be saved from MAREs at 5 years for every 10 primary prevention ICDs implanted using a risk cutoff of >5% and 1 patient for every 5 ICDs implanted using a risk cutoff of >10%.

Reviewer perspective:

Sudden death in aging survivors with palliated D-TGA or L-TGA with systemic RV remains an ongoing concern.  Given this concern, many patients undergo primary prevention ICD using basic risk assessment, yet many do not experience any shock therapy benefit over extended periods of follow-up but carry risks and experiences of inappropriate shocks and hardware-related complications.  This study further refines our understanding of sudden death risk in TGA patients with systemic RV, noting the influence of increasing age, myocardial fibrosis, and atrial arrhythmias contributing to substrate and triggers for potentially lethal ventricular arrhythmias.

Interestingly, the study investigators found a risk of at least moderate subpulmonary LV outflow obstruction to be an independent risk factor for MAREs.  Historically, the presence of subpulmonary LV outflow obstruction was felt to control and even reduce the degree of systemic tricuspid regurgitation by way of ventricular septal shift.  While this may still be true, moderate or greater degrees of obstruction may give rise to adverse myocardial remodeling and fibrotic substrate for arrhythmias.  This finding also highlights that attention must be paid to the “opposite” ventricle from the one that appears to pose the primary and dominant concern, as is also the case with tetralogy of Fallot with significant RV derangements as well as LV involvement (with high EDPs and/or systolic dysfunction).

The study also demonstrated that, while a higher rate of sudden arrhythmic death was calculated in this contemporary study, overall event rates remain proportionately low in comparison to other adult acquired cardiovascular disease states and substrates.   For example, recent risk models in post-MI patients have derived sudden arrhythmic death rates of 3.3 per 100 person-years over a median 2-year follow-up period compared to the 6.3 per 1000 over 9 years of follow-up reported in the current study.  This only further serves to highlight the challenges of developing risk stratification schemes in CHD patients.  The authors noted that their higher reported rate of sudden death may reflect the aging and older ACHD population studied in this contemporary era.

The risk calculator that was derived appears to carry some utility in predicting risk, particularly those with high risk of MAREs >10% at 5 years.  Furthermore, the application of this risk scoring tool prospectively holds some promise of refining candidacy for primary prevention ICDs and sparing some patients who may not derive the desired survival benefit.  The authors acknowledged some limitations to the risk score, given that certain variables that were either considered significant risk factors or potentially useful predictors were excluded from the risk model either due to limited numbers of events involving those factors or missing data across the study cohort.  The incorporation of certain biomarkers and advanced imaging data may help to further differentiate patients with similar risk profiles.

Though thoughtful overall, the study primarily reinforces what we currently know and frequently integrate into even basic risk assessment of TGA/systemic RV patients.  Increasing age, worsening systemic RV function, and associated atrial arrhythmias remain recognized dominant risk factors.  The incorporation of a quantified risk value may help to better group patients into those who should proceed with primary prevention ICD sooner and those who should undergo serial risk scoring assessments over time to trend quantifiable changes that may drive a change in management in the future.