Mortality Among Patients With Early-Onset Atrial Fibrillation and Rare Variants in Cardiomyopathy and Arrhythmia Genes

This cohort study assesses the association of rare variants of cardiomyopathy and arrhythmia genes with all-cause mortality among patients with early-onset atrial fibrillation.

All participants undergo written, informed consent. It is a prospective observational registry of subjects undergoing AF ablation (clinicaltrials.gov NCT #02404415). Whole blood is collected during the ablation procedure from which DNA is extracted and stored along with serum and plasma.
Baseline clinical data are manually extracted from the medical record and supplemented by patient interview. Pre-ablation imaging studies are performed (cardiac MRI or CT) and stored.
Electrophysiologic data obtained at the time of ablation is collected and stored (data from the baseline electrophysiologic study and data and images from the electroanatomic map). Participants are prospectively followed for arrhythmia recurrence post-ablation and longitudinally to track longer term clinical outcomes.  TAZ  TBX20  TCAP  TECRL  TGFB3  TMEM43  TMPO  TNNC1  TNNI3  TNNT2  TOR1AIP1  TPM1  TRDN  TRPM4  TTN  TTR  TXNRD2 VCL eAPPENDIX 3: Mortality and cause of death assessment For purpose of this analysis, vital status was censored up to 1/1/2020 and determined via two complementary methods. First, all participant records were reviewed up to the censor date for either: 1) mention of participant death prior to censoring or 2) follow up visit occurring after the censor date.
Second, all participant records were sent to the NDI for record matching. The NDI is the most complete source of death information in the United States and holds all death records from 1979 for all 50 states and includes the corresponding ICD-10 codes for causes of death. Based on information provided, the NDI provides record matches for adjudicating matched death certificates to participants using a probabilistic match score (https://www.cdc.gov/nchs/data/ndi/NDI_Users_Guide.pdf). 1 Based on the matching algorithm, the NDI assigns each potential match a score. Using the NDI's cut-off score, the NDI records were used to confirm the vital status of all participants for whom the date of last follow-up occurred prior to the censor date or whose vital status remained unknown after chart review.
Cause of death information was obtained via the death certificate listed for all participants who were determined to be deceased. Death certificates list a "primary" and "contributing" cause (or causes) of death; however, the reporting differs among providers and among states. Therefore, deaths were considered as "CM-related," "sudden death," or "stroke-related," based on the inclusion of a corresponding ICD-10 code on either the primary or any of the contributing causes of death. A complete list of corresponding ICD-10 codes is presented in Supplemental test that compared the full model with the interaction term to a reduced model without any terms that involved the disease-associated variant. The interaction between disease-associated variant status and age at AF diagnosis was graphically displayed (Figure 2 Panel B) where the "mortality risk" was calculated from the multivariable Cox model along with partial-effect plots generated from the model fitting results for visualization. Pre-specified secondary analyses grouped disease-associated variants according to 1) genes associated with specific inherited CM and arrhythmia syndromes, and 2) individual genes. A second pre-specified subgroup analysis tested the association between diseaseassociated variants and specific causes of death (CM-related and sudden death) using an adjusted eFIGURE 1: Survival curve for the sensitivity analysis that restricted disease-associated variants to only strong/definitive evidence genes (N=104 participants). Adjustment was made for age at AF diagnosis, sex, race, BMI, LVEF, and an interaction term for diseaseassociated variant status and age (Pinteraction=0.006). (P=0.005 likelihood ratio test). eFIGURE 2: Proportion of participants with a disease-associated variant according to LVEF at enrollment. Most participants with depressed LV systolic function did not have a disease-associated variant. The number of participants with a disease-associated variant that died (all-cause mortality) during follow-up in the LVEF ≤39% group was 7, 40-49% group was 5, and ≥50% group was 18.