Optimizing Screening Intervals for At-Risk Relatives of Dilated Cardiomyopathy Carrying a TTNtv
Steven A. Muller, Nina J. Beelen, Alessia Paldino, Clea Gonzalez-Maniega, Henning Bundgaard, Alex H. Christensen, Christoffer R. Vissing, Renee Johnson, Daria R. Kramarenko, Max F.G.H.M. Venner, Eva del Mestre, Guilielmus H.J.M. Ellenbroek, Fernando Dominiquez, Matteo Dal Ferro, Marco Merlo, Sophie L.V.M. Stroeks, Gianfranco Sinagra, Ahmad S. Amin, Diane Fatkin, Pablo Garcia-Pavia, Anneline S.J.M. Te Riele, Job A.J. VerdonschotBACKGROUND:
Cardiomyopathy guidelines recommend routine screening of at-risk relatives with dilated cardiomyopathy (DCM). Titin-truncating variants are the most prevalent cause. However, the diagnostic yield of screening is low. Risk-based stratification could optimize screening intervals and resource allocation. This study aims to develop a safe, evidence-based gene-specific longitudinal screening algorithm for DCM development.
METHODS:
We included likely pathogenic/pathogenic titin-truncating variant relatives from 7 centers who underwent cardiac screening. Relatives were stratified based on their baseline clinical phenotype: genotype-positive/phenotype-negative (no left ventricular dysfunction and dilatation) or partial DCM (ie, fulfilling only 1 criterion). DCM development predictors were identified based on follow-up data. Risk profiles were established and used to develop a multistate model to create a longitudinal screening algorithm to safely and effectively monitor titin-truncating variant relatives.
RESULTS:
Among 413 relatives, follow-up data were available in 301 relatives (median follow-up 5.7 years), of whom 24.6% developed left ventricular dysfunction or dilatation and 17.3% developed DCM. In total, 16 relatives (5.3%) experienced a major adverse cardiac event after DCM diagnosis. Based on the identified risk factors, age ≥30 years, male sex, and partial DCM, 3 distinct profiles were established: (1) relatives with partial DCM, (2) females ≥30 years and males, and (3) female relatives <30 years. A screening algorithm was developed, recommending intervals of 1, 3, and 5 years, optimizing the balance between safety and effectiveness.
CONCLUSIONS:
An evidence-based genotype-specific longitudinal screening algorithm that integrates age, sex, and echocardiographic measurements may improve patient care and improve efficiency of clinical resource allocation.