Background Genetic testing (GT) is established in ambulatory cardiomyopathy (CM), but its utility after heart transplantation (HTx) recipients remains poorly characterized. Objectives This study aimed to evaluate the clinical utility of GT in adult HTx recipients with CM, focusing on etiologic reclassification, family cascade screening, and the genetic architecture of end-stage disease. Methods GenbaseHTx is a nationwide, multicenter retrospective study of adult HTx recipients transplanted for CM across 12 Spanish centers (2010-2023). GT results were centrally adjudicated using American College of Medical Genetics and Genomics criteria. Outcomes included prevalence of pathogenic/likely pathogenic variants, etiologic reclassification after GT, and cascade screening activation. Results Among 657 HTx recipients, a pathogenic/likely pathogenic variant was identified in 53% (351/657). GT led to etiologic reclassification in 35% (231/657) (42% when performed post-HTx −106/253-). Family screening (performed in 69% of families −224/328-) identified affected relatives in 22% (19/90) of genotype-negative and 42% (49/107) of genotype-positive cases. Notably, a genetic etiology was identified in 36% (15/42) of CM initially attributed to acquired or “second-hit” causes. In dilated cardiomyopathy, the genetic architecture of transplanted patients differed from ambulatory cohorts, with lower TTN variant prevalence and enrichment of arrhythmogenic genes. Conclusions GT remains clinically actionable after HTx, enabling etiologic reclassification and driving cascade screening. These findings support systematic GT in HTx recipients with CM, including those with prior environmental triggers or second-hit etiologies, and regardless of time from transplantation.
C. Moliner-Abós, D. C. Cabrera Argana, David Belmar Cliville et al.· JACC: Advances· 2 citations
BACKGROUND
Fibrosis assessed through late gadolinium enhancement (LGE) in cardiac magnetic resonance imaging and genetics have emerged as risk markers of ventricular arrhythmias in nonischemic dilated cardiomyopathy. Conduction corridors detected within LGE (ie, LGE corridors) have been associated with ventricular arrhythmias in ischemic cardiomyopathy. This study sought to evaluate major ventricular arrhythmic events (MVAs) according to the presence of LGE corridors combined with high-risk genotypes (HRGs) in nonischemic dilated cardiomyopathy.
METHODS
We studied consecutive patients with nonischemic dilated cardiomyopathy from 22 European centers who had undergone genetic testing and cardiac magnetic resonance imaging.
RESULTS
Among 925 patients (mean age, 54.5 years [interquartile range, 43.7-63.9 years]; 64% men; mean left ventricular ejection fraction, 37.6% [26.9%-44.8%]; LGE in 24.3%), LGE corridors were present in 160 patients (17.3%), and HRG in 119 (12.9%). After a median follow-up of 5.4 years (interquartile range, 3.3-7.7), 95 patients (10.3%) experienced an MVA. In multivariable competing-risk analysis adjusted for left ventricular ejection fraction and extent of LGE, the number of LGE corridors and HRGs were independently associated with MVA (subdistribution hazard ratio, 1.25 [95% CI, 1.11-1.42]; P<0.001; and subdistribution hazard ratio, 2.28 [95% CI, 1.32-3.96]; P=0.003, respectively). An optimal cutoff of ≥4 LGE corridors predicted MVA. A stepwise risk stratification algorithm to predict MVA integrating LGE, the presence of ≥4 LGE corridors, and HRG outperformed left ventricular ejection fraction ≤35%-based classification proposed in guidelines (5-year time-dependent area under the curve, 0.72 [95% CI, 0.65-0.78] versus 0.57 [95% CI, 0.51-0.64]; P=0.001), showing a progressive increase in arrhythmic risk across categories (Gray test P<0.001), and allowing clinically meaningful arrhythmic risk classification.
CONCLUSIONS
LGE corridors and HRGs provide additive value for arrhythmic risk stratification in patients with nonischemic dilated cardiomyopathy. These findings support MVA multiparametric prediction over the traditional left ventricular ejection fraction ≤35% threshold.
Noemí Ramos-López, N. Mora-Ayestarán, Juan Pablo Ochoa et al.· Circulation· 0 citations
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