Impact of genetic testing on primary prevention ICD decision-making and clinical outcomes in dilated cardiomyopathy
A Bernabei, A Paldino, A Fluca, M Dal Ferro, M Merlo, A Aleksova, G SinagraAbstract
Background
Despite advances in clinical risk stratification, dilated cardiomyopathy (DCM) remains associated with a substantial risk of malignant ventricular arrhythmias and sudden cardiac death. Genetic testing may provide incremental value in arrhythmic risk assessment and primary prevention implantable cardioverter-defibrillator (ICD) decision-making.
Objective
To evaluate the impact of genetic testing on primary prevention ICD decision-making in patients with DCM and its association with clinical outcomes after implantation, including appropriate ICD interventions.
Methods
Between January 1, 2001, and December 1, 2025, 1,890 adult patients with DCM enrolled in our Familial Cardiomyopathy Registry were screened; those without genetic data were excluded. Genetic variants were classified according to current standards, and high-risk arrhythmogenic genes were defined per international guidelines (LMNA, FLNC, DSP, TMEM43, PLN, RBM20). Predictors of ICD implantation were evaluated using multivariable logistic regression, and associations with outcomes were assessed by time-to-event and competing-risk analyses.
Results
Among 699 eligible patients, 382 (55%) received an ICD, including 335 (88%) for primary prevention. Pre-implant genetic testing was performed in 36% (n=122) and increased after the introduction of exome-based panels (14% before 2018 vs 67% in 2018–2025; p<0.01). Patients tested before implantation more often carried likely pathogenic/pathogenic (LP/P) variants than those tested after (49% vs 37%; p=0.01), including variants in high-risk arrhythmogenic genes (20% vs 10%; p=0.04). LP/P variants were independently associated with primary prevention ICD implantation, together with history of syncope and persistent LVEF <35% after optimal medical therapy. Among patients with LVEF >35%, LP/P variants in high-risk arrhythmogenic genes were the only independent predictors (Table 1). During a median follow-up of 136 months (IQR 77–226), 32% (n=106) experienced appropriate device interventions. LP/P variants were associated with these interventions (p=0.01, Figure 1A) and were the sole independent predictor (OR 1.55, 95% CI 1.06–2.28; p=0.02), irrespective of LVEF. In patients with available cardiac magnetic resonance (CMR) data (n=183, 54.6%), late gadolinium enhancement (LGE) was the only independent predictor (OR 2.89, 95% CI 1.34–6.24; p=0.01).
Conclusions
In this large DCM cohort, genetic testing was independently associated with primary prevention ICD decision-making, including in patients with preserved or mildly reduced LVEF, and predicted appropriate ICD intervention beyond LVEF. Its incremental prognostic value was attenuated in the presence of CMR data, supporting a multimodal, guideline-consistent approach to arrhythmic risk stratification.