The evolving landscape of inherited arrhythmias and cardiomyopathies: two decades of multidisciplinary experience in the United States
K Abdelsayed, J Sengupta, S A Casey, E Halvorson, A Bahbah, M T Desouki, A A Berg, M P Katsiyiannis, R H Abdelhadi, W Katsiyiannis, R Hauser, S Sharkey, M K Bennett, E Zishiri, D WittAbstract
Background
Inherited arrhythmia and cardiomyopathy syndromes contribute substantially to sudden cardiac death (SCD) and remain under-diagnosed in routine care. Large, multidisciplinary, real-world registries are increasingly crucial to define contemporary phenotypes, provide genetic screening, and analyze long-term outcomes.
Objective
We describe the 20-year experience of our Genetic Arrhythmia and Cardiomyopathy Center (GACC), one of the largest multi-disciplinary clinics for hereditary causes of SCD in the US.
Methods
Consecutive patients referred to GACC between January 2006–December 2025 for suspected arrhythmogenic or cardiomyopathic conditions were enrolled. The registry (established since 2011) captured clinical, electrical, imaging, and genetic characteristics. Positive genetic testing was categorized as pathogenic/likely pathogenic (P/LP) or variant of uncertain significance (VUS). Prevalence and temporal patterns in common phenotypes, genotypes, and ICD use were quantified across 4 quartiles. Continuous variables were summarized as median (IQR) and categorical variables as n (%).
Results
Among 850 enrolled patients, median age was 44 (29–57) years with 45.1% male and 91.6% White. Baseline characteristics are summarized in Fig-1A. Palpitations and shortness of breath were the most common symptoms (Fig-1B). CMR was performed in 681 patients, showing LVEF 58 (48–64) %, late gadolinium enhancement in 28.9%, and wall-motion abnormalities in 32.6%. Apical hyper-trabeculation was detected in ~40.2%, mostly incidental. The most frequent phenotype was arrhythmogenic right ventricular cardiomyopathy (ARVC, 16%). Among patients who had genetic testing, the most prevalent P/LP variants were PKP2 (12%) and DSP (11%) (Fig-2A). Over time, the prevalence of overt ARVC phenotype at initial visit decreased while that of dilated cardiomyopathy and non-specific phenotypes increased (Fig-2B). An ICD was implanted in 27.2% of patients at baseline or within 6 months of the initial visit. Although 73.2% were primary prevention ICDs, the prevalence steadily decreased with time (Fig-2C). Over a median of 89 (31-143) months, 33.8% of patients with ICDs received therapies, of which 62.8% were appropriate. Primary ICDs delivered 61.2% of the appropriate therapies. Of total interventions by primary ICDs, 55.6% were appropriate.
Conclusions
In one of the largest inherited arrhythmia registries in the US, there was a high prevalence of desmosomal variants—particularly PKP2 and DSP. ARVC was the most common phenotype at initial presentation which is decreasing with time. Nearly one-third of patients who underwent ICD implants received therapies which were usually appropriate. These findings reflect real-world patterns in referral, diagnosis, and outcomes, emphasizing the value of integrated phenotyping and genetic evaluation for inherited arrhythmia and cardiomyopathy syndromes.