Atrial fibrillation (AF) is rare in children and young adults, but the last several years have expanded our understanding of genetic etiologies in young people with structurally normal hearts and brought new tools to treat AF in all patients.
In the last 5-7 years, new data have established that pathogenic variants in genes traditionally associated with cardiomyopathy are overrepresented in early-onset AF. AF can present as a distinct entity in these patients, not necessarily dependent on dilation, hypertrophy, abnormal loading conditions, or other macroscopic changes in ventricular physiology. Truncation variants in the large structural protein titin have been described most frequently (occurring in ~7% of early-onset AF), and the list of genes continues to expand (Table). For example, RBM20 encodes an RNA-binding protein that regulates the splicing of mRNA, including the splicing of the notoriously complex titin protein. This year, Dr. Vad and colleagues established that loss of function variants in RBM20 occurred more frequently in Scandinavian patients with early onset AF than in population controls.(1) In population data, RBM20 variants were also associated with larger left atrial volume by cardiac MRI. Rats with these RBM20 variants expressed abnormalities in functional assays (electron microscopy of sarcomeres and mitochondria) and protein products that require mRNA splicing were abnormally expressed (including titin). Fortunately for our understanding of the field, the story is considerably more complicated than just the relationship between RBM20 protein and titin. Genetic etiologies of AF in children are likely to be a fruitful area of inquiry for years.
Table.
Genes Associated with Monogenic Atrial Fibrillation in Children and Young Adults
| Genes Incorporated into Clinical Arrhythmia and Cardiomyopathy Panels | |
| LMNA, KCNQ1, MYBPC3, MYH7, MYL4, RBM20, PKP2, SCN5A, TTN | |
| Genes Incorporated into Congenital Heart Disease Panels | |
| GATA4*, MYH6, TBX5 | |
| Genes with Research Publications, but without Actionable Clinical Adjudication | |
| CTNNA3, KCNA5, KDM5B, TLR4 pathway | |
Clinical panels change quickly; for example, GATA4 is incorporated into some arrhythmia panels.
Table excludes genetic evaluations when another arrhythmia phenotype is present, e.g. long QT, short QT, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia or preexisting cardiomyopathy
Clinically, Dr. El-Harasis and colleagues provided early data that AF recurrence after catheter ablation was no higher in genotype-positive patients with AF than in genotype-negative patients. In a prospective, observational cohort study of adult patients who underwent AF catheter ablation, the presence of a pathogenic or likely pathogenic variant in a panel of candidate genes was not associated with AF recurrence after ablation in any group except the subset that included LMNA variants.(2) The sample size was small (109 genotype-positive patients), and further stratification may emerge in larger samples, but the early data suggest that ablation remains a tool in the armamentarium, even in the patients with pathogenic or likely pathogenic variants in cardiomyopathy or arrhythmia genes.
A major milestone this year was inclusion of genetic testing for patients with early-onset AF in a clinical guideline.(3) These are class IIB recommendations, reflecting the early state of the field, but the language of the guideline is, “In patents with an onset of AF before 45 years of age without obvious risk factors for AF, referral for genetic counseling, genetic testing for rare pathogenic variants, and surveillance for cardiomyopathy or arrhythmia syndromes may be reasonable.” There is no lower age limit placed on the recommendation, recognizing that monogenetic variants may occur in even higher prevalence in the very young with AF and structurally normal hearts.
While genetics continues to progress, the epidemiology of repaired congenital heart disease guarantees that electrophysiologists will continue to treat AF in children and young adults with repaired congenital heart disease. Pulsed field ablation (PFA) is the use of high-amplitude, rapidly oscillating electric fields to create irreversible electroporation in tissues, leading to cell death, fibrosis, and eventually conduction block without creating direct thermal injury. This year, Dr. Krause and the team in Göttingen, Germany reported using PFA for 21 patients with congenital heart disease (18 of 21 with AF), and provided 6 months of follow-up.(4) Acute procedural success was reported in all patients, with 1 episode of coronary vasospasm during ablation and sustained post-procedure macro-reentrant atrial tachycardia in 2 patients.
Pediatric AF is rare, and the data may be skewed by ascertainment bias. For example, most of the recent work in monogenetic AF has been performed in patients who self-report descent from European countries. Similarly, treatment and therapy in structural heart disease caused by congenital defects underrepresents the worldwide burden of rheumatic heart disease. This year, Dr. Constante and colleagues at Unidade Local de Saúde São José published an AF cohort with a mean age of 15 years (range 10-18) in which 52.8% had a prior diagnosis of rheumatic heart disease.(5) Stroke occurred in 8% of patients, all of whom had rheumatic heart disease, a reminder that the low rate of stroke in most pediatric publications may be higher in areas with endemic rheumatic heart disease.
In summary, the understanding that variants in traditional cardiomyopathy and congenital heart genes may be a critical pathway for early onset AF is new and provides additional insight, beyond the established associations of AF in arrhythmia substrates such as long QT syndrome, short QT syndrome, catecholaminergic polymorphic ventricular tachycardia, and Brugada syndrome. In addition, the field continues to apply new ablation technologies in young people, with the long-term goal to reduce morbidity and mortality in children and young adults.
Funding Sources:
The author is supported, in part, by NIH/NHLBI R01 HL164773.
Abbreviations:
- ACDH
adults with congenital heart disease
- AF
atrial fibrillation
- ICD
implantable cardioverter-defibrillator
- MRI
magnetic resonance imaging
Footnotes
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