Nonreentrant atrial tachycardia occurs independently of hypertrophiccardiomyopathy in RASopathy patients

摘要

Multifocal atrial tachycardia (MAT) has a well-known association with Costello syndrome, but is rarely described with related RAS/MAPK pathway disorders (RASopathies). We report 11 patients with RASopathies (Costello, Noonan, and Noonan syndrome with multiple lentigines [formerly LEOPARD syndrome]) and nonreentrant atrial tachycardias (MAT and ectopic atrial tachycardia) demonstrating overlap in cardiac arrhythmia phenotype. Similar overlap is seen in RASopathies with respect to skeletal, musculoskeletal and cutaneous abnormalities, dysmorphic facial features, and neurodevelopmental deficits. Nonreentrant atrial tachycardias may cause cardiac compromise if sinus rhythm is not restored expeditiously. Typical first-line supraventricular tachycardia anti-arrhythmics (propranolol and digoxin) were generally not effective in restoring or maintaining sinus rhythm in this cohort, while flecainide or amiodarone alone or in concert with propranolol were effective anti-arrhythmic agents for acute and chronic use. Atrial tachycardia resolved in all patients. However, a 4-month-old boy from the cohort was found asystolic (with concurrent cellulitis) and a second patient underwent cardiac transplant for heart failure complicated by recalcitrant atrial arrhythmia. Whilepropranolol alone frequently failed to convert or maintain sinus rhythm,fleccainide or amiodarone, occasionally in combination with propranolol, waseffective for RASopathy patient treatment for nonreentrant atrial arrhythmia.Our analysis shows that RASopathy patients may have nonreentrant atrialtachycardia with and without associated cardiac hypertrophy. While nonreentrantarrhythmia has been traditionally associated with Costello syndrome, this workprovides an expanded view of RASopathy cardiac arrhythmia phenotype as wedemonstrate mutant proteins throughout this signaling pathway can also give riseto ectopic and/or MAT.