The natural history of autosomal recessive atrial dilated cardiomyopathy associated with mutation of Natriuretic Peptide Precursor A

Background Natriuretic Peptide Precursor A (NPPA)–related atrial dilated cardiomyopathy (ADCM) is a rare monogenic atrial disease characterized by progressive electrical and mechanical atrial failure. In 2013, we reported 13 homozygous NPPA p.Arg150Gln carriers with ADCM and variable atrial standstill (1). Long-term data and early disease evolution remain limited. Purpose To describe long-term outcomes of the original NPPA-related ADCM cohort and early disease progression in a newly identified young homozygous carrier. Methods All surviving homozygous carriers from six unrelated families underwent updated clinical, ECG and echocardiographic evaluation in 2024–2025, with systematic collection of long-term events. A young asymptomatic homozygous carrier identified through population screening was prospectively followed. Results Eight patients were alive in 2013. Progressive atrial disease leading to near-complete or complete atrial standstill occurred in all, and all required permanent pacemaker implantation. Four ischemic strokes occurred (three before stable anticoagulation, one despite therapy). Three patients died from progressive heart failure between 2014 and 2022, two during hospitalization for correction of severe functional mitral regurgitation. Left ventricular size and systolic function remained largely preserved. In contrast, marked biatrial enlargement developed, often with functional mitral and tricuspid regurgitation. Right atrial enlargement was frequently more pronounced, and right ventricular dilation with variable dysfunction was observed in about half of cases. A 9-year-old homozygous carrier had normal baseline evaluation but developed symptomatic paroxysmal atrial fibrillation at 18 years, with current biatrial enlargement and preserved ventricular function. Despite pulmonary vein isolation, recurrent AF persists, requiring antiarrhythmic therapy and long-term anticoagulation. This case illustrates progression from a silent genetic preclinical stage to overt atrial cardiomyopathy in early adulthood and she represents the youngest symptomatic patient. Conclusions NPPA-related ADCM is a progressive atrial-restricted cardiomyopathy evolving from supraventricular arrhythmias to universal atrial standstill, thromboembolism, functional valvular disease and heart failure, with largely preserved ventricular function. The prospective observation of a young carrier demonstrates that clinical onset may follow a silent phase, supporting early genetic identification and longitudinal surveillance allowing timely initiation of rhythm control, anticoagulation and preventive pacing strategies.