Long term follow-up of autosomal recessive atrial dilated cardiomyopathy associated with mutation of natriuretic peptide precursor A
M Iseppi, M Marini, S Quintarelli, F Tedoldi, R Bonmassari, E ArbustiniAbstract
Background
Natriuretic Peptide Precursor A (NPPA) related atrial dilated cardiomyopathy (ADCM) represents a rare monogenic atrial disease characterized by progressive atrial electrical and mechanical failure. In 2013, we reported 13 homozygous carriers of NPPA p.Arg150Gln presenting with ADCM and variable degrees of atrial standstill (1). Long-term natural history data for this condition remain limited.
Purpose
To provide long-term clinical, structural and rhythm outcomes of the previously described NPPA-related ADCM cohort.
Methods
All surviving homozygous carriers from six unrelated families underwent updated clinical, electrocardiographic and echocardiographic evaluation in 2024–2025, and long-term events were systematically collected and analyzed.
Results
Eight patients were alive at baseline in 2013. Progressive atrial disease with transition to near-complete or complete atrial standstill occurred in all cases and ultimately all patients required permanent pacemaker implantation. Four ischemic strokes occurred, three before stable anticoagulation and one despite appropriate therapy. Three patients died between 2014 and 2022 from progressive heart failure, with two deaths occurring during hospitalization for surgical or percutaneous correction of severe mitral regurgitation. Left ventricular size and systolic function largely remained preserved. Conversely, progressive and marked biatrial enlargement developed, frequently accompanied by functional mitral and tricuspid regurgitation. Right atrial enlargement was often more pronounced than left, and right ventricular dilation with variable dysfunction was observed in approximately half of the cohort. These longitudinal clinical and structural features are summarized in Figure 1.
Conclusions
This study provides the first long-term characterization of the natural history of NPPA-related atrial dilated cardiomyopathy, showing a progressive atrial-restricted disease evolving from supraventricular arrhythmias to universal atrial standstill, thromboembolic events, atrial functional valvular disease and ultimately heart failure. In this condition, atrial dilation appears primarily driven by ANP deficiency, promoting progressive fibrosis and mechanical failure independent of loading conditions. This atrial-driven mechanism may help explain the limited benefit of valvular interventions, which target the consequence rather than the underlying cause. Ventricular structure and function remain largely preserved, supporting the concept of a truly atrial myopathy. Overall, these findings establish NPPA-related ADCM as a paradigmatic model of primary atrial cardiomyopathy and highlight the need for early recognition, lifelong anticoagulation, preventive pacing and future disease-modifying therapeutic strategies.For image description, please refer to the figure legend and surrounding text.