The natural history of autosomal recessive atrial dilated cardiomyopathy associated with mutation of natriuretic peptide precursor A

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Atrial dilated cardiomyopathy (ADCM) encompasses structural, contractile, and electrophysiological abnormalities of the atria that predispose patients to atrial arrhythmias and heart failure (HF) with preserved ejection fraction (HFpEF). Atrial standstill (AS) represents an extreme manifestation of ADCM, characterized by complete absence of atrial electrical and mechanical activity.1 Traditionally, ADCM has been regarded as secondary to systemic or cardiac disorders, including neuromuscular diseases, laminopathies, amyloidosis, and congenital heart disease. However, recent consensus statements have recognized ADCM as a potential primary myocardial disorder, reflecting intrinsic atrial pathology rather than haemodynamic stress.2 In 2013, we identified a homozygous natriuretic peptide precursor A (NPPA) c.449G>A (p.Arg150Gln) mutation in 13 patients presenting with ADCM and AS.3 Subsequently, the same variant was reported in patients with persistent AF and advanced atrial disease.4,5 We conducted a longitudinal follow-up study of patients carrying the homozygous NPPA p.Arg150Gln mutation.3 Eight living homozygous individuals from six unrelated families (A–F) were evaluated. Baseline data referred to 2013, with updated clinical, electrocardiographic, and echocardiographic assessments, together with a systematic review of clinical events during follow-up (Figure 1A). Clinical trajectory of NPPA-related atrial cardiomyopathy. (A) Individual patient characteristics at diagnosis and last follow-up. (B) Clinical features of the three patients who died during follow-up. (C) The preoperative chest radiograph of patient IV.5(A), the histopathological findings of the atrial wall excised at surgery demonstrating extensive fibrosis, and the postoperative chest radiograph. (D) The stereotyped clinical progression of NPPA-related atrial cardiomyopathy, illustrating the approximate temporal sequence from supraventricular arrhythmias to atrial standstill, thromboembolic events, atrial functional valvular disease, and HF. Legend: ID^ refers to the family members as in the original pedigrees shown in Disertori et al.3. Age, y: ages at diagnosis, in 2013, and last follow-up. *Patients deceased during follow-up. NPPA, natriuretic peptide precursor A; FU, follow-up; NYHA, New York Heart Association; NT-proBNP, N-terminal pro-B-type natriuretic peptide; LAVi, left atrial volume index; RAVi, right atrial volume index; MR, mitral regurgitation; TR, tricuspid regurgitation; HF, heart failure. LVEF, left ventricular ejection fraction; LVEDD, left ventricular end-diastolic diameter; RV, right ventricle; ACE-i, angiotensin-converting enzyme inhibitors; BB, beta-blocker; MRA, mineralocorticoid receptor antagonist; VKA, vitamin K antagonist. RA, right atrium; LA, left atrium. The study complied with the Declaration of Helsinki and was approved by the local ethics committee. The eight homozygous carriers represent the surviving subset of the original cohort. The mean age at first clinical presentation was in the fourth decade, with palpitations as the most common symptom. At baseline, left ventricular function was preserved, while atrial electrical and mechanical dysfunction and supraventricular arrhythmias (AF, atrial flutter, and atrial tachycardia) were frequent. Nearly half of the patients had undergone catheter ablation. Advanced atrial remodelling with marked biatrial enlargement was present in most cases, with complete AS already documented except in three patients [IV.1(D), III.1(E), III.2(F)], who still displayed residual atrial electrical and mechanical activity at that time. Progressive atrial disease with near-complete or complete loss of atrial electrical activity was observed in all patients. Three patients [IV.5(A), V.1(A), III.1(B), Figure 1B] died from progressive HF between 2014 and 2022, in the eighth decade. Two deaths occurred during hospitalization for transcatheter edge-to-edge mitral repair [III.1(B)] and one for surgical mitral and tricuspid valve repair with right atrial remodelling [IV.5(A)]. Histological analysis of the surgically resected atrial tissue demonstrated complete loss of cardiomyocytes (Figure 1C). All patients ultimately required permanent pacemaker implantation for AS, complete in seven cases and partial in one [III.1(E)]. This patient underwent left atrial flutter ablation and repeat electroanatomic mapping, showing progression of right atrial scarring from localized to diffuse involvement. No malignant ventricular arrhythmias or sudden cardiac death occurred. All patients received long-term anticoagulation during follow-up. Four patients experienced ischaemic stroke between the fourth and fifth decades of life. Three events occurred before anticoagulation initiation: one without documented atrial arrhythmias at that time [V.1(A)], one in a patient with AS in the late 1990s [III.1(B)], and one after atrial flutter ablation with subsequent discontinuation of anticoagulation [III.1(E)]. One event occurred despite Warfarin therapy [V.3(A)]. Left ventricular size and function remained stable. One patient [IV.2(D)] developed mild left ventricular dysfunction associated with severe aortic stenosis. Conversely, progressive biatrial enlargement was consistently observed, frequently associated with moderate-to-severe functional mitral and tricuspid regurgitation. Right-sided chambers, particularly the right atrium, showed a more pronounced degree of dilation than the left atrium in most patients. Right ventricular dilation with variable dysfunction was present in approximately half of the cohort. This long-term follow-up confirms the progressive nature of NPPA-related atrial cardiomyopathy.3 From the first clinical description,6 the disease progressed from atrial arrhythmias to universal AS, ultimately leading to permanent pacemaker implantation in all patients. Ventricular structure and function remained largely preserved, highlighting the selective atrial tropism of this genetic substrate (Figure 1D). These findings place NPPA-related disease within the spectrum of genetic atrial-selective cardiomyopathies, characterized by predominant atrial electrical, structural, and contractile dysfunction in the absence of significant ventricular involvement.7 We previously demonstrated a correlation between atrial fibrosis extent and AS using electroanatomic mapping and late gadolinium enhancement (LGE)-MRI,8 supporting the concept that progressive fibrotic remodelling constitutes the structural substrate for electromechanical silence. A key observation is the emergence of a secondary valvular phenotype characterized by atrial functional mitral and tricuspid regurgitation, occurring in the absence of intrinsic valve disease and with preserved ventricular geometry.9 Unlike typical atrial functional regurgitation related to AF or HFpEF, atrial dilation in NPPA-related disease appears driven by atrial natriuretic peptide (ANP) deficiency, leading to fibrosis and mechanical failure independent of loading conditions. The homozygous NPPA variant is predicted to cause loss of function of ANP, resulting in ANP deficiency. This leads to marked atrial enlargement and fibro-fatty replacement of atrial tissue, as also demonstrated in NPPA knockout mouse models.3 Complete fibrous substitution of the atrial wall was confirmed in surgical atrial samples from our patient. Serial sectioning revealed no residual atrial myocytes. This mechanism may explain the limited benefit of valve interventions, as they target the consequence rather than the cause. Consistently, both patients undergoing valve repair died during hospitalization. Notably, atrial remodelling was asymmetric, with more pronounced right atrial dilation in several patients as previously described.10 Long-term management of NPPA-related disease requires early rhythm surveillance, preventive pacing, and lifelong anticoagulation given the persistent thromboembolic risk; the role of additional strategies, such as l

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