Structural characterization of atrial natriuretic peptide amyloid fibrils from patients with atrial fibrillation

Luca Broggini, Marco Piccoli, Antonio Chaves-Sanjuan, Diane Marie Valérie Bonnet, Federica Cirillo, Cristina Visentin, Federica Sonzini, Paola Signorelli, Ivana Lavota, Melissa Milazzo, Simona Nonnis, Lorenzo Menicanti, Giuseppe Ciconte, Carlo Pappone, Luigi Anastasia and Stefano Ricagno ()
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Luca Broggini: IRCCS Policlinico San Donato
Marco Piccoli: IRCCS Policlinico San Donato
Antonio Chaves-Sanjuan: University of Milan
Diane Marie Valérie Bonnet: Università degli Studi di Milano
Federica Cirillo: IRCCS Policlinico San Donato
Cristina Visentin: University of Milan
Federica Sonzini: IRCCS Policlinico San Donato
Paola Signorelli: University of Milan
Ivana Lavota: IRCCS Policlinico San Donato
Melissa Milazzo: University of Milan
Simona Nonnis: University of Milan
Lorenzo Menicanti: Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Donato
Giuseppe Ciconte: IRCCS Policlinico San Donato
Carlo Pappone: IRCCS Policlinico San Donato
Luigi Anastasia: IRCCS Policlinico San Donato
Stefano Ricagno: IRCCS Policlinico San Donato

Nature Communications, 2025, vol. 16, issue 1, 1-10

Abstract: Abstract Isolated atrial amyloidosis (IAA) is a localized cardiac disorder characterized by atrial natriuretic peptide (ANP) amyloids deposition in the atria, linked to aging and atrial fibrillation (AF). While monomeric ANP regulates blood pressure, its dimeric form is associated with cardiovascular conditions, including AF. The mechanistic link between ANP aggregation, IAA, and AF remains unclear. Here, we present the first high-resolution structural characterization of ANP fibrils extracted from AF patients, revealing two distinct fibril polymorphs. Both present covalent ANP dimers as building blocks but diverge in their structural architecture: one features antiparallel dimers stabilized by a single disulfide bond, while the other consists of parallel dimers bridged by two interchain disulfide bonds. These fibril morphologies were conserved across patients, suggesting a common aggregation mechanism in IAA. Overall, our findings ascribe to dimeric ANP a critical role in amyloid formation, offering promising directions for earlier detection and treatment of IAA.

Date: 2025
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DOI: 10.1038/s41467-025-64618-1

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