Early biomarkers of atrial miopathy

PIANO NAZIONALE DI RIPRESA E RESILIENZA (PNRR)

Missione 6 - Componente 2 - Investimento 2.1

“Valorizzazione e Potenziamento della Ricerca Biomedica del SSN” - Finanziato dall’Unione europea – NextGenerationEU

Bando PNRR

Progetto “Early biomarkers of atrial myopathy”

Codice Identificativo Progetto: PNRR-MCNT2-2023-12378342- CUP: D73C24000550006

This project is aimed at identifying early biomarkers of atrial myopathy (AM), a condition characterized by morphological rearrangement and functional changes in left atrium (LA). AM can be caused by inflammation, atrial stretch, oxidative stres and other factors, and may precede and promote atrial fibrillation, pulmonary venous hypertension and thromboembolism (Shen, 2019; Packer, 2020). LA enlargement and dysfunction are usually detected by 2-dimensional echocardiography and speckle tracking analysis. Cardiac magnetic resonance (CMR) can also contribute to the atrial structure definition (Shen, 2019; Ezeani, 2022; Maheshwari, 2023). Among the diseases in which AM is seen, there are some autoimmune and inflammatory diseases, including systemic sclerosis (SSc) (Packer, 2020), and anthracycline-related cardiomyopathy (ARCD) (Laufer-Perl, 2021). In these contexts, AM emerges as a specific early sign and predictor of general left heart disease (LHD) and its early recognition is required for an effective conduct of therapy. Although the levels of some molecules, related to inflammation, hypercoagulability or myocardial damage, have been reported to be elevated in AM, their increase has been mainly related to the risk of systemic thromboembolism and stroke, late consequences of AM (Shen, 2019; Packer, 2020; Li, 2022), while there is an unmet need for specific markers of AM early stages. To identify AM early biomarkers, we will follow two parallel approaches. Since fibrosis underlies AM pathogenesis (Shen, 2019), and our results show that cardiac fibrosis is stimulated by BAG3 protein released by stressed cardiomyocytes, we will evaluate serum BAG3 protein levels in: a) SSc patients in the course of the disease; b) patients affected by breast cancer or leukemias/lymphomas and treated with anthracyclines; c) two animal models of AM, i.e. anthracycline(AC)-treated mice (Podyacheva, 2021) and TGF-ß1-overexpressing mice (Verheule, 2004). At the same time, we will investigate, by proteomic and metabolomic approaches, molecules that show increased levels in the serum of patients and mice. Results will be related to the detection of AM by speckle tracking echocardiography of the left atrium and clinical outcomes of the patients, and, in animals, to cardiac fibrosis.