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Natriuretic peptides (NPs) show increasing evidence of antagonising arrhythmia. Our previous study demonstrated that C-type NP (CNP) reduces arrhythmia after ischaemia\u2013reperfusion injury (I\/R) via the cGMP-dependent phosphodiesterase 2 (PDE2) in healthy mice. However, the clinical use of CNP is challenging due to its short plasma half-life. To address this, we investigated whether the more stable CNP analogue vosoritide (VO) reduces arrhythmia at cellular and organ levels in mice with STZ-induced type 1 diabetes (50 \u00b5g\/g, i.p. for 5 days). After 5 weeks, STZ treatment led to elevated blood glucose and HbA1c levels, impaired cardiac function, and an increased incidence of arrhythmia after I\/R in ex vivo perfused hearts. Cardiac PDE2 expression was similarly increased in diabetic mice and diabetic patients with dilated cardiomyopathy. Notably, cGMP-mediated PDE2 activation via VO clearly reduced arrhythmia generation after I\/R in ex vivo perfused hearts from diabetic mice (Cohen\u2019s d\u2009=\u20092.3). In cardiomyocytes, VO significantly decreased pro-arrhythmic signals upon \u03b2-adrenergic stress, such as spontaneous Ca\n                    <jats:sup>2+<\/jats:sup>\n                    waves and sparks (Cohen\u2019s d\u2009=\u20091.0) or L-type Ca\n                    <jats:sup>2+<\/jats:sup>\n                    \u00a0current amplitudes (Cohen\u2019s d\u2009=\u20091.6). Specific PDE2 inhibition with BAY\u00a060-7550 or genetic cardiomyocyte-specific PDE2 deletion prevented the anti-arrhythmic VO effects. Importantly, VO did not affect the QT interval, action potential duration, or contraction of cardiomyocytes from diabetic mice. Thus, the modified natriuretic peptide VO may serve as a promising therapeutic option to prevent lethal arrhythmias in susceptible diabetic patients.\n                  <\/jats:p>","DOI":"10.1007\/s00395-025-01141-w","type":"journal-article","created":{"date-parts":[[2025,9,18]],"date-time":"2025-09-18T11:36:04Z","timestamp":1758195364000},"page":"1173-1191","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The CNP analogue vosoritide mediates PDE2-sensitive anti-arrhythmogenic effects in mouse hearts with STZ-induced type 1 diabetes"],"prefix":"10.1007","volume":"120","author":[{"given":"Rebecca","family":"Firneburg","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katharina","family":"Tergau","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eleder","family":"Cachorro","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mario","family":"Schubert","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anindita","family":"Dhara","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaojing","family":"Luo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erik","family":"Klapproth","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kaomei","family":"Guan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ali","family":"El-Armouche","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-1895-4538","authenticated-orcid":false,"given":"Susanne","family":"K\u00e4mmerer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,9,18]]},"reference":[{"key":"1141_CR1","doi-asserted-by":"publisher","first-page":"2869","DOI":"10.1111\/jce.14218","volume":"30","author":"M Amin","year":"2019","unstructured":"Amin M, Kella D, Killu AM, Padmanabhan D, Hodge DO, Golafshar MA, Chamberlain AM, Lee JZ, Shen WK, Friedman PA, Asirvatham SJ, Roger VL, Gersh BJ, Mulpuru SK (2019) Sudden cardiac arrest and ventricular arrhythmias following first type I myocardial infarction in the contemporary era. 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