| First Author | Firneburg R | Year | 2025 |
| Journal | Basic Res Cardiol | Volume | 120 |
| Issue | 6 | Pages | 1173-1191 |
| PubMed ID | 40965622 | Mgi Jnum | J:391218 |
| Mgi Id | MGI:8398351 | Doi | 10.1007/s00395-025-01141-w |
| Citation | Firneburg R, et al. (2025) The CNP analogue vosoritide mediates PDE2-sensitive anti-arrhythmogenic effects in mouse hearts with STZ-induced type 1 diabetes. Basic Res Cardiol 120(6):1173-1191 |
| abstractText | Diabetes mellitus induces adverse structural, electrophysiological and autonomic remodelling increasing the risk for life-threatening arrhythmias, particularly after acute myocardial infarction. Natriuretic peptides (NPs) show increasing evidence of antagonising arrhythmia. Our previous study demonstrated that C-type NP (CNP) reduces arrhythmia after ischaemia-reperfusion 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 microg/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's d = 2.3). In cardiomyocytes, VO significantly decreased pro-arrhythmic signals upon beta-adrenergic stress, such as spontaneous Ca(2+) waves and sparks (Cohen's d = 1.0) or L-type Ca(2+) current amplitudes (Cohen's d = 1.6). Specific PDE2 inhibition with BAY 60-7550 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. |
