Circulating GDF11 exacerbates myocardial injury in mice and associates with increased infarct size in humans.

Aims: The heart rejuvenating effects of circulating growth differentiation factor 11 (GDF11), a transforming growth factor-β superfamily member that shares 90% homology with myostatin (MSTN), remains controversial. Here, we aimed to probe the role of GDF11 in acute myocardial infarction (MI), a frequent cause of heart failure and premature death during ageing.
Methods and Results: In contrast to endogenous Mstn, myocardial Gdf11 declined during the course of ageing and was particularly reduced following ischaemia/reperfusion (I/R) injury, suggesting a therapeutic potential of GDF11 signalling in MI. Unexpectedly, boosting systemic Gdf11 by recombinant GDF11 delivery (0.1 mg/kg body weight over 30 days) prior to myocardial I/R augmented myocardial infarct size in C57BL/6 mice irrespective of their age, predominantly by accelerating pro-apoptotic signalling. While intrinsic cardioprotective signalling pathways remained unaffected by high circulating GDF11, targeted transcriptomics and immunomapping studies focusing on GDF11-associated downstream targets revealed attenuated Nkx2-5 expression confined to CD105-expressing cells, with pro-apoptotic activity, as assessed by caspase-3 levels, being particularly pronounced in adjacent cells, suggesting an indirect effect. By harnessing a highly specific and validated liquid chromatography-tandem mass spectrometry-based assay, we show that in prospectively recruited patients with MI circulating GDF11 but not MSTN levels incline with age. Moreover, GDF11 levels were particularly elevated in those at high risk for adverse outcomes following the acute event, with circulating GDF11 emerging as an independent predictor of myocardial infarct size, as estimated by standardized peak creatine kinase-MB levels.
Conclusion: Our data challenge the initially reported heart rejuvenating effects of circulating GDF11 and suggest that high levels of systemic GDF11 exacerbate myocardial injury in mice and humans alike. Persistently high GDF11 levels during ageing may contribute to the age-dependent loss of cardioprotective mechanisms and thus poor outcomes of elderly patients following acute MI.
Competing Interests: Conflict of interest: S.K. declares research grants from the Swiss Heart Foundation, the Lindenhof Foundation, the Novartis Foundation for Medical-biological Research, the Swiss Society of Cardiology, the Jubiläumsstiftung SwissLife and the Theodor-Ida-Herzog-Egli Foundation, and equipment and materials from Roche Diagnostics outside the submitted work. Further, he has received travel support from the European Atherosclerosis Society, the European Society of Cardiology, the European Society of Clinical Investigation, Sphingotec GmbH, the 4TEEN4 Pharmaceuticals GmbH, and PAM Theragnostics GmbH. T.F.L. has no conflicts of interest related to this manuscript but has received institutional educational and research grants from Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Novartis, and Vifor and consulting fees from Daiichi Sankyo, Ineeo Inc., Philips, and Pfizer outside the submitted work. T.F.L. holds leadership positions at the European Society of Cardiology, Swiss Heart Foundation, and the Foundation for Cardiovascular Research—Zurich Heart House. G.G.C. and L.L. are co-inventors on the international patent WO/2020/226993 filed in April 2020. The patent relates to the use of antibodies which specifically bind IL-1α to reduce various sequelae of I/R injury to the central nervous system. G.G.C. is a consultant to Sovida Solutions Limited. L.L. reports speaker fees outside of this work from Daiichi Sankyo. F.A.W. received travel support by 4TEEN4 Pharmaceuticals GmbH, PAM Theragnostics GmbH, and Sphingotec GmbH. L.R. received research grants by Abbott, Biotronik, Boston Scientific, HeartFlow, Infraredx, Sanofi, and Regeneron and reports consultation/advisory board fees by Abbott, AstraZeneca, Amgen, Canon, Novo Nordisk, Medtronic, and Occlutech. C.M.M. has received research grants to the institution from Eli Lilly, AstraZeneca, Roche, Amgen, Novartis, Novo Nordisk, and MSD including speaker or consultant fees.
(© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)