Citation: Vergatti, A.; Abate, V.; Zarrella, A.F.; Manganelli,F.; Tozza, S.; Iodice, R.; De Filippo, G.; D’Elia, L.; Strazzullo, P.; Rendina, D. 25-Hydroxy-Vitamin D and Risk of Recurrent Stroke: A Dose Response Meta-Analysis. Nutrients 2023, 15, 512. https://doi.org/10.3390/ nu15030512 Academic Editor: Bruce W. Hollis Received: 12 December 2022 Revised: 4 January 2023 Accepted: 16 January 2023 Published: 18 January 2023 Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). nutrients Article 25-Hydroxy-Vitamin D and Risk of Recurrent Stroke: A Dose Response Meta-Analysis Anita Vergatti 1 , Veronica Abate 1 , Aquilino Flavio Zarrella 1 , Fiore Manganelli 2 , Stefano Tozza 2 , Rosa Iodice 2 , Gianpaolo De Filippo 3 , Lanfranco D’Elia 1, * , Pasquale Strazzullo 4 and Domenico Rendina 1 1 Department of Clinical Medicine and Surgery, University of Naples “Federico II”, 80131 Naples, Italy 2 Department of Neuroscience, Reproductive and Odontostomatology Science, University of Naples “Federico II”, 80131 Naples, Italy 3 Assistance Publique-Hôpitaux de Paris, Hôpital Robert-Debré, Service d ′ Endocrinologie-Diabétologie, 75019 Paris, France 4 Internal Medicine, University of Naples “Federico II”, 80131 Naples, Italy * Correspondence: lanfranco.delia@unina.it Abstract: Stroke recurrence significantly improves the prognosis quoad vitam et valetudinem of patients with a first ischemic or haemorrhagic stroke. Other than in bone and skeletal metabolism, vitamin D is involved in the pathogenesis of cardiovascular disorders. This meta-analysis was per- formed to evaluate the relationship between 25OH-vitamin D [25(OH)D] levels at the first stroke and the stroke recurrence. To 31 July 2022, four prospective studies were identified. The poten- tial non-linear relationship was evaluated by modelling 25(OH)D, using restricted cubic splines of 25(OH)D distribution. The pooled estimated risk (and 95% CI) of the recurrence of stroke, com- paring the highest and the lowest levels, was assessed using a random-effect model. A non-linear association was found by dose-response analysis. This study found that 25(OH)D levels at the first stroke ≥9.3 ng/mL were associated with a lower risk of stroke recurrence, compared with 25(OH)D levels ≤8.5 ng/mL. In the pooled analysis, higher 25(OH)D levels at the first stroke significantly reduce the risk of stroke recurrence, with a significant heterogeneity among studies. In conclusion, 25(OH)D levels ≤8.5 ng/mL at the first stroke are significantly associated with a higher risk of recurrent stroke. Keywords: stroke; 25-hydroxy-vitamin D; meta-analysis 1. Introduction 1.1. Stroke: Definition and Epidemiology A stroke is defined as a neurological deficit caused by an acute focal injury of the central nervous system, in extenso brain, retina, or spinal cord, and secondary to a vascular cause [1]. The large majority of strokes (ranging from 60 to 90%, according to regional stroke epidemiology) are ischemic and are caused by an impaired or absent perfusion through the blood vessels to the brain. From an etio-pathological point of view, an ischemic stroke can be caused by an arterial occlusion or, very rarely, by vein thrombosis. In the first case, ischemic strokes are usually due to arterial occlusion, secondary to cardio-embolic or endothelial disease. In the second case, an ischemic stroke, secondary to venous infarction, is linked to the occlusion of cerebral veins or venous sinuses. The remaining strokes are haemorrhagic and are etio-pathogenetically linked to the rupture of intracerebral or subarachnoid cerebral arteries. From an epidemiological point of view, a stroke is a very severe and common event, and it actually represents the third cause of disability and the second cause of death world- wide. The absolute number of prevalent and incident cases of stroke registered worldwide during the calendar year 2019 were over 100 million and 12 million, respectively. During the calendar year 2019, the disability adjusted life years (DALYs), secondary to stroke, were Nutrients 2023, 15, 512. https://doi.org/10.3390/nu15030512 https://www.mdpi.com/journal/nutrients