Vitamin D Deficiency and Cardiovascular Autonomic Dysfunction: A Systematic Review and Meta-Analysis

Background: Vitamin D deficiency has been associated with cardiovascular disease through several biological pathways,including activation of the renin-angiotensin-aldosterone system, endothelial dysfunction, inflammation, oxidative stress,altered calcium homeostasis, and neurohumoral dysregulation. Emerging evidence additionally suggests that inadequatevitamin D status may adversely affect cardiovascular autonomic regulation, reflected by reduced heart rate variability(HRV), impaired heart-rate recovery, abnormal cardiovascular autonomic reflex tests, and cardiovascular autonomicneuropathy (CAN). However, findings across healthy populations and patients with diabetes, hypertension, chronic kidneydisease, and other cardiometabolic disorders have been inconsistent. The objective is to systematically evaluate theassociation between vitamin D deficiency and cardiovascular autonomic dysfunction and to quantitatively synthesizedifferences in HRV parameters between individuals with deficient/lower vitamin D status and those with higher or sufficientvitamin D concentrations. Materials and Methods: A systematic review was structured according to the PreferredReporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement.[1] PubMed/MEDLINE, Embase,Scopus, Web of Science, and the Cochrane Library were designated as the principal information sources. Eligible studiesincluded human observational or interventional investigations measuring circulating 25-hydroxyvitamin D [25(OH)D]together with objective cardiovascular autonomic outcomes, including HRV, cardiovascular autonomic reflex testing, heartraterecovery, baroreflex sensitivity, or CAN. The principal quantitative outcome was the standard deviation of normal-tonormalRR intervals (SDNN). Because HRV was assessed using heterogeneous recording protocols, standardized meandifferences were calculated using Hedges g. Random-effects meta-analysis was performed using restricted maximumlikelihood estimation and Hartung-Knapp confidence intervals. Statistical heterogeneity was quantified using I² and τ².Results: Nineteen primary studies were identified as directly relevant to the systematic synthesis, spanning apparentlyhealthy adults, patients with type 1 or type 2 diabetes, prediabetes, hypertension, chronic heart failure, end-stage kidneydisease, diabetic foot disease, and diabetic kidney disease. Six studies provided sufficiently compatible group-level SDNNdata for quantitative pooling, comprising 634 participants, including 278 participants with deficient/lower vitamin D statusand 356 comparators.Vitamin D deficiency/lower vitamin D was associated with significantly reduced SDNN (Hedges g =−0.99, 95% CI −1.86 to −0.11), although heterogeneity was substantial (I² = 92.2%; τ² = 0.642; Q = 63.85, df = 5). Exclusionof the study with the largest effect attenuated but did not eliminate the association (Hedges g = −0.69, 95% CI −1.33 to−0.05; I² = 79.9%). Five studies comprising 532 participants contributed to the RMSSD meta-analysis. The pooled effectfavored lower parasympathetic HRV in vitamin D deficiency (Hedges g = −0.95), but the estimate was imprecise (95% CI−2.53 to 0.63; I² = 94.1%) and did not reach statistical significance. Recent studies in high-risk populations strengthened theobservational association. Vitamin D concentrations below 25 nmol/L were associated with CAN in prediabetes (OR 2.38,95% CI 1.21-4.69), while a 2025 study of 458 individuals with diabetic foot disease demonstrated a nonlinear relationship,with each standard-deviation increase in 25(OH)D below 50 nmol/L associated with lower odds of autonomic dysfunction(OR 0.56, 95% CI 0.44-0.72). Intervention findings remained inconsistent. Improvement in HRV was reported after vitaminD replacement in some severely deficient populations, whereas the randomized VITAH trial showed no significant overallimprovement in LF/HF following conventional or intensive vitamin D therapy.