Vitamin D Deficiency and Incident Onset of Orthostatic Hypotension in Older Adults: Preliminary Results from the ‘ <scp>MERE</scp> ’ Study

To the Editor: Orthostatic hypotension (OH), a condition commonly found in older adults, results from the inability to correct erect posture–related blood pressure drop1 and leads to greater risks of falls, institutionalization, and death.1 Prevention strategies rely in part on the elimination of causative factors of OH. An association between OH and vitamin D deficiency (VDD) has been reported in older adults.2-5 Previous reports were limited by their cross-sectional design, which prevented causal inferences.2-5 Because there are vitamin D receptors in blood vessel wall cells6 and in neurons of the baroreflex arc,7 which are both implicated in adaptive mechanisms to prevent OH,1 it was hypothesized that age-related VDD could precipitate OH. The objective of this prospective longitudinal observational study was to determine in older adults whether initial VDD was associated with OH onset after 12 months of follow-up. Older adults participating in the French MERE cohort study between 2008 and 2013 (ClinicalTrials.gov number NCT01315704) were studied. MERE is an observational prospective unicentric cohort study designed to examine gait changes over time in older adults visiting Angers University Memory Center, France. Study procedures have been described elsewhere in detail.8 The Angers ethical committee approved the study. Individuals with blood pressure (BP) measured at two visits separated by a 12-month interval who exhibited no OH during the first visit were included. Trained nurses measured BP in a quiet environment after 5 minutes of rest in the supine position. A second BP measure was performed after 3 minutes of standing. Global OH was defined as a systolic BP (SBP) drop of 20 mmHg or more (systolic OH, S-OH) or a diastolic BP (DBP) drop of 10 mmHg or more (diastolic OH, D-OH) after standing.2-5 Serum 25-hydroxyvitamin D (25OHD) was measured at each visit using radioimmunoassay (DiaSorin Inc., Stillwater, MN) at Angers University Hospital. As previously published, VDD was defined as serum 25OHD of 25 nmol/L or less, which indicated deep and chronic deficiency.3 The covariables of age, sex, number of comorbidities, use of antihypertensive drugs, use of vitamin D supplements, and serum parathyroid hormone (PTH) concentration were assessed at baseline. Comorbidities (diseases lasting ≥3 months and running a course with minimal change) and usual treatments (indication, dosage, date of commencement) were noted from medical records, family physician prescription, or by questioning participants and relatives. Antihypertensive drugs were diuretics, beta-blockers, calcium antagonists, angiotensin-converting enzyme inhibitors, of angiotensin-II receptor agonists, and central antihypertensive agents. Participants were separated into two groups based on OH onset at 12 months and compared using the nonparametric Mann–Whitney U-test or the chi-square test using SPSS version 19 (IBM Corp., Chicago, IL). Pearson correlations between VDD and onset of S-OH and D-OH were determined, and logistic regressions were used to examine the adjusted association between baseline VDD and onset of global OH. P < .05 was considered statistically significant. Of 58 individuals with BP measured at 12-month intervals, seven had OH at baseline. Thus, 51 participants initially without OH (mean age 82.0 ± 4.7 years; 49.0% female; mean baseline 25OHD 54.8 ± 26.9 nmol/L) were recruited. Ten participants had VDD at baseline and five after 12 months of follow-up. Eighteen participants (35.3%) who developed OH after 12 months were more likely to have had VDD at baseline (38.9% vs 9.1%, P = .01) (Table 1) and at 12 months (27.8% vs 0.0%, P = .001) than those without incident OH. Baseline VDD correlated positively with incident D-OH (P = .006) but not S-OH (P = .33). Final VDD correlated positively with D-OH (correlation coefficient (r) = 0.34, P = .02) and S-OH (r = 0.39, P = .005). Finally, after adjustment on confounders, baseline VDD was associated with onset of global OH (odds ratio (OR) = 18.20, P = .04) (Table 1). Additional adjustment for final VDD did not alter the association between baseline VDD and OH onset (OR = 68.33, P = .02). VDD at baseline, regardless of all measured potential confounders including vitamin D supplementation and final VDD, was associated with OH onset within 12 months in older adults. Despite growing research on vitamin D involvement in BP control, only five studies have examined the link between VDD and OH, and all were cross-sectional.2-5 Moreover, one large study reported no significant association,5 making the link questionable. Consequently, the results of the current study provide additional and novel evidence of the nature of the relationship by showing that deep, chronic VDD (≤25 nmol/L) precedes the onset of incident OH in older adults. Exactly how VDD and OH are associated is not clear. One possibility is that VDD results in dysfunction of arterial wall cells, with potential consequences for arterial compliance.6 This would be consistent with the correlation between baseline VDD and D-OH (Table 1) because DBP, unlike SBP, depends on vascular resistance.9 Another possibility is that, because of its neurosteroid properties,7 VDD may alter the baroreflex neural arc with consequent inefficient short-term adaptive response to standing up. Despite the small sample size, the main strength of this study was its longitudinal design, which supported that baseline VDD precedes OH onset. This new research orientation offers a powerful mechanism to elucidate the pathophysiology of falls in older adults with VDD.10 We are grateful to the participants for their cooperation. Conflict of Interest: Prof. Beauchet has served as an unpaid consultant for Ipsen Pharma company and serves as an associate editor for Gériatrie, Psychologie et Neuropsychiatrie du Vieillissement. He has no relevant financial interest in this manuscript. Dr. Annweiler has served as an unpaid consultant for Ipsen Pharma company and serves as an associate editor for Gériatrie, Psychologie et Neuropsychiatrie du Vieillissement and for the Journal of Alzheimer's Disease. He has no relevant financial interest in this manuscript. Author Contributions: Dr. Annweiler had full access to the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analyses. Study concept and design: Annweiler, Duval. Acquisition of data: Annweiler, Beauchet, Barré. Analysis and interpretation of data: Duval, Annweiler. Drafting of the manuscript: Duval, Annweiler. Critical revision of the manuscript for important intellectual content: Brangier, Barré, Launay, Beauchet. Statistical expertise: Annweiler. Administrative, technical, material support: Annweiler. Study supervision: Annweiler. Sponsor's Role: None.

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