LETTERS TO THE EDITOR RESEARCH VITAMIN D DEFICIENCY AND INCIDENT ONSET OF ORTHOSTATIC HYPOTENSION IN OLDER ADULTS: PRELIMINARY RESULTS FROM THE ‘MERE’ 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.
METHODS 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 12month 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,
JAGS 63:1245–1285, 2015 © 2015, Copyright the Authors Journal compilation © 2015, The American Geriatrics Society
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, angiotensinconverting 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.
RESULTS 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).
CONCLUSION 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
0002-8614/15/$15.00
JAGS
(0.93–1.21) (0.24–2.39) (0.85–1.39) (0.30–3.18) (0.34–3.46) (0.99–1.09)
.35 .63 .52 .97 .89 .09
0.80 0.53 0.98 3.54 3.97 1.06
(0.56–1.15) .22 (0.04–6.71) .62 (0.64–1.51) .94 (0.15–82.8) .43 (0.19–84.03) .38 (0.99–1.14) .12
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
0.14, 0.39, 0.05, 0.11, 0.13, 0.46,
.333 .005 .74 .45 .36 .01
1.06 0.75 1.08 0.98 1.09 1.04
Guillaume T. Duval, MD Antoine Brangier, MD Jean Barre, MD Cyrille P. Launay, MD, MS Department of Neuroscience, Division of Geriatric Medicine, University Memory Center, Angers University Hospital, Angers, France
.57 .63 .30 .97 .89 .17
0.13, 0.10, 0.06, 0.05, 0.01, 0.17,
.38 .48 .67 .75 .98 .38
Olivier Beauchet, MD, PhD Department of Neuroscience, Division of Geriatric Medicine, University Memory Center, Angers University Hospital, Angers, France UPRES EA 4638, University of Angers, UNAM, Angers, France
a
Between-group comparisons based on Mann–Whitney U-test or chi-square test, as appropriate. SD = standard deviation; OH = orthostatic hypotension.
82.8 4.6 8 (44.4) 3.6 2.0 7 (38.9) 8 (44.4) 45.1 32.8 81.5 4.8 17 (51.5) 3.1 2.5 13 (39.4) 14 (42.4) 27.4 11.7 82.0 4.7 25 (49) 3.3 2.3 20 (39.2) 22 (43.1) 32.9 21.6
18.20 (1.12–294.90) .04 3.36 (1.39–29.06) .02 0.38, .006 0.14, .33
JUNE 2015–VOL. 63, NO. 6
Vitamin D deficiency (serum 25-hydroxyvitamin D ≤ 25 nmol/L), n (%) Age, mean SD Female, n (%) Number of comorbidities, mean SD Use of antihypertensive drugs, n (%) Use of vitamin D supplements, n (%) Serum concentration of parathyroid hormone, pg/mL, mean SD
10 (19.6)
3 (9.1)
7 (38.9)
.01
Fully Adjusted Model Unadjusted Model Diastolic OH Systolic OH P-Valuea Yes, n = 18 No, n = 33 Total Cohort, n = 51 Baseline Characteristic
Orthostatic Hypotension
Correlation Coefficient, P-Value
Global OH, Odds Ratio (95% Confidence Interval) P-Value
LETTERS TO THE EDITOR
Table 1. Participant Characteristics at Baseline According to Onset of Global Orthostatic Hypotension After 12 Months of Follow-Up and Pearson Correlations and Logistic Regression Models Showing Associations Between Baseline Vitamin D Deficiency (Independent Variable) and Incident Orthostatic Hypotension (Dependent Variable)
1246
Cedric Annweiler, MD, PhD Department of Neuroscience, Division of Geriatric Medicine, University Memory Center, Angers University Hospital, Angers, France UPRES EA 4638, University of Angers, UNAM, Angers, France Robarts Research Institute, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada
ACKNOWLEDGMENTS 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 Geriatrie, 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 Geriatrie, 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, Barre. Analysis and interpretation of data: Duval, Annweiler. Drafting of the manuscript: Duval, Annweiler. Critical revision of the manuscript for important intellectual content: Brangier, Barre, Launay, Beauchet. Statistical expertise: Annweiler. Administrative, technical, material support: Annweiler. Study supervision: Annweiler. Sponsor’s Role: None.
JAGS
JUNE 2015–VOL. 63, NO. 6
LETTERS TO THE EDITOR
1247
REFERENCES
METHODS
1. Gupta V, Lipsitz LA. Orthostatic hypotension in the elderly: Diagnosis and treatment. Am J Med 2007;120:841–847. 2. McCarroll KG, Robinson DJ, Coughlan A et al. Vitamin D and orthostatic hypotension. Age Ageing 2012;41:810–813. 3. Annweiler C, Schott AM, Rolland Y et al. Vitamin D deficiency is associated with orthostatic hypotension in oldest-old women. J Intern Med 2014;276:285–295. 4. Soysal P, Yay A, Isik AT. Does vitamin D deficiency increase orthostatic hypotension risk in the elderly patients? Arch Gerontol Geriatr 2014;59:74–77. 5. Veronese N, Bolzetta F, De Rui M et al. Serum 25-hydroxyvitamin D and orthostatic hypotension in old people: The Pro.V.A. study. Hypertension 2014;64:481–486. 6. Yamamoto T, Kozawa O, Tanabe K et al. 1,25-dihydroxyvitamin D3 stimulates vascular endothelial growth factor release in aortic smooth muscle cells: Role of p38 mitogen-activated protein kinase. Arch Biochem Biophys 2002;398:1–6. 7. Annweiler C, Dursun E, Feron F et al. ‘Vitamin D and cognition in older adults’: Updated international recommendations. J Intern Med 2015;277:45–57. 8. Beauchet O, Launay CP, Allali G et al. Anti-dementia drugs and changes in gait: A pre-post quasi-experimental pilot study. BMC Neurol 2013;13:184. 9. Duron E, Lenoir H, Pequignot R et al. What is the most relevant definition of orthostatic hypotension: Systolic blood pressure drop, diastolic blood pressure drop, or both? Arch Mal Coeur Vaiss 2007;100:689–694. 10. American Geriatrics Society Workgroup on Vitamin. D Supplementation for Older Adults. Recommendations abstracted from the American Geriatrics Society Consensus Statement on vitamin D for Prevention of Falls and Their Consequences. J Am Geriatr Soc 2014;62:147–152.
Thirty women who practiced a regular exercise training program for 1.5 to 5 years and 30 sedentary women, all volunteers, participated in the study, which the Federal University of S~ ao Paulo Paulista School of Medicine ethics committee approved. The training protocol that the exercisers performed has been previously described.6 Sedentary subjects were independent and active but had not practiced regular physical exercise for at least 5 years. Blood was collected for biochemical analyses after a 12-hour fast approximately 24 hours after the last exercise training session had been performed. Blood biochemical analyses were performed using commercial kits. The in vitro assay of the transfer of radioactively labeled UC, EC, TAG, and PL from donor nanoemulsions to HDL was performed as described previously.7 Plasma samples were incubated with labeled nanoemulsions for 1 hour at 37°C; radioactivity was counted at the supernatant volume after chemical precipitation of the nanoemulsions and non-HDL fractions.
EXERCISE TRAINING IMPROVES PLASMA LIPID AND INFLAMMATORY PROFILES AND INCREASES CHOLESTEROL TRANSFER TO HIGH-DENSITY LIPOPROTEIN IN ELDERLY WOMEN To the Editor: Although proatherogenic alterations in plasma lipids and inflammatory factors accompany aging, moderate-intensity exercise can improve them. Low-density lipoprotein cholesterol (LDL-C) and triacylglycerol (TAG) levels typically increase in elderly adults, and highdensity lipoprotein cholesterol (HDL-C) levels decrease. Proinflammatory cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-a), increase.1,2 HDL has several atheroprotective functions and has been recognized as a longevity marker.3 HDL has chief roles in plasma cholesterol esterification and reverse cholesterol transport and additional anti-inflammatory, antioxidant, anticoagulant, antithrombotic, vasodilatory, and antiapoptotic properties. All those functions can be, at least in part, independent of HDL-C plasma levels. HDL is continuously remodeled, and lipid transfers involving this lipoprotein are essential parts of HDL metabolism and atheroprotective functions. The actions of cholesteryl ester (CE) transfer protein and phospholipid transfer protein, which are involved in the transfer of core (CE, TAG) and surface (phospholipids (PL), unesterified cholesterol (UC)) lipids, respectively, facilitate lipid transfers.4 An in vitro assay showed that transfers of EC and UC to HDL were low in individuals with coronary heart disease (CHD).4 Transfers of UC and EC were greater in marathon runners than in sedentary individuals.5 The hypothesis that regular moderate-intensity physical activity in older adults could increase cholesterol transfer rates to HDL as estimated using in vitro HDL transfer assay was tested.
RESULTS Body mass index was lower in exercisers than in sedentary women, and exercisers had higher HDL-C, lower TAG, and equal LDL-C. Apolipoprotein (Apo) A-I was higher in exercisers, and Apo B was equal. Transfers of UC and EC to HDL were higher in exercisers than in sedentary women, but PL transfer was lower in exercisers, whereas TAG transfer was equal. IL-6 and TNF-a serum concentrations were lower in exercisers than in sedentary women (Table 1).
DISCUSSION The differences in plasma lipid and apolipoprotein profiles between exercisers and sedentary women were in agreement with those found in previous studies.8 The main novel finding was that the UC transfer to HDL was higher in exercisers than in sedentary women. Because lower UC transfer has been found in individuals with CHD,4 regardless of whether they were older or had type 2 diabetes mellitus, this finding suggests a novel antiatherogenic action of exercise training in elderly adualts. Nascent HDL and subsequently mature HDL continuously receive UC, which is converted into EC. The newly formed EC is dislocated from the surface to the lipoprotein core, which is essential for stabilization in the plasma of this compound and creates the gradient for HDL to drive reverse cholesterol transport. Therefore, the lower entry of UC into the HDL fraction can be interpreted as reduction of substrate for the esterification reaction, which would impair important protective mechanisms.4 Although it is difficult to interpret the greater EC transfer in exercisers, reduction of EC in HDL, as occurs in hypertriglyceridemia, leads to low HDL-C.4 Thus, exercise training could be beneficial for elderly adults by increasing HDL-C through EC transfer. Exercise training reduces proinflammatory cytokines by inducing loss of adipose mass.9 The body mass index of exercisers was lower than that of sedentary women, which might account for the lower TNF-a and IL-6 levels. TNF-a
METHODS 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 12month 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,
JAGS 63:1245–1285, 2015 © 2015, Copyright the Authors Journal compilation © 2015, The American Geriatrics Society
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, angiotensinconverting 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.
RESULTS 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).
CONCLUSION 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
0002-8614/15/$15.00
JAGS
(0.93–1.21) (0.24–2.39) (0.85–1.39) (0.30–3.18) (0.34–3.46) (0.99–1.09)
.35 .63 .52 .97 .89 .09
0.80 0.53 0.98 3.54 3.97 1.06
(0.56–1.15) .22 (0.04–6.71) .62 (0.64–1.51) .94 (0.15–82.8) .43 (0.19–84.03) .38 (0.99–1.14) .12
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
0.14, 0.39, 0.05, 0.11, 0.13, 0.46,
.333 .005 .74 .45 .36 .01
1.06 0.75 1.08 0.98 1.09 1.04
Guillaume T. Duval, MD Antoine Brangier, MD Jean Barre, MD Cyrille P. Launay, MD, MS Department of Neuroscience, Division of Geriatric Medicine, University Memory Center, Angers University Hospital, Angers, France
.57 .63 .30 .97 .89 .17
0.13, 0.10, 0.06, 0.05, 0.01, 0.17,
.38 .48 .67 .75 .98 .38
Olivier Beauchet, MD, PhD Department of Neuroscience, Division of Geriatric Medicine, University Memory Center, Angers University Hospital, Angers, France UPRES EA 4638, University of Angers, UNAM, Angers, France
a
Between-group comparisons based on Mann–Whitney U-test or chi-square test, as appropriate. SD = standard deviation; OH = orthostatic hypotension.
82.8 4.6 8 (44.4) 3.6 2.0 7 (38.9) 8 (44.4) 45.1 32.8 81.5 4.8 17 (51.5) 3.1 2.5 13 (39.4) 14 (42.4) 27.4 11.7 82.0 4.7 25 (49) 3.3 2.3 20 (39.2) 22 (43.1) 32.9 21.6
18.20 (1.12–294.90) .04 3.36 (1.39–29.06) .02 0.38, .006 0.14, .33
JUNE 2015–VOL. 63, NO. 6
Vitamin D deficiency (serum 25-hydroxyvitamin D ≤ 25 nmol/L), n (%) Age, mean SD Female, n (%) Number of comorbidities, mean SD Use of antihypertensive drugs, n (%) Use of vitamin D supplements, n (%) Serum concentration of parathyroid hormone, pg/mL, mean SD
10 (19.6)
3 (9.1)
7 (38.9)
.01
Fully Adjusted Model Unadjusted Model Diastolic OH Systolic OH P-Valuea Yes, n = 18 No, n = 33 Total Cohort, n = 51 Baseline Characteristic
Orthostatic Hypotension
Correlation Coefficient, P-Value
Global OH, Odds Ratio (95% Confidence Interval) P-Value
LETTERS TO THE EDITOR
Table 1. Participant Characteristics at Baseline According to Onset of Global Orthostatic Hypotension After 12 Months of Follow-Up and Pearson Correlations and Logistic Regression Models Showing Associations Between Baseline Vitamin D Deficiency (Independent Variable) and Incident Orthostatic Hypotension (Dependent Variable)
1246
Cedric Annweiler, MD, PhD Department of Neuroscience, Division of Geriatric Medicine, University Memory Center, Angers University Hospital, Angers, France UPRES EA 4638, University of Angers, UNAM, Angers, France Robarts Research Institute, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada
ACKNOWLEDGMENTS 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 Geriatrie, 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 Geriatrie, 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, Barre. Analysis and interpretation of data: Duval, Annweiler. Drafting of the manuscript: Duval, Annweiler. Critical revision of the manuscript for important intellectual content: Brangier, Barre, Launay, Beauchet. Statistical expertise: Annweiler. Administrative, technical, material support: Annweiler. Study supervision: Annweiler. Sponsor’s Role: None.
JAGS
JUNE 2015–VOL. 63, NO. 6
LETTERS TO THE EDITOR
1247
REFERENCES
METHODS
1. Gupta V, Lipsitz LA. Orthostatic hypotension in the elderly: Diagnosis and treatment. Am J Med 2007;120:841–847. 2. McCarroll KG, Robinson DJ, Coughlan A et al. Vitamin D and orthostatic hypotension. Age Ageing 2012;41:810–813. 3. Annweiler C, Schott AM, Rolland Y et al. Vitamin D deficiency is associated with orthostatic hypotension in oldest-old women. J Intern Med 2014;276:285–295. 4. Soysal P, Yay A, Isik AT. Does vitamin D deficiency increase orthostatic hypotension risk in the elderly patients? Arch Gerontol Geriatr 2014;59:74–77. 5. Veronese N, Bolzetta F, De Rui M et al. Serum 25-hydroxyvitamin D and orthostatic hypotension in old people: The Pro.V.A. study. Hypertension 2014;64:481–486. 6. Yamamoto T, Kozawa O, Tanabe K et al. 1,25-dihydroxyvitamin D3 stimulates vascular endothelial growth factor release in aortic smooth muscle cells: Role of p38 mitogen-activated protein kinase. Arch Biochem Biophys 2002;398:1–6. 7. Annweiler C, Dursun E, Feron F et al. ‘Vitamin D and cognition in older adults’: Updated international recommendations. J Intern Med 2015;277:45–57. 8. Beauchet O, Launay CP, Allali G et al. Anti-dementia drugs and changes in gait: A pre-post quasi-experimental pilot study. BMC Neurol 2013;13:184. 9. Duron E, Lenoir H, Pequignot R et al. What is the most relevant definition of orthostatic hypotension: Systolic blood pressure drop, diastolic blood pressure drop, or both? Arch Mal Coeur Vaiss 2007;100:689–694. 10. American Geriatrics Society Workgroup on Vitamin. D Supplementation for Older Adults. Recommendations abstracted from the American Geriatrics Society Consensus Statement on vitamin D for Prevention of Falls and Their Consequences. J Am Geriatr Soc 2014;62:147–152.
Thirty women who practiced a regular exercise training program for 1.5 to 5 years and 30 sedentary women, all volunteers, participated in the study, which the Federal University of S~ ao Paulo Paulista School of Medicine ethics committee approved. The training protocol that the exercisers performed has been previously described.6 Sedentary subjects were independent and active but had not practiced regular physical exercise for at least 5 years. Blood was collected for biochemical analyses after a 12-hour fast approximately 24 hours after the last exercise training session had been performed. Blood biochemical analyses were performed using commercial kits. The in vitro assay of the transfer of radioactively labeled UC, EC, TAG, and PL from donor nanoemulsions to HDL was performed as described previously.7 Plasma samples were incubated with labeled nanoemulsions for 1 hour at 37°C; radioactivity was counted at the supernatant volume after chemical precipitation of the nanoemulsions and non-HDL fractions.
EXERCISE TRAINING IMPROVES PLASMA LIPID AND INFLAMMATORY PROFILES AND INCREASES CHOLESTEROL TRANSFER TO HIGH-DENSITY LIPOPROTEIN IN ELDERLY WOMEN To the Editor: Although proatherogenic alterations in plasma lipids and inflammatory factors accompany aging, moderate-intensity exercise can improve them. Low-density lipoprotein cholesterol (LDL-C) and triacylglycerol (TAG) levels typically increase in elderly adults, and highdensity lipoprotein cholesterol (HDL-C) levels decrease. Proinflammatory cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-a), increase.1,2 HDL has several atheroprotective functions and has been recognized as a longevity marker.3 HDL has chief roles in plasma cholesterol esterification and reverse cholesterol transport and additional anti-inflammatory, antioxidant, anticoagulant, antithrombotic, vasodilatory, and antiapoptotic properties. All those functions can be, at least in part, independent of HDL-C plasma levels. HDL is continuously remodeled, and lipid transfers involving this lipoprotein are essential parts of HDL metabolism and atheroprotective functions. The actions of cholesteryl ester (CE) transfer protein and phospholipid transfer protein, which are involved in the transfer of core (CE, TAG) and surface (phospholipids (PL), unesterified cholesterol (UC)) lipids, respectively, facilitate lipid transfers.4 An in vitro assay showed that transfers of EC and UC to HDL were low in individuals with coronary heart disease (CHD).4 Transfers of UC and EC were greater in marathon runners than in sedentary individuals.5 The hypothesis that regular moderate-intensity physical activity in older adults could increase cholesterol transfer rates to HDL as estimated using in vitro HDL transfer assay was tested.
RESULTS Body mass index was lower in exercisers than in sedentary women, and exercisers had higher HDL-C, lower TAG, and equal LDL-C. Apolipoprotein (Apo) A-I was higher in exercisers, and Apo B was equal. Transfers of UC and EC to HDL were higher in exercisers than in sedentary women, but PL transfer was lower in exercisers, whereas TAG transfer was equal. IL-6 and TNF-a serum concentrations were lower in exercisers than in sedentary women (Table 1).
DISCUSSION The differences in plasma lipid and apolipoprotein profiles between exercisers and sedentary women were in agreement with those found in previous studies.8 The main novel finding was that the UC transfer to HDL was higher in exercisers than in sedentary women. Because lower UC transfer has been found in individuals with CHD,4 regardless of whether they were older or had type 2 diabetes mellitus, this finding suggests a novel antiatherogenic action of exercise training in elderly adualts. Nascent HDL and subsequently mature HDL continuously receive UC, which is converted into EC. The newly formed EC is dislocated from the surface to the lipoprotein core, which is essential for stabilization in the plasma of this compound and creates the gradient for HDL to drive reverse cholesterol transport. Therefore, the lower entry of UC into the HDL fraction can be interpreted as reduction of substrate for the esterification reaction, which would impair important protective mechanisms.4 Although it is difficult to interpret the greater EC transfer in exercisers, reduction of EC in HDL, as occurs in hypertriglyceridemia, leads to low HDL-C.4 Thus, exercise training could be beneficial for elderly adults by increasing HDL-C through EC transfer. Exercise training reduces proinflammatory cytokines by inducing loss of adipose mass.9 The body mass index of exercisers was lower than that of sedentary women, which might account for the lower TNF-a and IL-6 levels. TNF-a
