Letter to the Editor
The Putative Role of Vitamin D in Essential Hypertension: Stepping Into the Light? Eugenia Gkaliagkousi,1 Eleni Gavriilaki,2 Georgios Triantafyllou,2 Barbara Nikolaidou,1 and Stella Douma2
Correspondence: Eugenia Gkaliagkousi ([email protected]). 12nd Propedeutic Department of Internal Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece; 23rd Department of Internal Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece.
Initially submitted December 5, 2013; date of first revision December 31, 2013; accepted for publication December 31, 2013. doi:10.1093/ajh/hpu005 © American Journal of Hypertension, Ltd 2014. All rights reserved. For Permissions, please email: [email protected]
process, but, to our knowledge, has not been established as an early marker of endothelial cell dysfunction.3 Finally, homocysteine has been used in the past as a marker of increased cardiovascular risk; however, this role has never been clearly established, and its significance has been gradually declined.4 In conclusion, none of the above markers is nowadays considered a robust marker of endothelial dysfunction according to the latest position statement on methods for the evaluation of endothelial dysfunction5 or the recent European Society of Hypertension guidelines.6 Second, the definition and clinical interpretation of blood pressure (BP) variation used as the dependent variable in the multiple logistic regression models is unclear. This term is not even included in the recent European Society of Hypertension guidelines.6 Have the authors assessed BP variability instead? If not, which is the “BP variation” definition? In addition, the authors use a series of multiple regression models leading to no clinically meaningful result. Which of the factors that correlate with 25(OH) D in the bivariable level retains an independent association in the multivariable level? Furthermore, are 25(OH)D levels associated with the presence of hypertension or BP levels after controlling for all other possible confounders (age, body mass index, smoking, pulse wave velocity, intima media thickness, and left ventricular mass)? Finally, it should be noted that 25(OH)D did not even correlate with any of the so-called “markers of endothelial function” used in the study. Taking this into consideration, based on which pathogenetic mechanism and how do the authors explain their
hypothesis that endothelial dysfunction and target organ damage may mediate the impact of 25(OH)D on “BP variation” or BP levels? The conclusion of the study by Sypniewska et al. seems rather speculative and ambitious as this study fails to answer to its objectives. Thus, the hypothesized association between 25(OH)D and endothelial dysfunction and its suggested role in hypertension and its pathogenesis need to be further investigated by large well-designed studies.
DISCLOSURE
The authors declared no conflict of interest.
References 1. Sypniewska G, Pollak J, Strozecki P, Camil F, Kretowicz M, Janikowski G, Mankowska-Cyl A, Pater A, Manitius J. 25-Hydroxyvitamin D, biomarkers of endothelial dysfunction and subclinical organ damage in adults with hypertension. Am J Hypertens 2014; 27:114–121. 2. Videm V, Albrigtsen M. Soluble ICAM-1 and VCAM-1 as markers of endothelial activation. Scand J Immunol 2008; 67:523–531. 3. Kaptoge S, Di Angelantonio E, Pennells L, Wood AM, White IR, Gao P, Walker M, Thompson A, Sarwar N, Caslake M, Butterworth AS, Amouyel P, Assmann G, Bakker SJ, Barr EL, Barrett-Connor E, Benjamin EJ, Bjorkelund C, Brenner H, Brunner E, Clarke R, Cooper JA, Cremer P, Cushman M, Dagenais GR, D’Agostino RB, Sr., Dankner R, Davey-Smith G, Deeg D, Dekker JM, Engstrom G, Folsom AR, Fowkes FG, Gallacher J, Gaziano JM, Giampaoli S, Gillum RF, Hofman A, Howard BV, Ingelsson E, Iso H, Jorgensen T, Kiechl S, Kitamura A, Kiyohara Y, Koenig W, Kromhout D, Kuller LH, Lawlor DA, Meade TW, Nissinen A, Nordestgaard BG, Onat A, Panagiotakos
American Journal of Hypertension 27(7) July 2014 985
Downloaded from http://ajh.oxfordjournals.org/ at University of Hawaii School of Medicine on July 6, 2015
To the Editor: We carefully read the study “25-Hydroxyvitamin D, Biomarkers of Endothelial Dysfunction and Subclinical Organ Damage in Adults With Hypertension,” by Sypniewska et al.1 that sought to investigate the association between 25-hydroxyvitamin D (25(OH)D) and markers of subclinical target organ damage and endothelial dysfunction in patients with untreated essential hypertension. Although this field represents an interesting and fruitful research area, the study by Sypniewska et al. raises several methodological, statistical, and clinical questions that need to be further clarified. First, the authors have measured soluble intercellular adhesion molecule, C-reactive protein, and homocysteine as markers of endothelial dysfunction in patients with essential hypertension. Soluble intercellular adhesion molecule is not solely produced by endothelial cells, rendering its value as a biochemical marker of endothelial dysfunction extremely limited.2 Furthermore, C-reactive protein is associated with the total inflammatory burden and has been linked to the atherosclerotic
Letter to the Editor avoiding publication bias. PLoS Med 2012; 9:e1001177. 5. Lekakis J, Abraham P, Balbarini A, Blann A, Boulanger CM, Cockcroft J, Cosentino F, Deanfield J, Gallino A, Ikonomidis I, Kremastinos D, Landmesser U, Protogerou A, Stefanadis C, Tousoulis D, Vassalli G, Vink H, Werner N, Wilkinson I, Vlachopoulos C. Methods for evaluating endothelial function: a position statement from the European Society of Cardiology Working Group on Peripheral Circulation. Eur J Cardiovasc Prev Rehabil 2011; 18:775–789. 6. Mancia G, Fagard R, Narkiewicz K, Redon J, Zanchetti A, Bohm M, Christiaens T, Cifkova R, De Backer G, Dominiczak A, Galderisi M, Grobbee DE, Jaarsma T, Kirchhof P, Kjeldsen SE, Laurent S, Manolis AJ, Nilsson PM, Ruilope LM, Schmieder RE, Sirnes PA, Sleight P, Viigimaa M, Waeber B, Zannad F, Burnier M, Ambrosioni E, Caufield M, Coca A, Olsen MH, Tsioufis C, van de Borne P, Zamorano JL, Achenbach
986 American Journal of Hypertension 27(7) July 2014
S, Baumgartner H, Bax JJ, Bueno H, Dean V, Deaton C, Erol C, Ferrari R, Hasdai D, Hoes AW, Knuuti J, Kolh P, Lancellotti P, Linhart A, Nihoyannopoulos P, Piepoli MF, Ponikowski P, Tamargo JL, Tendera M, Torbicki A, Wijns W, Windecker S, Clement DL, Gillebert TC, Rosei EA, Anker SD, Bauersachs J, Hitij JB, Caulfield M, De Buyzere M, De Geest S, Derumeaux GA, Erdine S, Farsang C, Funck-Brentano C, Gerc V, Germano G, Gielen S, Haller H, Jordan J, Kahan T, Komajda M, Lovic D, Mahrholdt H, Ostergren J, Parati G, Perk J, Polonia J, Popescu BA, Reiner Z, Ryden L, Sirenko Y, Stanton A, Struijker-Boudier H, Vlachopoulos C, Volpe M, Wood DA. 2013 ESH/ESC guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J 2013; 34:2159–2219.
Downloaded from http://ajh.oxfordjournals.org/ at University of Hawaii School of Medicine on July 6, 2015
DB, Psaty BM, Rodriguez B, Rosengren A, Salomaa V, Kauhanen J, Salonen JT, Shaffer JA, Shea S, Ford I, Stehouwer CD, Strandberg TE, Tipping RW, Tosetto A, Wassertheil-Smoller S, Wennberg P, Westendorp RG, Whincup PH, Wilhelmsen L, Woodward M, Lowe GD, Wareham NJ, Khaw KT, Sattar N, Packard CJ, Gudnason V, Ridker PM, Pepys MB, Thompson SG, Danesh J. C-reactive protein, fibrinogen, and cardiovascular disease prediction. New Engl J Med 2012; 367:1310–1320. 4. Clarke R, Bennett DA, Parish S, Verhoef P, Dotsch-Klerk M, Lathrop M, Xu P, Nordestgaard BG, Holm H, Hopewell JC, Saleheen D, Tanaka T, Anand SS, Chambers JC, Kleber ME, Ouwehand WH, Yamada Y, Elbers C, Peters B, Stewart AF, Reilly MM, Thorand B, Yusuf S, Engert JC, Assimes TL, Kooner J, Danesh J, Watkins H, Samani NJ, Collins R, Peto R. Homocysteine and coronary heart disease: meta-analysis of MTHFR case-control studies,
The Putative Role of Vitamin D in Essential Hypertension: Stepping Into the Light? Eugenia Gkaliagkousi,1 Eleni Gavriilaki,2 Georgios Triantafyllou,2 Barbara Nikolaidou,1 and Stella Douma2
Correspondence: Eugenia Gkaliagkousi ([email protected]). 12nd Propedeutic Department of Internal Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece; 23rd Department of Internal Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece.
Initially submitted December 5, 2013; date of first revision December 31, 2013; accepted for publication December 31, 2013. doi:10.1093/ajh/hpu005 © American Journal of Hypertension, Ltd 2014. All rights reserved. For Permissions, please email: [email protected]
process, but, to our knowledge, has not been established as an early marker of endothelial cell dysfunction.3 Finally, homocysteine has been used in the past as a marker of increased cardiovascular risk; however, this role has never been clearly established, and its significance has been gradually declined.4 In conclusion, none of the above markers is nowadays considered a robust marker of endothelial dysfunction according to the latest position statement on methods for the evaluation of endothelial dysfunction5 or the recent European Society of Hypertension guidelines.6 Second, the definition and clinical interpretation of blood pressure (BP) variation used as the dependent variable in the multiple logistic regression models is unclear. This term is not even included in the recent European Society of Hypertension guidelines.6 Have the authors assessed BP variability instead? If not, which is the “BP variation” definition? In addition, the authors use a series of multiple regression models leading to no clinically meaningful result. Which of the factors that correlate with 25(OH) D in the bivariable level retains an independent association in the multivariable level? Furthermore, are 25(OH)D levels associated with the presence of hypertension or BP levels after controlling for all other possible confounders (age, body mass index, smoking, pulse wave velocity, intima media thickness, and left ventricular mass)? Finally, it should be noted that 25(OH)D did not even correlate with any of the so-called “markers of endothelial function” used in the study. Taking this into consideration, based on which pathogenetic mechanism and how do the authors explain their
hypothesis that endothelial dysfunction and target organ damage may mediate the impact of 25(OH)D on “BP variation” or BP levels? The conclusion of the study by Sypniewska et al. seems rather speculative and ambitious as this study fails to answer to its objectives. Thus, the hypothesized association between 25(OH)D and endothelial dysfunction and its suggested role in hypertension and its pathogenesis need to be further investigated by large well-designed studies.
DISCLOSURE
The authors declared no conflict of interest.
References 1. Sypniewska G, Pollak J, Strozecki P, Camil F, Kretowicz M, Janikowski G, Mankowska-Cyl A, Pater A, Manitius J. 25-Hydroxyvitamin D, biomarkers of endothelial dysfunction and subclinical organ damage in adults with hypertension. Am J Hypertens 2014; 27:114–121. 2. Videm V, Albrigtsen M. Soluble ICAM-1 and VCAM-1 as markers of endothelial activation. Scand J Immunol 2008; 67:523–531. 3. Kaptoge S, Di Angelantonio E, Pennells L, Wood AM, White IR, Gao P, Walker M, Thompson A, Sarwar N, Caslake M, Butterworth AS, Amouyel P, Assmann G, Bakker SJ, Barr EL, Barrett-Connor E, Benjamin EJ, Bjorkelund C, Brenner H, Brunner E, Clarke R, Cooper JA, Cremer P, Cushman M, Dagenais GR, D’Agostino RB, Sr., Dankner R, Davey-Smith G, Deeg D, Dekker JM, Engstrom G, Folsom AR, Fowkes FG, Gallacher J, Gaziano JM, Giampaoli S, Gillum RF, Hofman A, Howard BV, Ingelsson E, Iso H, Jorgensen T, Kiechl S, Kitamura A, Kiyohara Y, Koenig W, Kromhout D, Kuller LH, Lawlor DA, Meade TW, Nissinen A, Nordestgaard BG, Onat A, Panagiotakos
American Journal of Hypertension 27(7) July 2014 985
Downloaded from http://ajh.oxfordjournals.org/ at University of Hawaii School of Medicine on July 6, 2015
To the Editor: We carefully read the study “25-Hydroxyvitamin D, Biomarkers of Endothelial Dysfunction and Subclinical Organ Damage in Adults With Hypertension,” by Sypniewska et al.1 that sought to investigate the association between 25-hydroxyvitamin D (25(OH)D) and markers of subclinical target organ damage and endothelial dysfunction in patients with untreated essential hypertension. Although this field represents an interesting and fruitful research area, the study by Sypniewska et al. raises several methodological, statistical, and clinical questions that need to be further clarified. First, the authors have measured soluble intercellular adhesion molecule, C-reactive protein, and homocysteine as markers of endothelial dysfunction in patients with essential hypertension. Soluble intercellular adhesion molecule is not solely produced by endothelial cells, rendering its value as a biochemical marker of endothelial dysfunction extremely limited.2 Furthermore, C-reactive protein is associated with the total inflammatory burden and has been linked to the atherosclerotic
Letter to the Editor avoiding publication bias. PLoS Med 2012; 9:e1001177. 5. Lekakis J, Abraham P, Balbarini A, Blann A, Boulanger CM, Cockcroft J, Cosentino F, Deanfield J, Gallino A, Ikonomidis I, Kremastinos D, Landmesser U, Protogerou A, Stefanadis C, Tousoulis D, Vassalli G, Vink H, Werner N, Wilkinson I, Vlachopoulos C. Methods for evaluating endothelial function: a position statement from the European Society of Cardiology Working Group on Peripheral Circulation. Eur J Cardiovasc Prev Rehabil 2011; 18:775–789. 6. Mancia G, Fagard R, Narkiewicz K, Redon J, Zanchetti A, Bohm M, Christiaens T, Cifkova R, De Backer G, Dominiczak A, Galderisi M, Grobbee DE, Jaarsma T, Kirchhof P, Kjeldsen SE, Laurent S, Manolis AJ, Nilsson PM, Ruilope LM, Schmieder RE, Sirnes PA, Sleight P, Viigimaa M, Waeber B, Zannad F, Burnier M, Ambrosioni E, Caufield M, Coca A, Olsen MH, Tsioufis C, van de Borne P, Zamorano JL, Achenbach
986 American Journal of Hypertension 27(7) July 2014
S, Baumgartner H, Bax JJ, Bueno H, Dean V, Deaton C, Erol C, Ferrari R, Hasdai D, Hoes AW, Knuuti J, Kolh P, Lancellotti P, Linhart A, Nihoyannopoulos P, Piepoli MF, Ponikowski P, Tamargo JL, Tendera M, Torbicki A, Wijns W, Windecker S, Clement DL, Gillebert TC, Rosei EA, Anker SD, Bauersachs J, Hitij JB, Caulfield M, De Buyzere M, De Geest S, Derumeaux GA, Erdine S, Farsang C, Funck-Brentano C, Gerc V, Germano G, Gielen S, Haller H, Jordan J, Kahan T, Komajda M, Lovic D, Mahrholdt H, Ostergren J, Parati G, Perk J, Polonia J, Popescu BA, Reiner Z, Ryden L, Sirenko Y, Stanton A, Struijker-Boudier H, Vlachopoulos C, Volpe M, Wood DA. 2013 ESH/ESC guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J 2013; 34:2159–2219.
Downloaded from http://ajh.oxfordjournals.org/ at University of Hawaii School of Medicine on July 6, 2015
DB, Psaty BM, Rodriguez B, Rosengren A, Salomaa V, Kauhanen J, Salonen JT, Shaffer JA, Shea S, Ford I, Stehouwer CD, Strandberg TE, Tipping RW, Tosetto A, Wassertheil-Smoller S, Wennberg P, Westendorp RG, Whincup PH, Wilhelmsen L, Woodward M, Lowe GD, Wareham NJ, Khaw KT, Sattar N, Packard CJ, Gudnason V, Ridker PM, Pepys MB, Thompson SG, Danesh J. C-reactive protein, fibrinogen, and cardiovascular disease prediction. New Engl J Med 2012; 367:1310–1320. 4. Clarke R, Bennett DA, Parish S, Verhoef P, Dotsch-Klerk M, Lathrop M, Xu P, Nordestgaard BG, Holm H, Hopewell JC, Saleheen D, Tanaka T, Anand SS, Chambers JC, Kleber ME, Ouwehand WH, Yamada Y, Elbers C, Peters B, Stewart AF, Reilly MM, Thorand B, Yusuf S, Engert JC, Assimes TL, Kooner J, Danesh J, Watkins H, Samani NJ, Collins R, Peto R. Homocysteine and coronary heart disease: meta-analysis of MTHFR case-control studies,
