Does a Vitamin D Boost Help in Resistant Hypertension Control? Carmine Zoccali and Francesca Mallamaci Hypertension. published online January 13, 2014; Hypertension is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2014 American Heart Association, Inc. All rights reserved. Print ISSN: 0194-911X. Online ISSN: 1524-4563
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://hyper.ahajournals.org/content/early/2014/01/13/HYPERTENSIONAHA.113.02298.citation
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Hypertension can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: http://www.lww.com/reprints Subscriptions: Information about subscribing to Hypertension is online at: http://hyper.ahajournals.org//subscriptions/
Downloaded from http://hyper.ahajournals.org/ at Universitaet Duesseldorf on January 14, 2014
Editorial Commentary Does a Vitamin D Boost Help in Resistant Hypertension Control? Carmine Zoccali, Francesca Mallamaci See related article, p xxx
R
esistant hypertension (RH) is an heterogeneous condition pragmatically defined on the basis of the number of drugs being taken by individual patients. Secondary forms of hypertension, including obesity, chronic kidney disease, renal artery stenosis, hyperaldosteronism, obstructive sleep apnea, and rare forms of hypertension such as pheochromocytoma and coarctation of the aorta, are more frequently resistant to treatment than essential hypertension (EH). However, due to the large prevalence of EH in the general population, at community level, EH is the most prevalent cause of RH. Resistance to treatment portends a high risk for cardiovascular events and left ventricular (LV) hypertrophy, which is per se a strong risk factor for heart failure, coronary heart disease events, and arrhythmia, is a hallmark of this condition. RH should be regarded as a relevant public health issue because observations in the frame of the National Health and Nutrition Examination Survey documented a doubling in the prevalence of RH for 20 years, the prevalence of RH being 5.5% in National Health and Nutrition Examination Survey 1988 to 1994 and 11.8% in National Health and Nutrition Examination Survey 2005 to 2008.1
Excess Adiposity, Hyperaldosteronism, Vitamin D, and Hypertension Obesity and excessive adipose mass is a dominant causal factor for hypertension and RH via insulin resistance. Several clinical studies documented a direct, strong link between plasma aldosterone levels and metrics of adiposity, including body mass index and waist circumference.2 Emerging data point to aldosterone, a steroid which is almost universally high in overweight and obese people, is a player in insulin resistance. The high prevalence (17%–22%) of primary aldosteronism in patients with RH3 suggests that aldosterone excess may be a causal factor in RH. High aldosterone impairs β-cell function in the pancreas and insulin sensitivity in skeletal muscles and promotes the synthesis of proinflammatory cytokines in the adipose tissue, resulting in inflammation and glucose intolerance. Mineralocorticoid receptor blockade improves
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the CNR National Research Council (Italy), Clinical Epidemiology and Physiopathology of Renal Disease and Hypertension Unit, Reggio Calabria, Italy; and Renal and Transplantation Unit, Ospedali Riuniti, Reggio Calabria, Italy. Correspondence to Carmine Zoccali, Nefrologia e CNR, Ospedali Riuniti, Reggio Calabria 89124, Italy. E-mail [email protected] (Hypertension. 2014;63:00-00.) © 2014 American Heart Association, Inc. Hypertension is available at http://hyper.ahajournals.org DOI: 10.1161/HYPERTENSIONAHA.113.02298
β-cell function, insulin-dependent glucose utilization, and dependent vasorelaxation. Thus, hyperaldosteendothelium- ronism has negative metabolic effects that contribute to insulin resistance, which may in turn trigger RH as well as cardiovascular disease and chronic kidney disease. However, biological pathways exist whereby vitamin D deficiency may be implicated in obesity-related RH. Relatively lower plasma levels of 25-hydroxyvitamin D (25 OH VD) associate with adiposity and metabolic disturbances, including insulin resistance and other components of the metabolic syndrome.4 Observational studies in humans and cogent findings in experimental models point to an inverse link between blood pressure and vitamin D levels.5 Furthermore, a randomized, double-masked clinical trial aimed at testing the effect of an active form of vitamin D on albuminuria in type 2 diabetes mellitus documented a significant, clinically relevant hypotensive effect of vitamin D in these patients.6 Vitamin D deficiency per se may be a relevant player in hyperaldosteronism because 25 OH vitamin D levels were definitely in the deficiency range in a large series of patients with aldosterone-producing adenoma or with bilateral adrenal hyperplasia.7 The mutual relationships among aldosterone, vitamin D, insulin sensitivity, inflammation, and the biological interplay among these factors are schematized in the Figure. Because of the heterogeneous nature of RH and the dominant focus on antihypertensive drugs in the therapeutic approach to RH, little attention has been dedicated to potentially modifiable intermediate mechanisms leading to hyperaldosteronism and hyperinsulinemia in this condition. The issue is of relevance because notwithstanding a formidable armamentarium of antihypertensive agents, control of RH remains largely unsatisfactory.1 Because of side effects of intensive application of these agents, the quality of life of patients with RH is often poor. In the pathophysiological scenario of RH (Figure), vitamin D supplementation seems to be as a rational, interesting possibility for mitigating RH. About 3% of the whole human genome is regulated by the vitamin D endocrine system and the vitamin D receptor is highly expressed in myocardiocytes and in vascular smooth muscle cells and endothelial cells.8 Vitamin D deficiency and insufficiency constitute a true public heal problem with a 30% prevalence or higher in the adult population.9 Although a meta-analysis of cohort studies suggests a cardiovascular-protective effect of vitamin D,10 to date there is no strong evidence demonstrating clear benefits of vitamin D on the cardiovascular system. The Paricalcitol capsules benefits in Renal failure Induced cardiac Morbidity (PRIMO), a randomized trial that tested whether paricalcitol (19-nor-1,25 OH2 vitamin D2) administered for 52 weeks may reduce LV hypertrophy in patients with chronic kidney disease, that is, a population where RH is much frequent, failed to show a benefit
Downloaded from http://hyper.ahajournals.org/ 1at Universitaet Duesseldorf on January 14, 2014
2 Hypertension April 2014
Angiotensin II ++ 25OH vitaminD deficiency or insufficiency
Aldosterone
H3C
Angiotensin IIReceptor
H 3C
InsulinReceptor
H 2C
Phosphorilation
NADPH oxidase
(triggering Insulin ( resistance)
Oxidative stress
Serine Kinases
Mineralocorticoid-R
CH3 OH CH3
25
HO
++
++
Protein Kinase B
++
INFLAMMATION
nucleus Figure. Obesity and overweight associate with renin–angiotensin–aldosterone system activation. Aldosterone activates NADPH and promotes oxidative stress via a genomic mechanism augmenting protein kinase B activity, which triggers the inflammation cascade. Oxidative stress promotes phosphorylation of the insulin receptor and by this mechanism induces insulin resistance. Insulin resistance then activates a positive feedback loop mediated by protein kinase B further amplifying resistance to insulin. Vitamin D deficiency, a common alteration in overweight and obese people, amplifies angiotensin II–dependent mechanism(s) of insulin resistance and vascular dysfunction in these conditions. Furthermore, vitamin D deficiency potentiates protein kinase B activation and inflammation in the same conditions.
of this compound on the primary end point and on blood pressure (BP) as well. Yet a post hoc, exploratory analysis of this trial showed a highly significant reduction in left atrial volume and an attenuated rise of brain natriuretic peptide overtime in paricalcitol-treated patients.11 Thus, testing the effect of vitamin D in chronic kidney disease is of relevance for advancing knowledge on the potential of these compounds for cardiovascular prevention in patients with RH.
Can Vitamin D Attenuate RH? Whether vitamin D supplementation may attenuate treatment RH has never been investigated. Thus, the authors of the study published in this issue12 should be commended for having performed an independent randomized controlled trial testing the effect of vitamin D3 (cholecalciferol, a safe and cheap form of vitamin D) on 24-hour ambulatory blood pressure and LV mass in patients with RH. Participants to this trial were adult patients with office blood pressure of >140/90 mm Hg who were on ≥3 antihypertensive drugs and with biochemical evidence of vitamin D deficiency, that is, with serum 25 OH vitamin D levels 95 g/m2 (women) entered a substudy where LV mass was measured by state-of-the-art MRI. The results of this study clearly documented that the vitamin D regimen tested was efficacious in correcting vitamin D deficiency but largely ineffective on BP control. Indeed, the main study end point (24-hour systolic BP) remained unchanged during the trial in patients in the active arm of the study. Similarly, treatment had no meaningful effect on LV mass index. Positive clinical studies make headlines and get immediate interest among patients and within the medical community. Negative data often remain in the desk drawer of the investigator and may not get published for years or be not published at all. However, these studies are important in that they may serve to set the stage for planning new trials with similar drugs and for better defining relevant clinical end points to be targeted in future trials. In the study by Witham et al,12 24-hour ambulatory blood pressure monitoring and office BP remained remarkably constant in the vitamin D arm but systolic BP clearly tended to fall in the placebo arm (24-hour ambulatory blood pressure monitoring, −7 mm Hg; and office BP, −9 mm Hg) documenting the difficulties of testing new interventions in trials in RH, a high -risk condition where cointerventions and changes in antihypertensive therapies are frequent. Although the present study makes a strong case against the hypothesis that vitamin D3 at the doses administered in this trial may produce tangible benefits in RH in whites, the issue clearly deserves further study. Patients enrolled into this trial
Downloaded from http://hyper.ahajournals.org/ at Universitaet Duesseldorf on January 14, 2014
Zoccali and Mallamaci Vitamin D Treatment in Resistant Hypertension 3 were all whites. Vitamin D produced a small dose-dependent BP-lowering effect in blacks in a trial published in the Journal this year.13 A beneficial effect of vitamin D on endothelial function in diabetics emerged in another trial by the same authors of this study.14 The number of patients with diabetes mellitus in the present study was small and although inactivated forms of vitamin D were apparently more effective than activated forms in a meta-analysis performed in 2009,15 the paricalcitol trial in diabetics6 published after this meta-analysis showed that this drug lowers BP in type 2 diabetes mellitus. However, because this study was not designed to examine the effect of paricalcitol on BP, new clinical studies are needed to confirm that active forms of vitamin D may ameliorate BP control in patients with diabetes mellitus, including those with RH. Finally, 6 months may be a too short period for detecting meaningful effects of vitamin D on LV mass and function. Also, in light of post hoc analyses in PRIMO and experimental data in rats showing that only activated forms of vitamin D reduce myocardial fibrosis,16 longer trials and detailed studies of diastolic function, a parameter critically dependent LV compliance, are needed to better investigate the cardiac effects of vitamin D in various forms of hypertension and in RH.
Disclosures None.
References 1. Kumar N, Calhoun DA, Dudenbostel T. Management of patients with resistant hypertension: current treatment options. Integr Blood Press Control. 2013;6:139–151. 2. Douma S, Petidis K, Doumas M, Papaefthimiou P, Triantafyllou A, Kartali N, Papadopoulos N, Vogiatzis K, Zamboulis C. Prevalence of primary hyperaldosteronism in resistant hypertension: a retrospective observational study. Lancet. 2008;371:1921–1926. 3. Sowers JR, Whaley-Connell A, Epstein M. Narrative review: the emerging clinical implications of the role of aldosterone in the metabolic syndrome and resistant hypertension. Ann Intern Med. 2009;150:776–783.
4. Beydoun MA, Boueiz A, Shroff MR, Beydoun HA, Wang Y, Zonderman AB. Associations among 25-hydroxyvitamin D, diet quality, and metabolic disturbance differ by adiposity in adults in the United States. J Clin Endocrinol Metab. 2010;95:3814–3827. 5. Tamez H, Kalim S, Thadhani RI. Does vitamin D modulate blood pressure? Curr Opin Nephrol Hypertens. 2013;22:204–209. 6. de Zeeuw D, Agarwal R, Amdahl M, Audhya P, Coyne D, Garimella T, Parving HH, Pritchett Y, Remuzzi G, Ritz E, Andress D. Selective vitamin D receptor activation with paricalcitol for reduction of albuminuria in patients with type 2 diabetes (VITAL study): a randomised controlled trial. Lancet. 2010;376:1543–1551. 7. Rossi GP, Ragazzo F, Seccia TM, Maniero C, Barisa M, Calò LA, Frigo AC, Fassina A, Pessina AC. Hyperparathyroidism can be useful in the identification of primary aldosteronism due to aldosterone-producing adenoma. Hypertension. 2012;60:431–436. 8. Bouillon R, Carmeliet G, Verlinden L, van Etten E, Verstuyf A, Luderer HF, Lieben L, Mathieu C, Demay M. Vitamin D and human health: lessons from vitamin D receptor null mice. Endocr Rev. 2008;29:726–776. 9. Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357:266–281. 10. Wang L, Song Y, Manson JE, Pilz S, März W, Michaëlsson K, Lundqvist A, Jassal SK, Barrett-Connor E, Zhang C, Eaton CB, May HT, Anderson JL, Sesso HD. Circulating 25-hydroxy-vitamin D and risk of cardiovascular disease: a meta-analysis of prospective studies. Circ Cardiovasc Qual Outcomes. 2012;5:819–829. 11. Tamez H, Zoccali C, Packham D, et al. Vitamin D reduces left atrial volume in patients with left ventricular hypertrophy and chronic kidney disease. Am Heart J. 2012;164:902–909. 12. Witham MD, Ireland S, Houston JG, Gandhy SJ, Waugh S, MacDonald TM, Mckenzie IS, Struthers AD. Vitamin D to reduce blood pressure and left ventricular hypertrophy in resistant hypertension. A randomized controlled trial. Hypertension. 2014;63:XXX–XXX. 13. Forman JP, Scott JB, Ng K, Drake BF, Suarez EG, Hayden DL, Bennett GG, Chandler PD, Hollis BW, Emmons KM, Giovannucci EL, Fuchs CS, Chan AT. Effect of vitamin D supplementation on blood pressure in blacks. Hypertension. 2013;61:779–785. 14. Sugden JA, Davies JI, Witham MD, Morris AD, Struthers AD. Vitamin D improves endothelial function in patients with Type 2 diabetes mellitus and low vitamin D levels. Diabet Med. 2008;25:320–325. 15. Witham MD, Nadir MA, Struthers AD. Effect of vitamin D on blood pressure: a systematic review and meta-analysis. J Hypertens. 2009;27:1948–1954. 16. Panizo S, Barrio-Vázquez S, Naves-Díaz M, Carrillo-López N, Rodríguez I, Fernández-Vázquez A, Valdivielso JM, Thadhani R, Cannata-Andía JB. Vitamin D receptor activation, left ventricular hypertrophy and myocardial fibrosis. Nephrol Dial Transplant. 2013;28:2735–2744.
Downloaded from http://hyper.ahajournals.org/ at Universitaet Duesseldorf on January 14, 2014
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://hyper.ahajournals.org/content/early/2014/01/13/HYPERTENSIONAHA.113.02298.citation
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Hypertension can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: http://www.lww.com/reprints Subscriptions: Information about subscribing to Hypertension is online at: http://hyper.ahajournals.org//subscriptions/
Downloaded from http://hyper.ahajournals.org/ at Universitaet Duesseldorf on January 14, 2014
Editorial Commentary Does a Vitamin D Boost Help in Resistant Hypertension Control? Carmine Zoccali, Francesca Mallamaci See related article, p xxx
R
esistant hypertension (RH) is an heterogeneous condition pragmatically defined on the basis of the number of drugs being taken by individual patients. Secondary forms of hypertension, including obesity, chronic kidney disease, renal artery stenosis, hyperaldosteronism, obstructive sleep apnea, and rare forms of hypertension such as pheochromocytoma and coarctation of the aorta, are more frequently resistant to treatment than essential hypertension (EH). However, due to the large prevalence of EH in the general population, at community level, EH is the most prevalent cause of RH. Resistance to treatment portends a high risk for cardiovascular events and left ventricular (LV) hypertrophy, which is per se a strong risk factor for heart failure, coronary heart disease events, and arrhythmia, is a hallmark of this condition. RH should be regarded as a relevant public health issue because observations in the frame of the National Health and Nutrition Examination Survey documented a doubling in the prevalence of RH for 20 years, the prevalence of RH being 5.5% in National Health and Nutrition Examination Survey 1988 to 1994 and 11.8% in National Health and Nutrition Examination Survey 2005 to 2008.1
Excess Adiposity, Hyperaldosteronism, Vitamin D, and Hypertension Obesity and excessive adipose mass is a dominant causal factor for hypertension and RH via insulin resistance. Several clinical studies documented a direct, strong link between plasma aldosterone levels and metrics of adiposity, including body mass index and waist circumference.2 Emerging data point to aldosterone, a steroid which is almost universally high in overweight and obese people, is a player in insulin resistance. The high prevalence (17%–22%) of primary aldosteronism in patients with RH3 suggests that aldosterone excess may be a causal factor in RH. High aldosterone impairs β-cell function in the pancreas and insulin sensitivity in skeletal muscles and promotes the synthesis of proinflammatory cytokines in the adipose tissue, resulting in inflammation and glucose intolerance. Mineralocorticoid receptor blockade improves
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the CNR National Research Council (Italy), Clinical Epidemiology and Physiopathology of Renal Disease and Hypertension Unit, Reggio Calabria, Italy; and Renal and Transplantation Unit, Ospedali Riuniti, Reggio Calabria, Italy. Correspondence to Carmine Zoccali, Nefrologia e CNR, Ospedali Riuniti, Reggio Calabria 89124, Italy. E-mail [email protected] (Hypertension. 2014;63:00-00.) © 2014 American Heart Association, Inc. Hypertension is available at http://hyper.ahajournals.org DOI: 10.1161/HYPERTENSIONAHA.113.02298
β-cell function, insulin-dependent glucose utilization, and dependent vasorelaxation. Thus, hyperaldosteendothelium- ronism has negative metabolic effects that contribute to insulin resistance, which may in turn trigger RH as well as cardiovascular disease and chronic kidney disease. However, biological pathways exist whereby vitamin D deficiency may be implicated in obesity-related RH. Relatively lower plasma levels of 25-hydroxyvitamin D (25 OH VD) associate with adiposity and metabolic disturbances, including insulin resistance and other components of the metabolic syndrome.4 Observational studies in humans and cogent findings in experimental models point to an inverse link between blood pressure and vitamin D levels.5 Furthermore, a randomized, double-masked clinical trial aimed at testing the effect of an active form of vitamin D on albuminuria in type 2 diabetes mellitus documented a significant, clinically relevant hypotensive effect of vitamin D in these patients.6 Vitamin D deficiency per se may be a relevant player in hyperaldosteronism because 25 OH vitamin D levels were definitely in the deficiency range in a large series of patients with aldosterone-producing adenoma or with bilateral adrenal hyperplasia.7 The mutual relationships among aldosterone, vitamin D, insulin sensitivity, inflammation, and the biological interplay among these factors are schematized in the Figure. Because of the heterogeneous nature of RH and the dominant focus on antihypertensive drugs in the therapeutic approach to RH, little attention has been dedicated to potentially modifiable intermediate mechanisms leading to hyperaldosteronism and hyperinsulinemia in this condition. The issue is of relevance because notwithstanding a formidable armamentarium of antihypertensive agents, control of RH remains largely unsatisfactory.1 Because of side effects of intensive application of these agents, the quality of life of patients with RH is often poor. In the pathophysiological scenario of RH (Figure), vitamin D supplementation seems to be as a rational, interesting possibility for mitigating RH. About 3% of the whole human genome is regulated by the vitamin D endocrine system and the vitamin D receptor is highly expressed in myocardiocytes and in vascular smooth muscle cells and endothelial cells.8 Vitamin D deficiency and insufficiency constitute a true public heal problem with a 30% prevalence or higher in the adult population.9 Although a meta-analysis of cohort studies suggests a cardiovascular-protective effect of vitamin D,10 to date there is no strong evidence demonstrating clear benefits of vitamin D on the cardiovascular system. The Paricalcitol capsules benefits in Renal failure Induced cardiac Morbidity (PRIMO), a randomized trial that tested whether paricalcitol (19-nor-1,25 OH2 vitamin D2) administered for 52 weeks may reduce LV hypertrophy in patients with chronic kidney disease, that is, a population where RH is much frequent, failed to show a benefit
Downloaded from http://hyper.ahajournals.org/ 1at Universitaet Duesseldorf on January 14, 2014
2 Hypertension April 2014
Angiotensin II ++ 25OH vitaminD deficiency or insufficiency
Aldosterone
H3C
Angiotensin IIReceptor
H 3C
InsulinReceptor
H 2C
Phosphorilation
NADPH oxidase
(triggering Insulin ( resistance)
Oxidative stress
Serine Kinases
Mineralocorticoid-R
CH3 OH CH3
25
HO
++
++
Protein Kinase B
++
INFLAMMATION
nucleus Figure. Obesity and overweight associate with renin–angiotensin–aldosterone system activation. Aldosterone activates NADPH and promotes oxidative stress via a genomic mechanism augmenting protein kinase B activity, which triggers the inflammation cascade. Oxidative stress promotes phosphorylation of the insulin receptor and by this mechanism induces insulin resistance. Insulin resistance then activates a positive feedback loop mediated by protein kinase B further amplifying resistance to insulin. Vitamin D deficiency, a common alteration in overweight and obese people, amplifies angiotensin II–dependent mechanism(s) of insulin resistance and vascular dysfunction in these conditions. Furthermore, vitamin D deficiency potentiates protein kinase B activation and inflammation in the same conditions.
of this compound on the primary end point and on blood pressure (BP) as well. Yet a post hoc, exploratory analysis of this trial showed a highly significant reduction in left atrial volume and an attenuated rise of brain natriuretic peptide overtime in paricalcitol-treated patients.11 Thus, testing the effect of vitamin D in chronic kidney disease is of relevance for advancing knowledge on the potential of these compounds for cardiovascular prevention in patients with RH.
Can Vitamin D Attenuate RH? Whether vitamin D supplementation may attenuate treatment RH has never been investigated. Thus, the authors of the study published in this issue12 should be commended for having performed an independent randomized controlled trial testing the effect of vitamin D3 (cholecalciferol, a safe and cheap form of vitamin D) on 24-hour ambulatory blood pressure and LV mass in patients with RH. Participants to this trial were adult patients with office blood pressure of >140/90 mm Hg who were on ≥3 antihypertensive drugs and with biochemical evidence of vitamin D deficiency, that is, with serum 25 OH vitamin D levels 95 g/m2 (women) entered a substudy where LV mass was measured by state-of-the-art MRI. The results of this study clearly documented that the vitamin D regimen tested was efficacious in correcting vitamin D deficiency but largely ineffective on BP control. Indeed, the main study end point (24-hour systolic BP) remained unchanged during the trial in patients in the active arm of the study. Similarly, treatment had no meaningful effect on LV mass index. Positive clinical studies make headlines and get immediate interest among patients and within the medical community. Negative data often remain in the desk drawer of the investigator and may not get published for years or be not published at all. However, these studies are important in that they may serve to set the stage for planning new trials with similar drugs and for better defining relevant clinical end points to be targeted in future trials. In the study by Witham et al,12 24-hour ambulatory blood pressure monitoring and office BP remained remarkably constant in the vitamin D arm but systolic BP clearly tended to fall in the placebo arm (24-hour ambulatory blood pressure monitoring, −7 mm Hg; and office BP, −9 mm Hg) documenting the difficulties of testing new interventions in trials in RH, a high -risk condition where cointerventions and changes in antihypertensive therapies are frequent. Although the present study makes a strong case against the hypothesis that vitamin D3 at the doses administered in this trial may produce tangible benefits in RH in whites, the issue clearly deserves further study. Patients enrolled into this trial
Downloaded from http://hyper.ahajournals.org/ at Universitaet Duesseldorf on January 14, 2014
Zoccali and Mallamaci Vitamin D Treatment in Resistant Hypertension 3 were all whites. Vitamin D produced a small dose-dependent BP-lowering effect in blacks in a trial published in the Journal this year.13 A beneficial effect of vitamin D on endothelial function in diabetics emerged in another trial by the same authors of this study.14 The number of patients with diabetes mellitus in the present study was small and although inactivated forms of vitamin D were apparently more effective than activated forms in a meta-analysis performed in 2009,15 the paricalcitol trial in diabetics6 published after this meta-analysis showed that this drug lowers BP in type 2 diabetes mellitus. However, because this study was not designed to examine the effect of paricalcitol on BP, new clinical studies are needed to confirm that active forms of vitamin D may ameliorate BP control in patients with diabetes mellitus, including those with RH. Finally, 6 months may be a too short period for detecting meaningful effects of vitamin D on LV mass and function. Also, in light of post hoc analyses in PRIMO and experimental data in rats showing that only activated forms of vitamin D reduce myocardial fibrosis,16 longer trials and detailed studies of diastolic function, a parameter critically dependent LV compliance, are needed to better investigate the cardiac effects of vitamin D in various forms of hypertension and in RH.
Disclosures None.
References 1. Kumar N, Calhoun DA, Dudenbostel T. Management of patients with resistant hypertension: current treatment options. Integr Blood Press Control. 2013;6:139–151. 2. Douma S, Petidis K, Doumas M, Papaefthimiou P, Triantafyllou A, Kartali N, Papadopoulos N, Vogiatzis K, Zamboulis C. Prevalence of primary hyperaldosteronism in resistant hypertension: a retrospective observational study. Lancet. 2008;371:1921–1926. 3. Sowers JR, Whaley-Connell A, Epstein M. Narrative review: the emerging clinical implications of the role of aldosterone in the metabolic syndrome and resistant hypertension. Ann Intern Med. 2009;150:776–783.
4. Beydoun MA, Boueiz A, Shroff MR, Beydoun HA, Wang Y, Zonderman AB. Associations among 25-hydroxyvitamin D, diet quality, and metabolic disturbance differ by adiposity in adults in the United States. J Clin Endocrinol Metab. 2010;95:3814–3827. 5. Tamez H, Kalim S, Thadhani RI. Does vitamin D modulate blood pressure? Curr Opin Nephrol Hypertens. 2013;22:204–209. 6. de Zeeuw D, Agarwal R, Amdahl M, Audhya P, Coyne D, Garimella T, Parving HH, Pritchett Y, Remuzzi G, Ritz E, Andress D. Selective vitamin D receptor activation with paricalcitol for reduction of albuminuria in patients with type 2 diabetes (VITAL study): a randomised controlled trial. Lancet. 2010;376:1543–1551. 7. Rossi GP, Ragazzo F, Seccia TM, Maniero C, Barisa M, Calò LA, Frigo AC, Fassina A, Pessina AC. Hyperparathyroidism can be useful in the identification of primary aldosteronism due to aldosterone-producing adenoma. Hypertension. 2012;60:431–436. 8. Bouillon R, Carmeliet G, Verlinden L, van Etten E, Verstuyf A, Luderer HF, Lieben L, Mathieu C, Demay M. Vitamin D and human health: lessons from vitamin D receptor null mice. Endocr Rev. 2008;29:726–776. 9. Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357:266–281. 10. Wang L, Song Y, Manson JE, Pilz S, März W, Michaëlsson K, Lundqvist A, Jassal SK, Barrett-Connor E, Zhang C, Eaton CB, May HT, Anderson JL, Sesso HD. Circulating 25-hydroxy-vitamin D and risk of cardiovascular disease: a meta-analysis of prospective studies. Circ Cardiovasc Qual Outcomes. 2012;5:819–829. 11. Tamez H, Zoccali C, Packham D, et al. Vitamin D reduces left atrial volume in patients with left ventricular hypertrophy and chronic kidney disease. Am Heart J. 2012;164:902–909. 12. Witham MD, Ireland S, Houston JG, Gandhy SJ, Waugh S, MacDonald TM, Mckenzie IS, Struthers AD. Vitamin D to reduce blood pressure and left ventricular hypertrophy in resistant hypertension. A randomized controlled trial. Hypertension. 2014;63:XXX–XXX. 13. Forman JP, Scott JB, Ng K, Drake BF, Suarez EG, Hayden DL, Bennett GG, Chandler PD, Hollis BW, Emmons KM, Giovannucci EL, Fuchs CS, Chan AT. Effect of vitamin D supplementation on blood pressure in blacks. Hypertension. 2013;61:779–785. 14. Sugden JA, Davies JI, Witham MD, Morris AD, Struthers AD. Vitamin D improves endothelial function in patients with Type 2 diabetes mellitus and low vitamin D levels. Diabet Med. 2008;25:320–325. 15. Witham MD, Nadir MA, Struthers AD. Effect of vitamin D on blood pressure: a systematic review and meta-analysis. J Hypertens. 2009;27:1948–1954. 16. Panizo S, Barrio-Vázquez S, Naves-Díaz M, Carrillo-López N, Rodríguez I, Fernández-Vázquez A, Valdivielso JM, Thadhani R, Cannata-Andía JB. Vitamin D receptor activation, left ventricular hypertrophy and myocardial fibrosis. Nephrol Dial Transplant. 2013;28:2735–2744.
Downloaded from http://hyper.ahajournals.org/ at Universitaet Duesseldorf on January 14, 2014
