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Vitamin D for hypertension: should we continue the search?
Accepted Manuscript Vitamin D for hypertension: Should we continue the search? C.A. Sternberg, B.J. Materson, A. Nayer PII:
S1933-1711(15)00707-X
DOI:
10.1016/j.jash.2015.09.012
Reference:
JASH 788
To appear in:
Journal of the American Society of Hypertension
Received Date: 8 April 2015 Accepted Date: 10 September 2015
Please cite this article as: Sternberg C, Materson B, Nayer A, Vitamin D for hypertension: Should we continue the search?, Journal of the American Society of Hypertension (2015), doi: 10.1016/ j.jash.2015.09.012. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Vitamin D for hypertension: Should we continue the search? Sternberg CA1, Materson BJ1,2, Nayer A3 Division of Hospital Medicine, 2Division of Clinical Pharmacology, 3Division of Nephrology and Hypertension, Miller School of Medicine, University of Miami, Miami, Florida, USA
RI PT
1
M AN U
SC
Vitamin D is not the cure for hypertension. That is what the most recent review, “Effect of Vitamin D on Blood Pressure”, tells us (1). The increasing popularity of complementary and alternative treatment modalities along with the advent of integrative medicine is leading more people to look for natural ways to treat common health ailments. From a theoretical perspective, vitamin D should lower blood pressure. If vitamin D could be used as an antihypertensive drug, it would represent a “natural” remedy as opposed to a more conventional therapy. The problem is that we do not have an understanding of how vitamin D can be used as a medication.
TE D
We have researched vitamin D, also known as the “sunshine vitamin”, and have discussed how it might be linked to hypertension (2). Mounting evidence indicates that vitamin D regulates the renin-angiotensin system. The pivotal role of the renin-angiotensin system in the regulation of blood pressure is well established. Renin is secreted by the juxtaglomerular cells of the kidney in response to decreased renal blood flow. Renin converts plasma angiotensinogen to angiotensin I, which is then converted to angiotensin II by the angiotensinconverting enzyme. Angiotensin II leads to increased sodium and water reabsorption in the kidney and vasoconstriction.
AC C
EP
Epidemiological studies demonstrated an inverse relationship between plasma vitamin D (25(OH)D) level and blood pressure (3,4). In a cross-sectional study, Forman et al. explored the relation between plasma 25(OH)D level and the renin-angiotensin system in 184 normotensive individuals (5). Individuals with vitamin D deficiency (<15.0 ng/mL) and insufficiency (15.0-29.9 ng/mL) had greater plasma angiotensin II levels and a trend for greater plasma renin activity. In addition, the activity of the renin-angiotensin system in the kidney, as measured by the renal plasma flow in response to angiotensin II infusion, was greater in vitamin D deficient than in vitamin D sufficient individuals. These results suggested that low plasma 25(OH)D levels were associated with increased activity of the renin angiotensin system. Li et al. provided further evidence for a link between vitamin D and blood pressure. They showed that vitamin D receptor-knockout mice suffered from hypertension and cardiac hypertrophy (6). These mice also showed increased renin gene expression in the kidney and angiotensin II levels in the plasma. Pharmacological inhibition of 1,25(OH)2D synthesis led to increased renin gene expression in the kidney of wild-type mice, whereas 1,25(OH)2D treatment suppressed renin
ACCEPTED MANUSCRIPT
gene expression. Subsequently, Yuan et al. showed that 1,25(OH)2D blocked the activity of the cyclic AMP response element in the renin gene promoter, thereby suppressing renin gene expression (7). Collectively, these studies provided evidence for a link between vitamin D and blood pressure.
SC
RI PT
In the light of the effect of vitamin D on blood pressure, clinical studies were conducted to evaluate the efficacy of vitamin D in the treatment of hypertension. However, the results were conflicting. Beveridge et al. carried out a systematic review and meta-analysis of randomized placebo-controlled clinical trials in which vitamin D was given for any indication and blood pressure was recorded (1). Data was examined both at trial-level and individual patient level. Some studies showed that vitamin D treatment was associated with reduced blood pressure. However, on a large scale a significant change in blood pressure was not seen. The authors concluded that vitamin D supplementation does not reduce blood pressure.
TE D
M AN U
There are still many unanswered questions regarding the effect of vitamin D on blood pressure. We have yet to understand clearly what level of vitamin D signifies deficiency. The Endocrine Society defines vitamin D deficiency as a plasma 25(OH)D level of less than 20 ng/mL and insufficiency as a plasma 25(OH)D level between 21 and 29 ng/mL. At the same time, the US Institute of Medicine notes that a plasma level above 20 ng/mL is optimal for bone health and should be sufficient for 97.5% of the population. Furthermore, the Institute of Medicine states that a plasma 25(OH)D level of 16 ng/mL may be high enough for half of the population. If that’s the case, then using a cutoff level of 20 ng/mL will overestimate the prevalence of vitamin D deficiency (8,9). It is important to note that certain individuals such as those with poor nutrition or dark skin and those living in northern latitudes or in institutions maybe at increased risk of not meeting their nutritional needs if the 25(OH)D level were below 16 ng/mL.
AC C
EP
Another issue with vitamin D as an antihypertensive drug is that we lack the understanding of what plasma levels are needed to achieve the desired effect. Some studies do not even use dosages that are considered necessary to normalize plasma 25(OH)D level. Therefore, monitoring vitamin D level maybe important. Furthermore, vitamin D was supplemented at various dosages, frequencies, and formulations in different studies (1). Therefore, it is difficult to know how vitamin D should be supplemented. Beveridge et al., however, did not find a dose-response relationship. It also remains to be seen whether vitamin D supplementation can have a differential effect on blood pressure depending on ethnic background of an individual. A number of studies have shown that plasma renin activity and aldosterone level are not the same across ethnicities (10). If in fact the effect of vitamin D on blood pressure is mediated mainly via suppression of renin production, it can be expected that vitamin D supplementation would be less effective in
ACCEPTED MANUSCRIPT
controlling hypertension in African Americans who are known to exhibit low plasma renin activity and aldosterone level.
SC
RI PT
In summary, research shows a link between vitamin D and blood pressure. The evidence tells us that vitamin D may regulate the renin-angiotensin system. Yet, at this time it is not clear how vitamin D can be used as a medication. Furthermore, it remains to be seen which ethnical/racial groups would benefit most from vitamin D supplementation. The target plasma vitamin D level also needs to be ascertained. There are no answers to many important questions. At this time, vitamin D may not be the most practical option for blood pressure management.
M AN U
Acknowledgement: This work received no funding from public, commercial or not-forprofit organizations. Conflicts of interest: Authors declare no conflicts of interest.
TE D
References
1. Beveridge LA, Struthers AD, Khan F et al.; D-PRESSURE Collaboration. Effect of Vitamin D Supplementation on Blood Pressure: A Systematic Review and Meta-analysis Incorporating Individual Patient Data. JAMA Intern Med. 2015 Mar 16.
EP
2. Ajabshir S, Asif A, Nayer A. The effects of vitamin D on the renin-angiotensin system. J Nephropathol. 2014;3(2):41-3.
AC C
3. Scragg R, Sowers M, Bell C. Serum 25-hydroxyvitamin D, ethnicity, and blood pressure in the Third National Health and Nutrition Examination Survey. Am J Hypertens. 2007 Jul; 20(7): 713-9.
4. Hintzpeter B, Mensink GB, Thierfelder W et al. Vitamin D status and health correlates among German adults. Eur J Clin Nutr. 2008 Sep; 62(9): 1079-89. 5. Forman JP, Williams JS, Fisher ND. Plasma 25-hydroxyvitamin D and regulation of the reninangiotensin system in humans. Hypertension. 2010; 55(5): 1283-8.
ACCEPTED MANUSCRIPT
6. Li YC, Kong J, Wei M et al. 1,25-Dihydroxyvitamin D(3) is a negative endocrine regulator of the renin-angiotensin system. J Clin Invest. 2002 Jul;110(2):229-38. 7. Yuan W, Pan W, Kong J et al. 1,25-dihydroxyvitamin D3 suppresses renin gene transcription
Biol Chem. 2007 Oct 12;282(41):29821-30.
RI PT
by blocking the activity of the cyclic AMP response element in the renin gene promoter. J
8. Pramyothin P, Holick M. Vitamin D Supplementation. Current Opinion in Gastroenterology. 2012;28(2):139-150.
SC
9. Catharine Ross A, Manson J, Abrams S et al. The 2011 Report on Dietary Reference Intakes for Calcium and Vitamin D from the Institute of Medicine: What Clinicians Need to Know. J Clin Endocrinol Metab. 2011 Jan; 96(1): 53–58.
M AN U
10. Rifkin DE, Khaki AR, Jenny NS et al. Association of renin and aldosterone with ethnicity and blood pressure: the Multi-Ethnic Study of Atherosclerosis. Am J Hypertens. 2014
AC C
EP
TE D
Jun;27(6):801-10.
S1933-1711(15)00707-X
DOI:
10.1016/j.jash.2015.09.012
Reference:
JASH 788
To appear in:
Journal of the American Society of Hypertension
Received Date: 8 April 2015 Accepted Date: 10 September 2015
Please cite this article as: Sternberg C, Materson B, Nayer A, Vitamin D for hypertension: Should we continue the search?, Journal of the American Society of Hypertension (2015), doi: 10.1016/ j.jash.2015.09.012. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Vitamin D for hypertension: Should we continue the search? Sternberg CA1, Materson BJ1,2, Nayer A3 Division of Hospital Medicine, 2Division of Clinical Pharmacology, 3Division of Nephrology and Hypertension, Miller School of Medicine, University of Miami, Miami, Florida, USA
RI PT
1
M AN U
SC
Vitamin D is not the cure for hypertension. That is what the most recent review, “Effect of Vitamin D on Blood Pressure”, tells us (1). The increasing popularity of complementary and alternative treatment modalities along with the advent of integrative medicine is leading more people to look for natural ways to treat common health ailments. From a theoretical perspective, vitamin D should lower blood pressure. If vitamin D could be used as an antihypertensive drug, it would represent a “natural” remedy as opposed to a more conventional therapy. The problem is that we do not have an understanding of how vitamin D can be used as a medication.
TE D
We have researched vitamin D, also known as the “sunshine vitamin”, and have discussed how it might be linked to hypertension (2). Mounting evidence indicates that vitamin D regulates the renin-angiotensin system. The pivotal role of the renin-angiotensin system in the regulation of blood pressure is well established. Renin is secreted by the juxtaglomerular cells of the kidney in response to decreased renal blood flow. Renin converts plasma angiotensinogen to angiotensin I, which is then converted to angiotensin II by the angiotensinconverting enzyme. Angiotensin II leads to increased sodium and water reabsorption in the kidney and vasoconstriction.
AC C
EP
Epidemiological studies demonstrated an inverse relationship between plasma vitamin D (25(OH)D) level and blood pressure (3,4). In a cross-sectional study, Forman et al. explored the relation between plasma 25(OH)D level and the renin-angiotensin system in 184 normotensive individuals (5). Individuals with vitamin D deficiency (<15.0 ng/mL) and insufficiency (15.0-29.9 ng/mL) had greater plasma angiotensin II levels and a trend for greater plasma renin activity. In addition, the activity of the renin-angiotensin system in the kidney, as measured by the renal plasma flow in response to angiotensin II infusion, was greater in vitamin D deficient than in vitamin D sufficient individuals. These results suggested that low plasma 25(OH)D levels were associated with increased activity of the renin angiotensin system. Li et al. provided further evidence for a link between vitamin D and blood pressure. They showed that vitamin D receptor-knockout mice suffered from hypertension and cardiac hypertrophy (6). These mice also showed increased renin gene expression in the kidney and angiotensin II levels in the plasma. Pharmacological inhibition of 1,25(OH)2D synthesis led to increased renin gene expression in the kidney of wild-type mice, whereas 1,25(OH)2D treatment suppressed renin
ACCEPTED MANUSCRIPT
gene expression. Subsequently, Yuan et al. showed that 1,25(OH)2D blocked the activity of the cyclic AMP response element in the renin gene promoter, thereby suppressing renin gene expression (7). Collectively, these studies provided evidence for a link between vitamin D and blood pressure.
SC
RI PT
In the light of the effect of vitamin D on blood pressure, clinical studies were conducted to evaluate the efficacy of vitamin D in the treatment of hypertension. However, the results were conflicting. Beveridge et al. carried out a systematic review and meta-analysis of randomized placebo-controlled clinical trials in which vitamin D was given for any indication and blood pressure was recorded (1). Data was examined both at trial-level and individual patient level. Some studies showed that vitamin D treatment was associated with reduced blood pressure. However, on a large scale a significant change in blood pressure was not seen. The authors concluded that vitamin D supplementation does not reduce blood pressure.
TE D
M AN U
There are still many unanswered questions regarding the effect of vitamin D on blood pressure. We have yet to understand clearly what level of vitamin D signifies deficiency. The Endocrine Society defines vitamin D deficiency as a plasma 25(OH)D level of less than 20 ng/mL and insufficiency as a plasma 25(OH)D level between 21 and 29 ng/mL. At the same time, the US Institute of Medicine notes that a plasma level above 20 ng/mL is optimal for bone health and should be sufficient for 97.5% of the population. Furthermore, the Institute of Medicine states that a plasma 25(OH)D level of 16 ng/mL may be high enough for half of the population. If that’s the case, then using a cutoff level of 20 ng/mL will overestimate the prevalence of vitamin D deficiency (8,9). It is important to note that certain individuals such as those with poor nutrition or dark skin and those living in northern latitudes or in institutions maybe at increased risk of not meeting their nutritional needs if the 25(OH)D level were below 16 ng/mL.
AC C
EP
Another issue with vitamin D as an antihypertensive drug is that we lack the understanding of what plasma levels are needed to achieve the desired effect. Some studies do not even use dosages that are considered necessary to normalize plasma 25(OH)D level. Therefore, monitoring vitamin D level maybe important. Furthermore, vitamin D was supplemented at various dosages, frequencies, and formulations in different studies (1). Therefore, it is difficult to know how vitamin D should be supplemented. Beveridge et al., however, did not find a dose-response relationship. It also remains to be seen whether vitamin D supplementation can have a differential effect on blood pressure depending on ethnic background of an individual. A number of studies have shown that plasma renin activity and aldosterone level are not the same across ethnicities (10). If in fact the effect of vitamin D on blood pressure is mediated mainly via suppression of renin production, it can be expected that vitamin D supplementation would be less effective in
ACCEPTED MANUSCRIPT
controlling hypertension in African Americans who are known to exhibit low plasma renin activity and aldosterone level.
SC
RI PT
In summary, research shows a link between vitamin D and blood pressure. The evidence tells us that vitamin D may regulate the renin-angiotensin system. Yet, at this time it is not clear how vitamin D can be used as a medication. Furthermore, it remains to be seen which ethnical/racial groups would benefit most from vitamin D supplementation. The target plasma vitamin D level also needs to be ascertained. There are no answers to many important questions. At this time, vitamin D may not be the most practical option for blood pressure management.
M AN U
Acknowledgement: This work received no funding from public, commercial or not-forprofit organizations. Conflicts of interest: Authors declare no conflicts of interest.
TE D
References
1. Beveridge LA, Struthers AD, Khan F et al.; D-PRESSURE Collaboration. Effect of Vitamin D Supplementation on Blood Pressure: A Systematic Review and Meta-analysis Incorporating Individual Patient Data. JAMA Intern Med. 2015 Mar 16.
EP
2. Ajabshir S, Asif A, Nayer A. The effects of vitamin D on the renin-angiotensin system. J Nephropathol. 2014;3(2):41-3.
AC C
3. Scragg R, Sowers M, Bell C. Serum 25-hydroxyvitamin D, ethnicity, and blood pressure in the Third National Health and Nutrition Examination Survey. Am J Hypertens. 2007 Jul; 20(7): 713-9.
4. Hintzpeter B, Mensink GB, Thierfelder W et al. Vitamin D status and health correlates among German adults. Eur J Clin Nutr. 2008 Sep; 62(9): 1079-89. 5. Forman JP, Williams JS, Fisher ND. Plasma 25-hydroxyvitamin D and regulation of the reninangiotensin system in humans. Hypertension. 2010; 55(5): 1283-8.
ACCEPTED MANUSCRIPT
6. Li YC, Kong J, Wei M et al. 1,25-Dihydroxyvitamin D(3) is a negative endocrine regulator of the renin-angiotensin system. J Clin Invest. 2002 Jul;110(2):229-38. 7. Yuan W, Pan W, Kong J et al. 1,25-dihydroxyvitamin D3 suppresses renin gene transcription
Biol Chem. 2007 Oct 12;282(41):29821-30.
RI PT
by blocking the activity of the cyclic AMP response element in the renin gene promoter. J
8. Pramyothin P, Holick M. Vitamin D Supplementation. Current Opinion in Gastroenterology. 2012;28(2):139-150.
SC
9. Catharine Ross A, Manson J, Abrams S et al. The 2011 Report on Dietary Reference Intakes for Calcium and Vitamin D from the Institute of Medicine: What Clinicians Need to Know. J Clin Endocrinol Metab. 2011 Jan; 96(1): 53–58.
M AN U
10. Rifkin DE, Khaki AR, Jenny NS et al. Association of renin and aldosterone with ethnicity and blood pressure: the Multi-Ethnic Study of Atherosclerosis. Am J Hypertens. 2014
AC C
EP
TE D
Jun;27(6):801-10.