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role of vitamin d in cardiovascular disease
G. Verhave1*, C.E.H. Siegert2
1VU Medical Centre, Amsterdam, the Netherlands, 2St. Lucas Andreas Hospital, Amsterdam, the Netherlands, *corresponding author: e-mail:[email protected] a b s t r a C t
there is increasing evidence for health benefits accomplished
benefits accomplished by activated vitamin D through by activated vitamin d through interaction with the vitamin d
interaction with the vitamin D receptor (VDR) that go receptor (vdr) that go beyond calcium and bone homeostasis
beyond these classical functions. The VDR is expressed and regulation of parathyroid hormone (Pth) secretion.
by many tissues and is present in, for instance, arteries, treatment with vitamin d receptor agonists (vdras) is
heart, the immune system and endocrine organs (table 1).1 associated with reduced mortality in (pre)dialysis patients.
As kidney function deteriorates, activated vitamin D levels interestingly, these relations are independent of Pth
decline.2 Therefore patients with renal dysfunction are levels and calcium x phosphorus product. this suggests
a suitable population to study the effects of vitamin D the presence of biological functions of vitamin d that
treatment. Low serum 1,25(OH) D levels cause an increase are independent of its interaction with the parathyroid
in PTH secretion and the development of secondary glands. because chronic kidney disease leads to increased
hyperparathyroidism (SHPT). High serum PTH and cardiovascular mortality, mechanisms in which vdras
hyperphosphataemia are known risk factors for increased can influence cardiovascular disease are discussed. these
mortality among patients on dialysis. Therefore, recent mechanisms comprise the potential ameliorating effects
guidelines have formulated new, stricter, target ranges for of vdras on atherosclerosis, arterial media calcification,
serum calcium, phosphorus and PTH levels.3,4 cardiac hypertrophy, the renin-angiotensin system and
In recent years, it has become clear that there is increased thrombosis. Moreover, treatment strategies with vdras are
mortality among vitamin D deficient patients on dialysis.5 discussed together with several recent observational studies.
Moreover, treatment with vitamin D receptor activators treatment advice consists of correction of 25(oh) vitamin
(VDRAs) is associated with reduced mortality in (pre) d deficiency, low-dose calcitriol in patients with secondary
dialysis patients.6-8 Interestingly, these relations are hyperparathyroidism, and activated vitamin d analogues may
be indicated when higher doses are needed to suppress Pth
secretion. new insights into biological and clinical effects of

table 1. Tissue distribution of the vitamin D receptor
vdras may broaden the patient group that may benefit from
vdra treatment to patients with creatinine clearances in the
30 to 60 ml/min range.
K e y w o r d s
Vitamin D receptor activation, cardiovascular disease, i n t r o d u C t i o n
Vitamin D is known for its primary role in calcium and bone homeostasis and regulation of parathyroid hormone (PTH) secretion. There is increasing evidence for health Van Zuiden Communications B.V. All rights reserved.
independent of PTH levels and calcium x phosphorus with a clinical history of atherosclerosis. Arterial media product. This suggests the presence of biological functions calcification was observed mainly in the younger group of vitamin D that are independent of its interaction without conventional atherosclerotic risk factors.11 Vitamin with the parathyroid glands. What these theoretical D can inhibit various aspects of inflammation leading mechanisms comprise and what the effects are of VDRA to intimal and medial calcification. Further on we will C a r d i o v a s C u l a r d i s e a s e
v d r a d i r e C t e d C y t o K i n e s :
e f f e C t s o n a t h e r o s C l e r o s i s

Below an estimated glomerular filtration rate (eGFR) of 60 ml/min, chronic kidney disease (CKD) leads to increased T lymphocytes and macrophages are known stimulators cardiovascular mortality in nondialysed patients.9 In of intimal thickening and plaque formation in arteries patients on dialysis this risk further increases: half of the susceptible of atherosclerosis. Th1 lymphocytes mortality rate is caused by cardiovascular events.10 secrete interferon-gamma (IFN-γ), which is a potent The two most important arterial complications leading macrophage activator and a Th2 lymphocyte suppressor. to cardiovascular events are intimal and medial Th2 lymphocytes, in their turn, are antiatherogenic calcification. Arterial intima calcification is associated through production of Il-10, which inhibits macrophage with atherosclerosis and leads to plaque formation and activation.17 The development of CD4+ T cells into rupture with subsequent blood vessel occlusion. Arterial either Th1 or Th2 cells determines the outcome of media calcification is associated with proliferation of an immune response, and is primarily directed by vascular smooth muscle cells and leads to calcification cytokines; Th1 cells develop in response to IL-12 and and stiffening of the vessel wall.11 The magnitude of IFN-γ, whereas IL-4 induces the development of Th2 coronary artery calcification, assessed by electron beam cells. VDRA have potential ameliorating effects on the computed tomography and ultrasound, is correlated with development of atherosclerosis by several mechanisms. clinical cardiac events.12 Studies evaluating patients with Firstly, they have a direct effect on naive CD4+ T cells stage 3 to 5 CKD (table 2) have demonstrated excessive by enhancing the development of Th 2 lymphocytes coronary artery calcification,13 even in young adults,14 and (through Il-4 production).18 Furthermore treatment suggest that coronary artery calcification is an independent with VDRA inhibits the transcription of IFN-γ that is predictor of death in patients on dialysis.15 Whether this either required for Th1 development or is a product excessive calcification is primarily due to intimal or medial of Th1 cells.18,19 Moreover, human and mouse naive calcification is subject of debate. There is evidence that in CD4+ cells differentiated into IL-10 producing T cells, patients with CKD increased arterial media calcification, after treatment with VDRAs and dexamethasone.20 more than arterial intima calcification, is responsible Through these mechanisms VDRAs may change the for the high cardiovascular mortality rate. This was Th1/Th2 balance and influence the production of (anti) demonstrated histologically through staining of inferior epigastric arteries from patients on dialysis that showed ‘pure’ medial calcification.16 In another study among patients on dialysis ultrasonography of carotid arteries v a s C u l a r C a l C i f i C a t i o n
showed arterial intima calcification in older patients Vascular smooth muscle cells (VSMCs) and osteoblasts derive from a similar mesenchymal precursor cell. Core table 2. Stages of kidney disease
binding alpha-1 (Cbfa1) is thought to be the switch that description
turns this mesenchymal cell into an osteoblast. Moe Normal kidney function but urine findings and Chen observed expression of Cbfa1 in inferior or structural abnormalities or genetic trait epigastric arteries of renal transplant patients while only minimal expression was found in noncalcified Mildly reduced kidney function, and other findings (as for stage 1) point to kidney arteries.21 Uraemic toxins present in serum from dialysis patients and the expression of osteogenic markers, such as bone morphogenetic protein-2 (BMP-2), also lead to accelerated transformation of VSMCs into osteoblast-like cells.16 These cells are capable of producing bone matrix proteins (type1 collagen, osteopontin, bone sialoprotein), gfr = glomerular filtration rate.
which may subsequently regulate mineralisation.22 Verhave, et al. Vitamin D and cardiovascular disease.
Once mineralisation is initiated, an increased calcium x r o l e o f v d r a s i n v a s C u l a r
phosphorus product, as occurs in patients with renal C a l C i f i C a t i o n
insufficiency, may accelerate the process of calcification which leads to stiffening of the vessel.23 In the past The survival benefit of the use of VDRAs seems accelerated calcification in patients on dialysis has been contradictory to the perception that VDRAs, due to their interpreted to be caused by the presence of potentiators potential impact of increasing serum phosphorus and of calcification. An alternative interpretation is that calcium, may cause vascular calcification.28 Yet there uraemic serum lacks calcification inhibitors.
is evidence for an inhibitory role of VDRAs in vascular Recently several inhibitors of vascular calcification calcification. For a start, VDRs are present in VSMCs and have been identified. Matrix gla protein (MGP) inhibits treatment with VDRAs inhibits the synthesis of type 1 vascular calcification in several possible ways. Muscle collagen.22 More importantly, VDRA treatment reduces phenotype transition was tested in vivo using MGP cbfa-1 synthesis,29 stimulates the synthesis of MGP and -/- mice that spontaneously develop calcification in inhibits BMP-2 production in cultured osteoblastic cells.30,31 all major arteries. The calcified arteries showed an upregulation of osteopontin and induction of Cbfa1 protein expression.24 Furthermore MGP is an inhibitor o t h e r M e C h a n i s M s
of BMP-2.25 A number of circulating proteins may inhibit the vascular calcification process, including fetuin-A,26 Decreased vitamin D activity increases renin expression, PTH-related-peptide and C-natriuretic protein.27 renin levels, atrial natriuretic peptide and angiotensin These mechanisms demonstrate that vascular calcification II levels and causes hypertension and cardiac myocyte is a highly regulated process resulting from an imbalance hypertrophy in mouse models.32-34 Recently it was found between the loss of inhibitory factors and the increase that VDR activation has ameliorating effects on cardiac of inducing factors present both in vessels and in the hypertrophy and inhibits several renin-angiotensin system circulation ( figure 1). Knowledge of the role of VDRAs in (RAS) components. Intravenous treatment with calcitriol in patients on haemodialysis has been demonstrated to be strongly associated with regression of myocardial hypertrophy.35 Treatment of nephrectomised rats with paricalcitol was associated with suppression of renin, renin receptor, angiotensinogen and angiotensin II type 1 receptor. Hypertension and the deterioration of figure 1. Development of vascular calcification
renal function were significantly improved with VDRA treatment.34 Furthermore VDR activation probably has impact on the cardiovascular system by preventing thrombosis. In vitamin D knockout mice platelet aggregation was enhanced, tissue factor expression was upregulated and thrombomodulin/antithrombin were downregulated,36 which are all prothrombotic conditions ( figure 2).
t r e a t M e n t s t r a t e g i e s
Loss of inhibitors:
Recently it has become clear that very low levels of 25(OH) vitamin D (<17.8 ng/ml or 44.5 nmol/l) are associated with increased all-cause mortality in patients with and without kidney disease.37,38 Studies examining replacement of 25(OH) vitamin D in patients without kidney disease support a small but beneficial effect on survival.39 Moreover, treatment with 25(OH) vitamin D results in significant reduction in PTH levels in patients with 25(OH) vitamin D levels <75 nmol/l, irrespective of their kidney function.40,41 Therefore patients with Cbfa-1 = core binding alpha-1; bMP-2 = bone morphogenetic protein-2;
25(OH) vitamin D levels below 75 nmol/l should receive MgP = Matrix gla protein.
replacement therapy with native vitamin D/ergocalciferol. Verhave, et al. Vitamin D and cardiovascular disease.
figure 2. Inhibitors of cardiac hypertrophy and vascular damage through vitamin D receptor activation
Usually this treatment is not sufficient to achieve slower progression of kidney disease and lower mortality suppression of SHPT in advanced chronic kidney disease risk.8 For reasons of convenience, in haemodialysis patients and VDRAs are needed. VDRA therapy in patients active vitamin D is often administered parenterally after with CKD has been associated with improved survival. dialysis. Oral treatment with calcitriol is presumably Intravenous calcitriol or paracalcitriol treatment of patients equally effective in reducing SHPT and mortality risk and on haemodialysis offered a significant survival advantage of 20 to 25% over patients who did not receive parental Clinical guidelines suggest stringent control of PTH, vitamin D.6 This has prompted some other observational calcium and phosphate in an attempt to lower the risk studies examining outcomes associated with the use of of vascular calcification and bone disease.3 Very recently VDRAs by patients on dialysis and predialysis patients.7,8 KDIGO (Kidney Disease: Improving Global Outcome) These studies consistently showed that patients treated guidelines stated that in patients with CKD stage 3 to 5 with any kind of VDRA experienced significantly lower not on dialysis, in whom serum PTH is rising above the all-cause and cardiovascular mortality rates compared with upper limit of normal, despite modifiable factors, VDRAs patients not receiving any treatment. Subgroup analyses are warranted.4 Implicit in these recommendations is indicated that virtually all patients benefited from VDRA the avoidance of the native VDR activator calcitriol if therapy, including patients with lower PTH or higher the calcium and phosphate levels exceed their upper calcium or phosphorus levels. These findings emphasise limits. This has advocated the use of several VDRAs that a physiological effect of VDRAs that is PTH independent. can suppress PTH production with less induction of Despite these convincing data we have to be cautious in concomitant hypercalcaemic and hyperphosphataemic using observational data as a final proof of a beneficial effects.45 One could question the importance of this effect and randomised trials are warranted.
favourable side-effect profile since the benefit of calcitriol extends to patient groups with high calcium and phosphorus levels. On the other hand long-term positive w h i C h v d r a , d o e s i t M a t t e r ?
calcium balance may contribute to vascular calcification. Moreover, observational data suggest a decreased rate Several studies using oral calcitriol in predialysis and of progression of established vascular calcification with dialysis patients have shown a reduced overall mortality non-calcium containing phosphate binders.46 risk ranging from -26 to -45%.8,42,43 The advantage Examples of activated vitamin D analogues with included patients with the highest levels of serum this favourable side-effect profile are doxercalciferol, calcium, phosphorus and PTH. In predialysis patients paricalcitol, and alfacalcidol. Animal models show high pharmacological doses of calcitriol may hasten loss a potential advantage for paricalcitol; it induces less of kidney function,44 but this effect is not seen with lower vascular calcification compared with calcitriol.47 Earlier we doses of calcitriol. On the contrary: low-dose calcitriol mentioned the historical cohort study by Teng et al., where (<0.25 µg/day) has been associated with a trend towards 67,339 patients on haemodialysis were examined. In this Verhave, et al. Vitamin D and cardiovascular disease.
study paricalcitol was associated with a 16% lower all-cause 9. Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease as cause of death, cardiovascular events and hospitalization. mortality compared with treatment with calcitriol.6 In another study these findings were not confirmed. Tentori 10. Sarnak MJ, Coronado BE, Greene T, et al. Cardiovascular disease risk et al. compared outcomes in patients receiving calcitriol, factors in chronic renal insufficiency. Clin Nephrol. 2002;57:327-35.
paricalcitol and doxercalciferol and found lower mortality 11. London GM, Guerin AP, Marchais SJ, Métivier F, Pannier B, Adda H. in patients on paricalcitol and doxercalciferol in unadjusted Arterial media calcification in end-stage renal disease: impact on all cause and cardiovascular mortality. Nephrol Dial Transplant. 2003;18:1731-40.
models. But in adjusted models this difference was 12. Wong ND, Hsu JC, Detrano RC, Diamond G, Eisenberg H, Gardin not statistically significant.7 Obviously, more studies JM. Coronary artery calcium evaluation by electron beam computed are needed to prove the benefit of activated vitamin D tomography and its relation to new cardiovascular events. Am J Cardiol. 2000;86:495-8.
13. Kramer H, Toto R, Peshock R, Cooper R, Victor R. Association between chronic kidney disease and coronary artery calcification: the Dallas Heart Study. J Am Soc Nephrol. 2005;16:507-13.
t r e a t M e n t a d v i C e
14. Goodman WG, Goldin J, Kuizon BD, et al. Coronary artery calcification in young adults with end-stage renal disease who are undergoing dialysis. N Engl J Med. 2000;342:1478-83.
Treatment of SHPT is the generally accepted and approved 15. Matsuoka M, Iseki K, Tamashiro M, et al. Impact of high coronary artery indication for treatment with vitamin D. It seems calcification score (CACS) on survival in patients on chronic hemodialysis. reasonable to correct 25(OH) vitamin D deficiency as a first step in the treatment of SHPT. New insights into biological 16. Moe SM, Duan D, Doehle BP, O’Neill KD, Chen NX. Uremia induces the and clinical effects of VDR activation may broaden the osteoblast differentiation factor Cbfa1 in human blood vessels. Kidney Int. 2003;63:1003-11.
patient group that may benefit from VDRA treatment to 17. Li AC, Glass CK. The macrophage foam cell as a target for therapeutic patients with creatinine clearances in the 30 to 60 ml/min intervention. Nat Med. 2002;8:1235-42.
range. Low-dose calcitriol is indicated for patients with 18. Boonstra A, Barrat FJ, Crain C, et al. 1,25-dihydroxyvitamin D3 has a direct early SHPT. A switch to activated vitamin D analogues effect on naïve CD4+ T cells to enhance the development of Th2 cells. J Immunol. 2001;167:4974-80.
is indicated when higher doses are needed to suppress PTH secretion and treatment goals concerning calcium x 19. Staeva-Vieira TP, Freedman LP. 1,25-dihydroxyvitamin D inhibits IFN-gamma and IL-4 levels during in vitro polarization of primary murine CD4+ T cells. J Immunol. 2002;168:1181-9.
20. Barrat FJ, Cua DJ, Boonstra A, et al. In vitro generation of interleukin 10-producing regulatory CD4+ T cells to enhance the development of TH2-inducing cytokines. J Exp Med. 2002;195:603-16.
a C K n o w l e d g e M e n t s
21. Moe SM, Chen NX. Pathophysiology of vascular calcification in chronic kidney disease. Circ Res. 2004;95:560-7.
We would like to thank Dr. Lukas C. Kapitein for the 22. Bellows CG, Reimers SM, Heersche JNM. Expression of mRNAs for type-1 collagen, bone sialoprotein, osteocalcin, and osteopontin at different stages of osteoblastic differentiation and their regulation by 1,25 dihydroxy vitamin D3. Cell Tissue Res. 1999;297:249-59.
23. Reynolds JL, Joannides AJ, Skepper JN, et al. Human vascular smooth r e f e r e n C e s
muscle cells undergo vesicle mediated calcification in response to changes in extracellular calcium and phosphate concentrations: a potential mechanism for accelerated vascular calcification in ESRD. J Am 1. Holick MF. Vitamin D: importance in prevention of cancers, type 1 diabetes, heart disease and osteoporosis. Am J Clin Nutr. 2004;79:362-71.
24. Steitz SA, Speer MY, Curinga G, et al. Smooth muscle cell phenotype 2. Levin A, Bakris GL, Molitch M, et al. Prevalence of abnormal serum transition associated with calcification: upregulation of Cbfa1 vitamin D, PRH, calcium, and phosphorus in patients with chronic kidney and downregulation of smooth muscle lineage markers. Circ Res. disease: Results of the study to evaluate early kidney disease. Kidney Int. 25. Speer MY, McKee MD, Guldberg RE, et al. Inactivation of the osteopontin 3. K/DOQI clinical practice guidelines for bone metabolism and disease in gene enhances vascular calcification of matrix gla protein-deficient mice: chronic kidney disease. Am J Kidney Dis. 2003;42:S1-202. evidence for osteopontin as an inducible inhibitor of vascular calcification in vivo. J Exp Med. 2002;196:1047-55.
4. KDIGO Clinical practice Guideline for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease-Mineral and Bone 26. Ketteler M, Bongartz P, Westenfeld R, et al. Association of low fetuin-A Disorder (CKD-MBD) Kidney Int. 2009;76:suppl 113.
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5. Wolf M, Shah A, Gutierrez O, et al. Vitamin D levels and early mortality among incident hemodialysis patients. Kidney Int. 2007;72:1004-13.
27. Huang Z, Li J, Jiang Z, Qi Y, Tang C, Du J. Effects of adrenomodulin, C-type natriuretic peptide, and parathyroid hormone-related peptide on 6. Teng M, Wolf M, Lowrie E, Ofsthun N, Lazarus JM, Thadhani R. Survival calcification in cultured rat vascular smooth muscle cells. J Cardiovasc of patients undergoing hemodialysis with paricalcitol or calcitriol therapy. 28. Jono S, Nishizawa Y, Shioi A, Morii H. 1,25 dihyroxyvitamin D3 in vitro 7. Tentori F Hunt WC, Stidley CA, et al. Mortality risk among vascular calcification by modulating secretion of endogenous parathyroid hemodialysis patients receiving different vitamin D analogs. Kidney Int. hormone-related peptide. Circulation. 1998;98:1302-6.
29. Drissi H, Pouliot A, Koolloos C, et al. 1,25-(OH)2-vitamin D3 8. Kovesdy CP, Ahmadzadeh S, Anderson JE, Kalantar-Zadeh K. Association suppresses the bone-related Runx2/Cbfa1 gene promoter. Exp Cell Res. of activated vitamin D treatment and mortality in chronic kidney disease. Verhave, et al. Vitamin D and cardiovascular disease.
30. Fraser JD, Otawara Y, Price PA. 1,25-dihhydroxy D3 stimulates the 39. Autier P, Gandini S. Vitamin D supplementation and total mortality: synthesis of gamma-carboxyglutamic acid protein by osteosarcoma cells. a meta-analysis of randomized controlled trials. Arch Intern Med. Mutually exclusive expression of vitamin K-dependent bone proteins in clonal osteoblastic cell lines. J Biol Chem. 1988;263:911-6.
40. Kooienga L, Fried L, Scragg R, Kendrick J, Smits G, Chonchol M. 31. Virdi AS, Cook LJ, Oreffo RO, Triffit JT. Modulation of bone The effect of combined calcium and vitamin D3 supplementation on morphogenetic protein-2 and bone morphogenetic protein-4 gene serum intact parathyroid hormone in moderate CKD. Am J Kidney Dis. expression in osteoblastic cell lines. Cell Mol Biol. 1998;44:1237-46.
32. Li YC, Kong J, Wei M, Chen ZF, Liu SQ, Cao LP. 1,25 dihydroxyvitamin 41. Zisman AL, Hristova M, Ho LT, Spraque SM. Impact of ergocalciferol D(3) is a negative endocrine regulator of the renin-angiotensin system. treatment of vitamin D deficiency on serum parathyroid hormone concentrations in chronic kidney disease. Am J Nephrol. 2007;27:36-43 33. Xiang W, Kong J, Chen S, et al. Cardiac hypertrophy in vitamin D receptor 42. Shoben AB, Rudser KD, de Boer IH, Young B, Kestenbaum B. Association knockout mice: role of the systemic and cardiac renin-angiotensin of oral calcitriol with improved survival in nondialyzed CKD. J Am Soc systems. Am J Physiol Endocrinol Metab. 2005;288:125-32.
34. FreundlichM, Quiroz Y, Zhang Z, et al. Suppression of renin-angiotensin 43. Naves-Diaz M, Alvarez-Hernandez D, Passlick-Deetjen K, et al. Oral active gene expression in the kidney by paricalcitol. Kidney Int. 2008;74:1394-1402.
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35. Kim HW, Park CW, Shin YS, et al. Calcitriol regresses cardiac hypertrophy and QT dispersion in secondary hyperparathyroidism on hemodialysis. 44. Schwarz S, Trivedi BK, Kalantar-Zadeh K, Kovesdy CP. Association of disorders in mineral metabolism with progression of chronic kidney disease. Clin J Am Soc Nephrol. 2006;1:825-31.
36. Aihara K, Azuma H, Akaike M, et al. Disruption of nuclear vitamin D receptor gene causes enhanced thrombogenicity in mice. J Biol Chem. 45. Coyne DW, Grieff M, Ahya SN, Giles K, Norwood K, Slatopolsky E. Differential effects of acute administration of 19-nor-1,25-dihydroxy-vitamin D2 and 1,25-dihydroxy-vitamin D3 on serum calcium and 37. Melamed ML, Michos ED, Post W, Astor B. 25-hydroxyvitamin D levels phosphorus in hemodialysis patients. Am J Kidney Dis. 2002;40:1283-8.
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Verhave, et al. Vitamin D and cardiovascular disease.

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