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Nefrologia 2011;31(6):644-647 | Doi. 10.3265/Nefrologia.pre2011.Oct.11175
Arterial calcification: cardiovascular function and clinical outcome

Enviado a Revisar: 28 Sep. 2011 | Aceptado el: 3 Oct. 2011  | En Publicación: 25 Nov. 2011
G.M. London
INSERM U970, Paris and Hopital F.H. Manhès. Fleury-Mérogis (France)
Correspondencia para G.M. London, INSERM U970, Paris and Hopital F.H. Manhès, Fleury-Mérogis, France
E-mail: glondon@club-internet.fr
Figure 1 - Correlations between the abdominal aortic calcification score and high-sensitive C-RP.
Abstract

Arterial calcification (AC) is a common complication of CKD and ESRD, and the extents of AC are predictive of subsequent cardiovascular mortality beyond established conventional risk factors. AC develop in two distinct sites: the intima and media layers of the large and medium-sized arterial wall. These two forms are frequently associated. AC is tightly associated with aging and arterial remodeling, including intima-media thickening, but also changes of the geometry and function of aortic valves. Evidence has accumulated pointing to the active and regulated nature of the calcification process. Elevated phosphate and calcium may stimulate sodiumdependent phosphate cotransport involving osteoblastlike changes in cellular gene expression. AC is responsible for stiffening of the arteries with increased left ventricular afterload and abnormal coronary perfusion as the principal clinical consequences.

Resumen

La calcificación arterial (CA) es una complicación común en la enfermedad renal crónica y la enfermedad renal en etapa terminal, y cuyo alcance es diagnóstico de una posterior mortalidad cardiovascular más allá de los factores de riesgo convencionales establecidos. La CA se desarrolla en dos ubicaciones diferentes: en las capas íntima y media de las paredes arteriales de gran y medio tamaño. Estas dos formas se encuentran frecuentemente asociadas. La CA está estrechamente relacionada con el envejecimiento y el remodelado arterial, que incluye el engrosamiento de la íntima-media y los cambios en la geometría y la función de las válvulas aórticas. Se han recogido evidencias que señalan la naturaleza activa y regulada del proceso de calcificación. Elevados niveles de fosfatos y calcio pueden estimular el cotransporte de fosfato dependiente del sodio que implique cambios osteoblásticos en la expresión genética celular. La CA es responsable del endurecimiento de las arterias, con un aumento de la poscarga ventricular izquierda y perfusión coronaria anormal como principales causas clínicas.

INTRODUCTION

The cardiovascular complications are leading cause of mortality and morbidity in chronic and end-stage renal diseases, in great part related to arterial diseases, i.e. atherosclerosis and arteriosclerosis1,2. While atherosclerosis and plaque-associated occlusive lesions are the frequent causes of these complications, arteriosclerosis is characterized by outward remodeling and stiffening of large arteries3. These arterial structural and functional changes are, in many aspects, similar to an accelerated age-related process3. One characteristic feature of arterial alterations observed in renal patients is the presence of extensive vascular calcifications4-6 whose extents are predictive of subsequent cardiovascular mortality beyond established conventional risk factors7-9. AC develop in two distinct sites: the intima and media layers of the large and medium-sized arterial wall10. These two forms are frequently associated. Intima calcification occurs within atherosclerotic plaque and is a progressive feature of common atherosclerosis, while media calcifications can occurs independently from atherosclerotic plaques and is frequently observed in medium sized arteries in CKD/ESRD, diabetes. AC is tightly associated with aging and arterial remodeling, including intima-media thickening, but also changes of the geometry and function of aortic valves, e.g., decreased aortic valve surface area and smaller valve opening11.

MECHANISMS OF ARTERIAL CALCIFICATION

The presence of dystrophic calcification in the arterial walls is a response to tissue injury, represents a repair process, and is a form of scar tissue12. Experimental and clinical studies have shown that AC is a process reflecting changes of the vascular smooth-muscle cells (VSMC) and pericytes from contractile to secretory phenotype). VSMC synthesize bone-associated proteins, including alkaline phosphatase, osteocalcin, osteopontin and a coat of collage-rich extracellular matrix, and includes the formation of matrix vesicles, nodules and apoptotic bodies, which serve as initiation sites for apatite crystallization13,14

In vitro, VSMC differentiation towards osteoblast-like cells, with subsequent mineralization, is regulated by the balance between promoters and inhibitors of calcification, and results from disruption of this balance in favor of promoters. The secretory phenotype is initiated by the activation of Runx2 (Cbfa1) and osterix (Osx), transcrition factors that promote the differentiation of mesenchymal cells into the osteoblastic lineage15,16. The Runx2 and Osx are activated upstream by several factors including Msx2, Wnt and b-catenin signaling17. The stimuli initiating this “osteogenic cascade” include bone morphogenic proteins (BMP 2, 4) and chronic injurious stimuli and metabolic toxicities including generation of reactive oxygen species (ROS)17-19. The result could be either VSMC apoptosis or stimulation of NFk-B and activation of inflammatory mediators TNFa, IL-1, IL-6, and activation of macrophages19-23. Experimental studies using molecular imaging clearly showed that calcifications develops in parallel with inflammation in two phases: early activation of macrophages and inflammation and calcification at later stage22 (figure 1).

Pooled uremic serum with high phophate concentration, induced expression of Runx224 and blocks the expression of genes responsibles for expression of contractile molecules13,14. In vitro, the phosphate-stimulated calcification process can be inhibited by adding pyrophosphates that antagonize the cellular sodium-phosphate cotransport system (PIT-1)25. Recent study has shown tha phosphate induces the calcification process through a common pathway: increasing mitochondrial ROS and activation of NFk-B pathway and transcription of osteogenic program with expression of Msx2-Wnt-Runx226.

In the presence of normal serum, VSMC do not calcified and can inhibit spontaneous calcium and phosphate precipitation in solution, indicating that systemic calcification inhibitors such as fetuin-A are present in the serum27 and also in VSMCs who constitutively express potent local inhibitors of calcification, such as matrix GLA protein28,29, which may limit AC by binding to bone morphogenic proteins (BMP-2)29. Osteopontin and osteoprotegerin are potent inhibitors of AC in vivo, and inactivation of their gene enhances the calcification process30,31.

CLINICAL IMPACT OF ARTERIAL CALCIFICATIONS

Intima calcification occurs in the context of common atherosclerosis, progresses in parallel with the plaque evolution. The arterial dysfunction result from narrowing of the arterial lumen with ischemia affecting the tissues and organs downstream. The acute coronary events and infarction are more related to biomechanical stability of atherosclerotic plaques and the rupture of the plaque’s fibrous cap. This results from mechanical discontinuity between the inclusion of rigid material (calcium crystals) into distensible material (lipid core) resulting in plaque vulnerability and rupture. Although a higher coronary AC score is associated with a poorer cardiovascular prognosis, the influence of calcification on plaque stability is controversial. The results of several studies indicated that AC does not increase plaque vulnerability, which seems more attributable to a large lipid pool, thin fibrous cap and intensity of local inflammation32,33.

Media calcification (Mönckeberg’s sclerosis or media calcinosis) is characterized by diffuse mineral deposits within the arterial tunica media. While media calcification is frequently observed with aging in the general population, it is significantly more pronounced in patients with metabolic disorders, such as metabolic syndrome, diabetes or CKD. Media calcification is concentric, not extending into arterial lumen in its typical pure form and is associated with abnormal cushioning function of blood vessels (arteriosclerosis-arterial hardening) by promoting arterial stiffness34. The principal consequences of arterial stiffening are an abnormal arterial pressure wave (characterized by increased systolic and decreased diastolic pressures, resulting in high pulse pressure) and increased aortic characteristic impedance, a measure of the opposition of the aorta to oscillatory input (i.e., stroke volume)35. Because the two forms of AC are frequently associated the conduit and cushioning abnormalities could be associated.

MANAGEMENT AND PREVENTION

AC rarely regress, therefore, the primary goals are prevention and stabilization of existing calcifications. Because intimal AC are related to atherosclerosis, the general approach is non-specific as advocated for patients with atherosclerosis: control of blood lipids (but no evidence of a benefit with statins), use of aspirin, treatment of obesity and hypertension, physical activity, smoking cessation, and control of diabetes. More specific preventive measures for patients with CKD or ESRD include controlling serum calcium and phosphate levels, thereby avoiding oversuppression of parathyroid activity and ABD36. Disturbances in calcium and phosphate metabolism are associated with uremic bone disease, and the results of several studies indicated that calcium overload is associated with AC development and progression, suggesting that the overuse of high doses of calcium-based phosphate binders, pharmacological doses of vitamin D, and high calcium concentration in the dialysate should be avoided36-39. Those data suggest that the use of calcium-containing phosphate binders, high intradialytic calcium load, and overuse of active vitamin D should be avoided in elderly patients and in those who already have AC.

Referencias Bibliográficas

1. Lindner A, Chara M, Sherrard D, Scribner BM. Accelerated atherosclerosis in prolonged maintenance hemodialysis. N Engl J Med 1974;290:697-702.[Pubmed]

2. London GM, Drüeke TB. Atherosclerosis and arteriosclerosis in chronic renal failure. Kidney Int 1997;51:1678-95.[Pubmed]

3. Pannier B, Guérin AP, Marchais SJ. Arterial structure and function in end-stage renal disease. Artery Research 2007;1:79-88.

4. Braun J, Oldendorf M, Moshage W. Electron beam computed tomography in the evaluation of cardiac calcifications in chronic dialysis patients. Am J Kidney Dis 1996;27:394-401.[Pubmed]

5. Goodman WG, Goldin J, Kuizon BD Coronary artery calcification in young adults with end-stage renal disease who are undergoing dialysis. N Engl J Med 2000;342:1478-83.[Pubmed]

6. Guérin AP, London GM, Marchais SJ, Métivier F. Arterial stiffening and vascular calcifications in end-stage renal disease. Nephrol Dial Transplant 2000;15:1014-21.[Pubmed]

7. Wilson PWF, Kauppila LI, O’Donnell CJ. Abdominal aortic calcific deposits are an important predictor of vascular morbidity and mortality. Circulation 2001;103:1529-34.[Pubmed]

8. Keelan PC, Bielak LF, Ashai K. Long-term prognostic value of coronary calcification detected by electron-beam computed tomography in patients undergoing coronary angiography. Circulation 2001;104:412-7.[Pubmed]

9. London GM, Guérin AP, Marchais SJ. Arterial media calcification in end-stage renal disease: impact on all-cause and cardiovascular mortality. Nephrol Dial Transplant 2003;18:1731-40.[Pubmed]

10. Amann K. Media calcification and intima calcification are distinct entities in chronic kidney disease. Clin J Am Soc Nephrol 2008;3:1599-605.[Pubmed]

11. Wang AY, Wang M, Woo J. Cardiac valve calcification as an important predictor for all-cause mortality and cardiovascular mortality in long-term peritoneal dialysis patients: a prospective study. J Am Soc Nephrol 2003;14:159-68.[Pubmed]

12. Hayden MR, Tyagi SC, Kolb L. Vascular ossification-calcification in metabolic syndrome, type 2 diabetes mellitus, chronic kidney disease, and calciphylaxis-calcific uremic arteriolopathy: the emerging rolo of sodium thiosulfate. Cardiovasc Diabetol 2005;4:4.[Pubmed]

13. Schoppet M, Shroff RC, Hofbauer LC, Shanahan CM. Exploring the biology of vascular calcification in chronic kidney disease: what’s circulating? Kidney Int 2008;73:384-90.[Pubmed]

14. Demer LL, Tintut Y. Vascular calcification: pathobiology of multifaceted disease. Circulation 2008;117:2938-48.[Pubmed]

15. Reynolds JL, Joannides AJ, Skepper JN. Human Vascular smooth 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 Soc Nephrol 2004;15:2857-67.[Pubmed]

16. Steitz SA, Speer ME, Curinga G. Smooth muscle cell phenotypic transition associated with calcification. Upregulation of Cbfa1 and downregulation of smooth muscle lineage markers. Circ Res 2001;89:1147-54.[Pubmed]

17. Shao J-S, Cheng SL, Sadhu J, Towler DA. Inflammation and the osteogenic regulation of vascular calcification. A review and perspective. Hypertension 2010;55:579-92.[Pubmed]

18. Parhami F, Morrow AD, Balucan J. Lipid oxidation products have opposite effects on calcifying vascular cell and bone cell differenciation: a possible explanation for the paradox of arterial calcification in osteoporosis patients. Arterioscler Thromb Vasc Biol 1997;17:680-7.[Pubmed]

19. Mody N, Parhami F, Sarafian TA, Demer LL. Oxidative stress modulates osteoblastic differentiation of vascular and bone cells. Free Radic Biol Med 2001;31:509-19.[Pubmed]

20. Wang TJ, Larson MG, Levy D. C-Reactive protein is associated with subclinical epicardial coronary calcification in men and women the Framingham Heart Study. Circulation 2002;106:1189-91.[Pubmed]

21. Koh JM, Khang YH, Jung CH. Higher circulating hsCRP levels are associated with lower bone mineral density in healthy pre- and postmenopausal women: evidence for a link between systemic inflammation and osteoporosis. Osteoporos Int 2005;16:1263-71.[Pubmed]

22. Aikawa E, Nahrendorf M, Figuiredo JL. Osteogenesis associates with inflammation in early-stage atherosclerosis evaluated by molecular imaging in vivo. Circulation 2007;116:2841-50.[Pubmed]

23. Tintut Y, Patel J, Territo M. Monocyte macrophage regulation of vascular calcification in vitro. Circulation 2002;105:650-5.[Pubmed]

24. Moe SM, Duan D, Doehle BP. Uremia induces the osteoblast differentiation factor Cbfa1 in human blood vessels. Kidney Int 2003;63:1003-11.[Pubmed]

25. Lomashvili K, Cobbs S, Hennigar RA. Phosphate-induced vascular calcification: role of pyrophosphate and osteopontin. J Am Soc Nephrol 2004;15:1392-401.[Pubmed]

26. Zhao MM, Xu MJ, Cai Y. Mitochondrial reactive oxygen species promote p85 nuclear translocation mediating high phosphate-induced vascular calcification in vitro and in vivo. Kidney Int 2011;79:1071-9.[Pubmed]

27. Schafer C, Heiss A, Schwarz A. The serum protein alpha 2-Heremans-Schmid glycoprotein/fetuin-A is a systemically acting inhibitor of ectopic calcification. J Clin Invest 2003;112:357-66.[Pubmed]

28. Luo G, Ducy P, McKee MD. Spontaneous calcification of arteries and cartilage in mice lacking matrix GLA protein. Nature 1997;386:78-81.[Pubmed]

29. Sweatt A, Sane DC, Hutson SM, Wallin R. Matrix Gla protein (MGP) and bone morphogenetic protein-2 in aortic calcified lesions of aging rats. J Thromb Haemost 2003;1:178-85.[Pubmed]

30. Wada T, McKee MD, Steitz S, Giachelli CM. Calcification of vascular smooth muscle cells: inhibition by osteopontin. Circ Res 1999;84:166-78.[Pubmed]

31. Price PA, June HH, Buckley JR, Williamson MK. Osteoprotegerin inhibits artery calcification induced by warfarin and by vitamin D. Arterioscler Thromb Vasc Biol 2001;21:1610-6.[Pubmed]

32. Lin TC, Tintut Y, Lyman A, Demer LL, Hsiai TK. Mechanical response of a calcified plaque model to fluid shear force. Ann Biomed Engl 2006;34:1535-41.

33. Hoshino T, Chow LA, Hsu JJ. Mechanical stress analysis of rigid inclusion in distensible material: a model of atherosclerotic calcification and plaque vulnerability. Am J Physiol Heart Circ Physiol 2009;297:H802-H810.[Pubmed]

34. Guérin AP, London GM, Marchais SJ, Métivier F. Arterial stiffness and vascular calcifications in end-stage renal disease. Nephrol Dial Transplant 2000;15:1014-21.[Pubmed]

35. O’Rourke MF. Mechanical principles in arterial disease. Hypertension 1995;26:2-9.[Pubmed]

36. Brandenburg VM, Floege J. Adynamic bone disease-bone and beyond. NDT Plus 2008;3:135-47.

37. Chertow GM, Burke SK, Raggi P. Sevelamer attenuates the progression of coronary and aortic calcification in hemodialysis patient. Kidney Int 2002;62:245-52.

38. Suki WN, Zabaneh R, Cangiano JL. Effects of sevelamer and calcium-based phosphate binders on mortality in hemodialysis patients. Kidney Int 2007;72:1130-7.[Pubmed]

39. Bolland MJ, Barber PA, Doughty RN. Vascular events in healthy older women receiving calcium supplementation: randomised controlled trial. BMJ 2008;336:262-6.[Pubmed]



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