Departments of Medicine and Physiology, UCLA School of Medicine, Box 951679, 10833 LeConte Ave, Los Angeles, CA 900951679, USA. E-mail: Ldemer{at}mednet.ucla.edu
Keywords Atherosclerosis, artery, osteoporosis, calcification
Accepted 25 April 2002
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The fact that complete bone tissue forms within the atherosclerotic artery wall has been known since at least the 1800s. In 1863, Virchow observed that vascular calcium deposits were not mere calcification, but ossification.1 In 1908, investigators reported red marrow elements in bone tissue within atherosclerotic plaque.2,3 Experimental models of atherosclerosis also have cartilage and marrow within plaque.4
As an overview, vascular calcification in general, and coronary calcification in particular, increase with ageing, are present in almost all subjects over age 65, are more frequent in diabetics, less common in African-Americans, and extremely common in end-stage renal disease. Current studies of coronary calcification utilize electron beam computed tomographic scanning (EBCT). This method has been described as an inaccurate predictor of stenosis severity. While this is not incorrect, it may leave the wrong impression since EBCT is accurate when used to predict the presence of significant coronary artery disease, and the degree of plaque burden.5
![]() |
Mechanism of vascular calcification |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Investigators in the 1980s recognized bone-like features of vascular calcification including the mineral hydroxyapatite and matrix vesicles. Similarities between artery and bone at the molecular level were identified by Giachelli et al.8 who discovered a bone matrix protein, osteopontin, expressed in immature vascular cells. Schor et al. demonstrated that microvascular pericytes were capable of producing mineralization in vitro.9 The possibility that atherosclerotic calcification occurs by the same molecular mechanism as embryonic bone formation was proposed by Bostrom et al. who demonstrated expression of the potent embryonic bone differentiation factor, BMP-2, in human calcified plaque.10 A variety of bone proteins were then found in atherosclerotic lesions.1116
Vascular calcification can be studied in tissue culture models. A subpopulation of cells from the aortic medial layer spontaneously produce bone mineral (hydroxyapatite) in tissue culture.10 These calcifying vascular cells (CVC) recapitulate the sequence of molecular events defining osteoblastic differentiation including co-ordinate expression of alkaline phosphatase, collagen I, osteopontin, osteonectin, and osteocalcin.17,18 Key mechanisms of vascular calcification include genetic determination, inflammatory mediators, apoptosis, matrix components, and homeobox genes.1924
![]() |
Clinical significance of vascular calcification |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Coronary events
The degree of coronary calcification by EBCT is a sensitive and specific predictor for future cardiac events. The earliest evidence for this was limited by the need to include soft endpoints to achieve sufficient numbers of events,25 such as interventional or surgical treatment, which could be influenced by the results of the EBCT scan. Other early studies suggested that there was not a relationship with hard endpoints at early follow-up.26 As follow-up time has increased, the correlation between EBCT results and the hard endpoints, myocardial infarction and coronary death, has remained positive.27 However, patients with the least circumferential extent of coronary calcification, measured by intravascular ultrasound, have more occasions of acute coronary syndrome.28 These findings are difficult to reconcile with those of EBCT, suggesting that the circumferential extent of calcification is not related to calcium score by EBCT, and that the circumferential versus longitudinal distribution have different implications.
Plaque rupture
Cardiac events are often the result of plaque rupture or ulceration.29 Plaque disruption may be prevented or promoted by calcium deposits because they may strengthen the plaque against circumferential mechanical stress,30 but they also introduce solid shear stress concentration where the non-distensible mineral interfaces with distensible tissue. Under mechanical stress induced by balloon angioplasty, calcified plaque is more likely to rupture than non-calcified plaque,31 and the rupture occurs along the interface between the calcium deposit and soft tissue.32 Thus, the ratio of surface area to volume in calcium deposits may determine whether they are harmful or protective. The presence of calcium deposits also correlates with adverse outcomes,33 and restenosis34 in coronary interventional procedures.
Loss of the Windkessel effect in aortic calcification
Mineralization of the aorta may have greater significance than of the coronaries. The normal aorta, with its multiple layers of elastin, is highly resilient. This resilience serves a pump function, known as the Windkessel effect. During systole, the aorta distends which reduces the work of the heart by reducing afterload. During diastole, the aorta recoils, with an energy that propels blood throughout the vasculature, particularly into the coronary tree, which depends on this diastolic aortic recoil for most of its perfusion. When the aorta calcifies and becomes rigid, it loses its Windkessel function,35 the work of the heart increases,36 and coronary flow is reduced37 leading to left ventricular hypertrophy, congestive heart failure and coronary insufficiency in patients with coronary disease.3841 Congestive heart failure and myocardial infarction are major health problems in the over 65 age group. Aortic calcification, present in the vast majority of these individuals,42 is considered a factor in both.4346
Cardiac valve calcification
Calcific valvular stenosis is responsible for significant cardiovascular morbidity and mortality. For decades, valvular stenosis was considered independent of atherosclerosis and its risk factors. However, it is now known that cardiac valvular calcification shares risk factors with atherosclerosis47 and it has many features of bone.4850 In addition, its progression is reduced in response to lipid lowering therapy.51
![]() |
Accelerated vascular calcification in dialysis patients |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
![]() |
Vascular calcification and osteoporosis |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
In general, postmenopausal women are advised to take calcium supplements to prevent or treat osteoporosis, implying that bone loss is due to insufficient dietary calcium. Yet, in many patients with osteoporosis, loss of bone tissue from the skeleton occurs at the same time as formation of bone in the artery wall. This paradox suggests that dietary calcium is not the limiting factor. The association of osteoporosis with vascular calcification has been reported widely,6166 and it may67 or may not6870 be explained by their mutual correlation with ageing. In rodents, vascular calcification and osteoporosis co-exist under at least three conditions: deficiency of osteoprotegerin, an osteoclast inhibitory factor,71 deficiency of dietary essential fatty acids72 and hyperlipidaemia.
Lipids and biomineralization
In vitro and in vivo studies show that oxidized lipids not only promote mineralization of vascular cells but they also inhibit mineralization of bone cells.73 Low density lipoprotein (LDL) levels correlate with both coronary and aortic valve calcification progression,74 and LDL proteins accumulate in calcified aortic valves.75 Hyperlipidaemia is associated with rapid progression of coronary calcification,76 and lipid-lowering therapy reduces progression of both coronary and valvular calcification.51,77 Oxidized lipids induce osteoblastic differentiation in vascular cells in vitro,78 and hyperlipidaemia reduces bone mineral density in vivo in mice.79
The paradox of simultaneous osteolysis and ectopic ossification
One possible unifying theme explaining this paradox is that accumulation and oxidation of lipid deposits in tissue may mimic chronic infection and stimulate immune responses that promote hardening of soft tissue and the softening of hard tissue. The bacterial cell wall contains lipids, and they are modified by oxidizing factors released by phagocytic cells, such as superoxide radical and nitric oxide from macrophages. Thus, oxidized lipids in general may trigger the immune system to respond as it does to persistent bacterial infection. It is well known that the immune response to longstanding infection or inflammation in bone is osteolysis,80 which would dissolve a substrate for bacterial infectious growth. It is also well known that the immune response to longstanding infection or inflammation in soft tissue is heterotopic bone formation around the site, which would wall off any infectious organism. Tuberculous granulomata result from this process. Thus, lipid accumulation and oxidation may lead to a reversal of the normal regional control of biomineralization, promoting calcification of soft tissue and osteolysis of bone, accounting for the paradox of bone formation in the arteries of patients who are losing bone from their skeletons.
Additional epidemiological considerations
In a case-control study from Thailand, serum biomarkers of osteoporosis and coronary heart disease were compared. No statistically significant difference was found in bone turnover markers between 118 coronary artery disease patients versus control subjects.81 Since a reduction in osteogenesis is not always accompanied by changes in turnover, however, such measures may not detect an association between coronary disease and reduced bone formation. If accurate markers of bone differentiation/formation are developed in the future, this type of study, comparing degree of vascular calcification with serum markers of bone differentiation or formation may help determine whether such a relation exists.
From a mechanical standpoint, whether calcium deposits in arteries are circumferential versus longitudinal may influence stability. These assessments are difficult to make by EBCT because of resolution limitations, and they are difficult by intravascular ultrasound because calcium deposits reflect the echoes allowing assessment only of the edge of the deposit closest to the tranducer. Beckman et al. compared the extent of cirumferential calcification (not longitudinal), and found that patients with acute coronary syndromes had less cirumferential extent than those with stable angina.82 Although there are potential confounding effects in this study, it raises the possibility that circumferential calcification has a stabilizing effect.
Although long-term warfarin use in atrial fibrillation, by reducing function of MGP, would be expected to promote arterial calcification, clinical events are generally reduced in treated patients. The likely reason, of course, is warfarins direct effect on blood coagulation and its contribution to thrombosis, the major event in atrial fibrillation. It also remains possible that calcification could stabilize plaque as well as reduce clot formation.
It remains controversial whether coronary heart disease risk factor profiles (e.g. the Framingham score) have a greater predictive value if the extent of arterial calcification is included. Arad et al. determined the areas under the receiver-operator characteristics curves as 0.84 and 0.86 for predicting non-fatal myocardial infarctions and deaths from coronary calcification score.83 Overall, the view is that calcification scores make a small improvement in predictive value.
Coronary calcification and osteoporosis have been associated with presence of infectious agents, such as Chlamydia pneumoniae and Helicobacter pylori, as well as markers of chronic infection, such as C-reactive protein. While this most likely suggests that arterial calcification is a chronic inflammatory process, it remains possible that inflammatory processes in bone alter the serum bone regulatory factor levels, resulting in indirect effects on vascular calcification.
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
2 Buergher L, Oppenheimer A. Bone formation in sclerotic arteries. J Exper Med 1908;10:35467.
3 Bunting CH. The formation of true bone with cellular (red) marrow in a sclerotic aorta. J Exper Med 1906;8:36576.
4 Haust MD, Moore RH. Spontaneous lesions of the aorta in the rabbit. In: Roberts JC, Straus R (eds). Comparative Atherosclerosis: The Morphology of Spontaneous and Induced Atherosclerotic Lesions in Animals and Its Relation to Human Disease. New York: Harper and Row, 1965, p. 268.
5 Sangiorgi G, Rumberger JA, Severson A et al. Arterial calcification and not lumen stenosis is highly correlated with atherosclerotic plaque burden in humans: a histologic study of 723 coronary artery segments using nondecalcifying methodology. J Am Coll Cardiol 1998;31:12633.[ISI][Medline]
6 Lehto S, Niskanen L, Suhonen M, Ronnemaa T, Laakso M. Medial artery calcification. A neglected harbinger of cardiovascular complications in non-insulin dependent diabetes mellitus. Arterioscler Thromb Vasc Biol 1995;16:97883.
7 Nicolosi AC, Pohl LL, Parsons P, Cabria RA, Olinger GN. Increased incidence of radial artery calcification in patients with diabetes mellitus. J Surg Res 2002;102:15.[CrossRef][ISI][Medline]
8 Giachelli C, Bae N, Lombardi D, Majesky M, Schwartz S. Molecular cloning and characterization of 2B7, a rat mRNA which distinguishes smooth muscle cell phenotypes in vitro and is identical to osteopontin (secreted phosphoprotein I, 2aR). iochem Biophys Res Commun 1991;177:86773.
9 Schor AM, Allen TD, Canfield AE, Sloan P, Schor SL. Pericytes derived from the retinal microvasculature undergo calcification in vitro. J Cell Sci 1990;97:44961.[Abstract]
10 Bostrom K, Watson KE, Horn S, Wortham C, Herman IM, Demer LL. Bone morphogenetic protein expression in human atherosclerotic lesions. J Clin Invest 1993;91:180009.[ISI][Medline]
11 Hirota S, Imakita M, Kohri K et al. Expression of osteopontin messenger RNA by macrophages in atherosclerotic plaques. A possible association with calcification. Am J Pathol 1993;143:100308.[Abstract]
12 Ikeda T, Shirasawa T, Esaki Y, Yoshiki S, Hirokawa K. Osteopontin mRNA is expressed by smooth muscle-derived foam cells in human atherosclerotic lesions of the aorta. J Clin Invest 1993;92:281420.[ISI][Medline]
13 OBrien ER, Garvin MR, Stewart DK et al. Osteopontin is synthesized by macrophage, smooth muscle, and endothelial cells in primary and restenotic human coronary atherosclerotic plaques. Arterioscler Thromb 1994;14:164856.[Abstract]
14 Shanahan CM, Cary NRB, Metcalfe JC, Weissberg PL. High expression of genes for calcificationregulating proteins in human atherosclerotic plaques. J Clin Invest 1994;93:2393402.[ISI][Medline]
15 Iimura T, Oida S, Takeda K, Maruoka Y, Sasaki S. Changes in homeobox-containing gene expression during ectopic bone formation induced by bone morphogenetic protein. Biochem Biophys Res Commun 1994;201:98087.[CrossRef][ISI][Medline]
16 Fitzpatrick LA, Severeson A, Edwards WD, Ingram RT. Diffuse calcification in human coronary arteries: Association of osteopontin with atherosclerosis. J Clin Invest 1994;94:1597604.[ISI][Medline]
17 Watson KE, Bostrom K, Ravindranath R, Lam T, Norton B, Demer LL. TGF-beta 1 and 25-hydroxycholesterol stimulate osteoblast-like vascular cells to calcify. J Clin Invest 1994;93:210613.[ISI][Medline]
18 Tintut Y, Parhami F, Bostrom K, Jackson SM, Demer LL. cAMP stimulates osteoblast-like differentiation of calcifying vascular cells. Potential signaling pathway for vascular calcification. J Biol Chem 1998;273:754753.
19 Qiao JH, Xie PZ, Fishbein MC et al. Pathology of atheromatous lesions in inbred and genetically engineered mice. Genetic determination of arterial calcification. Arterioscler Thromb 1994;14:148097.[Abstract]
20 Tintut Y, Patel J, Parhami F, Demer LL. Tumor necrosis factor-alpha promotes in vitro calcification of vascular cells via the cAMP pathway. Circulation 2000;102:263642.
21 Proudfoot D, Skepper JN, Hegyi L, Bennett MR, Shanahan CM, Weissberg PL. Apoptosis regulates human vascular calcification in vitro: evidence for initiation of vascular calcification by apoptotic bodies. Circ Res 2000;87:105562.
22 Canfield AE, Farrington C, Dziobon MD et al. The involvement of matrix glycoproteins in vascular calcification and fibrosis: an immunohistochemical study. J Pathol 2002;196:22834.[CrossRef][ISI][Medline]
23 Watson KE, Parhami F, Shin V, Demer LL. Fibronectin and collagen I matrixes promote calcification of vascular cells in vitro, whereas collagen IV matrix is inhibitory. Arterioscler Thromb Vasc Biol 1998;18:196471.
24 Towler DA, Bidder M, Latifi T, Coleman T, Semenkovich CF. Diet-induced diabetes activates an osteogenic gene regulatory program in the aortas of low density lipoprotein receptor-deficient mice. J Biol Chem 1998;273:3042734.
25 Arad Y, Newstein D, Cadet F, Roth M, Guerci AD. Association of multiple risk factors and insulin resistance with increased prevalence of asymptomatic coronary artery disease by an electron-beam computed tomographic study. Arterioscler Thromb Vasc Biol 2001; 21:205158.
26 Detrano RC, Wong ND, Doherty TM et al. Coronary calcium does not accurately predict near-term future coronary events in high-risk adults. Circulation 1999;99:263338.
27 Keelan PC, Bielak LF, Ashai K et al. Long-term prognostic value of coronary calcification detected by electron-beam computed tomography in patients undergoing coronary angiography. Circulation 2001;104:41217.
28 Beckman JA, Ganz J, Creager MA, Ganz P, Kinlay S. Relationship of clinical presentation and calcification of culprit coronary artery stenoses. Arterioscler Thromb Vasc Biol 2001;21:161822.
29 Farb A, Burke AP, Tang AL et al. Coronary plaque erosion without rupture into a lipid core. A frequent cause of coronary thrombosis in sudden coronary death. Circulation 1996;93:135463.
30 Huang H, Virmani R, Younis H, Burke AP, Kamm RD, Lee RT. The impact of calcification on the biomechanical stability of atherosclerotic plaques. Circulation 2001;103:105156.
31 Honye J, Mahon DJ, Jain A et al. Morphological effects of coronary balloon angioplasty in vivo assessed by intravascular ultrasound imaging. Circulation 1992;85:101225.[Abstract]
32 Fitzgerald PJ, Ports TA, Yock PG. Contribution of localized calcium deposits to dissection after angioplasty. An observational study using intravascular ultrasound. Circulation 1992;86:6470.[Abstract]
33 Ellis SG, DeCesare NB, Pinkerton CA et al. Relation of stenosis morphology and clinical presentation to the procedural results of directional coronary atherectomy. Circulation 1991;84:64453.[Abstract]
34 Tohma M, Yamaguchi T. Risk factors for later restenosis after successful coronary angioplasty: Mitsui Memorial Hospital experience. J Cardiol 1991;21:4352.[Medline]
35 Maeta H, Hori M. Effects of a lack of aortic Windkessel properties on the left ventricle. Jpn Circ J 1985;49:23237.[ISI][Medline]
36 Watanabe H, Ohtsuka, S, Kakihana M, Sugishita Y. Coronary circulation in dogs with an experimental decrease in aortic compliance. J Am Coll Cardiol 1993;21:1497506.[ISI][Medline]
37 Ohtsuka S, Kakihana M, Watanabe H, Sugishita Y. Chronically decreased aortic distensibility causes deterioration of coronary perfusion during increased left ventricular contraction. J Am Coll Cardiol 1994;24:140614.[ISI][Medline]
38 Simonson E, Nakagawa K. Effect of age on pulse wave velocity and aortic ejection time in healthy men and in men with coronary artery disease. Circulation 1960;22:12629.[ISI][Medline]
39 Niederhoffer N, Borbryshev YV, Lartaud-Idjouadiene I, Giummelly P, Atkinson J. Aortic calcification produced by vitamin D3 plus nicotine. J Vasc Res 1997;34:38698.[ISI][Medline]
40 Dart AM, Lacombe F, Yeoh JK et al. Aortic distensibility in patients with isolated hypercholesterolaemia, coronary artery disease, or cardiac transplant. Lancet 1991;338:27073.[ISI][Medline]
41 Bouthier JD, De Luca N, Safar ME, Simon AC. Cardiac hypertrophy and arterial distensibility in essential hypertension. Am Heart J 1985;109:134552.[ISI][Medline]
42 Newman AB, Naydeck BL, Sutton-Tyrrell K, Feldman A, Edmundowicz D, Kuller LH. Coronary artery calcification in older adults to age 99: prevalence and risk factors. Circulation 2001; 104:267984.
43 Mitchell JR, Adams JH. Aortic size and aortic calcification: a necropsy study. Atherosclerosis 1977;27:43746.[ISI][Medline]
44 Baedenkopf WG, Daoud AS, Love BM. Calcification in the coronary arteries and its relationship to arteriosclerosis and myocardial infarction. Am J Roentgenol 1964;92:86571.
45 Iribarren C, Sidney S, Sternfeld B, Browner WS. Calcification of the aortic arch: Risk factors and association with coronary heart disease, stroke, and peripheral vascular disease. JAMA 2000;283:281015.
46 Stefanadis C, Wooley CF, Bush CA, Koibash AJ, Boudoulas H. Aortic distensibility abnormalities in coronary artery disease. Am J Cardiol 1987;49:1300304.[CrossRef]
47 Pohle K, Maffert R, Ropers D et al. Progression of aortic valve calcification: association with coronary atherosclerosis and cardiovascular risk factors. Circulation 2001;104:192732.
48 Feldman T, Glagov S, Carroll JD. Restenosis following successful balloon valvuloplasty: Bone formation in aortic valve leaflets. Cathet Cardiovasc Diagn 1993;29:17.[ISI][Medline]
49 OBrien KD, Kuusisto J, Reichenbach DD et al. Osteopontin is expressed in human aortic valvular lesions. Circulation 1995;92:216368.
50 Mohler ER 3rd, Gannon F, Reynolds C, Zimmerman R, Keane MG, Kaplan FS. Bone formation and inflammation in cardiac valves. Circulation 2001;103:152228.
51 Novaro GM, Tiong IY, Pearce GL, Lauer MS, Sprecher DL, Griffin BP. Effect of hydroxymethylglutaryl coenzyme a reductase inhibitors on the progression of calcific aortic stenosis. Circulation 2001; 104:220509.
52 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;342:147883.
53 Varghese K, Cherian G, Abraham UT, Hayat NJ, Johny KV. Predictors of coronary disease in patients with end stage renal disease. Ren Fail 2001;23:797806.[CrossRef][ISI][Medline]
54 Jono S, Nishizawa Y, Shioi A, Morii H. 1,25-dihydroxyvitamin D3 increases in vitro vascular calcification by modulating secretion of endogenous parathyroid hormone-related peptide. Circulation 1998;98:130206.
55 Nash G. Vitamin K in anticoagulation therapy. Lancet 2001;357:638.[CrossRef]
56 Canfield AE, Doherty MJ, Kelly V et al. Matrix GLA protein is differentially expressed during the deposition of a calcified matrix by vascular pericytes. FEBS Lett 2000;487:26771.[CrossRef][ISI][Medline]
57 Bostrom K, Tsao D, Shen S, Wang Y, Demer LL. Matrix GLA protein modulates differentiation induced by bone morphogenetic protein-2 in C3H10T1/2 cells. J Biol Chem 2001;276:1404452.
58 Zebboudj AF, Imura M, Bostrom K. Matrix GLA protein, a regulatory protein for bone morphogenetic protein-2. J Biol Chem 2002; 277:438894.
59 Goodman WG. Vascular calcification in chronic renal failure. Lancet 2001;358:111516.[CrossRef][ISI][Medline]
60 Kinoshita H, Tamaki T, Hashimoto T, Kasagi F. Factors influencing lumbar spine bone mineral density assessment by dual-energy X-ray absorptiometry: comparison with lumbar spinal radiogram. J Orthop Sci 1998;3:39.[CrossRef][Medline]
61 Sugihara N, Matsuzaki M. The influence of severe bone loss on mitral annular calcification in postmenopausal osteoporosis of elderly Japanese women. Jpn Circ J 1993;57:1426.[ISI][Medline]
62 Ouchi Y, Akishita M, de Souza AC, Nakamura T, Orimo H. Age-related loss of bone mass and aortic/aortic valve calcificationreevaluation of recommended dietary allowance of calcium in the elderly. Ann N Y Acad Sci 1993;676:297307.[ISI][Medline]
63 Banks LM, Lees B, MacSweeney JE, Stevenson JC. Effect of degenerative spinal and aortic calcification on bone density measurements in post-menopausal women: Links between osteoporosis and cardiovascular disease? Eur J Clin Invest 1994;12:81317.
64 Broulik PD, Kapitola J. Interrelations between body weight, cigarette smoking and spine mineral density in osteoporotic Czech women. Endocr Regul 1993;27:5760.[Medline]
65 Boukhris R, Becker KL. Calcification of the aorta and osteoporosis. JAMA 1972;219:130711.[CrossRef][Medline]
66 Dent CE, Engelbrecht HE, Godfrey RC. Osteoporosis of lumbar vertebrae and calcification of abdominal aorta in women living in Durban. BMJ 1968;4:7679.[ISI][Medline]
67 Aoyagi K, Ross PD, Orloff J, Davis JW, Katagiri H, Wasnich RD. Low bone density is not associated with aortic calcification. Calcif Tissue Int 2001;69:2024.[CrossRef][ISI][Medline]
68 Jie KG, Bots ML, Vermeer C, Witteman JC, Grobbee DE. Vitamin K status and bone mass in women with and without aortic atherosclerosis: a population-based study. Calcif Tissue Int 1996; 59:35256.[CrossRef][ISI][Medline]
69 Kiel DP, Kauppila LI, Cupples LA, Hannan MT, ODonnell CJ, Wilson PW. Bone loss and the progression of abdominal aortic calcification over a 25 year period: the Framingham Heart Study. Calcif Tissue Int 2001;68:27176.[ISI][Medline]
70 Hak AE, Pols HA, van Hemert AM, Hofman A, Witteman JC. Progression of aortic calcification is associated with metacarpal bone loss during menopause: a population-based longitudinal study. Arterioscler Thromb Vasc Biol 2000;28:192631.
71 Bucay N, Sarosi I, Dunstan CR et al. Osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev 1998;12:126068.
72 Kruger MC, Horrobin DF. Calcium metabolism, osteoporosis and essential fatty acids: A review. Prog Lipid Res 1997;36:133151.
73 Parhami F, Morrow AD, Balucan J et al. Lipid oxidation products have opposite effects on calcifying vascular cell and bone cell differentiation. A possible explanation for the paradox of arterial calcification in osteoporotic patients. Arterioscler Thromb Vasc Biol 1997;17:68087.
74 Pohle K, Maffert R, Ropers D et al. Progression of aortic valve calcification: Association with coronary atherosclerosis and cardiovascular risk factors Circulation 2001;104:192732.
75 OBrien KD, Reichenbach DD, Marcovina SM, Kuusisto J, Alpers CE, Otto CM. Apolipoproteins B, (a), and E accumulate in the morphologically early lesion of degenerative valvular aortic stenosis. Arterioscler Thromb Vasc Biol 1996;16:52332.
76 Tamashiro M, Iseki K, Sunagawa O et al. Significant association between the progression of coronary artery calcification and dyslipidemia in patients on chronic hemodialysis. Am J Kidney Dis 2001;38:6469.[ISI][Medline]
77 Callister TQ, Raggi P, Cooil B, Lippolis NJ, Russo DJ. Effect of HMG-CoA reductase inhibitors on coronary artery disease as assessed by electron-beam computed tomography. N Engl J Med 1998; 339:197278.
78 Parhami F, Jackson SM, Tintut Y et al. Atherogenic diet and minimally oxidized low density lipoprotein inhibit osteogenic and promote adipogenic differentiation of marrow stromal cells. J Bone Miner Res 1999;14:206778.[ISI][Medline]
79 Parhami F, Tintut Y, Beamer WG, Gharavi N, Goodman W, Demer LL. Atherogenic high-fat diet reduces bone mineralization in mice. J Bone Miner Res 2001;16:18288.[ISI][Medline]
80 Chole RA, Hughes RM, Faddis BT. Keratin particle-induced osteolysis: a mouse model of inflammatory bone remodeling related to cholesteatoma. J Assoc Res Otolaryngol 2001;2:6571.[Medline]
81 Poungvarin N, Leowattana W, Mahanonda N, Bhuripanyo K, Pokum S, Worawattananon P. Biochemical markers of bone turnover in angiographically-demonstrated coronary artery disease patients and health Thais. J Med Assoc Tha 2000;83:S1318.
82 Beckman JA, Ganz J, Creager MA, Ganz P, Kinlay S. Relationship of clinical presentation and calcification of culprit coronary artery stenoses. Arterioscler Thromb Vasc Biol 2001;21:161822.
83 Arad Y, Spadaro LA, Goodman K, Newstein D, Guerci AD. Prediction of coronary events with electron beam computed tomography. J Am Coll Cardiol 2000;36:125360.[CrossRef][ISI][Medline]