Published online before print September 4, 2003, doi: 10.1161/01.STR.0000091394.42752.D5
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Stroke. 2003;34:2372.)
© 2003 American Heart Association, Inc.
Original Contributions |
Editorial Comment—Vascular Thickness and Calcification as Markers of Atherosclerotic Burden
Department of Neurology
Division of Internal Medicine and Cardiovascular Diseases and Department of Radiology, Mayo Clinic, Jacksonville, Florida
The study by Hollander et al1 provides an uncommon opportunity to directly compare the predictive value of various noninvasive tests of atherosclerotic burden for stroke in community dwellers. The study included a cohort of 
7000 stroke-free subjects. Slightly more than half of the subjects had a complete set of measures of carotid plaque, carotid intima-media thickness (IMT), ankle-arm index, and aortic calcification. Study participants were followed up for a mean of 6.1 years. On the basis of point estimates, measures of carotid IMT and aortic calcifications were stronger determinants of stroke than measures of carotid plaque and ankle-arm index. Carotid IMT, the most potent risk factor assessed in the study, imparted a relative risk of stroke of 2.23 for values in the highest tertile. Ankle-arm index, the least potent risk factor, imparted a relative risk of stroke of 1.55 for values in the lowest tertile.
Investigators also found that carotid IMT and aortic calcifications were independent risk factors. Statistical independence suggests that different pathophysiological processes may cause IMT and vascular calcifications and that these markers are not simply measures of atherosclerotic burden induced by so-called classic risk factors. B-mode ultrasonographic measurement of IMT of the extracranial carotid arteries assesses at least 2 responses of the blood vessel wall to cardiovascular risk factors. Intimal thickening resulting from cellular accumulation and matrix deposition can be seen in normal aging of the vascular system, even in the absence of atherosclerotic plaque.2 Medial thickening caused by smooth muscle cell hypertrophy is closely related to arterial hypertension,3 but the precise stimulus is not known.4
Vascular calcification in the form of hydroxyapatite begins early in the atherosclerotic process with microscopic amounts at the preatheroma stage (type III plaque) according to the histological classification system of Stary et al.5,6 Such calcium deposits commonly occur in the basal aspect of the intima. Bone morphogenetic proteins and noncollagenous matrix proteins associated with bone mineralization are present in atherosclerotic plaques.7,8 Extracellular matrix vesicles and injured smooth muscle cell organelles may become nidi for calcium precipitation.9,10 Moreover, plaque mineralization is related to extracellular calcium and phosphate concentrations11 and may be directly or indirectly induced by oxidized or otherwise modified lipids.12,13
There is substantial interindividual variability in the extent of atherosclerosis at every level of exposure to risk factors.14 Recent studies suggest a genetic basis for developing IMT and vascular calcification. To determine the extent of the familial aggregation of carotid IMT in the presence of type 2 diabetes, Lange et al15 studied 252 individuals with type 2 diabetes from 122 families. The age-, sex-, and race-adjusted heritability estimate for carotid IMT was 32%. After further adjustment for total cholesterol, hypertension, and current smoking status, the heritability estimate rose to 41%. Peyser et al16 quantified the relative contributions of measured risk factors and genetic influences on coronary artery calcification (CAC) measured by electron beam CT in 698 asymptomatic adults from 302 families. Before adjustment for any risk factors, 43.5% of the variation in CAC quantity was attributable to genetic factors. After adjustment for CAC risk factors (age, sex, fasting glucose level, systolic blood pressure, pack-years of smoking, and low-density lipoprotein cholesterol), 41.8% of the residual variation in CAC quantity was attributable to genetic factors. Clearly, the search for genetic factors that influence the susceptibility to cardiovascular risk factors must continue.
Carotid IMT and vascular calcifications are modifiable. Controlled studies show that cholesterol-lowering medications can favorably change both carotid IMT and vascular calcifications. In the Cholesterol Lowering Atherosclerosis Study (CLAS), taking colestipol and niacin caused significant progressive reduction in carotid IMT at 2 and 4 years, whereas placebo-treated patients showed significant increases over the same period.17 The Asymptomatic Carotid Artery Progression Study (ACAPS) showed that, for patients not taking warfarin, the mean maximum carotid IMT progression curves ran parallel for lovastatin (20 to 40 mg/d) and placebo groups for 6 to 12 months.18 Thereafter, the curves significantly diverge, and the lovastatin group showed IMT regression (annualized progression rates, -0.009 versus 0.006 mm/year). The Monitored Atherosclerosis Regression Study (MARS) of 188 patients with angiographically defined coronary atherosclerosis confirmed that lovastatin (80 mg/d) can favorably affect carotid IMT.19
The effects of cholesterol-lowering drugs on vascular calcification has been less studied. However, a prospective study of patients with low-density lipoprotein cholesterol levels >130 mg/dL showed that the median annualized absolute increase in coronary calcification volume measured by electron beam tomography significantly fell from 25 mm3 while untreated to 11 mm3 when treated with cerivastatin.20 Whether testing for IMT and vascular calcification will become components of routine clinical care depends on whether the results of such testing will have direct therapeutic consequences. At present, there are no pharmacotherapies specifically for vascular wall thickening or calcification beyond what is currently being prescribed for treating classic risk factors like hyperlipidemia and hypertension.
 |
References |
|---|
 Top References |
|---|
- Hollander M, Hak AE, Koudstaal PJ, Bots ML, Grobbee DE, Hofman A, Witteman JCM, Breteler MMB. Comparison between measures of atherosclerosis and risk of stroke: the Rotterdam Study. Stroke. 2003; 34: 2367–2373.
[Abstract/Free Full Text] - Virmani R, Avolio AP, Mergner WJ, Robinowitz M, Herderick EE, Cornhill JF, Guo SY, Liu TH, Ou DY, O’Rourke M. Effect of aging on aortic morphology in populations with high and low prevalence of hypertension and atherosclerosis: comparison between occidental and Chinese communities. Am J Pathol. 1991; 139: 1119–1129.[Abstract]
- Owens GK, Schwartz SM. Alterations in vascular smooth muscle mass in the spontaneously hypertensive rat: role of cellular hypertrophy, hyperploidy, and hyperplasia. Circ Res. 1982; 51: 280–289.
[Abstract/Free Full Text] - Dobrin PB. Mechanical factors associated with the development of intimal and medial thickening in vein grafts subjected to arterial pressure: a model of arteries exposed to hypertension. Hypertension. 1995; 26: 38–43.
[Abstract/Free Full Text] - Stary HC, Chandler AB, Glagov S, Guyton JR, Insull W Jr, Rosenfeld ME, Schaffer SA, Schwartz CJ, Wagner WD, Wissler RW. A definition of initial, fatty streak, and intermediate lesions of atherosclerosis: a report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Circulation. 1994; 89: 2462–2478.
[Abstract/Free Full Text] - Stary HC, Chandler AB, Dinsmore RE, Fuster V, Glagov S, Insull W Jr, Rosenfeld ME, Schwartz CJ, Wagner WD, Wissler RW. A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis: a report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Circulation. 1995; 92: 1355–1374.
[Abstract/Free Full Text] - 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: 1800–1809.[Medline] [Order article via Infotrieve]
- Fitzpatrick LA, Severson A, Edwards WD, Ingram RT. Diffuse calcification in human coronary arteries: association of osteopontin with atherosclerosis. J Clin Invest. 1994; 94: 1597–1604.[Medline] [Order article via Infotrieve]
- Kim KM. Calcification of matrix vesicles in human aortic valve and aortic media. Fed Proc. 1976; 35: 156–162.[Medline] [Order article via Infotrieve]
- Farber JL. The role of calcium in lethal cell injury. Chem Res Toxicol. 1990; 3: 503–508.[CrossRef][Medline] [Order article via Infotrieve]
- Proudfoot D, Shanahan CM. Biology of calcification in vascular cells: intima versus media. Herz. 2001; 26: 245–251.[CrossRef][Medline] [Order article via Infotrieve]
- Sarig S, Weiss TA, Katz I, Kahana F, Azoury R, Okon E, Kruth HS. Detection of cholesterol associated with calcium mineral using confocal fluorescence microscopy. Lab Invest. 1994; 71: 782–787.[Medline] [Order article via Infotrieve]
- Proudfoot D, Davies JD, Skepper JN, Weissberg PL, Shanahan CM. Acetylated low-density lipoprotein stimulates human vascular smooth muscle cell calcification by promoting osteoblastic differentiation and inhibiting phagocytosis. Circulation. 2002; 106: 3044–3050.
[Abstract/Free Full Text] - Greenland P, Abrams J, Aurigemma GP, Bond MG, Clark LT, Criqui MH, Crouse JR3rd, Friedman L, Fuster V, Herrington DM, et al. Prevention Conference V: beyond secondary prevention: identifying the high-risk patient for primary prevention: noninvasive tests of atherosclerotic burden: Writing Group III. Circulation. 2000; 101: E16–E22.[Medline] [Order article via Infotrieve]
- Lange LA, Bowden DW, Langefeld CD, Wagenknecht LE, Carr JJ, Rich SS, Riley WA, Freedman BI. Heritability of carotid artery intima-medial thickness in type 2 diabetes. Stroke. 2002; 33: 1876–1881.
[Abstract/Free Full Text] - Peyser PA, Bielak LF, Chu JS, Turner ST, Ellsworth DL, Boerwinkle E, Sheedy PF2nd. Heritability of coronary artery calcium quantity measured by electron beam computed tomography in asymptomatic adults. Circulation. 2002; 106: 304–308.
[Abstract/Free Full Text] - Blankenhorn DH, Selzer RH, Crawford DW, Barth JD, Liu CR, Liu CH, Mack WJ, Alaupovic P. Beneficial effects of colestipol-niacin therapy on the common carotid artery: two- and four-year reduction of intima-media thickness measured by ultrasound. Circulation. 1993; 88: 20–28.
[Abstract/Free Full Text] - Furberg CD, Adams HP Jr, Applegate WB, Byington RP, Espeland MA, Hartwell T, Hunninghake DB, Lefkowitz DS, Probstfield J, Riley WA, et al. Effect of lovastatin on early carotid atherosclerosis and cardiovascular events: Asymptomatic Carotid Artery Progression Study (ACAPS) Research Group. Circulation. 1994; 90: 1679–1687.
[Abstract/Free Full Text] - Hodis HN, Mack WJ, LaBree L, Selzer RH, Liu C, Alaupovic P, Kwong-Fu H, Azen SP. Reduction in carotid arterial wall thickness using lovastatin and dietary therapy: a randomized controlled clinical trial. Ann Intern Med. 1996; 124: 548–556.
[Abstract/Free Full Text] - Achenbach S, Ropers D, Pohle K, Leber A, Thilo C, Knez A, Menendez T, Maeffert R, Kusus M, Regenfus M, et al. Influence of lipid-lowering therapy on the progression of coronary artery calcification: a prospective evaluation. Circulation. 2002; 106: 1077–1082.
[Abstract/Free Full Text]
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||