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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1999;19:1491-1498.)
© 1999 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

The Natural Course of Atherosclerosis

Part II: Vascular Remodeling

Stefan Kiechl; Johann Willeit; for the Bruneck Study Group

From the Department of Neurology, Innsbruck University Hospital, Innsbruck, Austria

Correspondence to Dr J. Willeit, Department of Neurology, Innsbruck University Hospital, Anichstr. 35, A-6020 Innsbruck, Austria.

	Abstract

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Abstract—Arterial remodelling is a potentially important component in atherogenesis aimed at delaying the development of significant lumen compromise. Current knowledge on this phenomenon is mainly restricted to experimental evaluations and a few postmortem studies. We used high-resolution duplex ultrasound to study 5-year changes (1990 to 1995) in vessel geometry in a large random sample of the general population (Bruneck Study). Carotid arteries free of atherosclerosis and wall thickening preserved a normal size to high ages. In contrast, common and internal carotid arteries with elevated intima-media thickness (50th percentile) experienced marked age-dependent dilation that started already in the 5th decade and continuously accelerated thereafter (structural ageing). Vessel diameters were subject to complex regulation involving morphometric characteristics, sex, wall thickness, hypertension, LDL cholesterol levels, and alcohol consumption. Vascular remodelling secondary to incident or slowly progressive (mural) atherosclerosis included local compensation and a generalised dilation response of vascular segments not primarily affected. Adaptive enlargement at the site of active atherogenesis effectively preserved a near-normal lumen in most instances. The current study identified a second main type of plaque growth, characterized by episodic marked increase in lesion volume probably on the basis of plaque thrombosis. In this setting, we did not observe maximum but insufficient compensation but instead usually observed no compensation at all. Failure of vascular remodelling and marked expansion in plaque size acted synergistically in producing significant lumen compromise. The current prospective survey describes fundamental principles and various facets of arterial remodelling and vascular biology in the general population (in vivo). Vessel geometry was subject to marked temporal changes and showed a correspondingly complex (multifactorial) and dynamic regulation. Vascular remodelling emerged as an important compensatory process in human atherogenesis, which crucially contributed to the determination of lumen obstruction. Efficacy and failure of compensation primarily depended on the type and pathomechanisms of underlying atherogenesis and only in second instance on plaque size and location.

Key Words: atherosclerosis • vascular remodelling • vascular biology

	Introduction

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Traditionally, atherosclerosis research has mainly focused on investigating risk factors for plaque development and thickening of the intima-media tunica. Considerably less is known about compensatory phenomena of the vasculature in atherosclerosis. Contributions from a few experimental studies stimulated the hypothesis that vessels dilate in response to atherogenesis, thereby restoring normal blood flow and delaying the onset of clinically important stenosis.^{1 2 3 4 5} Vasculature was recognized as a complex organ capable of sensing its environment (eg, shear stress), transducing signals to effector cells or surrounding tissue and responding to various stimuli by releasing local regulatory mediators such as growth factors and vasoactive peptides.^{3 5 6 7 8} Prospective ultrasound-based surveys may assist in verifying the relevance of these experimental findings in vivo. The Bruneck Study was designed to investigate the natural course of atherosclerosis and accompanying adaptive changes in vessel geometry in a large random sample of men and women 40 to 85 years old.^{9 10} For the purpose of focus the current report was limited to the following key issues: 1) natural ageing of vasculature, 2) determination of vessel size in vivo and, most importantly, 3) local and systemic arterial remodelling secondary to atherogenesis.

	Methods

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Population recruitment, ultrasound, and laboratory protocol have been detailed previously.^{9 10} In brief, a large age- and sex-stratified random population was enrolled in Bruneck and its suburbs (1990; Bolzano Province, Italy) and a first follow-up performed at a 5-year interval (1995). Participation in both assessments was more than 90% complete.

Scanning protocol and definition of ultrasound endpoints were detailed previously (see Part I). Progression of atherosclerosis was coded present when the relative increase in the maximum plaque diameter between 1990 and 1995 exceeded the double measurement error of the method (proximal internal carotid artery [ICA], 30%; common carotid artery ([CCA], 20%). Development of stenosis was assumed when the progression criterion was met and a narrowing of the lumen>40% was achieved in the follow-up examination (for details, see part I).

The interadventitial diameter was defined as the distance between near and far wall media-adventitia interface. Minimum and maximum intima-media thickness (IMT) was measured at the far wall of each segment of both carotid arteries (Part I) with the ultrasound beam directed through the axis of the vessel. It was defined as the distance between the lumen-intima interface and the leading edge of the media-adventitia interface. The lumen diameter was calculated as the interadventitial diameter minus twice the maximum far wall IMT.^{11 12} All diameters were measured during diastole, which avoids image blurring due to arterial wall motion in the systole and safeguards against spurious associations with blood pressure characteristics. Current analysis focused on the CCA and on the proximal ICA defined as the bulbous and the initial 10 mm of the vessel.⁹ The vessel diameter in the ICA was measured from the flow divider at a normal angle to the outer wall of the bulbous. We did so for a low measurement variability and the fact that the vast majority of plaques emerged just opposite the flow divider.

Alcohol consumption was assessed in grams per day and LDL cholesterol calculated with the Friedewald formula.^{13 14} Hypercholesterolemia was defined by a total cholesterol level>6.2 mmol/L or the use of lipid lowering drugs. Systolic and diastolic blood pressure were the means of 3 independent measurements each taken with a standard sphygmomanometer after at least 10 minutes of rest. Hypertension was defined by a blood pressure 160/95 or the current use of antihypertensive drugs.

Statistics
Differences in vessel geometry across decades and between sexes were estimated using ANOVA procedure (SPSS-X statistical software). Unless otherwise specified, means presented were adjusted for age, sex, body weight and height, LDL cholesterol, systolic blood pressure, and daily alcohol consumption (MANOVA, SPSS-X statistical software). Determinants of vessel diameters were identified by means of standard linear regression analysis (forward stepwise selection; probability value for entry and removal, 0.05 and 0.10). We present regression coefficients, which permit us to estimate expected changes in vessel diameters afforded by a 1-unit change of given variables, standardized regression coefficients and R² as measures of the relative weight of variables in the prediction model and of the overall explanatory capacity of the regression models. Because of correlations existing between independent variables, these calculations were supplemented using best subset linear regression analysis¹⁵ (BMDP statistical software). The 5 best-fitting models were selected according to Mallows' C_p.

	Results

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Assessment of interadventitial diameters was highly reproducible with relative measurement errors amounting to 6.0% (CCA) and 7.5% (ICA). Far wall IMT could be assessed with adequate precision in virtually all CCA segments (relative measurement error, 7.9%) and about two-thirds of ICA segments (n=471; error, 10.5%). Table 1 depicts main age- and sex-specific features of vessel geometry in the CCA and ICA. Because we did not observe side-specific differences in vessel and wall diameters, all data presented are weighted averages of values obtained for the right and left arteries. Characteristics of vessel geometry are given for the entire population sample (general healthy population) and separately for subjects free of carotid atherosclerosis. The latter data may serve as reference (normative) values. Marked individual changes in vessel diameters during follow-up are visualized in Figure 1.

View this table: [in this window] [in a new window]   Table 1. Characteristics of Vessel Geometry by Age and Sex (Bruneck Study Population)

View larger version (48K): [in this window] [in a new window]   Figure 1. Distribution of changes in CCA and ICA diameters during follow-up (1990 to 1995). Dark bars symbolize changes that exceeded twice the measurement error of the ultrasound method. The ICA was defined as the carotid bulb and initial 10 mm of the vessel.

Determinants of interadventitial and lumen diameters in the nonatherosclerotic CCA and ICA were assessed by means of linear regression analysis (Table 2). Results are in part different for the CCA and ICA, which are typical representatives of the elastic and muscular vasculature, respectively.¹⁶ When the variables hypertension and hypercholesterolemia were substituted for systolic blood pressure and LDL cholesterol, the composition of the linear regression equations was virtually unchanged. Regression coefficients of these variables were as follows: CCA (interadventitial diameter) 0.137 and –0.169, P<0.05 each; CCA (lumen diameter) 0.144 and –0.166, P<0.05 each. Ageing predicted (marked) dilation of the CCA and ICA beyond its well-known effects on IMT. Notably, structural ageing was confined to subjects with elevated wall thickness (>50th percentile) (Table 3). Regression models of 5-year changes in the interadventitial diameter on the variables given in Table 2 provided a prospective confirmation of the results obtained. Changes in the levels of these variables (1990 to 1995) predicted corresponding changes in vessel size: cessation and initiation of moderate-to-severe alcohol consumption (CCA interadventitial diameter, regression coefficients [95%CI], –0.330 [–0.653 to –0.007] and 0.417 [0.160 to 0.674]), medical lowering of LDL levels by statin therapy (0.226 [0.026 to 0.426]), and incident hypertension (0.214 [0.012 to 0.416]). Vice versa, subjects with wide stiff vessels faced a 2-fold risk of incident systolic hypertension (P<0.05).

View this table: [in this window] [in a new window]   Table 2. Stepwise Multiple Linear Regression Analysis of CCA and ICA Interadventitial and Lumen Diameters on Wall Thickness, Morphometric Characteristics, and Vascular Risk Factors

View this table: [in this window] [in a new window]   Table 3. Changes in Vessel Geometry With Advancing Age in Nonatherosclerotic Carotid Arteries With Low and High Intima-Media Thickness (Ageing of Undiseased Vasculature)

Next, we studied vascular remodelling in response to atherosclerosis progression and incidence. Table 4 depicts age, sex, and risk factor-adjusted changes in vessel diameters according to 5-year changes in vascular status. Local dilation response was most pronounced in incident nonstenotic and slowly progressive atherosclerosis and mainly determined by the extent of plaque growth (dose-response relation: CCA and ICA diameters, 0.464 mm [0.262 to 0.666] and 0.297 mm [0.121 to 0.473] per 1 mm increase in plaque diameter). Local enlargement of vessel segments with emerging or progressive atherosclerosis must be viewed in the light of usually increased baseline diameters (Table 4) and additive effects of structural ageing (see above). In most instances these processes in concert (vascular remodelling) effectively preserved a normal or near-normal lumen independently of plaque size and location (Figure 2). However, vascular remodelling obviously failed in response to focal rapid plaque growth (atherothrombosis) (Table 4).

View this table: [in this window] [in a new window]   Table 4. Compensatory Dilation of Common and Internal Carotid Arteries in Response to Atherosclerosis Progression (Local Vascular Remodelling)

View this table: [in this window] [in a new window]   Table 4B. Continued

View larger version (45K): [in this window] [in a new window]   Figure 2. Mean interadventitial and lumen diameters according to plaque size in nonstenotic atherogenesis (local vascular remodeling).

Table 5 documented significant expansion of all segments of the carotid vasculature in response to localized active atherosclerosis, which was at least in part independent of increased wall thickness and over-representation of risk factors.

View this table: [in this window] [in a new window]   Table 5. Dilation of Undiseased Common and Internal Carotid Artery Segments in Response to Active Atherogenesis in Other Segments (Systemic Vascular Remodelling)

	Discussion

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
Determination of Vessel Geometry
Accumulating experimental data suggest a central (active) role of the vasculature in the control of blood flow.^{5 6 7 8} Short-term and sustained changes in vascular tone (vessel size) and long-term structural adaptation (growth stimulation^{17 18} ) are well-known regulatory phenomena in the maintenance of vascular homeostasis.^{4 5 6 7 8 19} This concept implies that vessel geometry may not be consistent over a long time span but, on the contrary, subject to continuous adaptive changes. In our cohort, vessel diameters of individuals indeed emerged as highly variable (Figure 1). Regulation and determination of vessel size were correspondingly complex.

Wall Thickness
Enlargement of vessels in response to wall thickening is experimentally well founded.^{2 4 5 20} The current study documented dilation of carotid arteries secondary to wall thickening in vivo (Table 2). In the CCA, enlargement was over-compensatory, whereas in the ICA, compensation did not keep pace with wall growth. The few previous epidemiologic surveys in this field agreed in that dilation of the vasculature compensates for wall thickening but disagreed on the efficacy of this process (over- versus under-compensation).^{1 11 21}

Hypertension
It has been proposed that elevated blood pressure causes dilation of exposed arteries.^{11 21 22 23 24} Vice versa, stiffness of wide arteries may facilitate manifestation and maintenance of systolic hypertension.²⁵ Our study yielded epidemiological support to both components of this bidirectional association.

Risk Factors
Alcohol consumption and levels of LDL cholesterol significantly predicted interadventitial and lumen diameters of the CCA beyond their effects on the IMT. Both associations were similar in strength but opposite in direction. These findings are in close agreement with the results of a recent comparable population survey.¹¹ Notably, enlargement of vessels evoked by regular alcohol intake appeared to normalize after cessation, as did the narrowing associated with high LDL cholesterol after successful medical intervention. Thus, the above associations may reflect inference of risk factors with vascular tone^{5 26 27 28} rather than structural alterations.

Gender and Morphometric Characteristics
Male gender, body height, and weight were strong positive predictors of ICA and CCA diameters. Such morphometric relationships have been reported previously and appear intuitively correct.^{11 12 21}

Age
Whether or not normal human vasculature experiences structural ageing and dilation due to loss of elasticity is a matter of dispute.^{1 11 12 21 23 29} For example, it was proposed that the obvious correlation between arterial size and age primarily reflects an advance of atherosclerosis.¹ To clarify this controversial issue, age trends in arterial size were assessed in subjects who remained free of carotid atherosclerosis during follow-up. In a subgroup without focal or diffuse wall thickening (IMT50th percentile), vessel and lumen diameters remained unchanged to high ages (Table 3). Once IMT exceeded the median of 0.75 mm (CCA) or 0.9 mm (ICA), however, vessels usually showed dilation with advancing age. Such process already started in the 5th decade and accelerated thereafter. Age-dependent dilation of the vasculature emerged as independent of elevated wall thickness and other determinants of vessel size and may thus reflect direct effects of ageing in terms of attrition or loss of elastic fibers. In all, structural ageing was not an obligatory phenomenon in our population but usually occurred once enhanced IMT indicated incipient wall pathology. Manifestation of definite atherosclerosis was not at all a precondition for the ageing process to emerge.

Vascular Remodelling in Atherogenesis
In animal-experimental research, various types of arteries have been shown to enlarge in response to diet-induced atherogenesis with a normal lumen preserved early in the course of disease.^{2 4} Relevancy of such a process in the human vasculature was first proposed by Glagov et al¹ and Zarins et al³⁰ based on post-mortem evaluations. In the late 1980s, advances in high-resolution duplex ultrasound provided a basis for a noninvasive and in vivo investigation of this phenomenon. On applying this technique, Steinke et al³¹ revealed a strong relation between plaque growth and consecutive dilation of carotid arteries in a small patient-based study (follow-up, 70 segment-years).

In our large ultrasound-based survey, atherogenesis was found to be a heterogeneous disease and, in analogy, arterial remodelling was not a uniform response to lesion progression. When first focusing on incident atherosclerosis and the progression of nonstenotic plaques (mural atherosclerosis), adaptive enlargement of affected vessel segments was a consistent phenomenon (Table 4 and Figure 2). In the CCA vascular remodelling effectively preserved a normal lumen even in advanced stages of disease when plaques even grew to 3 to 4 mm (Figure 2). In the ICA, the lumen diameter slightly decreased with extending plaque size (Figure 2). As plaques were mostly eccentric in this location, ie, did not occupy the whole circumference, compromise of the lumen area may not occur to the same extent as for the diameter. In this context, it is worth mentioning that the peak systolic flow velocity, which is an indirect measure of lumen compromise, did not increase with plaque size. Dilation of vessels in response to early atherogenesis has been postulated in previous cross-sectional studies, with the efficacy of such process varying in relation to given age ranges and types of arteries.^{1 12 30 31}

Our study identified one further common type of atherogenesis characterized by occasional marked increases in lesion size followed by long stable periods. This type of lesion extension primarily occurred at sites exposed to hemodynamic stress, depended on procoagulant risk factors, and probably resembles plaque thrombosis (see Part I). In segments with this type of plaque growth, we did not observe maximal though overcharged compensation but, on the contrary, no or only marginal enlargement of the vessel (Table 4). In view of the fact that we are probably speaking of plaque thrombosis, this finding may possibly reflect a preserved integrity of the vessel wall. Failure of vascular remodelling and usually marked expansions in plaque size act synergistically in producing significant lumen compromise. Actually, some 95% of incident stenosis>40% in our study originated from this synergism. Preferential manifestation of stenosis in the ICA is explained by the commonplace occurrence of rapid plaque growth at this site and only in second instance by peculiarities of vascular remodelling in the ICA.

Systemic Vascular Remodelling
Apart from focal changes in vessel geometry at the site of progressive atherosclerosis, the whole carotid vasculature, ie, also unaffected segments, responded to active atherosclerosis in terms of vasodilation. This as yet unrecognised component of arterial remodelling involved segments of the carotid arteries ipsi- and contralateral to the site of plaque growth to a similar extent, emerged as independent of wall thickening and other potential confounders (Table 5) and appeared to be reversible when atherosclerosis entered an inactive stage. These findings tempt us to speculate that para/endocrine mediators with relaxing properties are continuously released from active atherosclerotic tissue or surrounding endothelium. The biological significance of this finding awaits clarification in future research.

Methodological Issues and Limitations
1) The lumen diameter was assessed as a surrogate for the clinically important lumen area. We did so for reasons of practicability and marked inaccuracies in tracing lumen areas in the ICA. Implications for data interpretation are given in the text whenever relevant. 2) As in previous comparable studies, IMT and lumen of the ICA could not be obtained in all subjects due to poor visualization of relevant interfaces or lack of nondiseased segments.^{12 32} As visualization tends to decrease with increasing severity of atherosclerosis, the group with complete data assessment may not be random. This potential source of bias was addressed in supplementary analyses, in which missing data were replaced with an estimate calculated with linear regression equations. On doing so, we obtained results almost identical to those in the original analysis. Nevertheless, residual confounding cannot be ruled out and deserves attention when interpreting data on lumen diameters in the ICA.

Conclusions
So far, advances in the field of vascular biology have mainly depended on contributions from experimental studies. Our study is among the first to provide detailed insight into the fundamental principles and various facets of arterial remodelling from an epidemiological perspective. The role of carotid vasculature in atherogenesis is not simply a passive housing of atherosclerotic lesions. On the contrary, atherosclerosis progression and arterial remodelling are equivalent components in the atherogenesis process that crucially interact in determining vessel obstruction.

	Appendix 1

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The Bruneck Study Group
Martin Oberhollenzer, Stefan Brandt, Paula Eder, Klaus Oberlechner, Harald Steiner, Arno Gasperi: Department of Internal Medicine, Bruneck Hospital, Italy; Agnes Mair, Peter Santer: Department of Laboratory Medicine, Bruneck Hospital, Italy; Gregor Rungger, Franz Spögler: Department of Neurology, Innsbruck University Hospital, Austria; Elmar Jarosch, Maria Schober: Department of Laboratory Medicine, Innsbruck University Hospital, Austria; Christian Wiedermann: Department of Internal Medicine, Innsbruck University Hospital, Austria; Enzo Bonora, Michele Muggeo: Department of Endocrinology and Metabolism, Verona University Hospital, Italy.

Received June 12, 1998; accepted November 30, 1998.

	References

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1. Glagov S, Weisenberg E, Zarins CK, Stankunavicius R, Kolettis GJ. Compensatory enlargement of human atherosclerotic coronary arteries. N Engl J Med. 1987;316:1371–1375.[Abstract]
2. Armstrong ML, Heistad DD, Marcus ML, Megan MB, Piegors DJ. Structural and hemodynamic responses of peripheral arteries of macaque monkeys to atherogenic diet. Arteriosclerosis. 1985;5:336–346.[Abstract/Free Full Text]
3. Zarins CK, Zatina MA, Giddens DP, Ku DN, Glagov S. Shear stress regulation of artery lumen diameter in experimental atherogenesis. J Vasc Surg. 1987;5:413–420.[Medline] [Order article via Infotrieve]
4. Clarkson TB, Prichard RW, Morgan TM, Petrick GS, Klein KP. Remodeling of coronary arteries in human and nonhuman primates. JAMA. 1994;271:289–294.[Abstract]
5. Dzau VJ, Gibbons GH, Cooke JP, Omoigui N. Vascular biology and medicine in the 1990s: scope, concepts, potentials, and perspectives. Circulation. 1993;87:705–719.[Free Full Text]
6. Cooke JP, Stamler J, Andon N, Davies PF, McKinley G, Loscalzo J. Flow stimulates endothelial cells to release a nitrovasodilator that is potentiated by reduced thiol. Am J Physiol. 1990;259:H804–H812.[Abstract/Free Full Text]
7. Pohl V, Holtz J, Busse R, Bassenge E. Crucial role of the endothelium in the vasodilator response to increased flow in vivo. Hypertension. 1986;8:37–44.[Abstract/Free Full Text]
8. Frangos JA, Eskin SG, McIntire LV, Ives CL. Flow effects on prostacyclin production by cultured human endothelial cells. Science. 1985;227:1477–1479.[Abstract/Free Full Text]
9. Willeit J, Kiechl S. Prevalence and risk factors of asymptomatic extracranial carotid artery atherosclerosis: a population-based study. Arterioscler Thromb. 1993;13:661–668.[Abstract/Free Full Text]
10. Kiechl S, Willeit J, Egger G, Poewe W, Oberhollenzer F. Body iron stores and the risk of carotid atherosclerosis: prospective results from the Bruneck study. Circulation. 1997;96:3300–3307.[Abstract/Free Full Text]
11. Bonithon-Kopp C, Touboul PJ, Berr C, Magne C, Ducimetière P. Factors of carotid arterial enlargement in a population aged 59 to 71 years: the EVA Study. Stroke. 1996;27:654–660.[Abstract/Free Full Text]
12. Crouse JR, Goldbourt U, Evans G, Pinsky J, Sharrett AR, Sorlie P, Riley W, Heiss G, for the ARIC investigators. Arterial enlargement in the Atherosclerosis Risk in Communities (ARIC) cohort. Stroke. 1994;25:1354–1359.[Abstract]
13. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low density lipoprotein cholesterol in plasma, without use of preparative ultracentrifuge. Clin Chem. 1972;18:499–502.[Abstract]
14. Kiechl S, Willeit J, Rungger G, Egger G, Oberhollenzer F, Bonora E, for the Bruneck Study Group. Alcohol consumption and atherosclerosis: what is the relation? Prospective results from the Bruneck Study. Stroke. 1998;29:900–907.[Abstract/Free Full Text]
15. Neter J, Wasserman W, Kutner MH. Applied Linear Regression Models. Homewood, Ill: RD Irwin; 1989.
16. Heath D, Smith P, Harris P, Winson M. The atherosclerotic human carotid sinus. J Pathol. 1973;110:49–58.[Medline] [Order article via Infotrieve]
17. Hsieh HJ, Li NQ, Frangos JA. Shear stress increases endothelial platelet-derived growth factor mRNA levels. Am J Physiol. 1991;260:H642–H646.[Abstract/Free Full Text]
18. Ohno M, Cooke JP, Dzau VJ, Gibbons GH. Fluid shear stress induces endothelial transforming growth factor beta-1 transcription and production: modulation by potassium channel blockade. J Clin Invest. 1995;95:1363–1369.
19. Furchgott RF. Role of endothelium in responses of vascular smooth muscle. Circ Res. 1983;53:557–573.[Free Full Text]
20. Glagov S, Zarins CK, Giddens DP, Ku DN. Hemodynamics and atherosclerosis: insights and perspectives gained from studies of human arteries. Arch Pathol Lab Med. 1988;112:1018–1031.[Medline] [Order article via Infotrieve]
21. Polak JF, Kronmal RA, Tell GS, O'Leary DH, Savage PJ, Gardin JM, Rutan GH, Borhani NO, on behalf of the Cardiovascular Health Study: Compensatory increase in common carotid artery diameter: relation to blood pressure and artery intima-media thickness in older adults. Stroke. 1996;27:2012–2015.[Abstract/Free Full Text]
22. Roman MJ, Saba PS, Pini R, Spitzer M, Pickering TG, Rosen S, Alderman MH, Devereux RB. Parallel cardiac and vascular adaptation in hypertension. Circulation. 1992;86:1909–1918.[Abstract/Free Full Text]
23. Benetos A, Laurent S, Boutouyrie PH, Safar ME. Arterial alterations with aging and high blood pressure: a noninvasive study of carotid and femoral arteries. Arterioscler Thromb. 1993;13:90–97.[Abstract/Free Full Text]
24. Isnard RN, Pannier BM, Laurent S, London GM, Diebold B, Safar ME. Pulsatile diameter and elastic modulus of the aortic arch in essential hypertension: a noninvasive study. J Am Coll Cardiol. 1989;13:399–405.[Abstract]
25. Merillon JP, Motte G, Masquet C, Azancot I, Guiomard A, Gourgon R. Relationship between physical properties of the arterial system and left ventricular performance in the course of aging and arterial hypertension. Eur Heart J. 1982;3:95A–102A.
26. Mikhailidis DP, Jeremy JY, Barradas MA, Green N, Dandona P. Effect of ethanol on vascular prostacyclin (prostaglandin I₂) synthesis, platelet aggregation, and platelet thromboxane release. BMJ. 1983;287:1495–1498.
27. Cooke JP, Andon NA, Girerd XJ, Hirsch AT, Creager MA. Arginine normalizes cholinergic relaxation of hypercholesterolemic rabbit thoracic aorta. Circulation. 1991;83:1057–1062.[Abstract/Free Full Text]
28. Vallance P, Collier J, Moncada S. Effects of endothelium-derived nitric oxide on peripheral arteriolar tone in man. Lancet. 1989;2:997–1000.[Medline] [Order article via Infotrieve]
29. Ben-Ishay Z, Abramowitz A, Ungar H. Atherosclerosis and aging of the aorta in the adult Jewish population of Israel: an anatomic study. Am J Cardiol. 1962;10:407–415.[Medline] [Order article via Infotrieve]
30. Zarins CK, Weisenberg E, Kolettis GJ, Stankunavicius R, Glagov S. Differential enlargement of artery segments in response to enlarging atherosclerotic plaques. J Vasc Surg. 1988;7:386–394.[Medline] [Order article via Infotrieve]
31. Steinke W, Els T, Hennerici M. Compensatory carotid artery dilatation in early atherosclerosis. Circulation. 1994;89:2578–2581.[Abstract/Free Full Text]
32. Crouse JR III, Thompson CJ. An evaluation of methods for imaging and quantifying coronary and carotid lumen stenosis and atherosclerosis. Circulation. 1993;878:II-17–II-33

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				M. L. Bots, D. E. Grobbee, A. Hofman, and J. C.M. Witteman Common Carotid Intima-Media Thickness and Risk of Acute Myocardial Infarction: The Role of Lumen Diameter Stroke, April 1, 2005; 36(4): 762 - 767. [Abstract] [Full Text] [PDF]

				M. Furtner, S. Kiechl, A. Mair, K. Seppi, S. Weger, F. Oberhollenzer, W. Poewe, and J. Willeit Urinary albumin excretion is independently associated with carotid and femoral artery atherosclerosis in the general population Eur. Heart J., February 1, 2005; 26(3): 279 - 287. [Abstract] [Full Text] [PDF]

				R. P. Wildman, V. Mehta, T. Thompson, S. Brockwell, and K. Sutton-Tyrrell Obesity Is Associated With Larger Arterial Diameters in Caucasian and African-American Young Adults Diabetes Care, December 1, 2004; 27(12): 2997 - 2999. [Full Text] [PDF]

				M.L. Eigenbrodt, Z. Bursac, E.P. Eigenbrodt, D.J. Couper, R.E. Tracy, and J.L. Mehta Mathematical estimation of the potential effect of vascular remodelling/dilatation on B-mode ultrasound intima-medial thickness QJM, November 1, 2004; 97(11): 729 - 737. [Abstract] [Full Text] [PDF]

				G. Pasterkamp, Z. S. Galis, and D. P.V. de Kleijn Expansive Arterial Remodeling: Location, Location, Location Arterioscler. Thromb. Vasc. Biol., April 1, 2004; 24(4): 650 - 657. [Abstract] [Full Text] [PDF]

				M. Ogami, Y. Ikura, M. Ohsawa, T. Matsuo, S. Kayo, N. Yoshimi, E. Hai, N. Shirai, S. Ehara, R. Komatsu, et al. Telomere Shortening in Human Coronary Artery Diseases Arterioscler. Thromb. Vasc. Biol., March 1, 2004; 24(3): 546 - 550. [Abstract] [Full Text]

				R. M.A. Henry, P. J. Kostense, J. M. Dekker, G. Nijpels, R. J. Heine, O. Kamp, L. M. Bouter, and C. D.A. Stehouwer Carotid Arterial Remodeling: A Maladaptive Phenomenon in Type 2 Diabetes but Not in Impaired Glucose Metabolism: The Hoorn Study Stroke, March 1, 2004; 35(3): 671 - 676. [Abstract] [Full Text] [PDF]

				M. L. Bots, G. W. Evans, W. A. Riley, and D. E. Grobbee Carotid Intima-Media Thickness Measurements in Intervention Studies: Design Options, Progression Rates, and Sample Size Considerations: A Point of View Stroke, December 1, 2003; 34(12): 2985 - 2994. [Abstract] [Full Text] [PDF]

				C. Foerch, A. Buehler, S. von Kegler, and M. Sitzer Intima-Media Thickness Side Differences Are Limited to the Common Carotid Artery Hypertension, December 1, 2003; 42 (6): e17 - e17. [Full Text] [PDF]

				G. Chironi, J. Gariepy, N. Denarie, M. Balice, J.-L. Megnien, J. Levenson, and A. Simon Influence of Hypertension on Early Carotid Artery Remodeling Arterioscler. Thromb. Vasc. Biol., August 1, 2003; 23(8): 1460 - 1464. [Abstract] [Full Text] [PDF]

				E. F. Steinmetz, C. Buckley, and R. W. Thompson Prospects for the Medical Management of Abdominal Aortic Aneurysms Vascular and Endovascular Surgery, May 1, 2003; 37(3): 151 - 163. [Abstract] [PDF]

				E. Bonora, S. Kiechl, J. Willeit, F. Oberhollenzer, G. Egger, R. C. Bonadonna, and M. Muggeo Carotid Atherosclerosis and Coronary Heart Disease in the Metabolic Syndrome: Prospective data from the Bruneck Study Diabetes Care, April 1, 2003; 26(4): 1251 - 1257. [Abstract] [Full Text] [PDF]

				J. G. Terry, R. Tang, M. A. Espeland, D. H. Davis, J. L.C. Vieira, M. F. Mercuri, and J. R. Crouse III Carotid Arterial Structure in Patients With Documented Coronary Artery Disease and Disease-Free Control Subjects Circulation, March 4, 2003; 107(8): 1146 - 1151. [Abstract] [Full Text] [PDF]

				M. Mayr, S. Kiechl, M. A. Mendall, J. Willeit, G. Wick, and Q. Xu Increased Risk of Atherosclerosis Is Confined to CagA-Positive Helicobacter pylori Strains: Prospective Results From the Bruneck Study Stroke, March 1, 2003; 34(3): 610 - 615. [Abstract] [Full Text] [PDF]

				J. Willeit, S. Kiechl, T. Weimer, A. Mair, P. Santer, C. J. Wiedermann, and J. Roemisch Marburg I Polymorphism of Factor VII-Activating Protease: A Prominent Risk Predictor of Carotid Stenosis Circulation, February 11, 2003; 107(5): 667 - 670. [Abstract] [Full Text] [PDF]