Abstract
Various methods have been used to quantify atherosclerosis, beginning in the mid-1980s with ultrasound measurement of carotid intima–media thickness (IMT), and going on to coronary calcification assessed by electron-beam CT, measurement of carotid plaque by ultrasound, and measurement of carotid wall thickness by MRI. In recent years, it has become clear that carotid IMT, coronary calcification and carotid plaque reflect biologically and genetically different aspects of the atherosclerotic process, and will respond differentially to therapy. IMT represents mainly hypertensive medial hypertrophy; this measure is more predictive of stroke than of myocardial infarction, and is only weakly associated with traditional coronary risk factors. Carotid plaque area, on the other hand, is more strongly associated with traditional risk factors, and is more predictive of myocardial infarction than of stroke. A quantitative trait, called 'unexplained atherosclerosis', expresses the extent to which an individual has excess carotid plaque not explained by traditional risk factors, or the extent to which an individual is protected from traditional risk factors. Unexplained progression of plaque is an even more powerful tool for genetic research, because age, which accounts for the greatest proportion of baseline plaque, has much less influence on the rate of progression. Compared with IMT, measurement of carotid plaque volume by three-dimensional ultrasound reduces by two orders of magnitude the sample size and duration of treatment needed to evaluate new therapies. Measurement of carotid plaque is, therefore, an important tool for patient management, genetic research and evaluation of new therapies for stroke prevention.
Key Points
-
The burden of atherosclerosis can be measured as total carotid plaque area using two-dimensional ultrasound; this quantity is a strong predictor of cardiovascular outcomes
-
Patients in the top quartile of carotid plaque have 3.4 times the risk of stroke, death or myocardial infarction over 5 years compared with patients in the lowest quartile, after adjustment for age, sex, cholesterol, systolic blood pressure, smoking, diabetes, homocysteine, and treatment of lipids and blood pressure
-
Patients with plaque progression despite treatment of traditional risk factors have twice the risk, after adjustment for the same risk factors, as those with stable plaque or regression
-
Because plaque progresses along the carotid artery 2.4 times faster than it thickens, plaque area measurements are much more sensitive to effects of therapy than measuring thickness alone
-
Plaque is biologically and genetically distinct from intima–media thickness (IMT), stenosis and other phenotypes of atherosclerosis such as coronary calcium
-
Plaque area is more sensitive and specific for identifying patients free of coronary artery stenosis than are IMT or coronary calcium
-
Measurement of three-dimensional plaque volume reduces 100-fold compared with IMT, and 30-fold compared with MRI, the sample size and study duration required to study effects of new therapies for atherosclerosis
Similar content being viewed by others
References
Bond MG et al. (1990) Interventional clinical trials using noninvasive ultrasound end points: the Multicenter Isradipine/Diuretic Atherosclerosis Study. The MIDAS Research Group. J Cardiovasc Pharmacol 15 (Suppl 1): S30–S33
Riley WA et al. (2004) Reproducibility of noninvasive ultrasonic measurement of carotid atherosclerosis. Stroke 23: 1062–1068
Crouse JR et al. (1996) Risk factors and segment-specific carotid arterial enlargement in the Atherosclerosis Risk in Communities (ARIC) cohort. Stroke 27: 69–75
O'Leary DH et al. (1999) Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. N Engl J Med 340: 14–22
Adams MR et al. (1995) Carotid intimal-media thickness is only weakly correlated with the extent and severity of coronary artery disease. Circulation 92: 2127–2134
Linhart A et al. (1996) Carotid artery and left ventricular structural relationship in asymptomatic men at risk for cardiovascular disease. Atherosclerosis 127: 103–112
Megnien JL et al. (1998) Preclinical changes of extracoronary arterial structures as indicators of coronary atherosclerosis in men. J Hypertens 16: 157–163
Al Shali K et al. (2005) Differences between carotid wall morphological phenotypes measured by ultrasound in one, two and three dimensions. Atherosclerosis 178: 319–325
Spence JD et al. (1999) An approach to ascertain probands with a non traditional risk factor for carotid atherosclerosis. Atherosclerosis 144: 429–434
Brook RD et al. (2006) A negative carotid plaque area test is superior to other noninvasive atherosclerosis studies for reducing the likelihood of having significant coronary artery disease. Arterioscler Thromb Vasc Biol 26: 656–662
Spence JD (1977) Effects of antihypertensive drugs on blood velocity: implications for prevention of cerebral vascular disease. Can J Neurol Sci 4: 93–97
Spence JD (1989) Quantitative spectral analysis of carotid Doppler signal: evaluation as a method for measurement of drug effects. Clin Invest Med 12: 82–89
Barnett PA et al. (1997) Psychological stress and the progression of carotid atherosclerosis. J Hypertens 15: 49–55
Iemolo F et al. (2004) Sex differences in carotid plaque and stenosis. Stroke 35: 477–481
Touboul PJ et al. (2004) Mannheim intima–media thickness consensus. Cerebrovasc Dis 18: 346–349
Spence JD et al. (2002) Carotid plaque area: a tool for targeting and evaluating vascular preventive therapy. Stroke 33: 2916–2922
Spence JD (2005) Point: uses of carotid plaque measurement as a predictor of cardiovascular events. Prev Cardiol 8: 118–121
Robertson J et al. (2005) Vitamin B12, homocysteine and carotid plaque in the era of folic acid fortification of enriched cereal grain products. CMAJ 172: 1569–1573
Spence JD et al. (1999) Plasma homocyst(e)ine, but not MTHFR genotype, is associated with variation in carotid plaque area. Stroke 30: 969–973
Dayan CM et al. (2002) Whose normal thyroid function is better—yours or mine? Lancet 360: 353–354
Hak AE et al. (2000) Subclinical hypothyroidism is an independent risk factor for atherosclerosis and myocardial infarction in elderly women: the Rotterdam Study. Ann Intern Med 132: 270–278
Rundek T et al. (2002) Carotid intima–media thickness is associated with allelic variants of stromelysin-1, interleukin-6, and hepatic lipase genes: the Northern Manhattan Prospective Cohort Study. Stroke 33: 1420–1423
Liu ML et al. (2002) Association between carotid intima–media thickness and low-density lipoprotein size and susceptibility of low-density lipoprotein to oxidation in asymptomatic members of familial combined hyperlipidemia families. Stroke 33: 1255–1260
Chapman CM et al. (2001) Polymorphisms in the angiotensinogen gene are associated with carotid intimal–medial thickening in females from a community-based population. Atherosclerosis 159: 209–217
Tabara Y et al. (2001) Risk factor–gene interaction in carotid atherosclerosis: effect of gene polymorphisms of renin-angiotensin system. J Hum Genet 46: 278–284
Spence JD et al. (2003) Lipoprotein lipase (LPL) gene variation and progression of carotid artery plaque. Stroke 34: 1178–1182
Hegele RA et al. (2003) Infection-susceptibility alleles of mannose-binding lectin are associated with increased carotid plaque area. J Invest Med 48: 198–202
Hegele RA et al. (2005) Disparate associations of a functional promoter polymorphism in PCK1 with carotid wall ultrasound traits. Stroke 36: 2566–2570
Pollex RL and Hegele RA (2006) Genetic determinants of carotid ultrasound traits. Curr Atheroscler Rep 8: 206–215
Spence JD and Hegele RA (2004) Noninvasive phenotypes of atherosclerosis. Arterioscler Thromb Vasc Biol 24: e188–e189
Spence JD and Hegele RA (2004) Noninvasive phenotypes of atherosclerosis: similar windows but different views. Stroke 35: 649–653
Raitakari OT et al. (2003) Cardiovascular risk factors in childhood and carotid artery intima–media thickness in adulthood: the Cardiovascular Risk in Young Finns Study. JAMA 290: 2277–2283
Li S et al. (2003) Childhood cardiovascular risk factors and carotid vascular changes in adulthood: the Bogalusa Heart Study. JAMA 290: 2271–2276
Demer LL and Tintut Y (2003) Mineral exploration: search for the mechanism of vascular calcification and beyond: the 2003 Jeffrey M. Hoeg Award lecture. Arterioscler Thromb Vasc Biol 23: 1739–1743
Nitta K et al. (2004) Effects of cyclic intermittent etidronate therapy on coronary artery calcification in patients receiving long-term hemodialysis. Am J Kidney Dis 44: 680–688
Nissen SE et al. (2004) Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA 291: 1071–1080
Bots ML et al. (2003) Carotid intima–media thickness measurements in intervention studies: design options, progression rates, and sample size considerations: a point of view. Stroke 34: 2985–2994
Till U et al. (2005) Decrease of carotid intima–media thickness in patients at risk to cerebral ischemia after supplementation with folic acid, vitamins B6 and B12. Atherosclerosis 181: 131–135
Spence JD et al. (2002) Carotid plaque area: a tool for targeting and evaluating vascular preventive therapy. Stroke 33: 2916–2922
Landry A et al. (2005) Quantification of carotid plaque volume measurements using 3D ultrasound imaging. Ultrasound Med Biol 31: 751–762
Landry AM et al. (2004) Measurement of carotid plaque volume by 3-dimensional ultrasound. Stroke 35: 864–869
Ainsworth CD et al. (2005) 3D ultrasound measurement of change in carotid plaque volume: a tool for rapid evaluation of new therapies. Stroke 36: 1904–1909
Gualandri V et al. (1985) A-IMilano apoprotein identification of the complete kindred and evidence of a dominant genetic transmission. Am J Hum Genet 37: 1083–1097
Acknowledgements
I thank Maria DiCicco RVT for her original invention of plaque area measurement, and my colleagues Dr Aaron Fenster and Dr Robert Hegele for their invaluable collaboration in the development of 3D ultrasound methods for evaluating carotid plaque, and in genetic studies, respectively. The late Dr John Kreeft first suggested to me the multiple regression analysis for quantifying 'unexplained atherosclerosis'.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The author declares no competing financial interests.
Rights and permissions
About this article
Cite this article
Spence, J. Technology Insight: ultrasound measurement of carotid plaque—patient management, genetic research, and therapy evaluation. Nat Rev Neurol 2, 611–619 (2006). https://doi.org/10.1038/ncpneuro0324
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/ncpneuro0324
- Springer Nature Limited
This article is cited by
-
Risk of major adverse cardiovascular events in subjects with asymptomatic mild carotid artery stenosis
Scientific Reports (2018)
-
Definition of common carotid wall thickness affects risk classification in relation to degree of internal carotid artery stenosis: the Plaque At RISK (PARISK) study
Cardiovascular Ultrasound (2017)
-
Impact of diabetes duration and degree of carotid artery stenosis on major adverse cardiovascular events: a single-center, retrospective, observational cohort study
Cardiovascular Diabetology (2017)
-
Brachial artery flow-mediated dilatation and carotid intima medial thickness in pediatric nephrotic syndrome: a cross-sectional case–control study
Clinical and Experimental Nephrology (2015)
-
Racial differences in the burden of coronary artery calcium and carotid intima media thickness between Blacks and Whites
Netherlands Heart Journal (2015)