Stroke Prevention & Atherosclerosis Research Centre, Robarts Research Institute, Western University, London, Canada.
Our work with ultrasound began in 1974 with the study of effects of antihypertensive drugs on blood velocity (1). When we obtained our first duplex scanner in about 1985 for the purpose of using the spectral analysis capability of the equipment, it became obvious that besides assessing stenosis and effects of drugs on blood velocity (2), we could see plaques in the carotid wall.
At first, we assessed the burden of plaque, and change of plaque over time, with composite drawings of all the plaques that could be seen from the clavicle to the angle of the jaw on both sides. This included the right subclavian, and both common, internal and external carotid arteries. Our technologist, Maria DiCicco, would make these composite drawings, and when patients returned for followup each year, I would try to determine if plaques were progressing, stable, or improving. One day in 1990, I said to Maria "How do I know if you are making these drawings the same way each year?". Her response was "Well, there is software in the machine that I could use to measure the plaques, if you like." This was the beginning of TPA.
Each plaque that could be seen was isolated in the longitudinal view (in the axis of flow), panning around the artery to find the plane in which it appeared biggest. The image was frozen, the view was magnified, and the outline of the plaque traced with a cursor on the screen to give the area of the plaque in a longitudinal view. This was repeated until all plaques had been measured, and the total of all plaques was total plaque area. (Figure 1).
Figure 1. Measurement of plaque area
The outline of the plaque has been traced by a trackball in the longitudinal view in the plane in which it appears biggest. This plaque has an area of 18 mm2 (0.18 cm2).
Reproduced by permission of Wolters Kluver/LWW from: Barnett PA, Spence JD, Manuck SB, Jennings JR. Psychological stress and the progression of carotid atherosclerosis. J Hypertension. 1997;15:49-55.
Our first publication of this method was in 1997 (3), in a paper showing that the rise in blood pressure during mental stress was an independent predictor of plaque progression. In the meantime, I had told Dr. Jon Wikstrand about this method, and his group performed a study that was published in 1992 (4).
TPA predicts high risk of stroke, death or myocardial infarction
In 2002 we reported that TPA was a strong predictor of cardiovascular risk: after adjusting for age, sex, blood pressure, cholesterol, smoking, diabetes, homocysteine and treatment of blood pressure and cholesterol, patients in the top quartile of TPA had 3.4 times higher 5-year risk of stroke, death or myocardial infarction compared to those in the lowest quartile, and the risk by quartile gave a nice step function: 5.6%, 10.7%, 13.9%, and 19.5% (5) (Figure 1). Our findings were validated by the Tromsø study, a large ( n >6000) population-based study in Norway, showing that TPA, but not IMT in the common carotid, predicted myocardial infarction (6) and stroke (7).
Risk-factor–adjusted event-free survival from stroke, myocardial infarction, and vascular death by quartiles of carotid plaque area (cm2).
Reproduced by permission of Wolters Kluver/LWW from: Spence JD, et al. Carotid Plaque Area: A Tool for Targeting and Evaluating Vascular Preventive Therapy. Stroke. 2002;33:2916-22.
This leads to one of the important advantages of measuring TPA: risk stratification. In Switzerland, Romanens et al.(8) have shown that adding TPA to risk scores calculated on the basis of risk factors significantly increased the AUC of risk prediction. In Argentina, Blossom Health Care have found that measuring TPA reclassifies risk in a third of patients attending vascular prevention clinics.
In 2006 I reviewed the use of TPA for management of patients, genetic research and evaluation of new therapies (9).
Treating arteries instead of treating risk factors
In our 2002 study (3) we also observed that during the first year of followup, half our patients had plaque progression despite treatment according to guidelines, and patients with progression had twice the risk of those with stable plaque or regression, after adjustment for all the risk factors mentioned above (Figure 3. )
Figure 3. Risk-factor–adjusted event-free survival from stroke, myocardial infarction, and vascular death by status of carotid plaque area progression or regression during follow-up
Plaque area regression was defined as a decrease of > 0.05 cm2 from baseline; progression was defined as an increase of > 0.05 cm2 from baseline; and no change was defined as either an increase or decrease of no more than 0.049 cm2.
Reproduced by permission of Wolters Kluver/ LWW from: Spence JD, et al. Carotid Plaque Area: A Tool for Targeting and Evaluating Vascular Preventive Therapy. Stroke. 2002;33:2916-22.
This meant that treatment according to guidelines was failing half our patients. We therefore implemented in our clinic in 2003 a new approach to prevention, "treating arteries instead of treating risk factors".
Plaques progress and regress much more quickly than most physicians would expect (10). Figure 4 shows regression of plaque in just over 3 months, after a patient resumed taking rosuvastatin along with ezetimibe (11). Measurement of plaque burden by 3D ultrasound is even more sensitive to effects of therapy (12), and is more highly correlated with coronary calcium score than IMT (13).
Fig. 1. Plaque regression is much faster than most would expect.
Left, panel, A: soft plaque at the origin of the left external carotid in a 64-year-old man using ezetimibe alone because of myalgias and cramps with statins. His plaque had progressed from 20 mm2 6 months earlier, to 28 mm2 after stopping rosuvastatin. After restarting rosuvastatin 5 mg daily with CoQ10 200 mg daily to prevent myalgias, the plaque area regressed to 0.19 mm2 over 3.5 months (right, panel B). The plaque had also become denser, with regression of the soft plaque and more calcification. Reproduced by permission of Williams and Wilkins from: Spence JD, Hackam DG. Treating Arteries Instead of Risk Factors. A Paradigm Change in Management of Atherosclerosis. Stroke 2010; 41:1193e9.
The effect of this approach was that the proportions of patients in our clinic population with progression vs. regression reversed, from ~ 50/25% to 25/50% (11). More importantly, among high-risk patients with asymptomatic carotid stenosis (ACS), the results were remarkable. We had previously shown that among patients with ACS, detection of microemboli strongly predicted high risk: patients with two or more microemboli during one hour of monitoring by transcranial Doppler had a 15.6% one-year risk of stroke, vs. 1% risk without microemboli (14).
We analyzed the outcomes of patients with ACS who were referred to our clinic before and after 2003, the year in which we implemented the new approach, "treating arteries".
We found that the proportion of patients with microemboli on TCD declined from 12.6% to 3.7%, and the risk of events declined markedly: the two-year risk of stroke declined from 8.8% to 1%, and the two-year risk of myocardial infarction declined from 7.6% to 1%.
These findings led to the aphorism "treating arteries without measuring plaque would be like treating hypertension without measuring blood pressure". It is important to recognize that this approach is not possible with IMT because the average annual change in IMT (0.15 mm) is only half the spatial resolution of carotid ultrasound (~ 0.3 mm) (15).
Randomized trials are now being planned in China and Argentina to determine if such results can be generalized to other prevention clinics.
Measurement of carotid plaque burden is useful for risk stratification, management of high-risk patients, genetic research and evaluation of new therapies. Measurement by ultrasound is better than by coronary calcium because coronary calcium responds much less to therapy, and involves radiation. The spatial resolution of carotid ultrasound is better than that of CT scans or MRI scans, and the annual change of IMT is too small to measure by ultrasound.
(1) Spence JD, Pesout J, Melmon KL. Effects of antihypertensive drugs on blood velocity in rhesus monkeys. Stroke. 1977;8:589-94.
(2) Spence JD. Quantitative spectral analysis of carotid Doppler signal: evaluation as a method for measurement of drug effects. Clin Invest Med. 1989;12:82-9.
(3) Barnett PA, Spence JD, Manuck SB, Jennings JR. Psychological stress and the progression of carotid atherosclerosis. J Hypertension. 1997;15:49-55.
(4) Persson J, Stavenow L, Wikstrand J, Israelsson B, Formgren J, Berglund G. Noninvasive quantification of atherosclerotic lesions. Reproducibility of ultrasonographic measurement of arterial wall thickness and plaque size. Arterioscler Thromb. 1992;12:261-6.
(5) Spence JD, Eliasziw M, DiCicco M, Hackam DG, Galil R, Lohmann T. Carotid Plaque Area: A Tool for Targeting and Evaluating Vascular Preventive Therapy. Stroke. 2002;33:2916-22.
(6) Johnsen SH, Mathiesen EB, Joakimsen O, Stensland E, Wilsgaard T, Lochen ML et al. Carotid atherosclerosis is a stronger predictor of myocardial infarction in women than in men: a 6-year follow-up study of 6226 persons: the Tromso Study. Stroke. 2007;38:2873-80.
(7) Mathiesen EB, Johnsen SH, Wilsgaard T, Bonaa KH, Lochen ML, Njolstad I. Carotid Plaque Area and Intima-Media Thickness in Prediction of First-Ever Ischemic Stroke: A 10-Year Follow-Up of 6584 Men and Women: The Tromso Study. Stroke. 2011;42:972-8.
(8) Romanens M, Ackerman F, Schwenkglenks M, Szucs T, Spence JD. Posterior probabilities in sequential testing improve cardiovascular risk prediction using carotid total plaque area. Cardiovascular Medicine. 2011;14:53-7.
(9) Spence JD. Technology Insight: ultrasound measurement of carotid plaque--patient management, genetic research, and therapy evaluation. Nat Clin Pract Neurol. 2006;2:611-9.
(10) Spence JD. Time course of atherosclerosis regression. Atherosclerosis. 2014;235:347-8.
(11) Spence JD, Hackam DG. Treating Arteries Instead of Risk Factors. A Paradigm Change in Management of Atherosclerosis. Stroke. 2010;41:1193-9.
(12) Ainsworth CD, Blake CC, Tamayo A, Beletsky V, Fenster A, Spence JD. 3D ultrasound measurement of change in carotid plaque volume: a tool for rapid evaluation of new therapies. Stroke. 2005;36:1904-9.
(13) Sillesen H, Muntendam P, Adourian A, Entrekin R, Garcia M, Falk E et al. Carotid Plaque Burden as a Measure of Subclinical Atherosclerosis: Comparison With Other Tests for Subclinical Arterial Disease in the High Risk Plaque BioImage Study. JACC Cardiovasc Imaging. 2012;5:681-9.
(14) Spence JD, Tamayo A, Lownie SP, Ng WP, Ferguson GG. Absence of microemboli on transcranial Doppler identifies low-risk patients with asymptomatic carotid stenosis. Stroke. 2005;36:2373-8.
(15) Spence JD. The Importance of Distinguishing Between Diffuse Carotid Intima Medial Thickening and Focal Plaque. Can J Cardiol. 2008;24:61C-4C.