Non-invasive assessment of atherosclerosis

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1 Uday M Jadhav*, MD; Amit Saraf, MD; Snehal Tanna * Department of Cardiology, MGM New Bombay Hospital, Vashi, India Department of Medicine, Jupiter Hospital & Kaushalya Hospital, Thane, India Diabetology Department, Kaushalya Hospital, Thane, India, MBBS, Dip. in Diabetology Abstract Non Invasive assessment techniques of atherosclerosis include Pulse-wave velocity at the brachial artery, Intima media thickness (IMT) in the carotid artery, Multi (64)-slice computed tomography (MSCT) for imaging of coronary lesions, Arterial pulse wave form analysis, Ankle Brachial Index (ABI) and Computed Tomography for coronary calcium. The potentially applicable screening tools have to be simple, reproducible, widely applicable and independently able to predict risk. Carotid IMT testing using ultrasound imaging of the carotid artery far wall and all carotid segments with carotid plaque assessment is an important study for prognostication of future coronary vascular (CV) events, risk of stroke and MI. Carotid IMT has also been shown to correlate well in Indian studies with other risk factors such as microalbuminuria and apolipoprotein B. Flow-mediated dilatation (FMD) of the brachial artery also correlates with other noninvasive measures of cardiovascular risk, including CRP, carotid IMT, and measures of arterial stiffness. Non-invasive assessment of endothelial dysfunction by FMD has shown to be useful in prediction of coronary artery disease in Indian subjects The most commonly studied measures of arterial stiffness are aortic pulse wave velocity (PWV) and pulse wave analyses such as the aortic augmentation index. Non-invasive assessment of arterial stiffness by vascular profiler has shown a close correlation with the FMD assessment of endothelial dysfunction. Presence of coronary calcium on the cardiac CT scan has an excellent correlation with future coronary events and contrast-enhanced coronary CT with near 100% negative predictive value for presence of coronary lesions. Key Words Carotid IMT Brachial artery FMD Pulse wave velocity Coronary calcium score Introduction There are various methods to test noninvasive atherosclerotic risks. The prominent ones are Pulse-wave velocity at the brachial artery, Intima media thickness (IMT) in the carotid artery, Multi (64)-slice computed tomography (MSCT) for imaging of coronary lesions, Normal artery The Carotid artery Right side Damage artery Intime-media thickness Arterial pulse wave form analysis, Magnetic resonance imaging (MRI) of the plaque, Ankle Brachial Index (ABI), Exercise Electrocardiography, Stress Echocardiography, Computed Tomography for coronary calcium, Peripheral arterial tonometry (PAT) and Venous occlusion pletismography. The potentially applicable screening tools for noninvasive assessment of atherosclerosis have to be Simple, noninvasive, and widely applicable Reproducible, with low inter-observer error Standardized between laboratories, and have population normal data to inform interpretation Able to predict risk Add to the predictive value of established risk factor Received: ; Revised: ; Accepted: Disclosures: This article has not received any funding and has no vested commercial interest Acknowledgements: None 318

2 measurement, particularly in intermediate-risk subjects Able to demonstrate that improvement with the new test predicts a reduction in subsequent cardiovascular risk Carotid Intima-Media Thickness (CIMT) Carotid IMT testing is a noninvasive, nonionizing radiation test using ultrasound imaging of the carotid artery wall to define the combined thickness of the intimal and medial arterial wall components. It is most commonly measured in the far wall of the common carotid artery, however, it can also be measured in the near wall and other carotid segments (bulb, internal). The IMT plaque is defined as a focal structure that encroaches into the arterial lumen of at least 0.5 mm or 50% of the surrounding IMT value or a thickness > 1.5 mm as measured from the media-adventia interface to the intima- 1 lumen interface as shown in Figures 1 & 2. Of the various studies, carotid artery intima media thickness (IMT) has been studied the most because of reasons such as easily to be conducted; reproducible and 2 reliable results and cost effectiveness. Figures 3 & 4 shows the simple measurement of carotid IMT. In multiple studies, the relative risk of high versus low carotid intima- RT-CCA Intima-media Ultrasound measurement of CIMT Probe Internal carotid artery Carotid bulb Common carotid artery Blood flow Figure 3 Carotid artery Doppler for measuring IMT External carotid artery Carotid flow divider Carotid dilatation LT-CCA Figure 1 Ultrasound measurement of Carotid IMT Intima-media CIMT Thin IMT in CCA Figure 4 Carotid artery plaque Thicker IMT in CCA media thickness in the common carotid artery ranges from for myocardial infarction and for stroke. Carotid IMT has been shown to be an independent 3,4 predictor of CAD in Indian studies. Figure 2 Carotid IMT measurement Some of the important epidemiological studies linking CIMT and incident CVD endpoints include: 319

3 Jadhav UM, et al Association of coronary artery disease incidence with carotid arterial wall thickness and major risk factors: The atherosclerosis in risk in communities (ARIC) 5 study Common carotid intima-media thickness and the risk of stroke and myocardial infarction: The Rotterdam 6 Study Carotid artery intima-media thickness as a risk factor 320 for myocardial infarction and stroke in older adults: 7 The Cardiovascular Health Study Prospective data from the Carotid Atherosclerosis 8 Study (CAPS) The relationship between carotid IMT and incident Coronary Heart Disease (CHD) events was initially noted in the Kuopio Ischemic Heart Disease Risk Factor study, in which risk of future MI in Finnish men increased by 11% for every 0.1 mm increment in carotid IMT. For carotid IMT values >1 mm, there was a 2-fold greater risk of acute MI over three years. 9 Stein JH et al. advocated the use of carotid ultrasound to identify subclinical vascular disease and evaluated Cardiovascular disease (CVD) risk. The association between carotid IMT and incidence of MI and stroke has been noted in older populations and other high-risk populations. In the Cardiovascular Health Study, the RR for MI, adjusted for age, gender, and standard cardiovascular risk factors was 3.15 (95% CI 2.19 to 4.52) when an average IMT was used for the common carotid and internal carotid arteries and when comparing the highest quintile versus the lowest quintile. These differences held true for patients with and without known CVD. 10 Polak JF et al. in his study ascertained that the maximum internal and mean common carotid-artery intima-media thicknesses both predict cardiovascular outcomes, but only the maximum intima-media thickness of (and presence of plaque in) the internal carotid artery significantly (albeit modestly) improves the classification of risk of cardiovascular disease in the Framingham Offspring Study cohort. The study measured the mean intima-media thickness of the common carotid artery and the maximum intima-media thickness of the internal carotid artery in 2965 members of the Framingham Offspring Study cohort. Cardiovasculardisease outcomes were evaluated for an average follow-up of 7.2 years. The maximum internal and mean common carotid-artery intima-media thicknesses both predict cardiovascular outcomes, but only the maximum intimamedia thickness of (and presence of plaque in) the internal carotid artery significantly (albeit modestly) improved the classification of risk of cardiovascular disease in the Framingham Offspring Study cohort. When it came to comparing the Coronary Artery Calcium (CAC) to the Carotid Intima-Media Thickness (CIMT) in prediction of CVD incidence, the Multi Ethnic Study of 11 Atherosclerosis (MESA) measured the hazard ratio for incident CVD event in relation to the quartiles of CIMT or CAC and found that CIMT score (age, race and sex adjusted) was a better predictor of CVD events. Similar 12 results were obtained by Newman AB et al., wherein year-old adults were judged for their CV outcomes predicted by the coronary artery calcium and internal carotid wall thickness quartiles. 13 Newer insights from Framingham study provide us with cut-off values of a mean IMT of 0.9 mm and a plaque score (PS) of five to predict the presence of coronary artery disease and the intermediate or the high SX score. These cut-off values showed excellent sensitivity and negative predictive value. Carotid artery intima-media thickness and plaque score can also predict the SYNTAX score as shown in a recent study 14 by Nobutaka Ikeda et al. The severity of carotid artery atherosclerosis was evaluated using the mean Common Carotid Artery (CCA), Intima-Media Thickness (mean IMT) and PS. Carotid ultrasound was used to evaluate the mean IMT and the PS. The principal finding of this study was that carotid-us findings correlate with the complexity of coronary artery disease. Furthermore, the same study ascertained that noninvasive testing provides information on lesion complexity that is important for decision making by cardiologists. CAC and CIMT, in summary, seem to be reasonable tests to consider in the risk assessment stratification of asymptomatic, but otherwise clinically at risk individuals for potential cardiovascular events. The importance of pretest risk in identifying the relevant Percentage Correlation of Apolipoprotein Ratio with Carotid Intima-Media Thickness Without Diabetes/ ApoB: ApoA-1<1 Without Diabetes/ ApoB: ApoA-1>1 Groups Diabetes+ ApoB: ApoA-1<1 Figure 5 Correlation of Apolipoprotein B with carotid IMT IMT 0.60 mm IMT mm IMT mm IMT > 0.80 mm Diabetes/+ ApoB: ApoA-1>1

4 population for these tests should be emphasized. Carotid IMT has been shown to correlate well in Indian studies with 15 other risk factors, such as microalbuminuria and apolipoprotein B16 as shown in Figure 5. The future of Carotid IMT was ascertained by Lorenz et 17 al. in the PROG-IMT study group. They concluded that the individual progression of carotid intima media thickness was a surrogate for vascular risk. Carotid artery plaque assessment is also an important study for prognostication of future coronary vascular (CV) events. To answer the question, Will Carotid plaque assessment is better than IMT? Carotid plaques can be assessed qualitatively (plaque echogenicity and heterogeneity) and quantitatively (plaque numbers, area and volume) As plaques grow longitudinally along the carotid axis more than two-times faster than it thickens, IMT seems to be a relatively insensitive measure of plaque evolution Traditional coronary risk factors only explain 15 17% of IMT, but account for 52% of the carotid total plaque area Carotid plaque area is more representative of atherosclerosis than is carotid IMT Brachial/Peripheral flow-mediated dilation 18 Celermajer DS et al. in his study proved ultrasound technique of brachial artery flow mediated dilatation to be accurate and reproducible for measuring small changes in arterial diameter low rates of inter observer error in measuring flow-mediated dilatation (FMD). Percent maximum FMD is the most reproducible measure and the best discriminator between health and disease. Peripheral arterial FMD studies are not recommended for cardiovascular risk assessment in asymptomatic adults. Peripheral arterial FMD is a noninvasive measure of endothelial function. Augmented flow is produced by a sustained period (typically 4 5 min) of forearm compression accompanied by vascular occlusion followed by release. In the setting of healthy endothelium, increased flow stimulates release of nitric oxide, inducing local brachial artery vasodilation. The degree of dilation can be measured using high-resolution ultrasound. In research settings, brachial artery FMD has been shown to correlate with invasive measures of coronary artery FMD after adenosine triphosphate infusion, suggesting that peripheral FMD may be a suitable substitute for invasive coronary endothelial function testing. Endothelial dysfunction is 19 defined as FMD < 4.5%. FMD also correlates with other noninvasive measures of cardiovascular risk, including CRP, carotid IMT, and measures of arterial stiffness. Noninvasive assessment of endothelial dysfunction by brachial artery flow-mediated dilatation has shown to be useful in prediction of coronary 20 artery disease in Indian subjects by Jadhav et al. FMD was 0.9% in subjects with CAD as compared to 4.8% in subjects without CAD and 12.6% in healthy volunteers. FMD also had a positive correlation in subjects with diabetes mellitus where assessment of pre-clinical 21 atherosclerosis is more relevant. In a study in the western India population, endothelial dysfunction had 43% prevalence in hypertensive subjects and 84% prevalence in with concomitant 22 diabetes mellitus. Pulse wave velocity and other arterial abnormalities: Measures of arterial stiffness Arterial stiffness is a consequence of arteriosclerosis, the process of arterial wall thickening, and loss of elasticity that occurs with onset of vascular disease and advancing age. Besides pulse pressure (the numeric difference between the systolic and diastolic blood pressures), multiple other specific measures of arterial stiffness have been described. The most commonly studied measures of arterial stiffness are aortic pulse wave velocity (PWV) and pulse wave analyses, such as the aortic augmentation index. Non-invasive assessment of arterial stiffness by vascular profiler has shown a close correlation with the FMD assessment of endothelial dysfunction by Jadhav UM 23 et al. as shown in Figure 6. Because blood is a noncompressible fluid, transmission of the arterial pressure wave occurs along the arterial wall and is Arterial stiffness Flow-mediated dilatation (FMD) in percentage Right extremity arterial stiffness // FMD of the brachial artery r = 301, p = 0.002) Figure 6 Correlation of arterial stiffness (PWV) with endothelial dysfunction (FMD) 321

5 Jadhav UM, et al influenced by the biomechanical properties of the arterial wall. When the arteries are stiffened, the pulse wave is propagated at an increased velocity, and increased PWV is therefore correlated with stiffness of the arteries. Factors associated with PWV include advancing age as well as the long-term effects of cardiovascular risk factors on the structure and function of the arterial wall. PWV is generally measured using applanation tonometry but can also be measured by Doppler ultrasound or magnetic resonance imaging (MRI). Measurement of ankle-brachial index (ABI) The ABI is an office-based test to check for the presence of PAD. It is performed by Doppler measurement of blood pressure in all four extremities at the brachial, posterior tibial, and dorsalis pedis arteries. The highest lowerextremity blood pressure is divided by the highest of the upper-extremity blood pressures, with a value of <0.9 indicating the presence of PAD, which is defined as >50% stenosis. When defined in this way, the ABI has both a high sensitivity and specificity for anatomic stenosis. In addition to signifying PAD, an abnormally low ABI has also been shown to be a predictor of cardiovascular events. Intermediate values (0.9 to 1.1) also have a graded association with CVD risk. A high ABI (>1.3), which indicates calcified, noncompressible arteries, is also a marker of arterial disease. The prevalence of PAD as indicated by an abnormal ABI increases with age and is associated with traditional risk factors for CVD. Stress echocardiography Stress echocardiography can be performed with dynamic forms of exercise, including treadmill and bicycle, as well as with pharmacologic stress, most often using dobutamine. The manifestations of ischemia on echocardiography include segmental and global left ventricular dysfunction. The use of echocardiography during treadmill testing is indicated for those patients with an abnormal resting ECG, including findings of left bundle-branch block, electronically paced rhythm, and LVH, as well as for patients taking digoxin mm thick axial images obtained through the heart. The quantity of calcium within the coronary arteries is typically scored as the area affected on the scan, multiplied by a weighting factor depending on the Hounsfield unit density of the calcium deposits. The majority of published studies have reported that the total amount of coronary calcium (usually expressed as the Agatston score) provides information about future CAD events over and above the information provided by standard risk factors. In the imaging assessment of cardiovascular risk in 24 asymptomatic adults study, compared with a CAC score of zero, a CAC score between 100 and 400 indicated a relative risk of 4.3, a score > indicated a relative risk of 7.2, and a score of > 1000 indicated a relative risk of In multiple studies, the relative risk of high versus low carotid IMT in the common carotid artery ranges from for myocardial infarction and for stroke. Addition of carotid IMT and plaque information to traditional risk factors led to reclassification in approximately 38% of low to intermediate and intermediate-risk persons. 25 Naghavi et al. recommended noninvasive screening of all asymptomatic men of age group years and asymptomatic women of age group years (except those defined as very low risk), using either CT or ultrasound as initial test. C o r o n a r y c o m p u t e d t o m o g r a p h y angiography (CCTA) CCTA has been widely available, since around Two basic scanning protocols may be used; both require ECG Computed tomography for coronary calcium Cardiac CT, using either multidetector row CT or electron beam tomography, enables the acquisition of thin slices of the heart and coronary arteries gated to diastole to minimize coronary motion. Both are sensitive noninvasive techniques that can detect and quantify coronary calcium, a marker of atherosclerosis. The test is typically performed in a prospectively ECG-triggered scanning mode with PREVALENCE OF CAD IN SUBJECTS WITH ZERO CALCIUM UDAY M JADHAV ET AL. ESC 2008 VIENNA Figure 7 Coronary lesion in absence of coronary calcium on CT coronary angiography

6 monitoring and gating. Helical (or spiral) scanning uses continuous image acquisition while the patient moves slowly through the scanner plane. Axial scanning incorporates a scanning period, followed by a patient movement period, followed by another scanning period (step-and-shoot). CCTA has been compared with invasive coronary angiography for detection of atherosclerosis (typically defined as a 50% diameter stenosis) with excellent negative predictive value. Notably, presence of significant coronary lesions in 4.2% subjects in absence of any coronary calcium was noted in an Indian study by 26 Jadhav et al. as shown in Figure 7. Magnetic resonance imaging of plaque MRI is a noninvasive method of plaque measurement that does not involve ionizing radiation. Studies of the aorta and the femoral and carotid arteries have demonstrated the capability of MRI for detection and quantification of atherosclerosis and suggested its potential for risk assessment and evaluation of the response to treatment in asymptomatic patients. MRI seems to offer the greatest role for plaque characterization as distinct from lesion quantification. Several studies have demonstrated that MRI findings are correlated with atherosclerosis risk factors. Aortic MRI scanning in 318 patients participating in the Framingham Heart Study found that after age adjustment, plaque prevalence and burden correlated with FRS for both women and men. In another Framingham Heart Study, subclinical aortic atherosclerosis was seen in nearly half of subjects and increased with advancing age. Conclusion After reviewing all these noninvasive assessment methods for diagnosis of atherosclerosis, the questions that arise are: Why bother screening for risk? Why not treat everyone? Widespread application of preventive interventions (lifestyle, medications) without previous risk stratification (i.e., unconditional interventions for all) would be most appropriate if interventions were safe, inexpensive, easily implemented, highly effective, and associated with high compliance and low discontinuation rate. Unfortunately, in the real world, there is no such thing as universally effective, safe, and inexpensive prevention that carries a high degree of compliance. Lifestyle modification, although clearly important and effective, is difficult to implement on a wide scale because of social, cultural, and economic factors; drug therapy, specifically lipid-modifying therapy, although effective is limited by cost, need for lifelong use, intolerance because of nuisance type, and less commonly, more serious side effects, and overall resistance of many subjects to lifelong use, thereby limiting long-term compliance. Furthermore, drug therapy, specifically statin therapy, only addresses about 30 50% of the risk, leaving a considerable amount of residual risk. Therefore, we must continue to search for better ways of identifying at-risk individuals by noninvasive methods so that aggressive preventive measures can be targeted to this population while sparing those who are at no or extremely low risk the cost and side effects of protracted and potentially lifelong drug therapy. References 1. Pignoli P, Tremoli E, Poli A, Oreste P, Paoletti R. Individual measurement and significance of carotid intima-media thickness by B-mode ultrasonographic image processing Circulation. 1986;74: Touboul PJ, Hennerici MG, Meairs S, Adams H, Amarenco P, Bornstein N et al. Mannheim Carotid intima-media thickness consensus ( ). An update on behalf of the Advisory Board of the 3rd and 4th Watching the Risk Symposium, 13th and 15th European Stroke Conferences, Mannheim, Germany, 2004, and Brussels, Belgium, Cerebrovas Dis. 2007; 23: Jadhav UM, Kadam NN. Carotid intima-media thickness as predictor of coronary artery disease. Indian Heart J 2001;53: Jadhav UM. Non-invasive early prediction of atheroclerosis by Carotid intima-media thickness. Asian J Clin Cardio 2001;4: Chambless LE, Heiss G, Folsom AR, Rosamond W, Szklo M, Sharrett AR, et al. Association of Coronary artery disease incidence with carotid arterial wall thickness and major risk factors: The atherosclerosis in risk in communities (ARIC) study, Am J of Epidemiol. 1997;146: Bots ML, Hoes AW, Koudstaal PJ, Hofman A, Grobbee DE. Common carotid intima-media thickness and the risk of stroke and myocardial infarction: The Rotterdam study. Circulation. 1997;96: O'Leary DH, Polak JF, Kronmal RA, Manolio TA, Burke GL, Wolfson SK Jr. Carotid artery intima-media thickness as a risr factor for myocardial infarction and stroke in older adults: The Cardiovascular health study. N Engl J Med. 1999;340: Lorenz MW, von Kegler S, Steinmetz H, Markus HS, Sitzer M. Carotid intima-media thickness indicates a higher vascular risk across a wide age range: Prospective data from the carotid atherosclerosis study (CAPS). Stroke. 2006;37: Stein JH, Korcarz CE, Hurst RT, Lonn E, Kendall CB, Mohler ER, et al. Use of carotid ultrasound to identify subclinical vascular disease and evaluate cardiovascular disease risk: a consensus statement from the American Society of Echocardiography Carotid Intima-Media Thickness Task Force. Endorsed by the Society for Vascular Medicine. J Am Soc Echocardiogr. 2008;21: Polak JF, Pencina MJ, Pencina KM, O'Donnell CJ, Wolf PA, D'Agostino RB Sr. Carotid-wall intima-media thickness and CV events. 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7 Jadhav UM, et al 13.Budoff M. Atherosclerosis: Should we use CIMT testing? New insights from Framingham. Nat Rev Cardiol 2011;8: Ikeda N, Kogame N, Iijima R, Nakamura M, Sugi K. Carotid artery intima-media thickness and plaque score can predict the SYNTAX score. Eur Heart J. 2012;33: Jadhav UM, Kadam NN. Association of Microalbuminuria with Carotid intimal medial thickness and coronary artery disease A cross sectional study in Western India. J Assoc Physicians India. 2002;50: Jadhav UM, Kadam NN. Apolipoproteins: correlation with carotid intima media thickness and coronary artery disease. J Assoc Physicians India. 2004;52: Lorenz MW 2nd, Bickel H, Bots ML et al. Carotid intima media thickness: a suitable alternative for cardiovascular risk as outcome? Am Heart J. 2010;159(5): Celermajer DS, Sorensen KE, Gooch VM, Spiegelhalter DJ, Miller OI, Sullivan ID, et al. Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet 1992;340: Schroeder S, Enderle MD, Ossen R, Meisner C, Baumbach A, Pfohl M, et al. Noninvasive determination of endotheliummediated vasodilation as a screening test for coronary artery disease: Pilot study to assess the predictive value in comparison with angina pectoris, exercise electrocardiography, and myocardial perfusion imaging. Am Heart J. 1999; 138: Jadhav UM, Sivaramakrishnan A, Kadam NN. Noninvasive assessment of endothelial dysfunction by brachial artery flowmediated dilatation in prediction of coronary artery disease in Indian subject. Indian Heart J. 2003;55(1): Jadhav UM. Endothelium-dependant brachial artery flowmediated vasodilatation in patients with Diabetes mellitus with and without coronary artery disease. J Assoc Physicians India 2003;51: Jadhav U M et al. Endothelial dysfunction in hypertension Study in a Western India population India (Journal of the Society of India) 2002;16(2): Jadhav UM, Kadam NN. Non-Invasive assessment of Arterial stiffness by the pulse-wave Velocity correlates with endothelial dysfunction. Indian Heart J 2005; 57: Lin E, Hwang W. Imaging assessment of cardiovascular risk in asymptomatic adults. AJR Am J Roentgenol. 2011;197: W Naghavi M, Falk E, Hecht HS, Jamieson MJ, Kaul S, Berman D, et al. From Vulnerable Plaque to Vulnerable Patient Part III: Executive Summary of the Screening for Heart Attack Prevention and Education (SHAPE) Task Force Report. Am J Cardiol. 2006; 98:2H 15H. 26.Jadhav U M, Shetty R, et al. Coronary artery lesions in absence of coronary calcium on multi-slice CT Coronary Angiography. ESC Scientific Meeting. Vienna, Austria. September 1-5, Address for correspondence Dr. Uday M Jadhav: 324

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