Identifying patients at risk: novel diagnostic techniques

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1 European Heart Journal Supplements (2004) 6 (Supplement C), C15 C20 Identifying patients at risk: novel diagnostic techniques Department of Cardiology, The Cleveland Clinic Foundation, Cleveland, OH, USA KEYWORDS Carotid intima media thickness; Electron-beam-computed tomography; Intra-vascular ultrasound; Magnetic resonance imaging Techniques that enable the accurate and reproducible detection and measurement of the pathophysiological changes that occur in atherosclerosis, particularly early on in the disease process, will help to identify those who are at highest cardiovascular risk, and may, therefore, improve clinical outcome. It has become apparent that atherosclerosis begins much earlier in life than was previously thought. It is also now known that it is the extent and composition of atheromatous plaque, rather than the degree of stenosis, that determines the risk of plaque disruption and, therefore, has most impact on patient outcome. Traditional techniques that only provide information about lumen size, such as angiography, are thus of limited use in predicting clinical events. Improved understanding of the mechanisms underlying atherogenesis has resulted in the development of several potential techniques for assessing the disease process in humans. These include modalities that detect early structural changes in the coronary arteries, such as electron-beam-computed tomography, magnetic resonance imaging, and intra-vascular ultrasound; and those that detect surrogate markers for coronary atherosclerosis, such as the external vascular ultrasound measurement of carotid intima media thickness). c 2004 Published by Elsevier Ltd on behalf of The European Society of Cardiology. Introduction Guidelines for the management and treatment of cardiovascular disease (CVD), based on conventional risk factors, have several limitations: they define the risks and potential benefits of treatment for large groups in society the average patient rather than the individual; they tend to evolve slowly and only by consensus, often taking 5 years or more to catch up with scientific understanding; they try to balance benefit versus cost, based upon perceptions of what a human life, or what post-myocardial infarction (MI) quality of life, is worth; finally, they are largely driven by patient age, when, in fact, the most devastating consequence of CVD is premature death. In the USA, for example, nearly two-thirds Correspondence:, The Cleveland Clinic Foundation, Department of Cardiology, 9500 Euclid Avenue, Cleveland, OH 44195, USA. Tel.: þ ; fax: þ address: nissens@ccf.org (). of men and half of all women who suffer from coronary artery disease (CAD) present with either an acute MI or sudden cardiac death. Many of these people are not taking any preventive measures at the time the initial diagnosis is made. Although conventional risk factors are helpful in estimating cardiovascular risk, by themselves they may not be sufficient to assess total risk in an individual patient. In the past, clinicians have used angiography and the size of the lumen to predict coronary events. However, CVD is not a disease of the lumen, but a disease of the vessel wall. In the early stages of atherosclerosis, the lumen does not narrow, since the external elastic membrane of the vessel outwardly remodels, allowing plaque to develop without compromising the lumen. 1 A substantial plaque burden develops long before an event occurs. Stenosis may be delayed until a lesion occupies up to 40% of the internal lamina area, with the result that angiography may show a normal luminal cross-sectional area despite the presence of a large plaque. 2 Only late in the disease process does X/$ - see front matter c 2004 Published by Elsevier Ltd on behalf of The European Society of Cardiology. doi: /j.ehjsup

2 C16 luminal narrowing occur, enabling angiographic detection. 3 Silent plaque plaque that has not yet narrowed the lumen represents approximately 95% of the atherosclerotic disease burden. Necropsy studies have indicated that atherosclerosis begins at an early age. 4 8 This was clearly demonstrated in a study of 262 asymptomatic teenagers and young adults who died due to motor vehicle accidents, and whose hearts were subsequently used for transplantation. 9 When the coronary arteries of these individuals were examined using intravascular ultrasound (IVUS), unequivocal evidence of atherosclerosis was found in subjects as young as 13 years of age. One in 6 teenagers, 1 in 3 adults aged between 20 and 29 years, and over 50% of adults aged between 30 and 39 years already had coronary atherosclerosis (defined as the presence of P1 site with intimal thickness >0.5 mm). 9 However, 97% of subjects in this study had completely normal angiograms. 9 The fact that atherosclerosis starts at an early age has profound implications for drug therapy and underlines the limitations of current guidelines, since over two-thirds of those eligible for treatment, according to these guidelines, are P65 years of age. It is also apparent that the total burden of atherosclerotic disease, rather than the severity of an individual stenosis, is most predictive of future cardiovascular events. Multiple studies have shown that low-grade stenoses (<50% narrowings) are the cause of most MIs. Only approximately 1 in 7 cases of MI occur at a site containing a haemodynamically significant stenosis. A number of techniques have been developed to accurately and reproducibly detect and measure the early changes of atherosclerosis and/or to identify subjects at highest cardiovascular risk. Imaging techniques not only provide evidence that a patient is at risk of atherosclerotic disease, they demonstrate that the patient actually has the disease. For some modalities, the extent of disease burden, as measured by such techniques, adds substantially to the predictive value of conventional risk factors. Perhaps most importantly, imaging techniques allow the physician to identify and treat borderline patients, who might not otherwise be eligible for treatment. Intra-vascular ultrasound IVUS uses high-frequency ultrasound to image not only the coronary lumen but also the structure of the vessel wall, including the atherosclerotic plaque. IVUS has several inherent advantages for the precise quantification of atherosclerotic coronary disease (Fig. 1). Firstly, because of its tomographical orientation, IVUS allows the full 360 circumference of the vessel wall to be visualized. This means that lumen dimensions can be directly planimetered on a cross-sectional image. Secondly, the tomographical perspective of ultrasound allows the precise assessment of vessels that are often difficult to assess angiographically. Thirdly, the frequency range of modern ultrasound systems (20 45 MHz) allows excellent resolution of structures within the artery wall. IVUS has great potential as a means of accurately assessing the atherosclerotic disease process, since it has the ability to demonstrate changes in atheroma volume over a relatively short period of time, with fewer patients than required for large morbidity and mortality end-point trials. It is safe, and gives accurate and reproducible measurements. The recently published REVERSal of atherosclerosis with Aggressive Lipid Lowering (REVERSAL) trial provided convincing evidence of the ability of IVUS to discriminate differences between atherosclerotic therapies. In this study, 80 mg of atorvastatin significantly reduced the progression of coronary disease compared to 40 mg of pravastatin after 18 months. 13 Subsequently, the Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT) trial demonstrated a significant reduction in morbidity and mortality for the same two regimens, thereby providing compelling validation of the IVUS end-point as a surrogate marker for clinical outcome. IVUS does have some limitations. Firstly, the ultrasound operator and core laboratory technician must have a thorough knowledge and understanding of potential ultrasonic artifacts, which may adversely affect image quality, increase the difficulty of image interpretation, or reduce the accuracy of quantitative measurements. 14 Secondly, ultrasound catheters currently have a low specificity for the diagnosis of thrombus, although research is underway to overcome this drawback. 15;16 Fig. 1 IVUS images. This figure illustrates the volumetric approach, and images of the fiduciary points and several image slices in the selected segment are shown. Studies show that plaque plus medial volume calculated in this manner is highly reproducible, and that serial studies can detect very small changes in atheroma volume.

3 Identifying patients at risk: novel diagnostic techniques C17 Finally, the physical size of ultrasound catheters (approximately 1.0 mm in diameter) limits the size of vessel that can be imaged. Carotid intima media thickness measurement Carotid intima media thickness (CIMT) is a simple technique; it uses a transcutaneous transducer, operating in the 7 10 MHz range, to visualize the carotid artery, where the target of measurement is the thickness of the intima media complex (Fig. 2). Using this technique, the carotid artery is viewed as a window on the coronary arteries, since the risk factors that affect CAD also affect disease in the carotid arteries, and it has long been known that the presence of carotid disease is a powerful predictor of future coronary events. CIMT is a well-validated method for evaluation of the presence and extent of vascular disease. The technique is noninvasive, has no known biological hazards, is inexpensive, and the equipment is available in most clinical environments. CIMT also has a strong association with clinical outcome, and its ability to predict risk has been validated in large, carefully studied populations. In a study of 4476 subjects without clinical CVD, O Leary et al. 17 demonstrated that over a follow-up period of 6.2 years the relative risk of MI or stroke increased significantly with intima media thickness as measured by carotid ultrasound (P < 0:001); the cumulative risk of stroke or MI varied greatly according to the quintile of intima media thickness (the relative risk of stroke or MI, adjusted for age and sex, for the quintile with the highest thickness compared with the quintile with the lowest thickness was 3.87). The Atherosclerosis Risk In Communities (ARIC) study, which involved over 10,000 individuals, showed that over a mean period of 5.2 years CIMT was a powerful predictor of the risk of MI or cardiac death, in both men and women: in sex-specific Cox proportional hazards models, adjusted for age, race and centre, the hazard ratio, comparing abnormally high mean CIMT (P1 mm) to less extreme values (<1 mm), was 5.07 for women and 1.85 for men. 18 CIMT is now frequently used to assess the rate of progression of atherosclerosis, and to monitor the effects of CVD therapies. In the ASAP study, atorvastatin 80 mg was shown to dramatically reduce the rate of progression of disease compared to simvastatin 40 mg in patients with heterozygous familial hypercholesterolaemia (n ¼ 325; P ¼ 0:0001). 19 After 2 years of treatment with atorvastatin, CIMT actually decreased ( 0:031 mm; P ¼ 0:0017), whereas in the simvastatin group it increased (0.036 mm; P ¼ 0:0005). 19 Other studies are underway examining the progression rate of CIMT as a means to document the anti-atherosclerotic effects of emerging pharmaceutical agents. There are a few disadvantages of this technique. For precise quantification, you need a high level of technical expertise, particularly for multi-centre studies, since the precision of the technique depends upon the measurement of extremely small differences in thickness. There is also incomplete standardization of equipment, with varying devices and frequencies employed at different centres. Finally, for clinical trials a core laboratory is needed to measure CIMT images, in order to minimize variability between observers. Electron-beam-computed tomography Electron-beam-computed tomography (EBCT) is currently the technique of choice for evaluating atheroma calcification, and has become widely used for non-invasive direct coronary imaging 20 (Fig. 3). Studies have shown that the presence of calcification almost invariably indicates the presence of CAD and that the absence of calcification can nearly rule out significant CAD. 21;22 Moreover, a correlation exists between the amount of calcification and the severity of CAD. For example, Rumberger et al. 23 demonstrated that calcium area, measured by EBCT, correlates well with plaque area as measured using conventional necropsy techniques. Early studies of EBCT used angiography for comparison, which Fig. 2 Carotid IMT. Fig. 3 Individual axial CT image slice with calcification at the LAD/diagonal bifurcation. For calcium scoring, the calcified plaque in all image slices through the entire heart are integrated to a total score.

4 C18 may not have been ideal, since most CAD is extra-luminal. Despite this, studies have shown that there is a correlation between the prevalence of angiographically significant disease and the amount of calcium in the coronary arteries. 24 In some studies, EBCT-derived calcium score has been shown to be a better predictor of cardiovascular events than angiography. 25. Calcium score has also been shown to be a good predictor of survival. In one study, Raggi and co-workers 26 demonstrated that asymptomatic subjects with calcium scores P1000 are at a very much higher risk of suffering a hard coronary event (MI or coronary death) in the short term than those with lower calcium scores. Statin therapy has been shown to slow down the development of coronary calcification and, in some cases, to reduce the volume of coronary calcium. 27;28 EBCT provides a potentially useful means of tracking changes in coronary atherosclerosis by periodically quantifying coronary artery calcium, thereby non-invasively demonstrating the effects of therapy on this process. One study to use this technique is BELLES (Beyond Endorsed Lipid Lowering with EBCT Scanning). This is investigating the effects of aggressive lipid lowering with atorvastatin 80 mg/day compared with pravastatin 40 mg/day on coronary atherosclerosis regression in post-menopausal women. 29 EBCT may also be used in patients with risk factors at a young age to detect disease in preclinical stages, and to provide new information on the natural history of CAD. 30;31 In their most recent position statement, the American College of Cardiology (ACC)/American Heart Association (AHA) did not give overwhelming endorsement to this technique. Firstly, they do not recommend EBCT for the diagnosis of obstructive CAD, because of its low specificity (high percentage of false-positive results), which can result in additional expense and unnecessary testing. 32 However, proponents of EBCT have never recommended its use for diagnosing obstructive disease, since EBCT detects the presence of extra-luminal disease (plaque in the vessel wall) rather than intra-luminal disease (Fig. 4). The usefulness of EBCT is in detecting patients at risk of CAD, and in making treatment decisions. Secondly, the ACC/AHA also state that the published literature does not completely answer the question of whether the EBCT calcium score is additive to the Framingham score for defining CAD risk in asymptomatic patients. 32 However, data that have emerged since this statement was published show that, even when adjustments are made for all other risk factors, there is a substantial incremental value in obtaining a calcium score by EBCT. 33 Magnetic resonance imaging There has been an increasing awareness of the importance of the composition of atherosclerotic plaque as a major risk factor for acute coronary syndromes. 34 In vivo, high-resolution, multi-contrast magnetic resonance imaging (MRI) is a promising method of non-invasively imaging vulnerable plaques, and determining different plaque components such as lipid core, fibrosis, calcifications and thrombosis deposits in large arteries. 35;36 MRI findings have been extensively validated against pathology in ex vivo studies of carotid, aortic and coronary artery autopsy specimens (Fig. 5). 37 Imaging of carotid arteries in vivo in patients referred for endarterectomy showed a high correlation with pathology and with previous ex vivo results. 38 MRI methodology has been adapted for the study of plaque progression, regression and stabilization in transgenic and non-transgenic animal models. 39;40 However, at present, MRI specificity and sensitivity are not of sufficiently high quality for reliable clinical application. Moreover, there are difficulties in using MRI to image coronary arteries, because of problems caused by cardiac and respiratory motion, the small size and tortuous course of these vessels, and the limited special resolution of currently available MRI systems. Nevertheless, a high-resolution MRI technique has been used to charac- Fig. 4 Individual reconstructed MSCT image slice with calcified and noncalcified atherosclerotic plaque in the proximal and mid-lad (contrast enhanced.) Fig. 5 MRI image of an atherosclerotic plaque obtained from ex vivo imaging. Because of the small arterial size and rapid cardiac motion, in vivo coronary imaging is still limited.

5 Identifying patients at risk: novel diagnostic techniques C19 terize plaque composition in CAD both in an atherosclerotic porcine model 41 and in humans. 42 In addition, serial MRI has also recently been used to study the effect of statin therapy in asymptomatic, untreated hypercholesterolaemic patients with carotid and aortic atherosclerosis. 43 It is therefore likely that atherosclerotic assessment by MRI will lend itself for use as a screening tool for prediction of future cardiovascular events, and for further evaluation of therapeutic intervention benefits. Conclusion The prevalence and lethality of CAD requires the identification of more patients who might benefit from preventive therapy. New imaging techniques are rapidly altering conventional paradigms in the diagnosis and treatment of CAD. The expectation is that they may improve our risk stratification ability once the information derived with these tools is added to conventional risk factors for atherosclerosis. 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