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ACC/AHA 2008 Performance Measures for Adults With ST-Elevation and Non-ST-Elevation Myocardial Infarction

ACC/AHA 2008 Guidelines for the Management of Adults With Congenital Heart Disease
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J Am Coll Cardiol, 2004; 44:2099-2110, doi:10.1016/j.jacc.2004.06.077
© 2004 by the American College of Cardiology Foundation
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SPECIAL ARTICLES

The year in atherothrombosis

Pedro R. Moreno, MD, FACC*,{dagger} and Valentin Fuster, MD, PhD, FACC*,*

* Cardiovascular Institute, Mount Sinai School of Medicine, New York, New York
{dagger} Linda and Jack Gill Heart Institute, University of Kentucky, Lexington, Kentucky

Manuscript received June 15, 2004; revised manuscript received June 23, 2004, accepted June 23, 2004.

* Reprint requests and correspondence: Dr. Valentin Fuster, Cardiovascular Institute, One Gustave L. Levy Place, Box 1030, New York, New York 10029 (Email: valentin.fuster{at}mssm.edu).

Multiple achievements were obtained in the field of atherothrombosis in 2003 to 2004, from basic and experimental research to major clinical trials, setting up new standards, particularly in the understanding and treatment of coronary artery disease. The review is divided into four sections covering basic and experimental research, clinical imaging, serum markers for high-risk stratification, and emergent therapies for coronary and systemic atherothrombosis. Final selection of the cited articles was performed on the basis of clinical relevance and scientific merit.


   Basic and experimental
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 Basic and experimental
Clinical imaging of...
 Serum markers for high-risk...
 New therapies for coronary...
 References
 
Microvessels, plaque hemorrhage, and plaque destabilization.   Our understanding of high-risk atherosclerosis is now evolving from the traditional theory of passive lipid deposition to a more complex multifactorial theory of a mechanism involving the adventitial vasa-vasorum and the tunica media. Kolodgie et al. (1) tested the hypothesis that intraplaque hemorrhage may be a significant contributor to lipid-core expansion through the accumulation of free cholesterol from extravasated erythrocyte membranes. Coronary lesions were stained for markers of previous intraplaque hemorrhage. Coronary fibroatheromas with cores in a late stage of necrosis or thin caps had increased iron deposits, glycophorin A, and greater macrophage infiltration, as shown in Figure 1.



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  		Figure 1 (A) Low power view of a thin cap fibroatheroma with large necrotic core (Movat pentachrome, x20), heavily infiltrated by CD68-positive macrophages (B) (x200). (C) Shows intense staining for glycophorin A in erythrocyte membranes within the necrotic core, together with cholesterol clefts (x100). (D) Shows iron deposits (blue pigment) in a macrophage-rich region deep within the plaque (Mallory's stain, x200). (E) Shows diffuse, perivascular deposits of von Willebrand factor in microvessels, indicating that leaky vessels border the necrotic core (x400). Reproduced with permission from Kolodgie FD, Gold HK, Burke AP, et al. N Engl J Med 2003;349:2316–25.

 
These results suggest that accumulation of erythrocyte membranes within atherosclerotic plaques contributes to lipid core expansion as well as to macrophage infiltration, thus increasing the risk of plaque destabilization (1).

A step forward exploring the mechanistic relationship between intraplaque hemorrhage and high-risk atherosclerosis was elegantly described by Kockx et al. (2) who identified intraplaque hemorrhage from microvessels triggering macrophage activation and foam cell formation in carotid lesions, as shown in Figure 2. The investigators concluded that focal intraplaque microhemorrhage from leaking microvessels initiate platelet and erythrocyte deposition, leading to iron deposition, macrophage activation, and foam cell formation (2). More recently, Moreno et al. (3) identified microvessels as an independent predictor of plaque rupture. Again, all these features may lead to plaque destabilization, precipitating acute ischemic events.



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  		Figure 2 Microvessels (mv) with intracellular von Willebrand factor (vWf) in flat endothelial cells (A). Microvessels with perivascular macrophages and increased endothelial vWf expression and perivascular vWf deposition (B). Reproduced with permission from Kockx MM, Cromheeke KM, Knaapen MW, et al. Arterioscler Thromb Vasc Biol 2003;23:440–6.

 
Link between inflammation and thrombogenicity.   The link between inflammation and thrombogenicity was studied by Hutter et al. (4) by evaluating apoptosis and tissue factor (TF) expression in macrophages within human carotid and coronary lipid-rich plaques. Caspase-3 messenger ribonucleic acid, a marker of apoptosis and TF, was higher in lipid-rich compared with fibrous plaque components (p < 0.01) and correlated with high macrophage content (p < 0.05), as shown in Figure 3. Furthermore, induction and colocalization of TF and active caspase-3 were found in monocytes cultured in the presence of oxidized low-density lipoprotein (LDL) (p < 0.05). Both antigens were significantly decreased after co-treatment with a caspase inhibitor (p < 0.05) and were absent in untreated control cells.



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  		Figure 3 Active caspase-3 (A), tissue factor (B), and CD-68 immunostaining (C) show brown labeling of cells (arrows) along the border of the lipid-core (LIP) in serial sections of a human coronary atheroma. FIB = fibrotic. Reproduced with permission from Hutter R, Valdiviezo C, Sauter BV, et al. Circulation 2004;109:2001–8.

 
The study shows that expression of TF closely related to apoptotic macrophages in lipid-rich plaques, highlighting the possible mechanistic impact of high lipid content in macrophage apoptosis and plaque thrombogenicity (4).

The TF expression is also increased by activated platelets attached to monocytes. The effect of abciximab (non-selective glycoprotein IIb/IIIa-receptor antagonist) on monocyte TF expression was evaluated in whole blood in vitro by Steiner et al. (5). After thrombin receptor stimulation, abciximab (50 µg/ml) reduced the mass of platelets attached to monocytes with reduced expression of monocyte TF antigen, chromogenic TF activity, and TF messenger ribonucleic acid. The investigators concluded that abciximab suppresses monocyte TF through a reduction of monocyte-platelet cross-talk. This finding may explain the protective effect of abciximab on the microcirculation after acute coronary syndromes (5).

In experimental animal research, Danenberg et al. (6) evaluated direct proinflammatory and prothrombotic effects of complement reactive protein (CRP) on monocytes and endothelial cells in vivo by subjecting wild-type mice, which do not express CRP, and human CRP-transgenic (CRPtg) mice to two models of arterial injury (6). Baseline serum CRP levels were undetectable in wild-type mice and 18 ± 6 mg/l in CRPtg mice. Transluminal wire injury led to complete thrombotic occlusion of the femoral artery at 28 days in 17% of wild-type mice compared with 75% of CRPtg arteries (p < 0.05), as seen in Figure 4. The investigators concluded that arterial injury in CRPtg mice results in a higher rate of thrombotic occlusion, suggesting an inflammatory-thrombotic axis with a prothrombotic action of CRP.



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  		Figure 4 (A) Complete arterial occlusion at 28 days after femoral wire injury in complement reactive protein-transgenic (CRPtg) (n = 8) and wild-type mice (n = 12). (B to E) Photomicrographs of wild-type (left) and CRPtg (right) femoral arteries stained by Verhoeff elastin stain (B and C) and {alpha}-actin (D and E). Note the reduced smooth muscle cells content in the intraluminal lesion of the CRPtg mouse. Reproduced with permission from Danenberg HD, Szalai AJ, Swaminathan RV, et al. Circulation 2003;108:512–5.

 
Molecular imaging of inflammation, microvessels, and thrombus.   Conventional imaging relies on anatomic, physiologic, or metabolic heterogeneity to provide image contrast. Molecular imaging is based on a signal imaging element attached to a carrier that transports a ligand that recognizes the target molecule or process to image (7). A number of disease entities have molecular or cellular processes that can be investigated with this methodology. Examples of signal imaging elements based on magnetic resonance imaging (MRI) include ultrasmall superparamagnetic iron oxide nanoparticles (USPIO) or gadolinium chelates; examples of carriers include liposomes, lipid-encapsulated nanoparticles, and others; examples of ligands are small peptides, monoclonal antibodies, peptidomimetics, and so on; examples of target molecules, cells, or processes to image that may indicate a high-risk for atherosclerosis include macrophages, macrophage apoptosis, thrombus formation, angiogenesis, and activated endothelial integrins (7–12).

In vivo detection of macrophages using USPIO in human plaques by MRI was performed on 11 symptomatic patients scheduled for carotid endarterectomy. Histologic and electron microscopy analyses of the plaques showed USPIO in plaque macrophages in 10 of 11 patients. Histologic analysis showed USPIO in 27 of 36 (75%) of the ruptured and rupture-prone lesions and 1 of 14 (7%) of the stable lesions. These results suggest that USPIO-guided macrophage identification with MRI may offer noninvasive risk stratification of atherosclerotic plaques at the cellular level in vivo (8).

Identification of macrophage apoptosis, a major process in plaque rupture and thrombus formation, was performed using human recombinant annexin V labeled with technetium-99m in five hypercholesterolemic rabbits and compared with five controls. Intense uptake of radiolabel was observed in the experimental group, mostly at areas heavily infiltrated by macrophages with deoxyribonucleic acid fragmentation and apoptotic nuclei (9), suggesting that technetium-99 radiolabeled annexin V can identify molecular changes in macrophages undergoing apoptosis.

Thrombus imaging using molecular MRI continues to evolve as a potentially useful tool to detect complicated plaques responsible for acute or subacute thrombosis. Using a novel fibrin-binding, gadolinium-labeled peptide, EP-1873, MRI successfully identified 25 thrombi in the Russell's viper venom hypercholesterolemic rabbit model. These results confirm in vivo feasibility of molecular MRI for the detection of acute and subacute thrombosis in experimental atherosclerosis (10).

Another major step forward in molecular imaging was the successful imaging of angiogenesis in early atherosclerosis. Using {alpha}vß3 integrin-targeted, paramagnetic nanoparticles injected intravenously, angiogenesis was detected as a 47% enhancement in the MRI signal within the atherosclerotic wall of the abdominal aorta in hypercholesterolemic rabbits, as seen in Figure 5 (11). This molecular imaging approach might help to study the evolution of atherosclerosis in susceptible individuals as well as for determining the responsiveness of individual patients to antiatherosclerotic therapies.



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  		Figure 5 Percent enhancement of adventitial signal (false-colored from blue to red) from aortic segments at renal artery (A), mid-aorta (B), and diaphragm (C) 2 h after {alpha}vß3-targeted nanoparticles in cholesterol-fed rabbits. Immunohistochemistry of {alpha}vß3-integrin showing thickened intima (I) and {alpha}vß3-integrin staining in adventitial neovessels (black arrowheads) (D). Immunostaining of neovascular {alpha}vß3-integrin (E) and platelet endothelial cell adhesion molecule (F) in aorta from cholesterol-fed animal in (A) at 600x. Solid arrows delineate {alpha}vß3-integrin expression, and open arrows mark PECAM expression at interface between media (M) and adventitia (Av). Reproduced with permission from Winter PM, Morawski AM, Caruthers SD, et al. Circulation 2003;108:2270–4.

 
Invasive atherosclerotic molecular imaging with intravascular ultrasound also advanced significantly. Activated endothelial integrins including intercellular adhesion molecule-1, vascular cell adhesion molecule-1, fibrinogen, fibrin, and TF were imaged with targeted echogenic immunoliposome (ELIP) using intravascular ultrasound. Detection of coronary activated endothelium was successfully performed in hypercholesterolemic Yucatan mini-swine after ELIP injection by enhanced echogenicity using three-dimensional image reconstruction and videodensitometric analysis (12).

Metabolic syndrome and peroxisomal proliferator-activated receptors (PPAR).   Two major areas of research summarize recent advances in the metabolic syndrome and atherothrombosis. The first one is a consequence of the discovery of leptin (13), which lead to the elucidation of the role of cannabinoid receptor type 1 (CB1) in food intake. Cota et al. (14) showed that the lack of CB1 gene in mice causes hypophagia and leanness. Hypothalamic CB1 messenger ribonucleic acid was found to be co-expressed with neuropeptides known to modulate food intake, such as corticotropin-releasing hormone, cocaine-amphetamine-regulated transcript, melanin-concentrating hormone, and prepro-orexin, indicating a possible role for endocannabinoid receptors within central networks governing appetite. These results indicate that the cannabinoid system is an essential endogenous regulator of energy homeostasis via central orexigenic as well as peripheral lipogenic mechanisms and, therefore, might represent a very promising target with which to treat diseases like the metabolic syndrome.

The second area of research is related to PPARs, a group of ligand-activated transcription factors belonging to the nuclear receptor superfamily, which also includes the steroid and thyroid hormone. Three subfamilies have been described with different tissue distribution and effects: PPAR-{alpha}, PPAR-{gamma}, and PPAR-{delta}.

The PPAR-{alpha} is activated by polyunsaturated fatty acids, oxidized derivatives, and fibrates, including fenofibrate or gemfibrozil. The PPAR-{alpha} controls expression of genes implicated in lipid metabolism. The PPAR-{alpha} is expressed in endothelial cells, smooth muscle-cells, monocyte/macrophages, and T cells. Specific roles of PPAR-{alpha} in endothelial cells include interference with leukocyte cytokine-induced expression of adhesion molecules (VCAM-1) through inhibition of the master transcriptional nuclear factor-kappa-B in the VCAM-1 promoter (15), enhancing endothelial nitric oxide (NO) synthase expression and release (16), and reducing foam cell and fatty streak formation through the high-density lipoprotein (HDL) (Apo) A-I–mediated cholesterol efflux (17). Moreover, PPAR-{alpha} ligands downregulate the expression of the apoB48-remnant receptor in differentiated macrophages and reduce the uptake of glycated LDL and triglyceride-rich remnant lipoproteins (18); PPAR-{alpha} also regulates macrophage intracellular cholesterol metabolism and decreases the ratio of intracellular cholesteryl ester to free cholesterol by reducing acyl-coenzyme A:cholesterol acyltransferase-1 activity (19). As a result, PPAR-{alpha} is a major regulator in crucial steps of atherosclerosis.

The PPAR-{gamma}, in contrast, is a key regulator of glucose homeostasis and adipogenesis. Ligands of PPAR-{gamma} include naturally occurring fatty acids and prostaglandin derivatives, and glitazones, insulin-sensitizing drugs presently used to treat patients with type 2 diabetes. The PPAR-{gamma} is also expressed in endothelial cells, smooth muscle-cells, macrophages, and T cells. The PPAR-{gamma} activators increase endothelial production of NO and decrease endothelial recruitment of activated T cells (20). A major effect of PPAR-{gamma} in atherosclerosis is related to antiangiogenic effects, inhibiting vascular endothelial growth factor expression and reducing endothelial tube formation (21). The effects of PPAR-{gamma} activators on smooth muscle cells are related to inhibitory effects on migration, with decreased expression of matrix-degrading enzymes (15). These effects are also seen in macrophages reducing the expression of matrix metalloproteinase (MMP)-9, and osteopontin, and enhancing the release of the anti-inflammatory cytokine interleukin-1 receptor antagonist, suggesting a broad anti-inflammatory effect of PPAR-{gamma} in these cells (22). Of note, PPAR-{gamma} activators may also reduce the lipid content of plaques by enhancing reverse cholesterol transport and by upregulating the genes responsible for scavenger-receptor class B type I human homologue, for adenosine triphosphate-binding cassette transporter-1 and for apolipoprotein A1, thereby facilitating efflux of free cholesterol from the plaque and its transport to the liver. To investigate this mechanism, Corti et al. (23) documented plaque regression using MRI in atherosclerotic rabbits exposed to a new selective PPAR-{gamma}-activator (23). The combination of statin with PPAR-{gamma}-activator was superior to either medication alone, with decreased macrophage content and MMP activity and increased smooth muscle cell/collagen content in atherosclerotic lesions.

Positive results with PPAR-{gamma} agonists in humans are now emerging. Treatment of patients with type 2 diabetes with glitazones significantly reduced CRP levels as well as white blood cell count and MMP-9 serum levels (24). In addition, a randomized trial in patients with coronary artery disease and type 2 diabetes mellitus demonstrated a significant reduction of serum amyloid A after two weeks of rosiglitazone treatment and a significant decrease in tumor necrosis factor-{alpha} levels after six weeks (25). In addition, glitazone treatment decreased sCD40L levels as well as serum levels of MMP-9 two weeks after the initiation of treatment (26). Considering the popularity of PPAR-{gamma} agonists in clinical practice, these medications hold promise to reduce atherosclerosis in patients with or without diabetes mellitus.

Finally, PPAR-{delta} is a key regulator of inflammation and activation of macrophages and will play a pivotal role in atherosclerosis, but more studies are needed (27).

Genomics in atherothrombosis.   Many gene variants have been investigated for their effects on coronary artery disease and myocardial infarction (MI) risks. Polymorphisms in genes encoding ApoE, Lp(a) or Apo(a), ApoAI, ApoCIII, ApoIV, t-PA, fibrinogen, plasminogen activator inhibitor, von Willebrand factor, platelet glycoprotein IIIa, lipoprotein lipase, cholesterol ester hydrolase, cholesterol ester transfer protein, Factor V, Factor VII, angiotensin-converting enzyme, angiotensinogen, endothelial nitric oxide synthase, connexin 37, MMP-3, and other proteins have been associated in certain populations with a high risk of atherosclerosis, coronary artery disease, and MI (28). Within the field of single-nucleotide polymorphisms (SNP), previous studies have shown three members of the thrombospondin (TSP) family (TSP-1, -2, and -4) to be associated with MI (29). The results of these studies are very promising, but require independent replication and proof of cause-effect.

One of the most impressive advances in the genomics of atherothrombosis in 2004 was the simultaneous work by two independent groups implicating leukotriene coding genes and heart disease. The first study from The deCODE Genetics group in Iceland identified the first common gene associated with MI and stroke (30,31). The gene codes for a protein known as FLAP, or 5-lipoxygenase-activating protein, required for the synthesis of leukotrienes. By sifting through the genomes of 700 MI patients and their unaffected relatives, a broad band of deoxyribonucleic acid on chromosome 13 (13q12-13) was identified. A four-marker SNP haplotype in this locus was present in 30% of MI patients, stimulating neutrophils to produce more leukotriene B4, and nearly doubling the risk of heart attacks and stroke (30). Indeed, based on its discovery, the deCODE team is gearing up for a 200-person clinical trial in Iceland of an experimental inhibitor of FLAP, testing levels of certain molecular markers for cardiovascular disease (31). The second study, a collaborative effort from investigators at University of Southern California and University of California in Los Angeles, identified variant 5-lipoxygenase genotypes predisposing to early atherosclerosis. Carriers of two variant alleles developed increased intima-media carotid thickness similar to that observed in diabetic patients. In addition, plasma level of CRP was doubled. Of note, dietary arachidonic acid significantly enhanced the atherogenic effect of the genotype, whereas dietary intake of n-3 fatty acids blunted the effect (32).

In another study, Wang et al. (28) performed the first large-scale genomewide search for susceptibility genes for MI in a well-characterized U.S. cohort consisting of 1,613 individuals in 428 multiplex families with familial premature coronary artery disease and MI. Genotyping was performed at the National Heart, Lung, and Blood Institute Mammalian Genotyping Facility through the use of 408 markers that span the entire human genome every 10 cM. Using linkage analysis with multiple genome-wide scans, one novel significant susceptibility locus was detected for MI on chromosomal region 1p34-36, with a multipoint allele-sharing p value of –10–12 (LOD = 11.68) (28), introducing the utility of massive genotyping in the field of genomic atherothrombosis. These and others advances in the genomics of MI (33,34) provide a framework for the ultimate cloning of a gene in the fight against atherothrombosis and ischemic heart disease.


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Reliable, noninvasive imaging modalities able to detect atherothrombotic disease in the various stages and regions and to characterize the composition of the plaques are clinically desirable. Most of the invasive techniques, such as coronary angiography and intravascular ultrasound, identify luminal diameter or stenosis, wall thickness, and plaque volume. However, two emerging and most promising techniques—computed tomography and magnetic resonance—are likely to be facilitated and used by wider medical communities and applied to larger populations because these techniques are noninvasive and can evaluate calcification and luminal stenosis (computed tomography) and characterize plaque composition (magnetic resonance) (35). Within the last year, both technologies achieved significant progress. Furthermore, plaque imaging with invasive methods continues to be moving forward.

Computerized tomography and calcium scoring in primary prevention.   Today, two different modes of computed tomography are available (35). One employs non-mechanical movement of the X-ray source (i.e., electron beam computed tomography), and another involves the motion of the X-ray source and table, combined with multiple detectors to acquire the data in spiral or helical fashion (i.e., multidetector-row computed tomography). Although electron-beam computed tomography has been considered the gold standard for the assessment of calcified plaques, multidetector-row computed tomography usually includes an initial non-enhanced scan for the screening and quantification of coronary artery calcium followed by computer tomography angiography for direct visualization of coronary artery disease.

Cardiovascular prevention in asymptomatic individuals continues to be a changing target, even after the aggressive changes recently published by the Third Adult Treatment Panel of the National Cholesterol Education Program (36). As a matter of fact, these guidelines may require revision to improve risk stratification in addition to the Framingham risk score (FRS), as shown in Table 1 (37).


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  		Table 1. Pretest Probability of a Coronary Event Within 10 Years Is Derived From the Data on Coronary Risk Factors*
 
Greenland et al. (38) evaluated the additional benefit of using both coronary artery calcium scores plus the FRS in 1,461 asymptomatic, middle-aged (>45 years) adults with at least one coronary risk factor followed for 8.5 years after the computed tomography scan. Compared with a coronary artery calcium score of zero, a score >300 predicted MI and coronary death (hazard ratio, 3.9; 95% confidence interval [CI], 2.1 to 7.3; p < 0.001). Most importantly, coronary artery calcium scores were predictive of risk among patients with an FRS higher than 10% (p < 0.001) but not with an FRS lower than 10%, supporting the hypothesis that high coronary artery calcium scores can modify the predicted risk obtained from FRS alone, especially among patients in the intermediate-risk category in whom clinical decision-making is most uncertain (38).

Within the same prognostic context of calcium scores, Raggi et al. (39) conducted an observational study relating the occurrence of acute MI to coronary artery calcium progression in 817 asymptomatic subjects referred for sequential electron-beam tomographic imaging (average interval 2.2 years). Coronary artery calcium volume score progression was greater in patients with MI when compared with asymptomatic subjects without MI. In addition, coronary artery calcium scores were higher in patients with diabetes mellitus, although patients with score 0 demonstrated excellent survival rate independent of diabetes status (98.8% for diabetics and 99.4% for non-diabetics; p = NS) (40). Finally, for clinical practice, a small study suggested that a coronary artery calcium score >400 may justify nuclear stress testing (41) because the prevalence of obstructive coronary artery disease becomes particularly high at such levels.

Contrast-enhanced noninvasive coronary angiography.   Noninvasive coronary angiography is performed after the intravenous administration of iodinated contrast agent, with electrocardiogram synchronization and during breath-holding to minimize motion artifacts. The data are initially reconstructed into two-dimensional axial images with subsequent three-dimensional postprocessing. Multiplanar reformat, maximum intensity projection, volume rendering, or virtual angioscopy can be performed and aid in the diagnosis of coronary stenosis, as shown in Figure 6.



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  		Figure 6 Comparison between X-ray angiography (upper row, A) and postprocessed computed tomography (CT) coronary angiography (lower row, B) in the same patient. Three-dimensional volume-rendering postprocessed CT images can be adjusted to resemble conventional coronary angiography planes. DB = diagonal branch; Cx = circumflex; LAD = left anterior descending; LCx = left circumflex; OM = obtuse marginal; PDA = posterior descending artery; RCA = right coronary artery; RVD = right ventricular diagonal; V = vein. Reproduced with permission from Fayad ZA, Fuster V, Nikolaou K, Becker C. Circulation 2002;106:2026–34.

 
It appears that the diagnostic accuracy of multidetector-row computed tomography is reasonable, but complete assessment can be hindered by calcium deposits in the vessel wall and by motion artifacts, particularly in patients with high heart rates (35). Recent studies show a sensitivity of 89% to 92% and specificity of 93% to 98%, after the exclusion of arteries considered of subdiagnostic image quality (42–44). It is expected that resolution will improve with the newer generation 64-slice multidetector-row computed tomography that may offer marked improvement in diagnostic capability.

Noninvasive angiography may be of relevant clinical benefit in patients after percutaneous or surgical revascularization. Preliminary studies show good results in detecting total occlusions but rather low sensitivity and specificity to detect in-stent restenosis or saphenous vein graft lesions (45,46).

The use of computed tomography to detect non-calcified atherosclerotic plaques prone to rupture shows preliminary, promising results (47–50). Nevertheless, when compared with intravascular ultrasound, multidetector-row computed tomography underestimates plaque burden, probably due to lower spatial resolution, especially in distal segments (51,52).

Contrast, non-contrast coronary, and whole-body enhanced magnetic resonance angiography.   Recently, contrastenhanced coronary magnetic resonance angiography was found to have high specificity and sensitivity compared with X-ray angiography for the detection of luminal narrowing >50% (53,54). Technical advances of faster processing (55) and new contrast agents (56) are promising. In addition, contrast-enhanced magnetic resonance angiography methodology has been proposed as a technique for the assessment of coronary anomalies (57), patency of bypass grafts (58), post-stent improvement in coronary flow (59), and coronary in-stent restenosis (60). Thus far, the sensitivity and specificity are quite reasonable.

Global coherent-free precession (GCFP) is a new concept of MRI (61). In brief, protons in moving blood are "tagged" every few milliseconds as they travel through an arbitrary region in space. Simultaneous with tagging of new blood, previously tagged blood is maintained in the GCFP state, which allows visualization of pulsating blood flowing through three-dimensional space for distances of up to 16 cm. Such non-enhanced contrast technology can be of significant future value by outlining regional anatomy (i.e., coronary) and characteristics of flow.

Regional high-resolution MRI for plaque characterization.   Magnetic resonance differentiates plaque components on the basis of biophysical and biochemical parameters such as chemical composition, water content, physical state, molecular motion, or diffusion. Thus far, magnetic resonance plaque characterization of the carotid arteries and aorta has proven to be very sensitive and specific as compared with that of the coronary arteries (62,63). A crucial ultimate goal of cardiovascular noninvasive imaging is to have reliable technology for plaque characterization of the coronary arteries. Guided by contrast-enhanced computed tomography, high resolution MRI coupled with the previously mentioned contrast-enhanced molecular magnetic resonance angiography promise to fulfill this crucial ultimate goal (6,64–66).


   Serum markers for high-risk patients
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 Basic and experimental
 Clinical imaging of...
 Serum markers for high-risk...
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 References
 
CRP.   During the last year, research in the CRP continued to provide additional information for the practicing physician. Two studies and a consensus document require detailed evaluation. The first study evaluated the positive predictive value of very low (<0.5 mg/l) and very high levels of hsCRP (>10.0 mg/l) among 27,939 apparently healthy women who were followed up for MI, stroke, coronary revascularization, or cardiovascular death (67). Cardiovascular risks increased linearly from the very lowest (referent) to the very highest levels of hsCRP (p for trend <0.001), even after adjustment for FRS and after control of diabetes, as seen in Figure 7. The investigators concluded that both very low (<0.5 mg/l) and very high (>10 mg/l) levels of hsCRP provide important prognostic information on cardiovascular risk, and that hsCRP is clinically useful for risk prediction across a full range of values and across a full range of FRS.



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  		Figure 7 Relative risks of future cardiovascular events across a full clinical range of high sensitivity C-reactive protein (hsCRP) values. Blue bars = crude relative risks; red bars = risks adjusted for Framingham risk score. Adapted with permission from Ridker PM. Circulation 2004;109:1955–9.

 
The second study was less positive and generated significant controversy. Danesh et al. (68) evaluated the odds ratio for coronary heart disease using baseline measurements from the Reykjavik prospective study of 18,569 participants. After adjustment for established risk factors, the odds ratio for coronary artery disease was 1.45 (95% CI, 1.25 to 1.68) for participants in the highest third of the group with respect to those in the bottom third. Furthermore, a meta-analysis involving a total of 7,068 patients with coronary heart disease was also performed, with similar results. The investigators concluded than CRP is a relatively moderate predictor of coronary heart disease, and, therefore, recommendations regarding its use may need revision (68).

The consensus document, a statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association reviewed the scientific evidence on CRP and developed guidelines for clinical and public health practice. Using the traditional class I, IIa, IIb, and III categories, the workshop recommended the following indications for the measurement of hsCRP (69):

• Class I: none.
• Class IIa: as an independent marker of risk in those judged as intermediate risk by global risk assessment (10% to 20% risk of coronary heart disease in 10 years).
• Class IIb: as an independent marker for recurrent ischemic events (death, MI, and restenosis after percutaneous coronary intervention) in patients with chronic stable angina or acute coronary syndromes. The benefit of therapy based in this strategy remains uncertain. For laboratory testing, measurement of hsCRP should be done twice, optimally two weeks apart, fasting or non-fasting in metabolically stable patients. If hsCRP level is >10 mg/l, the test should be repeated and the patient examined for sources of infection or inflammation.
Relative risk category and average hsCRP level: low <1 mg/l; average: 1.0 to 3.0 mg/; high >3.0 mg/l.
• Class III: the adult population should not be screened for hsCRP for purposes of cardiovascular risk assessment. Application of secondary prevention measures or management guidelines for acute coronary syndromes should not depend on hsCRP determination.

The document offers additional practical information and reviews areas in which questions persist with serum markers for clinical use. This article is a must for the clinician interested in using hsCRP for patient risk-stratification and care.

B-type natriuretic peptide.   Natriuretic peptides are counter-regulatory hormones involved in volume homeostasis and cardiovascular remodeling. Nevertheless, the prognostic significance of plasma natriuretic peptide levels in apparently asymptomatic persons has not been established. The Framingham Heart study investigators prospectively studied 3,346 persons without heart failure and examined the relations of plasma B-type natriuretic peptide and N-terminal pro-atrial natriuretic peptide (BNP) to the risk of death from any cause, a first major cardiovascular event, heart failure, atrial fibrillation, stroke or transient ischemic attack, and coronary heart disease (70). During a mean follow-up of 5.2 years, 119 participants died, and 79 had a first cardiovascular event. After adjustment for cardiovascular risk factors, each increment of one standard deviation in log BNP levels was associated with a 27% increase in the risk of death (p = 0.009), a 28% increase in the risk of a first cardiovascular event (p = 0.03), a 77% increase in the risk of heart failure (p < 0.001), a 66% increase in the risk of atrial fibrillation (p < 0.001), and a 53% increase in the risk of stroke or transient ischemic attack (p = 0.002). The investigators concluded that plasma BNP levels predict the risk of death and cardiovascular events after adjustment for traditional risk factors.

Soluble CD40 ligand.   Increasing evidence suggests that CD40 ligand plays an important part in disease progression and plaque destabilization. The CD40-CD40 ligand system is widely distributed on a variety of leukocytic and non-leukocytic cells, including endothelial and smooth-muscle cells and on activated platelets. CD40 ligand also occurs in a fully active form, termed soluble CD40 ligand (sCD40L), which is proinflammatory for endothelial cells and promotes TF expression on monocytes and endothelial cells. Moreover, sCD40L ligand contains a KGD sequence that is specific for the major platelet integrin IIbß3 (glycoprotein IIb/IIIa) necessary for the stability of arterial thrombi (71).

Elevated plasma concentrations of sCD40L indicate increased risk for future cardiovascular events in apparently healthy people. Within the last year, three studies evaluating sCD40L required detailed review. The 7E3 Fab Antiplatelet Therapy in Unstable Refractory Angina (CAPTURE) study group investigated the predictive value of soluble CD40 ligand as a marker for clinical outcome and the therapeutic effect of glycoprotein IIb/IIIa receptor inhibition in 1,088 patients with acute coronary syndromes previously randomized in a trial comparing abciximab with placebo before coronary angioplasty. Additional information was obtained from a different cohort of 626 patients with acute chest pain (71). Among patients receiving placebo, elevated soluble CD40 ligand levels indicated a significantly increased risk of death or nonfatal MI during six months of follow-up. The increased risk in patients with elevated soluble CD40 ligand levels was significantly reduced by treatment with abciximab, whereas there was no significant treatment effect of abciximab in patients with low levels of soluble CD40 ligand. These results suggest that elevation of soluble CD40 ligand identifies a subgroup of patients at high risk who are likely to benefit from antiplatelet treatment with abciximab (71).

The Orbofiban in Patients with Unstable Coronary Syndromes-Thrombolysis In Myocardial Infarction-16 (OPUS-TIMI-16) group tested the hypothesis that plasma sCD40L, alone or in combination with troponin (cTnI) or CRP, may identify patients with acute coronary syndromes at heightened risk for recurrent cardiac events (72). Patients developing death, MI, or congestive heart failure had significantly higher sCD40L plasma levels than controls. After adjustment for other risk predictors, sCD40L levels were associated with higher risk for death/MI/congestive heart failure. The investigators concluded that elevated plasma levels of sCD40L identify patients with acute coronary syndromes at heightened risk of death and recurrent MI independent of other predictive variables, including cTnI and CRP.

The third study (73) evaluated the hypothesis that diabetic patients have elevated plasma levels of sCD40L and that treatment with the insulin-sensitizing thiazolidinediones lowers this index of inflammation. Subjects with type 1 or type 2 diabetes had higher (p < 0.001) sCD40L plasma levels compared with age-matched controls. Regression analysis demonstrated a significant (p < 0.001) association between plasma sCD40L and diabetes, independent of traditional and novel risk factors for coronary artery disease. Furthermore, administration of troglitazone to type 2 diabetics diminished sCD40L plasma levels by 29% (p < 0.001), suggesting that the inflammatory state in diabetics may be suitable for novel therapy (73).

Plasma levels of myeloperoxidase.   Myeloperoxidase, a leukocyte enzyme, is elevated in culprit lesions from patients with acute coronary syndromes. The Cleveland Clinic Foundation investigators assessed the value of plasma levels of myeloperoxidase as a predictor of the risk of cardiovascular events in 604 sequential patients presenting to the emergency department with chest pain (74). Initial plasma myeloperoxidase levels predicted the risk of MI, even in patients who are negative for troponin T (<0.1 ng/ml) at baseline (p < 0.001). Myeloperoxidase levels at presentation also predicted the risk of major adverse cardiac events (MI, the need for revascularization, or death) within 30 days and 6 months after presentation (p < 0.001). In patients without evidence of myocardial necrosis (defined as those who were negative for troponin T), the baseline myeloperoxidase levels independently predicted the risk of major adverse coronary events at 30 days and 6 months follow-up.

Circulating tissue factor.   Several studies suggest a role for an increased circulating pool of TF in atherothrombotic diseases. Sambola et al. (75) evaluated circulating TF activity and blood thrombogenicity in patients with type 2 diabetes mellitus, smokers, and hyperlipidemic subjects. Patients with poor glycemic control showed increased circulating TF (p = 0.0001), and increased blood thrombogenicity. Two hours after smoking two cigarettes, TF also increased (p = 0.003). Hyperlipidemic subjects also showed higher TF activity (p = 0.035) than healthy volunteers.


   New therapies for coronary artery disease
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References
 
Pharmacologic therapy.   HDL therapies
A major advance in the pharmacologic treatment of coronary artery disease is rapidly evolving by the stimulation of the reverse lipid transport system to stabilize or even regress coronary atheroma. Two studies published within the last year are worth mentioning. The first study was a randomized, double-blind, multicenter, parallel-treatment study to assess the effects of two different doses of intravenous rApo A-I Milano or placebo administered weekly for five weeks on coronary atheroma volume as measured by intravascular ultrasound in patients with acute coronary syndromes (76). The absolute reduction in atheroma volume in the combined treatment groups was –14.1 mm3 or a 4.2% decrease from baseline (p < 0.001). The investigators concluded that rApoA-I Milano produced significant regression of coronary atherosclerosis as measured by intravascular ultrasound. The authors also called for larger clinical trials with morbidity and mortality end points to confirm these results (76).

The second study evaluated the effects of torcetrapib, an inhibitor of cholesteryl ester transfer protein (CETP). This plasma glycoprotein facilitates transfer of cholesteryl esters from HDL cholesterol to apolipoprotein B-containing lipoproteins. Humans with CETP deficiency due to molecular defects in the CETP gene have markedly elevated plasma levels of HDL cholesterol and apolipoprotein A-I, leading to the concept that CETP inhibition might increase HDL cholesterol levels (77). A single-blind, placebo-controlled study in 19 subjects with low levels of HDL cholesterol (<40 mg/dl [1.0 mmol/l]), 9 of whom were also treated with 20 mg of atorvastatin daily, was performed. Treatment with 120 mg of torcetrapib daily increased plasma concentrations of HDL cholesterol by 61% in the atorvastatin cohort (p < 0.001), and by 46% in the non-atorvastatin cohort (p = 0.001). Treatment with 120 mg twice daily increased HDL cholesterol by 106% (p < 0.001). Torcetrapib also reduced LDL cholesterol levels by 17% in the atorvastatin cohort (p = 0.02). Finally, torcetrapib significantly altered the distribution of cholesterol among HDL and LDL subclasses, resulting in increases in the mean particle size of HDL and LDL in each cohort. The investigators concluded that, in subjects with low HDL cholesterol levels, CETP inhibition with torcetrapib markedly increased HDL cholesterol levels and also decreased LDL cholesterol levels, both when administered as monotherapy and when administered in combination with a statin.

Statin therapy
Additional relevant information was also published comparing different doses of statins. The first study, Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) (78), was a double-blind, randomized active control multicenter trial comparing the effects of two different statins administered for 18 months. Intravascular ultrasound was used to measure the progression of atherosclerosis in 654 patients randomly assigned to receive a moderate lipid-lowering regimen consisting of 40 mg of pravastatin or an intensive lipid-lowering regimen consisting of 80 mg of atorvastatin. Baseline LDL cholesterol level (mean, 150.2 mg/dl [3.89 mmol/l] in both treatment groups) was reduced to 110 mg/dl (2.85 mmol/l) in the pravastatin group and to 79 mg/dl (2.05 mmol/l) in the atorvastatin group (p < 0.001). C-reactive protein decreased 5.2% with pravastatin and 36.4% with atorvastatin (p < 0.001). The primary end point (percentage change in atheroma volume) showed a significantly lower progression rate in the atorvastatin (intensive) group (p = 0.02). Progression of coronary atherosclerosis occurred in the pravastatin group compared with baseline. Progression did not occur in the atorvastatin group compared with baseline. The investigators concluded that, for patients with coronary heart disease, intensive lipid-lowering treatment with atorvastatin reduced progression of coronary atherosclerosis compared with pravastatin.

The clinical relevance of these observed differences was elegantly addressed by the TIMI-22 investigators who randomized 4,162 patients with acute coronary syndromes to 40 mg of pravastatin daily (standard therapy) or 80 mg of atorvastatin daily (intensive therapy) (79). Median LDL cholesterol level achieved during treatment was 95 mg/dl (2.46 mmol/l) in the standard therapy group and 62 mg/dl (1.60 mmol/l) in the high-dose therapy group (p < 0.001). The primary end point, a composite of death from any cause, MI, documented unstable angina requiring rehospitalization, revascularization (performed at least 30 days after randomization), and stroke was 26.3% in the pravastatin group and 22.4% in the atorvastatin group (p = 0.005; 95% CI, 5% to 26%). The investigators concluded that, among patients who have recently had an acute coronary syndrome, an intensive lipid-lowering statin regimen provides greater protection against death or major cardiovascular events than does a standard regimen (79).

Antithrombotic therapy
In addition to HDL and statin therapy, antithrombotic therapy with the direct thrombin inhibitor ximelagatran offered additional benefit in the pharmacologic therapy of patients with coronary artery disease (80). In a placebo-controlled, double-blind, multicenter, multinational, dose-guiding study involving 1,883 patients with acute MI, oral ximelagatran significantly reduced the risk of death, nonfatal MI, and severe recurrent ischemia compared with placebo from 16.3% to 12.7% (hazard ratio 0.76, 95% CI 0.59 to 0.98, p = 0.036). The investigators concluded that oral direct thrombin inhibition with ximelagatran prevents major cardiovascular events during six months of treatment in patients who have had a recent MI. However, safety issues are still a major concern.

Interventional therapy.   Last year was especially productive in the interventional approach for patients with coronary artery disease. O'Neill and Dixon (81) elegantly summarized these advances in their review article entitled "The Year in Interventional Cardiology" previously published in JACC. Two important issues in the treatment of acute MI were successfully addressed with randomized trials: 1) in hospitals without percutaneous transluminal coronary angioplasty capabilities, should we give thrombolysis or refer the patient for emergent percutaneous transluminal coronary angioplasty? and 2) after successful thrombolysis, should we proceed with immediate stenting or continue with the recommended, more conservative, watchful waiting approach followed by elective stenting? In addition, major trials in the prevention of restenosis with drug-eluting stents were also published. The reader is referred to this article for details on these areas (81).


   Acknowledgments
 
The authors are indebted to Drs. Michael Poon, Javier Sanz, and Angelica Steinheimer for help with the manuscript.


   References
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 References
 

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