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Post by Admin on Feb 27, 2022 20:06:53 GMT
High-risk atherothrombotic plaque In spite of a common pathophysiologic pathway, atherosclerotic lesions are very heterogeneous and the “high-risk plaque” of each vascular bed has unique characteristics. Insights into the disease have advanced beyond the notion of progressive occlusion of the coronary artery into the recognition that plaque disruption and superimposed thrombus formation are the leading causes of acute coronary syndromes and cardiovascular death. Consequently, plaque composition (as a determinant of risk of disruption), rather than luminal stenosis, has become the major determinant of this disease.7
Histologically, these rupture-prone (also called vulnerable or high-risk) lesions consist of a large core of extracellular lipid, a dense accumulation of macrophages, reduced numbers of vascular smooth muscle cells, and a thin fibrous cap. Hence, is not surprising that these plaques are less stable and have a greater propensity to rupture than the fibrous, collagen-rich plaques. Plaque disruption usually occurs at the weakest point (“shoulder”), where the cap is often thinnest and most heavily infiltrated with inflammatory cells.8 Once the plaque is disrupted, the highly thrombogenic, lipid-rich core, with abundant tissue factor, is exposed to the bloodstream, triggering the formation of a superimposed thrombus that leads to vessel occlusion and subsequent ischaemic symptoms distal to it.9
In contrast with most high-risk coronary plaques, high-risk carotid plaques are considerably more stenotic. They are not lipid-rich but rather heterogeneous and very fibrous. Plaque disruption is often caused by an intramural haematoma or dissection that probably is related to the systolic stroke of blood against the resistance they offer.10 Although lipid accumulation in the carotid arteries is quite diffuse, a recent study reported the presence of ruptured lipid-rich plaques in patients with TIA and stroke.11 In addition, the so-called “cryptogenic strokes” also have an atherothrombotic origin. The source of emboli is usually a carotid or aortic thrombus.12
Similarly, high-risk plaques of the lower extremities appear to be very stenotic and fibrotic.13 Available evidence suggests that in PAD, plaque stenosis associated with hyperthrombogenicity of the blood seem to be major contributors to acute ischaemic syndromes (sudden ischaemic pain, gangrene). This is suggested by the high prevalence of known causes of a hyperthrombotic state of the blood, such as diabetes, cigarette smoking, and dyslipidaemia,14 in PAD patients.15
Conversely, high-risk plaques in the thoracic aorta frequently contain a high proportion of extracellular lipids and are characterised by a shift toward greater macrophage content relative to smooth muscle cells in the cap. At autopsy, aortic plaques from persons who died of ischaemic heart disease often have ulceration and mural thrombosis.16 Recent aortic plaque characterisation by magnetic resonance imaging (MRI) has confirmed their lipid-rich composition.17
Over the last decades, pathologic studies have shown an increased number of vasa vasorum in advanced atherosclerotic lesions. A correlation between the extent of vasa vasorum neovascularisation and severity of atherosclerotic disease has been demonstrated in human coronary arteries. Therefore, this observation indicates that the vasa vasorum might play a role in atherogenesis as a regulator of plaque progression and instability. Nevertheless, whether neovascularisation precedes or follows plaque development is still not known. Interestingly, a recent experimental study demonstrated that the angiogenesis inhibitor angiostatin reduces macrophage accumulation and progression of advanced atherosclerosis.
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Post by Admin on Feb 27, 2022 21:12:02 GMT
High-risk blood Two thirds of ACSs are caused by the disruption of a high-risk atherothrombotic plaque with superimposed thrombus formation. In one third of ACSs, particularly in sudden coronary death, there is no rupture of a high-risk atherothrombotic plaque but only a superficial erosion of a markedly stenotic and fibrotic lesion.18
Thrombus formation in such cases may depend on a hyperthrombogenic state triggered by systemic factors. Indeed, several cardiovascular risk factors, including elevated LDL cholesterol, cigarette smoking, and hyperglycaemia, have been associated with increased blood thrombogenicity.19
Circulating tissue factor has been associated with increased blood thrombogenicity in patients with unstable angina20 and chronic coronary artery disease. Blood levels of tissue factor have also been shown to predict outcome in patients with unstable angina.21
Several lines of evidence support the hypothesis that circulating apoptotic cells and cellular microparticles may play a significant role in blood thrombogenicity. Patients with ACS have elevated levels of circulating tissue factor,21 and there is evidence that acute thrombosis may be initiated by membrane-bound circulating tissue factor originating from activated or injured cells.22 It is believed that a major source of blood-borne tissue factor could be the circulating microparticles, which are endowed with potent procoagulant potential, attributable to the presence of phosphatidylserine on their surface.23 A significant increase in the number of circulating endothelial cells, some of them apoptotic, has also been reported in patients with ACS.24 The circulating procoagulant microparticles may also contribute to the blood thrombogenicity of patients with hyperlipidaemia or high blood glucose concentrations; these vascular risk factors are known to be responsible for increased apoptotic activity in vitro.25
Elevated LDL cholesterol levels have been found to increase blood thrombogenicity and the growth of thrombi under defined rheology conditions.26 Reducing LDL cholesterol levels with statins has been shown to decrease thrombus growth by approximately 20%.27 The extent to which this antithrombotic effect contributes to the reduction of total vascular events, including death, coronary events, and stroke, is a matter of debate.28
Diabetic patients, especially those with poorly controlled diabetes, have increased blood thrombogenicity.29 Platelets from patients with diabetes have been shown to have increased reactivity and hyperaggregability and expose a variety of activation-dependent adhesion proteins.30 Abnormal platelet function is reflected by increased platelet consumption and increased accumulation of platelets on the altered vessel wall. The increased procoagulant activity in diabetes is also attributed to leukocytes, which may, in part, activate the tissue factor pathway31 and contribute to the high blood thrombogenicity.30
Fibrinogen concentration was found to be associated with increased blood thrombogenicity.32 Several of the classic risk factors have been shown to modulate fibrinogen levels. Fibrinogen levels tend to be higher in patients with diabetes, hypertension, obesity, smoking habit, and sedentary lifestyles.33,34 However, further clinical trials are needed before it can be determined whether fibrinogen is directly involved in the pathogenesis of atherothrombosis or is merely a marker of the degree of vascular damage.
As previously described, lipid-rich atherosclerotic plaques contain tissue factor associated with macrophages within the lesion,35 which may account, in large part, for the high thrombogenicity of these lesions. In addition, specific inhibition of the tissue factor pathway by its physiologic inhibitor, tissue factor pathway inhibitor (TFPI), significantly reduces plaque thrombogenicity.36
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Post by Admin on Feb 28, 2022 1:45:04 GMT
Early detection with noninvasive imaging technology As discussed above, culprit lesions are often mildly stenotic owing to significant positive remodelling and, therefore, not detectable by angiography. Given the importance of plaque composition rather than degree of stenosis, over the last decade there has been a substantial improvement in different noninvasive imaging modalities that allow full characterisation of atherothrombotic plaques.6 Use of these imaging techniques to detect subclinical pathology and as a surrogate marker may supplement or improve cardiovascular risk assessment, especially in patients with intermediate cardiovascular risk. Ultrasound Measurements of carotid and aortic wall thickness, as well as qualitative and quantitative analysis of atherothrombotic plaques, can be made by ultrasound. Hypoechoic heterogeneous plaque is associated with both intraplaque haemorrhage and lipids, whereas hyperechoic homogeneous plaque is mostly fibrous.37 The North American Symptomatic Carotid Endarterectomy Trial and the Asymptomatic Carotid Artery Stenosis Study have shown that the degree of stenosis plays a significant role in producing stroke.38 Real-time B-mode ultrasound with Doppler flow imaging has emerged as the modality of choice for examining the carotid arteries. Real-time B-mode ultrasound can be used to measure the intima-media thickness of large- and medium-size arteries, such as the carotid, femoral, or radial. Several studies have found that carotid and aortic atherosclerosis are markers for coronary atherosclerosis.39,40 Patients with symptomatic CAD have increased intima-media thickness compared with asymptomatic controls.41 Carotid wall thickening was also found in patients with silent ischaemia.42 The relationship between intima-media thickness and the severity of CAD is rather constant. In addition, large prospective studies have demonstrated that intima-media thickness is a useful marker of CAD progression. For example, the Cardiovascular Health Study43 found associations between carotid intima-media thickness and the incidence of new myocardial infarction or stroke in patients 65 years of age. Prevention trials of lipid-lowering treatments using intima-media thickness as a surrogate endpoint have shown that retardation in the progress of intima-media thickness correlates with a reduction of clinical endpoints.44 Recently intima-media thickness was compared with C-reactive protein, a well known inflammation marker, and was found to be an independent and accurate predictor of ischaemic stroke.45 Magnetic resonance imaging High-resolution MRI has emerged as the potential leading noninvasive in vivo imaging modality for atherosclerotic plaque characterisation. Recently, Cai et al.46 published a classification of carotid atherothrombotic lesion with in vivo, multicontrast MRI. The authors found a strong correlation between the classification of the American Heart Association and the one obtained with MRI. More recently, Yuan et al.11 reported on the presence of a ruptured fibrous cap (identified with MRI) in patients who had experienced a stroke or TIA within 90 days. In addition, the use of gadolinium provides additional information, since it allows the identification of neovascularisation in atherothrombotic plaques and may distinguish a fibrous cap from a necrotic core.47 Experimental studies in a pig model showed that the difficulties of coronary wall imaging are due to a combination of cardiac and respiratory motion artefacts, nonlinear course, small size, and location of the coronary arteries.48 Our group extended the black-blood MRI methods used in the human carotid artery and aorta to imaging the coronary arterial lumen and wall.49 High-resolution black-blood MRI of both normal and atherosclerotic human coronary arteries was performed. The difference in maximum wall thickness between the normal subjects and patients (⩾40% stenosis) was statistically significant.49 This coronary plaque MRI study49 was performed during breath-holding to minimise respiratory motion. We have shown recently that MRI can be used to measure the effect of lipid-lowering therapy (statins) in asymptomatic, untreated, hypercholesterolaemic patients with carotid and aortic atherosclerosis.50 (see Fig. 3) Atherosclerotic plaques were assessed with MRI at different time points after initiation of lipid-lowering therapy. Significant regression of atherosclerotic lesions was observed. Despite the early and expected hypolipidaemic effect of the statins, a minimum of 12 months was needed to observe changes in the vessel wall. No changes were detected at 6 months. In agreement with previous experimental studies, there was a decrease in the vessel wall area and no change in the lumen area at 12 months.50
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Post by Admin on Feb 28, 2022 15:29:23 GMT
Ankle-brachial index The ankle-brachial index is a very simple noninvasive method for assessing the patency of the lower-limb arterial system and screening for the presence of PAD. Measurement of the ankle-brachial index is a simple procedure and requires only an ordinary blood pressure cuff and a Doppler ultrasound sensor. The ankle-brachial index is calculated from blood pressure measurements in the brachial artery in both arms and the left and right posterior tibial arteries and dorsalis pedis arteries. Low ankle-brachial index values (<0.90) are considered evidence of PAD, and progressively lower ankle-brachial index values indicate more severe obstruction. Low ankle-brachial index values are also considered to be indicative of generalised atherosclerosis.51
Biomarkers of atherothrombosis In recent years, a number of biomarkers have been proposed as significant predictors of atherosclerosis and its thrombotic complications (Table 1). Among them, C-reactive protein is one of the most studied. C-reactive protein is an acute-phase reactant that increases in inflammatory states. A growing body of evidence suggests that even small increases in C-reactive protein are predictive of future vascular events in apparently healthy, asymptomatic individuals.52 Recently, Danesh et al.53 reported a meta-analysis of 14 prospective studies on C-reactive protein and the risk of nonfatal myocardial infarction or death from coronary heart disease. The analysis comprised 2557 cases and a mean follow-up of 8 years. The adjusted risk ratio was 1.9 (95% confidence interval, 1.5–2.3) for the development of CAD amid the patients in the top tertile of baseline C-reactive protein concentrations compared with those in the bottom tertile. In addition, several studies demonstrated that C-reactive protein predicts recurrent events or increased mortality in patients with stroke, ACS, stable angina, and PAD.52,54–56
Table 1B
Inflammation markers Thrombosis markers C-reactive protein Fibrinogen Interleukins von Willebrand factor CD40 ligand Plasminogen activator inhibitor 1 Serum amyloid A Fibrinopeptide A Vascular molecules Prothrombin fragment 1+2
Among the prothrombotic markers, fibrinogen is one of the most studied.57 It is a circulating glycoprotein that acts at the final step of the coagulation cascade. Aside from its role in thrombosis, a number of other functions have been postulated, including regulation of cell adhesion and migration, vasoconstriction, stimulation of platelet aggregation, and determination of blood viscosity.58,59 Epidemiologic evidence supports an independent association between elevated fibrinogen and cardiovascular morbidity and mortality. Two recent meta-analyses involving 18 and 22 prospective studies demonstrated strong, statistically significant, risk ratios for the individuals in the upper tertile of baseline fibrinogen levels compared with those in the bottom tertile (risk ratio, 1.8, 95% CI 1.6–2.0, and odds ratio, 1.99, 95% CI 1.85–2.13, respectively).33,53 Additionally, other studies demonstrated an independent association between fibrinogen and stroke and PAD.34,60,61
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Post by Admin on Feb 28, 2022 21:13:27 GMT
Antithrombotic approaches Treatment of atherothrombotic patients must include the management of cardiovascular risk factors and antiplatelet treatment for the prevention of thrombotic complications. Secondary prevention of an ischaemic event in the index territory will provide primary prevention for other arterial beds that are still clinically silent. The aims of antiplatelet therapy are, firstly, to prevent the occurrence of acute ischaemic events through inhibition of platelet thrombus formation and, secondly, to protect distal tissues by inhibiting microembolisation. Due to the systemic nature of the disease, antiplatelet therapy (which has shown consistent benefit across all arterial beds) is essential for optimal prevention of ischaemic events in atherothrombotic patients.62
The significance of thrombosis in atherothrombotic disease is evidenced by the fact that antithrombotic therapy has reduced the relative risk of cardiovascular events by up to 25%.63 Several landmark trials have established the efficacy of aspirin in atherothrombosis (Table 2). Remarkably, the ISIS-2 study found that the effect of aspirin in acute myocardial infarction (MI) was comparable to the effect of a fibrinolytic agent (streptokinase).64 A recent meta-analysis by the Antithrombotic Trialists Collaboration suggests that the use of aspirin should be expanded to populations such as those with diabetes, peripheral arterial disease, carotid disease, and end-stage renal disease. They also concluded that there is no additional benefit by using chronic aspirin doses higher than 75 mg.62 The Thrombosis Prevention Trial (TPT)65 demonstrated a 20% relative reduction in the combined endpoint of coronary death and nonfatal MI with a dose of aspirin of 75 mg.
Table 2
Landmark acetylsalicylic acid trials Trial Patients Treatment ISIS-2 17,187 men with suspected MI ASA 160 mg daily vs. placebo US Physicians Health Study 22,701 healthy physicians ASA 325 mg every other day Thrombosis Prevention Trial (TPT) 5085 high-risk men from UK ASA 75 mg daily vs. placebo Hypertension Optimal Treatment (HOT) 18,790 hypertensive men and women ASA 75 mg daily vs. placebo
In the antiplatelet armamentarium, clopidogrel represents a critical advance and several clinical trials have been carried out with this drug (Table 3). A daily 75 mg dose of clopidogrel was compared with a daily 325 mg dose of aspirin in patients with cardiovascular disease in the CAPRIE66 (Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events) trial. After an average of 1.9 years follow-up, the data demonstrated a statistically significant 8.7% relative risk reduction in the composite endpoint of MI, ischaemic stroke, and vascular death. This is noteworthy when one takes into account that aspirin, which itself has a marked effect compared with placebo, was used as an active control.
Table 3
Landmark clopidogrel trials Trial Patients (n) Treatment CURE 17,187 ASA 160 mg daily vs. placebo CAPRIE 22,701 ASA 325 mg every other day vs. placebo CREDO 5085 ASA 75 mg daily vs. placebo PCI-CURE 18,790 ASA 75 mg daily vs. placebo
Clopidogrel for the Reduction of Events During Observation (CREDO) was a multicenter, double-blind study of patients with stable and unstable angina who were undergoing percutaneous coronary intervention. The trial demonstrated the safety and efficacy of clopidogrel treatment before the procedure, and the beneficial effect of prolonged (1 year) versus short-term (1 month) antiplatelet therapy.67
The combination of aspirin and clopidogrel has a synergistic effect in preventing thrombus formation. The CURE68 (Clopidogrel in Unstable angina to prevent Recurrent Events) trial tested the efficacy of this combination compared with aspirin alone. The results showed a 20% relative risk reduction of the composite endpoint of nonfatal MI, stroke, and cardiovascular death in the combination group. Patients assigned to the dual antiplatelet treatment had higher rates of major bleeding, but no increase in life-threatening bleeding. A subgroup analysis of patients who underwent percutaneous coronary intervention (PCI) during the CURE trial, PCI-CURE,69 demonstrated that pretreatment (mean=10 days) with clopidogrel and aspirin before percutaneous coronary intervention, as well as long-term treatment (mean=8 months), was useful in reducing ischaemic events. Many studies with clopidogrel are still ongoing (Table 4).
Table 4 Ongoing clopidogrel trials
Study Patients Maximum follow-up Patients (n) Results expected ACTIVE Atrial fibrillation 48 months ∼14,000 2007 CAMPER PAD (post-angioplasty) 30 months ∼2000 2006 CHARISMA Cardiovascular or cerebrovascular disease, PAD, or major risk factors 42 months ∼15,200 2005 COMMIT (CCS-2) Acute MI 4 weeks ∼45,000 2005 CLARITY Acute MI 4 weeks 3000 2004 MATCH TIA or ischaemic stroke 18 months 7601 2004
There have been 5 large randomised trials of oral glycoprotein (GP) IIb/IIIa antagonists in patients with CAD: OPUS-TIMI 16,70 EXCITE,71 SYMPHONY,72 SYMPHONY II,73 and BRAVO.74 Although these agents once held great potential, all the clinical trials consistently demonstrated an increased mortality with GP IIb/IIIa agent compared to placebo. A recent meta-analysis of 4 trials showed a significant 37% increase in mortality with the use of a GP IIb/IIIa antagonist.75
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