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1) Troponin I or T concentrations,
which are more specific for myocardial cell injury. These
proteins are involved in the calcium interaction necessary for muscle contraction.
Troponin-I and -T are structural components of cardiac muscle—highly
specific. 2) CRP
is not only an inflammatory marker of atherosclerosis, but also actively participates in the process
of atherogenesis, and is found within atherosclerotic plaques in both coronary and peripheral arterial vessels, The median level of hs-CRP, within apparently healthy individuals, has been found to be significantly
higher in those who later develop cardiovascular events than in those who do not. CRP is an independent predictor of ischaemic stroke,95 and in patients with peripheral vascular disease ( 3) 4) Fibrinogen: Epidemiological studies have shown that patients with peripheral arterial disease have an increased
plasma fibrinogen concentration. It has also been shown that in high-risk patients with PVD an elevated fibrinogen
concentration is predictive of fatal cardiovascular complications over a 10 yr follow-up period |
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ATHEROSCLEROSIS: Atherosclerosis affects the endothelial lining of arterial blood vessels, resulting in atheromatous plaque formation. The consequences of atherosclerosis include increased stiffness and a loss of elasticity in the blood vessel, stenosis of the artery, plaque rupture and aneurysm formation. Atherosclerosis is now recognized as an inflammatory process,7 70 with many known risk factors (Fig. 1). There is some evidence that infection may have a role in the aetiology with herpes viruses (Cytomegalovirus, Epstein-Barr virus and Herpes simplex-1 virus) and certain bacterial (Chalmydia pneumoniae and Helicobacter pylori) DNA having been detected in atherosclerotic plaques. Within an affected blood vessel, characteristic
alterations of blood flow occur resulting in increased turbulence and decreased shear stress leading
to endothelial changes. These early changes precede the formation of atherosclerotic lesions and are responsible
for endothelial cell dysfunction. Many factors are involved in the atherogenic process (Fig. 2). Increased permeability to lipoproteins and other plasma constituents is
mediated by increased concentrations of nitric oxide, prostacyclin, platelet-derived growth factor,
angiotensin II and endothelin. A separate process (the attraction, rolling, adherence and migration of monocytes
and T-cells to the arterial wall) is mediated by factors including the cell adhesion molecules, oxidized
low-density lipoprotein (LDL), cytokines and chemokines. Migrated monocytes are transformed into tissue
macrophages and ingest lipid deposits to form ‘foam cells’. The earliest visible evidence of the atherosclerotic
lesion is a fatty streak consisting of foam cells and activated T lymphocytes. More advanced atherosclerotic
lesions contain smooth muscle cells which form a fibrous cap walling the lesion off from the vessel
lumen. This is a protective response covering the inflammatory core of leukocytes, lipid and debris beneath,
which may be necrotic. Atherosclerotic lesions expand at their shoulders by continued leukocyte adhesion
and entry. Platelets adhere to dysfunctional endothelium, exposed collagen and macrophages becoming
activated and releasing cytokines and growth factors that together with thrombin contribute to the migration and
proliferation of monocytes and smooth muscle cells. Erosion and rupture of the plaque with consequent exposure
of thrombogenic material can lead to unstable coronary syndromes or MI. The different stages in the
development of an atherosclerotic plaque can be seen in Figure 3. There are two mechanisms involved in the causation of perioperative MI.40 THE PATHOPHYSIOLOGY OF PERIOPERATIVE
MYOCARDIA INFRACTION (i) Coronary artery occlusion: Plaque erosion or rupture leading to thrombogenesis and consequent occlusion or thromboembolic occlusion of an already narrowed coronary lumen. (ii) Prolonged ischaemia (usually silent) secondary to an imbalance between myocardial oxygen demand and supply. The first type resembles acute MI in the non-surgical setting and is related
to the concept of the ‘vulnerable plaque’. These plaques tend to be the newer, less stable coronary
atherosclerotic lesions that have undergone rapid progression and contain a substantial lipid core filled
with a large mass of thrombogenic lipids and macrophages along with various cytokines covered by a relatively
thin fibrous cap. This protective cap undergoes constant inflammation and repair, and the balance between these
two processes enables the plaque to expand in size but during this process the plaque is liable to fissure
and rupture. Figure 4 shows some of the histological features of a vulnerable plaque.
The older, more stable plaques have uniformly dense protective fibrous caps with a small lipid core and are
therefore less likely to rupture. In the non-surgical setting, there is evidence that small, non-occlusive
plaques rather than the large plaques contribute more to cardiovascular morbidity and mortality.26 These vulnerable plaques can be difficult to diagnose as they are not highly occlusive with angiography
being of limited value in identifying them.17 The second type of perioperative MI occurs most commonly in patients with severe but stable coronary artery disease, and is usually associated with prolonged silent postoperative ischaemia.40 This is thought to be the result of an imbalance between a limited myocardial oxygen supply and an increased perioperative oxygen demand. As these patients may have severe coronary artery disease, preoperative angiography can be useful in identifying those with highly occlusive coronary stenosis. Unlike the plaque rupture type of MI, the higher the grade of occlusion that a coronary stenosis causes, the more likely a prolonged stress-induced ischaemia type of MI is to occur. Therefore, identification of patients with high grade coronary artery stenosis is useful in allowing targeted interventions to minimize individual risk. Intensive monitoring of myocardial damage by biomarkers has added to the evidence that two distinct pathophysiological mechanisms of perioperative MI exist. The first type of infarction occurring in the postoperative period is not preceded by ischaemic myocardial damage, is associated with a sudden increase in the serum troponin concentration to a level diagnostic of MI, and is probably because of coronary occlusion secondary to plaque haemorrhage, rupture or thrombus formation. The later or delayed type of perioperative MI is preceded by a long period, >24 h, of ischaemic myocardial damage observed as a moderate increase in the troponin level, not initially in the range diagnostic of MI but above the upper reference limit of normal.42 Pathological studies examining the coronary vessels at autopsy of patients who have suffered fatal perioperative MI shows that the incidence of these two types of MI is roughly equal.14 17 As the pathophysiological mechanisms involved in these two types of perioperative MI are quite different, it follows that the tests to identify high-risk patients and treatment options available may also be different. PREDICTING PERIOPERATIVE CARDIOVASCULAR
EVENTS The adverse cardiovascular events that occur in the perioperative period are not limited to MI; acute coronary syndromes, congestive cardiac failure, arrhythmias and cerebrovascular accidents can all cause major morbidity and mortality. There are guidelines published on the recommended preoperative risk stratification of patients,5 12 21 22 and there is extensive literature studying the various different preoperative investigations that are available. Table 1 lists these different preoperative tests. BIOCHEMICAL MARKERS OF CARDIOVASCULAR
DISEASE A more recent and alternative approach has been measurement of biomarkers of cardiovascular disease in the blood before operation and after operation, and correlating the levels with the incidence of cardiovascular adverse events. (1) Traditional biomarkers (a) Creatine kinase (CK) (b) Aspartate aminotransferase (AST) (c) Lactate dehydrogenase (LDH) (d) Troponins An increase in cardiac troponin proteins perioperatively has been found to be useful in the prediction of cardiovascular events and is therefore a useful screening test in high-risk individuals perioperatively. Many studies have investigated the significance of early postoperative troponin increases above the upper reference limit of the test assay. These are summarized in Table 2. A meta-analysis of the 4910 patients included in the 18 studies listed show increased troponins to have a high sensitivity, specificity and negative predictive value. One problem in confirming results has been the difficulties in determining the upper reference limit of the normal range for different tests (2) Other biomarkers In addition, some plasma biomarkers appear to be risk factors for the atherosclerotic process (e.g. an unfavourable lipid profile). Other less routinely measured risk factors include uric acid, homocysteine and leptin. None of these has been investigated for their ability to predict perioperative cardiovascular events. (a) Acute phase reactants CRP is produced by hepatocytes in response to some pro-inflammatory cytokines, mainly interleukin-6 (IL-6), but also IL-1ß in the presence of IL-6. CRP is found as a trace constituent of normal plasma with the median level being 0.8 mg litre–1 and the interquartile range 0.3–1.7 mg litre–1. Most apparently healthy subjects have serum levels less than 3 mg litre–1 with levels greater than this not considered normal.61 However, an individual's baseline CRP level is fairly constant, substantially genetically predetermined,91 and there is no gender or age determined variation. CRP was the first protein to be discovered that acted as a positive acute phase reactant. With the onset of the acute phase reaction, CRP levels increase rapidly and reach peak levels, which may be as high as 300 mg litre–1, within 24–48 h. The half time of CRP in the plasma is 19 h and is constant in all conditions; hence levels decrease rapidly on resolution of the inflammatory stimulus. It is pro-inflammatory and pro-atherogenic, with the level reflecting the extent and activity of the disease process. Recent studies hypothesize that CRP is not only an inflammatory marker of atherosclerosis, but also actively participates in the process of atherogenesis, and is found within atherosclerotic plaques in both coronary and peripheral arterial vessels.84 86 In vitro, CRP binds to LDL and may become trapped in the vessel intima attached to the deposited lipids. It is well known that CRP can activate the complement system, and identification of activated complement system components along with CRP in early atherosclerotic lesions has led to the concept of CRP being involved in sustaining chronic inflammation within the arterial wall. Foam cells also stain positively for CRP, and it is hypothesized that CRP has a role in the formation of these cells by opsonization of lipid particles.84 However, CRP levels have not been shown to consistently correlate with the extent or burden of atherosclerotic disease when quantified by Doppler ultrasound of the carotid arteries24 and electron beam computerized tomography for coronary calcium.33 63 The many inflammatory processes known to raise CRP are shown in Table 3. In general, drugs or other treatments do not affect CRP production unless they also affect the disease process involved, while liver impairment will affect production of CRP. At present, most hospital biochemistry laboratories can measure CRP concentrations, but will not quantify low concentrations, reporting those under a certain threshold limit as ‘normal’. However, the accurate measurement of serum CRP concentrations up to 3 mg litre–1 is now possible with the advent of new high sensitivity assays (hs-CRP). Measurements at these low concentrations, which were previously considered to be within the normal range, have been shown to be a useful screening tool for the risk of coronary artery disease providing prognostic information in patients with known atherosclerotic disease. All individuals will have trace levels of CRP detectable on hs-CRP testing, but certain patient characteristics have been found to be associated with increased and decreased levels as shown in Table 4. According to guidelines from the American Heart Association and the Centers for Disease Control and Prevention, a hs-CRP level of greater than 3 mg litre–1 should be considered as a risk factor for future complications in patients with stable coronary disease, stroke and peripheral artery disease, while levels above 10 mg litre–1 have greater prognostic value in those suffering from acute coronary syndromes.60 The current utility of CRP. The median level of hs-CRP, within apparently healthy individuals, has been found to be significantly higher in those who later develop cardiovascular events than in those who do not,16 64 66 and these individual's risk of future cardiovascular disease can be stratified according to their hs-CRP level.38 The Framingham Risk Score was originally developed in 1991, and is a widely used scoring system designed to estimate 10 yr future risk of coronary heart disease in subjects without known disease. Recent work has shown that inclusion of the hs-CRP measurement can add additional prognostic information to this risk score especially in intermediate-risk men and high-risk women.15 CRP retains its independent association with incident coronary events even after adjusting for many of the confounding factors known to affect levels including age, total cholesterol, high-density lipoprotein (HDL) cholesterol, cigarette smoking, BMI, history of diabetes mellitus, history of hypertension, exercise level and family history of coronary heart disease.60 In patients with stable or unstable angina, CRP concentrations can act as a predictor of the patients at high risk of suffering a coronary event in the future.29 Similarly, CRP concentrations are an independent predictor of ischaemic stroke,95 and in patients with peripheral vascular disease (PVD), the CRP concentration acts as a predictor of the severity PVD and the risk of subsequent cardiovascular events.6 86 CRP and outcome. A preoperative CRP value of greater than 2 mg litre–1 was shown to be associated with postoperative complications in small group of patients undergoing cardiac surgery, and an uneventful recovery occurred in all patients with a concentration less than 2 mg litre–1.10 In patients undergoing non-cardiac surgery, there are few studies investigating preoperative CRP concentration and cardiovascular outcome. One study of 51 surgical patients undergoing revascularization procedures for PVD found that a CRP concentration greater than 9 mg litre–1 was predictive of perioperative MI (it should be noted that all patients with an ejection fraction of <40% were excluded).71 (ii) Serum amyloid A (SAA) (iii) Fibrinogen (iv) Complement proteins (b) Cell adhesion molecules (ii) Vascular cell adhesion molecule-1 (VCAM-1) (iii) Selectins (c) Cytokines and chemokines (ii) Tumor necrosis factor—TNF— is a multifunctional, pro-inflammatory cytokine with effects on many different tissues including the endothelium. It is involved in the acute phase reaction along with some of the IL. In the Cholesterol and Recurrent Events (CARE) trial, elevations of TNF- in patients after MI were associated with an increased risk of recurrent coronary events.67 (iii) Endothelins (d) Other (e) Risk factors (ii) Homocysteine (iii) Leptin A FUTURE ROLE FOR PLASMA BIOMARKERS? Of the tests described above, CRP appears the most promising for measurement in the perioperative period. CRP does not correlate with atherosclerotic burden, but may act as a marker of other atherosclerotic characteristics, possibly the activity of lymphocyte and macrophage populations within the plaque or the degree of plaque destabilization and ongoing ulceration or thrombosis.2 We question whether CRP could be useful in identifying patients with vulnerable plaques. If used as a preoperative test for unstable atherosclerotic plaques, the result would only be interpretable in those patients without other co-existing inflammatory conditions. This might limit its use. However, vascular surgical patients have the highest incidence of perioperative cardiovascular events and this test would be applicable in the majority of these patients. POSSIBLE PERIOPERATIVE MEDICAL TREATMENT
FOR VULNERABLE PLAQUES It would be extremely useful to identify patients with vulnerable plaques before operation if an intervention could then be initiated with the aim of reducing the risk of perioperative plaque rupture. Possible drugs of importance include the 3-hydroxy-3-methylglutaryl coenzyme
A (HMG-CoA) reductase inhibitors (statins), which modify lipid levels; lowering LDL and total cholesterol levels,
whilst increasing HDL levels. They have been shown to be highly effective drugs in reducing the risk
of cardiovascular events in the setting of both primary and secondary prevention. The magnitude of this risk
reduction is much greater than can be predicted on the basis of lowering LDL cholesterol alone, and it is postulated
that some of this risk reduction is because of pleiotrophic, non-lipid properties including the improvement
of endothelial function, plaque stabilization and the reduction of oxidative stress in vascular inflammation.80 The anti-inflammatory effects appear to be mediated via interference with the synthesis of isoprenoid
intermediates (mevalonate metabolites) and limitation of the nuclear factor- The question of whether or not inflammatory markers such as CRP are clinically useful in selecting patients who may benefit from statin therapy despite having normal LDL cholesterol levels has yet to be answered, and the JUPITER trial has been set up to address this question. Although statins lower CRP levels, it has yet to be proven that this represents a true reduction in inflammation. A recent study showed that CRP expression in human hepatocytes after statin therapy was blocked even in the presence of cytokines known to induce CRP,88 suggesting that statins block CRP expression at the level of transcription. Work has shown that CRP in itself may be a cardiovascular risk factor, by quenching the production of nitric oxide which in turn inhibits angiogenesis, an important compensatory mechanism in chronic ischaemia. Statin therapy has been shown to reduce the incidence of perioperative cardiovascular complications in patients undergoing major non-cardiac surgery in a large retrospective cohort study,44 and a prospective double-blind randomized controlled trial.20 After abdominal aortic aneurysm repair, long-term statin therapy has been shown to be associated with a 3-fold reduction in cardiovascular mortality.37 Concerns about an increased incidence of statin-associated myopathy within the surgical population are unfounded.75 Studies have shown that improvements in endothelial function, and reductions in serum inflammatory markers occur within 2–16 weeks after beginning statin therapy but the minimum period of preoperative and postoperative therapy has not yet been determined. The most efficacious dose of statin therapy in the perioperative period is another area lacking research. In acute coronary syndromes, high dose statin therapy is now advocated showing a reduction in future events over placebo or a standard dose regimen.56 The question of whether patients at increased risk of perioperative cardiovascular events with raised inflammatory markers would benefit from this sort of high dose statin regimen during the perioperative period has yet to be answered. Another class of drug known to reduce the concentrations of inflammatory mediators including CRP is the thiazolidinedione group,25 which are used in the treatment of diabetes mellitus type 2. These drugs have been found to have a beneficial effect on the cardiovascular system independent of their anti-diabetic effect but any potential protective role of these drugs in the perioperative period has not been studied. CONCLUSION: Most work to date has focused on the identification of a subgroup of surgical patients at high risk of PMI. 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billion, tops all drugs. Plavix at
$60 billion is second.
STATINS CANCER Link 52% short term LA Times, Health section, Vytorin, the
combination drug (simvastatin (better known by its commercial name Zocor) and ezetimibe--known as Zetia) prescribed to lower
cholesterol, sustained another blow today, when the author of a major clinical trial announced that the medication had failed
to drive down hospitalization and death due to heart failure in patients with narrowing of the aortic valve. In the process,
researchers in Today's findings
suggested something more ominous: the incidence of cancer -- and of dying of cancer -- was significantly higher in the patients
taking Vytorin. Altogether, 67 patients on placebo developed cancer during the trial.
Among subjects on Vytorin, 102 developed cancers of various kinds.* This
is the second adverse press—the first being in March 08, when the ENHANCE trial found that Vytorin fared no better than
a placebo at reducing plaque buildup on the walls of patients' arteries.* * Comments by jk Simvastatin (Zocor) is off patent. Thus in a scramble for profits a combination drug (on patent) was introduced. Direct to consumer market cost $155 in 07—mainly TV ads. * The pressing issue is that since the development of Statins, the very first animal studies in the 60s it has been known that Statins increase the incidents of cancer. However, nearly all studies done thereafter have not included cancer. *
Several studies have failed to find a reduction in the build of plaque, even thought the statins including Zocor, reduce
EXTENDED RELEASE NIACIN IS A SAFER, AND A MORE EFFECTIVE WAY TO LOWER MI RISK! |