The Past: Emergence of a Syndrome
The clinical description of a preinfarction syndrome closely followed that of angina almost 250 years ago, when Heberden wrote the following:
There is a disorder of the breast marked with strong and peculiar symptoms and considerable for the kind of danger belonging to it. … The seat of it, and sense of strangling and anxiety with which it is attended, may make it not improperly be called Angina pectoris. Those who are afflicted with it, are seized, while they are walking, and more particularly when they walk soon after eating, with a painful and most disagreeable sensation in the breast, which seems as if it would take their life away, if it were to increase or to continue: the moment they stand still, all this uneasiness vanishes. After it has continued some months, it will not cease so instantaneously upon standing still; and it will come on, not only when the persons are walking, but when they are lying down.
The component of instability of angina was then recognized; it is now still how acute coronary syndrome (ACS) is most often recognized. In 1910, Sir William Osler formalized the description of frequent symptoms often preceding myocardial infarction, setting the stage for 50 years of retrospective and prospective observations on manifestations, natural history, and discussions on definitions and potential causes. Wood, in 1948, first attempted to halt the progression of the disease to death and myocardial infarction (MI). He reported the occurrence of MI or death in 12 of among 25 patients with an acute coronary insufficiency not treated with an anticoagulant and, in 3 of 33 patients given oral anticoagulants. It was suggested that the acute coronary insufficiency state is caused by a coronary circulation insufficient to meet the full demands of the myocardium at rest, yet sufficient to prevent MI.
A Florid Period
The modern era of coronary care was modeled through the 1960s to the mid-1990s. It started with external cardiac reanimation, universal acceptance of cardiac care units (CCUs), and electrocardiographic monitoring, and progressed to coronary angiography and coronary artery bypass grafting (CABG), reperfusion, anti-ischemic and antithrombotic therapy, and then to percutaneous interventions and stenting.
In parallel, the art of clinical trials grew to the levels of sophistication and performance we now know, and became standard to guide treatment and set the basis for evidence-based therapy. Early trials compared emerging medical management with no less than CABG. Drugs tested then include beta blockers, calcium antagonists, nitrates, and antithrombotic therapy—first with aspirin, then with heparin, and finally their combination. Research focused on pathophysiology, recognizing that unstable symptoms were caused by a rapid progression of the severity of the coronary obstruction causing a primary reduction in flow. Coronary artery spasm as the main cause of this dynamic occlusion was rapidly ruled out, as coronary angiography performed during the very acute phase of the disease documented that thrombotic occlusion was the most frequent finding.
Keys to subsequent progress were the motivation of national cardiology organizations to master coronary artery disease, a major killer, and the strong commitment of many people, independent groups, pharmaceutical and industrial partnerships, and research and education at the local, national, and international levels.
Guidelines and Recommendations
The first official guidelines for the diagnosis and management of unstable angina (acute coronary syndromes) were published in 1994. They were the tenth of a series of clinical practice guidelines published by the U.S. Department of Health and Human Services under the auspices of the Agency for Health Care Policy and Research (AHCPR) and the National Heart, Lung, and Blood Institute (NHLBI). The working panel was chaired by Dr. Braunwald. These practice guidelines were specifically developed and written to educate practitioners about appropriate health care for specific clinical entities.
Unstable angina at the time was a well-defined syndrome, recognized as being responsible for a significant amount of disability and death, and termed acute coronary syndromes to cover the full spectrum of severity of the disease process and clinical manifestations, from unstable angina (UA) to non–ST-segment elevation myocardial infarction (NSTEMI), ST-segment elevation myocardial infarction (STEMI), and sudden death. Risk stratification, then based on clinical history, clinical features at presentation, and electrocardiographic changes, became a turning point for patient management. The biomarkers cardiac troponin I and T came a little later. Their high sensitivity and specificity to detect myocardial necrosis were soon recognized, along with their power for risk stratification and for identifying patients who most benefited from more aggressive antithrombotic therapy and from invasive procedures. Another important gain of troponins is to set the focus on culprit lesions, an elevation in troponin levels being seen as diagnosis of a micro zone of myocardial cell necrosis caused by distal embolization of thrombotic material shed from a thrombus on an activated ruptured plaque. Assessment of troponin levels was assigned a grade 1a priority by the first sets of official guidelines for the management of UA NSTEMI, produced independently by the European Society of Cardiology and the American College of Cardiology (ACC)/American Heart Association (AHA) in 2000. The counterpart of no troponin level elevation and a normal electrocardiogram (ECG) become a low-risk situation, with no need for aggressive and urgent intervention and printable for an outpatient evaluation.
Clinical Trials and Registries
Proof of concept in the development of new therapeutics is usually achieved through phase 2 investigation demonstrates that the underlying theory, concept, procedure, or drug has a potential to be exploitable in a useful manner for improving quality of care and/or to show the feasibility in human application of a new intervention or a new drug. Phase 3 investigations are more rigorous and seek unbiased and objective documentation that the intervention is really useful. Entry criteria and objectives need to be well predefined because they will establish the framework for future approval and use. Whether trial results are considered positive or negative is based on the analysis related to the primary objective(s); secondary objectives, nonpredefined analyses, or substudies usually also raise new hypotheses of major interest that can generate new research. Strong recommendations in practice guidelines are based on phase 3 trial results. When lacking, weaker recommendations based on lower levels of evidence are usually made.
Statistics and epidemiologic data on cardiovascular diseases, as for other diseases, are obtained from various sources. Incidence and prevalence data are best obtained from government statistics. Registry data provide a broader perspective on the characteristics of selected populations of interest that are more like those in the real world. In clinical trials, populations are more dedicated, responding to specific inclusion and exclusion criteria. Registry data have been widely used in the last 2 decades as they reached an international scale. They produce valuable information about the pulse of the disease, including epidemiology, risk factors, and sociodemographic data in different environments and different lifestyles. Adding follow-up data to these registries provides estimates on natural history and effects of treatment, and adding serial cross-sectional samplings helps evaluate the changing pattern of the disease and the success of various interventions applied. Registries have now evolved as a means to monitor and improve quality of care and resource utilization. A drawback of these registries is that they become rapidly obsolete as feedback on performance is provided that stimulates autocorrection of deficiencies observed.
The first section of this textbook highlights data from four modern registries relevant to acute coronary syndromes, two from academic groups that studied risk factors and the natural history of the disease, and two from organizations that attempt to improve quality of care. Finally, a fifth mixed registry will be discussed for its positive impact on practice standards.
The INTERHEART Study (see Chapter 2 ) was a case-control study of close to 30,000. Cases were patients with a first MI recruited from 262 centers from 52 countries; controls were recruited from the surrounding community and matched for age and gender. Nine simple risk factors could account for more than 95% of the attributable risk for MI; the observations held true across all regions, ethnic groups, genders, and ages. While demystifying the causes of acute coronary syndromes, the findings of mental stress, all forms of tobacco, obesity (best defined by abdominal obesity and waist-to-hip ratio), nonfasting apolipoprotein B (apo B)–to–apolipoprotein A1 (apo A1) ratio, and simple measures of dietary pattern as production factors.
The REACH registry (see Chapter 3 ) enrolled almost 70,000 patients from 44 countries. The goal was to look at the pattern of risk factors associated with atherothrombotic disease across various vascular beds (coronary artery disease [CAD], cardiovascular disease [CVD], and peripheral vascular disease [PVD]) in geographically and ethnically diverse populations, and at their impact on prognosis and treatment modalities. The registry showed considerable gaps between risk-reducing recommended measures and current practice. As for INTERHEART, traditional cardiovascular risk factors accounted for most of the risk of the disease. The current obesity epidemic plaguing the industrialized nations of the world, particularly North America, and threatening emerging countries was underlined as a major cause of disease on a global scale. Short-term ischemic events were relatively high in the registry, the more so in individuals with more than one-vessel bed disease. An interestingly observation for all clinicians is that the disease, in general, is more malignant in symptomatic patients than in asymptomatic patients.
The Euro Heart Survey program was launched by the European Society of Cardiology (see Chapter 4 ) to assess variations in management and treatment of cardiovascular disease across Europe, particularly with regard to diagnostic procedures and treatments. The first survey, launched in 2000, involved more than 10,000 patients and was mainly descriptive of diagnoses and subdiagnoses, investigative means, and treatment applied in-hospital and at discharge. The second survey, in 2004, enrolled 6385 patients and showed similar results but greater use of coronary angiography, percutaneous interventions (PCIs), and stents, mainly in ST-elevation ACS. An improvement in outcome was also observed that was to better adherence to guideline recommendations. Based on these observations and also on the wide variations in guideline adherence across different countries and in different centers within the same country, the Euro Heart Survey has moved from cyclic to continuous data collection in the ongoing ACS registry.
The U.S. counterparts of the Euro Heart Survey included the National Registry of Myocardial Infarction (NRMI), Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the ACC and AHA Guidelines (CRUSADE), and Get With The Guidelines (GWTG) programs. In addition to providing a large national database to collect information on patients with ACS, these registries act as benchmarking tools to compare performance of various hospitals and adherence to guideline-recommended therapies. To improve quality of care further, the NCDR (National Cardiovascular Data Registry)-ACTION was created in 2007 by combining the NRMI and CRUSADE registries (see Chapter 5 ). The ACTION (Acute Coronary Treatment and Intervention Outcomes Network) registry is the largest, most comprehensive national ACS database and quality improvement initiative developed in the United States, enabling hospitals to measure their performance against national benchmarks. With more than 60,000 patient records and 350 participating hospitals, the main objective of the ACTION registry is to assess and report treatment patterns and outcomes of STEMI and NSTEMI in the United States. ACTION also merged with the AHA’s GWTG program in 2009, forming ACTION-GWTG registry.
The GRACE registry, launched in 1999, recruited patients up to December 2007, it was supported by an unrestricted grant from Sanofi Aventis. More than 100,000 patients were recruited in up to 247 hospitals from 30 countries, from Europe, North and South America, and Australia and New Zealand. The first 10 to 20 patients qualifying for ACS symptoms plus other evidence of CAD were recruited monthly in each center. Data collection included admission and discharge diagnoses, clinical characteristics, treatment applied, with special attention to reperfusion therapy, in-hospital events, including bleeding events, and follow-up data for 6 months. Participating physicians received confidential quarterly reports showing patient outcomes side by side with aggregate outcomes of all participating hospitals, allowing disparities between centers and regions to be characterized. Some of the contributions of GRACE were temporal trends in the rates and prognoses of ACS subdiagnostic categories, patterns of drugs used, complications of anticoagulants and antiplatelet therapy, impact of prior aspirin, statin, atrial fibrillation, and congestive heart failure on outcome, influence of stenting and glycoprotein (GP) IIb/IIIa on survival, 6-month outcomes, predictors of readmission, death and MI, and the GRACE score.
The Present: A Well-Defined Entity
Diagnosis
The diagnosis of ACS is first based on the recognition of typical or suggestive symptoms; signs at the physical examination are only scanty unless complications supervene such as congestive heart failure, mitral regurgitation, or others. Various phenotypes are recognized on a common pathophysiology. A 12-lead electrocardiogram (ECG) is first obtained and repeated as needed for evolving symptoms to ruleout STEMI, which would mandate consideration of immediate reperfusion therapy. The absence of ST-T changes in the presence of pain or other symptoms still does not rule out an electrically silent ACS. Alternative diagnostic methods are then needed, starting with recording the dorsal leads V7, V8, and V9 and, as needed, pursuing with imaging methods to detect ischemia, while alternative diagnoses are considered. 2D-echocardiography is readily available in the emergency department and is highly sensitive to detect regional dysfunction; however, it cannot differentiate an old infarct from acute ischemia (see Chapter 14 ). Other useful methods are a radionuclide perfusion scan, a CT scan, or a nuclear magnetic resonance study (see Chapter 15 ). The differential diagnoses of acute MI include aortic dissection, pulmonary embolism, pericarditis and eventually a pneumothorax, an esophageal problem, or one of many other potential causes.
Typically, high-risk patients require immediate coronary catheterization. Less acute patients at low to intermediate risk are investigated with serial ECG, cardiac troponins, and, as needed, echocardiography and/or radionuclide perfusion imaging. In patients with chest pain but no clear evidence of a high-risk ACS whose symptoms may also be attributed to an acute life-threatening pathologic condition of the aorta or pulmonary arteries, a “triple rule-out” (TRO) 64-slice CT angiography scan may be the most appropriate diagnostic test. With this approach, a single scan incorporating the aortic arch down through the heart but not including the entire chest to limit radiation exposure, may eliminate the need for further diagnostic testing in over 75% of patients.
The timing of chest pain and its duration are important helps for the physician. Although ST resolution is generally accepted as the more practical marker for the success or failure of reperfusion therapy, chest pain that persists despite reperfusion therapy may suggest no effective reopening of the culprit lesion or no-reflow at the cellular level. Urgent angiography then needs to be considered. Chest pain that lasts more than 20 minutes is usually associated with an elevation of cardiac troponins. The third generation of cardiac troponin assays allows the detection of an elevation as early as 3 to 6 hours after the onset of pain, and enhances the sensitivity for the detection of very small microinfarcts. Further improvement is expected from the emerging sensitive troponin assays now being introduced in routine practice.
These assays will clearly increase the rates of detection of myocardial cell necrosis, and new care and diagnostic algorithms will be needed to avoid over diagnosing myocardial infarction. The new universal definition of myocardial infarction discussed in Chapter 12 is already a step in that direction. The ultimate gain with the ultrafast assays should be more refined risk stratification.
Incidence and Manifestations
Cardiovascular diseases claimed nearly 1 million deaths in North America in 2005 although this rate had decreased by a third in the preceding 10 years. In parallel with this decrease in mortality, the rates of in-hospital death from myocardial infarction decreased by one third in the Worcester Heart Attack Study between 1975 and 2005, whereas hospital survival rates increased by 10%. Of interest, there has been a shift in the phenotype profile of ACS during that period, and in the profile of risk factors.
Evolving Profile of NSTEMI and STEMI
Although they are manifestations of a similar disease, the profiles of NSTEMI and STEMI have diverged over the years with regard to occurrence, diagnostic methods, treatment, and prognosis. Thus, rates of STEMI decreased in the last 20 years, whereas those of NSTEMI have remained similar or increased. In the Worcester study, the yearly incidence of STEMI decreased from 0.71% to 0.10% between 1975 and 1997, whereas that of NSTEMI increased from 0.02% to 0.13%. The NMRI registry conducted in U.S. hospitals reported an increase in NSTEMI from 14.2% to 59.1% and a reduction in STEMI between 1990 and 1997 among 1,950,561 patients with a diagnosis of ACS. In practice, NSTEMI now accounts for more than 66% of ACS diagnosis, compared with 33% not long ago.
Reasons for this changing pattern are multiple and not all recognized. The new diagnostic tools with troponin at the forefront have an increased sensitivity and also specificity reducing-false positive diagnoses and favoring selective hospitalization of higher risk patients. The markers are less critical in STEMI since ST-segment elevation on the 12-lead ECG should prompt coronary angiography and angioplasty, hopefully before any rise in creative kinase isoenzyme MB (CK-MB) and cardiac troponin levels.
Other reasons that explain the shift in the relative rates of STEMI and NSTEMI include a better control of risk factors and of statins that reduced plaque vulnerability; the widespread use of aspirin, which decreases the thrombus load on plaques; and earlier medical consultation and treatment allowing prevention of a more severe ischemic event. A most important explanation could be an insidious shift in the pattern of risk factors, modifying the fundamentals of the disease.
Concomitantly, fibrinolysis was shown useful for STEMI but deleterious in NSTEMI, and health systems have evolved to provide facilities for timely primary percutaneous coronary intervention (PCI) in STEMI to further reduce mortality and the major complications of congestive heart failure and cardiogenic shock. This structure is now increasingly applied to all ACS. In-hospital mortality rates in the Worcester Study fell between 1994 and 2006 from 10.4% to 6.3% for all MIs, 11.5% to 8.0% for STEMI, and 7.1% to 5.2% for NSTEMI, for an odds ratio of 23%, 24%, and 22%, respectively (all P < 0.0001). In the international GRACE registry risk-adjusted hospital deaths declined 18% for STEMI and 0.7% for STEMI between 1999 and 2006 which could be imputed to greater adherence to practice guidelines and more appropriate use of reperfusion therapy, antithrombotic and antiplatelet therapies, statins, beta blockers and angiotensin-convering enzyme (ACE) inhibitors. The importance of adherence to guidelines was further stressed by the NMRI registry by showing 11% reduction in in-hospital mortality for STEMI and NSTEMI for each 10% better compliance to guidelines ( Fig. 1-1 ).
Of note, STEMI became more prevalent in younger patients and NSTEMI in older patients in the NRMI registry. In parallel with this shift, mean age increased from 64.1 years to 66.4 years and the proportion of women increased from 32% to 37% during the 16-year observation period. There were fewer patients reporting prior angina, prior MI, and a family history of CAD, but more patients with hypertension, dyslipidemia, current smoking, heart failure, and prior revascularization, stroke, and diabetes. The last three were more prevalent in NSTEMI. The same shifts in risk-factor profile were also seen in patients enrolled in clinical trials. Similar findings were also present in a 56-cent registry in France designed to test the validity of the new universal definition of MI. A total of 2151 consecutive patients were enrolled. STEMI patients were more often treated with a revascularization procedure than their NSTEMI counterparts (PCI:74% vs. 57%; P < 0.05), and received more aggressive secondary prevention therapies at discharge, which was not supported by the disease severity. Rehospitalization rates at 1 year were 38% for STEMI and 41% for NSTEMI, and 16% in each group were revascularized. In-hospital mortality was similar (4.6% and 4.%), and 1-year mortality was 9.0% in STEMI and 11.6% in NSTEMI. The independent correlates of in-hospital mortality were untreated dyslipidemia, advanced age, diabetes, and low blood pressure, and the strongest predictors of 1-year mortality were heart failure and age. The predictors were the same for STEMI and NSTEMI.
Clearly, the new risk-factor profiles of ACS are becoming the new the new challenges. They are very similar in STEMI and NSTEMI, but more extensive in NSTEMI resulting in more comorbidities.
The Future
Knowledge translation into clinical practice has become a priority. Indeed, the wide gap that existed not long ago between practice guidelines and actual practice has considerably narrowed due to educational efforts at various levels and timely updates of the recommendations. The European Society of Cardiology (ESC), ACC, and other organizations have implemented structures for monitoring practice and adherence to guidelines in various regions, hospitals, and medical practices providing a basis for eventual interventions (see Chapter 4 , Chapter 5 ).
Some of the pressing clinical needs in ACS are to develop better schemes for diagnosis and risk stratification, and for an individualized therapy. Because high-risk ACS is now recognized as an acute manifestation of atherothrombosis that mandates hospitalization and aggressive management-strategy treatment, the negative prognostic impact of the disease over the following months and years needs to be better addressed. Yet, our risk stratification schemes still mainly focus on markers of myocardial ischemia with the 12-lead ECG and cardiac troponins helped by 2-D echocardiography, radionuclide imaging, and provocative testing for ischemia. Time for an expanded perspective and a more holistic approach to patient management that incorporate new biomarkers, new technologies, and innovative therapies has come. The purpose of this section is to present an insight into a few emerging biomarkers in blood constituents including the liquid phase and circulating cells, and the genome and proteome. Not covered are the unlimited new imaging technologies that can be coupled with various biologic markers including those derived from nanotechnology.
Blood Biomarkers
There exist numerous opportunities to identify the mechanisms of ACS; still there is a need to recognize among these mechanisms those which are prevalent in individual patients and that can become treatment targets. A panel of markers allows the monitoring of endothelial dysfunction and disruption, activation of platelet function and of the coagulation cascade, inflammation and immune and autoimmune reactions, cell necrosis, and many others. Assuming that high throughput and affordable technologies become available, mass analyses could be done on the large banks of frozen serum, plasma, and genetic material accumulated from clinical trials and registries.
This subsection is limited to the discussion of a few promising blood markers, B-type brain natriuretic factor (BNP and NT-proBNP), C-reactive protein (CRP), myeloperoxidase (MPO), and lipoprotein-associated phospholipase A2 (Lp-PLA2) that could help identify the patients at risk.
BNP and NT-proBNP
These cardiac neurohormones are released on ventricular stretching. The precursor pro-BNP is enzymatically cleaved into the N-terminal pro-BNP and then to BNP. These markers were first shown useful for the diagnosis and evaluation of heart failure. Subsequently, numerous prospective studies and analyses of large databases documented their powerful prognostic value to predict mortality in patients with stable and unstable CAD independently of conventional predictors. The assessment of BNP or NT-proBNP is a class 1B recommendation in the ESC (see Chapter 33 ) and a class 2B recommendation in the ACC/AHA guidelines (see Chapter 34 ) as an instrument to supplement assessment of global risk in patients with suspected ACS. In the GUSTO study, the 1-year mortality rates across a large cohort of ACS patients were 1.8%, 3.9%, 7.7%, and 19.2% with increasing quartiles of NT-proBNP ( P < 0.001); this predictive value was independent of clinical and laboratory signs of left ventricular dysfunction.
This unique property of BNP and NT-proBNP to predict mortality was reproduced in many studies. The brain natriuretic peptides also help discriminate the 2% to 4% of patients with suspect ACS who will develop an ischemic outcome despite a normal ECG and normal cardiac troponin values. Thus, NT-proBNP was measured at hospital admission in two independent registries, one from Germany composed of 1131 patients with ACS, the other from Argentina that included 1483 patients with chest pain. The latter served as a derivation cohort, and the former as the validation cohort. Among the 1178 troponin T (TnT)–negative patients, the receiver-operating characteristics curve analysis yielded an optimal cutoff value of 474 pg/mL to discriminate patients at higher risk. Higher values were associated with a higher risk for death in the two registries with adjusted hazard ratios (HR) of 9.56 (95% confidence interval [CI] 2.42 to 37.7, P = 0.001) and 5.02 (CI 2.04 to 12.33, P < 0.001), respectively.
Inflammation Markers and CRP
None of the numerous inflammation markers studied to date in ACS could be validated as a therapeutic target (see Chapter 25 ). Although a nonspecific marker, CRP was shown useful to predict an adverse outcome. It was also suggested that the marker could contribute to the disease process, but the data in that direction remain controversial. CRPs half-life is 19 hours so that blood levels are mainly determined by the rate of production. The levels are very high in inflammatory and infectious diseases. They are also high in STEMI, rising within 6 to 12 hours after the onset of pain to peak within 48 hours. Elevated levels can be found at admission in NSTEMI when it has been preceded by unstable angina, suggesting that the disease process had been ongoing. Elevated levels during the acute phase correlate in general with peak elevation of CK-MB, activated complement proteins and lower ejection fraction.
Early elevation or persistent elevation past the acute phase lasting a few days is found in 40% to 50% of patients and is predictive of a higher rate of cardiac events, including death, MI, or recurrent ischemia at 12 months and death at 3 years. In the CAPTURE trial, early death or recurrent MI at 72 hours was predicted by troponin levels but not by those of CRP; by contrast, CRP levels greater than 10 mg/L predicted late events at 6 months (18.9% vs. 9.5%) independently of troponin levels.
The PROVE-IT TIMI 22 study randomized 3745 patients within 1 month after an ACS to high-dose of atorvastatin or moderate-dose of pravastatin. Patients low-density lipoprotein (LDL) who achieved cholesterol levels less than 70 mg/dlL (1.8 mmol/L) had a reduced rate of recurrent myocardial infarction or coronary death during the 2-year follow-up than those who did not (2.7 vs. 4.0 events/100 person-years; P = 0.008), as well as patients who achieved CRP levels less than 2 mg/L (2.8 vs. 3.9 events/100 person-years; P = 0.006). The lowest rate of recurrent events (1.9/100 person-years) was achieved in patients with LDL cholesterol levels less than 70 mg/dL and CRP levels less than 1 mg/L. These results in post ACS patients are convincing as they are very much similar to those recently found in the prospective JUPITER trial which evaluated rosuvastatin versus placebo in primary prevention among individuals with LDL-cholesterol levels less than 130 mg/dL (3.4 mmol/L) but CRP levels greater than 2.0 mg/L.
Other markers can also predict prognosis, particularly interleukin-6 which promotes the formation of CRP by the liver. A composite of markers can at times provide additional information because redundancy exists between the different inflammation pathways. One marker can add additive value, and the weight of different markers varies between patients. Figure 1-2 illustrates an example of the usefulness of multiple markers.
Myeloperoxidase
MPO is a lysosomal protein abundantly present in neutrophils. It produces hypochlorous acid from hydrogen peroxide (H 2 O 2 ) to destroy bacteria. MPO deficiency predisposes to immune deficiency. Antibodies against MPO have been implicated in various types of vasculitis. In one study of 604 sequential patients presenting to the emergency department with chest pain, initial plasma MPO levels predicted the risk of MI, need for revascularization, or death within 30 days and 6 months after presentation ( P < .001) even in patients without evidence of myocardial necrosis defined by negative TnT values. It was suggested that a single initial measurement of plasma MPO could independently predict the risk of major adverse events in the ensuing 6 months independently of the presence of myocardial necrosis. In a French-Canadian study, allele A of the MPO gene was less frequent in patients with CAD; the odds ratio for having documented CAD with the AA genotype was 0.138 (95% CI, 0.040 to 0.474), and with the AG genotype it was 0.639 (95% CI, 0.436 to 0.937) compared with the GG genotype. Myeloperoxidase is an interesting marker that needs further validation studies.
Lipoprotein-associated Phospholipase A2
The interest in Lp-PLA2 has been renewed by observations on its role in culprit lesions and by the availability of orally active inhibitors that are now tested in large clinical trials. Lp-PLA2 is produced by activated inflammatory cells (e.g., monocyte-derived macrophages, T cells, mast cells), carried in the circulation bound to lipoprotein B on low-density lipoprotein, and delivered in this form to monocytes and macrophages in lesion-prone segments of the arterial wall. Subsequent LDL oxidation leads to the formation of truncated phospholipids that can be hydrolyzed by Lp-PLA2. The process generates two bioactive lipid mediators, lysophosphatidylcholine (lysoPC) and oxidized nonesterified fatty acids (NEFAs), which promote homing of inflammatory cells into active lesions and local accumulation of inflammatory mediators that further increase the expression of Lp-PLA2 ( Fig. 1-3 ). These mediators are cytotoxic to macrophages, facilitating their apoptosis and formation of a necrotic core in plaques. A histopathologic and immunolocalization in 25 sudden coronary death patients showed absent or minimal Lp-PLA2 staining in early plaques, but overexpression in thin-cap atheroromas and ruptured plaques in necrotic cores and surrounding macrophage and in apoptotic cells in regions of high macrophages density.
