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CARDIOLOGY CASEBOOK |
A 57-year-old practicing attorney, moderately obese with a sedentary habitus, presented to the emergency department (ED) with precordial pressure radiating to the left jaw, shoulder, and inner aspects of the left arm to the third, fourth, and fifth fingers. These symptoms occurred after lunch and 30 minutes before arrival at the ED; they were accompanied by mild dyspnea, and the entire episode lasted 5 minutes. An electrocardiogram (ECG) taken about 5 minutes after spontaneous symptom relief with the patient asymptomatic revealed flattened ST-T segments with 1-mm "J" depression in leads I, aVL, V5, and V6. His blood pressure was 145/90 mm Hg, and his heart rate was 90 beats/minute and regular. There were an S4, S1, and S2, and a grade 2/6 aortic systolic murmur was heard at the base consistent with aortic valve sclerosis. The ED physician required further confirmation that this patient was either in the process of having an acute myocardial infarction (MI) or was at high risk of developing an acute MI in the near future.
(TNF-) ANSWERS
1. d. CRP
Measurement of levels of acute phase proteins has been used to determine the presence and degree of inflammation. Of all the acute phase proteins and plasma markers of vascular inflammation, CRP has been studied extensively and as a result has emerged as the most powerful inflammatory marker of future CV risk. CRP is a biochemical by-product that rises in level rapidly following an inflammatory stimulus (eg, acute MI). Hepatocytes produce CRP in response to elevated IL-6 levels that occur during the acute phase of inflammation. Endothelial tissue can produce low levels of CRP. The role of CRP as a culprit molecule or simply a bystander marker of vascular inflammation has been unclear; however, recent evidence suggests that CRP has a direct proinflammatory effect. CRP stimulates release and expression of inflammatory mediators and has been found within atheromatous plaques. CRP concentration is reflective of low-grade systemic inflammation and has been studied in a variety of CV diseases. In 1 study population, the CRP level in nearly 40% of unstable patients remained elevated for at least 12 months, suggesting a chronic inflammatory stimulus.
CRP concentration increases in the presence of inflammation, infection, and tissue injury. Depending on the severity of the inflammatory stimulus (infection, inflammation), CRP levels can increase up to levels 500 times normal. The 19-hour half-life makes CRP easy to detect in circulation. Although the sensitivity range of standard CRP assays (3–200+ mg/L) is adequate to evaluate clinically significant inflammatory processes, the tests are not precise enough to sense small changes in CRP levels associated with CV risk in apparently healthy individuals. As a result, a high-sensitivity CRP (hs-CRP) assay has been developed and is currently in use. The hs-CRP assays can detect low-grade inflammatory activity (as low as 0.15 mg/dL) within the vascular system, which helps predict the first or recurrent coronary events (see Table
). Baseline levels of CRP are strong independent risk predictors of future MI, stroke, and peripheral vascular disease. CRP levels help to stratify risk among patients with acute coronary syndromes (>0.16 mg/dL confers a higher rate of death, acute MI, or need for revascularization). In apparently healthy adults, a high CRP level (>0.16 mg/dL) is predictive of unstable angina, MI, stroke, a higher risk of restenosis, an increase in the incidence of complications after percutaneous transluminal coronary angiography and after coronary artery bypass graft surgery for the subsequent 8 years.1,2
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The following tests for predicting CV risk lack adequate specificity.
IL-6
IL-6, a cytokine and a nonantibody protein and intercellular mediator, is the primary driver of hepatic CRP synthesis. Cytokine IL-6 is involved in the pathogenesis of the acute coronary syndrome and has the following effects: stimulates the linear production of fibrinogen and CRP, stimulates the macrophage to produce tissue factor and matrix metalloproteinases, platelet aggregation, adhesion molecules, tumor necrosis factor, and vascular smooth muscle cell proliferation. Elevation of circulating IL-6 is a strong and independent marker of increased mortality in acute coronary events.4,5 Cytokine IL-6 predicts future MI in healthy men as well as total mortality in the elderly.6 Plasma concentrations of IL-6 reflect the intensity of plaque vulnerability to rupture and restenosis following percutaneous coronary intervention. Since this marker is produced by a variety of cells in the body, it is less specific than CRP.
Plasma D -Dimer
D -Dimer, a peptide, is the end product of fibrin breakdown and reflects the ongoing processes of thrombus formation and dissolution that occur at the site of active plaques in acute coronary syndromes. D -Dimer has been used conventionally in the diagnosis of deep vein thrombosis and pulmonary embolism; recent studies demonstrate an association between increased circulating levels of D -dimer and thrombotic complications in patients with MI.7 Levels of D -dimer can predict acute MI, recurrent coronary events, and peripheral atherothrombosis. Because of its role early in ischemic pathophysiology, D -dimer levels rise in acute coronary events before elevation in markers of cardiac injury (including myoglobin). However, D -dimer levels may be affected by other conditions that cause or are caused by thrombosis (eg, pulmonary embolism), or may involve other vascular pathologies (cerebrovascular disease, peripheral vascular disease, renal/hepatic insufficiency). Thus D -dimer is not as effective a screening test as CRP.
TNF-
TNF-is a pleiotropic cytokine produced by a variety of cells, including macrophages, endothelial cells, and smooth muscle cells.8,9 TNF-has a central role in the amplification of the inflammatory cascade. However, the plasma half-life of TNF-is short, a factor that limits its potential clinical utility as a screening tool.
PAPP-A
PAPP-A, a high molecular weight metalloproteinase, originally identified in the serum of pregnant women prior to delivery, was initially measured to help determine term date since levels increase to about 100 mIU/L at term. Metalloproteinase is a family of protein hydra-analyzing endopeptidases that contain zinc ions. The role of PAPP-A in tissue other than placenta has only recently been explored.10 PAPP-A, found equally in men and women, is abundant histo-logically in eroded and ruptured plaques but is not expressed in stable plaques.10 Serum PAPP-A levels are significantly elevated in patients with both unstable and acute MI, but are not influenced by gender, age, risk factors, or medications. Activated macrophage foam cells, located within unstable plaques, produce and release metalloproteinase enzymes into the extra-cellular matrix. These enzymes cause degradation of the matrix structure, leaving the fibrous plaque cap soft and vulnerable to rupture. PAPP-A is a possible culprit in extracellular matrix degradation.10 This also activates insulinlike growth factor (IGF-I), a mediator of atherosclerosis. PAPP-A levels are determined by means of an enzyme immunoassay. A threshold of 10 mIU/L has been considered to be a positive marker of patients with impending acute coronary syndromes.
In a recent study, the control group as well as those with stable angina had low PAPP-A levels (3.8–10.4 mIU/L) compared to those with unstable angina, who had elevated levels up to 22.5 mIU/L. In acute MI, levels increase to 46.6 mIU/L.7 Elevated PAPP-A levels identify patients with unstable angina even in the absence of elevations in cTn or hs-CRP. PAPP-A can detect plaque rupture before markers that indicate onset of MI and myocardial necrosis. The capability for early determination of event risk makes PAPP-A a promising stratification tool in classifying patients presenting with acute coronary syndromes. More clinical studies are needed to accurately define the role of PAPP-A as a marker for acute CV events compared to the established status of hs-CRP as a marker for risks.
cTn
The troponin proteins are located on the thin filament of the contractile apparatus in both striated and skeletal muscle tissue. The contractile protein, troponin, is composed of three isoforms: two found in both cardiac and skeletal muscle (cTnT, cTnC) and one specific to myocardial fibers (cTnI). This protein complex regulates the force and velocity of muscle contraction by modulating the interaction of actin and myosin. The troponin complex is not found in smooth muscle. Cardiac contractile proteins are the most abundant proteins in cardiomyocytes and are useful markers of myocardial damage. After injury or damage of cardiac cells, proteins of the contractile apparatus (troponins) are released into the circulation. The increase in serum concentration of the troponins that follows myocardial injury makes the measurement of this marker highly sensitive in acute MI. Troponin levels remain elevated 4 times longer than creatine kinase levels.
The cTnI marker facilitates both early and late diagnoses of MI even in the setting of concomitant skeletal muscle disease and especially after noncardiac surgery. Initial elevations of cTnI, which permit an early diagnosis, occur as a result of the release of this enzyme from a stored pool. Persistent elevations are considered to be due to a slow release of cTnI from the contractile apparatus. Prolonged elevations of cTnI permit evaluation for cardiac damage days after cardiac injury.11 Cardiac troponins are not inflammatory markers of the arterial plaque; they measure the sequelae of the inflammatory process in the plaque. However, increases in cTnI are not restricted to acute MI and have been detected in serial sampling of patients with unstable angina at rest. Measurements of cTnI are thus less specific for acute CV risk then CRP.
2. a. inflammation affects plaque composition
b. inflammation affects endothelial function
d. inflammation affects intervascular thrombosis
Coronary artery disease (CAD) is the leading cause of morbidity and mortality in the developed world. Although the process of atherosclerosis begins early in life and progresses over decades, the clinical manifestations of atherosclerosis (angina, stroke, MI, or death) may appear suddenly. Many theoretical causes of CAD have been studied, but recently inflammation has been shown to play a pivotal role in the initiation and progression of atherothrombogenesis and in plaque destabilization. These new insights into the role of inflammation in the atherosclerotic process have increased our knowledge of this disease and have aided in the clinical applications of risk stratification and in targeting acute coronary events. All of the known CV risk factors (eg, dyslipidemia, obesity, hypertension, heredity, smoking, sedentary habitus, diabetes, and older age) have been implicated in the progression of vascular disease and in the development of acute coronary and cerebrovascular events. Moreover inflammation has been implicated as a key ingredient in the progression of atherosclerosis from initial leukocyte congregation to the stage of rupture of the unstable atherosclerotic plaque. The trigger for this inflammatory response is still unclear.
A stable plaque is characterized by a thick collagenous fibrous cap and a small solid lipid core. Inflammation-sensitive T cells trigger macrophage activity, which produces metalloproteinase substances that aggressively break down the fibrous cap’s collagen supports. In addition, production of interferon-
by T cells slows normal collagen synthesis. Thus, a dynamic balance is maintained between collagen synthesis and breakdown. If the balance is altered because of an inflammatory state, the stable plaque undergoes degradation, the thick fibrous cap thins, and the lipid pool increases in the plaque core, which results in an unstable plaque prone to rupture. Inflammatory cells such as monocytes, macrophages, and T lymphocytes are found in abundance within atheromatous plaques, especially in the shoulder regions of plaques, the most vulnerable site for rupture in acute coronary syndromes. In laboratory studies, atherosclerotic plaques in patients with a history of unstable angina reveal a greater number of inflammatory cells when compared to the f indings in patients with chronic stable angina. These inflammatory cells, the proinflammatory cytokines (IL-6, TNF-), and the activated proteolytic substances may all be responsible for destabilizing intravascular plaques, which become more prone to rupture, resulting in thrombosis and vascular occlusion.
3. a. wide daily fluctuations
b. elevations due to minor injury
c. changes in CRP related to lifestyle practice
Inflammatory triggers and corresponding CRP concentrations may be interrelated to endothelial function and are affected by several CV risk factors. Hyperlipidemia, obesity, cigarette smoking, diabetes, hypertension, and infection are associated with increased inflammation and elevated CRP levels. This may explain the reduction in CV risk following LDL and very low LDL reduction, weight loss, smoking cessation, and improved glucose and blood pressure control. Oxidized low-density and very low density lipoprotein can activate inflammatory functions of vascular endothelial cells and induce expression of proinflammatory mediators. Hypertension may be linked to inflammation by angiotensin II. In addition to its vaso-constricting properties, angiotensin II can trigger intimal inflammation. Use of angiotensin-converting enzyme inhibitors may interrupt this process. Hyperglycemia associated with diabetes mellitus may alter certain macromolecules, leading to the production of proinflammatory substances. The diabetic state alone can promote oxidative stress. Obesity predisposes to insulin resistance and diabetes mellitus and contributes to atherogenic dyslipidemia. Adipose tissue itself is also capable of producing proinflammatory substances, potentiating atherogenesis. The presence of infectious agents can also produce an inflammatory response that triggers atherogenesis. Acute infections that alter hemodynamics and fibrinolytic systems can trigger an ischemic event. Chronic infection (bronchitis, prostatitis, gingivitis) can increase production of inflammatory substances and toxins that lead to accelerated growth of unstable atherosclerotic lesions. Helicobacter pylori, Chlamydia pneumonia, and cytomegalovirus have been found in numerous samples of human atherosclerotic plaques. There has been little evidence that antibody markers are predictive of CV risk. Physical exercise reduces the concentration of inflammatory markers and confers CV benefits by stabilizing arterial plaques.
General application of CRP testing and interpretation is not without serious limitations. (1) CRP levels may be transiently elevated for 2 to 3 weeks following a major infection or trauma, making it necessary to defer elective testing. (2) The value of CRP risk prediction may be limited in patients with chronic inflammatory conditions (rheumatoid arthritis, systemic lupus erythematosus). (3) Daily fluctuations in basal CRP levels are significant and 4 to 6 times greater than cholesterol fluctuations. One study reported a 46% within-subject variability compared to 9% variability seen in cholesterol levels.12 Reported variations have resulted from minor inflammatory stimuli such as a mild viral infection or a small skin laceration and some noninflammatory states such as low levels of physical activity, genetic factors, biological aging, chronic fatigue, high protein diets, high or low alcohol consumption, or depression. Knowledge of the other causes of CRP fluctuations help in accessing its use in CV risk assessment. It should be emphasized that CRP levels in assessing CV risk are very low and thus the hs-CRP must be measured. Causes other than acute CV events usually produce major changes in CRP measurements when compared to levels with hs-CRP used for coronary events.
Summary
Inflammation plays a major role in the pathogenesis of arterial atherosclerosis. The stages of atheroma development from early recruitment of leukocytes and fatty streaks to the unstable plaque and finally rupture are mediated by the inflammatory process. Several markers of vascular wall inflammation that can predict future risk of plaque rupture have been identified. However, these lack the specificity of CRP. Numerous large-scale prospective studies established hs-CRP as a strong biochemical marker for the prediction of future first or recurrent coronary events. A Food and Drug Administration–approved method for measuring hs-CRP is currently available.
ACKNOWLEDGMENT
Supported in part by a grant from the Applebaum Foundation in loving memory of Joseph Applebaum.
Reprint requests: Louis Lemberg, MD, University of Miami School of Medicine, Division of Cardiology (D-39), P O Box 016960, Miami, Fla 33101.
Ikeda U, Matsui K, Murakami Y, et al. Monocyte chemoattractant protein-1 and coronary artery disease. Clin Cardiol. 2002;25:143–147.[Medline]
Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation. 2002;105:1135–1143.
Meier C. Antibiotics in the prevention and treatment of coronary heart disease. J Infect Dis. 2000;181(suppl 3):S558–S562.
Munford RS. Statins and the acute-phase response. N Engl J Med. 2001;344:2016–2018.
Paimany B. Clinical application of high-sensitivity C-reactive protein. Cardiol Rev. 2002;19(2):19–22.
Ridker PM, Rifai N, Clearfield M, et al. Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events. N Engl J Med. 2001;344:1959–1965.
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