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CARDIOLOGY CASEBOOK |
Inflammation is an active process in atherogenic vasculature. Atherosclerosis is no longer considered the result of passive endothelial injury and lipid infiltration. Both local and systemic markers give evidence that atherosclerosis is an active inflammatory state that has no regard for age. Although prevention of atherosclerosis is multifactorial, nevertheless regular exercise is therapeutic and a deterrent.
QUESTIONS
ANSWERS
1. c. hs-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 is the most powerful inflammatory marker of CV risk. CRP is a biochemical by-product that rises rapidly following an inflammatory stimulus. Hepatocytes produce CRP in response to elevated IL-6 levels that occur during the acute phase of inflammation. Endothelium also produces CRP, but at a lower level. CRP, an effective prognostic measurement of acute coronary events, also has a direct proinflammatory effect. CRP stimulates release and expression of inflammatory mediators and has been found within atheromatous plaques. CRP concentration that is reflective of a low-grade systemic infection can remain elevated for 1 year in unstable patients.
CRP concentrations increase with inflammation, infection, and tissue injury and may reach levels 500 times normal depending on the severity of the inflammatory stimulus, disease, or infection. The 19-hour half-life for CRP facilitates its detection. Although the sensitivity range of standard CRP assays (3 to 200+ mg/L) is adequate to evaluate clinically significant inflammatory processes, the test is sufficiently precise to sense small changes in CRP levels associated with CV risk in healthy individuals. As a result, an hs-CRP assay was developed and is currently in use. The hs-CRP assays can detect low-grade inflammatory activity within the vascular system (as low as 1.0 mg/L), which helps predict the initial or recurrent coronary events (see Table
). Baseline levels of hs-CRP are strong independent risk predictors of future myocardial infarction, stroke, and peripheral vascular disease. In apparently healthy adults, a high hs-CRP level (>3.1 mg/L) is predictive of unstable angina, myocardial infarction, stroke, and a higher risk of restenosis. Elevation of hs-CRP level increases the incidence of complications following percutaneous transluminal coronary angiography, as well as for 8 years following coronary artery bypass graft surgery.
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2. b. plasma proteins (fibrinogen, IL-6)
d. CRP
Although several hundred inflammatory or hemostatic risk factors for coronary artery disease (CAD) have been identified, only a few are reliable markers of CV risks. Inflammation maintains an integral role in the origin and complications of CAD. The initial response to infection or tissue injury involves the production of cytokines, which facilitate the influx of lymphocytes, neutrophils, and monocytes that clear out antigens and facilitate tissue healing. The local inflammatory response is followed by a systemic response, that is, fever, increase in granulocyte production, or APR. Synthesis of plasma proteins fibrinogen, haptoglobin, ferritin, and CRP is accelerated, as are increases in cortisol and adrenal catecholamine levels, while plasma albumin, transferrin and glycoprotein production fall.2 These reactions assist survival by increasing resistance to infection, activating cellular and immune responses, and altering metabolism to promote wound repair.
3. f. any of the above
Inflammation, tissue necrosis, infections, and neoplasms initiate and release inflammatory responsive cytokine substances IL-6 and interleukin-1 (IL-1) and stimulate the liver to synthesize the acute phase reactant protein CRP.3–5 CRP is an abnormal serum globulin formed by the liver in response to inflammatory states. Elevated CRP levels are unaffected by anti-inflammatory agents.6 CRP is a key modulation of angiogenesis and can cause a marked and sustained reduction in nitric oxide production.6,7 CRP is also a mediator in atherosclerotic disease and promotes inflammation, contributing to the substrate that underlies lesion formation, plaque rupture, and thrombosis. CRP may activate the complement pathway and neutralize platelet-activating factors, induce adhesion molecule expression and inhibit angiogenesis, and promote cell injury and apoptosis. The serum CRP level does not correlate with the degree of LDL lowering. In inflammatory states (eg, serum hepatitis, acute regional ileitis, acute coronary syndrome, Creutzfeldt-Jakob disease) and metastatic disease, sedimentation rates as well as hs-CRP levels are elevated.
4. c. a fatty streak
Age, genetics, and lifestyle habits influence endothelial anatomy and function. The added effects of the CV risk factors result in endothelial inflammation, which if uncontrolled will lead to atherosclerotic arterial lesions. Inflammation is an integer in the onset, development, and evolution of atherosclerotic lesions, which lead to vasospasm and thrombosis. Atherosclerosis occurs principally in the medium to large muscular arteries in the cardiac, cerebral, and peripheral vascular systems. The fatty streak common in adults in the early onset of atherosclerosis has been identified in infants and young children. This was a significant finding since the young were generally considered "immune" to the ravages of the elderly.
5. d. a and b
Physical activity lessens the deleterious effects of chronic diseases. However, 25% of adults in the United States do not participate in any physical activity and 60% are not physically active or do not participate in a regular exercise regimen. Physical activity is inversely related to the CV risk factors and promotes favorable cardiac hemodynamics. The physically active often possess other behavioral habits that are associated with lower CAD risks.8
Regular strenuous exercise is cardioprotective and produces an APR similar to that in pathological inflammatory states; however, the etiology of exercise-induced inflammation differs from the inflammation associated with pathological states.2,8 The APR in strenuous exercise during and 24 hours following strenuous exercise results in an increase in CRP, white blood cells, IL-6, and IL-1. In vulnerable individuals, selective persistence of inflammatory and procoagulant factors may trigger acute cardiac events and sudden cardiac death during strenuous activity.9
Physical activity can lower the risk of CAD by mitigating inflammation.10,11 Regular exercise produces an increase in various anti-inflammatory mediators, including the cytokine inhibitors, IL-1 receptor antagonist, TNF receptors, and others.10
Cross-sectional studies associate higher levels of physical activity with lower levels of inflammatory markers such as white blood cells, fibrinogen, and CRP. Parallel protective anti-inflammatory activities occur with regular exercise and the APR is diminished (40% reduction in CRP concentration). In one study,10 the levels of inflammatory markers were lower in joggers and aerobic dancers than in cyclists and weight lifters. In another study, CRP levels were lowest among middle-aged men with high levels of strenuous aerobic exercise compared with those who rarely exercised. Variations in CRP levels occur in response to the type of exercise training (eg, greater reduction in swimmers than in soccer players).10 Intramuscular signaling stimulates the muscle to release IL-6 and is independent of muscle damage.10
Elevated levels of proinflammatory cytokines, TNF, and IL-1 were balanced by a cascade of cytokine inhibitors and antiinflammatory cytokines (IL-10). Despite the elevated levels of IL-6 and other proinflammatory cytokines that peaked during strenuous exercise (marathons), only a modest increase in CRP levels was detected, an indication that the APR initiated with strenuous exercise is not followed by a fully developed systemic response.
6. e. all of the above
The etiology and treatment of atherosclerosis are multifactorial. The mechanism by which exercise training reduces CRP levels and suppresses inflammation is unclear. Physical activity lessens the effects of CV risk factors age, smoking, glucose intolerance, blood pressure, BMI, waist to hip ratio (mental adipocytes in centrally obese persons decrease insulin sensitivity and produce more IL-6 than do abdominal subcutaneous adipocytes), and total and non-high-density lipoprotein cholesterol, triglyceride, and apolipoprotein levels. Physical exercise is directly related to factors such as insulin sensitivity and intake of fruits and vegetables.
Physical activity mitigates inflammation by improving endothelial function. Endothelial cells secrete IL-1 and IL-6, but regular physical training reduces levels of peripheral inflammatory markers associated with endothelial dysfunction. Restoration of endothelial function preserves nitric oxide availability, which is crucial for maintaining a healthy vascular milieu. Physical training decreases the expression of adhesion molecules on leukocytes, inhibiting inflammation. Isolated periods of exercise acutely increase oxidative metabolism and stress, whereas long-term physical activity increases antioxidant defenses through the up-regulation of antioxidant enzymes. Exercise training reduces the susceptibility of LDL to oxidation, which results in limiting endothelial injury and inflammation and also improves nitric oxide production. Normal nitric oxide production is protective of endothelial cells.
Summary
Atherosclerosis is an inflammatory disease. Strenuous exercise can be responsible for a short-term inflammatory response and an increase in hs-CRP level. On the other hand, exercise training and regular physical activity are anti-inflammatory, homeostatic, and reduce hs-CRP levels, improving endothelial function. All are elements that reduce the risks of atherosclerosis in the various vascular beds: coronary, cerebral, peripheral vascular, and renal.
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.
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Anderson JL, Carlquist JF. Cytokines, interleukin-18, and the genetic determinants of vascular inflammation. Circulation. 2005;112:620–623.
Berman D, Hachamovitch R, Lewin H, et al. Risk stratification in coronary artery disease: implications for stabilization and prevention. Am J Cardiol. 1997;97(12B):10–16.
Centers for Disease Control and Prevention. Physical Activity and Health: A Report of the Surgeon General. Atlanta, Ga: Centers for Disease Control and Prevention; 1996.
Libby P. Inflammation in atherosclerosis. Nature. 2002;420:868–874.[Medline]
Mauriello A, Gangiorgi G, Fratoni S, et al. Diffuse and active inflammation occurs in both vulnerable and stable plaques of the entire coronary tree: a histopathologic study of patients dying of acute myocardial infarction. J Am Coll Cardiol. 2005;45:1585–1593.
Ostrowski K, Rohde T, Asp S, et al. Pro- and anti-inflammatory cytokine balance in strenuous exercise in humans. J Physiol. 1999;515:287–291.
Pearson TA, Mensha GA, Alexander RW, et al. Markers of inflammation and cardiovascular disease: application to clinical and public health practice—a statement for healthcare professionals from the center for disease control and prevention and the American Heart Association. Circulation. 2003; 107:499–511.
Ross R. Atherosclerosis: an inflammatory disease. N Engl J Med. 1999; 340:115–126.
Tanaka A, Shimada K, Sano T, et al. Multiple plaque rupture and C-reactive protein in acute myocardial infarction. J Am Coll Cardiol. 2005;45:1594–1599.
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