Info

The Big Heart Disease Lie

Effective Treatments for Heart Disease

Get Instant Access

a strong influence on epicardial hemodynamics, it is important to understand microvascular disorders that characterize coronary artery disease in its most active phases.

One of the earliest events in acute myocardial ischemia is microvascular damage and dysfUnction (86). Although injury may be the direct result of diminished nutritive blood flow, evidence also suggests that platelet micro-embolism, platelet-leukocyte aggregates, and inflammatory cytokines play important roles. The restoration of epicardial blood flow following fibrinolytic therapy or percutaneous intervention may also contribute by supplying oxygen-derived free radicals and neutrophils, leading to complement activation and expression of adhesion molecules that incite a vicious cycle of inflammation, injury, reduced tissue perfusion, and myocardial ischemia (Fig. 10). Accordingly, the management of acute coronary syndromes, particularly ST-segment elevation MI, must consider therapies that address the macrovascular and microvascular circulatory systems (87).

VASCULAR BIOLOGY, BIOCHEMISTRY, AND EMERGING CONCEPTS IN ATHEROTHROMBOSIS

C-Reactive Protein

The link between inflammation and thrombosis in atherosclerotic vascular disease is complex; however, CRP may represent an important mediator given its association with both atherogenesis and thrombogenesis. In the Speedwell study (88), CRP correlated strongly with D-dimer levels, which is a marker of fibrin formation (and subsequent degradation). This observation is particularly relevant when one considers the ability of D-dimer (and other fibrin-related products) to activate neutrophils and monocytes, increase secretion of cytokines (IL-1, IL-6), and stimulate the hepatic synthesis of acute-phase proteins including CRP (89).

Epicardial Microvascular Ischemia

Fig. 10. Impaired myocardial perfusion in the setting of acute MI is a multidimensional process that is mediated by microcirculatory dysfunction. Impaired epicardial coronary blood flow impairs microvascular perfusion either directly or indirectly through myocardial necrosis-mediated inflammatory responses, which are either cytotoxic or compromise microvascular responsiveness. Epicardial to microcirculatory vessel platelet-fibrin microemboli also contribute to impaired distal flow and perfusion. Lastly, the restoration of blood flow may have either a transient or prolonged impact on microvascular performance by delivering leukocytes, platelet-leukocyte aggregates, and oxygen-derived free radicals.

Fig. 10. Impaired myocardial perfusion in the setting of acute MI is a multidimensional process that is mediated by microcirculatory dysfunction. Impaired epicardial coronary blood flow impairs microvascular perfusion either directly or indirectly through myocardial necrosis-mediated inflammatory responses, which are either cytotoxic or compromise microvascular responsiveness. Epicardial to microcirculatory vessel platelet-fibrin microemboli also contribute to impaired distal flow and perfusion. Lastly, the restoration of blood flow may have either a transient or prolonged impact on microvascular performance by delivering leukocytes, platelet-leukocyte aggregates, and oxygen-derived free radicals.

CRP can be found within macrophages of atheromatous plaques where it interacts with a specific cell surface receptor CD 32. The co-localization of CRP and LDL cholesterol suggest that it plays a major role in transport and atherosclerotic plaque development (Fig. 11). Once present, CRP up-regulates adhesion molecule expression, activates complement, and induces monocyte tissue factor expression (88-90).

The strong correlation between elevated CRP concentrations (measured by a high sensitivity assay) and vascular thrombotic events, while not proving cause and effect provides, at the very least, a readily attainable prognostic marker (Table 4) (91). The potential relevance both pathologically and clinically is further underscored by the ability of therapeutic agents, including "statins" and aspirin, to reduce CRP (and predict treatment response) (92,93).

Tissue Factor

Shortly after tissue injury, including even superficial trauma to the endothelium, thrombin-like activity can be detected that persists for weeks thereafter (94,95). The expression of tissue factor mRNA and antigen within atherosclerotic plaques has been characterized by in situ hybridization and immunohistochemistry (96). In atherectomy specimens obtained from human carotid arteries, tissue factor mRNA and antigen can be detected in macrophages, mesenchymal intimal cells, and extracellular matrix (97).

Crp Atherosclerosis

Fig. 11. CRP is more than an "epi phenomenon" of atherosclerotic vascular disease. In response to cytokine stimulation, it co-localizes with LDL-cholesterol, facilitating monocyte entry via CD32, a cell surface receptor. Once internalized, the CRP-LDL-cholesterol complex incites complement activation, tissue factor expression, and surface adhesion molecule "up-regulation."

Fig. 11. CRP is more than an "epi phenomenon" of atherosclerotic vascular disease. In response to cytokine stimulation, it co-localizes with LDL-cholesterol, facilitating monocyte entry via CD32, a cell surface receptor. Once internalized, the CRP-LDL-cholesterol complex incites complement activation, tissue factor expression, and surface adhesion molecule "up-regulation."

Table 4

High Sensitivity (HS) CRP and Its Correlation with Atherothrombotic Events

Endpoint

Coronary heart disease (CHD)-death

Was this article helpful?

0 0
Your Heart and Nutrition

Your Heart and Nutrition

Prevention is better than a cure. Learn how to cherish your heart by taking the necessary means to keep it pumping healthily and steadily through your life.

Get My Free Ebook


Post a comment