Cardiovascular disease has been the most common cause of death in the US each year with the exception of 1918. Of the various types of cardiovascular disease, coronary heart disease is by far the leading cause of death. When a coronary artery becomes blocked, blood supply to the myocardium is reduced. Prolonged or severe reduction of blood flow can damage the muscle, resulting in a heart attack. Over 1 million new and recurrent cases of myocardial infarction occurred in the US in 1998. Forty percent of these patients died, 220,000 before even reaching hospital, making coronary heart disease the single leading cause of death in America (one of every 5 deaths). Correspondingly, the socio-economic cost of coronary heart disease is massive. Death from myocardial infarction is most common in individuals who suffer angina and/or those that have previously suffered a heart attack.

Reduced coronary flow most commonly results from non-occlusive thrombosis on a pre-existing atherosclerotic plaque. When a pre-existing plaque is disrupted, platelet aggregation and thrombus formation occurs partially occluding the coronary artery. If this condition progresses, perfusion of blood to the myocardium is reduced, resulting in cardiac muscle death, leading to irreversible cardiac muscle damage, progressive heart failure, cardiac arrest and/or death. Atherosclerosis is particularly common in individuals with high plasma LDL levels and/or type II diabetics, and novel approaches to the prevention of this disease are currently being sought. Statins have been successfully developed to lower LDL levels and subsequent atherogenic activity. Chronic endothelial injury and related endothelial chemotaxis and adhesion of various immune cells represent a less well-developed target of atherosclerosis treatments. Endothelial injury also plays a major role in transplant vascular disease (TVD). Since the first successful kidney transplantation more than 40 years ago, the number of transplant procedures has increased dramatically and in 2001 approximately 2,000 heart transplants were performed in the US. The success of this procedure has been improved through the control of post-surgical infection and acute rejection. TVD or chronic rejection remains an unresolved problem, and 2-14% of heart-transplant recipients acquire significant coronary disease within the first year, increasing to 40-60% after 5 years. TVD is initiated by endothelial damage and is propagated by an ongoing immune response. Histologically, TVD is characterized by coronary vessel sclerosis, although thickening extends over long sections of the vessel, in contrast with the discrete plaques observed in atherosclerosis. Reducing the coronary immune responsiveness could therefore play a role in the development of both atherosclerosis and TVD.

Research emerging from the University of British Columbia has focused on the identification of chemokines responsible for the chemotaxis of inflammatory cells towards the endothelium, in particular fractalkine. This recently identified chemokine was originally predicted to be part of a 373-amino acid protein that carries the chemokine domain on top of an extended mucin-like stalk. Fractalkine can exist in 2 forms: as a membrane-anchored or as a shed 95-kD glycoprotein. Soluble fractalkine has potent chemoattractant activity for T cells and monocytes, and the cell surface-bound protein, which is induced on activated primary endothelial cells, promotes firm adhesion of those leukocytes independent of integrins. CX3CR1 has been identified as a 7-transmembrane high-affinity receptor that mediates both the adhesive and migratory functions of fractalkine. Fractalkine has recently been shown to play a role in the pathogenesis of acute organ rejection, atherosclerosis, and TVD . The British Columbia group has shown that while healthy coronary arteries showed no fractalkine immunoreactivity, this chemokine was identified in the intima, media, and adventitia of atherosclerotic arteries. Within the media, fractalkine expression was seen localized to macrophages, foam cells, and smooth muscle cells. Diabetic vessels showed similar staining patterns to atherosclerotic coronaries, with much stronger staining in the deep intima. Transplanted coronaries showed staining in the endothelium, intima, and adventitia in early disease, and intimal, medial, and adventitial staining in late disease. CX3CR1 staining was seen in the coronary arteries of all cases, with specific localization to regions with fractalkine staining. These distinctive staining patterns suggest that fractalkine and CX3CR1 may be important in the pathogenesis of atherosclerosis including at-risk diabetes patients and also of TVD. CX3CR1 receptor antagonists may therefore be of therapeutic use, however to date no therapeutic candidates have been advanced that target this receptor and only a limited number of patents have been filed to protect this approach. Recent literature has shown that antibodies directed against either fractalkine or its receptor, CX3CR1, can significantly reduce the contribution of the immune response post-transplantation. This suggests that the development of CX3CR1 receptor antagonists may offer a novel approach to coronary artery disease. 

Entry date January 2003

Adapted from Wong et al, Cardiovasc Pathol 2002 Nov-Dec;11(6):332-8 - Interested in collaborating with this group? Contact LeadDiscovery or the authors direct.