Cardiology Department, Papageorgiou Hospital, Solomou 12, Sykies, Thessaloniki, 56626 Greece
* Corresponding author. Tel: +30 2310204785; fax: +30 2310247450.E-mail address: aathanasiado{at}tee.gr
This editorial refers to Association of European population levels of thrombotic and inflammatory factors with risk of coronary heart disease: the MONICA Optional Haemostasis Study
by J. Yarnell et al., on page 332
Atherosclerosis has existed as a named entity for less than a century. It is, however, a pathological process of very considerable antiquity; changes consistent with atherosclerosis have been found in the 18th dynasty of the pharaohs of Egypt. Despite this long history,1 our understanding of many of the fundamental aspects of the genesis and progression of atherosclerosis is still far from complete. The mechanism by which atherosclerotic lesions form and expand has puzzled scientists for 150 years. Rudolf Virchow proposed in 1856 that atherosclerosis was caused when plasma components (including lipids) elicited an inflammatory response in the arterial wall. With the advent of molecular medicine, it became possible to formulate more specific hypotheses for the pathogenesis of atherosclerosis. New genetic disease models based on disturbances in lipid metabolism in gene knockout mice have permitted a detailed dissection of pathogenic steps and have advanced our understanding of atherosclerosis very significantly during the last 10 years.2
The haemostatic system plays a physiological role in prevention of bleeding after injury. Following vessel injury, blood platelets interact with subendothelial collagen: platelet adhesion and aggregation result in primary haemostatic plug. Activation of the blood coagulation system (by exposure to vessel wall tissue factor) results in the formation of thrombin, which converts soluble fibrinogen to insoluble fibrin which cross-links, stabilizing the platelet plug and ensuring secondary haemostasis. Subsequently, slow activation of the fibrinolytic system [by release of tissue plasminogen activator (tPA)] results in the formation of plasmin, which digests the fibrin plug in parallel with tissue repair processes. Recent advances in haemostasis research have illuminated its molecular biology and physiology, and reinforced the view that haemostatic mechanisms contribute not only in bleeding disorders, but also to atherogenesis and thrombotic disorders.
The role of haemostatic factors as predictors of coronary heart disease (CHD) and total mortality is poorly understood.3 Tissue factor (TF), von Willebrand Factor (vWF), and thrombomodulin (TM) are major haemostatic regulatory molecules synthesized by endothelium. Data from epidemiological studies aiming to evaluate the relation between plasma levels of these molecules and the development of CHD are sparse or contradictory.4 The adhesive glycoprotein vWF plays a dominant role in the initial adhesion of platelets to vascular subendothelium and regulates the plasma level of coagulant factor VIII. One of the fascinating aspects of the biology of vWF is its presence in a variety of physiological compartments within the body. The importance of vWF in clinical medicine has long been appreciated. Elevated levels of vWF are also observed in association with a wide variety of inflammatory conditions and have been proposed as a marker of endothelial and vessel wall damage.5
Normal vascular endothelial integrity and function are essential in diminishing the risk of atherogenesis and thrombotic events by providing an anticoagulant milieu and preserving vascular tone. Loss of endothelial integrity is present in atherosclerosis and its risk factors, and may be a causal link between each individual risk factor, the development of atherosclerosis, and clinical events such as myocardial infarction and stroke.6
Recent advances in basic science have linked some systemic risk factors to endothelial dysfunction, which gives rise to atherosclerotic disease and triggers the progression of thrombotic complications. Superficial erosion of the stenotic plaque can be observed in one-third of acute coronary syndromes (ACS). In these cases the presence of classic risk factors such as diabetes mellitus, hypercholesterolaemia and smoking favour a state of vulnerable blood or high risk. Increased thrombogenicity can exacerbate thrombus formation and is able to trigger an ACS. The vessel endothelium regulates contractile mitogenic and thrombotic activities of the vessel wall. Risk factors impair both homeostasis and haemostasis of the vessel wall and promote inflammatory signals. Platelet and monocyte activation favours the expression of TF, thus triggering the coagulation cascade with thrombin generation and clot formation. Increased blood thrombogenicity linked to classical risk factors may be associated with circulating TF levels which are much higher than those observed in healthy subjects without risk factors.
The absolute global coronary risk has recently been introduced as an indicator of the incidence predicted by the main risk factors. It offers numerous options for the treatment of individuals at high risk. The adequacy of the application of functions obtained by longitudinal studies depends on the characteristics of the population from which they were estimated. The management of patients with cardiovascular risk factors has changed over the past decade. The focus on single risk factors such as high blood pressure or cholesterol has given way to an approach that accounts for the multi-factorial origin of cardiovascular disease and the requirement for a comprehensive management of patients at high risk.
The World Health Organization (WHO) MONICA project was established to determine how trends in event rates for CHD and, optionally, stroke were related to trends in classic risk factors. This project was mounted to investigate and to complement the older cross-sectional studies of differences in disease rates, by means of longitudinal investigation of the dynamics of change. By replicating the same core of observations in diverse, contrasting communities to monitor multiple similar or dissimilar trends there was potential for the investigation of the determinants of the cardiovascular disease which would be beyond the scope of any single research unit or nation acting alone. Although there are limitations in ecological studies it is sometimes tempting to apply a statistical model derived from longitudinal studies of individuals to cross-sectional data that may be available only in aggregate form for groups of individuals. In this case we examine the assumptions and approximations that are made when average data for groups are used with predictive equations derived for individuals, particularly for proportional hazards model. It is shown that this method sometimes underestimates age-specific hazard functions but that if ratios of hazard functions are used to compare groups then the approach is valid provided certain plausible conditions hold.7 The important lesson learnt in the MONICA project is that in planning population surveys of cardiovascular risk factors there are great advantages in mounting big, well-controlled, high-quality surveys well separated in time, rather than opting for small, frequent, poorly controlled ones.
In the present issue of the Journal, Yarnell et al.,8 on behalf of the MONICA optional haemostasis study, give us relationships of thrombosis and inflammatory related variables with increased risk of CHD from a large international sample. The authors report, for the first time, association of vWF, nephelometric fibrinogen, and fibrin D-dimer plasma levels with risk of CHD in the real world of patients. These findings strengthen the conviction that the awaited results from randomized controlled trials of reducing thrombotic variables, as well as the need for new ones, will change the attitude to the management of high risk for CHD patients.
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References
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