Cardiovascular events in high risk patients: prognosis and etiology.

a. Overall aim Cardiovascular diseases are leading causes of morbidity and mortality in Westernized societies and are expected to increase in global importance in the years to come. The most important contribution by epidemiology over the last decades in understanding cardiovascular disease, is the gradual recognition and definition of risk factors that play a part in the initiation and promotion of cardiovascular disease. Landmark studies kike Framingham, the Seven Countries Studies, the MONICA study and many other subsequent studies have provided ample evidence that elevated serum cholesterol, reduced HDL-cholesterol, elevated bloodpressure, smoking, impaired glucose tolerance and a number of other factors are directly or inderictly related to the occurrence of cardiovascular disease. Knowledge of these risk factors, however, is insufficient to predict progression of cardiovascular disease and in particular the prediction of occurrence of new inchemic symptoms in patients with established cardiovascular disease. It is unclear why some patients with established cardiovascular disease. It is unclear why some patients with established cardiovascular disease have only a single clinical manifestation of the disease and others experience myocardial infarctions or other manifestations of ischemic vascular disease after their initial event. Most patients have similar levels of traditional risk factors and have more or less severe atherosclerosis. Other mechanism must determine whether (and when) and individual, in the presence of atherosclerossis will experience new cardiovascular events. Symptoms of coronary heart disease (or other ischemic symptoms in other vascular beds) are likely to manifest themselves in subjects with endorgans, e.g., myocardium or brain tissue vulnerwable for ischemia and reduced flow. Variouis factors have been proposed that affect tissue vulnerability to ischemic events including left ventricular hypertrophy, smoking and metabolic abnormalities. Another mechanism of potential major importance is the tendency of individuals to develop collateral circulation in areas of increased ischemia. This has so far received little attention in clinical epidemiological research. The proposal concentrates on the interaction of atherosclerotic burden and the propensity to develop collateral circulation in determining the occurrence of ischemic cardiovascular events in high risk patients. The overall aim is to unravel the role and importance of collateral circulation in the occurrence of these cardiovascular events and to define predictors for new clinical events in patients with established cardiovascular disease. The proposed research will concentrate on three major ischemic vascular diseases: myocardial infarction, stroke and peripheral arterial disease. Key objective: To determine whether and increased tendency to develop collateral circulation leads to a decreased ischemic vulnerability and improved prognosis ni cardiovascular compromised patients the following research questions will be addressed in two sub-projects: 1. Is the presence and extent of collateral circulation, as measured with coronary angiography and magnetic resonance imagting of the brain, a determinant of occurrence of new symptomatic cardiovascular events in subjects with extensive atherosclerosis. 2. Is the propensity to form new collateral arteries in areas of ischemic stress, as measured by circulating levels of VEGF, bFGF, G-CSF, related to the risk of symptomatic cardiovascular events in subjects with extensive atherosclerosis. 3. Is the propensity of a collateral vascular response, as juged by vascular reactivity, related to the risk of symptomatic cardiovascular events in subjedts with extensive atherosclerosisi. b. Approach The research will be performed within the recently established SMART cohort. The Second Manifestation of ARTerial disease study (present number 2100, 70% male) is an ongoing prospective cohort study in the University Medical Center Utrecht. Since September 1996, all patients, aged 18-79, are included who are newly referred to the uUIniversity Medical Center with cardiovascular disease or marked elevation of risk factors (hypertension, hyperlipidemia or diabetes). At enrolment extensive base-line data are obtained about medical history, medication use and presence of traditional risk factors. Height, weight, waist/hip ration and blood pressure are measured and blood is taken for lipid, gucose, homocysteine and creatinine levels. Micro-albuminuria and creatinine excretion in urine is measured. Additional blood and urine samples are stored for future study. 'Total atherosclerotic burden' is determined by measuring Intima Media Thickness (IMT) of the common carotid artery. Also a lead resting electro-cardiogram, ankle-brachial blood pressure index, ultrasonography of aorta and the kidneys and distensibility measurements of the common carotid artery are performed and plaques and degree of stenosis anre assessed using published protocols. Every 6 months questionnaires on hospitatlization and outpatient clinic visits are sent to the patients and follow-up of the cohort is virtually complete. The present proposal has two parts. First, collateral circulation and angiogenic potential of patients who were admitted for PTCA (in the period 1996-2001) will be studied in a nested-case control study. The presence and propensity of collateral circulation, as measured by visualization of the collateral/s on coronary angiography and circulating levels of angiogenic parameters (VEGF, bFGF, G-CSF) will be compared across tow groups of PTCA patients: those who experienced a new symptomatic cardiovascular event during follow-up (N=88) and those who did not (N=16). Second, in all patients who will enter the SMART cohort in 2001-2002 (N=680) MRA of the cerebral circulation will be performed to assess collateral flow in the brain and blood samples will be obtained for later analysis of biochemical indicators of angiogneic potential (VEGF, bFGF, G-CSF). In addition, flow mediated vasodiatroy response will be measured as an estimate of collateral vascular response. In PTCA patiens collateral circulation of the heart will be measured as well. In the follow-up period 184 new symptomatic cardiovascular events (myocardial infarction, stroke, vascular disease, vascular death, carotid artery surgery, PTCA, PTA and amputation) are expected. Using proportional hazard analysis, the protective effect of a larger collateral circulatory potential will be determined. Adjustments will be made for differences in age, gender, risk factor profile and degree of atherosclerosis as estimated by intima media thickness. Next, to determine the modifying effect of varying degrees of generalized or local atherosclerotic arterial disease, analyses will be repeated within strata of atherosclerosis. c. Elements of innovation There is a sizeable body of evidence about the role 'conventional' risk factors pay in the occurrence of cardiovascular disease. Still, for a given degree of atherosclerosis some patients suffer forom symptomatic disease and impairments while others do not. Therefore, apart form local and generalized atherosclerosis other mechanisms need to determine the likelihood of symptomatic ischemic events. It is well appreciated in clinical practice that the presence and development of collateral circulation markedly affects symptomatology and prognosis in individual patients. The role of collateral circulation has, however, been largely neglected in cardiovascular clinical epidemiology, and little is known about determinants of presence, use and development of collateral arterial circulation. The proposed project is one of the first to address this etiologically and clinically important aspect of cardiovascular disease in a group of patients for which this is particularly relevant. d. Relevance for health care. Ischemic diseases of the heart and the brain are major causes of morbidity and mortality in Westernized societies and an impending epidemic in the developing world. The Global Burden of Disease project has projected that in 2020 coronary heart disease will be topping the list of global mortality causes. In recent decades, results from epidemiological researdh supplemented with increasing insight in the pathophysiology of atherosclerosis have clarified the role of a range of risk factors that determine the occurrence and progression of atherosclerotic vascular lesions. While this has enabled preventive intervention, it remains problematic to predict and explain the occurrence of ischemic events in individual patients. One likely reasonfor this is that other phenomena, conditional on the presence of athersoclerosis, play a part in the eventual transition from vascular wall pathology to occlusion and to ischemia. On the one hand, sudden changes such as plaque rupture and thrombosis may lead to acute worsening of arterial flow. In addition, however, the vulnerability of organs such as the heart and the brain for impaired tissue perfusion is of potential critical importance. The presence and potential for collateral circulation may determine both short-term outcome and long-term prognosis. In a society where, in part due to demographic changes, a major part of the population may be expected to have at least some degree of atherosclerosis, the role of collateral circulation and its determinants is of clear public health relevance. Using the same approaches that have successfully clarified determinants and mechanisms of atherosclerosis, the proposed research aims at advancement of understanding of the role collateral circulation and factors that determine the presence, use and development of collateral circulatory flow to compromised tissues.