The genetic basis of coronary collateral formation - a molecular-epidemiological approach

Introduction: The effects of atherosclerotic changes in the vessels of the heart pose an important burden for public health. In 2003, ischemic heart disease in the Netherlands was the known cause of death of 15,536 people of whom 2646 aged under 65 years [1]. Sudden death is a presenting symptom of coronary heart disease. Therefore these figures are yet an underestimation. One of the challenges is to find the individual susceptibility of ischemic heart disease, to be able to trace high-risk patients and take measures of prevention. There is a natural escape mechanism to atherosclerotic changes. Upon local narrowing of vessels, the vascular system has an adaptive capacity by addressing an alternative blood-supply through vascular connections (collaterals) that can bridge the narrowing. The extent of adaptive capacity is a quality which varies between people. Theoretically a greater extent of adaptation should translate into a more favourable prognosis with higher life-expectancy and less symptoms of disease. This favourable effect has yet not been proven in the long term[2,3]. Furthermore it is not yet known which person-characteristics are related to this adaptive capacity. Previous research has shown that lifestyle factors such as smoking and alcohol, or concurrent diseases such as hypertension and diabetes are not a satisfactory explanation for these differences in collateral vessel formation [4,5,6,7]. Most likely, an additional explanation could be found in genetic variation [8]. Research in other species, has shown that collateral vessels arise from maturation of an innate network of vascular connections, already laid down in the embryo. Genes can affect this mechanisms in broadly two ways. First, by influencing the embryonal formation of a vascular network; second by influencing the process of recruitment of collateral vessels as a response to vascular narrowing. So far,the genes involved have not been studied. The current research project is a logical consequence of insights from pre-clinical and clinical studies. The goal is to identify the genes related to the capacity of recruiting collateral vessels, and explore how this adaptive capacity affects the course of patients with coronary atherosclerosis. Research questions 1) Are there genetic factors affecting the capacity of forming collateral vessels in patients with coronary atherosclerosis, and which are the involved genes ? 2) What is the difference in clinical course, between patients with coronary atherosclerosis, carrying a large capacity of collateral formation, compared with those with a small capacity of collateral formation ? Methods: This study comprises two distinct phases: Phase 1:Identifying candidate genes. Two groups of patients will be included in the study, recruited from two established Dutch patient cohorts: the SMART study [9] , and the REGRESS trial[10]. The extent of coronary atherosclerosis and grading of collateral vessel extent will be quantified by coronary angiography as has been described earlier [11]. Altogether, 1200 patients with moderate to extensive collaterals and 600 patients with little or absent collaterals are available. The DNA of the participants will be investigated by a genome-wide scan. This advanced technique visualizes which regions on the genome are important in the process studied. A search will then be done for candidate genes in those regions of the genome. It will then be investigated if common variations in genetic code of these candidate genes, relate to the capacity of forming collaterals. Phase 2: Prognosis. The health status of participants to the REGRESS Trial, will be drawn from national registers maintained by Statistics Netherlands, and these data will be analysed for groups of patients with high and low capacity of forming collaterals. Thereby, the question will be addressed whether this quality has an impact on individual susceptibility for recurrent ischemic heart disease. Yield: Knowing the genetic make-up related to a low adaptive capacity of ones circulation upon atherosclerotic changes, can contribute to an individual estimation of risk for recurrent ischemic heart disease. Knowledge about genetic constitution relating to the capacity of forming collateral vessels, may also point towards new therapeutic methods. Currently, new therapies are aiming for an artificial stimulation of the natural process of collateral formation, in those patients who are not amenable for (repeated) coronary interventions such as bypass-operation. Knowledge of genes responsible for collateral formation, will allow to diagnose genetic defects on an individual level, and will put forward new therapeutic targets.