Potential use of sFlt-1 and pterin to predict the clinical outcome of cardiovascular disease.
Degree GrantorUniversity of Canterbury
Degree NameMaster of Science
Formation of functional collateral circulation, to repair blocked or damaged arterial blood flow, is an important process in amending adverse outcomes after acute coronary occlusion events. Inadequate capillary growth during pressure overloads impairs myocardial perfusion, often contributing to the progression of coronary heart disease and ischaemia. Considered to be the critical rate-limiting step in physiological angiogenesis, the binding of VEGF (vascular endothelial growth factor) to VEGFR (vascular endothelial growth factor receptors) is essential for the growth and repair of arteries. Conversely, VEGF mediated angiogenesis has also been shown to promote atherosclerosis through arterial wall thickening. However, an alternatively spliced soluble form of VEGFR-1 (sFlt-1) has been shown to inhibit VEGF activity. sFlt-1 binds and sequesters free extracellular VEGF and/or heterodimerizes with VEGFR preventing the angiogenic pathway occurring. As a result, the primary pathway of angiogenesis does not occur. In recent years this has led to debate over the nature of sFlt-1 in the VEGF system. However, the level of sFlt-1 found in cardiovascular disease (CVD) patients, as well as its stability in plasma, has allowed for current research into its involvement with ischemic disorders to take place.
Enhanced T-cell activity that results in increased production of interferon-γ has been shown to have involvement in the pathogenesis of CVD. 7,8-dihydroneopterin (7,8 NP) production by monocytes and macrophages is primarily in response to stimulation by interferon-γ (IFN-γ) released by activated T-lymphocytes. When combined with neopterin, the oxidised product of 7,8 NP, the total neopterin is accounted for which is a measure of the total macrophage activation by interferon-γ. Therefore, the levels of total neopterin observed may reflect the level of cell-mediated immunity within individuals which could contribute to mortality post CVD event.
Progression of coronary heart disease is often clinically silent, without signs or symptoms. For this reason, the ability of markers to monitor progression is a powerful tool for predicting cardiovascular risk and the level of preventative treatment required. This study shows, that in 514 stable post-ACS (MI or unstable angina) patients, above median baseline sFlt-1, total neopterin and 7,8 NP levels, were strong predictors of mortality over a median 5 year period. Furthermore, above median sFlt-1 levels were specifically predictive of CVD death (p=0.001). This suggests that sFlt-1, total neopterin and 7,8 NP may be useful markers for risk prediction in CVD patients, post-acute event, with potential to aid prognosis in previously diagnosed patients.
In support of these findings, levels of sFlt-1 measured in plasma taken from patients, immediately prior to undergoing carotid endarterectomy procedures (n=27), were significantly raised in comparison to age and gender matched healthy controls (p<0.001). Furthermore, levels of sFlt-1 in patient and control groups were shown to be independent of both age and gender.
Another aspect of the study, analysis of excised live plaque tissue from carotid endarterectomy patients, showed the presence of live inflammatory cell populations. Macrophages, in the plaque sections, could be stimulated in the presence of IFN-γ to produce significantly elevated (p<0.01) levels of the antioxidant 7,8 NP. Since bivariate analysis of 7,8 NP and sFlt-1, in plasma from the endarterectomy patients, yields a positive correlation (r=0.323, p<0.01), further analysis of live plaque may give insight into the association between inflammation and hypoxic up-regulation of sFlt-1.
It is now generally accepted, in diseases with complex pathogenesis, that particular biomarkers are predominantly indicative of only a single variable in a wide range of contributing factors. The data generated in this study highlights the potential for sFlt-1, neopterin and 7,8 NP to be used as contributing biomarkers in the prognosis of patients suffering from CVD, which if confirmed, may have important clinical implications in the medical community.