In this study, we aimed to investigate whether sFasL level is correlated with the angiographic extent and severity of obstructive coronary atherosclerosis in patients with stable CAD through the potential role of apoptosis on CAD. We found that sFasL level was significantly higher in patients with stable CAD compared with patients with normal coronary arteries at coronary angiography. Serum sFasL level was positively correlated with extent and severity of the CAD, which was determined by either Azar score or coronary vessel score. To the best of our knowledge, our study is the first one to demonstrate a relationship between the extent of angiographic lesion and sFasL levels in patients with stable CAD.
Apoptosis or programmed cell death is a complex mechanism to control the tissue amount and architecture. This process is also shown to be effective in the development and progression of atherosclerosis. FasL is an important mediator in apoptotic cell death. It can bind Fas receptor and lead to inhibition of activated inflammatory cells within the atherosclerotic plaque.5,6
Certain immune system cells and vascular endothelial cells express FasL.12
The membrane-bound FasL can be converted to a soluble form (sFasL) by metalloproteinases.8
Hence, the plasma level of soluble form of FasL is mainly determined by the constitutive expression of FasL by the endothelial cells and their cleavage into plasma by metalloproteinases. Metalloproteinase activity increases in severe atherosclerosis.13,14
Thus, the compensatory protective effect of FasL in atherosclerosis may be further balanced by the increased conversion of FasL to the soluble form. This change in the form of FasL decreases its apoptotic capability and probably diminishes its protective effect against atherosclerosis progression.15
The finding of higher sFasL level in the patients with more severe and diffuse coronary atherosclerosis in our study is consistent with this mechanism. This finding is also in concordance with the previous findings. In hypertensive patients, the plasma level of sFasL was associated with increased carotid intima-media thickness.9
Thus, exaggeration in the conversion of FasL to its soluble form may be a risk marker for progression of CAD.
Several studies have shown that plasma level of sFasL is decreased in patients with higher cardiovascular risk.16,17
Statin treatment increased sFasL level.16
In our study, none of the cardiovascular risk factors seemed to have an independent effect on sFasL level in multivariate analysis. However, HDL levels in patients with normal coronary arteries were higher. This group had also higher sFasL level. Although this finding may be a reflection of the protective effect of higher HDL level against atherosclerosis, it may also be related with higher sFasL level detected in this group. The results of previous studies may be explained by the probable negative effect of the endothelial dysfunction on FasL expression by endothelial cells. The close relation between endothelial function and sFasL is confirmed by a recent study that showed a linear relation between forearm reactive hyperemia and sFasL level.18
In the light of these findings, expression of FasL seems to be closely associated with the correct functioning of endothelium. The severity of endothelial dysfunction may be variable in patients with atherosclerosis. Nitric oxide (NO) is the main determinant of the correct endothelial functioning, and may show different responses in different clinical pictures. Esaki et al demonstrated that Fas and FasL were expressed in the same areas that inducible form of nitric oxide synthase (iNOS) within the atherosclerotic plaque.19
Based on this finding, the investigators suggested that iNOS stimulates Fas/FasL-mediated apoptosis for regression of atherosclerosis. The main enzyme responsible of NO synthesis is endothelial nitric oxide synthase (eNOS) in the healthy endothelium. In diseased states, inducible nitric oxide synthase (iNOS) activity increases and becomes the principle enzyme in the NO synthesis.20
However, the NO synthesized by iNOS is different in quality then the NO synthesized by eNOS, and can show negative effects favoring the progression of atherosclerosis.21
The increased expression of Fas/FasL system in the areas with greater concentrations of iNOS may be the result of a compensatory response. In this way, the Fas/FasL system appears to exert a protective mechanism against atherosclerosis progression. On the other hand, as Fas system is a protective mechanism, its activation level should be correlated with the need for this protection. This means that if the progression of atherosclerosis is rapid, then necessity for Fas system increases. In previous studies, ischemia is shown to induce the expression of FasL.7,22
In several studies, sFas level was found to correlate with coronary and peripheral atherosclerosis in patients with end-stage renal disease (ESRD).23,24
However, in Roterdam Coronary Calcification study, which is a population-based study, the investigators could not show a significant relation between plasma sFas level and coronary/peripheral atherosclerosis.25
The challenge was explained by the inclusion of a highly selected population in previous studies. The higher sFas level in patients with chronic renal failure in comparison to the general population may be the result of chronic inflammation in patients with ESRD. The use of sFasL level instead of sFas level, as an indicator of the severity of atherosclerosis, is more logical because sFasL is also expressed by vascular endothelium. In the study investigating the relation between Fas/FasL system and atherosclerosis, the investigators found a relation between carotid intima-media thickness and sFasL level but not sFas level.9
Our study is not the first study indicating a relation between sFasL level and coronary atherosclerosis. sFasL was demonstrated to increase in patients with ACS in a previous study.10
However, ACS is a strong indication for coronary angiography according to current guidelines and most of these patients undergo routine coronary angiography during the hospitalization period.26,27
Thus, usage of biomarkers indicating the angiographic existence and severity of coronary atherosclerosis do not add so much to clinical practice. In patients with stable angina pectoris, the decision for an invasive diagnostic test and treatment is more controversial. Thus, use of biomarkers such as sFasL may give an idea about the requirement of further diagnostic tests. Although our findings do not prove that usage of sFasL for this purpose is beneficial, it may pave the way for studies investigating the use of sFasL as a biochemical surrogate of severe coronary atherosclerosis to decide to more invasive diagnostic strategies.
In conclusion, our study showed that sFasL level was associated with higher coronary atherosclerotic burden and this relation is independent of traditional cardiovascular risk factors. Our results suggest that sFasL level may be a biochemical surrogate of severe coronary atherosclerosis. This finding needs to be confirmed with further studies in larger patient populations.