Complementary Alternative Cardiovascular Medicine

194 Alternative Cardiovascular Medicine
Endothelial cell dysfunction contributes to the pathogenesis of cardiovascular
disease (CVD) and is modified by risk-reduction therapies.
A more current understanding of the mechanisms underlying atherogenesis
would suggest that chelation therapy may act by reducing oxidative
stress in the vascular wall, leading to improved vascular function, reduced
inflammation, and reduced risk for CVD events.
Chelation therapy may improve vascular function by several mechanisms.
One possibility is direct removal of calcium from the vascular
wall. Studies in animal models suggest a relationship between endothelial
function and arterial calcification (31). As mentioned, removal of
calcium from lesions and the vessel wall by EDTA chelation therapy has
been questioned. However, if operative, such an effect would likely
result in an improved response to both endothelium-dependent and independent
vasodilators.
Another potential mechanism is chelation of redox active transition
metals, such as iron and copper. Transition metals ions are a well-recognized
source of oxidative stress in the vasculature (32). Iron is a catalyst
for the formation of the highly reactive hydroxyl radical via the Fenton
reaction, and similar chemistry exists for copper (32). Free copper and
iron also induce lipid and protein oxidation (33,34). On the basis of these
observations, investigators have proposed that transition metals may
contribute to atherogenesis by stimulating low-density lipoprotein (LDL)
oxidation. In support of this proposal is the observation that human
atherosclerotic lesions contain redox active iron and copper (35,36),
whereas normal tissue does not (32).
In addition to impairing endothelial function by stimulating LDL
oxidation and forming reactive oxygen species (ROS), metal ions may
also have direct effects that may contribute to atherogenesis and vascular
dysfunction. For example, there is evidence that iron contributes to NFB
activation (37) and the expression of vascular cell adhesion molecule-1
(VCAM-1) in endothelial cells (38). The interactions with iron and nitric
oxide (NO) may also be relevant. NO reversibly binds to heme iron and
activates guanyl cyclase, which results in vasodilation. However, nonprotein-bound
iron may directly inactivate endothelium-derived NO
(39). Recently, iron chelation with iv deferoxamine improved NO-dependent
vasodilation in the coronary arteries of patients with diabetes
mellitus (40). A similar effect has been demonstrated in patients with
angiographically proven CAD (41). However, EDTA is a less effective
chelator of iron and copper than deferoxamine and other more specific
agents. Furthermore, there is data to suggest that iron, but not copper,
may remain in a redox active state when bound to EDTA (42). Importantly,
this effect does not occur when there is a molar excess of EDTA,
as is the case in plasma after high-dose EDTA infusion (43).