Thromb Haemost 2008; 99: 657–658 Aortic valve stenosis (AVS) is quite common, affecting some 30% of those over age 65 (1). It frequently progresses to severe obstruction necessitating surgical repair or replacement of the stenotic valve. Annually more than 50,000 aortic valves are replaced surgically in the USA, posing common and serious medical problems (2), yet our knowledge of the pathogenesis and optimal treatment of this condition is surprisingly limited. It may represent a manifestation of atherosclerosis affecting the endothelium lining the heart valve but this is still debated. There is mounting evidence that AVS is associated with systemic inflammation (3, 4). Some but not all studies found an association of AVS with elevated C-reactive protein (CRP) (3) and active atheroinflammatory processes (4), implying a role of inflammation in the pathogenesis of AVS. Even if true, however, there is little insight on exactly how or why mechanical perturbation of blood flow due to AVS leads to systemic inflammation, or what inflammatory processes promote the initiation and progression of AVS. Elucidation of this key issue could provide a rational basis for prevention and therapeutic strategies. The intriguing report by Diehl et al. in this issue of Thrombosis and Haemostasis (5) may offer an insight into this problem, and may be of potential clinical importance. They hypothesize that AVS induces generation of circulating cell-derived microparticles (MP) by shear stress, and that the resulting MP then promote systemic inflammation. Briefly, their scenario goes like this: high shear stress generates platelet microparticles (PMP), which in turn interact with leukocytes to activate them and elicit release of leukocyte MP (LMP) and monocyte MP (MoMP). These procoagulant and inflammatory MP, along with activated monocytes, can induce endothelial injury at the lining of the heart valve, thereby setting up a “vicious cycle,” as the authors put it, leading to further calcific stenosis of aortic valves as seen inAVS. Endothelial cell injury is reflected by release of endothelial MP (EMP) (6). This hypothesis is novel and intuitively appealing.To support it, they measured MP species including PMP, LMP, and EMP in 22 AVS patients, and report a significant increase in all of them relative to controls. In parallel, elevation of markers of systemic inflammation was observed, such as soluble P-selectin, interleukin-6, and activation of monocytes.These data convincingly support the hypothesis, although falling short of conclusively establishing a cause-effect relationship between MP-cell interaction and progression of AVS. In addition, since this is a cross-sectional study, more definitive support for an active role of MP in the pathogenesis of AVS will require a prospective longitudinal study correlating MP-cell interaction with progression ofAVS, as the authors acknowledge in their discussion. Thus, a central theme of this paper is the physiological relevance of MP-cell interactions. They demonstrate copious production of PMP in AVS, and correlation of PMP levels with valvular shear stress in vivo. Others have previously shown in vitro that PMP are readily generated by abnormally high shearing forces (7–9). It has also been shown that PMP can induce leukocyte activation (10, 11), and can act directly on endothelial cells (8, 12). High shear can also induce endothelial activation and release of EMP (13); and in turn, EMP can activate leukocytes (14–17). Indeed, EMP were reported to act on the endothelial cells that produce them (18). Mixed MP isolated from patients were shown to be deleterious on cells in vitro or ex vivo (19, 20). Finally, the LMP elicited by PMP or other MP are known to be injurious to endothelial cells (21, 22). In view of these and other reports cited by Diehl et al. (5), there is ample evidence in vitro to support their hypothesis, that interactions of shear-generated MP with blood cells and endothelium could be pivotal in the progression of AVS. Their report struck a chord with us because of our anecdotal observation some years back of a patient with severe AVS, who refused surgical intervention. Her PMP counts were among the highest we had ever seen. She suffered from numerous recurrent transient ischemic attacks, progressing to advanced dementia. Thus, it is gratifying to see our observation confirmed in a significant number of patients by the work by Diehl et al. What implications might this report have for therapeutic strategies? If the hypothesis of Diehl et al. reported in this issue is correct, then it may be time to begin thinking about ways to modulate MP-mediated injury. Two approaches come to mind,
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Oct 27, 2008
A.J Gerrits + 4
