Gandhi C, Motto DG , Jensen M, et al. ADAMTS 13 deficiency exacerbates VWF-dependent acute myocardial ischemia/reperfusion injury in mice. Blood. 2012:120:5224-5230.
In primary hemostasis, vessel injury initiates thrombosis through release of ultra-large von Willebrand factor (ULvWF) multimers from damaged endothelial cells. This process is dampened by the plasma metalloproteinase ADAMTS13 that digests thrombogenic ULvWF into smaller, less active low-molecular-weight vWF multimers, thereby diminishing vWF-platelet interaction and local thrombosis. In the absence of ADAMTS13, ULvWF-mediated microvascular thrombosis progresses unchecked, leading to diffuse small vessel thrombi in multiple organs, culminating in the syndrome of thrombotic thrombocytopenic purpura (TTP). Microvascular thrombotic lesions are commonly found in the heart of patients with TTP,1,2 and thrombotic microangiopathy, initiated by ischemia/reperfusion injury, appears to contribute to the pathophysiology of acute coronary syndrome (ACS).3 The mediators of ischemia/reperfusion injury (inflammation and oxidative stress) damage endothelial cells. During vessel injury, collagen-bound vWF binds to platelets, decelerating their flow and thereby promoting receptor interaction, cellular activation, and thrombus formation. At the same time, prothrombotic ULvWF is cleaved by ADAMTS13 to prevent excess thrombosis. These observations suggest the hypothesis that a disturbance in the balance between ADAMTS13 and vWF (i.e., abnormally low ADAMTS13 activity or abnormally high vWF activity) could contribute to the pathogenesis of coronary artery disease and that ADAMTS13 has therapeutic potential in the treatment of myocardial ischemia.4
Two independent investigative teams recently challenged the hypothesis in a murine myocardial injury model induced by coronary artery ligation. Following one hour of occlusion and 23 hours of reperfusion, De Meyer and colleagues observed larger myocardial infarct size in ADAMTS13-/- mice as compared with wild-type mice. The infarction injury in the ADAMTS13 null mice was also accompanied by greater inflammation, by greater granulocyte/monocyte infiltration and activation, and by greater myocardial apoptosis. To evaluate whether ADAMTS13 could reduce myocardial damage, recombinant human ADAMTS13 (rhADAMTS13) was infused into wild-type mice subjected to coronary artery ligation. Infarct size was reduced significantly as compared with infarct size in the control wild-type animals (those who did not receive rhADAMTS13 infusion) and accompanied by three-fold lower plasma cardiac troponin-1 concentrations and nine-fold lower neutrophil infiltration into ischemic myocardium. No adverse events were observed in the mice treated with rhADAMTS13.
Gandhi et al., using a similar coronary artery ligation model, independently confirmed the larger myocardial infarct size and higher troponin concentrations in ADAMTS13-/- mice as compared with wild-type mice and showed that infarct size and troponin levels in ADAMTS13+/- mice were similar to wild-type mice. In corollary experiments, they found that infarct size was smaller and troponin levels were lower in vWF-/- mice than in wild-type mice. When ADAMTS13-/-/vWF-/- double knockout mice were analyzed in the coronary artery ligation experiment, infarct size and troponin levels were found to be similar to those of vWF-/- single knockout mice, supporting the concept that the greater myocardial injury observed in the setting of ADAMTS13 deficiency is vWF-dependent.
In Brief
These studies provide evidence that ADAMTS13 deficiency exacerbates myocardial damage in an animal model of ischemia/reperfusion injury and that vWF deficiency or ADAMTS13 infusion ameliorates the process. Thus, it is reasonable to postulate that treatment with ADAMTS13 could lessen myocardial damage in patients with ACS. But whether the findings in mice are applicable to humans is speculative, and testing in humans will require carefully controlled trials as combinations of anticoagulation, platelet inhibition, and thrombolytics are standard therapy in patients with myocardial injury. Extrapolation of the findings in mice to humans is also tempered by differences in the pathology and cardiovascular physiology. For example, atherosclerotic plaque formation contributes to ACS in humans but is not part of the pathophysiology of the animal model used in the current studies; and arterial and venous flow rates differ between mice and men, and this difference may impact shear stress and local conditions that predispose to microvascular thrombosis. Additionally, the relative contribution to myocardial ischemia of ULvWF compared with cleaved, low-molecular-weight vWF multimers is unknown. Despite the unanswered questions, these provocative findings have potentially important clinical implications that merit further investigation.
References
Competing Interests
Dr. Ragni indicated no relevant conflicts of interest.
