The third-generation tyrosine kinase inhibitor (TKI) ponatinib has been associated with high rates of acute ischemic events. The pathophysiology responsible for these events is unknown. We hypothesized that ponatinib produces an endothelial angiopathy involving excessive endothelial-associated von Willebrand factor (VWF) and secondary platelet adhesion. In wild-type mice and ApoE−/− mice on a Western diet, ultrasound molecular imaging of the thoracic aorta for VWF A1-domain and glycoprotein-Ibα was performed to quantify endothelial-associated VWF and platelet adhesion. After treatment of wild-type mice for 7 days, aortic molecular signal for endothelial-associated VWF and platelet adhesion were five- to sixfold higher in ponatinib vs sham therapy (P < .001), whereas dasatinib had no effect. In ApoE−/− mice, aortic VWF and platelet signals were two- to fourfold higher for ponatinib-treated compared with sham-treated mice (P < .05) and were significantly higher than in treated wild-type mice (P < .05). Platelet and VWF signals in ponatinib-treated mice were significantly reduced by N-acetylcysteine and completely eliminated by recombinant ADAMTS13. Ponatinib produced segmental left ventricular wall motion abnormalities in 33% of wild-type and 45% of ApoE−/− mice and corresponding patchy perfusion defects, yet coronary arteries were normal on angiography. Instead, a global microvascular angiopathy was detected by immunohistochemistry and by intravital microscopy observation of platelet aggregates and nets associated with endothelial cells and leukocytes. Our findings reveal a new form of vascular toxicity for the TKI ponatinib that involves VWF-mediated platelet adhesion and a secondary microvascular angiopathy that produces ischemic wall motion abnormalities. These processes can be mitigated by interventions known to reduce VWF multimer size.
Background:
Complete mechanistic understanding of impaired microvascular reflow after MI will likely lead to new therapies for reducing infarct size. Myocardial contrast echocardiography (MCE) perfusion imaging and molecular imaging were used to evaluate the contribution of microvascular endothelial-associated Von Willebrand Factor (VWF) and platelet adhesion to microvascular “no-reflow”.
Methods and Results:
MI was produced by transient LAD ligation in wild-type mice, wild-type mice treated with rADAMTS13 (a proteolytic enzyme that regulates VWF), and ADAMTS13−/− mice. MCE perfusion imaging and molecular imaging of VWF and platelet GPIbα were performed 30 minutes after ischemia-reperfusion. Infarct size was measured at 3 days. Mortality during ischemia-reperfusion incrementally increased in wild-type+ADAMTS13, wild-type, and ADAMTS13−/− mice (14%, 43%, and 63%, respectively; p<0.05). For wild-type mice, molecular imaging signal for platelets and VWF in the post-ischemic risk area was 4–5-fold higher (p<0.05) compared to both the remote non-ischemic regions or to sham-treated mice. Signal enhancement in the risk area was completely abolished by ADAMTS13 treatment for both platelets (12.8±3.3 vs −1.0±4.4 IU, p<0.05) and VWF (13.9±4.0 vs −1.0±3.0 IU, p<0.05). ADAMTS13−/− compared with wild-type mice had 2–3-fold higher risk area signal for platelets (33.1±8.5 IU) and VWF (30.9±1.9 IU). Microvascular reflow in the risk area incrementally decreased for wild-type+ADAMTS13, wild-type, and ADAMTS13−/− mice (p<0.05), whereas infarct size incrementally increased (p<0.05).
Conclusions:
Mechanistic information on microvascular no-reflow is possible by combining perfusion and molecular imaging. In reperfused MI, excess endothelial-associated VWF and secondary platelet adhesion in the risk area microcirculation contribute to impaired reflow and are modifiable.
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