Transauricular embolization of the rabbit coronary artery for experimental myocardial infarction: comparison of a minimally invasive closed-chest model with open-chest surgery

<p>Abstract</p> <p>Introduction</p> <p>To date, most animal studies of myocardial ischemia have used open-chest models with direct surgical coronary artery ligation. We aimed to develop a novel, percutaneous, minimally-invasive, closed-chest model of experimental myocardial infarction (EMI) in the New Zealand White rabbit and compare it with the standard open-chest surgical model in order to minimize local and systemic side-effects of major surgery.</p> <p>Methods</p> <p>New Zealand White rabbits were handled in conformity with the "Guide for the Care and Use of Laboratory Animals" and underwent EMI under intravenous anesthesia. Group A underwent EMI with an open-chest method involving surgical tracheostomy, a mini median sternotomy incision and left anterior descending (LAD) coronary artery ligation with a plain suture, whereas Group B underwent EMI with a closed-chest method involving fluoroscopy-guided percutaneous transauricular intra-arterial access, superselective LAD catheterization and distal coronary embolization with a micro-coil. Electrocardiography (ECG), cardiac enzymes and transcatheter left ventricular end-diastolic pressure (LVEDP) measurements were recorded. Surviving animals were euthanized after 4 weeks and the hearts were harvested for Hematoxylin-eosin and Masson-trichrome staining.</p> <p>Results</p> <p>In total, 38 subjects underwent EMI with a surgical (n = 17) or endovascular (n = 21) approach. ST-segment elevation (1.90 ± 0.71 mm) occurred sharply after surgical LAD ligation compared to progressive ST elevation (2.01 ± 0.84 mm;p = 0.68) within 15-20 min after LAD micro-coil embolization. Increase of troponin and other cardiac enzymes, abnormal ischemic Q waves and LVEDP changes were recorded in both groups without any significant differences (p > 0.05). Infarct area was similar in both models (0.86 ± 0.35 cm in the surgical group vs. 0.92 ± 0.54 cm in the percutaneous group;p = 0.68).</p> <p>Conclusion</p> <p>The proposed model of transauricular coronary coil embolization avoids thoracotomy and major surgery and may be an equally reliable and reproducible platform for the experimental study of myocardial ischemia.</p

Abstract P6-11-03: HACE1 loss results in hyperactive Rac signaling conferring resistance to HER2 targeted therapies

Abstract HER2-targeted therapies have been instrumental in improving the treatment of HER2+ breast cancer. However, drug resistance usually emerges and remains a big challenge in using anti-HER2 therapies. Previous studies have implicated activation of the Rho GTPase Rac1 by PTEN loss or IGF-1R overexpression as a mechanism of resistance to HER2-targeted therapies. We identified HACE1, an E3 ubiquitin ligase for Rac1, as a tumor suppressor capable of cooperating with HER2 to transform normal mammary epithelial cells. While HACE1 loss alone resulted in enhanced Rac activation, HER2 activation of Rac1 combined with HACE1 loss resulted in even higher levels of activated Rac resulting in the ability to form tumors in immunocompromised mice. In this study, we show that loss of HACE1 confers resistance to the HER2 tyrosine kinase inhibitor (TKI) Lapatinib due to sustained Rac signaling irrespective of EGFR/HER2 signaling. While Lapatinib inhibition alone is capable of attenuating proliferation of HER2 overexpressing mammary epithelial cells, HACE1 loss continues to drive proliferation of in vitro tumor formation (clonogenicity) as well in vivo tumor growth. We demonstrate that Lapatinib sensitivity can be restored using a Rac inhibitor in HACE1 knockdown cells. Moreover, while the Rac inhibitor alone was capable of attenuating the effects of HER2 overexpression and HACE1 loss, simultaneous inhibition of both HER2 and Rac signaling was superior to either monotherapy alone. These results support Rac activation as a mechanism of resistance to HER2-targeted therapies and highlight the use of a Rac inhibitor to treat HER2+ refractory breast cancers. Citation Format: Erik T Goka, Dana S Senderoff, Gustavo Munguba, Marc E Lippman. HACE1 loss results in hyperactive Rac signaling conferring resistance to HER2 targeted therapies [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-11-03.</jats:p