‘3D angiographies of our swine model of recanalized acute ischemic stroke during baseline, occlusion and recanalization.’
Aladdin Taha1,2, MD; Joaquim Bobi1, DVM, PhD; Diederik W.J. Dippel2, MD, PhD; Heleen M.M. van Beusekom1, PhD.
- Erasmus MC University Medical Center, Division of Experimental Cardiology, Department of Cardiology, Rotterdam, the Netherlands.
- Erasmus MC University Medical Center, Stroke Center, Department of Neurology, Rotterdam, the Netherlands.
Large animal modeling
Despite numerous successful drug studies in rodents, translation of promising results to men has turned out to be a great challenge in acute ischemic stroke (AIS) research.1 To prevent futile clinical trials in humans, STAIR and RIGOR guidelines recommend studies in multiple species, including a gyrencephalic species.2,3 Rather than rodents, large animal gyrencephalic species allow for studies in a larger brain, with a structure that is more similar to the human brain. Larger species, such as swine, dogs, sheep and non-human primates can undergo imaging and catheterization procedures using the exact same clinical devices to further increase translational capacity. Furthermore, the larger circulating volume provides many opportunities in biomarker research that can be matched to clinical trial sampling strategies.
As part of the pre-clinical work package of the CONTRAST-Consortium we recently published a review comparing large gyrencephalic animals being used in translational AIS research, together with international leading experts in this field.4 In this review, we compared benefits and challenges of four species, aimed to assist researchers in selecting the appropriate model for their studies. In Rotterdam, we decided to work with the swine model. It is a well-characterized model in cardiovascular research and offers many opportunities for integrating comorbidities in AIS modeling.5,6
Cerebral ischemia-reperfusion in swine
We have set-up a swine model for cerebral ischemia-reperfusion, allowing us to study the additional value of neuroprotective treatments in the setting of a recanalized AIS. The model is established in both farm-bred swine and adult minipigs, and was presented at ESOC 2022.7 Working with swine allows us to use clinical MRI and CT-scanners, and (3D) digital subtraction angiography, which can be combined with extensive histopathological and ultrastructural outcome measures. Adding comorbidities such as atherosclerosis, hypertension and diabetes can further increase the translational power of these models.
Vessel wall injury due to Endovascular Treatment (EVT)
Following a study on endothelial injury due to coronary interventions,8 we studied vascular injury and healing due to stent-retriever and direct aspiration treatment in a swine model of autologous thrombo-embolic occlusion. Selecting arteries with similar size and anatomy to the human MCA, using the exact same EVT devices as in clinic, and having the opportunity to study the luminal damage and repair at an ultrastructural level is what makes this model particularly valuable. Our main goal is to understand injury and healing patterns, how this could affect patient outcome, and potentially optimize treatment strategies and pharmacologic treatment. The first results were presented at ESOC 2022.7 In addition, this model is used for EVT training and device optimization.
Combining the clinical and pre-clinical biobank
Within the CONTRAST-Consortium, we have built both clinical and pre-clinical biobanks of tissue, thrombus and serial plasma samples. For clinical studies,9-11 thrombi removed during EVT and plasma samples are stored systematically. For pre-clinical studies, brain samples, thrombi and serial plasma samples are collected. This way, biomarker findings from animal studies can be validated in patient samples and vice versa. Additionally, having studied thrombus characteristics in patient thrombi,12 we aim to recreate similar thrombi for our swine model of thrombo-embolic occlusion. This way, we link preclinical and clinical research. We hope that by this approach, we will improve our understanding of cerebrovascular disease mechanisms and progress, and ultimately, of ways to improve outcome not only of our animals but of our patients as well.
- O’Collins VE, Macleod MR, Donnan GA, Horky LL, van der Worp BH, Howells DW. 1,026 experimental treatments in acute stroke. Ann Neurol. 2006;59:467-477. doi: 10.1002/ana.20741
- Fisher M, Feuerstein G, Howells DW, Hurn PD, Kent TA, Savitz SI, Lo EH, Group S. Update of the stroke therapy academic industry roundtable preclinical recommendations. Stroke. 2009;40:2244-2250. doi: STROKEAHA.108.541128 10.1161/STROKEAHA.108.541128
- Lapchak PA, Zhang JH, Noble-Haeusslein LJ. RIGOR guidelines: escalating STAIR and STEPS for effective translational research. Transl Stroke Res. 2013;4:279-285. doi: 10.1007/s12975-012-0209-2209
- Taha A, Bobi J, Dammers R, Dijkhuizen RM, Dreyer AY, van Es A, Ferrara F, Gounis MJ, Nitzsche B, Platt S, et al. Comparison of Large Animal Models for Acute Ischemic Stroke: Which Model to Use? Stroke. 2022;53:1411-1422. doi: 10.1161/STROKEAHA.121.036050
- van de Wouw J, Sorop O, van Drie RWA, van Duin RWB, Nguyen ITN, Joles JA, Verhaar MC, Merkus D, Duncker DJ. Perturbations in myocardial perfusion and oxygen balance in swine with multiple risk factors: a novel model of ischemia and no obstructive coronary artery disease. Basic Res Cardiol. 2020;115:21. doi: 10.1007/s00395-020-0778-210.1007/s00395-020-0778-2
- van Ditzhuijzen NS, van den Heuvel M, Sorop O, van Duin RW, Krabbendam-Peters I, van Haeren R, Ligthart JM, Witberg KT, Duncker DJ, Regar E, et al. Invasive coronary imaging in animal models of atherosclerosis. Neth Heart J. 2011;19:442-446. doi: 10.1007/s12471-011-0187-0
- ESOC 2022 Abstract Book. Eur Stroke J. 2022;7:3-588. doi: 10.1177/23969873221087559
- Autar A, Taha A, van Duin R, Krabbendam-Peters I, Duncker DJ, Zijlstra F, van Beusekom HMM. Endovascular procedures cause transient endothelial injury but do not disrupt mature neointima in Drug Eluting Stents. Sci Rep. 2020;10:2173. doi: 10.1038/s41598-020-58938-z10.1038/s41598-020-58938-z
- LeCouffe NE, Kappelhof M, Treurniet KM, Rinkel LA, Bruggeman AE, Berkhemer OA, Wolff L, van Voorst H, Tolhuisen ML, Dippel DWJ, et al. A Randomized Trial of Intravenous Alteplase before Endovascular Treatment for Stroke. N Engl J Med. 2021;385:1833-1844. doi: 10.1056/NEJMoa2107727
- Pirson F, Hinsenveld WH, Goldhoorn RB, Staals J, de Ridder IR, van Zwam WH, van Walderveen MAA, Lycklama ANGJ, Uyttenboogaart M, Schonewille WJ, et al. MR CLEAN-LATE, a multicenter randomized clinical trial of endovascular treatment of acute ischemic stroke in The Netherlands for late arrivals: study protocol for a randomized controlled trial. Trials. 2021;22:160. doi: 10.1186/s13063-021-05092-010.1186/s13063-021-05092-0
- van der Steen W, van de Graaf RA, Chalos V, Lingsma HF, van Doormaal PJ, Coutinho JM, Emmer BJ, de Ridder I, van Zwam W, van der Worp HB, et al. Safety and efficacy of aspirin, unfractionated heparin, both, or neither during endovascular stroke treatment (MR CLEAN-MED): an open-label, multicentre, randomised controlled trial. Lancet. 2022;399:1059-1069. doi: S0140-6736(22)00014-9 10.1016/S0140-6736(22)00014-9
- Autar ASA, Hund HM, Ramlal SA, Hansen D, Lycklama ANGJ, Emmer BJ, de Maat MPM, Dippel DWJ, van der Lugt A, van Es A, et al. High-Resolution Imaging of Interaction Between Thrombus and Stent-Retriever in Patients With Acute Ischemic Stroke. J Am Heart Assoc. 2018;7. doi: JAHA.118.008563 10.1161/JAHA.118.008563