Mini-swine Model Of Hindlimb Ischemia On A Background Of Metabolic Syndrome Mimics Peripheral Artery Disease And Claudication

Background: There is an ongoing need for an animal model of PAD that is similar to the human patients in its size, anatomy, physiology, comorbidities and suitability for invasive/non-invasive testing and treatment. Methods: Three months old Ossabaw swine (N=9) were fed a high fat/fructose/sodium diet for 8 weeks. Right hindlimb ischemia was then induced (N=6, 2 female) using Right Superficial Femoral Artery (RSFA cutdown, right external iliac artery endovascular (R EIA) coil embolization/occlusion and RSFA resection (T0) vs sham (N=3, 1 female). At 4 weeks (T4), all swine underwent R carotid cutdown, 2-D angiography, and bilateral(b/l) gastrocnemius open biopsy. At 8 weeks (T8) swine underwent L carotid cutdown, 2-D angiography, b/l sampling of the gastrocnemius. During all procedures, b/l ankle brachial indices (ABIs), and tissue oximetry on the calf and thigh were measured. All swine underwent weekly measurement of their treadmill walking distance. Gastrocnemius muscle mitochondrial respiration was measured with an Oroboros Oxygraph-2k. Results: Blood draws showed hyperlipidemia and hyperglycemia in all swine at T0, T4, and T8 after a 12-hour fasting period. Hindlimb ischemia lowered right-sided ABIs at T4 and T8 by 45 and 39% (p<0.001) , and tissue oximetry on R calf (28 and 18% p<0.01) and thigh (22 and 18% P<.01 ) with no differences in the sham. Ischemia reduced treadmill times from T0 to T8 from 24 to 9.4 minutes (p<0.01) vs sham increase from 23.3 to 32.2 (p<0.09) . R internal Iliac artery had the largest growth of cross-sectional area at T4 and T8 (111.7 and 115.2%) compared to L EIA (40.6 and 46.1% - p< 0.02 and <0.5 ) and aorta (14.5 and 29% p <0.02 and <0.02 ). R profunda artery angiographic appearance was delayed at T4, which improved at T8 after normalization of the timing ratio from right to left (3.25 vs 2.3 p<0.008 ). Mitochondrial oxygen consumption in the ischemic right gastrocnemius was consistently lower ex-vivo (21.96±6.41 vs 15.11±11.1 p<0.03 ) with no differences in the sham. We had no fatalities. Discussion: We present a porcine model of hindlimb ischemia (iliofemoral artery occlusion) which recapitulates key aspects of the pathophysiology of human PAD/ claudication, and can support the development of new therapies for PAD.