Sex differences in the outcomes of stent implantation in mini-swine model

Abstract

Sex-related differences have been noted in cardiovascular anatomy, pathophysiology, and treatment responses, yet we continued to drive evaluation of vascular device development in animal models without consideration of animal sex. We aimed to understand sex-related differences in the vascular responses to stent implantation by analyzing the pooled data of endovascular interventions in 164 Yucatan mini-swine (87 female, 77 male). Bare metal stents (BMS) or drug-eluting stents (DES) were implanted in 212 coronary arteries (63 single BMS implantation, 68 single DES implantation, 33 overlapped BMS implantation, and 48 overlapped DES implantation). Histomorphological parameters were evaluated from vascular specimens at 3–365 days after stent implantation and evaluated values were compared between female and male groups. While neointima formation at all times after implantation was invariant to sex, statistically significant differences between female and male groups were observed in injury, inflammation, adventitial fibrosis, and neointimal fibrin deposition. These differences were observed independently, i.e., for different procedure types and at different follow-up timings. Only subtle temporal sex-related differences were observed in extent and timing of resolution of inflammation and fibrin clearance. These subtle sex-related differences may be increasingly important as interventional devices meld novel materials that erode and innovations in drug delivery. Erodible materials may act differently if inflammation has a different temporal sequence with sex, and drug distribution after balloon or stent delivery might be different if the fibrin clearance speaks to different modes of pharmacokinetics in male and female swine.

Sex and long-term outcomes after implantation of the Absorb bioresorbable vascular scaffold for treatment of coronary artery disease

“…Contrary to expectations, ongoing device-related events are observed up to three years after poly-lactic acid-based BVS implantation 1,8 . BVS elastic recoil due to the lower radial strength of poly-lactic acid-based BVS 3,22 , and ongoing inflammation accompanying the resorption process which promotes thrombosis and neoatherosclerosis might explain these findings 7,23,24 . The TLR rates in our study were 7.5% among women and 12.4% among men, which differ from rates reported in selected stable populations of randomised trials, 3.7% vs 4.8%, respectively 11 .…”

“…Since this tissue is most probably inflammation-triggered fibrin deposition, it leads to impaired neointimal BVS strut coverage, late malapposition and neoatherosclerosis formation. Although there are no data about sex-related differences in vascular response to BVS implantation, a large animal study demonstrated temporal sex-related differences in the extent and timing of resolution of inflammation and fibrin clearance after DES implantation 24 .…”

Fatal Ovarian Hemorrhage Associated With Anticoagulation Therapy in a Yucatan Mini-Pig Following Venous Stent Implantation

“…Although clinically several sex-related differences in cardiovascular anatomy, pathophysiology and intervention response have been identified (60)(61)(62), sex is rarely evaluated in short-term pre-clinical animal models as a confounding variable. In 2018 Kunio et al (63) examined the sex-related differences in the outcome of endovascular stent implantation in swine. They found that female swine had histopathological signs of vascular injury and inflammation for longer than males and that adventitial fibrosis and neointimal fibrin deposition (thickening of arterial walls and decreased arterial lumen space) were greater in males than females.…”

Estudo de anatomia comparada suína por angiotomografia: contribuições para modelos de pesquisa e treinamento em cirurgia vascular e endovascular

“…Animal experimentation is frequently employed to assess the efficacy and safety of new treatments before they are applied in clinical trials. [1][2][3][4][5][6][7][9][10][11][12][13][14][15]24 Although pigs have been used extensively in many areas, such as genomics, organ transplantation, oncology, trauma, and neurological and cardiovascular diseases, 2-4,10,18 many important physiological and anatomic factors remain unknown or have only been described superficially. 1,5,25 The literature contains several conflicting anatomic descriptions, such as the "bifurcation" of the aorta, 3,6,26 which is actually a "trifurcation" in pigs.…”

“…13 At 3 months of age, weighing from 32.4 to 34.5 kg, the same breed has been used to study microsurgical vascular anastomoses in a model of tibia transplantation 9 and, at 4 months of age, has been used to evaluate differences between the sexes with relationship to the results of coronary stenting. 24 The Göttingen minipig breed has been used in tomographic studies of vascular anatomy, more specifically with a focus on pediatric issues, since at 11 weeks of life, these animals have approximately the same weight as a newborn human being, 3 with an appropriate profile for these projects.…”