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.

Fig 1. Neointima area at each follow-up timing.

(A) Single BMS implantation, (B) Overlapped BMS implantation, (C) Single DES implantation, (D) Overlapped DES implantation. No significant differences between female and male groups were observed at any following timings.

Fig 2. Distribution of neointima area.

(A) Single BMS implantation, (B) Overlapped BMS implantation, (C) Single DES implantation, (D) Overlapped DES implantation. No significant differences between female and male groups were observed.

Fig 3. Luminal occlusion at each follow-up timing.

(A) Single BMS implantation, (B) Overlapped BMS implantation, (C) Single DES implantation, (D) Overlapped DES implantation. Higher luminal occlusion with statistically significant difference were observed 30 days after overlapped BMS implantation in the male group (B), 365 days after single DES implantation in the female group (C), and 180 days after overlapped DES implantation (D).

Fig 4. Distribution of luminal occlusion.

(A) Single BMS implantation, (B) Overlapped BMS implantation, (C) Single DES implantation, (D) Overlapped DES implantation. No significant differences between female and male groups were observed.

Fig 5. Injury score at each follow-up timing.

(A) Single BMS implantation, (B) Overlapped BMS implantation, (C) Single DES implantation, (D) Overlapped DES implantation. Higher injury scores were observed in the female group 180 days after single BMS implantation (A), 365 days after single DES implantation (C), and 180 days after overlapped DES implantation (D).

Fig 6. Adventitial fibrosis score at each follow-up timing.

(A) Single BMS implantation, (B) Overlapped BMS implantation, (C) Single DES implantation, (D) Overlapped DES implantation. Higher adventitial fibrosis scores were observed 180 days after single BMS implantation in the female group (A), 365 days after single BMS implantation in the male group (A), 30 days after overlapped BMS implantation in the male group (B), 30 and 90 days after single DES implantation in the male group (C), and 365 days after single DES implantation in the female group (C).

Fig 7. Inflammation score at each follow-up timing.

(A) Single BMS implantation, (B) Overlapped BMS implantation, (C) Single DES implantation, (D) Overlapped DES implantation. A higher inflammation score with statistical significance was observed in the male group 365 days after single BMS implantation (A).

Fig 8. Neointimal fibrin score at each follow-up timing.

(A) Single BMS implantation, (B) Overlapped BMS implantation, (C) Single DES implantation, (D) Overlapped DES implantation. Black lines in the male group at 90, 180, and 365 days after single BMS implantation and at 365 days after single DES implantation, and in the female group at 90 days after single BMS implantation, at 90 days after overlapped BMS implantation, and at 365 days after single DES implantation indicate that the neointimal fibrin scores were 0. A higher neointimal fibrin score was observed in male group 30 and 180 days after single DES implantation (C), and 90 days after overlapped DES implantation (D). The statistically significant decreases over time were observed in the female group after single and overlapped DES implantation (C, D).