Cardiac Lymphatic Dysfunction Causes Drug-Eluting Stent–Induced Coronary Hyperconstricting Responses in Pigs In Vivo

Abstract

Objective— We have previously demonstrated that coronary adventitial inflammation plays important roles in the pathogenesis of coronary vasomotion abnormalities, including drug-eluting stent (DES)–induced coronary hyperconstricting responses. Importantly, the adventitia also harbors lymphatic vessels, which may prevent inflammation by transporting extravasated fluid and inflammatory cells. We thus aimed to examine the roles of coronary adventitial lymphatic vessels in the pathogenesis of DES-induced coronary hyperconstricting responses in a porcine model in vivo. Approach and Results— We performed 2 experimental studies. In protocol 1, 15 pigs were divided into 3 groups with or without DES and with bare metal stent. Nonstented sites 20 mm apart from stent implantation also were examined. In the protocol 2, 12 pigs were divided into 2 groups with or without lymphatic vessels ligation followed by DES implantation at 2 weeks later (n=6 each). We performed coronary angiography 4 weeks after DES implantation, followed by immunohistological analysis. In protocol 1, the number and the caliber of lymphatic vessels were greater at only the DES edges after 4 more weeks. In protocol 2, coronary hyperconstricting responses were further enhanced in the lymphatic vessels ligation group associated with adventitial inflammation, Rho-kinase activation, and less adventitial lymphatic vessels formation. Importantly, there were significant correlations among these inflammation-related changes and enhanced coronary vasoconstricting responses. Conclusions— These results provide evidence that cardiac lymphatic vessel dysfunction plays important roles in the pathogenesis of coronary vasoconstrictive responses in pigs in vivo.

Immunoglobulin G4-related masses surrounding coronary arteries: a case report

“…In the heart, lymphatic vessels exist along coronary arteries, and their dysfunction induces the adventitial inflammation of coronary arteries. 12 This mechanism may be involved in the development of coronary arteritis in IgG4-RD.…”

Low-intensity pulsed ultrasound therapy suppresses coronary adventitial inflammatory changes and hyperconstricting responses after coronary stent implantation in pigs in vivo

“…Anti-platelet therapy with oral aspirin (100 mg/day) and clopidogrel (75 mg/day) was continued until euthanasia. At 4 weeks after DES implantation, we performed coronary angiography (CAG) to evaluate coronary vasomotion at the proximal and distal stent edge segments in vivo [ 4 – 7 , 9 , 16 ]. Median thoracotomy was then performed to examine cardiac lymph transport function [ 9 ].…”

“…At 4 weeks after DES implantation, we performed coronary angiography (CAG) to evaluate coronary vasomotion at the proximal and distal stent edge segments in vivo [ 4 – 7 , 9 , 16 ]. Median thoracotomy was then performed to examine cardiac lymph transport function [ 9 ]. Animals were finally euthanized with a lethal dose of potassium chloride (0.25 mEq/kg, IV) under deep anesthesia with inhaled 5% sevoflurane, and the hearts were dissected for ex vivo experiments.…”

“…At 4 weeks after DES implantation, we examined coronary vasomotor responses to serotonin [10 and 100 μg/kg, intracoronary injection (IC)] before and after hydroxyfasudil (30 and 300 μg/kg, IC for 3 min), a specific Rho-kinase inhibitor (Asahi Kasei Pharma, Tokyo, Japan) [ 16 ], nitroglycerin (10 μg/kg, IC), and bradykinin (0.1 μg/kg, IC) before and after N G -monomethyl-L-arginine (1 mg/kg, IC for 10 min) [ 4 – 7 , 9 , 16 ]. Quantitative coronary angiography (QCA) was performed at the proximal and distal stent edge segments 5 mm apart from the stent as previously described [ 4 – 7 , 9 ]. The segments 10 mm distal to the ostium of the left circumflex coronary arteries (LCx) were used for evaluating coronary vasomotion of the untreated vessels.…”

“…We previously demonstrated that coronary adventitial inflammation, including vasa vasorum formation, inflammatory cells migration, and cytokines secretion by perivascular adipose tissue (PVAT), is involved in coronary hyperconstricting responses after drug-eluting stents (DES) implantation in pigs and patients with vasospastic angina (VSA) [ 4 – 8 ]. Moreover, we recently demonstrated that impairment of cardiac lymphatic drainage function exacerbates adventitial inflammation, and medial vascular smooth muscle cell (VSMC) hyperconstriction through activation of Rho-kinase (a central molecular switch of coronary spasm) in pigs in vivo [ 9 ]. However, currently, no therapeutic approach that specifically targets on coronary adventitial inflammation is available.…”