Impaired Endothelial Vasomotor Function After Sirolimus-Eluting Stent Implantation

Abstract

he sirolimus-eluting stent (SES) is a stent coated with sirolimus, and is reported to prevent neo-intimal proliferation and injury-induced arterial intimal thickening. 1 It is widely used to treat coronary stenotic lesions because of the associated very low rates of in-stent restenosis and need for target lesion revascularization compared with conventional bare metal stents (BMS). [2][3][4] Sirolimus is a macrolide antifungal agent with antiproliferative and immunosuppressant properties. It inhibits vascular smooth muscle cell proliferation via cell cycle arrest in the late G1 phase. 5 It also inhibits endothelial cell proliferation and smooth muscle progenitor cell circulation. 6 Experimental studies using sirolimus 7,8 have reported a decrease in endothelial function in vitro, but the effects of SES on endothelial vasomotor function in humans is not well known. 9 The present study aimed to evaluate the influence of SES implantation on endothelial vasomotor function 6 months following stent implantation, using a pharmacological acetylcholine test. To clarify whether endothelial dysfunction was already present before SES implantation, we examined vasomotor tone of the coronary segment before stenting in a subgroup study, and compared endothelium-dependent vasomotor function before and 6 months after SES implantation. Methods Study PopulationFrom August 2004 to June 2005, a total of 23 patients who had stable angina pectoris and underwent successful SES (Cypher, Cordis Corp, Miami Lakes, FL, USA) implantation were included in this study. The control group consisted of 12 patients who had significant coronary artery stenosis, and were successfully treated with BMS. Exclusion criteria were acute coronary syndrome, any coronary revascularization site, reperfused coronary arteries, stent restenosis, history of coronary spasm, symptomatic congestive heart failure, atrial fibrillation, severe valvular heart disease, previous coronary bypass graft surgery, and left main coronary artery or bifurcation lesions. Risk factors for endothelial dysfunction were assessed, and patients with insulin-dependent diabetes mellitus, hypertension (systolic blood pressure ≥140 mmHg), currently smoking, hypercholesterolemia (total cholesterol ≥240 mg/dl) were also excluded. Patients in a stable condition who returned for the 6-month angiographic follow-up formed the final study population. Study ProtocolAll participants gave written informed consent for coronary angiography and the endothelial function test. The Background Sirolimus inhibits endothelial cell proliferation in vitro, but although the sirolimus-eluting stent (SES) is widely used because of the very low rates of in-stent restenosis, the influence of SES on coronary endothelial vasomotor function in humans is not well known. Methods and ResultsThe present study included 21 patients treated with SES, and 12 patients treated with conventional bare metal stent (BMS). Endothelium-dependent vasomotor function was evaluated 6 months after stent implantation, using intracoronary ace...

Downstream coronary effects of drug-eluting stents

“…[13][14][15] Recent studies also suggest that DESs may result in endothelial dysfunction manifested through impaired vascular responsiveness in the downstream vessel as well as contributing to late stent thrombosis through neoatherosclerosis. [16][17][18] However, several studies also suggest that cell-cycle inhibitors may possess antiatherogenic properties. [19][20][21][22][23] Although published data are conflicted, it appears that overall outcomes, including target vessel revascularization rates, are slightly more favorable in patients receiving DES, although this has to be weighed against higher stent costs and the necessity for prolonged, uninterrupted antiplatelet therapy.…”

“…Although this result is not expected with respect to a variety of studies demonstrating endothelial dysfunction in vessels treated with DES and neoatherosclerosis of the target lesion, the notion that antiproliferative agents could have an atheroprotective effect is not without precedent. 16,17 Multiple studies have demonstrated the atherosclerotic attenuation of sirolimus in Apolipoprotein E-deficient mice and human vascular smooth muscle cells. [19][20][21][22] A variety of studies investigating coronary artery disease in heart transplant patients, who have baseline endothelial dysfunction, have shown that antiproliferatives such as sirolimus attenuate the rate of atherosclerotic progression.…”

Long-Term Effects of Novel Biodegradable, Polymer-Coated, Sirolimus-Eluting Stents on Neointimal Formation in a Porcine Coronary Model

“…Although sirolimus, a potent immunosuppressive agent, possesses anti-inflammatory and antiproliferative effects, the drug may also impair endothelium regeneration and normal endothelial functions, 21,22) including the production of essential anti-inflammatory and antithrombotic factors. Thus, it is possible that sirolimus contributes toward creating a proinflammatory environment.…”

Bioresorbable scaffold — A magic bullet for the treatment of coronary artery disease?

“…Data from clinical trials suggested that after implantation of first generation of DES (sirolimus and paclitaxel), endothelium-dependent vasorelaxation is impaired (evaluated by intracoronary infusion of acetylcholine followed by bolus injection of nitrate and angiographic assessment of the artery segments adjacent to the implanted stent) (67)(68)(69)(70). More recent data suggested that second generation DES (everolimus-eluting, biolimus-eluting, zotarolimus eluting) do not cause this effect (71)(72)(73).…”