Intractable Prinzmetal’s Angina Three Months after Implantation of Sirolimus-Eluting Stent

ABSTRACT: Sirolimus-eluting stents (SES) prevent neointimal proliferation and have been widely used to treat stenotic lesions in coronary arteries because of a significant reduction of restenosis in comparison with bare-metal stents. Sirolimus, however, may cause endothelial dysfunction by damage to vascular endothelium or impairing vascular repair. Recent studies report the occurrence of exercise- or acetylcholine-induced coronary vasoconstriction in the vessel segments adjacent to the SES. We report here a clinical case of intractable Prinzmetal’s angina 3 months after SES implantation and recommend extended, thorough follow up of patients who have undergone SES implantation. J INVASIVE CARDIOL 2008;20:E306–E309 Sirolimus-eluting stents (SES) prevent neointimal proliferation and have been widely used to treat stenotic lesions in coronary arteries because of a significant reduction of restenosis in comparison with bare-metal stents (BMS).1 Sirolimus, however, may cause endothelial dysfunction by damage to vascular endothelium or impairing vascular repair.2 Recent studies report the occurrence of exercise- or acetylcholine-induced coronary vasoconstriction in the vessel segments adjacent to the SES, and there are several reports on Prinzmetal’s angina caused by SES-induced endothelial dysfunction within 2 weeks after SES placement. We report here a clinical case of intractable Prinzmetal’s angina 3 months after SES implantation. Case Presentation. A 35-year-old male patient with hypertension, hypercholesterolemia and no history of smoking or diabetes mellitus was admitted to our hospital 3 months earlier with a first episode of recurrent angina at rest day and night. Angiography and intravascular ultrasound (IVUS) performed on the following day showed severe stenosis in the proximal left anterior descending artery (LAD) (Figures 1A, 1B and 2A), and a 3.0 × 23 mm Cypher™ SES (Cordis Corp., Miami Lakes, Florida) was successfully implanted (Figure 1C, 1D and 2B). He was treated with aspirin 100 mg, ticlopidine 200 mg, enalapril 2.5 mg, and pitavastatin 4 mg daily. For 3 months since the angioplasty, the patient was angina-free without calcium antagonists and nitrates until the morning of the present admission. ST changes in the initial ECG and elevation of serum markers for cardiac muscle damage were undetected upon admission. Because the patient had chest pain at rest, we started a continuous intravenous (IV) infusion of heparin. On the following morning (Day-2) at the hospital, the patient complained of severe chest pain and developed significant ST elevation in ECG leads I, aVl and V2–V6 (Figure 3A), indicating an occlusion in the proximal LAD. The patient experienced relief from chest pain within 2 minutes after administration of nitrates followed by ST-elevation normalization within 7 minutes (Figure 3B). Emergent coronary angiography showed no evidence of occlusion in the SES implanted in the LAD (Figure 1E) or the right coronary artery (RCA) (Figure 1F). The patient was consequently diagnosed with Prinzmetal’s angina and was given diltiazem hydrochloride 200 mg daily. However, he developed chest pain again with ST-segment depression 40 minutes after discontinuing IV nitrates, indicating a reoccurrence of coronary vasospasm. He was thus started on oral isosorbide mononitrate 20 mg twice a day. On Day 4 during the current hospitalization, the patient developed chest pain for the third time with ST-segment depression 45 minutes after discontinuing IV nitrates. Administration of nitrates relieved chest pain within 2 minutes followed by the disappearance of ST depression within 9 minutes. Next, the medication for the patient was switched from diltiazem hydrochloride to nifedipine 40 mg daily. He was subjected to a provocation test with hyperventilation and a cold pressor to evaluate the effectiveness of these drugs. After 3-minute forced hyperventilation and a 1-minute bath of his 1 hand in ice water, he developed chest pain for the fourth time with nonsustained ventricular tachycardia (Figure 3C) and ST-segment elevation in ECG leads I, II, III, aVl, aVF and V1–V6 (Figure 3D). Administration of nitrates promptly diminished the chest pain and ST elevation on the ECG. After adding nicorandil 5 mg 3 times daily to nitrates and nifedipine, the patient had a negative provocation test and has been angina-free for more than 9 months since his hospital discharge. Discussion. SES have dramatically reduced the risk of restenosis by suppressing neointimal hyperplasia.1 Sirolimus, however, may cause endothelial dysfunction by damaging vascular endothelium or impairing vascular repair,2 and patients with coronary artery spasm may have endothelial dysfunction of the coronary arteries.3,4 Stent-based local delivery of sirolimus profoundly inhibited neointimal formation but caused vasomotor dysfunction in distal conduit vessel segments at 4 weeks after SES implantation in pigs.5 Previous studies in humans have reported that incomplete neointimal or endothelial coverage occurred in SES 3–6 months after implantation, as evaluated by angioscopy6 or optical coherence tomography,7 and reported exercise-induced coronary vasoconstriction in the vessel segments adjacent to the SES, but not to the BMS,8 and abnormal coronary vasoconstriction in the endothelium-dependent vasodilator acetylcholine proximally or distally to the site of SES implantation in asymptomatic patients.9–11 Although vascular endothelial dysfunction was reported to increase with hypertension and hypercholesterolemia,12 SES could cause additional endothelial dysfunction and finally induce coronary vasospasm. Recently, 7 patients with severe coronary spasm after SES deployment were reported,13 but aside from 1 asymptomatic patient identified by angiography alone 4 weeks after SES implantation, the other 6 patients developed chest pain symptoms within 2 weeks of stent deployment. We previously reported that peak peripheral blood concentrations of sirolimus in Japanese patients were observed approximately 4 hours after SES placement,14 and it was reported that around 80% of sirolimus was released within 30 days of SES implantation.9 Coronary spasm within 2 weeks after SES implantation as reported in previous cases is likely due to direct damage of the vascular endothelium by sirolimus. In the present case, however, Prinzmetal’s angina occurred 3 months after SES implantation, and no incidence of symptomatic coronary spasm during the 3 months after SES implantation was reported. Other possible mechanisms of coronary vasoconstriction are alterations in autonomic tone, reactive oxygen species, smooth muscle hypercontractility, inflammation and allergic responses.13 In particular, localized hypersensitivity to the polymer coating on SES and inflammation were reported,15 reactions that could cause coronary vasospasm. Therefore, coronary spasm in this case could have been caused not only by sirolimus-induced endothelial dysfunction, but also by hypersensitivity to the polymer coating on SES and the resultant inflammation. Coronary spasm in the present case was refractory to nitrates and calcium antagonists, but it was finally relieved by an addition of nicorandil. Nicorandil is a hybrid of a nitrate and an ATP-sensitive potassium channel-opener, and has a potent vasodilatory effect on coronary arteries. We previously reported 2 cases of refractory coronary spasm relieved by the administration of nicorandil.16 The type of stent must be carefully chosen depending on the lesion and patient characteristics. Only 1 case of diffuse spasm with the use of a BMS and 8 cases of diffuse spasm following DES implantation have been reported to the FDA over the past 5 years. Brott et al13 reported 2 other cases of coronary spasm with BMS. Because all cases occurred within 6 hours after BMS implantation and were successfully treated with nitrates or calcium antagonists, clinically significant spasm after BMS implantation seems to be a very rare event. BMS implantation may be recommended for patients with coronary spasm, but the higher rate of restenosis of BMS may offset the beneficial effects on endothelial function. In conclusion, we report a clinical case of intractable Prinzmetal’s angina 3 months after SES implantation and recommend extended careful follow up in patients who have undergone SES implantation.

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