Long-Term Follow Up after Coronary Sirolimus Drug-Eluting Stent Implantation for Cardiac Transplant Arteriopathy

Case Report. A 60-year-old male presented to the emergency department complaining of acute onset of precordial pain radiating to the left arm and neck. He denied any recent symptoms of exertional or nonexertional chest pain. The patient had undergone orthotopic heart transplantation 6 years earlier for Class IV heart failure secondary to ischemic cardiomyopathy. His postoperative course was uncomplicated, and subsequent surveillance endomyocardial biopsies have not shown evidence of rejection. A surveillance coronary angiogram 1 year prior showed evidence of mild coronary arteriopathy in the left anterior descending, diagonal, left circumflex and right coronary arteries. In the emergency department, the patient’s electrocardiogram showed biphasic T-waves in the anteroseptal leads, and initial troponin I was 306 ng/ml, creatine kinase 1,542 U/L, with an MB fraction of 248.7 U/L. Emergent coronary angiography revealed complete occlusion of the mid-left anterior descending artery, as well as diffuse arteriopathy in the diagonal and left circumflex arteries (Figure 1A). A proximal left anterior descending coronary artery-to-pulmonary artery fistula was also noted. Left ventriculography demonstrated apical and anterolateral hypokinesis, with an ejection fraction of 45%. Tandem stenting of the mid-left anterior descending artery was performed with 2 overlapping 2.5 x 28 mm Cypher™ sirolimus-eluting stents (Cordis Corp., Miami, Florida), with adjuvant intravenous eptifibatide (Figure 1B). The patient experienced no further chest pain and was discharged home 2 days after the procedure. A follow-up coronary angiography 8 months after the procedure showed a mild, focal area of in-stent restenosis of 25% by quantitative coronary angiography (Figure 1C). Diffuse arteriopathy distal to the area of stent deployment as well as in the other epicardial vessels was again noted, but had not significantly progressed. Discussion Transplant arteriopathy is the leading cause of late death in cardiac transplant patients.¹ In a multicenter study of 2,609 heart transplantation recipients, 42% had angiographic evidence of graft vasculopathy within 5 years after transplantation.² The vasculopathy is generally diffuse and concentric, originating in the distal small vessels, and takes an unrelenting course that is often clinically silent.³ Statin therapy has been shown to improve survival in these patients, but shows little benefit when started later in the course of the disease.⁴ Percutaneous interventions for transplant arteriopathy have yielded disappointing outcomes. Halle and colleagues reviewed 66 patients treated with balloon angioplasty in a multicenter study involving 97 procedures at 13 centers.5 Restenosis occurred in 55% of lesions studied at a mean of 8 months after the procedure. Bare metal stents appear to reduce the rate of restenosis compared to balloon angioplasty. Benza et al. reviewed 62 transplant patients treated at the University of Alabama from 1990 to 2000, and reported that at 8 months after the procedure, restenosis occurred in 71% of patients treated with balloon angioplasty, compared to 39% in those treated with bare metal stents.⁶ Jain et al. reported 19 lesions treated with bare metal stents and found a 19% restenosis rate at 8 months after the procedure.⁷ Differences in immunosuppressive regimens and statin use confound the interpretation of these data. Retransplantation is considered the only effective long-term therapy. Recent studies have shown that systemic sirolimus may attenuate the development of transplant vasculopathy. Patients randomized immediately after cardiac transplantation to oral sirolimus versus standard immunosuppressive therapy demonstrated significantly less transplant vasculopathy after 2 years as measured by intracoronary ultrasound.⁸ Mancini et al. showed that the addition of sirolimus slowed disease progression even in patients demonstrating significant vasculopathy years after transplantation, with significantly reduced rates of death, myocardial infarction and the need for revascularization.⁹ In animal models, sirolimus appears to inhibit proliferation and migration of vascular smooth muscle cells, increase nitric oxide levels and decrease extracellular matrix accumulation and fibrosis.¹⁰ There has been limited published experience with sirolimus-eluting stents in transplant vasculopathy.¹¹ In native coronary atherosclerosis, sirolimus-eluting stents have showed sustained protection against neointimal proliferation, resulting in reduced restenosis and target vessel revascularization.¹² It is unknown whether sirolimus-eluting stents are also effective in the immune-dysregulated milieu of transplant vasculopathy. The pharmacokinetic profile of sirolimus-eluting stents differs markedly from oral administration, resulting in much lower serum concentrations, and elimination of detectable drug levels within 40 to 50 days after stent implantation.¹³ However, the excellent angiographic outcome of this patient 8 months after the procedure, despite the presence of diffuse, severe and rapidly progressive vasculopathy, and risk factors for increased risk of restenosis including a long stented segment and a small diameter stent, demonstrates the safety and possible long-term benefit of sirolimus-eluting stents in the patient with advanced transplant arteriopathy. This outcome also raises the question of whether early, aggressive stenting of arteriopathic vessels may improve survival in the cardiac transplant patient. Indeed, “prophylactic” stenting could become a reasonable strategy, as these patients often show rapidly accelerating vasculopathy with minimal symptoms, as this patient did. While systemic sirolimus is frequently associated with renal insufficiency, pulmonary toxicity, hypertriglyceridemia and thrombocytopenia, sirolimus-eluting stents have not been associated with significant toxicity.¹⁴ Large-scale, randomized trials will be required to establish the efficacy, safety and long-term patency of sirolimus-eluting stents in the cardiac allograft population.

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