Percutaneous Treatment of Cardiac Allograft Vasculopathy

Orthotopic heart transplantation is an effective therapy for patients with end-stage congestive heart failure.¹ Complications and comorbidities associated with orthotopic heart transplant and the medications needed to prevent rejection include infection, malignancy, renal failure, and transplant coronary artery disease.² Transplant coronary artery disease (TCAD) is the Achilles’ heel of orthotopic heart transplantation, as it is a major cause of allograft failure and death in patients surviving more than one year post-transplant.^2-5 At 5 years post-transplant, the incidence of TCAD is approximately 40% to 50%.^6,7 The development of TCAD portends a poor prognosis, as the likelihood of death or repeat transplant at 5 years was 50% in patients with severe TCAD.⁸ Vascular smooth muscle cells proliferate as a repair response to immune-mediated cell death, ultimately leading to the development of TCAD.⁹ The etiology of TCAD is multifactorial. The presence of coronary artery disease in the donor allograft increases the risk of the development of TCAD.¹⁰ Older age, male gender, and hypertension are all risk factors for the donor or recipient. Transplant recipient risk factors include International Society of Heart and Lung Transplantation (ISHLT) rejection grade ≥3 (severe acute rejection), multiple rejection episodes in the first year post-transplant, positive cytomegalovirus status pre-transplant, glucose intolerance, hyperlipidemia, smoking, treatment with steroids, and high body mass index.^7,11-22 The diagnosis of TCAD can be difficult, as patients may not experience angina because of autonomic denervation of the allograft. Other symptoms of TCAD may include manifestations of congestive heart failure, arrhythmias, silent myocardial infarction, and sudden death.²³ Therefore, clinical history is generally unreliable for the diagnosis of TCAD. Non-invasive imaging modalities are relatively insensitive in detecting TCAD.^24,25 Because of the high prevalence of TCAD and the potential risk of adverse cardiac events, the guidelines recommend annual or biannual coronary angiography, as it appears to be the only reliable method to diagnose TCAD.²⁶ As a screening tool, coronary angiography has a lower sensitivity for detection of TCAD than for non-TCAD, because TCAD exhibits a combination of both typical atherosclerotic disease and diffuse concentric intimal thickening, as opposed to the more typical focal plaques observed in native coronary artery disease.²⁷ Coronary angiography may be performed less frequently if patients do not have TCAD at 3 to 5 years post-transplant. If percutaneous coronary intervention (PCI) is performed, surveillance angiography should be performed at 6 months, because of the high incidence of restenosis. Since TCAD is often a diffuse process and commonly associated with vascular remodeling, coronary angiography may not detect TCAD, as it only provides a luminal assessment of the vessel, rather than arterial wall anatomy. Intravascular ultrasound (IVUS) is a safe, highly sensitive imaging modality, and is one of the best surrogate markers for predicting future clinical events from TCAD.²⁸ IVUS parameters, like the percentage of atheroma volume, emerged as a favored end point in clinical trials. A change of ≥ 0.5 mm in maximal intimal thickness within the first year post-transplant predicted the development of TCAD, mortality, and myocardial infarction at 5 years post-transplant.^29-32 The prevalence of TCAD is related to the number of arteries imaged. In patients with one- and three-vessel imaging, TCAD was observed in 27% and 58% at one year, increasing to 39% and 74% at 3 years, respectively.³³ Increased cost and potential safety concerns with the use of IVUS in small-caliber vessels may limit its widespread adoption.³⁴ The ISHLT recommends IVUS at 4 to 6 weeks and at one year post-transplant to detect donor coronary artery, TCAD, and provide prognostic information (class IIa).³⁵ Measurement of fractional flow reserve (FFR) may have utility in determining the functional significance of TCAD lesions.³⁶ FFR values were abnormal in patients without angiographic evidence of TCAD, highlighting the diffuse nature of TCAD. Patients with a normal FFR may have an abnormal coronary flow reserve (CFR), reflecting involvement primarily of the microcirculation. Effective medical therapy to reverse TCAD is lacking. In addition to lifestyle modification, primary prevention of TCAD involves strict control of blood pressure, blood glucose levels, cholesterol levels, and maintaining ideal body weight.³⁵ Statins should be considered for all orthotopic heart transplant recipients, because they reduce TCAD and improve clinical outcomes after transplant.^37-39 However, TCAD is a progressive process with significant morbidity and mortality, despite maximal medical therapy. Anti-rejection medications are the mainstay of therapy after orthotopic heart transplantation. Calcineurin inhibitors (i.e. cyclosporine and tacrolimus), glucocorticoids, and mycophenolate mofetil (MMF) are commonly used immunosuppressive agents post-transplant. Although cyclosporine is effective in preventing cardiac allograft vasculopathy,^40,41 it has detrimental effects on endothelial function.^42-47 Furthermore, negative effects on the kidneys may preclude the widespread, long-term use of cyclosporine post transplant. MMF inhibits antibody production and smooth muscle cell proliferation.⁴⁸ MMF reduced intimal thickness and improved mortality within the first year post-tranplant.^49,50 Unlike cyclosporine, MMF is not nephrotoxic.⁵¹ Sirolimus (rapamycin) and everolimus are attractive alternatives to calcineurin inhibitors for the management of TCAD, because of their lower risk of nephrotoxicity. Sirolimus reduced coronary lumen stenosis compared with azathioprine, and exhibited greater inhibitory effects on smooth muscle cell proliferation compared with cyclosporine.^52,53 When calcineurin inhibitors were substituted with sirolimus, the progression of TCAD was reduced and renal function improved.⁵⁴ The ISHLT guidelines recommend the substitution of MMF with sirolimus or everolimus when TCAD is diagnosed (class IIa).²⁶ However, the use of sirolimus immediately post-transplant may be unsafe, because of the potential increase in post-surgical wound complications.⁵⁵ Although TCAD often involves diffuse luminal disease with concentric intimal hyperplasia, PCI is feasible, associated with high procedural success rates, and a viable therapeutic option for cardiac transplant recipients with TCAD, especially when lesions are focal.⁵⁶ In contrast, while balloon angioplasty was associated with acceptable procedural success rates, restenosis rates were high.^57,58 Even though the restenosis rates are higher compared with native coronary artery lesions, partly due to the aggressive lymphoproliferative effect of TCAD,^12,59 bare metal stents decreased early restenosis rates compared with balloon angioplasty.^58,60,61 However, late restenosis rates with bare metal stents caught up to those seen with balloon angioplasty.^57,62 In-stent restenosis observed in TCAD is characterized by endothelial damage and proliferation, and migration of vascular smooth muscle cells.⁵⁹ Data with drug-eluting stents for the treatment of TCAD are limited in size and number. Several studies reported a modest reduction in restenosis rates and target vessel revascularization with drug-eluting stents compared with bare metal stenosis when used to treat more focal TCAD lesions.^12,63,64 Drug-eluting stents are also recommended by the ISHLT for short-term palliation for appropriate focal lesions (class IIa).³⁵ In a multinational observational study, PCI with sirolimus- and paclitaxel-eluting stents provided similar outcomes in patients with TCAD.⁶⁵ Long-term data also suggest that PCI is safe and effective for the treatment of cardiac transplant recipients with unprotected left main TCAD.⁶⁶ There is a paucity of data with bypass surgery for the treatment of TCAD. Bypass surgery is rarely performed, because the diffuse nature of TCAD with poor distal targets makes surgical revascularization technically challenging and a poor treatment option. Furthermore, bypass surgery is associated with high perioperative mortality (35%),⁶⁷ and 5-year survival was as low as 20%.^68-72 Repeat orthotopic heart transplantation is the only definitive treatment of severe allograft vasculopathy and may be considered in patients with severe TCAD in the absence of contraindications. However, because of the paucity of organs and ethical considerations, PCI may be preferred as a palliative treatment option. Although pediatric patients have a higher mortality rate after repeat orthotopic heart transplantation compared to the initial transplant,⁷³ adults who underwent repeat orthotopic heart transplantation had similar mortality rates compared to the initial transplant.⁷⁴ In conclusion, TCAD is the main limitation to the survival of cardiac transplant recipients. Coronary angiography and IVUS are recommended for the diagnosis of TCAD. PCI is feasible, safe, and associated with good procedural success rates, as well as acceptable results at intermediate follow up, and is an effective treatment strategy for patients with TCAD. PCI with drug-eluting stents is the preferred treatment strategy for severe, focal TCAD, but is associated with higher restenosis rates compared with native coronary artery lesions. When PCI is not an option because of severe diffuse disease, repeat transplantation may be considered for these patients. Large, randomized trials are needed to identify the ideal treatment strategies for orthotopic heart transplantation recipients with severe TCAD. Dr. Lee can be contacted at mslee@mednet.ucla.edu

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———————————————————— This article received double-blind peer review from members of Cath Lab Digest’s editorial board.