Abstract: Cardiac allograft vasculopathy (CAV) is an immunologically-mediated phenomenon that occurs in up to 50% of patients surviving to 10 years post orthotopic heart transplant (OHT). While the pediatric subgroup of OHT recipients has a lower overall prevalence of CAV, prognosis is poor after development, with a 24% mortality within 2 years of diagnosis. Medical therapy, including statins, remains the mainstay of treatment. Diffuse intimal thickening often precludes coronary artery bypass grafting, while repeat OHT is associated with inferior outcomes including increased mortality. Percutaneous coronary intervention (PCI) is a therapeutic option for CAV with excellent initial success rates, but higher rates of major adverse cardiovascular events. Despite these challenges, PCI may be performed safely and can serve as a palliative bridge for repeat OHT. There is a paucity of data on PCI for CAV of the unprotected left main coronary artery (ULMCA). We report the case of a 13-year-old female with CAV involving the distal bifurcation of the ULMCA who underwent PCI with drug-eluting stents. While these cases are technically challenging, strategies that may predict success include an appropriately selected patient, use of predictive models for outcomes assessment, and operator expertise.
J INVASIVE CARDIOL 2014;26(11):E156-E160
Key words: heart transplantation, stenting, coronary disease
Cardiac allograft vasculopathy (CAV) is the main cause of morbidity and mortality after orthotopic heart transplantation (OHT).1 CAV is characterized by diffuse, progressive, concentric disease that is largely mediated by immunologic factors.2 Treatment options for OHT recipients with CAV include medical therapy, percutaneous and surgical revascularization, and repeat OHT. We present the case of a pediatric OHT recipient who had severe CAV involving the distal bifurcation of the unprotected left main coronary artery (ULMCA) who underwent percutaneous coronary intervention (PCI).
A 13-year-old female with a history of fetal myocarditis, cardiogenic shock requiring extracorporeal membrane oxygenation, and OHT at the age of 1 year underwent routine surveillance angiography. Previous surveillance angiography showed progressive coronary disease with the most recent angiogram demonstrating severe stenosis of the distal bifurcation of the ULMCA as well as the osmium of the left anterior descending (LAD) artery and left circumflex (LCX) artery (Figure 1). Previous endomyocardial biopsies revealed evidence of mild rejection. Echocardiography revealed normal biventricular function. The patient reported mild shortness of breath on exertion for several months relieved by rest. After a multidisciplinary discussion regarding possible therapeutic options, including percutaneous and surgical revascularization as well as repeat OHT, PCI was felt to be the best option for the treatment of ULMCA disease.
The patient, who was 59 kg, was preloaded with aspirin 325 mg and clopidogrel 600 mg 6 hours prior to PCI. Unfractionated heparin was given intravenously to attain an activated clotting time (ACT) of 260 seconds. The patient was under anesthesia for PCI. The blood pressure prior to starting the PCI was 75/50 mm Hg and decreased to 55/38 mm Hg during the PCI, which required intravenous phenylephrine to restore hemodynamic stability. A 6 Fr JL 3.0 catheter was used to engage the ULMCA. Guidewires were advanced into the LAD and LCX, respectively. A 2.5 x 15 mm balloon was positioned in the ULMCA and proximal LAD and inflated at 16 atm. Next, a 2.75 x 15 mm everolimus-eluting stent (Abbott Vascular) was positioned at the ostium of the LCX with minimal protrusion into the distal ULMCA and deployed at 16 atm (Figure 2). Then, the 2.75 x 15 mm balloon was inflated in the ULMCA/LAD to crush the stent in the LCX. Next, a 2.75 x 23 mm everolimus-eluting stent (Abbott Vascular) was advanced to the ULMCA and proximal LAD, and inflated at 16 atm. Intravascular ultrasound (IVUS) performed on the ULMCA, LAD, and LCX demonstrated that the stents were well opposed, but suboptimally expanded in the ostium of the LCX and distal ULMCA. Kissing balloon inflation was performed using non-compliant balloons in the proximal LAD (3.5 x 15 mm) and LCX (3.0 x 15 mm). Final cineangiogram demonstrated excellent results with TIMI 3 flow and no evidence of dissection (Figure 3). At 6-month follow-up exam, coronary angiography revealed patent stents with no evidence of in-stent restenosis, and the patient continues to do well with no ischemic and bleeding complications.
The pathophysiology of CAV consists of T-cell infiltration of the vessel walls associated with a strong cytotoxic inflammatory response.3 An augmentation of this response is thought to occur as a result of sustained allo-immune mechanisms against graft tissue antigens, including human leukocyte antigens (HLA) class I and II.4,5 Patient factors that exacerbate CAV are both non-immunologic and immunologic in etiology. Non-immunologic factors include hypertension, hyperlipidemia, cytomegalovirus infection, and donor age, whereas immunologic mechanisms include the presence of specific anti-HLA antibodies and the occurrence of rejection.6-9 The immunologic factors preferentially appear to cause the early development of CAV in the pediatric population (within 5 years of OHT). More specifically, repeat OHT and HLA sensitization (panel reactive antibody >10%) increase the likelihood of CAV development [relative risk, 2.13; 95% confidence interval [CI], 1.29-3.53; P<.001) and 1.45 (95% CI, 0.96-2.21; P=.08), respectively].10
Based on statistics from the International Society for Heart and Lung Transplant, CAV affects 8% by year 1, 30% by year 5, and 50% by year 10 of post-OHT patients surviving to follow-up.1 In comparison, pediatric OHT recipients have a lower prevalence of CAV, with the incidence dependent on the years of age at time of OHT. Development of CAV at 6 years was 27% in infants <1 year at the time of OHT, 27% for children ages 1-10 years, and 47% for those children >11 years. By year 10 post OHT, 34% of all pediatric patients develop CAV.10 The lower prevalence of CAV in pediatric OHT recipients may be secondary to less cardiovascular risk factors for atherosclerosis in younger donors and recipients along with the plasticity of an underdeveloped immune system in infants.11 Despite the lower prevalence of CAV in pediatric patients, prognosis is poor after development. A 9-year multi-institutional study of CAV in the pediatric population found a graft survival of 50% at 2.8 years after the diagnosis of severe CAV, with a mortality of 24% within 2 years for any patient who developed CAV.7
As a result of a denervated heart after OHT, clinical history, including classic anginal symptoms, is generally not reliable in the diagnosis of CAV. Although pediatric complaints of chest, arm, or abdominal pain have been shown to be strongly associated with CAV, symptomatology is variable in clinical practice and other methods are therefore relied upon to diagnose CAV.12 While coronary angiography is considered the gold standard for diagnosing and monitoring CAV, IVUS has been recommended for use given the ability to evaluate all layers of the vessel wall and detect early evidence of neointimal hyperplasia.13 Other modalities used in the diagnosis of CAV include cardiac computed tomography (CT), nuclear imaging (particularly when coupled with exercise testing), and various serum markers.14-17 Among the serum markers studied, intracellular adhesion molecule-1 levels have been shown to be significantly higher in pediatric patients with confirmed CAV as compared to those without evidence of CAV on coronary angiography.17
Options for management of CAV are largely inadequate. The current mainstay of therapy is aggressive risk-factor modification with the use of pharmacotherapy. Angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers have been shown to inhibit the proliferation of angiogenic mediators in the post-OHT period and therefore indirectly counter the progression of CAV.18-20 Perhaps more significantly, statins are effective in reducing the incidence and progression of CAV and have demonstrated improved outcomes, but do not reverse neointimal hyperplasia.21,22
While surgical revascularization may be a viable treatment option in some adult OHT recipients, diffuse intimal thickening of distal vessels frequently precludes it as a standard treatment option in the pediatric OHT population. Moreover, the data show poor efficacy along with perioperative mortality rates in the 40%-80% range.23,24 Repeat OHT, while definitive, is associated with increased mortality as well as inferior outcomes at 1 and 5 years.6,25,26 In addition, the paucity of organs and ethical issues surrounding organ allocation make repeat OHT a less viable option.
PCI is a viable therapeutic option for CAV, with excellent initial success rates (91%-100%).27-32 This is particularly the case for CAV lesions that are proximal and focal.33 Factors associated with a lower risk for recurrent stenosis and increased graft survival for OHT patients that undergo PCI include medical interventions such as early statin use, early reduction of steroid dosing, and higher antiproliferative immunosuppressant dosing, as well as procedural interventions such as the use of stents as opposed to balloon angioplasty.29,30 Despite this, stenting for CAV is associated with higher rates of in-stent restenosis, target vessel revascularization, myocardial infarction, and death.28,31,34-37 This is likely the result of a unique lymphoproliferative inflammatory response that accompanies the transplanted coronary artery, causing perturbation of endothelial function with consequent intimal hyperplasia, contrasting with the typical, lipid-rich plaque formation that develops in native coronary vasculature.38
Technical issues, such as smaller femoral and coronary arteries along with the requirement for smaller devices like guiding catheters and stents, hinder the use of PCI in the pediatric population.39 Stent thrombosis is postulated to occur more frequently due to the smaller diameter of the stents placed. A case series of 7 pediatric OHT recipients who underwent PCI resulted in 1 death and 2 patients experiencing cardiac arrest immediately after PCI, with 5 of 6 surviving patients developing moderate to severe restenosis.40 The largest study (12 patients) and longest study to date (1994 to 2010) of pediatric patients who underwent PCI for CAV has demonstrated that PCI is feasible and can serve as a palliative bridge for definitive therapies such as repeat OHT.39 Among the patients included in this study, 2 had successful angiographic placement of bare-metal stents in an ULMCA.
Data suggest promising results with PCI for ULMCA lesions resulting from atherosclerosis with no differences in rates of myocardial infarction or death, but with a higher risk of target vessel revascularization as opposed to surgical revascularization.26,41,42 The SYNTAX (Synergy between PCI with Taxus and Cardiac Surgery) trial demonstrated no significant differences in major adverse cardiovascular events or need for revascularization when comparing PCI with bypass surgery.26 ULMCA PCI in OHT recipients with CAV has previously been reported in the form of case reports and case series.43-49 A systemic analysis has demonstrated that PCI for ULMCA disease in patients with CAV is safe and effective, with very favorable short- and long-term clinical outcomes (up to 60 months).50 Moreover, the overall rate of target vessel revascularization was 26.4%, despite bare-metal stent implantation in over half of the patients in the analysis.50 Given the small number of patients in these published reports, along with publication and selection biases, it is difficult to extrapolate whether drug-eluting stents are superior to bare-metal stents for ULMCA disease due to CAV. Nonetheless, drug-eluting stent implantation has been associated with a lower binary restenosis rate (12% vs 30%; P=.02) with less lumen loss (0.24 ± 0.75 mm vs 0.82 ± 1.03 mm; P=.01) as compared to bare-metal stent implantation at 1 year in a study that included both ULMCA and non-ULMCA lesions.31
This case demonstrates successful PCI for ULMCA disease as a result of CAV in a pediatric OHT recipient. While such cases are technically challenging, strategies for success can be adapted based on previously published literature on PCI for ULMCA disease, which suggest the importance of appropriate patient selection, use of predictive models for outcomes assessment, as well as operator expertise in managing the anatomic complexities of ULMCA and multivessel disease, particularly as they relate to bifurcation disease, calcification, and hemodynamic support.51 Given anatomic differences (eg, smaller structure) as well as cognitive differences (eg, difficulty with compliance to therapy) with the pediatric population, the optimal treatment of ULMCA disease in pediatric patients with CAV will need to be better defined.
- Lund LH, Edwards LB, Kucheryavaya AY, et al; International Society for Heart and Lung Transplantation. The registry of the international society for heart and lung transplantation: thirtieth official adult heart transplant report-2013; focus theme: age. J Heart Lung Transplant. 2013;32(10):951-964.
- Zimmer RJ, Lee MS. Transplant coronary artery disease. JACC Cardiovasc Interv. 2010;3(4):367-377.
- van Loosdregt J, van Oosterhout MF, Bruggink AH, et al. The chemokine and chemokine receptor profile of infiltrating cells in the wall of arteries with cardiac allograft vasculopathy is indicative of a memory T-helper 1 response. Circulation. 2006;114(15):1599-1607.
- Tanaka M, Zwierzchoniewska M, Mokhtari GK, et al. Progression of alloresponse and tissue-specific immunity during graft coronary artery disease. Am J Transplant. 2005;5(6):1286-1296.
- Vasilescu ER, Ho EK, de la Torre L, et al. Anti-HLA antibodies in heart transplantation. Transpl Immunol. 2004;12(2):177-183.
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- Radovancevic B, Poindexter S, Birovljev S, et al. Risk factors for development of accelerated coronary artery disease in cardiac transplant recipients. Eur J Cardiothorac Surg. 1990;4(6):309-312; discussion 313.
- Zerbe T, Uretsky B, Kormos R, et al. Graft atherosclerosis: effects of cellular rejection and human lymphocyte antigen. J Heart Lung Transplant. 1992;11(3 Pt 2):S104-S110.
- Kirk R, Edwards LB, Kucheryavaya AY, et al. The Registry of the International Society for Heart and Lung Transplantation: thirteenth official pediatric heart transplantation report — 2010. J Heart Lung Transplant. 2010;29(10):1119-1128.
- Pahl E, Naftel DC, Kuhn MA, et al; Pediatric Heart Transplant Study. The impact and outcome of transplant coronary artery disease in a pediatric population: a 9-year multi-institutional study. J Heart Lung Transplant. 2005;24(6):645-651.
- Price JF, Towbin JA, Dreyer WJ, et al. Symptom complex is associated with transplant coronary artery disease and sudden death/resuscitated sudden death in pediatric heart transplant recipients. J Heart Lung Transplant. 2005;24(11):1798-1803.
- Mintz GS, Nissen SE, Anderson WD, et al. American College of Cardiology Clinical Expert Consensus Document on Standards for Acquisition, Measurement and Reporting of Intravascular Ultrasound Studies (IVUS). A report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents. J Am Coll Cardiol. 2001;37(5):1478-1492.
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- Elhendy A, Sozzi FB, van Domburg RT, et al. Accuracy of dobutamine tetrofosmin myocardial perfusion imaging for the noninvasive diagnosis of transplant coronary artery stenosis. J Heart Lung Transplant. 2000;19(4):360-366.
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- Bae JH, Rihal CS, Edwards BS, et al. Association of angiotensin-converting enzyme inhibitors and serum lipids with plaque regression in cardiac allograft vasculopathy. Transplantation. 2006;82(8):1108-1111.
- Yamamoto T, Sata M, Fukuda D, Takamoto S. The angiotensin II type 1 receptor blocker valsartan attenuates graft vasculopathy. Basic Res Cardiol. 2005;100(1):84-91.
- Yousufuddin M, Cook DJ, Starling RC, et al. Angiotensin II receptors from peritransplantation through first-year post-transplantation and the risk of transplant coronary artery disease. J Am Coll Cardiol. 2004;43(9):1565-1573.
- Kobashigawa JA, Katznelson S, Laks H, et al. Effect of pravastatin on outcomes after cardiac transplantation. N Engl J Med. 1995;333(10):621-627.
- Mehra MR, Uber PA, Vivekananthan K, et al. Comparative beneficial effects of simvastatin and pravastatin on cardiac allograft rejection and survival. J Am Coll Cardiol. 2002;40(9):1609-1614.
- Musci M, Loebe M, Wellnhofer E, et al. Coronary angioplasty, bypass surgery, and retransplantation in cardiac transplant patients with graft coronary disease. Thorac Cardiovasc Surg. 1998;46(5):268-274.
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- Simpson L, Lee EK, Hott BJ, Vega DJ, Book WM. Long-term results of angioplasty vs stenting in cardiac transplant recipients with allograft vasculopathy. J Heart Lung Transplant. 2005;24(9):1211-1217.
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From the Division of Cardiology, UCLA Medical Center, Los Angeles, California.
Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.
Manuscript submitted January 22, 2014, provisional acceptance given March 28, 2014, final version accepted May 5, 2014.
Address for correspondence: Dr Michael S. Lee, UCLA Medical Center, 100 Medical Plaza, Suite 630, Los Angeles, CA 90095. Email: firstname.lastname@example.org