Cardiac allograft vasculopathy (CAV) in the transplanted heart remains a major factor limiting long-term survival after cardiac transplantation. The diagnosis of CAV is made by angiography and is described as mild, moderate, or severe based on severity of angiographic lesions and presence of allograft dysfunction.¹ Ischemia-reperfusion, immunologic, and/or infectious insults are thought to incite chronic endothelial cell injury and inflammation, leading to a coronary vasculitis with diffuse concentric fibrous intimal thickening, the velocity of which is associated with worse graft survival.¹ As angiographic diagnosis lags behind disease, adjunct intravascular ultrasonography can assess for early intimal thickening, the rapid progression of which (i.e., ≥0.5 mm) in the first year after transplantation is associated with downstream mortality, nonfatal major adverse cardiac events, and development of angiographic CAV.² Intravascular ultrasonography is furthermore essential for defining lesion length, severity, and vessel size prior to coronary intervention.

In addition to the nontransplant coronary artery disease (CAD) findings of discrete or tubular lesions (CAV type A lesions), CAV can exhibit morphologic subtypes of diffuse concentric narrowing (type B), with sharp tapering (type B1) or gradual tapering (type B2), and irregularly narrowed vessels with occluded branches and distal obliteration (type C),³ the latter types of which are associated with worse prognosis.^1,4 Additionally, CAV is more likely to have poor or no collateral supply and, when occluded, is equally likely to be occluded in a proximal segment as a distal segment.³ Moreover, the compensatory arterial remodeling seen in nontransplant coronary arteries (the Glagov phenomenon) is impaired in CAV by a fibrous infiltration of the media and adventitia.⁵ Representative differences between CAV and CAD are illustrated in Table 1.

Table 1: Representative characteristics of CAV and nontransplant CAD^1,3,5

Nontransplant CAD	CAV
Discrete disease	Diffuse disease
Eccentric or mixed	Concentric
Epicardial vessels	Microvasculature also affected
Fibrous cap, atheroma, and calcification	Intimal hyperplasia with minimal calcification
Discrete or tubular lesions	Discrete or tubular lesions with or without distal arteriopathy
Variable collateral supply	Poor or no collateral supply
Total occlusions predominantly found in proximal segments	Proximal and distal segments equally affected
Presence of compensatory arterial remodeling (Glagov phenomenon)	Absence of compensatory arterial remodeling

The treatment of CAV is primarily prevention and risk factor modification including treatment of diabetes, pretransplant antibodies, selection of younger donor hearts when available, and prevention and treatment of cyclomegalovirus infections and allograft rejection. In addition, the use of mycophenolate and proliferation signal inhibitors reduces intimal thickening.^6,7 Statin therapy by their lipid-lowering and pleotropic effects decreases development of CAV and overall mortality,⁸ and many programs also utilize vitamins C and E and aspirin routinely after transplantation. Early intensification of immunosuppression⁹ and maintenance of an increased level of immunosuppression are furthermore associated with reduced intimal thickening.¹⁰ However, after development of severe and progressive CAV, definitive treatment is re-transplantation especially in the presence of distal arteriopathy (types B and C morphologies) for which revascularization is less effective.⁴ However, type A focal or tubular CAV is amenable to revascularization with percutaneous coronary intervention (PCI).³ Experience with surgical revascularization is limited, but perioperative mortality is high (approximating 30%), and bypass surgery has been largely abandoned.⁴

Early Experience With PCI: Balloon Angioplasty

Early experience with balloon angioplasty demonstrated high angiographic success (approximating 90%) in reducing lesion stenosis to ≤50%. However, in a multicenter registry of balloon angioplasty for CAV, restenosis occurred in 55% of lesions at 8 months. Patients with distal arteriopathy had significantly lower survival and increased need for repeat revascularization, and overall survival was 61% at 19 months.⁴ In latter cohorts of balloon angioplasty, procedural success remained high, as did restenosis rates, which occurred in 53-72% of lesions at 8-12 months.^11,12 This was worse than the expected restenosis rates in the use of angioplasty in nontransplant CAD, which approximates 30% at 1 year.

Decreased Restenosis With the Use of Balloon-Expandable Bare-Metal Stents

With the advent of bare-metal stents (BMS) and decreased restenosis rates in nontransplant CAD, the use of BMS in CAV also resulted in lower restenosis rates.^11,13 Early experience with BMS demonstrated angiographic restenosis of 44% at 4.6 months,¹³ with more contemporary cohorts demonstrating 1-year angiographic restenosis rates of 22-49%.^11,12,14-16 Clopidogrel and statin use were found to be higher in patients without restenosis,¹² which is an association replicated in a mixed PCI cohort.¹⁷ Higher doses of immunosuppression were also associated with less restenosis.¹¹ However, as compared with clinically driven target lesion revascularization in nontransplant CAD approximating 12% at 1 year,¹⁸ lesion failure by stent restenosis remained unexpectedly high in CAV. However, it is important to note that restenosis rates in CAV cohorts may be illusorily higher due to frequent use of surveillance angiography for the denervated heart with its paucity of symptoms post-transplantation. Most often in nontransplant cohorts, angiographic follow-up is clinically driven, and restenosis rates can be upwards of 50% lower than angiographic restenosis.¹⁸

Remote Lesion Progression in Patients With In-Stent Restenosis

Despite improved angiographic results with BMS for the treatment of CAV, there continued to be insufficient data on the impact of PCI on clinical outcomes. Of concern, one study of 25 patients who received BMS for treatment of CAV found that those who developed in-stent restenosis (ISR) had increased late lumen loss in nonstented reference lesions as compared with patients without ISR. The author did not observe this finding in a matched control of 36 patients with nontransplant CAD, leading to the concern that stenting may incite inflammation of nonstented lesions and may in fact be detrimental.¹⁹ However, increased lumen loss in nonstented lesions has in fact also been associated with ISR in nontransplant CAD,²⁰ and the more evident association in CAV may be due to the increased impact of shared risk factors for increased ISR and de novo plaque progression in CAV. Additional studies are needed to investigate this relationship.

First Generation Drug-Eluting Stents: Paclitaxel- and Sirolimus-Eluting Stents

Drug-eluting stents (DES) reduce restenosis rates in nontransplant CAD as compared with BMS, a finding also described in CAV^15,21 with recent cohorts demonstrating angiographic 1-year ISR rates with first generation DES of 12.5-16%.^14,22 However, some cohorts have demonstrated no differences in long-term lesion patency between DES and BMS, with suggestions of a catch-up phenomenon.^16,21 Moreover, ISR rates remain higher than expected. As reference, clinically driven target lesion revascularization rates approximate 7-8% in nontransplant CAD.²³ Representative studies of DES for treatment of CAV are summarized in Table 2.

Table 2: Select studies of DES for treatment of CAV

	Reddy et al. 200816	Gupta et al. 200915	Nfor et al. 200921	Beygui et al. 201026	Lee et al. 201022	Colombo et al. 201014	Azarbal et al. 201425
Patients (#)	51	32	25	48	108	-	21
Lesions (#)	-	39	36	65	-	84	34
Stents (#)	56	58	49	70	144	84	40
Paclitaxel-eluting stents (first generation DES)	0	0	11	20	48	-	0
Sirolimus-eluting stents (first generation DES)	56	32	38	50	96	-	0
Everolimus-eluting stents (second generation DES)	0	0	0	0	0	0	40
Time to first PCI (years)	10.7 ± 4.7	8.9 ± 4.9	8.0 ± 1.1	9.7 ± 5.9	10 ± 4	9.3 ± 4.8	9.2 ± 4.8
Procedural success	-	-	-	-	-	96%	100%
Angiographic follow-up (months)	-	11 ± 10	-	7.9 ± 4.9	-	18.1 ± 24	13.6 ± 6.7
Clinical follow-up (months)	-	15.6 ± 14.4	46.0 ± 6.2	31.2 ± 16.8	-	45.2 ± 41.7	18.3 ± 7.4
12-month ISR	22.6%	18.6%	0%	7.1%	13.8%	16.0%	5%
Target lesion revascularization	-	-	2.8%	6.6%	3.8%	-	5.9%
Target vessel revascularization	-	-	2.8%	8.2%	7.5%	-	11.1%

Second Generation DES and Future Directions

Second generation DES with everolimus or zotarolimus have consistently demonstrated improved clinical and angiographic outcomes as compared with first generation DES,²⁴ and the systemic use of everolimus has been shown to reduce intimal thickening in cardiac allografts.⁷ Our center's early experience with the use of everolimus-eluting DES in 21 patients and 34 lesions demonstrated 1-year binary restenosis and target lesion revascularization rates of 5.0 and 5.9%, respectively. Those rates were lower than those reported for first generation DES and comparable to the use of everolimus-eluting DES in nontransplant CAD.²⁵ Our center's more recent experience of 48 patients and 113 lesions demonstrate 1- and 3-year ISR rates approximating 3 and 10%, respectively, which are comparable to the use of everolimus-eluting DES in nontransplant CAD with 1- and 3-year target lesion failure rates of 4.2 and 8.9%.²⁴ With device iterations in drug, polymer, and stent design, the gap in stent patency rates between CAV and nontransplant CAD has narrowed significantly. PCI is now not only feasible with high procedural success but also increasingly associated with reliable mid- to long-term angiographic outcomes. However, several questions remain unanswered regarding the clinical benefit of PCI for CAV.

First, with unreliable ischemic symptoms, occluded vessels found on surveillance angiography are associated with unknown durations of ischemia. Are viability studies with scar quantification helpful in identifying patients most likely to benefit from revascularization? Moreover, are there specific patient or lesion characteristics that would most benefit from PCI? Second, distal arteriopathy portends worse prognosis after revascularization and may reflect a similar disease process in the microvasculature. Is microvascular disease assessment, such as with coronary flow reserve by positron emission tomography, helpful to identify patients least likely to benefit from PCI for which dual anti-platelet therapy may delay retransplantation? Third, with the concern that PCI may disrupt endothelium either directly or by polymer and/or drug interactions with the allograft coronary, is there any evidence of more rapid progression of nonstented lesions in the stented vessel as compared with those in nontarget vessels? Fourth, second generation DES may be associated with acceptable rates of lesion patency. Will there be a role for bioresorbable vascular scaffolds to replace the use of DES in treatment of CAV and/or for treatment of intermediate-severity lesions in proximal vessel segments? Lastly, dual anti-platelet therapy has been associated with decreased stent restenosis even in BMS. What is the optimal duration of dual anti-platelet therapy after PCI in CAV, and does its use stabilize nonstented lesions?

Summary

In summary, while the definitive treatment of severe and rapidly progressive CAV is re-transplantation, CAV often exhibits focal or tubular lesions that are amenable to PCI with high procedural success. While the use of balloon angioplasty and BMS in the treatment of CAV were associated with high restenosis rates, the use of DES have increased stent and lesion patency. With second generation DES, stent and lesion patency now closely resemble the expected rates in their use in nontransplant CAD. PCI in the transplanted heart has become an established therapy especially for patients who are ineligible for re-transplantation. In re-transplant candidates, whether PCI can be stabilizing and provide improved allograft function and safely delay re-transplantation remains to be established.

References

1. Mehra MR, Crespo-Leiro MG, Dipchand A, et al. International Society for Heart and Lung Transplantation working formulation of a standardized nomenclature for cardiac allograft vasculopathy-2010. J Heart Lung Transplant 2010;29:717-27.
2. Kobashigawa JA, Tobis JM, Starling RC, et al. Multicenter intravascular ultrasound validation study among heart transplant recipients: outcomes after five years. J Am Coll Cardiol 2005;45:1532-7.
3. Gao SZ, Alderman EL, Schroeder JS, Silverman JF, Hunt SA. Accelerated coronary vascular disease in the heart transplant patient: coronary arteriographic findings. J Am Coll Cardiol 1988;12:334-40.
4. Halle AA, 3rd, DiSciascio G, Massin EK, et al. Coronary angioplasty, atherectomy and bypass surgery in cardiac transplant recipients. J Am Coll Cardiol 1995;26:120-8.
5. Kobashigawa J, Wener L, Johnson J, et al. Longitudinal study of vascular remodeling in coronary arteries after heart transplantation. J Heart Lung Transplant 2000;19:546-50.
6. Kobashigawa JA, Tobis JM, Mentzer RM, et al. Mycophenolate mofetil reduces intimal thickness by intravascular ultrasound after heart transplant: reanalysis of the multicenter trial. Am J Transplant 2006;6:993-7.
7. Eisen HJ, Kobashigawa J, Starling RC, et al. Everolimus versus mycophenolate mofetil in heart transplantation: a randomized, multicenter trial. Am J Transplant 2013;13:1203-16.
8. Kobashigawa JA, Moriguchi JD, Laks H, et al. Ten-year follow-up of a randomized trial of pravastatin in heart transplant patients. J Heart Lung Transplant 2005;24:1736-40.
9. Azarbal B, Cheng R, Vanichsarn C, et al. Induction Therapy With Antithymocyte Globulin in Patients Undergoing Cardiac Transplantation Is Associated With Decreased Coronary Plaque Progression as Assessed by Intravascular Ultrasound. Circ Heart Fail 2016;9:e002252.
10. Cheng R, Azarbal B, Yung A, Chang DH, Patel JK, Kobashigawa JA. Elevated immune monitoring early after cardiac transplantation is associated with increased plaque progression by intravascular ultrasound. Clin Transplant 2015;29:103-9.
11. Benza RL, Zoghbi GJ, Tallaj J, et al. Palliation of allograft vasculopathy with transluminal angioplasty: a decade of experience. J Am Coll Cardiol 2004;43:1973-81.
12. 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;24:1211-7.
13. Wong PM, Piamsomboon C, Mathur A, et al. Efficacy of coronary stenting in the management of cardiac allograft vasculopathy. Am J Cardiol 1998;82:239-41.
14. Colombo P, Bruschi G, Sacco A, et al. Percutaneous coronary interventions in cardiac allograft vasculopathy: a single-center experience. Transplant Proc 2010;42:1286-90.
15. Gupta A, Mancini D, Kirtane AJ, et al. Value of drug-eluting stents in cardiac transplant recipients. Am J Cardiol 2009;103:659-62.
16. Reddy PR, Gulati A, Steen L, Sinacore J, Leya F, Heroux A. Outcomes of bare metal versus drug-eluting stents in allograft vasculopathy. J Heart Lung Transplant 2008;27:1222-8.
17. Wellnhofer E, Hiemann NE, Hug J, et al. A decade of percutaneous coronary interventions in cardiac transplant recipients: a monocentric study in 160 patients. J Heart Lung Transplant 2008;27:17-25.
18. Cutlip DE, Windecker S, Mehran R, et al. Clinical end points in coronary stent trials: a case for standardized definitions. Circulation 2007;115:2344-51.
19. Jonas M, Fang JC, Wang JC, et al. In-stent restenosis and remote coronary lesion progression are coupled in cardiac transplant vasculopathy but not in native coronary artery disease. J Am Coll Cardiol 2006;48:453-61.
20. Bauriedel G, Skowasch D, Vaerst J, Jabs A, Andrié R, Lüderitz B. [Association between progression of untreated coronary lesions and in-stent restenosis]. Dtsch Med Wochenschr 2002;127:2114-9.
21. Nfor T, Ansaarie I, Gupta A, Bajwa T, Allaqaband S. Comparing long-term outcomes between drug-eluting and bare-metal stents in the treatment of cardiac allograft vasculopathy. Catheter Cardiovasc Interv 2009;74:543-9.
22. Lee MS, Tarantini G, Xhaxho J, et al. Sirolimus- versus paclitaxel-eluting stents for the treatment of cardiac allograft vasculopathy. JACC Cardiovasc Interv 2010;3:378-82.
23. Kimura T, Morimoto T, Nakagawa Y, et al. Very late stent thrombosis and late target lesion revascularization after sirolimus-eluting stent implantation: five-year outcome of the j-Cypher Registry. Circulation 2012;125:584-91.
24. Dangas GD, Serruys PW, Kereiakes DJ, et al. Meta-analysis of everolimus-eluting versus paclitaxel-eluting stents in coronary artery disease: final 3-year results of the SPIRIT clinical trials program (Clinical Evaluation of the Xience V Everolimus Eluting Coronary Stent System in the Treatment of Patients With De Novo Native Coronary Artery Lesions). JACC Cardiovasc Interv 2013;6:914-22.
25. Azarbal B, Arbit B, Ramaraj R, et al. Clinical and angiographic outcomes with everolimus eluting stents for the treatment of cardiac allograft vasculopathy. J Interv Cardiol 2014;27:73-9.
26. Beygui F, Varnous S, Montalescot G, et al. Long-term outcome after bare-metal or drug-eluting stenting for allograft coronary artery disease. J Heart Lung Transplant 2010;29:316-22.

Keywords: Adventitia, Allografts, Angiography, Angioplasty, Angioplasty, Balloon, Ascorbic Acid, Aspirin, Blood Platelets, Cicatrix, Constriction, Pathologic, Coronary Artery Disease, Diabetes Mellitus, Drug Interactions, Drug-Eluting Stents, Endothelial Cells, Endothelium, Follow-Up Studies, Graft Survival, Heart Transplantation, Hyperplasia, Lipids, Microvessels, Paclitaxel, Percutaneous Coronary Intervention, Plaque, Atherosclerotic, Polymers, Positron-Emission Tomography, Prognosis, Registries, Reoperation, Risk Factors, Sirolimus, Ticlopidine, Ultrasonography, Interventional, Vasculitis, Angina, Stable

< Back to Listings