Transplant CAD: The Role of PCI in the Transplanted Heart

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 CAD1,3,5

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 CAV15,21 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

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  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.
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  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.
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Clinical Topics: Cardiac Surgery, Clinical Topic Collection: Dyslipidemia, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Stable Ischemic Heart Disease, Vascular Medicine, Aortic Surgery, Cardiac Surgery and Heart Failure, Cardiac Surgery and SIHD, Lipid Metabolism, Heart Transplant, Interventions and Coronary Artery Disease, Interventions and Imaging, Interventions and Vascular Medicine, Angiography, Computed Tomography, Echocardiography/Ultrasound, Nuclear Imaging, Chronic Angina

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


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