Long-term results of drug-eluting and bare metal intracoronary stent implantation in the same heart transplant recipient: a case report

Introduction

In patients who underwent orthotopic heart trans­plan­tation (OHT), allograft coronary artery disease (TxCAD) remains the main cause of long-term graft failure [1-3]. Results of numerous TxCAD-addressed studies agree that it eventually develops in over 40% of cases [4-7]. Pathologic examinations reveal diffuse, intimal proliferation foci, lea­ding to concentric occlusions, primarily in distal vessels [2]. Multiple factors are believed to contribute to its occurrence, such as immunosuppressive regimen, viral infections, donor age and presence of acute rejection episodes [8].

TxCAD symptoms, due to denervation of the graft, are usually atypical or completely absent [9]. It may present as a congestive heart failure, arrhythmia or sudden death. Cases presenting typically, with angina or acute myocardial infarction, are very rare [9-11].

Studies suggest that proper pharmacological manage­ment: statins and anti-hypertensive treatment may pre­vent or delay the occurrence of TxCAD. Likewise, the use of modern immunosuppressive agents (mycophenolate mo­fetil, sirolimus) contributes to TxCAD prevention. Still, the treatment of already established TxCAD is a major challenge in post-OHT patient management [12, 13].

The assessment of bare-metal (BMS) vs. drug-eluting stents (DES) was a subject of many studies. Still, a possibility of BMS and DES comparison in identical conditions (same patient, coronary artery, and implementation date) is an uncommon opportunity.

We present a case of OHT recipient transplanted and followed in the Silesian Center for Heart Disease showing significant LM stenosis in coronary angiography treated by means of percutaneous coronary intervention (PCI) with simultaneous DES and BMS implantation in LM and proximal parts of LAD (DES) and Cx (BMS).

Case report

A 42-year-old male patient underwent OHT in De­cem­ber 1992 due to post-ischemic heart failure, with no complications. His immunosuppression protocol consisted of cyclosporine A, azathioprine and steroids. Since 1998 he has been administered 20 mg of simvastatin daily. In 1998, he was diagnosed with type II diabetes. His antiplatelet treatment was started after the diagnosis of TxCAD and consisted of aspirin 75 mg daily (since PCI performed in 1999) and ticlopidine 250 mg twice a day (2004-2007) eventually replaced by clopidogrel 75 mg daily.

He was free from TxCAD, proven by systematic coronary angiography assessment, until 1999 when he was treated by means of PCI of circumflex branch (Cx) of the left coronary artery (due to early restenosis, BMS was implanted within 24 hours after the primary procedure). Subsequent coronary angiographies have shown no signs of stenosis for the following 3 years, when significant 70% in distal left main coronary artery (LMCA) and critical left anterior descending artery (LAD) stenosis was observed. Due to the patient’s general well-being and expected high periprocedural risk of surgical or percutaneous revascularization, no invasive treatment was undertaken at this time. The patient was discharged with a limited physical activity recommendation until further angiographic control.

There was no progression of patient’s TxCAD until March 2003, when he was admitted for a scheduled follow-up. On admission the patient was in a very good condition, hemodynamically stable, with no signs of decreased graft function and free from any stenocardial symptoms. Echo­cardiography revealed proper function and size of the left ventricle. Nonetheless, the following coronary angiography revealed further progression of LAD stenosis. Under such circumstances, percutaneous transluminal coronary angio­plasty (PTCA) was performed with BMS implantation into LAD. At balloon inflation the patient experienced typical stenocardial chest pain, proving the cardiac allograft’s reinnervation. The discomfort was relieved after balloon deflation. Troponin and CK-MB levels were not elevated. Further in-hospital stay of the patient was uncomplicated.

In March 2005, the patient was admitted for standard follow-up and underwent another corona­rography. The patient complained of irregular heartbeat. The assessment of previous

24 h ECG recordings confirmed an increased number of ventricular extrasystoles. The coronarography showed LM over Cx and LM over LAD critical (95%) stenoses as well as Cx and LAD in-stent restenosis (Fig. 1A). A team of interventional cardiologists and cardiac surgeons has opted for percutaneous treatment. The restenoses were treated by PTCA. Mi-Jazz 3.0 × 20 mm BMS was implanted in the LM over Cx and a CYPHER 3.5 × 33 mm DES was implanted in the LM over LAD stenosis (Fig. 1B). Both stents were inflated with the kissing-balloon method, resulting in complete vessel dilatation. No symptoms of ischemia were observed. Further in-hospital stay was uncomplicated.

During five years of follow-up the patient was under a standard post-OHT coronarographic regimen. Mild reste­nosis (30%) was observed in the LM over Cx (BMS) location in December 2005, June 2008 and January 2009. Critical restenosis in Cx developed in December 2007 (Fig. 1C). No signs of restenosis were observed in the LM over LAD location, where DES was implanted till the last angiography performed in June 2010 (Fig. 1D).

Discussion

TxCAD, along with graft rejection, is the leading cause of cardiac allograft function loss. It usually presents as diffuse, distal vessel stenoses. Its complex pathogenesis, along with comprehensible difficulties of PCI treatment stress the importance of the proper pharmacological approach in order to prevent or delay the manifestation of TxCAD [12].

Cardiac retransplantation remains the only definite solution for TxCAD, with satisfactory results in patients with chronic graft failure [14]. However, it is a highly limited option due to insufficient number of donors and poorer graft survival in comparison to primary transplantation [15]. High peri-operative risk, unsatisfactory long-term survival and frequent necessity of intravascular interventions limit the use of coronary artery bypass grafting (CABG) in cardiac allograft vasculopathy [16, 17].

This leads to PCI becoming a dominant therapeutic method in TxCAD patients, especially with focal narrowings of proximal vessels [15]. Although not common, involvement of major coronary arteries, such as LMCA, may also be observed, with possible prognosis similar to this of typical atherosclerotic disease. CABG, despite being the standard option for primary LMCA involvement, is regarded as a high-risk procedure in TxCAD. Under such circumstances, PCI, while burdened with some disadvantages – high risk of restenosis in post-OHT patients stealing the spotlight – may be seen as an attractive therapeutic option [18, 19].

Restenosis is the main factor limiting the long-term effectiveness of PCI. Although the use of DES does not seem to reduce patient mortality [20, 21], there is a number of recent studies showing that the use of DES significantly decreases the risk of restenosis [9, 20, 22, 23].

The possibility of long-term comparison of BMS and DES in one patient, simultaneously implanted to a large vessel (LMCA) is uncommon. The case of our patient shows a definite advantage of DES vs. BMS. Fully aware of the fact that large trials do not confirm mortality reduction [20, 21], we would like to underline that every possibility of restenosis risk reduction can be vital, especially in main coronary arteries. This position is supported by the International Society for Heart and Lung Transplantation in its current guidelines [24].

Higher long-term mortality rates in heart transplant recipients with TxCAD, regardless of proper, systematic angiographic surveillance, can be associated with the graft’s denervation. Atypical course of coronary artery disease, often completely asymptomatic, may lead to a graft failure or sudden cardiac death. There are only a few published reports of symptomatic angina and/or AMI in post-OHT patients, most of which were successfully managed by means of PCI. Although our patient was one of the rare examples of graft reinnervation, the possibility of asymptomatic severe ischemia occurrence is a strong indication that the reduction in restenosis risk, especially in LMCA, should be a major concern during post-OHT PCI procedures.

Conclusion

Our observation with over 5 years of follow-up suggests that even complex PCI associated with the application of drug-eluting stents to reduce the risk of restenosis in large vessel stenosis is the optimal solution both in terms of safety and effectiveness in patients with advanced TxCAD.

References

1. Mulli Mullins PA, Cary NR, Sharples L, Scott J, Aravot D, Large SR, Wallwork J, Schofield PM. Coronary occlusive disease and late graft failure after cardiac transplantation. Br Heart J 1992; 68: 260-265.

2. Aranda JM Jr, Hill J. Cardiac transplant vasculopathy. Chest 2000; 118:

1792-1800.

3. Suzuki J, Isobe M, Morishita R, Nagai R. Characteristics of chronic rejection in heart transplantation: important elements of pathogenesis and future treatments. Circ J 2010; 74: 233-239.

4. Weiss MJ, Madsen JC, Rosengard BR, Allan JS. Mechanisms of chronic re­jection in cardiothoracic transplantation. Front Biosci 2008; 13: 2980-2988.

5. Sarno G, Lerman A, Bae JH, Schukro C, Glogar D, Margolis PM, Goethals M, Verstreken S, Bartunek J, Koenig A, Wijns W, Vanderheyden M. Multicenter assessment of coronary allograft vasculopathy by intravascular ultrasound-derived analysis of plaque composition. Nat Clin Pract Cardiovasc Med 2009; 6: 61-69.

6. Costanzo MR, Naftel DC, Pritzker MR, Heilman JK 3rd, Boehmer JP, Broz­e­­­-

na SC, Dec GW, Ventura HO, Kirklin JK, Bourge RC, Miller LW. Heart trans­plant coronary artery disease detected by coronary angiography: a multiinsti­tutional study of preoperative donor and recipient risk factors. Cardiac Transplant Research Database. J Heart Lung Transplant 1998; 17: 744-753.

7. Schmauss D, Weis M. Cardiac allograft vasculopathy: recent developments. Circulation 2008; 117: 2131-2141.

8. Syeda B, Roedler S, Schukro C, Yahya N, Zuckermann A, Glogar D. Transplant coronary artery disease: Incidence, progression and interventional revascu­larization. Int J Cardiol 2005; 104: 269-274.

9. Di Cori A, Petronio AS, Gemignani C, Zucchelli G, Di Bello V, Mariani M. Symptomatic acute myocardial infarction in a cardiac transplant recipient successfully treated with primary coronary angioplasty: evidence of pro­gnostic importance of chest pain after cardiac transplantation. J Heart Lung Transplant 2005; 24: 1146-1149.

10. Fazio G, Sutera L, Vernuccio D, Fazio M, Novo S. Symptomatic acute myo­cardial infarction in a patient bearer of heart transplantation following ischemic heart disease. Int J Cardiol 2008; 124: 233-236.

11. Bildirici U, Celikyurt U, Ural E, Sahin T, Vural A, Koz C, Ural D. Successful percutaneous intervention to acute myocardial infarction presenting with typical chest pain in transplanted heart. Circ J 2009; 73: 2166-2168.

12. Mehra MR. Contemporary concepts in prevention and treatment of cardiac allograft vasculopathy. Am J Transplant 2006; 6: 1248-1256.

13. Zakliczynski M, Swierad M, Nozynski J, Maruszewski M, Zembala M. Survival benefit in heart transplant recipients who have coronary artery disease confirmed using angiography and are receiving sirolimus. Transplant Proc 2009; 41: 285-288.

14. Radovancevic B, McGiffin DC, Kobashigawa JA, Cintron GB, Mullen GM, Pitts DE, O'Donnell J, Thomas C, Bourge RC, Naftel DC. Retransplantation in 7,290 primary transplant patients: a 10-year multi-institutional study.

J Heart Lung Transplant 2003; 22: 862-868.

15. Tsao L, Uriel N, Leitz K, Naka Y, Mancini D. Higher rate of comorbidities after cardiac retransplantation contributes to decreased survival. J Heart Lung Transplant 2009; 28: 1072-1074.

16. Bhama JK, Nguyen DQ, Scolieri S, Teuteberg JJ, Toyoda Y, Kormos RL, McCurry KR, McNamara D, Bermudez CA. Surgical revascularization for cardiac allograft vasculopathy: Is it still an option? J Thorac Cardiovasc Surg 2009; 137: 1488-1492.

17. Musci M, Pasic M, Meyer R, Loebe M, Wellnhofer E, Weng Y, Kuppe H,

Hetzer R. Coronary artery bypass grafting after orthotopic heart transplan­tation. Eur J Cardiothorac Surg 1999; 16: 163-168.

18. Bader FM, Kfoury AG, Gilbert EM, Barry WH, Humayun N, Hagan ME, Thomas H, Renlund D. Percutaneous coronary interventions with stents in cardiac transplant recipients. J Heart Lung Transplant 2006; 25: 298-301.

19. Tarantini G, Favaretto E, Gardin A, Napodano M, Isabella G, Panfili M,

Gerosa G, Iliceto S, Ramondo A. Drug-eluting stents for the treatment of coronary lesions in cardiac transplant vasculopathy: acute and mid-term clinical and angiographic outcomes. J Cardiovasc Med (Hagerstown) 2008; 9: 396-402.

20. Beygui F, Varnous S, Montalescot G, Fernandez F, Collet JP, Leprince P, Le Feuvre C, Pavie A, Komajda M, Metzger JP, Gandjbakhch I. Long-term outcome after bare-metal or drug-eluting stenting for allograft coronary artery disease. J Heart Lung Transplant 2010; 29: 316-322.

21. Benza RL, Zoghbi GJ, Tallaj J, Brown R, Kirklin JK, Hubbard M, Rayburn B, Foley B, McGiffin DC, Pinderski LJ, Misra V, Bourge RC. Palliation of allograft vasculopathy with transluminal angioplasty: a decade of experience. J Am Coll Cardiol 2004; 43: 1973-1981.

22. Lee MS, Kobashigawa J, Tobis J. Comparison of percutaneous coronary intervention with bare-metal and drug-eluting stents for cardiac allograft vasculopathy. JACC Cardiovasc Interv 2008; 1: 710-715.

23. Lee MS, Chun KJ, Tobis JM. Drug-eluting stenting of unprotected left main coronary artery stenosis in patients with orthotopic heart transplantation: Initial clinical experience. Catheter Cardiovasc Interv 2008; 71: 306-311.

24. Costanzo MR, Dipchand A, Starling R, Anderson A, Chan M, Desai S,

Fedson S, Fisher P, Gonzales-Stawinski G, Martinelli L, McGiffin D, Smith J, Taylor D, Meiser B, Webber S, Baran D, Carboni M, Dengler T, Feldman D, Frigerio M, Kfoury A, Kim D, Kobashigawa J, Shullo M, Stehlik J, Teuteberg J,

Uber P, Zuckermann A, Hunt S, Burch M, Bhat G, Canter C, Chinnock R, Crespo-Leiro M, Delgado R, Dobbels F, Grady K, Kao W, Lamour J, Parry G, Patel J, Pini D, Towbin J, Wolfel G, Delgado D, Eisen H, Goldberg L, Hosenpud J,

Johnson M, Keogh A, Lewis C, O'Connell J, Rogers J, Ross H, Russell S, Vanhaecke J; International Society of Heart and Lung Transplantation Guidelines. The International Society of Heart and Lung Transplantation Guidelines for the care of heart transplant recipients. J Heart Lung Transplant 2010; 29: 914-956.