Cardiac allograft vasculopathy after heart transplantation: risk factors and management

https://doi.org/10.1016/j.healun.2004.03.009Get rights and content

Abstract

Cardiovascular disease post-transplant, particularly ischemic heart disease, is a significant problem for all transplant recipients. The major risk factors—smoking, obesity, diabetes, dyslipidemia and hypertension—are often more prevalent in heart transplant populations than in the general population. One of the main risk factors influencing graft loss and patient survival is cardiac allograft vasculopathy (CAV). Because CAV affects between 30% and 60% of cardiac transplant recipients within 5 years of surgery, prevention is a key focus for cardiac transplant teams today. CAV is caused by both immunologic mechanisms (e.g., acute rejection and anti-HLA antibodies) and non-immunologic mechanisms relating to the transplant itself or the recipient (e.g., donor age, hypertension, hyperlipidemia and pre-existing diabetes) or to the side effects often associated with immunosuppression with calcineurin inhibitors or corticosteroids (e.g., cytomegalovirus infection, nephrotoxicity and new-onset diabetes after transplantation). The calcineurin inhibitors, cyclosporine and tacrolimus, effectively prevent acute rejection, but do not prevent the development of CAV. CAV prevention will require a combined approach of new adjunct immunosuppressant agents (e.g., the proliferation signal inhibitors) and reduction in cardiovascular risk. Hypertension, hyperlipidemia and diabetes are also associated with the immunosuppression required to prevent organ rejection. Some studies have shown that hypertension is present more frequently in cyclosporine-treated patients than in tacrolimus-treated patients and that tacrolimus may be associated with a more favorable lipid profile. On the other hand, tacrolimus may be more diabetogenic than cyclosporine with current data suggesting a trend but no statistically significant supporting evidence. New-onset diabetes after transplantation is at times difficult to manage and may be an important determinant along with hypertension and hyperlipidemia of ischemic heart disease, cerebrovascular disease and peripheral vascular disease. The choice of calcineurin inhibitor for an immunosuppressive regimen in heart transplantation should consider the associated relative cardiovascular risks.

Section snippets

Cardiac allograft vasculopathy

Cardiac allograft vasculopathy (CAV), a type of cardiovascular disease that occurs uniquely in transplant recipients, is a rapidly progressive form of atherosclerosis characterized in its early stages by intimal proliferation and in its later stages by luminal stenosis of epicardial branches, occlusion of smaller arteries and myocardial infarction.5 Myocardial ischemia and infarction secondary to CAV in transplant patients are usually silent, due to a lack of cardiac innervation. Instead of

Immunologic risk factors for CAV

The risk of CAV increases as the number of HLA mismatches and the number and duration of rejection episodes increases.16 The occurrence of ≥2 major rejection episodes has been significantly associated with an increased prevalence of CAV assessed by arteriography or pathologic examination (Figure 1).2, 17, 18 Even recurrent mild rejection in the first 3 months after transplantation may increase the risk of intimal thickening according to IVUS.19 In a sophisticated study using IVUS, donor

Non-immunologic risk factors for CAV

Various non-immunologic factors have been associated with development of CAV after transplantation. For example, heart transplant recipients with cytomegalovirus (CMV) infection, whether symptomatic or not, more frequently have CAV, which is often more severe, than those without CMV infection.21 Donor- or recipient-related factors (e.g., age/gender, pre-transplant diagnosis) and those related to surgery (ischemia–reperfusion injury) also increase the risk of CAV.22, 23 In addition, the risk of

Management of CAV

Once CAV has developed, the only definitive treatment is re-transplantation, which has risks for the patient and poses an ethical dilemma for the clinician in view of the scarcity of donor organs. Other surgical approaches, such as stenting and angioplasty, may have a high re-stenosis rate and expose the patient to the risks of another surgical procedure.54, 55 Such procedures are inherently likely to be less effective than in non-transplant patients because of the diffuse nature of CAV

Conclusions

Cardiovascular risk, particularly of ischemic heart disease, is significantly increased in heart transplant recipients. This risk is a combination of pre-existing factors plus those that result from surgical intervention and immunosuppression. In particular, exposure to cardiovascular risk factors, such as hypertension, hyperlipidemia and new-onset diabetes after transplantation, can promote the development of CAV. Atherosclerotic narrowing of graft blood vessels may result in graft ischemia

References (61)

  • A Escobar et al.

    Cardiac allograft vasculopathy assessed by intravascular ultrasonography and nonimmunologic risk factors

    Am J Cardiol

    (1994)
  • M.I Hertz et al.

    The registry of the International Society for Heart and Lung TransplantationNineteenth official report—2002

    J Heart Lung Transplant

    (2002)
  • V Klauss et al.

    Cyclosporine versus tacrolimus (FK 506) for prevention of cardiac allograft vasculopathy

    Am J Cardiol

    (2000)
  • R.W Braith et al.

    High-dose angiotensin-converting enzyme inhibition restores body fluid homeostasis in heart-transplant recipients

    JAMA

    (2003)
  • M.R Mehra et al.

    An intravascular ultrasound study of the influence of angiotensin-converting enzyme inhibitors and calcium entry blockers on the development of cardiac allograft vasculopathy

    Am J Cardiol

    (1995)
  • E.H Hathout et al.

    Pediatric post-transplant diabetesData from a large cohort of pediatric heart-transplant recipients

    Am J Transplant

    (2003)
  • M.G Nieuwenhuis et al.

    Predictability and other aspects of post-transplant diabetes mellitus in heart transplant recipients

    J Heart Lung Transplant

    (2001)
  • R.S Woodward et al.

    Incidence and cost of new onset diabetes mellitus among U.S

    wait-listed and transplanted renal allograft recipients Am J Transplant

    (2003)
  • D Marelli et al.

    Heart transplantation in patients with diabetes mellitus in the current era

    J Heart Lung Transplant

    (2003)
  • C.C Lang et al.

    Morbidity and mortality in diabetic patients following cardiac transplantation

    J Heart Lung Transplant

    (2003)
  • A.A.I Halle et al.

    Coronary angioplasty, atherectomy, and bypass surgery in cardiac transplant recipients

    J Am Coll Cardiol

    (1995)
  • M Redonnet et al.

    Coronary angioplasty and stenting in cardiac allograft vasculopathy following heart transplantation

    Transplant Proc

    (2000)
  • J Koglin et al.

    Tacrolimus excels cyclosporine in prevention of cardiac allograft vasculopathyA prospective ivus, angiography and doppler study

    J Heart Lung Transplant

    (2002)
  • M.R Costanzo et al.

    Heart transplant coronary artery disease detected by coronary angiographyA multi-institutional study of preoperative donor and recipient risk factors

    J Heart Lung Transplant

    (1998)
  • ISHLT 2003 quarterly data report. www.ishlt.org/registries. Accessed January...
  • M.E Billingham

    Histopathology of graft coronary disease

    J Heart Lung Transplant

    (1992)
  • S Radio et al.

    Allograft vascular diseaseComparison of heart and other grafted organs

    Transplant Proc

    (1996)
  • J Kobashigawa

    What is the optimal prophylaxis for treatment of cardiac allograft vasculopathy?

    Curr Control Trials Cardiovasc Med

    (2000)
  • S.R Kapadia et al.

    Impact of intravascular ultrasound in understanding transplant coronary artery disease

    Curr Opin Cardiol

    (1999)
  • P.R Rickenbacher et al.

    Prognostic importance of intimal thickness as measured by intracoronary ultrasound after cardiac transplantation

    Circulation

    (1995)
  • Cited by (232)

    View all citing articles on Scopus
    View full text