Honoring 50 Years of Clinical Heart Transplantation in Circulation: In-Depth State-of-the-Art Review

Josef Stehlik, MD, MPH; Jon Kobashigawa, MD; Sharon A. Hunt, MD; Hermann Reichenspurner, MD, PhD; James K. Kirklin, MD


Circulation. 2018;137(1):71-87. 

In This Article

Allograft Rejection

Once the surgical technique and organ preservation allowed reliable execution of the heart transplantation procedure, acute rejection of the allograft became the primary consideration for patient survival. Rejection of the allograft is primarily a T cell–mediated response presenting as acute cellular rejection. Hyperacute rejection and antibody-mediated rejection (AMR) are caused by preformed antibodies against ABO blood group antigens or HLA antigens on the allograft. The original methods to detect rejection (signs of heart failure and electrocardiographic abnormalities) were insensitive and, when present, indicated that the rejection was severe. Philip Caves, a Scottish surgeon visiting at Stanford University, proposed a technique for percutaneous endomyocardial biopsy. His modification of an old Japanese bioptome allowed percutaneous access into the right internal jugular vein and right ventricle, from which small pieces of myocardium could be retrieved for pathological analysis.[22] Pathological assessment of the myocardium was codified by Margaret Billingham and became the gold standard for assessment of graft rejection.[23,24]

Biopsy grading of rejection has focused predominantly on cellular rejection,[24] and a standardized grading scale was proposed by the International Society for Heart and Lung Transplantation in 1990.[25] Over time, challenges in consistent application of the different grades became apparent because the pathological grading did not fully correspond with clinical treatment decisions. In 2005, this formulation was revised and simplified to include the grades of no rejection (0 R), mild rejection (1 R, nondamaging focal or interstitial lymphocytic infiltrates), moderate rejection (2 R, damaging focal or diffuse infiltrates), and severe rejection (3 R, dense diffuse infiltrates with disruption of myocardial architecture);[26] (Figure 3A and Figure 3B). Unless associated with hemodynamic compromise, treatment of acute cellular rejection with high-dose steroids typically results in full resolution of the changes without long-term consequences.

Figure 3.

Acute rejection.
A, Mild cellular rejection: focal lymphocytic infiltrate. B, Severe cellular rejection: dense lymphocytic infiltrate, myocyte necrosis, and disruption of myocardial architecture. C, Antibody-mediated rejection: endothelial swelling and macrophage infiltration in the capillaries. D, Antibody-mediated rejection: C4d (complement split product) deposition in perimyocyte capillary walls. A and B, Hematoxylin and eosin (H&E) stain, ×20 magnification. C, H&E stain, ×40 magnification. D, Immunofluorescence C4d stain, ×40 magnification. Images courtesy of Patricia Revelo, MD; Elizabeth Hammond, MD; and Dylan Miller, MD.

AMR is less frequent but is now an established entity. Circulating antibodies directed against the allograft can cause AMR, leading to endothelial damage, macrophage infiltration, deposition of complement and immunoglobulin, and thrombosis of myocardial microvasculature.[27,28] Non-HLA antibodies might also cause AMR but are not routinely tested for.[27] The pathology diagnosis and grading of AMR include light microscopy (evidence of endothelial swelling and presence of intravascular macrophages) and immunostaining for the presence of complement split products (Figure 3C and Figure 3D).[28] Symptomatic AMR predisposes for a higher incidence of cardiac allograft vasculopathy (CAV) and mortality.

The risk of acute rejection is highest in the first 6 months after transplantation, and most centers perform routine surveillance heart biopsies during the first few months, reducing the frequency thereafter. In the current era of more effective immunosuppressive strategies, the marked reduction in the risk of late cellular rejection has prompted most centers to stop routine surveillance biopsy after 1 to 3 years, although the practice varies among centers.[29]

The limitations of myocardial biopsy include its invasiveness, expense, and considerable interobserver variability in interpretation.[30] Therefore, concerted efforts over the years have focused on developing noninvasive and less expensive alternatives. Unfortunately, the proposed substitutes have had variable success. Use of cardiac imaging, including assessment by echocardiography and magnetic resonance imaging, has so far achieved relatively low accuracy.[31] More recently, gene-expression profiling of peripheral blood mononuclear cells has been investigated with an empirically derived quantitative assessment of mononuclear cell gene expression in peripheral blood specimens.[32] In the multicenter randomized IMAGE trial (Invasive Monitoring Attenuation Through Gene Expression) involving stable, low-risk patients >6 months after transplantation, a proprietary gene-expression profiling test commercially known as Allomap (CareDx Inc, Brisbane, CA) demonstrated a very high negative predictive value, thereby offering a reasonable alternative to routine biopsies.[33] Allomap has since gained regulatory clearance for clinical use to rule out rejection. Its key limitations are a low positive predictive value in the context of its cost and lack of information on AMR.

The search for new methods of rejection surveillance continues. The detection of cell-free DNA of donor origin in recipient blood has been tested as a means to predict rejection in the transplanted heart.[34] Molecular assessment of biopsy tissue examines mRNA expression and compares it with a reference set of RNA expression in specimens of known rejection grades. This technique has proved reproducible in kidney transplantation, and its utility in predicting cellular rejection and AMR in heart transplantation is now under investigation.[35]