Cardiac allograft immune activation: current perspectives

Figures & data

Table 1 ISHLT standardized cardiac biopsy grading: acute cellular rejection

2004
Grade 0 R^Table Footnotea	No rejection
Grade 1 R, mild	Interstitial and/or perivascular infiltrate with up to 1 focus of myocyte damage
Grade 2 R, moderate	Two or more foci of infiltrate with associated myocyte damage
Grade 3 R, severe	Diffuse infiltrate with multifocal myocyte damage ± edema, ± hemorrhage ± vasculitis

Notes:

a “R” denotes revised grade to avoid confusion with 1990 scheme. Reprinted from the Journal of Heart and Lung Transplantation, 24(11), Stewart S, Winters GL, Fishbein MC, et al, Revision of the 1990 working formulation for the standardization of nomenclature in the diagnosis of heart rejection, 1710–1720, Copyright © 2005, with permission from the International Society for Heart and Lung Transplantation.²⁶

Abbreviation: ISHLT, International Society for Heart and Lung Transplantation.

Table 2 The 2013 ISHLT working formulation for pathologic diagnosis of cardiac antibody-mediated rejection

Grade	Definition	Substrates
pAMR0	Negative for pathologic AMR	Histologic and immunopathologic studies are both negative
pAMRI (H+)	Histopathologic AMR alone	Histologic findings are present and immunopathologic findings are negative
pAMRI (I+)	Immunopathologic AMR alone	Histologic findings are negative and immunopathologic findings are positive (CD68+ and/or C4d+)
pAMR2	Pathologic AMR	Histologic and immunopathologic findings are both present
pAMR3	Severe pathologic AMR	Interstitial hemorrhage, capillary fragmentation, mixed inflammatory infiltrates, endothelial cell pyknosis, and/or karyorrhexis, and marked edema and immunopathologic findings are present. These cases may be associated with profound hemodynamic dysfunction and poor clinical outcomes

Notes: Histologic changes include interstitial capillary injury and activated mononuclear cells, which are characterized by endothelial cell swelling and intravascular macrophage accumulation. Severe AMR is characterized by hemorrhage, neutrophilic or mixed inflammatory cell infiltrates, intravascular thrombus, and myocyte necrosis. Reprinted from the Journal of Heart and Lung Transplantation, 32(12), Berry GC, Burke MM, Andersen C et al, The 2013 International Society for Heart and Lung Transplantation Working Formulation for the standardization of nomenclature in the pathologic diagnosis of antibody-mediated rejection in heart transplantation, 1147–1162, Copyright © 2013, with permission from the International Society for Heart and Lung Transplantation.⁷⁰

Abbreviations: AMR, antibody-mediated rejection; CD68+, cluster of differentiation 68; C4d+, complement factor 4 deposition; H+, histopathologic; I+, immunopathologic; ISHLT, International Society for Heart and Lung Transplantation; pAMR, pathologic AMR.

Table 3 Recommended nomenclature for cardiac allograft vasculopathy

ISHLT CAV0 (not significant): No detectable angiographic lesion

ISHLT CAV1 (mild): Angiographic LM <50%, or primary vessel with maximum lesion of <70%, or any branch stenosis <70% (including diffuse narrowing) without allograft dysfunction

ISHLT CAV2 (moderate): Angiographic LM <50%; a single primary vessel ≥70%, or isolated branch stenosis ≥70%, in branches of two systems, without allograft dysfunction

ISHLT CAV3 (severe): Angiographic LM ≥50%, or two or more primary vessels ≥70% stenosis, or isolated branch stenosis ≥70% in all three systems; or ISHLT CAV1 or CAV2 with allograft dysfunction (defined as LVEF ≤45% usually in the presence of regional wall motion abnormalities) or evidence of significant restrictive physiology (which is common but not specific; see the notes for definitions)

Definitions

A “primary vessel” denotes the proximal and middle 33% of the left anterior descending artery, the left circumflex, the ramus, and the dominant or co-dominant right coronary artery with the posterior descending and posterolateral branches

A “secondary branch vessel” includes the distal 33% of the primary vessels or any segment within a large septal perforator, diagonal and obtuse marginal branches, or any portion of a nondominant right coronary artery

Restrictive cardiac allograft physiology is defined as symptomatic failure with echocardiographic E to A velocity ratio >2 (< 1.5 in children), shortened isovolumetric relaxation time (<60 ms), shortened deceleration time (< 150 ms), or restrictive hemodynamic values (right atrial pressure >12 mmHg, pulmonary capillary wedge pressure >25 mmHg, cardiac index <2 L/min/m^2)

Notes: Reprinted from the Journal of Heart and Lung Transplantation, 30(3), Mehra MR, Crespo-Leiro MG, Dipchand A, et al, Erratum. J Heart Lung Transplant, 360, Copyright © 2011, with permission from the International Society for Heart and Lung Transplantation.³⁶

Abbreviations: CAV, cardiac allograft vasculopathy; ISHLT, International Society for Heart and Lung Transplantation; LM, left main; LVEF, left ventricular ejection fraction.

Table 4 Treatment modalities for cellular and/or humoral rejection

Type of rejection	Asymptomatic		Reduced EF	Heart failure/shock
Cellular	Target higher CNI levels Oral steroid bolus + taper MMF→PSI		Oral steroid bolus/taper or IV pulse steroid Oral steroid bolus/taper	IV pulse steroids Cytolytic therapy (ATG) Plasmapheresis (before ATG dose) IV immunoglobulin
	No DSA	Observe	or IV pulse steroids ± IV immunoglobulin	Inotropic therapy IABP or ECMO support
Antibody-mediated	DSA	Oral steroid bolus/taper	IV pulse steroids IV immunoglobulin Consider ATG

Notes: Slide courtesy of Dr Michelle Kittleson. Copyright © 2014, Future Medicine Ltd. Published by Future Medicine Ltd. Reproduced from Chang DH, Kittleson MM, Kobashigawa JA. Immunosuppression following heart transplantation: prospects and challenges. Immunotherapy. 2014;6(2):181–194.⁶⁹

Abbreviations: ATG, rabbit anti-thymocyte globulin; CNI, calcineurin inhibitors; DSA, donor-specific antibodies; ECMO, extracorporeal membrane oxygenation; EF, ejection fraction; IABP, intra-aortic balloon pump; IV, intravenous; MMF, mycophenolate mofetil; PSI, proliferation signal inhibition.

Stewart S, Winters GL, Fishbein MC, et al. Revision of the 1990 working formulation for the standardization of nomenclature in the diagnosis of heart rejection. J Heart Lung Transplant. 2005;24(11):1710–1720.

 PubMed Web of Science ®Google Scholar

Berry GC, Burke MM, Andersen C et al. The 2013 International Society for Heart and Lung Transplantation Working Formulation for the standardization of nomenclature in the pathologic diagnosis of antibody-mediated rejection in heart transplantation. J Heart Lung Transplant. 2013;32(12):1147–1162.

 PubMed Web of Science ®Google Scholar

Mehra MR, Crespo-Leiro MG, Dipchand A, et al. Erratum. J Heart Lung Transplant. 2011;30(3):360.

 Google Scholar

Chang DH, Kittleson MM, Kobashigawa JA. Immunosuppression following heart transplantation: prospects and challenges. Immunotherapy. 2014;6(2):181–194.

 Web of Science ®Google Scholar