ISHLT consensus statement
International Society for Heart and Lung Transplantation working formulation of a standardized nomenclature for cardiac allograft vasculopathy—2010

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The development of cardiac allograft vasculopathy remains the Achilles heel of cardiac transplantation. Unfortunately, the definitions of cardiac allograft vasculopathy are diverse, and there are no uniform international standards for the nomenclature of this entity. This consensus document, commissioned by the International Society of Heart and Lung Transplantation Board, is based on best evidence and clinical consensus derived from critical analysis of available information pertaining to angiography, intravascular ultrasound imaging, microvascular function, cardiac allograft histology, circulating immune markers, non-invasive imaging tests, and gene-based and protein-based biomarkers. This document represents a working formulation for an international nomenclature of cardiac allograft vasculopathy, similar to the development of the system for adjudication of cardiac allograft rejection by histology.

Section snippets

Objective

This effort, commissioned by the International Society of Heart and Lung Transplantation (ISHLT) Board and reviewed by Standards and Guidelines Committee as well as the Education Committee, is based on best evidence and clinical consensus. This effort is designed to develop a working formulation for an international nomenclature of CAV, similar to the development of the system for adjudication of cardiac allograft rejection by histology.3

Consensus #1

Coronary angiography coupled with assessment of cardiac allograft function maintains the highest level of evidence and consensus opinion for inclusion in the final nomenclature. The advantages of angiography are that it is universal in availability for both adult and pediatric patients, clinically accepted, and applicable at any time in the post-transplantation process (favorable for longitudinal and snap-shot assessments).

Consensus #2

IVUS-detected maximal intimal thickening may be most useful for its

Angiography

Coronary angiography has been the cornerstone of the diagnosis of CAV vasculopathy (CAV) before the advent of IVUS.1, 2 Although coronary angiography is not perfect, it provides a screening tool to grossly detect the presence of CAV. The main problem with coronary angiography is that the contrast agent merely fills the vessel lumen and does not inform us of the anatomy of the arterial wall. In addition, vascular remodeling (including vasodilation) occurs due to the development of CAV, which may

Non-invasive imaging

The commonly studied non-invasive techniques include perfusion scanning with technetium-99m sestamibi, stress echocardiography (usually with dobutamine), and multidetector computed tomography (MDCT).

Cardiac allograft histology

Yamani et al35 developed computerized scoring of endomyocardial biopsy specimens for predicting epicardial CAV that was validated by IVUS. The authors developed a mathematic model computing a biopsy specimen score for each patient based on the duration and severity of cellular rejection, vascular rejection, ischemia, and fibrosis and demonstrated that this score is an effective method for predicting the development of CAV and for predicting outcome in cardiac transplant recipients. Histologic

Immune monitoring markers

The endothelial cells of the cardiac vasculature express major histocompatibility complex (MHC) antigens and others, such as vimentin and MHC class I-related chain A (MICA), and appear to be primary targets of cell-mediated and humoral immune responses after heart transplant.52, 53, 54, 55 The possibility of using titers of these or other antibodies against known antigens for CAV-grading purposes is limited by a number of deficits in our knowledge of their behavior, clinical significance, and

Gene-based and protein-based biomarkers

Although a simple biomarker would be of great interest, no gene-based or protein-based biomarker rises to a level of definition as a detector of CAV. Patients with persistent elevation in cardiac-specific troponin I in the first year after transplant have greater progression of CAV and earlier graft failure than patients whose troponin levels normalize within the first 3 months.62 Elevated levels of C-reactive protein, a sensitive marker of systemic inflammation, have been associated with the

Pediatric considerations

Commensurate with the adult experience, CAV remains the leading cause of late mortality in pediatric heart transplant recipients.69 Moderate to severe CAV by angiography is associated with a poor prognosis, with the most comprehensive multicenter registry report from the Pediatric Heart Transplant Study (PHTS) citing graft survival with an angiographic diagnosis of severe CAV of 50% at 2.8 years after diagnosis or less than 30% freedom from death or graft loss within 4 years.70 In addition to

Disclosure statement

The authors are indebted to the ISHLT Board and Education Committee for their thoughtful comments during the preparation of this nomenclature document.

The authors were not provided any compensation for this work. Dr Crespo-Leiro reports receiving honoraria from Astellas, Roche, Novartis, and Laboratorios Menarini. Dr Kobashigawa reports a conflict of interest with Novartis, Genzyme, and Expression Diagnostics (clinical trial funding). Dr Starling reports a conflict of interest with Novartis

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