“Despite advances in immunosuppressive therapy, graft rejection is a significant cause of mortality and morbidity after heart transplant,” said lead author Dr. Filipa Cordeiro, a cardiology fellow in the Department of Cardiovascular Diseases, University Hospital Leuven, Belgium. “However, symptoms only occur when heart damage is already extensive and there is left ventricular dysfunction.”

Endomyocardial biopsy is the gold standard surveillance test to detect graft rejection. It is performed frequently in the first year after heart transplant, but after that, it is only done when there is a clinical suspicion of graft rejection. A non-invasive screening test is needed to detect graft rejection earlier and avoid the possible complications associated with endomyocardial biopsy.

The goal of this study was to investigate whether humoral and cellular graft rejection, which are the two types of graft rejection, are preceded by changes in transthoracic echocardiography measurements—in particular, strain imaging. If this was the case, clinicians could decide early in the occurrence of subclinical rejection to perform endomyocardial biopsy and, if necessary, begin treatment.

The researchers reviewed the medical records of 316 consecutive patients who had a heart transplant between 2003 and 2016 in a single center to identify episodes of severe cellular or humoral graft rejection.

A total of 17 patients with severe graft rejection were included in the study, including ten with cellular and seven with humoral graft rejection. Each heart transplant patient with severe graft rejection was matched to a control heart transplant patient without graft rejection by transplant age, donor age, and ischemic time, giving a control group of 17 patients.

Echocardiography measurements from the moment of graft rejection and approximately 3, 6, and 12 months before were analyzed and compared between groups.

The researchers found that at the moment of acute graft rejection, patients with humoral graft rejection had worse values of global longitudinal strain, circumferential strain, and left ventricular ejection fraction compared to controls and to heart transplant patients with cellular graft rejection.

Patients with humoral graft rejection showed normal myocardial strain values on average 1 year before the rejection episode and then presented with progressive decline of global longitudinal strain and circumferential strain in the months preceding acute graft rejection. This was in contrast to controls and cellular graft rejection patients, who had stable strain values except for the moment of acute graft rejection.

Left ventricular ejection fraction and other conventional echocardiography measurements did not significantly change in the months prior to an acute graft rejection episode and could not differentiate between the three groups.

Dr. Cordeiro said: “This study demonstrates a progressive decrease of global longitudinal strain and circumferential strain months before a humoral graft rejection becomes clinically apparent. Such alterations months before a severe graft rejection are not evident with conventional echocardiographic parameters and do not occur in cellular graft rejection.”

The researchers believe the observed differences between the two types of graft rejection are due to differing pathophysiology. Cellular graft rejection is an acute T-cell-mediated process, whereas humoral graft rejection develops when the recipient develops antibodies against the donor.

Dr. Cordeiro said: “Humoral graft rejection is a major limitation to long-term graft survival. Our data suggest that global strain assessment by echocardiography allows early detection of a developing humoral graft rejection. This could trigger maintenance immunosuppressive therapy optimization, increased surveillance or acute treatment, and prevent progression to graft failure.”