Molecular Testing for Long-term Rejection Surveillance in Heart Transplant Recipients: Design of the Invasive Monitoring Attenuation Through Gene Expression (IMAGE) Trial

doi:10.1016/j.healun.2007.05.017

The Journal of Heart and Lung Transplantation

Volume 26, Issue 8, August 2007, Pages 808-814

https://doi.org/10.1016/j.healun.2007.05.017 Get rights and content

Background

Acute rejection continues to occur beyond the first year after cardiac transplantation, but the optimal strategy for detecting rejection during this late period is still controversial. Gene expression profiling (GEP), with its high negative predictive value for acute cellular rejection (ACR), appears to be well suited to identify low-risk patients who can be safely managed without routine invasive endomyocardial biopsy (EMB).

Methods

The Invasive Monitoring Attenuation Through Gene Expression (IMAGE) study is a prospective, multicenter, non-blinded, randomized clinical trial designed to test the hypothesis that a primarily non-invasive rejection surveillance strategy utilizing GEP testing is not inferior to an invasive EMB-based strategy with respect to cardiac allograft dysfunction, rejection with hemodynamic compromise (HDC) and all-cause mortality.

Results

A total of 199 heart transplant recipients in their second through fifth post-transplant years have been enrolled in the IMAGE study since January 13, 2005. The study is expected to continue through 2008.

Conclusions

The IMAGE study is the first randomized, controlled comparison of two rejection surveillance strategies measuring outcomes in heart transplant recipients who are beyond their first year post-transplant. The move away from routine histologic evaluation for allograft rejection represents an important paradigm shift in cardiac transplantation, and the results of this study have important implications for the future management of heart transplant patients.

Section snippets

Study Objectives

The Invasive Monitoring Attenuation Through Gene Expression (IMAGE) study is a prospective, multi-center, non-blinded, randomized clinical trial designed to test the hypothesis that a non-invasive rejection surveillance strategy utilizing GEP is not inferior to a traditional, invasive strategy utilizing routine EMB, with respect to clinical outcomes (decrease in left ventricular ejection fraction [LVEF], acute rejection with associated HDC, or death) when used to monitor asymptomatic heart

Results

A total of 199 patients have been enrolled in the IMAGE study since January 13, 2005. The study is expected to continue through 2008 with an interim analysis expected in 2007.

Discussion

The IMAGE study compares a non-invasive, GEP-based rejection surveillance protocol to a traditional invasive (EMB-based) protocol, for monitoring heart transplant recipients in their second to fifth years post-transplant. The study will evaluate the impact of these two strategies on the incidence of cardiac allograft dysfunction, development of acute rejection with HDC, and all-cause mortality.

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Cited by (37)

Prognostic Utility of Right Ventricular Free Wall Strain in Low Risk Patients After Orthotopic Heart Transplantation
2017, American Journal of Cardiology
Global longitudinal strain (GLS) by speckle-tracking echocardiography is a sensitive measure of regional left and right ventricular (LV and RV) dysfunction, before onset of overt systolic dysfunction. We sought to evaluate the prognostic utility of measuring LV-GLS and RV free wall strain (FWS) in low risk patients at 1 year after orthotopic heart transplantation (OHT). We retrospectively studied 96 OHT recipients (age 52 ± 14 years, 64% men) free of antibody-mediated rejection or moderate to severe coronary allograft vasculopathy (CAV, grade 2 to 3) at 1 year after transplant. LV-GLS and RV-FWS were calculated using EchoPAC software. Cox models were developed after adjusting for the Index for Mortality Prediction After Cardiac Transplantation (IMPACT) score (post-transplant risk score), with the primary outcome of death, moderate to severe CAV, or treated rejection. At 1 year after transplant, LV ejection fraction and RV fractional area change (FAC) were 58 ± 7% and 42 ± 10%, respectively. LV-GLS was −17.0 ± 3.3% and RV-FWS −16.4 ± 4.5%. At an average follow-up of 4.5 years, 28 patients met the primary end point (10 death, 5 vasculopathy, 17 rejection). In sequential Cox models, markers of RV function were associated with the primary outcome (RV-FAC, p = 0.012; RV-FWS, p = 0.022), while LV ejection fraction and LV-GLS were not. We conclude that in low risk patients 1 year after OHT, markers of RV function (RV-FAC and RV-FWS) are independently associated with incident rejection, CAV, and death. Markers of RV dysfunction could potentially be incorporated into risk scores and future prospective studies to risk stratify patients after OHT.
Gene expression profiling to study racial differences after heart transplantation
2015, Journal of Heart and Lung Transplantation
Citation Excerpt :
The IMAGE study was a randomized trial conducted at 13 United States heart transplant centers between January 2005 and October 2009. The study design and procedures have been described previously.11,12 Adult heart transplant recipients, between 6 months and 5 years after transplant, were eligible for enrollment and were randomly assigned to undergo monitoring for rejection by means of gene expression profiling (GEP) or specimens obtained from routine endomyocardial biopsies (EMBs).
The basis for increased mortality after heart transplantation in African Americans and other non-Caucasian racial groups is poorly defined. We hypothesized that increased risk of adverse events is driven by biologic factors. To test this hypothesis in the Invasive Monitoring Attenuation through Gene Expression (IMAGE) study, we determined whether the event rate of the primary outcome of acute rejection, graft dysfunction, death, or retransplantation varied by race as a function of calcineurin inhibitor (CNI) levels and gene expression profile (GEP) scores.
We determined the event rate of the primary outcome, comparing racial groups, stratified by time after transplant. Logistic regression was used to compute the relative risk across racial groups, and linear modeling was used to measure the dependence of CNI levels and GEP score on race.
In 580 patients monitored for a median of 19 months, the incidence of the primary end point was 18.3% in African Americans, 22.2% in other non-Caucasians, and 8.5% in Caucasians (p < 0.001). There were small but significant correlations of race and tacrolimus trough levels to the GEP score. Tacrolimus levels were similar among the races. Of patients receiving tacrolimus, other non-Caucasians had higher GEP scores than the other racial groups. African American recipients demonstrated a unique decrease in expression of the FLT3 gene in response to higher tacrolimus levels.
African Americans and other non-Caucasian heart transplant recipients were 2.5-times to 3-times more likely than Caucasians to experience outcome events in the Invasive Monitoring Attenuation through Gene Expression study. The increased risk of adverse outcomes may be partly due to the biology of the alloimmune response, which is less effectively inhibited at similar tacrolimus levels in minority racial groups.
Usefulness of routine surveillance endomyocardial biopsy 6 months after heart transplantation
2012, Journal of Heart and Lung Transplantation
Endomyocardial biopsy (EMB) remains the gold standard for detecting rejection episodes in orthotopic heart transplant (OTH) patients. Follow-up protocols vary widely between transplant centers. At our center, we have implemented a conservative strategy protocol and here we report our outcomes.
Patients from 2 cohorts were used for comparison analysis. OHT recipients from 1990 to 1995 comprised the standard strategy group, and those from 2004 to 2009 comprised the conservative strategy group. Survival outcomes and rejection episodes were compared between groups.
Mean age at OHT was 56 ± 10 years in the standard strategy group and 53 ± 10 years in the conservative strategy group. Both groups were predominantly composed of white men. The etiology of congestive heart failure was ischemic cardiomyopathy in more than 50% of the patients in both groups. From 6 to 12 months after OHT, we found that the number of episodes of rejection/total number of EMBs was 4.9% (8/163) in the standard group vs 2.0% (1/50) in the conservative group. From 12 to 24 months after transplant, the rate was 2.5% (8/320) in the standard group vs 11.9% (5/42) in the conservative group (p < 0.05).
Surveillance EMB after 6 months post-OHT in patients receiving contemporary immunosuppression is associated with a low yield of EMB-confirmed rejection in the absence of a clinical indication or echocardiographic findings that support clinical rejection. Most episodes of cellular rejection are mild and do not warrant treatment or a change in immunosuppression. The frequency of EMBs did not correlate with an increased risk of cardiac allograft vasculopathy or death.
New-onset graft dysfunction after heart transplantationincidence and mechanism-related outcomes
2011, Journal of Heart and Lung Transplantation
Citation Excerpt :
Most common echocardiographic parameters of allograft function were analyzed, including ventricular wall motion, left ventricular ejection fraction (LVEF), valvular assessment and assessment for pericardial disease. Graft dysfunction was defined as LVEF ≤30%.11,12 Patients were followed from >3 months post-HTx onward for a hospitalization with a new-onset graft failure as defined by LVEF criteria.
Graft dysfunction (GD) after heart transplantation (HTx) is a major cause of morbidity and mortality. The impact of different pathophysiologic mechanisms on outcome is unknown. In this large, single-center study we aimed to assess the incidence of GD and compare the outcomes with different histopathologic mechanisms of rejection.
We analyzed a data set of 1,099 consecutive patients after their HTx at Columbia University Medical Center between January 1994 and March 2008, and identified all patients hospitalized with new-onset GD. Based on the histopathologic data, patients were divided into GD-unexplained (Group-GD-U), GD-antibody-mediated rejection (Group-GD-AMR), GD-cardiac allograft vasculopathy (Group-GD-CAV) and GD-acute cellular rejection (Group-GD-ACR) groups. We compared the in-hospital and 3-, 6- and 12-month mortality across these groups using the chi-square test. We also compared the 3-, 6- and 12-month survival curves across groups using the log-rank test.
Of 126 patients (12%) identified with GD, complete histology data were available for 100 patients. There were 21, 20, 27 and 32 patients identified in Group-GD-U, Group-GD-AMR, Group-GD-CAV and Group-GD-ACR, respectively. The in-hospital mortality rates were 52%, 20%, 15% and 6%, respectively. The in-hospital mortality rate was significantly higher in Group-GD-U compared with all other groups (p = 0.0006). The 3-, 6- and 12-month survival rate was also significantly lower in Group-GD-U compared with all other groups.
A significant proportion of patients presenting with new-onset GD have unexplained histopathology. Unexplained GD is associated with a significantly higher mortality rate. New diagnostic tools are necessary to better understand and detect/predict this malignant phenotype.
Gene expression profiling and cardiac allograft rejection monitoring: Is IMAGE just a mirage?
2010, Journal of Heart and Lung Transplantation
The search for an effective non-invasive monitoring technique for cardiac allograft rejection eluded us until the discovery and validation of a commercially available gene-based peripheral blood bio-signature signal. The Invasive Monitoring Attenuation through Gene Expression (IMAGE) trial tested the hypothesis of cardiac biopsy minimization using this gene-based panel in stable, low-risk survivors, late after cardiac transplantation and demonstrated non-inferiority of this strategy. We present a clinician's critical perspective on this important effort and outline the key caveats and highlights for the potential way forward in using these results. Furthermore, we contend that it may not be necessary to replace an invasive cardiac biopsy strategy with anything other than better standardized clinical and functional allograft vigilance in low-risk survivors.
Genomic Assessment of Cardiac Transplant Rejection
2010, Essentials of Genomic and Personalized Medicine
Heart failure (HF) is a leading cause of morbidity and mortality in the United States. The disease accounts for being the major cause of hospitalization for individuals aged 65 or greater. Despite major advances in the treatment of this disease over the past decade, a sizable number of patients with terminal or progressive myocardial dysfunction are fated to die or to be severely limited by symptoms. In these patients, biological replacement of the heart with human organs has become standard therapy and is widely accepted as a modality for prolonging life and improving its quality in carefully selected patients. Heart transplantation is the definitive therapy for end-stage HF, but is complicated by recipient immune responses to the transplanted heart, often resulting in cardiac allograft rejection. Different forms of rejection are recognized, including hyperacute rejection, acute cellular rejection, acute antibody-mediated rejection, mixed rejection, and chronic rejection. Most patients with acute rejection are asymptomatic and have no clinical findings of cardiac allograft dysfunction. The signs and symptoms of rejection are nonspecific and only manifest in the late stages of rejection. Thus, close surveillance of heart transplant recipients for acute rejection is critical. Protocols for the timing of rejection surveillance are variable among transplant programs, but are generally chosen to match the observed frequency of rejection episodes.

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Cardiac rejectionMolecular Testing for Long-term Rejection Surveillance in Heart Transplant Recipients: Design of the Invasive Monitoring Attenuation Through Gene Expression (IMAGE) Trial

Background

Methods

Results

Conclusions

Section snippets

Study Objectives

Results

Discussion

J Heart Lung Transplant

J Heart Lung Transplant

J Heart Lung Transplant

J Heart Lung Transplant

Ann Thorac Surg

Am J Cardiol

Am J Transplant

J Heart Lung Transplant

Am J Transplant

J Heart Lung Transplant

Daclizumab to prevent rejection after cardiac transplantation

N Engl J Med

Everolimus for the prevention of allograft rejection and vasculopathy in cardiac-transplant recipients

N Engl J Med

Cardiac rejection
Molecular Testing for Long-term Rejection Surveillance in Heart Transplant Recipients: Design of the Invasive Monitoring Attenuation Through Gene Expression (IMAGE) Trial