The liver in heart failure: a biopsy and explant series of the histopathologic and laboratory findings with a particular focus on pre-cardiac transplant evaluation.

The pathologic liver changes in chronic heart failure have been characterized mostly based on autopsy series and include sinusoidal dilation and congestion progressing to pericellular fibrosis, bridging fibrosis, and ultimately to cardiac cirrhosis or sclerosis. Liver biopsies are commonly obtained as part of the work up before heart transplantation in patients with longstanding right heart failure, particularly if ascites, abnormal liver function tests or abnormal abdominal imaging are noted as part of the pre-transplant evaluation. In these cases, the liver biopsy findings may be used to further risk stratify patients for isolated heart or combined heart and liver transplantation. Thus, it is important to be able to correlate the histologic changes with post-transplant outcomes. We report the pathologic and clinical findings in liver explants from six patients who underwent combined heart-liver transplantation. We also report preoperative liver biopsy findings from 21 patients who underwent heart transplantation without simultaneous liver transplantation. We staged the changes related to chronic passive congestion as follows: stage 0-no fibrosis; stage I-pericellular fibrosis; stage II-bridging fibrosis; and stage III-regenerative nodules. Nineteen biopsies showed fibrosis with bridging fibrosis in 13 and regenerative nodules in 6. Fifteen patients were alive at 1 year post transplant. Only three patients had a post-operative course that was characterized by signs and symptoms of chronic liver disease. Pre-transplant liver biopsies from these patients all showed at least stage II fibrosis. These patients survived for 3, 6, and 10 months after cardiac transplant. The presence of bridging fibrosis was not significantly associated with post-operative survival (P=0.336) or post-operative liver failure (P=0.257). We conclude that patients with bridging fibrosis may still be considered viable candidates for isolated heart transplantation. Because the pattern of fibrosis due to passive congestion is highly variable throughout the liver, a diagnosis of cirrhosis, which implies fibrosis and regenerative nodules throughout the liver, should be made with great caution on biopsy.

Utility of gene expression profiling score variability to predict clinical events in heart transplant recipients.

BACKGROUND: Gene expression profiling test scores have primarily been used to identify heart transplant recipients who have a low probability of rejection at the time of surveillance testing. We hypothesized that the variability of gene expression profiling test scores within a patient may predict risk of future events of allograft dysfunction or death. METHOD: Patients from the IMAGE study with rejection surveillance gene expression profiling tests performed at 1- to 6-month intervals were selected for this cohort study. Gene expression profiling score variability was defined as the standard deviation of an individual's cumulative test scores. Gene expression profiling ordinal score (range, 0-39), threshold score (binary value=1 if ordinal score ≥ 34), and score variability were studied in multivariate Cox regression models to predict future clinical events. RESULTS: Race, age at time of transplantation, and time posttransplantation were significantly associated with future events in the univariate analysis. In the multivariate analyses, gene expression profiling score variability, but not ordinal scores or scores over threshold, was independently associated with future clinical events. The regression coefficient P values were <0.001, 0.46, and 0.773, for gene expression profiling variability, ordinal, and threshold scores, respectively. The hazard ratio for a 1 unit increase in variability was 1.76 (95% CI, 1.4-2.3). DISCUSSION: The variability of a heart recipient's gene expression profiling test scores over time may provide prognostic utility. This information is independent of the probability of acute cellular rejection at the time of testing that is rendered from a single ordinal gene-expression profiling test score.

Gene-expression profiling for rejection surveillance after cardiac transplantation.

BACKGROUND: Endomyocardial biopsy is the standard method of monitoring for rejection in recipients of a cardiac transplant. However, this procedure is uncomfortable, and there are risks associated with it. Gene-expression profiling of peripheral-blood specimens has been shown to correlate with the results of an endomyocardial biopsy. METHODS: We randomly assigned 602 patients who had undergone cardiac transplantation 6 months to 5 years previously to be monitored for rejection with the use of gene-expression profiling or with the use of routine endomyocardial biopsies, in addition to clinical and echocardiographic assessment of graft function. We performed a noninferiority comparison of the two approaches with respect to the composite primary outcome of rejection with hemodynamic compromise, graft dysfunction due to other causes, death, or retransplantation. RESULTS: During a median follow-up period of 19 months, patients who were monitored with gene-expression profiling and those who underwent routine biopsies had similar 2-year cumulative rates of the composite primary outcome (14.5% and 15.3%, respectively; hazard ratio with gene-expression profiling, 1.04; 95% confidence interval, 0.67 to 1.68). The 2-year rates of death from any cause were also similar in the two groups (6.3% and 5.5%, respectively; P=0.82). Patients who were monitored with the use of gene-expression profiling underwent fewer biopsies per person-year of follow-up than did patients who were monitored with the use of endomyocardial biopsies (0.5 vs. 3.0, P<0.001). CONCLUSIONS: Among selected patients who had received a cardiac transplant more than 6 months previously and who were at a low risk for rejection, a strategy of monitoring for rejection that involved gene-expression profiling, as compared with routine biopsies, was not associated with an increased risk of serious adverse outcomes and resulted in the performance of significantly fewer biopsies. (ClinicalTrials.gov number, NCT00351559.)

Molecular testing for long-term rejection surveillance in heart transplant recipients: design of the Invasive Monitoring Attenuation Through Gene Expression (IMAGE) trial.

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.