Giant cell myocarditis (GCM) is a rare and highly lethal disorder. The only multicenter case series with treatment data lacked cardiac function assessments and had a retrospective design. We ...conducted a prospective, multicenter study of immunosuppression including cyclosporine and steroids for acute, microscopically-confirmed GCM. From June 1999 to June 2005 in a standard protocol, 11 subjects received high dose steroids and cyclosporine, and 9 subjects received muromonab-CD3. In these, 7 of 11 were women, the mean age was 60 ± 15 years, and the mean time from symptom onset to presentation was 27 ± 33 days. During 1 year of treatment, 1 subject died of respiratory complications on day 178, and 2 subjects received heart transplantations on days 2 and 27, respectively. Serial endomyocardial biopsies revealed that after 4 weeks of treatment the degree of necrosis, cellular inflammation, and giant cells decreased (p = 0.001). One patient who completed the trial subsequently died of a fatal GCM recurrence after withdrawal of immunosuppression. Her case demonstrates for the first time that there is a risk of recurrent, sometimes fatal, GCM after cessation of immunosuppression. In conclusion, this prospective study of immunosuppression for GCM confirms retrospective case reports that such therapy improves long-term survival. Additionally, withdrawal of immunosuppression can be associated with fatal GCM recurrence.
Human immunodeficiency virus (HIV) infection is widely considered a contraindication for cardiac transplantation. However, with the newer anti-retroviral drugs, the estimated 10-year survival after ...seroconversion is exceeds 90%. This case series describes the intermediate range outcome of HIV-positive cardiac transplant recipients.
A retrospective analysis of 1679 cardiac transplant patients was undertaken to identify HIV-positive recipients.
Seven patients were identified. Five (4 men) were diagnosed with HIV before transplantation and 2 patients seroconverted after transplantation. Dilated cardiomyopathy was the indication for transplant in all patients. The 5 HIV recipients were aged 42 +/- 8 years, and time after HIV seroconversion averaged 9.5 years. All underwent cardiac transplantation as high-risk candidates. The CD4 count was 554 +/- 169 cells/microl, and viral load was undetectable in all patients at the time of transplantation. Two patients seroconverted to HIV-positive status at 1 and 7 years after transplant. No AIDS-defining illness was observed in any patient before or after transplant. Six patients received highly active anti-retroviral therapy. Viral load remained low in the presence of immunosuppression. All patients are alive with a follow-up from transplant of 57 +/- 78.9 months.
Excellent intermediate term outcome is noted in carefully selected HIV-positive patients. No significant AIDS-related infections or complications occurred.
Objective Biomaterials and textured surfaces in early pulsatile left ventricular assist devices (HeartMate I; Thoratec Corporation, Pleasanton, Calif) may increase immunologic risk through ...allosensitization. We hypothesized that axial-flow devices without biologic membranes or textured surfaces (HeartMate II; Thoratec; and DeBakey; MicroMed Cardiovascular, Inc, Houston, Tex) would cause less allosensitization than devices with such membranes and surfaces. Methods HeartMate II and DeBakey (n = 24) and HeartMate I (n = 36) devices were implanted from 1999 to 2006 in patients with severe heart failure cohort-matched for age, etiology, and support duration. Serum samples reacting with more than 10% of the HLA reference panel were considered positive for anti-HLA antibodies. Endomyocardial biopsy samples were collected after transplant. Results There were no significant cohort differences in age, etiology, sex, blood transfusion, or support duration. Anti-HLA antibodies were not detected at implantation of either HeartMate II and DeBakey or HeartMate I devices; however, significant increases in anti-HLA antibodies were present within 1 and 3 months of support with HeartMate I but not HeartMate II and DeBakey devices. Overall, fewer patients with HeartMate II and DeBakey devices demonstrated positive anti-HLA antibodies during support (8% vs 28%, P = .02), and fewer episodes of acute rejection per patient were seen within the first 9 posttransplant months(0.31 vs 0.69, P = .052). Long-term posttransplant survival was not different between groups. Conclusion Hemodynamic support with HeartMate II and DeBakey devices produced less allosensitization than did HeartMate I devices. Device selection may improve clinical outcomes for high-risk patients.
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.
We have previously demonstrated that a peripheral blood transcriptional profile using 11 distinct genes predicts onset of cardiac allograft rejection weeks to months prior to the actual event.
In ...this analysis, we ascertained the performance of this transcriptional algorithm in a Bayesian representative population: 28 cardiac transplant recipients who progressed to moderate to severe rejection; 53 who progressed to mild rejection; and 46 who remained rejection-free. Furthermore, we characterized longitudinal alterations in the transcriptional gene expression profile before, during and after recovery from rejection.
In this patient cohort, we found that a gene expression score (range 0 to 40) of <or =20 represents very low risk of rejection in the subsequent 12 weeks: 0 progressed to treatable (ISHLT Grade > or =3A) rejection; 16 of 53 (30%) from the intermediate group (those who progressed to ISHLT Grade 1B or 2) and 13 of 46 (28%) controls (who remained Grade 0 or 1A) had scores < or =20. A gene score of > or =30 was associated with progression to moderate to severe rejection in 58% of cases. These two extreme scores (< or =20 or > or =30) represented 44% of the cardiac transplant population within 6 months post-transplant. In addition, longitudinal gene expression analysis demonstrated that baseline scores were significantly higher for those who went on to reject, remained high during an episode of rejection, and dropped post-treatment for rejection (p < 0.01).
The use of gene expression profiling early after transplantation allows for separation into low-, intermediate- or high-risk categories for future rejection, permitting development of discrete surveillance strategies.
Objective Ventricular assist devices (VADs) are associated with increased anti–human leukocyte antigen antibody production. The purpose of this study is to characterize differences in sensitization ...patterns in patients receiving axial flow, implantable VADs versus pulsatile, paracorporeal biventricular assist devices (BIVADs) as bridges to transplantation. Methods The study is a retrospective review of 68 patients who were bridged to transplantation with either a VAD or a BIVAD, as described, from January 2007 to June 2010, at a university medical center. Results Five of 15 (33.3%) VAD patients became sensitized during treatment, compared with 30 of 53 (56.6%) BIVAD patients, P = .15. Multivariable analysis comparing BIVAD with VAD, while controlling for previous cardiac surgery, pregnancy, and packed red blood cell transfusion produced an odds ratio of 2.99, P = .14. Of sensitized patients, all 5 (100%) of the VAD patients had pre-existing antibodies before VAD placement, compared with 9 of 30 (30.0%) BIVAD patients, P = .006. Maximum cumulative mean fluorescence intensities for BIVAD were 46,259 ± 66,349 versus 42,540 ± 12,840 for VAD, P = .90. Time to maximum antibody expression was shorter for the VAD group (34 ± 28 days vs 5.8 ± 9 days, P = .04). Conclusions Device type was not a factor in patient sensitization after implantation. However, VAD patients required pre-existing sensitization before implantation to produce antibodies during their treatment interval, whereas more than two thirds of BIVAD patients developed de novo antibodies. These data suggest that the mechanism of sensitization between VAD and BIVAD patients may differ, and further mechanistic studies into the impact of device types on patient sensitization are warranted.
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.
ACC Stage C heart failure includes those patients with prior or current symptoms of heart failure in the context of an underlying structural heart problem who are primarily managed with medical ...therapy. Although there is guideline-based medical therapy for those with heart failure with reduced ejection fraction (HFrEF), therapies in heart failure with preserved ejection fraction (HFpEF) have thus far proven elusive. Emerging therapies such as serelaxin are currently under investigation and may prove beneficial. The role of advanced surgical therapies, such as mechanical circulatory support, in this population is not well defined. Further investigation is warranted for these therapies in patients with Stage C heart failure.
Gene expression profiling distinguishes the absence or presence of moderate to severe grades of acute cellular rejection in cardiac allograft recipients using a 20-gene classifier. We explored the ...hypothesis that the rejection classifier also differentiates various forms of mild rejection and we performed sub-analyses based on time post-transplant and confirmatory pathology interpretations.
A post hoc analysis of 265 CARGO study patients and 714 clinical encounters focused on the correlation of rejection classifier-derived gene expression (GE) scores for blood samples accompanying endomyocardial biopsies. Biopsy grades assigned by a study center pathologist (center) were re-interpreted by three pathologists (panel) in a blinded manner.
Mean GE scores not only differentiated Grades >or=3A from Grade 0 (p < 0.00001, center or panel), but also from Grades 1A or 2 (p < 0.05, center or panel), based on mild rejection sub-groups defined by the ISHLT 1990 grading system. In contrast, mean GE scores for Grades 1B and >or=3A were indistinguishable, using either center or panel interpretation. Sub-group analyses of encounters from 2 to 6 months or >6 months post-transplant showed similar results for the classifier's ability to discriminate moderate to severe rejection from Grades 1A and 2 mild rejection, but indistinguishable mean GE scores for Grades >or=3A and the Grade 1B sub-group. Of the classifier's 11 informative genes, expression of MIR and WDR40 showed statistically significant increases for both Grade 1B and Grade >or=3A rejection, while expression of PDCD1 or SEMA7A showed similar directional patterns without achieving statistical significance.
These data demonstrate that GE scores discriminate moderate to severe rejection from Grades 1A and 2 mild rejection. However, a sub-group of mild rejection cases, defined as Grade 1B according to the 1990 grading system, share a molecular signature more consistent with moderate to severe rejection. The clinical relevance of these data remains to be defined.
Abstract Objectives We evaluated the reliability of the Stanford Integrated Psychosocial Assessment for Transplantation (SIPAT) in heart transplant (HT) recipients and explored its usefulness in ...predicting post-transplant outcomes. Background Pre-transplant psychosocial and behavioral risk is associated with post-transplant clinical outcomes. SIPAT is a risk assessment tool created for pre-transplant psychosocial evaluation. Methods Via retrospective chart review, three examiners applied the SIPAT to 51 adult HT recipients. Examiners blinded to SIPAT scores extracted data and interviewed clinicians for one-year post-transplant outcomes. Analysis included Intra-class correlation coefficient (ICC), Pearson's correlation coefficient and Chi-square. Results SIPAT demonstrated strong inter-rater reliability (ICC = 0.89, 95% CI = 0.76–0.96). Compared to those with SIPAT ratings of “Excellent/Good”, the “Minimally Acceptable Candidate/High Risk” group was more likely to miss clinic visits ( p = 0.004). Conclusions The SIPAT tool had strong IRR. Less favorable SIPAT ratings were associated with nonadherence to clinic visits. Further study is warranted to determine association of SIPAT ratings to clinical outcomes.
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