Clinical usefulness of gene-expression profile to rule out acute rejection after heart transplantation: CARGO II.

AIMS A non-invasive gene-expression profiling (GEP) test for rejection surveillance of heart transplant recipients originated in the USA. A European-based study, Cardiac Allograft Rejection Gene Expression Observational II Study (CARGO II), was conducted to further clinically validate the GEP test performance. METHODS AND RESULTS Blood samples for GEP testing (AlloMap(®), CareDx, Brisbane, CA, USA) were collected during post-transplant surveillance. The reference standard for rejection status was based on histopathology grading of tissue from endomyocardial biopsy. The area under the receiver operating characteristic curve (AUC-ROC), negative (NPVs), and positive predictive values (PPVs) for the GEP scores (range 0-39) were computed. Considering the GEP score of 34 as a cut-off (>6 months post-transplantation), 95.5% (381/399) of GEP tests were true negatives, 4.5% (18/399) were false negatives, 10.2% (6/59) were true positives, and 89.8% (53/59) were false positives. Based on 938 paired biopsies, the GEP test score AUC-ROC for distinguishing ≥3A rejection was 0.70 and 0.69 for ≥2-6 and >6 months post-transplantation, respectively. Depending on the chosen threshold score, the NPV and PPV range from 98.1 to 100% and 2.0 to 4.7%, respectively. CONCLUSION For ≥2-6 and >6 months post-transplantation, CARGO II GEP score performance (AUC-ROC = 0.70 and 0.69) is similar to the CARGO study results (AUC-ROC = 0.71 and 0.67). The low prevalence of ACR contributes to the high NPV and limited PPV of GEP testing. The choice of threshold score for practical use of GEP testing should consider overall clinical assessment of the patient's baseline risk for rejection.

Somebody Else's heart inside me: A descriptive study of psychological problems after a heart transplantation

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Heart Transplantation in Patients Older than 65 Years: Worthwhile or Wastage of Organs?

BACKGROUND: Patients older than 65 years have traditionally not been considered candidates for heart transplantation. However, recent studies have shown similar survival. We evaluated immediate and medium-term results in patients older than 65 years compared with younger patients. METHODS: From November 2003 to December 2013, 258 patients underwent transplantation. Children and patients with other organ transplantations were excluded from this study. Recipients were divided into two groups: 45 patients (18%) aged 65 years and older (Group A) and 203 patients (81%) younger than 65 years (Group B). RESULTS: Patients differed in age (67.0 ± 2.2 vs. 51.5 ± 9.7 years), but gender (male 77.8 vs. 77.3%; p = 0.949) was similar. Patients in Group A had more cardiovascular risk factors and ischemic cardiomyopathy (60 vs. 33.5%; p < 0.001). Donors to Group A were older (38.5 ± 11.3 vs. 34.0 ± 11.0 years; p = 0.014). Hospital mortality was 0 vs. 5.9% (p = 0.095) and 1- and 5-year survival were 88.8 ± 4.7 versus 86.8 ± 2.4% and 81.5 ± 5.9 versus 77.2 ± 3.2%, respectively. Mean follow-up was 3.8 ± 2.7 versus 4.5 ± 3.1 years. Incidence of cellular/humoral rejection was similar, but incidence of cardiac allograft vasculopathy was higher (15.6 vs. 7.4%; p = 0.081). Incidence of diabetes de novo was similar (p = 0.632), but older patients had more serious infections in the 1st year (p = 0.018). CONCLUSION: Heart transplantation in selected older patients can be performed with survival similar to younger patients, hence should not be restricted arbitrarily. Incidence of infections, graft vascular disease, and malignancies can be reduced with a more personalized approach to immunosuppression. Allocation of donors to these patients does not appear to reduce the possibility of transplanting younger patients.

Heart Transplantation in Patients Older than 65 Years: Worthwhile or Wastage of Organs?

BACKGROUND: Patients older than 65 years have traditionally not been considered candidates for heart transplantation. However, recent studies have shown similar survival. We evaluated immediate and medium-term results in patients older than 65 years compared with younger patients. METHODS: From November 2003 to December 2013, 258 patients underwent transplantation. Children and patients with other organ transplantations were excluded from this study. Recipients were divided into two groups: 45 patients (18%) aged 65 years and older (Group A) and 203 patients (81%) younger than 65 years (Group B). RESULTS: Patients differed in age (67.0 ± 2.2 vs. 51.5 ± 9.7 years), but gender (male 77.8 vs. 77.3%; p = 0.949) was similar. Patients in Group A had more cardiovascular risk factors and ischemic cardiomyopathy (60 vs. 33.5%; p < 0.001). Donors to Group A were older (38.5 ± 11.3 vs. 34.0 ± 11.0 years; p = 0.014). Hospital mortality was 0 vs. 5.9% (p = 0.095) and 1- and 5-year survival were 88.8 ± 4.7 versus 86.8 ± 2.4% and 81.5 ± 5.9 versus 77.2 ± 3.2%, respectively. Mean follow-up was 3.8 ± 2.7 versus 4.5 ± 3.1 years. Incidence of cellular/humoral rejection was similar, but incidence of cardiac allograft vasculopathy was higher (15.6 vs. 7.4%; p = 0.081). Incidence of diabetes de novo was similar (p = 0.632), but older patients had more serious infections in the 1st year (p = 0.018). CONCLUSION: Heart transplantation in selected older patients can be performed with survival similar to younger patients, hence should not be restricted arbitrarily. Incidence of infections, graft vascular disease, and malignancies can be reduced with a more personalized approach to immunosuppression. Allocation of donors to these patients does not appear to reduce the possibility of transplanting younger patients.

Outpatient follow-up during the first year after heart transplantation, is it feasible?

First year follow-up after heart transplantation requires invasive tests. Although patients used to be hospitalized for this purpose, ambulatory invasive procedures now offer the possibility of outpatient follow-up. The feasibility and security of this strategy is unknown. From 2007 we transitioned to outpatient follow-up. We have retrospectively reviewed the clinical course of the outpatient group (2007 to 2014) and an inpatient group (2000–2006). Basal characteristics, hospital stay, infections, rejection episodes and vascular complications were evaluated. 87 patients had Inpatient Follow-up (IF) and 98 Outpatient Follow-up (OF). Basal characteristics were similar, with significant differences in immunosuppression (tacrolimus IF 44.8% vs. OF 90.8%, and mycophenolate IF 86.2% vs OF 100%, both p values < 0.001) and age (IF 52 ± 11.5 years vs. OF 56.1 ± 11 years, p = 0.016). In the OF group more clinical visits were performed (IF 10 vs. OF 13, p < 0.001) while hospital stay was lower (IF 23 days vs. OF 3 days, p < 0.001). The rate of infection, rejection, and vascular complications was similar. No difference was found in 1-year mortality (IF 2.3% vs. 1.0%, p = 0.60). First year post-cardiac transplantation outpatient follow-up seems to be feasible and safe in terms of infection, rejection, vascular complications and mortality.

Outpatient follow-up during the first year after heart transplantation, is it feasible?

First year follow-up after heart transplantation requires invasive tests. Although patients used to be hospitalized for this purpose, ambulatory invasive procedures now offer the possibility of outpatient follow-up. The feasibility and security of this strategy is unknown. From 2007 we transitioned to outpatient follow-up. We have retrospectively reviewed the clinical course of the outpatient group (2007 to 2014) and an inpatient group (2000–2006). Basal characteristics, hospital stay, infections, rejection episodes and vascular complications were evaluated. 87 patients had Inpatient Follow-up (IF) and 98 Outpatient Follow-up (OF). Basal characteristics were similar, with significant differences in immunosuppression (tacrolimus IF 44.8% vs. OF 90.8%, and mycophenolate IF 86.2% vs OF 100%, both p values < 0.001) and age (IF 52 ± 11.5 years vs. OF 56.1 ± 11 years, p = 0.016). In the OF group more clinical visits were performed (IF 10 vs. OF 13, p < 0.001) while hospital stay was lower (IF 23 days vs. OF 3 days, p < 0.001). The rate of infection, rejection, and vascular complications was similar. No difference was found in 1-year mortality (IF 2.3% vs. 1.0%, p = 0.60). First year post-cardiac transplantation outpatient follow-up seems to be feasible and safe in terms of infection, rejection, vascular complications and mortality.

Transplantation of the heart after circulatory death of the donor: time for a change in law?

Australia has a shortfall in donated hearts for transplantation.Hearts are usually procured from brain dead donors, but procurement from circulatory dead donors is a potential additional source.However, heart transplantation after circulatory death of the donor may not conform to the dead donor rule.An amendment in law is required to permit heart procurement for transplantation after circulatory death.

Prostaglandin E1 testing in heart failure-associated pulmonary hypertension enables transplantation: the PROPHET study

BACKGROUND: Elevated pulmonary vascular resistance (PVR) is relevant to prognosis of congestive heart failure and heart transplantation. Proof of reversibility by pharmacologic testing in potential transplantation candidates is important because it indicates a reduced probability of right ventricular failure or death in the early post-transplant period. This study aimed to clarify the possible extent of acute reversibility of elevated PVR in a large, consecutive cohort of heart transplant candidates. METHODS: This study included 208 consecutive patients (age 52 +/- 10 years, 89% men and 11% women, ejection fraction 21 +/- 9%, Vo2max 12.6 +/- 4.2 ml/kg/min) being evaluated for heart transplantation in 7 transplant centers in Germany and Switzerland. Testing was performed with increasing intravenous doses of prostaglandin E1 (PGE1; average maximum dose 173 +/- 115 ng/kg/min for at least 10 minutes) in 92 patients exhibiting a baseline PVR of > 2.5 Wood units (WU) and/or a transpulmonary gradient (TPG) of > 12 mm Hg. RESULTS: PGE1 testing lowered PVR from 4.1 +/- 2.0 to 2.1 +/- 1.1 WU (p < 0.01), increased cardiac output from 3.8 +/- 1.0 to 5.0 +/- 1.5 liters/min (p < 0.01), and decreased TPG from 14 +/- 4 to 10 +/- 3 mm Hg (p < 0.01), mean pulmonary artery pressure (PAM) from 39 +/- 9 to 29 +/- 9 mm Hg (p < 0.01) and mean pulmonary capillary wedge pressure (PCWP) from 24 +/- 7 to 19 +/- 9 mm Hg (p < 0.01). Mean aortic pressure (MAP) decreased to 85% and systemic vascular resistance (SVR) to 65% of baseline values (p < 0.01). Symptomatic systemic hypotension was not observed. For the whole population the percentage of patients with PVR > 2.5 WU was reduced from 44.2% to 10.5% with PGE1. PVR decreased in each patient; only 2 patients (1%) remained ineligible for listing because of a final PVR of > 4.0 WU. TPG, ejection fraction and male gender were independent predictors of reversibility of PVR. CONCLUSIONS: Elevated PVR in heart transplant candidates is highly reversible and can be normalized during acute pharmacologic testing with PGE1.

Infections in lung and heart transplant recipients : Studies on the impact of bronchoscopy in the diagnosis of respiratory infections and detection of viral infections in blood and bronchoalveolar lavage fluid

Infection is a major cause of mortality and morbidity after thoracic organ transplantation. The aim of the present study was to evaluate the infectious complications after lung and heart transplantation, with a special emphasis on the usefulness of bronchoscopy and the demonstration of cytomegalovirus (CMV), human herpes virus (HHV)-6, and HHV-7. We reviewed all the consecutive bronchoscopies performed on heart transplant recipients (HTRs) from May 1988 to December 2001 (n = 44) and lung transplant recipients (LTRs) from February 1994 to November 2002 (n = 472). To compare different assays in the detection of CMV, a total of 21 thoracic organ transplant recipients were prospectively monitored by CMV pp65-antigenemia, DNAemia (PCR), and mRNAemia (NASBA) tests. The antigenemia test was the reference assay for therapeutic intervention. In addition to CMV antigenemia, 22 LTRs were monitored for HHV-6 and HHV-7 antigenemia. The diagnostic yield of the clinically indicated bronchoscopies was 41 % in the HTRs and 61 % in the LTRs. The utility of the bronchoscopy was highest from one to six months after transplantation. In contrast, the findings from the surveillance bronchoscopies performed on LTRs led to a change in the previous treatment in only 6 % of the cases. Pneumocystis carinii and CMV were the most commonly detected pathogens. Furthermore, 15 (65 %) of the P. carinii infections in the LTRs were detected during chemoprophylaxis. None of the complications of the bronchoscopies were fatal. Antigenemia, DNAemia, and mRNAemia were present in 98 %, 72 %, and 43 % of the CMV infections, respectively. The optimal DNAemia cut-off levels (sensitivity/specificity) were 400 (75.9/92.7 %), 850 (91.3/91.3 %), and 1250 (100/91.5 %) copies/ml for the antigenemia of 2, 5, and 10 pp65-positive leukocytes/50 000 leukocytes, respectively. The sensitivities of the NASBA were 25.9, 43.5, and 56.3 % in detecting the same cut-off levels. CMV DNAemia was detected in 93 % and mRNAemia in 61 % of the CMV antigenemias requiring antiviral therapy. HHV-6, HHV-7, and CMV antigenemia was detected in 20 (91 %), 11 (50 %), and 12 (55 %) of the 22 LTRs (median 16, 31, and 165 days), respectively. HHV-6 appeared in 15 (79 %), HHV-7 in seven (37 %), and CMV in one (7 %) of these patients during ganciclovir or valganciclovir prophylaxis. One case of pneumonitis and another of encephalitis were associated with HHV-6. In conclusion, bronchoscopy is a safe and useful diagnostic tool in LTRs and HTRs with a suspected respiratory infection, but the role of surveillance bronchoscopy in LTRs remains controversial. The PCR assay acts comparably with the antigenemia test in guiding the pre-emptive therapy against CMV when threshold levels of over 5 pp65-antigen positive leukocytes are used. In contrast, the low sensitivity of NASBA limits its usefulness. HHV-6 and HHV-7 activation is common after lung transplantation despite ganciclovir or valganciclovir prophylaxis, but clinical manifestations are infrequently linked to them.

Primary vascularization of the graft determines the immunodominance of murine minor H antigens during organ transplantation.

Grafts can be rejected even when matched for MHC because of differences in the minor histocompatibility Ags (mH-Ags). H4- and H60-derived epitopes are known as immunodominant mH-Ags in H2(b)-compatible BALB.B to C57BL/6 transplantation settings. Although multiple explanations have been provided to explain immunodominance of Ags, the role of vascularization of the graft is yet to be determined. In this study, we used heart (vascularized) and skin (nonvascularized) transplantations to determine the role of primary vascularization of the graft. A higher IFN-γ response toward H60 peptide occurs in heart recipients. In contrast, a higher IFN-γ response was generated against H4 peptide in skin transplant recipients. Peptide-loaded tetramer staining revealed a distinct antigenic hierarchy between heart and skin transplantation: H60-specific CD8(+) T cells were the most abundant after heart transplantation, whereas H4-specific CD8(+) T cells were more abundant after skin graft. Neither the tissue-specific distribution of mH-Ags nor the draining lymph node-derived dendritic cells correlated with the observed immunodominance. Interestingly, non-primarily vascularized cardiac allografts mimicked skin grafts in the observed immunodominance, and H60 immunodominance was observed in primarily vascularized skin grafts. However, T cell depletion from the BALB.B donor prior to cardiac allograft induces H4 immunodominance in vascularized cardiac allograft. Collectively, our data suggest that immediate transmigration of donor T cells via primary vascularization is responsible for the immunodominance of H60 mH-Ag in organ and tissue transplantation.

A model of sequential heart and composite tissue allotransplant in rats.

BACKGROUND: Some of the 600,000 patients with solid organ allotransplants need reconstruction with a composite tissue allotransplant, such as the hand, abdominal wall, or face. The aim of this study was to develop a rat model for assessing the effects of a secondary composite tissue allotransplant on a primary heart allotransplant. METHODS: Hearts of Wistar Kyoto rats were harvested and transplanted heterotopically to the neck of recipient Fisher 344 rats. The anastomoses were performed between the donor brachiocephalic artery and the recipient left common carotid artery, and between the donor pulmonary artery and the recipient external jugular vein. Recipients received cyclosporine A for 10 days only. Heart rate was assessed noninvasively. The sequential composite tissue allotransplant consisted of a 3 x 3-cm abdominal musculocutaneous flap harvested from Lewis rats and transplanted to the abdomen of the heart allotransplant recipients. The abdominal flap vessels were connected to the femoral vessels. No further immunosuppression was administered following the composite tissue allotransplant. Ten days after composite tissue allotransplantation, rejection of the heart and abdominal flap was assessed histologically. RESULTS: The rat survival rate of the two-stage transplant surgery was 80 percent. The transplanted heart rate decreased from 150 +/- 22 beats per minute immediately after transplant to 83 +/- 12 beats per minute on day 20 (10 days after stopping immunosuppression). CONCLUSIONS: This sequential allotransplant model is technically demanding. It will facilitate investigation of the effects of a secondary composite tissue allotransplant following primary solid organ transplantation and could be useful in developing future immunotherapeutic strategies.

Two Cases of Late Shone Syndrome With Pulmonary Hypertension: Heart-Lung Transplant or Valve Surgery?

Two cases of Shone syndrome with severe mitral and aortic valve problems and pulmonary hypertension were referred for heart-lung transplantation. Severely elevated pulmonary vascular resistance (PVR) was confirmed as was severe periprosthetic mitral and aortic regurgitation. Based on the severity of the valve lesions in both patients, surgery was decided upon and undertaken. Both experienced early pulmonary hypertensive crises, one more than the other, that gradually subsided, followed by excellent recovery and reversal of pulmonary hypertension and PVR. These cases illustrate Braunwald's concept that pulmonary hypertension secondary to left-sided valve disease is reversible.

Options chirurgicates pour l'insuffisance cardiaque terminale [Surgical options for terminal heart failure]

Terminal heart failure can be the cause or the result of major dysfunctions of the organisms. Although, the outcome of the natural history is the same in both situations, it is of prime importance to differentiate the two, as only heart failure as the primary cause allows for successful mechanical circulatory support as bridge to transplantation or towards recovery. Various objective parameters allow for the establishment of the diagnosis of terminal heart failure despite optimal medical treatment. A cardiac index <2.0 l/min, and a mixed venous oxygen saturation <60%, in combination with progressive renal failure, should trigger a diagnostic work-up in order to identify cardiac defects that can be corrected or to list the patient for transplantation with/without mechanical circulatory support.

An artificial nanoemulsion carrying paclitaxel decreases the transplant heart vascular disease: A study in a rabbit graft model

Objective: In previous studies cholesterol-rich nanoemulsions (LDE) resembling low-density lipoprotein were shown to concentrate in atherosclerotic lesions of rabbits. Lesions were pronouncedly reduced by treatment with paclitaxel associated with LDE. This study aimed to test the hypothesis of whether LDE-paclitaxel is able to concentrate in grafted hearts of rabbits and to ameliorate coronary allograft vasculopathy after the transplantation procedure. Methods: Twenty-one New Zealand rabbits fed 0.5% cholesterol were submitted to heterotopic heart transplantation at the cervical position. All rabbits undergoing transplantation were treated with cyclosporin A (10 mg . kg(-1) . d(-1) by mouth). Eleven rabbits were treated with LDE-paclitaxel (4 mg/kg body weight paclitaxel per week administered intravenously for 6 weeks), and 10 control rabbits were treated with 3 mL/wk intravenous saline. Four control animals were injected with LDE labeled with [(14)C]-cholesteryl oleate ether to determine tissue uptake. Results: Radioactive LDE uptake by grafts was 4-fold that of native hearts. In both groups the coronary arteries of native hearts showed no stenosis, but treatment with LDE-paclitaxel reduced the degree of stenosis in grafted hearts by 50%. The arterial luminal area in grafts of the treated group was 3-fold larger than in control animals. LDE-paclitaxel treatment resulted in a 7-fold reduction of macrophage infiltration. In grafted hearts LDE-paclitaxel treatment reduced the width of the intimal layer and inhibited the destruction of the medial layer. No toxicity was observed in rabbits receiving LDE-paclitaxel treatment. Conclusions: LDE-paclitaxel improved posttransplantation injury to the grafted heart. The novel therapeutic approach for heart transplantation management validated here is thus a promising strategy to be explored in future clinical studies. (J Thorac Cardiovasc Surg 2011;141:1522-8)