The Journal of Heart and Lung Transplantation

Effects of the 2006 U.S. thoracic organ allocation change: Analysis of local impact on organ procurement and heart transplantation

2009-09-28

Background: The United Network for Organ Sharing (UNOS) implemented a thoracic organ allocation policy change (APC) in July 2006 that aimed to reduce death on the waiting list by expanding regional organ sharing. As such, organs would be allocated to the sickest recipients with highest listing status across the region. Our aim was to determine the impact of the new policy on the procurement and transplant process within our program.Methods: We analyzed data supplied by UNOS as the contractor for the Organ Procurement and Transplantation Network and from the local organ procurement organization for 2 years before and 2 years after implementation of the APC.Results: The APC resulted in an increase in the proportion of Status 1A patients transplanted (24% to 43%, p = 0.015) and a decrease in the proportion of Status 2 patients transplanted (56% to 24%, p = 0.001). Significant increases were observed in mean graft ischemic time (196 minutes to 223 minutes, p = 0.022), number of patients transplanted with ventricular assist devices (17% to 31%, p = 0.036), and procurement costs. There was no significant difference in waiting-list mortality (6% to 5%, p = 0.75) and short-term post-transplant survival.Conclusions: The 2006 change in UNOS organ allocation policy resulted in an increase in Status 1A transplants, graft ischemic time and procurement costs, and a decrease in Status 2 transplants, but no effect on mortality on the waiting list within our center. To assess the full effect of the APC on outcomes, the long-term impact of the increased graft ischemic time on survival should be quantified.

Factors indicative of long-term survival after lung transplantation: A review of 836 10-year survivors

2009-11-23

Introduction: Despite 20 years of lung transplantation (LTx), factors influencing long-term survival remain largely unknown. The United Network for Organ Sharing (UNOS) data set provides an opportunity to examine long-term LTx survivors.Methods: We conducted a case-control study embedded within the prospectively collected UNOS LTx cohort to identify 836 adults from 1987 to 1997 who survived ≥10 years after first LTx. LTx patients within the same era and surviving 1 to 5 years served as controls. Multivariable logistic regression with incorporation of spline terms evaluated the odds of being a 10-year survivor. Two separate models were constructed. Model A incorporated pre-operative, operative, and donor-specific factors. Model B incorporated the factors used in Model A with post-operative covariates. Additional outcomes evaluated included hospitalizations for infection, rejection, and bronchiolitis obliterans.Results: Of 4,818 LTx patients from 1987 to 1997, 836 (17.3%) survived ≥10 years with a mean follow-up of 148.8 ± 21.6 months. Mean follow-up for 1,657 controls was 34.0 ± 13.9 months. The distribution of 10-year survivors by disease was cystic fibrosis, 170 (20%); chronic obstructive pulmonary disease, 254 (30%); and idiopathic pulmonary fibrosis, 92 (11%). On multivariable logistic regression, significant factors influencing 10-year survival included age ≤35 years (odds ratio [OR] 1.07, 95% confidence interval [CI], 1.03–1.11; p = 0.01), bilateral LTx (OR. 1.71; 95% CI, 1.25–2.34; p = 0.001), and hospitalizations for infections (OR, 1.40; 95% CI, 1.27–1.54; p < 0.001) and for rejection (OR, 0.55; 95% CI, 0.48–0.65; p < 0.001).Conclusions: Examination of a cohort of long-term LTx survivors in the UNOS data set indicates that bilateral LTx and fewer hospitalizations for rejection may portend improved long-term survival after LTx.

Social isolation and depression predict 12-month outcomes in the “waiting for a new heart study”

2009-10-05

Background: Identification of modifiable psychosocial characteristics related to survival of heart transplant (HTx) candidates is needed to prevent clinical deterioration and improve prognosis.Methods: A multi-site, prospective study was conducted with 318 HTx candidates (18% female, 82% male; 53 ± 11 years of age) newly listed at 17 hospitals in Germany and Austria. Baseline demographic and psychosocial characteristics were assessed by questionnaires. Indicators of disease severity (Heart Failure Survival Score, creatinine, cardiac index) and 12-month outcomes (death, high-urgency HTx, elective HTx, de-listing due to deterioration or improvement) were provided by Eurotransplant.Results: By 12 months, 33 patients died, 83 received an urgent HTx, 30 underwent an elective HTx, and 9 were de-listed due to clinical deterioration and 17 due to improvement. All measures of disease severity predicted outcomes. Controlling for disease severity, the number of social contacts contributed significantly to outcomes, favoring those who improved. Comparing socially isolated patients (<4 social contacts/month) who also had depression scores in the clinical range (high psychosocial risk group; n = 37) to those with >10 social contacts/month without depression (low psychosocial risk group; n = 47) revealed significant differences in the distribution of outcome frequencies (chi-square = 11.2, df = 4, p < 0.04). The high psychosocial risk group was more likely to have died/deteriorated and less likely to have improved than the low psychosocial risk group.Conclusions: Regardless of disease severity, socially isolated HTx candidates who are also depressed may be at increased risk for clinical deterioration and mortality, indicating a need for psychosocial intervention.

The change in heart allocation policy in the United States: Is it working as designed?

J. David Vega — 2009-12-25

See companion article on page 235.

Role of psychological factors in the clinical course of heart transplant patients

Willem J. Kop — 2009-12-14

See companion article on page 247.

Body mass, chronic heart failure, surgery and survival

Andrew L. Clark, Stefan D. Anker — 2009-10-19

Cardiac cachexia, associated with excessive activation of the sympathetic nervous system together with immune activation, is an important prognostic indicator in heart failure. Anecdotally, the prevalence of cardiac cachexia appears to be falling, perhaps due to the increased use of beta-blockers. However, chronic heart failure is so common that many patients continue to lose weight and continue to deteriorate to a point where transplantation or mechanical support is considered. The origin of cachexia remains elusive and further research is needed to explore the relation between weight, sympathetic activation, and the response to cardiac surgery or transplantation.

Olfactory performance before and after lung transplantation: Quantitative assessment and impact on quality of life

2009-09-28

Background: Although olfactory function significantly impacts quality of life (QoL) and factors that potentially interfere with the sense of smell are numerous in solid-organ recipients, no respective data exist for this population. In this study we investigate the olfactory function, QoL, and the accuracy of subjectively perceived olfactory dysfunction.Methods: Olfactory performance was assessed with the aid of a validated test battery (Sniffin' Sticks) in 70 randomly selected lung transplant recipients and 22 patients on the lung transplant waiting list. In addition to assess QoL, the Questions on Life Satisfaction Module (FLZM) and the Hospital Anxiety Depression Scale (HADS) were used.Results: Waiting list patients and lung transplant recipients did not show differences in terms of demographic data and olfactory performance. Compared with a normative population, patients <55 years of age had a significantly lower olfactory performance both before and after lung transplantation. Scores for general life satisfaction, health life satisfaction, and depression were significantly better in lung transplant recipients. In the multivariate analysis, better olfactory performance was significantly associated with better QoL before and after lung transplantation. Self-estimation of olfactory performance had a sensitivity of 36% and a specificity of 78%, respectively, to detect hyposmia/anosmia in our population.Conclusions: Although lung transplantation does not seem to have an impact on olfactory performance, sense of smell is significantly below the average in lung transplant recipients and patients on the waiting list. In both groups, olfactory performance is significantly associated with QoL. Furthermore, self-estimation of olfactory function shows inadequately low sensitivity and specificity.

Tachyarrhythmias after pediatric heart transplantation

Martin J. LaPage, Edward K. Rhee, Charles E. Canter — 2009-09-28

Background: Tachyarrhythmias in pediatric post–heart transplant patients are not well defined. In this study we sought to further characterize these arrhythmias in terms of presentation, course, and outcome.Methods: This investigation was a retrospective review of heart transplant recipients at St. Louis Children's Hospital during the period of 1991 to 2006. Patients were excluded if they were >18 years at transplantation or if follow-up information was unavailable. Patients with tachyarrhythmias beyond the first 2 weeks post-transplant were identified.Results: Twenty-eight tachyarrhythmias occurred in 25 of 237 heart transplant recipients. Freedom from arrhythmia was 92% at 1-year post-transplant and 86% at 15 years post-transplant. Intra-atrial reentry tachycardia (12 patients) and ectopic atrial tachycardia (10 patients) were the most common arrhythmias. Rejection was found in 3 (12%) and previously unrecognized coronary disease was found in another 2 (8%) at the time of presentation with arrhythmia. Fifteen of 25 (60%) were asymptomatic at presentation, but 4 of 25 (16%) presented with heart failure, including 3 without evidence of rejection. No risk factors for developing arrhythmia were identified. Twenty-one arrhythmias resolved with brief pharmacologic or no therapy. Only 3 had a recurrence after the initial arrhythmia. Five patients underwent catheter ablation.Conclusions: Our experience suggests that the presence of tachyarrhythmias after pediatric heart transplantation is not rare and usually not associated with rejection. Pediatric heart transplant recipients have a higher incidence of ectopic atrial tachycardia (EAT) than their adult counterparts. Most tachyarrhythmias resolve after a relatively brief period of medical treatment and recurrence is uncommon.

Quality of life and functional status in patients surviving 12 months after left ventricular assist device implantation

2009-10-19

Background: As left ventricular assist device (LVAD) support duration increases, quality of life (QoL) becomes a concern. We reviewed the QoL in patients on LVAD support for ≥1 year.Methods: We retrospectively reviewed our prospective database for patients supported ≥1 year by HeartMate pulsatile- (HM1) or continuous-flow (HM2) LVADs from 2000 to 2009. Transplant or death before 1 year merited exclusion. Metabolic equivalents of tasks (METs), the Minnesota Living with Heart Failure Questionnaire (MLHFQ), the 6-minute walk distance (6MWD), and New York Heart Association (NYHA) class were reviewed. Complications and re-admissions were assessed.Results: Thirty patients were supported for ≥1 year (7 HM1s, 23 HM2s). Mean support duration was 594 ± 173 days. Mean QoL metrics/functional status indicators at 12 months were: 6MWD, 393 ± 290 m; MET tolerance, 3.3 ± 1; MLHFQ, 35 ± 31; and NYHA, 1.4 ± 0.6. Mean re-admissions/year was 2.9 ± 2, with a duration of 13.8 ± 21 days. Three patients were never re-admitted. Mean out-of-hospital time was 471 ± 172 days (87.3% of days). Infectious complications led to 43% of re-admissions and occurred in the: drive-line (47%) at 442 ± 236 days; blood (37%) at 472 ± 257 days; and LVAD pocket (20%) at 550 ± 202 days. Twenty-three patients (77%) required additional operations (1.7 ± 1.8/year). The most common indication was drive-line infection, but ranged from ischemic bowel to defibrillator exchange. Eight required LVAD exchanges for mechanical (n = 4), electrical (n = 3), and thrombotic (n = 1) issues.Conclusions: Although LVAD support is not without complications, patients spend the majority of time outside the hospital enjoying a good quality of life.

Infections in heart transplant recipients in Brazil: The challenge of Chagas' disease

2009-09-28

Background: Despite the high incidence of infections after heart transplantation, there is limited information about its epidemiology in patients from countries where Chagas' disease is endemic.Methods: We analyzed the occurrence of infections in 126 patients aged older than 18 years who underwent transplantation from 1986 through 2007 at a Brazilian University Hospital and who survived at least 48 hours.Results: Heart failure diagnoses before transplantation were idiopathic dilated cardiomyopathy (38.6%), Chagas' disease (34.9%), coronary artery disease (19.8%), and others (6.3%). The respiratory tract was the most common site of infections (40.9%), followed by surgical wound site (18.1%). Trypanosoma cruzi reactivations occurred in 38.8% of Chagas' disease patients: 47.0% had myocarditis, 23.5% had skin lesions, and 29.4% had both. New-onset ventricular dysfunction was observed in 47.0%, with complete response after specific treatment, and 41.0% were asymptomatic cases, diagnosed by routine endomyocardial biopsies. No patient died from such events. No differences in survival were found after 5 years of follow-up between recipients with and without Chagas' disease (p = 0.231).Conclusions: In a heart transplant population from a developing country, infectious complications occurred at a high rate. Tropical illnesses were uncommon, except for the high rate of Chagas' disease reactivations. Despite that, the overall outcome of these patients was similar to that of recipients with other cardiomyopathies.

Interactions among donor characteristics influence post-transplant survival: A multi-institutional analysis

2009-10-05

Background: Quantification of donor-associated risk in a specific heart transplant recipient is often difficult. Our aim was to identify donor characteristics that affect survival in the contemporary era.Methods: Between 1990 and 2006, 7,322 patients from 32 centers in the Cardiac Transplant Research Database underwent heart transplantation. Multivariable logistic regression analysis was used to identify donor-associated risk predictors and important interactions between these donor characteristics. Recipient survival was examined using parametric regression analysis in the hazard function domain.Results: Donor characteristics associated with post-transplant death included donor age, donor requirement for vasoactive therapy, positive donor cytomegalovirus serology, longer graft ischemic time, and lower donor body weight. Several interactions between individual donor characteristics affected survival. In male donors, history of hypertension and diabetes mellitus were risk factors for death (p = 0.006, p = 0.04, respectively), but not in female donors (p = 0.5, p = 0.8, respectively). There was a significant interaction between donor age and recipient-donor weight difference. If the donor was of younger age, increasing recipient-donor weight difference did not result in increased death. With increasing donor age, weight difference did result in compromised survival (p < 0.0003). Donor and recipient gender further modified the degree of risk: risk was higher in female donors and when recipients were male (p < 0.0003).Conclusions: This multi-institutional analysis identified important interactions between donor characteristics that affect post-transplant survival that explain some of the discrepancies in the results of previous studies. The results are likely to aid in efficient organ allocation.

Low incidence of severe respiratory syncytial virus infections in lung transplant recipients despite the absence of specific therapy

2009-10-19

Background: Respiratory syncytial virus (RSV) infections in lung transplant recipients (LTRs) have been associated with significant morbidity and mortality. Immunoglobulins, ribavirin, and palivizumab are suggested treatments for both pre-emptive and therapeutic purposes. However, in the absence of randomized, placebo-controlled trials, efficacy is controversial and there is toxicity as well as cost concerns.Methods: We retrospectively reviewed cases of lower respiratory tract RSV infections in adult LTRs. Diagnosis was based on clinical history, combined with a positive polymerase chain reaction (PCR) and/or viral cultures of bronchoalveolar lavage (BAL) specimens.Results: Ten symptomatic patients were identified (7 men and 3 women, age range 28 to 64 years). All were hospitalized for community-acquired respiratory tract infections. Two patients had a concomitant acute Grade A3 graft rejection, and 1 patient had a concomitant bacterial pneumonia. Eight patients did not receive a specific anti-RSV treatment because of clinical stability and/or improvement at the time of RSV diagnosis. Only 2 patients (1 with Grade A3 allograft rejection and 1 requiring mechanical ventilation) received ribavirin and palivizumab. All patients recovered without complications and with no persistent RSV infection. However, bronchiolitis obliterans (BOS) staging worsened in 6 patients during the mean follow-up of 45 months.Conclusions: Our data suggest that mild RSV infections in LTRs might evolve favorably in the absence of specific anti-viral therapy. However, this observation needs confirmation in a large clinical trial specifically investigating the development of BOS in untreated vs treated patients.

Changing trends in infectious disease in heart transplantation

2009-10-26

Background: During the past 25 years, advances in immunosuppression and the use of selective anti-microbial prophylaxis have progressively reduced the risk of infection after heart transplantation. This study presents a historical perspective of the changing trends of infectious disease after heart transplantation.Methods: Infectious complications in 4 representative eras of immunosuppression and anti-microbial prophylaxis were analyzed: (1) 38 in the pre-cyclosporine era (1978–1980), (2) 72 in the early cyclosporine era (1982–1984), where maintenance immunosuppression included high-dose cyclosporine and corticosteroid therapy; (3) 395 in the cyclosporine era (1988–1997), where maintenance immunosuppression included cyclosporine, azathioprine, and lower corticosteroid doses; and (4) 167 in the more recent era (2002–2005), where maintenance immunosuppression included cyclosporine and mycophenolate mofetil.Results: The overall incidence of infections decreased in the 4 cohorts from 3.35 episodes/patient to 2.03, 1.35, and 0.60 in the more recent cohorts (p < 0.001). Gram-positive bacteria are emerging as the predominant cause of bacterial infections (28.6%, 31.4%, 51.0%, 67.6%, p = 0.001). Cytomegalovirus infections have significantly decreased in incidence and occur later after transplantation (88 ± 77 days, pre-cyclosporine era; 304 ± 238 days, recent cohort; p < 0.001). Fungal infections also decreased, from an incidence of 0.29/patient in the pre-cyclosporine era to 0.08 in the most recent era. A major decrease in Pneumocystis jiroveci and Nocardia infections has also occurred.Conclusions: The overall incidence and mortality associated with infections continues to decrease in heart transplantation and coincides with advances in immunosuppression, the use of selective anti-microbial prophylaxis, and more effective treatment regimens.

Long-term outcome after bare-metal or drug-eluting stenting for allograft coronary artery disease

2009-10-19

Background: Percutaneous coronary intervention (PCI) with bare-metal stenting (BMS) has been reported to be associated with high rates of target-lesion revascularization (TLR) in heart transplant recipients. We aimed to assess the outcome of successful PCI with BMS or drug-eluting stenting (DES) in such patients.Methods: Ninety-four consecutive heart transplant recipients with successful PCI of de novo lesions with BMS (n = 53) or DES (n = 60) were prospectively followed-up for 3.7 ± 2.5 years after PCI. An angiographic lesion-based analysis at 12-month follow-up and a long-term, patient-based survival analysis were performed.Results: The lesion-based analysis within 12 months after PCI showed a reduction of TLR rates with the use of DES (6.6% vs 26.4%, p < 0.01). DES were associated with better preservation of left ventricular function at this time-point. The patient-based, long-term analysis showed sustained local benefit of DES (hazard ratio 4.5 [1.4 to 14.5] for BMS vs DES), but no effect on mortality, remote-site PCI and total revascularization rates. Anti-hypertensive (hazard ratio 0.2 [0.1 to 0.5]) and aspirin (hazard ratio 0.3 [0.1 to 0.8]) therapy, and left ventricular ejection fraction (0.96 [0.94 to 0.98] per percent) were the only correlates of long-term mortality.Conclusions: Compared with BMS, DES are associated with a sustained reduction in rates of TLR and could safely be used in heart transplant recipients with coronary artery disease. Despite excellent local effects, DES use failed to reduce mortality. Anti-hypertensive and anti-platelet therapy, and left ventricular function preservation, may be considered as aims of treatment to improve long-term survival in such patients.

Cardiac hormones ANF and BNP modulate proliferation in the unidirectional mixed lymphocyte reaction

2009-09-28

Background: Previous investigations have shown that the plasma levels of the cardiac hormone brain natriuretic peptide (BNP) increase during acute cardiac allograft rejection as diagnosed by endomyocardial biopsy. Successful immunosuppressant treatment decreased plasma BNP levels, suggesting a role for BNP in transplantation immunity. We tested a possible immunomodulatory effect of the natriuretic peptides (NPs) BNP, atrial natriuretic factor (ANF), and C-type NP (CNP) using the unidirectional mixed lymphocyte reaction (MLR).Methods: Lymphocytes were isolated from the lymph nodes of Brown Norway (BN) and Lewis (L) rats. BN lymphocytes were gamma-irradiated to inhibit DNA synthesis. Lymphocytes at 2.5 × 106 cell/ml were mixed (at an L:BN ratio of 4:1) and incubated. On Days 2 and 3, ANF (10−6 to 10−11 mol/liter), BNP (10−5 to 10−11 mol/liter), or CNP (10−6 to 10−12 mol/liter) were added. Cell proliferation was measured on Day 4.Results: Reverse transcript–polymerase chain reaction (RT-PCR) analysis of BN and L lymphocytes detected NP receptor (NPR) mRNA amplicons of the expected size. MLR induced an increase in relative receptor abundance as follows: NPRA > NPRB > NPRC. ANF and BNP significantly inhibited up to ∼50% lymphocyte proliferation in a dose-dependent manner in the range of 10−11 to 10−6 mol/liter, whereas CNP significantly decreased lymphocyte proliferation only modestly (∼20%) at 10−8 mol/liter and at 10−6 mol/liter.Conclusions: Both ANF and BNP have immunomodulatory functions, although the response to cardiac rejection observed clinically involves increases in plasma levels of BNP only. This is likely related to BNP gene promoter sequences previously reported to be responsive to specific cytokines and related substances. The modulation of the MLR by NP suggests a possible clinical use of these peptides in transplantation immunity.

Exogenous surfactant in ischemia/reperfusion: Effects on endogenous surfactant pools

2009-09-28

Background: Pre-ischemic surfactant treatment attenuates ischemia/reperfusion (I/R) injury. In this study we investigate whether exogenous surfactant acts by influencing endogenous intra-alveolar and intracellular surfactant pools and subtype composition.Methods: Rat lungs from control with (C + S) or without (C − S) surfactant treatment and I/R with (I/R + S) or without (I/R − S) surfactant treatment were analyzed. In I/R groups, lungs underwent ischemic storage for 4 hours at 4°C and reperfusion for 60 minutes. The ultrastructure of intra-alveolar and intracellular surfactant forms fixed in their natural localization and microorganization was investigated by light- and electron-microscopic stereology.Results: Only slight differences in alveolar epithelial Type II cell number or volume and lamellar body parameters were observed. Intra-alveolar surfactant volume was significantly enhanced in C + S and I/R + S. I/R increased inactivated surfactant forms (unilamellar vesicles) in untreated [mean (SD): C − S: 26.0% (8.0%) vs I/R − S: 64.8% (5.5%); p < 0.01], but not in surfactant-treated rats [I/R + S: 23.5% (11.5%); p < 0.01 vs I/R − S]. The increase in unilamellar vesicles was closely correlated with intra-alveolar edema and decreased perfusate oxygenation.Conclusions: Attenuation of I/R injury by pre-ischemic exogenous surfactant treatment is mainly based on stabilizing and increasing the active endogenous intra-alveolar surfactant pool.

Intensity of transplant chronic rejection correlates with level of graft-infiltrating regulatory cells

Natalya V. Semiletova, Xiu-Da Shen, Boris Baibakov, Arthur Andakyan — 2010-01-18

Background: The understanding of chronic rejection (transplant vascular sclerosis, or TVS) mechanisms is a major goal of transplantation. In this study we tested a cardiac transplant model for TVS development in connection with emerging T-regulatory cells (T-regs). We used 40-mer peptides derived from the donor MHC Class I α1 helix of the α1-domain to make recipients tolerant.Methods: ACI recipients were transplanted with either RT1.Au (WF), RT1.Al (LEW), RT1.Ac (PVG), or RT1.Ab (BUF) cardiac grafts. The grafts were analyzed 120 days later for TVS and development of T-regs.Results: Donor MHC peptides were injected through the portal vein (0.1 mg) into ACI recipients of WF hearts in addition to sub-therapeutic cyclosporine (CsA, 10 mg/kg for 3 days post-operatively). Peptide treatment specifically prolonged graft survival for >100 days (n = 31). ACI recipients of WF or LEW hearts treated with PVG peptides promptly rejected the transplanted grafts (15 ± 4 and 20 ± 1 days, respectively). Presence of T-regs in tolerant recipients was confirmed by the adoptive transfer of T cells into a new cohort of syngeneic recipients (mean survival time [MST] >100 days, n = 3). CD4+ and FoxP3+ cells were detected in 70% of the chronically rejected grafts vs 38% (CD4) and 22% (FoxP3) in the well-preserved transplants. IgG and IgM deposits were found in only half of surviving cardiac grafts with a high level of TVS. Blood vessels in grafts with attenuated TVS were 80% IgG and IgM positive. Interleukin (IL)-4 and IL-2 were markedly down-regulated in the hearts with high TVS compared with well-preserved grafts. Long-term-surviving hearts demonstrated increased IL-10 expression. Interferon-gamma (IFN-γ) was more evident in the grafts with a high TVS.Conclusions: Donor MHC Class I peptides can specifically prolong transplant survival and generate T-regs. The level of intragraft T-regs correlates with severity of TVS and IL-2/IL-4 down-regulation.

Cytomegalovirus β2.7 RNA transcript protects endothelial cells against apoptosis during ischemia/reperfusion injury

2009-12-25

Background: Ischemia/reperfusion (I/R) injury causes endothelial cell (EC) dysfunction and can precipitate apoptosis. Complex I of the mitochondrial respiratory chain is a target for I/R injury. The β2.7 RNA transcript encoded by human cytomegalovirus (CMV) has been shown to stabilize Complex I by direct physical interaction. In this study, we investigated whether stabilizing Complex I in EC in an in vitro model of ischemia could prevent apoptosis.Methods: Lentiviral vectors expressing a full-length β2.7 RNA were generated from a human immunodeficiency virus-1 (HIV-1) construct, in which the viral promoter had been inactivated and virtually all the viral accessory proteins deleted in order to maximize safety. β2.7 gene expression in transduced endothelial cells was examined by reverse transcript–polymerase chain reaction (RT-PCR). EC were prepared from rat aorta. An in vitro hypoxia/reperfusion (H/R) and I/R injury models were set up and apoptosis was assessed using caspase-3 activity. Reactive oxygen species (ROS) production in the endothelial cells was assessed by the capacity to oxidize non-fluorescent dihydrorhodamine-123 (DHR-123) to fluorescent rhodamine-123 and measured by flow cytometry.Results: H/R and I/R injury induced formation of ROS and EC apoptosis. Overexpression of the viral β2.7 RNA, which stabilizes Complex I, reduced ROS production and inhibited EC apoptosis.Conclusions: β2.7 RNA is a novel effector molecule that can protect rat aortic endothelial cells from I/R injury causing apoptosis. As a non-coding RNA, β2.7 RNA will not induce an immune response in the recipient. We have shown that overexpression of β2.7 RNA can protect RAEC from H/R- or I/R-mediated apoptosis by reduction of ROS formation.

Activation of JAK-STAT and nitric oxide signaling as a mechanism for donor heart dysfunction

2009-12-18

Background: Donor heart dysfunction (DHD) precluding procurement for transplantation occurs in up to 25% of brain-dead (BD) donors. The molecular mechanisms of DHD remain unclear. We investigated the potential role of myocardial interleukin (IL)-6 signaling through the JAK2-STAT3 pathway, which can lead to the generation of nitric oxide (NO) and decreased cardiac myocyte contractility.Methods: Hearts were procured using standard technique with University of Wisconsin (UW) solution from 14 donors with a left ventricular (LV) ejection fraction of <35% (DHD). Ten hearts with normal function (NF) after BD served as controls. LV IL-6 was quantitated by enzyme-linked immunoassay (ELISA) and JAK2-STAT3 signaling was assessed by expression of phosphorylated STAT3. Inducible NO synthase (iNOS) and caspase-3 were measured by activity assays.Results: Myocardial IL-6 expression was 8-fold greater in the DHD group vs NF controls. Phosphorylated STAT3 expression was 5-fold higher in DHD than in NF, indicating increased JAK2-STAT3 signaling. LV activity of iNOS was 2.5-fold greater in DHD than in NF. LV expression of the pro-apoptotic gene Bnip3 and caspase-3 activity were 3-fold greater in the DHD group than in the NF group.Conclusions: Myocardial IL-6 expression is significantly higher in the setting of DHD compared with hearts procured with normal function. This may lead to increased JAK2-STAT3 signaling and upregulation of iNOS, which has been shown to decrease cardiac myocyte contractility. Increased NO production may also lead to increased apoptosis through upregulation of Bnip3 gene expression. Increased iNOS signaling may be an important mechanism of DHD and represents a novel therapeutic target to improve cardiac function after BD.

Upregulation of the apoptosis-related inflammasome in cardiac allograft rejection

2009-12-25

Background: Inflammation is a major factor in cardiac allograft rejection. Accumulating reports have demonstrated an important role of the inflammation-induced adaptor complex, called the inflammasome, in the field of immunology. The apoptosis-associated, speck-like protein containing a caspase recruitment domain (ASC) is an adaptor protein that forms the inflammasome and regulates caspase-1–dependent generation of inflammatory cytokines. The aim of the present study was to determine how ASC is associated with the development of cardiac allograft rejection.Methods: We used a murine heterotopic cardiac transplantation model between fully incompatible strains. Donor hearts (n = 9 for each time-point) were harvested for examination on Days 1, 4, 7 and 12 after transplantation. Histopathologic findings of cardiac grafts were evaluated using rejection scores. The expression of ASC and inflammatory cytokines in cardiac grafts were analyzed by immunohistochemistry and real-time reverse transcript–polymerase chain reaction (RT-PCR).Results: Expression levels of both ASC and IL-1β were higher in the myocardial interstitium of allografts in parallel to the progress of cardiac rejection during the acute phase after transplantation. In contrast, expression of ASC and IL-1β remained low in isografts. Cardiac allografts treated with tacrolimus showed decreased expression of both ASC and IL-1β similar to that seen in isografts. Real-time RT-PCR demonstrated similar alteration of ASC and IL-1β mRNA expression in cardiac grafts during the acute phase.Conclusions: Our results demonstrate a novel finding showing that upregulation of ASC is closely associated with the inflammation induced in cardiac grafts after transplantation in the mouse.

Transbronchial human interleukin-10 gene transfer reduces acute inflammation associated with allograft rejection and intragraft interleukin-2 and tumor necrosis factor-α gene expression in a rat model of lung transplantation

2010-03-01

Background: The ability to express genes with potential immunoregulatory capacity could reduce allograft rejection (AR). This study examined the effect of ex vivo lipid-mediated transbronchial human interleukin-10 (hIL-10) gene transfer on AR and the intragraft cytokine profile in a rat model of lung transplantation.Methods: Left single lung transplants were performed between a highly histoincompatible combination of inbred rats. The donor left lung was extracted and intrabronchially instilled with a plasmid encoding hIL-10 (IL-10 group) or Escherichia coli β-galactosidase (control group), mixed with a cationic lipid. At 3 and 6 days after transplantation, the degree of AR was graded histologically (stage 1–4) and several pathologic categories of inflammation were scored on a scale of 0 to 4 according to the percentage of involvement. Intragraft cytokine profile was examined by real-time reverse transcription polymerase chain reaction.Results: The stage of AR (3.1 ± 0.4 vs 3.8 ± 0.4) and the pathologic scores for edema (2.3 ± 0.8 vs 3.2 ± 0.4), intraalveolar hemorrhage (0.3 ± 0.5 vs 2.2 ± 0.8), and necrosis (0.3 ± 0.5 vs 1.2 ± 0.4) in the IL-10 group were significantly decreased compared with the control group at Day 6. IL-2 and tumor necrosis factor-α messenger RNA expression levels on Day 3 were significantly decreased in the IL-10 group.Conclusions: Ex vivo lipid-mediated transbronchial hIL-10 gene transfer attenuated acute inflammation associated with AR, which was related to decreased levels of proinflammatory cytokine gene expression in a rat model of lung transplantation.

Excision of native heart and relocation of a grown heterotopic donor heart to the orthotopic position 14 years after transplantation

Asghar Khaghani, Arup Ghosh, Mumin Noor, Nicholas Banner — 2009-12-25

Here we report the treatment of native heart complications (aortic regurgitation, ventricular fibrillation and heart failure) following a heterotopic heart transplant by excision of native heart and relocation the heterotopic heart in the orthotopic position. The patient was a 24 year old woman who had received a heterotopic transplant at the age of 9 years from a 9 year old donor. The donor heart had grown sufficiently to allow it to support her adult circulation.

Pericardial constriction after cardiac transplantation

Ramesh Bansal, Leandro Perez, Anees Razzouk, Nan Wang, Leonard Bailey — 2009-10-05

In this study we present a series of 5 cases that developed constrictive pericarditis after orthotopic heart transplantation. All 5 patients had pericardial effusion of non-infectious etiology in the early post-transplant period. They subsequently presented with heart failure unresponsive to standard medical management. The diagnosis was made by comprehensive echo-Doppler studies. Findings were confirmed at surgical inspection and complete pericardiectomy led to improvement in hemodynamics in 4 patients. One patient had relief from constriction but died of non-cardiac complications. One patient with constriction has been re-listed for transplantation due to intermittent heart block and associated cardiac allograft vasculopathy. Early diagnosis of pericardial constriction after orthotopic heart transplantation requires a high index of clinical suspicion and optimal use of Doppler echocardiography. Early diagnosis and timely surgical pericardiectomy may correct this condition entirely and result in satisfactory long-term results.

Mediastinal radiation and adverse outcomes after heart transplantation

2009-10-05

Orthotopic heart transplantation (OHT) may represent the only treatment option for patients with end-stage cardiovascular disease due to mediastinal radiation therapy (MRT). The primary aim of this study was to evaluate the safety and efficacy of OHT in this patient population. We conducted a retrospective, single-center cohort study of patients with MRT-associated cardiovascular disease who underwent OHT between January 1987 and September 2008. Nine patients (3 men), aged 46 ± 11 years at the time of their OHT, were identified. Time from MRT to OHT was 26 ± 11 years. Lymphoma was the indication for MRT in all patients. Five patients had non-ischemic dilated cardiomyopathy, 2 had ischemic cardiomyopathy and 2 had constrictive pericarditis. Three patients expired in the peri-operative period, whereas another patient died 3 years post-transplant from lung carcinoma. Two additional patients developed a secondary malignancy post-transplant. Five patients are still alive at a mean follow-up of 10 ± 8 years. Early survival rate is poor in patients who undergo OHT for MRT-associated end-stage cardiovascular disease. In addition, long-term follow-up shows an elevated incidence of malignancies. Our results raise concern about the safety and efficacy of performing OHT in patients with MRT-associated cardiovascular disease.

Alteration in systemic vascular resistance and cardiac output during acute cellular rejection and recovery in heart transplant recipients

2009-10-30

Coronary vascular reserve is impaired during acute cellular rejection of the orthotopically transplanted heart, but changes in the peripheral vasculature during rejection have not been well described. To investigate whether peripheral vascular compensatory mechanisms are preserved after orthotopic heart transplantation (OHT), we longitudinally observed systemic vascular resistance (SVR) and cardiac output (CO) during acute cellular rejection. CO decreased during high-grade acute cellular rejection, and maintenance of mean arterial pressure was achieved by increases in SVR, and these changes did not return to baseline until several months after histologic resolution of rejection.

B-Type natriuretic peptide levels late after transplant predict graft survival in pediatric heart transplant patients

2009-09-28

Elevations in natriuretic peptide levels are associated with acute rejection (AR) in pediatric heart transplant patients. The test characteristics for B-type natriuretic peptide (BNP) levels in pediatric patients demonstrate a high sensitivity and negative predictive value for AR, but only a modest specificity and poor positive predictive value. Thus, there are patients with elevated BNP levels in the absence of AR with seemingly normally functioning grafts. The long-term outcome of these patients is not known. Therefore, the purpose of this study was to test the hypothesis that elevated or rising BNP levels at ≥1 year post-transplant would be associated with graft loss in this population.

High-density lipoprotein cholesterol levels and risk of death in chronic heart failure patients referred for heart transplant evaluation

Maria Karolina Lizak, Michael Zakliczynski, Anna Jarosz, Marian Zembala — 2009-10-30

In a recent issue of the Journal of Heart and Lung Transplantation, Mehra et al reported adverse prognosis of clinical worsening or death in patients with advanced heart failure and lower high-density lipoprotein (HDL) cholesterol levels (<33 mg/dl [0.85 mmol/l]) independent of chronic heart failure (CHF) etiology. We would like to share our observations concerning HDL levels and death from a prospective follow-up of cohort comprising 276 CHF clinic patients (86% men, 100% Caucasian; age, 50.5 ± 9 years) with a mean observation time of 3.24 ± 2.21 years (range, 1–5.5 years).

2010-03-01

The Journal of Heart and Lung Transplantation

Effects of the 2006 U.S. thoracic organ allocation change: Analysis of local impact on organ procurement and heart transplantation

Factors indicative of long-term survival after lung transplantation: A review of 836 10-year survivors

Social isolation and depression predict 12-month outcomes in the “waiting for a new heart study”

The change in heart allocation policy in the United States: Is it working as designed?

Role of psychological factors in the clinical course of heart transplant patients

Body mass, chronic heart failure, surgery and survival

Olfactory performance before and after lung transplantation: Quantitative assessment and impact on quality of life

Tachyarrhythmias after pediatric heart transplantation

Quality of life and functional status in patients surviving 12 months after left ventricular assist device implantation

Infections in heart transplant recipients in Brazil: The challenge of Chagas' disease

Interactions among donor characteristics influence post-transplant survival: A multi-institutional analysis

Low incidence of severe respiratory syncytial virus infections in lung transplant recipients despite the absence of specific therapy

Changing trends in infectious disease in heart transplantation

Long-term outcome after bare-metal or drug-eluting stenting for allograft coronary artery disease

Cardiac hormones ANF and BNP modulate proliferation in the unidirectional mixed lymphocyte reaction

Exogenous surfactant in ischemia/reperfusion: Effects on endogenous surfactant pools

Intensity of transplant chronic rejection correlates with level of graft-infiltrating regulatory cells

Cytomegalovirus β2.7 RNA transcript protects endothelial cells against apoptosis during ischemia/reperfusion injury

Activation of JAK-STAT and nitric oxide signaling as a mechanism for donor heart dysfunction

Upregulation of the apoptosis-related inflammasome in cardiac allograft rejection

Transbronchial human interleukin-10 gene transfer reduces acute inflammation associated with allograft rejection and intragraft interleukin-2 and tumor necrosis factor-α gene expression in a rat model of lung transplantation

Excision of native heart and relocation of a grown heterotopic donor heart to the orthotopic position 14 years after transplantation

Pericardial constriction after cardiac transplantation

Mediastinal radiation and adverse outcomes after heart transplantation

Alteration in systemic vascular resistance and cardiac output during acute cellular rejection and recovery in heart transplant recipients

B-Type natriuretic peptide levels late after transplant predict graft survival in pediatric heart transplant patients

High-density lipoprotein cholesterol levels and risk of death in chronic heart failure patients referred for heart transplant evaluation

Contents