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Background Parenteral prostacyclin analogs that target the prostacyclin pathway have been used to treat pulmonary arterial hypertension (PAH) since the 1990s. Abrupt discontinuation of parenteral prostacyclin analogs can be associated with acute deterioration of PAH. Less is known about temporary interruption of oral therapies that target the prostacyclin pathway, such as selexipag. Methods We evaluated the frequency, duration, reasons, and consequences of temporary selexipag interruptions among PAH patients enrolled in the Prostacyclin (PGI 2 ) Receptor Agonist in Pulmonary Arterial Hypertension (GRIPHON) study. In GRIPHON, patients were randomized to selexipag or placebo and titrated to an individualized highest tolerated dose (200 to 1,600 µg twice daily) over 12 weeks, after which patients entered the maintenance phase. Treatment interruptions were allowed; if the interruption was < 3 days, treatment was restarted at the previous highest tolerated dose; if the interruption was ≥ 3 days, retitration from 200 µg twice daily was required. Descriptive analyses were performed. Results At least 1 treatment interruption occurred in 111 of 574 patients (19.3%) in the selexipag group and in 58 of 582 (10.0%) in the placebo group. Baseline characteristics were similar between patients with and without an interruption. Of the 111 patients in whom selexipag was temporarily interrupted, 94 (85%) were receiving background PAH therapy. Adverse events were the most common reason for selexipag interruption. Selexipag interruptions and reinstitution of treatment were well tolerated. There were no episodes of acute deterioration during treatment interruption. Conclusions Based on observations from GRIPHON, selexipag interruptions can be expected in clinical practice. However, temporarily interrupting selexipag was well tolerated and manageable. [ABSTRACT FROM AUTHOR]

The recent pig heart transplant in a patient at the University of Maryland Medical Center has stimulated renewed interest in the xenotransplantation of organs from genetically engineered pigs. The barriers to the use of pigs as sources of organs have largely been overcome by 2 approaches – (1) the deletion of expression of the three known pig carbohydrate xenoantigens against which humans have preformed antibodies, and (2) the transgenic introduction of human 'protective' proteins, such as complement-regulatory proteins. These gene modifications, coupled with immunosuppressive therapy based on blockade of the CD40/CD154 costimulation pathway, have resulted in survival of baboons with life-supporting pig heart grafts for almost 9 months. The initial clinical success at the University of Maryland reinforces encouraging preclinical results. It suggests that pig hearts are likely to provide an effective bridge to an allotransplant, but their utility for destination therapy remains uncertain. Because of additional complex immunobiological problems, the same approach has been less successful in preclinical lung xenograft transplantation, where survival is still measured in days or weeks. The first formal clinical trials of pig heart transplantation may include patients who do not have access to an allotransplant, those with contraindications for mechanical circulatory support, those in need of retransplantation or with a high level of panel-reactive antibodies. Infants with complex congenital heart disease, should also be considered. [ABSTRACT FROM AUTHOR]

Approaches to risk assessment in pulmonary arterial hypertension (PAH) include the noninvasive French risk assessment approach (number of low-risk criteria based on the European Society of Cardiology and European Respiratory Society guidelines) and Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL) 2.0 risk calculator. The prognostic and predictive value of these methods for morbidity/mortality was evaluated in the predominantly prevalent population of GRIPHON, the largest randomized controlled trial in PAH. GRIPHON randomized 1,156 patients with PAH to selexipag or placebo. Post-hoc analyses were performed on the primary composite end-point of morbidity/mortality by the number of low-risk criteria (World Health Organization functional class I-II; 6-minute walk distance >440 m; N-terminal pro-brain natriuretic peptide <300 ng/liter) and REVEAL 2.0 risk category. Hazard ratios and 95% confidence intervals were calculated using Cox proportional hazard models. Both the number of low-risk criteria and the REVEAL 2.0 risk category were prognostic for morbidity/mortality at baseline and any time-point during the study. Patients with 3 low-risk criteria at baseline had a 94% reduced risk of morbidity/mortality compared to patients with 0 low-risk criteria and were all categorized as low-risk by REVEAL 2.0. The treatment effect of selexipag on morbidity/mortality was consistent irrespective of the number of low-risk criteria or the REVEAL 2.0 risk category at any time-point during the study. Selexipag-treated patients were more likely to increase their number of low-risk criteria from baseline to week 26 than placebo-treated patients (odds ratio 1.69, p = 0.0002); similar results were observed for REVEAL 2.0 risk score. These results support the association between risk profile and long-term outcome and suggest that selexipag treatment may improve risk profile. [ABSTRACT FROM AUTHOR]

In the US, only 23% of lungs offered for transplantation are transplanted. Ex vivo lung perfusion (EVLP) allows for evaluation of additional donor lungs; its adoption has been limited by resources and expertise. Dedicated facilities with a centralized lung evaluation system (CLES) could expand access to EVLP. In this unblinded, nonrandomized, traditional feasibility study, 7 US transplant centers referred lungs declined for standard transplantation to a dedicated EVLP facility, which utilized a CLES. EVLP was remotely monitored by the transplant teams. CLES lungs were matched with contemporaneous conventional static cold-preserved controls at each center. A total of 115 recipients were enrolled, and 66 received allografts from 63 donors after EVLP at the dedicated CLES facility. Forty-nine contemporaneous patients served as controls. Primary graft dysfunction grade 3 at 72 hours (PGD3-72 hours) was higher in the CLES group with 16 (24%) vs 2 (4%) in the control (common RD 95% CI, 0.07-0.32; p = 0.0009). All recipients survived to 30 days and 1-year survival was similar for both groups (92% controls vs 89% CLES; common RD 95% CI, -0.14-0.08; p = 0.58). Total preservation time, hospital and ICU lengths of stay, and time to first extubation were longer in the CLES group. Remote ex vivo perfusion of lung allografts declined for conventional transplantation at a dedicated CLES facility is feasible and resulted in additional transplants. Recipients of allografts assessed with a CLES had a higher rate of PGD3-72 hours, but similar 30-day and 1-year outcomes compared to conventional lung recipients. (NCT02234128) [ABSTRACT FROM AUTHOR]

Background: Interferon-γ, produced by T-helper cells, activates macrophages and increases expression of major histocompatibility complex (MHC) products in acute and chronic rejection. We investigated the role of interferon-γ in murine heterotopic tracheal allografts. Methods: Tracheas from BALB/c mice were heterotopically transplanted to BALB/c (12 isografts: 2 weeks [n = 6] and 4 weeks [n = 6], C57BL/6 (12 allografts: 2 weeks [n = 6] and 4 weeks [n = 6]) and C57BL/6 interferon-γ knockout mice (12 interferon-γ knockout allografts: 2 weeks [n = 4] and 4 weeks [n = 8]). BALB/c interferon-γ knockout tracheas were transplanted to C57BL/6 mice (reverse knockout: 4 weeks [n = 6]) and BALB/c interferon-γ knockout mice (4 weeks [n = 2]). C57BL/6 tracheas were transplanted to Bm12 mice (MHC Class II mismatch allografts: 4 weeks [n = 6]). Conventional histology and immunohistochemistry for CD4, CD8 and CD11b were performed. Results: Minimal (&#60;20%) obliteration was seen at 2 weeks in the allograft groups. No obliteration was seen in the isograft groups. However, all allografts were completely obliterated at 4 weeks. Interferon-γ knockout allograft combinations displayed severe rejection characterized by intense intra- and extraluminal infiltration by CD4-, CD8- and CD11b-labeled cells. The MHC Class II mismatch allograft group showed normal epithelium and mild sub-epithelial infiltration by CD4+ cells at 4 weeks (CD8−, CD11b−). Conclusions: Absence of interferon-γ does not protect the allograft from obliteration. Epithelial destruction by cytotoxic T cells appears to be an important mechanism in the development of obliteration in murine heterotopic tracheal allografts. [Copyright &y& Elsevier]

Pulmonary arterial hypertension (PAH) is a highly morbid disease characterized by elevated pulmonary vascular resistance (PVR) and pathogenic right ventricular remodeling. Endothelial expression of the prometastatic protein NEDD9 is increased in fibrotic PAH arterioles, and NEDD9 inhibition decreases PVR in experimental PAH. We hypothesized that circulating NEDD9 is increased in PAH and informs the clinical profile of patients. Clinical data and plasma samples were analyzed retrospectively for 242 patients from 5 referral centers (2010–2017): PAH (n = 139; female 82%, 58 [48–67] years), non-PAH pulmonary hypertension (PH) (n = 54; female 56%, 63.4 ± 12.2 years), and dyspnea non-PH controls (n = 36; female 75%, 54.2 ± 14.0 years). Compared with controls, NEDD9 was increased in PAH by 1.82-fold (p < 0.0001). Elevated NEDD9 correlated with PVR in idiopathic PAH (ρ = 0.42, p < 0.0001, n = 54), connective tissue disease (CTD)-PAH (ρ = 0.53, p < 0.0001, n = 53), and congenital heart disease–PAH (ρ = 0.68, p < 0.0001, n = 10). In CTD-PAH, NEDD9 correlated with 6-minute walk distance (ρ = −0.35, p = 0.028, n = 39). In contrast to the PAH biomarker N-terminal pro-brain natriuretic peptide (n = 38), NEDD9 correlated inversely with exercise pulmonary artery wedge pressure and more strongly with right ventricular ejection fraction (ρ = −0.41, p = 0.006, n = 45) in a mixed population. The adjusted hazard ratio for lung transplant–free survival was 1.12 (95% confidence interval [CI], 1.02–1.22, p = 0.01) and 1.75 (95% CI, 1.12–2.73, p = 0.01) per 1 ng/ml and 5 ng/ml increase in plasma NEDD9, respectively, by Cox proportional hazard model. In PAH, plasma NEDD9 is increased and associates with key prognostic variables. Prospective studies that include hard end points are warranted to validate NEDD9 as a novel PAH biomarker. [ABSTRACT FROM AUTHOR]

Background: Current lung transplantation guidelines stipulate that the ideal donor is aged younger than 55 years, but several institutions have reported that outcomes using donors aged 55 years and older are comparable with those of younger donors. Methods: We retrospectively reviewed the United Network for Organ Sharing (UNOS) database to identify all adult lung transplants between 2000 and 2010 in the United States. Patients were stratified by donor age 18 to 34 (reference), 35 to 54, 55 to 64, and ≥ 65 years. Primary outcomes included survival at 30 days and at 1, 3, and 5 years and rates of bronchiolitis obliterans syndrome (BOS). Survival was assessed using the Kaplan-Meier method. Risk factors for mortality were identified by multivariable Cox and logistic regression. Results: We identified 10,666 recipients with median follow-up of 3 years (range, 0–10 years). Older donors were more likely to have died of cardiovascular or cerebrovascular causes, but there were no differences in recipient diagnosis, lung allocation score, or incidence of BOS as a function of donor age. The use of donors aged 55 to 64 years was not a risk factor for mortality at 1 year (odds ratio, 1.1; p = 0.304) or 3 years (odds ratio, 0.923; p = 0.571) compared with the reference group; however, use of donors aged > 65 years was associated with increased mortality at both time points (odds ratio, 2.8 and 2.4, p < 0.02). Conclusions: Outcomes after lung transplantation using donors aged 55 to 64 years were similar to those observed with donors meeting conventional age criteria. Donors aged ≥ 65 years, however, were associated with decreased intermediate-term survival, although there was no increased risk of BOS for this group. [Copyright &y& Elsevier]

In recent years, ex vivo lung perfusion has emerged as an effective tool for increasing the number of available lungs accepted for transplant. As ex vivo lung perfusion use becomes more widespread, questions have arisen regarding the metabolic activity of the donor lung during ex vivo lung perfusion, optimal perfusion-ventilation strategy, and which parameters best define organ improvement or deterioration. Answers to many of these questions can be found in the published experience with the isolated perfused lung in the study of lung mechanics, pulmonary metabolism, and the effects of various interventions on lung quality. The purpose of this review is to summarize past and present evidence and to provide important background for clinicians and investigators using the ex vivo lung perfusion/isolated perfused lung system. [ABSTRACT FROM AUTHOR]

Background: Inhaled treprostinil improved functional capacity as add-on therapy in the short-term management of patients with pulmonary arterial hypertension (PAH). This study investigated the long-term effects of inhaled treprostinil in patients concurrently receiving oral background therapy. Methods: A total of 206 patients (81% women) completing the 12-week double-blind phase of the Treprostinil Sodium Inhalation Used in the Management of Pulmonary Arterial Hypertension (TRIUMPH) study transitioned into an open-label extension. Patients were assessed every 3 months for changes in 6-minute walk distance (6MWD), Borg dyspnea score, New York Heart Association (NYHA) functional class, quality of life (QOL) scores, and signs and symptoms of PAH. Results: Patients were primarily NYHA class III (86%), with a mean baseline 6MWD of 349 ± 81 meters. A median change in 6MWD of 28, 31, 32, and 18 meters in patients continuing therapy was observed at 6, 12, 18, and 24 months, respectively. This effect was more prominent in those patients originally allocated to active therapy in the double-blind phase. Survival rates for patients remaining on therapy were 97%, 94%, and 91% at 12, 18, and 24 months, respectively. In addition, 82%, 74%, and 69% of patients maintained treatment benefit as evidenced by lack of clinical worsening at 12, 18, and 24 months. The most common adverse events were known effects of prostanoid therapy (headache [34%], nausea [21%], and vomiting [10%]) or were due to the route of administration (cough [53%], pharyngolaryngeal pain [13%], and chest pain [13%]). Conclusions: Long-term therapy with inhaled treprostinil demonstrated persistent benefit for PAH patients who remained on therapy for up to 24 months. [ABSTRACT FROM AUTHOR]

Background: The assessment of myocardial viability after global warm ischemia (WI) but before reperfusion is challenging. We hypothesized that fractional anisotropy (FA), a magnetic resonance imaging (MRI) parameter of water diffusion that characterizes cellular integrity within tissues, provides a rapid and useful method for evaluating the viability of hearts after WI. Methods: Dog hearts were exposed to 60 minutes of WI after exanguination, explanted and preserved in a cold, non-beating state for 6 hours, using continuous perfusion (CP) or static cold storage (CS). Toward the end of preservation, a global FA assessment, acquired using MRI, was compared with analyses obtained from myocardial biopsies that included adenosine triphosphate (ATP), endothelin-1 (ET-1) and caspase-3 levels, light microscopy and tetrazolium staining. Functional recovery was analyzed after restoration of blood flow on a non-working Langendorff preparation. Results: FA measured at the end of CP showed strong correlations with all parameters of functional recovery (developed pressure, R = 0.60; dP/dt, R = 0.96; −dP/dt, R = 0.96). Although FA also correlated with tissue levels of ATP, ET-1 and caspase-3 (R = 0.77, −0.84, −0.64), recovery of myocardial function did not correlate with these markers or any other conventional analyses of myocardial injury (troponin I, changes on light microscopy or tetrazolium staining). Conclusions: FA, an MRI-based parameter that indicates cellular integrity, was found to reflect better myocardial ATP stores, less induction of ET-1 and caspase-3 and improved functional recovery of hearts after global WI. As a clinically applicable tool capable of rapidly differentiating reversible from lethal injury, diffusion tensor imaging may prove useful in the eventual adoption of non-beating donor hearts for transplantation. [Copyright &y& Elsevier]

Background: Pre-transplant fixed pulmonary hypertension is associated with higher post-transplant mortality. In this study, we assessed the significance of pre-transplant reversible pulmonary hypertension in patients undergoing cardiac transplantation.Methods: Overall, we studied 182 patients with baseline normal pulmonary pressures or reversible pulmonary hypertension, defined as a decrease in pulmonary vascular resistance (PVR) to ≤2.5 Wood units (WU), who underwent cardiac transplantation. Multiple recipient and donor characteristics were assessed to identify independent predictors of mortality.Results: The average duration of follow-up was 42 ± 28 months. Forty patients (22%) died during the follow-up period. Baseline hemodynamics for alive vs dead patients were as follows: pulmonary artery systolic (PAS) 42 ± 15 vs 52 ± 15 mm Hg; PA diastolic 21 ± 9 vs 25 ± 9 mm Hg; PA mean 28 ± 11 vs 35 ± 10 mm Hg; transpulmonary gradient (TPG) 9 ± 4 vs 11 ± 7 mm Hg (all p < 0.05); total pulmonary resistance 7.7 ± 4.8 vs 8.8 ± 3.2 WU (p = 0.08); and PVR 2.3 ± 1.5 vs 2.9 ± 1.6 WU (p = 0.06). In an unadjusted analysis, patients with PAS >50 mm Hg had a higher risk of death (odds ratio [OR] 5.96, 95% confidence interval [CI] 1.46 to 19.84 as compared with PAS ≤30 mm Hg). There was no significant difference in survival among patients with baseline PVR <2.5, 2.5 to 4.0 or >4.0 WU, but patients with TPG ≥16 had a higher risk of mortality (OR 4.93, 95% CI 1.84 to 13.17). PAS pressure was an independent predictor of mortality (OR 1.04, 95% CI 1.02 to 1.06). Recipient body mass index, history of sternotomy; and donor ischemic time were the other independent predictors of mortality.Conclusion: Pre-transplant pulmonary hypertension, even when reversible to a PVR of ≤2.5 WU, is associated with a higher mortality post-transplant. [Copyright &y& Elsevier]

: BackgroundThe role of complement in hyperacute lung xenograft rejection has not been fully elucidated. The present study evaluates the effect of complement (C) 1 esterase inhibition on hyperacute rejection of human decay-accelerating factor (hDAF)-positive pig lung by human blood.: MethodsUsing a modification of an established ex vivo model, right and left lungs from individual animals were surgically isolated and separately perfused. Pigs homozygous for hDAF were perfused with fresh human blood that was either untreated or treated with complement 1 esterase inhibitor (C1-Inh) at doses of 1 U/ml (n = 5), 5 U/ml (n = 3) or 10 U/ml plasma (n = 5).: ResultsOnly C1-Inh at 10 U/ml prolonged survival time (230 ± 48.3 minutes) as compared with controls (65.6 ± 26.5 minutes, p < 0.05) and diminished complement activation (C3a and C5a, p < 0.05). Interestingly, a low concentration of C1-Inh increased the pulmonary vascular resistance (PVR; 1 U/ml: 0.54 ± 0.3; 10 U/ml: 0.19 ± 0.08). Sequestration of neutrophils (92 ± 3%) and platelets (64 ± 13%) was not prevented by any concentration of C1-Inh. Tissue deposition of C3b and C5b-9 were diminished by hDAF expression, and further blunted by treatment, with 10 U/ml C1-Inh.: ConclusionsComplement plays a critical role in early events of lung hyperacute rejection (HAR). However, even potent inhibition of C1 esterase and C3/C5 convertase, using serum C1-Inh in pig lungs homozygous for hDAF expression, does not prevent rapid lung injury. Our findings implicate innate immune pathways resistant to efficient complement regulation, and suggest a role for neutrophils and platelets in the lung’s particular vulnerability. [Copyright &y& Elsevier]

: Background:Health-related quality of life and functional performance are important outcome measures following heart transplantation. This study investigates the impact of pre-transplant functional performance and post-transplant rejection episodes, obesity and osteopenia on post-transplant health-related quality of life and functional performance.: Methods:Functional performance and health-related quality of life were measured in 70 adult heart transplant recipients. A composite health-related quality of life outcome measure was computed via principal component analysis. Iterative, multiple regression–based path analysis was used to develop an integrated model of variables that affect post-transplant functional performance and health-related quality of life.: Results:Functional performance, as measured by the Karnofsky scale, improved markedly during the first 6 months post-transplant and was then sustained for up to 3 years. Rejection Grade ≥2 was negatively associated with health-related quality of life, measured by Short Form-36 and reversed Psychosocial Adjustment to Illness Scale scores. Patients with osteopenia had lower Short Form-36 physical scores and obese patients had lower functional performance. Path analysis demonstrated a negative direct effect of obesity (β = − 0.28, p < 0.05) on post-transplant functional performance. Post-transplant functional performance had a positive direct effect on the health-related quality of life composite score (β = 0.48, p < 0.001), and prior rejection episodes grade ≥2 had a negative direct effect on this measure (β = −0.29, p < 0.05).: Conclusions:Either directly or through effects mediated by functional performance, moderate-to-severe rejection, obesity and osteopenia negatively impact health-related quality of life. These findings indicate that efforts should be made to devise immunosuppressive regimens that reduce the incidence of acute rejection, weight gain and osteopenia after heart transplantation. J Heart Lung Transplant 2003; 22:000–000. [Copyright &y& Elsevier]