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Background: Pulmonary hypertension (PH) is a progressive and life-threatening disorder characterized by elevated pulmonary arterial pressure, leading to right heart failure and reduced exercise capacity. Traditional pharmacological and surgical treatments offer limited efficacy and significant side effects, necessitating the exploration of alternative therapeutic options., Objective: This systematic review and meta-analysis aimed to evaluate the efficacy and safety of non-pharmacological interventions, including exercise, dietary modifications, and psychosocial therapies, in the management of pulmonary hypertension., Methods: Comprehensive searches were conducted in PubMed, Cochrane Library, and Scopus up to 2024, identifying randomized controlled trials and observational studies examining non-pharmacological interventions for PH. Primary outcomes assessed included pulmonary arterial pressure, right heart function, exercise capacity, and quality of life, with secondary analysis on safety and adverse effects. Data synthesis was performed using random-effects meta-analysis., Results: The review included 30 studies, totaling 2000 participants with various forms of PH. Meta-analysis demonstrated significant improvements in exercise capacity as measured by the 6-minute walk distance (mean increase of 45 meters, 95% CI: 30-60, p<0.001), enhanced quality of life scores, and reduction in pulmonary arterial pressure (mean reduction of 5 mmHg, 95% CI: 3-7, p<0.01). Non-pharmacological therapies also showed a favorable safety profile, with minor adverse effects reported., Conclusion: Non-pharmacological interventions provide a viable and effective complement to traditional treatments for pulmonary hypertension, significantly improving functional capacity and hemodynamic parameters without severe adverse effects. These findings support the integration of tailored non-pharmacological strategies into the therapeutic regimen for PH patients, emphasizing the need for broader implementation and further research to optimize intervention protocols., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this manuscript. The authors have no conflicts of interest to declare., (Copyright © 2024. Published by Elsevier Inc.)

While there has been a global decrease in rates of heart failure (HF) prevalence between 1990 and 2019, the Eastern Mediterranean region (EMR) is experiencing an increase. In 2019, approximately 1,229,766 individuals lived with moderate to severe HF in the EMR. Despite the growth in the utilization of advanced heart failure (AHF) therapies in the EMR in the past two decades, current volumes are yet to meet the growing AHF burden in the region. Heart transplantation (HT) volumes in EMR have grown from 9 in the year 2000 to 179 HTs in 2019. However, only a few centers provide the full spectrum of AHF therapies, including durable mechanical circulatory support (MCS) and HT. Published data on the utilization of left ventricular assist devices (LVAD) in the EMR are scarce. Notably, patients undergoing LVAD implantation in the EMR are on average, 13 year younger, and more likely to present with critical cardiogenic shock, as compared to their counterparts in the Western world. Furthermore, AHF care in the region is hampered by the paucity of multidisciplinary HF programs, inherent costs of AHF therapies, limited access to short and long-term MCS, organ shortage, and lack of public awareness and acceptance of AHF therapeutics. All stakeholders in the EMR should work together to strategize tackling the challenging AHF burden in the region., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

COVID-19 pandemic hampered operational efficiency of heart transplant (HT) programs worldwide. Little is known about the global and country-specific changes in HT volumes during the pandemic years 2020-2021. We aimed to describe the global and country-level impact of the COVID-19 pandemic on HT volumes in 2020-2021. This is a cross-sectional study of the Global Observatory on Donation and Transplantation, including the years 2019-2021. Among 60 countries that reported HT data in the years 2019-2020, we analyzed 52 countries with ≥1 transplant during each year. Overall, the number of HTs decreased during 2020 by 9.3% (1.82 to 1.65 PMP). While 75% (n = 39/52) of countries experienced a decrease in HT volumes in 2020, volumes were maintained/increased in the remaining countries. Countries with maintained HT volumes had a higher organ donation rate in 2020 compared to those with decreased volumes (P = 0.03), the only significant predictor of change in HT volumes (P = 0.005). In 2021, a 6.6% recovery from the previous year's drop in global HT rate was noticed, reaching 1.76 HT PMP. Only 1 in 5 countries with reduced volumes in 2020 recovered their baseline volumes in 2021. Only 30.8% of countries with maintained volumes in 2020 had continued growth in HT volumes in 2021. The latter group encompassed the United States of America, the Netherlands, Poland, and Portugal. Further work should define underlying causes of this heterogeneity in HT volume during the pandemic. Identifying policies and practices that helped certain countries mitigate the effect of the pandemic on HT activities may help other countries during similar health crises in the future., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Growing evidence suggests worse cardiac allograft vasculopathy and mortality in patients with asymptomatic antibody-mediated rejection (AMR). Debate continues about whether therapeutic intervention is warranted to avoid adverse outcomes. In this study we examine the course of individual episodes of untreated asymptomatic AMR on follow-up endomyocardial biopsy (EMB)., Methods: The U.T.A.H. Cardiac Transplant Program database was queried for transplant recipients between 1985 and 2009 who survived beyond 1 year and had at least 1 episode of lone AMR with a follow-up EMB. All EMBs were screened for AMR by immunofluorescence and graded for severity. Data were analyzed based on time from transplant (early, ≤12 months; late, >12 months)., Results: Nine hundred fifty-eight patients with a total of 15,448 biopsies qualified for the study. Average age at transplant was 46.7 years; 13% of the patients were female. Within the first year post-transplant, asymptomatic AMR was diagnosed in 13.6% of biopsies compared with 5.2% beyond 1 year. AMR resolved in 65% (early) vs 75% (late) on follow-up EMB. More severe AMR was less likely to improve regardless of time from transplant. Furthermore, after an episode of AMR had resolved, the recurrence rate at 3, 6 and 12 months was 44%, 50.1% and 56.2%, respectively., Conclusions: The incidence of AMR is higher in the first year post-transplant and the likelihood of resolution is less on follow-up EMB, especially when more severe. A small but significant number of cases became worse or did not change. These new findings may be helpful in planning future studies that test whether therapeutic interventions on asymptomatic AMR favorably impact outcomes., (Copyright © 2012 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Both pulsatile-flow and continuous-flow left ventricular assist devices (LVADs) successfully provide patients a bridge to transplantation. Some data suggest that continuous-flow pumps increase the risk of allograft rejection, contributing to posttransplantation morbidity and mortality. We sought to analyze the relationship between LVAD flow characteristics and subsequent allograft rejection in bridge to transplant (BTT) patients., Methods: Patients with LVADs from the UTAH Transplant Affiliated Hospitals were retrospectively analyzed. Rejection was determined pathologically according to the International Society for Heart and Lung Transplantation revised cardiac allograft rejection scale. Multimodal statistical analyses were applied., Results: Of 1,076 patients who underwent transplantation over a 26-year period, 151 had LVADs. Of these, 111 (77 pulsatile flow, 34 continuous flow) patients had pathologic data available. There was no difference in overall rejection (grades 1R to 3R) between the pulsatile-flow LVAD and continuous-flow LVAD groups (2.00 ± 1.43 versus 1.50 ± 1.16 episodes/year; p = 0.076.) Patients with pulsatile-flow LVADs had more clinically relevant (grades 2R to 3R) rejection than did patients with continuous-flow LVADs (0.49 ± 0.72 versus 0.12 ± 0.33 episodes/year; p < 0.001). There was no survival difference at 1 year (p = 0.920) or 4 years (p = 0.721) after transplantation., Conclusions: Patients with continuous-flow LVADs have similar overall rejection rates and a reduced rate of clinically relevant rejection compared with patients with pulsatile-flow LVADs during the first year after transplantation. Although there is theoretical concern that nonphysiologic, nonpulsatile flow could alter the neurohormonal profile of patients in heart failure, we are encouraged that the type of LVAD circulation does not influence posttransplantation allograft survival., (Copyright © 2011 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Recent efforts are being undertaken to update and refine current diagnostic criteria for antibody-mediated rejection (AMR) in heart transplantation. We believe that the appropriate reactants are those that best predict the adverse consequences of AMR and therefore tested various models using different reactants to find the best predictors of cardiovascular mortality in pathologically defined AMR., Methods: The study group included only patients in whom all immunofluorescence antibodies of interest had been tested on biopsy specimens obtained after 2002 when C4d was routinely added. We analyzed our data using 3 Cox proportional hazard models with time-varying covariates using an end point of cardiovascular mortality, as previously defined., Results: In 3,712 biopsy specimens from 422 patients, the 2-antibody model achieved a value of R(2) = 0.930 using C3d and C4d antibodies alone. A model that used 4 antibodies--C3d, C4d, human leukocyte antigen-D related (HLA-DR) and fibrin--was superior (R(2) = 0.988). The model that best predicted cardiovascular mortality included all 6 antibodies: HLA-DR, immunoglobulin (Ig) G, IgM, C3d, C4d, and fibrin (R(2) = 0.989). The models using 4 or 6 antibodies were significantly superior to the model using only C3d and C4d (for each interaction, p < 0.0001)., Conclusions: The combination of complement components, HLA-DR and fibrin, is valuable in defining AMR in patients at risk for allograft loss from cardiovascular causes. Fibrin is particularly important for detecting the presence of severe AMR, with a high likelihood of poor long-term patient outcome., (Copyright © 2011 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

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.

Background: Organ transplant candidates with serum antibodies directed against human leukocyte antigens (HLA) face longer waiting times and higher mortality while awaiting transplantation. This study examined the accuracy of virtual crossmatch, in which recipient HLA-specific antibodies, identified by solid-phase assays, are compared to the prospective donor HLA-type in heart transplantation., Methods: We examined the accuracy of virtual crossmatch in predicting immune compatibility of donors and recipients in heart transplantation and clinical outcomes in immunologically sensitized heart transplant recipients in whom virtual crossmatch was used in allograft allocation., Results: Based on analysis of 257 T-cell antihuman immunoglobulin complement-dependent cytotoxic (AHG-CDC) crossmatch tests, the positive predictive value of virtual crossmatch (the likelihood of an incompatible virtual crossmatch resulting in an incompatible T-cell CDC-AHG crossmatch) was 79%, and the negative predictive value of virtual crossmatch (the likelihood of a compatible virtual crossmatch resulting in a compatible T-cell CDC-AHG crossmatch) was 92%. When used in a cohort of 28 sensitized patients awaiting heart transplantation, 14 received allografts based on a compatible virtual crossmatch alone from donors in geographically distant locations. Compared with the other 14 sensitized patients who underwent transplant after a compatible prospective serologic crossmatch, the rejection rates and survival were similar., Conclusion: Our findings are evidence of the accuracy of virtual crossmatch and its utility in augmenting the opportunities for transplantation of sensitized patients.

Background: Little has been reported on the clinical significance of asymptomatic antibody-mediated rejection (AMR) alone or mixed rejection (MR), defined as concurrent cellular rejection (CR) and AMR in heart transplantation. In this study, we examined whether a differential impact on cardiovascular mortality (CVM) existed when comparing asymptomatic AMR, to stable MR or CR., Methods: The Utah Transplantation Affiliated Hospitals (UTAH) Cardiac Transplant Program pathology database of all heart transplant recipients between 1985 and 2004 was queried. Patients were classified as cellular, antibody-mediated, or mixed rejectors based on their predominant pattern of rejection type in the first three months post-transplant. Kaplan-Meier survival curves were fit to each of the three groups and analyses were adjusted for age at the time of transplant, gender, and underlying primary cardiac disease., Results: Eight hundred and sixty nine heart transplant recipients qualified for analysis. Over the study period, patients with asymptomatic AMR or stable MR patterns had significantly worse CVM when compared to patients with stable CR pattern (AMR, 21.2%; MR, 18.0%; CR, 12.6%; AMR vs. CR, p = 0.009; MR vs. CR, p = 0.001). In contrast, CVM was comparable in patients with asymptomatic AMR or stable MR patterns (p = 0.9)., Conclusions: Asymptomatic or subclinical AMR and MR are clinically relevant, should be recognized, and deserve consideration for therapeutic intervention in hopes of avoiding adverse outcomes.

The clinical presentation and disease course of tuberculosis (TB) in a solid-organ transplant (SOT) recipient may be atypical and the risk of mortality is high. Herein we examine the role of the different tests used in diagnosis of TB and review the specifics of anti-mycobacterial therapy and the public health implications of TB in a SOT recipient.

Background: The current International Society for Heart and Lung Transplantation (ISHLT) diagnostic criteria for antibody-mediated rejection (AMR) designate AMR as either absent (AMR 0) or present (AMR 1), without grading its severity. Yet, the extent of histologic and immunofluorescence (IF) findings of AMR varies across endomyocardial biopsies (EMBs). In this study, we hypothesized that the severity of AMR, as assessed on EMBs, correlates with cardiovascular mortality in heart transplant recipients., Methods: All EMBs from 1985 to 2005 were evaluated. Biopsy specimens were uniformly studied by light microscopy and IF early post-transplant. A comprehensive vascular score (V1: no AMR, to V5: severe AMR) was prospectively assigned to each EMB, based on severity of both histologic and IF findings. Univariate Cox proportional hazards regressions were performed using indicators of vascular scores alone, combined, and cumulatively., Results: Nine hundred six patients were transplanted and included in the study. Mean age was 46.6 +/- 15.5 years and 82% were male. A total of 26,236 EMBs comprised the study data. As expected, histologic and immunopathologic findings of AMR varied in severity. An incremental risk of cardiovascular mortality was found with more severe AMR whether vascular scores were analyzed individually (p = 0.001), in combination (p = 0.01) or cumulatively (p = 0.006)., Conclusions: The severity of AMR on EMBs correlates with an incremental cardiovascular mortality risk after heart transplantation, suggesting that AMR should be viewed as a spectrum rather than just as present or absent. Supplementing the ISHLT AMR diagnostic guidelines with a consensus severity scale is warranted.

Background: The International Society for Heart and Lung Transplantation (ISHLT) recently established a diagnostic scheme for antibody-mediated rejection (AMR). Currently, however, confirmatory immunohistochemistry studies are recommended only if AMR is clinically or histologically suspected. In this study, we examine whether a pattern of repetitive AMR occurred early enough after transplantation to warrant prospective immunohistochemistry screening in all recently transplanted recipients., Methods: We queried our pathology database of adult and pediatric endomyocardial biopsies (EMBs) from 1985 to 2005. All EMB specimens were prospectively studied by immunofluorescence in the early post-operative period. AMR was defined as the presence of complement and immunoglobulin deposits on frozen section. Only patients classified as antibody-mediated rejectors (>or=3 episodes of AMR) were included. Cumulative incidence and time from transplant to first and third AMR episodes were obtained., Results: Three hundred seventy-five of 870 heart transplant recipients had >or=3 episodes of AMR. Mean age of recipients was 45.6 years and 78% were male. A total of 19,569 EMBs comprised the study data. By 100 days post-transplant, 85% of patients had their first and 54% their third AMR. In addition, patients showed a clear trend of early clustering of AMR-positive biopsies. Results were similar regardless of whether or not muromonab-CD3 (Orthoclone OKT3) induction was used., Conclusions: We advocate early immunohistochemical surveillance testing for AMR to supplement the diagnostic algorithm established by the ISHLT, because a pattern of AMR becomes manifest soon after transplantation. This change will allow earlier detection of asymptomatic AMR and may prompt changes in immunosuppression strategies to avoid adverse outcomes.

Background: Allograft coronary vasculopathy is a major cause of death beyond the first year after cardiac transplantation. The aim of this study was to review our experience with percutaneous coronary intervention (PCI) with stents in cardiac transplant recipients., Methods: We identified patients who were treated with PCI using stents. Patient characteristics, procedure information and clinical outcomes were assessed for these patients by review of their medical records. We also compared results for those who had bare metal stents vs those who had drug-eluting stents., Results: Forty patients from our program's 865 cardiac transplant recipients received a total of 78 coronary stents. There were 35 males (87.5%) and 5 females (12.5%). The indication for PCI was progressive asymptomatic coronary vasculopathy in 18 patients (45%), angina in 5 (12.5%), acute myocardial infarction (MI) in 4 (10%) and congestive heart failure (CHF) in 6 (15%). Primary success (<50% residual stenosis) was obtained in 71 (91%) of 78 stents. During the mean follow-up of 40.8 +/- 34.5 months, 6 patients died (15%) and 2 (5%) were re-transplanted. There was a lower rate of re-stenosis with drug-eluting stents (2 of 13, 15%) compared with bare metal stents (20 of 65, 31%), although this difference was not statistically significant (p = 0.27)., Conclusions: In cardiac transplant recipients, PCI with stents can be performed with high rates of primary success. Restenosis rates are higher compared with PCI in native coronary arteries. A trend toward less restenosis with drug-eluting stents was observed, which needs to be confirmed in larger studies.

Background: Tricuspid valve insufficiency (TI) is common after orthotopic heart transplantation. However, tricuspid valve replacement or repair (TVR) is rare. The aim of this study is to evaluate our experience with TVR in cardiac transplant recipients., Methods: The Utah Transplantation Affiliated Hospitals (UTAH) Cardiac Transplant Program database was queried for TVR in all adult and pediatric heart transplant recipients. Pre-operative parameters and cardiac hemodynamics were compared with post-operative findings., Results: Since 1985, we identified in our database 17 patients who had 16 TVR, and 2 tricuspid valve repair procedures. Thirty-four heart transplant recipients from the same period were used as controls. The indication for TVR was symptomatic right heart failure (RHF) in 89% of cases, and there was no significant difference between the control group and the surgery group in the average number of biopsies. A flail leaflet was found in 16 cases (89%). One patient died post-operatively due to cardiogenic shock, and 1 patient died 8 months after TVR due to progressive RHF. Improvement in heart failure symptoms was seen in 12 cases. The central venous pressure (CVP) decreased from 17.8 +/- 4.1 mm Hg to 11.0 +/- 7.3 mm Hg (p = 0.013). There was no significant change in cardiac output or renal function. However, the furosemide dose decreased significantly from 47.69 +/- 56.44 mg/day to 26.54 +/- 46.43 mg/day (p = 0.009)., Conclusions: After orthotopic heart transplantation, TVR is a safe and effective procedure to alleviate RHF symptoms. Flail leaflets are the most common operative finding, suggesting that biopsy-induced trauma is the likely cause of severe TI in these patients.

Background: Beta-blockers are frequently used after cardiac transplantation for blood pressure control. There is no well-known interaction between beta-blockers and cyclosporine A (CsA). However, recent reports have suggested that carvedilol, but not metoprolol, modulates P-glycoprotein (P-gp), a membrane protein that regulates CsA absorption. We evaluated the effects of carvedilol and metoprolol on CsA level when initiated in cardiac transplant recipients., Methods: Using our cardiac transplant database, we identified patients who were started on either carvedilol or metoprolol for blood pressure control. We then compared their CsA doses and levels before and within 2 weeks after the initiation of beta-blocker therapy., Results: We found 20 patients taking metoprolol and 12 patients taking carvedilol. With initiation of metoprolol, CsA level decreased in 12 patients and increased in 8 patients. The mean CsA level before and after metoprolol initiation was 236 ng/ml and 253 ng/ml, respectively (p = 0.50). In an attempt to maintain a therapeutic CsA level, the mean CsA dose was not significantly adjusted (from a mean of 293 mg/day to a mean of 294 mg/day; p = 0.92). In the Carvedilol Group, CsA level increased in 10 of 12 patients. The mean CsA level before the initiation of carvedilol was 257 ng/ml. The mean CsA level after carvedilol initiation was 380 ng/ml (p = 0.009). In an attempt to maintain a therapeutic CsA level, the mean CsA dose was reduced by 10%, from a mean of 319 mg/day to a mean of 288 mg/day (p = 0.004)., Conclusion: Carvedilol, but not metoprolol, was associated with a significant increase in CsA levels after initiation in cardiac transplant recipients. Although carvedilol and CsA do not interact at the level of cytochrome P450 system, it appears that carvedilol influences CsA levels through its effects on P-gp. An average reduction of 10% is necessary on the CsA dose upon initiation of carvedilol, and close follow-up of the level is essential.

Pulmonary vein tumours are rare. They can cause significant morbidity and mortality. The present report discusses a rare case of pulmonary vein sarcoma in an elderly male patient.