Pulmonary hypertension (PH) is a fatal condition that affects individuals with systemic sclerosis (SSc), a multiorgan fibrotic disease with limited treatment options. A central feature of PH is vascular remodeling, defined by the narrowing of the arteriole lumen due to cell proliferation and extracellular matrix deposition. Herein, we identify a central mechanism that can regulate multiple transcripts important for vascular remodeling. The highlight of our study is the demonstration that reduced pulmonary artery smooth muscle (PASMC) Nudt21, which codes for the RNA binding protein Cleavage and Polyadenylation Specificity Factor Subunit 5 (CPSF5) The, known to regulate alternative polyadenylation, results in heightened right ventricle systolic pressures in mice exposed to hypoxia-sugen. We also report that increased PASMC proliferation is present in mice with reduced PASMC Nudt21 under normoxic conditions, recapitulating features of hypoxia-sugen exposure. Our studies reveal that reduced CPSF5 leads to 3' untranslated region shortening of PTGER3 and CBFB, the latter contributing to increased levels of proliferative transcription factor RUNX1. We also identify miR-3163 as novel negative regulator of NUDT21 expression in PH. These observations are validated in remodeled vessels from patients with SSc associated with PH and in and point to common mechanisms of RNA processing deficits that contribute to vascular remodeling in PH.

Background:Effective organ preservation before transplantation is pivotal for successful outcomes but can be limited by logistics. Organs are primarily preserved by flushing with a cold solution and storing on ice, then transplanted within 8 h of procurement. Controlled hypothermic preservation (CHP) at 4-8 °C has increasingly been used to extend ischemic times. Here we compared early outcomes of transplants using CHP (n = 41) and traditional preservation on ice (n = 41). Methods:Our institution used LUNGguard, a CHP device by Paragonix, for the extension of ischemic time to optimize operating room (OR), transplant team, and recipient logistics. We evaluated 1-y mortality, primary graft dysfunction, length of stay, time to liberation from mechanical ventilation, and time on oxygen support. Results:There were no differences in patient outcomes between storage on ice and CHP. In selected cases, extending ischemic times using CHP allowed for additional organ procurement as well as improved OR logistics. Conclusions:In our experience, CHP has been shown to be a safe and effective method of extending ischemic times in donor lungs, allowing for increased donor acceptance and improved OR efficiency. This supports a growing body of evidence favoring a shift from ice to CHP as the standard for donor lung storage in cases of extended ischemic time.

The prevalence of adult congenital heart disease (ACHD) is increasing, with heart failure being the leading cause of death. For many ACHD patients, heart transplantation is the only treatment option for advanced heart failure, though significant extracardiac involvement may require multi-organ transplantation. Despite the rising number of ACHD transplants, multi-organ transplants in this population remain challenging, and a substantial gap remains between those in need and those who receive a transplant. While short-term outcomes may be worse for ACHD patients, long-term outcomes are comparable and even superior to other cardiomyopathies. Extracardiac organ dysfunction is common in ACHD patients, often precluding heart-alone transplantation. Fontan-associated liver disease, pulmonary vascular and restrictive lung disease, and renal dysfunction frequently necessitate multi-organ transplantation. ACHD patients have a unique immunological and sensitization profile, increasing their risk for infection, rejection, and malignancies, requiring specialized pretransplant desensitization and post-transplant immunosuppression strategies. ACHD transplantation presents unique surgical challenges, including chest reentry, vascular access issues, bleeding risks, extensive anatomical reconstruction, the need for longer vascular segments from donors, and prolonged ischemic times. Decisions regarding heart-alone versus heart-liver, heart-lung, or heart-kidney transplantation demand careful evaluation. These complex surgical plans require extensive multimodal imaging and collaboration with ACHD cardiac imaging specialists and abdominal transplant teams. Comprehensive coordination and psychosocial support are crucial for ACHD patients throughout the transplant process. A dedicated multidisciplinary team and an established and separate pathway for pre-, peri-, and postoperative care in centers with ACHD and multi-organ transplant expertise are essential. There is need for a revised organ allocation system to ensure timely access to transplantation for ACHD patients.

Background Cardiac amyloidosis is a less common indication for orthotopic heart transplantation (OHT). Light chain (AL) amyloidosis specifically poses challenges. While previous small studies have established the validity of OHT for AL amyloidosis, we present experience from a large contemporary series at a single center. Methods This was a retrospective single-center study of patients receiving OHT between 2009 and 2023 at our institution. A data warehouse was curated from our electronic medical records and United Network for Organ Sharing databases. Univariable and multivariable analyses of donor and recipient characteristics were performed. Patients who received OHT after 2016 were active in our electronic medical record and hence AL-OHT patients after 2016 had granular details regarding immunosuppression, chemotherapy regimens, amyloidosis, and post-transplant-related outcomes within their first-year post-OHT. Results Thirty-one patients received an OHT for cardiac AL while 595 received OHT for non-amyloid indication during the study period. One-, three-, five-, and eight-year survival (87%, 83%, 73%, and 67%, respectively) was not statistically different compared to non-AL OHT patients (92%, 85%, 79%, and 68%, respectively). In a subset of 18 patients with access to electronic medical record data, all patients remained on tacrolimus and prednisone through 1-year post-OHT, but nearly half were off mycophenolate. Conclusion Select AL patients with advanced cardiac involvement can gain survival advantage with OHT similar to other advanced heart failure patients.

BACKGROUND:Pump exchange is an established strategy to treat LVAD-related complications such as thrombosis, infection, and driveline failure. Pump upgrades with an exchange to newer generation devices are being performed to the advantage of the patient on long-term support. The safety and efficacy of a repeat LVAD exchange with a concomitant upgrade to a third-generation pump have not been reported. METHODS:We performed a retrospective analysis of all consecutive patients who underwent a repeat LVAD device exchange and upgrade to HeartMate III (HMIII) at Houston Methodist Hospital between December 2018 and December 2020. RESULTS:Five patients underwent exchange and upgrade to HMIII within the specified timeframe. Four patients had already had two prior exchanges (all HMII to HMII), and one patient had one prior exchange (HVAD to HVAD). In all cases, implantation was performed as destination therapy. The surgical exchange was performed via redo median sternotomy on full cardiopulmonary bypass. No unplanned redo surgery of the device component was required. In-hospital mortality was 20% in this very high-risk population. At 1-, 3-, and 6-month follow-up, all discharged patients were on HMIII support, with no major LVAD-related adverse events reported. CONCLUSION:We report the feasibility and safety of a repeat pump exchange with an upgrade to HMIII in a high-volume center. The decision for medical therapy versus surgical exchange has to be tailored to individual cases based on risk factors and clinical stability but in expert hands, even a re-redo surgical approach grants options for good medium-term outcomes.

Background: Impella 5.5 provides robust support as temporary mechanical circulatory support (t-MCS) device in advanced heart failure patients in cardiogenic shock. Understanding short- and long-term outcomes is crucial. Hypothesis: Impella 5.5 supports advanced heart failure patients in cardiogenic shock and successfully bridges them to cardiac replacement without affecting long-term survival. Methods: From February 2020 to April 2024, all patients who received an Impella 5.5 and underwent evaluation for advanced therapies at Houston Methodist Hospital were identified. Implantation of Heartmate 3 (HM3) Left Ventricular Assist Device (LVAD), orthotopic heart transplantation (OHT), mortality, and device removal after Impella implantation were assessed. For HM3 LVAD patients, outcomes were categorized as death, transplantation, or survival. Survival after OHT was analyzed using Kaplan-Meier analysis and compared to patients who received OHT without Impella 5.5. Cumulative incidence rates was calculated using Competing risk regression. Results: 140 patients were identified, median age 59.4 years (50.4-66.5), majority Caucasian (54%) and Black (36%). 89 (63.6%) were either bridged to advanced therapies or recovered. 52 (37.1%) underwent OHT, 21 (15%) received an HM3 LVAD, and 51 (36.4%) died post-implantation. 3 (2.1%) died post-transplant. Post-LVAD, 6 (4.3%) died, 3 (2.1%) underwent OHT, and 12 (8.6%) were alive with LVAD. 10 (7.1%) survived after Impella 5.5 removal, 2 (1.4%) went to hospice, and 1 (0.7%) was transferred to another hospital. 3 (2.1%) are currently hospitalized. Fig1a shows outcomes. Fig1b indicates death within 90 days of Impella implantation. 3-year survival of patients bridged with Impella to OHT (N=55) was 94%, comparable (p=0.27) to patients receiving OHT without Impella (N=215)(Fig 1c). Conclusion: Mortality for cardiogenic shock patients remains high. Using Impella 5.5 with a cardiac replacement strategy can salvage some patients. Long-term outcomes for patients bridged to heart transplant with Impella 5.5 are similar to those without the device. Further studies on predictors of early adverse outcomes post-implant can help mitigate risks for advanced heart failure patients in cardiogenic shock.

Background: Right ventricular failure (RVF) impacts the prognosis of pulmonary arterial hypertension (PAH). Alternative polyadenylation (APA) generates transcript diversity and is implicated in diseases, including left heart failure. However, understanding genome-wide polyadenylation maps in RVF patients with PAH is limited, with no studies investigating RVF-specific APA events. Objective: This study mapped 3' untranslated regions (3'UTRs) to explore APA dynamics in RVF development, comparing healthy donors and RVF from patients with PAH. Methods and Results: RV tissues were obtained from patients with failing RV from heart and double lung transplant recipients. Poly(A)-ClickSeq (PAC-seq) RNA sequencing and PolyA-miner algorithm were used. Analysis revealed significant changes in cleavage site usage, identifying 690 genes with altered APA patterns in RVF. Notably, our investigation uncovered a significant finding related to CPSF6, a key factor involved in APA regulation. We observed a substantial lengthening of the 3'UTR in CPSF6, suggesting disrupted polyadenylation events in RVF. Intriguingly, this lengthening coincided with a noticeable decrease in CPSF6 protein levels, indicating a potential regulatory mechanism affecting its expression. Additionally, 530 genes had shortened 3'UTRs enriched for RNA binding and hypertrophic cardiomyopathy pathways, while 160 genes had lengthened 3'UTRs enriched for RNA surveillance and ribosomal RNA binding. Disease-specific APA signatures in RVF patients with PAH were identified. Conclusion: The present study highlights the significant role of APA in human RVF exerting its influence on multiple pathways and regulating specific gene expression. These findings offer insights into RVF in PAH patients and may guide the identification of therapeutic targets and strategies for improved management of the condition.

Introduction: Heparin-induced thrombocytopenia (HIT) is a concern in cardiac surgery patients, who routinely receive heparin during interventions. Diagnosis relies on detection of PF4 antibodies (Ab) and a functional serotonin-release assay (SRA). Treatment involves stopping heparin, but optimal management in future interventions requiring heparin remains unclear. This case presents the diagnosis, management, and surgical considerations of HIT in a heart transplant patient with temporary mechanical circulatory support (tMCS).

Introduction: The Impella 5.5 device provides mechanical circulatory support in those advanced heart failure as a bridge to recovery, durable left ventricular assist devices, or heart transplantation. Its use to assist in non-cardiac procedures has also been reported. We present a case of a patient with chronic hepatitis C cirrhosis and marginal cardiac function who underwent Impella 5.5 assisted liver-kidney transplantation.

Introduction: Right ventricular failure (RVF) is a common consequence of pulmonary hypertension, but effective treatment options are currently lacking. To develop precise molecular and cellular targets for therapeutic development, a comprehensive investigation of cell type-specific responses and cellular heterogeneity in RVF is needed. Hypothesis: Cellular heterogeneity exists within the myocardium of RVF patients with pulmonary hypertension, and identifying specific genes contributing to failure can be aided by studying these distinct subpopulations. Methods: To test this hypothesis, we performed single-nucleus transcriptome analysis of 120,000 nuclei from ventricle samples of RVF patients with advanced or end-stage pulmonary hypertension with severe right heart failure undergoing heart double lung transplantation and normal control (NC) subjects. Single nuclei RNA sequencing was performed using 10x genomics, and bioinformatics tools were used for analysis. Results: Unsupervised clustering of 120,000 nuclei led to the identification of transcriptionally distinct subpopulations within 6 major cell types. We identified a unique fibroblast subpopulation expressing SERPINE1 in RVF and observed extensive crosstalk between the fibroblast cells and the other cardiac cell types through Visfatin signaling. In addition, other major cardiac cell types, such as cardiomyocytes, endothelial cells, and macrophages within the failing hearts also exhibited significant alterations in the signaling pathways compared with the control hearts. Conclusions: Our study provides novel insights into the single-cell landscape within the myocardium of RVF patients, revealing remarkable changes in the expression patterns of fibroblast genes. The identified sub-cluster of the fibroblast cell population could serve as a specific and potential therapeutic target in the clinic.

Purpose Assays detecting donor-derived cell-free DNA (dd-cfDNA) are increasingly utilized as a non-invasive marker for rejection in solid organ transplantation. Expected baseline values and trends in multiorgan transplants (MOT) have not been reported. We describe our experience with dd-cfDNA in heart multiorgan transplantations. Methods This is a retrospective cohort of 26 MOT recipients who underwent concomitant endomyocardial biopsy and dd-cfDNA between 2016 and 2021. The results of the first dd-cfDNA assay and biopsy readouts for rejection of all 26 patients were assessed. The indications for dd-cfDNA assay were constraints to elective biopsies during the pandemic, receiving full-dose anti-coagulation, and center inaccessibility. Results Our cohort consisted of 6 heart/liver transplant (HLTx) and 20 heart/kidney transplant (HKTx) recipients. The cohort's median age was 59.5 years (95% CI, 46-64) and predominantly Caucasians (42.3%) (Table 1). The median time from transplant to dd-cfDNA was 5 months (IQR 3.0-9.0). The median dd-cfDNA was higher in the HLTx group, 0.6%; IQR (0.3-0.8)] compared to the HKTx group, 0.2%; IQR (0.1-0.3)]. One case of acute cellular rejection was recorded in the HKTx group with a corresponding dd-cfDNA of 0.28% with no antibody-mediated rejection detected. Conclusion In the largest single-center MOT cohort to date, we describe baseline values for dd-cfDNA in HLTx and HKTx. Prospective multicenter studies will be necessary to establish the role of dd-cfDNA in predicting MOT rejection.

We sought to evaluate whether differences in left ventricular assist device (LVAD) canula alignment are associated with stroke. There is a paucity of clinical data on contribution of LVAD canulae alignment to strokes. We conducted a retrospective analysis of patients who underwent LVAD implantation at Houston Methodist hospital from 2011 to 2016 and included those who had undergone cardiac computed tomography (CT) with contrast. LVAD graft alignment using X-ray, echocardiography, and cardiac CT was evaluated. The primary outcome was stroke within 1 year of LVAD implantation. Of the 101 patients that underwent LVAD Implantation and cardiac CT scan during the study period, 78 met inclusion criteria. The primary outcome occurred in 12 (15.4%) patients with a median time to stroke of 77 days (interquartile range: 42-132 days). Of these, 10 patients had an ischemic and two had hemorrhagic strokes. The predominant device type was Heart Mate II (94.8%). Patients with LVAD outflow cannula to aortic angle lesser than 37.5 degrees and those with outflow graft diameter of anastomosis less than 1.5 cm (assessed by cardiac CT) had significantly higher stroke risk (p < 0.001 and p = 0.01 respectively). In HMII patients, a lower LVAD speed at the time of CT scan was associated with stroke. Further studies are needed to identify optimal outflow graft configuration to mitigate stroke risk.

Background: Patients with coronavirus disease 2019 (COVID-19)-associated respiratory failure undergoing lung transplantation is an emerging subset of transplant patients in which gastroesophageal reflux disease (GERD) pre- or post-transplant is not well characterized. Methods: We retrospectively evaluated patients undergoing lung transplant for COVID-19, with attention to pre- and post-operative physiological testing for GERD. Results: Seventeen patients were identified who had undergone lung transplant for COVID-19. No patient underwent pre-transplant GERD testing. Post-transplant, 70.5% (12/17) patients reported reflux symptoms confirmed with additional testing. Three patients underwent anti-reflux surgery (ARS) based on results of testing, and none had complications or symptom-based recurrence of reflux. Conclusion: Our study depicts a unique cohort of patients who were unable to undergo pre-transplant testing for GERD in the setting of a global pandemic, and who were routinely assessed and managed post-transplant. J Curr Surg. 2023;13(1):12-16 doi: https://doi.org/10.14740/jcs467