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Background There is a paucity of data on depression, anxiety and post-traumatic stress disorder after left ventricular assist device (LVAD) implantation. We designed an observational study to integrate these with functional capacity and health-related quality of life (HR-QOL) in surviving LVAD patients. Methods and Results Consenting patients between 1 month and 9 years after LVAD implantation (n = 121) were screened for functional capacity (World Health Organization Disability Assessment Schedule 2.0 [WHODAS 2.0)]); HR-QOL (European Quality of Life [EQ-5D] and Visual Assessment Scales [EQ-VAS]), depression (Patient Health Questionnaire [PHQ-9], anxiety (Generalized Anxiety Disorder Scale [GAD-7]) and post-traumatic stress disorder (Impact of Event Scale Revised [IES-R]). Of the 94% of patients who consented, 34.7% reported impaired functional capacity (WHODAS 2.0 score of ≥25%), 23.1%–34.7% HR-QOL problems (domain EQ-5D of ≥3), 10.7% “poor health” (EQ-VAS of ≤40), 14.9% depression (PHQ-9 of >14), 11.7% suicidal ideation and 17.5% anxiety (GAD-7 of >10). Among these patients, 23.5% had a positive screen for post-traumatic stress disorder (IES-R of ≥24). An EQ-VAS of 80 or greater predicted good functional capacity (P Conclusions One-third of discharged LVAD patients reported impaired function, HR-QOL, and psychological issues. A standardized evaluation before and after LVAD implantation could facilitate psychologic prehabilitation, inform decision-making, and identify indications for mental health intervention.

To describe the use of levosimendan in a quaternary referral center with a dedicated heart failure service and compare its efficacy and safety to continuous outpatient support with inotropes (COSI) among patients with advanced heart failure (AHF) who require bridge-to-decision (BTD) or bridge-to-transplant (BTT) therapy. This study was a retrospective, single-center, descriptive study of patients with AHF who received either a single levosimendan infusion or COSI between 2018 and 2021. A total of 23 patients received a levosimendan infusion, and 14 were started on COSI. Three indications for levosimendan were identified: (1) to facilitate weaning of continuous inotropes, (2) to augment diuresis in cardiorenal syndrome, and (3) as first-line therapy for cardiogenic shock in selected patients. Eighty-three percent (19 of 23) of patients who received levosimendan survived to discharge, and there were few clinically significant adverse events. Overall survival at 12 months among patients who received levosimendan was 74%. No statistically significant difference in survival was observed at 12 months (P = 0.68) or beyond (P = 0.63) between patients who received levosimendan and were discharged with a plan for BTD or BTT and those who received COSI. Levosimendan is a safe and effective short-term therapy in AHF and offers comparable long-term survival to COSI in patients who require BTD or BTT therapy.

Background Home inotropes are utilised in those with end-stage heart failure as a bridge to cardiac transplantation. The use of intravenous dobutamine has been linked to cases of eosinophilic myocardial hypersensitivity (EMH), however, little is known about incidence and predictors. Purpose We sought to examine the incidence and possible predictors of eosinophilic myocardial hypersensitivity in a cohort of patients on home inotrope therapy at a cardiac transplant centre. Methods Patients enrolled in the home inotrope program with progression to heart transplantation or ventricular assist device (VAD) with available myocardial tissue for histopathology, from January 2000 to May 2020 were included. EMH was defined by a pathologist reporting eosinophilic infiltrate with hypersensitivity on myocardial histopathology. Results From a cohort of 74 patients, 58% (43) were on dobutamine and 42% (31) were on milrinone. There were zero cases of EMH in those on milrinone. EMH was identified in 14% (6/43) of patients receiving dobutamine. In the dobutamine cohort, the mean age was 52-±12 years, with 22% being female. Non-ischaemic dilated cardiomyopathy encompassed 62%, the remaining 38% were ischaemic cardiomyopathy. Median dobutamine dose (250 [200–282] mcg/min vs. 225 [200–291] mcg/min) and duration of therapy (41 [23–79] days vs. 53 [24–91] days) were similar between those with and without EMH. Rates of known allergy (27% vs. 33%) and asthma (1 patient in each group) were also similar between those with and without EMH. Those with EMH had a median peak eosinophil count of 0.40×109/L (IQR 0.21–0.66×109/L) compared to a peak of only 0.10×109/L (IQR 0.06–0.29×109/L) in the non-EMH cohort. There was a significant difference in the change in absolute eosinophil count between groups; over the duration of dobutamine therapy the median change in eosinophil count was 0.31×109/L (IQR 0.21–0.59×109/L) in the EMH group compared to 0.03×109/L (IQR 0.00–0.14×109/L) in the non-EMH cohort (p=0.02). Peak C-reactive protein was similar between groups (42±46mg/L vs. 44±45mg/L). Mean left ventricular ejection fraction (LVEF) reduced from 19% (±7%) to 17% (±2%) in those with EMH, while LVEF increased from 20% (±7%) to 22% (±9%) in non-EMH patients (Figure 1), p=NS. Re-presentation with heart failure requiring hospitalisation occurred in 83% in the EMH group compared to only 59% in the non-EMH group (p=0.26). The majority of patients with EMH (83%) required VAD as bridge to transplant, compared to only 41% of non-EMH (p=0.05). Conclusion(s) EMH occurred in 14% of patients receiving home dobutamine. Patients who developed EMH were more likely to require escalation in treatment to VAD as a bridge to heart transplant. In patients receiving dobutamine a reduction in LVEF, hospitalisation with decompensated heart failure and rising eosinophil count should prompt physicians to consider EMH. Funding Acknowledgement Type of funding sources: None. Figure 1

Congestive Heart Failure (CHF) is an emerging epidemic. Within one generation, the medical community has learned much of CHF syndromes. It has two distinct mechanisms, systolic and diastolic abnormalities, to account for the common CHF presentation. It is complex as it challenges the available health care services, resource, and funding models in providing an equitable service across the health continuum. Despite the improvement in many cardiovascular diseases, some CHF outcomes like readmissions and costs have increased. The reinvigoration of evidence- based medicine, the development of health services models of care, and standardisation of disease processes with taxonomies have also occurred within the same time span. These processes, however, need to be linked with health policy as presented in white papers. In this paper, we explore achieving optimal CHF guideline-recommended outcomes as the science approaches realworld translation.

Patients undergoing heart transplant are at high risk for postoperative vasoplegia. Despite its frequency and association with poor clinical outcomes, there remains no consensus definition for vasoplegia, and the predisposing risk factors for vasoplegia remain unclear. Accordingly, the aim of this study was to evaluate the prevalence, predictors, and clinical outcomes associated with vasoplegia in a contemporary cohort of patients undergoing heart transplantation.This was a retrospective cohort study of patients undergoing heart transplantation from January 2015 to December 2019. A binary definition of vasoplegia of a cardiac index of 2.5 L/min/mAfter exclusion of patients with primary cardiogenic shock, major bleeding, or overt sepsis, data were collected on 95 eligible patients. By binary definition, vasoplegia incidence was 66.3%. We separately stratified by actual vasopressor requirement tertile (high, intermediate, low). Stratified by tertile, patients with vasoplegia were older (52.7 ± 10.2 vs 46.8 ± 12.7 vs 44.4 ± 11.3 years, P = .02), with higher rates of chronic kidney disease (18.8% vs 32.3% vs 3.1%, P = .01) and were more likely to have been transplanted from left ventricular assist device support (n = 42) (62.5% vs 32.3% vs 37.5%, P = .03). Cardiopulmonary bypass time was prolonged in those that developed vasoplegia (155 min [interquartile range 135-193] vs 131 min [interquartile range 117-152] vs 116 min [interquartile range 102-155], P = .003). Intubation time and length of intensive care unit and hospital stay were significantly increased in those that developed vasoplegia; however, this difference did not translate to a significant increase in all-cause mortality at 30 days or 1 year.Vasoplegia occurs at a high rate after heart transplantation. Older age, chronic kidney disease, mechanical circulatory support, and prolonged bypass time are all associated with vasoplegia; however, this study did not demonstrate an associated increase in all-cause mortality LAY SUMMARY: Patients undergoing heart transplantation are at high risk of vasoplegia, a condition defined by low blood pressure despite normal heart function. We found that vasoplegia was common after heart transplant, occurring in 60%-70% of patients after heart transplant after excluding those with other causes for low blood pressure. Factors implicated included age, poor kidney function, prolonged cardiopulmonary bypass time and preoperative left ventricular assist device support. We found no increased risk of death in patients with vasoplegia despite longer lengths of stay in intensive care and in hospital.

Infections caused by carbapenemase-producing Enterobacteriaceae (CPE) are an emerging threat in both solid organ and stem cell transplant recipients. Invasive CPE infections in transplant recipients are associated with a high mortality, often due to limited therapeutic options and antibacterial toxicities. One of the most therapeutically challenging group of CPE are the metallo-β-lactamase (MBL)-producing Gram-negative bacteria, which are now found worldwide, and often need treatment with older, highly toxic antimicrobial regimens. Newer β-lactamase inhibitors such as avibactam have well-established activity against certain carbapenemases such as Klebsiella pneumoniae carbapenemases (KPC), but have no activity against MBL-producing organisms. Conversely, aztreonam has activity against MBL-producing organisms but is often inactivated by other co-existing β-lactamases. Here, we report four cases of invasive MBL-CPE infections in transplant recipients caused by IMP-4-producing Enterobacter cloacae who were successfully treated with a new, mechanism-driven antimicrobial combination of ceftazidime/avibactam with aztreonam. This novel antimicrobial combination offers a useful treatment option for high-risk patients with CPE infection, with reduced drug interactions and toxicity.

BACKGROUND Right ventricular (RV) failure after left ventricular assist device (VAD) implantation is a difficult problem. One solution is the implantation of continuous-flow VADs in a biventricular configuration. Disappointing survival and a concerning incidence of right-sided pump thrombosis have been previously reported. METHODS From May 2017 to April 2020, a total of 12 patients underwent implantation of HeartMate 3 (HM3) biventricular VADs (BiVADs) as a bridge to cardiac transplantation. The right-sided pump was implanted in the right atrium in all cases. Adverse events and patient outcomes were determined. RESULTS Patients were male, and the mean age was 44 years. The etiology was dilated cardiomyopathy (6 patients), sarcoid heart disease (2 patients), ischemic cardiomyopathy (1 patient), anthracycline cardiomyopathy (1 patient), non-compaction cardiomyopathy (1 patient), and arrhythmogenic RV cardiomyopathy with biventricular involvement (1 patient). There was 1 death from multisystem failure. There were 3 episodes of right VAD thrombus (thrombosis or clot ingestion); 1 managed medically, 1 recognized intraoperatively treated with clot retrieval, and 1 requiring pump exchange. There were 3 driveline infections. At 18 months after the procedure, 5 patients (41.7%) had undergone cardiac transplantation, 5 patients (41.7%) were alive and on biventricular support, 1 patient had died (8.3%), and 1 patient had VAD explantation for myocardial recovery (8.3%). Actuarial survival at 18 months was 91.7%. CONCLUSIONS In this small study, HM3 BiVAD in these critically ill patients was used with low mortality. This suggests that the timely deployment of biventricular support with HM3 can be associated with favorable outcomes.

Introduction Cardiac cirrhosis is common in patients with advanced heart failure and can limit heart transplant eligibility. We examined the outcomes of patients with cardiac cirrhosis following orthotopic heart transplantation. Material and methods A retrospective matched cohort study of adult patients with cirrhosis undergoing heart transplantation at an Australian hospital from 2009 to 2017 was performed. Cirrhosis was established by either (a) histopathology or (b) combination of radiological features of cirrhosis and portal hypertension plus clinical features of portal hypertension. Primary objectives were to assess mortality, perioperative, and long-term complications. Matching was performed with non-cirrhotic patients undergoing heart transplantation in a 4:1 ratio. Results Five patients with biopsy-proven cirrhosis or portal hypertension and 20 matched controls without cirrhosis were included. Additionally, 5 patients with clinical and radiological evidence of cirrhosis were assessed separately. The groups were well-matched for age at transplant, year of transplant, gender, and comorbidities. Mortality was more frequent but not significantly greater in the cirrhosis group with 2 deaths within 4 months of transplant compared to 1 death each in the no cirrhosis and suspected cirrhosis groups (40%, 5%, 20% P = .40). The median duration of intensive care unit stay was longer in the cirrhosis group compared to the suspected cirrhosis group (8 vs 6 days, P = .03); however, there was no difference in total hospitalization (P = .56) or in median duration of admission (0.64) compared to the no cirrhosis group. Conclusions These findings suggest that there is greater mortality associated with cases of definite cirrhosis compared to suspected or matched controls following orthotopic heart transplantation; however, statistical significance was not reached. Admission length and complication rates were similar compared to those without cirrhosis. Future studies are warranted to further evaluate mortality risk in a larger population.

Up to one-third of COVID-19 patients admitted to intensive care develop an acute cardiomyopathy, which may represent myocarditis or stress cardiomyopathy. Further, while mortality in older patients with COVID-19 appears related to multi-organ failure complicating acute respiratory distress syndrome (ARDS), the cause of death in younger patients may be related to acute heart failure. Cardiac involvement needs to be considered early on in critically ill COVID-19 patients, and even after the acute respiratory phase is passing. This Statement presents a screening algorithm to better identify COVID-19 patients at risk for severe heart failure and circulatory collapse, while balancing the need to protect health care workers and preserve personal protective equipment (PPE). The significance of serum troponin levels and the role of telemetry and targeted transthoracic echocardiography (TTE) in patient investigation and management are addressed, as are fundamental considerations in the management of acute heart failure in COVID-19 patients.

Background We identified variation in delivery of guideline recommended care at our institution, and undertook a project to design a heart failure (HF) model of care. Aim To maximise time patients with HF spend well in the community by delivering best practice guidelines to reduce variation in care improving overall outcomes. Methods This quality improvement project focused on reducing variation in process measures of care. The HF model of care included electronic HF care bundles, a patient education pack with staff training on delivering HF patient education, referral of all HF patients to the Hospital Admissions Risk Program for phone call within 72 h, and a nurse-pharmacist early follow-up clinic. Outcomes were assessed using interrupted time series analyses. Results The pre-intervention group comprised 1585 patients, and post-intervention 1720 patients with a primary diagnosis of HF admitted under general cardiology and general medicine. Interrupted time series analysis indicated 30-day readmissions did not change in overall trend (-0.2% per month, P = 0.479) but a significant immediate step-down of 7.8% was seen (P = 0.018). For 90-day readmissions, a significant trend reduction over the time period was seen (-0.6% per month, P = 0.017) with a significant immediate step-down (-9.4%, P = 0.001). Emergency department representations, in-patient mortality and length of stay did not change significantly. Improvements in process measures were seen at audit. Conclusion This model of care resulted in overall trends of reductions in 30- and 90-day readmissions, without increasing emergency department representations, mortality and length of stay. This model will be adapted as the electronic medical record is introduced at our institution.

Sudden unexpected death in epilepsy (SUDEP) is well recognised and widely reported but remains poorly understood. SUDEP in young adults is 27 times more common than sudden death in control populations. The incidence of SUDEP in New Zealand is not known but up to 40 people with epilepsy may die from SUDEP every year. A review of coroner's reports of SUDEP was undertaken to learn more about SUDEP in New Zealand.Coroner's reports of all cases of possible SUDEP in New Zealand from 2007-2016 (n=190) were obtained and post-mortem and toxicology results were reviewed. Cases were categorised using published criteria.We obtained reports of 190 cases from the coroner's office. Of these 190 cases, we determined that 123 were definite SUDEP, 40 were definite SUDEP plus, three were probable SUDEP, seven were possible SUDEP and 17 were probably not SUDEP. The number of cases per year varied from 11-26 (2013). Cases were aged 1.5-67 years, with 63% aged 15-45 (mean 37 years). Sixty-one percent were male. Eighty-seven percent of the deaths occurred at home, with 74% found dead in their bed or bedroom. The majority were not employed, with only 33% working or retired at the time of death; 15% were children or students. Information regarding work status was not available for 11%. Toxicology results were available for 155 cases; antiepileptic drug (AED) use was detected in 67% of these cases, with a single AED detected in 44%, two AEDs in 21%, and three AEDs in 3% of samples taken at autopsy. Approximately half who took an AED were taking either sodium valproate or carbamazepine.This study suggests that people with epilepsy who die from SUDEP in New Zealand are young and are often compliant with their medication. We plan to establish a nationwide SUDEP registry using the EpiNet database to determine the incidence of SUDEP in New Zealand, and to track changes in SUDEP rates. We are also planning to take part in an international case-control study of SUDEP in the hope that we might learn more about risk factors that predispose people with epilepsy to SUDEP, and factors that might reduce the risk.

Background: Renal dysfunction is a common complication following heart transplantation that may be worsened by the early initiation of calcineurin inhibitors. Antithymocyte globulin (ATG) or basiliximab has been used to delay or avoid calcineurin inhibitors. The most effective strategy for preventing early acute cellular rejection in this context is uncertain. Methods: We retrospectively reviewed all heart transplant cases between January 2012 and June 2017. The standard therapy consisted of mycophenolate mofetil, prednisolone, and tacrolimus. In patients at high risk of post-transplant renal dysfunction, an early calcineurin inhibitor-free regimen with basiliximab and/or ATG was used. Patients were assigned to cohorts based on the initial immunosuppressive strategy. The primary end point was the freedom rate of acute cellular rejection within 4 weeks post-transplant. Results: Of 93 cases, 21 patients received standard therapy, 64 patients received an initial calcineurin inhibitor-free regimen with basiliximab, and 8 patients received ATG and basiliximab. Freedom from acute rejection was greater in the ATG plus basiliximab group (all rejection free), compared to 40 (63%) of 64 patients treated with basiliximab and 10 (48%) of 21 patients treated with standard therapy ( P < .05, log rank test). In patients treated with basiliximab, early administration (Conclusions: The combination of ATG and basiliximab was more effective in preventing acute cellular rejection. In those patients treated with basiliximab, rejection rates were no worse than standard therapy; however, it was only effective when administered within 24 hours.

Background The mechanisms for cognitive impairment in heart failure (HF) are unclear. We investigated the relative contributions of cerebral blood flow velocity (BFV), oxidative stress, and inflammation to HF-associated cognitive impairment. Methods and Results Thirty-six HF patients (≥60 years) and 40 healthy controls (68 ± 7 vs 67 ± 5 years, P > .05; 69% vs 50% male, P > .05) completed the Cognitive Drug Research computerized assessment battery and Stroop tasks. Common carotid (CCA) and middle cerebral arterial BFV were obtained by transcranial Doppler. Blood samples were collected for oxidant (diacron-reactive oxygen metabolites; F 2 -isoprostanes), antioxidant (coenzyme Q 10 ; CoQ 10 ), and inflammatory markers (high-sensitivity C-reactive protein). Compared with controls, patients exhibited impaired attention (Cognitive Drug Research's Power of Attention domain, congruent Stroop) and executive function (incongruent Stroop). Multiple regression modeling showed that CCA-BFV and CoQ 10 but not group predicted performance on attention and executive function. Additionally, in HF patients, CCA-BFV and CoQ 10 ( β = −0.34 vs β = −0.35) were significant predictors of attention, and CCA-BFV ( β = −0.34) was a predictor of executive function. Conclusions Power of Attention and executive function is impaired in older HF patients, and reduced CCA-BFV and CoQ 10 are associated with worse cognition. Interventions addressing these mechanisms may improve cognition in older HF patients.

Advanced heart failure represents a small proportion of patients with heart failure that possess high-risk features associated with high hospital readmission rates, significant functional impairment and mortality. Identification of those who have progressed to, or are near a state of advanced heart failure should prompt referral to a service that offers therapies in mechanical circulatory support (MCS) and cardiac transplantation. MCS has grown as a management strategy in the care of these patients, most commonly as a bridge to cardiac transplantation. The predominant utilisation of MCS is implantation of left ventricular assist devices (LVAD), which have evolved significantly in their technology and application over the past 15-20 years. The technology has evolved to such an extent that Destination Therapy is now being utilised as a strategy in management of advanced heart failure in appropriately selected patients. Complication rates have decreased with VAD implantation, but remain a significant consideration in the decision to implant a device, and in the follow up of these patients.

Purpose Reported outcomes after left ventricular assist device (LVAD) implantation include mortality, hospital readmission and severe adverse events. We have less information about patients’ perceptions of their quality of life (QOL) after hospital discharge. We conducted a prospective two-center international pilot study to assess at-home functional capacity and QOL following LVAD implantation as a bridge to transplant (BTT) or destination therapy (DT). Methods 124 patients ≥ 30 days after discharge post-implantation were assessed telephonically or during on-site clinic visits. WHODAS 2.0 assesses disability in cognition, mobility, self-care, interpersonal relationships, work/household roles and societal participation. EQ-5D assesses impact of health status on 5 life dimensions. EQ-VAS reflects health self-assessment from 0-100 (worst to best imaginable). Results Mean patient age was 57.5±15.2 yrs; 15% female; 47% >1 yr post-implantation; 56% DT; 67% had HeartMate 3. Disability was minimal in 67% but moderate to severe in 33% (Figure). In the EQ-5D, moderate to extreme problems were reported with usual activities (33%), pain (32%), mobility (31%), self-care (24%) and anxiety (22%). At assessment, 42% reported an EQ-VAS ≥70, but 25% reported Conclusion The majority of LVAD out-patients reported good functional capacity, little impact of their health on major life domains, and high subjective health self-assessment. Yet a substantial minority did not enjoy a high QOL. A good EQ-VAS correlates with high functional ability, but some patients have a poor EQ-VAS even without disability. Routine assessment of functional ability and health status is feasible in post-discharge LVAD patients. Standardized, regular assessments could help us identify factors associated with a high versus low QOL.

Background Heart or lung transplantation alone in individuals with significant pre-existing renal impairment results in high mortality and morbidity. Simultaneous heart-kidney (SHK) or simultaneous lung-kidney (SLK) transplantation may be considered in patients with dual organ failure not suitable for single organ transplantation. Aim We aimed to outline the Australian and New Zealand experience of SHK and SLK transplantations, focussing on patient characteristics and survival. Methods We analysed all SHK and SLK transplants performed in four centres across Australia and New Zealand between 1990 and 2014. Results Over the study period, 35 SHK and 3 SLK transplants were performed across 4 transplant centres. Mean age at transplantation for SHK transplants was 45 years, and for SLK transplant was 27 years. The most common aetiology of renal failure was glomerulonephritis. Most SHK transplant patients (77%) required renal replacement therapy prior to transplantation, with only one of the three patients undergoing SLK transplant, dialysis dependent. One-year survival for the cohort was 79%, which is lower than reported for single organ transplantation. However, 5- and 10-year survivals of 76% and 68%, respectively, were comparable. Isolated renal graft loss was seen in five patients, with only one patient successfully re-transplanted and the rest commencing dialysis. Conclusion The Australian and New Zealand experience of SHK and SLK includes 38 patients with a high 1-year mortality, but excellent 5- and 10-year survivals. Based on this, it seems reasonable to continue to offer combined organ transplantation to select patients with dual organ failure.

A clinical case is described of a patient with a history of dextro-transposition of the great arteries (d-TGA) and prior atrial switch procedure who developed significant pulmonary hypertension whilst awaiting orthotopic cardiac transplantation. The increase in his pulmonary pressures necessitated de-listing for cardiac transplantation. A strategy of ventricular assist device (VAD) placement was then employed which provided improvement in his systemic cardiac output with left atrial off-loading to provide pulmonary vascular remodelling and consequently reduction in pulmonary vascular resistance (PVR). He was supported for a period of 408 days prior to successful orthotopic cardiac transplantation. A small number of cases with this abnormality undergoing VAD implantation have been described. Mechanical circulatory support has an important role in some patients with congenital heart disease.

Immune-mediated myocarditis is an uncommon adverse effect of immune checkpoint inhibition and is associated with a high rate of mortality. In this reported case, a 64-year-old woman with right temporo-parietal glioblastoma IDH-WT was treated with nivolumab, temozolomide and radiation therapy on a clinical trial. She developed malignant arrhythmias secondary to histologically confirmed severe immune-mediated myocarditis. She was treated with equine anti-thymocyte globulin (ATGAM) due to development of malignant arrhythmias refractory to high-dose corticosteroids. This report describes the only case of immune-mediated myocarditis treated with ATGAM resulting in a favourable outcome. Use of ATGAM should be considered in cases of steroid-refractory immune-mediated myocarditis and administered in close consultation with a cardiac transplant team experienced in the use of this agent.

A case is described of cardiogenic shock that occurred following use of sotalol in a patient with severe left ventricular dysfunction. The patient required left ventricular assist device (LVAD) placement with subsequent myocardial recovery to a degree that allowed eventual device removal following 140 days of support.

Microglia are the predominant resident immune cells of the brain and can assume a range of phenotypes. They are critical for normal brain development and function but can also contribute to many disease processes. Although they are widely studied, the transcriptional control of microglial phenotype and activation requires further research. PU.1 is a key myeloid transcription factor expressed by peripheral macrophages and rodent microglia. In this article, we report the presence of PU.1 specifically in microglia of the adult human brain and we examine its functional role in primary human microglia. Using siRNA, we achieved substantial PU.1 protein knock-down in vitro. By assessing a range of characteristic microglial proteins we found decreased viability of adult human microglia with reduced PU.1 protein expression. This observation was confirmed with PU.1 antisense DNA oligonucleotides. An important function of microglia is to clear debris by phagocytosis. We assessed the impact of loss of PU.1 on microglial phagocytosis and show that PU.1 siRNA reduces the ability of adult human microglia to phagocytose amyloid-beta1-42 peptide. These results show that PU.1 controls human microglial viability and function and suggest PU.1 as a molecular target for manipulation of human microglial phenotype.

Background Microglia are the primary immune cells of the brain whose phenotype largely depends on their surrounding micro-environment. Microglia respond to a multitude of soluble molecules produced by a variety of brain cells. Macrophage colony-stimulating factor (M-CSF) is a cytokine found in the brain whose receptor is expressed by microglia. Previous studies suggest a critical role for M-CSF in brain development and normal functioning as well as in several disease processes involving neuroinflammation. Methods Using biopsy tissue from patients with intractable temporal epilepsy and autopsy tissue, we cultured primary adult human microglia to investigate their response to M-CSF. Mixed glial cultures were treated with 25 ng/ml M-CSF for 96 hours. Proliferation and phagocytosis assays, and high through-put immunocytochemistry, microscopy and image analysis were performed to investigate microglial phenotype and function. Results We found that the phenotype of primary adult human microglia was markedly changed following exposure to M-CSF. A greater number of microglia were present in the M-CSF- treated cultures as the percentage of proliferating (BrdU and Ki67-positive) microglia was greatly increased. A number of changes in protein expression occurred following M-CSF treatment, including increased transcription factors PU.1 and C/EBPβ, increased DAP12 adaptor protein, increased M-CSF receptor (CSF-1R) and IGF-1 receptor, and reduced HLA-DP, DQ, DR antigen presentation protein. Furthermore, a distinct morphological change was observed with elongation of microglial processes. These changes in phenotype were accompanied by a functional increase in phagocytosis of Aβ1-42 peptide. Conclusions We show here that the cytokine M-CSF dramatically influences the phenotype of adult human microglia. These results pave the way for future investigation of M-CSF-related targets for human therapeutic benefit.

Essentials Relationship of acquired von Willebrand disease (VWD) and platelet dysfunction is explored. Patients with ventricular assist devices and on extracorporeal membrane oxygenation are investigated. Acquired VWD and platelet receptor shedding is demonstrated in the majority of patients. Loss of platelet adhesion receptors glycoprotein (GP) Ibα and GPVI may increase bleeding risk.Background Ventricular assist devices (VADs) and extracorporeal membrane oxygenation (ECMO) are associated with bleeding that is not fully explained by anticoagulant or antiplatelet use. Exposure of platelets to elevated shear in vitro leads to increased shedding. Objectives To investigate whether loss of platelet receptors occurs in vivo, and the relationship with acquired von Willebrand syndrome (AVWS). Methods Platelet counts, coagulation tests and von Willebrand factor (VWF) analyses were performed on samples from 21 continuous flow VAD (CF-VAD), 20 ECMO, 12 heart failure and seven aortic stenosis patients. Levels of platelet receptors were measured by flow cytometry or ELISA. Results The loss of high molecular weight VWF multimers was observed in 18 of 19 CF-VAD and 14 of 20 ECMO patients, consistent with AVWS. Platelet receptor shedding was demonstrated by elevated soluble glycoprotein (GP) VI levels in plasma and significantly reduced surface GPIbα and GPVI levels in CF-VAD and ECMO patients as compared with healthy donors. Platelet receptor levels were also significantly reduced in heart failure patients. Conclusions These data link AVWS and increased platelet receptor shedding in patients with CF-VADs or ECMO for the first time. Loss of the platelet surface receptors GPIbα and GPVI in heart failure, CF-VAD and ECMO patients may contribute to ablated platelet adhesion/activation, and limit thrombus formation under high/pathologic shear conditions.

Aim: To determine the impact of a pharmacist intervention on patient–guided diuretic dose adjustment in ambulatory patients with heart failure. Method: Patients with heart failure were randomised to usual care or usual care plus pharmacist intervention and followed for 3 months. Pharmacist intervention focused on patients improving self-care, recognising symptoms of fluid retention, measuring weight daily and self-adjusting diuretic dose using frusemide. The primary outcome was the number of appropriate weight-titrated frusemide dose adjustments. Secondary outcomes included the number of patients who correctly selfadjusted their frusemide dose, hospital readmissions due to fluid overload, heart failure-related knowledge and understanding, and quality of life (using validated tools). Results: 70 patients were recruited: 35 usual care (control) and 35 usual care plus pharmacist intervention. The average number of appropriate weight-titrated frusemide dose adjustments per patient per month in the control group was 0.32 ± 0.08 and in the intervention group was 0.85 ± 0.13 (p = 0.006). Hospital readmissions due to fluid overload was 31% in the control and 14% in the intervention groups (p = 0.04). There were significant differences between the groups regarding appropriate self-adjusted frusemide doses, heart failure-related knowledge and understanding, and quality of life. Conclusion: A pharmacist intervention improved the ability of heart failure patients to self-adjust their diuretic dose by using a flexible dosing regimen based on weight, resulting in quality of life improvement and a decrease in hospital readmissions due to fluid overload. J Pharm Pract Res 2011; 41: 126-31.

Valproic acid (VPA) is widely used for the treatment of mood disorders and epilepsy, but its mechanism of action is unclear. In vivo and in vitro studies using rodent models have demonstrated that VPA has both neuroprotective and neurotrophic effects. These beneficial effects are, in part, through modulation of glial cell function. Recently, we and others have shown that VPA selectively induces caspase-3 mediated apoptosis in rodent microglial cells. However, the effect of VPA on human microglia has not been tested. In this study, using microglia derived from adult human brains, we demonstrate that VPA does not induce microglial apoptosis as determined by the absence of caspase-3 cleavage. However, VPA does partially decrease the expression of the microglial markers PU.1 and CD45, as well as dramatically reducing microglial phagocytosis. Due to the many roles of microglia in the brain, these VPA-induced alterations in microglial phenotype could potentially have major effects on physiological and pathological actions of these cells.

We report our experience with an adolescent patient who required complex management leading to retransplantation for coronary allograft vasculopathy and also review the role of ventricular assist device support in patients with this clinical entity. doi: 10.1111/jocs.12412 (J Card Surg 2014;29:752–754)

Investigation into the contribution of the immune system and inflammatory cascade to acute rejection (AR) and cardiac allograft vasculopathy (CAV) has implicated vascular endothelial growth factor (VEGF). The endomyocardial biopsy (EB) has proved invaluable in the diagnosis of AR, and in providing information concerning the biological processes occurring following transplantation. The association between VEGF and AR and the development of CAV was examined in endomyocardial biopsies (EBs) from a cohort of 76 heart transplant recipients. VEGF mRNA levels were quantified through real time RT-PCR in 712 EBs, obtained at routine intervals during post-operative monitoring. VEGF and leukocyte and endothelial markers were assessed in a subset of biopsies through immunohistochemistry. The results of generalised linear modelling, adjusting for covariates, revealed VEGF mRNA expression was 19% greater during severe AR as compared to no rejection (p=0.007). Immunohistochemical results supported these findings. Mean VEGF mRNA levels were not significant predictors for the development of CAV (p=0.554). However the risk of cardiac related death increased 9-fold for a 1 unit increase in mean VEGF expression (p=0.006). Similarly, a single unit increase in mean AR severity equated to a 10-fold increase in the risk of cardiac related death (p0.005). Our data suggest that increased VEGF expression is strongly associated with severe AR and cardiac related death.

We present a case of a patient with longstanding transfusion-dependent congenital dyserythropoietic anaemia (CDA) who developed cardiomyopathy despite iron chelation therapy. She presented with severe heart failure that responded poorly to conventional therapy, recovering only when therapy was augmented with metabolic agents including antioxidants and with increased iron chelation. The present case gives support to the concept of treating oxidatively induced heart failure with metabolic and antioxidant therapy. This therapy may have wider application in refractory heart failure and in the prevention of cardiomyopathy in patients receiving regular red cell transfusions who are at risk of transfusional haemosiderosis.

Background The purpose of this study was to determine the incidence and type of malignancies in heart and/or lung transplant recipients at a single institution in Victoria, Australia, and to compare these findings with the non-transplant general Victorian population. Methods Recipients of heart and/or lung transplants at the Alfred Hospital between February 1989 and January 2004 were cross-referenced with the Victorian Cancer Registry. The medical records of all patients with a cancer diagnosis by January 1, 2005 were reviewed. Data were collected on baseline demographics, including cancer type, stage, treatment and survival. Cancer incidence was then compared with rates found in the Victorian population. Results There were 907 transplants (Tx) conducted between February 1989 and January 1, 2004 on 905 patients, which included 424 heart (HTx), 56 heart–lung (HLTx), 200 single-lung (SLTx), and 227 double-lung (DLTx) procedures. Of these patients, 606 (67%) were male and 299 (33%) were female. Mean age at transplantation was 46.4 years (range 12.6 to 70.4 years). Four hundred twenty-four (47%) deaths have occurred. Median survival for all patients after transplantation was 8.6 years. One hundred two cancers were confirmed, translating to a 7.1-fold increased incidence compared with the non-transplant population. The most common cancer diagnoses were lymphoproliferative disorders (692 per 100,000 person-years), head and neck cancer (336 per 100,000 person-years) and lung cancer (251 per 100,000 person-years). Compared with the non-transplant population this translates into a 26.2-, 21.0- and 9.3-fold increased risk for developing these cancers, respectively, after cardio-pulmonary transplantation. Conclusions Certain malignancies are more common after heart and/or lung transplantation. The most predominant in our cohort were lymphoproliferative disorders, head and neck cancer and lung cancer.

Introduction: The aim of this paper was to review the outcomes of cardiac transplantation with regards to short- and long-term survival, focusing particularly on patients who receive organs with long ischemic times and the resource utilization necessary to support such patients through their postoperative period. Methods: A retrospective review of 420 consecutive cardiac transplants in a single institution was undertaken. Results: The five- and 10-yr survival rates for the entire group were 0.76 (95% CI: 0.72–0.80) and 0.60 (0.54–0.66). There was no decrease in mid- or long-term survival in patients who received organs with ischemic times over 300 min. Longer donor organ ischemic time was not associated with increased 30 d mortality but was significantly associated with longer intensive care bed stay, increased incidence of primary graft failure, need for mechanical support, and complications such as acute renal failures. Conclusions: Although using donor organs with longer ischemic times for cardiac transplantation does not impact on survival, there is a significantly increased utilization of resources to ensure these patients survive the postoperative period.

Chronic heart failure (CHF) among Aboriginal/Indigenous Australians is endemic. There are also grave concerns for outcomes once acquired. This point is compounded by a lack of prospective and objective studies to plan care. To capture the essence of the presented topic it is essential to broadly understand Indigenous health. Key words such as 'worsening', 'gaps', 'need to do more', 'poorly studied', or 'future studies should inform' occur frequently in contrast to CHF research for almost all other groups. This narrative styled opinion piece attempts to discuss future directions for CHF care for Indigenous Australians. We provide a synopsis of the problem, highlight the treatment gaps, and define the impediments that present hurdles in optimising CHF care for Indigenous Australians.

A case is described of cardiogenic shock that occurred following use of sotalol in a patient with severe left ventricular dysfunction. The patient required left ventricular assist device (LVAD) placement with subsequent myocardial recovery to a degree that allowed eventual device removal following 140 days of support.

To compare and establish the relevance of the relative degree of sympathetic nervous system activity (SNSA) in groups of patients with congestive heart failure (CHF) and obstructive sleep apnea (OSA), and in a control group.Elevated SNSA is a characteristic feature of CHF, as well as of OSA and nonhypercapnic central sleep apnea (CSA). OSA and CSA commonly occur with CHF; however, the relative contribution of apnea-related hypoxemia and sleep fragmentation to the SNSA of patients with CHF is not known.This was a prospective, controlled, observational trial in which the overnight urinary norepinephrine (UNE) level, which is a measure of integrated overnight SNSA while asleep, was measured in 15 healthy male volunteers, 15 male OSA patients who did not have CHF, and 90 CHF patients (77 men). CHF patients also had right heart pressure measurements and then were grouped by the presence of sleep apnea.Compared with healthy individuals, the mean (+/- SD) UNE level was significantly elevated in the OSA group and was even further elevated in the CHF group (13.4 +/- 5.6 vs 19.7 +/- 12.3 vs 32.2 +/- 20.2 nmol/mmol creatinine, respectively; p0.001 [by analysis of variance]). Within the CHF group, the mean UNE levels were greatest in the CHF-CSA group compared with the CHF-OSA group and the CHF nonapnea group (43.9 +/- 24.1 vs 24.0 +/- 10.8 vs 22.4 +/- 8.9 nmol/mmol creatinine, respectively; p0.001). Using a multivariate regression model, the variance of the UNE level in the CHF group was predicted, in descending order, by pulmonary capillary wedge pressure (14% variance), rapid eye movement sleep (8%), and the mean sleep pulse oximetry level (7%).Overnight SNSA is significantly greater in CHF patients than in OSA patients. Moreover, the hemodynamic severity of CHF contributes to the elevation of SNSA in CHF patients to a greater degree than apnea-related hypoxemia.

Cardiac donation for transplantation following a lightning strike has the potential to provide satisfactory clinical outcomes. Magnetic resonance imaging (MRI) provides an excellent diagnostic modality for follow-up of cardiac injury in this clinical setting. A 22 year-old woman underwent prolonged cardiopulmonary resuscitation following a lightning strike (resuscitation time 115 minutes). An electrocardiogram demonstrated changes consistent with acute inferior myocardial injury (1 mm of ST elevation in the inferolateral leads with associated T wave inversion in anterior leads) and peak troponin I was 188,000 ng/L, however, an echocardiogram reported normal left ventricular systolic function. The patient was declared brain dead and was accepted for cardiac donation. The donor was haemodynamically stable without any cardiac abnormality during organ procurement. The recipient was a 52 year-old woman with an ischaemic cardiomyopathy. At the time of orthotopic cardiac transplantation, the implanting surgeon noted a circumscribed area of inferior wall oedema on the donor heart consistent with a recent acute myocardial injury (not identified at the time of procurement). The total ischaemic time was 368 minutes due to long distance transportation of the donor heart. The patient was weaned off cardiopulmonary bypass on moderate inotropic support with persisting inferior wall hypokinesis seen

This case series outlines the technique and results of right ventricular assist device (RVAD) support with the off-label use of the centrifugal HeartWare HVAD (HeartWare Inc., Framingham, MA, USA) for long-term support. Four patients in our institution have been implanted with BiVADs, using the Heartware device as the RVAD, and supported for between 117 days and 772 days. Three of the patients have been successfully supported for over 18 months. Three patients have successfully been transplanted and one patient remains on the device, now approaching two years of support. None of the patients have had RVAD device-related complications.

We report our experience with an adolescent patient who required complex management leading to retransplantation for coronary allograft vasculopathy and also review the role of ventricular assist device support in patients with this clinical entity.