An ISHLT consensus statement on strategies to prevent and manage hemocompatibility related adverse events in patients with a durable, continuous-flow ventricular assist device.

Life expectancy of patients with a durable, continuous-flow left ventricular assist device (CF-LVAD) continues to increase. Despite significant improvements in the delivery of care for patients with these devices, hemocompatability-related adverse events (HRAEs) are still a concern and contribute to significant morbility and mortality when they occur. As such, dissemination of current best evidence and practices is of critical importance. This ISHLT Consensus Statement is a summative assessment of the current literature on prevention and management of HRAEs through optimal management of oral anticoagulant and antiplatelet medications, parenteral anticoagulant medications, management of patients at high risk for HRAEs and those experiencing thrombotic or bleeding events, and device management outside of antithrombotic medications. This document is intended to assist clinicians caring for patients with a CF-LVAD provide the best care possible with respect to prevention and management of these events.

Comparison of survival by vasoactive-inotropic score in patients receiving veno-arterial extracorporeal life support.

After the initiation of veno-arterial extracorporeal membrane oxygenation (V-A ECMO) for hemodynamic support, patients often require vasopressor and inotropic medications to support their blood pressure and cardiac contractility. The vasoactive-inotropic score (VIS) is a standardized calculation of vasopressor and inotrope equivalence, which uses coefficients for each medication to calculate a total value. This study evaluated the association between the 30-day survival of patients receiving V-A ECMO support and the VIS calculated 24 h after ECMO cannulation (VIS24). This was a single-center, retrospective, observational cohort study. The median VIS24 of the entire cohort was 6.0, and was determined as a cutoff for comparison. Patients with a VIS24 < 6.0 were assigned to a group, and those with a VIS24 ≥ 6.0 were assigned to a second group. Patients with a VIS24 < 6.0 had higher 30-day survival than those with a VIS24 ≥ 6.0 (54.5% vs 41.4%; p = 0.03). The group with a VIS24 < 6.0 also had significantly improved survival to decannulation of ECMO support; however, there was no difference in the survival to hospital discharge. We conducted a secondary analysis of quartiles and determined that individuals with a VIS24 > 11.4 had the lowest survival in the cohort. This finding may help identify patients with the lowest probability of 30-day survival in those receiving V-A ECMO for hemodynamic support.

Evaluation of Vasoactive-Inotropic Score and Survival to Decannulation in Adult Patients on Venoarterial Extracorporeal Life Support: An Observational Cohort Study.

Extracorporeal life support with venoarterial extracorporeal membrane oxygenation (VA-ECMO) is used to assist circulation in patients with severe cardiogenic shock or cardiac arrest. The vasoactive-inotropic score (VIS) is a standardized calculation of vasoactive medication support which uses coefficients for each medication that converts them to an equivalent value. The purpose of this study was to assess the VIS as an early prognostication tool for survival to decannulation patients on adult VA-ECMO support. This was a single-center, observational cohort study of adult patients who received VA-ECMO support compared based on their survival to decannulation. The primary endpoint was the VIS at hour 24 postcannulation. Among the 265 patients included in this study, 140 patients (52.8%) survived to decannulation of VA-ECMO. At 24 hours postcannulation, a lower VIS was observed in the group that survived decannulation (6.5 ± 7.5 vs. 12.3 ± 16.9; p < 0.001). Multivariate analysis performed also demonstrates an association between 24-hour VIS and survival to decannulation (odds ratio 0.95; 95% confidence interval, 0.91-0.95). This study suggests that the 24-hour VIS may be an early prognostic indicator in patients on VA-ECMO patients. http://links.lww.com/ASAIO/B39.

The drebrin/EB3 pathway regulates cytoskeletal dynamics to drive neuritogenesis in embryonic cortical neurons.

Co-ordinating the dynamic behaviour of actin filaments (F-actin) and microtubules in filopodia is an important underlying process in neuritogenesis, but the molecular pathways involved are ill-defined. The drebrin/end-binding protein 3 (EB3) pathway is a candidate pathway for linking F-actin to microtubules in filopodia. Drebrin binds F-actin and, simultaneously, the microtubule-binding protein EB3 when bound to microtubule plus-ends. We assessed the effect on neuritogenesis of gain- or loss-of-function of proteins in the drebrin/EB3 pathway in rat embryonic cortical neurons in culture. Loss-of-function of drebrin by gene editing or pharmacological inhibition of drebrin binding to F-actin reduced the number of dynamic microtubules in the cell periphery and simultaneously delayed the initiation of neuritogenesis, whereas over-expression of drebrin induced supernumerary neurites. Similarly, loss of EB3 inhibited neuritogenesis, whereas loss of end-binding protein 1 (EB1), a related protein that does not bind to drebrin, did not affect neuritogenesis. Over-expression of EB3, but not EB1, induced supernumerary neurites. We discovered that EB3 is more proximally located at dynamic microtubule plus-ends than EB1 in growth cone filopodia allowing for continuous microtubule elongation as the drebrin/EB3 pathway zippers microtubules to F-actin in filopodia. Finally, we showed that preventing the entry of dynamic microtubules into filopodia using a pharmacological inhibitor of microtubule dynamics is associated with a loss of EB3, but not EB1, from microtubule plus-ends and a concurrent attenuation of neuritogenesis. Collectively, these findings support the idea that neuritogenesis depends on microtubule/F-actin zippering in filopodia orchestrated by the drebrin/EB3 pathway.

Optimizing anticoagulation for patients receiving Impella support.

Anticoagulation of patients treated with the Impella percutaneous mechanical circulatory support (MCS) devices is complex and lacks consistency across centers, potentially increasing the risk of complications. In order to optimize safety and efficacy, an expert committee synthesized all available evidence evaluating anticoagulation for patients receiving Impella support in order to provide consensus recommendations for the management of anticoagulation with these devices. The evidence synthesis led to the creation of 42 recommendations to improve anticoagulation management related to the use of the Impella devices. Recommendations address purge solution management, intravenous anticoagulation, monitoring, evaluation and management of heparin-induced thrombocytopenia (HIT), and management during combination MCS support. The use of a heparinized, dextrose-containing purge solution is critical for optimal device function, and a bicarbonate-based purge solution may be an alternative in certain situations. Likewise, intravenous (ie, systemic) anticoagulation with heparin is often necessary, although evidence supporting the optimal assay and target range for monitoring the level of anticoagulation is generally lacking. Patients treated with an Impella MCS device may develop HIT, which is more difficult to evaluate and treat in this setting. Lastly, the use of Impella with extracorporeal membrane oxygenation or for biventricular support creates additional anticoagulation challenges.

Management of reproductive health after cardiac transplantation.

Pregnancy after cardiac transplantation poses immense challenges. Maternal risks include hypertensive disorders of pregnancy, rejection, and failure of the cardiac allograft that may lead to death. Fetal risks include potential teratogenic effects of immunosuppression and prematurity. Because of the high-risk nature of pregnancy in a heart transplant patient, management of reproductive health after cardiac transplantation should include preconception counseling to all women in the reproductive age group before and after cardiac transplantation. Reliable contraception is vital as nearly half of the pregnancies in this population are unintended. Despite the associated risks, successful pregnancies after cardiac transplantation have been reported. A multidisciplinary approach proposed in this review is essential for successful outcomes. A checklist for providers to guide management is provided.

Report from the 2018 consensus conference on immunomodulating agents in thoracic transplantation: Access, formulations, generics, therapeutic drug monitoring, and special populations.

In 2009, the International Society for Heart and Lung Transplantation recognized the importance and challenges surrounding generic drug immunosuppression. As experience with generics has expanded and comfort has increased, substantial issues have arisen since that time with other aspects of immunomodulation that have not been addressed, such as access to medicines, alternative immunosuppression formulations, additional generics, implications on therapeutic drug monitoring, and implications for special populations such as pediatrics and older adults. The aim of this consensus document is to address critically each of these concerns, expand on the challenges and barriers, and provide therapeutic considerations for practitioners who manage patients who need to undergo or have undergone cardiothoracic transplantation.

Risk of pump thrombosis and stroke in patients with continuous-flow left ventricular assist devices and gastrointestinal bleeding.

Gastrointestinal (GI) bleeding is a common complication following the placement of continuous-flow left ventricular assist devices (LVADs) in patients with advanced heart failure. Secondary events arising as a result of GI bleeding have not been well-described. Furthermore, attribution of these events to bleeding is complicated by the interruption or de-intensification of antithrombotic therapy, while bleeding is controlled. The purpose of this study was to assess the incidence of pump thrombosis and ischemic stroke in patients with LVADs who experience GI bleeding, while on support. This was a single-center, retrospective, observational cohort study of consecutive patients with LVADs implanted from January 2012 to June 2018. Patients were assigned to comparator groups based on whether they experienced GI bleeding while on LVAD support. The primary endpoint assessed was the composite of pump thrombosis or ischemic stroke. Secondary endpoints assessed included incidence of pump thrombosis or ischemic stroke. A total of 250 patients were included after screening for exclusion criteria, 101 (40.4%) in the GI bleeding group, and 149 (59.6%) in the non-bleeding group. The incidence of pump thrombosis or ischemic stroke was not significantly greater in patients experiencing GI bleeding [23 (22.8%) vs. 21 (14.1%); P = .09]; however, the incidence of ischemic stroke alone was significantly greater [17 (16.8%) vs. 10 (6.7%); P = .01]. We conclude that GI bleeding in LVAD patients may be associated with a greater risk of ischemic stroke.

Anticoagulation of Impella with a Bivalirudin Purge Solution.

The use of percutaneous ventricular assist devices (VADs) in the acute management of cardiogenic shock is becoming increasingly common. The Impella is a percutaneous VAD, which requires a heparin-containing purge solution to prevent thrombosis and maintain proper pump functionality. In this report, we describe two patients with heparin-induced thrombocytopenia (HIT) supported with an Impella using a bivalirudin-containing purge solution. Case 1 involved a 39-year-old man with cardiogenic shock, initially implanted with an intraaortic balloon pump, who developed HIT early in his hospital course. His worsening hemodynamics necessitated the placement of an Impella and later venoarterial extracorporeal membrane oxygenation until he eventually underwent durable left VAD implantation. Case 2 involved a 69-year-old man who had an Impella implanted for worsening cardiogenic shock. HIT was suspected shortly after device insertion, necessitating switching his anticoagulation to bivalirudin. He was successfully bridged directly to heart transplantation. Both patients' courses resulted in therapeutic anticoagulation without major bleeding or thrombotic events. These cases demonstrate the safe and effective use of bivalirudin-containing purge solutions for patients with confirmed HIT requiring temporary mechanical circulatory support with Impella.

Comparison of polyspecific versus IgG specific ELISA in predominately cardiac patients with suspected heparin induced thrombocytopenia.

A diagnosis of heparin induced thrombocytopenia (HIT) must often be made based on clinical and laboratory evidence. This was a quasi-experimental study of patients admitted from June 2016 to October 2017. The primary endpoint was the incidence of false positive results in polyspecific and IgG specific enzyme-linked immunosorbent assay (ELISA); then we compared the sensitivity and specificity of each assays in predominately cardiac patients with suspected HIT. A sensitivity/specificity analysis was conducted using serotonin release assay (SRA) as the 'gold standard'. The secondary outcome measures included length of hospital stay. We identified a total of 155 patients who met the inclusion criteria. Confirmatory tests with SRA on both groups were completed; false positive result was higher in the polyspecific group when compared to the IgG group [60% vs. 5%]. The IgG specific ELISA test yielded a sensitivity of 100% and a specificity of 95% however, the polyspecific ELISA had a low yield for specificity of 24% but maintained 100% sensitivity. In the IgG specific group with HIT-, their median length of stay was halved compared to those who were HIT + ; hospital LOS in days, IQR [30 (27-81) vs. 15 (7-33) p = 0.023] and a shorter median LOS in the ICU, IQR [24 (5-47) vs. 6 (2-14); p = 0.079]. Hospital or ICU LOS was the same in both (HIT+ and HIT-) groups managed with polyspecific ELISA. The IgG specific test had few false positive results and a high sensitivity score. Ensuring appropriate testing can bring a substantial decrease in drug expenditure, reduced length of stay and prevent unnecessary anticoagulation.

Antiplatelet Therapy Bridging With Cangrelor in Patients With Coronary Stents: A Case Series.

BACKGROUND: Cangrelor is an intravenous P2Y12 receptor antagonist approved for use during percutaneous coronary intervention (PCI) to reduce ischemic events associated with new stent placement and has been used off-label at reduced doses guided by platelet function testing as a "bridge" from discontinuation of oral P2Y12 receptor antagonists to surgical procedures when the long-term effects of oral agents are undesirable. OBJECTIVE: To describe the dosing, laboratory monitoring, and clinical outcomes of a series of patients who received cangrelor as a "bridging" antiplatelet agent. METHODS: This study is a retrospective analysis of all patients within the study center with coronary stents who received cangrelor as a bridge to surgical procedure and had VerifyNow monitoring during treatment. RESULTS: A total of 11 patients were identified for inclusion. The median cangrelor dose was 0.5 µg/kg/min (interquartile range = 0.5-0.5) and was maintained in 7 of 11 patients. Doses ranged from 0.25 to 2 µg/kg/min during therapy, and 81.6% of VerifyNow results assessed were within goal range (⩽208 P2Y12 reaction units). Bleeding complications during therapy occurred in 3 patients, all of whom were receiving concomitant heparin infusions, and no stent thrombosis was reported. Conclusion and Relevance: Low-dose cangrelor may represent an effective option for bridging antiplatelet therapy in patients with coronary stents. This study demonstrated that the majority of patients received adequate platelet inhibition without any incidence of stent thrombosis on 0.5 µg/kg/min using the VerifyNow assay to monitor platelet inhibition, which represents a lower dose than previously reported in the literature.

Bivalirudin for left ventricular assist device thrombosis.

Pump thrombosis remains a serious complication of implantable ventricular assist device therapy and is associated with increased risk of morbidity and mortality. Optimal management strategies remain controversial and are guided largely by limited literature and expert opinion. Medical management of pump thrombosis, including the use of direct thrombin inhibitors, has been associated with mixed results. The purpose of this study is to report the outcomes associated with bivalirudin therapy in LVAD patients with suspected pump thrombosis. A single-center, retrospective observational study of 15 patients with suspected pump thrombosis that were all treated with bivalirudin therapy was conducted. The majority of subjects' initial treatment courses were unsuccessful [9/15 (60%)]; however, 6/15 (40%) achieved an initial improvement in serum lactate dehydrogenase (LDH) levels and were stabilized to be successfully discharged from the hospital. Of the subjects discharged, there was a high rate of recurrence of pump thrombosis within 6 months [5/6 (83.3%)]. Bivalirudin therapy was not associated with a consistent reduction in LDH among all subjects studied, and clinical responses to therapy appear to be associated with high rates of thrombosis recurrence. This study analyzes the largest cohort to date of LVAD patients with pump thrombosis treated with bivalirudin therapy, and suggests that alternative therapies should be considered in management.

Phosphorylation of Drebrin and Its Role in Neuritogenesis.

Neuritogenesis is an early event in neuronal development in which newborn neurons first form growth cones, as a prerequisite for the formation of axons and dendrites. Growth cones emerge from segmented regions of the lamellipodium of embryonic neurons and grow away from the cell body leaving behind a neurite that will eventually polarise into an axon or dendrite. Growth cones also function to navigate precise routes through the embryo to locate an appropriate synaptic partner. Dynamic interactions between two components of the neuronal cytoskeleton, actin filaments and microtubules, are known to be essential for growth cone formation and hence neuritogenesis. The molecular mechanisms that coordinate interactions between actin filaments and dynamic microtubules during neuritogenesis are beginning to be understood. One candidate pathway coupling actin filaments to microtubules consists of the actin filament-binding protein drebrin and the microtubule-binding +TIP protein EB3. This pathway is regulated proximally by cyclin-dependent kinase 5 phosphorylation of drebrin but the upstream elements in the pathway have yet to be identified.

The Role of Drebrin in Cancer Cell Invasion.

Cancer progression is characterized by the capacity of malignant cells to exploit an innate migratory ability in order to invade adjacent tissues, enter the vasculature and eventually metastasize to secondary organs. It is this spread of cancer cells that is the major cause of death in cancer patients. Understanding the basic biology of how cancer cells generate an invasive phenotype will be crucial to the identification of drug targets with the aim of impeding tumour dissemination. Ten years on from its initial description in neuronal cells, drebrin expression was found in a wide variety of non-neuronal cells that importantly included cancer cell lines. Since then mounting evidence suggests that drebrin may be a key player in the advancement of several diverse cancer types where its expression is frequently upregulated. Cancer cell motility and invasion are crucial elements in the metastatic cascade and involve dramatic changes in cellular morphology that are associated with dynamic remodelling of the cytoskeleton. Interestingly, it now appears that drebrin could deliver this role during cancer development.

Drebrin-mediated microtubule-actomyosin coupling steers cerebellar granule neuron nucleokinesis and migration pathway selection.

Neuronal migration from a germinal zone to a final laminar position is essential for the morphogenesis of neuronal circuits. While it is hypothesized that microtubule-actomyosin crosstalk is required for a neuron's 'two-stroke' nucleokinesis cycle, the molecular mechanisms controlling such crosstalk are not defined. By using the drebrin microtubule-actin crosslinking protein as an entry point into the cerebellar granule neuron system in combination with super-resolution microscopy, we investigate how these cytoskeletal systems interface during migration. Lattice light-sheet and structured illumination microscopy reveal a proximal leading process nanoscale architecture wherein f-actin and drebrin intervene between microtubules and the plasma membrane. Functional perturbations of drebrin demonstrate that proximal leading process microtubule-actomyosin coupling steers the direction of centrosome and somal migration, as well as the switch from tangential to radial migration. Finally, the Siah2 E3 ubiquitin ligase antagonizes drebrin function, suggesting a model for control of the microtubule-actomyosin interfaces during neuronal differentiation.

Treatment of Multiple Myeloma in a Heart Transplant Recipient.

Malignancy following solid organ transplant remains a significant threat to the survival of cardiac transplant recipients. Plasma cell dyscrasias including multiple myeloma have been encountered in this population, and medication treatments traditionally used to treat these disorders demonstrate immunomodulatory effects that may have implications on the transplanted allograft. Lenalidomide is an immunomodulatory agent that has been used to treat plasma cell disorders, including light-chain amyloidosis (AL) and multiple myeloma, and represents such a class of medications in which the risks and benefits in the solid organ transplant population remain to be fully elucidated. This report highlights a clinical practice issue where the treatment of a patient's multiple myeloma with lenalidomide may have potentiated an episode of severe acute cellular rejection and further demonstrates the need for future investigation of the optimal treatment of plasma cell disorders including AL amyloidosis and multiple myeloma following solid organ transplantation.

The role of the drebrin/EB3/Cdk5 pathway in dendritic spine plasticity, implications for Alzheimer's disease.

The drebrin/EB3/Cdk5 intracellular signalling pathway couples actin filaments to dynamic microtubules in cellular settings where cells are changing shape. The pathway has been most intensively studied in neuronal development, particularly neuritogenesis and neuronal migration, and in synaptic plasticity at dendritic spines in mature neurons. Drebrin is an actin filament side-binding and bundling protein that stabilises actin filaments. The end-binding (EB) proteins are microtubule plus-end tracking proteins (+TIPs) that localise to the growing plus-ends of dynamic microtubules and regulate their behavior and the binding of other +TIP proteins. EB3 binds specifically to drebrin when drebrin is bound to actin filaments, for example at the base of a growth cone filopodium, and EB3 is located at the plus-end of a growing microtubule inserting into the filopodium. This interaction therefore forms the basis for coupling dynamic microtubules to actin filaments in growth cones of developing neurons. Appropriate responses to growth cone guidance cues depend on actin filament/microtubule co-ordination in the growth cone, although the role of the drebrin/EB3/Cdk5 pathway in this context has not been directly tested. A similar cytoskeleton coupling pathway operates in dendritic spines in mature neurons where the activity-dependent insertion of dynamic microtubules into dendritic spines is facilitated by drebrin binding to EB3. Microtubule insertion into dendritic spines drives spine maturation during long-term potentiation and therefore has a role in synaptic plasticity and memory formation. In Alzheimer's disease and related chronic neurodegenerative diseases, there is an early and dramatic loss of drebrin from dendritic spines that precedes synapse loss and neurodegeneration and might contribute to a failure of synaptic plasticity and hence to cognitive decline.

Statin therapy in cardiac allograft vasculopathy progression in heart transplant patients: Does potency matter?

Cardiac allograft vasculopathy (CAV) is a unique multi-factorial pathologic process encountered following heart transplantation. Several risk factors have been identified including a combination of immunologic and non-immunologic processes. Significant research has been conducted to elucidate the driving forces of CAV as well as improved identification, prevention and treatment strategies. Statin therapy following transplant remains the standard of care to help prevent the progression of CAV. The benefits of statin therapy following transplantation correspond to cholesterol control, anti-inflammatory and immunomodulatory mechanisms as well as potentially unknown mechanisms. Despite known drug interactions with calcineurin inhibitors, the use of statins is highly recommended in the current International Society for Heart and Lung Transplantation guidelines. Limited research has been conducted on the impact of higher intensity statin therapy following heart transplant and the relative risks and benefits are unknown. This review focuses on risk factors and pathophysiology of CAV, the role of statin therapy in heart transplantation, and the potential added benefit of more intense statin therapy to limit the progression of this graft-limiting complication.

The Actin-Binding Protein Drebrin Inhibits Neointimal Hyperplasia.

OBJECTIVE: Vascular smooth muscle cell (SMC) migration is regulated by cytoskeletal remodeling as well as by certain transient receptor potential (TRP) channels, nonselective cation channels that modulate calcium influx. Proper function of multiple subfamily C TRP (TRPC) channels requires the scaffolding protein Homer 1, which associates with the actin-binding protein Drebrin. We found that SMC Drebrin expression is upregulated in atherosclerosis and in response to injury and investigated whether Drebrin inhibits SMC activation, either through regulation of TRP channel function via Homer or through a direct effect on the actin cytoskeleton. APPROACH AND RESULTS: Wild-type (WT) and congenic Dbn(-/+) mice were subjected to wire-mediated carotid endothelial denudation. Subsequent neointimal hyperplasia was 2.4±0.3-fold greater in Dbn(-/+) than in WT mice. Levels of globular actin were equivalent in Dbn(-/+) and WT SMCs, but there was a 2.4±0.5-fold decrease in filamentous actin in Dbn(-/+) SMCs compared with WT. Filamentous actin was restored to WT levels in Dbn(-/+) SMCs by adenoviral-mediated rescue expression of Drebrin. Compared with WT SMCs, Dbn(-/+) SMCs exhibited increased TRP channel activity in response to platelet-derived growth factor, increased migration assessed in Boyden chambers, and increased proliferation. Enhanced TRP channel activity and migration in Dbn(-/+) SMCs were normalized to WT levels by rescue expression of not only WT Drebrin but also a mutant Drebrin isoform that binds actin but fails to bind Homer. CONCLUSIONS: Drebrin reduces SMC activation through its interaction with the actin cytoskeleton but independently of its interaction with Homer scaffolds.