BACKGROUND The potential for myocardial reconditioning and device explantation after long-term continuous-flow left ventricular assist device (LVAD) support presents an opportunity to delay or avoid transplantation in select patients. METHODS Thirty of 657 patients with end-stage heart failure supported with continuous-flow LVADs were assessed for device explantation. Each patient underwent an individualized process of weaning focused on principles of ventricular unloading, gradual reconditioning, and transition to medical therapy. RESULTS After varying reconditioning periods, 27 patients (16 men, 11 women; age, 39 ± 12 years) underwent LVAD explant, and 3 patients (2 men, 1 woman; age, 22 ± 6 years) were evaluated for explantation but could not be weaned. The duration of LVAD support was 533 ± 424 days (range, 42– 1,937 days) for the explant cohort and 1,097 ± 424 days (range, 643–1,483) for the non-explant cohort. The LV end-diastolic dimension, LV ejection fraction, systolic pulmonary artery pressure, cardiac output, and cardiac index in the explant cohort were significantly improved at explantation (all, p < 0.05). Two late deaths occurred after LVAD explantation despite satisfactory native cardiac function, and 1 patient required resumption of LVAD support 2.7 years after device removal. The remaining explant patients remain in New York Heart Association classes I to II with medical management alone (mean survival post-explant, 1,172 ± 948 days). The 3 candidates who could not be weaned ultimately underwent transplantation. CONCLUSIONS The potential for recovery of native LV function after long-term continuous-flow LVAD support should encourage a more aggressive approach to ventricular reconditioning with the goal of device explantation and a return to medical management, particularly in young patients with dilated cardiomyopathy.

BACKGROUND Continuous-flow left ventricular assist devices (LVADs) expose blood cells to high shear stress, potentially resulting in the production of microparticles that express phosphatidylserine (PS+) and promote coagulation and inflammation. In this prospective study, we attempted to determine whether PS+ microparticle levels correlate with clinical outcomes in LVAD-supported patients. METHODS We enrolled 20 patients undergoing implantation of the HeartMate II LVAD and 10 healthy controls who provided reference values for the microparticle assays. Plasma was collected before LVAD implantation, at discharge, at 3-month follow-up, and when an adverse clinical event occurred. We quantified PS+ microparticles in the plasma using flow cytometry. RESULTS During the study period, 8 patients developed adverse clinical events: ventricular tachycardia storm (n=1), non–ST-elevation myocardial infarction (n=2), arterial thrombosis (n=2), gastrointestinal bleeding (n=2), and stroke (n=3). Levels of PS+ microparticles were higher in patients at baseline than in healthy controls (2.11%±1.26 vs 0.69±0.46, P=0.007). After LVAD implantation, patient PS+ microparticle levels increased to 2.39%±1.22 at discharge and then leveled to 1.97%±1.25 at 3-month follow-up. Importantly, patients who developed an adverse event had significantly higher levels of PS+ microparticles than did patients with no events (3.82%±1.17 vs 1.57%±0.59, P<0.001), even though the 2 patient groups did not markedly differ in other clinical and hematologic parameters. CONCLUSIONS Our results suggest that an elevation of PS+ microparticle levels may be associated with adverse clinical events. Thus, measuring PS+ microparticle levels in LVAD-supported patients may help identify patients at increased risk for adverse events.

A Large Single-Center StudyLeft ventricular assist device (LVAD) C irculatory support with left ventricular assist devices (LVADs) has emerged as a powerful therapy that can improve outcomes in patients who have advanced heart failure (HF) refractory to medical therapy.1-3 The scarcity of donor organs severely limits transplantation as an option for patients with advanced HF; moreover, transplant patients need lifelong immunosuppression, the medications for which can have their own serious side effects. The newest generation of LVADs comprises continuous-flow (CF) pumps, which use axial or centrifugal technology, deliver flows of up to 10 L/min, 2,4 and are smaller and more durable than previous models. Currently, these LVADs are implanted either as a bridge to transplantation (BTT) or as destination therapy (DT), which offers a permanent alternative to transplantation.Recently, patients with end-stage HF were given new options when the U.S. Food and Drug Administration (FDA) approved 2 continuous-flow LVADs: the HeartMate ® II (Thoratec Corporation; Pleasanton, Calif ) and the HeartWare ® Ventricular Assist System (HeartWare Inc.; Framingham, Mass). The HeartMate II was approved for BTT in 2008 and for DT in 2010, and the HeartWare was approved for BTT in 2012. These milestones initiated modern LVAD therapy, enabling this treatment to become available to a larger population of patients. [5][6][7][8][9] Consequently, LVAD use has dramatically increased throughout the world, particularly for DT, and growing numbers of medical centers are offering device therapy. [9][10][11] This trend has been bolstered by reports that LVAD use, in HF patients 70 years of age or older, is associated with

In our series of contemporary CF-VAD exchanges, a history of previous cerebrovascular events was a significant predictor for exchange. Exchange did not affect early or late survival. Our data suggest that aggressive surgical treatment of pump-related complications with exchange is safe and justified.

Continuous-flow LVAD support may significantly improve hepatic function, allowing patients with poor preimplant liver function to become better candidates for heart transplantation.

Patients supported by left ventricular assist devices (LVADs) often present with the loss of large von Willebrand factor (VWF) multimers. This VWF deficiency is believed to contribute to the bleeding diathesis of patients on LVAD support and is caused by excessive VWF cleavage by the metalloprotease ADAMTS-13 under high shear stress. However, only a small percentage of patients who have suffered the loss of large VWF multimers bleed. The actual rates of VWF cleavage in these patients have not been reported, primarily due to the lack of reliable detection methods. We have developed and validated a Selected Reaction Monitoring mass spectrometry method to quantify VWF cleavage as the ratio of the ADAMTS-13-cleaved peptide MVTGNPASDEIK to the ILAGPAGDSNVVK peptide. The rate of VWF cleavage was found to be 1.26 ± 0.36% in normal plasma. It varied significantly in patient samples, ranging from 0.23% to 2.5% of total VWF antigen, even though all patients had the loss of large VWF multimers. VWF cleavage was greater in post-LVAD samples from patients who had developed bleeding, but was mostly reduced in patients who had developed thrombosis. This SRM method is reliable to quantify the rate of VWF cleavage in patients on LVAD support.

Background: Advanced age is a relative contraindication for heart transplantation, but no age cutoff has been defined for patients receiving mechanical circulatory support. Methods: Between November 1, 2003 and November 1, 2012, we implanted the HeartMate II (HMII) left ventricular assist device (LVAD) in 319 patients. One hundred seven patients (89 men, 18 women) were over 60 years old (mean, 66 ± 4 years; range, 61-78 years) and received the HMII as a bridge to transplantation (n = 45) or as destination therapy (n = 62). We evaluated their experience by performing a retrospective analysis. Results: Seventy-two patients had ischemic cardiomyopathy, and 34 had idiopathic cardiomyopathy. Three patients (2.8%) already had a HeartMate XVE LVAD; 54 (50.5%) were receiving intra-aortic balloon pump support; 52 (48.6%) had undergone a previous cardiac procedure; and 9 (8.4%) had received renal replacement therapy (RRT) (continuous venovenous hemofiltration, hemodialysis, or both) before HMII implantation. The median duration of HMII support was 313 days (range, 1-3339 days). After device implantation, 36 patients (33.6%) had gastrointestinal bleeding, 24 (23%) required RRT, 18 (17.5%) had ventricular arrhythmias, and 24 (22.4%) had LVAD-related infections, and 9 (8.4%) had right ventricular failure requiring mechanical support, and 28 (26.2%) had neurologic complications. The actual survival rate was 69% at 6 months, 63% at 1 year, and 54% at 2 years. Eighty-one patients died; 9 are still receiving HMII support; and 17 are alive after heart transplantation. Conclusions: Older patients can benefit from LVAD therapy, and advanced age should not preclude LVAD implantation.

The objective of this trial is to determine the safety, tolerability, and toxicity of DNX-2401 in newly diagnosed DIPG patients (NCT03178032) followed by radiotherapy. Secondary endpoints are overall survival at 12 months, percentage of responses and induced immune response against tumor. Tumor biopsy was performed through the cerebellar peduncle, followed by intratumoral injection of DNX-2401 (N=12). Three patients were treated with 1x1010vp and given the lack of toxicity we escalated to 5x1010vp. The procedure was well tolerated and reduced tumor volume was demonstrated in all patients after combined treatment (virus + radiotherapy). We performed molecular studies (RNAseq and the Oncomine Childhood Research Panel from Thermo Fisher). The immune cell composition of the biopsies pre-virus injection was assessed using multiplexed quantitative immunofluorescence. T cells were hardly detectable in these tumors while macrophages were abundant. Using a multiplexed TCR-sequencing mRNA-based assay to analyze 18 available paired pre- and post-treatment samples from the trial, we detected increased clonal T cell diversity following treatment with the virus. We also measured pre and post treatment neutralizing antibodies and their relationship with survival. Finally, we performed functional studies using 2 cell lines isolated from patients included in this trial to assess the response to the virus (infectivity, viability, T-cell recognition). In summary, the virus has shown safety and efficacy in some patients. The information obtained in this clinical study would aid understanding the response of DIPG patients to viral therapies and, therefore, to better tailor this strategy to improve the survival of these patients.