A Novel Endothelial Damage Inhibitor Reduces Oxidative Stress and Improves Cellular Integrity in Radial Artery Grafts for Coronary Artery Bypass

The radial artery (RA) is a frequently used conduit in coronary artery bypass grafting (CABG). Endothelial injury incurred during graft harvesting promotes oxidative damage, which leads to graft disease and graft failure. We evaluated the protective effect of DuraGraft®, an endothelial damage inhibitor (EDI), on RA grafts. We further compared the protective effect of the EDI between RA grafts and saphenous vein grafts (SVG). Samples of RA (n = 10) and SVG (n = 13) from 23 patients undergoing CABG were flushed and preserved with either EDI or heparinized Ringer's lactate solution (RL). The effect of EDI vs. RL on endothelial damage was evaluated ex vivo and in vitro using histological analysis, immunofluorescence staining, Western blot, and scanning electron microscopy. EDI-treated RA grafts showed a significant reduction of endothelial and sub-endothelial damage. Lower level of reactive oxygen species (ROS) after EDI treatment was correlated with a reduction of hypoxic damage (eNOS and Caveolin-1) and significant increase of oxidation-reduction potential. Additionally, an increased expression of TGFβ, PDGFα/β, and HO-1 which are indicative for vascular protective function were observed after EDI exposure. EDI treatment preserves functionality and integrity of endothelial and intimal cells. Therefore, EDI may have the potential to reduce the occurrence of graft disease and failure in RA grafts in patients undergoing CABG

Activation of the Kynurenine Pathway in Human Malignancies Can Be Suppressed by the Cyclin-Dependent Kinase Inhibitor Dinaciclib

Indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO2) are the key enzymes of tryptophan (TRP) metabolism in the kynurenine pathway (KP). Both enzymes function as indicators of immunosuppression and poor survival in cancer patients. Direct or indirect targeting of either of these substances seems thus reasonable to improve therapy options for patients. In this study, glioblastoma multiforme (GBM) as well as head and neck squamous cell carcinomas (HNSCC) were examined because of their different mechanisms of spontaneous and treatment-induced immune escape. Effects on gene expression and protein levels were examined. Accompanying assessment of TRP metabolites from treated GBM cell culture supernatants was conducted. Our results show a heterogeneous and inversely correlated expression profile of TRP-metabolizing genes among GBM and HNSCC cells, with low, but inducible IDO1 expression upon IFNγ treatment. TDO2 expression was higher in GBM cells, while genes encoding kynurenine aminotransferases were mainly confined to HNSCC cells. These data indicate that the KP is active in both entities, with however different enzymes involved in TRP catabolism. Upon treatment with Temozolomide, the standard of care for GBM patients, IDO1 was upregulated. Comparable, although less pronounced effects were seen in HNSCC upon Cetuximab and conventional drugs (i.e., 5-fluorouracil, Gemcitabine). Here, IDO1 and additional genes of the KP (KYAT1, KYAT2, and KMO) were induced. Vice versa, the novel yet experimental cyclin-dependent kinase inhibitor Dinaciclib suppressed KP in both entities. Our comprehensive data imply inhibition of the TRP catabolism by Dinaciclib, while conventional chemotherapeutics tend to activate this pathway. These data point to limitations of conventional therapy and highlight the potential of targeted therapies to interfere with the cells' metabolism more than anticipated

Use of intraventricular ribbon gauze to reduce particulate emboli during aortic valve replacement

BACKGROUND: The incidence of cerebrovascular accidents following aortic valve surgery remains a devastating complication. The aim of this study was to determine the number of potential embolic material arising during aortic valve replacement and to examine the efficacy of using ribbon gauze in the left ventricle during removal of the native valve and decalcification of the aortic annulus. METHODS: Ribbon gauze was inserted into the left ventricular cavity prior to aortic valve excision in an unselected, prospectively studied series of 30 patients undergoing aortic valve replacement. A further 30 lengths of ribbon gauze were soaked in the pericardiotomy blood of the same patients and all were subjected to histological analysis. RESULTS: The median number of tissue fragments from the aortic valve replacement group was significantly higher than in the control group 5 (0–18) versus 0 (0–1) (p = 3.6 × 10(-5)). The size of tissue fragments varied between 0.1 and 9.0 mm with a mean of 0.61 ± 1.12 mm and a median of 0.2 mm. There was a significantly higher number of tissue fragments associated with patients having surgery for aortic stenosis when compared with patients who had aortic regurgitation with median of 5 (0–18) versus 0 (0–3) (p = 0.8 × 10(-3)). CONCLUSION: Significant capture of particulate debris by the intraventricular ribbon gauze suggests that the technique of left ventricular ribbon gauze insertion during aortic valve excision has merit

Propensity score-based analysis of long-term follow-up in patients supported with durable centrifugal left ventricular assist devices:the EUROMACS analysis

OBJECTIVES: The HeartWare HVAD (HW) and the HeartMate3 (HM3) are presently the most commonly used continuous-flow left ventricular assist devices worldwide. We compared the outcomes of patients supported with either of these 2 devices based on data from the EUROMACS (European Registry for Patients with Mechanical Circulatory Support). METHODS: A retrospective analysis of the survival and complications profile in propensity score-matched adult patients enrolled in the EUROMACS between 01 January 2016 and 01 September 2020 and supported with either an HW or HM3. Matching included demographic parameters, severity of cardiogenic shock and risk-modifying end-organ parameters that impact long-term survival. Survival on device and major postoperative adverse events were analysed. RESULTS: Following 1:1 propensity score matching, each group consisted of 361 patients. Patients were well balanced (<0.1 standardized mean difference). The median follow-up was similar in both groups [396 (interquartile range (IQR) 112-771) days for HW and 376 (IQR 100-816) days for HM3]. The 2-year survival was similar in both groups [HW: 61% 95% confidence interval (CI) (56-67%) vs HM3: 68% 95% CI (63-73%) (stratified hazard ratio for mortality: 1.13 95% CI (0.83-1.54), P = 0.435].The cumulative incidence for combined major adverse events and unexpected readmissions was similar in both groups [subdistribution hazard ratio (SHR) 1.0 (0.84-1.21), P = 0.96]. Patients in the HW group demonstrated a higher risk of device malfunction [SHR 2.44 (1.45-3.71), P < 0.001], neurological dysfunction [SHR 1.29 (1.02-1.61), P = 0.032] and intracranial bleeding [SHR 1.76 (1.13-2.70), P = 0.012]. CONCLUSIONS: Mid-term survival in both groups was similar in a propensity-matched analysis. The risk of device malfunction, neurological dysfunction and intracranial bleeding was significantly higher in HW patients

Impact of a surgical approach for implantation of durable left ventricular assist devices in patients on extracorporeal life support

Background The aim of this study was to evaluate the impact of the surgical approach on the postoperative outcome in patients who underwent left ventricular assist device (LVAD) implantation after having received veno-arterial extracorporeal life support (va-ECLS) using data from a European registry (ECLS-VAD). Five hundred and thirty-one patients were included. Methods A propensity score-adjusted outcome analysis was performed, resulting in 324 patients in the full sternotomy (FS) group and 39 in the less invasive surgery (LIS) group. Results The surgery lasted in median 236 min in the FS group versus 263 min in the LIS group (p = 0.289). The median chest tube output during the first 24 h was similar in both groups. Patients who underwent implantation with an FS required more blood products during the first 24 postoperative hours (median 16 vs. 12, p = 0.033). The incidence of revision due to bleeding was also higher (35.5 vs. 15.4%, p = 0.016). A temporary postoperative right ventricular assist device was necessary in 45.1 (FS) versus 23.1% (LIS) of patients, respectively (p = 0.067). No stroke occurred in the LIS group during the first 30 days after surgery (7.4% in the FS group). The incidence of stroke and of renal, hepatic, and respiratory failure during the follow-up was similar in both groups. The 30-day and one-year survival were similar in both groups. Conclusion LIS for implantation of a durable LVAD in patients on va-ECLS implanted for cardiogenic shock is associated with less revision due to bleeding, less administration of blood products and absence of perioperative stroke, with no impact on survival

Identifying patients at risk: multi-centre comparison of HeartMate 3 and HeartWare left ventricular assist devices

Aims: Since the withdrawal of HeartWare (HVAD) from the global market, there is an ongoing discussion if and which patients require prophylactically exchange for a HeartMate 3 (HM3). Therefore, it is important to study outcome differences between HVAD and HM3 patients. Because centres differ in patient selection and standard of care, we performed a propensity score (PS)-based study including centres that implanted both devices and aimed to identify which HVAD patients are at highest risk. Methods and results: We performed an international multi-centre study (n = 1021) including centres that implanted HVAD and HM3. PS-matching was performed using clinical variables and the implanting centre. Survival and complications were compared. As a sensitivity analysis, PS-adjusted Cox regression was performed. Landmark analysis with conditional survival >2 years was conducted to evaluate long-term survival differences. To identify which HVAD patients may benefit from a HM3 upgrade, Cox regression using pre-operative variables and their interaction with device type was performed. Survival was significantly better for HM3 patients (P 2 years after implantation (P = 0.03). None of the pre-operative variable interactions in the Cox regression were significant. Conclusions: HM3 patients have a significantly better survival and a lower incidence of ischaemic strokes and pump thrombosis than HVAD patients. This survival difference persisted after 2 years of implantation. Additional research using post-operative variables is warranted to identify which HVAD patients need an upgrade to HM3 or expedited transplantation

HVAD to HeartMate 3 left ventricular assist device exchange: Best practices recommendations

The HeartWare HVAD System (Medtronic) is a durable implantable left ventricular assist device that has been implanted in approximately 20,000 patients worldwide for bridge to transplant and destination therapy indications. In December 2020, Medtronic issued an Urgent Medical Device Communication informing clinicians of a critical device malfunction in which the HVAD may experience a delay or failure to restart after elective or accidental discontinuation of pump operation. Moreover, evolving retrospective comparative effectiveness studies of patients supported with the HVAD demonstrated a significantly higher risk of stroke and all-cause mortality when compared with a newer generation of a commercially available durable left ventricular assist device. Considering the totality of this new information on HVAD performance and the availability of an alternate commercially available device, Medtronic halted the sale and distribution of the HVAD System in June 2021. The decision to remove the HVAD from commercial distribution now requires the use of the HeartMate 3 left ventricular assist system (Abbott, Inc) if a patient previously implanted with an HVAD requires a pump exchange. The goal of this document is to review important differences in the design of the HVAD and HeartMate 3 that are relevant to the medical management of patients supported with these devices, and to assess the technical aspects of an HVAD-to-HeartMate 3 exchange. This document provides the best available evidence that supports best practices