Early Postoperative Neurologic Events Are Associated With Worse Outcome and Fatal Midterm Survival After Adult Heart Transplantation.

Background Neurologic events during primary stay in heart transplant (HTx) recipients may be associated with reduced outcome and survival, which we aim to explore with the current study. Methods and Results We screened and included all patients undergoing HTx in our center between September 2010 and December 2022 (n=268) and checked for the occurrence of neurologic events within their index stay. Neurologic events were defined as ischemic stroke, hemorrhage, hypoxic ischemic injury, or acute symptomatic neurologic dysfunction without central nervous system injury. The cohort was then divided into recipients with (n=33) and without (n=235) neurologic events after HTx. Using a multivariable Cox regression model, the association of neurologic events after HTx and survival was assessed. Recipients with neurologic events displayed a longer intensive care unit stay (30 versus 16 days; P=0.009), longer mechanical ventilation (192 versus 48 hours; P<0.001), and higher need for blood transfusion, and need for hemodialysis after HTx was substantially higher (81% versus 55%; P=0.01). Resternotomy (36% versus 26%; P=0.05) and mechanical life support (extracorporeal life support) after HTx (46% versus 24%; P=0.02) were also significantly higher in patients with neurologic events. Covariable-adjusted multivariable Cox regression analysis revealed a significant independent association of neurologic events and increased 30-day (hazard ratio [HR], 2.5 [95% CI, 1.0-6.0]; P=0.049), 1-year (HR, 2.2 [95% CI, 1.1-4.3]; P=0.019), and overall (HR, 2.5 [95% CI, 1.5-4.2]; P<0.001) mortality after HTx and reduced Kaplan-Meier survival up to 5 years after HTx (P<0.001). Conclusions Neurologic events after HTx were strongly and independently associated with worse postoperative outcome and reduced survival up to 5 years after HTx.

Reply to Thet et al. Comment on "Oehler et al. Outcome and Midterm Survival after Heart Transplantation Is Independent from Donor Length of Stay in the Intensive Care Unit. Life 2022, 12, 1053".

Myat Soe Thet et al. published a letter [...].

Donor Noradrenaline Support Is Not Associated with Decreased Survival in Heart Transplant Recipients.

Objective: Although the application of higher doses of norepinephrine (NE) in potential organ donors is a frequent reason for heart decline, its associations with outcomes after heart transplantation (HTx) are discussed controversially. Therefore, we aimed to explore donor NE support's potential impact on outcomes in our single-center heart transplant cohort. Methods: All patients who had undergone HTx in our center between September 2010 and April 2022 (n = 241) were screened for eligibility. From those, all patients with complete data on donor NE support (n = 238) were included. Recipients were divided into three groups according to their donor NE support: without support (n = 26), with low support of 0.01−0.2 µg/kg/min (n = 132), and with high support of > 0.2 µg/kg/min (n = 80). Receiver operating characteristics (ROC) and Kaplan Meier analysis was used to investigate the association of donor NE support and mortality after heart transplantation. Recipient and donor variables, including peri- and postoperative characteristics, were reviewed and compared. Results: NE support in donors ranged between 0 and 2.94 µg/kg/min (median 0.13 µg/kg/min, IQR 0.05−0.26 µg/kg/min). No association between donor NE support and mortality after HTx was observed (AUC for overall survival 0.494). Neither Kaplan-Meier analysis in survival up to 5 years after transplantation (Log Rank p = 0.284) nor group comparisons showed significant differences between the groups. With few exceptions, baseline characteristics in recipients and donors were comparable between the groups. Regarding peri- and postoperative parameters, increasing donor NE support was associated with a longer duration of mechanical ventilation (68 h and 95 h vs. 47 h), longer postoperative IMC/ICU stay (14 vs. 15 vs. 19 days), and a higher need for mechanical life support post-HTx (26% and 39% vs. 12%). Conclusion: In this retrospective analysis, NE support in donors prior to heart transplantation was unrelated to differing survival after heart transplantation. However, higher doses of donor NE were associated with prolonged ventilation, longer duration on IMC/ICU, and a higher need for extracorporeal life support in recipients post-HTx.

Donor hypernatremia is associated with increased mortality after heart transplantation: A retrospective study.

BACKGROUND AND AIMS: Donor hypernatremia has been associated with primary graft dysfunction in heart transplantation (HTx) and is correlated with impaired outcome following liver and renal transplantation. However, controversial data exist regarding the impact of sodium dysregulation on survival. This study aims to investigate the impact of donor sodium levels on early morbidity and short- and midterm survival following HTx. METHODS: Between September 2010 and June 2021, a total of n = 218 patients underwent HTx in our center. From those, 214 could be included retrospectively in our study. For each donor, sodium levels were collected and different cut-off levels from 145 to 159 mmol/L were investigated by Kaplan-Meier-analysis. Then, recipients were divided in three groups regarding donor sodium: Normonatremia (133-145 mmol/L, n = 73), mild hypernatremia (146-156 mmol/L, n = 105) and severe hypernatremia (>156 mmol/L, n = 35). Recipient and donor variables were reviewed and compared, including peri- and postoperative characteristics and recipient survival after up to 5 years after transplantation. RESULTS: All patients were comparable regarding baseline characteristics and perioperative parameters. Regarding early mortality, 90-day survival was significantly reduced only in patients with severe donor hypernatremia in comparison to normonatremia (90% vs. 71%, p = .02), but not in mild hypernatremia (89%, p = .89). One-year survival was comparable in all groups (p > .28). CONCLUSION: Severe donor hypernatremia was associated with reduced short-term survival, while the correlation weakens > 1 year after HTx. As our study is limited due to the nature of its retrospective, single-center approach, future prospective studies are needed to evaluate the importance of donor management with regard to hypernatremia.

Outcome and Midterm Survival after Heart Transplantation Is Independent from Donor Length of Stay in the Intensive Care Unit.

Prolonged treatment of organ donors in the intensive care unit (ICU) may be associated with complications influencing the outcome after heart transplantation (HTx). We therefore aim to explore the potential impact of the donor length of stay (LOS) in the ICU on outcomes in our cohort. We included all patients undergoing HTx in our center between September 2010 and April 2022 (n = 241). Recipients were divided around the median into three groups regarding their donor LOS in the ICU: 0 to 3 days (≤50th percentile, n = 92), 4 to 7 days (50th-75th percentile, n = 80), and ≥8 days (≥75th percentile, n = 69). Donor LOS in the ICU ranged between 0 and 155 days (median 4, IQR 3-8 days). No association between the LOS in the ICU and survival after HTx was observed (AUC for overall survival 0.514). Neither the Kaplan-Meier survival analysis up to 5 years after HTx (Log-Rank p = 0.789) nor group comparisons showed significant differences. Baseline recipient characteristics were comparable between the groups, while the donor baselines differed in some parameters, such as less cardiopulmonary resuscitation prior to HTx in those with a prolonged LOS. However, regarding the recipients' peri- and postoperative parameters, the groups did not differ in all of the assessed parameters. Thus, in this retrospective analysis, although the donors differed in baseline parameters, the donor LOS in the ICU was not associated with altered recipient survival or outcome after HTx.

IgM-enriched immunoglobulin as adjuvant therapy for heart transplant after infection of left ventricular assist devices.

Patients undergoing heart transplantation (HTx) with active infection of left ventricular assist devices (LVAD) are at high risk for postoperative infections. Between 2021 and 2022, five (P1-P5) of a total of n = 44 patients underwent HTx in our department while suffering from LVAD infection. Postoperatively, patients received adjuvant IgM-enriched human intravenous immunoglobulin (IGM-IVIG), consisting of 76% IgG, 12% IgM, and 12% IgA as a novel approach to prevent infective complications. While in P1, P2, and P4, LVAD driveline infection was known before HTx; in P3 and P5, abscess of device pocket was found incidentally during HTx. After a single dose of IGM-IVIG, all patients showed adequate rise in serum immunoglobulins. In the postoperative course, no patient developed infective complications. All patients were successfully discharged and in good condition at the last follow-up. Therefore, IGM-IVIG seems to be an effective adjuvant treatment for patients undergoing HTx with LVAD infections.

Cytomegalovirus mismatch after heart transplantation: Impact of antiviral prophylaxis and intravenous hyperimmune globulin.

OBJECTIVE: Cytomegalovirus (CMV) infections are correlated with complications following heart transplantation (HTx) and impaired outcome. The impact of a serologic mismatch between donor and recipient and the necessity of prophylactic virostatic medication is still a matter of concern. METHODS: We retrospectively reviewed all patients that underwent HTx between 2010 and 2020 in our department. The recipients (n = 176) could be categorized into four risk groups depending on their serologic CMV matching (D+ /R- = donor CMV-IgG positive and recipient CMV-IgG negative, n = 32; D- /R+ , n = 51; D- /R- , n = 35; D+ /R+ , n = 58). All patients followed the same protocol of CMV prophylaxis with application of ganciclovir/valganciclovir and intravenous CMV hyperimmune globulin. RESULTS: Incidence of postoperative morbidity such as primary graft dysfunction, neurological events, infections, and graft rejection were comparable between all groups (p > .05). However, the incidence of postoperative acute kidney injury with hemodialysis was by trend increased in the D- /R+ group (72.0%) compared to the other groups. In-hospital CMV-DNAemia was observed in serologic positive recipients only (D+ /R- : 0.0%, D- /R+ : 25.0%, D- /R- : 0.0%, D+ /R+ : 13.3%, p < .01). During the first year, a total of 18 patients developed CMV-DNAemia (D+ /R- : 31.6%, D- /R+ : 31.9%, D- /R- : 3.4%, D+ /R+ : 11.1%, p = .03). CONCLUSIONS: Seropositive recipients carry an important risk for CMV-DNAemia. However, we did not observe differences in perioperative morbidity and mortality regarding CMV matching, which might be related to regularly administer prophylactic virostatics and additional CMV-IVIG for risk constellations. For high-risk constellation, long-term application of CMV-IVIG during the first year after transplant may be beneficial.

Complications of left ventricular assist devices causing high urgency status on waiting list: impact on outcome after heart transplantation.

AIMS: Heart transplantation (HTx) represents optimal care for advanced heart failure. Left ventricular assist devices (LVADs) are often needed as a bridge-to-transplant (BTT) therapy to support patients during the wait for a donor organ. Prolonged support increases the risk for LVAD complications that may affect the outcome after HTx. METHODS AND RESULTS: A total of 342 patients undergoing HTx after LVAD as BTT in a 10-year period in two German high-volume HTx centres were retrospectively analysed. While 73 patients were transplanted without LVAD complications and with regular waiting list status (T, n = 73), the remaining 269 patients were transplanted with high urgency status (HU) and further divided with regard to the observed leading LVAD complications (infection: HU1, n = 91; thrombosis: HU2, n = 32; stroke: HU3, n = 38; right heart failure: HU4, n = 41; arrhythmia: HU5, n = 23; bleeding: HU6, n = 18; device malfunction: HU7, n = 26). Postoperative hospitalization was prolonged in patients with LVAD complications. Analyses of perioperative morbidity revealed no differences regarding primary graft dysfunction, renal failure, and neurological events except postoperative infections. Short-term survival, as well as Kaplan-Meier survival analysis, indicated comparable results between the different study groups without disadvantages for patients with LVAD complications. CONCLUSIONS: Left ventricular assist device therapy can impair the outcome after HTx. However, the occurrence of LVAD complications may not impact on outcome after HTx. Thus, we cannot support the prioritization or discrimination of HTx candidates according to distinct mechanical circulatory support-associated complications. Future allocation strategies have to respect that device-related complications may define urgency but do not impact on the outcome after HTx.

The cannabinoid WIN 55,212-2-mediated protection of dentate gyrus granule cells is driven by CB1 receptors and modulated by TRPA1 and Cav 2.2 channels.

Cannabinoids regulate numerous physiological and pathological events like inflammation or neurodegeneration via CB(1) and CB(2) receptors. The mechanisms behind cannabinoid effects show a high variability and may also involve transient receptor potential channels (TRP) and N-type voltage-gated Ca(2+) channels (Ca(v) 2.2). In the present study we investigated the neuroprotective effects of the synthetic cannabinoid WIN 55,212-2 (WIN) on dentate gyrus (DG) granule cells and elucidated the involvement of TRP and Ca(v) 2.2 that are shown to participate in inflammatory processes. Organotypic hippocampal slice cultures were excitotoxically lesioned using NMDA and subsequently incubated with different WIN concentrations (0.001-10 µM). WIN showed neuroprotective properties in an inverse concentration-dependent manner, most effectively at 0.01 µM. The CB(1) receptor antagonist AM251 blocked neuroprotection mediated by WIN whereas the CB(2) receptor antagonist AM630 showed no effects. Application of the TRPA1 blocker HC-030031 enhanced the neuroprotective efficacy of high (10 µM) WIN concentrations and the number of degenerating neurons became equal to that seen after application of the most effective WIN dose (0.01 µM). In contrast, the application of TRPA1 agonist icilin or allyl isothiocyanate (AITC) led to a stronger neurodegeneration. The use of TRPV1 blocker 6-iodo-nordihydrocapsaicin did not affect WIN-mediated neuroprotection. The selective Ca(v) 2.2 blocker ω-conotoxin (GVIA) completely blocked neuroprotection shown by 10 µM WIN. GVIA and HC-030031 exerted no effects at WIN concentrations lower than 10 µM. Our data show that WIN protects dentate gyrus granule cells in a concentration dependent manner by acting upon CB(1) receptors. At high (10 µM) concentrations WIN additionally activates TRPA1 and Ca(v) 2.2 within the hippocampal formation that both interfere with CB(1) receptor-mediated neuroprotection. This leads to the conclusion that physiological and pharmacological effects of cannabinoids strongly depend on their concentration and the neuroprotective efficacy of cannabinoids may be determined by interaction of activated CB(1) receptor, TRPA1, and Ca(v) 2.2.

Palmitoylethanolamide protects dentate gyrus granule cells via peroxisome proliferator-activated receptor-α.

Endocannabinoids like 2-arachidonoylglycerol strongly modulate the complex machinery of secondary neuronal damage and are shown to improve neuronal survival after excitotoxic lesion. Palmitoylethanolamide (PEA), the naturally occurring fatty acid amide of ethanolamine and palmitic acid, is an endogenous lipid known to mimic several effects of endocannabinoids even without binding to cannabinoid receptors. Here we show that PEA (0.001-1 µM) and the synthetic peroxisome proliferator-activated receptor (PPAR)-alpha agonist 4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio acetic acid (Wy-14,643; 0.1-1 µM) reduced the number of microglial cells and protected dentate gyrus granule cells in excitotoxically lesioned organotypic hippocampal slice cultures (OHSCs). Treatment with the PPAR-alpha antagonist N-((2S)-2-(((1Z)-1-Methyl-3-oxo-3-(4-(trifluoromethyl)phenyl)prop-1-enyl)amino)-3-(4-(2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy)phenyl)propyl)propanamide (GW6471; 0.05-5 µM) blocked PEA-mediated neuroprotection and reduction of microglial cell numbers whereas the PPAR-gamma antagonist 2-chloro-5-nitro-N-phenyl-benzamide (GW9662; 0.01-1 µM) showed no effects. Immunocytochemistry and Western blot analyses revealed a strong PPAR-alpha immunoreaction in BV-2 microglial cells and in HT22 hippocampal cells. Intensity and location of PPAR-alpha immunoreaction remained constant during stimulation with PEA (0.01 µM; 1-36 h). In conclusion our data provide evidence that (1) PEA counteracted excitotoxically induced secondary neuronal damage of dentate gyrus granule cells, (2) PPAR-alpha but not PPAR-gamma is the endogenous binding site for PEA-mediated neuroprotection, and (3) PEA may activate PPAR-alpha in microglial cells and hippocampal neurons to exert its neuroprotective effects. In addition to classical endocannabinoids, PEA-mediated PPAR-alpha activation represents a possible target for therapeutic interventions to mitigate symptoms of secondary neuronal damage.

2-Arachidonoylglycerol elicits neuroprotective effects on excitotoxically lesioned dentate gyrus granule cells via abnormal-cannabidiol-sensitive receptors on microglial cells.

Endocannabinoids like 2-arachidonoylglycerol (2-AG) exert neuroprotective effects after brain injuries. According to current concepts, these neuroprotective effects are due to interactions between 2-AG and cannabinoid (CB)1 receptors on neurons. Moreover, 2-AG modulates migration and proliferation of microglial cells which are rapidly activated after brain lesion. This effect is mediated via CB2- and abnormal-cannabidiol (abn-CBD)-sensitive receptors. In the present study, we investigated whether the abn-CBD-sensitive receptor on microglial cells contributes to 2-AG-mediated neuroprotection in organotypic hippocampal slice cultures (OHSCs) after excitotoxic lesion induced by NMDA (50 microM) application for 4 h. This lesion caused neuronal damage and accumulation of microglial cells within the granule cell layer. To analyze the role of abn-CBD-sensitive receptors for neuroprotection and microglial cell accumulation, two agonists of the abn-CBD-sensitive receptor, abn-CBD or 2-AG, two antagonists, 1,3-dimethoxy-5-methyl-2-[(1R,6R)-3-methyl-6-(1-methylethenyl)-2-cyclohexen1-yl]-benzene (O-1918) or cannabidiol (CBD), and the CB1 receptor antagonist AM251, were applied to NMDA-lesioned OHSC. Propidium iodide (PI) labeling was used as a marker of degenerating neurons and isolectin B(4) (IB(4)) as a marker of microglial cells. Application of both, abn-CBD or 2-AG to lesioned OHSC significantly decreased the number of IB(4)(+) microglial cells and PI(+) neurons in the dentate gyrus. In contrast to AM251, application of O-1918 or CBD antagonized these effects. When microglial cells were depleted by preincubation of OHSC with the bisphosphonate clodronate (100 microg/mL) for 5 days before excitotoxic lesion, 2-AG and abn-CBD lost their neuroprotective effects. We therefore propose that the endocannabinoid 2-AG exerts its neuroprotective effects via activation of abn-CBD-sensitive receptors on microglial cells.