Association between early postoperative hypoalbuminaemia and outcome after orthotopic heart transplantation.

OBJECTIVES: In patients undergoing heart transplantation (HTX), preoperative liver impairment and consecutive hypoalbuminaemia are associated with increased mortality. The role of early postoperative hypoalbuminaemia after HTX is unclear. This study investigated the association between early postoperative hypoalbuminaemia and 1-year mortality as well as 'days alive and out of hospital' (DAOH) after HTX. METHODS: This retrospective cohort study included patients who underwent HTX at the University Hospital Duesseldorf, Germany, between 2010 and 2022. The main exposure was serum albumin concentration at intensive care unit (ICU) arrival. The primary endpoints were mortality and DAOH within 1 year after surgery. Receiver operating characteristic (ROC) curve analysis was performed and logistic and quantile regression models with adjustment for 13 a priori defined clinical risk factors were conducted. RESULTS: Out of 241 patients screened, 229 were included in the analysis (mean age 55 ± 11 years, 73% male). ROC analysis showed moderate discrimination for 1-year mortality by postoperative serum albumin after HTX [AUC = 0.74; 95% confidence interval (CI): 0.66-0.83]. The cutoff for serum albumin at ICU arrival was 3.0 g/dl. According to multivariate logistic and quantile regression, there were independent associations between hypoalbuminaemia and mortality/DAOH [odds ratio of 4.76 (95% CI: 1.94-11.67) and regression coefficient of -46.97 (95% CI: -83.81 to -10.13)]. CONCLUSIONS: Postoperative hypoalbuminaemia <3.0 g/dl is associated with 1-year mortality and reduced DAOH after HTX and therefore might be used for early postoperative risk re-assessment in clinical practice.

International Survey on Perioperative Management of Patients With Infective Endocarditis.

OBJECTIVES: To estimate the current practice in the perioperative management of patients undergoing cardiac surgery due to infective endocarditis. DESIGN: A prospective, open, 24-item, web-based cross-sectional survey. SETTING: Online survey endorsed by the European Association of Cardiothoracic Anesthesiology and Intensive Care (EACTAIC). PARTICIPANTS: Members of the EACTAIC. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 156 responses from 44 countries were received, with a completion rate of 99%. The response rate was 16.6%. Most respondents (76%) practiced cardiac anesthesia in European hospitals, and most respondents stated that a multidisciplinary endocarditis team was not established at their center, that cardiac anesthesiologists appeared to be involved infrequently in those teams (36%), and that they were not involved in decision-making on indication and timing of surgery (88%). In contrast, the cardiac anesthesiologist performed intraoperative antibiotic therapy (62%) and intraoperative transesophageal echocardiography (90%). Furthermore, there was a relative heterogeneity concerning perioperative monitoring, as well as for coagulation and transfusion management. CONCLUSIONS: This international survey evaluated current practice among cardiac anesthesiologists in the perioperative management of patients with infective endocarditis and the anesthesiologist's role in multidisciplinary decision-making. Heterogeneity in treatment approaches was identified, indicating relevant knowledge gaps that should encourage further clinical research to optimize treatment and postoperative outcomes in this specific population.

Postoperative high-sensitivity troponin T predicts 1-year mortality and days alive and out of hospital after orthotopic heart transplantation.

BACKGROUND: Orthotopic heart transplantation (HTX) is the gold standard to treat end-stage heart failure. Numerous risk stratification tools have been developed in the past years. However, their clinical utility is limited by their poor discriminative ability. High sensitivity troponin T (hsTnT) is the most specific biomarker to detect myocardial cell injury. However, its prognostic relevance after HTX is not fully elucidated. Thus, this study evaluated the predictive value of postoperative hsTnT for 1-year survival and days alive and out of hospital (DAOH) after HTX. METHODS: This retrospective cohort study included patients who underwent HTX at the University Hospital Duesseldorf, Germany between 2011 and 2021. The main exposure was hsTnT concentration at 48 h after HTX. The primary endpoints were mortality and DAOH within 1 year after surgery. Receiver operating characteristic (ROC) curve analysis, logistic regression model and linear regression with adjustment for risk index for mortality prediction after cardiac transplantation (IMPACT) were performed. RESULTS: Out of 231 patients screened, 212 were included into analysis (mean age 55 ± 11 years, 73% male). One-year mortality was 19.7% (40 patients) and median DAOH was 298 days (229-322). ROC analysis revealed strongest discrimination for mortality by hsTnT at 48 h after HTX [AUC = 0.79 95% CI 0.71-0.87]. According to Youden Index, the cutoff for hsTnT at 48 h and mortality was 1640 ng/l. After adjustment for IMPACT score multivariate logistic and linear regression showed independent associations between hsTnT and mortality/DAOH with odds ratio of 8.10 [95%CI 2.99-21.89] and unstandardized regression coefficient of -1.54 [95%CI -2.02 to -1.06], respectively. CONCLUSION: Postoperative hsTnT might be suitable as an early prognostic marker after HTX and is independently associated with 1-year mortality and poor DAOH.

High On-Treatment Platelet Reactivity: Aspirin versus Clopidogrel.

BACKGROUND: Antithrombotic regimen in patients on oral anticoagulation (OAC) post-percutaneous coronary intervention (PCI) is challenging. At least, one antiplatelet agent in combination with OAC is recommended after PCI for 6-12 months. Clopidogrel is used most frequently in this setting. However, data comparing P2Y12 inhibition with clopidogrel versus cyclooxygenase inhibition by acetylsalicylic acid (ASA, aspirin) is missing. It is well known that the antiplatelet effects of ASA and clopidogrel are frequently impaired (high on-treatment platelet reactivity [HTPR]). In this pilot investigation, we compared the antiplatelet effects of clopidogrel versus ASA. METHODS: In this retrospective single-center database analysis, we investigated platelet reactivity by light transmission aggregometry in patients under different antiplatelet regimes. Results were presented as maximum of aggregation (MoA). HTPR to ASA and to clopidogrel were assessed. RESULTS: 755 patients were enrolled. 677 were on ASA, 521 were on clopidogrel, and 198 had OAC. Overall mean age was 73 ± 13.4 years, and 458 (60.7%) were male. HTPR to ASA occurred in 94/677 patients (13.9%), and mean arachidonic acid-induced MoA was 14.15 ± 19.04%. HTPR to clopidogrel occurred in 241/521 patients (46.3%), and mean adenosine diphosphate-induced MoA was 50.06 ± 20.42%. HTPR to clopidogrel was significantly more frequent than HTPR to ASA; single antiplatelet therapy (SAPT)-mono ASA: 27/199 (13.6%) versus mono clopidogrel: 6/18 (33.3%); p = 0.037; SAPT with OAC-OAC with ASA: 8/35 (22.9%) versus OAC with clopidogrel: 27/60 (45%); p = 0.046. Same difference in HTPR contingency could be shown in subgroups of dual antiplatelet therapy and ASA + clopidogrel + OAC therapy. CONCLUSION: Impaired pharmacodynamic response to clopidogrel was more frequent as HTPR to ASA. Hence, ASA should be tested in combination with OAC post-PCI.

Association between hypotension and myocardial injury in patients with severe trauma.

PURPOSE: During resuscitation of patients with severe trauma, guidelines recommend permissive hypotension prior to surgical bleeding control. However, hypotension may be associated with reduced organ perfusion and multiple organ dysfunction, e.g. myocardial injury. The association between hypotension and myocardial injury in trauma patients is underexplored. We hypothesized that hypotension is associated with myocardial injury in this population. MATERIALS AND METHODS: This retrospective study included patients ≥ 18 years suffering from severe trauma [defined as Injury Severity Score (ISS) ≥ 16] that were treated in the emergency department resuscitation room between 2016 and 2019. Primary endpoint was the incidence of myocardial injury defined as high-sensitive troponin T > 14 ng/l. Main exposure was the duration of arterial hypotension during resuscitation period defined as mean arterial pressure < 65 mmHg. RESULTS: Out of 368 patients screened, 343 were analyzed (73% male, age: 55 ± 21, ISS: 28 ± 12). Myocardial injury was detected in 143 (42%) patients. Overall in-hospital mortality was 26%. Multivariate binary logistic regression with forced entry of nine predefined covariables revealed an odds ratio of 1.29 [95% confidence interval 1.16-1.44]; p = 0.012) for the association between the duration of hypotension and myocardial injury. CONCLUSION: The duration of hypotension during resuscitation period is independently associated with the incidence of myocardial injury in patients with severe trauma.

Impact of Left Ventricular Assist Devices on Days Alive and Out of Hospital in Hemodynamically Stable Patients with End-Stage Heart Failure: A Propensity Score Matched Study.

The two main surgical options to treat end-stage heart failure are heart transplantation (HTx) or left ventricular assist device (LVAD) implantation. In hemodynamically stable patients, the decision for HTx listing with or without LVADs is challenging. We analyzed the impact of both options on days alive and out of hospital (DAOH) and survival. This retrospective study screened all patients with HTx or LVAD implantation between 2010 and 2020. The main inclusion criterion was hemodynamic stability defined as independence of intravenous inotropic/vasoactive support at decision. Propensity score matching (PSM) was performed. The primary endpoint was DAOH within one year after the decision. Secondary endpoints included survival, duration until HTx, and hospitalizations. In total, 187 patients received HTx and 227 patients underwent LVAD implantation. There were 21 bridge-to-transplant (BTT)-LVAD patients (implantation less than a month after HTx listing or listing after implantation) and 44 HTx-waiting patients included. PSM identified 17 matched pairs. Median DAOH at one year was not significantly different between the groups (BTT-LVAD: median 281, IQR 89; HTx waiting: median 329, IQR 74; p = 0.448). Secondary endpoints did not differ significantly. Our data suggest that BTT-LVAD implantation may not be favorable in terms of DAOH within one year for hemodynamically stable patients compared to waiting for HTx. Further investigations on quality of life and long-term outcomes are warranted.

Days alive and out of hospital after left ventricular assist device implantation.

AIMS: Implantation of left ventricular assist devices (LVADs) as a bridge to transplant or as destination therapy is increasing. The selection of suitable patients and outcome assessment belong to the key challenges. Mortality has traditionally been a focus of research in this field, but literature on quality of life is very limited. This study aimed to identify perioperative factors influencing patients' life as measured by days alive and out of hospital (DAOH) in the first year after LVAD implantation. METHODS AND RESULTS: This retrospective single-centre cohort study screened 227 patients who underwent LVAD implantation at the University Hospital Duesseldorf, Germany, between 2010 and 2020. First, the influence of 10 prespecified variables on DAOH was investigated by univariate analysis. Second, multivariate quantile regression was conducted including all factors with significant influence on DAOH in the univariate model. Additionally, the impact of all variables on 1 year mortality was investigated using Kaplan-Meier curves to oppose DAOH and mortality. In total, 221 patients were included into analysis. As pre-operative factors, chronic kidney disease (CKD), pre-operative mechanical circulatory support (pMCS), and Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) stadium < 3 were associated with lower DAOH at 1 year [CKD: 280 (155-322) vs. 230 (0-219), P = 0.0286; pMCS: 294 (155-325) vs. 243 (0-293), P = 0.0004; INTERMACS 1: 218 (0-293) vs. INTERMACS 2: 264 (6-320) vs. INTERMACS 3: 299 (228-325) vs. INTERMACS 4: 313 (247-332), P ≤ 0.0001]. Intra-operative additional implantation of a right ventricular assist device (RVAD) was also associated with lower DAOH [RVAD: 290 (160-325) vs. 174 (0-277), P ≤ 0.0001]. As post-operative values that were associated with lower DAOH, dialysis and tracheotomy could be identified [dialysis: 300 (252-326) vs. 186 (0-300), P ≤ 0.0001; tracheotomy: 292 (139-325) vs. 168 (0-269), P ≤ 0.0001]. Multivariate analysis revealed that all of these factors besides pMCS were independently associated with DAOH. According to Kaplan-Meier analysis, only post-operative dialysis was significantly associated with increased mortality at 1 year (survival: no dialysis 89.4% vs. dialysis 70.1%, hazard ratio: 0.56, 95% confidence interval: 0.33-0.94; P = 0.031). CONCLUSIONS: The results of this study indicate that there can be a clear discrepancy between hard endpoints such as mortality and more patient-centred outcomes reflecting life impact. DAOH may relevantly contribute to a more comprehensive selection process and outcome assessment in LVAD patients.

Cardioprotective Properties of Humoral Factors Released after Remote Ischemic Preconditioning in CABG Patients with Propofol-Free Anesthesia-A Translational Approach from Bedside to Bench.

The cardioprotective effect of remote ischemic preconditioning (RIPC) is well detectable in experimental studies but not in clinical trials. Propofol, a commonly used sedative, is discussed to negatively influence the release of humoral factors after RIPC. Further, results from experimental and clinical trials suggest various comorbidities interact with inducible cardioprotective properties of RIPC. In the present study, we went back from bedside to bench to investigate, in male patients undergoing CABG surgery, whether (1) humoral factors are released after RIPC during propofol-free anesthesia and/or (2) DM interacts with plasma factor release. Blood samples were taken from male patients with and without DM undergoing CABG surgery before (control) and after RIPC (RIPC). To investigate the release of cardioprotective humoral factors into the plasma, isolated perfused hearts of young rats (n = 5 per group) were used as a bioassay. The hearts were perfused with patients' plasma without (Con) and with RIPC (RIPC) for 10 min (1% of coronary flow) before global ischemia and reperfusion. In additional groups, the plasma of patients with DM was administered (Con DM, RIPC DM). Infarct size was determined by TTC staining. Propofol-free RIPC plasma of male patients without DM showed an infarct size of 59 ± 5% compared to 61 ± 13% with Con plasma (p = 0.973). Infarct sizes from patients with DM showed similar results (RIPC DM: 55 ± 3% vs. Con DM: 56 ± 4%; p = 0.995). The release of humoral factors into the blood after RIPC in patients receiving propofol-free anesthesia undergoing CABG surgery did not show any cardioprotective properties independent of a pre-existing diabetes mellitus.

Incidence and prognosis of myocardial injury in patients with severe trauma.

PURPOSE: Severe trauma can lead to end organ damages of varying severity, including myocardial injury. In the non-cardiac surgery setting, there is extensive evidence that perioperative myocardial injury is associated with increased morbidity and mortality. The impact of myocardial injury on outcome after severe trauma has not been investigated adequately yet. We hypothesized that myocardial injury is associated with increased in-hospital mortality in patients with severe trauma. MATERIALS/METHODS: This retrospective cohort study included patients ≥ 18 years with severe trauma [defined as injury severity score (ISS) ≥ 16] that were admitted to the resuscitation room of the Emergency Department of the University Hospital Duesseldorf, Germany, between 2016 and 2019. The main endpoint was in-hospital mortality. Main exposure was myocardial injury at arrival [defined as high-sensitive troponin T (hsTnT) > 14 ng/l]. For statistical analysis, receiver operating characteristic curve (ROC) and multivariate binary logistic regression were performed. RESULTS: Out of 368 patients, 353 were included into statistical analysis (72.5% male, age: 55 ± 21, ISS: 28 ± 12). Overall in-hospital mortality was 26.1%. Myocardial injury at presentation was detected in 149 (42.2%) patients. In-hospital mortality of patients with and without myocardial injury at presentation was 45% versus 12.3%, respectively. The area under the curve (AUC) for hsTnT and mortality was 0.76 [95% confidence interval (CI) 0.71-0.82]. The adjusted odds ratio of myocardial injury for in-hospital mortality was 2.27 ([95%CI 1.16-4.45]; p = 0.017). CONCLUSION: Myocardial injury after severe trauma is common and independently associated with in-hospital mortality. Thus, hsTnT might serve as a new prognostic marker in this cohort.

Life impact of VA-ECMO due to primary graft dysfunction in patients after orthotopic heart transplantation.

AIMS: Primary graft dysfunction (PGD) is a feared complication after heart transplantation (HTX). HTX patients frequently receive veno-arterial extracorporeal membrane oxygenation (VA-ECMO) until graft recovery. Long-term mortality of patients weaned from VA-ECMO after HTX is comparable with non-ECMO patients. However, impact on quality of life is unknown. This study investigated days alive and out of hospital (DAOH) as patient-centred outcome in HTX patients at 1 year after surgery. METHODS AND RESULTS: This retrospective single-centre cohort study included patients who underwent HTX at the University Hospital Düsseldorf, Germany, from 2010 to 2020. Main exposure was VA-ECMO due to PGD. VA-ECMO and non-VA-ECMO patients were compared regarding the primary endpoint DAOH at 1 year after HTX. Subgroup analysis for patients weaned from VA-ECMO was performed. In total, 144 patients were included into analysis; 1 year mortality was significantly lower in non-ECMO patients [non-ECMO 14.3% (14/98) vs. VA-ECMO 34.8% (16/46), adjusted hazard ratio: 0.32, 95% confidence interval: 0.15-0.74; P = 0.002]. Mortality did not differ significantly between patients weaned from VA-ECMO and non-ECMO patients [non-ECMO 14.3% (14/98) vs. VA-ECMO (weaned) 18.9% (7/37), adjusted hazard ratio: 0.72, 95% confidence interval: 0.27-1.90; P = 0.48]. DAOH were significantly higher in non-ECMO patients compared with VA-ECMO patients and patients weaned from VA-ECMO [non-ECMO vs. VA-ECMO: median 310 (inter-quartile range 277-327) days vs. 243 (0-288) days; P < 0.0001; non-ECMO vs. VA-ECMO (weaned): 310 (277-327) days vs. 253 (208-299) days; P < 0.0001]. These results were still significant after multivariable adjustment with forced entry of predefined covariables. CONCLUSIONS: Despite similar survival rates, VA-ECMO due to PGD has a relevant life impact as defined by DAOH in the first year after HTX. As a more patient-centred endpoint, DAOH may contribute to a more comprehensive assessment of outcome in HTX patients.

[Cardiac biomarkers in noncardiac surgery patients : Review of cardiac biomarkers for risk stratification and detection of postoperative adverse cardiac events]. / Kardiale Biomarker im nichtkardiochirurgischen Setting : Eine Übersicht über kardiale Biomarker zur Risikostratifizierung und Früherkennung postoperativer kardialer Komplikationen.

BACKGROUND: Yearly, more than 200 million people worldwide undergo noncardiac surgery of whom about 5% will suffer adverse cardiac events. Therefore, risk stratification and early detection of these events is crucial. OBJECTIVES: The goal of this review is to summarize the currently available evidence on the role of biomarkers in perioperative cardiac risk assessment. It presents current data of the established biomarkers troponin and brain natriuretic peptide (BNP), and it also reports on new biomarkers that are still under evaluation, e.g. copeptin (a marker of neurohumoral activation) and presepsin (an inflammation marker). MATERIALS AND METHODS: Narrative review. RESULTS AND CONCLUSION: According to currently available data, there is a strong association between preoperative troponin or BNP values and postoperative adverse cardiac events and mortality. However, to date, there is only a weak recommendation for routine measurement of these biomarkers even in high-risk patients because the evidence on outcome improvement is still very limited. The evidence on treatment options in case of increased postoperative troponin values is also scarce so that international guidelines come to different conclusions regarding postoperative measurement of toponin. Meanwhile, several new biomarkers are under evaluation.

Mediation of the Cardioprotective Effects of Mannitol Discovered, with Refutation of Common Protein Kinases.

The osmodiuretic agent Mannitol exerts cardioprotection against ischemia and reperfusion (I/R) injury when applied as a pre- and/or postconditioning stimulus. Previously, we demonstrated that these properties are mediated via the activation of mitochondrial ATP-sensitive potassium (mKATP) channels. However, considering Mannitol remains in the extracellular compartment, the question arises as to which receptor and intracellular signaling cascades are involved in myocardial protection by the osmodiuretic substance. Protein kinase B (Akt) and G (PKG), as part of the reperfusion injury salvage kinase (RISK) and/or endothelial nitric oxide (eNOS)/PKG pathway, are two well-investigated intracellular targets conferring myocardial protection upstream of mitochondrial potassium channels. Adenosine receptor subtypes have been shown to trigger different cardioprotective pathways, for example, the reperfusion injury. Further, Mannitol induces an increased activation of the adenosine 1 receptor (A1R) in renal cells conferring its nephroprotective properties. Therefore, we investigated whether (1) Akt and PKG are possible signaling targets involved in Mannitol-induced conditioning upstream of the mKATP channel and/or whether (2) cardioprotection by Mannitol is mediated via activation of the A1R. All experiments were performed on male Wistar rats in vitro employing the Langendorff isolated heart perfusion technique with infarct size determination as the primary endpoint. To unravel possible protein kinase activation, Mannitol was applied in combination with the Akt (MK2206) or PKG (KT5823) inhibitor. In further groups, an A1R blocker (DPCPX) was given with or without Mannitol. Preconditioning with Mannitol (Man) significantly reduced the infarct size compared to the control group. Co-administration of the A1R blocker DPXPC fully abolished myocardial protection of Mannitol. Interestingly and in contrast to the initial hypothesis, neither administration of the Akt nor the PKG blocker had any impact on the cardioprotective properties of Mannitol-induced preconditioning. These results are quite unexpected and show that the protein kinases Akt and PKG-as possible targets of known protective signaling cascades-are not involved in Mannitol-induced preconditioning. However, the cardioprotective effects of Mannitol are mediated via the A1R.

Risk Factors for Acute Kidney Injury Requiring Renal Replacement Therapy after Orthotopic Heart Transplantation in Patients with Preserved Renal Function.

Acute kidney injury (AKI), requiring renal replacement therapy (RRT). is a serious complication after orthotopic heart transplantation (HTX). In patients with preexisting impaired renal function, postoperative AKI is unsurprising. However, even in patients with preserved renal function, AKI requiring RRT is frequent. Therefore, this study aimed to identify risk factors associated with postoperative AKI requiring RRT after HTX in this sub-cohort. This retrospective cohort study included patients ≥ 18 years of age with preserved renal function (defined as preoperative glomerular filtration rate ≥ 60 mL/min) who underwent HTX between 2010 and 2021. In total, 107 patients were included in the analysis (mean age 52 ± 12 years, 78.5% male, 45.8% AKI requiring RRT). Based on univariate logistic regression, use of extracorporeal membrane oxygenation, postoperative infection, levosimendan therapy, duration of norepinephrine (NE) therapy and maximum daily increase in tacrolimus plasma levels were chosen to be included into multivariate analysis. Duration of NE therapy and maximum daily increase in tacrolimus plasma levels remained as independent significant risk factors (NE: OR 1.01, 95%CI: 1.00-1.02, p = 0.005; increase in tacrolimus plasma level: OR 1.18, 95%CI: 1.01-1.37, p = 0.036). In conclusion, this study identified long NE therapy and maximum daily increase in tacrolimus plasma levels as risk factors for AKI requiring RRT in HTX patients with preserved renal function.

Platelet reactivity is higher in e-cigarette vaping as compared to traditional smoking.

INTRODUCTION: Vaping emerges as alternative to standard tobacco smoking. However, there is evidence for critical cardiovascular, gastrointestinal and respiratory side effects. Nevertheless, long-term vaping effects on thrombocyte reactivity have not been investigated. Therefore, we investigated the influence of vaping on thrombocyte reactivity in comparison to standard smoking and non-smoking. METHODS: Platelet function was measured by Multiplate Impedance Aggregometry as area under the curve (AUC). Smoking habits and characteristics were assessed by questionnaire. Results were analyzed using inverse probability of treatment weighting (IPTW) and conventional t-tests to test for robustness. RESULTS: After IPTW adjustment, participants in all groups were balanced by age, gender, body height and weight. Collagen-induced aggregation was higher in vapers compared to non-smokers (non-smokers 52.55 ± 23.97 vs. vapers 66.63 ± 18.96 AUC, p = 0.002) and to smokers (vapers vs. smokers 49.50 ± 26.05 AUC, p < 0.0001). ADP-induced aggregation in vapers was higher compared to non-smokers (non-smokers 33.16 ± 16.61 vs. vapers 45.27 ± 18.67 AUC, p = 0.001) and was numerically increased compared to smokers (vapers vs. smokers 40.09 ± 19.80 AUC, p = 0.08). These findings remained robust in t-test analysis. CONCLUSION: This study provides first evidence that vaping leads to enhanced platelet reactivity compared to standard smoking and non-smoking. This suggests health effects of vaping might be more severe than previously assumed. Whether this effect translates to clinical outcome with a higher incidence of major cardiovascular events, should be evaluated in large-scaled clinical studies.

[Perioperative cardioprotection - From bench to bedside : Current experimental evidence and possible reasons for the limited translation into the clinical setting]. / Perioperative Kardioprotektion ­ "From bench to bedside" : Aktuelle experimentelle Evidenz und mögliche Gründe für die limitierte Translation in die klinische Praxis.

BACKGROUND: Perioperative cardioprotection aims to minimize the consequences of myocardial ischemia reperfusion injury. These strategies appear particularly relevant for anesthesia provision during on-pump cardiac surgery but they potentially affect any cause of perioperative myocardial ischemia. In recent years, several pharmacological and nonpharmacological strategies of cardioprotection have been explored. Results from studies in isolated tissue and animal experiments are promising; however, translation of myocardial conditioning strategies to the clinical setting has been disappointing: in large trials cardioprotective interventions failed to significantly improve outcome. OBJECTIVE: This review aims to provide an overview of the current experimental evidence regarding pharmacological and nonpharmacological cardioprotection. Moreover, it discusses reasons why translation from bench to bedside is hampered by potential confounders and suggests future approaches that might overcome these limitations. MATERIAL AND METHODS: Narrative review. RESULTS AND CONCLUSION: Results of experimental studies are convincing but translation into clinical practice remains challenging. Several confounders have been identified contributing to the mainly inconclusive results from clinical studies, such as comorbidities and comedications, choice of anesthetic regimen and also methodological issues. Carefully designed clinical trials in well-defined patient cohorts evaluating combinations of protective strategies targeting different pathways and cell types might support bench to bedside translation.

Intraneural Application of microRNA-1 Mimetic Nucleotides Does Not Resolve Neuropathic Pain After Chronic Constriction Injury in Rats.

BACKGROUND: Alterations of the expression of microRNAs (miRNAs) in chronic pain models seem to play a crucial role in the development of neuropathic pain, with microRNA-1 (miR-1) being of particular interest. Recently, we were able to show that decreased miR-1 levels were associated with increased expression of brain-derived neurotrophic factor (BDNF) and Connexin 43 (Cx43). We hypothesized that miR-1 mimetic nucleotides could alleviate neuropathic pain caused by chronic constriction injury in rats. METHODS: MiR-1 mimetic nucleotides were evaluated for effectiveness, functionality, and intracellular stability by transfecting human glioblastoma cells (U-87 MG). In vivo transfection with miR-1 mimics and corresponding scrambled miRNAs serving as control was performed by repetitive injection (days 0, 3, and 7) into the sciatic nerve following chronic constriction injury (CCI) in rats. Quantitative PCR was used to measure miR-1 content. Cx43 expression was determined by Western blot analysis. Effects on neuropathic pain were assessed by detecting paw withdrawal thresholds using an automated filament application. RESULTS: Transfection of miR-1 mimics was confirmed in U-87 MG cells, with miR-1 content being increased significantly after 48 h and after 96 h (p<0.05). Effective downregulation of Cx43 expression was observed 48 and 96 h after transfection (-44 ± 0.07% and -40 ± 0.11%; p<0.05). In vivo, repetitive transfection with miR-1 mimetic nucleotides led to a 17.9-fold (± 14.2) increase of miR-1 in the sciatic nerve. However, the protein expression of Cx43 in sciatic nerves as well as paw withdrawal thresholds for mechanical stimulation was not significantly increased 10 days after chronic constriction injury. CONCLUSION: While transfection with miR-1 mimics effective reduces Cx43 expression in vitro and restores miR-1 after CCI, we did neither observe altered levels of Cx43 protein level in nerves nor a beneficial effect on mechanical allodynia in vivo, most likely caused by insufficient Cx43 suppression.

MiR-21-5p but not miR-1-3p expression is modulated by preconditioning in a rat model of myocardial infarction.

Isoflurane (Iso) preconditioning (PC) is known to be cardioprotective against ischemia/reperfusion (I/R) injury. It was previously shown that microRNA-21-5p (miR-21-5p) is regulated by Iso-PC. It is unclear, if expression of cardiac enriched miR-1-3p is also affected by Iso-PC, and associated with activation of HIF1α (hypoxia-inducible factor 1-alpha).  Male Wistar rats (n = 6-8) were randomly assigned to treatment with or without 1 MAC Iso for 30 min, followed by 25 min of regional myocardial ischemia, with 120 min reperfusion. At the end of reperfusion, myocardial expression of miR-1-3p, miR-21-5p and mRNAs of two HIF-1α-dependent genes, VEGF (vascular endothelial growth factor) and HO-1 (heme oxygenase-1), were determined by quantitative PCR. Protein expression of a miR-21 target gene, PDCD4 (programmed cell death protein 4), was assessed by western blot analysis. Infarct sizes were analyzed with triphenyltetrazoliumchloride staining. MiR-21-5p expression was increased by Iso, whereas expression of miR-1-3p was not altered. The expression of VEGF but not HO-1 was induced by Iso. Iso-PC reduced infarct sizes compared to untreated controls. No regulation of miRNA and mRNA expression was detected after I/R. PDCD4 protein expression was not affected after Iso exposure. Expression of miR-21-5p, in contrast to miR-1-3p, is altered during this early time point of Iso-PC. HIF1α signaling seems to be involved in miR-21-5p regulation.

Activation of PKG and Akt Is Required for Cardioprotection by Ramelteon-Induced Preconditioning and Is Located Upstream of mKCa-Channels.

Ramelteon is a Melatonin 1 (MT1)-and Melatonin 2 (MT2)-receptor agonist conferring cardioprotection by pharmacologic preconditioning. While activation of mitochondrial calcium-sensitive potassium (mKCa)-channels is involved in this protective mechanism, the specific upstream signaling pathway of Ramelteon-induced cardioprotection is unknown. In the present study, we (1) investigated whether Ramelteon-induced cardioprotection involves activation of protein kinase G (PKG) and/or protein kinase B (Akt) and (2) determined the precise sequence of PKG and Akt in the signal transduction pathway of Ramelteon-induced preconditioning. Hearts of male Wistar rats were randomized and placed on a Langendorff system, perfused with Krebs-Henseleit buffer at a constant pressure of 80 mmHg. All hearts were subjected to 33 min of global ischemia and 60 min of reperfusion. Before ischemia, hearts were perfused with Ramelteon (Ram) with or without the PKG or Akt inhibitor KT5823 and MK2206, respectively (KT5823 + Ram, KT5823, MK2206 + Ram, MK2206). To determine the precise signaling sequence, subsequent experiments were conducted with the guanylate cyclase activator BAY60-2770 and the mKCa-channel activator NS1619. Infarct size was determined by 2,3,5-triphenyltetrazolium chloride (TTC) staining. Ramelteon-induced infarct size reduction was completely blocked by KT5823 (p = 0.0012) and MK2206 (p = 0.0005). MK2206 with Ramelteon combined with BAY60-2770 reduced infarct size significantly (p = 0.0014) indicating that PKG activation takes place after Akt. Ramelteon and KT5823 (p = 0.0063) or MK2206 (p = 0.006) respectively combined with NS1619 also significantly reduced infarct size, indicating that PKG and Akt are located upstream of mKCa-channels. This study shows for the first time that Ramelteon-induced preconditioning (1) involves activation of PKG and Akt; (2) PKG is located downstream of Akt and (3) both enzymes are located upstream of mKCa-channels in the signal transduction pathway.

Influence of Hyperglycemia During Different Phases of Ischemic Preconditioning on Cardioprotection-A Focus on Apoptosis and Aggregation of Granulocytes.

BACKGROUND: Ischemic preconditioning (IPC) protects the myocardium against ischemia/reperfusion injury. Evidence suggests that hyperglycemia inhibits IPC-induced cardioprotection. The effects of hyperglycemia initiated during different phases of IPC on myocardial injury were characterized with emphasis on apoptosis and aggregation of polymorphonuclear granulocytes (PMN). METHODS: Male Wistar rats were subjected to 35 min of myocardial ischemia and 2 h of reperfusion. Control animals were not further treated. IPC was induced by three cycles of 3 min ischemia and 5 min of reperfusion before major ischemia. Hyperglycemia (blood glucose more than 22.2 mmol/L) was induced by glucose administration with or without IPC during different phases (trigger- (before ischemia), mediator- (during ischemia), early reperfusion-phase). One additional group received an anti-PMN-antibody before ischemia. Infarct size was quantified by triphenyltetrazolium chloride staining. Cytochrome C release and B-cell lymphoma two (Bcl-2) expression were assessed by western blot analysis. Poly-ADP-Ribose staining and PMN accumulation were quantified with immunohistochemistry and histochemistry. RESULTS: IPC reduced infarct size compared with control. Hyperglycemia completely abolished IPC-induced cardioprotection independent of the time point of initiation. Hyperglycemia before and during major ischemia but without IPC also slightly reduced infarct size. IPC reduced the accumulation of PMNs. This effect was reversed by hyperglycemia during trigger- and mediator-phase but not by hyperglycemia during reperfusion. Hyperglycemia alone had no effect on PMN accumulation. In all treatment groups, signs of myocardial apoptosis were reduced compared with control. IPC alone, combined with hyperglycemia and anti-PMN treatment, reduced apoptosis by a Bcl-2-associated mechanism. Hyperglycemia alone reduced apoptosis by a Bcl-2-independent pathway. CONCLUSION: Hyperglycemia inhibits IPC-induced cardioprotection independent of its onset. Furthermore, hyperglycemia prevents apoptosis and IPC-induced reduction of PMN aggregation.

The age-adjusted Charlson comorbidity index in minimally invasive mitral valve surgery.

OBJECTIVES: Mitral valve repair is the preferred method used to address mitral valve regurgitation, whereas transcatheter mitral valve repair is recommended for high-risk patients. We evaluated the risk-predictive value of the age-adjusted Charlson comorbidity index (aa-CCI) in the setting of minimally invasive mitral valve surgery. METHODS: The perioperative course and 1-year follow-up of 537 patients who underwent isolated or combined minimally invasive mitral valve surgery were evaluated for 1-year mortality as the primary end point and other adverse events. The predictive values of the EuroSCORE II and STS score were compared to that of the aa-CCI by a comparative analysis of receiver operating characteristic curves. Restricted cubic splines were applied to find optimal aa-CCI cut-off values for the increased likelihood of experiencing the predefined adverse end points. Consequently, the perioperative course and postoperative outcome of the aa-CCI ≥8 patients and the remainder of the sample were analysed. RESULTS: The predictive value of the aa-CCI does not significantly differ from those of the EuroSCORE II or STS score. Patients with an aa-CCI ≥8 were identified as a subgroup with a significant increase of mortality and other adverse events. CONCLUSIONS: The aa-CCI displays a suitable predictive ability for patients undergoing minimally invasive mitral valve surgery. In particular, multimorbid or frail patients may benefit from the extension of the objectively assessed parameters, in addition to the STS score or EuroSCORE II. Patients with an aa-CCI ≥8 have a very high surgical risk and should receive very careful attention.