Immune-response gene 1 deficiency aggravates inflammation-triggered cardiac dysfunction by inducing M1 macrophage polarization and aggravating Ly6Chigh monocyte recruitment.

The immune response gene 1 (IRG1) and its metabolite itaconate are implicated in modulating inflammation and oxidative stress, with potential relevance to sepsis-induced myocardial dysfunction (SIMD). This study investigates their roles in SIMD using both in vivo and in vitro models. Mice were subjected to lipopolysaccharide (LPS)-induced sepsis, and cardiac function was assessed in IRG1 knockout (IRG1-/-) and wild-type mice. Exogenous 4-octyl itaconate (4-OI) supplementation was also examined for its protective effects. In vitro, bone marrow-derived macrophages and RAW264.7 cells were treated with 4-OI following Nuclear factor, erythroid 2 like 2 (NRF2)-small interfering RNA administration to elucidate the underlying mechanisms. Our results indicate that IRG1 deficiency exacerbates myocardial injury during sepsis, while 4-OI administration preserves cardiac function and reduces inflammation. Mechanistic insights reveal that 4-OI activates the NRF2/HO-1 pathway, promoting macrophage polarization and attenuating inflammation. These findings underscore the protective role of the IRG1/itaconate axis in SIMD and suggest a therapeutic potential for 4-OI in modulating macrophage responses.

Effect of dexmedetomidine on postoperative high-sensitivity cardiac troponin T in patients undergoing video-assisted thoracoscopic surgery: a prospective, randomised controlled trial.

BACKGROUND: One-lung ventilation and intrathoracic operations during thoracoscopic surgery often result in intraoperative hypoxaemia and haemodynamic fluctuations, resulting in perioperative myocardial injury. Dexmedetomidine, an alpha-2 (α-2) agonist, has demonstrated myocardial protection. We hypothesize that the routine intravenous administration of dexmedetomidine could reduce the extent of myocardial injury during video-assisted thoracoscopic surgery (VATS). METHODS: The study included patients aged ≥ 45 years, classified as American Society of Anesthesiologists physical status I-III, who underwent general anesthesia for video-assisted thoracoscopic surgery. The patients were randomly assigned to either the intervention group, receiving general anesthesia with dexmedetomidine, or the control group, receiving general anesthesia without dexmedetomidine. Patients in the intervention group received a loading dose of dexmedetomidine (0.5 µg·kg-1) before anesthesia induction, followed by a continuous infusion (0.5 µg·kg-1·h-1) until the completion of the surgery. Placebos (saline) were administered for the control group to match the treatment. The primary outcome assessed was the high-sensitivity cardiac troponin T on postoperative day 1. Additionally, the incidence of myocardial injury after noncardiac surgery (MINS) was noted. RESULTS: A total of 110 participants completed this study. The median [interquartile range (IQR)] concentration of hs-cTnT on postoperative day 1 was lower in the intervention group compared with the control group (7 [6-9] vs. 8 [7-11] pg·ml-1; difference in medians,1 pg·ml-1; 95% confidence interval [CI], 0 to 2; P = 0.005). Similarly, on postoperative day 3, the median [IQR] concentration of hs-cTnT in the intervention group was also lower than that in the control group (6 [5-7] vs. 7 [6-9]; difference in medians,1 pg·ml-1; 95%CI, 0 to 2; P = 0.011). Although the incidence of MINS was not statistically significant (the intervention group vs. the control group, 3.8% vs. 9.1%, P = 0.465), there was a decreasing trend in the incidence of MINS in the intervention group. CONCLUSION: The administration of perioperative dexmedetomidine in patients ≥ 45 years undergoing video-assisted thoracoscopic surgery could lower the release of postoperative hs-cTnT without reducing incidence of myocardial injury. TRIAL REGISTRATION: chictr.org.cn (ChiCTR2200063193); prospectively registered 1 September 2022.

Colchicine prevents perioperative myocardial injury in cardiac surgery by inhibiting the formation of neutrophil extracellular traps: evidence from rat models.

OBJECTIVES: Colchicine, an anti-inflammatory agent, has been reported to improve myocardial infarction prognosis by inhibiting neutrophil extracellular traps release. However, its role in cardiac surgery and the mechanisms behind neutrophil extracellular traps suppression remain unclear. This study aimed to explore colchicine's cardioprotective effects against perioperative myocardial injury in cardiac surgery, focusing on neutrophil extracellular traps inhibition as a novel therapeutic strategy. METHODS: Male Sprague-Dawley rats were pre-treated with colchicine (0.1 mg/kg/day) or CI-amidine (10 mg/kg/day) for seven days before undergoing cardiopulmonary bypass and myocardial ischaemia/reperfusion injury. The model was created by subjecting the rats to cardiopulmonary bypass and myocardial ischaemia/reperfusion injury. Under 4.0% sevoflurane anaesthesia, cardiopulmonary bypass was initiated by cannulating the tail artery and right atrium, and perfusion was maintained for 4 hours. Immunofluorescence detected neutrophil extracellular traps, and Hematoxylin and Eosin staining assessed inflammatory cell. RESULTS: We found colchicine treatment significantly reduced perioperative myocardial injury in rats. Furthermore, we observed a notable elevation of neutrophil extracellular traps in the myocardial tissue of animal models. Moreover, suppressing peptidylarginine deiminase 4(PAD-4) was found to markedly diminish perioperative myocardial injury in rats. Additionally, colchicine can mitigate the release of neutrophil extracellular traps by inhibiting PAD-4. CONCLUSIONS: NETs were significantly elevated during the perioperative period of cardiac surgery. Colchicine significantly mitigated myocardial injury in cardiac surgery by inhibiting neutrophil extracellular traps formation, with PAD-4 inhibition being one of its mechanisms.

Cardiovascular Magnetic Resonance Imaging in Physically Fit Young Patients Sans Comorbidities Who Recently Recovered from Coronavirus Disease 2019 (COVID-19).

INTRODUCTION AND OBJECTIVE: Multiple studies showed that patients with a severe course of COVID-19 may develop cardiovascular complications. Assessment of the incidence of myocardial injury in young, physically fit male patients with no comorbidities, and asymptomatic/mild course of the disease who recovered from COVID-19. MATERIAL AND METHODS: A prospective, single-center, observational cohort study of 75 young (median[IQR] age 22 years) physically fit male patients, without comorbidities and smoking who recently recovered from COVID-19. Results were compared with a control group of age-matched, physically fit men with no comorbidities who tested negative for SARS-CoV-2. RESULTS: 19(25%) patients had possible COVID-19 related myocardial injury[PCRMI] on cardiovascular magnetic resonance [CMR] including definitive myocarditis (n=1;1.3%) and possible myocarditis (n=3;4%). Other abnormalities: mildly decreased (<50%) left ventricular(LV) ejection fraction (n=4;5%), increased LV end-diastolic volume index (n=8;11%) and LV mass index (n=9;12%). Patients with PCRMI had higher NT-pro-BNP level (29 vs 20pg/mL respectively, P=0.02) and lower LV ejection fraction (55% vs 59% respectively, P=0.03). PCRMI was demonstrated in 3(27%) volunteers from the control group based on the presence of LGE (2/18%) and decreased LV ejection fraction (1/9%). No volunteer from the control group was diagnosed with definitive or possible myocarditis. CONCLUSIONS: PCRMI was a frequent finding in young, asymptomatic, physically-fit patients sans comorbidities relatively late after recovery from COVID-19. Whereas no definitive or possible myocarditis was found in the control group, LGE was relatively frequent suggesting that our findings might not be COVID-19 specific. This warrants a need for further investigation into the long-term cardiovascular consequences of COVID-19.

Rhein Alleviates Doxorubicin-Induced Myocardial Injury by Inhibiting the p38 MAPK/HSP90/c-Jun/c-Fos Pathway-Mediated Apoptosis.

Doxorubicin (Dox) has been limited in clinical application due to its cardiac toxicity that varies with the dose. This study aimed to explore how Rhein modulates Dox-induced myocardial toxicity. The general condition and echocardiographic changes of mice were observed to evaluate cardiac function and structure, with myocardial cell injury and apoptosis checked by TUNEL and HE staining. The ELISA assessed markers of myocardial damage and inflammation. The TCMSP and SwissTargetPrediction databases were used to retrieve Rhein's targets while GeneCards was used to find genes related to Dox-induced myocardial injury. Intersection genes were analyzed by Protein-Protein Interaction Networks. The core network genes underwent GO and KEGG enrichment analysis using R software. Western blot was used to detect protein expression. Compared to the Dox group, there was no remarkable difference in heart mass /body mass ratio in the Rhein+Dox group. However, heart mass/tibia length increased. Mice in the Rhein+Dox group had significantly increased LVEF, LVPWs, and LVFS compared to those in the Dox group. Myocardial cell damage, inflammation, and apoptosis significantly reduced in the Rhein+Dox group compared to the model group. Eleven core network genes were selected. Further, Rhein+Dox group showed significantly downregulated expression of p38/p-p38, HSP90AA1, c-Jun/p-c-Jun, c-Fos/p-c-Fos, Bax, and cleaved-caspase-3/caspase-3 while Bcl-2 expression significantly upregulated compared to the Dox group. The study suggests that Rhein mediates cardioprotection against Dox-induced myocardial injury, at least partly, by influencing multiple core genes in the MAPK signaling pathway to inhibit myocardial cell apoptosis.

Combined diosmin and bisoprolol attenuate cobalt chloride-induced cardiotoxicity and endothelial dysfunction through modulating miR-143-3P/MAPK/MCP-1, ERK5/CXCR4, Orai-1/STIM-1 signaling pathways.

Even while accelerated cardiomyocyte apoptosis is one of the primary causes of cardiac damage, the underlying mechanism is still mostly unknown. In addition to examining potential protective effects of bisoprolol and diosmin against CoCl2-induced cardiac injury, the goal of this study was to identify potential mechanisms regulating the hypoxic cardiac damage caused by cobalt chloride (CoCl2). For a period of 21 days except Cocl2 14 days from the first day of the experiment, rats were split into the following groups: Normal control group, rats received vehicle only (2 ml/kg/day, p.o.), (Cocl2, 150 mg/kg/day, p.o.), bisoprolol (25 mg/kg/day, p.o.); diosmin (100 mg/kg/day, p.o.) and bisoprolol + diosmin + Cocl2 groups. At the end of the experimental period, serum was taken for estimation of cardiac function, lipid profile, and pro/anti-inflammatory cytokines. Moreover, tissue samples were collected for evaluation of oxidative stress, endothelial dysfunction, α-SMA, PKC-α, MiR-143-3P, MAPK, ERK5, MCP-1, CXCR4, Orai-1, and STIM-1. Diosmin and bisoprolol, either alone or in combination, enhance heart function by reducing abnormalities in the electrocardiogram and the hypotension brought on by CoCl2. Additionally, they significantly ameliorate endothelial dysfunction by downregulating the cardiac expressions of α-SMA, PKC-α, MiR-143-3P, MAPK, ERK5, MCP-1, CXCR4, Orai-1, and STIM-1. Bisoprolol and diosmin produced modulatory activity against inflammatory state, redox balance, and atherogenic index concurrently. Together, diosmin and bisoprolol, either alone or in combination, significantly reduced all the cardiac alterations brought on by CoCl2. The capacity to obstruct hypoxia-induced α-SMA, PKC-α, MiR-143-3P/MAPK/MCP-1, MiR-143-3P/ERK5/CXCR4, Orai-1/STIM-1 signaling activation, as well as their anti-inflammatory, antioxidant, and anti-apoptotic properties, may be responsible for these cardio-protective results.

The predictive value of coronary computed tomography angiography-derived fractional flow reserve for perioperative cardiac events in lung cancer surgery.

PURPOSE: As a non-invasive coronary functional examination, coronary computed tomography angiography (CCTA)-derived fractional flow reserve (CT-FFR) showed predictive value in several non-cardiac surgeries. This study aimed to evaluate the predictive value of CT-FFR in lung cancer surgery. METHOD: We retrospectively collected 227 patients from January 2017 to June 2022 and used machine learning-based CT-FFR to evaluate the stable coronary artery disease (CAD) patients undergoing lung cancer surgery. The major adverse cardiac event (MACE) was defined as perioperative myocardial injury (PMI), myocardial infarction, heart failure, atrial and ventricular arrhythmia with hemodynamic disorder, cardiogenic shock and cardiac death. The multivariate logistic regression analysis was performed to identify risk factors for MACE and PMI. The discriminative capacity, goodness-of-fit, and reclassification improvement of prediction model were determined before and after the addition of CT-FFR≤0.8. RESULTS: The incidence of MACE was 20.7 % and PMI was 15.9 %. CT-FFR significantly outperformed CCTA in terms of accuracy for predicting MACE (0.737 vs 0.524). In the multivariate regression analysis, CT-FFR≤0.8 was an independent risk factor for both MACE [OR=10.77 (4.637, 25.016), P<0.001] and PMI [OR=8.255 (3.372, 20.207), P<0.001]. Additionally, we found that the performance of prediction model for both MACE and PMI improved after the addition of CT-FFR. CONCLUSIONS: CT-FFR can be used to assess the risk of perioperative MACE and PMI in patients with stable CAD undergoing lung cancer surgery. It adds prognostic information in the cardiac evaluation of patients undergoing lung cancer surgery.

Visualising myocardial injury after noncardiac surgery: a case series using postoperative cardiovascular MRI.

Myocardial injury after noncardiac surgery (MINS) and perioperative myocardial injury are associated with increased morbidity and mortality. Both are diagnosed by a perioperative increase in troponin, yet there is controversy if MINS is a genuine myocardial insult. We applied postoperative cardiovascular magnetic resonance T2 mapping techniques to visualise acute myocardial injury (i.e. oedema) in six patients with multiple cardiovascular risk factors who underwent aortic surgery. The burden of myocardial oedema was substantially higher in four patients with elevated troponin qualifying for MINS, compared with patients without MINS. The data and images suggest that MINS represents genuine myocardial injury.

Acute pericardial postischemic inflammatory responses: Characterization using a preclinical porcine model.

BACKGROUND: Pericardial fluid (PF) contains cells, proteins, and inflammatory mediators, such as cytokines, chemokines, growth factors, and matrix metalloproteinases. To date, we lack an adequate understanding of the inflammatory response that acute injury elicits in the pericardial space. OBJECTIVE: To characterize the inflammatory profile in the pericardial space acutely after ischemia/reperfusion. METHODS: Pigs were used to establish a percutaneous ischemia/reperfusion injury model. PF was removed from pigs at different time points postanesthesia or postischemia/reperfusion. Flow cytometry was used to characterize the immune cell composition of PF, while multiplex analysis was performed on the acellular portion of PF to determine the concentration of inflammatory mediators. There was a minimum of 3 pigs per group. RESULTS: While native PF mainly comprises macrophages, we show that neutrophils are the predominant inflammatory cell type in the pericardial space after injury. The combination of acute ischemia/reperfusion (IR) and repeatedly accessing the pericardial space significantly increases the concentration of interleukin-1 beta (IL-1ß) and interleukin-1 receptor antagonist (IL-1ra). IR significantly increases the pericardial concentration of TGFß1 but not TGFß2. We observed that repeated manipulation of the pericardial space can also drive a robust pro-inflammatory response, resulting in a significant increase in immune cells and the accumulation of potent inflammatory mediators in the pericardial space. CONCLUSION: In the present study, we show that both IR and surgical manipulation can drive robust inflammatory processes in the pericardial space, consisting of an increase in inflammatory cytokines and alteration in the number and composition of immune cells.

Association between C-reactive protein to albumin ratio and subclinical myocardial injury in the general population free from cardiovascular disease.

OBJECTIVE: The study aimed to examine the role of the C-reactive protein to albumin ratio (CAR) as an inflammatory biomarker in relation to subclinical myocardial injury (SC-MI), addressing the limited knowledge of their association. METHODS: The study included 5,949 individuals without cardiovascular disease (CVD) from the National Health and Nutrition Examination Survey. SC-MI was identified through a Cardiac Infarction Injury Score (CIIS) of ≥ 10 units based on a 12-lead electrocardiogram. The study used multivariate logistic regression models, adjusted for potential confounders, to evaluate the relationship between CAR and SC-MI. Subgroup analyses were conducted to substantiate the results, and the non-linear correlation was assessed via restricted cubic spline (RCS) regression. RESULTS: The RCS curve showed a significant positive correlation between CAR and SC-MI (P for nonlinear = 0.2496). When adjusted for all confounders, individuals in the highest tertile of CAR exhibited a higher likelihood of SC-MI compared to those in the lowest tertile, with an odds ratio (OR) of 1.21 (95% CI: 1.06-1.39, P for trend = 0.029). A 10-unit increment in CAR was linked to a 3.6% heightened risk of SC-MI [OR = 1.036 (95% CI: 1.006, 1.066)], with this association being more prominent among male adults, non-smokers, married individuals, those without diabetes mellitus, and those with no history of cancer. CONCLUSION: The findings of this study suggest a positive correlation between CAR and SC-MI among the US adult population, indicating the potential of CAR in enhancing SC-MI prevention strategies in the general population.

Development and Validation of an Explainable Machine Learning Model for Predicting Myocardial Injury After Noncardiac Surgery in Two Centers in China: Retrospective Study.

Background: Myocardial injury after noncardiac surgery (MINS) is an easily overlooked complication but closely related to postoperative cardiovascular adverse outcomes; therefore, the early diagnosis and prediction are particularly important. Objective: We aimed to develop and validate an explainable machine learning (ML) model for predicting MINS among older patients undergoing noncardiac surgery. Methods: The retrospective cohort study included older patients who had noncardiac surgery from 1 northern center and 1 southern center in China. The data sets from center 1 were divided into a training set and an internal validation set. The data set from center 2 was used as an external validation set. Before modeling, the least absolute shrinkage and selection operator and recursive feature elimination methods were used to reduce dimensions of data and select key features from all variables. Prediction models were developed based on the extracted features using several ML algorithms, including category boosting, random forest, logistic regression, naïve Bayes, light gradient boosting machine, extreme gradient boosting, support vector machine, and decision tree. Prediction performance was assessed by the area under the receiver operating characteristic (AUROC) curve as the main evaluation metric to select the best algorithms. The model performance was verified by internal and external validation data sets with the best algorithm and compared to the Revised Cardiac Risk Index. The Shapley Additive Explanations (SHAP) method was applied to calculate values for each feature, representing the contribution to the predicted risk of complication, and generate personalized explanations. Results: A total of 19,463 eligible patients were included; among those, 12,464 patients in center 1 were included as the training set; 4754 patients in center 1 were included as the internal validation set; and 2245 in center 2 were included as the external validation set. The best-performing model for prediction was the CatBoost algorithm, achieving the highest AUROC of 0.805 (95% CI 0.778-0.831) in the training set, validating with an AUROC of 0.780 in the internal validation set and 0.70 in external validation set. Additionally, CatBoost demonstrated superior performance compared to the Revised Cardiac Risk Index (AUROC 0.636; P<.001). The SHAP values indicated the ranking of the level of importance of each variable, with preoperative serum creatinine concentration, red blood cell distribution width, and age accounting for the top three. The results from the SHAP method can predict events with positive values or nonevents with negative values, providing an explicit explanation of individualized risk predictions. Conclusions: The ML models can provide a personalized and fairly accurate risk prediction of MINS, and the explainable perspective can help identify potentially modifiable sources of risk at the patient level.

Perioperative surveillance of myocardial injury after non-cardiac surgery in patients with hip fracture: A retrospective cohort study.

Myocardial injury after non-cardiac surgery is due to ischaemia either during non-cardiac surgery or within 30 days after it. Our surveillance protocol includes hip fracture template and high-sensitivity troponin stratification, as recommended in European countries. Our retrospective study cohort included surgical patients for hip fracture at our hospital in Japan. The primary outcome was the rate of myocardial injury after non-cardiac surgery in comparison to patients managed with (213) and without (176) hip fracture template. The hip fracture template was used more in patients with myocardial injury after non-cardiac surgery than those without myocardial injury after non-cardiac surgery. When hip fracture template was used, patients had a higher likelihood of myocardial injury after non-cardiac surgery after adjusting for age, time to operation, diabetes mellitus, and chronic kidney disease (odds ratio 41.3; 95% confidence interval: 12.1, 259.6). Patients with myocardial injury after non-cardiac surgery had higher in-hospital mortality than those without myocardial injury after non-cardiac surgery, even in adjusted analysis. There was a high detection rate of myocardial injury after non-cardiac surgery when patients with hip fractures were managed with hip fracture template. Myocardial injury after non-cardiac surgery was associated with in-hospital mortality.

Protosappanin A Protects DOX-Induced Myocardial Injury and Cardiac Dysfunction by Targeting ACSL4/FTH1 Axis-Dependent Ferroptosis.

Doxorubicin (DOX) is an effective anticancer agent, but its clinical utility is constrained by dose-dependent cardiotoxicity, partly due to cardiomyocyte ferroptosis. However, the progress of developing cardioprotective medications to counteract ferroptosis has encountered obstacles. Protosappanin A (PrA), an anti-inflammatory compound derived from hematoxylin, shows potential against DOX-induced cardiomyopathy (DIC). Here, it is reported that PrA alleviates myocardial damage and dysfunction by reducing DOX-induced ferroptosis and maintaining mitochondrial homeostasis. Subsequently, the molecular target of PrA through proteome microarray, molecular docking, and dynamics simulation is identified. Mechanistically, PrA physically binds with ferroptosis-related proteins acyl-CoA synthetase long-chain family member 4 (ACSL4) and ferritin heavy chain 1 (FTH1), ultimately inhibiting ACSL4 phosphorylation and subsequent phospholipid peroxidation, while also preventing FTH1 autophagic degradation and subsequent release of ferrous ions (Fe2+) release. Given the critical role of ferroptosis in the pathogenesis of ischemia-reperfusion (IR) injury, this further investigation posits that PrA can confer a protective effect against IR-induced cardiac damage by inhibiting ferroptosis. Overall, a novel pharmacological inhibitor is unveiled that targets ferroptosis and uncover a dual-regulated mechanism for cardiomyocyte ferroptosis in DIC, highlighting additional therapeutic options for chemodrug-induced cardiotoxicity and ferroptosis-triggered disorders.

Quercetin Alleviates LPS-Stimulated Myocardial Injury through Regulating ALOX5/PI3K/AKT Pathway in Sepsis.

Quercetin (QUE) has been found to inhibit the progression of sepsis-related diseases, including sepsis-induced cardiomyopathy (SIC). More information about the role and mechanism of QUE in SIC progression deserves further exploration. Human cardiomyocytes (AC16) were induced with LPS to mimic SIC cell models. Cell proliferation and apoptosis were determined using CCK8 assay, EdU assay, and flow cytometry. Cell inflammation and ferroptosis were evaluated by detecting IL-1ß, TNF-α, Fe2+, ROS, GSH, and GPX4 levels. 5-lipoxygenase (ALOX5) expression was examined by quantitative real-time PCR and western blot. LPS treatment reduced AC16 cell proliferation, while enhanced apoptosis, inflammation, and ferroptosis. QUE repressed LPS-induced AC16 cell apoptosis, inflammation, and ferroptosis. ALOX5 was upregulated in SIC patients, and its expression was reduced by QUE. ALOX5 knockdown restrained LPS-induced apoptosis, inflammation, and ferroptosis in AC16 cells. The inhibitory effect of QUE on LPS-induced myocardial injury could be reversed by ALOX5 overexpression. QUE promoted the activity of PI3K/AKT pathway by reducing ALOX5 expression. QUE could alleviate LPS-induced myocardial injury by regulating ALOX5/PI3K/AKT pathway, suggesting that QUE might be used for treating SIC.

Personalised perioperative dosing of ivabradine in noncardiac surgery: a single-centre, randomised, placebo-controlled, double-blind feasibility pilot trial.

BACKGROUND: Perioperative myocardial injury after noncardiac surgery is associated with postoperative mortality. Heart rate (HR) is an independent risk factor for perioperative myocardial injury. In this pilot trial we tested the feasibility of a randomised, placebo-controlled trial of personalised HR-targeted perioperative ivabradine. METHODS: This was a single-centre, randomised, placebo-controlled, double-blind, parallel group, feasibility pilot trial conducted at Geneva University Hospitals. We included patients ≥75 yr old or ≥45 yr old with cardiovascular risk factors planned for intermediate- or high-risk surgery. Patients were randomised to receive ivabradine (2.5, 5.0, or 7.5 mg) or placebo according to their HR, twice daily, from the morning of surgery until postoperative day 2. Primary outcomes were appropriate dosage and blinding success rates. RESULTS: Between October 2020 and January 2022, we randomised 78 patients (recruitment rate of 1.3 patients week-1). Some 439 of 444 study drug administrations were adequate (99% appropriate dosage rate). The blinding success rate was 100%. There were 137 (31%) administrations of Pill A (placebo in both groups for HR ≤70 beats min-1). Nine (11.5%) patients had a high-sensitive cardiac troponin T elevation ≥14 ng L-1 between any two measurements. The number of bradycardia episodes was eight in the placebo group and nine in the ivabradine group. CONCLUSIONS: This pilot study demonstrates the feasibility of, and provides guidance for, a future trial testing the efficacy of personalised perioperative ivabradine. Future studies should include patients at higher risk of cardiac complications. CLINICAL TRIAL REGISTRATION: NCT04436016.

Feasibility of aligning creatine kinase MB activity and mass data in multicentre trials using generalized additive modelling.

OBJECTIVES: Elevated serum creatine kinase isoenzyme MB (CK-MB) levels indicate myocardial ischaemia and periprocedural myocardial injury during treatment of heart diseases. We established a method to predict CK-MB mass from activity data based on a prospective pilot study in order to simplify multicentre trials. METHODS: 38 elective cardiac surgery patients without acute myocardial ischaemia and terminal renal failure were recruited. CK-MB mass and activity were determined in venous blood samples drawn preoperatively, postoperatively, 6 h post-op, and 12 h post-op. Linear regression and generalized additive models (GAMs) were applied to describe the relationship of mass and activity. Influences of demographic and perioperative factors on the fit of GAMs was evaluated. The agreement of predicted and measured CK-MB masses was assessed by Bland-Altman analyses. RESULTS: Linear regression provided an acceptable overall fit (r2 = 0.834) but showed deviances at low CK-MB levels. GAMs did not benefit from the inclusion of age, body mass index and surgical times. The minimal adequate model predicted CK-MB masses from activities, sex and sampling time with an r2 of 0.981. Bland-Altman analyses confirmed narrow limits of agreement (spread: 8.87 µg/l) and the absence of fixed (P = 0.41) and proportional (P = 0.21) biases. CONCLUSIONS: GAM-based modelling of CK-MB data in a representative patient cohort allowed to predict CK-MB masses from activities, sex and sampling time. This approach simplifies the integration of study centres with incompatible CK-MB data into multicentre trials in order to facilitate inclusion of CK-MB levels in statistical models.

The exploration of perioperative hypotension subtypes: a prospective, single cohort, observational pilot study.

Background: Hypotension is a risk factor for postoperative complications, but evidence from randomized trials does not support that a higher blood pressure target always leads to optimized outcomes. The heterogeneity of underlying hemodynamics during hypotension may contribute to these contradictory results. Exploring the subtypes of hypotension can enable optimal management of intraoperative hypotension. Methods: This is a prospective, observational pilot study. Patients who were ≥ 45 years old and scheduled to undergo moderate-to-high-risk noncardiac surgery were enrolled in this study. The primary objective of this pilot study was to investigate the frequency and distribution of perioperative hypotension and its subtypes (hypotension with or without cardiac output reduction). The exposure of hypotension and its subtypes in patients with and without myocardial or acute kidney injury were also explored. Results: Sixty patients were included in the analysis. 83% (50/60) of the patients experienced perioperative hypotension. The median duration of hypotension for each patient was 8.0 [interquartile range, 3.1-23.3] minutes. Reduced cardiac output was present during 77% of the hypotension duration. Patients suffering from postoperative myocardial or acute kidney injury displayed longer duration and more extensive exposure in all hypotension subtypes. However, the percentage of different hypotension subtypes did not differ in patients with or without postoperative myocardial or acute kidney injury. Conclusion: Perioperative hypotension was frequently accompanied by cardiac output reduction in moderate-to-high-risk noncardiac surgical patients. However, due to the pilot nature of this study, the relationship between hypotension subtypes and postoperative myocardial or acute kidney injury still needs further exploration. Clinical trial registration: https://www.chictr.org.cn/showprojEN.html?proj=134260, CTR2200055929.