Creatine Kinase Isoenzyme MB Levels Research Articles

Cardiovascular adverse events associated with immune checkpoint inhibitors: A retrospective multicenter cohort study.

Over the past decade, immune checkpoint inhibitors (ICIs) have significantly transformed cancer treatment. However, ICIs inevitably may cause a spectrum of immune-related adverse events, among which cardiovascular toxicity, particularly myocarditis, while infrequent, has garnered increasing attention due to its high fatality rate. We conducted a multicenter retrospective study to characterize ICI-associated cardiovascular adverse events. Logistic regression was performed to explore the risk factors for the development of myocarditis and severe myocarditis. Receiver operating characteristic curves were conducted to assess the diagnostic abilities of cardiac biomarkers to distinguish different cardiovascular toxicities, and the performance and calibration were evaluated using Hosmer-Lemeshow test. Forty-four patients were identified, including thirty-five myocarditis, five heart failure, three arrhythmias, and one myocardial infarction. Compared with other patients, myocarditis patients had higher cardiac troponin-I (cTnI) levels (p < 0.001), higher creatine kinase levels (p = 0.003), higher creatine kinase isoenzyme-MB (CK-MB) levels (p = 0.013), and shorter time to the incidence of adverse cardiovascular events (p = 0.022) after ICI treatment. Twenty-one patients (60%) were classified as severe myocarditis, and they presented higher cardiac troponin I (cTnI) levels (p = 0.013), higher N-terminal pro-B-type natriuretic peptide levels (p = 0.031), higher creatine kinase levels (p = 0.018), higher CK-MB levels (p = 0.026), and higher neutrophil to lymphocyte ratio (NLR) levels (p = 0.016) compared to non-severe myocarditis patients after ICI treatment. Multivariate logistic regression showed that CK-MB (adjusted odds ratio [OR]: 1.775, 95% confidence interval [CI]: 1.055-2.984, p = 0.031) was the independent risk factor of the development of ICI-associated myocarditis, and cTnI (adjusted OR: 1.021, 95% CI: 1.002-1.039, p = 0.03) and NLR (adjusted OR: 1.890, 95% CI: 1.026-3.483, p = 0.041) were the independent risk factors of ICI-associated severe myocarditis. The receiver operating characteristic curve showed an area under curve of 0.785 (95% CI: 0.642 to 0.928, p = 0.013) for CK-MB, 0.765 (95% CI: 0.601 to 0.929, p = 0.013) for cTnI, and 0.773 for NLR (95% CI: 0.597 to 0.948, p = 0.016). Elevated CK-MB after ICI treatment is the independent risk factor for the incidence of ICI-associated myocarditis, and elevated cTnI and NLR after ICI treatment are the independent risk factors for the development of ICI-associated severe myocarditis. CK-MB, cTnI, and NLR demonstrated a promising predictive utility for the identification of ICI-associated myocarditis and severe myocarditis.

Comparison of modified Del Nido and Custodiol® cardioplegia in minimally invasive mitral valve surgery.

In this study, we evaluated if modified Del Nido cardioplegia delivers comparable cardiac protection in comparison to Custodiol® in patients undergoing isolated minimally invasive mitral valve repair. From January 2018 to October 2021, all patients undergoing non-emergent isolated minimally invasive mitral valve repair were included in this study. The cardioplegia was chosen at the surgeons' discretion. The primary end points of this study were peak postoperative cardiac enzyme levels. Secondary end points were in-hospital mortality, hospital stay, occurrence of cardiac arrhythmias, pacemaker implantations, postoperative lactate and sodium levels and postoperative incidence of renal failure requiring dialysis. A total of 355 patients were included in this study. The mean age of patients was 57. After propensity score matching, a total of 156 pairs were identified. There was no difference in cross-clamp time between both groups. Postoperative creatine kinase levels were higher in patients receiving Custodiol on the 1st and 2nd postoperative days. Creatine kinase isoenzyme MB levels were higher in patients receiving Custodiol on the 2nd postoperative day (0.5 ± 0.2 vs 0.4 ± 0.1 µmol/l s; P < 0.001). Postoperative Troponin T concentrations were similar between both groups. Maximum lactate concentrations were higher in patients receiving Custodiol on the day of surgery (2.4 ± 1.9 vs 2.0 ± 1.1 mmol/l; P = 0.04). The overall hospital stay was longer in patients receiving Del Nido cardioplegia (10.6 ± 3.2 vs 8 ± 4.1 days; P < 0.01). Modified Del Nido cardioplegia based on Ionosteril® solution offers equivalent protection compared to Custodiol for isolated minimally invasive mitral valve repair.

Analysis of risk factors and changes in myocardial biomarker levels in 122 cases of early neonatal anemia.

Anemia in the first week after birth, which could affect growth, development, and organ function, should be an important warning sign to clinicians. The aim of this study was to assess the related risk factors of early neonatal anemia and to analyze the effect of anemia on the expression levels of myocardial markers in newborns. Clinical data from 122 confirmed cases of anemic newborns and 108 nonanemic newborns were collected to analyze the independent risk factors for early anemia using logistic regression analyses. Blood samples were collected from both groups for the detection of myocardial markers, including the protein marker cardiac troponin T (cTnT), as well as enzyme markers creatine kinase isoenzyme MB (CK-MB) and lactate dehydrogenase (LDH). Multivariate logistic regression analysis revealed that preterm birth (OR: 3.589 [1.119-11.506], p < 0.05), multiple pregnancy (OR: 4.117 [1.021-16.611], p < 0.05), and abnormal placenta (OR: 4.712 [1.077-20.625], p < 0.05) were independent risk factors for early neonatal anemia. The levels of myocardial markers, including cTnT (303.1 ± 244.7 vs. 44.2 ± 55.41 ng/L), CK-MB (6.803 ± 8.971 vs. 2.5326 ± 2.927 μkat/L), and LDH (32.42 ± 35.26 vs. 19.73 ± 17.13 μkat/L), were significantly higher in the anemic group than in the nonanemic group. Multiple pregnancy, preterm birth, and abnormal placenta were identified as risk factors for early neonatal anemia. The occurrence of early neonatal anemia was associated with increased levels of myocardial markers.

Tenofovir alafenamide significantly increased serum lipid levels compared with entecavir therapy in chronic hepatitis B virus patients.

Tenofovir alafenamide (TAF) has a serum lipid-raising effect in patients with HIV; however, its effect on serum lipids and nonalcoholic fatty liver disease (NAFLD) risk in patients with chronic hepatitis B (CHB) is unclear. To compare the effects of TAF and entecavir (ETV) on serum lipid levels in patients with CHB. In this retrospective cohort study, the data including the clinical features, serum lipids, and metabolic factors of patients with CHB at baseline and approximately 1 year after TAF or ETV treatment were collected and analyzed. We used propensity score-matched models to assess the effects on high-density lipoprotein, low-density lipoprotein, triglycerides, and total cholesterol (TCHO). A total of 336 patients (75.60% male) were included; 63.69% received TAF and 36.31% received ETV. Compared with the ETV group, the TAF group had significantly higher TCHO levels after treatment (4.67 ± 0.90 vs 4.36 ± 1.05, P = 0.006). In a propensity score-matched model for body mass index, age, sex, smoking, drinking, presence of comorbidities such as NAFLD, cirrhosis, diabetes mellitus, and hypertension, TAF-treated patients had significantly increased TCHO levels compared to that at baseline (P = 0.019). There was no difference for the ETV group. Body mass index, sex, hypertension, baseline TCHO, and creatine kinase-MB isoenzyme levels were significantly associated with elevated TCHO levels in logistic regression analysis. However, 1-year TAF treatment did not increase the incidence of NAFLD. A greater increase in TCHO was observed in patients with CHB receiving TAF compared to those receiving ETV. However, TAF-induced dyslipidemia did not increase the incidence of NAFLD.

Network Meta-analysis of oral Chinese patent medicine in adjuvant treatment of rotavirus gastroenteritis in children

This study aimed to evaluate the efficacy and safety of various oral Chinese patent medicines in the adjuvant treatment of rotavirus gastroenteritis(RVGE) in children based on network Meta-analysis. Randomized controlled trial(RCT) of oral Chinese patent medicine in the adjuvant treatment of RVGE in children was retrieved from the databases such as CNKI, Wanfang, VIP, SinoMed, PubMed, Cochrane Library, EMbase, and Web of Science from database inception to October 22, 2022. The quality of the included RCT was evaluated according to the Cochrane risk-of-bias tool, and the data were analyzed by RevMan 5.4 and Stata 16 software. Sixty-three RCTs were included, with 11 oral Chinese patent medicines involved, including Xingpi Yanger Granules, Weichang'an Pills, Qiuxieling Mixture, Erxieting Granules, and Changyanning Granules/Syrup. The results of the network Meta-analysis showed that in terms of clinical total effective rate, the top 3 optimal interventions were Changyanning Granules/Syrup, Xiaoer Guangpo Zhixie Oral Liquid, and Xiaoer Shuangjie Zhixie Granules combined with conventional western medicine. In terms of the anti-diarrheal time, the top 3 optimal interventions were Shenling Baizhu Granules, Qiuxieling Mixture, and Shuangling Zhixie Oral Liquid combined with conventional western medicine. In terms of the antiemetic time, the top 3 optimal interventions were Changyanning Granules/Syrup, Xingpi Yanger Granules, and Xiaoer Shuangjie Zhixie Granules combined with conventional western medicine. In terms of the antipyretic time, the top 3 optimal interventions were Shenling Baizhu Granules, Xiaoer Shuangjie Zhixie Granules, and Qiuxieling Mixture combined with conventional western medicine. In terms of the negative conversion rate of rotavirus, the top 3 optimal interventions were Xingpi Yanger Granules, Erxieting Granules, and Cangling Zhixie Oral Liquid combined with conventional western medicine. In terms of reducing creatine kinase isoenzyme MB(CK-MB) level, the top 3 optimal interventions were Weichang'an Pills, Xingpi Yanger Granules, and Xiaoer Shuangjie Zhixie Granules combined with conventional western medicine. In terms of adverse reactions, no se-rious adverse reactions were reported in all studies. Oral Chinese patent medicines in the adjuvant treatment of children with RVGE have their own advantages, Specifically, Changyanning Granules/Syrup + conventional western medicine focuses on improving the clinical total effective rate and shortening the antiemetic time, Shenling Baizhu Granules + conventional western medicine on shortening the anti-diarrheal time and antipyretic time, Xingpi Yanger Granules + conventional western medicine on improving the negative conversion rate of rotavirus, and Weichang'an Pills + conventional western medicine on reducing the CK-MB level. Limited by the quantity and quality of literature included in this study, the results need to be verified by high-quality RCT with a larger sample size.

Effects of electroacupuncture pretreatment on GABAA receptor of fastigial nucleus and sympathetic nerve activity in rats with myocardial ischemia reperfusion injury

To observe the effects of electroacupuncture (EA) pretreatment on cardiac function, sympathetic nerve activity, indexes of myocardial injury and GABAA receptor in fastigial nucleus in rats with myocardial ischemia reperfusion injury (MIRI), and to explore the neuroregulatory mechanism of EA pretreatment in improving MIRI. A total of 60 male SD rats were randomly divided into a sham operation group, a model group, an EA group, an agonist group and an agonist+EA group, 12 rats in each group. The MIRI model was established by ligation of the left anterior descending coronary artery. EA was applied at bilateral "Shenmen" (HT 7) and "Tongli" (HT 5) in the EA group and the agonist+EA group, with continuous wave, in frequency of 2 Hz and intensity of 1 mA, 30 min each time, once a day for 7 consecutive days. After intervention, the MIRI model was established. In the agonist group, the muscone (agonist of GABAA receptor, 1 g/L) was injected in fastigial nucleus for 7 consecutive days before modeling, 150 μL each time, once a day. In the agonist+EA group, the muscone was injected in fastigial nucleus 30 min before EA intervention. The data of electrocardiogram was collected by PowerLab standard Ⅱ lead, and ST segment displacement and heart rate variability (HRV) were analyzed; the serum levels of norepinephrine (NE), creatine kinase isoenzyme MB (CK-MB) and cardiac troponin I (cTnI) were detected by ELISA; the myocardial infarction area was measured by TTC staining; the morphology of myocardial tissue was observed by HE staining; the positive expression and mRNA expression of GABAA receptor in fastigial nucleus were detected by immunohistochemistry and real-time PCR. Compared with the sham operation group, in the model group, ST segment displacement and ratio of low frequency to high frequency (LF/HF) of HRV were increased (P<0.01), HRV frequency domain analysis showed enhanced sympathetic nerve excitability, the serum levels of NE, CK-MB and cTnI were increased (P<0.01), the percentage of myocardial infarction area was increased (P<0.01), myocardial fiber was broken and interstitial edema was serious, the positive expression and mRNA expression of GABAA receptor in fastigial nucleus were increased (P<0.01). Compared with the model group, in the EA group, ST segment displacement and LF/HF ratio were decreased (P<0.01), HRV frequency domain analysis showed reduced sympathetic nerve excitability, the serum levels of NE, CK-MB and cTnI were decreased (P<0.01), the percentage of myocardial infarction area was decreased (P<0.01), myocardial fiber breakage and interstitial edema were lightened, the positive expression and mRNA expression of GABAA receptor in fastigial nucleus were decreased (P<0.01). Compared with the EA group, in the agonist group and the agonist+EA group, ST segment displacement and LF/HF ratio were increased (P<0.01), HRV frequency domain analysis showed enhanced sympathetic nerve excitability, the serum levels of NE, CK-MB and cTnI were increased (P<0.01), the percentage of myocardial infarction area was increased (P<0.01), myocardial fiber breakage and interstitial edema were aggravated, the positive expression and mRNA expression of GABAA receptor in fastigial nucleus were increased (P<0.01). EA pretreatment can improve the myocardial injury in MIRI rats, and its mechanism may be related to the inhibition of GABAA receptor expression in fastigial nucleus, thereby down-regulating the excitability of sympathetic nerve.

Application Value of Limb Ischemic Preconditioning in Preventing Intradialytic Hypotension during Maintenance Hemodialysis

Introduction: The aim of this study was to investigate the efficacy and safety of limb ischemia preconditioning (LIPC) in the treatment of intradialytic hypotension (IDH) in patients with maintenance hemodialysis (MHD). Methods: This was a single-center, prospective, and randomized controlled case study. A total of 38 patients with MHD who met the inclusion criteria from September 2021 to August 2022 were selected from the Blood Purification Center of our hospital. They were randomly divided into the LIPC group (n = 19) and the control group (n = 19). For patients in the LIPC group, the femoral artery blood flow was blocked with an LIPC instrument for 5 min (pressurized to 200 mm Hg) before each dialysis, and they were reperfused for 5 min. The cycle was repeated five times, with a total of 50 min for 12 weeks. The control group was pressurized to 20 mm Hg with an LIPC instrument, and the rest was the same as the LIPC group. The blood pressure of 0 h, 1 h, 2 h, 3 h, 4 h, and body weight before and after hemodialysis were measured in the two groups during hemodialysis, the incidence of IDH and the changes of serum troponin I (TNI) and creatine kinase isoenzyme MB (CK-MB) levels before and after the intervention were observed, and the ultrafiltration volume and ultrafiltration rate were recorded. Results: At the 8th and 12th week after intervention, the MAP in the LIPC group was higher than that in the control group (103.28 ± 12.19 mm Hg vs. 93.18 ± 11.11 mm Hg, p = 0.04; 101.81 ± 11.36 mm Hg vs. 91.81 ± 11.92 mm Hg, p = 0.047). The incidence of IDH in the LIPC group was lower than that in the control group (36.5% vs. 43.1%, p = 0.01). The incidence of clinical treatment in IDH patients in the LIPC group was lower than that in the control group (6.3% vs. 12.4%, p = 0.00). The incidence of early termination of hemodialysis in the LIPC group was lower than that in the control group (1.6% vs. 3.8%, p = 0.01). The levels of TNI and CK-MB in the LIPC group after the intervention were lower than those in the control group (322.30 ± 13.72 ng/dL vs. 438.50 ± 24.72 ng/dL, p = 0.00; 159.78 ± 8.48 U/dL vs. 207.00 ± 8.70 U/dL, p = 0.00). The changes of MAP before and after the intervention were negatively correlated with the changes of TNI and CK-MB before and after the intervention (r = −0.473, p = 0.04; r = −0.469, p = 0.04). There were no differences in dry body mass and ultrafiltration rate between the two groups before and after the LIPC intervention (p > 0.05). Multiple linear regression analysis shows that TNI is the main influencing factor of ΔMAP. No LIPC-related adverse events were found during the study period. Conclusion: LIPC can effectively reduce the incidence of IDH in patients with MHD and may be associated with the alleviation of myocardial damage.

Improved methodology for efficient establishment of the myocardial ischemia-reperfusion model in pigs through the median thoracic incision.

To investigate the feasibility and effectiveness of establishing porcine ischemia-reperfusion models by ligating the left anterior descending (LAD) coronary artery, we first randomly divided 16 male Bama pigs into a sham group and a model group. After anesthesia, we separated the arteries and veins. Subsequently, we rapidly located the LAD coronary artery at the beginning of its first diagonal branch through a mid-chest incision. Then, we loosened and released the ligation line after five minutes of pre-occlusion. Finally, we ligated the LAD coronary artery in situ two minutes later and loosened the ligature 60 min after ischemia. Compared with the sham group, electrocardiogram showed multiple continuous lead ST-segment elevations, and ultrasound cardiogram showed significantly lower ejection fraction and left ventricular fractional shortening at one hour and seven days post-operation in the model group. Twenty-four hours after the operation, cardiac troponin T and creatine kinase-MB isoenzyme levels significantly increased in the model group, compared with the sham group. Hematoxylin and eosin staining showed the presence of many inflammatory cells infiltrating the interstitium of the myocardium in the model group but not in the sham group. Masson staining revealed a significant increase in infarct size in the ischemia/reperfusion group. All eight pigs in the model group recovered with normal sinus heart rates, and the survival rate was 100%. In conclusion, the method can provide an accurate and stable large animal model for preclinical research on ischemia/reperfusion with a high success rate and homogeneity of the myocardial infarction area.

Case report: One child with an autism spectrum disorder who had chronically elevated serum levels of CK and CK-MB

Some patients with autism spectrum disorder (ASD) exhibit elevated serum creatine kinase levels, which are believed to be associated with mitochondrial dysfunction. Although a few articles have reported this situation in the past and the increase mostly ranges from 100 to 300 U/L, there is a paucity of previous study focusing on the serum creatine kinase MB isoenzyme. This article discusses a 5-year-old girl with ASD, whose serum creatine kinase and creatine kinase MB isoenzyme have been rising for nearly 2 years, fluctuating at 584–993 and 111–625 U/L respectively. Except for behavioral and language symptoms associated with ASD, the child appears normal in other aspects. The child's laboratory tests showed no abnormality, except that the serum levels of lactic acid was slightly higher than normal (1.89 mmol/L, normal 1.33–1.78 mmol/L). The child was prescribed with a traditional Chinese medicine during the process and the serum creatine kinase MB isoenzyme level decreased dramatically to 111 U/L after the treatment. This study firstly recorded the serum creatine kinase levels and the MB isoenzyme in patients with autism spectrum disorder for nearly 2 years, indicating that patients with ASD may experience long-term increases in serum creatine kinase and creatine kinase MB isoenzyme, and that the traditional Chinese medicine decoction Xinfukang can temporarily reduce the serum creatine kinase MB isoenzyme level in patients. Nevertheless, the effect is not sustained. Therefore, it is of great importance to conduct long-term longitudinal studies so as to elucidate the potential mechanism responsible for long-term elevation of serum creatine kinase level.

Experimental study of mitochondrion-targeted small molecule IR-61 ameliorated exhaustive exercise-induced cardiac injury in rats

To investigate the effects of mitochondrion-targeted cyanine fluorescent small molecule IR-61 on cardiac injury induced by exhaustive exercise in rats. Thirty-six adult male SD rats were randomly divided into 3 groups(n=12),control group (Ctrl), exhaustive exercise group (EE) and IR-61+ exhaustive exercise group (IR-61+EE). IR-61+EE group were intraperitoneally injected with 2 mg/kg IR-61 at the same time on day 1, 4 and 7. One hour after the end of the last drug administration, the two exhaustive exercise groups were subjected to exhaustive exercise modeling. The rats were placed on an animal treadmill with a slope of 0° at a speed of 10~15 m/min to coordinate their limbs running posture, and then ran at a speed of 25~30 m/min until exhaustion about 15 minutes later. After the animal models established, ECG was recorded by physiological recorder, myocardial injury was observed by light microscope, mitochondrial injury was observed by transmission electron microscope, myocardial cell apoptosis was detected by TUNEL method, markers of myocardial injury were detected by ELISA, and myocardial mitochondrial respiration rate was measured by high-resolution Oxygraph-2K mitochondrial instrument. ① Compared with Ctrl group, heart rate was increased, PR interval was shortened, QRS interval was prolonged, QTc was prolonged and ST segment was depressed significantly in EE group (P＜0.05). In EE group, myocardial fiber fracture and mitochondrial inner chamber swelling were obvious, mitochondrial crest was fuzzy, mitochondrial outer membrane was incomplete, and a large number of mitochondrial rupture and fusion were visible. In EE group, TUNEL staining cells were abundant, chromatin concentration and marginalization, nuclear membrane lysis, chromatin fragmentation into massive apoptotic bodies, apoptosis score increased (P＜0.05). The levels of creatine kinase isoenzyme-MB (CK-MB), cardiac troponin I(cTn-I) and N-terminal B-type natriuretic peptide (NT-proBNP) were increased in EE group (P＜0.05). Basal respiration rate, oxidative respiration rate of fatty acids and respiration rate of complex Ⅰ, Ⅱ and Ⅳ were all decreased (P＜ 0.05). ② Compared with EE group, the heart rate in IR-61+EE group was increased, PR interval was prolonged, QRS interval was shortened, QTc was shortened, ST segment was not significantly depressed (P＜0.05). In IR-61+EE group, myocardial fiber arrangement was loose, no obvious fracture was observed, mitochondrial inner ventricle was swelling, mitochondrial outer membrane was intact, TUNEL stained cells and unstained cells were observed, the overall morphology was more similar to Ctrl group. Apoptosis index was decreased (P＜0.05), the levels of CK-MB and cTn-I were decreased in IR-61+EE group (P＜0.05). The oxidative respiration rate of fatty acids and the respiration rate of complex Ⅱ and Ⅳ were increased (P＜0.05). Mitochondrion-targeted cyanine fluorescent small molecule IR-61 can improve cardiac electrical activity, reduce myocardial cell injury and mitochondrial injury, reduce myocardial cell apoptosis, and improve the myocardial mitochondrial energy metabolism condition in exhausted rats.

Serum TP53 Protein Level as a Sensitive Biomarker for the Diagnosis of Myocardial Damage in Children.

BackgroundHigh levels of TP53 protein can lead to apoptosis of myocardial cells. However, TP53 protein influence of myocardial damage remains unclear. This prospective study investigated the involvement of TP53 protein in secondary myocardial damage in children up to 18 years of age.Material/MethodsSerum TP53 protein, N-terminal prohormone B-type natriuretic peptide (NT-ProBNP), cardiac troponin-I (cTnI), and creatine kinase isoenzyme MB (CK-MB) concentrations were measured in 50 hospitalized patients with secondary myocardial damage, 50 hospitalized patients without myocardial damage, and 50 healthy individuals (control). Cardiac damage was diagnosed based on cTnI, NT-ProBNP, and CK-MB levels, with electrocardiographic evidence as the reference. The appropriate cut-off value of TP53 protein for secondary myocardial damage was analyzed by receiver operating characteristic (ROC) curves.ResultsThe serum TP53 protein, NT-ProBNP, cTnI, and CK-MB concentrations of the patients with and without myocardial damage were 10.20±1.20 and 0.30±0.10 ng/L, 505.30 and 107.8 ng/L, 0.23±0.13 and 0.02±0.01 μg/L, and 28.30±5.13 and 12.24±4.29 IU/L, respectively. For the 50 patients with myocardial damage, the area under the ROC curve for serum TP53 protein, NT-ProBNP, cTnI, and CK-MB concentrations were 0.89 (95% CI: 0.81–0.95), 0.83 (95% CI: 0.77–0.91), 0.92 (95% CI: 0.84–0.97), and 0.85 (95% CI: 0.78–0.93), respectively, and the diagnostic cut-off values were 12.00 ng/L, 500.00 ng/L, 0.16 μg/L, and 27.00 IU/L, respectively, with positive likelihood ratios of 20.8, 13.2, 24.6, and 15.6.ConclusionsTP53 protein is a valid biomarker of secondary myocardial damage in pediatric patients and can be diagnostic.

Cardiotoxicity Related to Immune Checkpoint Inhibitors: A Real-World Retrospective Analysis

BackgroundCardiotoxicity related to immune checkpoint inhibitors (ICIs) is a rare but potentially lethal. In ICI-associated adverse events, evidence of cardiotoxicity and clinical predictive factors related to ICI is lacking. Here, we aim to assess the incidence and predictive factors of cardiotoxicity related to ICIs in real-world practice.ObjectiveWe retrospectively analyzed consecutive patients who received PD-1 or PD-L1 at the First Affiliated Hospital of Xi'an Jiaotong University. Clinical characteristics and cardiac lesion markers were collected both at baseline and during longitudinal follow-up from the Biobank database. Follow-up CKMB and NT-proBNP levels and ratios were then evaluated.ResultsA total of 2,304 patients with either PD-1 or PDL-1 utilization between August 2018 and April 2021 were collected. The average age was 59.44 ± 11.45 among PD-1 inhibitor utilizer and 58.97 ± 12.16 among PDL-1 inhibitor utilizer. The baseline creatine kinase isoenzyme MB (CKMB) levels were 17 ± 19 U/L in PD-1 inhibitor users and 17 ± 23 U/L in PDL-1 inhibitor users. Majority of patients were male, with advanced stage cancer, and received ICIs as second-line therapy. The longitudinal change of cardiac enzymes and NT-pro BNP were collected. Cardiac lesion as defined by three times increase of CKMB happens in only minority of patients receiving ICIs therapy. It is also identified that increased CKMB happened in PD-1 inhibitor groups, but not PDL-1 inhibitor groups.ConclusionWe evaluated the profile of cardiotoxicities caused by ICIs based on real-world experience. The cardiac lesion markers are generally unaltered, but it appears that the increased CKMB happened in PD-1 inhibitor groups, but not PDL-1 inhibitor groups.

Hypercholesterolemia attenuates cardioprotection of ischemic preconditioning and postconditioning with α7 nicotinic acetylcholine receptor agonist by enhancing inflammation and inhibiting the PI3K/Akt/eNOS pathway.

The present study aimed to evaluate the effects of hypercholesterolemia on cardioprotection of ischemic preconditioning and α7 nicotinic acetylcholine receptor (α7nAChR) agonist postconditioning and explore the potential mechanisms that hypercholesterolemia affected their cardioprotection. Hypercholesterolemic and normal rats were divided into the four groups that received the following treatments: i) Hypercholesterolemic control and normal control groups; ii) hypercholesterolemic ischemia/reperfusion (HI) and normal ischemia/reperfusion (NI) groups; iii) hypercholesterolemic ischemic preconditioning (HIPC) and normal ischemic preconditioning (NIPC) groups; and iv) hypercholesterolemic PNU282987 postconditioning (HPNU) and normal PNU282987 postconditioning (NPNU) groups. Serum lactate dehydrogenase (LDH), creatine kinase isoenzyme MB (CK-MB), cardiac troponin I (cTnI), tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6) levels after ischemia/reperfusion were assayed. Furthermore, infarct size and expression levels of Akt, phosphorylated (p)-Akt and endothelial nitric oxide synthase (eNOS) in ischemic myocardium were assessed. Compared with the NI group, serum LDH, CK-MB, cTnI, TNF-α and IL-6 levels and infarct size were significantly decreased, and myocardial p-Akt/Akt and eNOS/GAPDH ratios were significantly increased in the NIPC and NPNU groups. Compared with the HI group, serum CK-MB, cTnI, TNF-α and IL-6 levels and infarct size were significantly decreased in the HIPC group; however, myocardial p-Akt/Akt and eNOS/GAPDH ratios did not significantly change in the HIPC group. Furthermore, there were no significant difference between the HI and HPNU groups in serum LDH, CK-MB, cTnI, TNF-α and IL-6 levels, infarct size, myocardial p-Akt/Akt and eNOS/GAPDH ratios. In conclusion, hypercholesterolemia could aggravate myocardial ischemia/reperfusion injury, attenuate cardioprotection of ischemic preconditioning and eliminate cardioprotection from α7nAChR agonist postconditioning by enhancing inflammation and inhibiting PI3K/Akt/eNOS pathway.

Dulaglutide Alleviates LPS-Induced Injury in Cardiomyocytes

Background and purpose: Sepsis is a severe infection-induced disease with multiple organ failure, and sepsis-induced cardiomyopathy is a fatal condition. Inflammatory response and oxidative stress are reported to be involved in the development of sepsis-induced cardiomyopathy. Dulaglutide is a novel antidiabetic agent that is currently reported to exert an anti-inflammatory effect. The present study aims to explore the potential protective property of dulaglutide on lipopolysaccharide (LPS)-induced injury on cardiomyocytes. Methods: LPS was used to induce an in vitro injury model on cardiomyocytes. The mitochondrial reactive oxygen species (ROS) level was detected using MitoSOX red, and reduced glutathione (GSH) was measured to evaluate the status of oxidative stress in H9c2 myocardial cells. The expressions of NADPH oxidase-1 (NOX-1) and inducible nitric oxidesynthase (iNOS) were determined using real-time PCR and western blot analysis. Real-time PCR and enzyme-linked immunosorbent assay (ELISA) were both used to detect the expressions and concentrations of tumor necrosis factor-α, interleukin-1β, interleukin-17, matrix metalloproteinase-2, and matrix metalloproteinase-9 in H9c2 myocardial cells, respectively. The production of nitric oxide (NO) was measured using the Griess reagent. The levels of creatine kinase isoenzyme-MB (CK-MB) and cardiac troponin I (cTnI) were detected using ELISA. Western blot was utilized to determine the expressions of toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), and p-NF-κB p65 in H9c2 myocardial cells in the nucleus. Results: First, dulaglutide ameliorated LPS-induced oxidative stress by suppressing the production of mitochondrial ROS and elevating the level of reduced GSH, as well as downregulating NOX-1. Second, the LPS-induced cardiomyocyte injury was alleviated by dulaglutide through downregulating CK-MB and cTnI, accompanied by inhibiting iNOS expression and NO production. Lastly, the production of inflammatory factors and upregulation of MMPs induced by LPS were both significantly reversed by dulaglutide through suppressing the TLR4/Myd88/NF-κB signaling pathway. Conclusions: Dulaglutide alleviated LPS-induced injury in cardiomyocytes by inhibiting inflammation and oxidative stress.

Clinical value of microRNA-378a-3p in sepsis and its role in sepsis-induced inflammation and cardiac dysfunction

ABSTRACT This study explored the clinical meaning of miR-378a-3p in sepsis and its influence on sepsis-induced inflammation and cardiac dysfunction. Serum levels of miR-378a-3p were detected by quantitative Real-Time Polymerase Chain Reaction (qRT-PCR). The Receiver Operating Characteristic (ROC) curve was used to evaluate its diagnostic value. The effects of miR-378a-3p on inflammation and cardiac function were evaluated by monitoring left ventricular systolic pressure (LVSP), left ventricular and end-diastolic pressure (LVEDP), maximum rate of change in left ventricular pressure (± dp/dtmax) and detecting the levels of troponin I (cTnI), creatine kinase isoenzyme MB (CK-MB), tumor necrosis factor-a (TNF-a), interleukin-6 (IL-6), and interleukin-1β (IL-1β) via enzyme linked immunosorbent assay (ELISA). Serum miR-378a-3p was increased in sepsis patients and rat model. ROC curve indicated that miR-378a-3p might have diagnostic significance for sepsis miR-378a-3p antagomir improved the cardiac function by upregulating the levels of LVSP and ± dp/dtmax, and decreasing the levels of LVEDP, cTnI and CK-MB in rat model. miR-378a-3p antagomir also significantly alleviated the inflammatory responseby down-regulating the expression of TNF-a, IL-6, and IL-1β. Besides, logistics regression analysis illustrated that miR-378a-3p was an independent influencing factor for the onset of cardiac dysfunction in sepsis. miR-378a-3p has the potential as a diagnostic biomarker for sepsis and decreasing the level of miR-378a-3p had the ability to ameliorate cardiac dysfunction and inflammatory response caused by sepsis.

A frog antioxidant peptide protects against myocardial ischemia reperfusion injury in rats

Excessive reactive oxygen species (ROS) induced by myocardial ischemia reperfusion (IR) injury exert detrimental effects on cardiomyocytes. Antioxidant peptides can scavenge free radicals such as 2,2′-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS+), 2,2-diphenyl-1-picrylhydrazyl (DPPH) and nitic oxide (NO) in vitro, but little is known about their functions in vivo. Here, we evaluated the effects of an antioxidant peptide (antioxidant-RL) used at the beginning of reperfusion on myocardial IR injury. We performed 2, 3, 5-triphenyltetrazolium chloride staining (TTC) to determine myocardial infarct size. Creatine kinase isoenzyme-MB (CK-MB), cardiac troponin-T (CTnT), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6) levels were determined with enzyme-linked immunosorbent assays (ELISAs). The levels of ROS were measured with a fluorometric Intracellular ROS kit. The expression levels of apoptosis-related proteins in cardiomyocytes were detected by western blotting. Antioxidant-RL (10 mg/kg) reduced the infarct size and levels of CK-MB and CTnT in rats. The levels of TNF-α and IL-6 also decreased. Furthermore, ROS levels were ameliorated and the expression of apoptosis-related proteins in myocytes was down-regulated by antioxidant-RL (100 µg/mL). Antioxidant-RL exerted protective effects on myocardial IR injury by scavenging excessive ROS, suppressing inflammatory factors, and inhibiting cardiomyocytes apoptosis. Thus, antioxidant-RL may serve as a potent candidate for the treatment of IR injury.

Superselective arterial embolization with drug-loaded microspheres for the treatment of unresectable breast cancer.

To investigate the short-term efficacy and safety of drug-eluting bead transcatheter arterial chemoembolization (DEB-TACE) using CalliSpheres® microspheres in the treatment of unresectable locally advanced breast cancer (LABC). DEB-TACE using CSM was performed in 15 patients with LABC after failure of medical treatment. The efficacy was evaluated based on the modified Response Evaluation Criteria in Solid Tumors (mRECIST). The postoperative adverse reactions and complications were analyzed. The changes of white blood cell (WBC) count, creatine kinase isoenzyme-MB (CK-MB), B-type natriuretic peptide (BNP), and carbohydrate antigen15-3 (CA15-3) before and after treatment were compared by using Wilcoxon signed-rank test. The surgeries were successful in all patients. The subjects were followed up for 2-60 months (median: 10 months). According to the mRECIST, no patient achieved complete remission (CR) 1, 3, and 5 months after surgery, and partial response (PR) was achieved in 9, 11, and 11 cases; also, there were 6, 4, and 2 stable disease (SD) cases, and 0, 0, and 2 progressive disease (PD) cases. The postoperative WBC count, CK-MB level, and BNP level were not significantly different from those before surgery, whereas the CA15-3 level significantly decreased. The main postoperative adverse reactions were pain, fever, and gastrointestinal reactions. No severe adverse reactions were observed. DEB-TACE with CalliSpheres® microspheres is a safe and feasible treatment for LABC. However, more multi-center studies with larger sample sizes are still warranted.

Protective effect of supplementation with Lycium ruthenicum Murray extract from exhaustive exercise-induced cardiac injury in rats.

To the Editor: Lycium ruthenicum (L. ruthenicum) Murray contains abundant anthocyanins. The purpose of the present research was to investigate the protective effect of L. ruthenicum extract supplementation on the damage from exhaustive exercise in rats which were treated for seven days before the exhaustive exercise. Exhaustive exercise induced an increase of Serum nitrate (NO) and reactive oxygen species (ROS) levels, but supplementation of L. ruthenicum extract reduced them significantly (P < 0.05). Interleukin (IL)-1 and IL-6 were also significantly reduced by L. ruthenicum as compared to the control (P < 0.05). Supplementation with L. ruthenicum extract also decreased the creatine kinase isoenzyme MB (CK-MB) generation significantly and ameliorated the myocardial histopathology. L. ruthenicum belongs to the genus Lycium of the family Solanaceae and is a salinized desert plant distributed mainly in Qinghai and Xinjiang Provinces of China. Recently, studies have shown that L. ruthenicum exhibits a wide range of pharmacologic properties, such as anti-oxidation, anti-fatigue, and hypoglycemic activity.[1,2] Anthocyanins and their aglycones from L. ruthenicum have strong antioxidant activity.[3] Anthocyans are flavonols, which occur ubiquitously in the plant kingdom and confer bright red or blue coloration on berries and other fruits and vegetables. Anthocyanin concentration in the L. ruthenicum extract was determined by using the Nakata method[4] and the concentration in the L. ruthenicum extract was 24.1 ± 7.7 mg/g. However, we know anthocyanin has antioxidant properties and ROS induced by extreme temperatures can be protected by anthocyanins in several plants. Anthocyanin has an antioxidant role in plants against ROS and extreme temperatures. Exercise-induced oxidative stress has been reported and antioxidant supplementation can prevent muscle damage, protective effects on the endocrine-metabolic and immune profile.[5] Therefore, L. ruthenicum extract should have a protective effect against oxidative stress and we investigated that the possible protective effect of L. ruthenicum extract and anthocyanin supplementation on the oxidative stress generated by exhaustive exercise in SD rats. In this study, 30 Sprague-Dawley (SD) rats, males and aged 6 weeks, were randomly assigned to the control, anthocyanin (5 mg/rat as the positive control), and other three groups were given L. ruthenicum extract in distilled water orally (as vehicle, 10 and 30 mg/rat), for 7 days before the exhaustive exercise stress. Rats of the exhaustive exercise group were subjected to graded treadmill running started at 10% grade, 15 m/min for 10 min followed by gradual increases of treadmill speed and time as 25 m/min for 20 min, 28 m/min for 20 min, 31 m/min for 20 min, 34 m/min for 20 min, 37 m/min for 20 min until exhaustion. The heart was dissected and washed with saline for fixation with formalin. Exhaustive exercise causes oxidative stress and is defined as the inability of rats to run on the treadmill despite a mild electrical shocking.[6] Add some information on dietary antioxidants for exercise-induced oxidative stress.[7] Regular exercise is recommended for a healthy life, but exhaustive exercise generates the excessive oxidative stress that may exceed the beneficial effect from the regular exercise.[8] In the present study, an increasing CK-MB activity from the cardiac muscle consisted of myocardial damage was seen in tissue vacuoles and cell death from heart tissue. Exhaustive exercise also induced an increase of serum NO, ROS, IL-1, IL-6, and CK-MB levels, but supplementation of L. ruthenicum extract reduced them significantly. Supplementation with L. ruthenicum extract also significantly ameliorated the myocardial histopathology. Under the microscope, the photographs showed the heart section with a 400× magnification. The severity of damage in the exhaustive exercise group was exhibited by vacuoles and dead cells. However, changes in histopathology were significantly reduced by the treatment with anthocyanin and L. ruthenicum extract [Figure 1].Figure 1: Protective effect of Lycium ruthenicum extract on the exhaustive exercise-induced myocardial injury. Histopathology (hematoxylin and eosin staining) of myocardial slices from rats from (A) no treatment control group; (B) the exhaustion group; (C) the Anthocyanin group, exhaustive exercise treatment supplemented with 5 mg Anthocyanin/rat; and (D) the L. ruthenicum extract group, exhaustive exercise treatment supplemented with 30 mg L. ruthenicum/rat. Photographs show the myocardial section with 400× magnification. Tissue vacuoles (hollow triangle arrow heads ▿) and cell death (nuclei stained, black arrow heads ◂) were more severe in exhaustion than those in control or L. ruthenicum groups.In conclusion, 1-week oral supplementation of L. ruthenicum extracts present positive effects on the oxidative stress generated by exhaustive exercise in SD rats, possibly via promotion of antioxidant capacity. The mechanism of protection of L. ruthenicum extract supplementation was not investigated in this study and waits for further study in the future. Acknowledgements The authors are grateful for text proofreading support from Prof. Kee-Ching Jen. Funding None. Conflicts of interest None.

Puerarin pre-conditioning on the expression levels of CK-MB, cTnI and inflammatory factors in patients undergoing cardiac valve replacement.

Effect of puerarin preconditioning on the expression levels of nuclear factor κB (NF-κB), interleukin 6 (IL-6), interleukin 8 (IL-8), troponin I (cTnI), and creatine kinase isoenzyme MB (CK-MB) in the neutrophils of patients undergoing cardiac valve replacement under cardiopulmonary bypass (CPB) was evaluated. We enrolled 50 patients scheduled for cardiac valve replacement and assigned them randomly divided into either a puerarin or a control group. Puerarin was dissolved in 10 ml normal saline before CPB, and administered by intravenous infusion to patients in the puerarin group. The control group was administered an equivalent amount of saline. We used flow cytometry to determine the expression levels of NF-κB, IL-6 and IL-8 in neutrophils and an auto chemistry analyzer to determine the serum levels of cTnI and CK-MB before anesthesia induction (T0), 30 min after aortic declamping (T1), 4 h after aortic declamping (T2), and 8 h after aortic declamping (T3). We found the mean serum cTnI and CK-MB levels of the puerarin group tended to decrease with time. The positive rates of NF-κB, IL-6 and IL-8 at different time-points were lower in patients of the puerarin group than in those of the control group (and the differences at T3 were statistically significant). The clinical manifestations of patients in the puerarin group after operation were better than those in the control group (P<0.05). We found that the expression levels of NF-κB, IL-6 and IL-8 were positively correlated with the levels of CK-MB and cTnI (P<0.05). Puerarin preconditioning can reduce the NF-κB activation and the overexpression of IL-6 and IL-8 in neutrophils, and it inhibits the release of myocardial enzyme cTnI and CK-MB reflecting myocardial cell protection. Puerarin seems to improve safety and efficacy of valvular replacement operations.

Effect of Autophagy Inhibition on the Protection of Ischemia Preconditioning against Myocardial Ischemia/Reperfusion Injury in Diabetic Rats.

Background:Ischemia preconditioning (IPC) remains the most powerful intervention of protection against myocardial ischemia/reperfusion injury (IRI), but diabetes can weaken or eliminate its cardioprotective effect and detailed mechanisms remain unclear. In this study, we aimed to explore whether changes of autophagy in the diabetic condition are attributable to the decreased cardioprotective effect of IPC.Methods:Sixty diabetic male Sprague-Dawley rats were randomly divided into the control (C), IRI, rapamycin (R), wortmannin (W), rapamycin + IPC (R + IPC), and wortmannin + IPC (W + IPC) groups. The in vivo rat model of myocardial IRI was established by ligaturing and opening the left anterior descending coronary artery via the left thoracotomy. Durations of ischemia and reperfusion are 30 min and 120 min, respectively. Blood samples were taken at 120 min of reperfusion for measuring serum concentrations of troponin I (TnI) and creatine kinase isoenzyme MB (CK-MB) using the enzyme-linked immunosorbent assay. The infarct size was assessed by Evans blue and triphenyltetrazolium chloride staining. The expressions of LC3-II, beclin-1, phosphoinositide 3-kinase (PI3K), mammalian target of rapamycin (mTOR), and P-Akt/Akt ratio in the ischemic myocardium were assessed by Western blotting.Results:Compared to the IRI group, infarct size (56.1% ± 6.1% vs. 75.4 ± 7.1%, P < 0.05), serum cTnI (0.61 ± 0.21 vs. 0.95 ± 0.26 ng/ml, P < 0.05), and CK-MB levels (6.70 ± 1.25 vs. 11.51 ± 2.35 ng/ml, P < 0.05) obviously decreased in the W + IPC group. Compared with the C group, myocardial expressions of LC3-II (0.46 ± 0.04 and 0.56 ± 0.04 vs. 0.36 ± 0.04, P < 0.05) and beclin-1 (0.34 ± 0.08 and 0.38 ± 0.07 vs. 0.24 ± 0.03, P < 0.05) evidently increased, and myocardial expressions of mTOR (0.26 ± 0.08 and 0.25 ± 0.07 vs. 0.38 ± 0.06, P < 0.05), PI3K (0.29 ± 0.04 and 0.30 ± 0.03 vs. 0.38 ± 0.02, P < 0.05), and P-Akt/Akt ratio (0.49 ± 0.10 and 0.48 ± 0.06 vs. 0.72 ± 0.07, P < 0.05) markedly decreased in the IRI and R groups, indicating an increased autophagy. Compared with the IRI group, myocardial expression of beclin-1 (0.26 ± 0.03 vs. 0.34 ± 0.08, P < 0.05) significantly decreased, and myocardial expressions of mTOR (0.36 ± 0.04 vs. 0.26 ± 0.08, P < 0.05), PI3K (0.37 ± 0.03 vs. 0.29 ± 0.04, P < 0.05), and P-Akt/Akt ratio (0.68 ± 0.05 vs. 0.49 ± 0.10, P < 0.05) increased obviously in the W + IPC group, indicating a decreased autophagy.Conclusions:Increased autophagy in the diabetic myocardium is attributable to decreased cardioprotection of IPC, and autophagy inhibited by activating the PI3K-Akt-mTOR signaling pathway can result in an improved protection of IPC against diabetic myocardial IRI.