Japanese Traditional Herbal Medicine, Rikkunshito, Partially Suppresses Inflammatory Responses in Myocardial Ischemia/Reperfusion Injury.

INTRODUCTION: Myocardial ischemia/reperfusion (I/R) injury can cause additional damage to an ischemic myocardium, even after successful reperfusion therapy. Inflammation is a mechanism that exacerbates myocardial damage after I/R injury. Rikkunshito (RKT) is a traditional Japanese herbal medicine widely used to treat gastrointestinal symptoms. It attenuates inflammation and fibrosis in some diseases of the heart; however, it remains unclear whether RKT exerts cardioprotective effects against myocardial I/R injury. To elucidate this, we evaluated the effects of RKT pre-treatment by oral administration on the myocardium in a mouse model of in vivo I/R injury. METHODS: Mice were randomly assigned to a group receiving distilled water (DW) or one receiving RKT (1000 mg/kg/day) for 14 days orally. For each of the RKT and DW groups, a sham group, an I/R 2 h group, and an I/R 24 h group were created. On day 15, myocardial I/R surgery was performed. The left anterior descending coronary artery (LAD) was ligated for 30 min, and reperfusion time was set at 2 h or 24 h. The myocardial infarct size (IS) was measured after 2 h of reperfusion, and cardiac cytokine mRNA expression levels were evaluated by quantitative reverse transcription polymerase chain reaction (RT-PCR) after 2 h and 24 h of reperfusion. RESULTS: RKT pre-treatment significantly suppressed the cardiac mRNA expression level of interleukin-1ß in the RKT-I/R 2 h group compared to the DW-I/R 2 h group (P < 0.05). Additionally, RKT significantly suppressed the mRNA expression levels of transforming growth factor-ß compared to DW; the same result was obtained for the expression levels of interleukin-6. However, RKT did not reduce the IS or mRNA expression levels of the cardiac congestive markers natriuretic peptide a (NPPA) and natriuretic peptide b (NPPB). In addition, RKT did not alter the plasma concentration of ghrelin and sirtuin 1 (Sirt1), which have been reported to be stimulated by RKT. CONCLUSION: This study showed that pre-treatment of RKT for myocardial I/R injury partially suppressed inflammation-related cytokines. However, further studies are needed on the effect of RKT on the reduction of myocardial infarction size.

Validity and Utility of Early Parameters in TEG6s Platelet Mapping to Assess the Coagulation Status During Cardiovascular Surgery With Cardiopulmonary Bypass.

Background The aim of this retrospective observational study was to explore the early predictive parameters for maximum amplitudein the kaolin with heparinase (HKH) assay (MAHKH) of TEG6s Platelet Mapping in cardiovascular surgery including cardiopulmonary bypass (CPB) period. The relationship between each parameter of the assay and laboratory data was also assessed. Methods We included the patients who underwent TEG6s Platelet Mapping during cardiovascular surgery under CPB between November 2021 and May 2022. The correlation between MAHKH and the early parameters was assessed. The association between each parameter of Platelet Mapping and a combination of fibrinogen concentration > 150 mg/dL and platelet count > 100,000µL was also evaluated by the receiver operating characteristic (ROC) curve. Results In 23 patients who underwent TEG6s Platelet Mapping during the study period, 62 HKH assay data including 59 pairs of data (HKH assay and laboratory data) were analyzed. K and angle, but not R, were significantly correlated with MAHKH (r [95% CI]: -0.90 [-0.94, -0.83], p < 0.0001 for K, and 0.87 [0.79, 0.92], p < 0.0001 for angle). Furthermore, ROC curves suggested that these parameters predicted a combination of fibrinogen concentration > 150 mg/dL and platelet count > 100,000/µL with high accuracy. Similar results were confirmed in the heparinized blood samples obtained during CPB. Conclusion These findings suggest that not only MAKHK but also K and angle, which are early parameters in the HKH assay, provide clinically significant information that will facilitate rapid decision-making regarding coagulation strategies during cardiovascular surgery including the CPB period.

Albumin protects the ultrastructure of the endothelial glycocalyx of coronary arteries in myocardial ischemia-reperfusion injury in vivo.

Myocardial ischemia-reperfusion (I/R) injury induces endothelial glycocalyx (GCX) degradation. Several candidate GCX-protective factors including albumin have been identified, few have been demonstrated in in vivo studies and most albumins used to date have been heterologous. Albumin is a carrier protein for sphingosine 1-phosphate (S1P), which has protective effects on the cardiovascular system. However, changes inhibited by albumin in the endothelial GCX structure in I/R in vivo via the S1P receptor has not been reported. In this study, we aimed to determine whether albumin prevents the shedding of endothelial GCX in response to I/R in vivo. Rats were divided into four groups: control (CON), I/R, I/R with albumin preload (I/R + ALB), and I/R + ALB with S1P receptor agonist fingolimod (I/R + ALB + FIN). FIN acts as an initial agonist of S1P receptor 1 and downregulates the receptor in an inhibitory manner. The CON and I/R groups received saline and I/R + ALB and I/R + ALB + FIN groups received albumin solution before left anterior descending coronary artery ligation. Our study used rat albumin. Shedding of endothelial GCX was evaluated in the myocardium by electron microscopy, and the concentration of serum syndecan-1 was measured. Thus, albumin administration maintained the structure of endothelial GCX and prevented shedding of endothelial GCX via the S1P receptor in myocardial I/R, and FIN annihilated the protective effect of albumin against I/R injury.

Analysis of the radial and ulnar arteries using ultrasound and a vascular visualization device in children.

BACKGROUND: Radial artery is the preferred site for cannulation. Recently, the ulnar artery was chosen as an alternative in adults. AIMS: We aimed to measure the diameter and depth of the ulnar and radial arteries using ultrasound, and our secondary purpose was to evaluate their anatomical position using a near-infrared transcutaneous illumination device. METHODS: Forty-eight children (age range: 0-144 months) were assigned to the following groups: group Infant (aged <12 months), group Preschool (aged ≤12 to <72 months), and group School (aged ≥72 months). The diameter, depth, and position of the ulnar and radial arteries were compared between groups. RESULTS: There was no significant difference between the diameters of the ulnar and radial arteries. In group Infant, group Preschool, and group School, mean diameters of the ulnar artery were 1.27 ± 0.15 mm, 1.62 ± 0.27 mm, and 2.03 ± 0.28 mm, respectively, and the radial artery were 1.29 ± 0.15 mm, 1.69 ± 0.27 mm, and 2.06 ± 0.29 mm, respectively. The corresponding differences between the diameters of ulnar and radial arteries were -0.02 mm, -0.07 mm, and -0.02 mm [95% CI -0.16 mm to 0.12 mm, -0.25 mm to 0.11 mm, and -0.25 mm to 0.21 mm; p = .776, p = .411, and p = .852]. In groups Preschool and School, the ulnar artery was at the recommended depth of 2-4 mm for arterial cannulation compared with the radial artery. In the Infant, Preschool, and School age groups, the ulnar and radial arteries were at the recommended depth of 2-4 mm for arterial cannulation in 70.0%, 100.0%, 93.8%, and 80.0%, 65.0%, and 50.0% of the cases, respectively. (difference: -10.0%, 35.0%, and 43.8%, 95%; CI -43.4% to 23.4%, 14.1% to 55.9%, and 19.4% to 68.1%, respectively). CONCLUSIONS: The ulnar artery can be considered a promising alternative to the radial artery for facilitating arterial cannulation in children.

Remimazolam Anesthesia for MitraClip Implantation in a Patient with Advanced Heart Failure.

Remimazolam, a novel and ultrashort-acting benzodiazepine, has been available for general anesthesia in Japan. The administration of remimazolam does not induce injection pain, has been reported to have less cardiovascular depressant effects during general anesthesia, and flumazenil can antagonize the effects of remimazolam. However, in clinical trials, no patient who is complicated with severe heart failure or undergoes cardiac surgery was included. We present anesthetic management with remimazolam for MitraClip® implantation in a patient with severe mitral regurgitation and advanced heart failure. Remimazolam was administered both in anesthetic induction and maintenance with less cardiovascular depressant effects. After surgical procedures were completed, the patient smoothly recovered from anesthesia and the tracheal was extubated just after administration of flumazenil. Remimazolam may be able to achieve appropriate anesthetic management in patients complicated with severe cardiovascular diseases.

Acute Hypobaric and Hypoxic Preconditioning Reduces Myocardial Ischemia-Reperfusion Injury in Rats.

BACKGROUND: Chronic and/or intermittent exposure to hypobaric hypoxia reportedly exerts cardioprotective effects against ischemia-reperfusion injury. However, few studies have focused on the cardioprotective effects of acute and/or short-term hypobaric and hypoxic exposures. This study investigated the effects of acute hypobaric hypoxia on myocardial ischemia-reperfusion injury. MATERIALS AND METHODS: Rats were assigned to groups receiving normobaric normoxia (NN group), hypobaric hypoxia (HH group), or normobaric hypoxia (NH group). HH group rats were exposed to 60.8 kPa and 12.6% fraction of inspired oxygen in a hypobaric chamber for 6 h. NH group rats were exposed to hypoxic conditions under normal pressure. After each exposure, 30 min of myocardial ischemia was followed by 60 min of reperfusion. Cardiac function and infarct size were determined after reperfusion. Expression of hypoxia-inducible factor 1 alpha (HIF1α) was also measured. RESULTS: Cardiac function was better preserved in the HH and NH groups than in the NN group (p < 0.01 each). Median infarct size/area at risk was significantly lower in the HH group (50%, interquartile range [IQR] 48-54%; p < 0.01 vs. NN group) and NH group (45%, IQR 36-50%; p < 0.01 vs. NN group) than in the NN group (72%, IQR 69-75%). HIF1α expression was significantly higher in the HH group (p < 0.05 vs. NN group) and NH group (p < 0.01 vs. NN group) than in the NN group. CONCLUSIONS: Exposure to acute and/or short-term hypobaric and hypoxic conditions might exert cardioprotective effects against myocardial ischemia-reperfusion injury via HIF1α modulation.

Remote ischemic preconditioning reduces myocardial ischemia-reperfusion injury through unacylated ghrelin-induced activation of the JAK/STAT pathway.

Remote ischemic preconditioning (RIPC) offers cardioprotection against myocardial ischemia-reperfusion injury. The humoral factors involved in RIPC that are released from parasympathetically innervated organs have not been identified. Previous studies showed that ghrelin, a hormone released from the stomach, is associated with cardioprotection. However, it is unknown whether or not ghrelin is involved in the mechanism of RIPC. This study aimed to determine whether ghrelin serves as one of the humoral factors in RIPC. RIPC group rats were subjected to three cycles of ischemia and reperfusion for 5 min in two limbs before left anterior descending (LAD) coronary artery ligation. Unacylated ghrelin (UAG) group rats were given 0.5 mcg/kg UAG intravenously 30 min before LAD ligation. Plasma levels of UAG in all groups were measured before and after RIPC procedures and UAG administration. Additionally, JAK2/STAT3 pathway inhibitor (AG490) was injected in RIPC and UAG groups to investigate abolishment of the cardioprotection of RIPC and UAG. Plasma levels of UAG, infarct size and phosphorylation of STAT3 were compared in all groups. Infarct size was significantly reduced in RIPC and UAG groups, compared to the other groups. Plasma levels of UAG in RIPC and UAG groups were significantly increased after RIPC and UAG administration, respectively. The cardioprotective effects of RIPC and UAG were accompanied by an increase in phosphorylation of STAT3 and abolished by AG490. This study indicated that RIPC reduces myocardial ischemia and reperfusion injury through UAG-induced activation of JAK/STAT pathway. UAG may be one of the humoral factors involved in the cardioprotective effects of RIPC.

Identification of Candidate Genes and Pathways in Dexmedetomidine-Induced Cardioprotection in the Rat Heart by Bioinformatics Analysis.

Dexmedetomidine (DEX), a highly selective alpha2 adrenergic receptor agonist, directly protects hearts against ischemia/reperfusion (I/R) injury. However, the detailed mechanism has not been fully elucidated. We studied differentially expressed mRNAs and miRNAs after DEX administration in rat hearts by comprehensive analysis. Additionally, bioinformatics analysis was applied to explore candidate genes and pathways that might play important roles in DEX-induced cardioprotection. The results of microarray analysis showed that 165 mRNAs and 6 miRNAs were differentially expressed after DEX administration. Through bioinformatics analysis using differentially expressed mRNAs, gene ontology (GO) terms including MAP kinase tyrosine/serine/threonine phosphatase activity and pathways including the p53 pathway were significantly enriched in the down-regulated mRNAs. Dusp1 and Atm were associated with the GO term of MAP kinase tyrosine/serine/threonine phosphatase activity and the p53 pathway, respectively. On the other hand, no significant pathway was found in the target mRNAs of deregulated miRNAs. The results indicated some possible key genes and pathways that seem to be of significance in DEX-induced cardioprotection, although miRNAs seem to be unlikely to contribute to cardioprotection induced by DEX.