Electrophysiological evaluation of an anticancer drug gemcitabine on cardiotoxicity revealing down-regulation and modification of the activation gating properties in the human rapid delayed rectifier potassium channel.

Gemcitabine is an antineoplastic drug commonly used in the treatment of several types of cancers including pancreatic cancer and non-small cell lung cancer. Although gemcitabine-induced cardiotoxicity is widely recognized, the exact mechanism of cardiac dysfunction causing arrhythmias remains unclear. The objective of this study was to electrophysiologically evaluate the proarrhythmic cardiotoxicity of gemcitabine focusing on the human rapid delayed rectifier potassium channel, hERG channel. In heterologous hERG expressing HEK293 cells (hERG-HEK cells), hERG channel current (IhERG) was reduced by gemcitabine when applied for 24 h but not immediately after the application. Gemcitabine modified the activation gating properties of the hERG channel toward the hyperpolarization direction, while inactivation, deactivation or reactivation gating properties were unaffected by gemcitabine. When gemcitabine was applied to hERG-HEK cells in combined with tunicamycin, an inhibitor of N-acetylglucosamine phosphotransferase, gemcitabine was unable to reduce IhERG or shift the activation properties toward the hyperpolarization direction. While a mannosidase I inhibitor kifunensine alone reduced IhERG and the reduction was even larger in combined with gemcitabine, kifunensine was without effect on IhERG when hERG-HEK cells were pretreated with gemcitabine for 24 h. In addition, gemcitabine down-regulated fluorescence intensity for hERG potassium channel protein in rat neonatal cardiomyocyte, although hERG mRNA was unchanged. Our results suggest the possible mechanism of arrhythmias caused by gemcitabine revealing a down-regulation of IhERG through the post-translational glycosylation disruption possibly at the early phase of hERG channel glycosylation in the endoplasmic reticulum that alters the electrical excitability of cells.

Extensive Aortic Stent Graft Coverage for Thoracoabdominal Aortic Aneurysm is Associated With Hemorrhagic Complications Induced by Disseminated Intravascular Coagulation.

BACKGROUND: Hybrid endovascular repair for thoracoabdominal aortic aneurysm (TAAA) is a less invasive alternative treatment than conventional open repair. However, disseminated intravascular coagulation (DIC) and hemorrhagic complications can occur postoperatively. We investigated risk factors for hemorrhagic complications after hybrid endovascular TAAA repair. METHODS: Sixty-one patients who underwent elective hybrid endovascular TAAA repair between 2007 and 2020 were included. Laboratory data before and after placing stent graft were collected, and DIC was diagnosed using a scoring system established by the Japanese Association for Acute Medicine. The length of the stent graft used to cover the aorta was defined as the aortic coverage length, which was measured using the first postoperative computed tomography image. Predictors of unexpected hemorrhagic complications were evaluated. RESULTS: Postoperative thrombocytopenia was observed in 57 (93%) patients, and their platelet count decreased significantly after stent graft placement (14.3 [9.5-18.0] vs. 8.2 [5.4-10.9] × 104/µL, P < 0.001). Fifteen (25%) and 45 patients (74%) were diagnosed with DIC before and after stent graft placement, respectively. Hemorrhagic complications were observed in 21 patients (34%). Multivariate logistic regression analysis revealed that aortic coverage length was an independent risk factor for hemorrhagic complications (odds ratio 1.441/50 mm increase; 95% confidence interval, 1.041-1.994, P = 0.027). The cutoff value for aortic coverage length obtained from the receiver operating characteristic curve (area under the curve = 0.72) was 304.4 mm (sensitivity 0.76, specificity 0.70). CONCLUSION: Aortic coverage length is a risk factor for hemorrhagic complications. Patients undergoing extensive aortic coverage greater than 304 mm should be closely monitored.

Which factors have a great impact on coagulopathy and hemostatic impairment after cardiopulmonary bypass in cardiovascular surgery? An analysis based on rotational thromboelastometry.

OBJECTIVES: This study aimed to investigate which factors have a great impact on coagulopathy after cardiopulmonary bypass (CPB) using rotational thromboelastometry (ROTEM). METHODS: Ninety-eight patients undergoing cardiovascular surgery using CPB were enrolled. Data of amplitude 10 min after clotting time (A10) of ROTEM measured routinely before and after CPB were retrospectively collected. ROTEM has some assays by which we can evaluate the capacity of extrinsic coagulation (EXTEM), intrinsic coagulation (INTEM), fibrin polymerization (FIBTEM), and the effect of heparin (HEPTEM). The platelet component, defined as PLTEM, can be calculated by subtracting FIBTEM from EXTEM. Age, sex, total plasma volume, pre-CPB A10, lowest body temperature, in-out balance during CPB, intraoperative bleeding amount, and type of pumps were considered as possible factors. Univariate and multivariate analyses were performed for the rate of change of A10. RESULTS: The change rate of each A10 had a significant negative correlation with bleeding amount (p < 0.01 for EXTEM, p < 0.01 for INTEM, p = 0.02 for FIBTEM, p < 0.01 for PLTEM). Female sex was a significant contributive predictor for the greater decline of EXTEM (p < 0.01) and INTEM (p < 0.01), positive balance for EXTEM (p < 0.01), FIBTEM (p = 0.01), and PLTEM (p < 0.01), long CPB time for INTEM (p = 0.01), centrifugal pump for FIBTEM (p < 0.01), and large pre-CPB A10 for PLTEM (p < 0.01). CONCLUSION: In perioperative hemostatic management using ROTEM, attention should be given to the effects of these multiple factors.

Nitric oxide down-regulates voltage-gated Na+ channel in cardiomyocytes possibly through S-nitrosylation-mediated signaling.

Nitric oxide (NO) is produced from endothelial cells and cardiomyocytes composing the myocardium and benefits cardiac function through both vascular-dependent and-independent effects. This study was purposed to investigate the possible adverse effect of NO focusing on the voltage-gated Na+ channel in cardiomyocytes. We carried out patch-clamp experiments on rat neonatal cardiomyocytes demonstrating that NOC-18, an NO donor, significantly reduced Na+ channel current in a dose-dependent manner by a long-term application for 24 h, accompanied by a reduction of Nav1.5-mRNA and the protein, and an increase of a transcription factor forkhead box protein O1 (FOXO1) in the nucleus. The effect of NOC-18 on the Na+ channel was blocked by an inhibitor of thiol oxidation N-ethylmaleimide, a disulfide reducing agent disulfide 1,4-Dithioerythritol, or a FOXO1 activator paclitaxel, suggesting that NO is a negative regulator of the voltage-gated Na+ channel through thiols in regulatory protein(s) for the channel transcription.

True Aneurysm of the Left Main Trunk in a Marfan Syndrome Patient at Remote Period after Bentall Operation and Total Arch Replacement: A Case Report.

In 2002, a 37-year-old male with Marfan syndrome underwent the Bentall operation, total arch replacement, and aortobifemoral bypass for DeBakey type IIIb chronic aortic dissection, annuloaortic ectasia, and aortic regurgitation. In 2007, mild mitral regurgitation (MR) caused by mitral valve prolapse was identified. In April 2017, echocardiography revealed the worsening of MR and moderate tricuspid regurgitation (TR). Moreover, coronary angiography (CAG) revealed a coronary artery aneurysm in the left main trunk (LMT). In August 2017, the patient underwent mitral valve replacement (MVR), tricuspid annuloplasty (TAP), and coronary artery reconstruction. We reconstructed the LMT aneurysm using an artificial graft. True aneurysm of the coronary artery complicated with Marfan syndrome is a rare complication that has seldom been reported. This case highlights that it is essential to carefully follow-up patients with Marfan syndrome after the Bentall operation.

Successful cardiac surgery in a patient with Evans syndrome.

Evans syndrome is a rare haematological disease that may cause several complications during heart surgery. Herein we documented heart valve surgery in a patient with Evans syndrome who was receiving monoclonal antibody therapy, and valve replacement was successfully performed via prophylactic measures against haemolysis.