Contractility assessment using aligned human iPSC-derived cardiomyocytes.

INTRODUCTION: Cardiac safety assessment, such as lethal arrhythmias and contractility dysfunction, is critical during drug development. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have been shown to be useful in predicting drug-induced proarrhythmic risk through international validation studies. Although cardiac contractility is another key function, fit-for-purpose hiPSC-CMs in evaluating drug-induced contractile dysfunction remain poorly understood. In this study, we investigated whether alignment of hiPSC-CMs on nanopatterned culture plates can assess drug-induced contractile changes more efficiently than non-aligned monolayer culture. METHODS: Aligned hiPSC-CMs were obtained by culturing on 96-well culture plates with a ridge-groove-ridge nanopattern on the bottom surface, while non-aligned hiPSC-CMs were cultured on regular 96-well plates. Next-generation sequencing and qPCR experiments were performed for gene expression analysis. Contractility of the hiPSC-CMs was assessed using an imaging-based motion analysis system. RESULTS: When cultured on nanopatterned plates, hiPSC-CMs exhibited an aligned morphology and enhanced expression of genes encoding proteins that regulate contractility, including myosin heavy chain, calcium channel, and ryanodine receptor. Compared to cultures on regular plates, the aligned hiPSC-CMs also showed both enhanced contraction and relaxation velocity. In addition, the aligned hiPSC-CMs showed a more physiological response to positive and negative inotropic agents, such as isoproterenol and verapamil. DISCUSSION: Taken together, the aligned hiPSC-CMs exhibited enhanced structural and functional properties, leading to an improved capacity for contractility assessment compared to the non-aligned cells. These findings suggest that the aligned hiPSC-CMs can be used to evaluate drug-induced cardiac contractile changes.

[A Combination Therapy with Antibiotic and Surgical Treatment in a Patient with Patent Ductus Arteriosus with Pulmonary Vegetation:Report of a Case].

We present a case of a 24-year-old female who presented with a history of fever and back pain. She had no particular medical history and was not taking any medication. Transthoracic echocardiology and computed tomography showed a patent ductus arteriosus with vegetation in the pulmonary artery. She was treated with penicillin G;however, the vegetation embolized into the left pulmonary artery. After the antibiotics was changed to clindamycin and ceftriaxone, the resolution of the lung abscess was shown by computed tomography( CT). Two months later, a surgical repair of the patent ductus arteriosus was successfully performed. Patent ductus arteriosus-associated infectious endocarditis is relatively rare in adulthood.

Renal Biomarkers in the Early Detection of Acute Kidney Injury After Off-Pump Coronary Artery Bypass Grafting.

BACKGROUND: Cardiac surgery-associated (CSA) acute kidney injury (AKI) is a severe postoperative complication in patients undergoing off-pump coronary artery bypass grafting (OPCAB). Early detection of postoperative CSA-AKI may be key to improving patient outcomes. This study explored the use of renal biomarkers measured immediately after surgery for the early detection of CSA-AKI in patients undergoing OPCAB.Methods and Results: In all, 111 patients who underwent OPCAB at Kumamoto University Hospital between June 2020 and October 2022 were included in this study. Urinary neutrophil gelatinase-associated lipocalin, liver-type fatty acid-binding protein, and N-acetyl-ß-D-glucosaminidase (NAG) were measured upon arrival in the intensive care unit (ICU) after surgery. AKI was diagnosed using KDIGO criteria. Of the 111 patients, 32 (28.8%) developed postoperative AKI. Regarding AKI staging, 19 (59.4%), 11 (34.4%), and 2 (6.3%) patients had Stage 1, 2, and 3 AKI, respectively. There were significant differences in chronic kidney disease, preoperative estimated glomerular filtration rate (eGFR), and NAG between the AKI and non-AKI groups. Multivariate analysis showed that preoperative eGFR (odds ratio [OR] for 5-mL/min/1.73 m2increase in eGFR 0.75; 95% confidence interval [CI] 0.63-0.89) and increasing urinary NAG concentrations at ICU admission (OR 2.44; 95% CI 1.30-4.60) were significant risk factors for CSA-AKI in OPCAB patients. CONCLUSIONS: NAG and eGFR may be valuable biomarkers for the early detection of CSA-AKI in patients undergoing OPCAB.

Do chronic total occlusive lesions affect patency of coronary bypass grafts to the right coronary artery?

OBJECTIVES: To evaluate the impact of chronic total occlusion (CTO) lesions on the patency of bypass grafts to the right coronary artery territory. METHODS: Two hundred patients undergoing primary isolated coronary artery bypass grafting with revascularization to the right coronary artery territory between April 2015 and July 2022 were retrospectively analyzed. Study patients were divided into two groups according to their right coronary artery lesion: patients with CTO lesions (n = 76) and those without CTO lesions (n = 124). Graft flow of the right coronary artery territory was evaluated by intraoperative transit time flow measurement and patency of the bypass graft was evaluated by multidetector row computed tomography. RESULTS: A total of 200 patients (76 patients with CTO and 124 patients without CTO) were included in this study. Intraoperative transit time flow measurement demonstrated that there was no significant difference in the median mean graft flow (30 ml/min vs. 25 ml/min; p = 0.114), pulsatility index (2.1 vs. 2.4; p = 0.079), and diastolic filling rate (65% vs. 64%; p = 0.844) between patients with CTO and those without CTO. Postoperative multidetector row computed tomography demonstrated that the patency of bypass grafts to the right coronary artery territory was similar between the groups (94.7% in patients with CTO vs. 96.0% in those without CTO; p = 0.733). In patients with CTO, the patency of bypass graft tended to be worse in subgroup with rich collateral blood flow (Rentrop grade 3). CONCLUSIONS: Chronic total occlusion lesions do not affect the patency of bypass grafts to the right coronary artery territory.

Outcomes of mitral valve replacement with complete annular decalcification.

BACKGROUND: This study aimed to examine the clinical outcomes of mitral valve replacement (MVR) in patients with severe mitral annular calcification (MAC) who required extensive decalcification and mitral annular reconstruction. METHODS: We reviewed 15 patients with severe MAC who underwent MVR between January 2016 and May 2022. In all cases, the calcified mitral annulus was resected completely using a Cavitron Ultrasound Surgical Aspirator, and a new annulus was created using bovine pericardium. In the acute postoperative phase, strict afterload reduction therapy using an intra-aortic balloon pump (IABP) was administered. RESULTS: The mean age of patients was 73 ± 8 years, and 13 (86.7%) were women. Concomitant aortic valve replacement was performed in 11 (73.3%) patients, tricuspid annuloplasty in 9 (60.0%), coronary artery bypass grafting in 1 (6.7%), and arrhythmia surgery in 7 (46.7%). The mean aortic cross-clamp and cardiopulmonary bypass times were 143 ± 32 min and 175 ± 34 min, respectively. In 13 patients, an IABP was used for 2 or 3 days postoperatively. There were no in-hospital deaths, left ventricular ruptures, or other MAC-related complications. Postoperative echocardiography revealed no paravalvular leakages. CONCLUSION: Our strategy for managing severe MAC is safe and reproducible even in relatively high-risk patients. Afterload reduction using an IABP in the acute postoperative phase may reduce the risk of fatal complications after extensive decalcification and mitral annular reconstruction.

Mitral valve replacement with annuloplasty in a patient with infected mitral annular calcification.

Key Clinical Message: Extensive resection of the infected calcified annulus and the reconstruction with a pericardial patch for the debrided annulus is an effective surgical option for the treatment of infectious endocarditis in patients with mitral annular calcification. Abstract: A 78-year-old woman was referred to our hospital because of left-sided hemiparesis. During the treatment for cerebral infarction, the patient became feverish and lost consciousness. Transthoracic echocardiography revealed mitral annular calcification and a tumor-like mass on the posterior leaflet despite no findings of mitral regurgitation. She underwent successful mitral valve replacement with debridement of the infected mitral annulus and reconstruction of the posterior annulus (annuloplasty) with bovine pericardium after removal of the mitral annular calcification.

Factors Affecting Recovery of 6-Minute Walk Distance After Coronary Artery Bypass Grafting.

Background: This single-center retrospective analysis investigated the number of days required for postoperative 6-minute walk distance (6MWD) to recover to preoperative values after coronary artery bypass grafting (CABG) and the factors influencing this recovery. Methods and Results: The 6MWD was measured in 101 patients (median age 69 years; 18 women) before and every day after CABG. Univariate and multivariate analyses were performed to identify factors affecting 6MWD recovery to preoperative values after CABG. The median number of days required for recovery of 6MWD after CABG was 9 (interquartile range 7-11 days). Patients were divided into 2 groups based on the median number of days required for recovery of 6MWD; there were 60 patients in the early recovery group (<9 days) and 41 in the "non-early" recovery group (38 who recovered after the median 9 days, and 3 who did not recover during hospitalization). Using univariate logistic regression analysis, diabetes (P=0.01), stroke (P=0.26), left ventricular ejection fraction (P=0.27), and grip strength (P=0.13) were selected for multivariate analysis. Multivariate logistic regression analysis revealed that diabetes (odds ratio 2.955; 95% confidence interval 1.208-7.229; P=0.02) was the only independent predictor of 6MWD recovery. Conclusions: Diabetes was the single factor influencing the recovery of postoperative 6MWD in patients undergoing CABG.

Acute heart failure due to coronary subclavian steal syndrome after coronary artery bypass grafting.

Key clinical message: An axillo-axillary bypass grafting is useful for coronary subclavian steal syndrome when occlusion of the proximal left subclavian artery. Abstract: An 81-year-old female who had undergone coronary artery bypass grafting 15 years previously was admitted and diagnosed with coronary subclavian steal syndrome. Preoperative angiography showed backflow from the left anterior descending coronary artery to the left internal thoracic artery and occlusion of the proximal left subclavian artery. Axillo-axillary bypass grafting was successfully performed.

Free Jejunal Graft Interposition with Vascular Reconstruction in Patients Undergoing Pharyngo Laryngo Esophagectomy.

BACKGROUND: Pharyngo-esophageal reconstruction using free jejunal grafts has been widely used for the treatment of locally advanced carcinomas of the hypopharynx and cervical esophagus. However, the procedure is technically demanding and requires complex recontractions. The aim of this study was to evaluate our institutional outcomes of reconstruction using a free jejunal graft with vascular reconstruction in patients undergoing pharyngo laryngo esophagectomy with a multidisciplinary surgical team. METHODS: There were 90 consecutive patients between October 2006 and February 2021. The mean age was 64.6 ± 10.3 years, and there were 76 male patients. Of 90 patients, 49 underwent preoperative chemotherapy and/or radiotherapy. Jejunal vessels were commonly anastomosed to the common carotid artery and the internal jugular vein (77.8% and 92.2%, respectively). Continuous intravenous infusion of heparin was used postoperatively. RESULTS: Necrosis of the graft was observed in 5 patients. An isolated revision of vein was necessary in 1 patient. In all cases of graft failure, heparin was not used postoperatively. On the other hand, among the patients without graft failure, heparin was used for about two-thirds of the patients and was significantly different (0% vs. 66%, P = 0.01). CONCLUSIONS: Free jejunal graft with vessel reconstruction is a safe and effective method for patients undergoing pharyngo laryngo esophagectomy. The position for the prevention of kinking as well anastomosis maneuver of vein is especially important. Moreover, early postoperative anticoagulation is essential.

[Coronary Artery Bypass Grafting via Partial Sternotomy Late after Partial Chest Wall Resection:Report of a Case].

A 74-year-old man was referred to our department to receive coronary artery bypass grafting (CABG) because of severe triple vessel disease. He had undergone a chest wall resection including the right clavicle and the first and second ribs for the fibrosarcoma 40 years ago. The right internal thoracic artery was resected at the operation. Twenty-nine years after the operation, the plate used for the reconstruction of the chest wall was removed because of its infection. Off-pump CABG using left internal thoracic artery and vein grafts with lower partial sternotomy was successfully performed for the complete revascularization. This patient had a high possibility of sternum dehiscence and postoperative mediastinitis due to poor blood flow in the right upper sternum.

[Concurrent Surgical Venous Repair during Laser-assisted Pacemaker Lead Extraction].

Pacemakers are widely used to treat arrhythmia, however, one of problems after implantation of pacemaker is device infection. Total removal of leads and generator is recommended for radical cure. Recently, transvenous laser-assisted extraction of pacemaker leads has been developed and has achieved good results. However, catastrophic complications during pacemaker and implantable cardioverter-defibrillator leads extraction have been reported, and cases requiring surgical reconstruction have been also reported. Most of the repair technique include a direct suturing or a partial repair with patch. We herein report two cases of superior vena cava and innominate vein reconstruction with bovine pericardium during transvenous laser-assisted extraction. A hybrid approach using transvenous laser-assisted extraction and surgical repair through median sternotomy should be considered to perform complete lead extraction in complex cases with pacemaker lead infection.

Development and evaluation of the effectiveness of educational material for radiological protection that uses augmented reality and virtual reality to visualise the behaviour of scattered radiation.

Understanding the behaviour of scattered radiation is important for learning appropriate radiation protection methods, but many existing visualisation systems for radiation require special devices, making it difficult to use them in education. The purpose of this study was to develop teaching material for radiation protection that can help visualise the scattered radiation with augmented reality (AR) and virtual reality (VR) on a web browser, develop a method for using it in education and examine its effectiveness. The distribution of radiation during radiography was calculated using Monte Carlo simulation, and teaching material was created. The material was used in a class for department of radiological technology students and its influence on motivation was evaluated using a questionnaire based on the evaluation model for teaching materials. In addition, text mining was used to evaluate impressions objectively. Educational material was developed that can be used in AR and VR for studying the behaviour of scattered radiation. The results of the questionnaire showed that the average value of each item was more than four on a five-point scale, indicating that the teaching material attracted the interest of users. Through text mining, it could be concluded that there was improved understanding of, and confidence in, radiation protection.

[Cardiovascular safety pharmacology: in vitro strategies and improvements in technology and evaluation].

Safety pharmacology studies have been clearly defined through discussions at the International Council for Harmonization of Pharmaceutical Regulations (ICH), and are conducted as non-clinical studies according to the ICH S7A and S7B to ensure the safety of subjects participating in clinical studies. The representative of in vitro studies of cardiovascular system is hERG assay, but CiPA recommendations by FDA/HESI (multi-ion channel assays, simulation with in silico model using the multi-ion channel data, human iPS cell-derived cardiomyocyte assay), a new clinical risk prediction strategy that makes effective use of non-clinical data is being established. In addition, regarding the risk of heart failure that induced by anticancer drugs, which are attracting attention as a social problem, technology development has been made centering on human iPS cell-derived cardiomyocytes. There are many issues to be solved, but active challenges are being taken globally to bridge the gap between clinical and non-clinical.

Left atrial intramural hematoma after percutaneous coronary intervention.

Left atrial intramural hematoma is a rare complication of percutaneous coronary intervention. The combination treatment with surgery and interventional therapy is one of therapeutic options.

Chloroquine and hydroxychloroquine provoke arrhythmias at concentrations higher than those clinically used to treat COVID-19: A simulation study.

The risk of fatal arrhythmias is the major concern for using chloroquine (CQ) or hydroxychloroquine (HCQ) to treat coronavirus disease 2019 (COVID-19), but the reported number of life-threatening arrhythmic events or deaths is relatively small. The objective of this study was to assess the arrhythmogenic risk of these two drugs using a multiscale heart simulation, which allows testing even at high concentrations, including those that cause fatal arrhythmias. We measured the inhibitory action of CQ, HCQ, and HCQ with 30 µM azithromycin (AZ) on six ion currents (fast [INa] and late [INa,L] components of the sodium current, L-type calcium current [ICa,L], rapid [IKr/hERG], and slow [IKs] components of delayed rectifier potassium, and inward rectifier potassium [IK1]) over a wide range of concentrations using the automated patch-clamp system. Using the concentration-inhibition relationship that was thus obtained, we simulated the drug effects while increasing the concentration until the life-threatening arrhythmia, torsade de pointes (TdP), was observed. The obtained threshold concentrations for TdP were 12.5, 35, and 22.5 µM for CQ, HCQ, and HCQ with AZ, respectively. Adding therapeutic concentrations of mexiletine or verapamil successfully prevented the occurrence of TdP, and verapamil was more effective. CQ, HCQ, and HCQ with AZ thresholds for TdP were larger than both antiviral concentrations that were reported by in vitro experiments and free plasma concentrations that were attained by the clinically used dosage. The current simulation data provided a safety margin to the currently used clinical dose for CQ and HCQ/AZ. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Despite the potent in vitro antiviral effect, clinical trials have failed to show the therapeutic effects of chloroquine (CQ) and hydroxychloroquine (HCQ)/azithromycin (AZ) to treat coronavirus disease 2019. Torsadogenic potentials may limit the dosage of these drugs, but the reported incidence of fatal arrhythmias is rare. WHAT QUESTION DID THIS STUDY ADDRESS? Our objective was to assess the arrhythmogenicity of CQ and HCQ/AZ over a wide range of drug concentrations using a multiscale heart simulation. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? Our study showed that CQ and HCQ/AZ do not induce fatal arrhythmias even at concentrations much higher than in vitro antiviral half-maximal effective concentration (EC50 ) values at which QT prolongation exceeds 150 ms. We also found that estimated free plasma concentrations of CQ and HCQ/AZ achieved by currently used dosing protocols are lower than the antiviral EC50 for these drugs. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? Our simulation data provided a safety margin to the currently used clinical dose for CQ and HCQ/AZ.

Time for a Fully Integrated Nonclinical-Clinical Risk Assessment to Streamline QT Prolongation Liability Determinations: A Pharma Industry Perspective.

Defining an appropriate and efficient assessment of drug-induced corrected QT interval (QTc) prolongation (a surrogate marker of torsades de pointes arrhythmia) remains a concern of drug developers and regulators worldwide. In use for over 15 years, the nonclinical International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) S7B and clinical ICH E14 guidances describe three core assays (S7B: in vitro hERG current & in vivo QTc studies; E14: thorough QT study) that are used to assess the potential of drugs to cause delayed ventricular repolarization. Incorporating these assays during nonclinical or human testing of novel compounds has led to a low prevalence of QTc-prolonging drugs in clinical trials and no new drugs having been removed from the marketplace due to unexpected QTc prolongation. Despite this success, nonclinical evaluations of delayed repolarization still minimally influence ICH E14-based strategies for assessing clinical QTc prolongation and defining proarrhythmic risk. In particular, the value of ICH S7B-based "double-negative" nonclinical findings (low risk for hERG block and in vivo QTc prolongation at relevant clinical exposures) is underappreciated. These nonclinical data have additional value in assessing the risk of clinical QTc prolongation when clinical evaluations are limited by heart rate changes, low drug exposures, or high-dose safety considerations. The time has come to meaningfully merge nonclinical and clinical data to enable a more comprehensive, but flexible, clinical risk assessment strategy for QTc monitoring discussed in updated ICH E14 Questions and Answers. Implementing a fully integrated nonclinical/clinical risk assessment for compounds with double-negative nonclinical findings in the context of a low prevalence of clinical QTc prolongation would relieve the burden of unnecessary clinical QTc studies and streamline drug development.

Development of an application to visualise the spread of scattered radiation in radiography using augmented reality.

As radiation is widely used in medical institutions, the lack of radiation protection education for health workers increases the risk of radiation exposure. The purpose of this study is to develop an application for radiation medical personnel that visualises the distribution of scattered radiation by using augmented reality (AR). The irradiation conditions for mobile chest and pelvic radiography were simulated using Monte Carlo simulations (Particle and Heavy Ion Transport code System). Monte Carlo results were verified using physical measurements. The behaviour of scattered radiation was displayed three-dimensionally in virtual reality using ParaView. Subsequently, an application to visualise scattered rays was developed in Unity for tablet devices. An application with a sense of reality was developed by visualising the scattered radiation distribution of a mobile imaging in a real space in AR in a three-dimensional size, which is close to the actual size. The radiation dose could be estimated at any position and the behaviour of scattered radiation became easier to understand.

General Principles for the Validation of Proarrhythmia Risk Prediction Models: An Extension of the CiPA In Silico Strategy.

This white paper presents principles for validating proarrhythmia risk prediction models for regulatory use as discussed at the In Silico Breakout Session of a Cardiac Safety Research Consortium/Health and Environmental Sciences Institute/US Food and Drug Administration-sponsored Think Tank Meeting on May 22, 2018. The meeting was convened to evaluate the progress in the development of a new cardiac safety paradigm, the Comprehensive in Vitro Proarrhythmia Assay (CiPA). The opinions regarding these principles reflect the collective views of those who participated in the discussion of this topic both at and after the breakout session. Although primarily discussed in the context of in silico models, these principles describe the interface between experimental input and model-based interpretation and are intended to be general enough to be applied to other types of nonclinical models for proarrhythmia assessment. This document was developed with the intention of providing a foundation for more consistency and harmonization in developing and validating different models for proarrhythmia risk prediction using the example of the CiPA paradigm.

Risk of Out-of-Hospital Cardiac Arrest in Aged Individuals in Relation to Cold Ambient Temperature　- A Report From North Tochigi Experience.

BACKGROUND: The impact of cold ambient temperature on out-of-hospital cardiac arrest (OHCA) in aged individuals caused by cardiovascular events in indoor environments has not been investigated sufficiently.Methods and Results:We conducted a case-crossover study. The relationship between OHCA caused by cardiovascular events and exposure to minimum temperature <0℃ was analyzed. Conditional logistic regression analysis was performed to estimate the odds ratios for the relationship between exposure to minimum temperature <0℃ and the risk of OHCA. Between January 1, 2011, and December 31, 2015, a total of 1,452 cases of OHCA were documented, and patients were screened for enrollment. A total of 458 individuals were enrolled in this analysis, and were divided into 2 groups of 110 (elderly group: 65-74 years old) and 348 (aged group: ≥75 years old). The aged individuals had a significant increased risk of OHCA after exposure to minimum temperature <0℃ (odds ratio [OR]: 1.528, 95% confidence interval [CI] 1.009-2.315, P=0.045). Cold ambient temperature was an especially significant increased risk for OHCA occurrence for males (OR: 1.997, 95% CI 1.036-3.773, P=0.039) and during winter (OR: 2.391, 95% CI 1.312-4.360, P=0.004) in the aged group. CONCLUSIONS: Cold ambient temperature significantly affected aged individuals (≥75 years old) experiencing an OHCA caused by cardiovascular events in indoor environments.

Response of safety pharmacologists to challenges arising from the rapidly evolving changes in the pharmaceutical industry.

This commentary highlights and expands upon the thoughts conveyed in the lecture by Dr. Alan S. Bass, recipient of the 2017 Distinguished Service Award from the Safety Pharmacology Society, given on 27 September 2017 in Berlin, Germany. The lecture discussed the societal, scientific, technological, regulatory and economic events that dramatically impacted the pharmaceutical industry and ultimately led to significant changes in the strategic operations and practices of safety pharmacology. It focused on the emerging challenges and opportunities, and considered the lessons learned from drug failures and the influences of world events, including the financial crisis that ultimately led to a collapse of the world economies from which we are now recovering. Events such as these, which continue to today, challenge the assumptions that form the foundation of our discipline and dramatically affect the way that safety pharmacology is practiced. These include the latest scientific and technological developments contributing to the design and advancement of safe medicines. More broadly, they reflect the philosophical mission of safety pharmacology and the roles and responsibilities served by safety pharmacologists. As the discipline of Safety Pharmacology continues to evolve, develop and mature, the reader is invited to reflect on past experiences as a framework towards a vision of the future of the field.