Long-term administration of nicorandil abolishes ischemic and pharmacologic preconditioning of the human myocardium: Role of mitochondrial adenosine triphosphate–dependent potassium channels

AbstractBackground: Acute administration of mitochondrial adenosine triphosphate–dependent potassium channel openers preconditions the heart, but whether their long-term administration induces a permanent state of protection is unknown. These studies investigate the effect of long-term treatment with the mitochondrial adenosine triphosphate–dependent potassium channel opener nicorandil on the response of the human myocardium to ischemia and preconditioning. Methods: Right atrial tissue obtained from patients regularly treated with or without nicorandil (mean of 20 mg/d for 18.6 ± 2.5 months) and undergoing cardiac surgery was sliced and equilibrated for 30 minutes and then subjected to 90 minutes of simulated ischemia, followed by 120 minutes of reoxygenation. In study 1 the following groups were studied to investigate the effect of nicorandil on the susceptibility of the myocardium to ischemia and on the protective effect of ischemic and pharmacologic preconditioning: (1) aerobic control; (2) simulated ischemia and reoxygenation alone; (3) ischemic preconditioning with 5 minutes of simulated ischemia and 5 minutes of reoxygenation; and (4) phenylephrine (0.1 μmol/L) for 5 minutes and 5 minutes' washout before simulated ischemia and reoxygenation. In study 2 the following groups were studied to investigate the effect of nicorandil on the responsiveness of mitochondrial adenosine triphosphate–dependent potassium channels: (1) aerobic control; (2) simulated ischemia and reoxygenation; (3) ischemic preconditioning; (4) diazoxide (100 μmol/L) for 10 minutes before simulated ischemia and reoxygenation, and (5) 5-hydroxydecanoate (1 mmol/L) for 10 minutes before simulated ischemia and reoxygenation. In study 3 the following groups were included to investigate the effect of the long-term administration of nicorandil on the kinase pathway involved in preconditioning: (1) aerobic control; (2) simulated ischemia and reoxygenation alone; (3) ischemic preconditioning; (4) phorbol 12-myristate 13-acetate (1 μmol/L), a protein kinase C activator, for 10 minutes before simulated ischemia and reoxygenation; and (5) anisomycin (1 nmol/L), a p38 mitogen-activated protein kinase activator, for 10 minutes before simulated ischemia and reoxygenation. At the end of each protocol, the leakage of creatine kinase (in units per gram wet weight) and the reduction of 3-[4,5 dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide into insoluble formazan dye (in millimoles per gram wet weight) were measured. Results: In study 1 the leakage of creatine kinase and the reduction of 3-[4,5 dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide induced by simulated ischemia and reoxygenation were similar in the groups with or without nicorandil (creatine kinase, 3.4 ± 0.1 and 3.5 ± 0.2, respectively; 3-[4,5 dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide, 74.6 ± 3.9 and 67.9 ± 7.3, respectively; P >.2 in each instance). Ischemic preconditioning and pharmacologic preconditioning protected the myocardium from patients without nicorandil (creatine kinase, 2.3 ± 0.1 and 2.4 ± 0.1, respectively; 3-[4,5 dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide, 131.4 ± 4.9 and 128.4 ± 5.6, respectively; P < 0.001 vs simulated ischemia and reoxygenation alone in each instance) but not the myocardium from patients receiving nicorandil (creatine kinase, 3.3 ± 0.1 and 3.3 ± 0.2, respectively; 3-[4,5 dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide, 89.7 ± 6.5 and 86.4 ± 5.2, respectively; P >.2 vs simulated ischemia and reoxygenation alone in each instance). In study 2 the administration of diazoxide had identical protection to that of ischemic preconditioning in the myocardium of patients not receiving nicorandil (creatine kinase, 2.1 ± 0.2 and 2.3 ± 0.1, respectively; 3-[4,5 dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide, 141.4 ± 7.4 and 131.4 ± 4.9, respectively; P < 0.001 vs simulated ischemia and reoxygenation alone in each instance) but failed to precondition the myocardium from patients treated with nicorandil (creatine kinase, 3.3 ± 0.2 and 3.4 ± 0.1, respectively; 3-[4,5 dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide, 90.1 ± 7.2 and 86.4 ± 5.2, respectively; P > 0.2 vs simulated ischemia and reoxygenation alone in each instance). In study 3 phorbol 12-myristate 13-acetate or anisomycin given for 10 minutes before simulated ischemia and reoxygenation afforded similar protection to that of ischemic preconditioning in the myocardium from patients with (creatine kinase, 1.5 ± 0.3 and 1.4 ± 0.1, respectively; 3-[4,5 dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide, 147.0 ± 4.9 and 160.0 ± 16.1, respectively; P < 0.001 vs simulated ischemia and reoxygenation alone in each instance) and without nicorandil (creatine kinase, 1.7 ± 0.4 and 1.4 ± 0.2, respectively; 3-[4,5 dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide, 160.3 ± 13.6 and 158.3 ± 11.8, respectively; P <.001 vs simulated ischemia and reoxygenation alone in each instance). Conclusion: The myocardium of patients chronically treated with nicorandil cannot be preconditioned either by ischemia or pharmacologically, and this is because of unresponsive mitochondrial adenosine triphosphate–dependent potassium channels. However, protection can be obtained by protein kinase C and p38 mitogen-activated protein kinase activation, which are downstream of mitochondrial adenosine triphosphate–dependent potassium channels in the signaling transduction pathway of preconditioning.J Thorac Cardiovasc Surg 2002;124:750-

Une application pour téléphones intelligents facilitant l’accueil au début des stages en unité de soins intensifs

Implication Statement The Department of Critical Care at Dalhousie University developed a smartphone app to improve the quality of learner orientation to the intensive care unit (ICU). The app increased satisfaction with orientation and was perceived as useful. It was ranked as the second most valued resource for orientation after other residents. There is potential to improve the experience of learners with this popular technology.Énoncé des implications de la recherche Le département des soins critiques de l'Université Dalhousie a mis au point une application pour téléphones intelligents en vue d'améliorer la qualité de l’accueil des apprenants à l'unité de soins intensifs (USI). L'application a permis d'augmenter la satisfaction par rapport à l’accueil et elle a été jugée utile. Elle a été classée la deuxième ressource d’orientation la plus appréciée après «&nbsp;les autres résidents&nbsp;». L'expérience des apprenants peut être améliorée à l’aide de cette technologie populaire

Do age-associated changes of voltage-gated sodium channel isoforms expressed in the mammalian heart predispose the elderly to atrial fibrillation?

© The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved. Atrial fibrillation (AF) is the most common cardiac arrhythmia worldwide. The prevalence of the disease increases with age, strongly implying an age-related process underlying the pathology. At a time when people are living longer than ever before, an exponential increase in disease prevalence is predicted worldwide. Hence unraveling the underlying mechanics of the disease is paramount for the development of innovative treatment and prevention strategies. The role of voltage-gated sodium channels is fundamental in cardiac electrophysiology and may provide novel insights into the arrhythmogenesis of AF. Nav1.5 is the predominant cardiac isoform, responsible for the action potential upstroke. Recent studies have demonstrated that Nav1.8 (an isoform predominantly expressed within the peripheral nervous system) is responsible for cellular arrhythmogenesis through the enhancement of pro-arrhythmogenic currents. Animal studies have shown a decline in Nav1.5 leading to a diminished action potential upstroke during phase 0. Furthermore, the study of human tissue demonstrates an inverse expression of sodium channel isoforms; reduction of Nav1.5 and increase of Nav1.8 in both heart failure and ventricular hypertrophy. This strongly suggests that the expression of voltage-gated sodium channels play a crucial role in the development of arrhythmias in the diseased heart. Targeting aberrant sodium currents has led to novel therapeutic approaches in tackling AF and continues to be an area of emerging research. This review will explore how voltage-gated sodium channels may predispose the elderly heart to AF through the examination of laboratory and clinical based evidence

My patient is short of breath: is the problem in the lung tissue?

Undifferentiated dyspnoea is a common patient presentation in the intensive care unit, medical and surgical floors, and in the emergency department. Physical examination and chest radiography are notoriously insensitive for detection and differentiation of various lung pathologies while computed tomography consumes significant resources and exposes the patient to ionizing radiation. Point-of-care ultrasound (PoCUS) is a highly sensitive and specific diagnostic tool that, with appropriate operator experience, is capable of diagnosing and differentiating between the various causes of dyspnoea. PoCUS machines are readily available, images are rapidly generated and repeatable, and technical skills are easily taught during short training sessions. Furthermore, the development of PoCUS skills in one specific area enables and enhances the development of skills in other non-related areas. This article describes the benefits, technical aspects, and challenges associated with using PoCUS to examine the lung parenchyma in the acutely dyspnoeic patient

My patient is short of breath: is there pleural fluid, and will PoCUS help drain it safely?

Pathological pleural fluid is common in patients presenting to the emergency department, occurring in as many as 17% of patients presenting with shortness of breath, and as many as 20% of patients with blunt thoracic trauma. A typical chest X-ray may fail to identify as much as 175 mL of pleural fluid in the erect position, and as much as 500 mL in the supine position. Point-of-care ultrasound (PoCUS) on the other hand can detect as little as 20 mL of pleural fluid, and has consistently been shown to have sensitivities and specificities for the detection of pleural fluid close to 100% in both the trauma and critically ill populations. In addition, ultrasound identifies pleural fluid more rapidly than chest X-ray. PoCUS can be used to guide thoracentesis, resulting in improved success rates with decreased complications. Here we describe the evidence supporting the use of PoCUS in the management of pleural fluid collections

Detection of microplastics in human saphenous vein tissue using FTIR: a pilot study

Microplastics (MPs) are ubiquitous in the environment, in the human food chain, and have been recently detected in blood and lung tissues. To undertake a pilot analysis of MP contamination in human vein tissue samples with respect to their presence (if any), levels, and characteristics of any particles identified. This study analysed digested human saphenous vein tissue samples (n = 5) using μFTIR spectroscopy (size limitation of 5 m) to detect and characterise any MPs present. In total, 20 MP particles consisting of five MP polymer types were identified within 4 of the 5 vein tissue samples with an unadjusted average of 29.28 ± 34.88 MP/g of tissue (expressed as 14.99 ± 17.18 MP/g after background subtraction adjustments). Of the MPs detected in vein samples, five polymer types were identified, of irregular shape (90%), with alkyd resin (45%), poly (vinyl propionate/acetate, PVAc (20%) and nylon-ethylene-vinyl acetate, nylon-EVA, tie layer (20%) the most abundant. While the MP levels within tissue samples were not significantly different than those identified within procedural blanks (which represent airborne contamination at time of sampling), they were comprised of different plastic polymer types. The blanks comprised n = 13 MP particles of four MP polymer types with the most abundant being polytetrafluoroethylene (PTFE), then polypropylene (PP), polyethylene terephthalate (PET) and polyfumaronitrile:styrene (FNS), with a mean ± SD of 10.4 ± 9.21, p = 0.293. This study reports the highest level of contamination control and reports unadjusted values alongside different contamination adjustment techniques. This is the first evidence of MP contamination of human vascular tissues. These results support the phenomenon of transport of MPs within human tissues, specifically blood vessels, and this characterisation of types and levels can now inform realistic conditions for laboratory exposure experiments, with the aim of determining vascular health impacts

Do T2DM and Hyperglycaemia Affect the Expression Levels of the Regulating Enzymes of Cellular O-GlcNAcylation in Human Saphenous Vein Smooth Muscle Cells?

Protein O-GlcNAcylation, a dynamic and reversible glucose-dependent post-translational modification of serine and threonine residues on target proteins, has been proposed to promote vascular smooth muscle cell proliferation and migration events implicated in vein graft failure (VGF). Therefore, targeting the enzymes (glutamine fructose-6P amidotransferase (GFAT), O-GlcNAc transferase (OGT), and O-GlcNAcase (OGA)) that regulate cellular O-GlcNAcylation could offer therapeutic options to reduce neointimal hyperplasia and venous stenosis responsible for VGF. However, it is unclear how type 2 diabetes mellitus (T2DM) and hyperglycaemia affect the expression of these enzymes in human saphenous vein smooth muscle cells (HSVSMCs), a key cell type involved in the vascular dysfunction responsible for saphenous VGF. Therefore, our aim was to assess whether T2DM and hyperglycaemia affect GFAT, OGT, and OGA expression levels in HSVSMCs in vitro. Expression levels of GFAT, OGT, and OGA were determined in low-passage HSVSMCs from T2DM and non-T2DM patients, and in HSVSMCs treated for 48 h with hyperglycaemic (10 mM and 25 mM) glucose concentrations, by quantitative immunoblotting. Expression levels of OGT, OGA, and GFAT were not significantly different in HSVSMC lysates from T2DM patients versus non-T2DM controls. In addition, treatment with high glucose concentrations (10 mM and 25 mM) had no significant effect on the protein levels of these enzymes in HSVSMC lysates. From our findings, T2DM and hyperglycaemia do not significantly impact the expression levels of the O-GlcNAcylation-regulating enzymes OGT, OGA, and GFAT in HSVSMCs. This study provides a foundation for future studies to assess the role of O-GlcNAcylation on VGF in T2DM