Electrophysiological Disturbances Research Articles

Senescent CD8+ T cells: a novel risk factor in atrial fibrillation.

Immune cell alterations may play a role in the development of atrial fibrillation (AF). Our objective was to comprehensively characterize immune cells in AF, and investigate the potential mechanisms. Single-cell RNA sequencing and multicolor flow cytometry revealed that T cells constituted the most significant subset alterations in AF, and senescent CD8+ T cells were AF-associated subset. Senescent CD8+ T cells increased in both peripheral veins (p < 0.0001) and the left atria (p < 0.05) in patients with AF compared to non-AF control. Senescent CD8+ T cells were independently associated with AF prevalence (odds ratio = 2.876, p < 0.05) and postprocedural recurrence (hazard ratio = 22.955, p < 0.0001) using a cross-sectional study and a subsequent prospective cohort study. Senescent CD8+ T cells secreted an increased amount of interferon (IFN)-γ, which induces Ca2+ handling abnormalities in human induced pluripotent stem cell-derived atrial cardiomyocytes, and translated into an increased susceptibility to AF assessed by heart optical mapping. An increased amount of senescent CD8+ T cells may be a hallmark of the immune senescence phenotype in AF and potentially serve as a valid biomarker for assessing prevalence and postprocedural recurrence of AF. By connecting immune senescence with electrophysiological disturbances in AF, this research provides a potential mechanism for the involvement of senescent CD8+ T cells in proarrhythmic calcium disorders and suggests novel avenues for developing new immune-modulatory and senolytic therapies for AF.

Surgical Closure of Ventricular Septal Defect: Contemporary Results and Risk Factors for Electrophysiological Changes

Abstract Background The surgical closure of a ventricular septal defect is a commonly performed procedure. Postoperative ECG changes are common findings that needs a proper assessment to provide valuable insights into the outcomes of the patients. In this study, we investigate the potential risk factors associated with electrophysiological changes following surgical closure of ventricular septal defects. Methodology A Prospective, non-randomized study was conducted from October 2020 to December 2022 on patients scheduled for VSD closure. Patients with prior abnormal Congenital electrophysiological disturbances, Internal pacemaker, Ebstein's anomaly, associated sub-aortic membrane or Hypertrophic obstructive cardiomyopathy, Iatrogenic VSD, need Aortic root dilatation with VSD closure were excluded. 12-lead ECG was reported on ICU admission and daily thereafter till discharge. Various demographic and peri-operative data were recorded and its correlation to the presence of electrophysiological changes and final outcomes were analyzed. Results 200 patients who underwent surgical VSD closure were included. Arrhythmias occurred in 41 patients (20,5%). The encountered arrhythmias were sinus bradycardia with junctional escape in 24 patients, junctional ectopic tachycardia in 10 patients, supraventricular tachycardia in 2 patients, premature complex in 2 patients, 2nd degree heart block in 4 patients and 3rd degree block in 2 patients. Mother's hypertension, preoperative mechanical ventilation, Associated cardiac anomalies, Down syndrome, size of VSD, type of VSD, Total bypass time, Aortic cross clamp time, Concomitant procedures, Intra operative pacing, and residual VSD, were identified in a univariate analysis as Risk factors for occurrence of arrhythmias. The multivariate logistic regression analysis shows that the most significant risk factors for the occurrence of ECG changes were outlet VSD type, mitral valve repair as a concomitant procedure and aortic cross clamp time &amp;gt;45 minutes. Conclusion Surgical VSD closure is a safe procedure with low mortality and morbidity rates. Younger age and lower body weight are risk factors for prolonged hospitalization, intensive care unit stay and mechanical ventilation. Longer crossclamp and CPB times were significant predictors of post Op ECG changes and associated complications with prolonged ICU and hospital stay.

Reduced connexin-43 expression, slow conduction and repolarisation dispersion in a model of hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is an inherited heart muscle disease that is characterised by left ventricular wall thickening, cardiomyocyte disarray and fibrosis, and is associated with arrhythmias, heart failure and sudden death. However, it is unclear to what extent the electrophysiological disturbances that lead to sudden death occur secondary to structural changes in the myocardium or as a result of HCM cardiomyocyte electrophysiology. In this study, we used an induced pluripotent stem cell model of the R403Q variant in myosin heavy chain 7 (MYH7) to study the electrophysiology of HCM cardiomyocytes in electrically coupled syncytia, revealing significant conduction slowing and increased spatial dispersion of repolarisation - both well-established substrates for arrhythmia. Analysis of rhythmonome protein expression in MYH7 R403Q cardiomyocytes showed reduced expression of connexin-43 (also known as GJA1), sodium channels and inward rectifier potassium channels - a three-way hit that reduces electrotonic coupling and slows cardiac conduction. Our data represent a previously unreported, biophysical basis for arrhythmia in HCM that is intrinsic to cardiomyocyte electrophysiology. Later in the progression of the disease, these proarrhythmic phenotypes may be accentuated by myocyte disarray and fibrosis to contribute to sudden death.

Data-driven retrieval of population-level EEG features and their role in neurodegenerative diseases.

Electrophysiologic disturbances due to neurodegenerative disorders such as Alzheimer's disease and Lewy Body disease are detectable by scalp EEG and can serve as a functional measure of disease severity. Traditional quantitative methods of EEG analysis often require an a-priori selection of clinically meaningful EEG features and are susceptible to bias, limiting the clinical utility of routine EEGs in the diagnosis and management of neurodegenerative disorders. We present a data-driven tensor decomposition approach to extract the top 6 spectral and spatial features representing commonly known sources of EEG activity during eyes-closed wakefulness. As part of their neurologic evaluation at Mayo Clinic, 11 001 patients underwent 12 176 routine, standard 10-20 scalp EEG studies. From these raw EEGs, we developed an algorithm based on posterior alpha activity and eye movement to automatically select awake-eyes-closed epochs and estimated average spectral power density (SPD) between 1 and 45 Hz for each channel. We then created a three-dimensional (3D) tensor (record × channel × frequency) and applied a canonical polyadic decomposition to extract the top six factors. We further identified an independent cohort of patients meeting consensus criteria for mild cognitive impairment (30) or dementia (39) due to Alzheimer's disease and dementia with Lewy Bodies (31) and similarly aged cognitively normal controls (36). We evaluated the ability of the six factors in differentiating these subgroups using a Naïve Bayes classification approach and assessed for linear associations between factor loadings and Kokmen short test of mental status scores, fluorodeoxyglucose (FDG) PET uptake ratios and CSF Alzheimer's Disease biomarker measures. Factors represented biologically meaningful brain activities including posterior alpha rhythm, anterior delta/theta rhythms and centroparietal beta, which correlated with patient age and EEG dysrhythmia grade. These factors were also able to distinguish patients from controls with a moderate to high degree of accuracy (Area Under the Curve (AUC) 0.59-0.91) and Alzheimer's disease dementia from dementia with Lewy Bodies (AUC 0.61). Furthermore, relevant EEG features correlated with cognitive test performance, PET metabolism and CSF AB42 measures in the Alzheimer's subgroup. This study demonstrates that data-driven approaches can extract biologically meaningful features from population-level clinical EEGs without artefact rejection or a-priori selection of channels or frequency bands. With continued development, such data-driven methods may improve the clinical utility of EEG in memory care by assisting in early identification of mild cognitive impairment and differentiating between different neurodegenerative causes of cognitive impairment.

Inhibition of mTOR prevents glucotoxicity-mediated increase of SA-beta-gal, p16INK4a, and insulin hypersecretion, without restoring electrical features of mouse pancreatic islets

An over-activation of the mechanistic target of rapamycin (mTOR) pathway promotes senescence and age-related diseases like type 2 diabetes. Besides, the regenerative potential of pancreatic islets deteriorates with aging. Nevertheless, the role of mTOR on senescence promoted by metabolic stress in islet cells as well as its relevance for electrophysiological aspects is not yet known. Here, we investigated whether parameters suggested to be indicative for senescence are induced in vitro in mouse islet cells by glucotoxicity and if mTOR inhibition plays a protective role against this. Islet cells exhibit a significant increase (~ 76%) in senescence-associated beta-galactosidase (SA-beta-gal) activity after exposure to glucotoxicity for 72 h. Glucotoxicity does not markedly influence p16INK4a protein within 72 h, but p16INK4a levels increase significantly after a 7-days incubation period. mTOR inhibition with a low rapamycin concentration (1 nM) entirely prevents the glucotoxicity-mediated increase of SA-beta-gal and p16INK4a. At the functional level, reactive oxygen species, calcium homeostasis, and electrical activity are disturbed by glucotoxicity, and rapamycin fails to prevent this. In contrast, rapamycin significantly attenuates the insulin hypersecretion promoted by glucotoxicity by modifying the mRNA levels of Vamp2 and Snap25 genes, related to insulin exocytosis. Our data indicate an influence of glucotoxicity on pancreatic islet-cell senescence and a reduction of the senescence markers by mTOR inhibition, which is relevant to preserve the regenerative potential of the islets. Decreasing the influence of mTOR on islet cells exposed to glucotoxicity attenuates insulin hypersecretion, but is not sufficient to prevent electrophysiological disturbances, indicating the involvement of mTOR-independent mechanisms.

Chronic Ouabain Targets Pore-Forming Claudin-2 and Ameliorates Radiation-Induced Damage to the Rat Intestinal Tissue Barrier.

Ionizing radiation (IR) causes disturbances in the functions of the gastrointestinal tract. Given the therapeutic potential of ouabain, a specific ligand of the Na,K-ATPase, we tested its ability to protect against IR-induced disturbances in the barrier and transport properties of the jejunum and colon of rats. Male Wistar rats were subjected to 6-day intraperitoneal injections of vehicle or ouabain (1 µg/kg/day). On the fourth day of injections, rats were exposed to total-body X-ray irradiation (10 Gy) or a sham irradiation. Isolated tissues were examined 72 h post-irradiation. Electrophysiological characteristics and paracellular permeability for sodium fluorescein were measured in an Ussing chamber. Histological analysis and Western blotting were also performed. In the jejunum tissue, ouabain exposure did not prevent disturbances in transepithelial resistance, paracellular permeability, histological characteristics, as well as changes in the expression of claudin-1, -3, -4, tricellulin, and caspase-3 induced by IR. However, ouabain prevented overexpression of occludin and the pore-forming claudin-2. In the colon tissue, ouabain prevented electrophysiological disturbances and claudin-2 overexpression. These observations may reveal a mechanism by which circulating ouabain maintains tight junction integrity under IR-induced intestinal dysfunction.

FRI202 A Curious Case Of Psychosis

Abstract Disclosure: F. Waqar: None. A. Arif: None. A. Muazzam: None. R. Wadood: None. A.S. Khakwani: None. U.A. Khan: None. Ascertaining the cause of mental and behavioral changes can be challenging in patients with complex medical histories. We are sharing a thought-provoking case of psychosis. A 51-year-old woman with past medical history of ESRD, stroke, diabetes, depression, and endometrial cancer was brought to the hospital for lethargy and confusion. It was preceded by some nausea, vomiting, and abdominal pain. Upon admission, she was noted to be hypotensive and minimally responsive. She was given fluids (with subsequent improvement in blood pressure) and started on antibiotics empirically for concerns of sepsis. During her hospital course, her mental status fluctuated from being completely normal to having episodes of becoming still, with total lack of response to any stimulus. During these episodes, she would be awake, breathing spontaneously and vitally stable, but unresponsive, mimicking catatonia however lacked muscle stiffness/ rigidity. Each episode resolved spontaneously after a few hours. Multiple CT scans and a CT Angiogram of the Head &amp; Neck were negative for acute findings. Continuous EEG revealed no epileptic activity. Infectious work-up was unrevealing. Labs were within the expected range of the intra-dialytic period. Two of her medications, gabapentin and mirtazapine were thought to be the contributors and were stopped upon admission, however with little improvement. Her symptoms were ultimately deemed to be psychogenic in origin, and she was started on an anti-psychotic regimen. Fortunately, as part of her workup, a morning cortisol level was checked, which resulted to be quite low at 1.6 mcg/dL, consistent with adrenal insufficiency. Co-syntropin stimulation test confirmed adrenal insufficiency, the actual cause of her presentation. This explained her intermittent hypotension along with mental and behavioral changes. Interestingly, she was found to be on megestrol acetate which is notorious for causing secondary adrenal insufficiency. She was ultimately started on hydrocortisone replacement therapy, with subsequent improvement and stabilization of her mental status, mood, and behavior; and was discharged with outpatient Endocrinology follow-up. This case highlights the importance of the broad differentials to consider for mental and behavioral changes. We want to alert physicians to include adrenal insufficiency in the differentials of acute psychosis as symptoms and electrolyte abnormalities may be atypical and masked in dialysis patients. The exact mechanism of neuropsychiatric symptoms (which may precede metabolic abnormalities) is unknown but is hypothesized to involve elevated levels of endorphins and electrophysiological disturbances as glucocorticoid receptors are widely distributed in the brain, specifically in the hippocampus. Megestrol is an established cause of secondary adrenal insufficiency, and monitoring is essential with long-term use. Presentation: Friday, June 16, 2023

Exposure to real ambient particulate matter inflicts cardiac electrophysiological disturbances, vascular calcification, and mitochondrial bioenergetics decline more than diesel particulate matter: consequential impact on myocardial ischemia-reperfusion injury.

Particulate matter (PM) present in the air sample comprises different sizes and is derived from multiple sources, in particular from diesel engines. In the present study, we assessed the cardiotoxic effect of PM2.5 from real ambient air sample and diesel vehicular exhaust from a specific location and compared it with SRM-2975. Female Wistar rats were exposed to PM2.5 from real ambient PM (RA_PM), diesel particulate matter (DPM), and SRM-2975 for 3h daily for 21 days followed by cardiotoxicity assessment. Twenty-one days of daily PM2.5 exposure induced hypertrophy, vascular calcification, and alterations in cardiac electrophysiology, where the changes were more prominent in the animals exposed to RA_PM. The gross pathological changes were supported by altered mitochondrial function and increased oxidative stress in the myocardium. To evaluate the cardiac responsive ability, isolated rat hearts were subjected to ischemia-reperfusion injury (IR), and the results showed significantly low recovery in the RA_PM-exposed rat hearts. Chemical analysis of PM2.5 by ICPMS from different sources indicated the presence of additional metals like Cr, Ni, Ga, As, Rb, Cd, Ba, La, and Ce in the RA_PM sample. Additionally, the chelation of metals in the RA_PM enhanced the cell viability of H9c2 cells when compared to the non-chelated sample. Based on the above observations, we conclude that PM2.5 from the ambient air sample exhibited higher cardiovascular toxicity than DPM, emphasizing the contribution of non-diesel components of PM2.5 and the need for a comprehensive approach to tackle the PM2.5 in the air sample.

Pre-Procedure Intervention of Subclinical Hypothyroidism: Case Report

Background: Subclinical hypothyroidism (SH) is a very common disorder in the general population. In patients with known hypothyroidism or hypothyroidism who have been undergoing treatment, a TSH test should be included in the preoperative assessment to determine the adequacy of treatment and to ensure that thyroid therapy is optimized before surgery. Case Presentation: A 39 years old woman complains about a weakness that has been 4 years interfering with activities. Shortness of breath if doing strenuous activities, walking long distances, and climbing stairs, and shortness of breath decreases after rest. Sore throat found since 1 week of hospitalization, and fever for 1 day. A lump in the neck is not found. Previously, the patient had been treated for 8 days in the Department of Cardiology and planned the installation of a temporary pacemaker due to bradycardia that persisted until cardiac arrest. Conclusion: Subclinical hypothyroid patients undergoing pre-procedure intervention are predisposed to anemia, electrophysiologic disturbances, and hypotension, all of which can precipitate cardiovascular collapse. The goal of therapy in the perioperative patient with thyroid dysfunction centers around the attempt to normalize hormone levels before surgical intervention whenever possible and, when that is not feasible, to use other measures that will maximize hemodynamic stability and prevent decompensation.

The effect of physical activity on electrophysiological processes in the ventricular myocardium in child-athletes

Maladaptation processes in the cardiovascular system in child athletes are associated with changes in electrophysiological processes in the myocardium. To identify risk groups for the development of the cardiovascular system pathology among this contingent, it is possible to use a non-invasive technique: ECG dispersion mapping.Purpose. To identify changes in electrophysiological processes in the myocardium of the left and right ventricles in child athletes in response to physical activity.Material and methods. 279 healthy children without chronic disease aged from 12 to 18 years were under observation. A group of 209 children involved in sports has been identified. The gender distribution is as follows: 153 boys (73%) and 56 girls (27%). The reference group included 70 children not involved in sports. All child athletes had access to the training and competition process. Within the study group, 4 subgroups were allocated in accordance with sports: A subgroup — children attending the football section (51 boys); B — basketball (37 boys and 22 girls); C — volleyball (29 boys and 27 girls); D — martial arts (36 boys and 7 girls). All children underwent dispersion mapping of the electrocardiogram using the Cardiovisor software and hardware complex before and after the exercise test. The processes of depolarization and repolarization in the myocardium of the left and right ventricles were analyzed on the basis of G3–G6 indices. Statistical processing of the results was carried out using MS Excel, Stata.Results. The analysis of electrophysiological processes in the myocardium of the left and right ventricles in child athletes showed statistically significant differences in comparison with the reference group. In all G3-G6 indicators in the main group, a moderate deviation was noted, while all values in the reference group were within normal limits in more than 92%. Moderate physical exertion led to the registration of both moderate and pronounced electrophysiological disturbances in the myocardium, especially in children engaged in highly dynamic sports, namely basketball.

Electrophysiological Effect of Citreoviridin on Human InducedPluripotent Stem Cell-derived Cardiomyocytes

Citreoviridin (CTV) is a mycotoxin produced by various fungi, including Penicillium citreonigrum. One of the toxicities reportedly associated with CTV is neurotoxicity. CTV is also suspected to be associated with acute cardiac beriberi (also known as "Shoshin-kakke") and Keshan disease, which can have adverse effects on the heart, so the in vivo and in vitro toxicity of CTV on the heart or cardiomyocytes in experimental animal models have been reported. However, the toxicity of CTV for the human heart, especially its electrophysiological effect, remains poorly understood. Therefore, to investigate the electrophysiological effect of CTV on the human cardiomyocytes, we conducted a multi-electrode array (MEA) using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). The MEA revealed that 30 μmol/L of CTV stopped the beating of hiPSC-CMs, and the field potential duration and first peak amplitude were shortened at 10 μmol/L. Before the hiPSC-CMs stopped beating, the length of the inter-spike interval varied two- to four-fold. These results demonstrated that CTV induced an electrophysiological disturbance on human cardiomyocytes. This is first paper to elucidate the electrophysiological effect of CTV on human heart directly and may aid in analyzing the risk associated with CTV to ensure food safety.

1132 CATHETER INTERVENTION TO TREAT MIGRATED TEMPORARY EPICARDIAL PACING WIRE INTO THE PULMONARY ARTERY

Abstract Catheter intervention to treat migrated temporary epicardial pacing wire into the pulmonary artery Introduction Temporary epicardial pacing wires (TEPW) are routinely inserted postoperatively for treating electrophysiological disturbances after open-heart surgeries. They are typically placed on the surface of the right ventricle and the right atrial appendage. They are usually removed before discharge, but in case of difficult removal, they are cut flush to the skin, and thus retained. Leaving TEPW can be associated to complications, especially with wires migration. As described in literature, TEPW migration is rare and typically involves the right side of the heart, even if any part of the body can be involved. A review proposed an algorithm for removal decision making, based on the risk of serious complications like infection, dissection and perforation. We present a case of a transcatheter removal of a TEPW migrated into the pulmonary artery, in an asymptomatic patient. Case presentation A 52 year-old man, with previous history of Hodgkin Lymphoma treated with radiotherapy and Chemotherapy; CAD (inferior AMI treated with CABG); constrictive pericarditis causing many on-hospital admissions for heart failure; valvular disease: together with the CABG intervention, in 2012, he underwent mitral valvular repair and aortic valvuloplasty; in 2018, because of mitral valve repair failure, he underwent mitral valve substitution with a mechanic valve together with tricuspid repair; in the same year, because of worsening aortic regurgitation, he underwent TAVI. During routine follow-up exams, three years later, in 2021, the patient underwent a total body CT scan that showed the presence of a hyperintensity signal in the region between the right atrium and the right ventricle, crossing the tricuspid valve, with a final loop in the right ventricle infundibulum, suspected to be a TEPW. A transthoracic echocardiogram confirmed the position of the extraneous body, that was causing no impingement to the leaflets of the tricuspid valve, without worsening tricuspid regurgitation. A fluoroscopy showed the presence of a metallic wire, divided into two segments, the former extended from the right atrium till the right subclavian vein passing through the superior cava vein; the latter extended from the right ventricle till the left pulmonary artery. The patient underwent a transcatheter intervention with a right femoral vein access, to try to remove the TEPWs. The former located in the right atrium had a extravascular location, so it was left inside. The other one was removed. After advancing a Swan-Ganz catheter into the pulmonary artery, it was exchanged with a multipourpose catheter and a Multi-Snare 20 mm retrieval system captured the wire and dragged till the inferior cava vein; a second retrieval system, a Snare STD 12-20 mm, was finally able to anchor firmly the wire and to carry it outside. No complications occurred after the procedure; an echocardiogram excluded intracardiac problems. The patient was discharge the day after the procedure, in good clinical conditions. Discussion In this case, a transcatheter removal of the TEPW was performed, even if the presence of the wires caused no symptoms and/or complications to the patient. Anyway, because of the presence of both a prosthetic valve and a mechanic valve, in a setting of constrictive pericarditis and the consequent possibility of several in-hospital admission in conditions of acute heart failure with worsening of tricuspid regurgitation, the persistence of the wire could represent a risk factor for infective endocarditis and for severe tricuspid regurgitation. Removing it with a fast and safe transcatheter femoral approach, a potential cause of other complications was avoided.

Contributions of SGK3 to transporter-related diseases.

Serum- and glucocorticoid-induced kinase 3 (SGK3), which is ubiquitously expressed in mammals, is regulated by estrogens and androgens. SGK3 is activated by insulin and growth factors through signaling pathways involving phosphatidylinositol-3-kinase (PI3K), 3-phosphoinositide-dependent kinase-1 (PDK-1), and mammalian target of rapamycin complex 2 (mTORC2). Activated SGK3 can activate ion channels (TRPV5/6, SOC, Kv1.3, Kv1.5, Kv7.1, BKCa, Kir2.1, Kir2.2, ENaC, Nav1.5, ClC-2, and ClC Ka), carriers and receptors (Npt2a, Npt2b, NHE3, GluR1, GluR6, SN1, EAAT1, EAAT2, EAAT4, EAAT5, SGLT1, SLC1A5, SLC6A19, SLC6A8, and NaDC1), and Na+/K+-ATPase, promoting the transportation of calcium, phosphorus, sodium, glucose, and neutral amino acids in the kidney and intestine, the absorption of potassium and neutral amino acids in the renal tubules, the transportation of glutamate and glutamine in the nervous system, and the transportation of creatine. SGK3-sensitive transporters contribute to a variety of physiological and pathophysiological processes, such as maintaining calcium and phosphorus homeostasis, hydro-salinity balance and acid-base balance, cell proliferation, muscle action potential, cardiac and neural electrophysiological disturbances, bone density, intestinal nutrition absorption, immune function, and multiple substance metabolism. These processes are related to kidney stones, hypophosphorous rickets, multiple syndromes, arrhythmia, hypertension, heart failure, epilepsy, Alzheimer's disease, amyotrophic lateral sclerosis, glaucoma, ataxia idiopathic deafness, and other diseases.

Electrophysiological complexity in the rat dorsomedial hypothalamus and its susceptibility to daily rhythms and high-fat diet.

The dorsomedial hypothalamus (DMH) in amongst the most important brain structures involved in the regulation of feeding behaviour and metabolism. In contrast to other hypothalamic centres, its main role is related to the circadian rhythmicity of food intake and energy homeostasis; both reported to be disrupted in obesity. In modern world, overweight and obesity reached global epidemic proportions. Thus, not only is it important to study their negative implications but also the mechanism responsible for their development. Here, we exposed rats to short-term (2-4weeks) high-fat diet (HFD)-not long enough to induce obesity. Next, we performed electrophysiological patch-clamp recordings ex vivo from neurons in the DMH either during the day or at night. Our results showed a day-to-night change in the firing frequency of DMH cells, with higher activity during the dark phase. This was abolished by HFD consumption, resulting in a decreased threshold for action potential generation during the day and therefore increased electrical activity at this phase. We propose this electrophysiological disturbance as a mechanism for the induction of abnormal daytime feeding, previously observed for HFD-fed animals, which might in turn contribute to the development of obesity. In addition, we provide an electrophysiological characteristic of DMH neurons with a separation into three anatomically and functionally distinct subpopulations, namely, the compact part, separating the structure into the ventral and dorsal divisions. Our study is the first to show electrophysiological complexity of the DMH with its sensitivity to diet and daily rhythms.

Sudden Cardiac Death in Diabetes and Obesity: Mechanisms and Therapeutic Strategies

Ventricular arrhythmias and sudden cardiac death (SCD) occur most frequently in the setting of coronary artery disease, cardiomyopathy and heart failure but are also increasingly observed in persons suffering from diabetes mellitus and obesity. The incidence of these metabolic disorders is rising in Western countries, but adequate prevention and treatment of arrhythmias and SCD in affected patients is limited because of our incomplete knowledge of the underlying disease mechanisms. Here, an overview is presented of the prevalence of electrophysiological disturbances, ventricular arrhythmias, and SCD in the clinical setting of diabetes and obesity. Experimental studies are reviewed, which have identified disease pathways and associated modulatory factors, in addition to pro-arrhythmic mechanisms. Key processes are discussed, including mitochondrial dysfunction, oxidative stress, cardiac structural derangements, abnormal cardiac conduction, ion channel dysfunction, prolonged repolarization, and dysregulation of intracellular sodium and calcium homeostasis. In addition, the recently identified pro-arrhythmic effects of dysregulated branched chain amino acid metabolism, a common feature in patients with metabolic disorders, are addressed. Finally, current management options are discussed in addition to the potential development of novel preventive and therapeutic strategies based on recent insight gained from translational studies.

Prevention and management of hyperkalemia in patients treated with renin-angiotensin-aldosterone system inhibitors.

KEY POINTS Hyperkalemia, defined as a serum potassium level of 5.0 mmol/L or greater, can lead to severe electrophysiological disturbances, including cardiac arrythmias, that increase morbidity and risk of death.[1][1] It is common in patients with conditions that impair potassium excretion by the

Impact of percutaneous pulmonary valve replacement on repaired tetralogy of Fallot ventricular remodelling

Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart disease resulting in long-term right ventricular (RV) failure, ventricular arrhythmias and sudden cardiac death. Our team validated a swine chronic model of repaired TOF (r-TOF) and characterized several levels of ventricular detrimental remodelling. We aimed to evaluate the potential reversibility of this structural remodelling following percutaneous pulmonary valve implantation (PPVI). Significant pulmonary regurgitation, mild stenosis and RV outflow tract scars were created in 21 piglets. Subsequently, 12 animals underwent PPVI at different time intervals using the Melody® valve. Ventricular remodelling was evaluated by TTE, MRI, ventricular optical mapping, histological and biomolecular study. Initial results showed a significant RV hypertrophy on MRI with a prolongation of RV activation time beyond the surgical scar and the LV in rTOF models compared to sham-models. Four animals died during PPVI procedure. Among survival animals, the valvular function was excellent, and a significant decrease in RV volume was observed on MRI evaluation. Regarding the first ex vivo results, a significant RV hypertrophy together with a prolongation of RV activation time (APD80) beyond the surgical scar and the LV was found in r-TOF control animals while a limitation of the prolongation of APD80 beyond RVOT and LV has been observed in PPVI pigs. Subsequent experiments (including electrophysiological and biomolecular study) are currently undertaken. The creation of a swine survival r-TOF model mimicking the essential features of postoperative TOF, and its subsequent pulmonary valve replacement, is feasible. PPVI so far appears to have a beneficial effect on RV hypertrophy and ventricular electrophysiological disturbances, suggesting potential reversibility on ventricular remodelling after this targeted therapy.

Electrophysiological and Pathological Impact of Medium-Dose External Carbon Ion and Proton Beam Radiation on the Left Ventricle in an Animal Model.

BackgroundMedium‐dose (25 gray) x‐ray radiation therapy has recently been performed on patients with refractory ventricular tachyarrhythmias. Unlike x‐ray, carbon ion and proton beam radiation can deliver most of their energy to the target tissues. This study investigated the electrophysiological and pathological changes caused by medium‐dose carbon ion and proton beam radiation in the left ventricle (LV).Methods and ResultsExternal beam radiation in the whole LV was performed in 32 rabbits. A total of 9 rabbits were not irradiated (control). At the 3‐month or 6‐month follow‐up, the animals underwent an open‐chest electrophysiological study and were euthanized for histological analyses. No acute death occurred. Significant LV dysfunction was not seen. The surface ECG revealed a significant reduction in the P and QRS wave voltages in the radiation groups. The electrophysiological study showed that the local conduction times in each LV site were significantly longer and that the local LV bipolar voltages were significantly lower in the radiation groups than in the control rabbits. Histologically, apoptosis, fibrotic changes, and a decrease in the expression of the connexin 43 protein were seen in the LV myocardium. These changes were obvious at 3 months, and the effects were sustained 6 months after radiation. No histological changes were seen in the coronary artery and esophagus, but partial radiation pneumonitis was observed.ConclusionsMedium‐dose carbon ion and proton beam radiation in the whole LV resulted in a significant electrophysiological disturbance and pathological changes in the myocardium. Radiation of the arrhythmogenic substrate would modify the electrical status and potentially induce the antiarrhythmic effect.

Patch-Clamp Recording of Low Frequency Stimulation-induced Long-Term Synaptic Depression in Rat Hippocampus Slices During Early and Late Neurodevelopment.

Studying synaptic plasticity in the rat hippocampus slice is a well-established way to analyze cellular mechanisms related to learning and memory. Different modes of recording can be used, such as extracellular field excitatory post-synaptic potential (EPSP) and diverse patch-clamp methods. However, most studies using these methods have examined only up to the juvenile stage of brain maturation, which is known to terminate during late adolescence/early adulthood. Moreover, several animal models of human diseases have been developed at this late stage of brain development. To study the vulnerability of adolescent rat to the cognitive impairment of alcohol, we developed a model of binge-like exposure in which ethanol selectively abolishes low frequency stimulation (LFS)-induced, field EPSP long-term depression (LTD) in the rat hippocampus slice. In the present study, we sought to use whole-cell patch-clamp recording in the voltage-clamp mode to further investigate the mechanisms involved in the abolition of LFS-induced LTD in our model of binge-like exposure in adolescent rat hippocampus slices. In addition, we investigated LFS-induced NMDAR-LTD and mGluR-LTD at different ages and changed several parameters to improve the recordings. Using patch-clamp recording, LFS-induced NMDAR-LTD and mGluR-LTD could be measured until 4weeks of age, but not in older animals. Similarly, chemical mGluR-LTD and a combined LFS-LTD involving both N-Methyl-D-Aspartate Receptor (NMDAR) and mGluR were not measured in older animals. The absence of LFS-LTD was not due to the loss of a diffusible intracellular agent nor the voltage mode of recording or intracellular blockade of either sodium or potassium currents. In contrast to voltage-clamp recordings, LFS-induced LTD tested with field recordings was measured at all ages and the effects of EtOH were visible in all cases. We concluded that whole-cell patch-clamp recordings are not suitable for studying synaptic LFS-induced LTD in rats older than 4weeks of age and therefore cannot be used to explore electrophysiological disturbances, such as those induced by alcohol binge drinking during adolescence, which constitutes a late period of brain maturation.

Opium-associated QT Interval Prolongation: A Cross-sectional Comparative Study.

BackgroundToxicity and side effects of long-term use of opioids are well studied, but little information exists regarding electrophysiological disturbances of opium consumption. While natural opium has been regarded safe to a great extent among traditional communities, concerns are emerging owing to the available evidence of QT prolongation that have been exposed during recent outcome surveillance of patients under opioid use. Potential QT prolonging interactions would raise a higher level of such concern in opium users during COVID pandemic and warrant attention.Materials and methodsThis study was designed to detect the prevalence of QTc prolongation among opium users and nonusers. Two groups were compared with regard to gender, age, and median QTc interval. Normal and prolonged QTc intervals of user group were compared with respect to age, sex, dose of opium consumption, and duration of opium consumption.Results123 opium users and 39 controls were investigated. Median QTc interval in opium user and non-user group was 460 vs 386 milliseconds, respectively (p value < 0.001). In all, 59.3%, (95% CI: 50.51–67.62%) of cases and none of non-user had prolonged QTc interval (p value < 0.001). There was no significance between normal and prolonged QTc intervals with respect to dose and duration of opium use.ConclusionThis study indicated that opium consumption is associated with QTc prolongation. This prolongation does not relate to dose and duration of opium use. Further study is propounded to assess the clinical significance of these results and to determine risk rating of opium compared to other opioids in this regard.How to cite this articleJavadi HR, Mirakbari SM, Allami A, Yazdi Z, Katebi K. Opium-associated QT Interval Prolongation: A Cross-sectional Comparative Study. Indian J Crit Care Med 2021;25(1):43–47.