Perspective: a dynamics-based classification of ventricular arrhythmias

Despite key advances in the clinical management of life-threatening ventricular arrhythmias, culminating with the development of implantable cardioverter-defibrillators and catheter ablation techniques, pharmacologic/biologic therapeutics have lagged behind. The fundamental issue is that biological targets are molecular factors. Diseases, however, represent emergent properties at the scale of the organism that result from dynamic interactions between multiple constantly changing molecular factors. For a pharmacologic/biologic therapy to be effective, it must target the dynamic processes that underlie the disease. Here we propose a classification of ventricular arrhythmias that is based on our current understanding of the dynamics occurring at the subcellular, cellular, tissue and organism scales, which cause arrhythmias by simultaneously generating arrhythmia triggers and exacerbating tissue vulnerability. The goal is to create a framework that systematically links these key dynamic factors together with fixed factors (structural and electrophysiological heterogeneity) synergistically promoting electrical dispersion and increased arrhythmia risk to molecular factors that can serve as biological targets. We classify ventricular arrhythmias into three primary dynamic categories related generally to unstable Ca cycling, reduced repolarization, and excess repolarization, respectively. The clinical syndromes, arrhythmia mechanisms, dynamic factors and what is known about their molecular counterparts are discussed. Based on this framework, we propose a computational-experimental strategy for exploring the links between molecular factors, fixed factors and dynamic factors that underlie life-threatening ventricular arrhythmias. The ultimate objective is to facilitate drug development by creating an in silico platform to evaluate and predict comprehensively how molecular interventions affect not only a single targeted arrhythmia, but all primary arrhythmia dynamics categories as well as normal cardiac excitation-contraction coupling

The role of e-liquid constituents in e-cigarette-induced cardiac arrhythmia and autonomic imbalance.

Introduction. Accumulating evidence indicates that exposure to electronic cigarettes (e-cigs) promotes sympathetic dominance and electrophysiologic instability in the heart, potentially culminating in arrhythmogenesis. E-liquids contain various formulations of nicotine and flavorings, but the effects of specific e-liquid constituents and their concentrations on e-cig-induced autonomic imbalance and electrical dysfunction are unresolved. To that end, we tested the hypothesis that e-cigs modify cardiac autonomic balance and ventricular arrhythmogenesis in mice dependent on e-liquid constituent type and concentration. Methods. Using a crossover design and a serial exposure regimen, ECG-telemetered male C57BL/6J mice underwent whole-body exposure to e-cig aerosols generated from e-liquids containing different cooling agents or nicotine formulations. On a given exposure day, mice were exposed to either increasing coolant concentrations (0.25%, 1%, and 2.5%) or increasing nicotine concentrations (1%, 2.5%, and 5%) for three 18 min exposure cycles (9 min puffing phase followed by 9 min washout phase) per concentration with time-matched periods for filtered air (FA) and vehicle controls. Spontaneous ventricular premature beat (VPB) incidence rates, heart rate, and heart rate variability (HRV) were quantified and compared between exposures. Atenolol was used to test the role of β1-adrenergic activation in e-cig induced changes in autonomic balance. Results. Exposure to 1% menthol and racemic nicotine at 2.5% and 5% reduced heart rate and increased HRV, suggesting parasympathetic dominance. Conversely, exposure to 5% nicotine salt and WS-3 and WS-23 at 2.5% elevated heart rate and decreased HRV, indicating sympathetic dominance, and also increased VPBs. Pretreatment with atenolol abolished the heart rate elevations and HRV declines during exposure to nicotine salt, signifying β1-adrenergic mediation of e-cig-induced sympathetic dominance. Conclusions. Exposure to e-cig aerosols containing commercially relevant levels of synthetic cooling agents and nicotine salts may enhance the cardiac risks of vaping by promoting sympathetic dominance and ventricular arrhythmias. Importantly, β1-adrenergic activation mediates nicotine salt-evoked increases in sympathetic influence. These findings may aid the design of human studies or inform tobacco regulatory initiatives that reduce the public health risks of vaping

Multi-scale approaches for the simulation of cardiac electrophysiology: II - tissue-level structure and function

Computational models of the heart, from cell-level models, through one-, two- and three-dimensional tissue-level simplifications, to biophysically-detailed three-dimensional models of the ventricles, atria or whole heart, allow the simulation of excitation and propagation of this excitation, and have provided remarkable insight into the normal and pathological functioning of the heart. In this article we present equations for modelling cellular excitation (i.e. the cell action potential) from both a phenomenological and a biophysical perspective. Hodgkin-Huxley formalism is discussed, along with the current generation of biophysically-detailed cardiac cell models. Alternative Markovian formulations for modelling ionic currents are also presented. Equations describing propagation of this cellular excitation, through one-, two- and three-dimensional idealised or realistic tissues, are then presented. For all types of model, from cell to tissue, methods for discretisation and integration of the underlying equations are discussed. The article finishes with a discussion of two tissue-level experimental imaging techniques – diffusion tensor magnetic resonance imaging and optical imaging – that can be used to provide data for parameterisation and validation of cell- and tissue-level cardiac models

Vaping During Pregnancy: Effects on Vascular and Behavioral Outcomes in Offspring

Electronic cigarette (e-cig) use is increasing due to aggressive marketing, tempting flavors, and seemingly higher acceptability in the community (lesser perceived social stigma) despite unproven claims of safety. In an alarming trend, pregnant women smokers have turned to novel “modified risk” products, such as e-cigs, in response to heavy marketing of e-cigs as safer alternatives to cigarettes and a tool to help quit smoking. This is despite proven detrimental effects of nicotine on a growing fetus, and scarcity of information regarding toxicity of e-liquid (with and without nicotine) on child development. Moreover, rampant e-cig use among youth (nearly 4 million in 2018, CDC) reflects a growing population of experienced and addicted female users who may become pregnant. This project addresses this emerging public health issue by providing information regarding consequences of maternal e-cig use and its long-term effects on child health outcomes. It is established that both mother and fetus are vulnerable to environmental exposures during pregnancy. Prenatal exposure to nicotine leads to preterm births and is linked to adverse health, behavioral and cognitive outcomes in newborns. E-cigs have been shown to deliver physiologically significant amounts of nicotine to its users. Currently, little is known about the effects of e-cig use on perinatal and developmental outcomes and whether adverse effects can be attributed to nicotine delivery alone. Given the paucity of data, this overall goal project seeks to elucidate the impact of maternal e-cig use during pregnancy using an animal model to test cardiovascular and behavioral outcomes. The first objective of this work was to determine dose-dependent effects of maternal e-cig exposure on functional vascular outcomes in conduit and resistance vessel beds and to investigate potential pathways that lead to this impairment. The second objective is to evaluate the effect of on cognitive development and behavioral deficits in the pups and compare between levels of exposure. The hypothesis is that 1) maternal e-cig exposure will lead to increased arterial stiffness and reduced vascular reactivity in aorta and middle cerebral artery, and this impairment will be at least partially mediated by the nitric oxide pathway; and 2) pups exposed to e-cig aerosol in utero will demonstrate hyperactivity, exploratory behavior, and impaired spatial and aversive learning as well as impaired memory. The specific aims are to (1) determine dose-dependent effect of maternal e-cig vapor exposure (with and without nicotine) on arterial stiffness and vascular reactivity in offspring and (2) evaluate cognitive development and behavioral changes in pups exposed to e-cig vapor in utero using a battery of tests to tap different functional domains of learning and memory

Pharmacol Ther

Electronic cigarettes (e-cigarettes) were introduced in the United States in 2007 and by 2014 they were the most popular tobacco product amongst youth and had overtaken use of regular tobacco cigarettes. E-cigarettes are used to aerosolize a liquid (e-liquid) that the user inhales. Flavorings in e-liquids is a primary reason for youth to initiate use of e-cigarettes. Evidence is growing in the scientific literature that inhalation of some flavorings is not without risk of harm. In this review, 67 original articles (primarily cellular in vitro) on the toxicity of flavored e-liquids were identified in the PubMed and Scopus databases and evaluated critically. At least 65 individual flavoring ingredients in e-liquids or aerosols from e-cigarettes induced toxicity in the respiratory tract, cardiovascular and circulatory systems, skeletal system, and skin. Cinnamaldehyde was most frequently reported to be cytotoxic, followed by vanillin, menthol, ethyl maltol, ethyl vanillin, benzaldehyde and linalool. Additionally, modern e-cigarettes can be modified to aerosolize cannabis as dried plant material or a concentrated extract. The U.S. experienced an outbreak of lung injuries, termed e-cigarette, or vaping, product use-associated lung injury (EVALI) that began in 2019; among 2,022 hospitalized patients who had data on substance use (as of January 14, 2020), 82% reported using a delta-9-tetrahydrocannabinol (main psychoactive component in cannabis) containing e-cigarette, or vaping, product. Our literature search identified 33 articles related to EVALI. Vitamin E acetate, a diluent and thickening agent in cannabis-based products, was strongly linked to the EVALI outbreak in epidemiologic and laboratory studies; however, e-liquid chemistry is highly complex, and more than one mechanism of lung injury, ingredient, or thermal breakdown product may be responsible for toxicity. More research is needed, particularly with regard to e-cigarettes (generation, power settings, etc.), e-liquids (composition, bulk or vaped form), modeled systems (cell type, culture type, and dosimetry metrics), biological monitoring, secondhand exposures and contact with residues that contain nicotine and flavorings, and causative agents and mechanisms of EVALI toxicity.CC999999/ImCDC/Intramural CDC HHSUnited States/2022-01-01T00:00:00Z33746051PMC82516829933vault:3724

Central and Peripheral Chemoreflex Function in the Supine and Upright Postures in Women throughout the Menstrual Cycle with a Comparison to Men

The primary purpose of the study was to examine sex differences and menstrual cycle time-points on chemoreflex function during supine and 70o upright (HUT) positions during: 1) normoxia, 2) hypercapnia (5% CO2), or 3) hyperoxia (100% O2). Women were tested during the early-follicular phase (EF; days 2-5) and the mid-luteal phase (ML; days 18-24). Compared to baseline, men and women had lower cardiac output index (Qi), mean arterial pressure (MAP), cerebrovascular resistance index, and respiratory rate during HUT. In response to hypercapnia during HUT (compared to supine), men had an augmented increase in MAP, while all groups had an augmented increase in ventilation suggesting sexually dimorphic interactions between the baroreflex and central chemoreflex. In response to hyperoxia during HUT, men and women displayed an attenuated increase of total peripheral resistance index and an attenuated decrease of Qi suggesting upright posture activated peripheral chemoreceptors

Multiscale Cohort Modeling of Atrial Electrophysiology : Risk Stratification for Atrial Fibrillation through Machine Learning on Electrocardiograms

Patienten mit Vorhofflimmern sind einem fünffach erhöhten Risiko für einen ischämischen Schlaganfall ausgesetzt. Eine frühzeitige Erkennung und Diagnose der Arrhythmie würde ein rechtzeitiges Eingreifen ermöglichen, um möglicherweise auftretende Begleiterkrankungen zu verhindern. Eine Vergrößerung des linken Vorhofs sowie fibrotisches Vorhofgewebe sind Risikomarker für Vorhofflimmern, da sie die notwendigen Voraussetzungen für die Aufrechterhaltung der chaotischen elektrischen Depolarisation im Vorhof erfüllen. Mithilfe von Techniken des maschinellen Lernens könnten Fibrose und eine Vergrößerung des linken Vorhofs basierend auf P Wellen des 12-Kanal Elektrokardiogramms im Sinusrhythmus automatisiert identifiziert werden. Dies könnte die Basis für eine nicht-invasive Risikostrat- ifizierung neu auftretender Vorhofflimmerepisoden bilden, um anfällige Patienten für ein präventives Screening auszuwählen. Zu diesem Zweck wurde untersucht, ob simulierte Vorhof-Elektrokardiogrammdaten, die dem klinischen Trainingssatz eines maschinellen Lernmodells hinzugefügt wurden, zu einer verbesserten Klassifizierung der oben genannten Krankheiten bei klinischen Daten beitra- gen könnten. Zwei virtuelle Kohorten, die durch anatomische und funktionelle Variabilität gekennzeichnet sind, wurden generiert und dienten als Grundlage für die Simulation großer P Wellen-Datensätze mit genau bestimmbaren Annotationen der zugrunde liegenden Patholo- gie. Auf diese Weise erfüllen die simulierten Daten die notwendigen Voraussetzungen für die Entwicklung eines Algorithmus für maschinelles Lernen, was sie von klinischen Daten unterscheidet, die normalerweise nicht in großer Zahl und in gleichmäßig verteilten Klassen vorliegen und deren Annotationen möglicherweise durch unzureichende Expertenannotierung beeinträchtigt sind. Für die Schätzung des Volumenanteils von linksatrialem fibrotischen Gewebe wurde ein merkmalsbasiertes neuronales Netz entwickelt. Im Vergleich zum Training des Modells mit nur klinischen Daten, führte das Training mit einem hybriden Datensatz zu einer Reduzierung des Fehlers von durchschnittlich 17,5 % fibrotischem Volumen auf 16,5 %, ausgewertet auf einem rein klinischen Testsatz. Ein Long Short-Term Memory Netzwerk, das für die Unterscheidung zwischen gesunden und P Wellen von vergrößerten linken Vorhöfen entwickelt wurde, lieferte eine Genauigkeit von 0,95 wenn es auf einem hybriden Datensatz trainiert wurde, von 0,91 wenn es nur auf klinischen Daten trainiert wurde, die alle mit 100 % Sicherheit annotiert wurden, und von 0,83 wenn es auf einem klinischen Datensatz trainiert wurde, der alle Signale unabhängig von der Sicherheit der Expertenannotation enthielt. In Anbetracht der Ergebnisse dieser Arbeit können Elektrokardiogrammdaten, die aus elektrophysiologischer Modellierung und Simulationen an virtuellen Patientenkohorten resul- tieren und relevante Variabilitätsaspekte abdecken, die mit realen Beobachtungen übereinstim- men, eine wertvolle Datenquelle zur Verbesserung der automatisierten Risikostratifizierung von Vorhofflimmern sein. Auf diese Weise kann den Nachteilen klinischer Datensätze für die Entwicklung von Modellen des maschinellen Lernens entgegengewirkt werden. Dies trägt letztendlich zu einer frühzeitigen Erkennung der Arrhythmie bei, was eine rechtzeitige Auswahl geeigneter Behandlungsstrategien ermöglicht und somit das Schlaganfallrisiko der betroffenen Patienten verringert

Composite hydrogel-nanofibre vessels for vascular graft applications

A vascular graft should mimic the structure and properties of the native artery which has a layered structure. The media layer of native arteries contributes the main mechanical support to the vessel and the intima layer, lined with endothelial cells, provides a smooth antithrombogenic surface for circulating blood. To mimic this arterial structure and property, this study focused on fabricating a layered vascular graft with hydrogel and fibre layers to match the compliance properties of native arteries, which is a critical property to smooth the pulsatile blood flow in circulation. Firstly, the feasibility of preparing polyvinyl alcohol (PVA) based hydrogels with controllable mechanical property was investigated. Three PVA based hydrogels were prepared by blending PVA with chitosan, gelatin or starch and by treatment with freeze-thaw cycles and coagulation. The synergistic crosslinking with the freeze-thaw technique and coagulation was found as a versatile method to control the structure and mechanical properties of PVA-based hydrogels. A further study was focused on the microstructure formation of PVA/Gelatin hydrogel. The results showed that the freeze-thaw cycles increased the strength of hydrogels by growing the crystal domains in the PVA matrix. The coagulation treatment strengthened the mechanical properties of the hydrogels by increasing the overall polymer fraction of the hydrogels. Polyvinyl alcohol with styrylpyridinium pendent groups (PVA-SbQ) is a photosensitive polymer. PVA-SbQ fibres were fabricated by electrospinning and photocrosslinking techniques. The photocrosslinked PVA-SbQ fibre presented water-insoluble properties. Preliminary endothelial cell culture result showed evidence that the PVA-SbQ fibres could potentially act as a cell lining substrate. Finally, a duo-layer vascular graft was constructed with one outer layer composed of a PVA based hydrogel and one inner layer of composed of PVA-SbQ fibres. The mechanical properties, especially the compliance, of the as-prepared duo-layer graft were shown to closely match with that of selected native arteries

Mechanisms of Atrial Arrhythmia: Investigations of the Neuro-Myogenic Interface in the Mouse

Arrhythmia mechanisms rely on multiple factors including structural (myogenic), nervous (neurogenic), and interrelated (the neuro-myogenic interface) factors. I hypothesized that due to this neuro-myogenic interface, the intrinsic cardiac autonomic nervous system (ICANS) is involved in most atrial arrhythmias. This thesis also provides a Threshold Model as a tool to assess the role of different physiological factors influencing arrhythmia. This model allows relative comparison and interpretation of the role of various factors influencing arrhythmogenesis. The mouse allows relatively simple manipulation of genes to determine their role in arrhythmia. This thesis determined what atrial arrhythmias are inducible in the mouse (in vivo) and how to systematically study those arrhythmias. I found that atrial tachycardia/fibrillation (AT/F) and junctional tachycardia (JT) are inducible in the mouse. AF and JT pose significant clinical challenges as many patients do not respond well to current interventions. Neurogenic AF relies on acetylcholine, while myogenic AF relies, in part on gap junctions formed by connexins (Cxs). The atria has muscarinic M2 and M3 receptors. The duration of M2R/M3R G protein signalling is regulated by GTP hydrolysis, a process accelerated by the regulators of G protein signalling (RGS). RGS2 deficient (RGS2-/-) mice had reduced refractory periods that were normalized with a selective M3R blocker (Darifenacin) and increased susceptibility to AT/F induction compared to littermates. For the first time, this showed a role of M3 and RGS in atrial arrhythmia. Cx40 deficient (Cx40-/-) mice were protected from carbachol induced AT/F, while Cx43 G60S mutant (Cx43G60S/+) mice, with an 80% reduction in phospho-Cx43 in the atria were highly susceptible to AT/F that was terminated by darifenacin. This shows a novel neurogenic component to what was previously described as myogenic arrhythmia. Another novel finding was that JT has a neurogenic component, resulting from inappropriate AV nodal pacemaker activation initiated by autonomics. Ivabradine hydrochloride, a selective pacemaker channel blocker, prevented JT and may be useful in patients with JT. In conclusion, this thesis has provided novel findings of the vital role of the neuro-myogenic interface in atrial arrhythmias and has provided the basis for future investigations of potential therapeutic options for patients