scholarly journals Arrhythmogenic Mechanisms in Hypokalaemia: Insights From Pre-clinical Models

2021 ◽  
Vol 8 ◽  
Author(s):  
Gary Tse ◽  
Ka Hou Christien Li ◽  
Chloe Kwong Yee Cheung ◽  
Konstantinos P. Letsas ◽  
Aishwarya Bhardwaj ◽  
...  
Keyword(s):  
Action Potential ◽  
Ventricular Arrhythmias ◽  
Molecular Mechanisms ◽  
Clinical Findings ◽  
Excitation Wavelength ◽  
Early Afterdepolarizations ◽  
Intracellular Ca ◽  
Life Threatening ◽  
Clinical Models ◽  
Delayed Afterdepolarizations

Potassium is the predominant intracellular cation, with its extracellular concentrations maintained between 3. 5 and 5 mM. Among the different potassium disorders, hypokalaemia is a common clinical condition that increases the risk of life-threatening ventricular arrhythmias. This review aims to consolidate pre-clinical findings on the electrophysiological mechanisms underlying hypokalaemia-induced arrhythmogenicity. Both triggers and substrates are required for the induction and maintenance of ventricular arrhythmias. Triggered activity can arise from either early afterdepolarizations (EADs) or delayed afterdepolarizations (DADs). Action potential duration (APD) prolongation can predispose to EADs, whereas intracellular Ca2+ overload can cause both EADs and DADs. Substrates on the other hand can either be static or dynamic. Static substrates include action potential triangulation, non-uniform APD prolongation, abnormal transmural repolarization gradients, reduced conduction velocity (CV), shortened effective refractory period (ERP), reduced excitation wavelength (CV × ERP) and increased critical intervals for re-excitation (APD–ERP). In contrast, dynamic substrates comprise increased amplitude of APD alternans, steeper APD restitution gradients, transient reversal of transmural repolarization gradients and impaired depolarization-repolarization coupling. The following review article will summarize the molecular mechanisms that generate these electrophysiological abnormalities and subsequent arrhythmogenesis.

scholarly journals Cellular basis of ventricular arrhythmias and abnormal automaticity in heart failure

1999 ◽  
Vol 277 (1) ◽  
pp. H80-H91 ◽  
Author(s):  
H. Bradley Nuss ◽  
Stefan Kääb ◽  
David A. Kass ◽  
Gordon F. Tomaselli ◽  
Eduardo Marbán
Keyword(s):  
Heart Failure ◽  
Sudden Death ◽  
Ventricular Arrhythmias ◽  
Torsade De Pointes ◽  
Resting Potential ◽  
Unexpected Finding ◽  
Early Afterdepolarizations ◽  
Ventricular Cells ◽  
High Incidence ◽  
Delayed Afterdepolarizations

The high incidence of sudden death in heart failure may reflect an increased propensity to abnormal repolarization and long Q-T interval-related arrhythmias. If so, cells from failing hearts would logically be expected to exhibit a heightened susceptibility to early afterdepolarizations (EAD). We found that midmyocardial ventricular cells isolated from dogs with pacing-induced heart failure exhibited an increased action potential duration and many more EAD than cells from nonpaced controls; this was the case both under basal conditions ( P < 0.01) and after lowering external K+concentration ([K+]o) to 2 mM and exposing cells to cesium (3 mM; P < 0.05). An unexpected finding was the occurrence of spontaneous depolarizations (SD, >5 mV) from the resting potential that were not coupled to prior action potentials. These SD were observed in 20% of failing cells ( n = 5 of 25) under basal ionic conditions but in none of the normal cells ( n = 0 of 27, P < 0.05). The net inward current that underlies SD is not triggered by Ca2+ oscillations and thus differs fundamentally from the currents that underlie delayed afterdepolarizations. We conclude that cardiomyopathic canine ventricular cells are intrinsically predisposed to EAD and SD. Because EAD have been linked to the pathogenesis of torsade de pointes, our results support the hypothesis that sudden death in heart failure often arises from abnormalities of repolarization. The frequent occurrence of SD points to a novel cellular mechanism for abnormal automaticity in heart failure.

scholarly journals Why Pacing Frequency Affects the Production of Early Afterdepolarizations in Cardiomyocytes: An Explanation Revealed by Slow/Fast Analysis of a Minimal Model

2019 ◽  
Author(s):  
Theodore Vo ◽  
Richard Bertram
Keyword(s):  
Action Potential ◽  
Intermediate Frequency ◽  
Tissue Level ◽  
Phase 2 ◽  
Fast Analysis ◽  
Early Afterdepolarizations ◽  
Low Frequencies ◽  
Pharmacological Agents ◽  
Intracellular Ca ◽  
Biophysical Mechanism

AbstractEarly afterdepolarizations (EADs) are pathological voltage oscillations in cardiomyocytes that have been observed in response to a number of pharmacological agents and disease conditions. Phase-2 EADs consist of small voltage fluctuations that occur during the plateau of an action potential, typically under conditions in which the action potential is elongated. Although a single-cell behavior, EADs can lead to tissue-level arrhythmias, including ventricular tachycardia. Much is currently known about the biophysical mechanisms (i.e., the roles of ion channels and intracellular Ca2+ stores) for the various forms of EADs, due partially to the development and analysis of mathematical models. This includes the application of slow/fast analysis, which takes advantage of timescale separation inherent in the system to simplify its analysis. We take this further, using a minimal 3D model to demonstrate that the phase-2 EADs are canards that are formed in the neighborhood of a folded node singularity. This knowledge allows us to determine the number of EADs that can be produced for a given parameter set without performing computer simulations, and provides guidance on parameter changes that can facilitate or inhibit EAD production. With this approach, we demonstrate why periodic stimulation, as would occur in an intact heart, preferentially facilitates EAD production when applied at low frequencies,. We also explain the origin of complex alternan dynamics that can occur with intermediate-frequency stimulation, in which varying numbers of EADs are produced with each stimulation. These revelations fall out naturally from an understanding of folded node singularities, but are hard or impossible to glean from a knowledge of the biophysical mechanism for EADs alone. Therefore, an understanding of the canard mechanism is a useful complement to an understanding of the biophysical mechanism that has been developed over years of experimental and computational investigations.

scholarly journals Constitutive overexpression of phosphomimetic phospholemman S68E mutant results in arrhythmias, early mortality, and heart failure: potential involvement of Na+/Ca2+ exchanger

2012 ◽  
Vol 302 (3) ◽  
pp. H770-H781 ◽  
Author(s):  
Jianliang Song ◽  
Erhe Gao ◽  
JuFang Wang ◽  
Xue-Qian Zhang ◽  
Tung O. Chan ◽  
...  
Keyword(s):  
Action Potential ◽  
Ventricular Arrhythmias ◽  
Left Ventricular ◽  
Resting Membrane Potential ◽  
Protein Levels ◽  
Disease States ◽  
Plasmic Reticulum ◽  
Lv Mass ◽  
Intracellular Ca ◽  
Constitutive Overexpression

Expression and activity of cardiac Na+/Ca2+ exchanger (NCX1) are altered in many disease states. We engineered mice in which the phosphomimetic phospholemman S68E mutant (inhibits NCX1 but not Na+-K+-ATPase) was constitutively overexpressed in a cardiac-specific manner (conS68E). At 4–6 wk, conS68E mice exhibited severe bradycardia, ventricular arrhythmias, increased left ventricular (LV) mass, decreased cardiac output (CO), and ∼50% mortality compared with wild-type (WT) littermates. Protein levels of NCX1, calsequestrin, ryanodine receptor, and α1- and α2-subunits of Na+-K+-ATPase were similar, but sarco(endo)plasmic reticulum Ca2+-ATPase was lower, whereas L-type Ca2+ channels were higher in conS68E hearts. Resting membrane potential and action potential amplitude were similar, but action potential duration was dramatically prolonged in conS68E myocytes. Diastolic intracellular Ca2+ ([Ca2+]i) was higher, [Ca2+]i transient and maximal contraction amplitudes were lower, and half-time of [Ca2+]i transient decline was longer in conS68E myocytes. Intracellular Na+ reached maximum within 3 min after isoproterenol addition, followed by decline in WT but not in conS68E myocytes. Na+/Ca2+ exchange, L-type Ca2+, Na+-K+-ATPase, and depolarization-activated K+ currents were decreased in conS68E myocytes. At 22 wk, bradycardia and increased LV mass persisted in conS68E survivors. Despite comparable baseline CO, conS68E survivors at 22 wk exhibited decreased chronotropic, inotropic, and lusitropic responses to isoproterenol. We conclude that constitutive overexpression of S68E mutant was detrimental, both in terms of depressed cardiac function and increased arrhythmogenesis.

scholarly journals Cardiac Sympathetic Nerve Sprouting and Susceptibility to Ventricular Arrhythmias after Myocardial Infarction

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Chang-Yi Li ◽  
Yi-Gang Li
Keyword(s):  
Myocardial Infarction ◽  
Sudden Cardiac Death ◽  
Cardiac Death ◽  
Ventricular Arrhythmias ◽  
Molecular Mechanisms ◽  
Therapeutic Option ◽  
Therapeutic Implications ◽  
Neural Modulation ◽  
Nerve Sprouting ◽  
Life Threatening

Ventricular arrhythmogenesis is thought to be a common cause of sudden cardiac death following myocardial infarction (MI). Nerve remodeling as a result of MI is known to be an important genesis of life-threatening arrhythmias. It is hypothesized that neural modulation might serve as a therapeutic option of malignant arrhythmias. In fact, left stellectomy orβ-blocker therapy is shown to be effective in the prevention of ventricular tachyarrhythmias (VT), ventricular fibrillation (VF), and sudden cardiac death (SCD) after MI both in patients and in animal models. Results from decades of research already evidenced a positive relationship between abnormal nerve density and ventricular arrhythmias after MI. In this review, we summarized the molecular mechanisms involved in cardiac sympathetic rejuvenation and mechanisms related to sympathetic hyperinnervation and arrhythmogenesis after MI and analyzed the potential therapeutic implications of nerve sprouting modification for ventricular arrhythmias and SCD control.

scholarly journals Transfusion-Related Acute Lung Injured (TRALI): Current Concepts

2015 ◽  
Vol 9 (1) ◽  
pp. 92-96 ◽  
Author(s):  
P Álvarez ◽  
R Carrasco ◽  
C Romero-Dapueto ◽  
R.L Castillo
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Molecular Mechanisms ◽  
Clinical Symptoms ◽  
Clinical Problem ◽  
Clinical Findings ◽  
Cellular Targets ◽  
Immune Mediated ◽  
Life Threatening

Transfusion-related acute lung injury (TRALI) is a life-threatening intervention that develops within 6 hours of transfusion of one or more units of blood, and is an important cause of morbidity and mortality resulting from transfusion. It is necessary to dismiss other causes of acute lung injury (ALI), like sepsis, acute cardiogenic edema, acute respiratory distress syndrome (ARDS) or bacterial infection. There are two mechanisms that lead to the development of this syndrome: immune-mediated and no immune- mediated TRALI. A common theme among the experimental TRALI models is the central importance of neutrophils in mediating the early immune response, and lung vascular injury. Central clinical symptoms are dyspnea, tachypnea, tachycardia, cyanosis and pulmonary secretions, altogether with other hemodynamic alterations, such as hypotension and fever. Complementary to these clinical findings, long-term validated animal models for TRALI should allow the determination of the cellular targets for TRALI-inducing alloantibodies as well as delineation of the underlying pathogenic molecular mechanisms, and key molecular mediators of the pathology. Diagnostic criteria have been established and preventive measures have been implemented. These actions have contributed to the reduction in the overallnumber of fatalities. However, TRALI still remains a clinical problem. Any complication suspected of TRALI should immediately be reported.

scholarly journals Impairing flow-mediated endothelial remodeling reduces extravasation of tumor cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Gautier Follain ◽  
Naël Osmani ◽  
Valentin Gensbittel ◽  
Nandini Asokan ◽  
Annabel Larnicol ◽  
...  
Keyword(s):  
Blood Flow ◽  
Tumor Cells ◽  
Molecular Mechanisms ◽  
Metastatic Progression ◽  
Metastatic Dissemination ◽  
Secondary Tumors ◽  
Flow Profiles ◽  
Endothelial Response ◽  
Life Threatening

AbstractTumor progression and metastatic dissemination are driven by cell-intrinsic and biomechanical cues that favor the growth of life-threatening secondary tumors. We recently identified pro-metastatic vascular regions with blood flow profiles that are permissive for the arrest of circulating tumor cells. We have further established that such flow profiles also control endothelial remodeling, which favors extravasation of arrested CTCs. Yet, how shear forces control endothelial remodeling is unknown. In the present work, we aimed at dissecting the cellular and molecular mechanisms driving blood flow-dependent endothelial remodeling. Transcriptomic analysis of endothelial cells revealed that blood flow enhanced VEGFR signaling, among others. Using a combination of in vitro microfluidics and intravital imaging in zebrafish embryos, we now demonstrate that the early flow-driven endothelial response can be prevented upon specific inhibition of VEGFR tyrosine kinase and subsequent signaling. Inhibitory targeting of VEGFRs reduced endothelial remodeling and subsequent metastatic extravasation. These results confirm the importance of VEGFR-dependent endothelial remodeling as a driving force of CTC extravasation and metastatic dissemination. Furthermore, the present work suggests that therapies targeting endothelial remodeling might be a relevant clinical strategy in order to impede metastatic progression.

scholarly journals Catheter Ablation of Life-Threatening Ventricular Arrhythmias in Athletes

Medicina ◽  
2021 ◽  
Vol 57 (3) ◽  
pp. 205
Author(s):  
Nicola Tarantino ◽  
Domenico G. Della Rocca ◽  
Nicole S. De Leon De La Cruz ◽  
Eric D. Manheimer ◽  
Michele Magnocavallo ◽  
...  
Keyword(s):  
Catheter Ablation ◽  
Ventricular Arrhythmias ◽  
Individual Factors ◽  
Substantial Part ◽  
Arrhythmogenic Substrate ◽  
Life Threatening ◽  
History Of ◽  
Anatomic Distribution ◽  
Artery Disease ◽  
Surveillance Analysis

A recent surveillance analysis indicates that cardiac arrest/death occurs in ≈1:50,000 professional or semi-professional athletes, and the most common cause is attributable to life-threatening ventricular arrhythmias (VAs). It is critically important to diagnose any inherited/acquired cardiac disease, including coronary artery disease, since it frequently represents the arrhythmogenic substrate in a substantial part of the athletes presenting with major VAs. New insights indicate that athletes develop a specific electro-anatomical remodeling, with peculiar anatomic distribution and VAs patterns. However, because of the scarcity of clinical data concerning the natural history of VAs in sports performers, there are no dedicated recommendations for VA ablation. The treatment remains at the mercy of several individual factors, including the type of VA, the athlete’s age, and the operator’s expertise. With the present review, we aimed to illustrate the prevalence, electrocardiographic (ECG) features, and imaging correlations of the most common VAs in athletes, focusing on etiology, outcomes, and sports eligibility after catheter ablation.

scholarly journals The role of calcium homeostasis remodeling in inherited cardiac arrhythmia syndromes

2021 ◽  
Author(s):  
Shanna Hamilton ◽  
Roland Veress ◽  
Andriy Belevych ◽  
Dmitry Terentyev
Keyword(s):  
Cardiac Arrhythmia ◽  
Cardiac Death ◽  
Ventricular Arrhythmias ◽  
Polymorphic Ventricular Tachycardia ◽  
Genetic Mutations ◽  
Strong Basis ◽  
Functional Changes ◽  
Intracellular Ca ◽  
Qt Syndrome

AbstractSudden cardiac death due to malignant ventricular arrhythmias remains the major cause of mortality in the postindustrial world. Defective intracellular Ca2+ homeostasis has been well established as a key contributing factor to the enhanced propensity for arrhythmia in acquired cardiac disease, such as heart failure or diabetic cardiomyopathy. More recent advances provide a strong basis to the emerging view that hereditary cardiac arrhythmia syndromes are accompanied by maladaptive remodeling of Ca2+ homeostasis which substantially increases arrhythmic risk. This brief review will focus on functional changes in elements of Ca2+ handling machinery in cardiomyocytes that occur secondary to genetic mutations associated with catecholaminergic polymorphic ventricular tachycardia, and long QT syndrome.

scholarly journals Pathophysiology of Atherosclerotic Plaque Development-Contemporary Experience and New Directions in Research

2021 ◽  
Vol 22 (7) ◽  
pp. 3513
Author(s):  
Michal Kowara ◽  
Agnieszka Cudnoch-Jedrzejewska
Keyword(s):  
Atherosclerotic Plaque ◽  
Molecular Mechanisms ◽  
Cellular Heterogeneity ◽  
Ldl Oxidation ◽  
Plaque Development ◽  
New Directions ◽  
Life Threatening ◽  
Non Coding Rnas ◽  
Cellular Pathways ◽  
Key Aspects

Atherosclerotic plaque is the pathophysiological basis of important and life-threatening diseases such as myocardial infarction. Although key aspects of the process of atherosclerotic plaque development and progression such as local inflammation, LDL oxidation, macrophage activation, and necrotic core formation have already been discovered, many molecular mechanisms affecting this process are still to be revealed. This minireview aims to describe the current directions in research on atherogenesis and to summarize selected studies published in recent years—in particular, studies on novel cellular pathways, epigenetic regulations, the influence of hemodynamic parameters, as well as tissue and microorganism (microbiome) influence on atherosclerotic plaque development. Finally, some new and interesting ideas are proposed (immune cellular heterogeneity, non-coding RNAs, and immunometabolism) which will hopefully bring new discoveries in this area of investigation.

scholarly journals Cardiac small-conductance calcium-activated potassium channels in health and disease

2021 ◽  
Vol 473 (3) ◽  
pp. 477-489 ◽  
Author(s):  
Xiao-Dong Zhang ◽  
Phung N. Thai ◽  
Deborah K. Lieu ◽  
Nipavan Chiamvimonvat
Keyword(s):  
Ventricular Myocytes ◽  
Pulmonary Veins ◽  
Differential Sensitivity ◽  
Sk Channels ◽  
Sk Channel ◽  
Ventricular Cells ◽  
Intracellular Ca ◽  
Life Threatening ◽  
Health And Disease ◽  
Small Conductance

AbstractSmall-conductance Ca2+-activated K+ (SK, KCa2) channels are encoded by KCNN genes, including KCNN1, 2, and 3. The channels play critical roles in the regulation of cardiac excitability and are gated solely by beat-to-beat changes in intracellular Ca2+. The family of SK channels consists of three members with differential sensitivity to apamin. All three isoforms are expressed in human hearts. Studies over the past two decades have provided evidence to substantiate the pivotal roles of SK channels, not only in healthy heart but also with diseases including atrial fibrillation (AF), ventricular arrhythmia, and heart failure (HF). SK channels are prominently expressed in atrial myocytes and pacemaking cells, compared to ventricular cells. However, the channels are significantly upregulated in ventricular myocytes in HF and pulmonary veins in AF models. Interests in cardiac SK channels are further fueled by recent studies suggesting the possible roles of SK channels in human AF. Therefore, SK channel may represent a novel therapeutic target for atrial arrhythmias. Furthermore, SK channel function is significantly altered by human calmodulin (CaM) mutations, linked to life-threatening arrhythmia syndromes. The current review will summarize recent progress in our understanding of cardiac SK channels and the roles of SK channels in the heart in health and disease.

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