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Circulation Research Sep 2020Postoperative atrial fibrillation (POAF) is a common and troublesome complication of cardiac surgery. POAF is generally believed to occur when postoperative triggers act...
RATIONALE
Postoperative atrial fibrillation (POAF) is a common and troublesome complication of cardiac surgery. POAF is generally believed to occur when postoperative triggers act on a preexisting vulnerable substrate, but the underlying cellular and molecular mechanisms are largely unknown.
OBJECTIVE
To identify cellular POAF mechanisms in right atrial samples from patients without a history of atrial fibrillation undergoing open-heart surgery.
METHODS AND RESULTS
Multicellular action potentials, membrane ion-currents (perforated patch-clamp), or simultaneous membrane-current (ruptured patch-clamp) and [Ca]-recordings in atrial cardiomyocytes, along with protein-expression levels in tissue homogenates or cardiomyocytes, were assessed in 265 atrial samples from patients without or with POAF. No indices of electrical, profibrotic, or connexin remodeling were noted in POAF, but Ca-transient amplitude was smaller, although spontaneous sarcoplasmic reticulum (SR) Ca-release events and L-type Ca-current alternans occurred more frequently. CaMKII (Ca/calmodulin-dependent protein kinase-II) protein-expression, CaMKII-dependent phosphorylation of the cardiac RyR2 (ryanodine-receptor channel type-2), and RyR2 single-channel open-probability were significantly increased in POAF. SR Ca-content was unchanged in POAF despite greater SR Ca-leak, with a trend towards increased SR Ca-ATPase activity. Patients with POAF also showed stronger expression of activated components of the NLRP3 (NACHT, LRR, and PYD domains-containing protein-3)-inflammasome system in atrial whole-tissue homogenates and cardiomyocytes. Acute application of interleukin-1β caused NLRP3-signaling activation and CaMKII-dependent RyR2/phospholamban hyperphosphorylation in an immortalized mouse atrial cardiomyocyte cell-line (HL-1-cardiomyocytes) and enhanced spontaneous SR Ca-release events in both POAF cardiomyocytes and HL-1-cardiomyocytes. Computational modeling showed that RyR2 dysfunction and increased SR Ca-uptake are sufficient to reproduce the Ca-handling phenotype and indicated an increased risk of proarrhythmic delayed afterdepolarizations in POAF subjects in response to interleukin-1β.
CONCLUSIONS
Preexisting Ca-handling abnormalities and activation of NLRP3-inflammasome/CaMKII signaling are evident in atrial cardiomyocytes from patients who subsequently develop POAF. These molecular substrates sensitize cardiomyocytes to spontaneous Ca-releases and arrhythmogenic afterdepolarizations, particularly upon exposure to inflammatory mediators. Our data reveal a potential cellular and molecular substrate for this important clinical problem.
Topics: Action Potentials; Aged; Animals; Atrial Fibrillation; Calcium Signaling; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Cardiac Surgical Procedures; Case-Control Studies; Cell Line; Female; Heart Atria; Heart Rate; Humans; Inflammasomes; Inflammation Mediators; Male; Mice; Middle Aged; Myocytes, Cardiac; NLR Family, Pyrin Domain-Containing 3 Protein; Phosphorylation; Ryanodine Receptor Calcium Release Channel; Sarcoplasmic Reticulum
PubMed: 32762493
DOI: 10.1161/CIRCRESAHA.120.316710 -
Journal of Education & Teaching in... Oct 2020This simulation is designed to educate emergency medicine residents and medical students on the recognition and management of cardiac tamponade, as well as encourage...
AUDIENCE
This simulation is designed to educate emergency medicine residents and medical students on the recognition and management of cardiac tamponade, as well as encourage providers to become familiar with their states' disclosure laws for sentinel events.
INTRODUCTION
Cardiac tamponade is an emergent condition in which the accumulation of pericardial fluid and the consequent increase in hydrostatic pressure becomes severe enough to compromise the normal diastolic and systolic function of the heart, resulting in hemodynamic instability.1 The causes of cardiac tamponade are numerous because it is a potential complication of any of a number of pericardial disease processes, including infectious, inflammatory, traumatic, and malignant etiologies.1,2 Clinical presentations may vary and symptoms can be non-specific, which can lead to delayed or missed diagnoses and poor patient outcomes.3 In addition to this, the incidence of this condition is rising due to the increasing frequency of cardiac procedures performed (ie, pacemaker placement).4 Therefore, it is important for medical providers to have a high index of suspicion for the diagnosis based on patient presentation and to quickly provide necessary treatment to stabilize the patient.
EDUCATIONAL OBJECTIVES
By the end of this simulation session, the learner will be able to: (1) describe a diagnostic differential for dizziness (2) describe the pathophysiology of cardiac tamponade (3) describe the acute management of cardiac tamponade, including fluid bolus and pericardiocentesis (4) describe the electrocardiogram (ECG) findings of pericardial effusion (5) describe the ultrasound findings of cardiac tamponade (6) describe the indications for emergent bedside pericardiocentesis versus medical stabilization and delayed pericardiocentesis for cardiac tamponade (7) describe the procedural steps for pericardiocentesis, and (8) describe your state's laws regarding disclosure for sentinel events.
EDUCATIONAL METHODS
This session is conducted using high-fidelity simulation, followed by a debriefing session on evaluation and treatment of cardiac tamponade. However, it may also be run as an oral board case.
EDUCATIONAL METHODS
Our residents were provided an electronic survey at the completion of the debriefing session so they may rate different aspects of the simulation, as well as provide qualitative feedback on the scenario. This survey is specific to the local institution's simulation center.
RESULTS
Feedback was largely positive because many learners mentioned during debriefing that they are not comfortable with pericardiocentesis and have limited opportunities to practice the procedure. None of our residents were familiar with our state's or institution's disclosure laws for sentinel events.The local institution's simulation center feedback form is based on the Center of Medical Simulation's Debriefing Assessment for Simulation in Healthcare (DASH) Student Version Short Form with the inclusion of required qualitative feedback if an element was scored less than a 6 or 7.5 This session received a majority of 6 (consistently effective/very good) and 7 scores (extremely effective/outstanding).
DISCUSSION
This is a potential method for educating future medical providers on the diagnosis and management of cardiac tamponade in an emergency department setting. Learners initially had a wide range of differentials for the chief complaint of dizziness. We used an ECG with low voltage but without electrical alternans. When asked to provide an ECG interpretation, low voltage was intermittently explicitly interpreted by learners. We were concerned that if we showed an ECG with electrical alternans, learners may quickly arrive at the diagnosis without focusing on the subtleties of a physical exam, including looking for jugular venous distention (JVD) or pulsus paradoxus.We did not have the patient decompensate if their international normalized ratio (INR) was not immediately reversed, given likely delay for coagulation to occur in the face of life-threatening tamponade, but this provided a robust discussion during debriefing if reversal should be emergently initiated.Many residents voiced that they were uncomfortable performing a pericardiocentesis because they only had a few opportunities to do so on human cadavers, and they appreciated the opportunity to review this.Unexpectedly, when the patient asked the learners if he should sue the cardiologist, the majority of groups told the patient that the cardiologist was not liable because tamponade is a known complication of cardiac ablation and likely reviewed this while obtaining informed consent. None of the learners were familiar with Ohio's disclosure laws for sentinel events. This identified a gap in knowledge that may be addressed in future learning sessions.Our main take-away is to continue providing low-frequency, high-acuity cases that provide the opportunity to review infrequent pathologies and procedures, as well as including patient safety and administrative learning points.
TOPICS
Medical simulation, cardiac tamponade, pericardial effusion, cardiac emergencies, obstructive shock, sentinel events, iatrogenic injury, medical disclosure.
PubMed: 37465332
DOI: 10.21980/J81D1D -
JACC. Case Reports Nov 2023A young man presented with acute stabbing chest pain. A 12-lead electrocardiogram revealed electrical alternans with phasic variation of the QRS amplitude in all leads....
A young man presented with acute stabbing chest pain. A 12-lead electrocardiogram revealed electrical alternans with phasic variation of the QRS amplitude in all leads. Lung auscultation revealed absent left hemithorax breath sounds. Chest radiography confirmed a left-sided tension pneumothorax. Tension pneumothorax is a very rare cause for electrical alternans. ().
PubMed: 38094176
DOI: 10.1016/j.jaccas.2023.102061 -
Cells Nov 2021For both the atria and ventricles, fibrosis is generally recognized as one of the key determinants of conduction disturbances. By definition, fibrosis refers to an... (Review)
Review
For both the atria and ventricles, fibrosis is generally recognized as one of the key determinants of conduction disturbances. By definition, fibrosis refers to an increased amount of fibrous tissue. However, fibrosis is not a singular entity. Various forms can be distinguished, that differ in distribution: replacement fibrosis, endomysial and perimysial fibrosis, and perivascular, endocardial, and epicardial fibrosis. These different forms typically result from diverging pathophysiological mechanisms and can have different consequences for conduction. The impact of fibrosis on propagation depends on exactly how the patterns of electrical connections between myocytes are altered. We will therefore first consider the normal patterns of electrical connections and their regional diversity as determinants of propagation. Subsequently, we will summarize current knowledge on how different forms of fibrosis lead to a loss of electrical connectivity in order to explain their effects on propagation and mechanisms of arrhythmogenesis, including ectopy, reentry, and alternans. Finally, we will discuss a histological quantification of fibrosis. Because of the different forms of fibrosis and their diverging effects on electrical propagation, the total amount of fibrosis is a poor indicator for the effect on conduction. Ideally, an assessment of cardiac fibrosis should exclude fibrous tissue that does not affect conduction and differentiate between the various types that do; in this article, we highlight practical solutions for histological analysis that meet these requirements.
Topics: Animals; Confounding Factors, Epidemiologic; Disease Models, Animal; Electrophysiological Phenomena; Fibrosis; Heart Conduction System; Humans; Myocardium
PubMed: 34831442
DOI: 10.3390/cells10113220 -
Journal of Arrhythmia Oct 2016Pre-existing heterogeneities present in cardiac tissue are essential for maintaining the normal electrical and mechanical functions of the heart. Exacerbation of such... (Review)
Review
Pre-existing heterogeneities present in cardiac tissue are essential for maintaining the normal electrical and mechanical functions of the heart. Exacerbation of such heterogeneities or the emergence of dynamic factors can produce repolarization alternans, which are beat-to-beat alternations in the action potential time course. Traditionally, this was explained by restitution, but additional factors, such as cardiac memory, calcium handling dynamics, refractory period restitution, and mechano-electric feedback, are increasingly recognized as the underlying causes. The aim of this article is to review the mechanisms that generate cardiac repolarization alternans and convert spatially concordant alternans to the more arrhythmogenic spatially discordant alternans. This is followed by a discussion on how alternans generate arrhythmias in a number of clinical scenarios, and concluded by an outline of future therapeutic targets for anti-arrhythmic therapy.
PubMed: 27761166
DOI: 10.1016/j.joa.2016.02.009 -
Circulation Research Jan 2023Cardiac alternans arises from dynamical instabilities in the electrical and calcium cycling systems of the heart, and often precedes ventricular arrhythmias and sudden... (Review)
Review
Cardiac alternans arises from dynamical instabilities in the electrical and calcium cycling systems of the heart, and often precedes ventricular arrhythmias and sudden cardiac death. In this review, we integrate clinical observations with theory and experiment to paint a holistic portrait of cardiac alternans: the underlying mechanisms, arrhythmic manifestations and electrocardiographic signatures. We first summarize the cellular and tissue mechanisms of alternans that have been demonstrated both theoretically and experimentally, including 3 voltage-driven and 2 calcium-driven alternans mechanisms. Based on experimental and simulation results, we describe their relevance to mechanisms of arrhythmogenesis under different disease conditions, and their link to electrocardiographic characteristics of alternans observed in patients. Our major conclusion is that alternans is not only a predictor, but also a causal mechanism of potentially lethal ventricular and atrial arrhythmias across the full spectrum of arrhythmia mechanisms that culminate in functional reentry, although less important for anatomic reentry and focal arrhythmias.
Topics: Humans; Calcium; Heart; Arrhythmias, Cardiac; Death, Sudden, Cardiac; Electrocardiography
PubMed: 36603066
DOI: 10.1161/CIRCRESAHA.122.321668 -
Clinical and Experimental Pharmacology... Jul 2014Cardiac alternans refers to a condition in which there is a periodic beat-to-beat oscillation in electrical activity and the strength of cardiac muscle contraction at a... (Review)
Review
Cardiac alternans refers to a condition in which there is a periodic beat-to-beat oscillation in electrical activity and the strength of cardiac muscle contraction at a constant heart rate. Clinically, cardiac alternans occurs in settings that are typical for cardiac arrhythmias and has been causally linked to these conditions. At the cellular level, alternans is defined as beat-to-beat alternations in contraction amplitude (mechanical alternans), action potential duration (APD; electrical or APD alternans) and Ca(2+) transient amplitude (Ca(2+) alternans). The cause of alternans is multifactorial; however, alternans always originate from disturbances of the bidirectional coupling between membrane voltage (Vm ) and intracellular calcium ([Ca(2+) ]i ). Bidirectional coupling refers to the fact that, in cardiac cells, Vm depolarization and the generation of action potentials cause the elevation of [Ca(2+) ]i that is required for contraction (a process referred to as excitation-contraction coupling); conversely, changes of [Ca(2+) ]i control Vm because important membrane currents are Ca(2+) dependent. Evidence is mounting that alternans is ultimately caused by disturbances of cellular Ca(2+) signalling. Herein we review how two key factors of cardiac cellular Ca(2+) cycling, namely the release of Ca(2+) from internal stores and the capability of clearing the cytosol from Ca(2+) after each beat, determine the conditions under which alternans occurs. The contributions from key Ca(2+) -handling proteins (i.e. surface membrane channels, ion pumps and transporters and internal Ca(2+) release channels) are discussed.
Topics: Blood Pressure; Calcium; Heart; Heart Conduction System; Humans; Myocardium; Myocytes, Cardiac
PubMed: 25040398
DOI: 10.1111/1440-1681.12231 -
PLoS Computational Biology Jul 2020Heart failure (HF) is associated with an increased propensity for atrial fibrillation (AF), causing higher mortality than AF or HF alone. It is hypothesized that...
Heart failure (HF) is associated with an increased propensity for atrial fibrillation (AF), causing higher mortality than AF or HF alone. It is hypothesized that HF-induced remodelling of atrial cellular and tissue properties promotes the genesis of atrial action potential (AP) alternans and conduction alternans that perpetuate AF. However, the mechanism underlying the increased susceptibility to atrial alternans in HF remains incompletely elucidated. In this study, we investigated the effects of how HF-induced atrial cellular electrophysiological (with prolonged AP duration) and tissue structural (reduced cell-to-cell coupling caused by atrial fibrosis) remodelling can have an effect on the generation of atrial AP alternans and their conduction at the cellular and one-dimensional (1D) tissue levels. Simulation results showed that HF-induced atrial electrical remodelling prolonged AP duration, which was accompanied by an increased sarcoplasmic reticulum (SR) Ca2+ content and Ca2+ transient amplitude. Further analysis demonstrated that HF-induced atrial electrical remodelling increased susceptibility to atrial alternans mainly due to the increased sarcoplasmic reticulum Ca2+-ATPase (SERCA) Ca2+ reuptake, modulated by increased phospholamban (PLB) phosphorylation, and the decreased transient outward K+ current (Ito). The underlying mechanism has been suggested that the increased SR Ca2+ content and prolonged AP did not fully recover to their previous levels at the end of diastole, resulting in a smaller SR Ca2+ release and AP in the next beat. These produced Ca2+ transient alternans and AP alternans, and further caused AP alternans and Ca2+ transient alternans through Ca2+→AP coupling and AP→Ca2+ coupling, respectively. Simulation of a 1D tissue model showed that the combined action of HF-induced ion channel remodelling and a decrease in cell-to-cell coupling due to fibrosis increased the heart tissue's susceptibility to the formation of spatially discordant alternans, resulting in an increased functional AP propagation dispersion, which is pro-arrhythmic. These findings provide insights into how HF promotes atrial arrhythmia in association with atrial alternans.
Topics: Action Potentials; Algorithms; Animals; Atrial Fibrillation; Atrial Remodeling; Calcium Signaling; Calcium-Binding Proteins; Computer Simulation; Dogs; Electric Conductivity; Heart Atria; Heart Failure; Heart Ventricles; Humans; Mice; Models, Cardiovascular; Myocardial Contraction; Myocytes, Cardiac; Phosphorylation; Sarcoplasmic Reticulum
PubMed: 32658888
DOI: 10.1371/journal.pcbi.1008048