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Reactive γ-ketoaldehydes promote protein misfolding and preamyloid oligomer formation in rapidly-activated atrial cells.
Sidorova TN, Yermalitskaya LV, Mace LC, Wells KS, Boutaud O, Prinsen JK, Davies SS, Roberts LJ, Dikalov SI, Glabe CG, Amarnath V, Barnett JV, Murray KT
(2015) J Mol Cell Cardiol 79: 295-302
MeSH Terms: Aldehydes, Amines, Amyloid, Animals, Atrial Natriuretic Factor, Cardiac Pacing, Artificial, Cell Line, Curcumin, Cytosol, Heart Atria, Humans, Mice, Models, Biological, Oxidative Stress, Protein Folding, Protein Multimerization, Superoxides
Show Abstract · Added December 5, 2014
Rapid activation causes remodeling of atrial myocytes resembling that which occurs in experimental and human atrial fibrillation (AF). Using this cellular model, we previously observed transcriptional upregulation of proteins implicated in protein misfolding and amyloidosis. For organ-specific amyloidoses such as Alzheimer's disease, preamyloid oligomers (PAOs) are now recognized to be the primary cytotoxic species. In the setting of oxidative stress, highly-reactive lipid-derived mediators known as γ-ketoaldehydes (γ-KAs) have been identified that rapidly adduct proteins and cause PAO formation for amyloid β1-42 implicated in Alzheimer's. We hypothesized that rapid activation of atrial cells triggers oxidative stress with lipid peroxidation and formation of γ-KAs, which then rapidly crosslink proteins to generate PAOs. To investigate this hypothesis, rapidly-paced and control, spontaneously-beating atrial HL-1 cells were probed with a conformation-specific antibody recognizing PAOs. Rapid stimulation of atrial cells caused the generation of cytosolic PAOs along with a myocyte stress response (e.g., transcriptional upregulation of Nppa and Hspa1a), both of which were absent in control, unpaced cells. Rapid activation also caused the formation of superoxide and γ-KA adducts in atriomyocytes, while direct exposure of cells to γ-KAs resulted in PAO production. Increased cytosolic atrial natriuretic peptide (ANP), and the generation of ANP oligomers with exposure to γ-KAs and rapid atrial HL-1 cell stimulation, strongly suggest a role for ANP in PAO formation. Salicylamine (SA) is a small molecule scavenger of γ-KAs that can protect proteins from modification by these reactive compounds. PAO formation and transcriptional remodeling were inhibited when cells were stimulated in the presence of SA, but not with the antioxidant curcumin, which is incapable of scavenging γ-KAs. These results demonstrate that γ-KAs promote protein misfolding and PAO formation as a component of the atrial cell stress response to rapid activation, and they provide a potential mechanistic link between oxidative stress and atrial cell injury.
Copyright © 2014 Elsevier Ltd. All rights reserved.
2 Communities
6 Members
0 Resources
17 MeSH Terms
Ictal asystole and ictal syncope: insights into clinical management.
Bestawros M, Darbar D, Arain A, Abou-Khalil B, Plummer D, Dupont WD, Raj SR
(2015) Circ Arrhythm Electrophysiol 8: 159-64
MeSH Terms: Adult, Anticonvulsants, Cardiac Pacing, Artificial, Disease-Free Survival, Electrocardiography, Electroencephalography, Female, Heart Arrest, Humans, Male, Middle Aged, Neurosurgical Procedures, Pacemaker, Artificial, Patient Selection, Predictive Value of Tests, Retrospective Studies, Risk Factors, Seizures, Syncope, Time Factors, Treatment Outcome, Video Recording
Show Abstract · Added January 20, 2015
BACKGROUND - Ictal asystole is a rare, serious, and often treatable cause of syncope. There are currently limited data to guide management. Characterization of ictal syncope predictors may aid in the selection of high-risk patients for treatments such as pacemakers.
METHODS AND RESULTS - We searched our epilepsy monitoring unit database from October 2003 to July 2013 for all patients with ictal asystole events. Clinical, electroencephalogram, and ECG data for each of their seizures were examined for their relationships with ictal syncope events. In 10 patients with ictal asystole, we observed 76 clinical seizures with 26 ictal asystole episodes, 15 of which led to syncope. No seizure with asystole duration≤6 s led to syncope, whereas 94% (15/16) of seizures with asystole duration>6 s led to syncope (P=0.02). During ictal asystole events, 4 patients had left temporal seizure onset, 4 patients had right temporal seizure onset, and 2 patients had both. Syncope was more common with left temporal (40%) than with right temporal seizures (10%; P=0.002). Treatment options included antiepileptic drug changes, epilepsy surgery, and pacemaker implantation. Eight patients received pacemakers. During follow-up of 72±95 months, all patients remained syncope free.
CONCLUSIONS - Ictal asystole>6 s is strongly associated with ictal syncope. Ictal syncope is more common in left than in right temporal seizures. A permanent pacemaker should be considered in patients with ictal syncope if they are not considered good candidates for epilepsy surgery.
© 2014 American Heart Association, Inc.
0 Communities
1 Members
0 Resources
22 MeSH Terms
Suppression of spontaneous ca elevations prevents atrial fibrillation in calsequestrin 2-null hearts.
Faggioni M, Savio-Galimberti E, Venkataraman R, Hwang HS, Kannankeril PJ, Darbar D, Knollmann BC
(2014) Circ Arrhythm Electrophysiol 7: 313-20
MeSH Terms: Animals, Atrial Fibrillation, Calcium, Calsequestrin, Cardiac Pacing, Artificial, Disease Models, Animal, Mice, Mice, Knockout, Muscle Cells, Propafenone, Treatment Outcome, Voltage-Gated Sodium Channel Blockers
Show Abstract · Added May 29, 2014
BACKGROUND - Atrial fibrillation (AF) risk has been associated with leaky ryanodine receptor 2 (RyR2) Ca release channels. Patients with mutations in RyR2 or in the sarcoplasmic reticulum Ca-binding protein calsequestrin 2 (Casq2) display an increased risk for AF. Here, we examine the underlying mechanisms of AF associated with loss of Casq2 and test mechanism-based drug therapy.
METHODS AND RESULTS - Compared with wild-type Casq2+/+ mice, atrial burst pacing consistently induced atrial flutter or AF in Casq2-/- mice and in isolated Casq2-/- hearts. Atrial optical voltage maps obtained from isolated hearts revealed multiple independent activation sites arising predominantly from the pulmonary vein region. Ca and voltage mapping demonstrated diastolic subthreshold spontaneous Ca elevations (SCaEs) and delayed afterdepolarizations whenever the pacing train failed to induce AF. The dual RyR2 and Na channel inhibitor R-propafenone (3 μmol/L) significantly reduced frequency and amplitude of SCaEs and delayed afterdepolarizations in atrial myocytes and intact atria and prevented induction of AF. In contrast, the S-enantiomer of propafenone, an equipotent Na channel blocker but much weaker RyR2 inhibitor, did not reduce SCaEs and delayed afterdepolarizations and failed to prevent AF.
CONCLUSIONS - Loss of Casq2 increases risk of AF by promoting regional SCaEs and delayed afterdepolarizations in atrial tissue, which can be prevented by RyR2 inhibition with R-propafenone. Targeting AF caused by leaky RyR2 Ca channels with R-propafenone may be a more mechanism-based approach to treating this common arrhythmia.
0 Communities
2 Members
0 Resources
12 MeSH Terms
Transmembrane current imaging in the heart during pacing and fibrillation.
Gray RA, Mashburn DN, Sidorov VY, Roth BJ, Pathmanathan P, Wikswo JP
(2013) Biophys J 105: 1710-9
MeSH Terms: Action Potentials, Algorithms, Animals, Cardiac Pacing, Artificial, Membrane Potentials, Models, Cardiovascular, Rabbits, Ventricular Fibrillation, Voltage-Sensitive Dye Imaging
Show Abstract · Added March 7, 2014
Recently, we described a method to quantify the time course of total transmembrane current (Im) and the relative role of its two components, a capacitive current (Ic) and a resistive current (Iion), corresponding to the cardiac action potential during stable propagation. That approach involved recording high-fidelity (200 kHz) transmembrane potential (Vm) signals with glass microelectrodes at one site using a spatiotemporal coordinate transformation via measured conduction velocity. Here we extend our method to compute these transmembrane currents during stable and unstable propagation from fluorescence signals of Vm at thousands of sites (3 kHz), thereby introducing transmembrane current imaging. In contrast to commonly used linear Laplacians of extracellular potential (Ve) to compute Im, we utilized nonlinear image processing to compute the required second spatial derivatives of Vm. We quantified the dynamic spatial patterns of current density of Im and Iion for both depolarization and repolarization during pacing (including nonplanar patterns) by calibrating data with the microelectrode signals. Compared to planar propagation, we found that the magnitude of Iion was significantly reduced at sites of wave collision during depolarization but not repolarization. Finally, we present uncalibrated dynamic patterns of Im during ventricular fibrillation and show that Im at singularity sites was monophasic and positive with a significant nonzero charge (Im integrated over 10 ms) in contrast with nonsingularity sites. Our approach should greatly enhance the understanding of the relative roles of functional (e.g., rate-dependent membrane dynamics and propagation patterns) and static spatial heterogeneities (e.g., spatial differences in tissue resistance) via recordings during normal and compromised propagation, including arrhythmias.
Copyright © 2013 Biophysical Society. Published by Elsevier Inc. All rights reserved.
1 Communities
2 Members
0 Resources
9 MeSH Terms
Acoustic radiation force impulse imaging of mechanical stiffness propagation in myocardial tissue.
Hsu SJ, Byram BC, Bouchard RR, Dumont DM, Wolf PD, Trahey GE
(2012) Ultrason Imaging 34: 142-58
MeSH Terms: Animals, Cardiac Pacing, Artificial, Cardiac-Gated Imaging Techniques, Dogs, Echocardiography, Elasticity Imaging Techniques, Electrocardiography, Image Enhancement, Least-Squares Analysis, Systole, Transducers
Show Abstract · Added May 29, 2014
Acoustic radiation force impulse (ARFI) imaging has been shown to be capable of imaging local myocardial stiffness changes throughout the cardiac cycle. Expanding on these results, the authors present experiments using cardiac ARFI imaging to visualize and quantify the propagation of mechanical stiffness during ventricular systole. In vivo ARFI images of the left ventricular free wall of two exposed canine hearts were acquired. Images were formed while the heart was externally paced by one of two electrodes positioned on the epicardial surface and either side of the imaging plane. Two-line M-mode ARFI images were acquired at a sampling frequency of 120 Hz while the heart was paced from an external stimulating electrode. Two-dimensional ARFI images were also acquired, and an average propagation velocity across the lateral field of view was calculated. Directions and speeds of myocardial stiffness propagation were measured and compared with the propagations derived from the local electrocardiogram (ECG), strain, and tissue velocity measurements estimated during systole. In all ARFI images, the direction of myocardial stiffness propagation was seen to be away from the stimulating electrode and occurred with similar velocity magnitudes in either direction. When compared with the local epicardial ECG, the mechanical stiffness waves were observed to travel in the same direction as the propagating electrical wave and with similar propagation velocities. In a comparison between ARFI, strain, and tissue velocity imaging, the three methods also yielded similar propagation velocities.
0 Communities
1 Members
0 Resources
11 MeSH Terms
Risk factors for bradycardia requiring pacemaker implantation in patients with atrial fibrillation.
Barrett TW, Abraham RL, Jenkins CA, Russ S, Storrow AB, Darbar D
(2012) Am J Cardiol 110: 1315-21
MeSH Terms: Age Distribution, Aged, Aged, 80 and over, Atrial Fibrillation, Bradycardia, Cardiac Pacing, Artificial, Case-Control Studies, Confidence Intervals, Electrocardiography, Female, Follow-Up Studies, Humans, Incidence, Logistic Models, Male, Middle Aged, Multivariate Analysis, Odds Ratio, Pacemaker, Artificial, Retrospective Studies, Risk Factors, Severity of Illness Index, Sex Distribution, Survival Analysis, Treatment Outcome
Show Abstract · Added January 20, 2015
Symptomatic bradycardia may complicate atrial fibrillation (AF) and necessitate a permanent pacemaker. Identifying patients at increased risk for symptomatic bradycardia may reduce associated morbidities and health care costs. The aim of this study was to investigate predictors for developing bradycardia requiring a permanent pacemaker in patients with AF. The records of all patients treated for AF or atrial flutter in an academic hospital's emergency department from August 1, 2005, to July 31, 2008, were reviewed. Survival and the presence of a pacemaker as of November 1, 2011, were determined. Cases were defined as patients with pacemakers placed for bradycardia after their AF diagnoses. Patients without pacemakers who were followed constituted the control group. Variables for the logistic regression analysis were identified a priori. A post hoc model was fit adjusting for AF type and atrioventricular nodal blocker use. Of the 362 patients in the cohort, 119 cases had permanent pacemakers implanted for bradycardia after AF diagnosis, and 243 controls were alive without pacemakers. The median follow-up time was 4.5 years (interquartile range 3.8 to 5.4). Odds ratios were determined for age at the time of AF diagnosis (1.02, 95% confidence interval [CI] 1 to 1.04), female gender (1.58, 95% CI 0.95 to 2.63), previous heart failure (2.72, 95% CI 1.47 to 5.01), and African American race (0.33, 95% CI 0.12 to 0.94). The post hoc model identified permanent AF (odds ratio 2.99, 95% CI 1.61 to 5.57) and atrioventricular nodal blocker use (odds ratio 1.43, 95% CI 0.85 to 2.4). In conclusion, in patients with AF, heart failure and permanent AF each nearly triple the odds of developing bradycardia requiring a permanent pacemaker; although not statistically significant, our results suggest that women are more likely and African Americans less likely to develop bradycardia requiring pacemaker implantation.
Copyright © 2012 Elsevier Inc. All rights reserved.
0 Communities
1 Members
0 Resources
25 MeSH Terms
Regional increase of extracellular potassium leads to electrical instability and reentry occurrence through the spatial heterogeneity of APD restitution.
Sidorov VY, Uzelac I, Wikswo JP
(2011) Am J Physiol Heart Circ Physiol 301: H209-20
MeSH Terms: Action Potentials, Anesthetics, Local, Animals, Arrhythmias, Cardiac, Cardiac Pacing, Artificial, Coronary Circulation, Coronary Vessels, Data Interpretation, Statistical, Electric Stimulation, Electrophysiological Phenomena, Extracellular Space, Female, Fluorescent Dyes, Heart Conduction System, Heart Rate, In Vitro Techniques, Kinetics, Male, Myocardial Ischemia, Myocardium, Potassium, Rabbits
Show Abstract · Added May 29, 2014
The heterogeneities of electrophysiological properties of cardiac tissue are the main factors that control both arrhythmia induction and maintenance. Although the local increase of extracellular potassium ([K(+)](o)) due to coronary occlusion is a well-established metabolic response to acute ischemia, the role of local [K(+)](o) heterogeneity in phase 1a arrhythmias has yet to be determined. In this work, we created local [K(+)](o) heterogeneity and investigated its role in fast pacing response and arrhythmia induction. The left marginal vein of a Langendorff-perfused rabbit heart was cannulated and perfused separately with solutions containing 4, 6, 8, 10, and 12 mM of K(+). The fluorescence dye was utilized to map the voltage distribution. We tested stimulation rates, starting from 400 ms down to 120 ms, with steps of 5-50 ms. We found that local [K(+)](o) heterogeneity causes action potential (AP) alternans, 2:1 conduction block, and wave breaks. The effect of [K(+)](o) heterogeneity on electrical stability and vulnerability to arrhythmia induction was largest during regional perfusion with 10 mM of K(+). We detected three concurrent dynamics: normally propagating activation when excitation waves spread over tissue perfused with normal K(+), alternating 2:2 rhythm near the border of [K(+)](o) heterogeneity, and 2:1 aperiodicity when propagation was within the high [K(+)](o) area. [K(+)](o) elevation changed the AP duration (APD) restitution and shifted the restitution curve toward longer diastolic intervals and shorter APD. We conclude that spatial heterogeneity of the APD restitution, created with regional elevation of [K(+)](o), can lead to AP instability, 2:1 block, and reentry induction.
1 Communities
2 Members
0 Resources
22 MeSH Terms
Relation of QRS width in healthy persons to risk of future permanent pacemaker implantation.
Cheng S, Larson MG, Keyes MJ, McCabe EL, Newton-Cheh C, Levy D, Benjamin EJ, Vasan RS, Wang TJ
(2010) Am J Cardiol 106: 668-72
MeSH Terms: Adult, Aged, Aged, 80 and over, Bundle-Branch Block, Cardiac Pacing, Artificial, Case-Control Studies, Cohort Studies, Electrocardiography, Female, Humans, Incidence, Male, Middle Aged, Pacemaker, Artificial, Proportional Hazards Models, Risk Assessment, Severity of Illness Index, Young Adult
Show Abstract · Added April 15, 2014
In the setting of acute myocardial infarction, prolongation of the QRS interval on electrocardiography identifies patients at risk for needing permanent pacemaker implantation. However, the implications of prolonged QRS intervals in healthy subjects are unclear, especially given that the QRS prolongation encountered in this setting is typically mild. The aim of this study was to assess the relation between QRS duration and incident pacemaker implantation in a community-based cohort of 8,311 subjects (mean age 54 years, 55% women) who attended 17,731 routine examinations with resting 12-lead electrocardiography. QRS duration was analyzed as a continuous and a categorical variable (<100, 100 to <120, and > or =120 ms). During up to 35 years of follow-up, 157 participants (56 women) developed need for permanent pacemakers. In multivariable Cox regression models adjusting for cardiovascular risk factors and previous myocardial infarction or heart failure, mild QRS prolongation was associated with a threefold risk for pacemaker implantation (adjusted hazard ratio 2.90, 95% confidence interval 1.81 to 4.66, p <0.0001), and bundle branch block was associated with a fourfold risk for pacemaker implantation (hazard ratio 4.43, 95% confidence interval 2.94 to 6.68, p <0.0001). Each standard deviation increment in QRS duration (11 ms) was associated with an adjusted hazard ratio of 1.14 (95% confidence interval 1.11 to 1.18, p <0.0001) for pacemaker placement. This association remained significant after excluding subjects with QRS durations > or =120 ms. In conclusion, subjects with prolonged QRS durations, even without bundle branch block, are at increased risk for future pacemaker implantation. Such individuals may warrant monitoring for progressive conduction disease.
2010 Elsevier Inc. All rights reserved.
0 Communities
1 Members
0 Resources
18 MeSH Terms
Transcatheter aortic valve implantation: anesthetic considerations.
Billings FT, Kodali SK, Shanewise JS
(2009) Anesth Analg 108: 1453-62
MeSH Terms: Aged, Aged, 80 and over, Anesthesia, General, Aortic Valve, Aortic Valve Stenosis, Cardiac Catheterization, Cardiac Pacing, Artificial, Cardiovascular Agents, Echocardiography, Transesophageal, Electrocardiography, Feasibility Studies, Female, Heart Valve Prosthesis, Heart Valve Prosthesis Implantation, Hemodynamics, Humans, Intraoperative Care, Male, Prospective Studies, Prosthesis Design, Radiography, Interventional, Treatment Outcome
Show Abstract · Added January 20, 2015
Aortic valvular stenosis remains the most common debilitating valvular heart lesion. Despite the benefit of aortic valve (AV) replacement, many high-risk patients cannot tolerate surgery. AV implantation treats aortic stenosis without subjecting patients to sternotomy, cardiopulmonary bypass (CPB), and aorta cross-clamping. This transcatheter procedure is performed via puncture of the left ventricular (LV) apex or percutaneously, via the femoral artery or vein. Patients undergo general anesthesia, intense hemodynamic manipulation, and transesophageal echocardiography (TEE). To elucidate the role of the anesthesiologist in the management of transcatheter AV implantation, we review the literature and provide our experience, focusing on anesthetic care, intraoperative events, TEE, and perioperative complications. Two approaches to the aortic annulus are performed today: transfemoral retrograde and transapical antegrade. Iliac artery size and tortuosity, aortic arch atheroma, and pathology in the area of the (LV) apex help determine the preferred approach in each patient. A general anesthetic is tailored to achieve extubation after procedure completion, whereas IV access and pharmacological support allow for emergent sternotomy and initiation of CPB. Rapid ventricular pacing and cessation of mechanical ventilation interrupts cardiac ejection and minimizes heart translocation during valvuloplasty and prosthesis implantation. Although these maneuvers facilitate exact prosthesis positioning within the native annulus, they promote hypotension and arrhythmia. Vasopressor administration before pacing and cardioversion may restore adequate hemodynamics. TEE determines annulus size, aortic pathology, ventricular function, and mitral regurgitation. TEE and fluoroscopy are used for positioning the introducer catheter within the aortic annulus. The prosthesis, crimped on a valvuloplasty balloon catheter, is implanted by inflation. TEE immediately measures aortic regurgitation and assesses for aortic dissection. After repair of femoral vessels or LV apex, patients are allowed to emerge and assessed for extubation. Observed and published complications include aortic regurgitation, prosthesis embolization, mitral valve disruption, hemorrhage, aortic dissection, CPB, stroke, and death. Transcatheter AV implantation relies on intraoperative hemodynamic manipulation for success. Transfemoral and transapical approaches pose unique management challenges, but both require rapid ventricular pacing, the management of hypotension and arrhythmias during beating-heart valve implantation, and TEE. Anesthesiologists will care for debilitated patients with aortic stenosis receiving transcatheter AV implantation.
0 Communities
1 Members
0 Resources
22 MeSH Terms
Repolarization reserve: a moving target.
Roden DM
(2008) Circulation 118: 981-2
MeSH Terms: Animals, Cardiac Pacing, Artificial, Cells, Cultured, Dogs, Heart Ventricles, Humans, KCNQ1 Potassium Channel, MicroRNAs, Myocardium, Myocytes, Cardiac, Phenethylamines, Potassium, Potassium Channel Blockers, RNA, Messenger, Sodium, Sulfonamides, Up-Regulation
Added June 26, 2014
0 Communities
1 Members
0 Resources
17 MeSH Terms