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Early Effects of Prolonged Cardiac Arrest and Ischemic Postconditioning during Cardiopulmonary Resuscitation on Cardiac and Brain Mitochondrial Function in Pigs.
Matsuura TR, Bartos JA, Tsangaris A, Shekar KC, Olson MD, Riess ML, Bienengraeber M, Aufderheide TP, Neumar RW, Rees JN, McKnite SH, Dikalova AE, Dikalov SI, Douglas HF, Yannopoulos D
(2017) Resuscitation 116: 8-15
MeSH Terms: Animals, Brain, Cardiopulmonary Resuscitation, Disease Models, Animal, Heart, Ischemic Postconditioning, Mitochondria, Mitochondria, Heart, Out-of-Hospital Cardiac Arrest, Random Allocation, Swine, Ventricular Fibrillation
Show Abstract · Added March 26, 2019
BACKGROUND - Out-of-hospital cardiac arrest (CA) is a prevalent medical crisis resulting in severe injury to the heart and brain and an overall survival of less than 10%. Mitochondrial dysfunction is predicted to be a key determinant of poor outcomes following prolonged CA. However, the onset and severity of mitochondrial dysfunction during CA and cardiopulmonary resuscitation (CPR) is not fully understood. Ischemic postconditioning (IPC), controlled pauses during the initiation of CPR, has been shown to improve cardiac function and neurologically favorable outcomes after 15min of CA. We tested the hypothesis that mitochondrial dysfunction develops during prolonged CA and can be rescued with IPC during CPR (IPC-CPR).
METHODS - A total of 63 swine were randomized to no ischemia (Naïve), 19min of ventricular fibrillation (VF) CA without CPR (Untreated VF), or 15min of CA with 4min of reperfusion with either standard CPR (S-CPR) or IPC-CPR. Mitochondria were isolated from the heart and brain to quantify respiration, rate of ATP synthesis, and calcium retention capacity (CRC). Reactive oxygen species (ROS) production was quantified from fresh frozen heart and brain tissue.
RESULTS - Compared to Naïve, Untreated VF induced cardiac and brain ROS overproduction concurrent with decreased mitochondrial respiratory coupling and CRC, as well as decreased cardiac ATP synthesis. Compared to Untreated VF, S-CPR attenuated brain ROS overproduction but had no other effect on mitochondrial function in the heart or brain. Compared to Untreated VF, IPC-CPR improved cardiac mitochondrial respiratory coupling and rate of ATP synthesis, and decreased ROS overproduction in the heart and brain.
CONCLUSIONS - Fifteen minutes of VF CA results in diminished mitochondrial respiration, ATP synthesis, CRC, and increased ROS production in the heart and brain. IPC-CPR attenuates cardiac mitochondrial dysfunction caused by prolonged VF CA after only 4min of reperfusion, suggesting that IPC-CPR is an effective intervention to reduce cardiac injury. However, reperfusion with both CPR methods had limited effect on mitochondrial function in the brain, emphasizing an important physiological divergence in post-arrest recovery between those two vital organs.
Copyright © 2017 Elsevier B.V. All rights reserved.
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Variants in the SCN5A Promoter Associated With Various Arrhythmia Phenotypes.
Yagihara N, Watanabe H, Barnett P, Duboscq-Bidot L, Thomas AC, Yang P, Ohno S, Hasegawa K, Kuwano R, Chatel S, Redon R, Schott JJ, Probst V, Koopmann TT, Bezzina CR, Wilde AA, Nakano Y, Aiba T, Miyamoto Y, Kamakura S, Darbar D, Donahue BS, Shigemizu D, Tanaka T, Tsunoda T, Suda M, Sato A, Minamino T, Endo N, Shimizu W, Horie M, Roden DM, Makita N
(2016) J Am Heart Assoc 5:
MeSH Terms: Adolescent, Adult, Aged, Aged, 80 and over, Arrhythmias, Cardiac, Atrial Fibrillation, Brugada Syndrome, Cardiac Conduction System Disease, Child, Female, Genetic Predisposition to Disease, Genetic Variation, Humans, Male, Middle Aged, Mutation, NAV1.5 Voltage-Gated Sodium Channel, Phenotype, Promoter Regions, Genetic, Sick Sinus Syndrome, Ventricular Fibrillation, Young Adult
Show Abstract · Added March 24, 2020
BACKGROUND - Mutations in the coding sequence of SCN5A, which encodes the cardiac Na(+) channel α subunit, have been associated with inherited susceptibility to various arrhythmias. Variable expression of SCN5A is a possible mechanism responsible for this pleiotropic effect; however, it is unknown whether variants in the promoter and regulatory regions of SCN5A also modulate the risk of arrhythmias.
METHODS AND RESULTS - We resequenced the core promoter region of SCN5A and the regulatory regions of SCN5A transcription in 1298 patients with arrhythmia phenotypes (atrial fibrillation, n=444; sinus node dysfunction, n=49; conduction disease, n=133; Brugada syndrome, n=583; and idiopathic ventricular fibrillation, n=89). We identified 26 novel rare variants in the SCN5A promoter in 29 patients affected by various arrhythmias (atrial fibrillation, n=6; sinus node dysfunction, n=1; conduction disease, n=3; Brugada syndrome, n=14; idiopathic ventricular fibrillation, n=5). The frequency of rare variants was higher in patients with arrhythmias than in controls. In the alignment with chromatin immunoprecipitation sequencing data, the majority of variants were located at regions bound by transcription factors. Using a luciferase reporter assay, 6 variants (Brugada syndrome, n=3; idiopathic ventricular fibrillation, n=2; conduction disease, n=1) were functionally characterized, and each displayed decreased promoter activity compared with the wild-type sequences. We also identified rare variants in the regulatory region that were associated with atrial fibrillation, and the variant decreased promoter activity.
CONCLUSIONS - Variants in the core promoter region and the transcription regulatory region of SCN5A were identified in multiple arrhythmia phenotypes, consistent with the idea that altered SCN5A transcription levels modulate susceptibility to arrhythmias.
© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.
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Dantrolene: from better bacon to a treatment for ventricular fibrillation.
Roden DM, Knollmann BC
(2014) Circulation 129: 834-6
MeSH Terms: Animals, Calcium, Dantrolene, Myocardial Contraction, Ventricular Fibrillation
Added February 12, 2015
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5 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.
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9 MeSH Terms
Quantification of transmembrane currents during action potential propagation in the heart.
Gray RA, Mashburn DN, Sidorov VY, Wikswo JP
(2013) Biophys J 104: 268-78
MeSH Terms: Action Potentials, Animals, Computer Simulation, Female, Heart, In Vitro Techniques, Male, Membranes, Microelectrodes, Rabbits, Ventricular Fibrillation
Show Abstract · Added September 26, 2013
The measurement, quantitative analysis, theory, and mathematical modeling of transmembrane potential and currents have been an integral part of the field of electrophysiology since its inception. Biophysical modeling of action potential propagation begins with detailed ionic current models for a patch of membrane within a distributed cable model. Voltage-clamp techniques have revolutionized clinical electrophysiology via the characterization of the transmembrane current gating variables; however, this kinetic information alone is insufficient to accurately represent propagation. Other factors, including channel density, membrane area, surface/volume ratio, axial conductivities, etc., are also crucial determinants of transmembrane currents in multicellular tissue but are extremely difficult to measure. Here, we provide, to our knowledge, a novel analytical approach to compute transmembrane currents directly from experimental data, which involves high-temporal (200 kHz) recordings of intra- and extracellular potential with glass microelectrodes from the epicardial surface of isolated rabbit hearts during propagation. We show for the first time, to our knowledge, that during stable planar propagation the biphasic total transmembrane current (I(m)) dipole density during depolarization was ∼0.25 ms in duration and asymmetric in amplitude (peak outward current was ∼95 μA/cm(2) and peak inward current was ∼140 μA/cm(2)), and the peak inward ionic current (I(ion)) during depolarization was ∼260 μA/cm(2) with duration of ∼1.0 ms. Simulations of stable propagation using the ionic current versus transmembrane potential relationship fit from the experimental data reproduced these values better than traditional ionic models. During ventricular fibrillation, peak I(m) was decreased by 50% and peak I(ion) was decreased by 70%. Our results provide, to our knowledge, novel quantitative information that complements voltage- and patch-clamp data.
Copyright © 2013 Biophysical Society. Published by Elsevier Inc. All rights reserved.
1 Communities
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11 MeSH Terms
Common variation in the NOS1AP gene is associated with drug-induced QT prolongation and ventricular arrhythmia.
Jamshidi Y, Nolte IM, Dalageorgou C, Zheng D, Johnson T, Bastiaenen R, Ruddy S, Talbott D, Norris KJ, Snieder H, George AL, Marshall V, Shakir S, Kannankeril PJ, Munroe PB, Camm AJ, Jeffery S, Roden DM, Behr ER
(2012) J Am Coll Cardiol 60: 841-50
MeSH Terms: Adaptor Proteins, Signal Transducing, Adult, Aged, Aged, 80 and over, Amiodarone, Anti-Arrhythmia Agents, Case-Control Studies, Female, Humans, Long QT Syndrome, Male, Middle Aged, Polymorphism, Single Nucleotide, Sequence Analysis, DNA, Torsades de Pointes, Ventricular Fibrillation, Young Adult
Show Abstract · Added June 26, 2014
OBJECTIVES - This study sought to determine whether variations in NOS1AP affect drug-induced long QT syndrome (LQTS).
BACKGROUND - Use of antiarrhythmic drugs is limited by the high incidence of serious adverse events including QT prolongation and torsades de pointes. NOS1AP gene variants play a role in modulating QT intervals in healthy subjects and severity of presentation in LQTS.
METHODS - This study carried out an association study using 167 single nucleotide polymorphisms (SNP) spanning the NOS1AP gene in 58 Caucasian patients experiencing drug-induced LQTS (dLQTS) and 87 Caucasian controls from the DARE (Drug-Induced Arrhythmia Risk Evaluation) study.
RESULTS - The rs10800397 SNP was significantly associated with dLQTS (odds ratio [OR]: 3.3, 99.95% confidence interval [CI]: 1.0 to 10.8, p = 3.7 × 10(-4)). The associations were more pronounced in the subgroup of amiodarone users, in which 3 SNPs, including rs10800397, were significantly associated (most significant SNP: rs10919035: OR: 5.5, 99.95% CI: 1.1 to 27.9, p = 3.0 × 10(-4)). We genotyped rs10919035 in an independent replication cohort of 28 amiodarone dLQTS cases versus 173 control subjects (meta-analysis of both studies: OR: 2.81, 99.95% CI: 1.62 to 4.89, p = 2.4 × 10(-4)). Analysis of corrected QT interval among 74 control subjects from our dataset showed a similar pattern of significance over the gene region as the case-control analysis. This pattern was confirmed in 1,480 control subjects from the BRIGHT (British Genetics of Hypertension Study) cohort (top SNP from DARE: rs12734991 in meta-analysis: increase in corrected QT interval per C allele: 9.1 ± 3.2 ms, p = 1.7 × 10(-4)).
CONCLUSIONS - These results provide the first demonstration that common variations in the NOS1AP gene are associated with a significant increase in the risk of dLQTS. This study suggests that common variations in the NOS1AP gene may have relevance for future pharmacogenomic applications in clinical practice permitting safer prescription of drugs for vulnerable patients.
Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
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17 MeSH Terms
Cardiovascular disease: several small shocks beat one big one.
Gray RA, Wikswo JP
(2011) Nature 475: 181-2
MeSH Terms: Animals, Atrial Fibrillation, Dogs, Electric Countershock, Electrodes, Heart, Humans, Ventricular Fibrillation
Added March 27, 2014
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8 MeSH Terms
Genome-wide association study identifies a susceptibility locus at 21q21 for ventricular fibrillation in acute myocardial infarction.
Bezzina CR, Pazoki R, Bardai A, Marsman RF, de Jong JSSG, Blom MT, Scicluna BP, Jukema JW, Bindraban NR, Lichtner P, Pfeufer A, Bishopric NH, Roden DM, Meitinger T, Chugh SS, Myerburg RJ, Jouven X, Kääb S, Dekker LRC, Tan HL, Tanck MWT, Wilde AAM
(2010) Nat Genet 42: 688-691
MeSH Terms: Acute Disease, Aged, Anterior Wall Myocardial Infarction, Arrhythmias, Cardiac, Death, Sudden, Cardiac, Disease Susceptibility, Female, Genome-Wide Association Study, Heart Arrest, Humans, Male, Middle Aged, Myocardial Infarction, Netherlands, Odds Ratio, Ventricular Fibrillation
Show Abstract · Added June 26, 2014
Sudden cardiac death from ventricular fibrillation during acute myocardial infarction is a leading cause of total and cardiovascular mortality. To our knowledge, we here report the first genome-wide association study for this trait, conducted in a set of 972 individuals with a first acute myocardial infarction, 515 of whom had ventricular fibrillation and 457 of whom did not, from the Arrhythmia Genetics in The Netherlands (AGNES) study. The most significant association to ventricular fibrillation was found at 21q21 (rs2824292, odds ratio = 1.78, 95% CI 1.47-2.13, P = 3.3 x 10(-10)). The association of rs2824292 with ventricular fibrillation was replicated in an independent case-control set consisting of 146 out-of-hospital cardiac arrest individuals with myocardial infarction complicated by ventricular fibrillation and 391 individuals who survived a myocardial infarction (controls) (odds ratio = 1.49, 95% CI 1.14-1.95, P = 0.004). The closest gene to this SNP is CXADR, which encodes a viral receptor previously implicated in myocarditis and dilated cardiomyopathy and which has recently been identified as a modulator of cardiac conduction. This locus has not previously been implicated in arrhythmia susceptibility.
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16 MeSH Terms
Keep the QT interval: it is a reliable predictor of ventricular arrhythmias.
Roden DM
(2008) Heart Rhythm 5: 1213-5
MeSH Terms: Arrhythmias, Cardiac, Heart Conduction System, Humans, Long QT Syndrome, Prognosis, Risk Factors, Tachycardia, Ventricular, Time Factors, Ventricular Fibrillation
Added March 24, 2020
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Experimental evidence of improved transthoracic defibrillation with electroporation-enhancing pulses.
Malkin RA, Guan D, Wikswo JP
(2006) IEEE Trans Biomed Eng 53: 1901-10
MeSH Terms: Animals, Computer Simulation, Electric Countershock, Electroporation, Evidence-Based Medicine, Guinea Pigs, Male, Models, Cardiovascular, Swine, Therapy, Computer-Assisted, Thorax, Treatment Outcome, Ventricular Fibrillation
Show Abstract · Added February 2, 2015
UNLABELLED - There is considerable work on defibrillation wave form optimization. This paper determines the impedance changes during defibrillation, then uses that information to derive the optimum defibrillation wave form.
METHODS PART I - Twelve guinea pigs and six swine were used to measure the current wave form for square voltage pulses of a strength which would defibrillate about 50% of the time. In guinea pigs, electrodes were placed thoracically, abdominally and subcutaneously using two electrode materials (zinc and steel) and two electrode pastes (Core-gel and metallic paste).
RESULTS PART I - The measured current wave form indicated an exponentially increasing conductance over the first 3 ms, consistent with enhanced electroporation or another mechanism of time-dependent conductance. We fit this current with a parallel conductance composed of a time-independent component (g0 = 1.22 +/- 0.28 mS) and a time-dependent component described by g delta (1-e(-t/tau)), where g delta = 0.95 +/- 0.20 mS and tau = 0.82 +/- 0.17 ms in guinea pigs using zinc and Cor-gel. Different electrode placements and materials had no significant effect on this fit. From our fit, we determined the stimulating wave form that would theoretically charge the myocardial membrane to a given threshold using the least energy from the defibrillator. The solution was a very short, high voltage pulse followed immediately by a truncated ascending exponential tail.
METHODS PART II - The optimized wave forms and similar nonoptimized wave forms were tested for efficacy in 25 additional guinea pigs and six additional swine using methods similar to Part I.
RESULTS PART II - Optimized wave forms were significantly more efficacious than similar nonoptimized wave forms. In swine, a wave form with the short pulse was 41% effective while the same wave form without the short pulse was 8.3% effective (p < 0.03) despite there being only a small difference in energy (111 J versus 116 CONCLUSIONS: We conclude that a short pulse preceding a defibrillation pulse significantly improves efficacy, perhaps by enhancing electroporation.
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13 MeSH Terms