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Darwin Jeyaraj - One of the best experts on this subject based on the ideXlab platform.
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circadian rhythms govern cardiac repolarization and Arrhythmogenesis
Nature, 2012Co-Authors: Darwin Jeyaraj, Yuan Lu, Saptarsi M. Haldar, Mark D Mccauley, Juergen Ripperger, Kun Hu, Betty L Eapen, Nikunj Sharma, Eckhard Ficker, Michael J CutlerAbstract:Circadian rhythmicity of cardiac ion-channel expression and of an index of myocardial repolarization is under the control of Klf15, a clock-dependent oscillator that is required for generating transient outward potassium current, and deficiencies or excesses of which cause loss of rhythmic variation in myocardial and abnormal repolarization, and an enhanced susceptibility to ventricular arrhythmias. Several physiological parameters in the cardiovascular system show diurnal variation. Mukesh Jain and colleagues now provide a link between circadian rhythms and Arrhythmogenesis in mice. They show that the transcription factor Klf15 is regulated by components of the circadian clock, and Klf15 in turn regulates expression of the ion channel KChIP2. In gain- and loss-of-function experiments, the authors show that Klf15 regulates temporal variation in cardiac repolarization and susceptibility to arrhythmias. The findings raise the possibility that circadian factors contribute to the diurnal variation seen in occurrence of sudden cardiac death. Sudden cardiac death exhibits diurnal variation in both acquired and hereditary forms of heart disease1,2, but the molecular basis of this variation is unknown. A common mechanism that underlies susceptibility to ventricular arrhythmias is abnormalities in the duration (for example, short or long QT syndromes and heart failure)3,4,5 or pattern (for example, Brugada’s syndrome)6 of myocardial repolarization. Here we provide molecular evidence that links circadian rhythms to vulnerability in ventricular arrhythmias in mice. Specifically, we show that cardiac ion-channel expression and QT-interval duration (an index of myocardial repolarization) exhibit endogenous circadian rhythmicity under the control of a clock-dependent oscillator, kruppel-like factor 15 (Klf15). Klf15 transcriptionally controls rhythmic expression of Kv channel-interacting protein 2 (KChIP2), a critical subunit required for generating the transient outward potassium current7. Deficiency or excess of Klf15 causes loss of rhythmic QT variation, abnormal repolarization and enhanced susceptibility to ventricular arrhythmias. These findings identify circadian transcription of ion channels as a mechanism for cardiac Arrhythmogenesis.
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circadian rhythms govern cardiac repolarization and Arrhythmogenesis
Nature, 2012Co-Authors: Darwin Jeyaraj, Saptarsi M. Haldar, Mark D Mccauley, Juergen Ripperger, Betty L Eapen, Nikunj Sharma, Eckhard Ficker, Michael J Cutler, Xiaoping Wan, James GulickAbstract:Sudden cardiac death exhibits diurnal variation in both acquired and hereditary forms of heart disease, but the molecular basis of this variation is unknown. A common mechanism that underlies susceptibility to ventricular arrhythmias is abnormalities in the duration (for example, short or long QT syndromes and heart failure) or pattern (for example, Brugada's syndrome) of myocardial repolarization. Here we provide molecular evidence that links circadian rhythms to vulnerability in ventricular arrhythmias in mice. Specifically, we show that cardiac ion-channel expression and QT-interval duration (an index of myocardial repolarization) exhibit endogenous circadian rhythmicity under the control of a clock-dependent oscillator, kruppel-like factor 15 (Klf15). Klf15 transcriptionally controls rhythmic expression of Kv channel-interacting protein 2 (KChIP2), a critical subunit required for generating the transient outward potassium current. Deficiency or excess of Klf15 causes loss of rhythmic QT variation, abnormal repolarization and enhanced susceptibility to ventricular arrhythmias. These findings identify circadian transcription of ion channels as a mechanism for cardiac Arrhythmogenesis.
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enhanced dispersion of repolarization explains increased Arrhythmogenesis in severe versus therapeutic hypothermia
Circulation-arrhythmia and Electrophysiology, 2011Co-Authors: Joseph S Piktel, Darwin Jeyaraj, Tamer H Said, David S Rosenbaum, Lance D WilsonAbstract:Background— Hypothermia is proarrhythmic, and, as the use of therapeutic hypothermia (TH) increases, it is critically important to understand the electrophysiological effects of hypothermia on cardiac myocytes and arrhythmia substrates. We tested the hypothesis that hypothermia-enhanced transmural dispersion of repolarization (DOR) is a mechanism of Arrhythmogenesis in hypothermia. In addition, we investigated whether the degree of hypothermia, the rate of temperature change, and cooling versus rewarming would alter hypothermia-induced arrhythmia substrates. Methods and Results— Optical action potentials were recorded from cells spanning the transmural wall of canine left ventricular wedge preparations at baseline (36°C), during cooling and during rewarming. Electrophysiological parameters were examined while varying the depth of hypothermia. On cooling to 26°C, DOR increased from 26±4 ms to 93±18 ms ( P =0.021); conduction velocity decreased from 35±5 cm/s to 22±5 cm/s ( P =0.010). On rewarming to 36°C, DOR remained prolonged, whereas conduction velocity returned to baseline. Conduction block and reentry was observed in all severe hypothermia preparations. Ventricular fibrillation/ventricular tachycardia was seen more during rewarming (4/5) versus cooling (2/6). In TH (n=7), cooling to 32°C mildly increased DOR (31±6 to 50±9, P =0.012), with return to baseline on rewarming and was associated with decreased arrhythmia susceptibility. Increased rate of cooling did not further enhance DOR or Arrhythmogenesis. Conclusions— Hypothermia amplifies DOR and is a mechanism for Arrhythmogenesis. DOR is directly dependent on the depth of cooling and rewarming. This provides insight into the clinical observation of a low incidence of arrhythmias in TH and has implications for protocols for the clinical application of TH.
Michael J Cutler - One of the best experts on this subject based on the ideXlab platform.
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circadian rhythms govern cardiac repolarization and Arrhythmogenesis
Nature, 2012Co-Authors: Darwin Jeyaraj, Yuan Lu, Saptarsi M. Haldar, Mark D Mccauley, Juergen Ripperger, Kun Hu, Betty L Eapen, Nikunj Sharma, Eckhard Ficker, Michael J CutlerAbstract:Circadian rhythmicity of cardiac ion-channel expression and of an index of myocardial repolarization is under the control of Klf15, a clock-dependent oscillator that is required for generating transient outward potassium current, and deficiencies or excesses of which cause loss of rhythmic variation in myocardial and abnormal repolarization, and an enhanced susceptibility to ventricular arrhythmias. Several physiological parameters in the cardiovascular system show diurnal variation. Mukesh Jain and colleagues now provide a link between circadian rhythms and Arrhythmogenesis in mice. They show that the transcription factor Klf15 is regulated by components of the circadian clock, and Klf15 in turn regulates expression of the ion channel KChIP2. In gain- and loss-of-function experiments, the authors show that Klf15 regulates temporal variation in cardiac repolarization and susceptibility to arrhythmias. The findings raise the possibility that circadian factors contribute to the diurnal variation seen in occurrence of sudden cardiac death. Sudden cardiac death exhibits diurnal variation in both acquired and hereditary forms of heart disease1,2, but the molecular basis of this variation is unknown. A common mechanism that underlies susceptibility to ventricular arrhythmias is abnormalities in the duration (for example, short or long QT syndromes and heart failure)3,4,5 or pattern (for example, Brugada’s syndrome)6 of myocardial repolarization. Here we provide molecular evidence that links circadian rhythms to vulnerability in ventricular arrhythmias in mice. Specifically, we show that cardiac ion-channel expression and QT-interval duration (an index of myocardial repolarization) exhibit endogenous circadian rhythmicity under the control of a clock-dependent oscillator, kruppel-like factor 15 (Klf15). Klf15 transcriptionally controls rhythmic expression of Kv channel-interacting protein 2 (KChIP2), a critical subunit required for generating the transient outward potassium current7. Deficiency or excess of Klf15 causes loss of rhythmic QT variation, abnormal repolarization and enhanced susceptibility to ventricular arrhythmias. These findings identify circadian transcription of ion channels as a mechanism for cardiac Arrhythmogenesis.
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circadian rhythms govern cardiac repolarization and Arrhythmogenesis
Nature, 2012Co-Authors: Darwin Jeyaraj, Saptarsi M. Haldar, Mark D Mccauley, Juergen Ripperger, Betty L Eapen, Nikunj Sharma, Eckhard Ficker, Michael J Cutler, Xiaoping Wan, James GulickAbstract:Sudden cardiac death exhibits diurnal variation in both acquired and hereditary forms of heart disease, but the molecular basis of this variation is unknown. A common mechanism that underlies susceptibility to ventricular arrhythmias is abnormalities in the duration (for example, short or long QT syndromes and heart failure) or pattern (for example, Brugada's syndrome) of myocardial repolarization. Here we provide molecular evidence that links circadian rhythms to vulnerability in ventricular arrhythmias in mice. Specifically, we show that cardiac ion-channel expression and QT-interval duration (an index of myocardial repolarization) exhibit endogenous circadian rhythmicity under the control of a clock-dependent oscillator, kruppel-like factor 15 (Klf15). Klf15 transcriptionally controls rhythmic expression of Kv channel-interacting protein 2 (KChIP2), a critical subunit required for generating the transient outward potassium current. Deficiency or excess of Klf15 causes loss of rhythmic QT variation, abnormal repolarization and enhanced susceptibility to ventricular arrhythmias. These findings identify circadian transcription of ion channels as a mechanism for cardiac Arrhythmogenesis.
Mark D Mccauley - One of the best experts on this subject based on the ideXlab platform.
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circadian rhythms govern cardiac repolarization and Arrhythmogenesis
Nature, 2012Co-Authors: Darwin Jeyaraj, Yuan Lu, Saptarsi M. Haldar, Mark D Mccauley, Juergen Ripperger, Kun Hu, Betty L Eapen, Nikunj Sharma, Eckhard Ficker, Michael J CutlerAbstract:Circadian rhythmicity of cardiac ion-channel expression and of an index of myocardial repolarization is under the control of Klf15, a clock-dependent oscillator that is required for generating transient outward potassium current, and deficiencies or excesses of which cause loss of rhythmic variation in myocardial and abnormal repolarization, and an enhanced susceptibility to ventricular arrhythmias. Several physiological parameters in the cardiovascular system show diurnal variation. Mukesh Jain and colleagues now provide a link between circadian rhythms and Arrhythmogenesis in mice. They show that the transcription factor Klf15 is regulated by components of the circadian clock, and Klf15 in turn regulates expression of the ion channel KChIP2. In gain- and loss-of-function experiments, the authors show that Klf15 regulates temporal variation in cardiac repolarization and susceptibility to arrhythmias. The findings raise the possibility that circadian factors contribute to the diurnal variation seen in occurrence of sudden cardiac death. Sudden cardiac death exhibits diurnal variation in both acquired and hereditary forms of heart disease1,2, but the molecular basis of this variation is unknown. A common mechanism that underlies susceptibility to ventricular arrhythmias is abnormalities in the duration (for example, short or long QT syndromes and heart failure)3,4,5 or pattern (for example, Brugada’s syndrome)6 of myocardial repolarization. Here we provide molecular evidence that links circadian rhythms to vulnerability in ventricular arrhythmias in mice. Specifically, we show that cardiac ion-channel expression and QT-interval duration (an index of myocardial repolarization) exhibit endogenous circadian rhythmicity under the control of a clock-dependent oscillator, kruppel-like factor 15 (Klf15). Klf15 transcriptionally controls rhythmic expression of Kv channel-interacting protein 2 (KChIP2), a critical subunit required for generating the transient outward potassium current7. Deficiency or excess of Klf15 causes loss of rhythmic QT variation, abnormal repolarization and enhanced susceptibility to ventricular arrhythmias. These findings identify circadian transcription of ion channels as a mechanism for cardiac Arrhythmogenesis.
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circadian rhythms govern cardiac repolarization and Arrhythmogenesis
Nature, 2012Co-Authors: Darwin Jeyaraj, Saptarsi M. Haldar, Mark D Mccauley, Juergen Ripperger, Betty L Eapen, Nikunj Sharma, Eckhard Ficker, Michael J Cutler, Xiaoping Wan, James GulickAbstract:Sudden cardiac death exhibits diurnal variation in both acquired and hereditary forms of heart disease, but the molecular basis of this variation is unknown. A common mechanism that underlies susceptibility to ventricular arrhythmias is abnormalities in the duration (for example, short or long QT syndromes and heart failure) or pattern (for example, Brugada's syndrome) of myocardial repolarization. Here we provide molecular evidence that links circadian rhythms to vulnerability in ventricular arrhythmias in mice. Specifically, we show that cardiac ion-channel expression and QT-interval duration (an index of myocardial repolarization) exhibit endogenous circadian rhythmicity under the control of a clock-dependent oscillator, kruppel-like factor 15 (Klf15). Klf15 transcriptionally controls rhythmic expression of Kv channel-interacting protein 2 (KChIP2), a critical subunit required for generating the transient outward potassium current. Deficiency or excess of Klf15 causes loss of rhythmic QT variation, abnormal repolarization and enhanced susceptibility to ventricular arrhythmias. These findings identify circadian transcription of ion channels as a mechanism for cardiac Arrhythmogenesis.
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ryanodine receptor phosphorylation by calcium calmodulin dependent protein kinase ii promotes life threatening ventricular arrhythmias in mice with heart failure
Circulation, 2010Co-Authors: Ralph J Van Oort, Mark D Mccauley, Sayali S Dixit, Laetitia Pereira, Yi Yang, Jonathan L Respress, Qiongling Wang, Angela C De Almeida, Darlene G Skapura, Mark E AndersonAbstract:Background Approximately half of patients with heart failure die suddenly as a result of ventricular arrhythmias. Although abnormal Ca2+ release from the sarcoplasmic reticulum through ryanodine receptors (RyR2) has been linked to Arrhythmogenesis, the molecular mechanisms triggering release of arrhythmogenic Ca2+ remain unknown. We tested the hypothesis that increased RyR2 phosphorylation by Ca2+/calmodulin-dependent protein kinase II is both necessary and sufficient to promote lethal ventricular arrhythmias. Methods and Results Mice in which the S2814 Ca2+/calmodulin-dependent protein kinase II site on RyR2 is constitutively activated (S2814D) develop pathological sarcoplasmic reticulum Ca2+ release events, resulting in reduced sarcoplasmic reticulum Ca2+ load on confocal microscopy. These Ca2+ release events are associated with increased RyR2 open probability in lipid bilayer preparations. At baseline, young S2814D mice have structurally and functionally normal hearts without arrhythmias; however, they develop sustained ventricular tachycardia and sudden cardiac death on catecholaminergic provocation by caffeine/epinephrine or programmed electric stimulation. Young S2814D mice have a significant predisposition to sudden arrhythmogenic death after transverse aortic constriction surgery. Finally, genetic ablation of the Ca2+/calmodulin-dependent protein kinase II site on RyR2 (S2814A) protects mutant mice from pacing-induced arrhythmias versus wild-type mice after transverse aortic constriction surgery. Conclusions Our results suggest that Ca2+/calmodulin-dependent protein kinase II phosphorylation of RyR2 Ca2+ release channels at S2814 plays an important role in Arrhythmogenesis and sudden cardiac death in mice with heart failure. # Clinical Perspective {#article-title-40}
Ruben Coronel - One of the best experts on this subject based on the ideXlab platform.
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Fibrosis and Conduction Abnormalities as Basis for Overlap of Brugada Syndrome and Early Repolarization Syndrome
International Journal of Molecular Sciences, 2021Co-Authors: Bastiaan Boukens, Mark Potse, Ruben CoronelAbstract:Brugada syndrome and early repolarization syndrome are both classified as J-wave syndromes, with a similar mechanism of Arrhythmogenesis and with the same basis for genesis of the characteristic electrocardiographic features. The Brugada syndrome is now considered a conduction disorder based on subtle structural abnormalities in the right ventricular outflow tract. Recent evidence suggests structural substrate in patients with the early repolarization syndrome as well. We propose a unifying mechanism based on these structural abnormalities explaining both Arrhythmogenesis and the electrocardiographic changes. In addition, we speculate that, with increasing technical advances in imaging techniques and their spatial resolution, these syndromes will be reclassified as structural heart diseases or cardiomyopathies.
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dispersion of repolarization and Arrhythmogenesis
Heart Rhythm, 2009Co-Authors: Ruben Coronel, Francien J G Wilmsschopman, Tobias Opthof, Michiel J JanseAbstract:Background The relation between induction of arrhythmias and dispersion of repolarization is not completely understood. Objective The purpose of this study was to study the relation between heterogeneity in repolarization and Arrhythmogenesis under conditions of selective regional action potential prolongation and shortening. Methods Pig hearts were perfused in a Langendorff setup. The left anterior descending artery (LAD) was cannulated and perfused. Sotalol (220 μM) was infused in the aortic cannula, and pinacidil (20 μM) was infused through the LAD, causing a gradient in repolarization time between the two myocardial regions. Premature stimulation was performed from the LAD region. Results No transmural repolarization gradients developed after infusion of the drugs. High-density epicardial activation/repolarization mapping (176 unipolar electrodes, 2-mm interelectrode spacing) revealed a maximum repolarization gradient of approximately 120 ms over 14 mm. The critical parameter for differentiating between the occurrence of reentry and the mere occurrence of a line of activation block between the two myocardial regions (and no reentry) was not the magnitude of the repolarization gradient but the timing of arrival of the premature activation wave at the distal side of the line of activation block relative to the repolarization time of the premature beat proximal to the line of block. No spontaneous arrhythmias were observed despite the presence of the repolarization gradient. Conclusion It is not the repolarization gradient but the restitution characteristics of the tissue with the shorter action potential, in combination with the time of arrival of the premature wavefront at the distal side of the line of block, that determines the occurrence of reentry.
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acute ischemia induced gap junctional uncoupling and Arrhythmogenesis
Cardiovascular Research, 2004Co-Authors: Joris R De Groot, Ruben CoronelAbstract:Sudden cardiac death forms a major cause of mortality. Myocardial ischemia-induced ventricular fibrillation (VF) is frequently the underlying mechanism. Ventricular arrhythmias arise in two distinct phases during the first hour of ischemia. The first, the 1A phase, has been extensively studied, and few studies relate to the 1B phase. The latter is associated with intercellular electrical uncoupling, mediated by decreased conductance of gap junction channels. Although the relation between gap junctional uncoupling and decreased conduction velocity appears clear under normoxic conditions, additional factors contribute to conduction slowing during ischemia, and VF occurs preferentially at moderate levels of uncoupling. A potential mechanism of arrhythmias depends on temporary electrotonic depression of intrinsically viable tissue by the large bulk of the ischemic zone. This causes conduction slowing and conduction block in the surviving layers, leading to arrhythmias. These arrhythmias then resolve with progression of uncoupling. It is unknown whether either accelerated uncoupling or maintenance of gap junctional communication is antiarrhythmic. Ischemic preconditioning postpones both gap junctional uncoupling and occurrence of VF. Given the burden of sudden death and the large number of casualties in the low-risk population, there is, even in the era of implantable cardiac defibrillators, need for further understanding the mechanism of ischemia-induced VF.
Lars S Maier - One of the best experts on this subject based on the ideXlab platform.
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dantrolene reduces camkiiδc mediated atrial arrhythmias
Europace, 2020Co-Authors: Steffen Pabel, Stefan Wagner, Julian Mustroph, Simon Lebek, Nataliya Dybkova, Andreas Keyser, Leopold Rupprecht, Stefan Neef, Thomas Stehle, Lars S MaierAbstract:Aims In atrial fibrillation (AF), an increased diastolic Ca2+ leak from the sarcoplasmic reticulum (SR) mediated by calcium/calmodulin-dependent-protein-kinaseIIδC (CaMKII) can serve as a substrate for arrhythmia induction and persistence. Dantrolene has been shown to stabilize the cardiac ryanodine-receptor. This study investigated the effects of dantrolene on Arrhythmogenesis in human and mouse atria with enhanced CaMKII activity. Methods and results Human atrial cardiomyocytes (CMs) were isolated from patients with AF. To investigate CaMKII-mediated Arrhythmogenesis, atrial CMs from mice overexpressing CaMKIIδC (TG) and the respective wildtype (WT) were studied using confocal microscopy (Fluo-4), patch-clamp technique, and in vivo atrial catheter-based burst stimulations. Dantrolene potently reduced Ca2+ spark frequency (CaSpF) and diastolic SR Ca2+ leak in AF CMs. Additional CaMKII inhibition did not further reduce CaSpF or leak compared to dantrolene alone. While the increased SR CaSpF and leak in TG mice were reduced by dantrolene, no effects could be detected in WT. Dantrolene also potently reduced the pathologically enhanced frequency of diastolic SR Ca2+ waves in TG without having effects in WT. As an increased diastolic SR Ca2+ release can induce a depolarizing transient inward current, we could demonstrate that the incidence of afterdepolarizations in TG, but not in WT, mice was significantly diminished in the presence of dantrolene. To translate these findings into an in vivo situation we could show that dantrolene strongly suppressed the inducibility of AF in vivo in TG mice. Conclusion Dantrolene reduces CaMKII-mediated atrial Arrhythmogenesis and may therefore constitute an interesting antiarrhythmic drug for treating patients with atrial arrhythmias driven by an enhanced CaMKII activity, such as AF.