Early afterdepolarizations and cardiac arrhythmias

Weiss, James N.; Garfinkel, Alan; Karagueuzian, Hrayr S.; Chen, Peng Sheng; Qu, Zhilin

doi:10.1016/j.hrthm.2010.09.017

Cited by 334 publications

(298 citation statements)

References 38 publications

(43 reference statements)

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“…Following that, we also measured the early after-depolarization (EAD) and autonomous action potentials (APs), two hallmarks of cardiac arrhythmias. 15,16 Our data showed the occurrence of EAD in exon 33…”

Section: Exon 33mentioning

confidence: 61%

Characterization of Ca_V1.2 exon 33 heterozygous knockout mice and negative correlation between Rbfox1 and Ca_V1.2 exon 33 expressions in human heart failure

Wang

et al. 2018

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Recently, we reported that homozygous deletion of alternative exon 33 of Ca V 1.2 calcium channel in the mouse resulted in ventricular arrhythmias arising from increased Ca V 1.2 D33 I CaL current density in the cardiomyocytes. We wondered whether heterozygous deletion of exon 33 might produce cardiac phenotype in a dose-dependent manner, and whether the expression levels of RNA splicing factors known to regulate alternative splicing of exon 33 might change in human heart failure. Unexpectedly, we found that exon 33 C/¡ cardiomyocytes showed similar Ca V 1.2 channel properties as wild-type cardiomyocyte, even though Ca V 1.2 D33 channels exhibit a gain-in-function. In human hearts, we found that the mRNA level of splicing factor Rbfox1, but not Rbfox2, was downregulated in dilated cardiomyopathy, and CACNA1C mRNA level was dramatically decreased in the both of dilated and ischemic cardiomyopathy. These data imply Rbfox1 may be involved in the development of cardiomyopathies via regulating the alternative splicing of Ca V 1.2 exon 33. (149 words) KEYWORDS alternative splicing; cardiomyopathy; Ca V 1.2 calcium channel; heterozygous knockout; Rbfox

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Section: Exon 33mentioning

confidence: 61%

Characterization of Ca_V1.2 exon 33 heterozygous knockout mice and negative correlation between Rbfox1 and Ca_V1.2 exon 33 expressions in human heart failure

Wang

et al. 2018

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“…As expected, Ru360 reduced mitochondrial Ca 2+ uptake. The mechanism of reduced EADs with Ru360 appeared to be reduced sarcolemmal NCX current, a key depolarizing current known to be involved in EADs 2. This effect is most easily explained by Ru360 reducing mitochondrial Ca 2+ loading, reducing mitochondrial Ca 2+ efflux, and decreasing sarcolemmal NCX.…”

Section: Discussionmentioning

confidence: 95%

Mitochondrial Ca ²⁺ Influx Contributes to Arrhythmic Risk in Nonischemic Cardiomyopathy

Xie

Song

Liu

et al. 2018

JAHA

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BackgroundHeart failure (HF) is associated with increased arrhythmia risk and triggered activity. Abnormal Ca2+ handling is thought to underlie triggered activity, and mitochondria participate in Ca2+ homeostasis.Methods and ResultsA model of nonischemic HF was induced in C57BL/6 mice by hypertension. Computer simulations were performed using a mouse ventricular myocyte model of HF. Isoproterenol‐induced premature ventricular contractions and ventricular fibrillation were more prevalent in nonischemic HF mice than sham controls. Isolated myopathic myocytes showed decreased cytoplasmic Ca2+ transients, increased mitochondrial Ca2+ transients, and increased action potential duration at 90% repolarization. The alteration of action potential duration at 90% repolarization was consistent with in vivo corrected QT prolongation and could be explained by augmented L‐type Ca2+ currents, increased Na+‐Ca2+ exchange currents, and decreased total K+ currents. Of myopathic ventricular myocytes, 66% showed early afterdepolarizations (EADs) compared with 17% of sham myocytes (P<0.05). Intracellular application of 1 μmol/L Ru360, a mitochondrial Ca2+ uniporter–specific antagonist, could reduce mitochondrial Ca2+ transients, decrease action potential duration at 90% repolarization, and ameliorate EADs. Furthermore, genetic knockdown of mitochondrial Ca2+ uniporters inhibited mitochondrial Ca2+ uptake, reduced Na+‐Ca2+ exchange currents, decreased action potential duration at 90% repolarization, suppressed EADs, and reduced ventricular fibrillation in nonischemic HF mice. Computer simulations showed that EADs promoted by HF remodeling could be abolished by blocking either the mitochondrial Ca2+ uniporter or the L‐type Ca2+ current, consistent with the experimental observations.ConclusionsMitochondrial Ca2+ handling plays an important role in EADs seen with nonischemic cardiomyopathy and may represent a therapeutic target to reduce arrhythmic risk in this condition.

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“…As a first step we explored the changes in AP and individual currents induced by three representative drugs (one taken from each one of the CiPA TdP risk categories), using pharmacology data as used in Li et al (2017). Since it is known that the subtle balance between inward (such as INaL and ICaL) and outward (such as IKr, IKs, IK1, and Ito) currents underlies the generation of EADs, a mechanistic precursor to TdP (Vos et al, 1995;Volders et al, 2000;Wu et al, 2002;Weiss et al, 2010), we also examined the net current between inward and outward currents (Inet) in addition to individual currents. (Crumb et al, 2016); using the block suggested in the ORd paper of 90% INaL block (O'Hara et al, 2011), the sum of squares error is of 38.48, changing the average error to 48.70. using our optimized model.…”

Section: Candidate Metricsmentioning

confidence: 99%

“…Based on ideas from non-linear dynamic theory and studies demonstrating mechanisms of EAD generation (Guo et al, 2007;Weiss et al, 2010;Xie et al, 2010;Chang et al, 2013;Kurata et al, 2017), we established a theoretical framework to quantitatively evaluate the physiological consequences of the change of the qNet (and in principle any) metric. A key concept here is the system robustness (Kurata et al, 2008), which is defined as the level of a specific perturbation the system can tolerate without a qualitative change of stability (e.g., emergence or annihilation of oscillations).…”

Section: Qnet Correlates With the System's Robustness Against Eadsmentioning

confidence: 99%

Optimization of an In Silico Cardiac Cell Model for Proarrhythmia Risk Assessment

Dutta¹,

Strauss²,

Colatsky³

et al. 2016

2016 Computing in Cardiology Conference (CinC)

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Drug-induced Torsade-de-Pointes (TdP) has been responsible for the withdrawal of many drugs from the market and is therefore of major concern to global regulatory agencies and the pharmaceutical industry. The Comprehensive in vitro Proarrhythmia Assay (CiPA) was proposed to improve prediction of TdP risk, using in silico models and in vitro multi-channel pharmacology data as integral parts of this initiative. Previously, we reported that combining dynamic interactions between drugs and the rapid delayed rectifier potassium current (IKr) with multi-channel pharmacology is important for TdP risk classification, and we modified the original O'Hara Rudy ventricular cell mathematical model to include a Markov model of IKr to represent dynamic drug-IKr interactions (IKr-dynamic ORd model). We also developed a novel metric that could separate drugs with different TdP liabilities at high concentrations based on total electronic charge carried by the major inward ionic currents during the action potential. In this study, we further optimized the IKr-dynamic ORd model by refining model parameters using published human cardiomyocyte experimental data under control and drug block conditions. Using this optimized model and manual patch clamp data, we developed an updated version of the metric that quantifies the net electronic charge carried by major inward and outward ionic currents during the steady state action potential, which could classify the level of drug-induced TdP risk across a wide range of concentrations and pacing rates. We also established a framework to quantitatively evaluate a system's robustness against the induction of early afterdepolarizations (EADs), and demonstrated that the new metric is correlated with the cell's robustness to the pro-EAD perturbation of IKr conductance reduction. In summary, in this work we present an optimized model that is more consistent with experimental data, an improved metric that can classify drugs at concentrations both near and higher than clinical exposure, and a physiological framework to check the relationship between a metric and EAD. These findings provide a solid foundation for using in silico models for the regulatory assessment of TdP risk under the CiPA paradigm.

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Early afterdepolarizations and cardiac arrhythmias

Cited by 334 publications

References 38 publications

Characterization of Ca_V1.2 exon 33 heterozygous knockout mice and negative correlation between Rbfox1 and Ca_V1.2 exon 33 expressions in human heart failure

Characterization of Ca_V1.2 exon 33 heterozygous knockout mice and negative correlation between Rbfox1 and Ca_V1.2 exon 33 expressions in human heart failure

Mitochondrial Ca ²⁺ Influx Contributes to Arrhythmic Risk in Nonischemic Cardiomyopathy

Optimization of an In Silico Cardiac Cell Model for Proarrhythmia Risk Assessment

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Early afterdepolarizations and cardiac arrhythmias

Cited by 334 publications

References 38 publications

Characterization of CaV1.2 exon 33 heterozygous knockout mice and negative correlation between Rbfox1 and CaV1.2 exon 33 expressions in human heart failure

Characterization of CaV1.2 exon 33 heterozygous knockout mice and negative correlation between Rbfox1 and CaV1.2 exon 33 expressions in human heart failure

Mitochondrial Ca 2+ Influx Contributes to Arrhythmic Risk in Nonischemic Cardiomyopathy

Optimization of an In Silico Cardiac Cell Model for Proarrhythmia Risk Assessment

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Characterization of Ca_V1.2 exon 33 heterozygous knockout mice and negative correlation between Rbfox1 and Ca_V1.2 exon 33 expressions in human heart failure

Characterization of Ca_V1.2 exon 33 heterozygous knockout mice and negative correlation between Rbfox1 and Ca_V1.2 exon 33 expressions in human heart failure

Mitochondrial Ca ²⁺ Influx Contributes to Arrhythmic Risk in Nonischemic Cardiomyopathy