Animal models of arrhythmia: classic electrophysiology to genetically modified large animals

Clauß, Sebastian; Bleyer, Christina; Schüttler, Dominik; Tomsits, Philipp; Renner, Simone; Klymiuk, Nikolai; Wakili, Reza; Maßberg, Steffen; Wolf, Eckhard; Kääb, Stefan

doi:10.1038/s41569-019-0179-0

Cited by 160 publications

(172 citation statements)

References 302 publications

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“…Electrophysiology has been the workhorse for monitoring single‐unit action potentials and extracellular local field potentials (LFPs) with high temporal resolution for more than a century. [ 1,2 ] Advances in microelectronics have allowed the development of high‐resolution microelectrode arrays for electrophysiological monitoring and stimulation. Recently, optical techniques with high spatial resolution such as optogenetics, [ 3 ] calcium imaging, [ 4 ] and photometry [ 5,6 ] have been developed, allowing for optophysiology to serve as an alternative to electrophysiology for biomedical research.…”

Section: Introductionmentioning

confidence: 99%

Multifunctional Flexible Biointerfaces for Simultaneous Colocalized Optophysiology and Electrophysiology

Obaid

Yin

Tian

et al. 2020

Adv Funct Materials

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Recent developments in optophysiology techniques such as optogenetics have revolutionized the ability to actuate cell activity. Further combining optophysiology and electrophysiology will integrate the advantages from both optical and electrical modalities and yield enabling technologies that allow simultaneous monitoring of cellular activity in response to modulation, which are crucial for biomedical applications. However, multifunctional devices that can deliver optical stimuli to regions beneath the electrodes and perform simultaneous sensing remain largely unexplored. Existing transparent microelectrode technologies depend on external bulk optical instruments for optical interventions. Here, innovative monolithic integrated multifunctional microsystems are demonstrated by applying transparent nanogrid electrodes onto microscale light sources to permit simultaneous electrophysiology and optical modulation at the same anatomical site. The nanogrid electrodes have transmittances > 70% with a low normalized impedance of 5.9 Ω cm2. Additional features of the devices include superior mechanical flexibility, minimized light‐induced electrical artifacts, and excellent biocompatibility. Ex vivo experiments demonstrate that the multifunctional devices can record abnormal heart rhythm in transgenic mouse hearts and simultaneously restore the sinus rhythm via optogenetic pacing. This work provides a versatile approach for constructing multifunctional colocalized biointerfaces containing crosstalk‐free optical and electrical modalities with expanded opportunities in both fundamental and applied biomedical research.

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Section: Introductionmentioning

confidence: 99%

Multifunctional Flexible Biointerfaces for Simultaneous Colocalized Optophysiology and Electrophysiology

Obaid

Yin

Tian

et al. 2020

Adv Funct Materials

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“…Limitations of animal models have generally hampered unravelling the underlying molecular and cellular mechanisms of cardiac disease, slowing development of new drugs. Historically, heterologous expression systems (e.g., HEK cells heterologously expressing a disease-specific mutation) and animal models (small and large) have played an important role in studying the pathophysiological mechanisms of arrhythmias and in developing targeted therapies [7,8]. Transgenic animal models have largely contributed to our current understanding of the pathogenic mechanisms associated with these diseases [7].…”

Section: Introductionmentioning

confidence: 99%

“…Historically, heterologous expression systems (e.g., HEK cells heterologously expressing a disease-specific mutation) and animal models (small and large) have played an important role in studying the pathophysiological mechanisms of arrhythmias and in developing targeted therapies [7,8]. Transgenic animal models have largely contributed to our current understanding of the pathogenic mechanisms associated with these diseases [7]. However, major differences in cardiac electrophysiological properties between small animals and humans largely limit the extrapolation of results, making the translation of results to humans difficult [8].…”

Section: Introductionmentioning

confidence: 99%

The Emergence of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes (hiPSC-CMs) as a Platform to Model Arrhythmogenic Diseases

Pourrier

Fedida

2020

IJMS

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There is a need for improved in vitro models of inherited cardiac diseases to better understand basic cellular and molecular mechanisms and advance drug development. Most of these diseases are associated with arrhythmias, as a result of mutations in ion channel or ion channel-modulatory proteins. Thus far, the electrophysiological phenotype of these mutations has been typically studied using transgenic animal models and heterologous expression systems. Although they have played a major role in advancing the understanding of the pathophysiology of arrhythmogenesis, more physiological and predictive preclinical models are necessary to optimize the treatment strategy for individual patients. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have generated much interest as an alternative tool to model arrhythmogenic diseases. They provide a unique opportunity to recapitulate the native-like environment required for mutated proteins to reproduce the human cellular disease phenotype. However, it is also important to recognize the limitations of this technology, specifically their fetal electrophysiological phenotype, which differentiates them from adult human myocytes. In this review, we provide an overview of the major inherited arrhythmogenic cardiac diseases modeled using hiPSC-CMs and for which the cellular disease phenotype has been somewhat characterized.

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“…In this study, we used genetic mouse models to examine the role of interplay between RyR2-mediated SR Ca leak and SERCA2-dependent SR Ca uptake in cardiac arrhythmogenesis. Compared with larger animals, including human, rodents exhibit marked difference in their cardiac electrophysiological, and intracellular Ca handling properties [45][46][47]. Thus caution must be taken in translating current findings to humans.…”

Section: Discussionmentioning

confidence: 93%

Conditional Up-Regulation of SERCA2a Exacerbates RyR2-Dependent Ventricular and Atrial Arrhythmias

Liu

Lou

Smith

et al. 2020

IJMS

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Ryanodine receptor 2 (RyR2) and SERCA2a are two major players in myocyte calcium (Ca) cycling that are modulated physiologically, affected by disease and thus considered to be potential targets for cardiac disease therapy. However, how RyR2 and SERCA2a influence each others’ activities, as well as the primary and secondary consequences of their combined manipulations remain controversial. In this study, we examined the effect of acute upregulation of SERCA2a on arrhythmogenesis by conditionally overexpressing SERCA2a in a mouse model featuring hyperactive RyR2s due to ablation of calsequestrin 2 (CASQ2). CASQ2 knock-out (KO) mice were crossbred with doxycycline (DOX)-inducible SERCA2a transgenic mice to generate KO-TG mice. In-vivo ECG studies have shown that induction of SERCA2a (DOX+) overexpression markedly exacerbated both ventricular and atrial arrhythmias in vivo, compared with uninduced KO-TG mice (DOX-). Consistent with that, confocal microscopy in both atrial and ventricular myocytes demonstrated that conditional upregulation of SERCA2a enhanced the rate of occurrence of diastolic Ca release events. Additionally, deep RNA sequencing identified 17 downregulated genes and 5 upregulated genes in DOX+ mice, among which Ppp1r13l, Clcn1, and Agt have previously been linked to arrhythmias. Our results suggest that conditional upregulation of SERCA2a exacerbates hyperactive RyR2-mediated arrhythmias by further elevating diastolic Ca release.

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Animal models of arrhythmia: classic electrophysiology to genetically modified large animals

Cited by 160 publications

References 302 publications

Multifunctional Flexible Biointerfaces for Simultaneous Colocalized Optophysiology and Electrophysiology

Multifunctional Flexible Biointerfaces for Simultaneous Colocalized Optophysiology and Electrophysiology

The Emergence of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes (hiPSC-CMs) as a Platform to Model Arrhythmogenic Diseases

Conditional Up-Regulation of SERCA2a Exacerbates RyR2-Dependent Ventricular and Atrial Arrhythmias

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