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Species-Dependent Mechanisms of Cardiac Arrhythmia: A Cellular Focus

View Article: PubMed Central - PubMed

ABSTRACT

Although ventricular arrhythmia remains a leading cause of morbidity and mortality, available antiarrhythmic drugs have limited efficacy. Disappointing progress in the development of novel, clinically relevant antiarrhythmic agents may partly be attributed to discrepancies between humans and animal models used in preclinical testing. However, such differences are at present difficult to predict, requiring improved understanding of arrhythmia mechanisms across species. To this end, we presently review interspecies similarities and differences in fundamental cardiomyocyte electrophysiology and current understanding of the mechanisms underlying the generation of afterdepolarizations and reentry. We specifically highlight patent shortcomings in small rodents to reproduce cellular and tissue-level arrhythmia substrate believed to be critical in human ventricle. Despite greater ease of translation from larger animal models, discrepancies remain and interpretation can be complicated by incomplete knowledge of human ventricular physiology due to low availability of explanted tissue. We therefore point to the benefits of mathematical modeling as a translational bridge to understanding and treating human arrhythmia.

No MeSH data available.


Computational models represent the most concise, precise, and simple means of storing current information of myocyte electrophysiology. They also present the most simple means of comparing dynamic characteristics between species or those resulting from disease. Human: the left ventricular epicardial model of Grandi et al,34 which has been widely used by others.35,36 The relatively fast and large transient outward current is a characteristic of epicardial myocytes, and humans exhibit more subtle expression of the delayed rectifiers than other larger mammals. In particular, the rapidly activating delayed rectifier dominates over the slowly activating form, which has important implications for repolarization reserve. Canine: epicardial model from Hund and Rudy37 (see also the work by Benson et al38 and Panthee et al39), showing the pronounced Ito,f expression in these cells, which is responsible for the characteristic peak and dome action potential (AP) of this cell type and alters time courses of both ICaL and sarcoplasmic reticulum calcium release. Rabbit: the rabbit model of Shannon et al40 (see also the work by Restrepo et al41) was one of the first to accurately reflect large mammal excitation-contraction coupling. Like humans, rabbits rely more heavily on IKr for late repolarization, and this has made them a popular model for studying long QT–associated arrhythmia mechanisms. Guinea pig: Luo and Rudy developed the first biophysically detailed models of ventricular myocyte electrophysiology. These models have been continually revised, and here, we show output of the Faber-Rudy42 model published in 2007. Note the high expression of all currents, and particularly IKs, which makes a major contribution to the stability of the phase 2 plateau. Inward (reverse mode) INaCa is only substantial in this model at high intracellular Na (15 mM), and normal [Na]i is ~7 mM. Mouse: the detailed mouse model of Morotti et al43 (see also the work by Gray et al44 and Schilling et al45) showing how high expression of both Ito,f and IKur overwhelms all inward currents in these cells and thereby markedly abbreviates the AP. This eliminates almost all opportunities for activation of IKs and IKr, both of which are included in the model.
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f1-10.1177_1179546816686061: Computational models represent the most concise, precise, and simple means of storing current information of myocyte electrophysiology. They also present the most simple means of comparing dynamic characteristics between species or those resulting from disease. Human: the left ventricular epicardial model of Grandi et al,34 which has been widely used by others.35,36 The relatively fast and large transient outward current is a characteristic of epicardial myocytes, and humans exhibit more subtle expression of the delayed rectifiers than other larger mammals. In particular, the rapidly activating delayed rectifier dominates over the slowly activating form, which has important implications for repolarization reserve. Canine: epicardial model from Hund and Rudy37 (see also the work by Benson et al38 and Panthee et al39), showing the pronounced Ito,f expression in these cells, which is responsible for the characteristic peak and dome action potential (AP) of this cell type and alters time courses of both ICaL and sarcoplasmic reticulum calcium release. Rabbit: the rabbit model of Shannon et al40 (see also the work by Restrepo et al41) was one of the first to accurately reflect large mammal excitation-contraction coupling. Like humans, rabbits rely more heavily on IKr for late repolarization, and this has made them a popular model for studying long QT–associated arrhythmia mechanisms. Guinea pig: Luo and Rudy developed the first biophysically detailed models of ventricular myocyte electrophysiology. These models have been continually revised, and here, we show output of the Faber-Rudy42 model published in 2007. Note the high expression of all currents, and particularly IKs, which makes a major contribution to the stability of the phase 2 plateau. Inward (reverse mode) INaCa is only substantial in this model at high intracellular Na (15 mM), and normal [Na]i is ~7 mM. Mouse: the detailed mouse model of Morotti et al43 (see also the work by Gray et al44 and Schilling et al45) showing how high expression of both Ito,f and IKur overwhelms all inward currents in these cells and thereby markedly abbreviates the AP. This eliminates almost all opportunities for activation of IKs and IKr, both of which are included in the model.

Mentions: The ensemble of K+ currents contributing to repolarization is relatively large, and varying expression of the different K+ currents is the primary explanation for major species differences in cardiac electrophysiology (Figure 1). To simplify our perspective with respect to these species differences, we separate the major K+ currents into 2 groups: (1) those that develop rapidly during the AP (several to 10s of ms) and (2) those that develop slowly (50–100s of ms). This framework is subtly different to conventional nomenclature, which describes cardiac repolarization in terms of (1) the transient outward currents (Ito) and (2) the delayed rectifier currents (IK).31,32 This distinction in convention is important for our purpose because it is more tailored to differentiating among species. For example, in the context of brief APs of mouse and rat myocytes, repolarization proceeds so rapidly that channel species which conduct current after 50 ms will rarely be recruited, even if they are expressed and measurable in conventional square pulse protocols. In this way, the repolarization characteristics in these ubiquitous model species are determined more by differences in the activation kinetics of the repolarizing currents (even among the rapidly activating currents) than by the inactivation kinetics that are conventionally used to separate and classify them. As we discuss below, for several of the rapidly activating currents, the details of these activation kinetics remain somewhat mysterious and they are likely to be critical for shaping and maintaining the stability of repolarization in lower species and perhaps also atrial myocytes of larger species.33


Species-Dependent Mechanisms of Cardiac Arrhythmia: A Cellular Focus
Computational models represent the most concise, precise, and simple means of storing current information of myocyte electrophysiology. They also present the most simple means of comparing dynamic characteristics between species or those resulting from disease. Human: the left ventricular epicardial model of Grandi et al,34 which has been widely used by others.35,36 The relatively fast and large transient outward current is a characteristic of epicardial myocytes, and humans exhibit more subtle expression of the delayed rectifiers than other larger mammals. In particular, the rapidly activating delayed rectifier dominates over the slowly activating form, which has important implications for repolarization reserve. Canine: epicardial model from Hund and Rudy37 (see also the work by Benson et al38 and Panthee et al39), showing the pronounced Ito,f expression in these cells, which is responsible for the characteristic peak and dome action potential (AP) of this cell type and alters time courses of both ICaL and sarcoplasmic reticulum calcium release. Rabbit: the rabbit model of Shannon et al40 (see also the work by Restrepo et al41) was one of the first to accurately reflect large mammal excitation-contraction coupling. Like humans, rabbits rely more heavily on IKr for late repolarization, and this has made them a popular model for studying long QT–associated arrhythmia mechanisms. Guinea pig: Luo and Rudy developed the first biophysically detailed models of ventricular myocyte electrophysiology. These models have been continually revised, and here, we show output of the Faber-Rudy42 model published in 2007. Note the high expression of all currents, and particularly IKs, which makes a major contribution to the stability of the phase 2 plateau. Inward (reverse mode) INaCa is only substantial in this model at high intracellular Na (15 mM), and normal [Na]i is ~7 mM. Mouse: the detailed mouse model of Morotti et al43 (see also the work by Gray et al44 and Schilling et al45) showing how high expression of both Ito,f and IKur overwhelms all inward currents in these cells and thereby markedly abbreviates the AP. This eliminates almost all opportunities for activation of IKs and IKr, both of which are included in the model.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
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getmorefigures.php?uid=PMC5392019&req=5

f1-10.1177_1179546816686061: Computational models represent the most concise, precise, and simple means of storing current information of myocyte electrophysiology. They also present the most simple means of comparing dynamic characteristics between species or those resulting from disease. Human: the left ventricular epicardial model of Grandi et al,34 which has been widely used by others.35,36 The relatively fast and large transient outward current is a characteristic of epicardial myocytes, and humans exhibit more subtle expression of the delayed rectifiers than other larger mammals. In particular, the rapidly activating delayed rectifier dominates over the slowly activating form, which has important implications for repolarization reserve. Canine: epicardial model from Hund and Rudy37 (see also the work by Benson et al38 and Panthee et al39), showing the pronounced Ito,f expression in these cells, which is responsible for the characteristic peak and dome action potential (AP) of this cell type and alters time courses of both ICaL and sarcoplasmic reticulum calcium release. Rabbit: the rabbit model of Shannon et al40 (see also the work by Restrepo et al41) was one of the first to accurately reflect large mammal excitation-contraction coupling. Like humans, rabbits rely more heavily on IKr for late repolarization, and this has made them a popular model for studying long QT–associated arrhythmia mechanisms. Guinea pig: Luo and Rudy developed the first biophysically detailed models of ventricular myocyte electrophysiology. These models have been continually revised, and here, we show output of the Faber-Rudy42 model published in 2007. Note the high expression of all currents, and particularly IKs, which makes a major contribution to the stability of the phase 2 plateau. Inward (reverse mode) INaCa is only substantial in this model at high intracellular Na (15 mM), and normal [Na]i is ~7 mM. Mouse: the detailed mouse model of Morotti et al43 (see also the work by Gray et al44 and Schilling et al45) showing how high expression of both Ito,f and IKur overwhelms all inward currents in these cells and thereby markedly abbreviates the AP. This eliminates almost all opportunities for activation of IKs and IKr, both of which are included in the model.
Mentions: The ensemble of K+ currents contributing to repolarization is relatively large, and varying expression of the different K+ currents is the primary explanation for major species differences in cardiac electrophysiology (Figure 1). To simplify our perspective with respect to these species differences, we separate the major K+ currents into 2 groups: (1) those that develop rapidly during the AP (several to 10s of ms) and (2) those that develop slowly (50–100s of ms). This framework is subtly different to conventional nomenclature, which describes cardiac repolarization in terms of (1) the transient outward currents (Ito) and (2) the delayed rectifier currents (IK).31,32 This distinction in convention is important for our purpose because it is more tailored to differentiating among species. For example, in the context of brief APs of mouse and rat myocytes, repolarization proceeds so rapidly that channel species which conduct current after 50 ms will rarely be recruited, even if they are expressed and measurable in conventional square pulse protocols. In this way, the repolarization characteristics in these ubiquitous model species are determined more by differences in the activation kinetics of the repolarizing currents (even among the rapidly activating currents) than by the inactivation kinetics that are conventionally used to separate and classify them. As we discuss below, for several of the rapidly activating currents, the details of these activation kinetics remain somewhat mysterious and they are likely to be critical for shaping and maintaining the stability of repolarization in lower species and perhaps also atrial myocytes of larger species.33

View Article: PubMed Central - PubMed

ABSTRACT

Although ventricular arrhythmia remains a leading cause of morbidity and mortality, available antiarrhythmic drugs have limited efficacy. Disappointing progress in the development of novel, clinically relevant antiarrhythmic agents may partly be attributed to discrepancies between humans and animal models used in preclinical testing. However, such differences are at present difficult to predict, requiring improved understanding of arrhythmia mechanisms across species. To this end, we presently review interspecies similarities and differences in fundamental cardiomyocyte electrophysiology and current understanding of the mechanisms underlying the generation of afterdepolarizations and reentry. We specifically highlight patent shortcomings in small rodents to reproduce cellular and tissue-level arrhythmia substrate believed to be critical in human ventricle. Despite greater ease of translation from larger animal models, discrepancies remain and interpretation can be complicated by incomplete knowledge of human ventricular physiology due to low availability of explanted tissue. We therefore point to the benefits of mathematical modeling as a translational bridge to understanding and treating human arrhythmia.

No MeSH data available.