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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.


Related in: MedlinePlus

Early afterdepolarization (EAD) mechanisms differ across species and tissues. (A) Schematic representation of EAD mechanisms in large mammal ventricular myocytes. The long action potential plateau observed in ventricular myocytes from humans and other large mammals promotes EADs that initiate within the activation range of ICaL. As a result, the broad range of maneuvers or defects that can destabilize repolarization in these cells converge at ICaL reactivation, which carries most of the inward current in all cases. In some cases, discoordinated intracellular calcium release (systolic calcium waves) can act as the initiating factor and generate sufficient INaCa to drive these reactivation events. Because INaCa is favored at negative potentials, these types of events are more likely to generate an EAD during terminal repolarization and still ICaL carries most of the current during the EAD upstroke. (B) Murine EADs involve fundamentally different mechanisms. At left, an action potential clamp experiment showing the lidocaine-sensitive current during an EAD waveform is recorded in a mouse ventricular myocyte. At these concentrations, lidocaine binds primarily to inactivated Na+ channels, and this current indicates a reactivating component of INa. Because this component is sensitive to the trajectory of repolarization, it represents nonequilibrium dynamics rather than window-range reactivation. At right, the same EAD waveform is imposed on a mouse ventricular myocyte model, which shows that compared with the other major inward currents, INa is by far the greatest contributor to EADs in mice. (C) EAD mechanisms associated with reinitiation of atrial fibrillation (AF) in a human atrial myocyte model. Rapid pacing and acetylcholine administration can be used to simulate atrial fibrillation in atria of large mammals (AF115). When the pacing is stopped to simulate termination of AF, spontaneous EADs occur at sinus rates, as has been observed in canine atria.119 These events result from INa reactivation very similar to that occurring in the mouse ventricle. This may be important in certain specific contexts of human atrial disease.
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f2-10.1177_1179546816686061: Early afterdepolarization (EAD) mechanisms differ across species and tissues. (A) Schematic representation of EAD mechanisms in large mammal ventricular myocytes. The long action potential plateau observed in ventricular myocytes from humans and other large mammals promotes EADs that initiate within the activation range of ICaL. As a result, the broad range of maneuvers or defects that can destabilize repolarization in these cells converge at ICaL reactivation, which carries most of the inward current in all cases. In some cases, discoordinated intracellular calcium release (systolic calcium waves) can act as the initiating factor and generate sufficient INaCa to drive these reactivation events. Because INaCa is favored at negative potentials, these types of events are more likely to generate an EAD during terminal repolarization and still ICaL carries most of the current during the EAD upstroke. (B) Murine EADs involve fundamentally different mechanisms. At left, an action potential clamp experiment showing the lidocaine-sensitive current during an EAD waveform is recorded in a mouse ventricular myocyte. At these concentrations, lidocaine binds primarily to inactivated Na+ channels, and this current indicates a reactivating component of INa. Because this component is sensitive to the trajectory of repolarization, it represents nonequilibrium dynamics rather than window-range reactivation. At right, the same EAD waveform is imposed on a mouse ventricular myocyte model, which shows that compared with the other major inward currents, INa is by far the greatest contributor to EADs in mice. (C) EAD mechanisms associated with reinitiation of atrial fibrillation (AF) in a human atrial myocyte model. Rapid pacing and acetylcholine administration can be used to simulate atrial fibrillation in atria of large mammals (AF115). When the pacing is stopped to simulate termination of AF, spontaneous EADs occur at sinus rates, as has been observed in canine atria.119 These events result from INa reactivation very similar to that occurring in the mouse ventricle. This may be important in certain specific contexts of human atrial disease.

Mentions: Differences in IK1 expression are prominent across regions of the heart. In particular, IK1 is virtually absent in the sinus node, and in nearly all species, the atria exhibit 2- to 3-fold lower IK1 than the ventricles.95–97 The rectification properties are also exaggerated in the ventricles96,98 and may represent differences in polyamine concentration, their interaction with the channel,94 or differing contributions from the various Kir2 isoforms.95,99 Characterization of species differences in early investigations was less systematic, but differences in current expression and rectification were observed. Guinea pig IK1 is relatively large and may also exhibit greater contribution of Mg2+-dependent rectification compared with cat and rabbit,100 but not sheep.95 Among species that are commonly used to model human physiology, both the rabbit78 and dog79 exhibit larger ventricular IK1 expression than humans, whereas rectification properties are relatively similar. Both species exhibit 2-to 3-fold larger currents within the range relevant to repolarization, and this appears to extend to the inward portion of the voltage range.79 The mouse is unique among species in that the tissue distribution of IK1 appears to be the opposite of larger species. Murine IK1 is at least as large in the atria compared with ventricles, with the left atrium having slightly higher expression at potentials negative to EK.101 In sum, these characteristics may leave human myocytes more susceptible to diastolic depolarization accompanying events such as spontaneous calcium release and slightly reduce the rate of terminal repolarization compared with other large mammals (Figure 1).


Species-Dependent Mechanisms of Cardiac Arrhythmia: A Cellular Focus
Early afterdepolarization (EAD) mechanisms differ across species and tissues. (A) Schematic representation of EAD mechanisms in large mammal ventricular myocytes. The long action potential plateau observed in ventricular myocytes from humans and other large mammals promotes EADs that initiate within the activation range of ICaL. As a result, the broad range of maneuvers or defects that can destabilize repolarization in these cells converge at ICaL reactivation, which carries most of the inward current in all cases. In some cases, discoordinated intracellular calcium release (systolic calcium waves) can act as the initiating factor and generate sufficient INaCa to drive these reactivation events. Because INaCa is favored at negative potentials, these types of events are more likely to generate an EAD during terminal repolarization and still ICaL carries most of the current during the EAD upstroke. (B) Murine EADs involve fundamentally different mechanisms. At left, an action potential clamp experiment showing the lidocaine-sensitive current during an EAD waveform is recorded in a mouse ventricular myocyte. At these concentrations, lidocaine binds primarily to inactivated Na+ channels, and this current indicates a reactivating component of INa. Because this component is sensitive to the trajectory of repolarization, it represents nonequilibrium dynamics rather than window-range reactivation. At right, the same EAD waveform is imposed on a mouse ventricular myocyte model, which shows that compared with the other major inward currents, INa is by far the greatest contributor to EADs in mice. (C) EAD mechanisms associated with reinitiation of atrial fibrillation (AF) in a human atrial myocyte model. Rapid pacing and acetylcholine administration can be used to simulate atrial fibrillation in atria of large mammals (AF115). When the pacing is stopped to simulate termination of AF, spontaneous EADs occur at sinus rates, as has been observed in canine atria.119 These events result from INa reactivation very similar to that occurring in the mouse ventricle. This may be important in certain specific contexts of human atrial disease.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f2-10.1177_1179546816686061: Early afterdepolarization (EAD) mechanisms differ across species and tissues. (A) Schematic representation of EAD mechanisms in large mammal ventricular myocytes. The long action potential plateau observed in ventricular myocytes from humans and other large mammals promotes EADs that initiate within the activation range of ICaL. As a result, the broad range of maneuvers or defects that can destabilize repolarization in these cells converge at ICaL reactivation, which carries most of the inward current in all cases. In some cases, discoordinated intracellular calcium release (systolic calcium waves) can act as the initiating factor and generate sufficient INaCa to drive these reactivation events. Because INaCa is favored at negative potentials, these types of events are more likely to generate an EAD during terminal repolarization and still ICaL carries most of the current during the EAD upstroke. (B) Murine EADs involve fundamentally different mechanisms. At left, an action potential clamp experiment showing the lidocaine-sensitive current during an EAD waveform is recorded in a mouse ventricular myocyte. At these concentrations, lidocaine binds primarily to inactivated Na+ channels, and this current indicates a reactivating component of INa. Because this component is sensitive to the trajectory of repolarization, it represents nonequilibrium dynamics rather than window-range reactivation. At right, the same EAD waveform is imposed on a mouse ventricular myocyte model, which shows that compared with the other major inward currents, INa is by far the greatest contributor to EADs in mice. (C) EAD mechanisms associated with reinitiation of atrial fibrillation (AF) in a human atrial myocyte model. Rapid pacing and acetylcholine administration can be used to simulate atrial fibrillation in atria of large mammals (AF115). When the pacing is stopped to simulate termination of AF, spontaneous EADs occur at sinus rates, as has been observed in canine atria.119 These events result from INa reactivation very similar to that occurring in the mouse ventricle. This may be important in certain specific contexts of human atrial disease.
Mentions: Differences in IK1 expression are prominent across regions of the heart. In particular, IK1 is virtually absent in the sinus node, and in nearly all species, the atria exhibit 2- to 3-fold lower IK1 than the ventricles.95–97 The rectification properties are also exaggerated in the ventricles96,98 and may represent differences in polyamine concentration, their interaction with the channel,94 or differing contributions from the various Kir2 isoforms.95,99 Characterization of species differences in early investigations was less systematic, but differences in current expression and rectification were observed. Guinea pig IK1 is relatively large and may also exhibit greater contribution of Mg2+-dependent rectification compared with cat and rabbit,100 but not sheep.95 Among species that are commonly used to model human physiology, both the rabbit78 and dog79 exhibit larger ventricular IK1 expression than humans, whereas rectification properties are relatively similar. Both species exhibit 2-to 3-fold larger currents within the range relevant to repolarization, and this appears to extend to the inward portion of the voltage range.79 The mouse is unique among species in that the tissue distribution of IK1 appears to be the opposite of larger species. Murine IK1 is at least as large in the atria compared with ventricles, with the left atrium having slightly higher expression at potentials negative to EK.101 In sum, these characteristics may leave human myocytes more susceptible to diastolic depolarization accompanying events such as spontaneous calcium release and slightly reduce the rate of terminal repolarization compared with other large mammals (Figure 1).

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.


Related in: MedlinePlus