scholarly journals Cardiac repolarization. The long and short of it*

EP Europace ◽  
2005 ◽  
Vol 7 (s2) ◽  
pp. S3-S9 ◽  
Author(s):  
Charles Antzelevitch
Keyword(s):  
Action Potential ◽  
Cell Types ◽  
Ventricular Myocardium ◽  
Left Ventricular ◽  
Cardiac Repolarization ◽  
M Cell ◽  
Long Qt ◽  
Epicardial Cells ◽  
Dispersion Of Repolarization ◽  
Life Threatening

Abstract Heterogeneity of transmural ventricular repolarization in the heart has been linked to a variety of arrhythmic manifestations. Electrical heterogeneity in ventricular myocardium is due to ionic distinctions among the three principal cell types: Endocardial, M and Epicardial cells. A reduction in net repolarizing current generally leads to a preferential prolongation of the M cell action potential. An increase in net repolarizing current can lead to a preferential abbreviation of the action potential of right ventricular epicardium or left ventricular endocardium. These changes can result in amplification of transmural heterogeneities of repolarization and thus predispose to the development of potentially lethal reentrant arrhythmias. The long QT, short QT, Brugada and catecholaminergic VT syndromes are all examples of pathologies that have very different phenotypes and aetiologies, but share a common final pathway in causing sudden death via amplification transmural or other spatial dispersion of repolarization within the ventricular myocardium. These same mechanisms are likely to be responsible for life-threatening arrhythmias in a variety of other cardiomyopathies ranging from heart failure and hypertrophy, which may involve mechanisms very similar to those operative in long QT syndrome, to isch-aemia and infarction, which may involve mechanisms more closely resembling those responsible for the Brugada syndrome.

scholarly journals Extracellular proton depression of peak and late Na+ current in the canine left ventricle

2011 ◽  
Vol 301 (3) ◽  
pp. H936-H944 ◽  
Author(s):  
Lisa Murphy ◽  
Danielle Renodin ◽  
Charles Antzelevitch ◽  
José M. Di Diego ◽  
Jonathan M. Cordeiro
Keyword(s):  
Action Potential ◽  
Cell Types ◽  
Left Ventricular ◽  
Extracellular Acidosis ◽  
Epicardial Cells ◽  
Ventricular Cells ◽  
Recovery From Inactivation ◽  
Ventricular Tissue ◽  
Steady State Inactivation ◽  
Acidic Conditions

Cardiac ischemia reduces excitability in ventricular tissue. Acidosis (one component of ischemia) affects a number of ion currents. We examined the effects of extracellular acidosis (pH 6.6) on peak and late Na+ current ( INa) in canine ventricular cells. Epicardial and endocardial myocytes were isolated, and patch-clamp techniques were used to record INa. Action potential recordings from left ventricular wedges exposed to acidic Tyrode solution showed a widening of the QRS complex, indicating slowing of transmural conduction. In myocytes, exposure to acidic conditions resulted in a 17.3 ± 0.9% reduction in upstroke velocity. Analysis of fast INa showed that current density was similar in epicardial and endocardial cells at normal pH (68.1 ± 7.0 vs. 63.2 ± 7.1 pA/pF, respectively). Extracellular acidosis reduced the fast INa magnitude by 22.7% in epicardial cells and 23.1% in endocardial cells. In addition, a significant slowing of the decay (time constant) of fast INa was observed at pH 6.6. Acidosis did not affect steady-state inactivation of INa or recovery from inactivation. Analysis of late INa during a 500-ms pulse showed that the acidosis significantly reduced late INa at 250 and 500 ms into the pulse. Using action potential clamp techniques, application of an epicardial waveform resulted in a larger late INa compared with when an endocardial waveform was applied to the same cell. Acidosis caused a greater decrease in late INa when an epicardial waveform was applied. These results suggest acidosis reduces both peak and late INa in both cell types and contributes to the depression in cardiac excitability observed under ischemic conditions.

Modeling of IK1 mutations in human left ventricular myocytes and tissue

2007 ◽  
Vol 292 (1) ◽  
pp. H549-H559 ◽  
Author(s):  
Gunnar Seemann ◽  
Frank B. Sachse ◽  
Daniel L. Weiss ◽  
Louis J. Ptáček ◽  
Martin Tristani-Firouzi
Keyword(s):  
Action Potential ◽  
Cardiac Tissue ◽  
Ventricular Myocytes ◽  
Torsade De Pointes ◽  
Low Frequency ◽  
Mechanistic Explanation ◽  
Left Ventricular ◽  
Autosomal Dominant Disorder ◽  
Modeling Approach ◽  
Dispersion Of Repolarization

Elucidation of the cellular basis of arrhythmias in ion channelopathy disorders is complicated by the inherent difficulties in studying human cardiac tissue. Thus we used a computer modeling approach to study the mechanisms of cellular dysfunction induced by mutations in inward rectifier potassium channel (Kir)2.1 that cause Andersen-Tawil syndrome (ATS). ATS is an autosomal dominant disorder associated with ventricular arrhythmias that uncommonly degenerate into the lethal arrhythmia torsade de pointes. We simulated the cellular and tissue effects of a potent disease-causing mutation D71V Kir2.1 with mathematical models of human ventricular myocytes and a bidomain model of transmural conduction. The D71V Kir2.1 mutation caused significant action potential duration prolongation in subendocardial, midmyocardial, and subepicardial myocytes but did not significantly increase transmural dispersion of repolarization. Simulations of the D71V mutation at shorter cycle lengths induced stable action potential alternans in midmyocardial, but not subendocardial or subepicardial cells. The action potential alternans was manifested as an abbreviated QRS complex in the transmural ECG, the result of action potential propagation failure in the midmyocardial tissue. In addition, our simulations of D71V mutation recapitulate several key ECG features of ATS, including QT prolongation, T-wave flattening, and QRS widening. Thus our modeling approach faithfully recapitulates several features of ATS and provides a mechanistic explanation for the low frequency of torsade de pointes arrhythmia in ATS.

scholarly journals Effect of activation sequence on transmural patterns of repolarization and action potential duration in rabbit ventricular myocardium

2010 ◽  
Vol 299 (6) ◽  
pp. H1812-H1822 ◽  
Author(s):  
Rachel C. Myles ◽  
Olivier Bernus ◽  
Francis L. Burton ◽  
Stuart M. Cobbe ◽  
Godfrey L. Smith
Keyword(s):  
Action Potential ◽  
Action Potential Duration ◽  
Single Cells ◽  
Ventricular Myocardium ◽  
Left Ventricular ◽  
Isolated Cells ◽  
Electrophysiological Properties ◽  
Relative Contribution ◽  
Rabbit Ventricular Myocardium ◽  
Transmural Heterogeneity

Although transmural heterogeneity of action potential duration (APD) is established in single cells isolated from different tissue layers, the extent to which it produces transmural gradients of repolarization in electrotonically coupled ventricular myocardium remains controversial. The purpose of this study was to examine the relative contribution of intrinsic cellular gradients of APD and electrotonic influences to transmural repolarization in rabbit ventricular myocardium. Transmural optical mapping was performed in left ventricular wedge preparations from eight rabbits. Transmural patterns of activation, repolarization, and APD were recorded during endocardial and epicardial stimulation. Experimental results were compared with modeled data during variations in electrotonic coupling. A transmural gradient of APD was evident during endocardial stimulation, which reflected differences previously seen in isolated cells, with the longest APD at the endocardium and the shortest at the epicardium (endo: 165 ± 5 vs. epi: 147 ± 4 ms; P < 0.05). During epicardial stimulation, this gradient reversed (epi: 162 ± 4 vs. endo: 148 ± 6 ms; P < 0.05). In both activation sequences, transmural repolarization followed activation and APD shortened along the activation path such that significant transmural gradients of repolarization did not occur. This correlation between transmural activation time and APD was recapitulated in simulations and varied with changes in intercellular coupling, confirming that it is mediated by electrotonic current flow between cells. These data suggest that electrotonic influences are important in determining the transmural repolarization sequence in rabbit ventricular myocardium and that they are sufficient to overcome intrinsic differences in the electrophysiological properties of the cells across the ventricular wall.

Transmural action potential and ionic current remodeling in ventricles of failing canine hearts

2002 ◽  
Vol 283 (3) ◽  
pp. H1031-H1041 ◽  
Author(s):  
Gui-Rong Li ◽  
Chu-Pak Lau ◽  
Anique Ducharme ◽  
Jean-Claude Tardif ◽  
Stanley Nattel
Keyword(s):  
Left Ventricle ◽  
Action Potential ◽  
Action Potentials ◽  
Slow Component ◽  
Ionic Current ◽  
Ionic Currents ◽  
Cell Types ◽  
Delayed Rectifier ◽  
Cardiac Repolarization ◽  
Early Afterdepolarizations

Heart failure (HF) produces important alterations in currents underlying cardiac repolarization, but the transmural distribution of such changes is unknown. We therefore recorded action potentials and ionic currents in cells isolated from the endocardium, midmyocardium, and epicardium of the left ventricle from dogs with and without tachypacing-induced HF. HF greatly increased action potential duration (APD) but attenuated APD heterogeneity in the three regions. Early afterdepolarizations (EADs) were observed in all cell types of failing hearts but not in controls. Inward rectifier K+ current ( I K1) was homogeneously reduced by ∼41% (at −60 mV) in the three cell types. Transient outward K+ current ( I to1) was decreased by 43–45% at +30 mV, and the slow component of the delayed rectifier K+ current ( I Ks) was significantly downregulated by 57%, 49%, and 58%, respectively, in epicardial, midmyocardial, and endocardial cells, whereas the rapid component of the delayed rectifier K+ current was not altered. The results indicate that HF remodels electrophysiology in all layers of the left ventricle, and the downregulation of I K1, I to1, and I Ks increases APD and favors occurrence of EADs.

scholarly journals Arrhythmogenic left ventricular cardiomyopathy

2020 ◽  
Vol 6 (1) ◽  
pp. 20190079
Author(s):  
Seyedeh Mojdeh Mirmomen ◽  
Andrew Jay Bradley ◽  
Andrew Ernest Arai ◽  
Arlene Sirajuddin
Keyword(s):  
Right Ventricular ◽  
Cardiac Death ◽  
Arrhythmogenic Right Ventricular Cardiomyopathy ◽  
Ventricular Myocardium ◽  
Left Ventricular ◽  
Ventricular Cardiomyopathy ◽  
Cardiotoxic Effect ◽  
Life Threatening ◽  
Muscle Disorder ◽  
The Right

Arrhythmogenic ventricular cardiomyopathy (AVC) is a heritable heart muscle disorder characterized by fibrofatty infiltration of the myocardium. Intramyocardial fat deposition is considered arrhythmogenic and predisposes patients to life-threatening arrhythmias and sudden cardiac death. The classic subtype of AVC is characterized by fibrofatty replacement of the right ventricular myocardium (i.e. arrhythmogenic right ventricular cardiomyopathy). In advanced cases of arrhythmogenic right ventricular cardiomyopathy, the left ventricle may be involved as well. Predominantly left ventricular involvement by AVC is exceedingly rare and lack of specific diagnostic criteria as well as its potential cardiotoxic effect make its diagnosis challenging and of high importance.

In vivo gene transfer of Kv1.5 normalizes action potential duration and shortens QT interval in mice with long QT phenotype

2003 ◽  
Vol 285 (1) ◽  
pp. H194-H203 ◽  
Author(s):  
Michael Brunner ◽  
Sodikdjon A. Kodirov ◽  
Gary F. Mitchell ◽  
Peter D. Buckett ◽  
Katsushi Shibata ◽  
...  
Keyword(s):  
Action Potential ◽  
Action Potential Duration ◽  
Qt Interval ◽  
Direct Injection ◽  
Dominant Negative ◽  
Dominant Negative Effect ◽  
Long Qt ◽  
Dispersion Of Repolarization ◽  
Surface Ecg

Mutations in cardiac voltage-gated K+channels cause long QT syndrome (LQTS) and sudden death. We created a transgenic mouse with a long QT phenotype (Kv1DN) by overexpression of a truncated K+channel in the heart and investigated whether the dominant negative effect of the transgene would be overcome by the direct injection of adenoviral vectors expressing wild-type Kv1.5 (AV-Kv1.5) into the myocardium. End points at 3–10 days included electrophysiology in isolated cardiomyocytes, surface ECG, programmed stimulation of the right ventricle, and in vivo optical mapping of action potentials and repolarization gradients in Langendorff-perfused hearts. Overexpression of Kv1.5 reconstituted a 4-aminopyridine-sensitive outward K+current, shortened the action potential duration, eliminated early afterdepolarizations, shortened the QT interval, decreased dispersion of repolarization, and increased the heart rate. Each of these changes is consistent with a physiologically significant primary effect of adenoviral expression of Kv1.5 on ventricular repolarization of Kv1DN mice.

scholarly journals Role of spatial dispersion of repolarization in inherited and acquired sudden cardiac death syndromes

2007 ◽  
Vol 293 (4) ◽  
pp. H2024-H2038 ◽  
Author(s):  
Charles Antzelevitch
Keyword(s):  
Sudden Cardiac Death ◽  
Cardiac Death ◽  
Spatial Dispersion ◽  
Ventricular Myocardium ◽  
Polymorphic Ventricular Tachycardia ◽  
Long Qt ◽  
Dispersion Of Repolarization ◽  
Qt Syndrome ◽  
Transmural Dispersion

This review examines the role of spatial electrical heterogeneity within the ventricular myocardium on the function of the heart in health and disease. The cellular basis for transmural dispersion of repolarization (TDR) is reviewed, and the hypothesis that amplification of spatial dispersion of repolarization underlies the development of life-threatening ventricular arrhythmias associated with inherited ion channelopathies is evaluated. The role of TDR in long QT, short QT, and Brugada syndromes, as well as catecholaminergic polymorphic ventricular tachycardia (VT), is critically examined. In long QT syndrome, amplification of TDR is often secondary to preferential prolongation of the action potential duration (APD) of M cells; in Brugada syndrome, however, it is thought to be due to selective abbreviation of the APD of the right ventricular epicardium. Preferential abbreviation of APD of the endocardium or epicardium appears to be responsible for the amplification of TDR in short QT syndrome. In catecholaminergic polymorphic VT, reversal of the direction of activation of the ventricular wall is responsible for the increase in TDR. In conclusion, long QT, short QT, Brugada, and catecholaminergic polymorphic VT syndromes are pathologies with very different phenotypes and etiologies, but they share a common final pathway in causing sudden cardiac death.

scholarly journals Absence of Functional Nav1.8 Channels in Non-diseased Atrial and Ventricular Cardiomyocytes

2019 ◽  
Vol 33 (6) ◽  
pp. 649-660 ◽  
Author(s):  
Simona Casini ◽  
Gerard A. Marchal ◽  
Makiri Kawasaki ◽  
Fransisca A. Nariswari ◽  
Vincent Portero ◽  
...  
Keyword(s):  
Action Potential ◽  
Cardiac Electrophysiology ◽  
Sodium Current ◽  
Association Studies ◽  
Induced Pluripotent Stem Cell ◽  
Cell Types ◽  
Left Ventricular ◽  
Resting Membrane Potential ◽  
Genome Wide Association Studies ◽  
Ventricular Cardiomyocytes

Abstract Purpose Several studies have indicated a potential role for SCN10A/NaV1.8 in modulating cardiac electrophysiology and arrhythmia susceptibility. However, by which mechanism SCN10A/NaV1.8 impacts on cardiac electrical function is still a matter of debate. To address this, we here investigated the functional relevance of NaV1.8 in atrial and ventricular cardiomyocytes (CMs), focusing on the contribution of NaV1.8 to the peak and late sodium current (INa) under normal conditions in different species. Methods The effects of the NaV1.8 blocker A-803467 were investigated through patch-clamp analysis in freshly isolated rabbit left ventricular CMs, human left atrial CMs and human-induced pluripotent stem cell-derived CMs (hiPSC-CMs). Results A-803467 treatment caused a slight shortening of the action potential duration (APD) in rabbit CMs and hiPSC-CMs, while it had no effect on APD in human atrial cells. Resting membrane potential, action potential (AP) amplitude, and AP upstroke velocity were unaffected by A-803467 application. Similarly, INa density was unchanged after exposure to A-803467 and NaV1.8-based late INa was undetectable in all cell types analysed. Finally, low to absent expression levels of SCN10A were observed in human atrial tissue, rabbit ventricular tissue and hiPSC-CMs. Conclusion We here demonstrate the absence of functional NaV1.8 channels in non-diseased atrial and ventricular CMs. Hence, the association of SCN10A variants with cardiac electrophysiology observed in, e.g. genome wide association studies, is likely the result of indirect effects on SCN5A expression and/or NaV1.8 activity in cell types other than CMs.

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