Increasing I Ks corrects abnormal repolarization in rabbit models of acquired LQT2 and ventricular hypertrophy

2002 ◽  
Vol 283 (2) ◽  
pp. H664-H670 ◽  
Author(s):  
Xiaoping Xu ◽  
Joseph J. Salata ◽  
Jixin Wang ◽  
Ying Wu ◽  
Gan-Xin Yan ◽  
...  
Keyword(s):  
Ventricular Arrhythmias ◽  
Ventricular Hypertrophy ◽  
Voltage Dependence ◽  
Ventricular Myocytes ◽  
Delayed Rectifier ◽  
Long Qt ◽  
Early Afterdepolarizations ◽  
New Strategy ◽  
Rabbit Ventricular Myocytes ◽  
Qt Syndrome

Excessive action potential (AP) prolongation and early afterdepolarizations (EAD) are triggers of malignant ventricular arrhythmias. A slowly activating delayed rectifier K+ current ( I Ks) is important for repolarization of ventricular AP. We examined the effects of I Ks activation by a new benzodiazepine (L3) on the AP of control, dofetilide-treated, and hypertrophied rabbit ventricular myocytes. In both control and hypertrophied myocytes, L3 activated I Ks via a negative shift in the voltage dependence of activation and a slowing of deactivation. L3 had no effect on L-type Ca2+ current or other cardiac K+ currents tested. L3 shortened AP of control, dofetilide-treated, and hypertrophied myocytes more at 0.5 than 2 Hz. Selective activation of I Ks by L3 attenuates prolonged AP and eliminated EAD induced by rapidly activating delayed rectifier K+ current inhibition in control myocytes at 0.5 Hz and spontaneous EAD in hypertrophied myocytes at 0.2 Hz. Pharmacological activation of I Ks is a promising new strategy to suppress arrhythmias resulting from excessive AP prolongation in patients with certain forms of long QT syndrome or cardiac hypertrophy and failure.

scholarly journals Suppression of ventricular arrhythmias by targeting late L-type Ca2+ current

2021 ◽  
Vol 153 (12) ◽  
Author(s):  
Marina Angelini ◽  
Arash Pezhouman ◽  
Nicoletta Savalli ◽  
Marvin G. Chang ◽  
Federica Steccanella ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Ventricular Arrhythmias ◽  
Ventricular Myocytes ◽  
Ex Vivo ◽  
Selective Reduction ◽  
Antiarrhythmic Action ◽  
Early Afterdepolarizations ◽  
Rat Hearts ◽  
New Strategy ◽  
Early Peak

Ventricular arrhythmias, a leading cause of sudden cardiac death, can be triggered by cardiomyocyte early afterdepolarizations (EADs). EADs can result from an abnormal late activation of L-type Ca2+ channels (LTCCs). Current LTCC blockers (class IV antiarrhythmics), while effective at suppressing EADs, block both early and late components of ICa,L, compromising inotropy. However, computational studies have recently demonstrated that selective reduction of late ICa,L (Ca2+ influx during late phases of the action potential) is sufficient to potently suppress EADs, suggesting that effective antiarrhythmic action can be achieved without blocking the early peak ICa,L, which is essential for proper excitation–contraction coupling. We tested this new strategy using a purine analogue, roscovitine, which reduces late ICa,L with minimal effect on peak current. Scaling our investigation from a human CaV1.2 channel clone to rabbit ventricular myocytes and rat and rabbit perfused hearts, we demonstrate that (1) roscovitine selectively reduces ICa,L noninactivating component in a human CaV1.2 channel clone and in ventricular myocytes native current, (2) the pharmacological reduction of late ICa,L suppresses EADs and EATs (early after Ca2+ transients) induced by oxidative stress and hypokalemia in isolated myocytes, largely preserving cell shortening and normal Ca2+ transient, and (3) late ICa,L reduction prevents/suppresses ventricular tachycardia/fibrillation in ex vivo rabbit and rat hearts subjected to hypokalemia and/or oxidative stress. These results support the value of an antiarrhythmic strategy based on the selective reduction of late ICa,L to suppress EAD-mediated arrhythmias. Antiarrhythmic therapies based on this idea would modify the gating properties of CaV1.2 channels rather than blocking their pore, largely preserving contractility.

Differential contribution of sialic acid to the function of repolarizing K+ currents in ventricular myocytes

2001 ◽  
Vol 281 (2) ◽  
pp. C464-C474 ◽  
Author(s):  
Carmen A. Ufret-Vincenty ◽  
Deborah J. Baro ◽  
L. F. Santana
Keyword(s):  
Sialic Acid ◽  
Voltage Dependence ◽  
Ventricular Myocytes ◽  
Chinese Hamster ◽  
Ovary Cell ◽  
Early Afterdepolarizations ◽  
Kv4 Channels ◽  
Ovary Cell Line ◽  
Differential Contribution ◽  
K Currents

We investigated the contribution of sialic acid residues to the K+ currents involved in the repolarization of mouse ventricular myocytes. Ventricular K+ currents had a rapidly inactivating component followed by slowly decaying and sustained components. This current was produced by the summation of three distinct currents: I to, which contributed to the transient component; I ss, which contributed to the sustained component; and I K,slow, which contributed to both components. Incubation of ventricular myocytes with the sialidase neuraminidase reduced the amplitude of I to without altering I K,slow and I ss. We found that the reduction in I to amplitude resulted from a depolarizing shift in the voltage of activation and a reduction in the conductance of I to. Expression of Kv4.3 channels, a major contributor to I to in the ventricle, in a sialylation-deficient Chinese hamster ovary cell line (lec2) mimicked the effects of neuraminidase on the ventricular I to. Furthermore, we showed that sialylated glycolipids have little effect on the voltage dependence of I to. Finally, consistent with its actions on I to, neuraminidase produced an increase in the duration of the action potential of ventricular myocytes and the frequency of early afterdepolarizations. We conclude that sialylation of the proteins forming Kv4 channels is important in determining the voltage dependence and conductance of I to and that incomplete glycosylation of these channels could lead to arrhythmias.

scholarly journals Fever-induced QTc prolongation and ventricular arrhythmias in individuals with type 2 congenital long QT syndrome

2008 ◽  
Author(s):  
Ahmad S. Amin ◽  
Lucas J. Herfst ◽  
Brian P. Delisle ◽  
Christine A. Klemens ◽  
Martin B. Rook ◽  
...  
Keyword(s):  
Long Qt Syndrome ◽  
Ventricular Arrhythmias ◽  
Qtc Prolongation ◽  
Long Qt ◽  
Qt Syndrome ◽  
Congenital Long Qt Syndrome

scholarly journals Trafficking-deficient hERG K+ channels linked to long QT syndrome are regulated by a microtubule-dependent quality control compartment in the ER

2011 ◽  
Vol 301 (1) ◽  
pp. C75-C85 ◽  
Author(s):  
Jennifer L. Smith ◽  
Christie M. McBride ◽  
Parvathi S. Nataraj ◽  
Daniel C. Bartos ◽  
Craig T. January ◽  
...  
Keyword(s):  
Golgi Apparatus ◽  
Long Qt Syndrome ◽  
Functional Expression ◽  
Delayed Rectifier ◽  
Temperature Sensitive ◽  
Missense Mutations ◽  
Long Qt ◽  
Delayed Rectifier Current ◽  
Golgi Compartment ◽  
Qt Syndrome

The human ether-a-go-go related gene ( hERG) encodes the voltage-gated K+ channel that underlies the rapidly activating delayed-rectifier current in cardiac myocytes. hERG is synthesized in the endoplasmic reticulum (ER) as an “immature” N-linked glycoprotein and is terminally glycosylated in the Golgi apparatus. Most hERG missense mutations linked to long QT syndrome type 2 (LQT2) reduce the terminal glycosylation and functional expression. We tested the hypothesis that a distinct pre-Golgi compartment negatively regulates the trafficking of some LQT2 mutations to the Golgi apparatus. We found that treating cells in nocodazole, a microtubule depolymerizing agent, altered the subcellular localization, functional expression, and glycosylation of the LQT2 mutation G601S-hERG differently from wild-type hERG (WT-hERG). G601S-hERG quickly redistributed to peripheral compartments that partially colocalized with KDEL (Lys-Asp-Glu-Leu) chaperones but not calnexin, Sec31, or the ER golgi intermediate compartment (ERGIC). Treating cells in E-4031, a drug that increases the functional expression of G601S-hERG, prevented the accumulation of G601S-hERG to the peripheral compartments and increased G601S-hERG colocalization with the ERGIC. Coexpressing the temperature-sensitive mutant G protein from vesicular stomatitis virus, a mutant N-linked glycoprotein that is retained in the ER, showed it was not restricted to the same peripheral compartments as G601S-hERG at nonpermissive temperatures. We conclude that the trafficking of G601S-hERG is negatively regulated by a microtubule-dependent compartment within the ER. Identifying mechanisms that prevent the sorting or promote the release of LQT2 channels from this compartment may represent a novel therapeutic strategy for LQT2.

Abstract 3503: Hydrogen Peroxide-Induced Afterdepolarizations are Dependent on Calmodulin Kinase II Signaling

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Lai-Hua Xie ◽  
Fuhua Chen ◽  
James N Weiss
Keyword(s):  
Oxidative Stress ◽  
Hydrogen Peroxide ◽  
Ventricular Myocytes ◽  
Heart Association ◽  
Early Afterdepolarizations ◽  
Calmodulin Kinase ◽  
Repolarization Reserve ◽  
Delayed Afterdepolarizations ◽  
Rabbit Ventricular Myocytes ◽  
Camkii Activation

Background: In the heart, hydrogen peroxide (H 2 O 2 ) has been shown to cause early afterdepolarizations (EADs) and triggered activity by impairing Na current (I Na ) inactivation. Since H 2 O 2 has been recently shown to activate Ca 2+ /calmodulin kinase II (CaMKII), and since CaMKII activation has also been reported to impair I Na inactivation and predispose to EADs, we hypothesized that CaMKII activation by H 2 O 2 may be an important factor in the genesis of EADs induced by oxidative stress. Methods and Results: Patch-clamped Fluo-4 AM-loaded rabbit ventricular myocytes were exposed to H 2 O 2 (0.1–1mM), which induced spontaneous EADs after 5–15 min. Both the I Na blocker tetrodoxtin (TTX, 10 μM) and the I Ca,L blocker nifedipine shortened AP duration (APD) and suppressed EADs. H 2 O 2 increased both peak and steady-state I Ca,L under square-pulse voltage clamp, and enhanced I Ca,L to a greater extent during the AP plateau than during the AP upstroke under AP clamp conditions. In addition, by prolonging the AP plateau and increasing Ca influx via maintained I Ca,L , H 2 O 2 -induced EADs frequently caused DADs delayed afterdepolarizations (DADs) due to spontaneous SR Ca release waves after repolarization. KN-93(1 μM), a CaMKII inhibitor, prevented H 2 O 2 -induced EADs (n=4), whereas the inactive analogue KN-92 did not (n=5). Conclusion: These findings indicate that H 2 O 2 -induced EADs depend on both impaired I Na inactivation to reduce repolarization reserve and enhanced I Ca,L to reverse repolarization. Intact CaMKII signaling is necessary for EAD generation in this setting, presumably via its actions on I Na and I Ca,L , although direct redox effects on other ion channels/transporters may also be important. Our observations support a link between increased oxidative stress, CaMKII activation and afterdepolarizations as triggers of lethal ventricular arrhythmias in diseased heart. This research has received full or partial funding support from the American Heart Association, AHA National Center.

The Electrophysiological Mechanism of Ventricular Arrhythmias in the Long QT Syndrome

1996 ◽  
Vol 79 (3) ◽  
pp. 474-492 ◽  
Author(s):  
Nabil El-Sherif ◽  
Edward B. Caref ◽  
Hong Yin ◽  
Mark Restivo
Keyword(s):  
Long Qt Syndrome ◽  
Ventricular Arrhythmias ◽  
Long Qt ◽  
Qt Syndrome ◽  
Electrophysiological Mechanism

ECG patterns related to arrhythmias and sudden death: channelopathies, early repolarization, and pre-excitation

ESC CardioMed ◽  
2018 ◽  
pp. 382-389
Author(s):  
Wojciech Zareba ◽  
Pyotr Platonov
Keyword(s):  
Sudden Death ◽  
Long Qt Syndrome ◽  
Ventricular Arrhythmias ◽  
Prior History ◽  
Long Qt ◽  
Early Repolarization ◽  
Genes Encoding ◽  
History Of ◽  
Qt Syndrome ◽  
Characteristic Features

Electrocardiogram (ECG) patterns recognized in patients with sudden death without structural abnormalities in the heart have guided cardiology over the last few decades towards a better understanding of the role of cardiac ion channels in physiology and in arrhythmogenicity in rare electrical diseases. The long QT syndrome became the paradigm for evaluating the association between specific ion channel abnormalities caused by mutations in genes encoding predominantly potassium and sodium channels and phenotypic ECG expression. Specific ECG patterns observed in long QT syndrome help in diagnosis and improve prognosis in patients affected by this disorder. Short QT syndrome also is characterized by specific patterns in repolarization morphology that relate to affected potassium current or calcium handling genes. Brugada syndrome and early repolarization syndrome are considered as J-wave syndromes, having some similarities in ECG features but with distinctive patterns associated with classical forms of these disorders. Spontaneous appearance of cove-type Brugada pattern is associated with a worse prognosis. Early repolarization patterns may also indicate prognosis in subjects with a prior history of cardiac arrest or ventricular arrhythmias or a family history of cardiac arrests. Catecholaminergic polymorphic ventricular tachycardia is another channelopathy without characteristic features in standard resting ECG but with characteristic polymorphic ventricular arrhythmias during catecholaminergic challenge (exercise test, stressing situations). Pre-excitation syndromes associated with sudden cardiac death are well recognized and current understanding of these disorders leads to a better therapy.

Long QT syndrome: beyond making a diagnosis

2020 ◽  
pp. 189-200
Author(s):  
Gabrielle Norrish ◽  
Juan Pablo Kaski
Keyword(s):  
Long Qt Syndrome ◽  
Ventricular Arrhythmias ◽  
Beta Blockers ◽  
Psychological Impact ◽  
Population Screening ◽  
Implantable Cardioverter Defibrillators ◽  
Long Qt ◽  
Arrhythmic Death ◽  
Arrhythmic Event ◽  
Qt Syndrome

Long QT syndrome (LQTS) is an uncommon, but important, cause of ventricular arrhythmias. The diagnosis is straightforward in symptomatic patients with marked QT prolongation on a resting 12-lead electrocardiogram (ECG). However, in many patients, the ECG findings are dynamic, and to make the diagnosis, clinicians need to be aware of suggestive features. The greatest challenge in managing these patients is risk stratification for a sudden arrhythmic event. Beta-blockers have been shown to reduce the risk for ventricular arrhythmias in all genotype-positive patients, regardless of 12-lead ECG findings. For patients in whom beta-blockers are contraindicated, left cardiac sympathetic denervation may be a useful therapy. Implantable cardioverter–defibrillators have a role to play in preventing sudden cardiac death, although their use should be balanced with associated complications and psychological impact. Population screening for LQTS remains controversial. Screening of first-degree relatives in sudden arrhythmic death syndrome is recommended, but population screening is not currently undertaken in the United Kingdom.

scholarly journals Balance Between Rapid Delayed Rectifier K + Current and Late Na + Current on Ventricular Repolarization

2020 ◽  
Vol 13 (4) ◽  
Author(s):  
Bence Hegyi ◽  
Ye Chen-Izu ◽  
Leighton T. Izu ◽  
Sridharan Rajamani ◽  
Luiz Belardinelli ◽  
...  
Keyword(s):  
Heart Failure ◽  
Long Qt Syndrome ◽  
Therapeutic Potential ◽  
Heart Diseases ◽  
Ionic Currents ◽  
Close Correlation ◽  
Delayed Rectifier ◽  
Long Qt ◽  
Comparable Amount ◽  
Qt Syndrome

Background: Rapid delayed rectifier K + current (I Kr ) and late Na + current (I NaL ) significantly shape the cardiac action potential (AP). Changes in their magnitudes can cause either long or short QT syndromes associated with malignant ventricular arrhythmias and sudden cardiac death. Methods: Physiological self AP-clamp was used to measure I NaL and I Kr during the AP in rabbit and porcine ventricular cardiomyocytes to test our hypothesis that the balance between I Kr and I NaL affects repolarization stability in health and disease conditions. Results: We found comparable amount of net charge carried by I Kr and I NaL during the physiological AP, suggesting that outward K + current via I Kr and inward Na + current via I NaL are in balance during physiological repolarization. Remarkably, I Kr and I NaL integrals in each control myocyte were highly correlated in both healthy rabbit and pig myocytes, despite high overall cell-to-cell variability. This close correlation was lost in heart failure myocytes from both species. Pretreatment with E-4031 to block I Kr (mimicking long QT syndrome 2) or with sea anemone toxin II to impair Na + channel inactivation (mimicking long QT syndrome 3) prolonged AP duration (APD); however, using GS-967 to inhibit I NaL sufficiently restored APD to control in both cases. Importantly, I NaL inhibition significantly reduced the beat-to-beat and short-term variabilities of APD. Moreover, I NaL inhibition also restored APD and repolarization stability in heart failure. Conversely, pretreatment with GS-967 shortened APD (mimicking short QT syndrome), and E-4031 reverted APD shortening. Furthermore, the amplitude of AP alternans occurring at high pacing frequency was decreased by I NaL inhibition, increased by I Kr inhibition, and restored by combined I NaL and I Kr inhibitions. Conclusions: Our data demonstrate that I Kr and I NaL are counterbalancing currents during the physiological ventricular AP and their integrals covary in individual myocytes. Targeting these ionic currents to normalize their balance may have significant therapeutic potential in heart diseases with repolarization abnormalities. Visual Overview: A visual overview is available for this article.

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