scholarly journals Prediction of Thorough QT study results using action potential simulations based on ion channel screens

2014 ◽  
Vol 70 (3) ◽  
pp. 246-254 ◽  
Author(s):  
Gary R. Mirams ◽  
Mark R. Davies ◽  
Stephen J. Brough ◽  
Matthew H. Bridgland-Taylor ◽  
Yi Cui ◽  
...  
Keyword(s):  
Action Potential ◽  
Ion Channel ◽  
Thorough Qt Study ◽  
Study Results

scholarly journals Ion Channel and Structural Remodeling in Obesity-Mediated Atrial Fibrillation

2020 ◽  
Vol 13 (8) ◽  
Author(s):  
Mark D. McCauley ◽  
Liang Hong ◽  
Arvind Sridhar ◽  
Ambili Menon ◽  
Srikanth Perike ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Action Potential ◽  
Ion Channel ◽  
Sodium Channel ◽  
Action Potential Duration ◽  
Obese Mice ◽  
Atrial Fibrosis ◽  
Structural Remodeling ◽  
Cardiac Sodium Channel ◽  
Channel Expression

Background: Epidemiological studies have established obesity as an independent risk factor for atrial fibrillation (AF), but the underlying pathophysiological mechanisms remain unclear. Reduced cardiac sodium channel expression is a known causal mechanism in AF. We hypothesized that obesity decreases Nav1.5 expression via enhanced oxidative stress, thus reducing I Na , and enhancing susceptibility to AF. Methods: To elucidate the underlying electrophysiological mechanisms a diet-induced obese mouse model was used. Weight, blood pressure, glucose, F 2 -isoprostanes, NOX2 (NADPH oxidase 2), and PKC (protein kinase C) were measured in obese mice and compared with lean controls. Invasive electrophysiological, immunohistochemistry, Western blotting, and patch clamping of membrane potentials was performed to evaluate the molecular and electrophysiological phenotype of atrial myocytes. Results: Pacing-induced AF in 100% of diet-induced obese mice versus 25% in controls ( P <0.01) with increased AF burden. Cardiac sodium channel expression, I Na and atrial action potential duration were reduced and potassium channel expression (Kv1.5) and current ( I Kur ) and F 2 -isoprostanes, NOX2, and PKC-α/δ expression and atrial fibrosis were significantly increased in diet-induced obese mice as compared with controls. A mitochondrial antioxidant reduced AF burden, restored I Na , I Ca,L , I Kur , action potential duration, and reversed atrial fibrosis in diet-induced obese mice as compared with controls. Conclusions: Inducible AF in obese mice is mediated, in part, by a combined effect of sodium, potassium, and calcium channel remodeling and atrial fibrosis. Mitochondrial antioxidant therapy abrogated the ion channel and structural remodeling and reversed the obesity-induced AF burden. Our findings have important implications for the management of obesity-mediated AF in patients. Graphic Abstract: A graphic abstract is available for this article.

scholarly journals Inhibition of Histone Deacetylases Induces K+ Channel Remodeling and Action Potential Prolongation in HL-1 Atrial Cardiomyocytes

2018 ◽  
Vol 49 (1) ◽  
pp. 65-77 ◽  
Author(s):  
Patrick Lugenbiel ◽  
Katharina Govorov ◽  
Ann-Kathrin Rahm ◽  
Teresa Wieder ◽  
Dominik Gramlich ◽  
...  
Keyword(s):  
Action Potential ◽  
Ion Channel ◽  
Action Potential Duration ◽  
Histone Deacetylases ◽  
Trichostatin A ◽  
Class I ◽  
K Channel ◽  
Hdac Inhibition ◽  
Atrial Cardiomyocytes ◽  
Channel Expression

Background/Aims: Cardiac arrhythmias are triggered by environmental stimuli that may modulate expression of cardiac ion channels. Underlying epigenetic regulation of cardiac electrophysiology remains incompletely understood. Histone deacetylases (HDACs) control gene expression and cardiac integrity. We hypothesized that class I/II HDACs transcriptionally regulate ion channel expression and determine action potential duration (APD) in cardiac myocytes. Methods: Global class I/II HDAC inhibition was achieved by administration of trichostatin A (TSA). HDAC-mediated effects on K+ channel expression and electrophysiological function were evaluated in murine atrial cardiomyocytes (HL-1 cells) using real-time PCR, Western blot, and patch clamp analyses. Electrical tachypacing was employed to recapitulate arrhythmia-related effects on ion channel remodeling in the absence and presence of HDAC inhibition. Results: Global HDAC inhibition increased histone acetylation and prolonged APD90 in atrial cardiomyocytes compared to untreated control cells. Transcript levels of voltage-gated or inwardly rectifying K+ channels Kcnq1, Kcnj3 and Kcnj5 were significantly reduced, whereas Kcnk2, Kcnj2 and Kcnd3 mRNAs were upregulated. Ion channel remodeling was similarly observed at protein level. Short-term tachypacing did not induce significant transcriptional K+ channel remodeling. Conclusion: The present findings link class I/II HDAC activity to regulation of ion channel expression and action potential duration in atrial cardiomyocytes. Clinical implications for HDAC-based antiarrhythmic therapy and cardiac safety of HDAC inhibitors require further investigation.

Abstract MP110: Inhibition of the Unfolded Protein Response Reduces Arrhythmic Risk After Myocardial Infarction

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Man Liu ◽  
Hong Liu ◽  
Preethy Parthiban ◽  
guangbin shi ◽  
Gyeoung-Jin Kang ◽  
...  
Keyword(s):  
Ion Channels ◽  
Action Potential ◽  
Ion Channel ◽  
Unfolded Protein Response ◽  
Coronary Artery Ligation ◽  
Unfolded Protein ◽  
Cardiac Ion Channels ◽  
Increased Risk ◽  
The Unfolded Protein Response ◽  
Protein Response

Background: Ischemic cardiomyopathy is associated with an increased risk of sudden death, activation of the unfolded protein response (UPR), and reductions in multiple cardiac ion channels and transporters. When activated, the protein kinase-like ER kinase (PERK) arm of the unfolded protein response (UPR) reduces protein translation and abundance. We hypothesize that inhibition of PERK could prevent cardiac ion channel downregulation and reduce arrhythmic risk after myocardial infarct (MI). Methods: The MI mouse model was induced by a left anterior descending coronary artery ligation. Pharmacological inhibition of PERK was achieved with a specific inhibitor, GSK2606414. Genetic inhibition of PERK was achieved by cardiac-specific PERK knockout in C57BL/6J mice (PERKKO). Echocardiography, telemetry, and electrophysiological measurements were performed to monitor cardiac function and arrhythmias. Results: Three weeks after surgery, the wild type MI mice exhibited decreased ejection fraction (EF%), ventricular tachycardia (VT) and prolonged QTc intervals. The UPR effectors (phospho-PERK, phospho-IRE1, and ATF6N) were elevated significantly (1.7- to 5.9-fold) at protein levels, and all major cardiac ion channels showed decreased protein expression in MI hearts. MI cardiomyocytes showed decreased currents for all major channels (I Na , I CaL , I to , I K1 , and I Kur : 60±6%, 53±9%, 27±6%, 55±7%, and 40±7% of sham, respectively, P<0.05 vs. sham) with significantly prolonged action potential duration (APD 90 : 291±43 ms of MI vs. 100±12 ms of sham, P<0.05) and decreased maximum upstroke velocity (dV/dt max : 95±4 V/s of MI vs. 132±6 ms of sham, P<0.05) of the action potential phase 0. GSK treatment restored I Na and I to , shortened APD, and increased dV/dt max . PERKKO mice exhibited reduced electrical remodeling in response to MI with shortened QTc intervals, less VT episodes, and higher survival rates. Conclusion: PERK is activated during MI and contributes to arrhythmic risk by downregulation of select cardiac ion channels. PERK inhibition prevented these changes and reduced arrhythmic risk. These results suggest that ion channel downregulation during MI is a fundamental arrhythmic mechanism and maintaining ion channel levels is antiarrhythmic.

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