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.

Hypertension-induced remodeling of cardiac excitation-contraction coupling in ventricular myocytes occurs prior to hypertrophy development

2007 ◽  
Vol 293 (6) ◽  
pp. H3301-H3310 ◽  
Author(s):  
Ye Chen-Izu ◽  
Ling Chen ◽  
Tamás Bányász ◽  
Stacey L. McCulle ◽  
Byron Norton ◽  
...  
Keyword(s):  
Cardiac Output ◽  
Heart Disease ◽  
Action Potential ◽  
Cardiac Hypertrophy ◽  
Ventricular Myocytes ◽  
Myocardial Contraction ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Window Period ◽  
Coupling System

Hypertension is a major risk factor for developing cardiac hypertrophy and heart failure. Previous studies show that hypertrophied and failing hearts display alterations in excitation-contraction (E-C) coupling. However, it is unclear whether remodeling of the E-C coupling system occurs before or after heart disease development. We hypothesized that hypertension might cause changes in the E-C coupling system that, in turn, induce hypertrophy. Here we tested this hypothesis by utilizing the progressive development of hypertensive heart disease in the spontaneously hypertensive rat (SHR) to identify a window period when SHR had just developed hypertension but had not yet developed hypertrophy. We found the following major changes in cardiac E-C coupling during this window period. 1) Using echocardiography and hemodynamics measurements, we found a decrease of left ventricular ejection fraction and cardiac output after the onset of hypertension. 2) Studies in isolated ventricular myocytes showed that myocardial contraction was also enhanced at the same time. 3) The action potential became prolonged. 4) The E-C coupling gain was increased. 5) The systolic Ca2+ transient was augmented. These data show that profound changes in E-C coupling already occur at the onset of hypertension and precede hypertrophy development. Prolonged action potential and increased E-C coupling gain synergistically increase the Ca2+ transient. Functionally, augmented Ca2+ transient causes enhancement of myocardial contraction that can partially compensate for the greater workload to maintain cardiac output. The increased Ca2+ signaling cascade as a molecular mechanism linking hypertension to cardiac hypertrophy development is also discussed.

Transient Receptor Potential Vanilloid 4 channel participates in mouse ventricular electrical activity

2021 ◽  
Author(s):  
Sebastien Chaigne ◽  
Guillaume Cardouat ◽  
Julien Louradour ◽  
Fanny Vaillant ◽  
Sabine Charron ◽  
...  
Keyword(s):  
Action Potential ◽  
Electrical Activity ◽  
Transient Receptor Potential ◽  
Ventricular Myocytes ◽  
Receptor Potential ◽  
Left Ventricular ◽  
Transient Receptor Potential Vanilloid ◽  
Western Blots ◽  
Transient Receptor ◽  
Trpv4 Channel

Introduction: Transient Receptor Potential Vanilloid 4 (TRPV4) channel is a calcium permeable channel (PCa/PNa ~ 10). Its expression was reported in ventricular myocytes where it is involved in several cardiac pathological mechanisms. In this study, we investigated the implication of TRPV4 in ventricular electrical activity. Methods and Results: Left ventricular myocytes were isolated from trpv4+/+ and trpv4-/- mice. TRPV4 membrane expression and its colocalization with Cav1.2 was confirmed using western-blots biotinylation, immunoprecipitation and immunostaining experiments. Then, electrocardiograms (ECGs) and patch-clamp recordings showed shortened QTc and action potential (AP) duration in trpv4-/- compared to trpv4+/+ mice. Thus, TRPV4 activator GSK1016790A produced a transient and dose-dependent increase in AP duration at 90 % of repolarization (APD90) in trpv4+/+, but not in trpv4-/- myocytes or when combined with TRPV4 inhibitor GSK2193874 (100 nM). Hence, GSK1016790A increased CaT amplitude in trpv4+/+ but not in trpv4-/- myocytes, suggesting that TRPV4 carries an inward Ca2+ current in myocytes. Conversely, TRPV4 inhibitor GSK2193874 (100 nM) alone reduced APD90 in trpv4+/+ but not in trpv4-/- myocytes, suggesting that TRPV4 prolongs AP duration (APD) in basal condition. Finally, introducing TRPV4 parameters in a mathematical model predicted the development of an inward TRPV4 current during repolarization that increases AP duration and CaT amplitude, in accordance with what found experimentally. Conclusion: This study shows for the first time that TRPV4 modulates AP and QTc durations and constitutes thereby a good therapeutical target against long QT-mediated ventricular arrhythmias. Keywords: TRPV4 channel, action potential, QT interval, mathematical modeling, trpv4-/-, calcium transient.

Antagonism of forskolin effects by adenosine in isolated hearts and ventricular myocytes

1986 ◽  
Vol 250 (5) ◽  
pp. H769-H777
Author(s):  
G. A. West ◽  
G. Isenberg ◽  
L. Belardinelli
Keyword(s):  
Action Potential ◽  
Ventricular Myocytes ◽  
Left Ventricular Pressure ◽  
Left Ventricular ◽  
Ventricular Pressure ◽  
Dibutyryl Camp ◽  
Isolated Hearts ◽  
Ventricular Tissue ◽  
Single Ventricular Myocytes ◽  
Isolated Ventricular Myocytes

Adenosine is known to antagonize the effects of catecholamine stimulation in atrial and ventricular tissue; however, its mechanism of action is unknown. Forskolin is an inotropic agent that causes an increase in cyclic AMP (cAMP) levels independent of receptor stimulation. We sought to test whether adenosine could attenuate the effects of forskolin in isolated perfused guinea pig hearts and isolated single ventricular myocytes. In isolated perfused hearts (n = 18), forskolin caused a concentration-dependent increase in left ventricular pressure and dP/dt. Adenosine (5 microM) antagonized the forskolin (0.35 microM)-induced increase in left ventricular pressure and dP/dt by 96 +/- 2 and 92 +/- 4% (means +/- SE), respectively. In contrast, in four hearts, adenosine was ineffective in attenuating the inotropic response to dibutyryl cAMP. In isolated ventricular myocytes (n = 10) 150 nM forskolin caused a significant increase in action potential duration and plateau. In voltage-clamp experiments (n = 8), 150 nM forskolin caused a 39 +/- 3% increase in the calcium current, which was antagonized by adenosine (50 microM) by 80%. Forskolin also caused an increase in contractility, as estimated by sarcomere shortening of the cell. Adenosine, and its analogue N6-R-phenylisopropyladenosine (L-PIA), antagonized the effects of 150 nM forskolin on the action potential and on sarcomere shortening. Dibutyryl cAMP had similar effects as forskolin, but they were not antagonized by adenosine. At higher concentrations of forskolin, above 300 nM, delayed after depolarizations and sustained spontaneous activity occurred that could be abolished by L-PIA. Forskolin caused a concentration-dependent increase in cAMP, measured in isolated ventricular myocytes.(ABSTRACT TRUNCATED AT 250 WORDS)

Chronic Single Nephrectomy Prolongs Action Potential Duration by Inhibiting Transient Outward Currents in Left Ventricular Myocytes

Heart Rhythm ◽  
2009 ◽  
Vol 6 (11) ◽  
pp. 1690
Author(s):  
Kuan-Cheng Chang ◽  
Shih-Sheng Chang ◽  
Hsin-Yueh Liang ◽  
An-Sheng Lee ◽  
Ming-Jai Su
Keyword(s):  
Action Potential ◽  
Action Potential Duration ◽  
Ventricular Myocytes ◽  
Left Ventricular ◽  
Outward Currents

scholarly journals High rate pacing guided by short-term variability of repolarization prevents imminent ventricular arrhythmias autonomically by an ICD

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
A Smoczynska ◽  
V Loen ◽  
A.A Hernandez ◽  
H.D.M Beekman ◽  
M Meine ◽  
...  
Keyword(s):  
Ventricular Arrhythmias ◽  
Torsade De Pointes ◽  
Left Ventricular ◽  
High Rate ◽  
Monophasic Action Potential ◽  
Funding Source ◽  
Short Term ◽  
Dispersion Of Repolarization ◽  
Temporal Dispersion ◽  
Short Term Variability

Abstract Background The anesthetized, chronic complete atrioventricular block (CAVB) dog model allows reproducible inducibility of Torsade de Pointes (TdP) arrhythmias due to ventricular remodeling and after a challenge with an IKr-blocker. High rate pacing (HRP) prevents ventricular arrhythmias, but has long-term detrimental effects on cardiac function when applied continuously. Temporal dispersion of repolarization, quantified as short-term variability (STV), increases prior to ventricular arrhythmias and has been proposed as a marker to guide HRP. Purpose A proof-of-principle study to show STV determined automatically and in real-time by an ICD can guide HRP to prevent imminent ventricular arrhythmias. Methods Eight CAVB dogs were implanted with an ICD (Medtronic, lead in the right ventricular (RV) apex), with software to automatically determine STV online (STV-ICD). STV was determined from the activation recovery interval (ARI) of 31 consecutive beats with the formula: STV = Σ|ARI(n+1) − ARI(n)|/(N*√2). The CAVB dogs were challenged twice with dofetilide (0.025 mg/kg i.v. in 5 minutes or until the first TdP). In the first experiment, the individual STV-ICD threshold was determined prior to the first arrhythmic event and programmed into the ICD. In a serial experiment, HRP was initiated automatically once the STV-ICD threshold was reached, by gradually increasing the heart rate to 100 bpm. Occurrence of TdPs was monitored for 10 minutes from the start of dofetilide infusion in both experiments. During HRP, STV was measured offline from RV electrograms (EGM) and left ventricular (LV) monophasic action potential durations (MAPD) (STV-offline). Results During the inducibility experiment, 8/8 dogs had repetitive TdPs and STV-ICD increased from 0.96±0.42 to 2.10±1.26 ms* (*p<0.05). During the prevention experiment, all dogs reached the STV threshold. HRP decreased STV-offline from 2.02±1.12 to 0.78±0.28 ms*, which was accompanied by prevention of TdPs in 7/8 dogs* (Figure 1). Conclusion Temporal dispersion of repolarization, quantified as STV, can guide HRP automatically by an ICD to prevent ventricular arrhythmias. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Dutch Heart Foundation Public Private Partnership

scholarly journals Severe Bradycardia Increases the Incidence and Severity of Torsade de Pointes Arrhythmias by Augmenting Preexistent Spatial Dispersion of Repolarization in the CAVB Dog Model

2021 ◽  
Vol 12 ◽  
Author(s):  
Valerie Y. H. van Weperen ◽  
Albert Dunnink ◽  
Alexandre Bossu ◽  
Jet D. M. Beekman ◽  
Veronique M. F. Meijborg ◽  
...  
Keyword(s):  
Spatial Dispersion ◽  
Torsade De Pointes ◽  
Left Ventricular ◽  
Dispersion Of Repolarization ◽  
Dog Model ◽  
Severe Bradycardia ◽  
Idioventricular Rhythm ◽  
Surface Electrocardiogram ◽  
Temporal Dispersion ◽  
Unipolar Electrograms

IntroductionTorsade de pointes arrhythmias (TdP) in the chronic atrioventricular block (CAVB) dog model result from proarrhythmic factors, which trigger TdP and/or reinforce the arrhythmic substrate. This study investigated electrophysiological and arrhythmogenic consequences of severe bradycardia for TdP.MethodsDofetilide (25 μg/kg per 5 min) was administered to eight anesthetized, idioventricular rhythm (IVR) remodeled CAVB dogs in two serial experiments: once under 60 beats per minute (bpm), right ventricular apex paced (RVA60) conditions, once under more bradycardic IVR conditions. Recordings included surface electrocardiogram and short-term variability (STV) of repolarization from endocardial unipolar electrograms. TdP inducibility (three or more episodes within 10 min after start of dofetilide) and arrhythmic activity scores (AS) were established. Mapping experiments in 10 additional dogs determined the effect of lowering rate on STV and spatial dispersion of repolarization (SDR) in baseline.ResultsIVR-tested animals had longer baseline RR-interval (1,403 ± 271 ms) and repolarization intervals than RVA60 animals. Dofetilide increased STV similarly under both rhythm strategies. Nevertheless, TdP inducibility and AS were higher under IVR conditions (6/8 and 37 ± 27 vs. 1/8 and 8 ± 12 in RVA60, respectively, both p < 0.05). Mapping: Pacing from high (128 ± 10 bpm) to middle (88 ± 10 bpm) to experimental rate (61 ± 3 bpm) increased all electrophysiological parameters, including interventricular dispersion, due to steeper left ventricular restitution curves, and intraventricular SDR: maximal cubic dispersion from 60 ± 14 (high) to 69 ± 17 (middle) to 84 ± 22 ms (p < 0.05 vs. high and middle rate).ConclusionIn CAVB dogs, severe bradycardia increases the probability and severity of arrhythmic events by heterogeneously causing electrophysiological instability, which is mainly reflected in an increased spatial, and to a lesser extent temporal, dispersion of repolarization.

scholarly journals A Mathematical Model of Action Potential Heterogeneity in Adult Rat Left Ventricular Myocytes

2001 ◽  
Vol 81 (6) ◽  
pp. 3029-3051 ◽  
Author(s):  
Sandeep V. Pandit ◽  
Robert B. Clark ◽  
Wayne R. Giles ◽  
Semahat S. Demir
Keyword(s):  
Mathematical Model ◽  
Action Potential ◽  
Ventricular Myocytes ◽  
Left Ventricular ◽  
Adult Rat

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.

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