P2564Levosimendan shortens action potential duration, decreases alternans threshold and prevents ventricular arrhythmia during therapeutic hypothermia in isolated rabbit hearts

Abstract Background Therapeutic hypothermia (TH) increases the susceptibility to ventricular arrhythmias (VA) by prolonging action potential duration (APD) and facilitating arrhythmogenic spatially discordant alternans (SDA). The calcium sensitizer levosimendan has been reported to shorten APD by enhancing ATP-sensitive K current. We hypothesize that levosimendan might shorten the already prolonged APD during TH, decreasing SDA threshold, and prevent the occurrence of VA. Methods Langendorff-perfused isolated rabbit hearts were subjected to 15-min TH (30°C) followed by 30-min treatment with levosimendan (0.5 μM, n=9) or vehicle (n=8). Using an optical mapping system, epicardial APD was evaluated by S1 pacing. SDA threshold was defined as the longest pacing cycle length (PCL) that induced SDA phenomenon. Ventricular fibrillation (VF) inducibility was evaluated by burst pacing for 30 s using the shortest PCL that achieved 1:1 ventricular capture. Results Levosimendan shortened the ventricular APD (at PCL 300 ms, from 229±9 ms to 211±18 ms, p=0.02) and decrease the SDA threshold (from 327±88 ms to 311±68 ms, p=0.001) during TH. The VF inducibility was decreased by levosimendan from 39±30% at 30°C to 14±12% after levosimendan infusion. In control hearts, the APD (p=0.75), SDA threshold (p=ns) and VF inducibility (p=0.12) were not changed by vehicle during TH. Conclusions Levosimendan protects the hearts against VA during TH by shortening APD and decreasing SDA threshold. Enhancing ATP-sensitive K current with levosimendan might be a novel approach to prevent VA during TH.

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Reverse use dependence of calcium sensitizer levosimendan on action potential duration shortening prevents ventricular arrhythmia during therapeutic hypothermia

European Heart Journal ◽

10.1093/ehjci/ehaa946.3698 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

Y.C Hsieh ◽

C.H Li ◽

J.C Lin ◽

C.J Weng ◽

Y.S Chien ◽

...

Keyword(s):

Ventricular Arrhythmia ◽

Action Potential ◽

Therapeutic Hypothermia ◽

Action Potential Duration ◽

Heart Failure Treatment ◽

Novel Approach ◽

Mapping System ◽

Diastolic Interval ◽

K Current ◽

Calcium Sensitizer

Abstract Background Therapeutic hypothermia (TH) increases the risk of ventricular arrhythmia (VA) by prolonging action potential duration (APD) and steepening the APD restitution (APDR). The calcium sensitizer levosimendan, a medication for heart failure treatment, has been reported to shorten APD by enhancing ATP-sensitive K current and affect the APDR. Purpose We hypothesized that levosimendan might shorten the already prolonged APD particularly at long pacing cycle length (PCL), thus decreases the maximal slope of APDR, and prevent VA during TH. Methods Langendorff-perfused isolated rabbit hearts were subjected to 15-min TH (30°C) followed by 30-min treatment with levosimendan (0.5 μM, n=9) or vehicle (n=8). Using an optical mapping system, APD was evaluated by S1 pacing and APDR curve was plotted using APD70 versus diastolic interval. Ventricular fibrillation (VF) inducibility was evaluated by burst pacing for 30 s at the shortest PCL that achieved 1:1 ventricular capture. Results The APD was shortened from 259±8 ms at TH to 241±18 ms after levosimendan infusion at long PCL of 400 ms (p=0.024). However, at short PCL of 280 ms, the APD was not changed before (194±19) and after (188±23) levosimendan during TH (p=0.61). Levosimendan decreases the maximal slope of APDR curve from 1.99±0.65 at TH to 1.41±0.32 after adding levosimendan (p=0.034). The VF inducibility was decreased by levosimendan from 39±30% at 30°C to 14±12% with levosimendan (p=0.023). In control hearts, the maximal slope of APDR (p=0.75) and VF inducibility (p=0.12) were not changed by vehicle during TH. Conclusion Levosimendan might protect the hearts against VA during TH by shortening APD at long PCL and flattening the APDR. Enhancing ATP-sensitive K current with levosimendan during TH might be a novel approach to prevent VA during TH. Funding Acknowledgement Type of funding source: None

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Intramural optical mapping of Vm and Cai2+ during long-duration ventricular fibrillation in canine hearts

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00426.2011 ◽

2012 ◽

Vol 302 (6) ◽

pp. H1294-H1305 ◽

Cited By ~ 9

Author(s):

Wei Kong ◽

Raymond E. Ideker ◽

Vladimir G. Fast

Keyword(s):

Ventricular Fibrillation ◽

Action Potential ◽

Short Duration ◽

Action Potential Duration ◽

Cycle Length ◽

The Other ◽

Membrane Voltage ◽

Long Duration ◽

Intracellular Ca ◽

Rapid Pacing

Intramural gradients of intracellular Ca2+ (Cai2+) Cai2+ handling, Cai2+ oscillations, and Cai2+ transient (CaT) alternans may be important in long-duration ventricular fibrillation (LDVF). However, previous studies of Cai2+ handling have been limited to recordings from the heart surface during short-duration ventricular fibrillation. To examine whether abnormalities of intramural Cai2+ handling contribute to LDVF, we measured membrane voltage ( Vm) and Cai2+ during pacing and LDVF in six perfused canine hearts using five eight-fiber optrodes. Measurements were grouped into epicardial, midwall, and endocardial layers. We found that during pacing at 350-ms cycle length, CaT duration was slightly longer (by ≃10%) in endocardial layers than in epicardial layers, whereas action potential duration (APD) exhibited no difference. Rapid pacing at 150-ms cycle length caused alternans in both APD (APD-ALT) and CaT amplitude (CaA-ALT) without significant transmural differences. For 93% of optrode recordings, CaA-ALT was transmurally concordant, whereas APD-ALT was either concordant (36%) or discordant (54%), suggesting that APD-ALT was not caused by CaA-ALT. During LDVF, Vm and Cai2+ progressively desynchronized when not every action potential was followed by a CaT. Such desynchronization developed faster in the epicardium than in the other layers. In addition, CaT duration strongly increased (by ∼240% at 5 min of LDVF), whereas APD shortened (by ∼17%). CaT rises always followed Vm upstrokes during pacing and LDVF. In conclusion, the fact that Vm upstrokes always preceded CaTs indicates that spontaneous Cai2+ oscillations in the working myocardium were not likely the reason for LDVF maintenance. Strong Vm-Cai2+ desynchronization and the occurrence of long CaTs during LDVF indicate severely impaired Cai2+ handling and may potentially contribute to LDVF maintenance.

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Dynamic restitution of action potential duration during electrical alternans and ventricular fibrillation

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1998.275.5.h1635 ◽

1998 ◽

Vol 275 (5) ◽

pp. H1635-H1642 ◽

Cited By ~ 125

Author(s):

Marcus L. Koller ◽

Mark L. Riccio ◽

Robert F. Gilmour Jr.

Keyword(s):

Ventricular Fibrillation ◽

Action Potential ◽

Action Potential Duration ◽

Cycle Length ◽

Strong Relationship ◽

Standard Protocol ◽

Diastolic Interval ◽

Cycle Lengths ◽

Electrical Alternans ◽

Kinetics Of

The restitution kinetics of action potential duration (APD) were investigated in paced canine Purkinje fibers (P; n = 9) and endocardial muscle (M; n = 9), in isolated, perfused canine left ventricles during ventricular fibrillation (VF; n = 4), and in endocardial muscle paced at VF cycle lengths (simulated VF; n = 4). Restitution was assessed with the use of two protocols: delivery of a single extrastimulus after a train of stimuli at cycle length = 300 ms (standard protocol), and fixed pacing at short cycle lengths (100–300 ms) that induced APD alternans (dynamic protocol). The dynamic protocol yielded a monotone increasing restitution function with a maximal slope of 1.13 ± 0.13 in M and 1.14 ± 0.17 in P. Iteration of this function reproduced the APD dynamics found experimentally, including persistent APD alternans. In contrast, the standard protocol yielded a restitution relation with a maximal slope of 0.57 ± 0.18 in M and 0.84 ± 0.20 in P, and iteration of this function did not reproduce the APD dynamics. During VF, the restitution kinetics at short diastolic interval were similar to those determined with the dynamic protocol (maximal slope: 1.72 ± 0.47 in VF and 1.44 ± 0.49 in simulated VF). Thus APD dynamics at short coupling intervals during fixed pacing and during VF were accounted for by the dynamic, but not the standard, restitution relation. These results provide further evidence for a strong relationship among the kinetics of electrical restitution, the occurrence of APD alternans, and complex APD dynamics during VF.

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Preconditioning reduces infarct size but accelerates time to ventricular fibrillation in ischemic pig heart

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1995.269.1.h72 ◽

1995 ◽

Vol 269 (1) ◽

pp. H72-H79 ◽

Cited By ~ 12

Author(s):

M. Ovize ◽

J. F. Aupetit ◽

G. Rioufol ◽

J. Loufoua ◽

X. Andre-Fouet ◽

...

Keyword(s):

Ventricular Fibrillation ◽

Action Potential ◽

Infarct Size ◽

Action Potential Duration ◽

Ventricular Arrhythmias ◽

Monophasic Action Potential ◽

Control Group ◽

Large Animal ◽

Large Animal Models ◽

Ventricular Fibrillation Threshold

Preconditioning protects the rat heart from ventricular arrhythmias. However, the mechanism of this beneficial effect and its existence in large animal models remain unknown. We submitted 49 pigs to 40 min of left anterior descending coronary occlusion and 2 h of reperfusion and assessed the incidence of ventricular fibrillation (VF) and time to VF. Monophasic action potential duration (MAPD) and ventricular fibrillation threshold (VFT) were measured throughout the experiment. Preconditioning significantly reduced infarct size but failed to reduce the incidence of VF either during the 40-min ischemic insult or the following reperfusion. Moreover, preconditioning accelerated the onset of VF during the prolonged ischemia; time to VF averaged 8 +/- 2 min in the preconditioned group vs. 18 +/- 2 min in the control group (P < 0.05). This premature peak of VF in preconditioned hearts was associated with a significant decrease of VFT and shortening of MAPD. This suggests that preconditioning does not limit the incidence of VF in the pig model. Rather, preconditioning decreases the time to VF in this species, likely through lowering of the VFT and shortening of the action potential duration.

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Effect of Amiodarone and Hypothermia on Arrhythmia Substrates During Resuscitation

Journal of the American Heart Association ◽

10.1161/jaha.120.016676 ◽

2021 ◽

Author(s):

Joseph S. Piktel ◽

Yi Suen ◽

Shalen Kouk ◽

Danielle Maleski ◽

Gary Pawlowski ◽

...

Keyword(s):

Cardiac Arrest ◽

Ventricular Fibrillation ◽

Action Potential ◽

Therapeutic Hypothermia ◽

Action Potential Duration ◽

Left Ventricular ◽

Targeted Temperature Management ◽

Temperature Management

Background Amiodarone is administered during resuscitation, but its antiarrhythmic effects during targeted temperature management are unknown. The purpose of this study was to determine the effect of both therapeutic hypothermia and amiodarone on arrhythmia substrates during resuscitation from cardiac arrest. Methods and Results We utilized 2 complementary models: (1) In vitro no‐flow global ischemia canine left ventricular transmural wedge preparation. Wedges at different temperatures (36°C or 32°C) were given 5 µmol/L amiodarone (36‐Amio or 32‐Amio, each n=8) and subsequently underwent ischemia and reperfusion. Results were compared with previous controls. Optical mapping was used to measure action potential duration, dispersion of repolarization (DOR), and conduction velocity (CV). (2) In vivo pig model of resuscitation. Pigs (control or targeted temperature management, 32–34°C) underwent ischemic cardiac arrest and were administered amiodarone (or not) after 8 minutes of ventricular fibrillation. In vitro: therapeutic hypothermia but not amiodarone prolonged action potential duration. During ischemia, DOR increased in the 32‐Amio group versus 32‐Alone (84±7 ms versus 40±7 ms, P <0.05) while CV slowed in the 32‐Amio group. Amiodarone did not affect CV, DOR, or action potential duration during ischemia at 36°C. Conduction block was only observed at 36°C (5/8 36‐Amio versus 6/7 36‐Alone, 0/8 32‐Amio, versus 0/7 32‐Alone). In vivo: QTc decreased upon reperfusion from ischemia that was ameliorated by targeted temperature management. Amiodarone did not worsen DOR or CV. Amiodarone suppressed rearrest caused by ventricular fibrillation (7/8 without amiodarone, 2/7 with amiodarone, P =0.041), but not pulseless electrical activity (2/8 without amiodarone, 5/7 with amiodarone, P =0.13). Conclusions Although amiodarone abolishes a beneficial effect of therapeutic hypothermia on ischemia‐induced DOR and CV, it did not worsen susceptibility to ventricular tachycardia/ventricular fibrillation during resuscitation.

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Cardiac contractility modulation increases action potential duration dispersion and decreases ventricular fibrillation threshold via β1-adrenoceptor activation in the crystalloid perfused normal rabbit heart

International Journal of Cardiology ◽

10.1016/j.ijcard.2013.12.184 ◽

2014 ◽

Vol 172 (1) ◽

pp. 144-154 ◽

Cited By ~ 7

Author(s):

James Winter ◽

Kieran E. Brack ◽

John H. Coote ◽

G. André Ng

Keyword(s):

Ventricular Fibrillation ◽

Action Potential ◽

Action Potential Duration ◽

Cardiac Contractility ◽

Rabbit Heart ◽

Cardiac Contractility Modulation ◽

Ventricular Fibrillation Threshold

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SK channel blockade prevents hypoxia-induced ventricular arrhythmias through inhibition of Ca2+/voltage uncoupling in hypertrophied hearts

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00777.2020 ◽

2021 ◽

Vol 320 (4) ◽

pp. H1456-H1469

Author(s):

Masayuki Takahashi ◽

Hisashi Yokoshiki ◽

Hirofumi Mitsuyama ◽

Masaya Watanabe ◽

Taro Temma ◽

...

Keyword(s):

Action Potential ◽

Action Potential Duration ◽

Ventricular Arrhythmias ◽

Channel Blockade ◽

Sk Channel ◽

Small Conductance

We demonstrated that hypoxia-induced ventricular arrhythmias were mainly initiated by Ca2+-loaded triggered activities in hypertrophied hearts. The blockades of small-conductance Ca2+-activated K+ channels, especially “apamin,” showed anti-arrhythmic effects by alleviation of not only action potential duration shortening but also Ca2+ handling abnormalities, most notably the “Ca2+/voltage uncoupling.”

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Dual effects of external magnesium on action potential duration in guinea pig ventricular myocytes

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1995.268.6.h2321 ◽

1995 ◽

Vol 268 (6) ◽

pp. H2321-H2328 ◽

Cited By ~ 3

Author(s):

S. Zhang ◽

T. Sawanobori ◽

H. Adaniya ◽

Y. Hirano ◽

M. Hiraoka

Keyword(s):

Guinea Pig ◽

Action Potential ◽

Decay Time ◽

Action Potential Duration ◽

Time Course ◽

Ventricular Myocytes ◽

Membrane Surface ◽

Surface Charges ◽

Whole Cell Patch Clamp ◽

K Current

Effects of extracellular magnesium (Mg2+) on action potential duration (APD) and underlying membrane currents in guinea pig ventricular myocytes were studied by using the whole cell patch-clamp method. Increasing external Mg2+ concentration [Mg2+]o) from 0.5 to 3 mM produced a prolongation of APD at 90% repolarization (APD90), whereas 5 and 10 mM Mg2+ shortened it. [Mg2+]o, at 3 mM or higher, suppressed the delayed outward K+ current and the inward rectifier K+ current. Increases in [Mg2+]o depressed the peak amplitude and delayed the decay time course of the Ca2+ current (ICa), the latter effect is probably due to the decrease in Ca(2+)-induced inactivation. Thus 3 mM Mg2+ suppressed the peak ICa but increased the late ICa amplitude at the end of a 200-ms depolarization pulse, whereas 10 mM Mg2+ suppressed both components. Application of 10 mM Mg2+ shifted the voltage-dependent activation and inactivation by approximately 10 mV to more positive voltage due to screening the membrane surface charges. Application of manganese (1-5 mM) also caused dual effects on APD90, similar to those of Mg2+, and suppressed the peak ICa with slowed decay. These results suggest that the dual effects of Mg2+ on APD in guinea pig ventricular myocytes can be, at least in part, explained by its action on ICa with slowed decay time course in addition to suppressive effects on K+ currents.

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