IKr contributes to the altered ventricular repolarization that determines long-term cardiac memory

Obreztchikova, M.; Patberg, Kornelis W.; Plotnikov, Alexei N.; Özgen, Nazira; Shlapakova, Irina N.; Rybin, Andrew; Sosunov, Eugene A.; Danilo, Peter; Anyukhovsky, Evgeny P.; Robinson, Richard B.; Rosen, Michael R.

doi:10.1016/j.cardiores.2006.02.028

Cited by 36 publications

(35 citation statements)

References 30 publications

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“…In animal experiments using long-term asynchronous activation by ventricular pacing or LBBB, several changes in ionic membrane currents have been observed, including changes in I CaL (40), I to (62), I Kr , and I Ks (37). In addition to changes in I CaL and calcium handling, Aiba et al (2) observed differences in several potassium currents, including I K , I Kl , and I to in their DHF model.…”

Section: Discussionmentioning

confidence: 95%

Mechano-electrical coupling as framework for understanding functional remodeling during LBBB and CRT

Kuijpers

Hermeling

Lumens

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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It is not understood why, after onset of left bundle-branch block (LBBB), acute worsening of cardiac function is followed by a further gradual deterioration of function, whereas most adverse cardiac events lead to compensatory adaptations. We investigated whether mechano-electrical coupling (MEC) can explain long-term remodeling with LBBB and cardiac resynchronization therapy (CRT). To this purpose, we used an integrative modeling approach relating local ventricular electrophysiology, calcium handling, and excitation-contraction coupling to global cardiovascular mechanics and hemodynamics. Each ventricular wall was composed of multiple mechanically and electrically coupled myocardial segments. MEC was incorporated by allowing adaptation of L-type Ca(2+) current aiming at minimal dispersion of local external work, an approach that we previously applied to replicate T-wave memory in a synchronous heart after a period of asynchronous activation. LBBB instantaneously decreased left-ventricular stroke work and increased end-diastolic volume. During sustained LBBB, MEC reduced intraventricular dispersion of mechanical workload and repolarization. However, MEC-induced reduction in contractility in late-activated regions was larger than the contractility increase in early-activated regions, resulting in further decrease of stroke work and increase of end-diastolic volume. Upon the start of CRT, stroke work increased despite a wider dispersion of mechanical workload. During sustained CRT, MEC-induced reduction in dispersion of workload and repolarization coincided with a further reduction in end-diastolic volume. In conclusion, MEC may represent a useful framework for better understanding the long-term changes in cardiac electrophysiology and contraction following LBBB as well as CRT.

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Section: Discussionmentioning

confidence: 95%

Mechano-electrical coupling as framework for understanding functional remodeling during LBBB and CRT

Kuijpers

Hermeling

Lumens

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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“…1). Changes in ARI in the intramural and subendocardial layers during AVS were presumably caused by an increase in the current density (I Ks ) [4] and inversion of the current gradient (I Kr ), respectively [5]. Left ventricular apical myocardium possesses no transmural heterogeneity of ARI in supraventricular rhythm and in AVS.…”

Section: Resultsmentioning

confidence: 99%

Repolarization of ventricular myocardium in atrioventricular electrical stimulation of the heart in dogs

et al. 2008

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The duration of ventricular myocardium excitation increases during atrioventricular stimulation of dog heart and the sequence of depolarization of the right and left ventricles is desynchronized. Significant shortening of the activation-recovery interval in the intramural and subendocardial layers of the left ventricular base leads to modification of the repolarization sequence in this area and to an increase of total dispersion of activation-recovery intervals in the cardiac ventricles, as a result of which repolarization sequence starts partially repeating the depolarization sequence.

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“…1, 4–6, 16 Moreover, cardiac memory provides a useful framework for understanding the evolution of remodeling because the pacing used to induce memory initiates two different yet complimentary processes. While long-term cardiac memory is the result of transcriptional changes of ion channels and Cx43, 4, 5, 25, 26 short-term memory has been proposed to result from ion channel trafficking initiated by altered myocardial stretch-induced synthesis and release of angiotensin II. 7,8 In this study, we demonstrated in intact animals that the internalization of I to channel subunits initiated by the binding of angiotensin II to the AT1R previously shown in single cell studies contributes to the induction of short-term cardiac memory and this internalization process uses a microtubule-mediated pathway.…”

Section: Discussionmentioning

confidence: 99%

Microtubules and angiotensin II receptors contribute to modulation of repolarization induced by ventricular pacing

Özgen

Boink

et al. 2012

Heart Rhythm

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Background Left ventricular pacing (LVP) in canine heart alters ventricular activation leading to reduced transient outward potassium current, Ito, loss of the epicardial action potential notch, and T wave vector displacement (TVD). These repolarization changes, referred to as cardiac memory, are initiated by locally increased angiotensin II (AngII) levels. In HEK293 cells in which Kv4.3 and KChIP2, the channel subunits contributing to Ito, are overexpressed with the AngII receptor 1 (AT1R), AngII induces a decrease in Ito as the result of internalization of a Kv4.3/KChIP2/AT1R macromolecular complex. Objective We tested the hypothesis that in canine heart in situ, 2h LVP-induced decreases in membrane KChIP2, AT1R and Ito are prevented by blocking subunit trafficking. Methods We used standard electrophysiologic, biophysical and biochemical methods to study 4 groups of dogs: 1) Sham, 2) 2h LVP, 3) LVP+colchicine (microtubule disrupting agent) and 4) LVP+losartan (AT1R blocker). Results TVD was significantly greater in LVP than Shams and was inhibited by colchicine or losartan. Epicardial biopsies showed significant decreases in membrane KChIP2 and AT1R protein after LVP but not after sham treatment, and these decreases were prevented by colchicine or losartan. Colchicine but not losartan significantly reduced microtubular polymerization. In isolated ventricular myocytes AngII-induced Ito reduction and loss of action potential notch were blocked by colchicine. Conclusions LVP-induced reduction of KChIP2 in plasma light membranes depends on an AngII-mediated pathway and intact microtubular status. Loss of Ito and the action potential notch appear to derive from AngII-initiated trafficking of channel subunits.

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IKr contributes to the altered ventricular repolarization that determines long-term cardiac memory

Abstract: A transcriptionally induced change in epicardial I(Kr) contributes to the altered ventricular repolarization that characterizes CM.

Cited by 36 publications

References 30 publications

Mechano-electrical coupling as framework for understanding functional remodeling during LBBB and CRT

Mechano-electrical coupling as framework for understanding functional remodeling during LBBB and CRT

Repolarization of ventricular myocardium in atrioventricular electrical stimulation of the heart in dogs

Microtubules and angiotensin II receptors contribute to modulation of repolarization induced by ventricular pacing

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