Alternans in atria: Mechanisms and clinical relevance

Kanaporis, Giedrius; Blatter, Lothar A.

doi:10.1016/j.medici.2017.04.004

Cited by 23 publications

(30 citation statements)

References 108 publications

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“…; Jousset et al . ; Kanaporis & Blatter, 2017 a ). Atrial fibrillation (AF), the most prevalent cardiac arrhythmia, is associated with an increased risk of stroke, cardiomyopathies and heart failure, and accounts for significant morbidity and mortality (Chinitz et al .…”

Section: Introductionmentioning

confidence: 99%

“…On the other hand, AP morphology affects intracellular Ca 2+ handling by regulating Ca 2+ entry through L‐type Ca 2+ channels and extrusion through Na + /Ca 2+ exchange. Although it is still debated whether disturbances of V m or [Ca 2+ ] i regulation are the primary cause of alternans (Edwards & Blatter, ; Kanaporis & Blatter, 2017 a ), growing evidence indicates that alternans is initiated by disturbances in intracellular Ca 2+ handling (Chudin et al . ; Diaz et al .…”

Section: Introductionmentioning

confidence: 99%

“…At the cellular level cardiac alternans is observed as periodic beat-to-beat variation in contraction amplitude, action potential (AP) morphology and cytosolic Ca 2+ transient (CaT) amplitude at constant stimulation frequency. Atrial alternans is closely linked to the development of atrial arrhythmias such as atrial fibrillation and flutter (Narayan et al 2002;Hiromoto et al 2005;Jousset et al 2012;Kanaporis & Blatter, 2017a). Atrial fibrillation (AF), the most prevalent cardiac arrhythmia, is associated with an increased risk of stroke, cardiomyopathies and heart failure, and accounts for significant morbidity and mortality (Chinitz et al 2013;Chugh et al 2014).…”

Section: Introductionmentioning

confidence: 99%

“…On the other hand, AP morphology affects intracellular Ca 2+ handling by regulating Ca 2+ entry through L-type Ca 2+ channels and extrusion through Na + /Ca 2+ exchange. Although it is still debated whether disturbances of V m or [Ca 2+ ] i regulation are the primary cause of alternans (Edwards & Blatter, 2014;Kanaporis & Blatter, 2017a), growing evidence indicates that alternans is initiated by disturbances in intracellular Ca 2+ handling (Chudin et al 1999;Diaz et al 2004;Goldhaber et al 2005;Shkryl et al 2012;Kanaporis & Blatter, 2015). However, recently we have demonstrated that AP morphology and its beat-to-beat alternation have strong effects on the development and degree of alternans in atrial myocytes (Kanaporis & Blatter, 2017b) by regulating diastolic sarcoplasmic reticulum (SR) Ca 2+ load and affecting the kinetics of L-type Ca 2+ currents.…”

Section: Introductionmentioning

confidence: 99%

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Action potential shortening rescues atrial calcium alternans

Kanaporis

Kalik

Blatter

2018

The Journal of Physiology

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Key points Cardiac alternans refers to a beat‐to‐beat alternation in contraction, action potential (AP) morphology and Ca2+ transient (CaT) amplitude, and represents a risk factor for cardiac arrhythmia, including atrial fibrillation. We developed strategies to pharmacologically manipulate the AP waveform with the goal to reduce or eliminate the occurrence of CaT and contraction alternans in atrial tissue. With combined patch‐clamp and intracellular Ca2+ measurements we investigated the effect of specific ion channel inhibitors and activators on alternans. In single rabbit atrial myocytes, suppression of Ca2+‐activated Cl− channels eliminated AP duration alternans, but prolonged the AP and failed to eliminate CaT alternans. In contrast, activation of K+ currents (IKs and IKr) shortened the AP and eliminated both AP duration and CaT alternans. As demonstrated also at the whole heart level, activation of K+ conductances represents a promising strategy to suppress alternans, and thus reducing a risk factor for atrial fibrillation. Abstract At the cellular level alternans is observed as beat‐to‐beat alternations in contraction, action potential (AP) morphology and magnitude of the Ca2+ transient (CaT). Alternans is a well‐established risk factor for cardiac arrhythmia, including atrial fibrillation. This study investigates whether pharmacological manipulation of AP morphology is a viable strategy to reduce the risk of arrhythmogenic CaT alternans. Pacing‐induced AP and CaT alternans were studied in rabbit atrial myocytes using combined Ca2+ imaging and electrophysiological measurements. Increased AP duration (APD) and beat‐to‐beat alternations in AP morphology lowered the pacing frequency threshold and increased the degree of CaT alternans. Inhibition of Ca2+‐activated Cl− channels reduced beat‐to‐beat AP alternations, but prolonged APD and failed to suppress CaT alternans. In contrast, AP shortening induced by activators of two K+ channels (ML277 for Kv7.1 and NS1643 for Kv11.1) abolished both APD and CaT alternans in field‐stimulated and current‐clamped myocytes. K+ channel activators had no effect on the degree of Ca2+ alternans in AP voltage‐clamped cells, confirming that suppression of Ca2+ alternans was caused by the changes in AP morphology. Finally, activation of Kv11.1 channel significantly attenuated or even abolished atrial T‐wave alternans in isolated Langendorff perfused hearts. In summary, AP shortening suppressed or completely eliminated both CaT and APD alternans in single atrial myocytes and atrial T‐wave alternans at the whole heart level. Therefore, we suggest that AP shortening is a potential intervention to avert development of alternans with important ramifications for arrhythmia prevention and therapy.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Action potential shortening rescues atrial calcium alternans

Kanaporis

Kalik

Blatter

2018

The Journal of Physiology

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“…The 250 discussion of whether Ca 2+ diffusion in the SR is fast or slow has been ongoing for more than a decade [21][22][23], without a resolution in sight. We illustrate in alternans have also been observed in non-tubulated cells such as atrial myocytes and failing ventricular myocytes [54][55][56][57][58][59][60]. In these cells, L-type Ca 2+ channels are only located at the cell periphery, where they trigger Ca 2+ release from the SR through the RyR.…”

Section: Discussionmentioning

confidence: 73%

Calcium buffers and L-type calcium channels as modulators of cardiac subcellular alternans

Lai

Coombes

Thul

2019

Preprint

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In cardiac myocytes, calcium cycling links the dynamics of the membrane potential to the activation of the contractile filaments. Perturbations of the calcium signalling toolkit have been demonstrated to disrupt this connection and lead to numerous pathologies including cardiac alternans. This rhythm disturbance is characterised by alternations in the membrane potential and the intracellular calcium concentration, which in turn can lead to sudden cardiac death. In the present computational study, we make further inroads into understanding this severe condition by investigating the impact of calcium buffers and L-type calcium channels on the formation of subcellular calcium alternans when calcium diffusion in the sarcoplasmic reticulum is strong. Through numerical simulations of a two dimensional network of calcium release units, we show that increasing calcium entry is proarrhythmogenic and that this is modulated by the calcium-dependent inactivation of the L-type calcium channel. We also find that while calcium buffers can exert a stabilising force and abolish subcellular Ca 2+ alternans, they can significantly shape the spatial patterning of subcellular calcium alternans. Taken together, our results demonstrate that subcellular calcium alternans can emerge via various routes and that calcium diffusion in the sarcoplasmic reticulum critically determines their spatial patterns. alternans, saddle-node bifurcation 1. Intoduction Cardiac arrhythmias constitute a leading public health problem and cause most cases of sudden cardiac death. In the US alone, sudden cardiac death accounts for approximately 300, 000 − 450, 000 lives every year [1]. Among the many forms of cardiac arrhythmias, cardiac alternans feature prominently. This 5 rhythm disturbance at the level of a single cardiac myocyte is characterised by alternating patterns of the membrane potential and the intracellular calcium (Ca 2+ ) concentration on successive beats. For instance, at one beat, a long action potential duration (APD) is accompanied by a large intracellular Ca 2+ transient, while on the next beat, the APD is shortened concomitant with a 10 small amplitude Ca 2+ transient. As a consequence, contractile efficiency is impaired, which in turn can cause a detrimental reduction in blood flow. In early experimental studies, the intracellular Ca 2+ concentration was averaged across a cardiac myocyte. The advent of high-resolution microscopy revealed that alternating Ca 2+ dynamics were already present at individual Ca 2+ release units 15 (CRU). While one CRU follows a pattern of large-small-large Ca 2+ transients, neighbouring CRUs exhibit small-large-small Ca 2+ transients. Crucially, both CRUs experience the same membrane potential. These findings gave rise to the concept of subcellular Ca 2+ alternans [2-10] and illustrated that nonlinear processes govern cardiac dynamics across multiple scales: the cell wide membrane 20 potential and the Ca 2+ fluxes restricted to single dyadic clefts.The existence of subcellular Ca 2+ alternans reinforces the n...

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A master stability function approach to cardiac alternans

et al. 2019

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During a single heartbeat, muscle cells in the heart contract and relax. Under healthy conditions, the behaviour of these muscle cells is almost identical from one beat to the next. However, this regular rhythm can be disturbed giving rise to a variety of cardiac arrhythmias including cardiac alternans. Here, we focus on so-called microscopic calcium alternans and show how their complex spatial patterns can be understood with the help of the master stability function. Our work makes use of the fact that cardiac muscle cells can be conceptualised as a network of networks, and that calcium alternans correspond to an instability of the synchronous network state. In particular, we demonstrate how small changes in the coupling strength between network nodes can give rise to drastically different activity patterns in the network.

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Alternans in atria: Mechanisms and clinical relevance

Cited by 23 publications

References 108 publications

Action potential shortening rescues atrial calcium alternans

Action potential shortening rescues atrial calcium alternans

Calcium buffers and L-type calcium channels as modulators of cardiac subcellular alternans

A master stability function approach to cardiac alternans

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