Remodeling of cardiomyocyte ion channels in human atrial fibrillation

Dobrev, Dobromir; Ravens, Ursula

doi:10.1007/s00395-003-0409-8

Cited by 178 publications

(124 citation statements)

References 94 publications

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“…2A, black vs. grey lines), as shown in experiments (Fig. 2D vs. F) 4, 17, 18 . The reduced I CaL could explain the reduced sarcoplasmic reticulum (SR) Ca 2+ release and CaT amplitude (Fig.…”

Section: Resultssupporting

confidence: 65%

“…Similarly, simulated APs following 50% I CaL block (Figure 4F) exhibited impaired APD rate-adaptation (Figure 4J, grey open circles). Myocytes from chronic AF patients (Figure 4B) are characterized by shorter APD 90 values 16, 19, 21-23 , with less variation as a function of cycle length than control (sinus rhythm) myocytes (Figure 4M, squares) 4, 16, 19, 22, 23 . Analogously, our cAF model predicts shorter APs than sinus rhythm (solid vs. dashed line in Fig.…”

Section: Resultsmentioning

confidence: 99%

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Human Atrial Action Potential and Ca ²⁺ Model

Grandi

Pandit

Voigt

et al. 2011

Circulation Research

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Rationale Understanding atrial fibrillation (AF) requires integrated understanding of ionic currents and Ca2+ transport in remodeled human atrium, but appropriate models are limited. Objective To study AF we developed a new human atrial action potential (AP) model, derived from atrial experimental results and our human ventricular myocyte model. Methods and Results Atria vs. ventricles have lower IK1, resulting in more depolarized resting membrane potential (~7mV). We used higher Ito,fast density in atrium, removed Ito,slow, and included an atrial-specific IKur. INCX and INaK densities were reduced in atrial vs. ventricular myocytes according to experimental results. SERCA function was altered to reproduce human atrial myocyte Ca2+ transients. To simulate chronic AF, we reduced ICaL, Ito, IKur and SERCA, and increased IK1, IKs and INCX. We also investigated the link between Kv1.5 channelopathy, [Ca2+]i, and AF. The sinus rhythm model showed a typical human atrial AP morphology. Consistent with experiments, the model showed shorter APs and reduced AP duration shortening at increasing pacing frequencies in AF or when ICaL was partially blocked, suggesting a crucial role of Ca2+ and Na+ in this effect. This also explained blunted Ca2+ transient and rate-adaptation of [Ca2+]i and [Na+]i in chronic AF. Moreover, increasing [Na+]i and altered INaK and INCX causes rate-dependent atrial AP shortening. Blocking IKur to mimic Kv1.5 loss-of-function increased [Ca2+]i and caused early-afterdepolarizations under adrenergic stress, as observed experimentally. Conclusions Our study provides a novel tool and insights into ionic bases of atrio-ventricular AP differences, and shows how Na+ and Ca2+ homeostasis critically mediate abnormal repolarization in AF.

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Section: Resultssupporting

confidence: 65%

Section: Resultsmentioning

confidence: 99%

Human Atrial Action Potential and Ca ²⁺ Model

Grandi

Pandit

Voigt

et al. 2011

Circulation Research

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321

339

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“…The transition from paroxysmal to persistent AF is facilitated by atrial remodeling of ion channels at the level of expression and electrophysiological properties [9, 13, 23, 42, 45]. These AF-related electrical adaptations generally promote shortening of the atrial action potential and blunting of the atrial effective refractory period, which increases vulnerability to AF by providing a proarrhythmogenic substrate prone to premature beats [9, 23]. In AF patients, Kv4.3 channel mRNA and protein are downregulated leading to a 60 % decrease in I to , which is thought to indirectly increase the upstroke velocity of the atrial action potential leading to augmented wave propagation that promotes maintenance of AF [5, 51].…”

Section: Discussionmentioning

confidence: 99%

Expression and function of Kv1.1 potassium channels in human atria from patients with atrial fibrillation

et al. 2015

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Voltage-gated Kv1.1 channels encoded by the Kcna1 gene are traditionally regarded as being neural-specific with no known expression or intrinsic functional role in the heart. However, recent studies in mice reveal low-level Kv1.1 expression in heart and cardiac abnormalities associated with Kv1.1-deficiency suggesting that the channel may have a previously unrecognized cardiac role. Therefore, this study tests the hypothesis that Kv1.1 channels are associated with arrhythmogenesis and contribute to intrinsic cardiac function. In intra-atrial burst pacing experiments, Kcna1-null mice exhibited increased susceptibility to atrial fibrillation (AF). The atria of Kcna1-null mice showed minimal Kv1 family ion channel remodeling and fibrosis as measured by qRT-PCR and Masson’s trichrome histology, respectively. Using RT-PCR, immunocytochemistry, and immunoblotting, KCNA1 mRNA and protein were detected in isolated mouse cardiomyocytes and human atria for the first time. Patients with chronic AF (cAF) showed no changes in KCNA1 mRNA levels relative to controls; however, they exhibited increases in atrial Kv1.1 protein levels, not seen in paroxysmal AF patients. Patch-clamp recordings of isolated human atrial myocytes revealed significant dendrotoxin-K (DTX-K)-sensitive outward current components that were significantly increased in cAF patients, reflecting a contribution by Kv1.1 channels. The concomitant increases in Kv1.1 protein and DTX-K-sensitive currents in atria of cAF patients suggest that the channel contributes to the pathological mechanisms of persistent AF. These findings provide evidence of an intrinsic cardiac role of Kv1.1 channels and indicate that they may contribute to atrial repolarization and AF susceptibility.

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“…In addition, under different pathologies, such as atria fibrillation, ischemia or a substantial increase of myocyte to fibroblast coupling, both APD and CV values can be significantly decreased. For instance, whereas APD values can be as short as 140 ms in healthy atria, it is reduced to 56 ms under chronic atrial fibrillation [11, 40, 41]. Likewise, CV values may be as slow as 44 cm/s within normal atrial, whereas under chronic atrial fibrillation CV can be even slower, with reported values at 37 cm/s [11, 40–43].…”

Section: Methodsmentioning

confidence: 99%

Reentry and Ectopic Pacemakers Emerge in a Three-Dimensional Model for a Slab of Cardiac Tissue with Diffuse Microfibrosis near the Percolation Threshold

Alonso¹,

Santos²,

Bär³

2016

PLoS ONE

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Arrhythmias in cardiac tissue are generally associated with irregular electrical wave propagation in the heart. Cardiac tissue is formed by a discrete cell network, which is often heterogeneous. Recently, it was shown in simulations of two-dimensional (2D) discrete models of cardiac tissue that a wave crossing a fibrotic, heterogeneous region may produce reentry and transient or persistent ectopic activity provided the fraction of conducting connections is just above the percolation threshold. Here, we investigate the occurrence of these phenomena in three-dimensions by simulations of a discrete model representing a thin slab of cardiac tissue. This is motivated (i) by the necessity to study the relevance and properties of the percolation-related mechanism for the emergence of microreentries in three dimensions and (ii) by the fact that atrial tissue is quite thin in comparison with ventricular tissue. Here, we simplify the model by neglecting details of tissue anatomy, e. g. geometries of atria or ventricles and the anisotropy in the conductivity. Hence, our modeling study is confined to the investigation of the effect of the tissue thickness as well as to the comparison of the dynamics of electrical excitation in a 2D layer with the one in a 3D slab. Our results indicate a strong and non-trivial effect of the thickness even for thin tissue slabs on the probability of microreentries and ectopic beat generation. The strong correlation of the occurrence of microreentry with the percolation threshold reported earlier in 2D layers persists in 3D slabs. Finally, a qualitative agreement of 3D simulated electrograms in the fibrotic region with the experimentally observed complex fractional atrial electrograms (CFAE) as well as strong difference between simulated electrograms in 2D and 3D were found for the cases where reentry and ectopic activity were triggered by the micro-fibrotic region.

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Remodeling of cardiomyocyte ion channels in human atrial fibrillation

Cited by 178 publications

References 94 publications

Human Atrial Action Potential and Ca ²⁺ Model

Human Atrial Action Potential and Ca ²⁺ Model

Expression and function of Kv1.1 potassium channels in human atria from patients with atrial fibrillation

Reentry and Ectopic Pacemakers Emerge in a Three-Dimensional Model for a Slab of Cardiac Tissue with Diffuse Microfibrosis near the Percolation Threshold

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Remodeling of cardiomyocyte ion channels in human atrial fibrillation

Cited by 178 publications

References 94 publications

Human Atrial Action Potential and Ca 2+ Model

Human Atrial Action Potential and Ca 2+ Model

Expression and function of Kv1.1 potassium channels in human atria from patients with atrial fibrillation

Reentry and Ectopic Pacemakers Emerge in a Three-Dimensional Model for a Slab of Cardiac Tissue with Diffuse Microfibrosis near the Percolation Threshold

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Human Atrial Action Potential and Ca ²⁺ Model

Human Atrial Action Potential and Ca ²⁺ Model