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Editorial

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6 pages, 266 KiB

Open AccessEditorial

Electrical Remodelling in Cardiac Disease

by Ursula Ravens and Rémi Peyronnet

Cells 2023, 12(2), 230; https://doi.org/10.3390/cells12020230 - 05 Jan 2023

Cited by 3 | Viewed by 1333

Abstract

The human heart responds to various diseases with structural, mechanical, and electrical remodelling processes [...] Full article

(This article belongs to the Special Issue Electrical Remodeling in Cardiac Disease)

Research

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13 pages, 2997 KiB

Open AccessArticle

Consecutive-Day Ventricular and Atrial Cardiomyocyte Isolations from the Same Heart: Shifting the Cost–Benefit Balance of Cardiac Primary Cell Research

by Joachim Greiner, Teresa Schiatti, Wenzel Kaltenbacher, Marica Dente, Alina Semenjakin, Thomas Kok, Dominik J. Fiegle, Thomas Seidel, Ursula Ravens, Peter Kohl, Rémi Peyronnet and Eva A. Rog-Zielinska

Cells 2022, 11(2), 233; https://doi.org/10.3390/cells11020233 - 11 Jan 2022

Cited by 7 | Viewed by 3041

Abstract

Freshly isolated primary cardiomyocytes (CM) are indispensable for cardiac research. Experimental CM research is generally incompatible with life of the donor animal, while human heart samples are usually small and scarce. CM isolation from animal hearts, traditionally performed by coronary artery perfusion of [...] Read more.

Freshly isolated primary cardiomyocytes (CM) are indispensable for cardiac research. Experimental CM research is generally incompatible with life of the donor animal, while human heart samples are usually small and scarce. CM isolation from animal hearts, traditionally performed by coronary artery perfusion of enzymes, liberates millions of cells from the heart. However, due to progressive cell remodeling following isolation, freshly isolated primary CM need to be used within 4–8 h post-isolation for most functional assays, meaning that the majority of cells is essentially wasted. In addition, coronary perfusion-based isolation cannot easily be applied to human tissue biopsies, and it does not straightforwardly allow for assessment of regional differences in CM function within the same heart. Here, we provide a method of multi-day CM isolation from one animal heart, yielding calcium-tolerant ventricular and atrial CM. This is based on cell isolation from cardiac tissue slices following repeated (usually overnight) storage of the tissue under conditions that prolong CM viability beyond the day of organ excision by two additional days. The maintenance of cells in their near-native microenvironment slows the otherwise rapid structural and functional decline seen in isolated CM during attempts for prolonged storage or culture. Multi-day slice-based CM isolation increases the amount of useful information gained per animal heart, improving reproducibility and reducing the number of experimental animals required in basic cardiac research. It also opens the doors to novel experimental designs, including exploring same-heart regional differences. Full article

(This article belongs to the Special Issue Electrical Remodeling in Cardiac Disease)

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17 pages, 2156 KiB

Open AccessArticle

Abnormal Calcium Handling in Atrial Fibrillation Is Linked to Changes in Cyclic AMP Dependent Signaling

by Franziska Reinhardt, Kira Beneke, Nefeli Grammatica Pavlidou, Lenard Conradi, Hermann Reichenspurner, Leif Hove-Madsen and Cristina E. Molina

Cells 2021, 10(11), 3042; https://doi.org/10.3390/cells10113042 - 05 Nov 2021

Cited by 13 | Viewed by 2983

Abstract

Both, the decreased L-type Ca²⁺ current (I_Ca,L) density and increased spontaneous Ca²⁺ release from the sarcoplasmic reticulum (SR), have been associated with atrial fibrillation (AF). In this study, we tested the hypothesis that remodeling of 3′,5′-cyclic adenosine monophosphate (cAMP)-dependent [...] Read more.

Both, the decreased L-type Ca²⁺ current (I_Ca,L) density and increased spontaneous Ca²⁺ release from the sarcoplasmic reticulum (SR), have been associated with atrial fibrillation (AF). In this study, we tested the hypothesis that remodeling of 3′,5′-cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA) signaling is linked to these compartment-specific changes (up- or down-regulation) in Ca²⁺-handling. Perforated patch-clamp experiments were performed in atrial myocytes from 53 patients with AF and 104 patients in sinus rhythm (Ctl). A significantly higher frequency of transient inward currents (I_TI) activated by spontaneous Ca²⁺ release was confirmed in myocytes from AF patients. Next, inhibition of PKA by H-89 promoted a stronger effect on the I_TI frequency in these myocytes compared to myocytes from Ctl patients (7.6-fold vs. 2.5-fold reduction), while the β-agonist isoproterenol (ISO) caused a greater increase in Ctl patients (5.5-fold vs. 2.1-fold). I_Ca,L density was larger in myocytes from Ctl patients at baseline (p < 0.05). However, the effect of ISO on I_Ca,L density was only slightly stronger in AF than in Ctl myocytes (3.6-fold vs. 2.7-fold). Interestingly, a significant reduction of I_Ca,L and Ca²⁺ sparks was observed upon Ca²⁺/Calmodulin-dependent protein kinase II inhibition by KN-93, but this inhibition had no effect on I_TI. Fluorescence resonance energy transfer (FRET) experiments showed that although AF promoted cytosolic desensitization to β-adrenergic stimulation, ISO increased cAMP to similar levels in both groups of patients in the L-type Ca²⁺ channel and ryanodine receptor compartments. Basal cAMP signaling also showed compartment-specific regulation by phosphodiesterases in atrial myocytes from 44 Ctl and 43 AF patients. Our results suggest that AF is associated with opposite changes in compartmentalized PKA/cAMP-dependent regulation of I_Ca,L (down-regulation) and I_TI (up-regulation). Full article

(This article belongs to the Special Issue Electrical Remodeling in Cardiac Disease)

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15 pages, 3230 KiB

Open AccessArticle

Fibrotic Remodeling during Persistent Atrial Fibrillation: In Silico Investigation of the Role of Calcium for Human Atrial Myofibroblast Electrophysiology

by Jorge Sánchez, Beatriz Trenor, Javier Saiz, Olaf Dössel and Axel Loewe

Cells 2021, 10(11), 2852; https://doi.org/10.3390/cells10112852 - 22 Oct 2021

Cited by 11 | Viewed by 2781

Abstract

During atrial fibrillation, cardiac tissue undergoes different remodeling processes at different scales from the molecular level to the tissue level. One central player that contributes to both electrical and structural remodeling is the myofibroblast. Based on recent experimental evidence on myofibroblasts’ ability to [...] Read more.

During atrial fibrillation, cardiac tissue undergoes different remodeling processes at different scales from the molecular level to the tissue level. One central player that contributes to both electrical and structural remodeling is the myofibroblast. Based on recent experimental evidence on myofibroblasts’ ability to contract, we extended a biophysical myofibroblast model with Ca²⁺ handling components and studied the effect on cellular and tissue electrophysiology. Using genetic algorithms, we fitted the myofibroblast model parameters to the existing in vitro data. In silico experiments showed that Ca²⁺ currents can explain the experimentally observed variability regarding the myofibroblast resting membrane potential. The presence of an L-type Ca²⁺ current can trigger automaticity in the myofibroblast with a cycle length of 799.9 ms. Myocyte action potentials were prolonged when coupled to myofibroblasts with Ca²⁺ handling machinery. Different spatial myofibroblast distribution patterns increased the vulnerable window to induce arrhythmia from 12 ms in non-fibrotic tissue to 22 ± 2.5 ms and altered the reentry dynamics. Our findings suggest that Ca²⁺ handling can considerably affect myofibroblast electrophysiology and alter the electrical propagation in atrial tissue composed of myocytes coupled with myofibroblasts. These findings can inform experimental validation experiments to further elucidate the role of myofibroblast Ca²⁺ handling in atrial arrhythmogenesis. Full article

(This article belongs to the Special Issue Electrical Remodeling in Cardiac Disease)

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21 pages, 3093 KiB

Open AccessArticle

Artificial Intelligence-Assisted Identification of Genetic Factors Predisposing High-Risk Individuals to Asymptomatic Heart Failure

by Ning-I Yang, Chi-Hsiao Yeh, Tsung-Hsien Tsai, Yi-Ju Chou, Paul Wei-Che Hsu, Chun-Hsien Li, Yun-Hsuan Chan, Li-Tang Kuo, Chun-Tai Mao, Yu-Chiau Shyu, Ming-Jui Hung, Chi-Chun Lai, Huey-Kang Sytwu and Ting-Fen Tsai

Cells 2021, 10(9), 2430; https://doi.org/10.3390/cells10092430 - 15 Sep 2021

Cited by 7 | Viewed by 3445

Abstract

Heart failure (HF) is a global pandemic public health burden affecting one in five of the general population in their lifetime. For high-risk individuals, early detection and prediction of HF progression reduces hospitalizations, reduces mortality, improves the individual’s quality of life, and reduces [...] Read more.

Heart failure (HF) is a global pandemic public health burden affecting one in five of the general population in their lifetime. For high-risk individuals, early detection and prediction of HF progression reduces hospitalizations, reduces mortality, improves the individual’s quality of life, and reduces associated medical costs. In using an artificial intelligence (AI)-assisted genome-wide association study of a single nucleotide polymorphism (SNP) database from 117 asymptomatic high-risk individuals, we identified a SNP signature composed of 13 SNPs. These were annotated and mapped into six protein-coding genes (GAD2, APP, RASGEF1C, MACROD2, DMD, and DOCK1), a pseudogene (PGAM1P5), and various non-coding RNA genes (LINC01968, LINC00687, LOC105372209, LOC101928047, LOC105372208, and LOC105371356). The SNP signature was found to have a good performance when predicting HF progression, namely with an accuracy rate of 0.857 and an area under the curve of 0.912. Intriguingly, analysis of the protein connectivity map revealed that DMD, RASGEF1C, MACROD2, DOCK1, and PGAM1P5 appear to form a protein interaction network in the heart. This suggests that, together, they may contribute to the pathogenesis of HF. Our findings demonstrate that a combination of AI-assisted identifications of SNP signatures and clinical parameters are able to effectively identify asymptomatic high-risk subjects that are predisposed to HF. Full article

(This article belongs to the Special Issue Electrical Remodeling in Cardiac Disease)

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15 pages, 14468 KiB

Open AccessArticle

TRPM4 Participates in Aldosterone-Salt-Induced Electrical Atrial Remodeling in Mice

by Christophe Simard, Virginie Ferchaud, Laurent Sallé, Paul Milliez, Alain Manrique, Joachim Alexandre and Romain Guinamard

Cells 2021, 10(3), 636; https://doi.org/10.3390/cells10030636 - 12 Mar 2021

Cited by 9 | Viewed by 1850

Abstract

Aldosterone plays a major role in atrial structural and electrical remodeling, in particular through Ca²⁺-transient perturbations and shortening of the action potential. The Ca²⁺-activated non-selective cation channel Transient Receptor Potential Melastatin 4 (TRPM4) participates in atrial action potential. The [...] Read more.

Aldosterone plays a major role in atrial structural and electrical remodeling, in particular through Ca²⁺-transient perturbations and shortening of the action potential. The Ca²⁺-activated non-selective cation channel Transient Receptor Potential Melastatin 4 (TRPM4) participates in atrial action potential. The aim of our study was to elucidate the interactions between aldosterone and TRPM4 in atrial remodeling and arrhythmias susceptibility. Hyperaldosteronemia, combined with a high salt diet, was induced in mice by subcutaneously implanted osmotic pumps during 4 weeks, delivering aldosterone or physiological serum for control animals. The experiments were conducted in wild type animals (Trpm4^+/+) as well as Trpm4 knock-out animals (Trpm4^-/-). The atrial diameter measured by echocardiography was higher in Trpm4^-/- compared to Trpm4^+/+ animals, and hyperaldosteronemia-salt produced a dilatation in both groups. Action potentials duration and triggered arrhythmias were measured using intracellular microelectrodes on the isolated left atrium. Hyperaldosteronemia-salt prolong action potential in Trpm4^-/- mice but had no effect on Trpm4^+/+ mice. In the control group (no aldosterone-salt treatment), no triggered arrythmias were recorded in Trpm4^+/+ mice, but a high level was detected in Trpm4^-/- mice. Hyperaldosteronemia-salt enhanced the occurrence of arrhythmias (early as well as delayed-afterdepolarization) in Trpm4^+/+ mice but decreased it in Trpm4^-/- animals. Atrial connexin43 immunolabelling indicated their disorganization at the intercalated disks and a redistribution at the lateral side induced by hyperaldosteronemia-salt but also by Trpm4 disruption. In addition, hyperaldosteronemia-salt produced pronounced atrial endothelial thickening in both groups. Altogether, our results indicated that hyperaldosteronemia-salt and TRPM4 participate in atrial electrical and structural remodeling. It appears that TRPM4 is involved in aldosterone-induced atrial action potential shortening. In addition, TRPM4 may promote aldosterone-induced atrial arrhythmias, however, the underlying mechanisms remain to be explored. Full article

(This article belongs to the Special Issue Electrical Remodeling in Cardiac Disease)

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Review

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19 pages, 3443 KiB

Open AccessReview

Electrophysiological Consequences of Cardiac Fibrosis

by Sander Verheule and Ulrich Schotten

Cells 2021, 10(11), 3220; https://doi.org/10.3390/cells10113220 - 18 Nov 2021

Cited by 28 | Viewed by 3029

Abstract

For both the atria and ventricles, fibrosis is generally recognized as one of the key determinants of conduction disturbances. By definition, fibrosis refers to an increased amount of fibrous tissue. However, fibrosis is not a singular entity. Various forms can be distinguished, that [...] Read more.

For both the atria and ventricles, fibrosis is generally recognized as one of the key determinants of conduction disturbances. By definition, fibrosis refers to an increased amount of fibrous tissue. However, fibrosis is not a singular entity. Various forms can be distinguished, that differ in distribution: replacement fibrosis, endomysial and perimysial fibrosis, and perivascular, endocardial, and epicardial fibrosis. These different forms typically result from diverging pathophysiological mechanisms and can have different consequences for conduction. The impact of fibrosis on propagation depends on exactly how the patterns of electrical connections between myocytes are altered. We will therefore first consider the normal patterns of electrical connections and their regional diversity as determinants of propagation. Subsequently, we will summarize current knowledge on how different forms of fibrosis lead to a loss of electrical connectivity in order to explain their effects on propagation and mechanisms of arrhythmogenesis, including ectopy, reentry, and alternans. Finally, we will discuss a histological quantification of fibrosis. Because of the different forms of fibrosis and their diverging effects on electrical propagation, the total amount of fibrosis is a poor indicator for the effect on conduction. Ideally, an assessment of cardiac fibrosis should exclude fibrous tissue that does not affect conduction and differentiate between the various types that do; in this article, we highlight practical solutions for histological analysis that meet these requirements. Full article

(This article belongs to the Special Issue Electrical Remodeling in Cardiac Disease)

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29 pages, 4881 KiB

Open AccessReview

Arrhythmogenic Remodeling in the Failing Heart

by Zoltán Husti, András Varró and István Baczkó

Cells 2021, 10(11), 3203; https://doi.org/10.3390/cells10113203 - 17 Nov 2021

Cited by 19 | Viewed by 2994

Abstract

Chronic heart failure is a clinical syndrome with multiple etiologies, associated with significant morbidity and mortality. Cardiac arrhythmias, including ventricular tachyarrhythmias and atrial fibrillation, are common in heart failure. A number of cardiac diseases including heart failure alter the expression and regulation of [...] Read more.

Chronic heart failure is a clinical syndrome with multiple etiologies, associated with significant morbidity and mortality. Cardiac arrhythmias, including ventricular tachyarrhythmias and atrial fibrillation, are common in heart failure. A number of cardiac diseases including heart failure alter the expression and regulation of ion channels and transporters leading to arrhythmogenic electrical remodeling. Myocardial hypertrophy, fibrosis and scar formation are key elements of arrhythmogenic structural remodeling in heart failure. In this article, the mechanisms responsible for increased arrhythmia susceptibility as well as the underlying changes in ion channel, transporter expression and function as well as alterations in calcium handling in heart failure are discussed. Understanding the mechanisms of arrhythmogenic remodeling is key to improving arrhythmia management and the prevention of sudden cardiac death in patients with heart failure. Full article

(This article belongs to the Special Issue Electrical Remodeling in Cardiac Disease)

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52 pages, 920 KiB

Open AccessReview

Inherited and Acquired Rhythm Disturbances in Sick Sinus Syndrome, Brugada Syndrome, and Atrial Fibrillation: Lessons from Preclinical Modeling

by Laura Iop, Sabino Iliceto, Giovanni Civieri and Francesco Tona

Cells 2021, 10(11), 3175; https://doi.org/10.3390/cells10113175 - 15 Nov 2021

Cited by 8 | Viewed by 5223

Abstract

Rhythm disturbances are life-threatening cardiovascular diseases, accounting for many deaths annually worldwide. Abnormal electrical activity might arise in a structurally normal heart in response to specific triggers or as a consequence of cardiac tissue alterations, in both cases with catastrophic consequences on heart [...] Read more.

Rhythm disturbances are life-threatening cardiovascular diseases, accounting for many deaths annually worldwide. Abnormal electrical activity might arise in a structurally normal heart in response to specific triggers or as a consequence of cardiac tissue alterations, in both cases with catastrophic consequences on heart global functioning. Preclinical modeling by recapitulating human pathophysiology of rhythm disturbances is fundamental to increase the comprehension of these diseases and propose effective strategies for their prevention, diagnosis, and clinical management. In silico, in vivo, and in vitro models found variable application to dissect many congenital and acquired rhythm disturbances. In the copious list of rhythm disturbances, diseases of the conduction system, as sick sinus syndrome, Brugada syndrome, and atrial fibrillation, have found extensive preclinical modeling. In addition, the electrical remodeling as a result of other cardiovascular diseases has also been investigated in models of hypertrophic cardiomyopathy, cardiac fibrosis, as well as arrhythmias induced by other non-cardiac pathologies, stress, and drug cardiotoxicity. This review aims to offer a critical overview on the effective ability of in silico bioinformatic tools, in vivo animal studies, in vitro models to provide insights on human heart rhythm pathophysiology in case of sick sinus syndrome, Brugada syndrome, and atrial fibrillation and advance their safe and successful translation into the cardiology arena. Full article

(This article belongs to the Special Issue Electrical Remodeling in Cardiac Disease)

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28 pages, 4391 KiB

Open AccessFeature PaperReview

Cardiac Conduction Velocity, Remodeling and Arrhythmogenesis

by Bo Han, Mark L. Trew and Callum M. Zgierski-Johnston

Cells 2021, 10(11), 2923; https://doi.org/10.3390/cells10112923 - 28 Oct 2021

Cited by 17 | Viewed by 5700

Abstract

Cardiac electrophysiological disorders, in particular arrhythmias, are a key cause of morbidity and mortality throughout the world. There are two basic requirements for arrhythmogenesis: an underlying substrate and a trigger. Altered conduction velocity (CV) provides a key substrate for arrhythmogenesis, with slowed CV [...] Read more.

Cardiac electrophysiological disorders, in particular arrhythmias, are a key cause of morbidity and mortality throughout the world. There are two basic requirements for arrhythmogenesis: an underlying substrate and a trigger. Altered conduction velocity (CV) provides a key substrate for arrhythmogenesis, with slowed CV increasing the probability of re-entrant arrhythmias by reducing the length scale over which re-entry can occur. In this review, we examine methods to measure cardiac CV in vivo and ex vivo, discuss underlying determinants of CV, and address how pathological variations alter CV, potentially increasing arrhythmogenic risk. Finally, we will highlight future directions both for methodologies to measure CV and for possible treatments to restore normal CV. Full article

(This article belongs to the Special Issue Electrical Remodeling in Cardiac Disease)

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46 pages, 5776 KiB

Open AccessReview

Two-Pore-Domain Potassium (K_2P-) Channels: Cardiac Expression Patterns and Disease-Specific Remodelling Processes

by Felix Wiedmann, Norbert Frey and Constanze Schmidt

Cells 2021, 10(11), 2914; https://doi.org/10.3390/cells10112914 - 27 Oct 2021

Cited by 15 | Viewed by 3615

Abstract

Two-pore-domain potassium (K_2P-) channels conduct outward K⁺ currents that maintain the resting membrane potential and modulate action potential repolarization. Members of the K_2P channel family are widely expressed among different human cell types and organs where they were shown [...] Read more.

Two-pore-domain potassium (K_2P-) channels conduct outward K⁺ currents that maintain the resting membrane potential and modulate action potential repolarization. Members of the K_2P channel family are widely expressed among different human cell types and organs where they were shown to regulate important physiological processes. Their functional activity is controlled by a broad variety of different stimuli, like pH level, temperature, and mechanical stress but also by the presence of lipids or pharmacological agents. In patients suffering from cardiovascular diseases, alterations in K_2P-channel expression and function have been observed, suggesting functional significance and a potential therapeutic role of these ion channels. For example, upregulation of atrial specific K_2P3.1 (TASK-1) currents in atrial fibrillation (AF) patients was shown to contribute to atrial action potential duration shortening, a key feature of AF-associated atrial electrical remodelling. Therefore, targeting K_2P3.1 (TASK-1) channels might constitute an intriguing strategy for AF treatment. Further, mechanoactive K_2P2.1 (TREK-1) currents have been implicated in the development of cardiac hypertrophy, cardiac fibrosis and heart failure. Cardiovascular expression of other K_2P channels has been described, functional evidence in cardiac tissue however remains sparse. In the present review, expression, function, and regulation of cardiovascular K_2P channels are summarized and compared among different species. Remodelling patterns, observed in disease models are discussed and compared to findings from clinical patients to assess the therapeutic potential of K_2P channels. Full article

(This article belongs to the Special Issue Electrical Remodeling in Cardiac Disease)

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27 pages, 3460 KiB

Open AccessFeature PaperReview

Ion Channel Impairment and Myofilament Ca²⁺ Sensitization: Two Parallel Mechanisms Underlying Arrhythmogenesis in Hypertrophic Cardiomyopathy

by Lorenzo Santini, Raffaele Coppini and Elisabetta Cerbai

Cells 2021, 10(10), 2789; https://doi.org/10.3390/cells10102789 - 18 Oct 2021

Cited by 12 | Viewed by 3703

Abstract

Life-threatening ventricular arrhythmias are the main clinical burden in patients with hypertrophic cardiomyopathy (HCM), and frequently occur in young patients with mild structural disease. While massive hypertrophy, fibrosis and microvascular ischemia are the main mechanisms underlying sustained reentry-based ventricular arrhythmias in advanced HCM, [...] Read more.

Life-threatening ventricular arrhythmias are the main clinical burden in patients with hypertrophic cardiomyopathy (HCM), and frequently occur in young patients with mild structural disease. While massive hypertrophy, fibrosis and microvascular ischemia are the main mechanisms underlying sustained reentry-based ventricular arrhythmias in advanced HCM, cardiomyocyte-based functional arrhythmogenic mechanisms are likely prevalent at earlier stages of the disease. In this review, we will describe studies conducted in human surgical samples from HCM patients, transgenic animal models and human cultured cell lines derived from induced pluripotent stem cells. Current pieces of evidence concur to attribute the increased risk of ventricular arrhythmias in early HCM to different cellular mechanisms. The increase of late sodium current and L-type calcium current is an early observation in HCM, which follows post-translation channel modifications and increases the occurrence of early and delayed afterdepolarizations. Increased myofilament Ca²⁺ sensitivity, commonly observed in HCM, may promote afterdepolarizations and reentry arrhythmias with direct mechanisms. Decrease of K⁺-currents due to transcriptional regulation occurs in the advanced disease and contributes to reducing the repolarization-reserve and increasing the early afterdepolarizations (EADs). The presented evidence supports the idea that patients with early-stage HCM should be considered and managed as subjects with an acquired channelopathy rather than with a structural cardiac disease. Full article

(This article belongs to the Special Issue Electrical Remodeling in Cardiac Disease)

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14 pages, 1547 KiB

Open AccessReview

Electrical Ventricular Remodeling in Dilated Cardiomyopathy

by Christine Mages, Heike Gampp, Pascal Syren, Ann-Kathrin Rahm, Florian André, Norbert Frey, Patrick Lugenbiel and Dierk Thomas

Cells 2021, 10(10), 2767; https://doi.org/10.3390/cells10102767 - 15 Oct 2021

Cited by 7 | Viewed by 3280

Abstract

Ventricular arrhythmias contribute significantly to morbidity and mortality in patients with heart failure (HF). Pathomechanisms underlying arrhythmogenicity in patients with structural heart disease and impaired cardiac function include myocardial fibrosis and the remodeling of ion channels, affecting electrophysiologic properties of ventricular cardiomyocytes. The [...] Read more.

Ventricular arrhythmias contribute significantly to morbidity and mortality in patients with heart failure (HF). Pathomechanisms underlying arrhythmogenicity in patients with structural heart disease and impaired cardiac function include myocardial fibrosis and the remodeling of ion channels, affecting electrophysiologic properties of ventricular cardiomyocytes. The dysregulation of ion channel expression has been associated with cardiomyopathy and with the development of arrhythmias. However, the underlying molecular signaling pathways are increasingly recognized. This review summarizes clinical and cellular electrophysiologic characteristics observed in dilated cardiomyopathy (DCM) with ionic and structural alterations at the ventricular level. Furthermore, potential translational strategies and therapeutic options are highlighted. Full article

(This article belongs to the Special Issue Electrical Remodeling in Cardiac Disease)

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29 pages, 4674 KiB

Open AccessReview

Ventricular Arrhythmias in Ischemic Cardiomyopathy—New Avenues for Mechanism-Guided Treatment

by Matthew Amoni, Eef Dries, Sebastian Ingelaere, Dylan Vermoortele, H. Llewelyn Roderick, Piet Claus, Rik Willems and Karin R. Sipido

Cells 2021, 10(10), 2629; https://doi.org/10.3390/cells10102629 - 01 Oct 2021

Cited by 21 | Viewed by 5928

Abstract

Ischemic heart disease is the most common cause of lethal ventricular arrhythmias and sudden cardiac death (SCD). In patients who are at high risk after myocardial infarction, implantable cardioverter defibrillators are the most effective treatment to reduce incidence of SCD and ablation therapy [...] Read more.

Ischemic heart disease is the most common cause of lethal ventricular arrhythmias and sudden cardiac death (SCD). In patients who are at high risk after myocardial infarction, implantable cardioverter defibrillators are the most effective treatment to reduce incidence of SCD and ablation therapy can be effective for ventricular arrhythmias with identifiable culprit lesions. Yet, these approaches are not always successful and come with a considerable cost, while pharmacological management is often poor and ineffective, and occasionally proarrhythmic. Advances in mechanistic insights of arrhythmias and technological innovation have led to improved interventional approaches that are being evaluated clinically, yet pharmacological advancement has remained behind. We review the mechanistic basis for current management and provide a perspective for gaining new insights that centre on the complex tissue architecture of the arrhythmogenic infarct and border zone with surviving cardiac myocytes as the source of triggers and central players in re-entry circuits. Identification of the arrhythmia critical sites and characterisation of the molecular signature unique to these sites can open avenues for targeted therapy and reduce off-target effects that have hampered systemic pharmacotherapy. Such advances are in line with precision medicine and a patient-tailored therapy. Full article

(This article belongs to the Special Issue Electrical Remodeling in Cardiac Disease)

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21 pages, 1619 KiB

Open AccessReview

Atrial Cardiomyopathy: Pathophysiology and Clinical Consequences

by Andreas Goette and Uwe Lendeckel

Cells 2021, 10(10), 2605; https://doi.org/10.3390/cells10102605 - 30 Sep 2021

Cited by 37 | Viewed by 4390

Abstract

Around the world there are 33.5 million patients suffering from atrial fibrillation (AF) with an annual increase of 5 million cases. Most AF patients have an established form of an atrial cardiomyopathy. The concept of atrial cardiomyopathy was introduced in 2016. Thus, therapy [...] Read more.

Around the world there are 33.5 million patients suffering from atrial fibrillation (AF) with an annual increase of 5 million cases. Most AF patients have an established form of an atrial cardiomyopathy. The concept of atrial cardiomyopathy was introduced in 2016. Thus, therapy of underlying diseases and atrial tissue changes appear as a cornerstone of AF therapy. Furthermore, therapy or prevention of atrial endocardial changes has the potential to reduce atrial thrombogenesis and thereby cerebral stroke. The present manuscript will summarize the underlying pathophysiology and remodeling processes observed in the development of an atrial cardiomyopathy, thrombogenesis, and atrial fibrillation. In particular, the impact of oxidative stress, inflammation, diabetes, and obesity will be addressed. Full article

(This article belongs to the Special Issue Electrical Remodeling in Cardiac Disease)

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21 pages, 1669 KiB

Open AccessFeature PaperReview

Electrophysiological Remodeling: Cardiac T-Tubules and ß-Adrenoceptors

by Peter T. Wright, Julia Gorelik and Sian E. Harding

Cells 2021, 10(9), 2456; https://doi.org/10.3390/cells10092456 - 17 Sep 2021

Cited by 2 | Viewed by 3077

Abstract

Beta-adrenoceptors (βAR) are often viewed as archetypal G-protein coupled receptors. Over the past fifteen years, investigations in cardiovascular biology have provided remarkable insights into this receptor family. These studies have shifted pharmacological dogma, from one which centralized the receptor to a new focus [...] Read more.

Beta-adrenoceptors (βAR) are often viewed as archetypal G-protein coupled receptors. Over the past fifteen years, investigations in cardiovascular biology have provided remarkable insights into this receptor family. These studies have shifted pharmacological dogma, from one which centralized the receptor to a new focus on structural micro-domains such as caveolae and t-tubules. Important studies have examined, separately, the structural compartmentation of ion channels and βAR. Despite links being assumed, relatively few studies have specifically examined the direct link between structural remodeling and electrical remodeling with a focus on βAR. In this review, we will examine the nature of receptor and ion channel dysfunction on a substrate of cardiomyocyte microdomain remodeling, as well as the likely ramifications for cardiac electrophysiology. We will then discuss the advances in methodologies in this area with a specific focus on super-resolution microscopy, fluorescent imaging, and new approaches involving microdomain specific, polymer-based agonists. The advent of powerful computational modelling approaches has allowed the science to shift from purely empirical work, and may allow future investigations based on prediction. Issues such as the cross-reactivity of receptors and cellular heterogeneity will also be discussed. Finally, we will speculate as to the potential developments within this field over the next ten years. Full article

(This article belongs to the Special Issue Electrical Remodeling in Cardiac Disease)

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17 pages, 907 KiB

Open AccessReview

Remodeling of Cardiac Gap Junctional Cell–Cell Coupling

by Stefan Dhein and Aida Salameh

Cells 2021, 10(9), 2422; https://doi.org/10.3390/cells10092422 - 14 Sep 2021

Cited by 31 | Viewed by 3012

Abstract

The heart works as a functional syncytium, which is realized via cell-cell coupling maintained by gap junction channels. These channels connect two adjacent cells, so that action potentials can be transferred. Each cell contributes a hexameric hemichannel (=connexon), formed by protein subuntis named [...] Read more.

The heart works as a functional syncytium, which is realized via cell-cell coupling maintained by gap junction channels. These channels connect two adjacent cells, so that action potentials can be transferred. Each cell contributes a hexameric hemichannel (=connexon), formed by protein subuntis named connexins. These hemichannels dock to each other and form the gap junction channel. This channel works as a low ohmic resistor also allowing the passage of small molecules up to 1000 Dalton. Connexins are a protein family comprising of 21 isoforms in humans. In the heart, the main isoforms are Cx43 (the 43 kDa connexin; ubiquitous), Cx40 (mostly in atrium and specific conduction system), and Cx45 (in early developmental states, in the conduction system, and between fibroblasts and cardiomyocytes). These gap junction channels are mainly located at the polar region of the cardiomyocytes and thus contribute to the anisotropic pattern of cardiac electrical conductivity. While in the beginning the cell–cell coupling was considered to be static, similar to an anatomically defined structure, we have learned in the past decades that gap junctions are also subject to cardiac remodeling processes in cardiac disease such as atrial fibrillation, myocardial infarction, or cardiomyopathy. The underlying remodeling processes include the modulation of connexin expression by e.g., angiotensin, endothelin, or catecholamines, as well as the modulation of the localization of the gap junctions e.g., by the direction and strength of local mechanical forces. A reduction in connexin expression can result in a reduced conduction velocity. The alteration of gap junction localization has been shown to result in altered pathways of conduction and altered anisotropy. In particular, it can produce or contribute to non-uniformity of anisotropy, and thereby can pre-form an arrhythmogenic substrate. Interestingly, these remodeling processes seem to be susceptible to certain pharmacological treatment. Full article

(This article belongs to the Special Issue Electrical Remodeling in Cardiac Disease)

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19 pages, 2097 KiB

Open AccessFeature PaperReview

Remodeling of Ion Channel Trafficking and Cardiac Arrhythmias

by Camille E. Blandin, Basile J. Gravez, Stéphane N. Hatem and Elise Balse

Cells 2021, 10(9), 2417; https://doi.org/10.3390/cells10092417 - 14 Sep 2021

Cited by 12 | Viewed by 3528

Abstract

Both inherited and acquired cardiac arrhythmias are often associated with the abnormal functional expression of ion channels at the cellular level. The complex machinery that continuously traffics, anchors, organizes, and recycles ion channels at the plasma membrane of a cardiomyocyte appears to be [...] Read more.

Both inherited and acquired cardiac arrhythmias are often associated with the abnormal functional expression of ion channels at the cellular level. The complex machinery that continuously traffics, anchors, organizes, and recycles ion channels at the plasma membrane of a cardiomyocyte appears to be a major source of channel dysfunction during cardiac arrhythmias. This has been well established with the discovery of mutations in the genes encoding several ion channels and ion channel partners during inherited cardiac arrhythmias. Fibrosis, altered myocyte contacts, and post-transcriptional protein changes are common factors that disorganize normal channel trafficking during acquired cardiac arrhythmias. Channel availability, described notably for hERG and K_V1.5 channels, could be another potent arrhythmogenic mechanism. From this molecular knowledge on cardiac arrhythmias will emerge novel antiarrhythmic strategies. Full article

(This article belongs to the Special Issue Electrical Remodeling in Cardiac Disease)

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