Publications by authors named "Dobromir Dobrev"

283 Publications

Oxidative stress: a baystander or a causal contributor to atrial remodeling and fibrillation?

Cardiovasc Res 2021 Apr 2. Epub 2021 Apr 2.

Division of Cardiology, Department of Medicine, Lillehei Heart Institute, University of Minnesota Twin Cities, Minneapolis, Minnesota, USA.

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http://dx.doi.org/10.1093/cvr/cvab124DOI Listing
April 2021

Why translation from basic discoveries to clinical applications is so difficult for atrial fibrillation and possible approaches to improving it.

Cardiovasc Res 2021 Mar 25. Epub 2021 Mar 25.

Department of Medicine, Montreal Heart Institute and Université de Montréal, Montreal, Canada.

Atrial fibrillation (AF) is the most common sustained clinical arrhythmia, with a lifetime incidence of up to 37%, and is a major contributor to population morbidity and mortality. Important components of AF management include control of cardiac rhythm, rate and thromboembolic risk. In this narrative review article, we focus on rhythm control therapy. The available therapies for cardiac rhythm control include antiarrhythmic drugs and catheter-based ablation procedures; both of these are presently neither optimally effective nor safe. In order to develop improved treatment options it is necessary to use preclinical models, both to identify novel mechanism-based therapeutic targets and to test the effects of putative therapies before initiating clinical trials. Extensive research over the past 30 years has provided many insights into AF mechanisms that can be used to design new rhythm-maintenance approaches. However, it has proven very difficult to translate these mechanistic discoveries into clinically applicable safe and effective new therapies. The aim of the present paper is to explore the challenges that underlie this phenomenon. We begin by considering the basic problem of AF, including its clinical importance, the current therapeutic landscape, the drug development pipeline, and the notion of upstream therapy. We then discuss the currently available preclinical models of AF and their limitations, and move on to regulatory hurdles and considerations and then review industry concerns and strategies. Finally, we evaluate potential paths forward, attempting to derive insights from the developmental history of currently used approaches and suggesting possible paths for the future. While the introduction of successful conceptually innovative new treatments for AF control is proving extremely difficult, one significant breakthrough is likely to revolutionize both AF management and the therapeutic development landscape.
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http://dx.doi.org/10.1093/cvr/cvab093DOI Listing
March 2021

A disproportional rise in the growing submission rate to International Journal of Cardiology Heart & Vasculature during the COVID‑19 pandemic.

Int J Cardiol Heart Vasc 2021 Apr 27;33:100749. Epub 2021 Feb 27.

Institute of Pharmacology, West German Heart and Vascular Center, Faculty of Medicine, University Duisburg-Essen, Essen, Germany.

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http://dx.doi.org/10.1016/j.ijcha.2021.100749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957093PMC
April 2021

Oral anticoagulation and therapy of atrial flutter: discontinuation of anticoagulation revisited.

Int J Cardiol 2021 Jun 17;333:117-118. Epub 2021 Mar 17.

(a)Institute of Pharmacology, West German Heart and Vascular Center, University Duisburg-Essen, Essen, Germany; (c)Montréal Heart Institute, University de Montréal, Montréal, Quebec, Canada; (d)Department of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, USA. Electronic address:

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http://dx.doi.org/10.1016/j.ijcard.2021.03.022DOI Listing
June 2021

Implantable cardioverter-defibrillator therapy in primary versus secondary prevention: Reliable prediction of appropriate therapies and mortality is still an unmet need.

Int J Cardiol Heart Vasc 2021 Feb 23;32:100740. Epub 2021 Feb 23.

Institute of Pharmacology, West German Heart and Vascular Center, University Duisburg-Essen, Essen, Germany.

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http://dx.doi.org/10.1016/j.ijcha.2021.100740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7910703PMC
February 2021

Mapping genetic changes in the cAMP-signaling cascade in human atria.

J Mol Cell Cardiol 2021 Feb 22;155:10-20. Epub 2021 Feb 22.

Université Paris-Saclay, Inserm, UMR-S 1180, Châtenay-Malabry, France; Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Germany; German Center for Cardiovascular Research (DZHK), partner site Hamburg/Kiel/Lübeck, Germany.

Aim: To obtain a quantitative expression profile of the main genes involved in the cAMP-signaling cascade in human control atria and in different cardiac pathologies.

Methods And Results: Expression of 48 target genes playing a relevant role in the cAMP-signaling cascade was assessed by RT-qPCR. 113 samples were obtained from right atrial appendages (RAA) of patients in sinus rhythm (SR) with or without atrium dilation, paroxysmal atrial fibrillation (AF), persistent AF or heart failure (HF); and left atrial appendages (LAA) from patients in SR or with AF. Our results show that right and left atrial appendages in donor hearts or from SR patients have similar expression values except for AC7 and PDE2A. Despite the enormous chamber-dependent variability in the gene-expression changes between pathologies, several distinguishable patterns could be identified. PDE8A, PI3Kγ and EPAC2 were upregulated in AF. Different phosphodiesterase (PDE) families showed specific pathology-dependent changes.

Conclusion: By comparing mRNA-expression patterns of the cAMP-signaling cascade related genes in right and left atrial appendages of human hearts and across different pathologies, we show that 1) gene expression is not significantly affected by cardioplegic solution content, 2) it is appropriate to use SR atrial samples as controls, and 3) many genes in the cAMP-signaling cascade are affected in AF and HF but only few of them appear to be chamber (right or left) specific.

Topic: Genetic changes in human diseased atria.

Translational Perspective: The cyclic AMP signaling pathway is important for atrial function. However, expression patterns of the genes involved in the atria of healthy and diseased hearts are still unclear. We give here a general overview of how different pathologies affect the expression of key genes in the cAMP signaling pathway in human right and left atria appendages. Our study may help identifying new genes of interest as potential therapeutic targets or clinical biomarkers for these pathologies and could serve as a guide in future gene therapy studies.
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http://dx.doi.org/10.1016/j.yjmcc.2021.02.006DOI Listing
February 2021

Therapy-refractory AF: A clear unmet need for the development of novel antiarrhythmic drugs.

Int J Cardiol 2021 May 8;331:114-115. Epub 2021 Feb 8.

(b)Institute of Pharmacology, University Duisburg-Essen, Hufelandstraße 55, 45122 Essen, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.ijcard.2021.02.007DOI Listing
May 2021

Dynamic risk assessment to improve quality of care in patients with atrial fibrillation: the 7th AFNET/EHRA Consensus Conference.

Europace 2021 Mar;23(3):329-344

Atrial Fibrillation NETwork (AFNET), Münster, Germany.

Aims: The risk of developing atrial fibrillation (AF) and its complications continues to increase, despite good progress in preventing AF-related strokes.

Methods And Results: This article summarizes the outcomes of the 7th Consensus Conference of the Atrial Fibrillation NETwork (AFNET) and the European Heart Rhythm Association (EHRA) held in Lisbon in March 2019. Sixty-five international AF specialists met to present new data and find consensus on pressing issues in AF prevention, management and future research to improve care for patients with AF and prevent AF-related complications. This article is the main outcome of an interactive, iterative discussion between breakout specialist groups and the meeting plenary. AF patients have dynamic risk profiles requiring repeated assessment and risk-based therapy stratification to optimize quality of care. Interrogation of deeply phenotyped datasets with outcomes will lead to a better understanding of the cardiac and systemic effects of AF, interacting with comorbidities and predisposing factors, enabling stratified therapy. New proposals include an algorithm for the acute management of patients with AF and heart failure, a call for a refined, data-driven assessment of stroke risk, suggestions for anticoagulation use in special populations, and a call for rhythm control therapy selection based on risk of AF recurrence.

Conclusion: The remaining morbidity and mortality in patients with AF needs better characterization. Likely drivers of the remaining AF-related problems are AF burden, potentially treatable by rhythm control therapy, and concomitant conditions, potentially treatable by treating these conditions. Identifying the drivers of AF-related complications holds promise for stratified therapy.
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http://dx.doi.org/10.1093/europace/euaa279DOI Listing
March 2021

NLRP3 inflammasome is a key driver of Obesity-Induced atrial arrhythmias.

Cardiovasc Res 2021 Feb 1. Epub 2021 Feb 1.

Department of Molecular Physiology and Biophysics.

Aims: Obesity, an established risk factor of atrial fibrillation (AF), is frequently associated with enhanced inflammatory response. However, whether inflammatory signaling is causally linked to AF pathogenesis in obesity remains elusive. We recently demonstrated that the constitutive activation of the 'NACHT, LRR & PYD Domains-containing Protein 3' (NLRP3) inflammasome promotes AF susceptibility. In this study, we hypothesized that the NLRP3 inflammasome is a key driver of obesity-induced AF.

Methods And Results: Western blotting was performed to determine the level of NLRP3 inflammasome activation in atrial tissues of obese patients, sheep, and diet-induced obese (DIO) mice. The increased bodyweight in patients, sheep, and mice was associated with enhanced NLRP3-inflammasome activation. To determine whether NLRP3 contributes to the obesity-induced atrial arrhythmogenesis, wildtype (WT) and NLRP3 homozygous knockout (NLRP3-/-) mice were subjected to high-fat diet (HFD) or normal chow (NC) for 10 weeks. Relative to NC-fed WT mice, HFD-fed WT mice were more susceptible to pacing-induced AF with longer AF duration. In contrast, HFD-fed NLRP3-/- mice were resistant to pacing-induced AF. Optical mapping in DIO mice revealed an arrhythmogenic substrate characterized by abbreviated refractoriness and action potential duration (APD), two key determinants of reentry-promoting electrical remodeling. Upregulation of ultra-rapid delayed-rectifier K+-channel (Kv1.5) contributed to the shortening of atrial refractoriness. Increased profibrotic signaling and fibrosis along with abnormal Ca2+ release from sarcoplasmic reticulum (SR) accompanied atrial arrhythmogenesis in DIO mice. Conversely, genetic ablation of Nlrp3 (NLRP3-/-) in HFD-fed mice prevented the increases in Kv1.5 and the evolution of electrical remodeling, the upregulation of profibrotic genes, and abnormal SR Ca2+ release in DIO mice.

Conclusions: These results demonstrate that the atrial NLRP3 inflammasome is a key driver of obesity-induced atrial arrhythmogenesis and establishes a mechanistic link between obesity-induced AF and NLRP3-inflammasome activation.
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http://dx.doi.org/10.1093/cvr/cvab024DOI Listing
February 2021

Potential antiarrhythmic actions of anticoagulants: Do they exist and can they be clinically unmasked?

Int J Cardiol 2021 May 28;331:73-74. Epub 2021 Jan 28.

Institute of Pharmacology, West German Heart and Vascular Center, University Duisburg-Essen, Essen, Germany.

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http://dx.doi.org/10.1016/j.ijcard.2021.01.010DOI Listing
May 2021

Postoperative Atrial Fibrillation: Features, Mechanisms, and Clinical Management.

Card Electrophysiol Clin 2021 03;13(1):123-132

Department of Medicine and Research Center, Montreal Heart Institute and Université de Montréal, 5000 Belanger Street, Montréal, Québec H1T 1C8, Canada; Institute of Pharmacology, West German Heart and Vascular Center, University Duisburg-Essen, Hufelandstr. 55, Essen 45122, Germany; IHU LIRYC and Fondation Bordeaux Université, Bordeaux, France.

Advances in atrial fibrillation (AF) management, perioperative medicine, and surgical techniques have reignited an interest in postoperative AF (POAF). POAF results from the interaction among subclinical atrial substrate, surgery-induced substrate, and transient postoperative factors. Prophylaxis for POAF after cardiac surgery is well established but the indications for preoperative treatment in noncardiac surgery need further investigation. A rate-control strategy is adequate for most asymptomatic patients with POAF and anticoagulation should be initiated for POAF more than 48 to 72 hours postsurgery. Research is needed to improve evidence-based management of POAF and guide long-term management in view of the substantial late recurrence-rate.
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http://dx.doi.org/10.1016/j.ccep.2020.11.010DOI Listing
March 2021

Pericardial adipose tissue: An emerging biomarker of atrial fibrillation?

Int J Cardiol 2021 May 27;331:122-123. Epub 2021 Jan 27.

Institute of Pharmacology, West German Heart and Vascular Center, University Duisburg-Essen, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.ijcard.2021.01.009DOI Listing
May 2021

The crosstalk between cardiomyocyte calcium and inflammasome signaling pathways in atrial fibrillation.

Pflugers Arch 2021 Mar 28;473(3):389-405. Epub 2021 Jan 28.

Department of Medicine (Section of Cardiovascular Research), Baylor College of Medicine, Houston, TX, USA.

Atrial fibrillation (AF) is the most frequent arrhythmia in adults. The prevalence and incidence of AF is going to increase substantially over the next few decades. Because AF increases the risk of stroke, heart failure, dementia, and others, it severely impacts the quality of life, morbidity, and mortality. Although the pathogenesis of AF is multifaceted and complex, focal ectopic activity and reentry are considered as the fundamental proarrhythmic mechanisms underlying AF development. Over the past 2 decades, large amount of evidence points to the key role of intracellular Ca dysregulation in both initiation and maintenance of AF. More recently, emerging evidence reveal that NLRP3 (NACHT, LRR, PYD domain-containing 3) inflammasome pathway contributes to the substrate of both triggered activity and reentry, ultimately promoting AF. In this article, we review the current state of knowledge on Ca signaling and NLRP3 inflammasome activity in AF. We also discuss the potential crosstalk between these two quintessential contributors to AF promotion.
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http://dx.doi.org/10.1007/s00424-021-02515-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940593PMC
March 2021

One Ring to Rule Them All: Continuous Monitoring of Patients With Secondary Atrial Fibrillation Points to a Unifying Underlying Mechanism.

Can J Cardiol 2021 May 23;37(5):686-689. Epub 2021 Jan 23.

Department of Medicine and Research Centre, Montréal Heart Institute and University of Montréal, Montréal, Québec, Canada; Institute of Pharmacology, West German Heart and Vascular Center, University of Duisburg-Essen, Essen, Germany; L'Institut Hospitalo-Universitaire L'Institut de Rythmologie et Modélisation Cardiaque (IHU LIRYC) and Fondation Bordeaux Université Bordeaux, Bordeaux, France. Electronic address:

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http://dx.doi.org/10.1016/j.cjca.2021.01.018DOI Listing
May 2021

Soluble fibrin monomer complex as a candidate sentinel for adverse events in patients with heart failure.

Int J Cardiol Heart Vasc 2021 Feb 9;32:100712. Epub 2021 Jan 9.

Institute of Pharmacology, West German Heart and Vascular Center, University Duisburg-Essen, Essen, Germany.

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http://dx.doi.org/10.1016/j.ijcha.2020.100712DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7809182PMC
February 2021

Kv1.1 potassium channel subunit deficiency alters ventricular arrhythmia susceptibility, contractility, and repolarization.

Physiol Rep 2021 01;9(1):e14702

Department of Cellular Biology & Anatomy, Louisiana State University Health Sciences Center, Shreveport, LA, USA.

Epilepsy-associated Kv1.1 voltage-gated potassium channel subunits encoded by the Kcna1 gene have traditionally been considered absent in heart, but recent studies reveal they are expressed in cardiomyocytes where they could regulate intrinsic cardiac electrophysiology. Although Kv1.1 now has a demonstrated functional role in atria, its role in the ventricles has never been investigated. In this work, electrophysiological, histological, and gene expression approaches were used to explore the consequences of Kv1.1 deficiency in the ventricles of Kcna1 knockout (KO) mice at the organ, cellular, and molecular levels to determine whether the absence of Kv1.1 leads to ventricular dysfunction that increases the risk of premature or sudden death. When subjected to intracardiac pacing, KO mice showed normal baseline susceptibility to inducible ventricular arrhythmias (VA) but resistance to VA under conditions of sympathetic challenge with isoproterenol. Echocardiography revealed cardiac contractile dysfunction manifesting as decreased ejection fraction and fractional shortening. In whole-cell patch-clamp recordings, KO ventricular cardiomyocytes exhibited action potential prolongation indicative of impaired repolarization. Imaging, histological, and transcript analyses showed no evidence of structural or channel gene expression remodeling, suggesting that the observed deficits are likely electrogenic due to Kv1.1 deficiency. Immunoblots of patient heart samples detected the presence of Kv1.1 at relatively high levels, implying that Kv1.1 contributes to human cardiac electrophysiology. Taken together, this work describes an important functional role for Kv1.1 in ventricles where its absence causes repolarization and contractility deficits but reduced susceptibility to arrhythmia under conditions of sympathetic drive.
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http://dx.doi.org/10.14814/phy2.14702DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7798052PMC
January 2021

Surgery-related cardiac stress: A susceptibility test of late atrial fibrillation recurrence?

Int J Cardiol Heart Vasc 2021 Feb 28;32:100693. Epub 2020 Dec 28.

Institute of Pharmacology, West German Heart and Vascular Center, University Duisburg-Essen, Germany.

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http://dx.doi.org/10.1016/j.ijcha.2020.100693DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7777499PMC
February 2021

Inositol Trisphosphate Receptors and Nuclear Calcium in Atrial Fibrillation.

Circ Res 2020 Dec 30. Epub 2020 Dec 30.

Montreal Heart Institute, Universite de Montreal / McGill University, CANADA.

The mechanisms underlying atrial fibrillation (AF), the most common clinical arrhythmia, are poorly understood. Nucleoplasmic Ca regulates gene-expression, but the nature and significance of nuclear Ca-changes in AF are largely unknown. To elucidate mechanisms by which AF alters atrial cardiomyocyte (CM) nuclear Ca ([Ca]) and Ca/calmodulin-dependent protein kinase-II (CaMKII)-related signaling. Atrial CMs were isolated from control and AF-dogs (kept in AF by atrial tachypacing [600 bpm x 1 week]). [Ca] and cytosolic [Ca] (Ca]) were recorded via confocal microscopy. Diastolic [Ca] was greater than [Ca] under control conditions, while resting [Ca] was similar to [Ca]; both diastolic and resting [Ca] increased with AF. Inositol-trisphosphate-receptor (IPR) stimulation produced larger [Ca] increases in AF versus control CMs, and IPR-blockade suppressed the AF-related [Ca]-differences. AF upregulated nuclear protein-expression of IPR-type 1 (IPR1) and of phosphorylated CaMKII (immunohistochemistry and immunoblot), while decreasing the nuclear/cytosolic expression-ratio for histone deacetylase type-4 (HDAC4). Isolated atrial CMs tachypaced at 3 Hz for 24 hours mimicked AF-type [Ca] changes and L-type calcium current (ICaL) decreases versus 1-Hz-paced CMs; these changes were prevented by IP3R knockdown with short-interfering RNA directed against IPR1. Nuclear/cytosolic HDAC4 expression-ratio was decreased by 3-Hz pacing, while nuclear CaMKII and HDAC4 phosphorylation were increased. Either CaMKII-inhibition (by autocamtide-2-related peptide) or IPR-knockdown prevented the CaMKII-hyperphosphorylation and nuclear-to-cytosolic HDAC4 shift caused by 3-Hz pacing. In human atrial CMs from AF patients, nuclear IPR1-expression was significantly increased, with decreased nuclear/non-nuclear HDAC4 ratio. MicroRNA-26a was predicted to target ITPR1 (confirmed by Luciferase assay) and was downregulated in AF atrial CMs; microRNA-26a silencing reproduced AF-induced IP3R1 upregulation and nuclear diastolic Ca-loading. AF increases atrial CM nucleoplasmic Ca-handling by IPR1-upregulation involving miR-26a, leading to enhanced IPR1-CaMKII-HDAC4 signaling and I-downregulation.
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http://dx.doi.org/10.1161/CIRCRESAHA.120.317768DOI Listing
December 2020

Sleep apnea and atrial fibrillation: Update 2020.

Int J Cardiol Heart Vasc 2020 Dec 27;31:100681. Epub 2020 Nov 27.

Institute of Pharmacology, West German Heart and Vascular Center, University Duisburg-Essen, Germany.

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http://dx.doi.org/10.1016/j.ijcha.2020.100681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708811PMC
December 2020

Contemporary plaque imaging for risk stratification of coronary artery disease: Are we getting there?

Int J Cardiol Heart Vasc 2020 Dec 24;31:100678. Epub 2020 Nov 24.

Institute of Pharmacology, West German Heart and Vascular Center, University Duisburg-Essen, Essen, Germany.

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http://dx.doi.org/10.1016/j.ijcha.2020.100678DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695964PMC
December 2020

SPEG: a key regulator of cardiac calcium homeostasis.

Cardiovasc Res 2020 Oct 17. Epub 2020 Oct 17.

Cardiovascular Research Institute.

Proper cardiac Ca2+ homeostasis is essential for normal excitation-contraction coupling. Perturbations in cardiac Ca2+ handling through altered kinase activity has been implicated in altered cardiac contractility and arrhythmogenesis. Thus, a better understanding of cardiac Ca2+ handling regulation is vital for a better understanding of various human disease processes. 'Striated muscle preferentially expressed protein kinase' (SPEG) is a member of the myosin light chain kinase family that is key for normal cardiac function. Work within the last five years has revealed that SPEG has a crucial role in maintaining normal cardiac Ca2+ handling through maintenance of transverse tubule formation and phosphorylation of junctional membrane complex proteins. Additionally, SPEG has been causally impacted in human genetic diseases such as centronuclear myopathy and dilated cardiomyopathy as well as in common acquired cardiovascular disease such as heart failure and atrial fibrillation. Given the rapidly emerging role of SPEG as a key cardiac Ca2+ regulator, we here present this review in order to summarize recent findings regarding the mechanisms of SPEG regulation of cardiac excitation-contraction coupling in both physiology and human disease. A better understanding of the roles of SPEG will be important for a more complete comprehension of cardiac Ca2+ regulation in physiology and disease.
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http://dx.doi.org/10.1093/cvr/cvaa290DOI Listing
October 2020

On-demand mobile health infrastructures to allow comprehensive remote atrial fibrillation and risk factor management through teleconsultation.

Clin Cardiol 2020 Nov 8;43(11):1232-1239. Epub 2020 Oct 8.

Department of Cardiology, Maastricht University Medical Centre and Cardiovascular Research Institute Maastricht, Maastricht, The Netherlands.

Background: Although novel teleconsultation solutions can deliver remote situations that are relatively similar to face-to-face interaction, remote assessment of heart rate and rhythm as well as risk factors remains challenging in patients with atrial fibrillation (AF).

Hypothesis: Mobile health (mHealth) solutions can support remote AF management.

Methods: Herein, we discuss available mHealth tools and strategies on how to incorporate the remote assessment of heart rate, rhythm and risk factors to allow comprehensive AF management through teleconsultation.

Results: Particularly, in the light of the coronavirus disease 2019 (COVID-19) pandemic, there is decreased capacity to see patients in the outpatient clinic and mHealth has become an important component of many AF outpatient clinics. Several validated mHealth solutions are available for remote heart rate and rhythm monitoring as well as for risk factor assessment. mHealth technologies can be used for (semi-)continuous longitudinal monitoring or for short-term on-demand monitoring, dependent on the respective requirements and clinical scenarios. As a possible solution to improve remote AF care through teleconsultation, we introduce the on-demand TeleCheck-AF mHealth approach that allows remote app-based assessment of heart rate and rhythm around teleconsultations, which has been developed and implemented during the COVID-19 pandemic in Europe.

Conclusion: Large scale international mHealth projects, such as TeleCheck-AF, will provide insight into the additional value and potential limitations of mHealth strategies to remotely manage AF patients. Such mHealth infrastructures may be well suited within an integrated AF-clinic, which may require redesign of practice and reform of health care systems.
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http://dx.doi.org/10.1002/clc.23469DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7661648PMC
November 2020

The anticoagulation dilemma and future treatment avenues in patients with breast cancer and atrial fibrillation.

Int J Cardiol 2021 Jan 1;323:194-196. Epub 2020 Oct 1.

Institute of Pharmacology, West German Heart and Vascular Center, University Duisburg-Essen, Essen, Germany.

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http://dx.doi.org/10.1016/j.ijcard.2020.09.067DOI Listing
January 2021

COVID-19 associated atrial fibrillation: Incidence, putative mechanisms and potential clinical implications.

Int J Cardiol Heart Vasc 2020 Oct 1;30:100631. Epub 2020 Sep 1.

Department of Cardiology, Maastricht University Medical Centre and Cardiovascular Research Institute Maastricht, Maastricht, The Netherlands.

Coronavirus disease 2019 (COVID-19) is a novel, highly transmittable and severe strain disease, which has rapidly spread worldwide. Despite epidemiological evidence linking COVID-19 with cardiovascular diseases, little is known about whether and how COVID-19 influences atrial fibrillation (AF), the most prevalent arrhythmia in clinical practice. Here, we review the available evidence for prevalence and incidence of AF in patients infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and discuss disease management approaches and potential treatment options for COVID-19 infected AF patients.
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http://dx.doi.org/10.1016/j.ijcha.2020.100631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7462635PMC
October 2020

Recurrence of atrial fibrillation following non-cardiac surgery or acute illness: A common but rarely detected complication.

Int J Cardiol Heart Vasc 2020 Aug 6;29:100609. Epub 2020 Aug 6.

Department of Cardiology, CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine, and Life Sciences, Maastricht University, Maastricht, the Netherlands.

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http://dx.doi.org/10.1016/j.ijcha.2020.100609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7452374PMC
August 2020

The gut microbial-derived metabolite trimethylamine N-oxide: A missing link between lifestyle-components and atrial fibrillation?

Int J Cardiol Heart Vasc 2020 Aug 23;29:100581. Epub 2020 Jul 23.

Department of Cardiology, Maastricht University Medical Centre and Cardiovascular Research Institute Maastricht, Maastricht, the Netherlands.

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http://dx.doi.org/10.1016/j.ijcha.2020.100581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7452559PMC
August 2020

Polypill revisited - Unity in diversity.

Int J Cardiol Heart Vasc 2020 Aug 10;29:100607. Epub 2020 Aug 10.

Institute of Pharmacology, Faculty of Medicine, University Duisburg-Essen, Germany.

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http://dx.doi.org/10.1016/j.ijcha.2020.100607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7452522PMC
August 2020

Atrial Myocyte NLRP3/CaMKII Nexus Forms a Substrate for Postoperative Atrial Fibrillation.

Circ Res 2020 Sep 30;127(8):1036-1055. Epub 2020 Jul 30.

Institute of Pharmacology, West German Heart and Vascular Center, University Duisburg-Essen, Essen, Germany (J.H., A.P.M., T.V., C.E.M., M.T., I.H.A.-T., M.G., S.N., D.D.).

Rationale: Postoperative atrial fibrillation (POAF) is a common and troublesome complication of cardiac surgery. POAF is generally believed to occur when postoperative triggers act on a preexisting vulnerable substrate, but the underlying cellular and molecular mechanisms are largely unknown.

Objective: To identify cellular POAF mechanisms in right atrial samples from patients without a history of atrial fibrillation undergoing open-heart surgery.

Methods And Results: Multicellular action potentials, membrane ion-currents (perforated patch-clamp), or simultaneous membrane-current (ruptured patch-clamp) and [Ca]-recordings in atrial cardiomyocytes, along with protein-expression levels in tissue homogenates or cardiomyocytes, were assessed in 265 atrial samples from patients without or with POAF. No indices of electrical, profibrotic, or connexin remodeling were noted in POAF, but Ca-transient amplitude was smaller, although spontaneous sarcoplasmic reticulum (SR) Ca-release events and L-type Ca-current alternans occurred more frequently. CaMKII (Ca/calmodulin-dependent protein kinase-II) protein-expression, CaMKII-dependent phosphorylation of the cardiac RyR2 (ryanodine-receptor channel type-2), and RyR2 single-channel open-probability were significantly increased in POAF. SR Ca-content was unchanged in POAF despite greater SR Ca-leak, with a trend towards increased SR Ca-ATPase activity. Patients with POAF also showed stronger expression of activated components of the NLRP3 (NACHT, LRR, and PYD domains-containing protein-3)-inflammasome system in atrial whole-tissue homogenates and cardiomyocytes. Acute application of interleukin-1β caused NLRP3-signaling activation and CaMKII-dependent RyR2/phospholamban hyperphosphorylation in an immortalized mouse atrial cardiomyocyte cell-line (HL-1-cardiomyocytes) and enhanced spontaneous SR Ca-release events in both POAF cardiomyocytes and HL-1-cardiomyocytes. Computational modeling showed that RyR2 dysfunction and increased SR Ca-uptake are sufficient to reproduce the Ca-handling phenotype and indicated an increased risk of proarrhythmic delayed afterdepolarizations in POAF subjects in response to interleukin-1β.

Conclusions: Preexisting Ca-handling abnormalities and activation of NLRP3-inflammasome/CaMKII signaling are evident in atrial cardiomyocytes from patients who subsequently develop POAF. These molecular substrates sensitize cardiomyocytes to spontaneous Ca-releases and arrhythmogenic afterdepolarizations, particularly upon exposure to inflammatory mediators. Our data reveal a potential cellular and molecular substrate for this important clinical problem.
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http://dx.doi.org/10.1161/CIRCRESAHA.120.316710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7604886PMC
September 2020

Molecular Basis of Atrial Fibrillation Pathophysiology and Therapy: A Translational Perspective.

Circ Res 2020 06 18;127(1):51-72. Epub 2020 Jun 18.

Institute of Pharmacology, West German Heart and Vascular Center, Faculty of Medicine, University Duisburg-Essen, Germany (S.N., J.H., D.D.).

Atrial fibrillation (AF) is a highly prevalent arrhythmia, with substantial associated morbidity and mortality. There have been significant management advances over the past 2 decades, but the burden of the disease continues to increase and there is certainly plenty of room for improvement in treatment options. A potential key to therapeutic innovation is a better understanding of underlying fundamental mechanisms. This article reviews recent advances in understanding the molecular basis for AF, with a particular emphasis on relating these new insights to opportunities for clinical translation. We first review the evidence relating basic electrophysiological mechanisms to the characteristics of clinical AF. We then discuss the molecular control of factors leading to some of the principal determinants, including abnormalities in impulse conduction (such as tissue fibrosis and other extra-cardiomyocyte alterations, connexin dysregulation and Na-channel dysfunction), electrical refractoriness, and impulse generation. We then consider the molecular drivers of AF progression, including a range of Ca-dependent intracellular processes, microRNA changes, and inflammatory signaling. The concept of key interactome-related nodal points is then evaluated, dealing with systems like those associated with CaMKII (Ca/calmodulin-dependent protein kinase-II), NLRP3 (NACHT, LRR, and PYD domains-containing protein-3), and transcription-factors like TBX5 and PitX2c. We conclude with a critical discussion of therapeutic implications, knowledge gaps and future directions, dealing with such aspects as drug repurposing, biologicals, multispecific drugs, the targeting of cardiomyocyte inflammatory signaling and potential considerations in intervening at the level of interactomes and gene-regulation. The area of molecular intervention for AF management presents exciting new opportunities, along with substantial challenges.
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http://dx.doi.org/10.1161/CIRCRESAHA.120.316363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7398486PMC
June 2020

Acute effects of alcohol on cardiac electrophysiology and arrhythmogenesis: Insights from multiscale in silico analyses.

J Mol Cell Cardiol 2020 09 22;146:69-83. Epub 2020 Jul 22.

Department of Cardiology, CARIM School for Cardiovascular Diseases, Maastricht University, the Netherlands. Electronic address:

Acute excessive ethyl alcohol (ethanol) consumption alters cardiac electrophysiology and can evoke cardiac arrhythmias, e.g., in 'holiday heart syndrome'. Ethanol acutely modulates numerous targets in cardiomyocytes, including ion channels, Ca-handling proteins and gap junctions. However, the mechanisms underlying ethanol-induced arrhythmogenesis remain incompletely understood and difficult to study experimentally due to the multiple electrophysiological targets involved and their potential interactions with preexisting electrophysiological or structural substrates. Here, we employed cellular- and tissue-level in-silico analyses to characterize the acute effects of ethanol on cardiac electrophysiology and arrhythmogenesis. Acute electrophysiological effects of ethanol were incorporated into human atrial and ventricular cardiomyocyte computer models: reduced I, I, I, I and I, dual effects on I and I (inhibition at low and augmentation at high concentrations), and increased I and SR Ca leak. Multiscale simulations in the absence or presence of preexistent atrial fibrillation or heart-failure-related remodeling demonstrated that low ethanol concentrations prolonged atrial action-potential duration (APD) without effects on ventricular APD. Conversely, high ethanol concentrations abbreviated atrial APD and prolonged ventricular APD. High ethanol concentrations promoted reentry in tissue simulations, but the extent of reentry promotion was dependent on the presence of altered intercellular coupling, and the degree, type, and pattern of fibrosis. Taken together, these data provide novel mechanistic insight into the potential proarrhythmic interactions between a preexisting substrate and acute changes in cardiac electrophysiology. In particular, acute ethanol exposure has concentration-dependent electrophysiological effects that differ between atria and ventricles, and between healthy and diseased hearts. Low concentrations of ethanol can have anti-fibrillatory effects in atria, whereas high concentrations promote the inducibility and maintenance of reentrant atrial and ventricular arrhythmias, supporting a role for limiting alcohol intake as part of cardiac arrhythmia management.
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http://dx.doi.org/10.1016/j.yjmcc.2020.07.007DOI Listing
September 2020