Publications by authors named "Jordi Heijman"

94 Publications

Antiarrhythmic drugs for atrial fibrillation: lessons from the past and opportunities for the future.

Europace 2021 Apr;23(Supplement_2):ii14-ii22

Cardiovascular and Cell Sciences Research Institute, Cardiology Clinical Academic Group, St George's, University of London, London, UK.

Atrial fibrillation (AF) remains a highly prevalent and troublesome cardiac arrhythmia, associated with substantial morbidity and mortality. Restoration and maintenance of sinus rhythm (rhythm-control therapy) is an important element of AF management in symptomatic patients. Despite significant advances and increasing importance of catheter ablation, antiarrhythmic drugs (AADs) remain a cornerstone of rhythm-control therapy. During the past 50 years, experimental and clinical research has greatly increased our understanding of AADs. As part of the special issue on paradigm shifts in AF, this review summarizes important milestones in AAD research that have shaped their current role in AF management, including (i) awareness of the proarrhythmic potential of AADs; (ii) increasing understanding of the pleiotropic effects of AADs; (iii) the development of dronedarone; and (iv) the search for AF-specific AADs. Finally, we discuss short- and long-term opportunities for better AF management through advances in AAD therapy, including personalization of AAD therapy based on individual AF mechanisms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/europace/euaa426DOI Listing
April 2021

The road goes ever on: innovations and paradigm shifts in atrial fibrillation management.

Europace 2021 Apr;23(Supplement_2):ii1-ii3

Department of Cardiology, Thoraxcentre, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/europace/euab061DOI Listing
April 2021

The walk of life: Remote monitoring provides insights into physical activity during a pandemic.

Int J Cardiol Heart Vasc 2021 Apr 1;33:100772. Epub 2021 Apr 1.

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

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijcha.2021.100772DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8012064PMC
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/cvr/cvab093DOI Listing
March 2021

Cardiovascular magnetic resonance accurately detects obstructive coronary artery disease in suspected non-ST elevation myocardial infarction: a sub-analysis of the CARMENTA Trial.

J Cardiovasc Magn Reson 2021 Mar 22;23(1):40. Epub 2021 Mar 22.

Department of Cardiology, Maastricht UMC+, Maastricht, The Netherlands.

Background: Invasive coronary angiography (ICA) is still the reference test in suspected non-ST elevation myocardial infarction (NSTEMI), although a substantial number of patients do not have obstructive coronary artery disease (CAD). Early cardiovascular magnetic resonance (CMR) may be a useful gatekeeper for ICA in this setting. The main objective was to investigate the accuracy of CMR to detect obstructive CAD in NSTEMI.

Methods: This study is a sub-analysis of a randomized controlled trial investigating whether a non-invasive imaging-first strategy safely reduced the number of ICA compared to routine clinical care in suspected NSTEMI (acute chest pain, non-diagnostic electrocardiogram, high sensitivity troponin T > 14 ng/L), and included 51 patients who underwent CMR prior to ICA. A stepwise approach was used to assess the diagnostic accuracy of CMR to detect (1) obstructive CAD (diameter stenosis ≥ 70% by ICA) and (2) an adjudicated final diagnosis of acute coronary syndrome (ACS). First, in all patients the combination of cine, T2-weighted and late gadolinium enhancement (LGE) imaging was evaluated for the presence of abnormalities consistent with a coronary etiology in any sequence. Hereafter and only when the scan was normal or equivocal, adenosine stress-perfusion CMR was added.

Results: Of 51 patients included (63 ± 10 years, 51% male), 34 (67%) had obstructive CAD by ICA. The sensitivity, specificity and overall accuracy of the first step to diagnose obstructive CAD were 79%, 71% and 77%, respectively. Additional vasodilator stress-perfusion CMR was performed in 19 patients and combined with step one resulted in an overall sensitivity of 97%, specificity of 65% and accuracy of 86%. Of the remaining 17 patients with non-obstructive CAD, 4 (24%) had evidence for a myocardial infarction on LGE, explaining the modest specificity. The sensitivity, specificity and overall accuracy to diagnose ACS (n = 43) were 88%, 88% and 88%, respectively.

Conclusion: CMR accurately detects obstructive CAD and ACS in suspected NSTEMI. Non-obstructive CAD is common with CMR still identifying an infarction in almost one-quarter of patients. CMR should be considered as an early diagnostic approach in suspected NSTEMI.

Trial Registration: The CARMENTA trial has been registered at ClinicalTrials.gov with identifier NCT01559467.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12968-021-00723-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983380PMC
March 2021

Both beat-to-beat changes in RR-interval and left ventricular filling time determine ventricular function during atrial fibrillation.

Europace 2021 Mar;23(Supplement_1):i21-i28

Department of Biomedical Engineering, Cardiovascular Research Institute Maastricht, Maastricht University, PO Box 616, 6200 MD Maastricht, Netherlands.

Aims: The irregular atrial electrical activity during atrial fibrillation (AF) is associated with a variable left ventricular (LV) systolic function. The mechanisms determining LV function during AF remain incompletely understood. We aimed at elucidating how changes in RR-interval and LV preload affect LV function during AF.

Methods And Results: Beat-to-beat speckle-tracking echocardiography was performed in 10 persistent AF patients. We evaluated the relation between longitudinal LV peak strain and preceding RR-interval during AF. We used the CircAdapt computational model to evaluate beat-to-beat preload and peak strain during AF for each patient by imposing the patient-specific RR-interval sequences and a non-contractile atrial myocardium. Generic simulations with artificial RR-interval sequences quantified the haemodynamic changes induced by sudden irregular beats. Clinical data and simulations both showed a larger sensitivity of peak strain to changes in preceding RR-interval at slow heart rate (HR) (cycle length, CL <750 ms) than at faster HR. Simulations explained this by a difference in preload of the current beat. Generic simulations confirmed a larger sensitivity of peak strain to preceding RR-interval at fast HR (CL = 600 ms: Δ peak strain = 3.7% vs. 900 ms: Δ peak strain = 0.3%) as in the patients. They suggested that longer LV activation with respect to preceding RR-interval is determinant for this sensitivity.

Conclusions: During AF, longitudinal LV peak strain is highly variable, particularly at fast HR. Beat-to-beat changes in preload explain the differences in LV systolic function. Simulations revealed that a reduced diastolic LV filling time can explain the increased variability at fast HR.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/europace/euaa387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7943365PMC
March 2021

Non-extensitivity and criticality of atomic hydropathicity around a voltage-gated sodium channel's pore: a modeling study.

J Biol Phys 2021 Mar 18;47(1):61-77. Epub 2021 Mar 18.

Department of Data Science and Knowledge Engineering, Maastricht University, PO Box 616, 6200 MD, Maastricht, The Netherlands.

Voltage-gated sodium channels (NavChs) are pore-forming membrane proteins that regulate the transport of sodium ions through the cell membrane. Understanding the structure and function of NavChs is of major biophysical, as well as clinical, importance given their key role in cellular pathophysiology. In this work, we provide a computational framework for modeling system-size-dependent, i.e., cumulative, atomic properties around a NavCh's pore. We illustrate our methodologies on the bacterial NavAb channel captured in a closed-pore state where we demonstrate that the atomic environment around its pore exhibits a bi-phasic spatial organization dictated by the structural separation of the pore domains (PDs) from the voltage-sensing domains (VSDs). Accordingly, a mathematical model describing packing of atoms around NavAb's pore is constructed that allows-under certain conservation conditions-for a power-law approximation of the cumulative hydropathic dipole field effect acting along NavAb's pore. This verified the non-extensitivity hypothesis for the closed-pore NavAb channel and revealed a long-range hydropathic interactions law regulating atom-packing around the NavAb's selectivity filter. Our model predicts a PDs-VSDs coupling energy of [Formula: see text] kcal/mol corresponding to a global maximum of the atom-packing energy profile. Crucially, we demonstrate for the first time how critical phenomena can emerge in a single-channel structure as a consequence of the non-extensive character of its atomic porous environment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10867-021-09565-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7981368PMC
March 2021

Association of low-voltage areas with the regional wall deformation and the left atrial shape in patients with atrial fibrillation: A proof of concept study.

Int J Cardiol Heart Vasc 2021 Apr 26;33:100730. Epub 2021 Feb 26.

University of Pittsburgh, Pittsburgh, PA, USA.

Background: Left atrium (LA) remodeling is associated with atrial fibrillation (AF) and reduced success after AF ablation, but its relation with low-voltage areas (LVA) is not known. This study aimed to evaluate the relation between regional LA changes and LVAs in AF patients.

Methods: Pre-interventional CT data of patients (n = 24) with LA-LVA (<0.5 mV) in voltage mapping after AF ablation were analyzed (Surgery Explorer, QuantMD LLC). To quantify asymmetry (ASI = LA-A/LAV) a cutting plane parallel to the rear wall and along the pulmonary veins divided the LA-volume (LAV) into anterior (LA-A) and posterior parts. To quantify sphericity (LAS = 1-R/S), a patient-specific best-fit LA sphere was created. The average radius (R) and the mean deviation (S) from this sphere were calculated. The average local deviation (D) was measured for the roof, posterior, septum, inferior septum, inferior-posterior and lateral walls.

Results: The roof, posterior and septal regions had negative local deviations. There was a correlation between roof and septum (r = 0.42, p = 0.04), lateral and inferior-posterior (r = 0.48, p = 0.02) as well as posterior and inferior-septal deviations (r = -0.41, p = 0.046). ASI correlated with septum deformation (r = -0.43, p = 0.04). LAS correlated with dilatation (LAV, r = 0.49, p = 0.02), roof (r = 0.52, p = 0.009) and posterior deformation (r = -0.56, p = 0.005). Extended LVA correlated with local deformation of all LA walls, except the roof and the septum. LVA association with LAV, ASI and LAS did not reach statistical significance.

Conclusion: Extended LVA correlates with local wall deformations better than other remodeling surrogates. Therefore, their calculation could help predict LVA presence and deserve further evaluation in clinical studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijcha.2021.100730DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933256PMC
April 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

Institute of Cardiovascular Sciences, University of Birmingham, UK.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/europace/euaa279DOI Listing
March 2021

Risk Factors for Atrial Fibrillation Progression.

Card Electrophysiol Clin 2021 03 8;13(1):201-209. Epub 2021 Jan 8.

Department of Cardiology, CARIM School for Cardiovascular Diseases, Maastricht University Medical Center+, PO Box 5800, Maastricht 6202 AZ, The Netherlands. Electronic address:

Atrial fibrillation is a chronic, progressive condition that presents a major health burden. This review summarizes recent studies assessing atrial fibrillation progression and its associated risk factors, describes the mechanisms underlying atrial fibrillation progression, and discusses the clinical implications of the progressive nature of atrial fibrillation. Progression of atrial fibrillation burden, and clinical progression from paroxysmal to more advanced (persistent/permanent) forms is common, but progression rates are variable. Atrial fibrillation progression parallels progressive atrial remodeling induced by atrial fibrillation risk factors and atrial fibrillation itself, and is associated with worse clinical outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ccep.2020.10.011DOI Listing
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 Jan 23. 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 Centre, University of Duisburg-Essen, Essen, Germany; IHU LIRYC and Fondation Bordeaux Université, Bordeaux, France. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

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

Caveolin3 Stabilizes McT1-Mediated Lactate/Proton Transport in Cardiomyocytes.

Circ Res 2021 Mar 25;128(6):e102-e120. Epub 2021 Jan 25.

Cellular Biophysics and Translational Cardiology Section, Heart Research Center Göttingen (J.P., D.K.-D., G.W., S.B., T.K., G.H., J.W., S.E.L.), University Medical Center Göttingen.

[Figure: see text].
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCRESAHA.119.316547DOI Listing
March 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCRESAHA.120.317768DOI Listing
December 2020

Left atrial activation and asymmetric anatomical remodeling in patients with atrial fibrillation: The relation between anatomy and function.

Clin Cardiol 2021 Jan 17;44(1):116-122. Epub 2020 Nov 17.

Department of Electrophysiology, Heart Center at University of Leipzig, Leipzig, Germany.

Background: Identifying patients with advanced left atrial (LA) remodeling before catheter ablation (CA) of atrial fibrillation (AF) is crucial.

Hypothesis: This study aimed to identify echocardiographic parameters associated with changes in anatomy and conduction properties of the left atrium (LA).

Methods: We examined 75 AF patients prior to CA and measured the intervals from the P-wave-onset to four mitral annulus sites by pulsed-wave tissue Doppler imaging (PW-TDI). Patients were grouped to an upward U-pattern (delayed anterior activation) and a downward D-pattern (earliest LA activation anterior). CT-data were used to measure the LA volume (LAV). LAV was divided into anterior- (LA-A) and posterior-parts by a plane, parallel to the posterior wall and between the veins and the appendage, to calculate the asymmetry index (ASI = LA-A/LAV).

Results: Patients with U-pattern (n = 66) had a higher ASI (65 ± 6 vs. 61 ± 3%, p = .014), older age (61 ± 11 vs. 51 ± 11 years, p = .03) and more diastolic dysfunction (71 vs. 22%, p = .008) Multivariate regression showed that age (OR 1.1 per year, CI 1.007-1.199) and diastolic dysfunction (OR 6.36, CI 1.132-35.7, p = .036) were independent predictors of the U-pattern. Diastolic dysfunction (B 4.49, CI 1.61-7.37, p = .003) was the only independent predictor of ASI in linear regression analysis.

Conclusion: AF patients with a U-pattern have an increased LA asymmetry. Diastolic dysfunction is a common cause of this LA activation and remodeling. Therefore, detection of a U-pattern signifies patients with advanced AF and may facilitate selection for an appropriate ablation strategy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/clc.23515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803371PMC
January 2021

Beta-Adrenergic Receptor Stimulation Modulates the Cellular Proarrhythmic Effects of Chloroquine and Azithromycin.

Front Physiol 2020 22;11:587709. Epub 2020 Oct 22.

Department of Cardiology, Cardiovascular Research Institute Maastricht (CARIM) School for Cardiovascular Diseases, Maastricht University, Maastricht, Netherlands.

The antimalarial drug, chloroquine (CQ), and antimicrobial drug, azithromycin (AZM), have received significant attention during the COVID-19 pandemic. Both drugs can alter cardiac electrophysiology and have been associated with drug-induced arrhythmias. Meanwhile, sympathetic activation is commonly observed during systemic inflammation and oxidative stress (e.g., in SARS-CoV-2 infection) and may influence the electrophysiological effects of CQ and AZM. Here, we investigated the effect of beta-adrenergic stimulation on proarrhythmic properties of CQ and AZM using detailed models of ventricular electrophysiology. Concentration-dependent alterations in ion-channel function were incorporated into the Heijman canine and O'Hara-Rudy human ventricular cardiomyocyte models. Single and combined drug effects on action-potential (AP) properties were analyzed using a population of 1,000 models accommodating inter-individual variability. Sympathetic stimulation was simulated by increasing pacing rate and experimentally validated isoproterenol (ISO)-induced changes in ion-channel function. In the canine ventricular model at 1 Hz pacing, therapeutic doses of CQ and AZM (5 and 20 μM, respectively) individually prolonged AP duration (APD) by 33 and 13%. Their combination produced synergistic APD prolongation (+161%) with incidence of proarrhythmic early afterdepolarizations in 53.5% of models. Increasing the pacing frequency to 2 Hz shortened APD and together with 1 μM ISO counteracted the drug-induced APD prolongation. No afterdepolarizations occurred following increased rate and simulated application of ISO. Similarly, CQ and AZM individually prolonged APD by 43 and 29% in the human ventricular cardiomyocyte model, while their combination prolonged APD by 76% without causing early afterdepolarizations. Consistently, 1 μM ISO at 2 Hz pacing counteracted the drug-induced APD prolongation. Increasing the I window current produced afterdepolarizations, which were exacerbated by ISO. In both models, reduced extracellular K reduced the repolarization reserve and increased drug effects. In conclusion, CQ- and AZM-induced proarrhythmia is promoted by conditions with reduced repolarization reserve. Sympathetic stimulation limits drug-induced APD prolongation, suggesting the potential importance of heart rate and autonomic status monitoring in particular conditions (e.g., COVID-19).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphys.2020.587709DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642988PMC
October 2020

A Novel Computational Model of the Rabbit Atrial Cardiomyocyte With Spatial Calcium Dynamics.

Front Physiol 2020 9;11:556156. Epub 2020 Oct 9.

Simula Research Laboratory, Computational Physiology Department, Lysaker, Norway.

Models of cardiac electrophysiology are widely used to supplement experimental results and to provide insight into mechanisms of cardiac function and pathology. The rabbit has been a particularly important animal model for studying mechanisms of atrial pathophysiology and atrial fibrillation, which has motivated the development of models for the rabbit atrial cardiomyocyte electrophysiology. Previously developed models include detailed representations of membrane currents and intracellular ionic concentrations, but these so-called "common-pool" models lack a spatially distributed description of the calcium handling system, which reflects the detailed ultrastructure likely found in cells . Because of the less well-developed T-tubular system in atrial compared to ventricular cardiomyocytes, spatial gradients in intracellular calcium concentrations may play a more significant role in atrial cardiomyocyte pathophysiology, rendering common-pool models less suitable for investigating underlying electrophysiological mechanisms. In this study, we developed a novel computational model of the rabbit atrial cardiomyocyte incorporating detailed compartmentalization of intracellular calcium dynamics, in addition to a description of membrane currents and intracellular processes. The spatial representation of calcium was based on dividing the intracellular space into eighteen different compartments in the transversal direction, each with separate systems for internal calcium storage and release, and tracking ionic fluxes between compartments in addition to the dynamics driven by membrane currents and calcium release. The model was parameterized employing a population-of-models approach using experimental data from different sources. The parameterization of this novel model resulted in a reduced population of models with inherent variability in calcium dynamics and electrophysiological properties, all of which fall within the range of observed experimental values. As such, the population of models may represent natural variability in cardiomyocyte electrophysiology or inherent uncertainty in the underlying experimental data. The ionic model population was also able to reproduce the U-shaped waveform observed in line-scans of triggered calcium waves in atrial cardiomyocytes, characteristic of the absence of T-tubules, resulting in a centripetal calcium wave due to subcellular calcium diffusion. This novel spatial model of the rabbit atrial cardiomyocyte can be used to integrate experimental findings, offering the potential to enhance our understanding of the pathophysiological role of calcium-handling abnormalities under diseased conditions, such as atrial fibrillation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphys.2020.556156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583320PMC
October 2020

Dynamics of Atrial Fibrillation Mechanisms and Comorbidities.

Annu Rev Physiol 2021 02 16;83:83-106. Epub 2020 Oct 16.

Department of Cardiology, Cardiovascular Research Institute Maastricht, Maastricht University, 6200 MD Maastricht, The Netherlands; email:

Atrial fibrillation (AF) contributes to morbidity and mortality of millions of individuals. Its molecular, cellular, neurohumoral, and hemodynamic pathophysiological mechanisms are complex, and there is increasing awareness that a wide range of comorbidities can contribute to AF-promoting atrial remodeling. Moreover, recent research has highlighted that AF risk is not constant and that the temporal variation in concomitant conditions contributes to the complexity of AF dynamics. In this review, we provide an overview of fundamental AF mechanisms related to established and emerging comorbidities or risk factors and their role in the AF-promoting effects. We focus on the accumulating evidence for the relevance of temporally dynamic changes in these risk factors and the consequence for AF initiation and maintenance. Finally, we highlight the important implications for future research and clinical practice resulting from the dynamic interaction between AF risk factors and mechanisms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1146/annurev-physiol-031720-085307DOI Listing
February 2021

The ESC Working Group Cardiac Cellular Electrophysiology.

Eur Heart J 2020 12;41(46):4374-4376

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

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/eurheartj/ehaa646DOI Listing
December 2020

QTc evaluation in patients with bundle branch block.

Int J Cardiol Heart Vasc 2020 Oct 19;30:100636. Epub 2020 Sep 19.

Department of Cardiology, Maastricht University Medical Center (MUMC+) and Cardiovascular Research Institute Maastricht (CARIM), Maastricht, the Netherlands.

Proper measurement of the QT interval on the 12-lead body-surface ECG is challenging in daily practice. Even more difficult is its correct estimation in the presence of repolarization abnormalities, arrhythmias or bundle-branch blocks (BBB). The QT interval results from two parts of the ECG: (1) the QRS complex, describing the excitation of the ventricles and (2) the JT interval, describing the repolarisation of the ventricles. Prolongation of the QRS width - like in the presence of BBB - entails prolongation of the QT interval, making the estimation of the true repolarisation time challenging. The US recommendations for the standardization and interpretation of the ECG suggest focusing on the JT interval in presence of BBB. However, in clinical practice physicians have become more familiar with the interpretation of QT-interval measurements than with the interpretation of the JT Interval. In the last decade, a simple formula for the estimation of the "modified QT interval" in the presence of left or right BBB has been developed and evaluated. In this formula, the modified QT interval is calculated by subtracting 50% of the length of the BBB-QRS from the measured QT interval (QT = QT - 50% QRS). Subsequently, rate-correction formula should be applied as usual. In this review, we discuss the determination of the QT-interval in the presence of BBB and summarize the origin and application of the modified QT-interval formula.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijcha.2020.100636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7509006PMC
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.

View Article and Find Full Text PDF

Download full-text PDF

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

Repolarization instability and arrhythmia by IKr block in single human-induced pluripotent stem cell-derived cardiomyocytes and 2D monolayers.

Europace 2020 09;22(9):1431-1441

Department of Cardiology, CARIM, Maastricht University Medical Center+, PO Box 5800, 6202 AZ Maastricht, The Netherlands.

Aims: Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have proven valuable for studies in drug discovery and safety, although limitations regarding their structural and electrophysiological characteristics persist. In this study, we investigated the electrophysiological properties of Pluricyte® CMs, a commercially available hiPSC-CMs line with a ventricular phenotype, and assessed arrhythmia incidence by IKr block at the single-cell and 2D monolayer level.

Methods And Results: Action potentials were measured at different pacing frequencies, using dynamic clamp. Through voltage-clamp experiments, we determined the properties of INa, IKr, and ICaL. Intracellular Ca2+ measurements included Ca2+-transients at baseline and during caffeine perfusion. Effects of IKr block were assessed in single hiPSC-CMs and 2D monolayers (multi-electrode arrays). Action-potential duration (APD) and its rate dependence in Pluricyte® CMs were comparable to those reported for native human CMs. INa, IKr, and ICaL revealed amplitudes, kinetics, and voltage dependence of activation/inactivation similar to other hiPSC-CM lines and, to some extent, to native CMs. Near-physiological Ca2+-induced Ca2+ release, response to caffeine and excitation-contraction coupling gain characterized the cellular Ca2+-handling. Dofetilide prolonged the APD and field-potential duration, and induced early afterdepolarizations. Beat-to-beat variability of repolarization duration increased significantly before the first arrhythmic events in single Pluricyte® CMs and 2D monolayers, and predicted pending arrhythmias better than action-potential prolongation.

Conclusion: Taking their ion-current characteristics and Ca2+ handling into account, Pluricyte® CMs are suitable for in vitro studies on action potentials and field potentials. Beat-to-beat variability of repolarization duration proved useful to evaluate the dynamics of repolarization instability and demonstrated its significance as proarrhythmic marker in hiPSC-CMs during IKr block.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/europace/euaa111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7478319PMC
September 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCRESAHA.120.316710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7604886PMC
September 2020

Differentiating the effects of β-adrenergic stimulation and stretch on calcium and force dynamics using a novel electromechanical cardiomyocyte model.

Am J Physiol Heart Circ Physiol 2020 09 31;319(3):H519-H530. Epub 2020 Jul 31.

Department of Biomedical Engineering, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands.

Cardiac electrophysiology and mechanics are strongly interconnected. Calcium is crucial in this complex interplay through its role in cellular electrophysiology and sarcomere contraction. We aim to differentiate the effects of acute β-adrenergic stimulation (β-ARS) and cardiomyocyte stretch (increased sarcomere length) on calcium-transient dynamics and force generation, using a novel computational model of cardiac electromechanics. We implemented a bidirectional coupling between the O'Hara-Rudy model of human ventricular electrophysiology and the MechChem model of sarcomere mechanics through the buffering of calcium by troponin. The coupled model was validated using experimental data from large mammals or human samples. Calcium transient and force were simulated for various degrees of β-ARS and initial sarcomere lengths. The model reproduced force-frequency, quick-release, and isotonic contraction experiments, validating the bidirectional electromechanical interactions. An increase in β-ARS increased the amplitudes of force (augmented inotropy) and calcium transient, and shortened both force and calcium-transient duration (lusitropy). An increase in sarcomere length increased force amplitude even more, but decreased calcium-transient amplitude and increased both force and calcium-transient duration. Finally, a gradient in relaxation along the thin filament may explain the nonmonotonic decay in cytosolic calcium observed with high tension. Using a novel coupled human electromechanical model, we identified differential effects of β-ARS and stretch on calcium and force. Stretch mostly contributed to increased force amplitude and β-ARS to the reduction of calcium and force duration. We showed that their combination, rather than individual contributions, is key to ensure force generation, rapid relaxation, and low diastolic calcium levels. This work identifies the contribution of electrical and mechanical alterations to regulation of calcium and force under exercise-like conditions using a novel human electromechanical model integrating ventricular electrophysiology and sarcomere mechanics. By better understanding their individual and combined effects, this can uncover arrhythmogenic mechanisms in exercise-like situations. This publicly available model is a crucial step toward understanding the complex interplay between cardiac electrophysiology and mechanics to improve arrhythmia risk prediction and treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1152/ajpheart.00275.2020DOI Listing
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.yjmcc.2020.07.007DOI Listing
September 2020

MINOCA: The caveat of absence of coronary obstruction in myocardial infarction.

Int J Cardiol Heart Vasc 2020 Aug 1;29:100572. Epub 2020 Jul 1.

Department of Cardiology, Maastricht University Medical Centre, Maastricht, the Netherlands.

Aims: Whether patients with MINOCA (myocardial infarction with non-obstructive coronary arteries) have better outcomes than patients with obstructive coronary artery disease remains contradictory. The current study focussed on the clinical profile and prognosis of MINOCA patients.

Methods And Results: We performed a retrospective analysis of patients with acute coronary syndrome (ACS) admitted to the Isala hospital in Zwolle, the Netherlands, between 2006 and 2014. A total of 7693 patients were categorized into three groups: MINOCA, single-vessel obstructive ACS (SV-ACS), and multi-vessel obstructive ACS (MV-ACS). MINOCA patients (5.2% of the total population) were more likely to be female (51.5% vs. 30.3% and 26.0% in SV-ACS and MV-ACS, respectively, p < 0.001 for both). The prevalence of risk factors in the MINOCA group was in between the SV-ACS and MV-ACS groups. Logistic regression revealed a lower odds of dying in SV-ACS (odds ratio (OR) = 0.70 (p = 0.04)) and a similar odds in MV-ACS (OR = 0.88, p = 0.45) compared to MINOCA.

Conclusions: Patients with MINOCA show an 'intermediate' risk profile with mortality rates in between those of both ACS groups. Hence, MINOCA should be recognised as a potential risk factor for mortality, requiring adequate treatment and follow-up.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijcha.2020.100572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334364PMC
August 2020

Cumulative hydropathic topology of a voltage-gated sodium channel at atomic resolution.

Proteins 2020 10 13;88(10):1319-1328. Epub 2020 Jun 13.

Department of Genetics and Cell Biology, Section Clinical Genomics, Maastricht University, Maastricht, the Netherlands.

Voltage-gated sodium channels (NavChs) are biological pores that control the flow of sodium ions through the cell membrane. In humans, mutations in genes encoding NavChs can disrupt physiological cellular activity thus leading to a wide spectrum of diseases. Here, we present a topological connection between the functional architecture of a NavAb bacterial channel and accumulation of atomic hydropathicity around its pore. This connection is established via a scaling analysis methodology that elucidates how intrachannel hydropathic density variations translate into hydropathic dipole field configurations along the pore. Our findings suggest the existence of a nonrandom cumulative hydropathic topology that is organized parallel to the membrane surface so that pore's stability, as well as, gating behavior are guaranteed. Given the biophysical significance of the hydropathic effect, our study seeks to provide a computational framework for studying cumulative hydropathic topological properties of NavChs and pore-forming proteins in general.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/prot.25951DOI Listing
October 2020

Sleep Apnea, Intermittent Hypoxemia, and Effects on Ischemic Myocardial Damage: Friend or Foe?

Can J Cardiol 2020 06 22;36(6):809-812. Epub 2020 Feb 22.

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

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cjca.2020.02.075DOI Listing
June 2020

Cardiomyocyte calcium handling in health and disease: Insights from in vitro and in silico studies.

Prog Biophys Mol Biol 2020 11 15;157:54-75. Epub 2020 Mar 15.

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

Calcium (Ca) plays a central role in cardiomyocyte excitation-contraction coupling. To ensure an optimal electrical impulse propagation and cardiac contraction, Ca levels are regulated by a variety of Ca-handling proteins. In turn, Ca modulates numerous electrophysiological processes. Accordingly, Ca-handling abnormalities can promote cardiac arrhythmias via various mechanisms, including the promotion of afterdepolarizations, ion-channel modulation and structural remodeling. In the last 30 years, significant improvements have been made in the computational modeling of cardiomyocyte Ca handling under physiological and pathological conditions. However, numerous questions involving the Ca-dependent regulation of different macromolecular complexes, cross-talk between Ca-dependent regulatory pathways operating over a wide range of time scales, and bidirectional interactions between electrophysiology and mechanics remain to be addressed by in vitro and in silico studies. A better understanding of disease-specific Ca-dependent proarrhythmic mechanisms may facilitate the development of improved therapeutic strategies. In this review, we describe the fundamental mechanisms of cardiomyocyte Ca handling in health and disease, and provide an overview of currently available computational models for cardiomyocyte Ca handling. Finally, we discuss important uncertainties and open questions about cardiomyocyte Ca handling and highlight how synergy between in vitro and in silico studies may help to answer several of these issues.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pbiomolbio.2020.02.008DOI Listing
November 2020

Both Prediabetes and Type 2 Diabetes Are Associated With Lower Heart Rate Variability: The Maastricht Study.

Diabetes Care 2020 05 11;43(5):1126-1133. Epub 2020 Mar 11.

CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, the Netherlands

Objective: Low heart rate variability (HRV), a marker for cardiac autonomic dysfunction, is a known feature of type 2 diabetes, but it remains incompletely understood whether this also applies to prediabetes or across the whole glycemic spectrum. Therefore, we investigated the association among prediabetes, type 2 diabetes, and measures of glycemia and HRV.

Research Design And Methods: In the population-based Maastricht Study ( = 2,107; mean ± SD age 59 ± 8 years; 52% men; normal glucose metabolism [ = 1,226], prediabetes [ = 331], and type 2 diabetes [ = 550, oversampled]), we determined 24-h electrocardiogram-derived HRV in time and frequency domains (individual -scores, based upon seven and six variables, respectively). We used linear regression with adjustments for age, sex, and major cardiovascular risk factors.

Results: After adjustments, both time and frequency domain HRV were lower in prediabetes and type 2 diabetes as compared with normal glucose metabolism (standardized β [95% CI] for time domain: -0.15 [-0.27; -0.03] and -0.34 [-0.46; -0.22], respectively, for trend <0.001; for frequency domain: -0.14 [-0.26; -0.02] and -0.31 [-0.43; -0.19], respectively, for trend <0.001). In addition, 1-SD higher glycated hemoglobin, fasting plasma glucose, and 2-h postload glucose were associated with lower HRV in both domains (time domain: -0.16 [-0.21; -0.12], -0.16 [-0.21; -0.12], and -0.15 [-0.20; -0.10], respectively; frequency domain: -0.14 [-0.19; -0.10], -0.14 [-0.18; -0.09], and -0.13 [-0.18; -0.08], respectively).

Conclusions: Both prediabetes and type 2 diabetes were independently associated with lower HRV. This is further substantiated by independent continuous associations between measures of hyperglycemia and lower HRV. These data strongly suggest that cardiac autonomic dysfunction is already present in prediabetes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2337/dc19-2367DOI Listing
May 2020