Publications by authors named "Ulrich Schotten"

197 Publications

Association between comorbidities and left and right atrial dysfunction in patients with paroxysmal atrial fibrillation: Analysis of AF-RISK.

Int J Cardiol 2022 May 23. Epub 2022 May 23.

CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht University Medical Center, Maastricht, the Netherlands.; Department of Cardiology, Maastricht University, Maastricht University Medical Center, Maastricht, the Netherlands.; Department of Cardiology, Radboud University Medical Centre, Nijmegen, the Netherlands.; Centre for Heart Rhythm Disorders, University of Adelaide and Royal Adelaide Hospital, Adelaide, Australia.; Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.. Electronic address:

Background: To identify the association between comorbidities and left atrial (LA) and right atrial (RA) function in patients with paroxysmal atrial fibrillation (AF).

Methods: This is a cross-sectional study. Speckle-tracking echocardiography was performed in 344 patients with paroxysmal AF at baseline, and available in 298 patients after 1-year follow-up. The number of comorbidities (hypertension, diabetes mellitus, coronary artery disease, body mass index >25 kg/m, age > 65 years, moderate to severe mitral valve regurgitation and kidney dysfunction (estimated glomerular filtration rate < 60 ml/min/1.73m)) was determined and the association with atrial strain was tested.

Results: Mean age of the patients was 58 (SD 12) years and 137 patients were women (40%). Patients with a higher number of comorbidities had larger LA volumes (p for trend <0.001), and had a decrease in all strain phases from the LA and RA, except for the RA contraction phase (p for trend 0.47). A higher number of comorbidities was associated with LA reservoir and conduit strain decrease independently of LA or RA volumes (p < 0.001, p < 0.001 respectively). Patients with 1-2 comorbidities, but not patients with 3 or more comorbidities, showed a further progression of impaired LA and RA function in almost all atrial strain phases at 14 (Heijman et al., 2021; Kirchhof et al., 2020; Vieira et al., 2014; Ramkumar et al., 2017; Greiser et al., 2009 [13-17]) months follow-up.

Conclusions: In patients with paroxysmal AF, individual and combined comorbidities are related to lower LA and RA strain. In patients with few comorbidities, impairment in atrial function progresses during one year of follow-up. Whether comorbidity management prevents or reverses decrease in atrial function warrants further study.
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http://dx.doi.org/10.1016/j.ijcard.2022.05.044DOI Listing
May 2022

Remote Design of a Smartphone and Wearable Detected Atrial Arrhythmia in Older Adults Case Finding Study: Smart in OAC - AFNET 9.

Front Cardiovasc Med 2022 21;9:839202. Epub 2022 Mar 21.

Department of Cardiology, University Heart and Vascular Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Introduction: Screening for atrial fibrillation and timely initiation of oral anticoagulation, rhythm management, and treatment of concomitant cardiovascular conditions can improve outcomes in high-risk populations. Whether wearables can facilitate screening in older adults is not known.

Methods And Analyses: The multicenter, international, investigator-initiated, single-arm case-finding Smartphone and wearable detected atrial arrhythmia in older adults case finding study (Smart in OAC - AFNET 9) evaluates the diagnostic yield of a validated, cloud-based analysis algorithm detecting atrial arrhythmias via a signal acquired by a smartphone-coupled wristband monitoring system in older adults. Unselected participants aged ≥65 years without known atrial fibrillation and not receiving oral anticoagulation are enrolled in three European countries. Participants undergo continuous pulse monitoring using a wristband with a photo plethysmography (PPG) sensor and a telecare analytic service. Participants with PPG-detected atrial arrhythmias will be offered ECG loop monitoring. The study has a virtual design with digital consent and teleconsultations, whilst including hybrid solutions. Primary outcome is the proportion of older adults with newly detected atrial arrhythmias (NCT04579159).

Discussion: Smart in OAC - AFNET 9 will provide information on wearable-based screening for PPG-detected atrial arrhythmias in Europe and provide an estimate of the prevalence of atrial arrhythmias in an unselected population of older adults.
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http://dx.doi.org/10.3389/fcvm.2022.839202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8977585PMC
March 2022

A Novel Laser Energy Ablation Catheter for Endocardial Cavo-Tricuspid Isthmus Ablation and Epicardial Ventricular Lesion Formation: An Proof-of-Concept Study.

Front Med Technol 2022 21;4:834856. Epub 2022 Mar 21.

Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University, Aachen, Germany.

Aim: This proof-of-concept study aimed to investigate atrial and ventricular lesion formation by a 20-mm linear laser ablation catheter, regarding lesion depth and tissue damage.

Methods: In total, 6 female swines underwent standard femoral vein access to introduce a novel 20-mm linear laser ablation catheter in the right atrium to perform endocardial cavotricuspid isthmus (CTI) ablations. The navigation took place under fluoroscopy with additional visualization by intracardiac echocardiograph. a sternotomy, epicardial ablations were performed on the surface of the left ventricle (LV), right ventricle (RV), and right atrial appendage (RAA). Procedural safety was assessed by registration of intraprocedural adverse events and by macroscopic examination of the excised hearts for the presence of charring or tissue disruption at the lesion site.

Results: Altogether 39 lesions were created, including 8 endocardial CTI (mean lesion length 20.6 ± 1.65 mm), 26 epicardial ventricle (mean lesion length LV: 25.3 ± 1.35 mm, RV: 24.9 ± 2.40 mm), and 5 epicardial appendage ablations (mean lesion length RAA: 26.0 ± 3.16 mm). Transmurality was achieved in all CTI and atrial appendage ablations, in 62% of the RV ablations and in none of the LV ablations. No perforation or steam pop occurred, and no animal died during the procedure.

Conclusion: In this porcine study, the 20-mm linear laser ablation catheter has shown excellent results for endocardial cavotricuspid isthmus ablation, and it resulted in acceptable lesion depth during atrial and ventricular epicardial ablation. The absence of tissue charring, steam pops, or microbubbles under the experimental conditions suggests a high degree of procedural safety.
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http://dx.doi.org/10.3389/fmedt.2022.834856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8979165PMC
March 2022

Endomysial fibrosis, rather than overall connective tissue content, is the main determinant of conduction disturbances in human atrial fibrillation.

Europace 2022 Mar 28. Epub 2022 Mar 28.

Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands.

Aims: Although in persistent atrial fibrillation (AF) a complex AF substrate characterized by a high incidence of conduction block has been reported, relatively little is known about AF complexity in paroxysmal AF (pAF). Also, the relative contribution of various aspects of structural alterations to conduction disturbances is not clear. In particular, the contribution of endomysial fibrosis to conduction disturbances during progression of AF has not been studied yet.

Methods And Results: During cardiac surgery, epicardial high-density mapping was performed in patients with acutely induced (aAF, n = 11), pAF (n = 12), and longstanding persistent AF (persAF, n = 9) on the right atrial (RA) wall, the posterior left atrial wall (pLA) and the LA appendage (LAA). In RA appendages, overall and endomysial (myocyte-to-myocyte distances) fibrosis and connexin 43 (Cx43) distribution were quantified. Unipolar AF electrogram analysis showed a more complex pattern with a larger number of narrower waves, more breakthroughs and a higher fractionation index (FI) in persAF compared with aAF and pAF, with no differences between aAF and pAF. The FI was consistently higher at the pLA compared with the RA. Structurally, Cx43 lateralization increased with AF progression (aAF = 7.5 ± 8.9%, pAF = 24.7 ± 11.1%, persAF = 35.1 ± 11.4%, P < 0.001). Endomysial but not overall fibrosis correlated with AF complexity (r = 0.57, P = 0.001; r = 0.23, P = 0.20; respectively).

Conclusions: Atrial fibrillation complexity is highly variable in patients with pAF, but not significantly higher than in patients with acutely induced AF, while in patients with persistent AF complexity is higher. Among the structural alterations studied, endomysial fibrosis, but not overall fibrosis, is the strongest determinant of AF complexity.
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http://dx.doi.org/10.1093/europace/euac026DOI Listing
March 2022

Extended ECG Improves Classification of Paroxysmal and Persistent Atrial Fibrillation Based on P- and f-Waves.

Front Physiol 2022 4;13:779826. Epub 2022 Mar 4.

Cardiovascular Research Institute Maastricht (CARIM), Physiology, Maastricht, Netherlands.

Background: The standard 12-lead ECG has been shown to be of value in characterizing atrial conduction properties. The added value of extended ECG recordings (longer recordings from more sites) has not been systematically explored yet.

Objective: The aim of this study is to employ an extended ECG to identify characteristics of atrial electrical activity related to paroxysmal vs. persistent atrial fibrillation (AF).

Methods: In 247 participants scheduled for AF ablation, an extended ECG was recorded (12 standard plus 3 additional leads, 5 min recording, no filtering). For patients presenting in sinus rhythm (SR), the signal-averaged P-wave and the spatiotemporal P-wave variability was analyzed. For patients presenting in AF, f-wave properties in the QRST (the amplitude complex of the ventricular electrical activity: Q-, R-, S-, and T-wave)-canceled ECG were determined.

Results: Significant differences between paroxysmal ( = 152) and persistent patients with AF ( = 95) were found in several P-wave and f-wave parameters, including parameters that can only be calculated from an extended ECG. Furthermore, a moderate, but significant correlation was found between echocardiographic parameters and P-wave and f-wave parameters. There was a moderate correlation of left atrial (LA) diameter with P-wave energy duration ( = 0.317, < 0.001) and f-wave amplitude in lead A3 ( = -0.389, = 0.002). The AF-type classification performance significantly improved when parameters calculated from the extended ECG were taken into account [area under the curve (AUC) = 0.58, interquartile range (IQR) 0.50-0.64 for standard ECG parameters only vs. AUC = 0.76, IQR 0.70-0.80 for extended ECG parameters, < 0.001].

Conclusion: The P- and f-wave analysis of extended ECG configurations identified specific ECG features allowing improved classification of paroxysmal vs. persistent AF. The extended ECG significantly improved AF-type classification in our analyzed data as compared to a standard 10-s 12-lead ECG. Whether this can result in a better clinical AF type classification warrants further prospective study.
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http://dx.doi.org/10.3389/fphys.2022.779826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8931504PMC
March 2022

Cardiac chamber-specific genetic alterations suggest candidate genes and pathways implicating the left ventricle in the pathogenesis of atrial fibrillation.

Genomics 2022 03 24;114(2):110320. Epub 2022 Feb 24.

Department of Genetic Epidemiology, Institute of Human Genetics, University of Münster, Münster, Germany; Department of Biochemistry, Genetic Epidemiology and Statistical Genetics, CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, the Netherlands. Electronic address:

It is believed that the atria play a predominant role in the initiation and maintenance of atrial fibrillation (AF), while the role of left ventricular dysfunction in the pathophysiology remains enigmatic. We sought to dissect chamber specificity of AF-associated transcriptional changes using RNA-sequencing. We performed intra- and inter-chamber differential expression analyses comparing AF against sinus rhythm to identify genes specifically dysregulated in human left atria, right atria, and left ventricle (LV), and integrated known AF genetic associations with expression quantitative trait loci datasets to inform the potential for disease causal contributions within each chamber. Inter-chamber patterns changed drastically. Vast AF-associated transcriptional changes specific to LV, enriched for biological pathway terms implicating mitochondrial function, developmental processes and immunity, were supported at the genetic level, but no major enrichments for candidate genes specific to the atria were found. Our observations suggest an active role of the LV in the pathogenesis of AF.
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http://dx.doi.org/10.1016/j.ygeno.2022.110320DOI Listing
March 2022

MRI-Detected Brain Lesions and Cognitive Function in Patients With Atrial Fibrillation Undergoing Left Atrial Catheter Ablation in the Randomized AXAFA-AFNET 5 Trial.

Circulation 2022 03 9;145(12):906-915. Epub 2022 Feb 9.

Atrial Fibrillation Network (AFNET), Münster, Germany (K.G.H., B.B., U.S., P.K.).

Background: We aimed to assess the prevalence of ischemic brain lesions detected by magnetic resonance imaging and their association with cognitive function 3 months after first-time ablation using continuous oral anticoagulation in patients with paroxysmal atrial fibrillation (AF).

Methods: We performed a prespecified analysis of the AXAFA-AFNET 5 trial (Anticoagulation Using the Direct Factor Xa Inhibitor Apixaban During Atrial Fibrillation Catheter Ablation: Comparison to Vitamin K Antagonist Therapy), which randomized 674 patients with AF 1:1 to uninterrupted apixaban or vitamin K antagonist therapy before first-time ablation. Brain magnetic resonance imaging using fluid-attenuated inversion recovery and high-resolution diffusion-weighted imaging was obtained within 3 to 48 hours after AF ablation in all eligible patients enrolled in 25 study centers in Europe and the United States. Patients underwent cognitive assessment 3 to 6 weeks before ablation and 3 months after ablation using the Montreal Cognitive Assessment (MoCA).

Results: In 84 (26.1%) of 321 patients with analyzable magnetic resonance imaging, high-resolution diffusion-weighted imaging detected at least 1 acute brain lesion, including 44 (27.2%) patients treated with apixaban and 40 (24.8%) patients treated with vitamin K antagonist (=0.675). Median MoCA score was similar in patients with or without acute brain lesions at 3 months after ablation (28 [interquartile range (IQR), 26-29] versus 28 [IQR, 26-29]; =0.948). Cerebral chronic white matter damage (defined as Wahlund score ≥4 points) detected by fluid-attenuated inversion recovery was present in 130 (40.5%) patients and associated with lower median MoCA scores before ablation (27 [IQR, 24-28] versus 27 [IQR, 25-29]; =0.026) and 3 months after ablation (27 [IQR, 25-29] versus 28 [IQR, 26-29]; =0.011). This association was no longer significant when adjusted for age and sex. Age was associated with lower MoCA scores before ablation (relative risk, 1.02 per 10 years [95% CI, 1.01-1.03]) and 3 months after ablation (relative risk, 1.02 per 10 years [95% CI, 1.01-1.03]).

Conclusions: Chronic white matter damage as well as acute ischemic lesions detected by brain magnetic resonance imaging were found frequently after first-time ablation for paroxysmal AF using uninterrupted oral anticoagulation. Acute ischemic brain lesions detected by high-resolution diffusion-weighted imaging were not associated with cognitive function at 3 months after ablation. Lower MoCA scores before and after ablation were associated only with older age, highlighting the safety of AF ablation on uninterrupted oral anticoagulation.

Registration: URL: https://www.

Clinicaltrials: gov; Unique identifier: NCT02227550.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.121.056320DOI Listing
March 2022

Animal models and animal-free innovations for cardiovascular research: current status and routes to be explored. Consensus document of the ESC working group on myocardial function and the ESC Working Group on Cellular Biology of the Heart.

Cardiovasc Res 2022 Jan 6. Epub 2022 Jan 6.

Université de Paris, INSERM, PARCC, Paris, F-75015 France.

Cardiovascular diseases represent a major cause of morbidity and mortality, necessitating research to improve diagnostics, and to discover and test novel preventive and curative therapies. All of which warrant experimental models that recapitulate human disease. The translation of basic science results to clinical practice is a challenging task. In particular for complex conditions such as cardiovascular diseases, which often result from multiple risk factors and co-morbidities. This difficulty might lead some individuals to question the value of animal research, citing the translational 'valley of death', which largely reflects the fact that studies in rodents are difficult to translate to humans. This is also influenced by the fact that new, human-derived in vitro models can recapitulate aspects of disease processes. However, it would be a mistake to think that animal models cannot provide a vital step in the translational pathway as they do provide important pathophysiological insights into disease mechanisms particularly on a organ and systemic level. While stem cell-derived human models have the potential to become key in testing toxicity and effectiveness of new drugs, we need to be realistic, and carefully validate all new human-like disease models. In this position paper, we highlight recent advances in trying to reduce the number of animals for cardiovascular research ranging from stem cell-derived models to in situ modelling of heart properties, bioinformatic models based on large datasets, and improved current animal models, which show clinically relevant characteristics observed in patients with a cardiovascular disease. We aim to provide a guide to help researchers in their experimental design to translate bench findings to clinical routine taking the replacement, reduction and refinement (3R) as a guiding concept.
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http://dx.doi.org/10.1093/cvr/cvab370DOI Listing
January 2022

New-onset perioperative atrial fibrillation in cardiac surgery patients: transient trouble or persistent problem?-Authors' reply.

Europace 2021 Dec 24. Epub 2021 Dec 24.

Department of Cardiothoracic Surgery, Heart and Vascular Centre Maastricht University Medical Centre, Professor Debyelaan 25, 6229 HX Maastricht, The Netherlands.

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http://dx.doi.org/10.1093/europace/euab317DOI Listing
December 2021

State Space Embedding of Atrial Electrograms to Detect Repetitive Conduction Patterns During Atrial Fibrillation.

Annu Int Conf IEEE Eng Med Biol Soc 2021 11;2021:508-511

Repetitive atrial conduction patterns are often observed during human atrial fibrillation (AF). Repetitive patterns may be associated with AF drivers such as focal and micro-reentrant mechanisms. Therefore, tools for repetitive activity detection are of great interest as they may allow to identify the leading electrophysiological AF mechanism in an individual patient. Recurrence plots (RP) are efficient tools for repetitive activity visualization. Construction of an RP requires embedding of epicardial atrial electrograms into a phase space. In this study, we compared the conventional Takens' embedding approach and three novel approaches based on a priori AF cycle length (AFCL) information. Approaches were bench-marked based on the similarity of the RPs they produce with a previously proposed technique, the sensitivity and specificity to detect the repetitive patterns, as well as the capability to estimate overall repetitive pattern prevalence. All techniques were applied to high-density epicardial direct contact mapping recordings in AF patients with paroxysmal AF (n=12) and persistent AF (n=9). Compared to a reference method the proposed novel techniques achieved significantly higher similarity and sensitivity values (p<0.01) than conventional embedding, in both paroxysmal and persistent patients. Moreover, estimated prevalences were robust against the various degrees of AF complexity present in the recordings.Clinical relevance- This study presents three novel approaches for detection of repetitive patterns of conduction during AF in atrial direct contact recordings, which may aid in the identification of the leading AF mechanism in an individual patient.
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http://dx.doi.org/10.1109/EMBC46164.2021.9630766DOI Listing
November 2021

Thrombin generation by calibrated automated thrombography in goat plasma: Optimization of an assay.

Res Pract Thromb Haemost 2021 Dec 21;5(8):e12620. Epub 2021 Nov 21.

Department of Biochemistry and Internal Medicine Cardiovascular Research Institute Maastricht Maastricht University Medical Center Maastricht The Netherlands.

The goat model of atrial fibrillation (AF) allows investigation of the effect of AF on coagulation. However, assays for goat plasma are not available from commercial sources. Calibrated automated thrombography (CAT) provides a global view of the coagulation profile by assessing thrombin generation (TG). We describe the customization of the CAT assay in goat platelet-poor plasma (PPP) and in factor Xa (FXa)-inhibitor-anticoagulated PPP. TG was initiated in the presence of phospholipids and either (a) PPP reagent, reagent low, or reagent high; (b) goat brain protein extraction (GBP); or (c) Russell's viper venom-factor X activator (RVV-X). Contact activation was assessed by adding corn trypsin inhibitor. Different concentrations of prothrombin complex concentrate (PCC) were used to determine the sensitivity of both the GBP and RVV-X method. To obtain FXa-inhibitor anticoagulated plasma, rivaroxaban was added to plasma. TG settings with human reagents were not suitable for goat plasma. TG triggered with GBP increased peak height and ETP values. Similarly, the RVV-X method produced comparable TG curves and was more sensitive to PCC titration. Finally, both methods were able to detect the decrease in clotting potential induced by FXa inhibition. This is the first study that reports the customization of the CAT assay for goats. The GBP and RVV-X methods were comparable in triggering TG in goat plasma. The RVV-X method seemed to better discriminate changes in TG curves due to increases in clotting potential as well as to FXa inhibition by rivaroxaban in goat plasma.
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http://dx.doi.org/10.1002/rth2.12620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8606030PMC
December 2021

Electrophysiological Consequences of Cardiac Fibrosis.

Cells 2021 11 18;10(11). Epub 2021 Nov 18.

Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, 6200 MD Maastricht, The Netherlands.

For both the atria and ventricles, fibrosis is generally recognized as one of the key determinants of conduction disturbances. By definition, fibrosis refers to an increased amount of fibrous tissue. However, fibrosis is not a singular entity. Various forms can be distinguished, that differ in distribution: replacement fibrosis, endomysial and perimysial fibrosis, and perivascular, endocardial, and epicardial fibrosis. These different forms typically result from diverging pathophysiological mechanisms and can have different consequences for conduction. The impact of fibrosis on propagation depends on exactly how the patterns of electrical connections between myocytes are altered. We will therefore first consider the normal patterns of electrical connections and their regional diversity as determinants of propagation. Subsequently, we will summarize current knowledge on how different forms of fibrosis lead to a loss of electrical connectivity in order to explain their effects on propagation and mechanisms of arrhythmogenesis, including ectopy, reentry, and alternans. Finally, we will discuss a histological quantification of fibrosis. Because of the different forms of fibrosis and their diverging effects on electrical propagation, the total amount of fibrosis is a poor indicator for the effect on conduction. Ideally, an assessment of cardiac fibrosis should exclude fibrous tissue that does not affect conduction and differentiate between the various types that do; in this article, we highlight practical solutions for histological analysis that meet these requirements.
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http://dx.doi.org/10.3390/cells10113220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8625398PMC
November 2021

Coagulation Factor Xa Induces Proinflammatory Responses in Cardiac Fibroblasts via Activation of Protease-Activated Receptor-1.

Cells 2021 10 30;10(11). Epub 2021 Oct 30.

Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, 6200 MD Maastricht, The Netherlands.

Coagulation factor (F) Xa induces proinflammatory responses through activation of protease-activated receptors (PARs). However, the effect of FXa on cardiac fibroblasts (CFs) and the contribution of PARs in FXa-induced cellular signalling in CF has not been fully characterised. To answer these questions, human and rat CFs were incubated with FXa (or TRAP-14, PAR-1 agonist). Gene expression of pro-fibrotic and proinflammatory markers was determined by qRT-PCR after 4 and 24 h. Gene silencing of (PAR-1) and (PAR-2) was achieved using siRNA. MCP-1 protein levels were measured by ELISA of FXa-conditioned media at 24 h. Cell proliferation was assessed after 24 h of incubation with FXa ± SCH79797 (PAR-1 antagonist). In rat CFs, FXa induced upregulation of (MCP-1; >30-fold at 4 h in atrial and ventricular CF) and (IL-6; ±7-fold at 4 h in ventricular CF). Increased MCP-1 protein levels were detected in FXa-conditioned media at 24 h. In human CF, FXa upregulated the gene expression of (>3-fold) and (>4-fold) at 4 h. Silencing of (PAR-1 gene), but not (PAR-2 gene), downregulated this effect. Selective activation of PAR-1 by TRAP-14 increased and gene expression; this was prevented by (PAR-1 gene) knockdown. Moreover, SCH79797 decreased FXa-induced proliferation after 24 h. In conclusion, our study shows that FXa induces overexpression of proinflammatory genes in human CFs via PAR-1, which was found to be the most abundant PARs isoform in this cell type.
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http://dx.doi.org/10.3390/cells10112958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8616524PMC
October 2021

Considerations for the Assessment of Substrates, Genetics and Risk Factors in Patients with Atrial Fibrillation.

Arrhythm Electrophysiol Rev 2021 Oct;10(3):132-139

Department of Physiology, Cardiovascular Research Institute Maastricht, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, the Netherlands.

Successful translation of research focussing on atrial arrhythmogenic mechanisms has potential to provide a mechanism-tailored classification and to support personalised treatment approaches in patients with AF. The clinical uptake and clinical implementation of new diagnostic techniques and treatment strategies require translational research approaches on various levels. Diagnostic translation involves the development of clinical diagnostic tools. Additionally, multidisciplinary teams are required for collaborative translation to describe genetic mechanisms, molecular pathways, electrophysiological characteristics and concomitant risk factors. In this article, current approaches for AF substrate characterisation, analysis of genes potentially involved in AF and strategies for AF risk factor assessment are summarised. The authors discuss challenges and obstacles to clinical translation and implementation into clinical practice.
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http://dx.doi.org/10.15420/aer.2020.51DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8576487PMC
October 2021

A VIRTUAL Sleep Apnoea management pathway For the work-up of Atrial fibrillation patients in a digital Remote Infrastructure: VIRTUAL-SAFARI.

Europace 2022 04;24(4):565-575

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

Aims: In atrial fibrillation (AF) patients, untreated sleep-disordered breathing (SDB) is associated with lower success rates of rhythm control strategies and as such structured SDB testing is recommended. Herein, we describe the implementation of a virtual SDB management pathway in an AF outpatient clinic and examine the utility and feasibility of this new approach.

Methods And Results: Prospectively, consecutive AF patients accepted for AF catheter ablation procedures without previous diagnosis of SDB were digitally referred to a virtual SDB management pathway and instructed to use WatchPAT-ONE (ITAMAR) for one night. Results were automatically transferred to a virtual sleep laboratory, upon which a teleconsultation with a sleep physician was planned. Patient experience was measured using surveys. SDB testing was performed in 119 consecutive patients scheduled for AF catheter ablation procedures. The median time from digital referral to finalization of the sleep study report was 18 [11-24] days. In total, 65 patients (55%) were diagnosed with moderate-to-severe SDB. Patients with SDB were prescribed more cardiovascular drugs and had higher body mass indices (BMI, 29 ± 3.3 vs. 27 ± 4.4kg/m2, P < 0.01). Patients agreed that WatchPAT-ONE was easy to use (91%) and recommended future use of this virtual pathway in AF outpatient clinics (86%). Based on this remote SDB testing, SDB treatment was recommended in the majority of patients.

Conclusion: This novel virtual AF management pathway allowed remote SDB testing in AF outpatient clinics with a short time to diagnosis and high patient satisfaction. Structured SDB testing results in a high detection of previously unknown SDB in AF patients scheduled for AF ablation.
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http://dx.doi.org/10.1093/europace/euab229DOI Listing
April 2022

Atrial function in paroxysmal AF patients with and without heart failure with preserved ejection fraction: Data from the AF-RISK study.

Am Heart J 2022 02 21;244:36-41. Epub 2021 Oct 21.

Department of Cardiolog, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands. Electronic address:

Atrial fibrillation (AF) and heart failure with preserved ejection fraction (HFpEF) are 2 cardiovascular conditions that often coexist. Strain phases of both the left and right atria are more impaired in paroxysmal AF patients with HFpEF than those without HFpEF in spite of comparable global longitudinal strain of the left ventricle. Atrial function may differentiate paroxysmal AF patients with HFpEF from those without HFpEF.
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http://dx.doi.org/10.1016/j.ahj.2021.10.183DOI Listing
February 2022

Clinical utility of rhythm control by electrical cardioversion to assess the association between self-reported symptoms and rhythm status in patients with persistent atrial fibrillation.

Int J Cardiol Heart Vasc 2021 Oct 15;36:100870. Epub 2021 Sep 15.

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

Background: The best strategy to assess the association between symptoms and rhythm status (symptom-rhythm correlation) in patients with atrial fibrillation (AF) remains unclear. We aimed to determine the clinical utility of rhythm control by electrical cardioversion (ECV) to assess symptom-rhythm correlation in patients with persistent AF.

Methods: We used ECV to examine symptom-rhythm correlation in 81 persistent AF patients. According to current clinical practice, the presence of self-reported symptoms before ECV and at the first outpatient clinic follow-up visit (within 1-month) was assessed to determine the prevalence of a symptom-rhythm correlation (defined as self-reported symptoms present during AF and absent in sinus rhythm or absent in AF and yet relief during sinus rhythm). In addition, we evaluated symptom patterns around ECV.

Results: Only in 18 patients (22%), a symptom-rhythm correlation could be documented. Twenty-eight patients (35%) did not show any symptom-rhythm correlation and 35 patients (43%) had an unevaluable symptom-rhythm correlation as these patients were in symptomatic AF both at baseline and at the first outpatient AF clinic follow-up visit. Importantly, self-reported symptom patterns around ECV were intra-individually variable in 10 patients (12%) without symptom-rhythm correlation (of which 9 patients (11%) had AF recurrence) and in 2 patients (2%) with an unevaluable symptom-rhythm correlation.

Conclusions: In patients with persistent AF, symptom assessment around rhythm control by ECV, once before ECV and once within 1-month follow-up, rarely identifies a symptom-rhythm correlation and often suggests changes in symptom pattern. Better strategies are needed to assess symptom-rhythm correlation in patients with persistent AF.
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http://dx.doi.org/10.1016/j.ijcha.2021.100870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8449169PMC
October 2021

Gut microbiota, dysbiosis and atrial fibrillation. Arrhythmogenic mechanisms and potential clinical implications.

Cardiovasc Res 2021 Sep 22. Epub 2021 Sep 22.

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

Recent preclinical and observational cohort studies have implicated imbalances in gut microbiota composition as a contributor to atrial fibrillation (AF). The gut microbiota is a complex and dynamic ecosystem containing trillions of microorganisms, which produces bioactive metabolites influencing host health and disease development. In addition to host-specific determinants, lifestyle-related factors such as diet and drugs are important determinants of the gut microbiota composition. In this review, we discuss the evidence suggesting a potential bidirectional association between AF and gut microbiota, identifying gut microbiota-derived metabolites as possible regulators of the AF substrate. We summarize the effect of gut microbiota on the development and progression of AF risk-factors, including heart failure, hypertension, obesity and coronary artery disease. We also discuss the potential antiarrhythmic effects of pharmacological and diet-induced modifications of gut microbiota composition, which may modulate and prevent the progression to AF. Finally, we highlight important gaps in knowledge and areas requiring future investigation. Although data supporting a direct relationship between gut microbiota and AF are very limited at the present time, emerging preclinical and clinical research dealing with mechanistic interactions between gut microbiota and AF is important as it may lead to new insights into AF pathophysiology and the discovery of novel therapeutic targets for AF.
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http://dx.doi.org/10.1093/cvr/cvab292DOI Listing
September 2021

Evolutionarily conserved transcriptional landscape of the heart defining the chamber specific physiology.

Genomics 2021 11 8;113(6):3782-3792. Epub 2021 Sep 8.

Institute of Human Genetics, Division of Genetic Epidemiology, University of Muenster, Muenster, Germany; Department of Biochemistry, Genetic Epidemiology and Statistical Genetics, CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, the Netherlands. Electronic address:

Cardiovascular disease (CVD) remains the leading cause of death worldwide. A deeper characterization of regional transcription patterns within different heart chambers may aid to improve our understanding of the molecular mechanisms involved in myocardial function and further, our ability to develop novel therapeutic strategies. Here, we used RNA sequencing to determine differentially expressed protein coding (PC) and long non-coding (lncRNA) transcripts within the heart chambers across seven vertebrate species and identified evolutionarily conserved chamber specific genes, lncRNAs and pathways. We investigated lncRNA homologs based on sequence, secondary structure, synteny and expressional conservation and found most lncRNAs to be conserved by synteny. Regional co-expression patterns of transcripts are modulated by multiple factors, including genomic overlap, strandedness and transcript biotype. Finally, we provide a community resource designated EvoACTG, which informs researchers on the conserved yet intertwined nature of the coding and non-coding cardiac transcriptome across popular model organisms in CVD research.
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http://dx.doi.org/10.1016/j.ygeno.2021.09.002DOI Listing
November 2021

Increased fibroblast accumulation in the equine heart following persistent atrial fibrillation.

Int J Cardiol Heart Vasc 2021 Aug 20;35:100842. Epub 2021 Jul 20.

Department of Veterinary Clinical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Agrovej 8, DK-2630 Taastrup, Denmark.

Background: Fibroblasts maintain the extracellular matrix homeostasis and may couple to cardiomyocytes through gap junctions and thereby increase the susceptibility to slow conduction and cardiac arrhythmias, such as atrial fibrillation (AF). In this study, we used an equine model of persistent AF to characterize structural changes and the role of fibroblasts in the development of an arrhythmogenic substrate for AF.

Material And Methods: Eleven horses were subjected to atrial tachypacing until self-sustained AF developed and were kept in AF for six weeks. Horses in sinus rhythm (SR) served as control. In terminal open-chest experiments conduction velocity (CV) was measured. Tissue was harvested and stained from selected sites. Automated image analysis was performed to assess fibrosis, fibroblasts, capillaries and various cardiomyocyte characteristics.

Results: Horses in SR showed a rate-dependent slowing of CV, while in horses with persistent AF this rate-dependency was completely abolished (CV•basic cycle length relation ). Overall and interstitial amounts of fibrosis were unchanged, but an increased fibroblast count was found in left atrial appendage, Bachmann's bundle, intraatrial septum and pulmonary veins ( for all) in horses with persistent AF. The percentage of α-SMA expressing fibroblasts remained the same between the groups.

Conclusion: Persistent AF resulted in fibroblast accumulation in several regions, particularly in the left atrial appendage. The increased number of fibroblasts could be a mediator of altered electrophysiology during AF. Targeting the fibroblast proliferation and differentiation could potentially serve as a novel therapeutic target slowing down the structural remodeling associated with AF.
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http://dx.doi.org/10.1016/j.ijcha.2021.100842DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8322305PMC
August 2021

Different circulating biomarkers in women and men with paroxysmal atrial fibrillation: results from the AF-RISK and RACE V studies.

Europace 2022 Feb;24(2):193-201

Department of Cardiology, University of Groningen, University Medical Centre Groningen, Groningen, Hanzeplein 1, 9713 GZ, The Netherlands.

Aims: The clinical risk profile of atrial fibrillation (AF) patients is different in men and women. Our aim was to identify sex differences in blood biomarkers in patients with paroxysmal AF.

Methods And Results: Sex differences in 92 blood biomarkers were measured in 364 patients included in our discovery cohort, the identification of a risk profile to guide atrial fibrillation therapy (AF-RISK) study, assessed by multivariable logistic regression and enrichment pathway analysis. Findings were subsequently confirmed in 213 patients included in our validation cohort, the Reappraisal of Atrial Fibrillation: Interaction between HyperCoagulability, Electrical remodelling, and Vascular Destabilisation in the Progression of AF (RACE V) study. In the discovery cohort, mean age was 59 ± 12 years, 41% were women. CHA2DS2-VASc-score was 1.6 ± 1.4. A total of 46% had hypertension, 10% diabetes, and 50% had heart failure, predominantly with preserved ejection fraction (47%). In women, activated leucocyte cell adhesion molecule (ALCAM) and fatty acid binding protein-4 (FABP-4) were higher. In men, matrix metalloproteinase-3 (MMP-3), C-C motif chemokine-16 (CCL-16), and myoglobin were higher. In the validation cohort, four out of five biomarkers could be confirmed: levels of ALCAM (P = 1.73 × 10-4) and FABP-4 (P = 2.46 × 10-7) and adhesion biological pathways [false discovery rate (FDR) = 1.23 × 10-8] were higher in women. In men, levels of MMP-3 (P = 4.31 × 10-8) and myoglobin (P = 2.10 × 10-4) and markers for extracellular matrix degradation biological pathways (FDR = 3.59 × 10-9) were higher.

Conclusion: In women with paroxysmal AF, inflammatory biomarkers were more often higher, while in men with paroxysmal AF, biomarkers for vascular remodelling were higher. Our data support the clinical notion that pathophysiological mechanisms in women and men with AF may differ.

Trial Registration: Clinicaltrials.gov identifier NCT01510210 for AF-RISK; Clinicaltrials.gov NCT02726698 for RACE V.
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http://dx.doi.org/10.1093/europace/euab179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8824515PMC
February 2022

Feasibility of digital atrial fibrillation screening in an elderly population : The Ulm heart rhythm weeks.

Herzschrittmacherther Elektrophysiol 2021 Sep 9;32(3):346-352. Epub 2021 Jul 9.

Kompetenznetz Vorhofflimmern e. V., Münster, Germany.

Aims: Atrial fibrillation (AF) screening in risk populations has the potential to prevent strokes. The authors tested the feasibility of a digital program with initial photoplethysmographic (PPG) self-screening and cardiologist-attended electrocardiographic (ECG) confirmation of screen-positive cases.

Methods: Inhabitants of the city of Ulm aged ≥ 65 years were invited to participate. After digital consent, participants were given access to a smartphone application for 14 days of self-screening (two recordings per day recommended). Screen-positive participants without known AF were invited to present to a cardiologist for AF confirmation with a 14-day ECG event recorder. PPG recordings were first analyzed by algorithm using a combination of linear and non-linear methods. The quality of pathological (classified by algorithm) PPG and all ECG recordings were checked by a telecare service. Primary outcomes included adherence to the screening protocol defined as the proportion of participants performing at least 14 PPG recordings (or until documentation of absolute arrhythmia) and the proportion of pathological PPG and all ECG recordings rejected by the telecare center.

Results: A total of 215 participants registered. Of these, 204 (95%) performed at least one recording and 169 (79%) reached the performance target of two sufficient measurements per day; 75 PPG recordings were automatically classified as pathological by algorithm; 14 (19%) were rejected by the telecare service due to poor quality. Of the 12 participants with a suspected first diagnosis of AF, five visited a cardiologist as part of the study. Of 1090 ECG recordings obtained, 390 (36%) were qualified as non-diagnostic. AF was confirmed in three cases.

Conclusions: A digital AF screening program with initial self-screening and referral of screen-positive cases to a cardiologist-attended ECG-confirmation service is feasible with meaningful results in an elderly risk population. However, the availability of the target population of persons > 65 years of age for such a digital screening program appears to be limited despite extensive public relations activities.
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http://dx.doi.org/10.1007/s00399-021-00783-2DOI Listing
September 2021

Clinical and electrophysiological predictors of device-detected new-onset atrial fibrillation during 3 years after cardiac surgery.

Europace 2021 Dec;23(12):1922-1930

Department of Physiology, Maastricht University, The Netherlands.

Aims: Postoperative atrial fibrillation (POAF) after cardiac surgery is an independent predictor of stroke and mortality late after discharge. We aimed to determine the burden and predictors of early (up to 5th postoperative day) and late (after 5th postoperative day) new-onset atrial fibrillation (AF) using implantable loop recorders (ILRs) in patients undergoing open chest cardiac surgery.

Methods And Results: Seventy-nine patients without a history of AF undergoing cardiac surgery underwent peri-operative high-resolution mapping of electrically induced AF and were followed 36 months after surgery using an ILR (Reveal XT™). Clinical and electrophysiological predictors of late POAF were assessed. POAF occurred in 46 patients (58%), with early POAF detected in 27 (34%) and late POAF in 37 patients (47%). Late POAF episodes were short-lasting (mostly between 2 min and 6 h) and showed a circadian rhythm pattern with a peak of episode initiation during daytime. In POAF patients, electrically induced AF showed more complex propagation patterns than in patients without POAF. Early POAF, right atrial (RA) volume, prolonged PR time, and advanced age were independent predictors of late POAF.

Conclusions: Late POAF occurred in 47% of patients without a history of AF. Patients who develop early POAF, with higher age, larger RA, or prolonged PR time have a higher risk of developing late POAF and may benefit from intensified rhythm follow-up after cardiac surgery.

Clinicaltrials.gov Number: NCT01530750.
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http://dx.doi.org/10.1093/europace/euab136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8651165PMC
December 2021

Corrected QT interval prolongation after ganglionated plexus ablation: myth or reality?-Authors' reply.

Europace 2021 12;23(12):2047-2048

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

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http://dx.doi.org/10.1093/europace/euab148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8651171PMC
December 2021

Does pulmonary vein isolation prolong QT-interval?- Authors' reply.

Europace 2021 12;23(12):2046-2047

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

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http://dx.doi.org/10.1093/europace/euab153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8651172PMC
December 2021

From translation to integration: how to approach the complexity of atrial fibrillation mechanisms.

Authors:
Ulrich Schotten

Cardiovasc Res 2021 06;117(7):e88-e90

Department of Physiology, Cardiovascular Research Institute Maastricht, PO Box 616, 6200 MD Maastricht, The Netherlands.

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http://dx.doi.org/10.1093/cvr/cvab168DOI Listing
June 2021

The relation between the atrial blood supply and the complexity of acute atrial fibrillation.

Int J Cardiol Heart Vasc 2021 Jun 19;34:100794. Epub 2021 May 19.

Maastricht University and Cardiovascular Research Institute Maastricht (CARIM), Department of Physiology, Universiteitssingel 50, 6229 ER Maastricht, the Netherlands.

Background: Patients with a history of myocardial infarction and coronary artery disease (CAD) have a higher risk of developing AF. Conversely, patients with atrial fibrillation (AF) have a higher risk of developing myocardial infarction, suggesting a link in underlying pathophysiology. The aim of this study was to assess whether coronary angiographic parameters are associated with a substrate for AF in patients without a history of AF.

Methods: During cardiac surgery in 62 patients (coronary artery bypass grafting (CABG;n = 47), aortic valve replacement (AVR;n = 9) or CABG + AVR (n = 6)) without a history of clinical AF (age 65.4 ± 8.5 years, 26.2% female), AF was induced by burst pacing. The preoperative coronary angiogram (CAG) was assessed for the severity of CAD, and the adequacy of atrial coronary blood supply as quantified by a novel scoring system including the location and severity of right coronary artery disease in relation to the right atrial branches. Epicardial mapping of the right atrium (256 unipolar electrodes) was used to assess the complexity of induced AF.

Results: There was no association between the adequacy of right atrial coronary blood supply on preoperative CAG and AF complexity parameters. Multivariable analysis revealed that only increasing age (B0.232 (0.030;0.433),p = 0.03) and the presence of 3VD (B3.602 (0.187;7.018),p = 0.04) were independently associated with an increased maximal activation time difference.

Conclusions: The adequacy of epicardial right atrial blood supply is not associated with increased complexity of induced atrial fibrillation in patients without a history of clinical AF, while age and the extent of ventricular coronary artery disease are.
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http://dx.doi.org/10.1016/j.ijcha.2021.100794DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8164021PMC
June 2021

Effective termination of atrial fibrillation by SK channel inhibition is associated with a sudden organization of fibrillatory conduction.

Europace 2021 11;23(11):1847-1859

Department of Physiology, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands.

Aims: Pharmacological termination of atrial fibrillation (AF) remains a challenge due to limited efficacy and potential ventricular proarrhythmic effects of antiarrhythmic drugs. SK channels are proposed as atrial-specific targets in the treatment of AF. Here, we investigated the effects of the new SK channel inhibitor AP14145.

Methods And Results: Eight goats were implanted with pericardial electrodes for induction of AF (30 days). In an open-chest study, the atrial conduction velocity (CV) and effective refractory period (ERP) were measured during pacing. High-density mapping of both atrial free-walls was performed during AF and conduction properties were assessed. All measurements were performed at baseline and during AP14145 infusion [10 mg/kg/h (n = 1) or 20 mg/kg/h (n = 6)]. At an infusion rate of 20 mg/kg/h, AF terminated in five of six goats. AP14145 profoundly increased ERP and reduced CV during pacing. AP14145 increased spatiotemporal instability of conduction at short pacing cycle lengths. Atrial fibrillation cycle length and pathlength (AF cycle length × CV) underwent a strong dose-dependent prolongation. Conduction velocity during AF remained unchanged and conduction patterns remained complex until the last seconds before AF termination, during which a sudden and profound organization of fibrillatory conduction occurred.

Conclusion: AP14145 provided a successful therapy for termination of persistent AF in goats. During AF, AP14145 caused an ERP and AF cycle length prolongation. AP14145 slowed CV during fast pacing but did not lead to a further decrease during AF. Termination of AF was preceded by an abrupt organization of AF with a decline in the number of fibrillation waves.
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http://dx.doi.org/10.1093/europace/euab125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8576281PMC
November 2021

Role of pre-operative transthoracic echocardiography in predicting post-operative atrial fibrillation after cardiac surgery: a systematic review of the literature and meta-analysis.

Europace 2021 11;23(11):1731-1743

Department of Cardiothoracic Surgery, Heart and Vascular Centre Maastricht University Medical Centre, Professor Debyelaan 25, 6229 HX Maastricht, The Netherlands.

Aims: This systematic review and meta-analysis aims to evaluate the role of pre-operative transthoracic echocardiography in predicting post-operative atrial fibrillation (POAF) after cardiac surgery.

Methods And Results: Electronic databases were searched for studies reporting on pre-operative echocardiographic predictors of POAF in PubMed, Cochrane library, and Embase. A meta-analysis of echocardiographic predictors of POAF that were identified by at least five different publications was performed. Forty-three publications were included in this systematic review. Echocardiographic predictors for POAF included surrogate parameters for total atrial conduction time (TACT), structural cardiac changes, and functional disturbances. Meta-analysis showed that prolonged pre-operative PA-TDI interval [5 studies, Cohen's d = 1.4, 95% confidence interval (CI) 0.9-1.9], increased left atrial volume indexed for body surface area (LAVI) (23 studies, Cohen's d = 0.8, 95% CI 0.6-1.0), and reduced peak atrial longitudinal strain (PALS) (5 studies, Cohen's d = 1.4, 95% CI 1.0-1.8), were associated with POAF incidence. Left atrial volume indexed for body surface was the most important predicting factor in patients without a history of AF. These parameters remained important predictors of POAF in heterogeneous populations with variable age and comorbidities such as coronary artery disease and valvular disease.

Conclusion: This meta-analysis shows that increased TACT, increased LAVI, and reduced PALS are valuable parameters for predicting POAF in the early post-operative phase in a large variety of patients.
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http://dx.doi.org/10.1093/europace/euab095DOI Listing
November 2021
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