Extracellular matrix remodeling precedes atrial fibrillation: Results of the PREDICT-AF trial

Berg, Nicoline W. E. van den; Neefs, Jolien; Kawasaki, Masanori; Nariswari, Fransisca A; Wesselink, Robin; Fabrizi, Benedetta; Jongejan, Aldo; Klaver, Martijn N; Havenaar, H; Hulsman, E. L.; Wintgens, Lisette I S; Baalman, Sarah W.E.; Meulendijks, Eva R.; Boven, Wim Jan van; Jong, Jonas S.S.G. de; Putte, Bart P. van; Driessen, Antoine H.G.; Boersma, Lucas V.A.; Groot, Joris R. de; Investigators, Predict-Af

doi:10.1016/j.hrthm.2021.07.059

Cited by 23 publications

(17 citation statements)

References 33 publications

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“…We recently reported that an upregulation of glycoproteins and proteoglycans may even precede the first onset of AF. 6 These findings suggest that changes in ECM composition and morphology may be an early, dominant feature of ECM remodeling in AF.…”

Section: Discussionmentioning

confidence: 88%

“…We lately reported that signs of atrial EMT may even precede the first occurrence of incident AF. 6 The re‐activation of quiescent epicardial cells has long been recognized in lower vertebrates such as zebrafish 38 and has been described in the setting of acute myocardial infarction. 39 However, EPC re‐activation was only recently reported in association with fibro‐fatty infiltration in mitral valve disease‐related AF.…”

Section: Discussionmentioning

confidence: 99%

“…Control subjects without a history of AF participated in the previously described PREDICT‐AF study (NCT03130985 April 27, 2017). 6 , 18 In the PREDICT‐AF study, 150 patients without a history of AF, who underwent cardiothoracic surgery for coronary artery bypass grafting (CABG) and/or valve surgery between 2015 and 2018, were prospectively followed to determine the development of incident AF. As part of the study, the left atrial appendage (LAA) was removed for molecular and histopathological analyses.…”

Section: Methodsmentioning

confidence: 99%

“…Atrial structural remodeling precedes the first onset of AF and is associated with AF progression. 4 , 5 , 6 However, the key processes underlying the AF substrate remain incompletely understood. Structural remodeling generally refers to atrial fibrosis: a pathological accumulation of extracellular matrix (ECM) proteins, among which type I collagen and type III collagen are most abundant.…”

Section: Introductionmentioning

confidence: 99%

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Epicardial and endothelial cell activation concurs with extracellular matrix remodeling in atrial fibrillation

Berg

Kawasaki

Fabrizi

et al. 2021

Clinical & Translational Med

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BackgroundImproved understanding of the interconnectedness of structural remodeling processes in atrial fibrillation (AF) in patients could identify targets for future therapies.MethodsWe present transcriptome sequencing of atrial tissues of patients without AF, with paroxysmal AF, and persistent AF (total n = 64). RNA expression levels were validated in the same and an independent cohort with qPCR. Biological processes were assessed with histological and immunohistochemical analyses.ResultsIn AF patients, epicardial cell gene expression decreased, contrasting with an upregulation of epithelial‐to‐mesenchymal transition (EMT) and mesenchymal cell gene expression. Immunohistochemistry demonstrated thickening of the epicardium and an increased proportion of (myo)fibroblast‐like cells in the myocardium, supporting enhanced EMT in AF. We furthermore report an upregulation of endothelial cell proliferation, angiogenesis, and endothelial signaling. EMT and endothelial cell proliferation concurred with increased interstitial (myo)fibroblast‐like cells and extracellular matrix gene expression including enhanced tenascin‐C, thrombospondins, biglycan, and versican. Morphological analyses discovered increased and redistributed glycosaminoglycans and collagens in the atria of AF patients. Signaling pathways, including cell–matrix interactions, PI3K‐AKT, and Notch signaling that could regulate mesenchymal cell activation, were upregulated.ConclusionOur results suggest that EMT and endothelial cell proliferation work in concert and characterize the (myo)fibroblast recruitment and ECM remodeling of AF. These processes could guide future research toward the discovery of targets for AF therapy.

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Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Epicardial and endothelial cell activation concurs with extracellular matrix remodeling in atrial fibrillation

Berg

Kawasaki

Fabrizi

et al. 2021

Clinical & Translational Med

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“…Moreover, the degree of collagen crosslinking was associated with cardiac function. A more compliant and less stiff collagen fibers would hinder the force development of the myocytes and disrupted the systolic function of hearts ( 13 ). Taken together, collagen fibers in the cardiac extra cellular matrix (ECM) contribute to keeping the rigidity and the architecture of hearts ( 12 ).…”

Section: Introductionmentioning

confidence: 99%

Cardiovascular abnormalities and its correlation with genotypes of children with osteogenesis imperfecta

Zhao

Liu²,

Liu³

et al. 2022

Front. Endocrinol.

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Background and objectivesOsteogenesis imperfecta (OI) is a rare disorder of abnormal production or modification of type I collagen, which is caused by mutations in COL1A1, COL1A2 or other genes. We investigate the cardiac abnormalities and its correlation with pathogenic mutations in OI children.MethodsA cross-sectional comparative study was completed in a relatively large sample of OI children, who were matched in body surface area (BSA) with healthy controls. All echocardiography was performed by experienced cardiologists using Vivid 7 equipment (GE Medical Systems, Horton, Norway). The resting standard 12-lead electrocardiogram (ECG) were obtained in OI patients by FX-8600 machine. Skeletal phenotypes of OI patients were evaluated, including information of bone fractures, deformities, motility, and bone mineral density (BMD). Pathogenic mutations of OI were detected by a next-generation sequencing panel and confirmed by Sanger sequencing.ResultsA total of 69 OI children and 42 healthy children matched in BSA were enrolled. Abnormalities of echocardiography were found in 6 OI children, including enlarged left atrium (n=5), increased internal diameter of the left ventricle (n=1), who all carried the COL1A1 mutation. Mild regurgitation of mitral or tricuspid valves was observed in 26 OI patients. Abnormal ECG manifestations were found in 8 OI children, including deep Q wave, T wave change, premature ventricular complexes, short P-R interval, incomplete bundle branch block and high voltage of left ventricular. Compared with healthy controls, OI children had significant larger values in the main pulmonary artery (1.84 vs 1.60 cm, P < 0.01), left atrial diameter (2.58 vs 2.11 cm, P < 0.001), left ventricular internal dimension at end-diastolic (LVEDd) (3.85 vs 3.50 cm, P < 0.05) and lower left ventricular ejection fraction (LVEF) (68.40% vs 71.74%, P < 0.01). Moreover, OI patients with COL1A1 mutation tended to have greater main pulmonary artery, larger diameters of left atrial and LVEDd, and lower LVEF than healthy controls. COL1A1 mutation was correlated to dilated MPA (β = 1.557, P < 0.01), LAD (β = 3.915, P < 0.001), and LVEDd (β = 2.714, P < 0.01), and decreased LVEF (β = -3.249, P < 0.01).ConclusionsCardiovascular alterations were identified in OI children, including increased dimensions of the main pulmonary artery and left chamber, and low LVEF. The cardiovascular abnormalities seemed to be correlated to COL1A1 mutation and defects of type I collagen, which expanded our understandings of the cardiac phenotypes of OI children.

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Interventions to prevent postoperative atrial fibrillation in Dutch cardiothoracic centres: a survey study

Emiola,

Kluin,

el Mathari

et al. 2024

Neth Heart J

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Introduction Postoperative atrial fibrillation (POAF) is a common phenomenon following cardiac surgery. In this study, we assessed current preventive strategies used by Dutch cardiothoracic centres, identified common views on this matter and related these to international guidelines. Methods We developed an online questionnaire and sent it to all cardiothoracic surgery centres in the Netherlands. The questionnaire concerned the management of POAF and the use of pharmaceutical therapies (beta-blockers and calcium antagonists) and non-pharmaceutical methods (posterior left pericardiotomy, pericardial flushing and epicardial botulinum toxin type A injections). Usage of electrical cardioversions, anticoagulants and left atrial appendage closure were also enquired. Results Of the 15 centres, 14 (93%) responded to the survey and 13 reported a POAF incidence, ranging from 20 to 30%. Of these 14 centres, 6 prescribed preoperative AF prophylaxis to their patients, of which non-sotalol beta-blockers were prescribed most commonly (57%). Postoperative medication was administered by all centres and included non-sotalol beta-blockers (38%), sotalol (24%), digoxin (14%), calcium antagonists (13%) and amiodarone (10%). Only 2 centres used posterior left pericardiotomy or pericardial flushing as surgical manoeuvres to prevent POAF. Moreover, respondents expressed the need for guidance on anticoagulant use. Conclusion Despite the use of various preventive strategies, the reported incidence of POAF was similar in Dutch cardiothoracic centres. This study highlights limited use of prophylactic amiodarone and colchicine, despite recommendations by numerous guidelines, and restricted implementation of surgical strategies to prevent POAF.

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Extracellular matrix remodeling precedes atrial fibrillation: Results of the PREDICT-AF trial

Cited by 23 publications

References 33 publications

Epicardial and endothelial cell activation concurs with extracellular matrix remodeling in atrial fibrillation

Epicardial and endothelial cell activation concurs with extracellular matrix remodeling in atrial fibrillation

Cardiovascular abnormalities and its correlation with genotypes of children with osteogenesis imperfecta

Interventions to prevent postoperative atrial fibrillation in Dutch cardiothoracic centres: a survey study

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