Endothelial function and atrial fibrillation: A missing piece of the puzzle?

Black, Nicholas; Mohammad, Fahad; Saraf, Karan; Morris, Gwilym M.

doi:10.1111/jce.15277

Cited by 22 publications

(13 citation statements)

References 90 publications

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“…Additionally, during atrial pacing in pigs, Vcam-1 has been shown to be upregulated, contributing to inflammation and generating a prothrombotic environment within atrial tissue. 33,34,[63][64][65] Together, these findings correlate with the thrombus formation observed in mice lacking Zfhx3. Despite the relatively low expression of Zfhx3 in the ventricles, the striking LV phenotype in older Zfhx3 knockout mice may be related to total ablation of Zfhx3 expression in cardiomyocytes compared with the human phenotype where much ZFHX3 expression is retained.…”

Section: Discussionsupporting

confidence: 69%

Loss of the Atrial Fibrillation-Related Gene, Zfhx3 , Results in Atrial Dilation and Arrhythmias

Jameson,

Hanley,

Hill

et al. 2023

Circulation Research

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Background: ZFHX3 , a gene that encodes a large transcription factor, is at the second-most significantly associated locus with atrial fibrillation (AF), but its function in the heart is unknown. This study aims to identify causative genetic variation related to AF at the ZFHX3 locus and examine the impact of Zfhx3 loss on cardiac function in mice. Methods: CRISPR-Cas9 genome editing, chromatin immunoprecipitation, and luciferase assays in pluripotent stem cell–derived cardiomyocytes were used to identify causative genetic variation related to AF at the ZFHX3 locus. Cardiac function was assessed by echocardiography, magnetic resonance imaging, electrophysiology studies, calcium imaging, and RNA sequencing in mice with heterozygous and homozygous cardiomyocyte-restricted Zfhx3 deletion ( Zfhx3 Het and knockout, respectively). Human cardiac single-nucleus ATAC-sequencing data was analyzed to determine which genes in atrial cardiomyocytes are directly regulated by ZFHX3 . Results: We found SNP rs12931021 modulates an enhancer regulating ZFHX3 expression, and the AF risk allele is associated with decreased ZFHX3 transcription. We observed a gene-dose response in AF susceptibility with Zfhx3 knockout mice having higher incidence, frequency, and burden of AF than Zfhx3 Het and wild-type mice, with alterations in conduction velocity, atrial action potential duration, calcium handling and the development of atrial enlargement and thrombus, and dilated cardiomyopathy. Zfhx3 loss results in atrial-specific differential effects on genes and signaling pathways involved in cardiac pathophysiology and AF. Conclusions: Our findings implicate ZFHX3 as the causative gene at the 16q22 locus for AF, and cardiac abnormalities caused by loss of cardiac Zfhx3 are due to atrial-specific dysregulation of pathways involved in AF susceptibility. Together, these data reveal a novel and important role for Zfhx3 in the control of cardiac genes and signaling pathways essential for normal atrial function.

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Section: Discussionsupporting

confidence: 69%

Loss of the Atrial Fibrillation-Related Gene, Zfhx3 , Results in Atrial Dilation and Arrhythmias

Jameson,

Hanley,

Hill

et al. 2023

Circulation Research

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“…Endothelial dysfunction, a hallmark of AS, is known to have a strong association with AF. Raised levels of endothelial damage/dysfunction markers such as von Willebrand Factor, asymmetric dimethylarginine, vascular adhesion molecules and reduced levels of endothelial nitric oxide synthase have been documented in AF, however it remains unclear whether endothelial dysfunction forms part of the cause or the consequence of AF [41]. Data from large-scale studies suggests that reduced brachial flow-mediated dilatation [42,43] and reduced coronary flow reserve [44], as surrogate indicators of endothelial dysfunction, precede the occurrence of AF.…”

Section: Shared Molecular and Pathophysiological Mechanismsmentioning

confidence: 99%

Arterial stiffness and atrial fibrillation: shared mechanisms, clinical implications and therapeutic options

Vio

Giordani

Stefil

et al. 2022

Journal of Hypertension

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Arterial stiffness (AS) and atrial fibrillation (AF) share commonalities in molecular and pathophysiological mechanisms and numerous studies have analyzed their reciprocal influence. The gold standard for AS diagnosis is represented by aortic pulse wave velocity, whose measurement can be affected by arrhythmias characterized by irregularities in heart rhythm, such as AF. Growing evidence show that patients with AS are at high risk of AF development. Moreover, the subset of AF patients with AS seems to be more symptomatic and rhythm control strategies are less effective in this population. Reducing AS through de-stiffening interventions may be beneficial for patients with AF and can be a new appealing target for the holistic approach of AF management.In this review, we discuss the association between AS and AF, with particular interest in shared mechanisms, clinical implications and therapeutic options.

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“…[36][37][38] Additionally, while the levels of NO were significantly reduced in AF patients, the levels of asymmetric dimethylarginine (ADMA), Von Willebrand factor (vWF), circulating microparticles, C-reactive protein (CRP), interleukin-6 (IL-6), adhesion molecules (such as E-selectin and VCAM-1), and circulating extracellular vesicles have shown to be increased in patients with AF, suggesting the possible contribution of oxidative stress and inflammation to endothelial dysfunction in development and progression of AF. 41 Additionally, increased levels of clotting factors (tissue factor, factor VIII, fibrinogen), platelet activation markers (platelet factor 4, β-thrombomodulin, P-selectin), and fibrinolysis markers (D-dimer, tissue plasminogen activator, plasminogen activator inhibitor-1) are observed in AF which is associated with increased frequency of thromboembolic events in AF patients. 42 In our current study, the levels of endogenous GAGs were elevated in AF patient plasma, compared to NHP, which is possibly a reflection of endothelial damage and glycocalyx degradation leading to the development of AF in these patient groups.…”

Section: Discussionmentioning

confidence: 99%

Endogenous Glycosaminoglycans in Various Pathologic Plasma Samples as Measured by a Fluorescent Quenching Method

Kantarcıoğlu

Mehrotra

Papineni

et al. 2022

Clin Appl Thromb Hemost

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Endogenous glycosaminoglycans (GAGs) with a similar structure to heparin are widely distributed in various tissues. A fluorescence probe, namely Heparin Red, can detect polyanionic GAGs in plasma samples. The purpose of this study is to measure endogenous GAGs in various plasma samples obtained from different pathologic states in comparison to healthy controls utilizing this method. Plasma samples were obtained from patient groups including atrial fibrillation (AF), end-stage-renal-disease (ESRD), diabetes mellitus (DM), sepsis, cancer, liver disease (LD), and pulmonary embolism (PE). Normal human plasma (NHP) was used as healthy controls. The Heparin Red kit from Red Probes (Münster, Germany) was used for the quantification of endogenous GAGs in each sample before and after heparinase I degradation. All results were compiled as group means ± SD for comparison. NHP was found to have relatively low levels of endogenous GAGs with a mean concentration of 0.06 μg/mL. The AF, ESRD, DM, and sepsis patient samples had a mean endogenous GAG concentration of 0.55, 0.72, 0.92, and 0.94 μg/mL, respectively. The levels of endogenous GAGs were highest in cancer, LD, and PE patient plasma samples with a mean concentration of 1.95, 2.78, and 2.83 μg/mL, respectively. Heparinase I degradation resulted in a decline in GAG levels in plasma samples. These results clearly show that detectable Heparin Red sensitive endogenous GAGs are present in circulating plasma at varying levels in various patient groups. Additional studies are necessary to understand this complex pathophysiology.

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Endothelial function and atrial fibrillation: A missing piece of the puzzle?

Cited by 22 publications

References 90 publications

Loss of the Atrial Fibrillation-Related Gene, Zfhx3 , Results in Atrial Dilation and Arrhythmias

Loss of the Atrial Fibrillation-Related Gene, Zfhx3 , Results in Atrial Dilation and Arrhythmias

Arterial stiffness and atrial fibrillation: shared mechanisms, clinical implications and therapeutic options

Endogenous Glycosaminoglycans in Various Pathologic Plasma Samples as Measured by a Fluorescent Quenching Method

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