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Circulation Research Aug 2023(zinc finger homeobox 3), a gene that encodes a large transcription factor, is at the second-most significantly associated locus with atrial fibrillation (AF), but its...
BACKGROUND
(zinc finger homeobox 3), 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 locus and examine the impact of 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 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 loss ( Het and knockout, respectively). Human cardiac single-nucleus ATAC (assay for transposase-accessible chromatin)-sequencing data was analyzed to determine which genes in atrial cardiomyocytes are directly regulated by .
RESULTS
We found single-nucleotide polymorphism (SNP) rs12931021 modulates an enhancer regulating expression, and the AF risk allele is associated with decreased transcription. We observed a gene-dose response in AF susceptibility with Zfhx3 knockout mice having higher incidence, frequency, and burden of AF than 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. loss results in atrial-specific differential effects on genes and signaling pathways involved in cardiac pathophysiology and AF.
CONCLUSIONS
Our findings implicate as the causative gene at the 16q22 locus for AF, and cardiac abnormalities caused by loss of cardiac are due to atrial-specific dysregulation of pathways involved in AF susceptibility. Together, these data reveal a novel and important role for in the control of cardiac genes and signaling pathways essential for normal atrial function.
Topics: Animals; Humans; Mice; Atrial Fibrillation; Calcium; Dilatation; Homeodomain Proteins; Myocytes, Cardiac; Transcription Factors
PubMed: 37449401
DOI: 10.1161/CIRCRESAHA.123.323029 -
Clinical Medicine (London, England) Nov 2023Dilatation of the gut occurs in response to either mechanical obstruction or aperistalsis. The hallmark features are symptoms of bowel obstruction with vomiting,... (Review)
Review
Dilatation of the gut occurs in response to either mechanical obstruction or aperistalsis. The hallmark features are symptoms of bowel obstruction with vomiting, constipation, abdominal pain and distension. This review will primarily deal with the non-mechanical causes of gut dilatation, both intestinal and colonic, and differentiate between acute and chronic presentations.
Topics: Humans; Vomiting; Abdominal Pain; Diagnosis, Differential
PubMed: 38065609
DOI: 10.7861/clinmed.2023-GA2 -
World Journal of Gastroenterology Jan 2024Esophageal intramural pseudodiverticulosis (EIPD) is a disease of unknown pathogenesis characterized by usually systemic, cystic dilatation of the excretory ducts of... (Review)
Review
Esophageal intramural pseudodiverticulosis (EIPD) is a disease of unknown pathogenesis characterized by usually systemic, cystic dilatation of the excretory ducts of esophageal submucosal glands. In this article, I review the epidemiology, clinical manifestations, endoscopic findings, esophagographic findings, and histopathology of EIPD. I also discuss the etiology and possible pathogenesis of EIPD based on my experiences with this disease and a review of the literature. EIPD usually presents with dysphagia in middle-aged individuals. It is often complicated with secondary infections, most commonly candidiasis. On esophagography, EIPD is delineated as small, multiple, flask-shaped outward projections within the esophageal wall. In recent years, EIPD has been mainly diagnosed by endoscopic findings of multiple, localized, small mucosal depressions. The orifices of the "pseudodiverticula" periodically open and close, and excrete mucus onto the mucosal surface. On histopathological examination, the luminal surface of dilated ducts in EIPD is covered by multilayered, hyperplastic epithelial cells, but myoepithelial cells in the glandular acini are well preserved. Treatment of EIPD is usually symptomatic therapy, and prevention of the infectious complications is important. The etiology and pathogenesis of EIPD are largely unknown, but functional abnormalities of autonomic nerve fibers innervating the esophageal glands likely play an important role, since the structures of the glands are basically preserved in this disease.
Topics: Middle Aged; Humans; Diverticulum, Esophageal; Deglutition Disorders; Diverticulum; Mucous Membrane; Esophageal Stenosis
PubMed: 38312118
DOI: 10.3748/wjg.v30.i2.137