RESUMEN
BACKGROUND: The relationship between heart failure (HF) and atrial fibrillation (AF) is clear, with up to half of patients with HF progressing to AF. The pathophysiological basis of AF in the context of HF is presumed to result from atrial remodeling. Upregulation of the transcription factor FOG2 (friend of GATA2; encoded by ZFPM2) is observed in human ventricles during HF and causes HF in mice. METHODS: FOG2 expression was assessed in human atria. The effect of adult-specific FOG2 overexpression in the mouse heart was evaluated by whole animal electrophysiology, in vivo organ electrophysiology, cellular electrophysiology, calcium flux, mouse genetic interactions, gene expression, and genomic function, including a novel approach for defining functional transcription factor interactions based on overlapping effects on enhancer noncoding transcription. RESULTS: FOG2 is significantly upregulated in the human atria during HF. Adult cardiomyocyte-specific FOG2 overexpression in mice caused primary spontaneous AF before the development of HF or atrial remodeling. FOG2 overexpression generated arrhythmia substrate and trigger in cardiomyocytes, including calcium cycling defects. We found that FOG2 repressed atrial gene expression promoted by TBX5. FOG2 bound a subset of GATA4 and TBX5 co-bound genomic locations, defining a shared atrial gene regulatory network. FOG2 repressed TBX5-dependent transcription from a subset of co-bound enhancers, including a conserved enhancer at the Atp2a2 locus. Atrial rhythm abnormalities in mice caused by Tbx5 haploinsufficiency were rescued by Zfpm2 haploinsufficiency. CONCLUSIONS: Transcriptional changes in the atria observed in human HF directly antagonize the atrial rhythm gene regulatory network, providing a genomic link between HF and AF risk independent of atrial remodeling.
Asunto(s)
Fibrilación Atrial , Remodelación Atrial , Insuficiencia Cardíaca , Humanos , Ratones , Animales , Fibrilación Atrial/genética , Redes Reguladoras de Genes , Calcio/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Atrios Cardíacos , Insuficiencia Cardíaca/genética , Genómica , Factor de Transcripción GATA4/genéticaRESUMEN
OBJECTIVE: To assess demographic, substance use, and mental wellbeing factors associated with high-intensity drinking (HID; 10+ drinks on one occasion) among college- and non-college young adults, to inform prevention and intervention efforts. PARTICIPANTS: A total of 1,430 young adults (819 in college and 611 not attending college) in a Midwestern state who reported trying alcohol at least once. METHODS: Participants were recruited via social media between November 2019 and February 2020 to complete a web-based survey assessing demographics, substance use, and mental well-being. Logistic regression was conducted to assess relationships between these measures and HID among (1) college students and (2) non-college young adults. RESULTS: About 14.0% of participants reported past-month HID. Among both college- and non-college young adults, men, those who perceived slight or no risk of harm from binge drinking, and those who used alcohol and marijuana simultaneously in the past year had greater odds of reporting past-month HID. Among students, past-year prescription drug misuse was also associated with HID. CONCLUSIONS: High intensity-drinking is concerning given potential adverse consequences. Campus programming should address norms that may promote such drinking and other high-risk substance use associated with HID.