Chamber-specific transcriptional responses in atrial fibrillation.

Catherine E Lipovsky,Carlos Perez-Cervantez,Qiusha Guo,Brittany D Brumback,Gang Li,Tiankai Yin,Somya Bhatnagar,Bo Zhang,Stephanie C Hicks,Ivan P Moskowitz,Rangarajan D Nadadur,David M Zhang,Uri Goldsztejn,Kentaro Takahashi,Jesus Jimenez,Stacey L Rentschler,Shaopeng Liu

doi:10.1172/jci.insight.135319

Catherine E Lipovsky, Carlos Perez-Cervantez + Show 15 more

Open Access

https://doi.org/10.1172/jci.insight.135319

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Abstract

Atrial fibrillation (AF) is the most common cardiac arrhythmia, yet the molecular signature of the vulnerable atrial substrate is not well understood. Here, we delineated a distinct transcriptional signature in right versus left atrial cardiomyocytes (CMs) at baseline and identified chamber-specific gene expression changes in patients with a history of AF in the setting of end-stage heart failure (AF+HF) that are not present in heart failure alone (HF). We observed that human left atrial (LA) CMs exhibited Notch pathway activation and increased ploidy in AF+HF but not in HF alone. Transient activation of Notch signaling within adult CMs in a murine genetic model is sufficient to increase ploidy in both atrial chambers. Notch activation within LA CMs generated a transcriptomic fingerprint resembling AF, with dysregulation of transcription factor and ion channel genes, including Pitx2, Tbx5, Kcnh2, Kcnq1, and Kcnip2. Notch activation also produced distinct cellular electrophysiologic responses in LA versus right atrial CMs, prolonging the action potential duration (APD) without altering the upstroke velocity in the left atrium and reducing the maximal upstroke velocity without altering the APD in the right atrium. Our results support a shared human/murine model of increased Notch pathway activity predisposing to AF.

Highlights

Atrial fibrillation (AF) is the most common cardiac arrhythmia, affecting approximately 2% of the population, and is characterized by rapid and irregular impulse initiation and propagation throughout the atrial myocardium, predisposing to increased risk of stroke, heart failure (HF), and death [1, 2]
The murine LA posterior wall (LAPW) has a different embryologic origin than the LA appendage (LAA) [40], and LAPW action potentials (APs) are 40% longer when compared with the LAA APs [41], suggesting there is regional heterogeneity within the atria
AF is a highly complex and heterogeneic disease [69], which manifests in the presence of various clinical backgrounds ranging from classic systolic HF to lone familial AF [3, 70]

Summary

Introduction

Atrial fibrillation (AF) is the most common cardiac arrhythmia, affecting approximately 2% of the population, and is characterized by rapid and irregular impulse initiation and propagation throughout the atrial myocardium, predisposing to increased risk of stroke, heart failure (HF), and death [1, 2]. As many as 50% of patients with severe HF have AF [3,4,5], which is not surprising given the number of shared risk factors, including hypertension, obesity, diabetes, and coronary artery disease, underlying the pathophysiology of both HF and AF [6]. AF is classified as paroxysmal if sinus rhythm returns spontaneously or following intervention within 7 days, persistent if it lasts greater than 7 days, and long-standing persistent when AF lasts longer than 1 year and is refractory to treatment [7]. While HF patients with concomitant AF have higher rates of hospitalization and death [8, 9], current pharmacologic and catheter-based therapies aimed at maintaining normal sinus rhythm remain limited in efficacy. A more in-depth molecular understanding of disease pathogenesis may enable recognition of patient-specific factors and development of precision medicine–based therapies targeting underlying mechanisms

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