Chamber-specific transcriptional responses in atrial fibrillation
Catherine E. Lipovsky, … , Bo Zhang, Stacey L. Rentschler
Catherine E. Lipovsky, … , Bo Zhang, Stacey L. Rentschler
Published August 25, 2020
Citation Information: JCI Insight. 2020;5(18):e135319. https://doi.org/10.1172/jci.insight.135319.
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Research Article Cardiology Development

Chamber-specific transcriptional responses in atrial fibrillation

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.

Authors

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

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Figure 5

Notch signaling prolongs the murine LA AP and is not responsive to the IKr blocker dofetilide.

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Notch signaling prolongs the murine LA AP and is not responsive to the I...
Sharp microelectrode recordings were performed ex vivo on the LA of intact murine hearts while in sinus rhythm in control and iNICD mice after a 4-month washout period (A–I) versus during active Notch activation (J–N). In addition, during active Notch activation, recordings were taken at baseline (-Dof) versus after 10 nM dofetilide administration, a class III antiarrhythmic drug that blocks IKr (+Dof, J–N). (A) Representative averaged LA APs in control (blue) and iNICD (red). (B–E) APDs at 20% (B), 50% (C), 70% (D), and 90% (E) repolarization. AP characteristics, including RMP (F), dVm/dtmax (G), max amplitude (H), and ERP (I). n = 9 control mice and n = 10 iNICD mice for B–H. n = 7 control mice and n = 7 iNICD mice for I. (J) Representative averaged LA APs in iNICD mice at baseline (blue) and after 10 nm dofetilide administration (red) demonstrate no shortening of the AP, suggesting absence of IKr current despite transcriptional upregulation of Kcnh2 in iNICD mice. (K–N) APDs at 20% (K), 50% (L), 70% (M), and 90% (N) repolarization are also unchanged with dofetilide. n = 7 iNICD mice. Data are presented as the mean from each mouse ± SEM. P < 0.05 was considered statistically significant. **P < 0.01; ***P < 0.001; ****P < 0.0001; NS, not significant. Unpaired Student’s 2-tailed t test with a Welch’s correction was performed for comparisons in B–I. Paired Student’s 2-tailed t test with a Welch’s correction was performed for all comparisons in K–N.