Abstract
Underlying normal cardiac rhythm is a network of transcriptional programs that ensures normal impulse initiation and impulse propagation. We highlight work that shows how alterations in individual transcriptional networks can lead to increased arrhythmia susceptibility, cardiomyopathy, and congenital heart defects. Lastly, we focus on a study that leverages transcription factor biology to therapeutically modulate heart rhythm.
Cross-ancestry Genome-Wide Analysis of Atrial Fibrillation Unveils Disease Biology and Enables Cardioembolic Risk Prediction
To date, large genome-wide association studies (GWAS) have predominantly focused on European populations, limiting applicability to other groups. Miyazawa and colleagues used a large genetic repository of Japanese individuals to identify candidate loci associated with atrial fibrillation (AF).1 By combining their genetic repository with previous GWAS, 35 new candidate loci were identified and used to create a polygenic risk score that predicted increased risks of cardiovascular and stroke mortalities. Utilizing enrichment analysis from the ChIP-Atlas dataset, estrogen-related receptor gamma (ERRg) binding was found to be significantly enriched in AF-associated loci. ERRg ChIP-seq peaks overlapped with AF-associated loci near cardiac ion channel genes. To validate their findings, an inverse agonist of ERRg was applied to human induced pluripotent stem cell-derived cardiomyocytes, which altered mechanical properties and caused irregularity in beat rate. Future in-vivo experiments will be required to explore the role of ERRg in the pathogenesis of AF.
Loss of the Atrial Fibrillation-Related Gene Zfhx3, Results in Atrial Dilation and Arrhythmias
As GWAS have identified many candidate loci linked to AF, defining the role of these loci in AF pathogenesis has become a priority. Jameson, Hanley, and colleagues present compelling data that supports ZFHX3, a transcription factor located within a major AF locus, as a causative gene for AF.2 A single nucleotide polymorphism located within the candidate locus modulates the expression of ZFHX3. Zfhx3 deficient mice developed severe ventricular cardiomyopathy, atrial dilatation, atrial thrombus formation, and increased atrial arrhythmia susceptibility. Isolated left atrial cardiomyocytes exhibited abnormalities in calcium handling and increased spontaneous calcium release events. This work reinforces the urgency of finding causal links between GWAS identified loci and AF mechanisms.
Cardiac GR Mediates the Diurnal Rhythm in Ventricular Arrhythmia Susceptibility
Sudden cardiac death occurs more frequently in the morning upon waking. Tikhomirov, Oakley, Anderson, and colleagues identified the glucocorticoid receptor (GR), a ligand-gated transcription factor, as an important modulator of diurnal expression of ion channels that may underlie enhanced arrhythmia susceptibility.3 Enrichment of GR binding motifs in open chromatin profiles was observed in mice during their most active periods, times corresponding with higher serum corticosteroid levels. Transcriptional profiling showed that GR alters expression of ion channels and gap junctions implicated in arrhythmogenesis, including Scn5a, Kcnh2, and Gja1. Pharmacologic and genetic models of GR deficiency similarly disrupt expression of ion channels and reduce circadian susceptibility to pacing-induced ventricular arrhythmias. Importantly, there is conservation between mice and humans of GR binding sites on SCN5A and KCNH2 genes, making it an appealing new therapeutic target for suppressing ventricular arrhythmias.
An Anterior Second Heart Field Enhancer Regulates the Gene Regulatory Network of the Cardiac Outflow Tract
Cyanotic conotruncal defects are associated with defects in right bundle branch (RBB) formation, indicating a common myocardial lineage defect in the anterior second heart field (A-SHF). Transcription factors GATA6, NKX2–5, and TBX1 have all been implicated in cyanotic conotruncal defects, however a genetic mechanism that links these factors in the A-SHF had not been defined. Yamaguchi, Chang and colleagues showed that deletion of a highly conserved NKX2–5 enhancer containing two GATA binding sites is sufficient to cause cyanotic conotruncal defects and right bundle branch hypoplasia.4 GATA6 was shown to interact with the NKX2–5 enhancer and regulate its accessibility, enriching for NKX2–5 expression selectively in the A-SHF. Enhancer-dependent NKX2–5 enrichment in the A-SHF is essential for normal RBB formation and for upregulation of TBX1 and other important morphogenetic genes that regulate proper OFT rotation and septation. Whether genetic variations within this enhancer is associated with cyanotic conotruncal defects and right bundle branch block in humans will need to be studied.
Transient Pacing in Pigs with Complete Heart Block via Myocardial Injection of mRNA Coding for TBX18
Current treatment of complete heart block is limited to the implantation of an electronic pacemaker. Wolfson, Kim, Lee, Beyersdorf, and colleagues build on previous work utilizing Tbx18, a transcription factor well established for influencing sinoatrial node development, to create an mRNA delivery system that promotes spontaneous cardiac pacing in rat and pig models of complete heart block.5 Previous work using adenoviral delivery of Tbx18 resulted in significant off target expression and inflammatory response tempering enthusiasm. Tbx18 mRNA injection into the interventricular septum of a pig model of complete heart block produced rate-adaptive cardiac pacing over a one-month period. With clinical trials as an exciting upcoming possibility, this novel approach has the potential to provide a less invasive approach to treating conduction disorders.
Funding Sources:
NHLBI R01HL165130 and R01HL171989 (David S. Park)
Footnotes
Disclosures: The authors have no relevant conflicts of interest to disclose.
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References:
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