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Early sarcomere and metabolic defects in a zebrafish pitx2c cardiac arrhythmia model
Edited by Calum A. MacRae, Harvard Medical School, Boston, MA, and accepted by Editorial Board Member Christine E. Seidman October 2, 2019 (received for review August 12, 2019)

Significance
Atrial fibrillation (AF) is the most common cardiac arrhythmia, affecting 2 to 3% of the general population and leading to significant morbidity and mortality. Genome-wide association studies identified the 4q25 AF risk locus, a region that forms long-range interactions with the promoter of PITX2, which encodes a critical transcriptional regulator of cardiac development. Using a zebrafish pitx2c loss-of-function model, we find that larval and adult zebrafish phenocopy many hallmarks of human AF. Our data further indicate that the pathogenesis of arrhythmia and AF-like phenotypes in pitx2c mutants is driven by developmental perturbations to sarcomere organization and metabolic pathways. We also find that antioxidant treatment reduces the incidence and severity of cardiac arrhythmia, suggesting avenues for therapeutic strategies.
Abstract
Atrial fibrillation (AF) is the most common type of cardiac arrhythmia. The major AF susceptibility locus 4q25 establishes long-range interactions with the promoter of PITX2, a transcription factor gene with critical functions during cardiac development. While many AF-linked loci have been identified in genome-wide association studies, mechanistic understanding into how genetic variants, including those at the 4q25 locus, increase vulnerability to AF is mostly lacking. Here, we show that loss of pitx2c in zebrafish leads to adult cardiac phenotypes with substantial similarities to pathologies observed in AF patients, including arrhythmia, atrial conduction defects, sarcomere disassembly, and altered cardiac metabolism. These phenotypes are also observed in a subset of pitx2c+/− fish, mimicking the situation in humans. Most notably, the onset of these phenotypes occurs at an early developmental stage. Detailed analyses of pitx2c loss- and gain-of-function embryonic hearts reveal changes in sarcomeric and metabolic gene expression and function that precede the onset of cardiac arrhythmia first observed at larval stages. We further find that antioxidant treatment of pitx2c−/− larvae significantly reduces the incidence and severity of cardiac arrhythmia, suggesting that metabolic dysfunction is an important driver of conduction defects. We propose that these early sarcomere and metabolic defects alter cardiac function and contribute to the electrical instability and structural remodeling observed in adult fish. Overall, these data provide insight into the mechanisms underlying the development and pathophysiology of some cardiac arrhythmias and importantly, increase our understanding of how developmental perturbations can predispose to functional defects in the adult heart.
Footnotes
- ↵1To whom correspondence may be addressed. Email: michelle.collins{at}mpi-bn.mpg.de, didier.stainier{at}mpi-bn.mpg.de, or plundegaard{at}sund.ku.dk.
Author contributions: M.M.C., M.S.O., D.Y.R.S., and P.R.L. designed research; M.M.C., C.V.H., S.G., J.P., Y.H., and P.R.L. performed research; R.M.-J., A.M.S., and H.E.-S. contributed new reagents/analytic tools; M.M.C., G.A., C.V.H., S.G., M.S.O., D.Y.R.S., and P.R.L. analyzed data; and M.M.C., D.Y.R.S., and P.R.L. wrote the paper.
The authors declare no competing interest.
This article is a PNAS Direct Submission. C.A.M. is a guest editor invited by the Editorial Board.
Data deposition: The data reported in this paper have been deposited in the Gene Expression Omnibus (GEO) database, https://www.ncbi.nlm.nih.gov/geo (accession no. GSE128511).
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1913905116/-/DCSupplemental.
Published under the PNAS license.
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