Michael Broman

Pitx2 modulates a Tbx5-dependent gene regulatory network to maintain atrial rhythm

A mouse model reveals how seven atrial fibrillation–related risk genes form a network to control heartbeat. The genetic underpinnings of atrial fibrillation The irregular heartbeat of atrial fibrillation puts people in danger of stroke and heart disease; genomic studies have identified gene variants that increase the risk for this abnormality. Nadadur et al. now reveal how these genes influence the beat of the heart’s atrium. In a mouse model of atrial fibrillation, which lacks one of these genes, Tbx5, the authors describe a multitiered transcriptional network that links seven of these atrial fibrillation risk loci. Organized as an incoherent feed-forward loop, this network tightly controls expression of atrial rhythm genes, and its perturbation by the risk loci causes susceptibility to atrial fibrillation. Cardiac rhythm is extremely robust, generating 2 billion contraction cycles during the average human life span. Transcriptional control of cardiac rhythm is poorly understood. We found that removal of the transcription factor gene Tbx5 from the adult mouse caused primary spontaneous and sustained atrial fibrillation (AF). Atrial cardiomyocytes from the Tbx5-mutant mice exhibited action potential abnormalities, including spontaneous depolarizations, which were rescued by chelating free calcium. We identified a multitiered transcriptional network that linked seven previously defined AF risk loci: TBX5 directly activated PITX2, and TBX5 and PITX2 antagonistically regulated membrane effector genes Scn5a, Gja1, Ryr2, Dsp, and Atp2a2. In addition, reduced Tbx5 dose by adult-specific haploinsufficiency caused decreased target gene expression, myocardial automaticity, and AF inducibility, which were all rescued by Pitx2 haploinsufficiency in mice. These results defined a transcriptional architecture for atrial rhythm control organized as an incoherent feed-forward loop, driven by TBX5 and modulated by PITX2. TBX5/PITX2 interplay provides tight control of atrial rhythm effector gene expression, and perturbation of the co-regulated network caused AF susceptibility. This work provides a model for the molecular mechanisms underpinning the genetic implication of multiple AF genome-wide association studies loci and will contribute to future efforts to stratify patients for AF risk by genotype.

FOG-2 mediated recruitment of the NuRD complex regulates cardiomyocyte proliferation during heart development

FOG-2 is a multi-zinc finger protein that binds the transcriptional activator GATA4 and modulates GATA4-mediated regulation of target genes during heart development. Our previous work has demonstrated that the Nucleosome Remodeling and Deacetylase (NuRD) complex physically interacts with FOG-2 and is necessary for FOG-2 mediated repression of GATA4 activity in vitro. However, the relevance of this interaction for FOG-2 function in vivo has remained unclear. In this report, we demonstrate the importance of FOG-2/NuRD interaction through the generation and characterization of mice homozygous for a mutation in FOG-2 that disrupts NuRD binding (FOG-2(R3K5A)). These mice exhibit a perinatal lethality and have multiple cardiac malformations, including ventricular and atrial septal defects and a thin ventricular myocardium. To investigate the etiology of the thin myocardium, we measured the rate of cardiomyocyte proliferation in wild-type and FOG-2(R3K5A) developing hearts. We found cardiomyocyte proliferation was reduced by 31±8% in FOG-2(R3K5A) mice. Gene expression analysis indicated that the cell cycle inhibitor Cdkn1a (p21(cip1)) is up-regulated 2.0±0.2-fold in FOG-2(R3K5A) hearts. In addition, we demonstrate that FOG-2 can directly repress the activity of the Cdkn1a gene promoter, suggesting a model by which FOG-2/NuRD promotes ventricular wall thickening by repression of this cell cycle inhibitor. Consistent with this notion, the genetic ablation of Cdkn1a in FOG-2(R3K5A) mice leads to an improvement in left ventricular function and a partial rescue of left ventricular wall thickness. Taken together, our results define a novel mechanism in which FOG-2/NuRD interaction is required for cardiomyocyte proliferation by directly down-regulating the cell cycle inhibitor Cdkn1a during heart development.

Impact of high-grade atrioventricular block and cumulative frequent pacing on atrial arrhythmias

The relationship between high‐grade atrioventricular block (HGAVB) with cumulative frequent pacing and risk of atrial arrhythmias (AAs) has not been well characterized. We hypothesized HGAVB and pacing may have significant impact on incidence and prevalence of AAs by modulating atrial substrate.

ATRIAL FIBRILLATION IS ASSOCIATED WITH SEVERE METABOLIC DISRUPTION IN ATRIAL MYOCARDIUM IN PATIENTS WITH HEART FAILURE

Background: Myocardial energetics is essential for cardiac contractility and electrical property. However, it is not known whether atrial myocardial energetics is disrupted in disease condition such as atrial fibrillation (AF) and heart failure (HF). We hypothesized that AF and HF are associated

Electroanatomic Characterization of a “No Access” Hypoplastic Left Ventricle

A 35-year-old man with congenital mitral atresia, a double outlet right ventricle with a hypoplastic left ventricle (HLV), and post-bidirectional Glenn and Fontan status was referred for ablation of symptomatic premature ventricular contractions (PVCs) and nonsustained ventricular tachycardia. He