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Pitx2-microRNA pathway that delimits sinoatrial node development and inhibits predisposition to atrial fibrillation.

ABSTRACT: The molecular mechanisms underlying atrial fibrillation, the most common sustained cardiac arrhythmia, remain poorly understood. Genome-wide association studies uncovered a major atrial fibrillation susceptibility locus on human chromosome 4q25 in close proximity to the paired-like homeodomain transcription factor 2 (Pitx2) homeobox gene. Pitx2, a target of the left-sided Nodal signaling pathway that initiates early in development, represses the sinoatrial node program and pacemaker activity on the left side. To address the mechanisms underlying this repressive activity, we hypothesized that Pitx2 regulates microRNAs (miRs) to repress the sinoatrial node genetic program. MiRs are small noncoding RNAs that regulate gene expression posttranscriptionally. Using an integrated genomic approach, we discovered that Pitx2 positively regulates miR-17-92 and miR-106b-25. Intracardiac electrical stimulation revealed that both miR-17-92 and miR-106b-25 deficient mice exhibit pacing-induced atrial fibrillation. Furthermore electrocardiogram telemetry revealed that mice with miR-17-92 cardiac-specific inactivation develop prolonged PR intervals whereas mice with miR-17-92 cardiac-specific inactivation and miR-106b-25 heterozygosity develop sinoatrial node dysfunction. Both arrhythmias are risk factors for atrial fibrillation in humans. Importantly, miR-17-92 and miR-106b-25 directly repress genes, such as Shox2 and Tbx3, that are required for sinoatrial node development. Together, to our knowledge, these findings provide the first genetic evidence for an miR loss-of-function that increases atrial fibrillation susceptibility.

SUBMITTER: Wang J

PROVIDER: S-EPMC4078868 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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Pitx2-microRNA pathway that delimits sinoatrial node development and inhibits predisposition to atrial fibrillation.

Wang Jun J Bai Yan Y Li Na N Ye Wenduo W Zhang Min M Greene Stephanie B SB Tao Ye Y Chen Yiping Y Wehrens Xander H T XH Martin James F JF

Proceedings of the National Academy of Sciences of the United States of America 20140610 25

The molecular mechanisms underlying atrial fibrillation, the most common sustained cardiac arrhythmia, remain poorly understood. Genome-wide association studies uncovered a major atrial fibrillation susceptibility locus on human chromosome 4q25 in close proximity to the paired-like homeodomain transcription factor 2 (Pitx2) homeobox gene. Pitx2, a target of the left-sided Nodal signaling pathway that initiates early in development, represses the sinoatrial node program and pacemaker activity on ...[more]

PMID: 24927531

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Project description:ImportanceAtrial fibrillation (AF) can develop following thoracic irradiation. However, the critical cardiac substructure responsible for AF has not been properly studied.ObjectiveTo describe the incidence of AF in patients with lung cancer and determine predictive cardiac dosimetric parameters.Design, setting, and participantsThis retrospective cohort study was performed at a single referral center and included 239 patients diagnosed with limited-stage small cell lung cancer (SCLC) and 321 patients diagnosed with locally advanced non-small cell lung cancer (NSCLC) between August 2008 and December 2019 who were treated with definitive chemoradiotherapy.ExposuresRadiation dose exposure to cardiac substructures, including the chambers, coronary arteries, and cardiac conduction nodes, were calculated for each patient.Main outcomes and measuresMain outcomes were AF and overall survival.ResultsOf the 239 and 321 patients with SCLC and NSCLC, the median (IQR) age was 68 (60-73) years and 67 (61-75) years, and 207 (86.6%) and 261 (81.3%) were men, respectively. At a median (IQR) follow-up time of 32.7 (22.1-56.6) months, 9 and 17 patients experienced new-onset AF in the SCLC and NSCLC cohorts, respectively. The maximum dose delivered to the sinoatrial node (SAN Dmax) exhibited the highest predictive value for prediction of AF. A higher SAN Dmax significantly predicted an increased risk of AF in patients with SCLC (adjusted hazard ratio [aHR], 14.91; 95% CI, 4.00-55.56; P < .001) and NSCLC (aHR, 15.67; 95% CI, 2.08-118.20; P = .008). However, SAN Dmax was not associated with non-AF cardiac events. Increased SAN Dmax was significantly associated with poor overall survival in patients with SCLC (aHR, 2.68; 95% CI, 1.53-4.71; P < .001) and NSCLC (aHR, 1.97; 95% CI, 1.45-2.68; P < .001).Conclusions and relevanceIn this cohort study, results suggest that incidental irradiation of the SAN during chemoradiotherapy may be associated with the development of AF and increased mortality. This supports the need to minimize radiation dose exposure to the SAN during radiotherapy planning and to consider close follow-up for the early detection of AF in patients receiving thoracic irradiation.

Dataset Information

Pitx2-microRNA pathway that delimits sinoatrial node development and inhibits predisposition to atrial fibrillation.

Publications

Pitx2-microRNA pathway that delimits sinoatrial node development and inhibits predisposition to atrial fibrillation.

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