<i>Pitx2</i>
            prevents susceptibility to atrial arrhythmias by inhibiting left-sided pacemaker specification

Wang, Jun; Klysik, Elzbieta; Sood, Subeena; Johnson, Randy L.; Wehrens, Xander H.T.; Martin, James F.

doi:10.1073/pnas.0912585107

Cited by 283 publications

(338 citation statements)

References 43 publications

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“…To gain insight into miRs involved in AF pathogenesis, we performed miR expression profiling using hearts from Pitx2 null/null mutant and wild type, and ChIP-sequencing (ChIP-Seq) using hearts from the Pitx2-Flag allele (16,18), which express Pitx2 with a C-terminal Flag epitope tag ( Fig. 1 A and C).…”

Section: Resultsmentioning

confidence: 99%

“…To determine the miR-17-92 expression pattern in heart, we generated an miR-17-92 bacterial artificial chromosome transgenic LacZ reporter line (20) and compared it with a Pitx2 LacZ knock-in allele (16). In E12.5 hearts, LacZ staining indicated that miR-17-92 is expressed in the outflow tract (OFT), left atrium (LA), coronary sinus, and atrioventricular canal (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Pitx2 is expressed on the left side of multiple organ primordia and mature organs including the heart. Within the developing heart, Pitx2 is highly expressed in multiple sites that are prone to ectopic electrical activity, such as the left atrium, pulmonary vein, interatrial septum, crista terminalis, and left caval vein myocardium (15,16). Pitx2 haploinsufficient (Pitx2 null/+ ) adult mice are prone to AF under intracardiac electrical stimulation, revealing a direct functional connection between AF and reduced Pitx2 levels (16, 17).…”

mentioning

confidence: 99%

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

Wang¹,

Bai

Li³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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107

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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. irregular heart rate | single nucleotide variant | mouse genetics A trial fibrillation (AF), the most common arrhythmia in adult patients, increases in prevalence with age to almost 5% of the population over 65. Patients with AF have an increased risk of stroke, dementia, and heart failure (1). Electrical impulses that are critical for a coordinated, physiologic heartbeat originate in the sinoatrial node (SAN). In AF, abnormal fibrillatory atrial impulses override normal SAN function, with resultant irregular conduction to the ventricles. Many cases of ectopic electrical activity originate in the pulmonary vein (2). Other sites of ectopy include the left atrial posterior wall, superior vena cava, interatrial septum, crista terminalis, and coronary sinus myocardium (3, 4).Multiple approaches have been used to uncover genes that may contribute to the AF phenotype in adult patients. A seminal genome-wide association study (GWAS), subsequently replicated by multiple studies, uncovered a single nucleotide variant (SNV) on human 4q25 that was strongly associated with familial AF (5). Patients with the 4q25 variant exhibited early onset AF that was independent from other risk factors such as hypertension and diabetes, suggesting a novel biologic mechanism involving genes located on chromosome 4q25. The presence of the 4q25 SNV also had prognostic value because patients with the SNV are prone to cardioembolic str...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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

Wang¹,

Bai

Li³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

107

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“…5.1) [62,65,66]. Jako potencjalne mechanizmy leżące u podłoża zwiększonego ryzyka AF u nosicieli częstych wariantów genetycznych postuluje się zmiany charakterystyki potencjału czynnościowego komórek przedsionków [67][68][69][70], przebudowę przedsionków oraz zmodyfikowaną penetrację rzadkich defektów genetycznych [61]. Warianty genetyczne mogłyby w przyszłości stać się użyteczne podczas doboru pacjentów do strategii kontroli rytmu serca lub kontroli częstości rytmu komór [71][72][73][74].…”

Section: Skłonność Genetycznaunclassified

2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS

Kirchhof

Benussi

Kotecha³

et al. 2016

Kardiol Pol

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“…The gene most closely located to the risk variants encodes the two-domain transcription factor, PITX2. Low expression levels of PITX2 mRNA induce complex left atrial gene expression changes, without apparent structural alter ations, that predispose to AF 19,67 . Thus, altered expression of atrial ion channels as a result of genetic alterations in the atria could be a common path by which subtle genetic changes predispose patients to AF, subsequently influencing the response to antiarrhythmic drugs 68 .…”

Section: Ion-channel Dysfunctionmentioning

confidence: 99%

Defining the major health modifiers causing atrial fibrillation: a roadmap to underpin personalized prevention and treatment

et al. 2015

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Despite the important advances that have enabled better stroke prevention in atrial fibrillation (AF) and more effective maintenance of sinus rhythm over the past decades, a large unmet need to improve the prevention and treatment of AF remains. Mortality for AF remains at 3.5% per year, and death is often experienced as sudden death or as a result of heart failure 1,2 . Each year, approximately 20% of patients with AF need to be hospitalized 3,4 , and stroke occurs in 1.5% of patients with AF who are receiving anticoagulant drugs 5 . Furthermore, more than half of the patients with AF are symptomatic despite adequate anticoagulation and rate control 4,6 . In view of the projected increase in the incidence and prevalence of AF 7-9 , as well as the substantial burden of death and dis ability that is still associated with this condition 10 , the status quo is unacceptable.Current management of patients with AF comprises treatment of the accompanying cardiovascular conditions, oral anticoagulation, rate control -with medications that slow atrioventricular nodal recovery or, rarely, with atrioventricular nodal ablation -and rhythm-control therapy with antiarrhythmic drugs, electrical cardioversion, catheter ablation or, at times, AF surgery 11,12 . Unfortunately, most of these current approaches are disconnected from our understanding of the major mechanisms that cause AF 1,13,14 1,2,7,19,20 Abstract | Despite remarkable advances in antiarrhythmic drugs, ablation procedures, and stroke-prevention strategies, atrial fibrillation (AF) remains an important cause of death and disability in middle-aged and elderly individuals. Unstructured management of patients with AF sharply contrasts with our detailed, although incomplete, knowledge of the mechanisms that cause AF and its complications. Altered calcium homeostasis, atrial fibrosis and ageing, ion-channel dysfunction, autonomic imbalance, fat-cell infiltration, and oxidative stress, in addition to a susceptible genetic background, contribute to the promotion, maintenance, and progression of AF. However, clinical management of patients with AF is currently guided by stroke risk parameters, AF pattern, and symptoms. In response to this apparent disconnect between the known pathophysiology of AF and clinical management, we propose a roadmap to develop a set of clinical markers that reflect the major causes of AF in patients. Thereby, the insights into the mechanisms causing AF will be transformed into a format that can underpin future personalized strategies to prevent and treat AF, ultimately informing better patient care.230 | APRIL 2016 | VOLUME 13 www.nature.com/nrcardio CONSENSUS STATEMENT © 2 0 1 6 M a c m i l l a n P u b l i s h e r s L i m i t e d . A l l r i g h t s r e s e r v e d .

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Pitx2 prevents susceptibility to atrial arrhythmias by inhibiting left-sided pacemaker specification

Cited by 283 publications

References 43 publications

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

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

2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS

Defining the major health modifiers causing atrial fibrillation: a roadmap to underpin personalized prevention and treatment

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