PITX2c Is Expressed in the Adult Left Atrium, and Reducing Pitx2c Expression Promotes Atrial Fibrillation Inducibility and Complex Changes in Gene Expression

Abstract

Background-Intergenic variations on chromosome 4q25, close to the PITX2 transcription factor gene, are associated with atrial fibrillation (AF). We therefore tested whether adult hearts express PITX2 and whether variation in expression affects cardiac function. Methods and Results-mRNA for PITX2 isoform c was expressed in left atria of human and mouse, with levels in right atrium and left and right ventricles being 100-fold lower. In mice heterozygous for Pitx2c (Pitx2c), left atrial Pitx2c expression was 60% of wild-type and cardiac morphology and function were not altered, except for slightly elevated pulmonary flow velocity. Isolated Pitx2c ϩ/Ϫ hearts were susceptible to AF during programmed stimulation. At short paced cycle lengths, atrial action potential durations were shorter in Pitx2c ϩ/Ϫ than in wild-type. Perfusion with the ␤-receptor agonist orciprenaline abolished inducibility of AF and reduced the effect on action potential duration. Spontaneous heart rates, atrial conduction velocities, and activation patterns were not affected in Pitx2c ϩ/Ϫ hearts, suggesting that action potential duration shortening caused wave length reduction and inducibility of AF. Expression array analyses comparing Pitx2c ϩ/Ϫ with wild-type, for left atrial and right atrial tissue separately, identified genes related to calcium ion binding, gap and tight junctions, ion channels, and melanogenesis as being affected by the reduced expression of Pitx2c.Conclusions-These findings demonstrate a physiological role for PITX2 in the adult heart and support the hypothesis that dysregulation of PITX2 expression can be responsible for susceptibility to AF. (Circ Cardiovasc Genet. 2011;4:123-133.)Key Words: action potentials Ⅲ atrium Ⅲ fibrillation Ⅲ genes Ⅲ transgenic mice Ⅲ genetic predisposition A trial fibrillation (AF) is by far the most common sustained arrhythmia and causes important morbidity and mortality. 1,2 Unfortunately, the causes of the arrhythmia are not sufficiently understood to allow effective therapy to prevent AF. 3,4 Both rare and common forms of AF can be heritable, and the genes responsible may provide important clues toward therapy. Familial forms of AF associate with mutations in genes encoding sodium and potassium ion channels, connexin40, the natriuretic peptide precursor A (NPPA) but also transcription factor genes, either in candidate or genome-wide association studies. 3,[5][6][7][8] Editorial see p 105 Clinical Perspective on p 133A polymorphic locus on chromosome 4q25 (SNP rs2200733) associates with AF, particularly of early onset, in several independent studies of European and Asian populations 9,10 and conveys an approximately 1.7-fold risk of developing AF. 11 This locus is intergenic, with the gene in closest proximity being PITX2, which encodes a homeobox transcription factor of the paired type. Mutations of PITX2 are responsible for autosomal dominant anterior eye defects, including the Axenfeld-Rieger syndrome, 12 albeit without reports of AF in affected patients.During embryonic development in ...

Atrial fibrillation: the role of common and rare genetic variants

“…They furthermore showed that isolated PITX2c þ / À mice hearts were susceptible to AF during programmed pacing, because of shortening of atrial action potential durations (APDs) and the effective refractory period (ERP). 26 In line with these results, human studies have recently revealed that PITX2c expression is significantly decreased in patients with sustained AF, thus providing a molecular link between PITX2 loss-of-function and AF. 27 Although a lot of studies indicate PITX2 as having a role in AF, evidence regarding the expression of PITX2 and its target genes in patients with AF is still missing.…”

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

“…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].…”

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

“…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 .…”

“…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.…”

“…and mechanisms, and which presents with a variety of symptoms and evolution patterns 2,[15][16][17][18][19][20][21][22][23] . However, none of the current management decisions considers the variable pathophysiology of AF, thereby ignoring the opportunity for tailored, personalized approaches that target the major drivers for AF 24 .…”