Normal and abnormal development of pulmonary veins: State of the art and correlation with clinical entities

Douglas, Yvonne L.; Jongbloed, Monique R.M.; DeRuiter, Marco C.; Groot, Adriana C. Gittenberger‐de

doi:10.1016/j.ijcard.2010.07.004

Cited by 87 publications

(56 citation statements)

References 114 publications

(234 reference statements)

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“…Anterior pole development has been studied extensively, but less information is available regarding posterior pole development. Many major issues, such as the functional identity of the pulmonary vein (PV) myocardium in relation to the myocardial sleeves of the systemic venous return, remain to be resolved (Douglas et al, 2011;Gittenberger-de Groot, 2011;Lescroart et al, 2012;Moorman and Anderson, 2011;van den Berg and Moorman, 2011). Ectopic triggers in the PV myocardium often account for focally induced atrial fibrillation (AF) (Douglas et al, 2011;Haïssaguerre et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

“…Many major issues, such as the functional identity of the pulmonary vein (PV) myocardium in relation to the myocardial sleeves of the systemic venous return, remain to be resolved (Douglas et al, 2011;Gittenberger-de Groot, 2011;Lescroart et al, 2012;Moorman and Anderson, 2011;van den Berg and Moorman, 2011). Ectopic triggers in the PV myocardium often account for focally induced atrial fibrillation (AF) (Douglas et al, 2011;Haïssaguerre et al, 1998). The PV myocardium was initially thought to be derived from atrial myocardium (Millino et al, 2000), but was recently reported to be differentiated from mesenchymal cells surrounding the developing venous pole (Mommersteeg et al, 2007a;Moorman et al, 2007;Peng et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

“…The PV myocardium was initially thought to be derived from atrial myocardium (Millino et al, 2000), but was recently reported to be differentiated from mesenchymal cells surrounding the developing venous pole (Mommersteeg et al, 2007a;Moorman et al, 2007;Peng et al, 2013). The PV myocardium is also positive for HNK-1 and CCS-lacZ, two putative cardiac conduction system (CCS) markers (Douglas et al, 2011;Jongbloed et al, 2004;Wenink et al, 2000). The association of mutations in NKX2-5 with AF patients Xie et al, 2013), and the switch of the PV myocardium to an Hcn4…”

Section: Introductionmentioning

confidence: 99%

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A common Shox2-Nkx2-5 antagonistic mechanism primes the pacemaking cell fate in the pulmonary vein myocardium and sinoatrial node

et al. 2015

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In humans, atrial fibrillation is often triggered by ectopic pacemaking activity in the myocardium sleeves of the pulmonary vein (PV) and systemic venous return. The genetic programs that abnormally reinforce pacemaker properties at these sites and how this relates to normal sinoatrial node (SAN) development remain uncharacterized. It was noted previously that Nkx2-5, which is expressed in the PV myocardium and reinforces a chamber-like myocardial identity in the PV, is lacking in the SAN. Here we present evidence that in mice Shox2 antagonizes the transcriptional output of Nkx2-5 in the PV myocardium and in a functional Nkx2-5 + domain within the SAN to determine cell fate. Shox2 deletion in the Nkx2-5 + domain of the SAN caused sick sinus syndrome, associated with the loss of the pacemaker program. Explanted Shox2 + cells from the embryonic PV myocardium exhibited pacemaker characteristics including node-like electrophysiological properties and the capability to pace surrounding Shox2 − cells. Shox2 deletion led to Hcn4 ablation in the developing PV myocardium. Nkx2-5 hypomorphism rescued the requirement for Shox2 for the expression of genes essential for SAN development in Shox2 mutants. Similarly, the pacemaker-like phenotype induced in the PV myocardium in Nkx2-5 hypomorphs reverted back to a working myocardial phenotype when Shox2 was simultaneously deleted. A similar mechanism is also adopted in differentiated embryoid bodies. We found that Shox2 interacts with Nkx2-5 directly, and discovered a substantial genomewide co-occupancy of Shox2, Nkx2-5 and Tbx5, further supporting a pivotal role for Shox2 in the core myogenic program orchestrating venous pole and pacemaker development.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A common Shox2-Nkx2-5 antagonistic mechanism primes the pacemaking cell fate in the pulmonary vein myocardium and sinoatrial node

et al. 2015

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“…31 During this developmental process, incomplete PV incorporation can result in a unilateral common PV ostium, whereas extreme PV incorporation can lead to more than 4 PV ostia. 32 The atrioventricular sulcus and cushions develop concurrently with PV development, and the continuity of atrial and ventricular muscle is interrupted gradually. At the end of the third month of gestation, the atrial myocardium and ventricular myocardium are almost completely separated in normal subjects.…”

Section: Development Of Pv and Atrioventricular Septationmentioning

confidence: 99%

Coexistence of Left-Sided Atrioventricular Accessory Pathways With a Common Inferior Pulmonary Vein Ostium

Ihara

Nitta²,

Sato³

et al. 2011

Circ: Arrhythmia and Electrophysiology

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Background-As the technique for radiofrequency catheter ablation for atrial fibrillation (AF) has progressed, so has our knowledge of both normal and abnormal anatomy of the left atrium and pulmonary veins (PV). We treated several AF patients with accessory conduction pathways (ACP) who were also found to have a common ostium of inferior PVs (CIPV), a relatively rare PV anomaly. No relation between ACP and PV anomalies has ever been reported, and the aim of our study was to study this association. Methods and Results-This

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“…In human, the PITX2c gene is predominantly expressed in the embryonic and adult hearts (Clauss and Kä ä b, 2011), and is crucial for the normal embryonic development of left atrium, cardiac conduction system, and pulmonary venous myocardium (Douglas et al, 2011). In mice, deletion of PITX2c has been associated with a wide variety of CHDs, including atrial isomerism, double-outlet right ventricle, atrial septal defect, ventricular septal defect, transposition of the great artery, persistent truncus arteriosus, and abnormal aortic arch as well as incomplete closure of the body wall (Gage et al, 1999;Lin et al, 1999;Liu et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Prevalence and Spectrum of PITX2c Mutations Associated with Congenital Heart Disease

Wang

Yin

et al. 2013

DNA and Cell Biology

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Congenital heart disease (CHD) is the most common form of birth defect and is the leading noninfectious cause of infant death. A growing body of evidence demonstrates that genetic risk factors are involved in the pathogenesis of CHD. However, CHD is a genetically heterogeneous disease and the genetic defects underlying CHD in an overwhelming majority of patients remain unclear. In this study, the whole coding region and splice junction sites of the PITX2c gene, which encodes variant 3 of paired-like homeodomain transcription factor 2 crucial for normal cardiovascular morphogenesis, were sequenced in 382 unrelated patients with CHD, and 2 novel heterozygous mutations, p.W147X and p.N153D, were identified in 2 unrelated patients with CHD, respectively, including a 1-year-old male patient with double outlet right ventricle in combination with ventricular septal defect and a 4-year-old female patient with ventricular septal defect. The mutations were absent in 400 control chromosomes and were both predicted to be disease-causing by MutationTaster. Multiple alignments of PITX2c proteins across species displayed that the altered amino acids were completely conserved evolutionarily. Functional analysis revealed that the mutated PITX2c proteins were associated with a significantly reduced transactivational activity compared with their wild-type counterpart. These findings provide a novel insight into the molecular mechanisms implicated in CHD, suggesting potential implications for the antenatal prophylaxis and allele-specific treatment of CHD.

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Normal and abnormal development of pulmonary veins: State of the art and correlation with clinical entities

Cited by 87 publications

References 114 publications

A common Shox2-Nkx2-5 antagonistic mechanism primes the pacemaking cell fate in the pulmonary vein myocardium and sinoatrial node

A common Shox2-Nkx2-5 antagonistic mechanism primes the pacemaking cell fate in the pulmonary vein myocardium and sinoatrial node

Coexistence of Left-Sided Atrioventricular Accessory Pathways With a Common Inferior Pulmonary Vein Ostium

Prevalence and Spectrum of PITX2c Mutations Associated with Congenital Heart Disease

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