Pitx2c and Nkx2-5 are required for the formation and identity of the pulmonary myocardium

The pulmonary vein is sleeved by myocardium, which is a major source of atrial fibrillation and is involved in congenital sinus venosus defects. Little is known about the cellular origin and mechanism of formation of the pulmonary myocardium. We observed a biphasic process of pulmonary myocardium formation in mice. Firstly, a myocardial cell population forms de novo at the connection of the pulmonary vein and the atrium. Genetic labeling revealed that atrial cells do not contribute to this population, indicating it forms by differentiation of pulmonary mesenchymal cells. Secondly, these pulmonary myocardial cells initiate a phase of rapid proliferation and form the pulmonary myocardial sleeve. Pitx2c-deficient mice do not develop a pulmonary myocardial sleeve because they fail to form the initial pulmonary myocardial cells. Genetic-labeling analyses demonstrated that whereas the systemic venous return derives from Nkx2-5-negative precursors, the pulmonary myocardium derives from Nkx2-5-expressing precursors, indicating a distinct origin of the 2 venous systems. Nkx2-5 and its target gap-junction gene Cx40 are expressed in the atria and in the pulmonary myocardium but not in the systemic venous return, which expresses the essential pacemaker channel Hcn4. When Nkx2-5 protein level was lowered in a hypomorphic model, the pulmonary myocardium switched to a Cx40-negative, Hcn4-positive phenotype resembling that of the systemic venous return. In conclusion, our data suggest a cellular mechanism for pulmonary myocardium formation and highlight the key roles played by Pitx2c and Nkx2-5 in its formation and identity.     

Arrangement of the systemic and pulmonary venous components of the atrial chambers in hearts with isomeric atrial appendages

BACKGROUND: The morphological definition of atrial chambers, and the determination of atrial laterality, are based on analysis of the structure of the atrial appendages. The systemic and pulmonary venous connections to the heart, nonetheless, are important in the management of patients having isomeric appendages. In this study, therefore, we analysed the morphology of the postero-superior walls of the atrial chambers so as to provide evidence concerning the morphogenetic background of those hearts, and to improve operative management. METHODS: We reviewed 15 autopsied specimens with isomeric right appendages, and 10 with isomeric left appendages, paying particular attention to the morphology of the systemic and pulmonary venous connections. The postero-superior walls of the atrial chambers can be made up of the atrial body, the systemic venous components, or the pulmonary venous component. We analysed the contributions made by each of these components. RESULTS: The postero-superior walls of the atrial chambers were markedly variable, but could be grouped into five patterns. Bilaterally well-developed systemic venous components and absence of the pulmonary venous component within the hypoplastic atrial body were present in 9 hearts with extracardiac pulmonary venous connections in the setting of right isomerism. Bilaterally well-developed systemic venous components, and a hypoplastic pulmonary venous component within the hypoplastic atrial body, were present in 5 hearts with intracardiac pulmonary venous connections in right isomerism. Bilaterally well-developed systemic venous components, and a hypoplastic pulmonary venous component within the sizable atrial body, were present in 1 heart with an intracardiac pulmonary venous connection in right isomerism. A well-developed pulmonary venous component within the atrial body, and hypoplasia of one systemic venous component, were present in 7 hearts with left isomerism. A well-developed pulmonary venous component within the atrial body, and hypoplasia of bilateral systemic venous components, were present in 3 hearts with left isomerism. CONCLUSIONS: The postero-superior walls of the atrial chambers in hearts with isomeric atrial appendages can be analysed on the basis of a compound structure made of bilateral systemic venous components, a central pulmonary venous component, and the body of the atrium. Hearts with isomeric right appendages have absence or hypoplasia of the pulmonary venous component, while hearts with isomeric left appendages have hypoplastic systemic venous components.     

Every heart beat is under neural command: an hypothesis relating to the cardiac rhythm

In the human heart there is a sequential contraction of the systemic veins, systemic venous sinus and the pectinated right atrium, 'the systemic waltz', and sequential contraction of the pulmonary veins, pulmonary venous sinus and pectinated left atrium, 'the pulmonary waltz'. The systemic veins contract earlier than the pulmonary veins creating a 'duet. We hypothesise that this waltz and duet point to a complex extracardiac control of the cardiac rhythm on a beat-to-beat neural basis.     

Alternate pathways to pulmonary venous flow in left-sided obstructive anomalies.

In cardiac anomalies causing severe obstruction in the left side of the heart, such as aortic atresia, mitral atresia, or occasionally severe aortic stenosis, maintenance of circulation depends upon shunting of pulmonary venous blood into the right atrium. The usual pathway by which the shunt is achieved is across the atrial septum through the foramen ovale. When this route is closed or severely narrowed, alternate but less common pathways may exist. These involve either anomalous connections of pulmonary veins to systemic veins or communications with the coronary venous system. In the latter, as commonly occurs in aortic atresia, left ventricular myocardial sinusoids carry pulmonary venous blood from the left ventricular cavity and into the cardiac veins. In other instances of severe left-sided obstruction, a direct communication may exist between the left atrium and the coronary sinus.     

Haemodynamics after Mustard's operation for transposition of the great arteries.

Cardiac catheterization data from 54 investigations after Mustard's procedure were examined to study the influence of the operation on pressure events in the atria, great veins, and pulmonary circulation. Systemic venous atrial pressure tracings were characterized by a rapid, sharp 'y' descent. Pressure gradients between the venae cavae and systemic venous atrium were invariable, whether or not vena caval pathway obstruction was present, the 'y' trough and 'a' wave gradients being greater than the mean gradient. Pulmonary venous atrial pressure tracings were not different from normal except when tricuspid regurgitation was present. It is suggested that the baffle effectively reduces the size and compliance of the systemic venous atrium, but influences the pulmonary venous atrium to a lesser degree. The systolic pressure gradient from the left ventricle to pulmonary artery was decreased postoperatively, suggesting that it may be flow-related; the greatest changes were seen in the group with preoperative ventricular septal defect. The ratio of pulmonary: systemic vascular resistance did not change significantly after operation, and it is suggested that both the pre- and postoperative values were higher than normal. Examination of the left ventricular or pulmonary arterial mean pressure postoperatively should raise the suspicion of a complication, e.g. pulmonary venous obstruction or tricuspid regurgitation.     

High-density mapping of left atrial endocardial activation during sinus rhythm and coronary sinus pacing in patients with paroxysmal atrial fibrillation

INTRODUCTION: This study was designed to record global high-density maps of left atrial endocardial activation during sinus rhythm and coronary sinus pacing. METHOD AND RESULTS: Noncontact mapping of the left atrium was performed in nine patients with paroxysmal atrial fibrillation undergoing pulmonary vein ablation procedures. High-density isopotential and isochronal activation maps were superimposed on three-dimensional reconstructions of left atrial geometry. Mapping was repeated during pacing from sites within the coronary sinus. Earliest left atrial endocardial activation occurred anterior to the right pulmonary veins in seven patients and on the anterosuperior septum in two patients. A line of conduction block was seen in the posterior wall and inferior septum in all patients. The direction of activation in the left atrial myocardium overlying the coronary sinus was different from the electrogram sequence in the coronary sinus catheter in 6 of 9 patients. During coronary sinus pacing, activation entered the left atrium a mean (SD) of 41 (13) ms after the pacing stimulus at a site 12 (10) mm from the endocardium overlying the pacing electrode. Lines of conduction block were present in the posterior wall and inferior septum. CONCLUSION: In patients with paroxysmal atrial fibrillation, lines of conduction block are present in the left atrium during sinus rhythm and coronary sinus pacing. Electrograms recorded in the coronary sinus infrequently correspond to the direction of activation in the overlying left atrial myocardium.     

Isolated atrial inversion Visceral situs solitus, visceroatrial discordance, discordant ventricular d loop without transposition, dextrocardia: Diagnosis and surgical correction

After cardiac catheterization and angiocardiographic studies an infant with cyanosis from birth was found to have visceral situs solitus, visceroatrial discordance without venoatrial discordance, a discordant ventricular d loop without transposition, and dextrocardia. The circulatory pathway was from the venae cavae to right atrium to left ventricle to aorta, and from the pulmonary veins to left atrium to right ventricle to pulmonary artery. An atrial defect was present allowing some mixing between the pulmonary and systemic circulations, but this appeared inadequate and the defect was enlarged surgically. Subsequently, a corrective operation using an atrial baffle to direct the pulmonary venous return to the left ventricle and the systemic venous return to the right ventricle was successfully undertaken.     

Development of the human pulmonary vein and its incorporation in the morphologically left atrium

OBJECTIVE: Using a newly acquired archive of previously prepared material, we sought to re-examine the origin of the pulmonary vein in the human heart, aiming to determine whether it originates from the systemic venous sinus ("sinus venosus"), or appears as a new structure draining to the left atrium. In addition, we examined the temporal sequence of incorporation of the initially solitary pulmonary vein to the stage at which four venous orifices opened to the left atrium. METHODS: We studied 26 normal human embryos, ranging from 3.8 mm to 112 mm crown-rump length, and representing the period from the 12th Carnegie stage to 15 weeks of gestation. RESULTS: The pulmonary vein canalised as a solitary vessel within the mediastinal tissues so as to connect the intraparenchymal pulmonary venous networks to the heart, using the regressing dorsal mesocardium as its portal of cardiac entry. The vein was always distinct from the tributaries of the embryonic systemic venous sinus. The orifice of the solitary vein became committed to the left atrium by growth of the vestibular spine. During development, a marked disparity was seen between the temporal and morphological patterns of incorporation of the left-sided and right-sided veins into the left atrium. The pattern of the primary bifurcation was asymmetrical, a much longer tributary being formed on the left than on the right. Contact between the atrial wall and the venous tributary on the left initially produced a shelf, which became effaced with incorporation of the two left-sided veins into the atrium. CONCLUSIONS: The initial process of formation of the human pulmonary vein is very similar to that seen in animal models. The walls of the initially solitary vein in humans become incorporated by a morphologically asymmetric process so that four pulmonary veins eventually drain independently into the left atrium. Failure of incorporation on the left side may provide the substrate for congenital division of the left atrium.     

Rapid ventricular pacing: a fast, reliable, and safe technique for optimization of image acquisition during rotational angiography for catheter ablation of atrial fibrillation

Rotational angiography is a novel method for three-dimensional reconstruction of the left atrium and pulmonary veins during catheter ablation for atrial fibrillation, but is still hampered by suboptimal reconstructions in a considerable number of patients. We describe the results of rapid pacing of the right ventricle for optimization of image acquisition during rotational angiography.     

Left atrial myocardial extension onto pulmonary veins in humans: anatomic observations relevant for atrial arrhythmias

INTRODUCTION: Electrophysiologic studies have shown that spontaneous initiation of atrial fibrillation (AF) by ectopic beats may originate from within pulmonary veins. The extensions of left atrial myocardium are considered to play a role, but there is little detailed anatomic information available, particularly in humans. METHODS AND RESULTS: Thirty-nine human autopsy hearts were studied; 22 with AF and 17 without atrial arrhythmias. The muscle fiber arrangement of the left atrial wall and pulmonary veins was dissected. In 18 hearts, myocardial sleeves were studied microscopically; in five hearts, three-dimensional reconstruction of the fiber arrangement in the myocardial sleeves was performed. Of 99 pulmonary veins examined, 96 contained a myocardial sleeve. The length of the sleeves was largest in the superior pulmonary veins (P < 0.01). There were no statistically significant differences between uniform and nonuniform muscle fiber arrangements. Microscopic evaluation revealed myocardial sleeves positioned on the adventitial side of the pulmonary vein, separated from the muscular media by a fibrofatty tissue plane. The most distal zone of the myocardial sleeves showed increasing fibrosis with encapsulation of small groups of myocardial cells and eventually with total disappearance of atrophic cells within fibrous tissue. Node-like structures were not encountered. There was no relationship with presence or absence of AF. CONCLUSION: The observation that the peripheral zones of myocardial sleeves are associated with increasing connective tissue deposition between myocardial muscle groups suggests a degenerative change that, from the histologic viewpoint, fits with progressive ischemia. These changes could provide a basis for microreentry and, hence, for atrial arrhythmias.     

One-Stage Correction with Intra- and Extraatrial Rerouting of Anomalous Systemic and Pulmonary Venous Return and Intraventricular Repair of Double Outlet Right Ventricle in a Patient with Heterotaxy Syndrome

We report a very rare case of successful intracardiac correction in a patient with heterotaxy syndrome. The cardiac malformations included dextrocardia, double outlet right ventricle, pulmonary stenosis, interrupted inferior vena cava, hemiazygos continuation and total anomalous pulmonary venous return. One-stage correction was performed. The atrial procedure consisted of intra- and extraatrial rerouting of the anomalous systemic and pulmonary venous return. The hepatic veins were detached and diverted to the left atrium via an extracardiac conduit. The correction of the double outlet right ventricle was accomplished by intraventricular redirection of the blood flow from the left ventricle to the aorta. The right ventricular outflow was ultimately remodeled using a valved conduit. For better perception of the complex morphology, a three-dimensional model was designed, using CT scan images. This proved to be very useful for surgical planning, especially with regard to the intraatrial reconstruction of the systemic and pulmonary venous rerouting.     

Response of pulmonary vein potentials to premature stimulation

INTRODUCTION: Pulmonary vein potentials reflect depolarization of muscle fascicles within the myocardial sleeves that surround the pulmonary veins. The response of pulmonary vein potentials to premature stimulation has not been described. METHODS AND RESULTS: In 31 patients with paroxysmal atrial fibrillation referred for segmental isolation of the pulmonary veins, programmed stimulation with a single atrial extrastimulus was performed from the coronary sinus. Bipolar and unipolar electrograms were recorded with a decapolar Lasso catheter positioned sequentially within the left superior, left inferior, and right superior pulmonary veins, near the ostium. Premature stimulation often resulted in greater separation of the atrial and pulmonary vein potentials recorded within the pulmonary veins, fractionation of the pulmonary vein potentials, a change in the circumferential activation sequence of the pulmonary vein potentials, and dropout of pulmonary vein potentials. CONCLUSION: In response to premature stimulation, the muscle fascicles within the myocardial sleeves that surround the pulmonary veins display a greater degree of decremental conduction than do the myocardial fibers in the adjacent left atrium, and they display heterogeneity in conduction properties and refractoriness. Discrimination of pulmonary vein potentials from atrial electrograms is facilitated by premature stimulation.     

Normal development of the pulmonary veins in human embryos and formulation of a morphogenetic concept for sinus venosus defects

A sinus venosus defect is a form of interatrial communication associated with abnormal drainage of the right pulmonary veins. Its morphogenesis still remains unclear. We therefore studied the normal development of pulmonary veins in human embryos in relation to the sinus venosus and the dorsal mesocardium using graphic reconstructions and HNK-1 immunohistochemistry. Twenty embryos, ranging from 4 to 7 weeks' gestation, were examined. At 4 weeks, the orifice of the nonlumenized common pulmonary vein is visible as an endothelial invagination within the sinus venosus segment. Development of the muscular septum primum and the ventral proliferation of extracardiac mesenchyme from the dorsal mesocardium positions the common pulmonary vein (CPV) eventually into the left atrium. The right wall of the CPV contributes to the posterior part of the atrial septum and is continuous with the dorsal sinuatrial fold (the future left venous valve). With the use of HNK-1 antigen expression as a marker for sinus venosus myocardium, this common wall between the right-sided sinus venosus and the CPV is demonstrated, and at 7 weeks the proximal part of the right upper pulmonary vein also becomes part of this common wall. This study demonstrates that the CPV develops within the sinus venosus segment and that later a common myocardial wall is present between the sinus venosus in the right atrium and the CPV. A deficiency of this wall explains the development of sinus venosus defects.     

Transesophageal Echocardiographic Findings in Complete Unilateral Anomalous Pulmonary Venous Connection of Right Lung to Right Atrium

Transesophageal echocardiographic findings in a patient with anomalous drainage of both right- sided pulmonary veins into the right atrium are described. The atrial septum was intact and the left- sided veins connected normally with the left atrium.
transesophageal echocardiography, partial anomalous pulmonary venous connection of the right pulmonary veins to the right atrium     

Left atrial isomerism combined with right-sided heart, common atrium, incomplete atrioventricular septal defect and partial anomalous systemic and pulmonary venous drainage. Report of a case with successful surgical correction

Precise preoperative diagnostic clarification was accomplished in an infant with left atrial isomerism. The inner/outer arrangement of the pulmonary/systemic veins in relation to the posterior wall of the common atrium necessitated a specific baffle in order to prevent pulmonary or systemic venous obstruction. The development of a sick sinus syndrome six months after surgery is in keeping with the natural history of the disease.     

Typical counterclockwise atrial flutter occurring despite absence of the inferior vena cava.

A 74-year-old man with a structurally normal heart presented with typical atrial flutter, after treatment of atrial fibrillation with propafenone. Catheterization and computed tomographic imaging revealed absence of the inferior vena caval segment that normally traverses the liver to enter the right atrium. Abdominal venous return occurred via the hemi-azygous vein, draining into the superior vena cava. Hepatic veins inserted postero-inferiorly into the right atrium. Pacing atrial myocardium between the hepatic veins and the tricuspid valve resulted in concealed entrainment. Radiofrequency catheter ablation directed (via a superior approach from the right internal jugular vein) to this extraordinary "isthmus" abolished atrial flutter. The implications of this congenital abnormality on posterior barriers maintaining the atrial flutter circuit are discussed.     

Contemporary approach to ablation of paroxysmal atrial fibrillation

Pulmonary veins have been shown to play an important role in the initiation and maintenance of paroxysmal atrial fibrillation. Seg-mental ostial isolation of the pulmonary veins results in cure in about 2/3 of the patients. This approach does not address non-pulmonary venous triggers of atrial fibrillation or the importance of the left atrium itself. Left atrial circumferential ablation has also been shown to be efficacious in patients with paroxysmal atrial fibrillation. This approach seems to address not only the various triggers of atrial fibrillation but also the left atrial substrate. Recently, a randomized study compared the 2 strategies and showed that left atrial ablation is superior to segmental ostial isolation. This review will highlight the anatomy and electrophysiology of the pulmonary veins, and the possible mechanisms by which they initiate and maintain paroxysms of atrial fibrillation. Segmental ostial isolation of the pulmonary veins and left atrial ablation will be compared as well.     

Myocardium of the Superior Vena Cava,Coronary Sinus,Vein of Marshall,and the Pulmonary Vein Ostia: Gross Anatomic Studies in 620 Hearts

Anatomy of Myocardial Extensions in Thoracic Veins. Introduction: Radiofrequency ablation for atrial fibrillation (AF) frequently involves energy delivery at the ostia of the thoracic veins. Detailed evaluation of the myocardium extending into the caval veins, vein of Marshall, as well as at the pulmonary vein ostia has not been completely evaluated. Methods and Results: Post‐mortem assessment of 620 formalin‐fixed hearts (mean age 60 ± 23 years, 44% female) was performed. The hearts were examined for integrity of venous structures and their atrial connections. Systematic gross anatomic evaluation including measurements on myocardial extensions in these veins was performed. Macroscopic myocardial extensions into pulmonary veins were noted in 99% of specimens evaluated and were circumferentially symmetric (99.6%). Myocardial extensions into the superior vena cava (SVC) occurred in 78% with the majority being circumferentially asymmetric (61%). Occasionally, myocardium extended into the azygos vein (6%). There were no myocardial extensions in the inferior vena cava (IVC). In some cases, the right atrial pectinate muscle extended into the coronary sinus (7%). The vein of Marshall was consistently located anterior to the left‐sided pulmonary veins and posterior to the left atrial appendage, overlying the left atrial endocardial ridge. Conclusions: Myocardial extensions into the pulmonary veins are usually circumferential at the ostia validating the necessity for wide area rather than segmental ablation to isolate these veins during AF ablation. Myocardial extensions into the SVC are common and less likely to be circumferential, whereas extensions into the IVC are not present. The left atrial ridge is a reliable endocardial target for radiofrequency ablation of the vein of Marshall. (J Cardiovasc Electrophysiol, Vol. 23, pp. 1304‐1309, December 2012)