Myocardial Sleeves Research Articles

Three-Dimensional and Molecular Analysis of the Venous Pole of the Developing Human Heart

Various congenital malformations and many abnormal rhythms originate from the venous pole of the heart. Because of rapid changes during morphogenesis, lack of molecular and lineage data, and difficulties in presenting complex morphogenetic changes in the developing heart in a clear fashion, the development of this region in human has been difficult to grasp. To gain insight into the development of the different types of myocardium forming the venous pole of the human heart, we performed an immunohistochemical and 3-dimensional analysis of serial sections of human embryos ranging from 22 through 40 days of development. Three-dimensional models were prepared in a novel interactive portable format providing crucial spatial information and facilitating interpretation. As in the mouse, the systemic venous myocardium expresses the transcription factor TBX18, whereas the pulmonary venous myocardium expresses NKX2-5. In contrast to the mouse, a systemic venous sinus is identified upstream from the atrial chambers, albeit initially with nonmyocardial walls. From the outset, as in the mouse, the pulmonary vein empties to a chamber with atrial, rather than systemic venous, characteristics. Compared with the mouse, the vestibular spine is a more prominent structure. The similarities in gene expression in the distinctive types of myocardium surrounding the systemic and pulmonary venous tributaries in man and mouse permit extrapolation of the conclusions drawn from transgenic and lineage studies in the mouse to the human, showing that the systemic and pulmonary venous myocardial sleeves are derived from distinct developmental lineages.

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

Interest for the pulmonary veins has increased in the past decade after the potential arrhythmogenicity of the myocardial sleeve surrounding these structures has been recognized. Furthermore, there are several clinical entities, such as anomalous connection pattern and pulmonary vein stenosis, that are related to abnormal pulmonary vein development. In this review, we will describe current literature and aim to elucidate and reorganize current opinions on normal and abnormal pulmonary vein development in relation to clinical (management of) diseases. Several unresolved questions will be addressed, as well as current conceptual controversies. First, a general overview of development of structures at the venous pole of the heart, including normal development of the pulmonary vein from a primitive Anlage, will be provided. Recent insights indicate an important contributory role of the mesoderm behind the heart, the so-called second heart field, to this area. Subsequently, the formation of a myocardial and smooth muscle vascular wall of the pulmonary veins and the left atrium is described, as well as current insights in the mechanisms involved in the differentiation of these different cell types in this area. Next, developmental concepts of normal pulmonary venous drainage patterns are reviewed, and an overview is provided of clinical entities related to abnormal development at several anatomical levels. Lastly, attention is paid to arrhythmogenesis in relation to pulmonary vein development, as well the consequences for clinical management.

Is verapamil a double-edged sword in rate control of paroxysmal atrial fibrillation?

Over the last decade, remarkable progress has been made in the field of atrial fibrillation (AF) pathophysiology and management. There is no doubt that radiofrequency catheter ablation therapy improves the quality of life and left ventricular function in patients with symptomatic AF by improving the maintenance of sinus rhythm. 1 A new antiarrhythmic agent, dronedarone, was recently shown to reduce the composite outcome of cardiovascular hospitalization and death in patients with AF. 2 Moreover, novel approaches such as the dominant frequency (DF) analysis of atrial electrograms have offered clinicians a better insight into the pathogenesis of AF. 3 Despite these advancements, longterm maintenance of sinus rhythm is challenging, and persistent or permanent AF still develops in many patients. In these cases, control of the ventricular rate has an essential role in alleviating the symptoms and preventing the development of tachycardia-induced cardiomyopathy. Spectral analysis of atrial recordings increasingly has been used to detect areas with high atrial activation rate during AF. The main benefit of frequency domain analysis is that it can be applied to the complex electrograms of AF more easily than time domain measurements. 3 Experimental and clinical studies indicate that the DF sites within the pulmonary veins (PV) have an important role in the initiation and maintenance of paroxysmal AF. 4,5 Furthermore, it has been postulated that DF mapping can be used to guide rapid identification of extrapulmonary sites that drive AF. 6 In this issue, Kushiyama et al 7 report the results of a study that evaluated the effects of verapamil on regional distribution of DFs in the PVs and atria in 43 patients undergoing catheter ablation of paroxysmal AF. They found that the highest DF was localized in the PVs and showed that there was a substantial PV-to-atria DF gradient at baseline. These findings are in agreement with previous studies indicating that the PVs are the main drivers of paroxysmal AF. 4,5 It is well established that beta-blockers, calcium channel antagonists, and digitalis slow ventricular rate, but much fewer data are available on their effect on atrial arrhythmogenesis. Verapamil is a nondihydropyridine calcium channel antagonist with potent negative chronodropic and dromodropic effects. Due to its use-dependent dromodropic action, verapamil is highly effective in controlling rapid ventricular rate in AF, but has less effect on atrioventricular (AV) nodal conduction at a normal rate. Kushiyama et al 7 showed that verapamil caused variable changes in the PV excitation. The maximum PV DF increased in 65% of the patients and decreased in the remaining 35%. In contrast, verapamil consistently increased the DFs in all of the atrial recording sites. As a result of these tissue-specific effects, verapamil eliminated the PV-to-atria DF gradient. According to the investigators, this is attributable to regional heterogeneities of action potential morphology and ionic currents responsible for the repolarization (e.g., I CaL ) in the PV myocardial muscle sleeves and atria rather than to a reflex increase in sympathetic tone in response to a reduction in blood pressure. Prior studies indicate that the extrapulmonary DF areas and the absence of the PV-to-atria frequency gradient can be used to identify additional ablation targets. For example, Lin et al 6 have shown that the DF shifts to the right atrium when AF is initiated in the superior vena cava. Sanders et al 5 reported that termination of permanent AF requires ablation of extrapulmonary high-frequency sites in addition to PV isolation. Hence, it is tempting to speculate that ablation of the verapamil-induced atrial high-frequency areas may improve the long-term efficacy of catheter ablation of paroxysmal AF. The results of Kushiyama et al 7 are also important with regard to rate control of AF because they raise the possibility that verapamil may provoke paroxysmal AF by creating new high-frequency sources in the atria. In keeping with this, verapamil facilitated the induction of sustained AF. That is, in all of the 6 patients with no inducible AF at baseline, sustained AF was easily induced after verapamil by burst pacing from the coronary sinus. These findings are consistent with experimental data indicating that verapamil promotes maintenance of AF by shortening the atrial refractory period and AF cycle length and enhancing reentrant activity in the atria. 8 In lieu of these data, the usefulness of verapamil for ventricular rate control in patients with paroxysmal AF may be limited by its profibrillatory effect in

Atrial fibrillation: A developmental point of view

The myocardial sleeves of the systemic venous tributaries and the pulmonary veins are known to be common anatomic substrates for atrial fibrillation. Rapidly evolving evidence has shown that a substantial part of the paroxysmal variant of this abnormal rhythm has a familial heritage, and the number of genes found to be involved is increasing. One of the mechanisms underlying the condition is ectopic pacemaking activity. Knowledge of the normal embryological development of the atrial myocardium, in particular the myocardial sleeves clothing the systemic venous tributaries and the pulmonary veins at their junctions with the atrial chambers, may contribute to the understanding of the origins of such ectopic pacing. In this respect, it is now well established that the myocardial sleeves of the systemic venous tributaries have a distinct origin and program of gene expression when compared with the pulmonary venous myocardium. The myocardium clothing the pulmonary veins, however, is particularly susceptible to changes in the levels of gene expression, with the changes then favoring the presence of genes responsible for pacemaking. Only recently has interest developed in the genetic and heritable bases of atrial fibrillation, and much is still to be learned. Better understanding of both the developmental and genetic factors, nonetheless, will surely be helpful in the diagnosis, prevention, and treatment of this troublesome arrhythmia. With this in mind, therefore, we have reviewed the current knowledge concerning the initial development of the pulmonary venous myocardium, emphasizing its crucial differences from the systemic venous myocardium.

Supravalvular Arrhythmia

Supravalvar ablation has now been well documented to be the ideal mode for ablating specific forms of ventricular tachycardia, atrial tachycardia, and accessory pathways. A studied appreciation of the anatomy of the supravalvar region is a prerequisite for electrophysiologists to safely and effectively approach these arrhythmias. In addition, the consistent ability to correlate the recorded electrograms with fluoroscopic anatomy and intracardiac ultrasound images enhances the chance of successful elimination of supravalvar arrhythmias.

CT Visualization of Cryoablation in Pulmonary Veins

Over 2 million adults in the United States are affected by atrial fibrillation (AF), a common cardiac arrhythmia that is associated with decreased survival, increased cardiovascular morbidities, and a decrease in quality of life. AF can be initiated by ectopic beats originating in the myocardial sleeves surrounding the pulmonary viens. Pulmonary vein (PV) isolation via radio frequency ablation is the current gold standard for treating patients with drug-refractory AF. However, cryoablation is emerging as a new minimally-invasive technique to achieve PV isolation. Cryoablation is fast gaining acceptance due to its minimal tissue disruption, decreased thrombogenicity, and reduced complications (RF can lead to low rate of stenosis). One important question in regard to this technology is whether the PV lesion is transmural and circumferential and to what extent adjacent tissues are involved in the freezing process. As ice formation lends itself to image contrast in the body, we hypothesized that intraprocedural CT visualization of the iceball formation would allow us to predict the extent of the cryolesion and provide us with a measure of the adjacent tissue damage. Cryoablation was performed using a prototype balloon catheter cryoablation system (Boston Scientific Corporation). CT visualization of iceball formation was assessed both in vitro and in vivo. Initial in vitro studies were performed in agarose gel phantoms immersed in a 37°C water bath. Subsequently, in vivo cryoablations were performed in 5 PV ostia in 3 crossbred farm swine. The catheters were positioned in the ostia under fluoroscopic guidance. CT scans of the thoracic region were obtained every 2.5 minutes. Animals were sacrified 6 days after the procedures. Gross pathology and histology of tissues in the region of interest were evaluated. Significant metal artifacts from the catheter and edge artifacts from the tissues surrounding the cryoballoon were observed under CT imaging both in vitro and in vivo. In vitro, it was found that the size of the iceball was comparable to that observed visually during freezing of agarose gel phantoms. In vivo, contrast change consistent with iceball formation was observed during the ablation in two out of five veins. The most clearly delineated iceball also yielded the clearest morbidity. In this case, esophageal injury on the anterior side proximal to the cryoablation site was noticed during necropsy of the animal in which the iceball was visualized. Transmural and circumferential lesions were obtained in all PVs ablated. We have shown that CT can be used to visualize iceball formation in vitro and in vivo (with limitations) using our cryoablation system. While the iceball in vitro is easily visualized, iceball growth in vivo is most evident once the iceball has grown beyond the PV into the adjacent tissues. This suggests that while CT cannot easily visualize iceball growth in the PV wall itself, it may still be an important tool to guide clinicians and reduce potential morbidities in adjacent tissues. The authors acknowledge Dan Busian (Fairview University Medical Center, Minneapolis, MN) and Dr. Erik Cressman for assistance with CT imaging.

Morphological evidence of muscular connections between contiguous pulmonary venous orifices: Relevance of the interpulmonary isthmus for catheter ablation in atrial fibrillation

Electrophysiological studies in patients with atrial fibrillation demonstrated the presence of electrical conduction between superior and inferior left pulmonary veins (PVs) that makes electrical disconnection of individual PVs difficult. Anatomically, the prevalence, sizes, and locations of the interpulmonary connections have not been investigated systematically. We retrieved 112 PVs from 28 patients who died from noncardiac causes (43 +/- 13 years, 17 males). Dissections of subepicardial myocardial strands at the venoatrial junctions were made in 10 hearts, and histological sections were made in the remaining 18 hearts. We found histological variations in the muscular width of the interpulmonary isthmus between ipsilateral left and right PVs (2.7 +/- 0.5 mm vs 1.7 +/- 0.5 mm; P <.05). Histologic sections of 15 hearts revealed myocardial strands 0.2-3.5 mm thick crossing obliquely at the left isthmus in 53%, at the right isthmus in 33%, and at both isthmuses in 14% of hearts to connect with the myocardial sleeves of adjacent veins. In 40% of hearts there were additional direct bridges connecting the anterior or posterior walls of the veins. The crossing myocardial strands were at the epicardial (27% of hearts), subendocardial (53% of hearts), and both (20%) aspects of the PV wall. The mean distance between the endocardium of the interpulmonary isthmus to the muscular connections was 2.5 +/- 0.5 mm in the left-sided PVs and 1.5 +/- 0.5 mm in the right-sided PVs. Crossing myocardial strands and bridges at the interpulmonary isthmus may be the anatomical substrate for electrical connection between superior and inferior PVs and may have implications for local PV isolation in patients with atrial fibrillation.

Pulmonary vein and atrial wall pathology in human total anomalous pulmonary venous connection

Background Normally, the inside of the left atrial (LA) body and pulmonary veins (PVs) is lined by vessel wall tissue covered by myocardium. In total anomalous pulmonary venous connection (TAPVC), no connection of the PVs with the LA body exists. These veins have an increased incidence of PV stenosis. We describe the consequences of the absent connection for the histopathology of the wall of the LA body and the PVs, and hypothesize on a mechanism predisposing to PV stenosis. Methods and results In 10 human neonates with TAPVC, the wall of the LA body and PVs were studied using histological and immunohistochemical techniques. As controls, 2 normal neonatal and adult hearts and 5 neonatal hearts with partial anomalous venous connection (PAPVC) or situs inversus were studied. In hearts with TAPVC no vessel wall tissue was found in the LA body and its myocardial layer was hypoplastic. No myocardial sleeve was found around the abnormally draining PVs. In hearts with PAPVC, only the non-LA draining PV lacked myocardial covering, whereas in situs inversus PVs connecting to the right-sided LA, were normally myocardialized. Conclusion An open connection of the PVs with the morphological LA is necessary for the presence of vessel wall tissue in the LA and myocardialization of the PVs. Absence of myocardium covering the PVs is hypothesized to enhance susceptibility to PV stenosis and prevent onset of PV originating arrhythmias. The embryonic posterior heart field may be responsible for the abnormal myocardialization and smooth muscle cell formation in TAPVC.

Spontaneous onset of atrial fibrillation

Most commonly, atrial fibrillation is triggered by rapid bursts of electrical impulses originating in the myocardial sleeves of pulmonary veins (PVs). However, the nature of such bursts remains poorly understood. Here, we propose a mechanism of bursting consistent with the extensive empirical information about the electrophysiology of the PVs. The mechanism is essentially non-local and involves the spontaneous initiation of non-sustained spiral waves in the distal end of the muscle sleeves of the PVs. It reproduces the experimentally observed dynamics of the bursts, including their frequency, their intermittent character, and the unusual shape of the electrical signals in the pulmonary veins that are reminiscent of so-called early afterdepolarizations (EADs).

Refractoriness of the Sheep Superior Vena Cava Myocardial Sleeve

The cardiomyocytes in the superior vena cava (SVC) myocardial sleeve have distinct action potentials and ionic current profiles, but the refractoriness of these cells has not been reported. Using standard intracellular microelectrode techniques, we demonstrated in sheep that the effective refractory period (ERP) of the cardiomyocytes in the SVC (114.7 +/- 6.5 ms) is shorter than that in the inferior vena cava (IVC) (166.7 +/- 6.2 ms), right atrial free wall (RAFW) (201.0 +/- 6.0 ms) and right atrial appendage (RAA) (203.1 +/- 5.8 ms) (P < 0.05). The right atrial cardiomyocyte ERP was heterogeneously shortened by acetylcholine, a muscarinic type 2 receptor (M(2)R) agonist. After perfusion with 15 microM acetylcholine, the shortest ERP occurred in the SVC (the ERP in the SVC, IVC, RAFW and RAA was 53.6 +/- 2.7, 98.9 +/- 2.2, 121.8 +/- 6.0 and 109.7 +/- 5.1 ms, respectively; P < 0.05). Carbachol (1 microM), another M(2)R agonist, produced a similar effect as acetylcholine. Furthermore, we used methoctramine, a M(2)R blocker, 4-DAMP, a muscarinic type 3 receptor (M(3)R) blocker, and tropicamide, a muscarinic type 4 receptor (M(4)R) blocker to inhibit the acetylcholine-induced ERP shortening of SVC cardiomyocytes, and found that the 50% inhibitory concentration for methoctramine, 4-DAMP and tropicamide was 5.91, 45.72 and 80.34 nM, respectively. Therefore, we conclude that the sheep SVC myocardial sleeve is a unique electrophysiological region of the right atrium with the shortest ERP both under physiological condition and under cholinergic agonist stimulation. M(2)R might play a major role in the response of the SVC myocardial sleeve to parasympathetic nerve tone. The association between the distinct refractoriness in SVC and atrial fibrillation originating from the region deserves further investigation.

Interstitial Cajal‐like cells (ICLC) in myocardial sleeves of human pulmonary veins

We present here evidence for the existence of a new type of interstitial cell in human myocardial sleeves of pulmonary veins: interstitial Cajal-like cell (ICLC). This cell fulfils the criteria for positive diagnosis of ICLC, including CD 117/c-kit positivity. Transmission electron microscopy revealed typical ICLC with 2 or 3 very long processes (several tens of mm) suddenly emerging from the cellular body. Also, these processes appear moniliform but extremely thin (0.1–0.4 mm) under the resolving power of the usual microscopy. Cell processes establish close spatial relationships between each other, as well as with capillaries and nerve endings. ICLC appear located among the myocardial cells and particularly at the border between the myocardial sleeve and pulmonary vein wall.

Role of the Calpain System in Pulmonary Vein Connexin Remodeling in Dogs with Atrial Fibrillation

Objectives: Changes in connexins and calpains of the myocardial sleeve of the pulmonary vein and the left atrium were investigated in chronic atrial fibrillation (AF) animal models. Background: There are no reports of changes in the calpain system and connexins in the pulmonary vein where AF is initiated. Methods: An AF animal model was prepared by rapid pacing of the right atrium for 8 weeks. Histological changes of pulmonary veins were analyzed by Masson trichrome staining, and mRNA as well as protein expression of connexins and calpains were measured by real-time fluorescence quantitative PCR and Western blotting. Results: In AF dogs, the fibrous collagen reticulum surrounding individual myocardial cells was reduced or disrupted. In the myocardial sleeve of the AF dogs, Cx40 protein expression was significantly downregulated compared to the control group (60.78 ± 10.91 vs. 88.31 ± 14.73, p < 0.05), but calpain 1 was significantly upregulated (94.00 ± 7.24 vs. 81.77 ± 5.82, p < 0.05), and they were negatively correlated (r = –0.66, p < 0.05). Cx40 protein expression was significantly lower in the myocardial sleeve tissue than in the left atrium in the AF dogs (60.78 ± 10.91 vs. 91.38 ± 17.16, p < 0.05). Conclusions: Varied gap junctional remodeling around the pulmonary vein may be one of the underlying mechanisms for pulmonary vein-left atrial reentry. During AF, the calpain system of the myocardial sleeve tissue is activated and may hydrolyze Cx40 protein, which is a possible important molecular mechanism for gap junctional remodeling that merits further investigation.

Distinguishing Properties of Cells From the Myocardial Sleeves of the Pulmonary Veins

Background— A common source of arrhythmogenic spontaneous activity instigating atrial fibrillation is the myocardial tissue, or sleeves, at the base of the pulmonary veins. This study compared the properties of cells from the myocardial sleeves of the pulmonary veins (PV m ) with cells from the normal cardiac pacemaker (the sinoatrial node) and regions of the atria. Our objective was to identify key features of these cells that predispose them to becoming the focus of cardiac arrhythmias. Methods and Results— Single cells were isolated from samples of rabbit PV m , central and peripheral sinoatrial node, crista terminalis, and left and right atria. Detailed morphology of cells was assessed and intracellular calcium concentrations measured with the use of Fluo-3. Cells from the PV m were smaller than atrial cells and showed large elevations in diastolic calcium during activation at physiological rates, a feature the PV m cells shared with cells from the sinoatrial node. Unstimulated spontaneous activity was observed in a minority of cells from the PV m , but numerous cells from this region showed spontaneous activity for a brief period immediately subsequent to stimulation at physiological rates. This was not observed in atrial cells. Assessment of calcium removal pathways showed sarcolemmal calcium extrusion in cells from the PV m to have a high reliance on “slow” extrusion pathways to maintain intracellular calcium homeostasis because of a low expression of sodium–calcium exchanger. Conclusions— We conclude that cells from the PV m share some features with cells from the sinoatrial node but also have distinctly unique features that predispose them to the development of spontaneous activity.

Abstract 742: Inducibility of Atrial Fibrillation in the Myocardial Sleeve of the Superior Vena Cava is Mediated by the Ganglionated Plexi on the Right Pulmonary Artery

Introduction: Previous studies have shown that electrical stimulation of the ganglionated plexi (GP) on the right pulmonary artery (RPA), the so-called “3rd fat pad (FP)” causes slowing of the sinus rate and AV conduction. Ablation of this GP prevents induction of atrial fibrillation (AF) caused by vagosympathetic nerve (VNS) stimulation and atrial premature beats (APBs). Methods: Eleven dogs anesthetized with Na-pentobarbital were subjected to a right thoracotomy at the 4 th intercostal space. The RPA at the upper lobe of the right lung was dissected and the distal end tied in order to insert and stabilize an 8 Fr. Sheath into the RPA. A small basket electrode catheter, consisting of 5 splines, each spline containing 3 pairs of bipolar electrodes, was inserted into the RPA underneath the superior vena cava (SVC). A Lasso catheter, inserted through a sheath in the right jugular vein was positioned in the SVC contacting the sleeve of myocardium at the SVC-right atrial (RA) junction. Octapolar electrode catheters were sutured against the right superior, inferior pulmonary veins (PVs), RA and RA appendage. Through a left sided thoracotomy, similar placements of recording electrode catheters were made at the left superior, inferior PVs and left atrium (LA) body and appendage. Right and left vagosympathetic nerve stimulation (VNS, frequency, 20 Hz; stimulus duration, 0.01 ms; voltage 1.5– 4.5 Volts) slowed the heart rate (HR) by 50% or induced 2:1 AV block. The RPA GP was also stimulated to achieve similar effects on HR and AV block. Results: RPA GP stimulation consistently and significantly reduced the threshold for AF inducibility (control 8±3; RPA GP stimulation 3.2±1.5 volts, p&lt;0.01) whereas after RPA GP ablation, the averaged voltage to induce AF was increased to 11.5±1.5 although 7 of 11 showed non-inducibility at the maximum voltage used (12 volts). The inducibility threshold at the other atrial and PV sites were unchanged by RPA GP stimulation before or after RPA GP ablation (p=NS). Moreover, there was a loss of HR slowing and AV block with VNS stimulation. Conclusion: RPA GP stimulation which markedly decreased HR or AV conduction selectively suppressed AF inducibility at the myocardial sleeve of the SVC but did not affect AF inducibility at other atrial sites.

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.

Bidirectional superior vena cava: right atrial conduction delay during tachycardia

The superior vena cava, like all the thoracic veins, has myocardial sleeves and plays a role in initiation and perpetuation of atrial fibrillation. Conduction delay between it and the right atrium has been shown previously. This case study shows delay in both directions during different arrhythmias in the same patient.

Noncontact mapping of small pulmonary artery potentials preceding ectopy from the right ventricular outflow tract

Idiopathic right ventricular tachycardia typically originates from the right ventricular outflow tract (RVOT). However, it also may originate from above the pulmonic valve. We describe a patient with a 2-year history of symptoms of palpitations associated with premature ventricular contractions (PVCs) in whom radiofrequency catheter ablation at the PVC exit site in the lateral RVOT failed despite the presence of several favorable criteria. However, using a multiple electrode array catheter, we demonstrated above the pulmonic valve clear evidence of low-amplitude preceding electrical activity ("blue ghost") that swept 3 cm inferolaterally over 20 ms to the previously identified lateral RVOT exit. Catheter mapping even at 128x gain demonstrated only very-low-amplitude potentials at this site, and pacing was unable to capture the ventricle from this region. However, ablation at this site immediately terminated the arrhythmia, and the patient has remained PVC-free after 1 year. This case supports the existence of previously hypothesized myocardial sleeves above the pulmonary valve that may be responsible for RVOT tachycardia and shows that they can be detected using noncontact mapping.

Versican proteolysis mediates myocardial regression during outflow tract development

An important phase of cardiac outflow tract (OFT) formation is the remodeling of the distal region of the common outlet in which the myocardial sleeve is replaced by with smooth muscle. Here we demonstrate that expression of the proteoglycan versican is reduced before the loss of myocardium from the distal cardiac outlet concomitant with an increase in production of the N-terminal cleavage fragment of versican. To test whether versican proteolysis plays a role in OFT remodeling, we determined the effects of adenoviral-mediated expression of a versican isoform devoid of known matrix metalloproteinase cleavage sites (V3) and an N-terminal fragment of versican (G1). V3 expression promoted an increase in thickness of the proximal OFT myocardial layer independent of proliferation. In contrast, the G1 domain caused thinning and interruptions of the OFT myocardium. These in vivo findings were consistent with findings using cultured primary cardiomyocytes showing that the V3 promoted myocardial cell-cell association while the G1 domain caused a loss of myocardial cell-cell association. Taken together, we conclude that intact versican and G1-containing versican cleavage products have opposing effects on myocardial cells and that versican proteolysis may facilitate the loss of distal myocardium during OFT remodeling.

Arrangement of the Autonomic Nerves Around the Pulmonary Vein-Left Atrial Junctions —Histologic and Immunohistochemical Analyses—

Introduction: Imbalanced autonomic activity in the area of the pulmonary veins (PVs) can result in spontaneous atrial fibrillation (AF). Histologic characteristics of the PV sleeve musculature and associated autonomic nerve are not fully understood. We investigated the arrangement of autonomic nerve fibers around PV‐left atrium (LA) junctional musculature.Methods: Thirteen autopsied adult hearts (9 men and 4 women; mean age at death, 66.2 years were studied. The atria were removed from each heart, along with all PV stalks, and cut longitudinally to each PV myocardial sleeve. After treatment with azan‐Mallory stain and immunohistochemical staining for S‐100 and tyrosine hydroxylase (TH), autonomic nerve distribution was assessed by counting the numbers of TH‐positive (adrenergic and ‐negative (non‐adrenergic) fibers within S‐100‐positive fibers (&gt;50 mm in diameter) in the anterior, posterior, and septal junctions.Results: TH‐positive adrenergic fibers, consisting of sympathetic nerves, were most predominant in the anterior and septal junctions. In the anterior junction, these fibers were packed tightly among myocardial sleeve fascicles. In the posterior junction, the numbers of adrenergic and non‐adrenergic fibers were fewer. In the septal junction, the number of THnegative non‐adrenergic fibers (predominantly parasympathetic nerves) was greater, concomitant diffuse ganglionic nodule distribution in the interatrial fat pad.Conclusions: In each PV‐LA junction, autonomic nerves were localized on the anterior and septal walls. Heterogeneous distribution of TH‐positive and TH‐negative fibers and ganglion nodules around each PV opening appears to represent the major histologic characteristic in these areas.

The neural basis of atrial fibrillation

This review addresses recent basic and clinical studies which suggest that targeting autonomic nerves and ganglia on the heart can result in suppression of atrial fibrillation (AF) with less damage to myocardium than the presently employed procedure which involves extensive pulmonary vein (PV) isolation from the rest of the left atrium. Clinical studies Clinical electrophysiologists in 1998 discovered that the majority of patients with paroxysmal form of AF, resistant to drugs and cardioversion, had focal, ectopic firing arising from the myocardial sleeves covering the PVs. They developed a strategy which called for inducing radiofrequency lesions which would supposedly isolate the PVs from the atria thereby curing this form of AF. To date this strategy has had limited success (70-85%). A new approach relies on targeting the ganglionated plexi (GP) at the entrances of the PVs. Several clinical reports provide evidence that this new approach can increase the success rate for radiofrequency ablation of paroxysmal AF (91-99%). Basic studies Experimental investigations in animal studies, both in vivo and in vitro, have accumulated evidence for a mechanistic basis for the ablation of GP to terminate paroxysmal AF. Specifically, release of the neurotransmitter, acetylcholine, from these GP causes shortening of atrial and PV sleeve refractoriness. In addition, the concomitant release of adrenergic neurotransmitters mobilizes excess calcium intracellularly leading to early afterdepolarizations and triggered firing particularly in PV cells. We conclude that hyperactivity of these local cardiac GP play a critical role in initiating the paroxysmal form of AF resistant to drugs and cardioversion. Targeting the GP for ablation can substantially increase the success rate for terminating AF in these patients.