Treatment outcome of patients with synchronous oligometastatic non-small cell lung cancer in the immunotherapy era: Analysis of a real-life intention-to-treat population.

The standard first-line treatment for non-oncogene driven metastatic non-small cell lung cancer (NSCLC) is an immune checkpoint inhibitor (ICI) based strategy. Although guidelines increasingly advise adding local radical treatment (LRT) to patients with synchronous oligometastatic (sOMD) NSCLC responding to systemic therapy, this recommendation is based on the studies without ICI. Furthermore, the majority of published oligometastatic studies were not on an intention-to-treat basis, resulting in selection bias. Moreover, staging Positron Emission Tomography-Computed Tomography (PET-CT) and brain imaging were often not mandatory and definitions of oligometastatic were heterogeneous. Therefore, this study focused on a single centre retrospective series, including all adequately staged patients with sOMD NSCLC according to the European Organisation for Research and Treatment of Cancer definition (maximum of 5 metastases in 3 organs) that were treated with induction (chemo)-ICI and compared outcomes to those treated with chemotherapy only, with and without LRT. The primary end-points were median progression-free survival (PFS) and overall survival (OS) for patients treated with induction (chemo)-ICI versus chemotherapy. Out of 68 included patients, 38 (56%) eventually received LRT. With a median follow-up of 26.7 months, the median PFS was 19.0 months for (chemo)-ICI (n = 18) versus 6.8 for chemotherapy-only (n = 50) (HR 0.5, p = 0.03), the median OS was 19.3 versus 15.7 months, respectively (HR 0.8, p = 0.4). In patients having received LRT, median PFS was 19.0 months for (chemo)-ICI versus 8.3 for chemotherapy-only (HR 0.6, p = 0.2). In conclusion, an ICI-based systemic treatment is feasible and may result in superior survival outcomes. This should be investigated in prospective trials. Strategies to improve response rates to systemic treatment are also needed.

A percutaneous treatment strategy of an adult patient with a bicuspid aortic valve, coarctation of the aorta, and an exceptionally large aneurysm of a collateral artery: Case report and literature overview.

Coarctation of the aorta (CoA) is a congenital heart defect that is associated with a bicuspid aortic valve (BAV), ascending aorta dilatation, intracerebral aneurysms, and premature atherosclerotic disease. The first presentation during late adulthood is rare and is frequently driven by late sequelae. Hypertrophic collateral arteries can develop aneurysms which are at risk for spontaneous rupture, however, treatment recommendations for these aneurysms are scarce. Here, we describe the clinical course and percutaneous treatment strategy of a patient with a late diagnosis of a pin-point CoA, a BAV with moderate regurgitation, and an exceptionally large aneurysm of a collateral artery. A 59-year-old woman was diagnosed with Streptococcus bovis endocarditis of a BAV with moderate aortic valve regurgitation and small vegetation (<5 mm) on the non-coronary cusp. Work-up revealed hypertension and adenocarcinoma in situ of the ascending colon, considered the bacteremia porte d'entrée, for which a curative hemicolectomy was performed. Echocardiography showed a narrowing of the aorta distal from the origin of the left subclavian artery with the antegrade diastolic flow with a pathognomonic "sawtooth" pattern and an estimated pressure gradient of >70 mmHg. Computed tomography angiography (CTA) showed a network of well-developed collateral arteries and a levoatriocardinal vein. One of the collateral arteries arising from the left subclavian artery revealed an exceptionally large aneurysmatic dilation (29 × 24 × 24 mm). The invasive assessment confirmed a hemodynamically significant CoA. Treatment involved balloon dilatation and placement of a covered stent at the site of the pin-point CoA and a percutaneous coronary intervention (PCI) of the stenosis in the left anterior descending artery. No residual gradient over the CoA was observed. Antihypertensive drugs could be discontinued, and CTA performed 4 months later showed regression and thrombosis of the numerous collaterals and, importantly, thrombosis of the large aneurysm. This case illustrates the late diagnosis of CoA with associated congenital heart defects and late sequelae including hypertension, BAV endocarditis, coronary artery disease, and aneurysm formation of the extensive collateral network. The patient underwent pharmacological and percutaneous treatment, ultimately resulting in the alleviation of the CoA, normalization of the blood pressure, reduction of collateral flow, and thrombosis of the large aneurysm of the collateral artery.

The first multicentre study on coronary anomalies in the Netherlands: MuSCAT.

BACKGROUND: Current guidelines on coronary anomalies are primarily based on expert consensus and a limited number of trials. A gold standard for diagnosis and a consensus on the treatment strategy in this patient group are lacking, especially for patients with an anomalous origin of a coronary artery from the opposite sinus of Valsalva (ACAOS) with an interarterial course. AIM: To provide evidence-substantiated recommendations for diagnostic work-up, treatment and follow-up of patients with anomalous coronary arteries. METHODS: A clinical care pathway for patients with ACAOS was established by six Dutch centres. Prospectively included patients undergo work-up according to protocol using computed tomography (CT) angiography, ischaemia detection, echocardiography and coronary angiography with intracoronary measurements to assess anatomical and physiological characteristics of the ACAOS. Surgical and functional follow-up results are evaluated by CT angiography, ischaemia detection and a quality-of-life questionnaire. Patient inclusion for the first multicentre study on coronary anomalies in the Netherlands started in 2020 and will continue for at least 3 years with a minimum of 2 years of follow-up. For patients with a right or left coronary artery originating from the pulmonary artery and coronary arteriovenous fistulas a registry is maintained. RESULTS: Primary outcomes are: (cardiac) death, myocardial ischaemia attributable to the ACAOS, re-intervention after surgery and intervention after initially conservative treatment. The influence of work-up examinations on treatment choice is also evaluated. CONCLUSIONS: Structural evidence for the appropriate management of patients with coronary anomalies, especially (interarterial) ACAOS, is lacking. By means of a structured care pathway in a multicentre setting, we aim to provide an evidence-based strategy for the diagnostic evaluation and treatment of this patient group.

Lack of diagnostic utility of the ECG-derived ventricular gradient in patients with suspected acute pulmonary embolism.

INTRODUCTION: The YEARS algorithm was successfully developed to reduce the number of computed tomography pulmonary angiography (CTPA) investigations in the diagnostic management of patients with suspected pulmonary embolism (PE), although half of patients still needed to be referred for CTPA. We hypothesized that ECG derived ventricular gradient optimized for right ventricular pressure overload (VG-RVPO), an easy to use tool for detecting PE-induced pulmonary hypertension (PH), may further improve the efficiency of the YEARS algorithm. METHODS: In this post-hoc analysis of the Years study, ECGs of 479 patients with suspected PE managed according to the YEARS algorithm were available for analysis. The diagnostic performance of VG-RVPO was assessed and likelihood ratios were calculated. RESULTS: PE was diagnosed in 88 patients (18%). In patients with confirmed PE, 34% had an abnormal VG-RVPO versus 24% of those without PE (odds ratio 1.6; 95%CI 0.94-2.6). The mean VG-RVPO was -22 ± 13 and did not differ between the two patient groups (-22 versus -20; mean difference - 2, 95% CI -4.8 to 1.3). The sensitivity of VG-RVPO for PE was 24% (95%CI 34-45), the specificity 76% (95%CI 71-80) and the c-statistic 0.45 (95% CI 0.38-0.51). When combined with the YEARS algorithm, the likelihood ratios of VG-RVPO remained close to 1.0. Ruling out PE in patients with an indication for CTPA based on a normal VG-RVPO would have resulted in 58 missed cases. CONCLUSIONS: The VG-RVPO has no diagnostic value for suspected acute PE, either as stand-alone diagnostic test or combined with the YEARS algorithm. CONDENSED ABSTRACT: This post-hoc analysis of the YEARS study failed to demonstrate incremental diagnostic value of VG-RVPO for acute PE, either as stand-alone diagnostic test or combined with the YEARS algorithm. Nevertheless, the role of VG-RVPO recorded on admission could potentially be valuable in the risk stratification of PE during hospitalization, although this remains to be studied.

Human adult cardiac autonomic innervation: Controversies in anatomical knowledge and relevance for cardiac neuromodulation.

BACKGROUND: Cardiac sympathetic blockade is a therapeutic approach for arrhythmias and heart failure and may be a beneficial effect of high thoracic epidural anesthesia. These treatments require detailed knowledge of the spatial location and distribution of cardiac autonomic nerves, however, there are controversies on this subject in humans. OBJECTIVE: To provide a systematic overview of current knowledge on human anatomy of the cardiac autonomic nervous system. RESULTS: In contrast to the often claimed assumption that human preganglionic sympathetic cardiac neurons originate mainly from thoracic spinal segments T1-T4 or T5, there is ample evidence indicating involvement of cervical spinal segment C8 and thoracic spinal segments below T5. Whether cervical ganglia besides the stellate ganglion play a role in transmission of cardiac sympathetic signals is unclear. Similarly, there is debate on the origin of cardiac nerves from different thoracic ganglia. Most human studies report thoracic cardiac nerves emerging from the first to fourth thoracic paravertebral ganglia; others report contributions from the fifth, sixth and even the seventh thoracic ganglia. There is no agreement on the precise composition of nerve plexuses at the cardiac level. After years of debate, it is generally accepted that the vagal nerve contributes to ventricular innervation. Vagal distribution appears higher in atria, whereas adrenergic fibers exceed the number of vagal fibers in the ventricles. CONCLUSION: Anatomy of the human cardiac autonomic nervous system is highly variable and likely extends beyond generally assumed boundaries. This information is relevant for thoracic epidural anesthesia and procedures targeting neuronal modulation of cardiac sympathetic innervation.

Ventricular assist device implantation in patients with a failing systemic right ventricle: a call to expand current practice.

Ventricular assist device (VAD) implantation is an established treatment modality for patients with end-stage heart failure, and improves symptoms and survival. In the Netherlands, it is not yet routinely considered in patients with congenital heart disease and failing systemic right ventricle (SRV). Recently, a VAD was implanted in 2 SRV patients, one who underwent a Mustard procedure during infancy for transposition of the great arteries (male, 47 years old) and one with a congenitally corrected transposition of the great arteries (male, 54 years old). The first patient is doing well >1 year after implantation; the second patient will be discharged home soon. These examples and other reports demonstrate the feasibility of adopting VAD implantation into routine care for SRV failure. In conclusion, patients with SRV failure may be suitable candidates for VAD implantation: they are relatively young, usually have a preserved subpulmonary left ventricular function, and their specific anatomical and physiological characteristics often make them unsuitable for cardiac transplantation. Therefore it is important to recognise the possibility of VAD implantation early in the process of SRV failure, and to timely refer these patients to a heart failure clinic with experience in VAD implantation in this group of patients for optimisation, screening, and implantation.

ECG derived ventricular gradient exceeds echocardiography in the early detection of pulmonary hypertension in scleroderma patients.

BACKGROUND: Patients with systemic sclerosis (SSc) are at risk for developing pulmonary hypertension (PH) which is a major cause of death in this population. Echocardiographic (TTE) derived pulmonary arterial pressure (PAP) can be unreliable for the early detection of PH. Previous studies demonstrate that the ECG derived ventricular gradient optimized for right ventricular pressure overload (VG-RVPO) can detect PH in a heterogeneous population suspected of PH. The aim of this study is to assess the use of the VG-RVPO as a screening and monitoring instrument of early PH in SSc patients. METHODS: Serial ECGs and TTEs from twenty-seven SSc patients who underwent right heart catheterization (RHC) were retrospectively analyzed. The changes in PAP and VG-RVPO over time were studied in patients with and without diagnosed PH. RESULTS: Twenty-four patients (52.5% female, mean age 58.4 years SD 14.3) were studied. In eleven patients PH was confirmed with RHC. In these patients VG-RVPO was significantly higher -8 ±â€¯19 than in patients without PH -23 ±â€¯10 mV·ms, (P < 0.05). In addition, in PH patients the VG-RVPO increased over time in contrast to patients without PH (P < 0.01). The VG was more sensitive to detect disease progression in earlier stages of disease as compared to echocardiographic derived PAP. CONCLUSIONS: The VG-RVPO is a sensitive, non-invasive and cost effective tool for early detection of PH in SSc patients. Serial measurements indicate that the VG-RVPO can be used as a follow-up instrument and outperforms TTE to detect early changes in right ventricular pressure over time.

Clinical course of tricuspid regurgitation in repaired tetralogy of Fallot.

BACKGROUND: Little is known on the clinical course of tricuspid regurgitation (TR) in patients with repaired tetralogy of Fallot (rTOF) and which patients are at particular risk. This study aims to determine TR course, characteristics associated with TR progression, and the prognostic relevance of TR in rTOF patients. METHODS: In this dualcenter cohort study, rTOF patients from a prospective national registry with ≥1 cardiac magnetic resonance imaging study and ≥2 echocardiograms available were included. Clinical and imaging data were collected. Cox hazards regression analysis was used to assess patient characteristics associated with progression to severe TR and whether severe TR was associated with the combined clinical endpoint of tachyarrhythmia, heart failure, and death, as time-dependent factor. RESULTS: A total of 216 patients were included (57% men, age 34±12years); 11 patients (5%) had severe TR at baseline. During 7.6±3.5years of follow-up, progression to severe TR occurred in 15 patients (7%). NYHA class ≥2 (HR 5.38, 95%-C.I. 1.91-15.16, p=0.001) and moderate baseline TR (HR 13.10, 95%-C.I. 2.95-58.21, p=0.001) were independently associated with progression to severe TR. Adverse events occurred in 47 patients (22%). The occurrence of severe TR was independently associated with adverse events (HR 3.48, 95%-C.I. 1.68-7.21, p=0.001). CONCLUSIONS: In this study, severe TR was present in 12% of adult rTOF patients during 7.6years, and progression to severe TR was most likely in symptomatic patients with moderate baseline TR. In these patients, close surveillance is warranted, because the occurrence of severe TR was associated with worse prognosis.

NT-proBNP and exercise capacity in adult patients with congenital heart disease and a prosthetic valve: a multicentre PROSTAVA study.

OBJECTIVES: N-terminal B­type natriuretic peptide (NT-proBNP) is an important biomarker for the detection of heart failure. Adults with congenital heart disease (ACHD) and a prosthetic heart valve are at risk for heart failure. This study aimed to determine the value of NT-proBNP in ACHD patients with a prosthetic valve and investigate its relationship with cardiac function and exercise capacity. METHODS: In this multi-centre cross-sectional observational study, data regarding medical history, echocardiography, exercise testing (VO2peak) and laboratory blood evaluation (including NT-proBNP) were collected in ACHD patients with a single prosthetic valve (either homografts, heterografts or mechanical valves). RESULTS: A total of 306 ACHD patients with pulmonary valve replacement (PVR, n = 139), aortic valve replacement (n = 141), mitral valve replacement (n = 21) or tricuspid valve replacement (n = 5) were investigated. The majority of patients (77 %) were in NYHA class I or II. Elevated NT-proBNP levels (cut-off ≥125 pg/ml) were found in 50 % of the patients, with the highest levels in patients with mitral valve replacements. In this study population, NT-proBNP levels were associated with gender (p = 0.029) and VO2max (p < 0.001). In PVR patients, NT-proBNP levels were associated with lower VO2peak, also after adjustment for age, gender and age at valve replacement in a multivariate model (p = 0.015). CONCLUSIONS: In patients with ACHD and a prosthetic valve, elevated NT-proBNP levels are frequently observed despite preserved NYHA class. In PVR patients, a higher NT-proBNP level was associated with a lower VO2peak. These results may be of importance in the ongoing discussion about the timing of valve replacement in patients with CHD.

Cardiac adaption during pregnancy in women with congenital heart disease and healthy women.

OBJECTIVE: Pregnancy in women with congenital heart disease (CHD) is associated with deterioration in cardiac function. However, longitudinal data are scarce. This study describes serial changes in cardiac dimensions and function during pregnancy in women with CHD and compares these with healthy pregnant women (controls). METHODS: Eight tertiary centres prospectively enrolled 125 pregnant women with CHD (pregnancy duration <20 weeks). Controls (N=49) were recruited from low-risk midwife practices. Standardised echocardiography at 20 and 32 weeks gestation and 1 year postpartum was performed. RESULTS: Age and parity were comparable between both groups (p>0.1). Left ventricular ejection fraction (LVEF) <45% was present in 3.2% of women with CHD and 14.4% had tricuspid annular plane systolic excursion (TAPSE) <16 mm. Absolute values of ventricular function parameters and diameters were less favourable in women with CHD. No permanent changes occurred in right and left ventricular function parameters and dimensions in women with CHD. The patterns of change in cardiac function and dimensions were comparable between women with CHD and controls, except for LVEF (p=0.026). In women with right-sided CHD the pattern of TAPSE over time differed from controls (p=0.043) (no decrease in TAPSE postpregnancy in CHD). In women with left-sided CHD left ventricular end-diastolic diameter (LVEDD) tended to increase compared with controls (p=0.045). CONCLUSIONS: Absolute levels of ventricular function parameters and diameters differ between CHD and controls, but changes during and after pregnancy are generally comparable. However, different patterns over time seen for TAPSE and LVEDD in women with right-sided and left-sided CHD, respectively, compared with controls indicate the importance of echocardiographic follow-up during pregnancy in women with CHD.

Tailored circulatory intervention in adults with pulmonary hypertension due to congenital heart disease.

BACKGROUND: Adults with pulmonary hypertension associated with congenital heart disease (PH-CHD) often have residual shunts. Invasive interventions aim to optimise pulmonary flow and prevent right ventricular failure. However, eligibility for procedures strongly depends on the adaptation potential of the pulmonary vasculature and right ventricle to resultant circulatory changes. Current guidelines are not sufficiently applicable to individual patients, who exhibit great diversity and complexity in cardiac anomalies. METHODS AND RESULTS: We present four complex adult PH-CHD patients with impaired pulmonary flow, including detailed graphics of the cardiopulmonary circulation. All these patients had an ambiguous indication for shunt intervention. Our local multidisciplinary Grown-Ups with Congenital Heart Disease team reached consensus regarding a patient-tailored invasive treatment strategy, adjacent to relevant guidelines. Interventions improved pulmonary haemodynamics and short-term clinical functioning in all cases. CONCLUSIONS: Individual evaluation of disease characteristics is mandatory for tailored interventional treatment in PH-CHD patients, adjacent to relevant guidelines. Both strict registration of cases and multidisciplinary and multicentre collaboration are essential in the quest for optimal therapy in this patient population.

The extent of the raphe in bicuspid aortic valves is associated with aortic regurgitation and aortic root dilatation.

BACKGROUND: The clinical course of bicuspid aortic valves (BAVs) is variable. Data on predictors of aortopathy and valvular dysfunction mainly focus on valve morphology. AIM: To determine whether the presence and extent of the raphe (fusion site of valve leaflets) is associated with the degree of aortopathy and valvular dysfunction in patients with isolated BAV and associated aortic coarctation (CoA). METHODS: Valve morphology and aortic dimensions of 255 BAV patients were evaluated retrospectively by echocardiography. RESULTS: BAVs with a complete raphe had a significantly higher prevalence of valve dysfunction (especially aortic regurgitation) than BAVs with incomplete raphes (82.9 vs. 66.7 %, p = 0.01). Type 1A BAVs (fusion of right and left coronary leaflets) and complete raphe had larger aortic sinus diameters compared with the rest of the population (37.74 vs. 36.01, p = 0.031). Patients with CoA and type 1A BAV had significantly less valve regurgitation (13.6 vs. 55.8 %, p < 0.001) and smaller diameters of the ascending aorta (33.7 vs. 37.8 mm, p < 0.001) and aortic arch (25.8 vs. 30.2 mm, p < 0.001) than patients with isolated BAV. CONCLUSIONS: Type 1A BAV with complete raphe is associated with more aortic regurgitation and root dilatation. The majority of CoA patients have incomplete raphes, associated with smaller aortic root diameters and less valve regurgitation.

Normal and abnormal development of the aortic wall and valve: correlation with clinical entities.

Dilation of the wall of the thoracic aorta can be found in patients with a tricuspid (TAV) as well as a bicuspid aortic valve (BAV) with and without a syndromic component. BAV is the most common congenital cardiovascular malformation, with a population prevalence of 0.5-2 %. The clinical course is often characterised by aneurysm formation and in some cases dissection. The non-dilated aortic wall is less well differentiated in all BAV as compared with TAV, thereby conferring inherent developmental susceptibility. Furthermore, a turbulent flow, caused by the inappropriate opening of the bicuspid valve, could accelerate the degenerative process in the aortic wall. However, not all patients with bicuspidy develop clinical complications during their life. We postulate that the increased vulnerability for aortic complications in a subset of patients with BAV is caused by a defect in the early development of the aorta and aortic valve. This review discusses histological and molecular genetic aspects of the normal and abnormal development of the aortic wall and semilunar valves. Aortopathy associated with BAV could be the result of a shared developmental defect during embryogenesis.

Prosthetic valves in adult patients with congenital heart disease: Rationale and design of the Dutch PROSTAVA study.

BACKGROUND: Data on long-term complications in adult patients with congenital heart disease (ACHD) and a prosthetic valve are scarce. Moreover, the influence of prosthetic valves on quality of life (QoL) and functional outcome in ACHD patients with prosthetic valves has not been studied. OBJECTIVES: The primary objective of the PROSTAVA study is to investigate the relation between prosthetic valve characteristics (type, size and location) and functional outcome as well as QoL in ACHD patients. The secondary objectives are to investigate the prevalence and predictors of prosthesis-related complications including prosthesis-patient mismatch. METHODS: The PROSTAVA study, a multicentre cross-sectional observational study, will include approximately 550 ACHD patients with prosthetic valves. Primary outcome measures are maximum oxygen uptake during cardiopulmonary exercise testing and QoL. Secondary outcomes are the prevalence and incidence of valve-related complications including prosthesis-patient mismatch. Other evaluations are medical history, physical examination, echocardiography, MRI, rhythm monitoring and laboratory evaluation (including NT-proBNP). IMPLICATIONS: Identification of the relation between prosthetic valve characteristics in ACHD patients on one hand and functional outcome, QoL, the prevalence and predictors of prosthesis-related complications on the other hand may influence the choice of valve prosthesis, the indication for more extensive surgery and the indication for re-operation.

Expression of Id2 in the second heart field and cardiac defects in Id2 knock-out mice.

The inhibitor of differentiation Id2 is expressed in mesoderm of the second heart field, which contributes myocardial and mesenchymal cells to the primary heart tube. The role of Id2 in cardiac development is insufficiently known. Heart development was studied in sequential developmental stages in Id2 wildtype and knockout mouse embryos. Expression patterns of Id2, MLC-2a, Nkx2.5, HCN4, and WT-1 were analyzed. Id2 is expressed in myocardial progenitor cells at the inflow and outflow tract, in the endocardial and epicardial lineage, and in neural crest cells. Id2 knockout embryos show severe cardiac defects including abnormal orientation of systemic and pulmonary drainage, abnormal myocardialization of systemic and pulmonary veins, hypoplasia of the sinoatrial node, large interatrial communications, ventricular septal defects, double outlet right ventricle, and myocardial hypoplasia. Our results indicate a role for Id2 in the second heart field contribution at both the arterial and the venous poles of the heart.

Development of the cardiac conduction system and the possible relation to predilection sites of arrhythmogenesis.

The cardiac conduction system (CCS) encompasses a complex system responsible for the coordinated contraction of the heart. In the developing heart, as well as in the adult heart, tissues of the (putative) CCS are characterized by different properties than the surrounding working myocardium, which can be observed on a histological level, as well as by the expression patterns of several immunohistological and molecular markers. In recent years, many markers have been studied that have helped to elucidate the processes involved in CCS development. It has become clear that multiple genes, cells and their interactions are involved in this complex process. In this article, an overview of the current knowledge of CCS development is supplied. Furthermore, several controversies regarding conduction system development are discussed, as well as the possible significance of embryologic development of the CCS for the development of arrhythmias later in life.

Contrast echocardiography as a useful additional diagnostic tool in evaluating a primary cardiac tumor.

The current report describes a case of a primary cardiac lymphoma. For early and appropriate treatment of a cardiac mass it is not only important to determine its localization and extension but also to differentiate between malignant and benign lesions. This report demonstrates that not only transthoracic echocardiography but also the other different forms of echocardiography such as transesophageal echocardiography, as well as contrast and intracardiac echocardiography, are useful tools in the diagnostic workup of cardiac masses.

Development of the right ventricular inflow tract and moderator band: a possible morphological and functional explanation for Mahaim tachycardia.

Atriofascicular accessory bundles with AV-node like conduction properties can sustain atrioventricular (AV) re-entrant tachycardia (Mahaim tachycardia). During early embryogenesis, the AV canal is situated above the primitive left ventricle (LV), and a right AV connection has not been achieved yet. We studied the formation of the right ventricular (RV) inflow tract in relation to the developing cardiac conduction system and hypothesized a morphological explanation for functional atriofascicular bypass tracts. Analysis of lacZ-expression during sequential stages of cardiogenesis was performed in CCS-lacZ transgenic mice (E9.5 to 15.5). Embryos were stained for beta-galactosidase activity and the myocardial marker HHF35. At early stages CCS-lacZ expression was observed in a ring surrounding the AV canal, which connected at the inner curvature to the primary fold. The first sign of formation of the (CCS-lacZ negative) RV inlet component was a groove in the CCS-lacZ positive tissue of the primary fold. Outgrowth of the RV inlet tract resulted in division of the primary fold in a septal part, the trabecula septomarginalis and a lateral part, the moderator band, which extended laterally up to the right AV ring. Electrophysiological measurements in embryonic hearts (E15.5) in which the right atrium (RA) and RV were isolated from the left atrium (LA) and LV supported the functionality of this AV-connection via the moderator band, by demonstrating sequential atrial and ventricular activation in both RA/RV and LA/LV preparations. In conclusion, our observations may provide a possible morphological and functional explanation for atriofascicular accessory pathways via the moderator band, underlying Mahaim tachycardia.