Familial Atrial Enlargement, Conduction Disorder and Symmetric Cardiac Hypertrophy Are Early Signs of PRKAG2 R302Q.

PRKAG2 cardiac syndrome (PS) is a rare inherited disease due to PRKAG2 gene mutation and characterized by Wolff-Parkinson-White syndrome (WPWs), conduction system lesions and myocardial hypertrophy. It can also lead to serious consequences, such as sudden death. But the genetic and clinical heterogeneity makes the early diagnosis of PS difficult. Here we studied a family with familial hypertrophic cardiomyopathy and other diverse manifestations. Gene analysis identified a missense mutation (Arg302Gln) in the five affected subjects of the family. The electrocardiograph performance of the five was composed of sinus bradycardia (SB), WPWs, right bundle branch block (RBBB), atrioventricular block (AVB), left bundle branch block (LBBB), supraventricular tachycardia (SVT) and atrial premature beat (APB). Among them, the youngest one began to show paroxysmal palpitation at the age of nine and was confirmed to have WPWs at 17 years old; two members progressed over time to serious conduction damage, and the proband received a pacemaker at the age of 27 due to AVB. Besides, according to cardiac magnetic resonance and echocardiography, the youngest one showed symmetric hypertrophy; three older members showed asymmetric myocardial hypertrophy characterized with a diffuse pattern of middle-anterior-lateral-inferior wall hypertrophy and especially interventricular septal hypertrophy; all five affected patients showed atrial enlargement regardless of myocardial hypertrophy at an earlier stage. In conclusion, the conduction system disorder, familial atrial enlargement and symmetric cardiac hypertrophy may occur in the early stage of PRKAG2 R302Q mutation.

Wolff-Parkinson-White syndrome: De novo variants and evidence for mutational burden in genes associated with atrial fibrillation.

BACKGROUND: Wolff-Parkinson-White (WPW) syndrome is a relatively common arrhythmia affecting ~1-3/1,000 individuals. Mutations in PRKAG2 have been described in rare patients in association with cardiomyopathy. However, the genetic basis of WPW in individuals with a structurally normal heart remains poorly understood. Sudden death due to atrial fibrillation (AF) can also occur in these individuals. Several studies have indicated that despite ablation of an accessory pathway, the risk of AF remains high in patients compared to general population. METHODS: We applied exome sequencing in 305 subjects, including 65 trios, 80 singletons, and 6 multiple affected families. We used de novo analysis, candidate gene approach, and burden testing to explore the genetic contributions to WPW. RESULTS: A heterozygous deleterious variant in PRKAG2 was identified in one subject, accounting for 0.6% (1/151) of the genetic basis of WPW in this study. Another individual with WPW and left ventricular hypertrophy carried a known pathogenic variant in MYH7. We found rare de novo variants in genes associated with arrhythmia and cardiomyopathy (ANK2, NEBL, PITX2, and PRDM16) in this cohort. There was an increased burden of rare deleterious variants (MAF ≤ 0.005) with CADD score ≥ 25 in genes linked to AF in cases compared to controls (P = .0023). CONCLUSIONS: Our findings show an increased burden of rare deleterious variants in genes linked to AF in WPW syndrome, suggesting that genetic factors that determine the development of accessory pathways may be linked to an increased susceptibility of atrial muscle to AF in a subset of patients.

Adult onset tubulo-interstitial nephropathy in MT-ND5-related phenotypes.

Kidney is a highly adenosine triphosphate dependent organ in human body. Healthy and functional mitochondria are essential for normal kidney function. Clinical and genetic variability are the hallmarks of mitochondrial disorders. We report here the involvement of two MT-ND5 pathogenic variants encoding for ND5 subunit of respiratory chain complex I, the m.13513G>A and the m.13514A>G, in adult-onset kidney disease in three unrelated patients. The first patient had myopathy encephalopathy lactic acidosis and stroke syndrome, left ventricular hypertrophy with Wolff-Parkinson-White syndrome and tubulo-interstitial kidney disease. The second presented Leber hereditary optic neuropathy associated with tubulo-interstitial kidney disease. The third presented with an isolated chronic tubulo-interstitial kidney disease. These mutations have never been associated with adulthood mitochondrial nephropathy. These case reports highlight the importance to consider mitochondrial dysfunction in tubulo-interstitial kidney disease.

Sudden cardiac death due to the Wolff-Parkinson-White syndrome: A case report with genetic analysis.

RATIONALE: The Wolff-Parkinson-White syndrome (WPW) is a benign heart disease with accessory pathways, which can result in cardiac arrhythmias. The purpose of this case report is to introduce a rare case of sudden cardiac death (SCD) with a mild myocardial bridge and a history of WPW. PATIENT CONCERNS: A 25-year-old man with known WPW syndrome died at night while sleeping. DIAGNOSES: Diagnosis of WPW syndrome is based on typical electrocardiogram findings with a documented dysrhythmia before the victim's death. INTERVENTIONS: At autopsy, no traumatic injury or common poisons were found, only a slight myocardial bridge was detected. We performed whole exome sequencing and identified several genetic variations related to SCD. OUTCOMES: We considered that the cause of death in this case was SCD in which arrhythmia might play an important role. LESSONS: This case highlights SCD can occur in WPW patients with mild or unrecognized structural abnormality. Postmortem genetic examination can assist the diagnosis of sudden cardiac death, especially when no lethal structural abnormality is found in the decedent.

Three-dimensional histologic reconstruction of remnant functional accessory atrioventricular myocardial connections in a case of Wolff-Parkinson-White syndrome.

Myocardial bundles working as accessory pathways in Wolff-Parkinson-White (WPW) syndrome are generally tiny tissues, so elucidating the culprit histology of atrioventricular (AV) myocardial connections requires careful serial sectioning of the AV junction. We performed a postmortem examination of accessory AV myocardial connections in an 84-year-old man who died from pneumonia 20 years after surgical cryoablation for WPW syndrome. Three-dimensional reconstruction images of serial histologic sections revealed accessory AV connections between the atrial and ventricular myocardium in the vicinity of the cryoablation scar. The remnant myocardial bridge was 4 mm wide and made up of multiple discontinuous fibers. This case was informative in that it provided for visualization of the histologic morphology of a remnant bundle of Kent.

Clinical course and treatment of children and adolescents with the preexcitation syndrome - own studies.

INTRODUCTION: Essentially, preexcitation syndrome is the presence of an accessory pathway in the heart, which can lead to serious consequences, ranging from atrioventricular reentrant tachycardia to sudden cardiac death. Wolff-Parkinson-White syndrome is the most common preexcitation syndrome. AIM OF THE STUDY: The aim of the study was to evaluate the clinical course of the disease, as well as the treatment of children and adolescents hospitalized in the Department of Pediatric Cardiology in the years 2008-2015. MATERIALS AND METHODS: The study was carried out in 45 children (62 % male, 38% female; the mean age 11 years). During the study we analyzed 12-lead ECG, 24-hour Holter ECG, echocardiography and the cycloergometric exercise test. The results of treatment were also discussed. RESULTS: Apart from the typical features of preexcitation, the most prevalent abnormality found in ECG was atrioventricular reentrant tachycardia. In 24-hour Holter ECG the most frequently detected disorders were premature ventricular beats and premature atrial contractions. Structural heart defects were detected in 8.9% of the children. The cycloergometric exercise test was positive in 8.9% of patients. The mean duration of symptoms before the diagnosis was 2.5 years. 25% of the patients were asymptomatic. 42.2% of the children needed antiarrhythmic therapy, while 44.4% had accessory pathways ablated. CONCLUSIONS: The most common symptom of preexcitation in the study group were heart palpitations. The most frequent type of arrhythmia in children with preexcitation syndrome was orthodromic atrioventricular reentrant tachycardia. For the majority of older children ablation of the accessory pathway was a recommended form of treatment. In younger children the standard preventive pharmacological treatment was applied for 6 to 12 months.

Altered myocardial characteristics of the preexcited segment in Wolff-Parkinson-White syndrome: A pilot study with cardiac magnetic resonance imaging.

PURPOSE: The preexcited myocardium of Wolff-Parkinson-White (WPW) syndrome would have different characteristics from normal myocardium and these findings might be related to persistent left ventricular systolic dysfunction. We evaluated myocardial tissue characteristics at the preexcited segment in adult WPW syndrome patients and their implicated findings. METHODS: For this prospective study, we enrolled 22 adult WPW syndrome patients (16 male, mean 45.4 ± 17.8 years) with echocardiographic findings of regional wall motion abnormality in our electrophysiology clinic. Of these patients, 14 underwent radiofrequency ablation before cardiac magnetic resonance imaging. All patients underwent cardiac magnetic resonance imaging including cine and late gadolinium enhancement. The ventricular morphology, function and myocardial characteristics of the preexcited segment were analyzed. RESULTS: A relatively high prevalence of late gadolinium enhancement (9/22, 40.9%) was observed exclusively at the basal septum. The septal accessory pathway was significantly more prevalent in patients with late gadolinium enhancement (P = 0.011). The prevalences of regional myocardial wall thinning and regional akinesia were significantly higher (P = 0.001 for both) and left ventricular function was significantly decreased in patients with late gadolinium enhancement (P < 0.001). In addition, there were no significant relationships between radiofrequency ablation and regional akinesia (P > 0.999), regional myocardial wall thinning (P > 0.999), late gadolinium enhancement (P = 0.662) and low ejection fraction (P > 0.999). CONCLUSION: Myocardial fibrosis was observed at the preexcited myocardium of adult WPW syndrome patients with septal accessory pathway, which could accompany regional akinesia and regional myocardial wall thinning and might be related to persistent left ventricular systolic dysfunction even after radiofrequency ablation.

CRISPR correction of the PRKAG2 gene mutation in the patient's induced pluripotent stem cell-derived cardiomyocytes eliminates electrophysiological and structural abnormalities.

BACKGROUND: Mutations in the PRKAG2 gene encoding the γ-subunit of adenosine monophosphate kinase (AMPK) cause hypertrophic cardiomyopathy (HCM) and familial Wolff-Parkinson-White (WPW) syndrome. Patients carrying the R302Q mutation in PRKAG2 present with sinus bradycardia, escape rhythms, ventricular preexcitation, supraventricular tachycardia, and atrioventricular block. This mutation affects AMPK activity and increases glycogen storage in cardiomyocytes. The link between glycogen storage, WPW syndrome, HCM, and arrhythmias remains unknown. OBJECTIVE: The purpose of this study was to investigate the pathological changes caused by the PRKAG2 mutation. We tested the hypothesis that patient's induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) display clinical aspects of the disease. METHODS: Using clustered regularly interspaced short palindromic repeats (CRISPR) technology, we corrected the mutation and then generated isogenic iPSC-CMs. Action potentials were recorded from spontaneously firing and paced cardiomyocytes using the patch clamp technique. Using a microelectrode array setup, we recorded electrograms from iPSC-CMs clusters. Transmission electron microscopy was used to detect ultrastructural abnormalities in the mutated iPSC-CMs. RESULTS: PRKAG2-mutated iPSC-CMs exhibited abnormal firing patterns, delayed afterdepolarizations, triggered arrhythmias, and augmented beat rate variability. Importantly, CRISPR correction eliminated the electrophysiological abnormalities, the augmented glycogen, storage, and cardiomyocyte hypertrophy. CONCLUSION: PRKAG2-mutated iPSC-CMs displayed functional and structural abnormalities, which were abolished by correcting the mutation in the patient's iPSCs using CRISPR technology.

Physiological Expression of AMPKγ2RG Mutation Causes Wolff-Parkinson-White Syndrome and Induces Kidney Injury in Mice.

Mutations of the AMP-activated kinase gamma 2 subunit (AMPKγ2), N488I (AMPKγ2NI) and R531G (AMPKγ2RG), are associated with Wolff-Parkinson-White (WPW) syndrome, a cardiac disorder characterized by ventricular pre-excitation in humans. Cardiac-specific transgenic overexpression of human AMPKγ2NI or AMPKγ2RG leads to constitutive AMPK activation and the WPW phenotype in mice. However, overexpression of these mutant proteins also caused profound, non-physiological increase in cardiac glycogen, which might abnormally alter the true phenotype. To investigate whether physiological levels of AMPKγ2NI or AMPKγ2RG mutation cause WPW syndrome and metabolic changes in other organs, we generated two knock-in mouse lines on the C57BL/6N background harboring mutations of human AMPKγ2NI and AMPKγ2RG, respectively. Similar to the reported phenotypes of mice overexpressing AMPKγ2NI or AMPKγ2RG in the heart, both lines developed WPW syndrome and cardiac hypertrophy; however, these effects were independent of cardiac glycogen accumulation. Compared with AMPKγ2WT mice, AMPKγ2NI and AMPKγ2RG mice exhibited reduced body weight, fat mass, and liver steatosis when fed with a high fat diet (HFD). Surprisingly, AMPKγ2RG but not AMPKγ2NI mice fed with an HFD exhibited severe kidney injury characterized by glycogen accumulation, inflammation, apoptosis, cyst formation, and impaired renal function. These results demonstrate that expression of AMPKγ2NI and AMPKγ2RG mutations at physiological levels can induce beneficial metabolic effects but that this is accompanied by WPW syndrome. Our data also reveal an unexpected effect of AMPKγ2RG in the kidney, linking lifelong constitutive activation of AMPK to a potential risk for kidney dysfunction in the context of an HFD.

Genome editing with CRISPR/Cas9 in postnatal mice corrects PRKAG2 cardiac syndrome.

PRKAG2 cardiac syndrome is an autosomal dominant inherited disease resulted from mutations in the PRKAG2 gene that encodes γ2 regulatory subunit of AMP-activated protein kinase. Affected patients usually develop ventricular tachyarrhythmia and experience progressive heart failure that is refractory to medical treatment and requires cardiac transplantation. In this study, we identify a H530R mutation in PRKAG2 from patients with familial Wolff-Parkinson-White syndrome. By generating H530R PRKAG2 transgenic and knock-in mice, we show that both models recapitulate human symptoms including cardiac hypertrophy and glycogen storage, confirming that the H530R mutation is causally related to PRKAG2 cardiac syndrome. We further combine adeno-associated virus-9 (AAV9) and the CRISPR/Cas9 gene-editing system to disrupt the mutant PRKAG2 allele encoding H530R while leaving the wild-type allele intact. A single systemic injection of AAV9-Cas9/sgRNA at postnatal day 4 or day 42 substantially restores the morphology and function of the heart in H530R PRKAG2 transgenic and knock-in mice. Together, our work suggests that in vivo CRISPR/Cas9 genome editing is an effective tool in the treatment of PRKAG2 cardiac syndrome and other dominant inherited cardiac diseases by selectively disrupting disease-causing mutations.

[Sudden death of a 16-year-old girl with WPW syndrome: a case report]. / Plötzliches Versterben einer 16-Jährigen mit WPW-Syndrom: ein Fallbericht.

The Wolff-Parkinson-White syndrome is a usually benign heart disease with accessory pathways. Circling excitations arise between atria and ventricles which can lead to cardiac arrhythmias. Cases of sudden cardiac death are rare (0.2 %). Risk factors for sudden cardiac death in patients with WPW syndrome are old age, several accessory pathways, male sex and previous syncopes. A 16-year-old girl was found lying dead in her bed. The evening before, she didn't feel well and complained about abdominal pain. The girl had known epilepsy and Wolff- Parkinson-White syndrome. The macroscopic and histological findings are presented and discussed with reference to the pertinent literature.

Prophylactic accessory-pathway ablation in asymptomatic patients with a Wolff-Parkinson-White electrocardiographic pattern.

OBJECTIVES: The optimal approach is controversial in asymptomatic patients who are coincidentally found to have evidence of an accessory pathway (AP) on an ECG. The risk of sudden cardiac death (SCD) is low, and the risk of developing symptoms also appears to be low, although a wide range of incidences have been reported. In our trial, we tested the hypothesis that if prophylactic accessory-pathway ablation performed at the time of the initial electrophysiological testing would improve the long-term outcome in asymptomatic patients with a Wolff-Parkinson-White electrocardiographic pattern. PATIENTS AND METHODS: Recruitment of patients began on February 1, 2004, and ended on February 5, 2009. All 110 asymptomatic patients were hospitalized and underwent electrophysiological testing the same day to assess the inducibility of atrioventricular reciprocating tachycardia. The anterograde effective refractory period of the accessory pathway was defined as the longest coupling interval at which anterograde block in the bypass tract was observed. For the statistical analysis, the statistical software SPSS version 15.0 for Windows (SPSS Inc., Chicago, IL, USA). RESULTS: Of 110 asymptomatic patients with a Wolff-Parkinson-White electrocardiographic pattern, 80 patients were ablated. Ablation group consisted of these patients. Control group consisted of remaining 30 and were divided into two groups according to the anterograde effective refractory period of the accessory pathway. There was no significant difference between three groups in terms of arrhythmic events (p: 0.58). CONCLUSIONS: Asymptomatic patients with the Wolff-Parkinson-White syndrome do not require prophylactic ablation, since they remain asymptomatic for many years.

LV dyssynchrony as assessed by phase analysis of gated SPECT myocardial perfusion imaging in patients with Wolff-Parkinson-White syndrome.

PURPOSE: The purpose of this study was to evaluate left ventricular (LV) mechanical dyssynchrony in patients with Wolff-Parkinson-White (WPW) syndrome pre- and post-radiofrequency catheter ablation (RFA) using phase analysis of gated single photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI). METHODS: Forty-five WPW patients were enrolled and had gated SPECT MPI pre- and 2-3 days post-RFA. Electrophysiological study (EPS) was used to locate accessory pathways (APs) and categorize the patients according to the AP locations (septal, left and right free wall). Electrocardiography (ECG) was performed pre- and post-RFA to confirm successful elimination of the APs. Phase analysis of gated SPECT MPI was used to assess LV dyssynchrony pre- and post-RFA. RESULTS: Among the 45 patients, 3 had gating errors, and thus 42 had SPECT phase analysis. Twenty-two patients (52.4%) had baseline LV dyssynchrony. Baseline LV dyssynchrony was more prominent in the patients with septal APs than in the patients with left or right APs (p < 0.05). RFA improved LV synchrony in the entire cohort and in the patients with septal APs (p < 0.01). CONCLUSION: Phase analysis of gated SPECT MPI demonstrated that LV mechanical dyssynchrony can be present in patients with WPW syndrome. Septal APs result in the greatest degree of LV mechanical dyssynchrony and afford the most benefit after RFA. This study supports further investigation in the relationship between electrical and mechanical activation using EPS and phase analysis of gated SPECT MPI.

Two-dimensional speckle-tracking echocardiography for atrioventricular accessory pathways persistent ventricular pre-excitation despite successful radiofrequency ablation.

AIMS: The present study was undertaken to investigate the concordance between longitudinal two-dimensional (2D)-speckle-tracking data and endocardial mapping for localizing atrioventricular accessory pathways (AP), and whether longitudinal 2D-speckle-tracking imaging accurately identifies the contractile abnormalities associated with AP and the effect of radiofrequency ablation. METHODS AND RESULTS: Echocardiograms were repeated twice in 40 patients with Wolff-Parkinson-White (WPW) syndrome (before and early after ablation) and in 40 healthy controls to obtain longitudinal 2D strain and strain rate data. The site of ablation was considered as the gold standard for the AP localization. While control patients had a homogeneous strain pattern, all but two patients with WPW had an abnormal deformation pattern with three peaks in one or two basal contiguous segments: an early peak concomitantly with the delta wave followed by a systolic and a post-sytolic one. The rapid increase in LV longitudinal deformation within the basal pre-excited zone resulted in a pre-systolic peak strain rate at the beginning of the delta wave by SR imaging that was not found in controls. The early basal contraction spread towards the mid-ventricle before merging with the normal activated segments in 15 patients (39%). Contractile abnormalities were no more than one adjacent segment different compared with the AP ablation site in all these 38 patients. Regional strain was impaired in the pre-excited areas especially in AP localized in the interventricular septum. The abnormal deformation pattern persisted in 16 (42%) patients despite successful radiofrequency ablation. However, the difference in the regional strain between WPW patients and controls did not remain after ablation. CONCLUSION: Longitudinal 2D-speckle-tracking data accurately match with endocardial mapping findings for localizing AP. Longitudinal 2D-speckle-tracking imaging accurately identifies AP-associated contractile abnormalities. Longitudinal 2D-speckle-tracking identifies persistence of local ventricular pre-excitation immediately after successful ablation.

Localizing the accessory pathway in ventricular preexcitation patients using a score based algorithm.

OBJECTIVES: Clinical data was analyzed to find an efficient way to localize the accessory pathway in patients with ventricular preexcitation. METHODS: The delta wave morphologies and ablation sites of 186 patients who underwent catheter ablation were analyzed and an algorithm ("locAP") to localize the accessory pathway was developed from the 84 data sets with a PQ interval ≤0.12s and a QRS width ≥0.12s. Fifty additional patients were included for a prospective validation. The locAP algorithm ranks 13 locations according to the likelihood that the accessory pathway is localized there. The algorithm is based on the locAP score which uses the standardized residuals of the available data sets. RESULTS: The locAP algorithm's accuracy is 0.54 for 13 locations, with a sensitivity of 0.84, a specificity of 0.97, and a positive likelihood ratio of 24.94. If the two most likely locations are regarded, the accuracy rises to 0.79, for the three most likely locations combined the accuracy is 0.82. This new algorithm performs better than Milstein's, Fitzpatrick's, and Arruda's algorithm both in the original study population as well as in a prospective study. CONCLUSIONS: The locAP algorithm is a valid and valuable tool for clinical practice in a cardiac electrophysiology laboratory. It could be shown that use of the locAP algorithm is favorable over the localizing algorithms that are in clinical use today.

Role of tissue C-reactive protein in atrial cardiomyocytes of patients undergoing catheter ablation of atrial fibrillation: pathogenetic implications.

AIMS: Histological studies support the important role of inflammation in the initiation and maintenance of atrial fibrillation (AF). We describe a novel and safe technique of atrial biopsy during AF radiofrequency catheter ablation (RFCA) to investigate the role of atrial tissue inflammation. METHODS AND RESULTS: We enrolled 70 consecutive patients (age 60 ± 12 years, 49 males) undergoing RFCA for AF. The control group was represented by 10 patients with Wolff-Parkinson-White syndrome undergoing trans-septal puncture. Atrial biopsies were obtained by washing the dilator and needle used for trans-septal puncture with 20 mL sterile phosphate-buffered saline. The presence of intracytoplasmic C-reactive protein was assessed in formalin-fixed atrial specimens by immunohistochemistry. A sufficient amount of atrial tissue was obtained in 23/70 (32%) patients with AF and in 4/10 (40%) of the control group. Intracytoplasmic localization of C-reactive protein was found in isolated atrial cardiomyocytes in 11 (73%) of 15 patients with paroxysmal AF as compared with 2 (25%) of eight patients with persistent AF (P= 0.02). CONCLUSION: In this study, we demonstrate the safety and feasibility of a novel technique to obtain atrial specimens during routine trans-septal puncture. Local inflammation assessed by atrial tissue localization of C-reactive protein is more likely involved in paroxysmal rather than in persistent AF.

Defective Tbx2-dependent patterning of the atrioventricular canal myocardium causes accessory pathway formation in mice.

Ventricular preexcitation, a feature of Wolff-Parkinson-White syndrome, is caused by accessory myocardial pathways that bypass the annulus fibrosus. This condition increases the risk of atrioventricular tachycardia and, in the presence of atrial fibrillation, sudden death. The developmental mechanisms underlying accessory pathway formation are poorly understood but are thought to primarily involve malformation of the annulus fibrosus. Before birth, slowly conducting atrioventricular myocardium causes a functional atrioventricular activation delay in the absence of the annulus fibrosus. This myocardium remains present after birth, suggesting that the disturbed development of the atrioventricular canal myocardium may mediate the formation of rapidly conducting accessory pathways. Here we show that myocardium-specific inactivation of T-box 2 (Tbx2), a transcription factor essential for atrioventricular canal patterning, leads to the formation of fast-conducting accessory pathways, malformation of the annulus fibrosus, and ventricular preexcitation in mice. The accessory pathways ectopically express proteins required for fast conduction (connexin-40 [Cx40], Cx43, and sodium channel, voltage-gated, type V, α [Scn5a]). Additional inactivation of Cx30.2, a subunit for gap junctions with low conductance expressed in the atrioventricular canal and unaffected by the loss of Tbx2, did not affect the functionality of the accessory pathways. Our results suggest that malformation of the annulus fibrosus and preexcitation arise from the disturbed development of the atrioventricular myocardium.

Notch signaling regulates murine atrioventricular conduction and the formation of accessory pathways.

Ventricular preexcitation, which characterizes Wolff-Parkinson-White syndrome, is caused by the presence of accessory pathways that can rapidly conduct electrical impulses from atria to ventricles, without the intrinsic delay characteristic of the atrioventricular (AV) node. Preexcitation is associated with an increased risk of tachyarrhythmia, palpitations, syncope, and sudden death. Although the pathology and electrophysiology of preexcitation syndromes are well characterized, the developmental mechanisms are poorly understood, and few animal models that faithfully recapitulate the human disorder have been described. Here we show that activation of Notch signaling in the developing myocardium of mice can produce fully penetrant accessory pathways and ventricular preexcitation. Conversely, inhibition of Notch signaling in the developing myocardium resulted in a hypoplastic AV node, with specific loss of slow-conducting cells expressing connexin-30.2 (Cx30.2) and a resulting loss of physiologic AV conduction delay. Taken together, our results suggest that Notch regulates the functional maturation of AV canal embryonic myocardium during the development of the specialized conduction system. Our results also show that ventricular preexcitation can arise from inappropriate patterning of the AV canal-derived myocardium.

Absent left and right superior vena cava and azygos continuation of inferior vena cava: a rare anomaly of systemic venous return.

We report a case of a complicated vascular access secondary to systemic venous defects which have not been previously reported. Further evaluation revealed congenital absence of superior vena cava with two brachiocephalic veins draining separately. He also had absence of the hepatic segment of the inferior vena cava with azygos continuation. The patient did not have congenital anomalies of the remaining thoracoabdominal vasculature and viscera.