Value of provocative electrophysiology testing in the management of pediatric patients after congenital heart surgery.

OBJECTIVE: To determine the impact of provocative electrophysiology testing in postoperative congenital heart disease (CHD) patients on the management of supraventricular tachycardia (SVT) and clinical outcomes. METHODS: This is a retrospective study including patients <18 years of age with surgery for CHD who had postoperative SVT between 2006 and 2017. Postoperative outcomes were compared between patients with and without postoperative electrophysiology testing using the Wilcoxon rank sum test, Fisher's exact test, Kaplan-Meier method with the log-rank test, and Cox proportional hazard model. RESULTS: From 341 patients who had SVT after surgery for CHD, 65 (19%) had postoperative electrophysiology testing. There was no significant difference in baseline patient characteristics or surgical complexity between patients with and without electrophysiology testing. Patients with inducible SVT on electrophysiology testing were more likely to have recurrence of SVT prior to hospital discharge with an odds ratio 4.0 (95% confidence interval 1.3, 12.0). Patients who underwent postoperative electrophysiology testing had shorter intensive care unit (12 [6, 20] vs 16 [9, 32] days, HR 2.1 [95% CI 1.6, 2.8], P < .001) and hospital (25 [13, 38] vs 31 [18, 54] days, HR 1.8 [95% CI 1.4, 2.4], P < .001) length of stay. CONCLUSION: Postoperative electrophysiology testing was associated with improved postoperative outcomes, likely related to the ability to predict recurrence of arrhythmia and tailored antiarrhythmic management.

Alpha2-adrenergic dysregulation in congenic DxH recombinant inbred mice selectively bred for a high fear-sensitized (H-FSS) startle response.

Patients with anxiety disorders and posttraumatic stress disorder (PTSD) exhibit exaggerated fear responses and noradrenergic dysregulation. Fear-related responses to α2-adrenergic challenge were therefore studied in DxH C3H/HeJ-like recombinant inbred (C3HLRI) mice, which are a DBA/2J-congenic strain selectively bred for a high fear-sensitized startle (H-FSS). C3HLRI mice showed an enhanced acoustic startle response and immobility in the forced swim test compared to DBA/2J controls. The α2-adrenoceptor antagonist yohimbine (Yoh; 5.0 mg/kg) induced an anxiogenic and the α2-adrenoceptor agonist clonidine (Clon; 0.1 mg/kg) an anxiolytic effect in the open field (OF) in C3HLRI but not DBA/2J mice. In auditory fear-conditioning, Yoh (5.0 mg/kg)-treated C3HLRI mice showed higher freezing during fear recall and extinction learning than DBA/2J mice, and a higher ceiling for the Yoh-induced deficit in fear extinction. No strain differences were observed in exploration-related anxiety/spatial learning or the Clon-induced (0.1 mg/kg) corticosterone surge. A global analysis of the behavioral profile of the two mouse strains based on observed and expected numbers of significant behavioral outcomes indicated that C3HLRI mice showed significantly more often fear- and stress-related PTSD-like behaviors than DBA/2J controls. The analysis of the robustness of significant outcomes based on false discovery rate (FDR) thresholds confirmed significant differences for the strain-Yoh-interactions in the OF center and periphery, the Yoh-induced general extinction deficit, strain differences in conditioned fear levels, and at the dose of 5.0 mg/kg for the Yoh-induced ceiling in freezing levels among others. The current findings are consistent with previous observations showing alterations in the central noradrenergic system of C3HLRI mice (Browne et al., 2014, Stress 17:471-83). Based on their behavioral profile and response to α2-adrenergic stimulation, C3HLRI mice are a valuable genetic model for studying adrenergic mechanisms of anxiety disorders and potentially also of PTSD.

Catheter ablation for atrioventricular nodal reentrant tachycardia in patients with congenital heart disease.

BACKGROUND: Variability in atrioventricular (AV) node location in congenital heart disease (CHD) can make catheter ablation for atrioventricular nodal reentrant tachycardia (AVNRT) challenging. OBJECTIVE: The purpose of this study was to describe institutional technique and outcomes for slow pathway modification in a cohort with CHD. METHODS: The study consisted of a retrospective review of CHD patients who underwent study from 2001 to 2013 with a diagnosis of AVNRT. Outcomes for slow pathway modification were recorded. In cases in which ablation was deferred, the reasons for this choice were examined. RESULTS: Forty-nine patients (median age 19 years) were included. CHD anatomy involved d-transposition of the great arteries (n = 6), "congenitally corrected" transposition of the great arteries (n = 4), Ebstein anomaly (n = 4), tetralogy of Fallot (n = 5), venous anomalies (n = 8), single ventricle (n = 16), and miscellaneous (n = 6). Ablation was attempted in 39 patients, using radiofrequency energy in 24, cryoablation in 8, and both in 7. Acute success rate was 92% (36/39). One patient had first-degree block in response to cryoablation, but no other complications occurred. At median follow-up 32 months, 1 patient had AVNRT recurrence. Most of the 10 patients in whom ablation was deferred had single-ventricle anatomy with uncertain AV node location. CONCLUSION: Ablation for AVNRT in CHD can be accomplished successfully with attention to underlying anatomy and prior surgery. Patients with single ventricle are a difficult subgroup, and a pharmacologic approach may be indicated in some cases if node localization is ambiguous.

Mechanism and ablation of arrhythmia following total cavopulmonary connection.

BACKGROUND: The ability to identify and ablate different arrhythmia mechanisms after the total cavopulmonary connection has not been studied in detail. METHODS AND RESULTS: After obtaining Institutional Review Board approval according to institutional guidelines, consecutive patients after a total cavopulmonary connection undergoing electrophysiology study over a 6-year period were included (2006-2012). Arrhythmia mechanism was determined, and the procedural outcome was defined as complete, partial success, or failure. A 12-point arrhythmia severity score was calculated for each patient at baseline and on follow-up. Fifty-seven procedures were performed on 52 patients (18.4 ± 11.8 years; 53.0 ± 27.2 kg). Access to the pulmonary venous atrium was necessary in 33 procedures, via fenestration (16) or transbaffle puncture (17), and in 2 cases, an additional retrograde approach was used. In total, 80 arrhythmias were identified in 47 cases: macroreentrant (n = 25) or focal atrial tachycardia (n = 8), atrioventricular nodal reentry tachycardia (n = 13), reentry via an accessory pathway (n = 4) or via twin atrioventricular nodes (n = 4), ventricular tachycardia (n = 5), and undefined atrial tachycardia (n = 21). Procedural outcome in 32 patients who underwent ablation was complete success (n = 25), partial success (n = 3), failure (n = 3), or empirical ablation (n = 1). After successful ablation, there was a significant decrease in arrhythmia score over 18.2 (4-32) months follow-up, with a sustained trend even in the face of arrhythmia recurrence (50%). CONCLUSIONS: Arrhythmia mechanism post total cavopulmonary connection is highly varied, encompassing simple and more complex substrates, documentation of which facilitates a strategic approach to invasive arrhythmia management. Despite the anatomic limitations, successful and clinically meaningful ablation is possible.

The use of an integrated electroanatomic mapping system and intracardiac echocardiography to reduce radiation exposure in children and young adults undergoing ablation of supraventricular tachycardia.

AIMS: Non-fluoroscopic imaging (NFI) devices are increasingly used in ablations. The objective was to determine the utility of intracardiac echocardiography (ICE) in ablating paediatric supraventricular tachycardias (SVTs) and assess whether its integrated use with electroanatomic mapping (EAM) resulted in lower radiation exposure than use of EAM alone. METHODS AND RESULTS: Prospective, controlled, single-centre study of patients (pts) age ≥10 years, weight ≥35 kg, with SVT and normal cardiac anatomy. Patients were randomized to ICE + EAM (ICE) or EAM only (no ICE). Both had access to fluoroscopy as needed. Eighty-four pts were enroled (42 ICE, 42 no ICE). Median age was 15 years (range 10.4-23.7 years); 57% had accessory pathways, 42% atrioventricular nodal reentry tachycardia. There was no difference in radiation dose (9 mGy ICE vs. 23 mGy no ICE, P = 0.37) or fluoroscopy time (1.1 min ICE vs. 1.5 min no ICE, P = 0.38). Transseptal punctures were performed in 25 pts (16 ICE, 9 no ICE), with ICE reducing radiation (8 mGy ICE vs. 62 mGy no ICE, P = 0.002) and fluoroscopy time (1.1 min ICE vs. 4.5 min no ICE, P = 0.01). Zero fluoroscopy was achieved in 13 pts (15% of total, 5 ICE, 8 no ICE), and low-dose cases (<50 mGy) in 57 pts (68% of total, 33 ICE, 24 no ICE). Acute success was 95% for ICE, 88% for no ICE. CONCLUSION: Use of an integrated EAM/ICE system was no better than EAM alone in limiting radiation, but can be helpful for transseptal punctures. Given the low dose savings, use of ICE may be weighed against its financial cost. Low-fluoroscopy cases are performed in most NFI procedures.

Radiofrequency-assisted transseptal perforation for electrophysiology procedures in children and adults with repaired congenital heart disease.

BACKGROUND: Patients with congenital heart disease carry a high burden of arrhythmias and may pose special challenges when these arrhythmias are addressed invasively. We sought to describe our early experience with radiofrequency (RF) needle transseptal perforation to facilitate ablation procedures in this population. METHODS: Retrospective chart review to identify all cases of attempted transseptal access with a commercial RF needle at Children's Hospital Boston between February 2007 and January 2010. RESULTS: A total of 10 patients had attempted RF transseptal perforation. Median age was 27 years. Five patients had undergone atrial switch procedures (Mustard/Senning), four had undergone Fontan operations, and one had atrial septal defect repair. The indication for left atrial access was mapping/ablation of atrial flutter in nine cases, and left-sided accessory pathway in one case. The RF needle was chosen primarily in eight of 10 cases, whereas in the remaining two cases RF was used only after failed attempts with a conventional Brockenbrough needle. Septal material was atrial muscle in five cases, pericardium in three, and synthetic fabric in two. In nine of 10 patients, RF transseptal perforation was successful, including both patients in whom a conventional needle had failed. There were no clinically significant complications. CONCLUSIONS: RF transseptal perforation can be an effective method of obtaining left atrial access for electrophysiologic procedures in patients with complex congenital heart disease, including cases where a conventional Brockenbrough needle has failed.

Probing cochlear tuning and tonotopy in the tiger using otoacoustic emissions.

Otoacoustic emissions (sound emitted from the ear) allow cochlear function to be probed noninvasively. The emissions evoked by pure tones, known as stimulus-frequency emissions (SFOAEs), have been shown to provide reliable estimates of peripheral frequency tuning in a variety of mammalian and non-mammalian species. Here, we apply the same methodology to explore peripheral auditory function in the largest member of the cat family, the tiger (Panthera tigris). We measured SFOAEs in 9 unique ears of 5 anesthetized tigers. The tigers, housed at the Henry Doorly Zoo (Omaha, NE), were of both sexes and ranged in age from 3 to 10 years. SFOAE phase-gradient delays are significantly longer in tigers--by approximately a factor of two above 2 kHz and even more at lower frequencies--than in domestic cats (Felis catus), a species commonly used in auditory studies. Based on correlations between tuning and delay established in other species, our results imply that cochlear tuning in the tiger is significantly sharper than in domestic cat and appears comparable to that of humans. Furthermore, the SFOAE data indicate that tigers have a larger tonotopic mapping constant (mm/octave) than domestic cats. A larger mapping constant in tiger is consistent both with auditory brainstem response thresholds (that suggest a lower upper frequency limit of hearing for the tiger than domestic cat) and with measurements of basilar-membrane length (about 1.5 times longer in the tiger than domestic cat).

Inferior frontal regions underlie the perception of phonetic category invariance.

The problem of mapping differing sensory stimuli onto a common category is fundamental to human cognition. Listeners perceive stable phonetic categories despite many sources of acoustic variability. What are the neural mechanisms that underlie this perceptual stability? In this functional magnetic resonance imaging study, a short-interval habituation paradigm was used to investigate neural sensitivity to acoustic changes within and between phonetic categories. A region in the left inferior frontal sulcus showed a pattern of activation consistent with phonetic invariance: insensitivity to acoustic changes within a phonetic category and sensitivity to changes between phonetic categories. Left superior temporal regions, in contrast, showed graded sensitivity to both within- and between-category changes. These results suggest that perceptual insensitivity to changes within a phonetic category may arise from decision-related mechanisms in the left prefrontal cortex and add to a growing body of literature suggesting that the inferior prefrontal cortex plays a domain-general role in computing category representations.

Development of cochlear amplification, frequency tuning, and two-tone suppression in the mouse.

It is generally believed that the micromechanics of active cochlear transduction mature later than passive elements among altricial mammals. One consequence of this developmental order is the loss of transduction linearity, because an active, physiologically vulnerable process is superimposed on the passive elements of transduction. A triad of sensory advantage is gained as a consequence of acquiring active mechanics; sensitivity and frequency selectivity (frequency tuning) are enhanced and dynamic operating range increases. Evidence supporting this view is provided in this study by tracking the development of tuning curves in BALB/c mice. Active transduction, commonly known as cochlear amplification, enhances sensitivity in a narrow frequency band associated with the "tip" of the tuning curve. Passive aspects of transduction were assessed by considering the thresholds of responses elicited from the tuning curve "tail," a frequency region that lies below the active transduction zone. The magnitude of cochlear amplification was considered by computing tuning curve tip-to-tail ratios, a commonly used index of active transduction gain. Tuning curve tip thresholds, frequency selectivity and tip-to-tail ratios, all indices of the functional status of active biomechanics, matured between 2 and 7 days after tail thresholds achieved adultlike values. Additionally, two-tone suppression, another product of active cochlear transduction, was first observed in association with the earliest appearance of tuning curve tips and matured along an equivalent time course. These findings support a traditional view of development in which the maturation of passive transduction precedes the maturation of active mechanics in the most sensitive region of the mouse cochlea.

The very large G-protein-coupled receptor VLGR1: a component of the ankle link complex required for the normal development of auditory hair bundles.

Sensory hair bundles in the inner ear are composed of stereocilia that can be interconnected by a variety of different link types, including tip links, horizontal top connectors, shaft connectors, and ankle links. The ankle link antigen is an epitope specifically associated with ankle links and the calycal processes of photoreceptors in chicks. Mass spectrometry and immunoblotting were used to identify this antigen as the avian ortholog of the very large G-protein-coupled receptor VLGR1, the product of the Usher syndrome USH2C (Mass1) locus. Like ankle links, Vlgr1 is expressed transiently around the base of developing hair bundles in mice. Ankle links fail to form in the cochleae of mice carrying a targeted mutation in Vlgr1 (Vlgr1/del7TM), and the bundles become disorganized just after birth. FM1-43 [N-(3-triethylammonium)propyl)-4-(4-(dibutylamino)styryl) pyridinium dibromide] dye loading and whole-cell recordings indicate mechanotransduction is impaired in cochlear, but not vestibular, hair cells of early postnatal Vlgr1/del7TM mutant mice. Auditory brainstem recordings and distortion product measurements indicate that these mice are severely deaf by the third week of life. Hair cells from the basal half of the cochlea are lost in 2-month-old Vlgr1/del7TM mice, and retinal function is mildly abnormal in aged mutants. Our results indicate that Vlgr1 is required for formation of the ankle link complex and the normal development of cochlear hair bundles.

Ablation of nonautomatic focal atrial tachycardia in children and adults with congenital heart disease.

INTRODUCTION: Nonautomatic focal atrial tachycardia (NAFAT) has been characterized in adults with structurally normal hearts. This article characterizes NAFAT in a population of patients with complex congenital heart disease. METHODS AND RESULTS: Electrophysiologic and electroanatomic mapping data and acute outcomes were reviewed in patients undergoing mapping and ablative procedures for atrial tachycardia at Children's Hospital, Boston, between January 1999 and December 2003. Twenty-two NAFAT foci were identified in 17 patients out of 216 patients studied. Fourteen of these 17 patients had congenital heart disease. The average age of the patients with a NAFAT mechanism was 27 years and there was no gender predilection. The presumptive diagnosis based on clinical grounds and surface ECG assessment in 11 of 17 patients with NAFAT was atrial flutter. None of the 17 patients were suspected of having a NAFAT mechanism by noninvasive assessment. Four of the 10 patients had both NAFAT and macroreentrant atrial tachycardias. NAFAT cycle lengths varied widely (200-680 ms) between patients. Sixteen of the 22 NAFAT foci were mapped to the anatomic right atrium (RA). Acute ablative success was achieved in 17 out of 22 foci (77%). CONCLUSION: NAFAT is relatively uncommon in a pediatric tertiary care setting, and in that setting occurs most often in adults with congenital heart disease. NAFAT is indistinguishable from other forms of atrial tachycardia by noninvasive means and can mimic other forms of atrial tachycardia on electrocardiogram. The foci were predominantly found in the RA and were, in most cases, acutely amenable to catheter ablation therapy.

Radiofrequency catheter ablation of septal accessory pathways in the pediatric age group.

Radiofrequency catheter ablation (RCA) of septal accessory pathways may be technically challenging in children due to the risk of inadvertent atrioventricular (AV) block in the setting of small cardiac dimensions. Outcomes were reviewed for all patients aged < or =19 years with manifest and concealed septal accessory pathways undergoing RCA since 1990 at a single institution. One hundred forty-five procedures were performed in 127 patients (mean age 11.6 years). The number of studies according to accessory pathway location were: anteroseptal (n = 36), midseptal (n = 20), mouth of coronary sinus (n = 40), middle cardiac vein (n = 6), right posteroseptal (n = 21), and left posteroseptal (n = 22). Ablation was deferred for 9 patients (6 anteroseptal and 3 midseptal) in favor of additional pharmacologic trials. Acute success rates for targeted accessory pathways were: anteroseptal (96%), midseptal (94%), mouth of coronary sinus (88%), middle cardiac vein (100%), right posteroseptal (100%), and left posteroseptal (96%). Recurrence rates during follow-up were: anteroseptal (14%), midseptal (12%), mouth of coronary sinus (3%), right posteroseptal (4%), and left posteroseptal (4%). Permanent second or third degree AV block occurred in 4 of 136 RCA attempts (3%), involving 2 anteroseptal and 2 midseptal pathways. In 3 of these 4 cases, a high probability of block was anticipated from prior ablation efforts, prompting pacemaker insertion before or in conjunction with RCA. Thus, in the pediatric age group, acute RCA success rates for septal accessory pathways can exceed 90%. The risks of AV block and accessory pathway recurrence are most relevant to anteroseptal and midseptal pathways. These data may be factored into patient selection and the decision whether to ablate.