Margaret J. Strieper

Congenital sick sinus syndrome caused by recessive mutations in the cardiac sodium channel gene (SCN5A)

Sick sinus syndrome (SSS) describes an arrhythmia phenotype attributed to sinus node dysfunction and diagnosed by electrocardiographic demonstration of sinus bradycardia or sinus arrest. Although frequently associated with underlying heart disease and seen most often in the elderly, SSS may occur in the fetus, infant, and child without apparent cause. In this setting, SSS is presumed to be congenital. Based on prior associations with disorders of cardiac rhythm and conduction, we screened the alpha subunit of the cardiac sodium channel (SCN5A) as a candidate gene in ten pediatric patients from seven families who were diagnosed with congenital SSS during the first decade of life. Probands from three kindreds exhibited compound heterozygosity for six distinct SCN5A alleles, including two mutations previously associated with dominant disorders of cardiac excitability. Biophysical characterization of the mutants using heterologously expressed recombinant human heart sodium channels demonstrate loss of function or significant impairments in channel gating (inactivation) that predict reduced myocardial excitability. Our findings reveal a molecular basis for some forms of congenital SSS and define a recessive disorder of a human heart voltage-gated sodium channel.

Efficacy of atrial antitachycardia pacing using the Medtronic AT500 pacemaker in patients with congenital heart disease.

Patients with congenital heart disease are vulnerable to atrial tachyarrhythmias, especially after atrial surgeries. We evaluated the efficacy of atrial arrhythmia detection and antitachycardia pacing (ATP) using the Medtronic AT500 pacemaker in 28 patients with congenital heart disease (age 30 +/- 18 years). Of 15 patients with atrial arrhythmias, 14 had atrial tachycardia events that were appropriately detected. ATP was enabled for 167 treatable episodes, successfully converting 90 (54%). Rhythms classified as ventricular tachycardia were detected 127 times, yet most were actually atrial or sinus tachycardia with 1:1 atrioventricular conduction. Atrial tachycardias in congenital heart disease are amenable to ATP algorithms in the AT500 pacemaker.

Efficacy of venovenous extracorporeal membrane oxygenation for neonates with respiratory and circulatory compromise

We report a 12-month experience at Egleston Childrens Hospital in Atlanta, Ga., with a protocol under which venovenous extracorporeal membrane oxygenation (ECMO) was used instead of venoarterial ECMO. Fifty-five newborn infants were referred for ECMO, four of whom had disqualifying conditions (all four died). Thirty-one infants were supported without recourse to ECMO, one of whom died. Of the 20 remaining patients, three were placed on a venoarterial ECMO regimen because of our early uncertainty about the efficacy of venovenous ECMO or because of technical constraints. All other patients (n = 17), including three with congenital diaphragmatic hernia, were supported with venovenous perfusion. No patient begun on a venovenous ECMO regimen required conversion to venoarterial bypass. Before ECMO, venovenous patients required an average dopamine dose of 16 micrograms/kg per minute and an average dobutamine dose of 6 micrograms/kg per minute. Of 15 patients studied before ECMO, three had significantly impaired contractility, and all had evidence of pulmonary hypertension on an echocardiogram. Mean blood pressure did not change while heart rate fell from 172 to 146 beats/min during the first 2 hours of ECMO and vasoactive drug doses were reduced. Of the 17 venovenous ECMO patients, 15 (88%) survived. We conclude that neonatal patients with severe hypoxia and substantial circulatory compromise can be effectively supported by venovenous ECMO in most cases.

Efficacy of alpha-adrenergic agonist therapy for prevention of pediatric neurocardiogenic syncope

OBJECTIVES The purpose of our study was to determine whether alpha-adrenergic agonist therapy could prevent neurocardiogenic syncope in pediatric patients. BACKGROUND Recent reports from adult patients suggest that withdrawal of alpha-sympathetic stimulation contributes to neurocardiogenic syncope. METHODS Sixteen young patients (mean age 13.1 years, range 7 years 10 months to 17 years 10 months) with recurrent syncope and a positive baseline head-up tilt response were studied. After a positive baseline tilt response, phenylephrine was infused and repeat tilt was performed for 30 min or until the test result was positive. At discharge, patients were followed up on a regimen of oral pseudoephedrine to evaluate treatment effectiveness and side effects. RESULTS During baseline tilt, seven patients experienced vasodepressor syncope, seven had mixed vasodepressor-cardioinhibitory syncope and two had cardioinhibitory responses. All patients became symptomatic, reproducing their clinical symptoms. Baseline mean arterial pressure decreased slightly immediately on tilt testing and significantly at the end point (82 +/- 13 vs. 77 +/- 18 vs. 30 +/- 14 mm Hg, respectively, p < 0.0001). Although heart rate varied, the changes were not statistically significant (78 +/- 17 vs. 105 +/- 19 vs. 87 +/- 46 beats/min, respectively, p = NS). Phenylephrine was infused (mean 1.74, range 0.6 to 3.0 micrograms/kg per min) as patients underwent follow-up tilt testing. Fifteen patients remained asymptomatic without hemodynamic changes; the remaining patient manifested a blunted mixed response. During phenylephrine infusion, heart rate (64 +/- 12 vs. 81 +/- 17 vs. 76 +/- 16 beats/min, respectively, p = NS) and mean arterial pressure (96 +/- 15 vs. 83 +/- 19 vs. 80 +/- 18 mm Hg, respectively, p = NS) did not change. During outpatient oral pseudoephedrine treatment (mean 11.7, range 6 to 14) 15 of 16 patients reported that their clinical condition was controlled without side effects. CONCLUSIONS Alpha-adrenergic stimulation prevents pediatric neurocardiogenic syncope. Intravenous phenylephrine prevents neurocardiogenic syncope during head-up tilt, despite reflex vagal bradycardia. Oral pseudoephedrine alleviates symptoms in patients with neurocardiogenic syncope without causing significant side effects.

Effects of venovenous extracorporeal membrane oxygenation on cardiac performance as determined by echocardiographic measurements.

We evaluated the effects of venovenous extracorporeal membrane oxygenation (ECMO) on cardiac performance by echocardiographic measurements in 15 infants. Heart rate and blood pressure were also recorded. Echocardiographic measurements included aortic and pulmonary peak blood flow velocities, pulmonary time to peak velocity, left ventricular shortening fraction, velocity of circumferential fiber shortening corrected for heart rate, and peak systolic wall stress before, during, and after venovenous ECMO. Pre-ECMO echocardiograms showed borderline or normal indexes of cardiac function. After initiation of venovenous ECMO, all infants had normalization and no infant had deterioration of cardiac performance. The inotropic agents dopamine and dobutamine were decreased from average doses of 12 and 3.6 micrograms/kg per minute, respectively, to 3.7 and 1.3 micrograms/kg per minute, respectively, within 8.8 hours of the institution of venovenous ECMO. During this time the mean arterial pressure remained stable, and the heart rate decreased (169 +/- 21 vs 136 +/- 15 beats/min; p < 0.001). During the course of ECMO there were no changes in left ventricular shortening fraction, velocity of circumferential fiber shortening corrected for heart rate, or aortic peak blood flow velocities. Pulmonary artery peak blood flow velocity (69 +/- 22 vs 92 +/- 28 cm/sec; p = 0.04) and pulmonary time to peak velocity improved (47 +/- 11 vs 65 +/- 16 msec; p = 0.026). We conclude that venovenous ECMO does not have deleterious effects on cardiac performance.

Long-Term Risk of Fatal Malignancy Following Pediatric Radiofrequency Ablation

Children undergoing radiofrequency ablation (RFA) are believed to be at increased risk of developing malignancy caused by radiation, although the magnitude of this risk is incompletely understood. We previously reported a strategy to reduce radiation exposure during pediatric RFA. In a cohort of 15 subjects (median age 12 years, range 9 to 17), radiation was measured using dosimeters at 5 sites. The risk of malignancy using measured radiation absorbed dose was calculated. International Council for Radiation Protection 60 risk estimates were applied to calculate absorbed organ doses. Median duration of combined biplane fluoroscopy was 14.4 minutes. Of the 5 dosimeter locations, the right scapular location had the highest median radiation exposure (43 mGy). Incorporating data from the 5 dosimeters, the risk model calculated that the organ with the greatest absorbed dose and at greatest risk of malignancy was the lung, followed by bone marrow, then breast. Thyroid and ovary exposures were negligible. The increased lifetime risk of fatal malignancy was 0.02% per single RFA procedure. In conclusion, with appropriate measures to reduce radiation exposure, the increased risk of malignancy after a single RFA procedure in children is low. These data should be of help counseling families and will contribute to analysis of the relative risk reduction benefits of such novel imaging approaches as a magnetic resonance imaging-based catheterization laboratory.

Quantifying and Minimizing Radiation Exposure During Pediatric Cardiac Catheterization

This study reports findings from evaluations of new technologies to measure radiation exposure during pediatric cardiac catheterization procedures. A strategy of pulsed fluoroscopy and low power settings resulted in significantly lower patient radiation exposure compared to conventional 60 frames/sec, high-power settings during fluoroscopy. During radiofrequency ablation procedures, thyroid and thoracic skin sites outside the direct fluoroscopic field received minimal radiation exposure. Intrathoracic radiation exposure was measured with the use of an esophageal dosimeter. In conclusion, strategies to reduce total radiation exposure should be employed, radiation dose should be measured, and assessment of radiation skin injury should be included in postcatheterization assessment.

Saphenous vein homograft: a superior conduit for the systemic arterial shunt in the Norwood operation

BACKGROUND Excessive pulmonary blood flow increases ventricular volume work in the face of inadequate systemic cardiac output, low diastolic blood pressure, and inadequate coronary perfusion. Using the smallest available 3-mm polytetrafluoroethylene shunts have been successful, although catastrophic shunt thrombosis has occasionally been observed. To avoid thrombosis with a smaller conduit, saphenous vein homografts (SVG) were used to construct the modified Blalock-Taussig (BT) shunts. METHODS From January 1998 to April 1999, 25 patients weighing 3.1 kg (3.0 kg or less, n = 9), at a mean age of 8.9 days, underwent stage I Norwood using an SVG BT shunt. Common heart defects were aortic atresia (n = 8), mitral atresia and double-outlet right ventricle (n = 5), and unbalanced AVC (n = 5). Mean BT shunt size was 3.2 mm, with 12 patients having shunts that were 3 mm or smaller. RESULTS Thirty-day hospital mortality was 8% (2 of 25). No shunt thrombosis was seen, despite banding the BT shunt in 3 patients. One patient had BT revision because of an anatomic issue not directly related to the shunt material. CONCLUSIONS Excellent results may be achieved using SVG BT shunts in the Norwood operation. This conduit seems less likely to thrombose, both acutely and chronically, allowing the use of appropriately smaller-sized shunts in small neonates.

The medical therapy of cardioinhibitory syncope in pediatric patients

A small percentage of pediatric patients with neurally mediated syncope will have an asystolic response during upright tilt table testing. The purpose of this study is to evaluate the incidence of asystole during tilt table testing, and to assess the outcome of medical management of such patients. Of 398 patients undergoing evaluation for recurrent syncope between January 1989 and 1994, 18 (4.5%) experienced asystole lasting ≥ 5 seconds during baseline tilt test. Patients had experienced a mean of four episodes of syncope, with a mean age at the time of tilt test of 11.1 ± 4.0 years. The median duration of asystole was 10 seconds (range 5–40 s). Treatment was individualized to increased fluids and salt intake (3 patients), metoprolol (8 patients), pseudoephedrine (4 patients), disopyramide (1 patient), or combination therapy with fludrohydrocortisone (2 patients). During a median duration of follow‐up of 31 months, no additional syncope was experienced by 78% of patients. Recurrent syncope in 4 patients was associated with either noncompliance or discontinuation of therapy in 3 patients; in 1 patient, increasing the dose of metoprolol was effective in preventing recurrences. We conclude that young patients with recurrent syncope and asystole during tilt test may be safely and effectively managed with pharmacological therapy, without resorting to pacemaker implantation.

Outcomes Following Electroanatomic Mapping and Ablation for the Treatment of Ectopic Atrial Tachycardia in the Pediatric Population

Ectopic atrial tachycardia (EAT) is often resistant to medical therapy, with radiofrequency ablation (RFA) being a preferred treatment option. Three-dimensional (3-D) electroanatomic mapping was introduced as a tool for improved substrate localization, although there are no published data with this technology in pediatric patients with EAT. The objective of this study was to examine our experience with 3-D mapping and standard mapping in this patient population. We used retrospective chart review of pediatric patients with EAT requiring RFA from 1993 to 2004. We analyzed the method of ablation, acute success and recurrence rates, procedure and fluoroscopy times, and cardiac function. Twenty-five patients underwent 31 RFA procedures. All patients had been followed for >6 months (6 months to 7 years). Standard mapping (Group 1) was used in 11 patients (5F/6M, 1.4–11.8 years) who underwent 13 RFA procedures; 3-D mapping (Group 2, October 2000–2004) was used in 16 patients (8 F/8M, 2.7–17 years) who underwent 18 RFA procedures. Left-sided focus was present in 6/13 in Group 1 and 7/18 in Group 2 (all transeptal, NS). There was a trend toward fewer lesions with 3-D mapping (15 ± 14, median 9.5 in Group 1; 8 ± 6, median 6.5 in Group 2, NS). Acute success was more likely for patients in which 3-D mapping was utilized (10/13 Group 1 vs. 18/18 Group 2, p < 0.04). Recurrence or persistence of tachycardia at follow-up (2 weeks to 1 year) was documented in 7/13 cases in Group 1, compared to only 2/18 cases in Group 2 (p = 0.01). Six patients underwent repeat RFA: two patients using standard mapping (one failure, one success) and four patients using 3-D mapping [all acute and long-term (>1 year) success]. Procedure times (232 ± 84 vs. 268 ± 72 min, skin-to-skin) and fluoroscopy times (47 ± 24 vs. 40 ± 20 min) were similar (NS). Of the 25 pts, 17 (7 in Group 1, 10 in Group 2, NS) presented with cardiomyopathy [Ejection fraction (EF), 38.6 ± 12.1%]. Successful RFA resulted in improved EF (61.1 ± 11.6%, p < 0.0001) in the 14 patients in whom pre-RFA and post-RFA echocardiograms were available. Compared to standard techniques, 3-D electroanatomic mapping has resulted in no acute failures, statistically reduced recurrence rates, and improved overall success in the management of EAT.