ATP1A3-Encoded Sodium-Potassium ATPase Subunit Alpha 3 D801N Variant Is Associated With Shortened QT Interval and Predisposition to Ventricular Fibrillation Preceded by Bradycardia.

Background Pathogenic variation in the ATP1A3-encoded sodium-potassium ATPase, ATP1A3, is responsible for alternating hemiplegia of childhood (AHC). Although these patients experience a high rate of sudden unexpected death in epilepsy, the pathophysiologic basis for this risk remains unknown. The objective was to determine the role of ATP1A3 genetic variants on cardiac outcomes as determined by QT and corrected QT (QTc) measurements. Methods and Results We analyzed 12-lead ECG recordings from 62 patients (male subjects=31, female subjects=31) referred for AHC evaluation. Patients were grouped according to AHC presentation (typical versus atypical), ATP1A3 variant status (positive versus negative), and ATP1A3 variant (D801N versus other variants). Manual remeasurements of QT intervals and QTc calculations were performed by 2 pediatric electrophysiologists. QTc measurements were significantly shorter in patients with positive ATP1A3 variant status (P<0.001) than in patients with genotype-negative status, and significantly shorter in patients with the ATP1A3-D801N variant than patients with other variants (P<0.001). The mean QTc for ATP1A3-D801N was 344.9 milliseconds, which varied little with age, and remained <370 milliseconds throughout adulthood. ATP1A3 genotype status was significantly associated with shortened QTc by multivariant regression analysis. Two patients with the ATP1A3-D801N variant experienced ventricular fibrillation, resulting in death in 1 patient. Rare variants in ATP1A3 were identified in a large cohort of genotype-negative patients referred for arrhythmia and sudden unexplained death. Conclusions Patients with AHC who carry the ATP1A3-D801N variant have significantly shorter QTc intervals and an increased likelihood of experiencing bradycardia associated with life-threatening arrhythmias. ATP1A3 variants may represent an independent cause of sudden unexplained death. Patients with AHC should be evaluated to identify risk of sudden death.

Variability in radiation dose and image quality: A comparison across fluoroscopy-system vendors, generations of equipment and institutions.

OBJECTIVES: To evaluate differences in radiation dose and image quality across institutions, fluoroscope vendors and generations of fluoroscopes for pediatric cardiac catheterization. BACKGROUND: Increased recognition of the potentially harmful effects of ionizing radiation has spurred technological advances in fluoroscopes, as well as increased focus on optimizing fluoroscope performance. There is currently little understanding of variability in the dose-image quality relationship across institutions, fluoroscope vendor and/or generation of equipment. METHODS: We evaluated latest generation fluoroscopes from Phillips, Siemens, GE, and Toshiba, and an older generation Phillips fluoroscope (release date 2003) at three different institutions. Radiation dose was measured using an anthropomorphic dose-assessment phantom with effective dose in mSv estimated from Monte Carlo simulations. Image quality phantom images were scored on a 12-point scale by three blinded reviewers. RESULTS: Fluoroscope effective doses ranged from 0.04 to 0.14 mSv/1,000 pulses for fluoroscopy with associated composite image quality scores ranging from 8.0 ± 0.6 to 10.4 ± 1.3. For cineangiography, effective doses ranged from 0.17 to 0.57 mSv/1,000 frames with image quality scores ranging from 10.1 ± 0.3 to 11.1 ± 0.3. There was modest correlation between effective dose and image quality (r = 0.67, P = 0.006). The older generation fluoroscope delivered consistently higher doses than the newer generation systems (2.3- to 3.5-fold higher for fluoroscopy; 1.1- to 3.4-fold higher for cineangiography) without appreciable differences in image quality. CONCLUSION: Technological advances have markedly improved fluoroscope performance. Comparing latest generation systems across vendors and institutions, we found variability in the dose-IQ relationship and speculate that this reflects both equipment and institutional optimization practices.

The Second Annual Think Tank on Prevention of Sudden Cardiac Death in the Young: Developing a rational, reliable, and sustainable national health care resource. A report from the Cardiac Safety Research Consortium.

Sudden cardiac death in the young (SCDY) spans gender, race, ethnicity, and socioeconomic class. The loss of any pediatric patient is a matter of national and international public health concern, and focused efforts should be aimed at preventing these burdensome tragedies. Prepared by members of the Cardiac Safety Research Consortium, this White Paper summarizes and reports the dialogue at the second Think Tank related to the issues and the proposed solutions for the development of a national resource for screening and prevention of SCDY. This Think Tank, sponsored by the Cardiac Safety Research Consortium and the United States Food and Drug Administration, convened on February 18, 2016, in Miami, FL, to identify and resolve the barriers that prevent early identification of patients at risk for SCDY. All potential stakeholders including national and international experts from industry, medicine, academics, engineering, and community advocacy leaders had an opportunity to share ideas and collaborate.

Development and impact of arrhythmias after the Norwood procedure: A report from the Pediatric Heart Network.

OBJECTIVES: The study objective was to determine the predictors of new-onset arrhythmia among infants with single-ventricle anomalies during the post-Norwood hospitalization and the association of those arrhythmias with postoperative outcomes (ventilator time and length of stay) and interstage mortality. METHODS: After excluding patients with preoperative arrhythmias, we used data from the Pediatric Heart Network Single Ventricle Reconstruction Trial to identify risk factors for tachyarrhythmias (atrial fibrillation, atrial flutter, supraventricular tachycardia, junctional ectopic tachycardia, and ventricular tachycardia) and atrioventricular block (second or third degree) among 544 eligible patients. We then determined the association of arrhythmia with outcomes during the post-Norwood hospitalization and interstage period, adjusting for identified risk factors and previously published factors. RESULTS: Tachyarrhythmias were noted in 20% of subjects, and atrioventricular block was noted in 4% of subjects. Potentially significant risk factors for tachyarrhythmia included the presence of modified Blalock-Taussig shunt (P = .08) and age at Norwood (P = .07, with risk decreasing each day at age 8-20 days); the only significant risk factor for atrioventricular block was undergoing a concomitant procedure at the time of the Norwood (P = .001), with the greatest risk being in those undergoing a tricuspid valve procedure. Both tachyarrhythmias and atrioventricular block were associated with longer ventilation time and length of stay (P < .001 for all analyses). Tachyarrhythmias were not associated with interstage mortality; atrioventricular block was associated with mortality among those without a pacemaker in the unadjusted analysis (hazard ratio, 2.3; P = .02), but not after adding covariates. CONCLUSIONS: Tachyarrhythmias are common after the Norwood procedure, but atrioventricular block may portend a greater risk for interstage mortality.

Vibrating interventional device detection using real-time 3-D color Doppler.

Ultrasound image guidance of interventional devices during minimally invasive surgery provides the clinician with improved soft tissue contrast while reducing ionizing radiation exposure. One problem with ultrasound image guidance is poor visualization of the device tip during the clinical procedure. We have described previously guidance of several interventional devices using a real-time 3-D (RT3-D) ultrasound system with 3-D color Doppler combined with the ColorMark technology. We then developed an analytical model for a vibrating needle to maximize the tip vibrations and improve the reliability and sensitivity of our technique. In this paper, we use the analytical model and improved radiofrequency (RF) and color Doppler filters to detect two different vibrating devices in water tank experiments as well as in an in vivo canine experiment. We performed water tank experiments with four different 3- D transducers: a 5 MHz transesophageal (TEE) probe, a 5 MHz transthoracic (TTE) probe, a 5 MHz intracardiac catheter (ICE) transducer, and a 2.5 MHz commercial TTE probe. Each transducer was used to scan an aortic graft suspended in the water tank. An atrial septal puncture needle and an endomyocardial biopsy forceps, each vibrating at 1.3 kHz, were inserted into the vascular graft and were tracked using 3-D color Doppler. Improved RF and wall filters increased the detected color Doppler sensitivity by 14 dB. In three simultaneous planes from the in vivo 3-D scan, we identified both the septal puncture needle and the biopsy forceps within the right atrium using the 2.5 MHz probe. A new display filter was used to suppress the unwanted flash artifact associated with physiological motion.

Real-time 3D laparoscopic ultrasonography.

We have previously described 2D array ultrasound transducers operating up to 10 MHz for applications including real time 3D transthoracic imaging, real time volumetric intracardiac echocardiography (ICE), real time 3D intravascular ultrasound (IVUS) imaging, and real time 3D transesophageal echocardiography (TEE). We have recently built a pair of 2D array transducers for real time 3D laparoscopic ultrasonography (3D LUS). These transducers are intended to be placed down a trocar during minimally invasive surgery. The first is a forward viewing 5 MHz, 11 x 19 array with 198 operating elements. It was built on an 8 layer multilayer flex circuit. The interelement spacing is 0.20 mm yielding an aperture that is 2.2 mm x 3.8 mm. The O.D. of the completed transducer is 10.2 mm and includes a 2 mm tool port. The average measured center frequency is 4.5 MHz, and the -6 dB bandwidth ranges from 15% to 30%. The 50 omega insertion loss, including Gore MicroFlat cabling, is -81.2 dB. The second transducer is a 7 MHz, 36 x 36 array with 504 operating elements. It was built upon a 10 layer multilayer flex circuit. This transducer is in the forward viewing configuration and the interelement spacing is 0.18 mm. The total aperture size is 6.48 mm x 6.48 mm. The O.D. of the completed transducer is 11.4 mm. The average measured center frequency is 7.2 MHz, and the -6 dB bandwidth ranges from 18% to 33%. The 50 omega insertion loss is -79.5 dB, including Gore MicroFlat cable. Real-time in vivo 3D images of canine hearts have been made including an apical 4-chamber view from a substernal access with the first transducer to monitor cardiac function. In addition, we produced real time 3D rendered images of the right pulmonary veins from a right parastemal access with the second transducer, which would be valuable in the guidance of cardiac ablation catheters for treatment of atrial fibrillation.

Real-time 3D color flow Doppler for guidance of vibrating interventional devices.

The goal of this investigation was to examine the feasibility of guiding interventional devices using piezoelectric buzzers to create velocity sources, which were imaged and tracked with real-time 3D color flow Doppler. The interventional devices examined in this study included a pacemaker lead, Brockenbrough needle for cardiac septal puncture, cardiac guidewire and radiofrequency ablation needles for cancer therapy. Each was mechanically coupled to a piezoelectric buzzer and was imaged using a commercial real-time 3D ultrasound system with either a 2.5 MHz matrix array transducer or a 5 MHz, 22 F catheter transducer equipped with a tool port. In vitro images acquired in tissue phantoms, excised liver with a 'tumor' target and an excised sheep heart show strong vibration signals in 3D color flow Doppler, enabling real-time tracking and guidance of all the devices in three dimensions. In a sheep model, in vivo tracking of the pacing lead was performed in the superior vena cava as well as the right atrium using RT3D color flow Doppler images. The vibrating rf ablation needles were guided through the liver toward "tumor" targets in vivo with real-time 3D color flow Doppler images.

Dual lumen transducer probes for real-time 3-D interventional cardiac ultrasound.

We have developed dual lumen probes incorporating a forward-viewing matrix array transducer with an integrated working lumen for delivery of tools in real-time 3-D (RT3-D) interventional echocardiography. The probes are of 14 Fr and 22 Fr sizes, with 112 channel 2-D arrays operating at 5 MHz. We obtained images of cardiac anatomy and simultaneous interventional device delivery with an in vivo sheep model, including: manipulation of a 0.36-mm diameter guidewire into the coronary sinus, guidance of a transseptal puncture using a 1.2-mm diameter Brockenbrough needle, and guidance of a right ventricular biopsy using 3 Fr biopsy forceps. We have also incorporated the 22 Fr probe within a 6-mm surgical trocar to obtain apical four-chamber ultrasound (US) scans from a subcostal position. Combining the imaging catheter with a working lumen in a single device may simplify cardiac interventional procedures by allowing clinicians to easily visualize cardiac structures and simultaneously direct interventional tools in a RT3-D image.