Reveal LINQ Versus Reveal XT Implantable Loop Recorders: Intra- and Post-Procedural Comparison.

OBJECTIVES: To compare the procedure, recovery, hospitalization times, and costs along with patient/parent satisfaction after newer-generation cardiac implantable loop recorder (Reveal LINQ; Medtronic Inc, Minneapolis, Minnesota) and previous-generation implantable loop recorder (Reveal XT; Medtronic Inc). STUDY DESIGN: A prospective study of patients undergoing LINQ implantations between April 2014 and October 2015 was performed. Retrospective chart review of patients undergoing XT implantations was performed for comparison. RESULTS: Thirty-one patients received LINQ and 15 patients received XT. Indications included syncope/palpitations (28/46, 61%), history of arrhythmias (9/46, 20%), arrhythmia burden in congenital heart disease (5/46, 10%), and monitoring in channelopathies (4/46, 9%). The LINQ group underwent more conscious sedation procedures than the XT group (8/31 vs 0/15, P = .04) with shorter procedural time (9 vs 34 minutes, P <.001), room occupation time (38 vs 81 minutes, P <.001), recovery time (21 vs 67 minutes, P <.001), and total hospital time (214 vs 264 minutes, P = .046). The LINQ group also had shorter return to activity time (2 vs 5 days, P = 1). Three device erosions in the LINQ group required reintervention. The LINQ group had fewer body image issues than the XT group (1/26 vs 5/14, P = .01) with both groups scoring 5/5 overall patient/parent satisfaction score at follow-up. Both groups had comparable total direct hospital costs (US $5905 vs $5438, P = .8). CONCLUSIONS: LINQ offers better procedural and recovery time compared with XT. LINQ implantations under conscious sedation reduce total hospitalization time.

Assessment of intrathoracic impedance algorithm in the pediatric and adult congenital population.

BACKGROUND: Decreased intrathoracic impedance has been used in adults to predict heart failure (HF) exacerbations. A commercial algorithm, OptiVol® (Medtronic Inc., Minneapolis, MN, USA), identifies patients with decreased impedance. We sought to determine the specificity, sensitivity, and positive predictive value (PPV) of OptiVol for predicting HF exacerbation or increased arrhythmia burden in pediatric and adult congenital heart disease (CHD) patients. METHODS: A multicenter retrospective chart review was undertaken. Inclusion criteria were: (1) <19 years or CHD adults, (2) an implanted device with OptiVol capability, (3) implanted between April 9 and September 6, and (4) follow-up of >30 days postimplant. Clinical events were defined as clinical HF exacerbation/hospital admission, initiation/uptitration of medication, or increased arrhythmia burden. RESULTS: Seventy-two patients (19 ± 9 years) were identified with the following indications: 20% dilated cardiomyopathy (DCM), 11% hypertrophic cardiomyopathy (HCM), 43% CHD, 15% channelopathy, and 11% other. Thirty-nine had 122 OptiVol crossings (median 2, range 1-11); 30% were linked to a cause. The remaining 33 had no crossing, though 17 had 89 clinical events. The clinical event rate was 19% greater in patients with crossings, though not statistically significant (P = 0.4). The algorithm had a 59% sensitivity, 52% specificity, and 62% PPV. Clinical HF exacerbation and arrhythmia burden did not significantly correlate with decreased impedance though uptitration or initiation of HF medication did correlate significantly (P = 0.03). CONCLUSION: The algorithm sensitivity for pediatric DCM, HCM, CHD, and adult CHD was equivalent to the general adult population. Further studies are warranted to assess whether inaccuracy in prediction is secondary to the algorithm or to differences in the clinical response of pediatric/CHD patients.

Coronary sinus morphology in pediatric patients with supraventricular tachycardia.

PURPOSE: The anatomic basis of atrioventricular node reentrant tachycardia (AVNRT) remains incompletely characterized in children. Differences in coronary sinus (CS) size and morphology have been observed in adults with AVNRT but have not been well characterized in children. METHODS: Children (< 18 years) brought to the EP lab with supraventricular tachycardia for ablation underwent CS venography. A blinded pediatric interventional cardiologist performed CS measurements, which were indexed to body surface area. Patients were excluded if they were < 25 kg or had significant congenital heart disease. RESULTS: Forty-six patients (age 14.2 ± 3.3 years) met inclusion criteria, 17 with AVNRT and 32 with an accessory pathway (AP). CS ostium (LAO projection, end-systole) was 7.8 ± 2.9 mm/m2 for the AVNRT group versus 6.0 ± 2.5 mm/m2 for the AP group (p = 0.04). CS "windsock" morphology was more prevalent in the AVNRT group (16/17, 94.1%) than the AP group (11/32, 34.3%) (p < 0.001). Within the AVNRT group, there was no correlation between CS ostium size and tachycardia cycle length (R = 0.01, p = 0.96), fast-pathway ERP (FPERP) (R = 0.42, p = 0.12), or A2-H2 at the FPERP (R = 0.25, p = 0.39). CONCLUSIONS: Children with AVNRT have larger CS ostia and more prevalent windsock morphology. CS size/morphology did not correlate with EP properties of the AVNRT substrate. These features may explain the basis for the development of the electrophysiologic substrate for dual AV node physiology in children.

Activation of stat3 in primary tumors from high-risk breast cancer patients is associated with elevated levels of activated SRC and survivin expression.

PURPOSE: Constitutive activation of signal transducer and activator of transcription 3 (Stat3) protein has been observed in a wide variety of tumors, including breast cancer, and contributes to oncogenesis at least in part by prevention of apoptosis. In a study of 45 patients with high-risk breast cancer enrolled in a phase II neoadjuvant chemotherapy trial with docetaxel and doxorubicin, we evaluated the levels of Stat3 activation and potentially associated molecular biomarkers in invasive breast carcinoma compared with matched nonneoplastic tissues. EXPERIMENTAL DESIGN: Using immunohistochemistry and image analysis, we quantified the levels of phospho-Stat3 (pY-Stat3), phospho-Src (pY-Src), epidermal growth factor receptor, HER2/neu, Ki-67, estrogen receptor, Bcl-2, Bcl-xL, Survivin, and apoptosis in formalin-fixed, paraffin-embedded sections from invasive carcinomas and their paired nonneoplastic parenchyma. The levels of molecular biomarkers in nonneoplastic and tumor tissues were analyzed as continuous variables for statistically significant correlations. RESULTS: Levels of activated pY-Stat3 and pY-Src measured by immunohistochemistry were significantly higher in invasive carcinoma than in nonneoplastic tissue (P < 0.001). In tumors, elevated levels of pY-Stat3 correlated with those of pY-Src and Survivin. Levels of pY-Stat3 were higher in partial pathologic responders than in complete pathologic responders. In partial pathologic responders, pY-Stat3 levels correlated with Survivin expression. CONCLUSIONS: Our findings suggest important roles for elevated activities of Stat3 and Src, as well as Survivin expression, in malignant progression of breast cancer. Furthermore, elevated Stat3 activity correlates inversely with complete pathologic response. These findings suggest that specific Stat3 or Src inhibitors could offer clinical benefits to patients with breast cancer.

Persistent activation of stat3 signaling induces survivin gene expression and confers resistance to apoptosis in human breast cancer cells.

PURPOSE: Signal transducer and activator of transcription 3 (Stat3) protein is persistently activated in breast cancer and promotes tumor cell survival. To gain a better understanding of the role of constitutive Stat3 signaling in breast cancer progression, we evaluated the expression profile of potential Stat3-regulated genes that may confer resistance to apoptosis. EXPERIMENTAL DESIGN: Stat3 signaling was blocked with antisense oligonucleotides in human MDA-MB-435s breast cancer cells and Affymetrix GeneChip microarray analysis was done. The candidate Stat3 target gene Survivin was further evaluated in molecular assays using cultured breast cancer cells and immunohistochemistry of breast tumor specimens. RESULTS: Survivin, a member of the inhibitor of apoptosis protein family, was identified as a potential Stat3-regulated gene by microarray analysis. This was confirmed in Survivin gene promoter studies and chromatin immunoprecipitation assays showing that Stat3 directly binds to and regulates the Survivin promoter. Furthermore, direct inhibition of Stat3 signaling blocked the expression of Survivin protein and induced apoptosis in breast cancer cells. Direct inhibition of Survivin expression also induced apoptosis. Increased Survivin protein expression correlates significantly (P = 0.001) with elevated Stat3 activity in primary breast tumor specimens from high-risk patients who were resistant to chemotherapy treatment. CONCLUSIONS: We identify Survivin as a direct downstream target gene of Stat3 in human breast cancer cells that is critical for their survival in culture. Our findings suggest that activated Stat3 signaling contributes to breast cancer progression and resistance to chemotherapy by, at least in part, inducing expression of the antiapoptotic protein, Survivin.

Force-Sensing Catheters During Pediatric Radiofrequency Ablation: The FEDERATION Study.

BACKGROUND: Based on data from studies of atrial fibrillation ablations, optimal parameters for the TactiCath (TC; St. Jude Medical, Inc) force-sensing ablation catheter are a contact force of 20 g and a force-time integral of 400 g·s for the creation of transmural lesions. We aimed to evaluate TC in pediatric and congenital heart disease patients undergoing ablation. METHODS AND RESULTS: Comprehensive chart and case reviews were performed from June 2015 to March 2016. Of the 102 patients undergoing electrophysiology study plus ablation, 58 (57%) underwent ablation initially with a force-sensing catheter. Patients had an average age of 14 (2.4-23) years and weight of 58 (18-195) kg with 15 patients having abnormal cardiac anatomy. Electrophysiology diagnoses for the +TC group included 30 accessory pathway-mediated tachycardia, 24 atrioventricular nodal reentrant tachycardia, and 7 other. Baseline generator settings included a power of 20 W, temperature of 40°, and 6 cc/min flow during lesion creation with 11 patients (19%) having alterations to parameters. Seventeen patients (30%) converted to an alternate ablation source. A total of 516 lesions were performed using the TC with a median contact force of 6 g, force-time integral of 149 g·s, and lesion size index of 3.3. Median-term follow-up demonstrated 5 (10%) recurrences with no acute or median-term complications. CONCLUSIONS: TactiCath can be effectively employed in the treatment of pediatric patients with congenital heart disease with lower forces than previously described in the atrial fibrillation literature. Patients with atrioventricular nodal reentrant tachycardia or atrioventricular reciprocating tachycardia may not require transmural lesions and the TC may provide surrogate markers for success during slow pathway ablation.

Constitutive activation of Stat3 in human prostate tumors and cell lines: direct inhibition of Stat3 signaling induces apoptosis of prostate cancer cells.

Signal transducers and activators of transcription (STATs) were identified originally as key components of cytokine signaling pathways. More recently, constitutive activation of STAT proteins has been detected in a wide variety of human tumor specimens and tumor cell lines. Here, we examined the activation of one STAT family member, Stat3, in human prostate cancer cell lines and primary prostate tumors. An analysis of 45 adenocarcinomas obtained at radical prostatectomy revealed elevated levels of constitutive Stat3 activation in 37 (82%) of 45 of the tumors compared with matched adjacent nontumor prostate tissues. A highly specific immunohistochemical assay for detection of phospho-Stat3 revealed that elevated Stat3 activity was localized primarily in the tumor cells of prostate carcinoma specimens. Furthermore, higher levels of Stat3 activation in patient specimens were correlated significantly with more malignant tumors exhibiting higher Gleason scores. In addition, all of the three human prostate cancer cell lines examined (DU145, PC3, and LNCaP) displayed constitutive activation of Stat3. Substantially lower levels of Stat3 activation were detected in LNCaP cells; however, stimulation with interleukin 6 induced a significant increase in Stat3 DNA-binding activity in these cells. Moreover, the direct inhibition of constitutive Stat3 signaling in DU145 cells using antisense Stat3 oligonucleotides induced growth inhibition and apoptosis. Our findings demonstrate that constitutive activation of Stat3 occurs frequently in primary prostate adenocarcinomas and is critical for the growth and survival of prostate cancer cells. These studies further suggest that Stat3 signaling represents a potentially novel molecular target for prostate cancer therapy.

Implantable Loop Recorder Monitoring for Refining Management of Children With Inherited Arrhythmia Syndromes.

BACKGROUND: Implantable loop recorders (ILRs) are conventionally utilized to elucidate the mechanism of atypical syncope. The objective of this study was to assess the impact of these devices on management of pediatric patients with known or suspected inherited arrhythmia syndromes. METHODS AND RESULTS: A retrospective chart review was undertaken of all pediatric patients with known or suspected inherited arrhythmia syndromes in whom an ILR was implanted from 2008 to 2015. Captured data included categorization of diagnosis, treatment, transmitted tracings, and the impact of ILR tracings on management. Transmissions were categorized as symptomatic, autotriggered, or routine. Actionable transmissions were abnormal tracings that directly resulted in a change of medical or device therapy. A total of 20 patients met the stated inclusion criteria (long QT syndrome, n=8, catecholaminergic polymorphic ventricular tachycardia,n=9, Brugada syndrome, n=1, arrhythmogenic right ventricular cardiomyopathy, n=2), with 60% of patients being genotype positive. Primary indication for implantation of ILR included ongoing monitoring +/- symptoms (n=15, 75%), suspicion of noncompliance (n=1, 5%), and liberalization of recommended activity restrictions (n=4, 25%). A total of 172 transmissions were received in patients with inherited arrhythmia syndromes, with 7% yielding actionable data. The majority (52%) of symptom events were documented in the long QT syndrome population, with only 1 tracing (5%) yielding actionable data. Automatic transmissions were mostly seen in the catecholaminergic polymorphic ventricular tachycardia cohort (81%), with 21% yielding actionable data. There was no actionable data in routine transmissions. CONCLUSIONS: ILRs in patients with suspected or confirmed inherited arrhythmia syndromes may be useful for guiding management. Findings escalated therapies in 30% of subjects. As importantly, in this high-risk population, the majority of symptom events represented normal or benign rhythms, reassuring patients and physicians that no further intervention was required.

Roles of activated Src and Stat3 signaling in melanoma tumor cell growth.

Activation of protein tyrosine kinases is prevalent in human cancers and previous studies have demonstrated that Stat3 signaling is a point of convergence for many of these tyrosine kinases. Moreover, a critical role for constitutive activation of Stat3 in tumor cell proliferation and survival has been established in diverse cancers. However, the oncogenic signaling pathways in melanoma cells remain to be fully defined. In this study, we demonstrate that Stat3 is constitutively activated in a majority of human melanoma cell lines and tumor specimens examined. Blocking Src tyrosine kinase activity, but not EGF receptor or JAK family kinases, leads to inhibition of Stat3 signaling in melanoma cell lines. Consistent with a role of Src in the pathogenesis of melanoma, we show that c-Src tyrosine kinase is activated in melanoma cell lines. Significantly, melanoma cells undergo apoptosis when either Src kinase activity or Stat3 signaling is inhibited. Blockade of Src or Stat3 is also accompanied by down-regulation of expression of the anti-apoptotic genes, Bcl-x(L) and Mcl-1. These findings demonstrate that Src-activated Stat3 signaling is important for the growth and survival of melanoma tumor cells.

SPEAR Trial: Smartphone Pediatric ElectrocARdiogram Trial.

OBJECTIVES: Smartphone-enabled ECG devices have the potential to improve patient care by enabling remote ECG assessment of patients with potential and diagnosed arrhythmias. This prospective study aimed to assess the usefulness of pediatric ECG tracings generated by the AliveCor device (Oklahoma City, OK) and to assess user satisfaction. STUDY DESIGN: Enrolled pediatric patients with documented paroxysmal arrhythmia used the AliveCor device over a yearlong study period. Pediatric electrophysiologists reviewed all transmitted ECG tracings. Patient completed surveys were analyzed to assess user satisfaction. RESULTS: 35 patients were enrolled with the following diagnoses: supraventricular tachycardia (SVT, 57%), atrial fibrillation (AF, 11%), ectopic atrial tachycardia (EAT, 6%), atrial tachycardia (AT, 3%), and ventricular tachycardia (VT, 23%). A total of 238 tracings were received from 20 patients, 96% of which were of diagnostic quality for sinus rhythm, sinus tachycardia, SVT, and AF. 126 patient satisfaction surveys (64% from parents) were completed. 98% of the survey responses indicated that it was easy to obtain tracings, 93% found it easy to transmit the tracings, 98% showed added comfort in managing arrhythmia by having the device, and 93% showed interest in continued use of the device after the study period ended. CONCLUSIONS: Smartphone-enabled ECG devices can generate tracings of diagnostic quality in children. User satisfaction was extremely positive. Use of the device to manage certain patients with AF and SVT showcases the future role of remote ECGs in the successful outpatient management of arrhythmias in children by potentially reducing Emergency Department visits and healthcare costs.

Management of pediatric tachyarrhythmias on mechanical support.

BACKGROUND: Pediatric patients with persistent arrhythmias may require mechanical cardiopulmonary support. We sought to classify the population, spectrum, and success of current treatment strategies. METHODS AND RESULTS: A multicenter retrospective chart review was undertaken at 11 sites. Inclusion criteria were (1) patients <21 years, (2) initiation of mechanical support for a primary diagnosis of arrhythmias, and (3) actively treated on mechanical support. A total of 39 patients were identified with a median age of 5.5 months and median weight of 6 kg. A total of 69% of patients were cannulated for supraventricular tachycardia with a median rate of 230 beats per minute. A total of 90% of patients were supported with extracorporeal membrane oxygenation for an average of 5 days. The remaining 10% were supported with ventricular assist devices for an average of 38 (20-60) days. A total of 95% of patients were treated with antiarrhythmics, with 43% requiring >1 antiarrhythmic. Amiodarone was the most frequently used medication alone or in combination. A total of 33% patients underwent electrophysiology study/transcatheter ablation. Radiofrequency ablation was successful in 9 patients on full flow extracorporeal membrane oxygenation with 3 radiofrequency-failures/conversion to cryoablation. One patient underwent primary cryoablation. A total of 15% of complications were related to electrophysiology study/ablation. At follow-up, 23 patients were alive, 8 expired, and 8 transplanted. CONCLUSIONS: Younger patients were more likely to require support in the presented population. Most patients were treated with antiarrhythmics and one third required electrophysiology study/ablation. Radiofrequency ablation is feasible without altering extracorporeal membrane oxygenation flows. There was a low frequency of acute adverse events in patients undergoing electrophysiology study/ablation, while on extracorporeal membrane oxygenation.

Electrophysiologic substrate and intraventricular left ventricular dyssynchrony in nonischemic heart failure patients undergoing cardiac resynchronization therapy.

BACKGROUND: Electrocardiographic imaging (ECGI) is a method for noninvasive epicardial electrophysiologic mapping. ECGI previously has been used to characterize the electrophysiologic substrate and electrical synchrony in a very heterogeneous group of patients with varying degrees of coronary disease and ischemic cardiomyopathy. OBJECTIVE: The purpose of this study was to characterize the left ventricular electrophysiologic substrate and electrical dyssynchrony using ECGI in a homogeneous group of nonischemic cardiomyopathy patients who were previously implanted with a cardiac resynchronization therapy (CRT) device. METHODS: ECGI was performed during different rhythms in 25 patients by programming their devices to biventricular pacing, single-chamber (left ventricular or right ventricular) pacing, and native rhythm. The electrical dyssynchrony index (ED) was computed as the standard deviation of activation times at 500 sites on the LV epicardium. RESULTS: In all patients, native rhythm activation was characterized by lines of conduction block in a region with steep activation-recovery interval (ARI) gradients between the epicardial aspect of the septum and LV lateral wall. A native QRS duration (QRSd) >130 ms was associated with high ED (≥30 ms), whereas QRSd <130 ms was associated with minimal (25 ms) to large (40 ms) ED. CRT responders had very high dyssynchrony (ED = 35.5 ± 3.9 ms) in native rhythm, which was significantly lowered (ED = 23.2 ± 4.4 ms) during CRT. All four nonresponders in the study did not show significant difference in ED between native and CRT rhythms. CONCLUSION: The electrophysiologic substrate in nonischemic cardiomyopathy is consistent among all patients, with steep ARI gradients co-localizing with conduction block lines between the epicardial aspect of the septum and the LV lateral wall. QRSd wider than 130 ms is indicative of substantial LV electrical dyssynchrony; however, among patients with QRSd <130 ms, LV dyssynchrony may vary widely.

Cardiac resynchronization therapy in pediatric congenital heart disease: insights from noninvasive electrocardiographic imaging.

BACKGROUND: Electrocardiographic imaging (ECGI) is a novel electrophysiologic imaging modality that may help guide patient selection and lead placement for cardiac resynchronization therapy (CRT). OBJECTIVE: The purpose of this study was to apply noninvasive ECGI to pediatric heart failure patients with congenital heart disease (CHD) undergoing evaluation for CRT. METHODS: ECGI was applied in eight patients with CHD who were either being evaluated for CRT or undergoing CRT. An electrical dyssynchrony (ED) index was computed from the ECGI epicardial activation maps as the standard deviation of activation times at 500 epicardial sites of the systemic ventricle. A normal ED of 20 +/- 4 ms was calculated from a control group of normal pediatric patients. RESULTS: Four patients had an ECGI assessment for ED but did not undergo CRT implant. Two other patients had ECGI assessment pre-CRT that demonstrated abnormal ED and went on to CRT implant. In both cases, the resynchronization lead was placed at the site of latest electrical activation (as determined by ECGI) in pre-CRT baseline rhythm. A total of four patients (two responders, two nonresponders) were studied with post-CRT in multiple rhythms. Responders had an average ED of 22 ms in optimal CRT conditions. The nonresponder had very elevated ED (37 ms) in all rhythms including optimal CRT settings. ED and ECG QRS duration showed weak correlation (r = 0.58). CONCLUSIONS: ECGI can be used in pediatric heart failure patients to evaluate ventricular ED and identify suitable candidates for CRT. In addition, ECGI can guide resynchronization lead placement to the area of latest electrical activation. It could also be used in noninvasive follow-ups for assessing synchrony and the electrophysiological substrate over time.