Arrhythmias In Long QT Syndrome Research Articles

Bifurcations to transient and oscillatory excitations in inhomogeneous excitable media: Insights into arrhythmogenesis in long QT syndrome.

Ventricular arrhythmias are the leading cause of sudden cardiac death. Understanding the mechanisms of arrhythmia initiation is important for developing effective therapeutics for prevention. Arrhythmias can be induced via premature external stimuli or occur spontaneously via dynamical instabilities. Computer simulations have shown that a large repolarization gradient due to regional prolongation of the action potential duration can result in instabilities leading to premature excitations and arrhythmias, but the bifurcation remains to be elucidated. In this study we carry out numerical simulations and linear stability analyses using a one-dimensional heterogeneous cable consisting of the FitzHugh-Nagumo model. We show that a Hopf bifurcation leads to local oscillations, which, once their amplitudes are large enough, lead to spontaneous propagating excitations. Depending on the degree of heterogeneities, these excitations can range from one to many and to be sustained oscillations, manifesting as premature ventricular contractions (PVCs) and sustained arrhythmias. The dynamics depends on the repolarization gradient and the length of the cable. Complex dynamics is also induced by the repolarization gradient. The mechanistic insights from the simple model may help in the understanding of the genesis of PVCs and arrhythmias in long QT syndrome.

Effects of β-blockers on ventricular repolarization documented by 24-hour electrocardiography in long QT syndrome type 2

Long QT syndrome (LQTS) is an inherited arrhythmia disorder characterized by ventricular repolarization abnormalities and a risk of sudden cardiac death. The electrophysiological components generating the high risk of arrhythmias in LQTS are prolonged repolarization, increased dispersion of repolarization, and early afterdepolarizations, which are clinically estimated as QT interval, T-wave peak to T-wave end (TPE) interval, and T2/T1-wave amplitude ratio, respectively. In experimental LQTS type 2 (LQT2) models, β-blockers decrease dispersion of repolarization and prevent early afterdepolarizations. In clinical studies in patients with LQT2 , β-blockers are more effective against exercise-induced than arousal-induced cardiac events. The aim of the study was to investigate the effects of β-blocker therapy on repolarization properties in LQT2. QT and TPE intervals and maximal T2/T1-wave amplitude ratios recorded by 24-hour electrocardiograms before and during β-blocker therapy were evaluated in 25 patients with LQT2. β-Blocker therapy decreased the maximal T2/T1-wave amplitude ratio from 2.9 ± 1.1 to 1.8 ± 0.7 (P < .001), but did not change the pause-induced T2/T1-wave amplitude ratio. Under medication, abrupt maximal TPE intervals were shorter at heart rates of ≥75 beats/min and maximal QT intervals were shorter at a heart rate of 100 beats/min. β-Blockers stabilize ventricular repolarization in LQT2 by reducing electrocardiographic early afterdepolarizations and by reducing abrupt prolongation of electrocardiographic dispersion of repolarization and ventricular repolarization duration at elevated heart rates. The effect of β-blockers on pause-induced electrocardiographic early afterdepolarizations is weak. The findings provide electrocardiographic explanation for the protective effects of β-blockers against exercise-induced cardiac events in LQT2.

Comparative Characteristics of Beta-Blockers in Patients with Congenital Long QT Syndrome

Congenital long QT syndrome is a pathology that requires special attention and knowledge about the safety and effectiveness of various medications. Prolongation of the QT interval due to congenital or acquired causes is an important factor in the development of an unfavorable life forecast with the formation of an elongated QT syndrome. With an unfavorable course, patients suffer from loss of consciousness, episodes of tachycardia. Often, stable polymorphic ventricular tachycardia develops. The risk of sudden cardiac death in this pathology can vary from 0.33% to 5%. In people who have suffered an episode of cardiac arrest, and do not have a permanent prescribed antiarrhythmic therapy, the mortality rate reaches 50% within 15 years. Preventive administration of antiarrhythmic drugs is not always effective. A positive result of treatment depends on the severity of long QT syndrome and its genotype. Beta-blockers are often prescribed to patients of different ages with various cardiac pathologies, including for the prevention of arrhythmia in long QT syndrome. Beta-blockers differ in various pharmacokinetic and pharmacodynamic parameters (lipophilicity/hydrophilicity, selectivity, presence/absence of internal sympathomimetic activity), which, along with the variant of the disease genotype, can affect their effectiveness and safety in the considered pathology. This review article presents the results of major studies on the safety and effectiveness of different groups of beta blockers in various variants of long QT syndrome. The preferred beta-blockers for various genotypes of the syndrome were determined, and a comparative characteristic of beta-blockers for their safety and preventive effectiveness was given.

Conditions for the genesis of early afterdepolarization in a model of a ventricular myocyte.

Early afterdepolarization (EAD) is a major arrhythmogenic factor in the long QT syndrome (LQTS), whose conditions for genesis have puzzled people for several decades. Here, we employ the phase I Luo-Rudy ventricular myocyte model to investigate EAD using methods from nonlinear dynamics and provide valuable insights into EAD genesis from a physical perspective. Two major results are obtained: (i) Sufficient parametric conditions for EAD are analytically determined and then used to analyze in detail the effects of the physiological parameters. (ii) The normal form of the Hopf bifurcation that leads to EAD is derived and then used to determine whether the Hopf bifurcation is subcritical or supercritical for EAD genesis and the corresponding amplitude and period of the EAD oscillation. Our work here paves the way for further studies of more complicated multi-scale dynamics of EAD and may lead to effective treatments for LQTS arrhythmias.

Multiple Dynamical Mechanisms of Phase-2 Early Afterdepolarizations in a Human Ventricular Myocyte Model: Involvement of Spontaneous SR Ca 2+ Release.

Early afterdepolarization (EAD) is known to cause lethal ventricular arrhythmias in long QT syndrome (LQTS). In this study, dynamical mechanisms of EAD formation in human ventricular myocytes (HVMs) were investigated using the mathematical model developed by ten Tusscher and Panfilov (Am J Physiol Heart Circ Physiol 291, 2006). We explored how the rapid (IKr) and slow (IKs) components of delayed-rectifier K+ channel currents, L-type Ca2+ channel current (ICaL), Na+/Ca2+ exchanger current (INCX), and intracellular Ca2+ handling via the sarcoplasmic reticulum (SR) contribute to initiation, termination and modulation of phase-2 EADs during pacing in relation to bifurcation phenomena in non-paced model cells. Parameter-dependent dynamical behaviors of the non-paced model cell were determined by calculating stabilities of equilibrium points (EPs) and limit cycles, and bifurcation points to construct bifurcation diagrams. Action potentials (APs) and EADs during pacing were reproduced by numerical simulations for constructing phase diagrams of the paced model cell dynamics. Results are summarized as follows: (1) A modified version of the ten Tusscher-Panfilov model with accelerated ICaL inactivation could reproduce bradycardia-related EADs in LQTS type 2 and β-adrenergic stimulation-induced EADs in LQTS type 1. (2) Two types of EADs with different initiation mechanisms, ICaL reactivation–dependent and spontaneous SR Ca2+ release–mediated EADs, were detected. (3) Termination of EADs (AP repolarization) during pacing depended on the slow activation of IKs. (4) Spontaneous SR Ca2+ releases occurred at higher Ca2+ uptake rates, attributable to the instability of steady-state intracellular Ca2+ concentrations. Dynamical mechanisms of EAD formation and termination in the paced model cell are closely related to stability changes (bifurcations) in dynamical behaviors of the non-paced model cell, but they are model-dependent. Nevertheless, the modified ten Tusscher-Panfilov model would be useful for systematically investigating possible dynamical mechanisms of EAD-related arrhythmias in LQTS.

Exercise worsening of electromechanical disturbances: A predictor of arrhythmia in long QT syndrome.

BackgroundElectromechanical (EM) coupling heterogeneity is significant in long QT syndrome (LQTS), particularly in symptomatic patients; EM window (EMW) has been proposed as an indicator of interaction and a better predictor of arrhythmia than QTc.HypothesisTo investigate the dynamic response of EMW to exercise in LQTS and its predictive value of arrhythmia.MethodsForty‐seven LQTS carriers (45 ± 15 years, 20 with arrhythmic events), and 35 controls underwent exercise echocardiogram. EMW was measured as the time difference between aortic valve closure on Doppler and the end of QT interval on the superimposed electrocardiogram (ECG). Measurements were obtained at rest, peak exercise (PE) and 4 minutes into recovery.ResultsPatients did not differ in age, gender, heart rate, or left ventricular ejection fraction but had a negative resting EMW compared with controls (−42 ± 22 vs 17 ± 5 ms, P < 0.0001). EMW became more negative at PE (−89 ± 43 vs 16 ± 7 ms, P = 0.0001) and recovery (−65 ± 39 vs 16 ± 6 ms, P = 0.001) in patients, particularly the symptomatic, but remained unchanged in controls. PE EMW was a stronger predictor of arrhythmic events than QTc (AUC:0.765 vs 0.569, P < 0.001). B‐blockers did not affect EMW at rest but was less negative at PE (BB: −66 ± 21 vs no‐BB: −113 ± 25 ms, P < 0.001). LQT1 patients had worse PE EMW negativity than LQT2.ConclusionLQTS patients have significantly negative EMW, which worsens with exercise. These changes are more pronounced in patients with documented arrhythmic events and decrease with B‐blocker therapy. Thus, EMW assessment during exercise may help improve risk stratification and management of LQTS patients.

Mechanisms linking T-wave alternans to spontaneous initiation of ventricular arrhythmias in rabbit models of long QT syndrome.

T-wave alternans (TWA) and T-wave lability (TWL) are precursors of ventricular arrhythmias in long QT syndrome; however, the mechanistic link remains to be clarified. Computer simulations show that action potential duration (APD) prolongation and slowed heart rates promote APD alternans and chaos, manifesting as TWA and TWL, respectively. Regional APD alternans and chaos can exacerbate pre-existing or induce de novo APD dispersion, which combines with enhanced ICa,L to result in premature ventricular complexes (PVCs) originating from the APD gradient region. These PVCs can directly degenerate into re-entrant arrhythmias without the need for an additional tissue substrate or further exacerbate the APD dispersion to cause spontaneous initiation of ventricular arrhythmias. Experiments conducted in transgenic long QT rabbits show that PVC alternans occurs at slow heart rates, preceding spontaneous intuition of ventricular arrhythmias. T-wave alternans (TWA) and irregular beat-to-beat T-wave variability or T-wave lability (TWL), the ECG manifestations of action potential duration (APD) alternans and variability, are precursors of ventricular arrhythmias in long QT syndromes. TWA and TWL in patients tend to occur at normal heart rates and are usually potentiated by bradycardia. Whether or how TWA and TWL at normal or slow heart rates are causally linked to arrhythmogenesis remains unknown. In the present study, we used computer simulations and experiments of a transgenic rabbit model of long QT syndrome to investigate the underlying mechanisms. Computer simulations showed that APD prolongation and slowed heart rates caused early afterdepolarization-mediated APD alternans and chaos, manifesting as TWA and TWL, respectively. Regional APD alternans and chaos exacerbated pre-existing APD dispersion and, in addition, APD chaos could also induce APD dispersion de novo via chaos desynchronization. Increased APD dispersion, combined with substantially enhanced ICa,L , resulted in a tissue-scale dynamical instability that gave rise to the spontaneous occurrence of unidirectionally propagating premature ventricular complexes (PVCs) originating from the APD gradient region. These PVCs could directly degenerate into re-entrant arrhythmias without the need for an additional tissue substrate or could block the following sinus beat to result in a longer RR interval, which further exacerbated the APD dispersion giving rise to the spontaneous occurrence of ventricular arrhythmias. Slow heart rate-induced PVC alternans was observed in experiments of transgenic LQT2 rabbits under isoproterenol, which was associated with increased APD dispersion and spontaneous occurrence of ventricular arrhythmias, in agreement with the theoretical predictions.

Autonomic conflict exacerbates long QT associated ventricular arrhythmias

This study tested the hypothesis that concomitant sympathetic and parasympathetic stimulation (“autonomic conflict”) may act as a trigger for arrhythmias in long QT syndrome (LQTS). Studies were performed in isolated innervated rabbit hearts treated with clofilium (100 nmol/L); a potassium channel blocker. The influence of vagus nerve stimulation (VNS) on spontaneous ventricular arrhythmias was assessed in the absence/presence of sustained noradrenaline perfusion (100 nmol/L) and with sudden adrenergic stress (injections of noradrenaline into the perfusion line). Hearts were instrumented for a pseudo-electrocardiogram and monophasic action potential recordings. VNS, which slows heart rate, was associated with a stimulation frequency-dependent incidence of spontaneous early after-depolarisations (EADs) and ventricular tachycardia (VT), best predicted by the duration of the electrocardiographic T-wave and by triangulation of the ventricular action potential. In the presence of sustained (steady-state) noradrenaline perfusion, the incidence of EADs and VT with VNS was decreased from 73/55% to 45/27%, respectively. However, sudden adrenergic stress, imposed during periods of sustained VNS, was associated with a transient increase in the incidence of severity of observed arrhythmias, as indicated by an increase in the average arrhythmias score (1.6 ± 0.4 vs. 2.1 ± 0.7, p = .01). Analysis of electrophysiological parameters suggests that sudden adrenergic stress is associated with a transient prolongation, and increased triangulation, of the ventricular action potential, which may predispose to triggered activity. This study demonstrates that autonomic conflict is a pro-arrhythmic stimulus in LQTS. However, combined adrenergic and parasympathetic stimulation has a complex relationship with arrhythmogenicity, with differences in the effects of steady-state adrenergic activation vs. sudden adrenergic stress.

Genetic biomarkers for the risk of seizures in long QT syndrome.

The coprevalence, severity, and biomarkers for seizures and arrhythmias in long QT syndrome (LQTS) remain incompletely understood. Using the Rochester-based LQTS Registry, this study included large cohorts of LQTS1-3 participants (LQTS+, n = 965) and those without a LQTS mutation (LQTS-, n = 936). Compared to LQTS- participants, there was a higher prevalence of LQTS1, LQTS2, and LQTS+ participants classified as having seizures (p < 0.001, i.e., history of seizures/epilepsy or antiseizure medication). LQTS+ participants with longer corrected QT interval (QTc) durations were more likely to have seizures. LQTS2 mutations in the KCNH2 pore domain were positive predictors for both arrhythmias and seizures. In contrast, mutations in the cyclic nucleotide binding domain (cNBD) of KCNH2 conferred a negative risk of seizures, but not arrhythmias. LQTS2, KCNH2-pore, KCNH2-cNBD, QTc duration, and sex were independent predictors of seizures. LQTS+ participants with seizures had significantly longer QTc durations, and a history of seizures was the strongest independent predictor of arrhythmias (hazard ratio 4.09, 95% confidence interval 2.63-6.36, p < 0.001). This study highlights potential biomarkers for neurocardiac electrical abnormalities in LQTS.

Sympathetic denervation in the treatment of fatal arrhythmias in long QT syndrome with restrictive cardiomyopathy

Sympathetic denervation in the treatment of fatal arrhythmias in long QT syndrome with restrictive cardiomyopathy

Electrical Disturbances in the Brain and Heart in Long QT Syndrome: A Dangerous Synergy

Patients with genetic ion channel diseases, such as Long QT Syndrome (LQTS), experience electrical disturbances in the brain (seizures) and heart (arrhythmias) that can lead to sudden death. Mutated genes in LQTS1‐3 are expressed in the heart and brain. The objective was to determine the co‐prevalence and severity of seizures and arrhythmias in LQTS. We hypothesized: 1) LQTS mutations and QT prolongation are associated with seizures; 2) LQTS subjects with seizures have an increased risk of cardiac arrhythmias.Prevalence of seizures and arrhythmias were assessed using the Rochester LQTS Registry. LQTS analyses were limited to LQTS1‐3 subjects (LQTS+,n=965) and those with no known LQTS mutation (LQTS‐,n=936). Patients were assigned to the seizure group if they answered yes to seizures/epilepsy or were prescribed an anti‐seizure medication.LQTS+, particularly LQTS2, patients were at a 3‐4x higher total risk of seizures, compared to LQTS‐ subjects (p&lt;0.0001), and at each 10 year mark over 40 years of follow‐up (p&lt;0.01). There was a positive correlation of QTc to the percentage of subjects in the seizure group (R2=0.998). The percentage of LQTS genotype/phenotype positive subjects in the seizure group was 4x greater than LQTS genotype/phenotype negatives (p&lt;0.0001). Those in the seizure group had longer QTc and a 4‐9x higher risk of cardiac arrhythmias, compared to non‐seizure group, with a higher probability of arrhythmias over time in LQTS1 &amp; LQTS2 (p&lt;0.001). A complex network of factors coalesces to promote neuro‐cardiac electrical disturbances.

The safety of modern anesthesia for children with long QT syndrome.

Patients with long QT syndrome (LQTS) may experience a clinical spectrum of symptoms, ranging from asymptomatic, through presyncope, syncope, and aborted cardiac arrest, to sudden cardiac death. Arrhythmias in LQTS are often precipitated by autonomic changes. This patient population is believed to be at high risk for perioperative arrhythmia, specifically torsades de pointes (TdP), although this perception is largely based on limited literature that predates current anesthetic drugs and standards of perioperative monitoring. We present the largest multicenter review to date of anesthetic management in children with LQTS. We conducted a multicentered retrospective chart review of perioperative management of children with clinically diagnosed LQTS, aged 18 years or younger, who received general anesthesia (GA) between January 2005 and January 2010. Data from 8 institutions were collated in an anonymized database. One hundred three patients with LQTS underwent a total of 158 episodes of GA. The median (interquartile range) age and weight of the patients at the time of GA was 9 (3-15) years and 30.3 (15.4-54) kg, respectively. Surgery was LQTS-related in 81 (51%) GA episodes (including pacemaker, implantable cardioverter-defibrillator, and loop recorder insertions and revisions and lead extractions) and incidental in 77 (49%). β-blocker therapy was administered to 76% of patients on the day of surgery and 47% received sedative premedication. Nineteen percent of patients received total IV anesthesia, 30% received total inhaled anesthesia, and the remaining 51% received a combination. No patient received droperidol. There were 5 perioperative episodes of TdP, all in neonates or infants, all in surgery that was LQTS-related, and none of which was overtly attributable to anesthetic regimen. Thus the incidence (95% confidence interval) of perioperative TdP in incidental versus LQTS-related surgery was 0/77 (0%; 0%-5%) vs 5/81 (6.2%; 2%-14%). With optimized perioperative management, modern anesthesia for incidental surgery in patients with LQTS is safer than anecdotal case report literature might suggest. Our series suggests that the risk of perioperative TdP is concentrated in neonates and infants requiring urgent interventions after failed first-line management of LQTS.

Arrhythmia Phenotype During Fetal Life Suggests Long-QT Syndrome Genotype

Background— Fetal arrhythmias characteristic of long QT syndrome (LQTS) include torsades de pointes (TdP) and/or 2° atrioventricular block, but sinus bradycardia, defined as fetal heart rate &lt;3% for gestational age, is most common. We hypothesized that prenatal rhythm phenotype might predict LQTS genotype and facilitate improved risk stratification and management. Method and Results— Records of subjects exhibiting fetal LQTS arrhythmias were reviewed. Fetal echocardiograms, neonatal ECG, and genetic testing were evaluated. We studied 43 subjects exhibiting fetal LQTS arrhythmias: TdP±2° atrioventricular block (group 1, n=7), isolated 2° atrioventricular block (group 2, n=4), and sinus bradycardia (group 3, n=32). Mutations in known LQTS genes were found in 95% of subjects tested. SCN5A mutations occurred in 71% of group 1, whereas 91% of subjects with KCNQ1 mutations were in group 3. Small numbers of subjects with KCNH2 mutations (n=4) were scattered in all 3 groups. Age at presentation did not differ among groups, and most subjects (n=42) were live-born with gestational ages of 37.5±2.8 weeks (mean±SD). However, those with TdP were typically delivered earlier. Prenatal treatment in group 1 terminated (n=2) or improved (n=4) TdP. The neonatal heart rate–corrected QT interval (mean±SE) of group 1 (664.7±24.9) was longer than neonatal heart rate–corrected QT interval in both group 2 (491.2±27.6; P =0.004) and group 3 (483.1±13.7; P &lt;0.001). Despite medical and pacemaker therapy, postnatal cardiac arrest (n=4) or sudden death (n=1) was common among subjects with fetal/neonatal TdP. Conclusions— Rhythm phenotypes of fetal LQTS have genotype-suggestive features that, along with heart rate–corrected QT interval duration, may risk stratify perinatal management.

KCNQ Channels and Novel Insights Into Coronary Perfusion

See related article, pp 1090–1097 Kv7 (KCNQ) voltage-gated potassium channels are encoded by the KCNQ gene family, many of which display highly restricted and distinct tissue distribution. Cloning experiments have identified 5 KCNQ genes ( KCNQ 1–5).1 Mutations in 4 of the 5 genes of the KCNQ gene family have been associated with inherited diseases. KCNQ1 mutations cause cardiac arrhythmia in long QT syndrome with or without deafness. KCNQ2 and KCNQ3 mutations cause benign familial neonatal seizures and peripheral nerve hyperexcitability. Mutations in KCNQ4 underlie congenital deafness and modulate cutaneous touch sensitivity in man.1,2 No human disease has been related to KCNQ5 until now. KCNQ1, 3, 4 , and 5 gene products are widely expressed in systemic arteries with KCNQ 4 and 5 being predominant.3–5 Current data suggest important roles for Kv7 family in systemic peripheral arteries, namely myogenic response6 and vasoregulation by vasopressin,7 β-adrenoceptors,8 hydrogen sulfide, and perivascular adipose tissue.5,9 In this current issue, Khanamiri et …

Tpeak‐Tend Interval in 12‐Lead Electrocardiogram of Healthy Children and Adolescents Tpeak‐Tend Interval in Childhood

Tpeak (Tp) to the Tend (Te) interval is an index of transmural dispersion of repolarization. Prolongation of this interval predisposes to life-threatening ventricular arrhythmias in long QT syndrome, polymorphic catecholaminergic ventricular tachycardia, Brugada syndrome and short QT syndrome and may be an indicator of increased risk of sudden cardiac death. Very little is known about TpTe interval in children and adolescents. In 131 healthy children (64 girls) aged from 2.3 to 18.5 years (mean 9.1 years) the RR, QT, JT and TpTe intervals were measured manually in all leads of resting electrocardiogram (ECG). The statistical analysis were performed. TpTe intervals vary significantly (P < 0.0001) between individual leads-the longest were in lead V3 , the shortest ones in leads III and V1 . Boys had longer TpTe intervals, with statistically significant differences in leads I, aVR and precordial V2 -V6 . Greater values were also observed in older children. TpTe dispersion varied from 6 to 80 ms (mean 38.6 ms ± 14.6 ms, median 40 ms) with no gender differences and greater values in older subjects (P = 0.003). In most leads, higher TpTe/QT and TpTe/JT ratios were seen in boys regardless of age. The TpTe intervals lengthens with lowering heart rate. In healthy children and adolescents, TpTe intervals vary between individual leads of ECG, with the longest in lead V3 . The TpTe interval is longer in boys and in older children and prolongs as heart rate decelerates. TpTe/QT and TpTe/JT ratios are higher in boys. TpTe interval should be measured in precordial leads.

Concealed Long QT Syndrome and Intractable Partial Epilepsy: A Case Report

Herein, we describe a patient with concealed type 2 long QT syndrome with concomitant electroencephalogram-documented epilepsy. Although syncope in patients with long QT syndrome is common and often secondary to cerebral hypoxia after a protracted ventricular arrhythmia, this article demonstrates the importance of avoiding “tunnel vision” as patients with long QT syndrome could also have a primary seizure disorder. Identification of the etiology underlying seizurelike activity is paramount in instituting effective therapy. Furthermore, we theorize that abnormal KCHN2-encoded potassium channel repolarization in the brain could result in epilepsy and arrhythmias in long QT syndrome.

Triggering of cardiac arrhythmic events in long QT syndrome: lessons from funny bunnies

Triggering of cardiac arrhythmic events in long QT syndrome: lessons from funny bunnies

Index of Suspicion in the Nursery

A woman is admitted for induction of labor at 40-3/7 weeks' gestation. Prenatal care was initiated at 21 weeks' gestation. Ultrasonographic examinations at 23 and 34 weeks' gestation revealed a slightly enlarged right kidney and polyhydramnios, with amniotic fluid indices of 18.6 and 26.7, respectively. An emergency cesarean section is performed for fetal distress. Meconium-stained fluid is noted at delivery. A female infant weighing 3,140 g (10th to 25th percentile for weight) is delivered and assigned Apgar scores of 2, 5, and 9 at 1, 5, and 10 minutes, respectively. At delivery, she is flaccid and apneic but responds quickly to nasal and oral suctioning, stimulation, and bag-mask ventilation. She requires endotracheal intubation for worsening respiratory distress and desaturations. Her initial chest radiograph shows an enlarged cardiac silhouette and diffusely hazy lung fields (Fig. 1). An additional study is performed, which helps to explain the infant's presentation. Figure 1. Chest radiograph shows an enlarged cardiac silhouette and bilateral streaky opacities. Physical examination reveals a grade II/VI systolic ejection murmur along the left sternal border without radiation. Peripheral pulses are diminished in all extremities. She is having moderate respiratory distress on mechanical ventilation support. Her abdomen is soft but distended, and the liver edge is palpable 4 cm below the right costal margin and extends across the midline. No splenomegaly is noted. A palpable mass in the right flank is also detected. A three-vessel cord is present, with a prominent umbilical vein. An abdominal radiograph demonstrates a paucity of bowel gas consistent with ascites and hepatomegaly (Fig. 2). Laboratory results include a white blood cell count of 8.0×103/μL (8.0×109/L) with a normal differential count, a hematocrit of 24% (0.24), and a platelet count of 71×103/μL (71×109/L). Bacterial and viral cultures are negative. Figure 2. Abdominal radiograph of …

Risk of Fatal Arrhythmic Events in Long QT Syndrome Patients After Syncope

The aim of this study was to identify risk factors for fatal arrhythmias in long QT syndrome (LQTS) patients presenting with syncope. Syncope is highly predictive for future fatal arrhythmias in the LQTS. However, there are no data regarding risk stratification and management strategies in the high-risk subset of LQTS patients presenting with syncope. A total of 1,059 LQTS patients with a corrected QT interval > or =450 ms presenting with syncope as a first symptom were drawn from the International LQTS Registry. Cox proportional hazards regression was used to identify risk factors for a severe arrhythmic events comprising aborted cardiac arrest, appropriate implantable cardioverter-defibrillator therapy, and sudden cardiac death. The lowest risk was found in patients with only 1 syncopal episode occurring before the start of beta-blocker therapy. In contrast, patients experiencing syncope after starting beta-blocker therapy had a 3.6-fold increase in the risk of severe arrhythmic events (p < 0.001) relative to this low-risk group and displayed a risk of severe arrhythmic events similar to that of patients not treated with beta-blockers. Multiple syncopal episodes occurring before initiation of beta-blocker therapy were associated with an intermediate risk (hazard ratio: 1.8, p < 0.001). The risk of syncope during beta-blocker therapy is high during childhood in both sexes but is higher in women than in men (hazard ratio: 2.3, p < 0.001). Patients with syncope during beta-blocker therapy are at high risk of life-threatening events, and implantable cardioverter-defibrillator therapy should be considered in these patients. The risk of beta-blocker failure is highest in young children and in women.

Molecular determinants of local anesthetic action of beta-blocking drugs: Implications for therapeutic management of long QT syndrome variant 3

The congenital long QT syndrome (LQTS) is a heritable arrhythmia in which mutations in genes coding for ion channels or ion channel associated proteins delay ventricular repolarization and place mutation carriers at risk for serious or fatal arrhythmias. Triggers and therapeutic management of LQTS arrhythmias have been shown to differ in a manner that depends strikingly on the gene that is mutated. Additionally, beta-blockers, effective in the management of LQT-1, have been thought to be potentially proarrhythmic in the treatment of LQT-3 because of concomitant slowing of heart rate that accompanies decreased adrenergic activity. Here we report that the beta-blocker propranolol interacts with wild type (WT) and LQT-3 mutant Na + channels in a manner that resembles the actions of local anesthetic drugs. We demonstrate that propranolol blocks Na + channels in a use-dependent manner; that propranolol efficacy is dependent on the inactivated state of the channel; that propranolol blocks late non-inactivating current more effectively than peak sodium current; and that mutation of the local anesthetic binding site greatly reduces the efficacy of propranolol block of peak and late Na + channel current. Furthermore our results indicate that this activity, like that of local anesthetic drugs, differs both with drug structure and the biophysical changes in Na + channel function caused by specific LQT-3 mutations.