Johnson, Jonathan N.

Background— Long QT syndrome (LQTS) is a potentially lethal but highly treatable cardiac channelopathy. Treatment options include pharmacotherapy, device therapy, and left cardiac sympathetic denervation (LCSD). Here, we sought to determine the characteristics of LQTS patients who have had ≥1 LQTS-related breakthrough cardiac event (BCE) after LCSD. Methods and Results— We performed retrospective chart review for 52 consecutive patients (24 males; mean age at diagnosis, 10.0±10 years; mean QTc, 528±74 ms) with LQTS who underwent LCSD between 2005 and 2010 (mean age at LCSD, 14.1±10 years) and have been followed up for 3.6±1.3 years. A BCE was defined as either (1) an appropriate ventricular fibrillation-terminating implantable cardioverter defibrillator shock or (2) arrhythmogenic syncope, seizures, or aborted cardiac arrest after LCSD. Thirty-three patients (61%) had LCSD as primary prevention because of either high-risk assessment or β-blocker intolerance. So far, 12 of 52 (23%) patients (7 males) have experienced ≥1 BCE post LCSD. The clinical phenotype of patients with BCEs was significantly more severe than patients without a BCE. No BCEs were seen in patients undergoing LCSD for β-blocker intolerance (0/12 versus 17/40; P <0.001). Conclusions— Although a marked reduction in number of cardiac events is usually seen after LCSD, ≈50% of high-risk LQTS patients have experienced ≥1 post-LCSD breakthrough. Therefore, LCSD must not be viewed as curative or as an alternative in implantable cardioverter defibrillator for high-risk patients. Prophylactic LCSD may provide another option to counter a suboptimal quality of life resulting from medication-related side effects.

AbstractPosterior reversible encephalopathy syndrome (PRES) is a disorder characterized by gray and white matter abnormalities in the temporal, parietal, and occipital lobes of the brain. Its etiology has been attributed to renal failure, immunosuppressive drugs such as cyclosporine and tacrolimus, and other potential entities leading to acute hypertension. Clinical findings include headaches, altered mental status, seizures, visual changes, and focal neurologic deficits. We report the case of a child who developed PRES with intracerebral and subarachnoid hemorrhages associated with tacrolimus exposure 10 days after heart transplantation for restrictive cardiomyopathy. The patient initially presented with complex partial seizures, headache, agitation, and hypertension. Head MRI was suggestive of PRES along with intracerebral and subarachnoid hemorrhages. Tacrolimus was discontinued and blood pressure was controlled. The patient's encephalopathy resolved, but he has had ongoing neurologic symptoms secondary to hemorrhage. Generally, PRES is less common in children than in the adult population and is a rare complication of calcineurin inhibitors (CNI). Presentation with secondary hemorrhage also can occur. In children receiving CNIs presenting with new neurologic symptoms, PRES should be considered as prompt discontinuation of the offending agent can induce resolution of symptoms. Children can develop hemorrhage in the context of PRES, leading to increased morbidity.

BackgroundIn recent years, percutaneous device closure has become commonplace for treatment of atrial septal defect (ASD) and patent foramen ovale (PFO). However, the effect of device closure on aortic valve regurgitation (AR) has been questioned.ObjectiveThe purpose of this study was to define changes in AR using echocardiography, before and after device closure of ASD or PFO.MethodsWe retrospectively reviewed all patients who had percutaneous device closure of ASD or PFO at our institution between 2005 and 2009. We compared the preprocedure echocardiogram to the most recent follow‐up study. All investigators were blinded to referral diagnosis, patient demographics, and size and type of the device placed. Aortic regurgitation was graded as none/trivial, mild, moderate, or severe.ResultsOverall, 322 patients qualified for inclusion; 204 with PFO and 118 with ASD. Mean age at time of closure was 48 ± 20 years (range 3–85 years). Mean duration of follow‐up was 1.2 years (range 2 months to 5 years). Only two patients (0.6%) demonstrated any appreciable increase in AR severity. However, both of these patients manifested a clinically insignificant change from a trivial to mild grade of aortic regurgitation.ConclusionsPercutaneous device closure of PFO or ASD does not increase the incidence or severity of AR over medium‐term follow‐up. © 2012 Wiley Periodicals, Inc.

R231H Causes a High Penetrance for Familial AFBackgroundAtrial fibrillation (AF) is the most common cardiac arrhythmia, and its incidence is expected to grow. A genetic predisposition for AF has long been recognized, but its manifestation in these patients likely involves a combination of rare and common genetic variants. Identifying genetic variants that associate with a high penetrance for AF would represent a significant breakthrough for understanding the mechanisms that associate with disease.Method and ResultsCandidate gene sequencing in 5 unrelated families with familial AF identified the KCNQ1 missense mutation p.Arg231His (R231H). In addition to AF, several of the family members have abnormal QTc intervals, syncope or experienced sudden cardiac arrest or death. KCNQ1 encodes the voltage‐gated K+ channel that conducts the slowly activating delayed rectifier K+ current in the heart. Functional and computational analyses suggested that R231H increases KCNQ1 current (IKCNQ1) to shorten the atrial action potential (AP) duration. R231H is predicted to minimally affect ventricular excitability, but it prevented the increase in IKCNQ1 following PKA activation. The unique properties of R231H appeared to be caused by a loss in voltage‐dependent gating.ConclusionsThe R231H variant causes a high penetrance for interfamilial early‐onset AF. Our study indicates R231H likely shortens atrial refractoriness to promote a substrate for reentry. Additionally, R231H might cause abnormal ventricular repolarization by disrupting PKA activation of IKCNQ1. We conclude genetic variants, which increase IKs during the atrial AP, decrease the atrial AP duration, and/or shorten atrial refractoriness, present a high risk for interfamilial AF.

Background— Treatment options for patients with recurrent ventricular arrhythmias refractory to pharmacotherapy and ablation are minimal. Although left cardiac sympathetic denervation (LCSD) is well established in long-QT syndrome, its role in non–long-QT syndrome arrhythmogenic channelopathies and cardiomyopathies is less clear. Here, we report our single-center experience in performing LCSD in this setting. Methods and Results— In this institutional review board–approved study, we retrospectively reviewed the electronic medical records of all patients (N=91) who had videoscopic LCSD at our institution from 2005 to 2011. Data were analyzed for the subset (n=27) who were denervated for an underlying diagnosis other than autosomal dominant or sporadic long-QT syndrome. The spectrum of arrhythmogenic disease included catecholaminergic polymorphic ventricular tachycardia (n=13), Jervell and Lange-Nielsen syndrome (n=5), idiopathic ventricular fibrillation (n=4), left ventricular noncompaction (n=2), hypertrophic cardiomyopathy (n=1), ischemic cardiomyopathy (n=1), and arrhythmogenic right ventricular cardiomyopathy (n=1). Five patients had LCSD because of high-risk assessment and β-blocker intolerance, none of whom had a sentinel breakthrough cardiac event at early follow-up. Among the remaining 22 previously symptomatic patients who had LCSD as secondary prevention, all had an attenuation in cardiac events, with 18 having no breakthrough cardiac events so far and 4 having experienced ≥1 post-LCSD breakthrough cardiac event. Conclusions— LCSD may represent a substrate-independent antifibrillatory treatment option for patients with life-threatening ventricular arrhythmia syndromes other than long-QT syndrome. The early follow-up seems promising, with a marked reduction in the frequency of cardiac events postdenervation.

OBJECTIVE: Long-QT syndrome (LQTS) is both underdiagnosed and overdiagnosed. Many patients are incorrectly diagnosed as having LQTS after presenting to an emergency department (ED) with presyncope/syncope and demonstrating “borderline” QT-interval prolongation (QTc ≥ 440 milliseconds) in a sentinel ED-obtained electrocardiogram (ECG). We sought to evaluate the distribution and clinical significance of QT intervals in the ED. METHODS: We retrospectively reviewed data for all patients 22 years of age or younger (N = 626; 369 females; age, mean ± SD: 17 ± 5 years) who had ECGs obtained in our ED between July 1, 2007, and June 30, 2008. A total of 223 patients were excluded because of known structural heart disease, arrhythmias, electrolyte abnormalities, or exposure to QT-interval–prolonging medications. RESULTS: The average QTc was 428 ± 28 milliseconds (range: 344–566 milliseconds), and approximately one-third of patients had QTc values of ≥440 milliseconds (females: 41%; males: 21%). Overall, 104 patients presented with presyncope/syncope, of whom 14 (13%) had follow-up ECGs. On follow-up, these patients demonstrated significant decreases in QTc values of 33 ± 43 milliseconds (P &lt; .04). Only 8 (31%) of 26 patients with presyncope/syncope with borderline QT values had follow-up ECGs performed, in 5 of which the QTc values were decreased significantly. No patients ultimately received LQTS diagnoses. CONCLUSIONS: In the ED setting, approximately one-third of pediatric patients exhibited QTc values of ≥440 milliseconds and had significant normalization of QTc values in follow-up evaluations. First-time ECGs obtained after a syncopal episode must be interpreted with caution, particularly in the context of so-called borderline QT intervals.

Sudden unexpected death in epilepsy is the sudden, unexplained, unexpected death of an individual with epilepsy in which postmortem examination does not reveal an anatomic or toxicologic cause of death. Patients with congenital long QT syndrome and catecholaminergic polymorphic ventricular tachycardia have been frequently initially diagnosed with epilepsy. A cardiac channel molecular autopsy of the common long QT syndrome and catecholaminergic polymorphic ventricular tachycardia-susceptibility genes was performed on an archived necropsy specimen from an 8-year-old victim of sudden unexpected death in epilepsy. A novel, sporadic missense mutation in exon 104 of the RYR2-encoded ryanodine receptor/calcium release channel (c. 14806G>A, p.Gly4936Arg) was discovered. This mutation was absent in >600 reference alleles including both parents, involved a highly conserved amino acid, and localized to a key structure-function domain. To our knowledge, this is the first postmortem molecular diagnosis of catecholaminergic polymorphic ventricular tachycardia in a patient with sudden unexpected death in epilepsy.