Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a potentially lethal inherited arrhythmia syndrome in which drug therapy is often ineffective. We discovered that flecainide prevents arrhythmias in a mouse model of CPVT by inhibiting cardiac ryanodine receptor-mediated Ca 2+ release and thereby directly targeting the underlying molecular defect. Flecainide completely prevented CPVT in two human subjects who had remained highly symptomatic on conventional drug therapy, indicating that this currently available drug is a promising mechanism-based therapy for CPVT.CPVT is an inherited arrhythmia syndrome characterized by a normal baseline electrocardiogram (ECG), polymorphic ventricular tachycardia induced by adrenergic stress in the absence of structural heart disease, and a high mortality rate in young individuals1. Treatment with β-adrenergic blockers reduces arrhythmia burden and mortality but is not completely effective1, and implantable cardioverter defibrillators (ICDs) are used for the prevention of sudden death. However, painful appropriate or inappropriate defibrillation shocks can trigger further adrenergic stress and arrhythmias, and deaths have occurred despite appropriate ICD shocks2 , 3. In such instances, stellate ganglionectomy4 or even cardiac transplantation5 have been considered. Two CPVT disease-related genes have been identified: RYR2, encoding the cardiac ryanodine receptor Ca 2+ release channel (RyR2), and CASQ2, encoding cardiac calsequestrin 6,7 . Mutations in these genes destabilize the RyR2 Ca 2+ release complex 8,9 . In mice with CPVT-linked mutations, catecholamines cause spontaneous sarcoplasmic reticulum Ca 2+ release resulting in delayed after depolarizations (DADs), and they produce triggered activity in myocytes and polymorphic ventricular tachycardia in ©2009 Nature America, Inc. All rights reserved NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript vivo 10, 11. Here we identify a therapy that directly targets the underlying arrhythmia mechanisms: we found that flecainide, an approved antiarrhythmic drug known to block sodium channels, showed remarkable efficacy in suppressing spontaneous sarcoplasmic reticulum Ca 2+ release by inhibiting RyR2. Flecainide treatment completely prevented adrenergic stress-induced arrhythmias in a mouse model of CPVT and in humans with CASQ2 or RYR2 mutations that are refractory to standard drug treatment.The local anesthetic tetracaine has been used to inhibit RyR2 and suppress spontaneous sarcoplasmic reticulum Ca 2+ release in isolated myocytes 12 . However, tetracaine causes a rebound increase in sarcoplasmic reticulum Ca 2+ release events during prolonged exposure 13 , effective inhibitory concentrations 14 are too high for clinical use, and systemic administration is contraindicated in humans. We searched among clinically available antiarrhythmic drugs for a more useful RyR2 inhibitor and found that flecainide inhibited RyR2 more potently than tetracaine and by a different mechanism. Whereas tetrac...

The CYP2D6 gene encodes an enzyme important in the metabolism of many commonly used medications. Variation in CYP2D6 is associated with inter-individual differences in medication response, and genetic testing is used to optimize medication therapy. This report describes a retrospective study of CYP2D6 allele frequencies in a large population of 104,509 de-identified patient samples across all regions of the United States (US). Thirty-seven unique CYP2D6 alleles including structural variants were identified. A majority of these alleles had frequencies which matched published frequency data from smaller studies, while eight had no previously published frequencies. Importantly, CYP2D6 structural variants were observed in 13.1% of individuals and accounted for 7% of the total variants observed. The majority of structural variants detected (73%) were decreased-function or no-function alleles. As such, structural variants were found in approximately one-third (30%) of CYP2D6 poor metabolizers in this study. This is the first CYP2D6 study to evaluate, with a consistent methodology, both structural variants and single copy alleles in a large US population, and the results suggest that structural variants have a substantial impact on CYP2D6 function.

Since the downregulation of I(tof) was observed with overexpression of calcineurin and was also reversed by the calcineurin inhibitor CsA, we conclude that downregulation of I(tof) is a consequence of calcineurin overexpression.

The purpose of this work was to determine the temporal origins of the standard deviation of successive 5-min mean heart period sequences (SDANN) and the power of the ultralow-frequency (ULF) spectral band (<0.0033 Hz). We hypothesized that SDANN and ULF might have their origins in changes in human activity rather than slow oscillatory rhythms. Heart period sequences were obtained from 24-h Holter electrocardiograms of 10 healthy ambulatory subjects. There was no evidence of any persistent oscillation within the ULF band. Using moving 4-h windows in short-time Fourier transforms, we showed that the amplitude of ULF fluctuated markedly, particularly during times bordering sleep. The local ULF amplitude correlated ( r = 0.59 ± 0.09) with large-scale changes in heart period quantified with 2- and 4-h wavelet transforms. Local SDANN also fluctuated, mainly around times of sleep. Although the 24-h SDANN and ULF values correlated highly, there was little correlation between their temporal distributions ( r = 0.10 ± 0.25). The temporal distributions of measures of long-range heart period variability suggest that they reflect changes in human activity levels.