Atrial fibrillation is a rhythm disorder characterized by chaotic electrical activity of cardiac atria. Predisposing to stroke and heart failure, this common condition is increasingly recognized as a heritable disorder. To identify genetic defects conferring disease susceptibility, patients with idiopathic atrial fibrillation, lacking traditional risk factors, were evaluated. Genomic DNA scanning revealed a nonsense mutation in KCNA5 that encodes Kv1.5, a voltage-gated potassium channel expressed in human atria. The heterozygous E375X mutation, present in a familial case of atrial fibrillation and absent in 540 unrelated control individuals, introduced a premature stop codon disrupting the Kv1.5 channel protein. The truncation eliminated the S4-S6 voltage sensor, pore region and C-terminus, preserving the N-terminus and S1-S3 transmembrane domains that secure tetrameric subunit assembly. Heterologously expressed recombinant E375X mutant failed to generate the ultrarapid delayed rectifier current I(Kur) vital for atrial repolarization and exerted a dominant-negative effect on wild-type current. Loss of channel function translated into action potential prolongation and early after-depolarization in human atrial myocytes, increasing vulnerability to stress-provoked triggered activity. The pathogenic link between compromised Kv1.5 function and susceptibility to atrial fibrillation was verified, at the organism level, in a murine model. Rescue of the genetic defect was achieved by aminoglycoside-induced translational read-through of the E375X premature stop codon, restoring channel function. This first report of Kv1.5 loss-of-function channelopathy establishes KCNA5 mutation as a novel risk factor for repolarization deficiency and atrial fibrillation.

Summary Metabolic processes that regulate muscle energy use are major determinants of bodily energy balance. Here we find that sarcolemmal ATP-sensitive K+ (KATP) channels, which couple membrane excitability with cellular metabolic pathways, set muscle energy expenditure under physiological stimuli. Disruption of KATP channel function provoked, in conditions of unaltered locomotor activity and blood substrate availability, an extra energy cost of cardiac and skeletal muscle performance. Inefficient fuel metabolism in KATP channel-deficient striated muscles reduced glycogen and fat body depots promoting a lean phenotype. The propensity to lesser body weight imposed by KATP channel deficit persisted under a high-fat diet, yet obesity restriction was achieved at the cost of compromised physical endurance. Thus, sarcolemmal KATP channels govern muscle energy economy, and their down-regulation in a tissue-specific manner could present an anti-obesity strategy by rendering muscle increasingly thermogenic at rest and less fuel efficient during exercise.

Inheritance plays a significant role in defining drug response and toxicity. Advances in molecular pharmacology and modern genomics emphasize genetic variation in dictating inter-individual pharmacokinetics and pharmacodynamics. A case in point is the homeostatic ATP-sensitive potassium (K ATP ) channel, an established drug target that adjusts membrane excitability to match cellular energetic demand. There is an increased recognition that genetic variability of the K ATP channel impacts therapeutic decision-making in human disease.Genetic variations account for 15-30% of inter-individual differences in drug metabolism and as much as 95% of variability in individual drug response. 1 Individualization of therapy is aimed at achieving the best therapeutic outcome using patient-stratified genomic information. Integrated pharmacology with genetics provides an attractive strategy poised to decipher the heterogeneity of disease phenotypes and dissect variations in drug response, leading to therapeutic optimization. The information gained through pharmacogenomics holds particular promise in improving drug efficacy while minimizing toxicity, with subgrouping of patients based on genetic variations fostering early and personalized treatment. 2 Pharmacogenomics has established genetic variations in drug-metabolizing pathways, transporters, receptors, and signaling cascades as critical in defining pharmacokinetic and/or pharmacodynamic outcomes. 3 A therapeutic target that has recently received attention is the K ATP channel, widely distributed in tissue beds of high metabolic activity. 4 K ATP channels exhibit unique energetic decoding capabilities based on a heteromultimeric structure comprised of an inwardly rectifying K + -conducting (Kir) pore and a larger regulatory subunit, an ATPaseharboring ATP-binding cassette protein-the sulfonylurea receptor (SUR). By matching membrane excitability with fluctuations in cellular metabolic demand, K ATP channels link energetic flux and cell homeostasis. K ATP channels play cytoprotective roles throughout the body, including in the myocardium, vasculature, brain, skeletal muscle, and pancreas. 5 Indeed, in the pancreas, antagonism of K ATP channel activity with sulfonylurea agents facilitates insulin release and is a first-line treatment in adult-onset diabetes mellitus. K ATP channel openers display protective properties, although their clinical use is less common. 5 Here, we highlight how the K ATP genetic variability influences disease susceptibility, and delineate how this knowledge translates into advances in therapeutic management.Correspondence: A Terzic (E-mail: terzic.andre@mayo.edu). CONFLICT OF INTERESTThe authors declared no conflict of interest. 6,7 Nucleotide fluxes in the submembrane space influence channel function, which sets membrane excitability to ultimately control insulin release (Figure 1). In response to hyperglycemia and high intracellular glucose, channel closure permits membrane depolarization and associated calcium influx, facilitating insulin r...

Tramadol is a commonly prescribed synthetic opioid analgesic. In humans, electrocardiogram (ECG) changes consistent with sodium-channel blockade have not been described in overdoses with tramadol. We report a case of isolated tramadol overdose associated with a Brugada ECG pattern. A review of the literature reveals no previous human cases of tramadol overdose causing ECG changes consistent with sodium-channel blockade. However, in vitro blockade of sodium-channels has been demonstrated with high concentrations of tramadol. Tramadol overdose should be recognized as a cause for the manifestation of a Brugada ECG pattern in the setting of suicidal intoxication.

The characteristic electrocardiographic (ECG) findings of Brugada syndrome, specifically the down sloping coved elevation of the ST-segment ending in an inverted T-wave in the right precordial leads, have been linked to reduced inward sodium current due to dysfunctional sodium channels. Additionally, however, many sodium channel blocking agents are known to either unmask or induce this ECG pattern. Severe hyponatraemia may be expected to have the same effect by reducing inward sodium current. Here, we report a case in which the presenting ECG exhibited a 'Brugada-like' pattern during severe isolated hyponatraemia, with subsequent normalization as hyponatraemia improved.