Blockade of HERG channels by the class III antiarrhythmic azimilide: mode of action

1. The class III antiarrhythmic azimilide has previously been shown to inhibit I(Ks) and I(Kr) in guinea-pig cardiac myocytes and I(Ks) (minK) channels expressed in Xenopus oocytes. Because HERG channels underly the conductance I(Kr) in human heart, the effects of azimilide on HERG channels expressed in Xenopus oocytes were the focus of the present study. 2. In contrast to other well characterized HERG channel blockers, azimilide blockade was reverse use-dependent, i.e., the relative block and apparent affinity of azimilide decreased with an increase in channel activation frequency. Azimilide blocked HERG channels at 0.1 and 1 Hz with IC(50) s of 1.4 μM and 5.2  μM respectively. 3. In an envelope of tail test, HERG channel blockade increased with increasing channel activation, indicating binding of azimilide to open channels. 4. Azimilide blockade of HERG channels expressed in Xenopus oocytes and I(Kr) in mouse AT-1 cells was decreased under conditions of high [K(+)](e), whereas block of slowly activating I(Ks) channels was not affected by changes in [K(+)](e). 5. In summary, azimilide is a blocker of cardiac delayed rectifier channels, I(Ks) and HERG. Because of the distinct effects of stimulation frequency and [K(+)](e) on azimilide block of I(Kr) and I(Ks) channels, we conclude that the relative contribution of block of each of these cardiac delayed rectifier channels depends on heart frequency. [K(+)](e) and regulatory status of the respective channels

HERG mutation predicts short QT based on channel kinetics but causes long QT by heterotetrameric trafficking deficiency

OBJECTIVE: Mutations in the KCNH2 (hERG, human ether-a-go-go related gene) gene may cause a reduction of the delayed rectifier current I(Kr), thereby leading to the long QT syndrome (LQTS). The reduced I(Kr) delays the repolarisation of cardiac cells and renders patients vulnerable to ventricular arrhythmias and sudden death. We identified a novel mutation in a LQTS family and investigated its functional consequences using molecular and microscopic techniques. METHODS AND RESULTS: Genetic screening in the LQTS family revealed a heterozygous frameshift mutation p.Pro872fs located in the C-terminus of the KCNH2 gene. The mutation leads to a premature truncation of the C-terminus of the hERG protein. p.Pro872fs channels lack 282 amino acids at the C-terminus and possess an extra 4-amino acid tail. Both the kinetic and biochemical properties of the p.Pro872fs and p.Pro872fs/WT channels were studied in HEK293 cells and resulted in a novel proof of concept for heterozygous LQTS mutations: homotetrameric p.Pro872fs channels displayed near-normal expression, trafficking, and channel kinetics. Unexpectedly, upon co-expression of p.Pro872fs and WT channels, the repolarising power (the proportion of hERG current contributing to the action potential as the percentage of the total current available) was substantially higher during action potential clamp experiments as compared to WT channels alone. This would lead to a shorter rather than a prolonged QT interval. However, at the same time, heterotetramerisation of p.Pro872fs and WT channels also caused a dominant negative effect on trafficking by an increase in ER retention of these heterotetrameric channels, which surpassed the former gain in repolarising power. CONCLUSION: The LQTS phenotype in the studied family is caused by a mutation with novel properties. We demonstrate that a KCNH2 mutation that clinically leads to long QT syndrome causes at the cellular level both a "gain" and a "loss" of HERG channel function due to a kinetic increase in repolarising power and a decrease in trafficking efficiency of heteromultimeric channels

Resource and Infrastructure-Appropriate Management of ST-Segment Elevation Myocardial Infarction in Low- and Middle-Income Countries

The 143 low- and middle-income countries (LMICs) of the world constitute 80% of the world's population or roughly 5.86 billion people with much variation in geography, culture, literacy, financial resources, access to health care, insurance penetration, and healthcare regulation. Unfortunately, their burden of cardiovascular disease in general and acute ST-segment-elevation myocardial infarction (STEMI) in particular is increasing at an unprecedented rate. Compounding the problem, outcomes remain suboptimal because of a lack of awareness and a severe paucity of resources. Guideline-based treatment has dramatically improved the outcomes of STEMI in high-income countries. However, no such focused recommendations exist for LMICs, and the unique challenges in LMICs make directly implementing Western guidelines unfeasible. Thus, structured solutions tailored to their individual, local needs, and resources are a vital need. With this in mind, a multicountry collaboration of investigators interested in LMIC STEMI care have tried to create a consensus document that extracts transferable elements from Western guidelines and couples them with local realities gathered from expert experience. It outlines general operating principles for LMICs focused best practices and is intended to create the broad outlines of implementable, resource-appropriate paradigms for management of STEMI in LMICs. Although this document is focused primarily on governments and organizations involved with improvement in STEMI care in LMICs, it also provides some specific targeted information for the frontline clinicians to allow standardized care pathways and improved outcomes.Cardiolog