Hypoxia Promotes Atrial Tachyarrhythmias via Opening of ATP-Sensitive Potassium Channels.

BACKGROUND: Hypoxia-ischemia predisposes to atrial arrhythmia. Atrial ATP-sensitive potassium channel (KATP) modulation during hypoxia has not been explored. We investigated the effects of hypoxia on atrial electrophysiology in mice with global deletion of KATP pore-forming subunits. METHODS: Whole heart KATP RNA expression was probed. Whole-cell KATP current and action potentials were recorded in isolated wild-type (WT), Kir6.1 global knockout (6.1-gKO), and Kir6.2 global knockout (6.2-gKO) murine atrial myocytes. Langendorff-perfused hearts were assessed for atrial effective refractory period (ERP), conduction velocity, wavefront path length (WFPL), and arrhymogenicity under normoxia/hypoxia using a microelectrode array and programmed electrical stimulation. Heart histology was assessed. RESULTS: Expression patterns were essentially identical for all KATP subunit RNA across human heart, whereas in mouse, Kir6.1 and SUR2 (sulphonylurea receptor subunit) were higher in ventricle than atrium, and Kir6.2 and SUR1 were higher in atrium. Compared with WT, 6.2-gKO atrial myocytes had reduced tolbutamide-sensitive current and action potentials were more depolarized with slower upstroke and reduced peak amplitude. Action potential duration was prolonged in 6.1-gKO atrial myocytes, absent of changes in other ion channel gene expression or atrial myocyte hypertrophy. In Langendorff-perfused hearts, baseline atrial ERP was prolonged and conduction velocity reduced in both KATP knockout mice compared with WT, without histological fibrosis. Compared with baseline, hypoxia led to conduction velocity slowing, stable ERP, and WFPL shortening in WT and 6.1-gKO hearts, whereas WFPL was stable in 6.2-gKO hearts due to ERP prolongation with conduction velocity slowing. Tolbutamide reversed hypoxia-induced WFPL shortening in WT and 6.1-gKO hearts through ERP prolongation. Atrial tachyarrhythmias inducible with programmed electrical stimulation during hypoxia in WT and 6.1-gKO mice correlated with WFPL shortening. Spontaneous arrhythmia was not seen. CONCLUSIONS: KATP block/absence leads to cellular and tissue level atrial electrophysiological modification. Kir6.2 global knockout prevents hypoxia-induced atrial WFPL shortening and atrial arrhythmogenicity to programmed electrical stimulation. This mechanism could be explored translationally to treat ischemically driven atrial arrhythmia.

Cardiogenetics: the role of genetic testing for inherited arrhythmia syndromes and sudden death.

There have been remarkable advances in our knowledge of the underlying heritability of cardiac arrhythmias. Long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, progressive cardiac conduction disease and the short QT syndrome comprise the inherited arrhythmia syndromes (IASs). Pathogenic variants in cardiac ion channel and calcium handling protein genes lead to these conditions, usually in the absence of overt structural cardiac disease. Diagnosis is contingent on the ECG phenotype but genetic testing may help to confirm the diagnosis and provide information on the mechanism of arrhythmogenesis that may guide treatment and provide prognostic information in relation to the risk of sudden arrhythmic death. Clinical genetic testing uses 'panels' of genes that are the likely culprits for the IASs being investigated. An International Consortium (Clinical Genome Resource) has curated gene panels based on genetic and experimental evidence of causation of inherited conditions and that have a role in clinical genetic testing. A 'single gene' or monogenic basis for IASs exists but in future, missing heritability and incomplete penetrance will be uncovered by association of common variants through genome-wide association studies. Novel rare variants will also be detected through whole-genome sequencing. The formulation of polygenic risk scores will likely help to predict phenotypic expression and response to treatments/risk stratification and move genetic testing very much to the fore of the diagnostic process.