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Ms Karin Sipido,
News and views on Na channels
The session gave an excellent overview on novel molecular data as well as exciting perspectives for translation of mechanistic findings to therapy.
Dr. Mike Rosen from Columbia University, New York , USA, started by reminding us of the current concept that in cardiac myocytes two types of Na channels co-exist with specific location. NaV1.5 is considered the cardiac Na channel, and is found predominantly in the intercalated disc. There it may associate with connexins and cadherin, participating predominantly in conduction of the impulse in the longitudinal fibre direction. The so-called neuronal isoform, NaV1.1 is the isoform found in the T-tubules, probably conducting the impulse throughout the cell. The skeletal muscle isoform, NaV1.4, is normally not expressed in the heart and has different properties. In particular, in contrast to NaV1.5, it will remain available even when the cell is depolarized as occurs in the border zone of a myocardial infarction. So the group explored the possibility of rescuing conduction in the border zone by expressing the skeletal Na channels in these myocytes. The hypothesis proved correct as they could show restoration of impulse conduction and also reduction of arrhythmias in a pre-clinical model. These data are still being completed with additional mechanistic studies but offer an exciting novel possibility for treatment in MI.
Dr. David Fedida from the University of British Columbia at Vancouver, Canada, presented an overview of chaperones of both K and Na channels. These proteins have emerged as regulators at different levels: the expression of channels , post-translational modification and the response of channels to stimuli such as oxidative stress or calcium. Originally described for K channels, there appears to be crosstalk between different chaperones and channels, involving both K and Na channels. NaVBeta1 interacts not only with the Na channels but also with KV4.3. In cellular expression systems, there are coordinated changes in expression of KV4.3 and Nav1.5 related to the presence of NaVBeta1. KCHiP2 on the other hand appears to be associated with the KV4.3 but not the Na channel during co-immunoprecipitation studies. Yet, suppression of KCHiP2 reduces mRNA levels for NaV1.5 revealing the different interaction at transcription and protein level. Lastly, also Ca channels appear to be modified by the KCHiP2, opening a wider area of channel regulation and interaction with similar chaperones. This is a field that is in full discovery and more functional data are on the way.
Dr. Lars Maier from the University of Goettingen, Germany, presented an overview of Na balance in heart failure and the link to Na channel regulation with potential targets for therapy. Emphasis was on the late component of Na current, the late Na current, which could be important in the increased Na load in ischemia/reperfusion and heart failure. Ranolazine is a drug that blocks the late Na current and in the experimental setting rescues damage during ischemia/reperfusion and has potential as an anti-arrhythmic at the cellular level. Myocytes from patients with chronic atrial fibrillation also appear to have an increased late Na current, though the peak current was rather decreased. This late component was, particularly in AF, very sensitive to ranolazine. In ventricular muscle strips from patients with end-stage heart failure undergoing heart transplantation, the well-known diastolic dysfunction could be improved with ranolazine, indicating a link between Na influx and balance, and diastolic Ca levels. A dichotomy between lowering diastolic Ca and preserved systolic Ca could be a therapeutic advantage though the underlying mechanisms are not yet well understood. During the discussion it emerged that we need better knowledge of the molecular nature of this late Na current which provides a unique link between the ion channel changes and the contractile function.
Dr. Sebastian Maier from Wuerzburg University, Germany, gave an excellent overview of the different genetic diseases associated Na channels mutations. Originally these were recognized in arrhythmic diseases with sudden death such as the long QT syndrome 3 with gain-of-function mutations, or the Brugada syndrome, with several loss-of-function mutations described. Mutations in associated or regulatory proteins in long QT syndrome 9 and 10 also lead to a gain-of function of Na channels. Novel arrhythmic disease entities have joined the list such as progressive cardiac conduction defect and sick sinus syndrome. Novel perspectives come from association of Na channel mutations with dilated cardiomyopathy, fibrosis and conduction defects. From an overview of all known mutations and disease association it emerges that both gain- and loss-of-function mutations can give rise to a combination of phenotypes involving the sinus node, conduction and chronic remodelling. Also in the atrium, both loss-of- function as well as gain-of-function mutations may be involved in atrial fibrillation. This overview underscored the complexity of the phenotypes. Dr. Maier ended by highlighting that we may gain more insight in this complexity from the distribution of different channel isoforms throughout the heart, exciting ongoing work from his lab.
News and views on cardiac sodium channels - from bench to bedside