Role of Late Sodium Current During Repolarization and Its Pathophysiology
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Voltage-gated Na channels produce the rapid upstroke of the action potential and are critical elements for maintaining electrical excitability and assuring the coordination of excitation-contraction coupling in the heart. During their activity, these channels cycle between three processes: closing, activation, and inactivation. There is much evidence for the existence of additional channel conformations, modal gating, for instance. The existence of these modes has been observed in cardiac sodium channels. It, therefore, is an intrinsic property of these channels that is in some way related to their proper function. The model gating is thought to underlie the persistent activity of these channels known as late sodium current. Therefore, sodium channels are also involved in determining the duration of action potentials. Excessive residency of sodium channels in a slow mode of gating increases the late sodium current and causes an increase in intracellular sodium and may result in calcium overload and early afterdepolarizations which are substrates for myocyte abnormal electrical activity. This abnormal sodium activity has been found in different pathologies such as type 3 long QT syndrome or heart failure. Ranolazine, an antianginal and a well-tolerated drug, exhibited some beneficial effects in reducing late sodium channel currents and exhibited beneficial effect in animal models of heart failure and proven to be beneficial in several clinical trials.
KeywordsHeart Voltage-gated sodium channels Nav1.5 Late sodium current Persistent sodium current Ranolazine Antiarrhythmic drugs Heart failure Long QT syndrome Cardiac repolarization
Supported by the Canadian Institutes of Health Research (MOP-111072 and MOP-130373 to MC). Association Française contre les Myopathies (AFM) – Téléthon (Research Grant AFM19962 to MC).
- 13.Coraboeuf E, Deroubaix E, Coulombe A. Effect of tetrodotoxin on action potentials of the conducting system in the dog heart. Am J Phys. 1979;236(4):H561–H7.Google Scholar
- 32.Schwartz PJ, Priori SG, Locati EH, Napolitano C, Cantù F, Towbin JA, et al. Long QT syndrome patients with mutations of the SCN5A and HERG genes have differential responses to Na+ channel blockade and to increases in heart rate. Implications for gene-specific therapy. Circulation. 1995;92(12):3381–6.PubMedCrossRefGoogle Scholar
- 37.Undrovinas AI, Belardinelli L, Undrovinas NA, Sabbah HN. Ranolazine improves abnormal repolarization and contraction in left ventricular myocytes of dogs with heart failure by inhibiting late sodium current. J Cardiovasc Electrophysiol. 2006;17(Suppl 1):S169–s77.PubMedPubMedCentralCrossRefGoogle Scholar
- 44.Chaitman BR, Pepine CJ, Parker JO, Skopal J, Chumakova G, Kuch J, et al. Effects of ranolazine with atenolol, amlodipine, or diltiazem on exercise tolerance and angina frequency in patients with severe chronic angina: a randomized controlled trial. JAMA. 2004;291(3):309–16.PubMedCrossRefGoogle Scholar
- 45.Alexopoulos D, Kochiadakis G, Afthonidis D, Barbetseas J, Kelembekoglou P, Limberi S, et al. Ranolazine reduces angina frequency and severity and improves quality of life: observational study in patients with chronic angina under ranolazine treatment in Greece (OSCAR-GR). Int J Cardiol. 2016;205:111–6.PubMedCrossRefGoogle Scholar
- 46.Kosiborod M, Arnold SV, Spertus JA, McGuire DK, Li Y, Yue P, et al. Evaluation of ranolazine in patients with type 2 diabetes mellitus and chronic stable angina: results from the TERISA randomized clinical trial (type 2 diabetes evaluation of ranolazine in subjects with chronic stable angina). J Am Coll Cardiol. 2013;61(20):2038–45.PubMedCrossRefGoogle Scholar
- 48.Rastogi S, Sharov VG, Mishra S, Gupta RC, Blackburn B, Belardinelli L, et al. Ranolazine combined with enalapril or metoprolol prevents progressive LV dysfunction and remodeling in dogs with moderate heart failure. Am J Physiol Heart Circ Physiol. 2008;295(5):H2149–55.PubMedPubMedCentralCrossRefGoogle Scholar