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If current inhibition and mortality reduction in heart failure: more than just a 'pure' effect of lowering heart rate.

Copyright © Polskie Towarzystwo Kardiologiczne IF IN THE HEALTHY HEART: SINOATRIAL NODE-LIMITED F-CHANNEL EXPRESSION AND ‘PURE’ HEART RATE REGULATION Cardiac pacemaking is a basic process in health and disease. The If current (often called ‘funny’ due to its many unusual properties) is an inward mixed Na+ and K+ current which is activated at negative cell membrane potentials (hence hyperpolarisation-activated) but whose activation causes spontaneous diastolic depolarisation [1]. These If properties are suited to the generation of repetitive electrical activity and the modulation of spontaneous rate [1]. Indeed, the degree of activation of the funny current determines the steepness of spontaneous depolarisation and thus the frequency of spontaneous firing in sino-atrial node (SAN) cells [1]. Because If is controlled by intracellular cAMP and thus is regulated by beta-adrenergic and muscarinic receptor agonists, it mediates the autonomic regulation of heart rate (HR) [1]. Furthermore, independent of autonomic modulation [2, 3], If is regulated by nitric oxide (NO) [4] through an intracellular pathway that involves cGMP and mobilisation of intracellular calcium [5]. The inhibition of endogenous NO production is associated with a reduction in HR both in vitro [6] and in vivo [2, 7], indicating that endogenous NO exerts a tonic positive chronotropic effect [2, 6]. Because of the many unusual features of If, it had been queried whether such a large body of properties could correspond to one single current. This was until the If molecular basis became clear with cloning the f-channels [8], which confirmed a unique structural basis for this specific membrane current [9]. Under normal physiological conditions, If is functionally expressed exclusively in the SAN cells [1]. Thus the principal publication from SHIfT (Systolic Heart Failure Treatment with the If Inhibitor Ivabradine Trial) in Lancet in 2010 rightly states that: “[beyond If inhibition in SAN] in healthy hearts (...) ivabradine has no action on other channels in the heart or vascular system” [9].