What is the role of ivabradine in the treatment of sinus node dysfunction (SND)?

Updated: Nov 30, 2018
  • Author: Bharat K Kantharia, MD, FRCP, FAHA, FACC, FESC, FHRS; Chief Editor: Mikhael F El-Chami, MD  more...
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Answer

Spontaneous depolarization of the sinus node involves "funny" (I(f)) current in sinoatrial (SA) node myocytes. This is an inward current that is activated on hyperpolarization to the diastolic range of voltages, thereby generating repetitive activity and modulating spontaneous rate. The degree of activation of the funny current determines the steepness of phase 4 depolarization and, hence, the frequency of action potential firing.

I(f) is controlled by intracellular cyclic adenosine monophosphate (cAMP) and is thus activated and inhibited by beta-adrenergic and muscarinic M2 receptor stimulation, respectively; it represents a basic physiologic mechanism for mediating autonomic regulation of the heart rate. Typically, given their exclusive role, f-channels are ideal targets of drugs aiming for pharmacologic control of the cardiac rate. Molecules able to bind specifically to and block f-channels can therefore be used as pharmacologic tools for heart rate control with little or no adverse cardiovascular side effects. 

In addition, several loss-of-function mutations of HCN4 (hyperpolarization-activated, cyclic-nucleotide gated 4), the major constitutive subunit of f-channels in pacemaker cells, are known to cause rhythm disturbances (eg, inherited sinus bradycardia). Finally, gene- or cell-based methods for in situ delivery of f-channels to silent or defective cardiac muscle represent novel approaches for the development of biologic pacemakers that may eventually be able to replace electronic devices.

Current status of ivabradine

A selective f-channel inhibitor, ivabradine, is now commercially available and used in patients with heart failure (HF) and sinus tachycardia.

The 2016 American College of Cardiology, American Heart Association, and the Heart Failure Society of America (ACC/AHA/HFSA) guideline update on new pharmacologic therapy for HF gives a class IIa recommendation for the use of ivabradine to reduce HF hospitalization in patients with symptomatic (New York Heart Association [NYHA] class II-III) stable chronic HF with reduced ejection fraction (HFrEF) (left ventricular ejection fraction [LVEF] ≤35%) receiving guideline-directed evaluation and management, including a beta blocker at the maximum tolerated dose, as well as who are in sinus rhythm with a resting heart rate of 70 bpm or more. [39] The guideline indicates that, "given the well-proven mortality benefits of beta-blocker therapy, it is important to initiate and up titrate these agents to target doses, as tolerated, before assessing the resting heart rate for consideration of ivabradine initiation." [39]

Ivabradine is contraindicated in patients with HF and SND without a permanent cardiac pacemaker.


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