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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This 12-lead electrocardiogram (ECG) is from an asymptomatic girl aged 10 years, which was brought to our attention because of the irregularity of the P-P intervals. This ECG shows sinus arrhythmia at a rate of 65-75 beats per minute. The P waves all originate from the sinus node (SN) because they have a positive axis (upright) in leads I, II, and aVF. The PR interval is 104ms, and the QRS is narrow at 86ms, with a normal axis of 64°. The corrected QT (QTc) interval measures 402ms. Therefore, this is a normal ECG.
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Below is an electrocardiogram (ECG) of a girl aged 2 years who was referred to the clinic by a pediatrician for evaluation of a heart murmur. This ECG shows atrial rhythm originating most likely from the lower left atrium (P waves are inverted in lead I and are positive in II and aVF, with a frontal axis of 124°). The PR interval measures 113 ms, and the QRS is narrow at 90 ms. Right ventricular (RV) conduction delay is shown and is best seen in the precordial leads V1 and V2. The QRS frontal axis shows right axis deviation (reference range for a child aged 2 years is 0-110°). The patient does not have RV hypertrophy by voltage criteria. The inverted T waves in V1 are a normal finding at this age. An echocardiogram showed a moderately sized atrial septal defect. Nonsinus atrial rhythm is not a synonym of sinus node dysfunction.
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This is a 12-lead electrocardiogram (ECG) from a boy aged 12 years with a history of syncope. This patient was healthy until 1 month earlier, when he started to experience episodes of lightheadedness. The ECG shows sinus arrhythmia (bradycardia) at a rate of 50-79 beats per minute, with a PR interval of 136 ms. Two junctional escape beats are present after a prolonged pause. The QRS is narrow at 85 ms, with a normal frontal axis of 70°. The corrected QT interval (QTc) is 411 ms. A later electrophysiologic study showed prolonged sinus node recovery time (SNRT) and sinoatrial conduction time (SACT). Because of the patient's symptoms and his sinus node (SN) dysfunction, he received an atrial pacemaker. If this 12-lead ECG had been recorded from an asymptomatic patient, the findings would be considered within normal limits and no further workup would be indicated. In this case, the lightheadedness and, ultimately, the syncope defined sick sinus syndrome, with the patient requiring pacemaker therapy.
