Inappropriate sinus tachycardia (IST) is a poorly understood dysrhythmia characterized by palpitations and activity intolerance with an elevated daytime heart rate, exaggerated heart rate response to exercise, and otherwise normal cardiac structure and function. First described in 1979, the disorder is most commonly diagnosed in young women but is not limited to that population ((1),2). In addition to symptoms related to elevated heart rate, there are often dysautonomic symptoms such as orthostatic intolerance, recurrent syncope, gastrointestinal distress, and anxiety. Various abnormalities have been proposed to explain the pathophysiology of IST, including autonomic nervous system dysfunction (1), sinoatrial node (SAN) abnormalities (3), and anti–beta-adrenergic receptor antibodies (4), with some proposing a significant psychological overlay.

IST can be frustratingly difficult to treat (5). The mainstays of therapy include negative chronotropic agents such as beta-blockers and calcium channel blockers, often ineffectual at doses high enough to cause intolerable side effects. Medical management frequently requires a prolonged period of trial and error, dose adjustments, and lifestyle changes for the patient. For refractory disease, sinus node modification using a variety of catheter ablation techniques can be attempted ((6),7). Although the short-term results of ablation are generally good, symptoms and elevated heart rate commonly recur after successful sinus node modification. In addition, ablative procedures carry the risk of sinus node suppression with the need for permanent pacing. Other drugs used with unpredictable efficacy include clonidine, pyrodystigamine, and serotonin-specific reuptake inhibitors, leaving most of these patients both with persistent symptoms as well as potential side effects of administered drugs.

Clearly, what is needed is a treatment that can provide long-term inhibition of SAN automaticity without engendering unwelcome side effects. Over the past several decades, the cellular basis of sinoatrial electrophysiology has gradually come into focus. Unlike other cardiac myocytes, which are quiescent during diastole unless excited by a neighboring cell, SAN myocytes possess cell autonomous mechanisms that permit depolarization during diastole, and hence automaticity. According to a contemporary but hotly debated model (8), cellular rhythmicity in the SAN results from mutual entrainment of a membrane clock, driven by oscillating inward and outward ionic currents at the plasma membrane, and a calcium clock, driven by spontaneous calcium release events from the sarcoplasmic reticulum (9). A key component of the membrane clock is an inward depolarizing cation current that is activated in early diastole by hyperpolarization, known as the “funny current” or I_f ((10),11). Owing to cyclic nucleotide responsiveness, the current–voltage relationship and kinetics of I_f change with autonomic tone, such that diastolic depolarization occurs more rapidly with increasing sympathetic tone and more slowly with enhanced vagal tone. I_f is thus an important regulator of the SAN response to autonomic inputs.

I_f is carried by the hyperpolarization-activated cyclic nucleotide–gated ion channels (Hcn1-4), members of the voltage-gated ion channel superfamily (12). Of the 4 Hcn isoforms, Hcn4 is the most highly expressed in cardiac tissue. During vertebrate cardiogenesis, Hcn4 is initially widely expressed, but subsequently becomes restricted to the specialized myocytes of the cardiac conduction system ((13),14). In the developed human heart, it is highly expressed in the central SAN (the area of densest autonomic innervation), with a negative gradient of expression extending to the peripheral SAN, atrioventricular node, and ventricular conduction system (15). Cardiac-specific deletion of Hcn4 in mouse models using different methodologies results in bradycardia that varies from a sick sinus syndrome–like disorder to lethal sinus arrest ((16),17). Definitive proof that Hcn4 is an important regulator of heart rate in humans has come from rare instances of loss-of-function mutations that cause familial sinus bradycardia in the absence of other cardiac abnormalities (18).

Because of its restricted expression pattern and key role in SAN function, blockade of Hcn channels would be predicted to cause pure heart rate reduction without other cardiovascular effects. Moreover, because I_f regulates the SAN firing rate under resting conditions as well as in response to autonomic inputs, Hcn channels are attractive targets for the treatment of IST, a condition in which both autonomic and intrinsic cardiac mechanisms may be involved. Ivabradine, a specific blocker of Hcn channels, functions as a pure negative chronotrope (19) and was first used clinically for patients with symptomatic stable coronary disease to reduce myocardial oxygen demand (20). Subsequent trials have tested or sought to test ivabradine in acute coronary syndromes (21), in chronic angina with left ventricular dysfunction (22), and in heart failure (23). Although a few case reports and nonrandomized studies have suggested that ivabradine may have efficacy for patients with IST ((24),(25),26), defining the role of ivabradine in the routine treatment of this disease using rigorous methods has not been undertaken until the elegant study, a double-blind, randomized, placebo-controlled trial with a crossover design, of Cappato et al. (27) in this issue of the Journal. Patients were included if they had typical symptoms of IST with average daytime heart rate >95 beats/min and/or exaggerated heart rate response to exercise or orthostatic challenge. The patients were randomized to receive either ivabradine (using a stepwise dosing algorithm) or placebo for 6 weeks, with subsequent crossover after a brief washout period, permitting within-subject comparisons. Symptoms and heart rate parameters were determined for each patient on and off therapy. The results were striking: 75% of IST-related symptoms were eliminated, with nearly 50% of patients experiencing prompt and complete resolution of all symptoms on the drug. Ivabradine consistently lowered daytime, nighttime, and maximum ambulatory heart rates. In addition, exercise capacity improved with ivabradine in association with a marked decrease in maximum heart rate on a treadmill test, alleviating one of the hallmarks of the disease. Adverse events were infrequent, with only 1 patient stopping the drug because of visual changes, a known and reversible side effect of the drug. Taken together, the results suggest great promise for ivabradine with an excellent side effect profile for many, if not most, patients with IST.

What about the patients who did not experience symptom resolution with the medication? Because this relatively small study was not powered to do subgroup analysis, we can only speculate about why some subjects did not benefit as much from the drug. For some, a longer course of therapy might have provided some additional benefit, as was found in a case series of IST patients taking ivabradine for up to 9 months (24). To the extent that systemic dysautonomia is responsible for some symptoms, pure heart rate reduction might not be expected to provide complete relief. Additionally, functional abnormalities in other components of SAN machinery such as the calcium clock might play important roles in the pathophysiology of IST and might not be responsive to ivabradine. In addition, possible benefits of combining ivabradine with beta-blockers were not defined.

What, if anything, do the results of this trial teach us about the pathophysiology of IST? Ivabradine is a pure heart rate reducer, so the positive response to therapy clearly implicates the elevated heart rate as a major contributor to the symptoms experienced by IST patients. However, because I_f functions at the interface between the autonomic nervous system and the heart, the data cannot settle the question of whether IST is a primarily cardiac or extracardiac disorder or a combination of the 2. However, if the efficacy of ivabradine holds up in larger studies and the drug becomes first-line therapy for IST, settling this question may be of less clinical importance.

In summary, the rigorous methodology and positive results of this study provide compelling evidence of the short-term efficacy of ivabradine in IST. However, the long-term safety and efficacy are not defined. Therefore, before ivabradine can be routinely adopted as first-line therapy, additional data on long-term efficacy and long-term safety will be needed in this patient population, as will studies involving multiple centers and larger numbers of patients. Data from other large studies of ivabradine use in sicker patient populations ((22),23) suggest that the drug is likely to be well tolerated by the majority of patients, even with long-term use, but a larger and long-term randomized trial in IST patients will be required nonetheless. The study by Cappato et al. (27) provides a superb rationale for initiating such a trial without delay. Until then, because IST is a rare disease, consideration of drug approval under the orphan or compassionate route should be seriously considered for those with IST and disabling symptoms.

⁎Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.