Inappropriate sinus tachycardia (IST), a syndrome characterized by unexpectedly fast sinus rates at rest, with minimal physical activity, or both, is manifest by a spectrum of symptoms including palpitations, weakness, fatigue, dizziness, or near syncope. Acceleration in rate with minimal exercise is excessive and heart rate recovery is prolonged. Sinus tachycardia, even if excessively fast, generally is a transient and reversible condition with an explainable cause and a rate appropriate for the circumstance (caffeine ingestion, anxiety, deconditioning, and so on.) (1). IST is a more long-standing problem that is not as easy to explain. Herein, we review IST, explore its mechanisms, and review management strategies.

Healthy, normal individuals, at rest, have sinus rates of 50 to 90 beats/min, generally lower than the intrinsic sinus rate (i.e., devoid of autonomic influence), in part because of vagal tone ((2),(3),4). In 432 otherwise normal medical staff and prisoners, the intrinsic resting sinus rate was age dependent (3). Individuals 15 years of age had an average intrinsic heart rate of more than 118 beats/min; 15% of those 15 to 30 years of age had intrinsic rates of more than 115 beats/min. There was a greater distribution of faster intrinsic rates in younger individuals. For those older than 45 years, 15% had an intrinsic sinus rate of more than 100 beats/min. Rates were reproducible, not dependent on time of day, and only slightly dependent on exercise.

In CORDIS (Israeli Cardiovascular Occupational Risk Factors Determination in Israel Study), the percent difference in mean heart rate (supine to standing) in 5,428 subjects (mean age: 40.4 ± 11.5 years, 74% blue collar, 58% physically active) was greater among women than men (12.7% vs. 11.6%, p < 0.03). Heart rate was associated independently with height (p < 0.0001), cigarette smoking (p < 0.0001), and coffee drinking (p < 0.001) and was associated inversely with age (p < 0.002), blood pressure elevation (p < 0.0005), and physical activity (p < 0.0001) (5).

No specific heart rate best defines IST, yet patients with IST generally have resting daytime sinus rates of more than 100 beats/min and average 24-h heart rates of more than 90 beats/min that are not explained by physiologic demands or conditions known commonly to increase heart rate. Patients with IST often have multiple, incapacitating symptoms including palpitations, dyspnea, dizziness, lightheadedness, and near syncope, but the symptoms may not be dependent on heart rate. Associated emotional and psychiatric problems often are identified, but any relationship to IST is uncertain. Treatment of tachycardia alone may not ameliorate debilitating symptoms, the predominant problem in this condition. IST may be difficult to distinguish from a normal physiologic response or postural orthostatic tachycardia syndrome (POTS).

Most patients are young and female, but the epidemiologic characteristics are uncertain. Episodes tend to become noticed abruptly and persist over months or years, but the natural history is obscure and the onset may be surreptitious. The prognosis generally is benign. Perhaps one reason for a benign prognosis is that although IST patients have faster heart rates, the rate slows somewhat during sleep and in various diurnal patterns (6). Long-term consequences are few, yet reported series are small, follow-up is limited, and populations are diverse. IST rarely is associated with tachycardia-induced cardiomyopathy (7), although isolated reports do exist ((8),9).

Still et al. (10) identified 7 of 604 middle-aged subjects from OPERA (Oulu Project Elucidating Risk of Atherosclerosis) as meeting criteria for IST (resting daytime sinus rate >100 beats/min or average 24-h rate > 90 beats/min). Personality measurements (except hostility scores) were normal. Over 6.0 ± 2.4 years, these and 9 IST patients diagnosed previously had a benign course, although they had palpitations and fast average heart rates (90 ± 2 beats/min vs. 89 ± 8 beats/min) over the long term. IST has been identified in older individuals, as well (11). In this group, no significant differences in echocardiographic parameters were noted between baseline and follow-up examinations.

As a multicomponent hierarchical structure, the sinus node is complex and tightly controlled (12) by more than 16 regionally varying, autonomically influenced currents. The role of calcium cycling (13) versus I_f (14) remains controversial (15). The I_f current is commonly regarded as the predominant current responsible for sinus rate, but this is clearly a simplification (13). No specific channelopathy is implicated in IST, although some have been suspected (16).

Parasympathetic regulation of resting sinus rate depends on M2 muscarinic receptor-mediated activation of I_KAch via G protein-coupled, inwardly rectifying potassium channels (Figure 74_gr1) (17). M2 receptors activate L-type calcium channels (I_Ca-L), negatively influencing adenylate cyclase and having a stimulatory effect on G1 proteins to suppress I_f.

Calcium clocks and cellular membrane voltage, driven by β-adrenergic sympathetic nervous system activation or extrinsic catecholamines, can be blocked, in part, by I_f blockade. Although several drugs and ions can block the I_f current, their effects are nonspecific. Other I_f blockers have been developed, but only ivabradine is available commercially. Subsidiary pacemakers, residing in the superior portion of the sinus node, are activated by sympathetic stimulation such that a depolarizing shift in the I_f activation curve, a potentiation of I_Ca-L, a potentiation of I_K, a hyperpolarized shift in I_K activation curve, an acceleration of the deactivation of I_K, and a potentiation of I_ST occur (14).

Although phasic vagal (parasympathetic) activation supersedes sympathetic activation (called accentuated antagonism) (18), tonic sympathetic activation overshadows intermittent vagal activation. Catecholamine excess or sympathetic activation, with or without vagal inhibition, could cause IST.

Explanatory mechanisms for IST (Table 1), likely multifactorial and complex, amount to a form of dysautonomia (19), an intrinsic sinus node problem, or both. A viable, consistent, unified mechanism has yet to be identified.

Catecholamine injections into the sinus node fat pad containing autonomic ganglia (20) or high-frequency stimulation of the anterior right ganglionated plexi (21) accelerate the sinus rate, but so do many things. Thus, we find these data unconvincing as a mechanism for IST in patients (1). Hyposensitivity of muscarinic receptors (22); central and peripheral nociceptive effects ((23),24); depressed efferent vagal activation (25); neurohormonal modulation (26); nonmuscarinic, nonadrenergic, vagally mediated mechanisms (27); or hypothalamic paraventricular nucleus stimulation (28) likewise can cause sinus tachycardia.

Vasointestinal peptide, twice as potent as norepinephrine (29) and more potent than epinephrine (30), can increase sinus rate. Central gamma-aminobutyric acid (GABA)-nergic (31) and serotonin 1-A receptor activation (32) in the medullary raphe and parapyramidal regions affecting autonomic outflow can initiate sinus tachycardia. Histamine (33), neuropeptides (29) (including neuropeptide Y), phenyl-histidine-isoleucine, substance P (34), α-opioid receptor activation (35), or other mediators (36) may be involved. M2 receptor abnormalities, sinus node channelopathies, or circulating mediators could cause IST, but none have been identified. Indeed, much remains to be learned about inappropriate and, for that matter, appropriate sinus tachycardia.

Clinical reports include small, select populations of patients with IST. Autoantibodies to ganglionic acetylcholine receptors, described in POTS (37), have been postulated to be responsible for, but have not been identified in, IST. Chiale et al. (38) suspected anti-β-receptor immunoglobulin G antibodies as a cause for IST. Studying 21 IST patients versus 15 controls, β-anti-adrenergic receptor antibodies were identified in 11 IST patients. Immunoglobulin G fractions showing anti-β-receptor antibodies caused long-lasting increases in cyclic AMP. In 5 IST patients (and 5 controls), immunoglobulin G fractions were evaluated using COS-7 cells transfected with genes encoding for the β-1 and β-2 adrenergic receptors. No anti-M2 cholinergic receptor antibodies were identified.

Heart rate variability (HRV) in IST patients is inconsistent. In one report, all temporal and power spectral HRV parameters were reduced, suggesting reduced parasympathetic tone, after correcting for heart rate (39). However, some data support sinus rate elevation in IST independent of an autonomic mechanism (40). In another report, the low-frequency HRV spectrum was higher in IST patients (consistent with higher sympathetic tone) versus controls, but no consistent pattern was observed, and results may be dependent on population and age (11).

Morillo et al. (41) evaluated 6 women with IST (age range 23 to 38 years) and 10 controls. HRV low to high frequency ratio in supine and head-up tilt positions was similar in both groups. The cardiovagal response measured by the cold-face test was seen less frequently in IST than in controls (6% of IST patients vs. 24% of controls, p < 0.001). Patients with IST were hypersensitive to isoproterenol. However, intrinsic heart rates were higher in IST patients. In these patients, β-blockers often were effective (41); this is not our general experience.

Leon et al. (42) investigated whether baroreflex gain differed in 8 IST patients versus 9 controls. Individuals with IST had a higher mean heart rate (78.8 ± 5.3 beats/min vs. 58.5 ± 4.2 beats/min) and blood pressure, but heart rates for IST patients were not in the range many consider IST. Baroreflex gain during orthostatic stress was reduced significantly in IST patients, and the change in baroreceptor gain during head-up tilt stabilization was blunted markedly in those considered to have IST. The intrinsic heart rate (3) observed in 7 of 8 patients was faster than predicted (115.7 ± 2.7 observed beats/min vs. 110.6 ± 1.4 expected beats/min, p < 0.01). Only 25% considered to have IST showed a hypersensitive response to catecholamines, pointing to the sinus node as the problem, rather than the autonomic nervous system.

Still et al. (16) studied the response to adenosine after β-adrenergic and cholinergic blockade in 18 IST patients (mean age 46 ± 15 years) versus controls (114 ± 17 beats/min vs. 79 ± 11 beats/min). Adenosine did not stop or slow the sinus rate. After adenosine, reflex increase in the sinus rate was greater in controls than in IST patients (21.2 ± 9.7% vs. 8.5 ± 8.8%, p < 0.001), supporting the tenet that an accelerated intrinsic sinus rate may be the primary abnormality. They postulated that IST may be the result of deficient function of the acetylcholine-sensitive and adenosine-sensitive potassium channel. In clinical studies, β-adrenergic receptor supersensitivity (43), M2 receptor blockade ((44),45), or the role of neuropeptide neurotransmitters (46) have been considered. Variations in diurnal patterns have been speculated to help to characterize forms of IST (6).

Ultimately, the causal mechanism for the abnormally fast sinus rate is unknown. The initial event may be a trigger, such as a viral infection or toxin exposure (47), but evidence is scant. In our experience, excess hydrocarbon exposure may be one mechanism; halogenated hydrocarbons can sensitize the myocardium to catecholamines and can increase the sinus rate ((48),49). The problem, however, may lie in the sinus node itself. Lipofuscin-laden vacuoles have been identified as an ultrastructural marker noted in 3 patients with IST for whom the sinus node was excised (50).

Critical to the diagnosis of IST is the need to exclude specific physiological and psychological triggers for appropriate sinus tachycardia, including exercise, anxiety, panic attacks, and pain. Anticholinergics, catecholamines, alcohol, caffeine, cocaine, tobacco, β-blocker withdrawal, and supraventricular tachycardia ablation causing vagal denervation increase sinus rate ((51),(52),(53),54). Several medical conditions can explain sinus tachycardia as well (Table 2). Central mechanisms may be responsible for sinus tachycardia caused by insults to the brain, including head trauma, especially to the brainstem.

Most IST patients are otherwise completely healthy. Because IST seems to be more common in health care providers (55), consideration of access to stimulants and other drugs (e.g., insulin) must be considered in the evaluation of appropriate versus inappropriate sinus tachycardia. Occult substance abuse and psychiatric causes such as panic attacks must be considered in the differential diagnosis. In one report, 100% of patients with IST had some psychiatric diagnosis (schizophrenia, depression, panic disorder, or somatoform disorder) (56).

The diagnosis of IST is based on persistent or recurrent sinus tachycardia on 12-lead electrogram or by long-term monitoring that is not otherwise explainable. Invasive testing, such as electrophysiology studies, is not useful for making the diagnosis, although it may be useful to exclude a concomitant supraventricular tachycardia mechanism (57). The evaluation of sinus tachycardia must take into account whether the rhythm is paroxysmal or persistent. Careful analysis of a 12-lead electrocardiogram should consider P-wave morphological features. If the P-wave is the same or similar to that in normal sinus rhythm, IST is possible. If paroxysmal, atrial tachycardia, including sinus node re-entry, should be excluded. If tachycardia occurs gradually with postural change, a tilt-table test may indicate POTS; with tilting, the increase in heart rate is nearly immediate in IST (58). If tachycardia is persistent and an underlying cause can be determined, IST is not present. In the patient with generally persistent episodes for which no cause can be determined, however, IST may be diagnosed. IST is a diagnosis of exclusion.

Commonly, there is confusion between IST and POTS; overlap between the 2 exists (Table 3) (59). Tachycardia in IST is not postural as it is in POTS. In POTS, there is a persistent increase in heart rate by more than 30 beats/min or a rate of more than 120 beats/min within 10 minutes of changing from a supine to an upright position in the absence of orthostatic hypotension. As with IST, patients with POTS often have multisystem symptoms. There is venous (including splanchnic) pooling, α-hypersensitivity and β-hypersensitivity, baroreceptor dysfunction, hypovolemia, the presence of brainstem dysregulation, or a combination thereof. One has to wonder: is tachycardia in POTS inappropriate? Probably so.

Managing IST (controlling symptoms and reducing rate) remains a substantial challenge, especially because the syndrome itself is nebulous. Heart rate control, however, does not necessarily eliminate symptoms. Controlling the sinus rate in asymptomatic patients with IST is controversial because the treatment may be worse than the syndrome itself. In IST, no one therapy reduces heart rate and symptoms completely and effectively, likely related to the complexity of the problem and the lack of full understanding of the causes.

Many treatment recommendations have been made for patients with IST, but these therapies have not been well tested. β-adrenergic blockers, even at high doses, generally are ineffective and tend to be associated with other symptoms. Other treatments (fludrocortisone, volume expansion, pressure stockings, phenobarbital, clonidine, psychiatric evaluation, erythropoietin) have been suggested, but may be harmful and have not been proven (59).

A study of 19 patients with POTS supported the use of exercise training to improve quality of life and to maintain upright cardiac output compared with the use of propranolol (60). We suspect that exercise training also may help IST patients. Benzodiazepines may be helpful, but this drug class has not been evaluated carefully. It is likely that many IST patients have a superimposed anxiety disorder. Although not reported, benzodiazepine and β-blocker combinations, in the hands of an empathetic physician, may be effective for many IST patients (Coghlan CH, personal communication). Indeed, effective patient communication and attention seem to improve outcomes (56).

Radiofrequency ablation in attempts to modify the sinus node or eliminate sympathetic inputs, at best, is partially effective, but has been tested only in small populations. Early reports suggested that ablation had value; we remain tentative and do not recommend aggressive attempts to ablate the sinus node in patients with IST on a routine basis.

In 16 drug-refractory, highly symptomatic patients with IST, total sinus node ablation (n = 4) or sinus node modification (n = 12) was performed via radiofrequency energy delivery to sites of earliest atrial activation. For those who had sinus node modification, a chronotropic response was still present with a reduction in maximal heart rate (132.8 ± 6.5 beats/min vs. 179.5 ± 3.6 beats/min, p < 0.001). Holter monitoring showed a decrease in maximal and mean heart rate (167.2 ± 2.6 beats/min vs. 96.7 ± 5.0 beats/min, p < 0.001, and 125.6 ± 5.0 beats/min vs. 54.1 ± 5.3 beats/min, p < 0.001, respectively) with long-term benefits. Two patients required pacing, one had transient right diaphragmatic paralysis and another had transient superior vena cava syndrome (61).

In a report of 29 IST patients, ablation reduced sinus rates to less than 90 beats/min acutely in 22 patients (62). For 13 acutely successful ablations, radiofrequency ablation at the site of earliest endocardial activation resulted in migration of earliest activation from the high lateral right atrium with a progressive reduction in rate. For the other 9 patients with a successful acute outcome, reduction in rate occurred abruptly. Symptoms recurred 4.4 ± 3 months after the procedure in 6 of 22 patients, but after additional procedures in 3 patients, symptoms were eliminated successfully (62).

In a more recent report, long-term results of 3-dimensional map-guided ablation of IST were reported in 39 patients (35 women, mean age 31 ± 9 years) (56). The shift in the earliest sinus node activation site after β-adrenergic blockade was compared with the shift after ablation. After ablation, the mean sinus rate normalized (72 ± 8 beats/min) with a more pronounced shift in caudal activation along the crista terminalis than with esmolol, but 21% of patients experienced recurrent IST and underwent repeat ablation. The authors concluded that adrenergic hypersensitivity is not the only mechanism responsible for IST and that 3-dimensional guidance helped facilitate ablation (56). In some cases, with a thick terminal crest, an epicardial ablation approach has been used (63). Ablation of the arcuate ridge in a combined epicardial and endocardial approach has been described ((63),64).

Although we agree that detailed 3-dimensional mapping helps to identify sinus nodal sites to ablate in patients with IST, including the use of noncontact mapping ((65),66), we have observed migrating tachycardia rates with progressive ablation at superior sites in the sinus node in patients with IST. We are not convinced that a single 3-dimensional mapping approach, even one that uses unipolar mapping, in an attempt to derive the origin of the sinus node activation, is any better than bipolar mapping ((66),67).

Such ablation can be fruitless because tachycardia ultimately may come from other sinus nodal sites or from the atrioventricular junction after complete sinus node obliteration. This has been observed in surgical ablations and even after sinus node removal (68). Furthermore, symptoms can persist despite sinus node slowing, and the benefits may be only short term (69).

It becomes extraordinarily important to distinguish the potential mechanisms responsible for sinus tachycardia, because for patients with POTS, radiofrequency ablation of the sinus node will have devastating effects, exacerbating symptoms or making hemodynamics worse. If POTS was the original problem, incorrectly diagnosed as IST, blunting the acceleration in heart rate during position change by sinus node ablation could prevent the needed sinus response to overcome inappropriate vasodilation or lack of appropriate vasoconstriction. Severe postural hypotension therefore may ensue.

Narrowing of the superior vena cava (70), damage to the phrenic nerve (71), and bradycardia requiring a pacemaker can occur. The latter complication may develop days after ablation. Because complications are probably underreported, these devastating outcomes for an otherwise young healthy person who may continue to have symptoms and tachycardia should raise serious concerns about proceeding with interventional approaches. Patients and referring physicians must be cognizant that although symptoms may be substantial and patients may be highly motivated, consequences of aggressive therapeutic attempts may seriously outweigh any potential benefit.

Surgical ablation of the sinus node may be ineffective because in patients with IST, escape rhythms, including those from the atrioventricular junction, also may be inappropriately fast. Over a 17-year period, 9 medically refractory patients (mean age 33 ± 6 years) with symptoms lasting 13.4 ± 10.9 years underwent median sternotomy (cardiopulmonary bypass time 73 ± 25 min) for surgical isolation of the sinus node, cryoablation, or both; 2 patients underwent radiofrequency ablation via a right inframammary incision. Over a mean of 6.4 ± 5.9 years, 4 underwent repeat postoperative ablation attempts; 1 required a pacemaker (72). Other methods have been used to ablate the sinus node surgically, either using a thoracoscopic approach ((68),73), an off-pump beating-heart sinus isolation and ablation through a minithoracotomy (72), or direct complete removal of the sinus node (74). Partial cardiac denervation and sinus node ablation have been attempted (75).

Complete surgical sympathectomy has not been well tested yet. However, innervation may remain via the intrinsic cardiac nervous system (76). Even complete sympathectomy may not address the primary problem, and therefore may treat IST ineffectively. Further, IST has been observed after heart transplantation even after complete central autonomic denervation (77). Surgical ablation is not recommended, except for patients who are completely debilitated symptomatically and for whom everything else has failed. The aggressiveness of the surgical therapies testifies to the fact that patients with IST can be highly motivated to pursue substantial and risky procedures to eliminate their symptoms.

Small studies ((78),(79),80) and several case reports have demonstrated the potential value of the I_f blocker ivabradine to treat IST; the drug is not available in the United States. Ivabradine can have a dramatic effect on heart rate and can slow it from a mean of 100 beats/min to fewer than 75 beats/min. The maximum heart rate can slow from a mean of 160 beats/min to 120 beats/min. The minimum heart rate also can slow over time.

Ivabradine was evaluated in 10 female patients (median age 32.5 years, range: 12 to 57 years) with IST (78). Ivabradine (5 to 7.5 mg twice daily) with a β-blocker (n = 3) or as monotherapy (n = 7) reduced maximum and mean heart rates (baseline: maximal heart rate 176 ± 45 beats/min, mean heart rate: 84 ± 11 beats/min; ivabradine: maximal heart rate: 137 ± 36 beats/min, mean heart rate: 74 ± 8 beats/min, both p < 0.05). The minimum heart rate did not change, but symptoms were ameliorated or suppressed in all 8 contacted after a mean of 16 ± 9 months (78).

In another report (79), the efficacy and safety of ivabradine were tested in 18 consecutive symptomatic patients (mean age: 45 ± 15 years); 16 completed the study. There was a significant reduction of median and maximal heart rates over 6 months, with small changes in the minimal heart rate. There was improvement in exercise tolerance. Phosphene toxicity limited use of the drug in small numbers of patients, but otherwise, it was well tolerated.

Ivabradine may precipitate excess bradycardia (especially in combination with β-blockers or calcium-channel blockers) and may cause headaches or other side effects. It should not be used with strong CYP 3A4 inhibitors or in patients with liver or severe renal dysfunction. It should be avoided in patients who are hypotensive, pregnant, or breastfeeding. These latter are of most concern for the IST patient.

Our general approach to patients in whom sinus tachycardia is present and IST is presumed includes the following:

• 1Determine if, and when, sinus tachycardia is present and if the problem is reproducible and persistent. Consider if any explainable cause of tachycardia exists and determine if symptoms are postural, because this may be the result of POTS, or exacerbated by physical activity. Consider psychiatric issues, exclude substance abuse, and carefully counsel the patient on the risks and benefits of any interventional therapy. Consider that there is no necessity to move to aggressive ablation interventions if simpler approaches do not work. Ensure the patient is aware that the therapeutic options, including ablation, have limited value and may cause tremendous harm.
• 2If IST is diagnosed, determine if there is a trigger or an event that precipitated the symptoms because this may help to determine the longevity of the problem. For some, a postviral syndrome can be associated with POTS and this may be short lived. If the patient is otherwise young and healthy, the problem may last 5 years or more before dissipating.
• 3Patients with IST often have symptoms independent of heart rate. It is critical to determine if the heart rate is associated directly with the symptoms, because in this setting, treatment of the heart rate likely will make a difference. Consider a multidisciplinary approach to rule out psychiatric issues that may be exacerbating the symptoms and may be alleviated by other approaches.
• 4Treatment begins with modest doses of β-blockers. No specific β-blocker is more effective than another. Exercise training is recommended. Potential stimulants in the diet (such as caffeine or alcohol) should be eliminated.
• 5Ivabradine at a dose of 5.0 to 7.5 mg twice daily, if available, may be highly effective and should be considered.
• 6Consider radiofrequency ablation only if sinus rates are extremely fast, the patient clearly has IST with symptoms resulting from sinus tachycardia, and all other therapies have failed.

Sinus tachycardia generally is explainable. When it is not, it may be the result of IST, a difficult to characterize, symptomatic condition that represents a spectrum of disorders related to increased sinus node automaticity, disordered autonomic activation, or both. There may be an overlap between conditions caused by orthostatic intolerance (e.g., POTS) or anxiety. Evaluation of patients with this condition begins with assessment and exclusion of all possible explainable causes for sinus tachycardia. In some cases, this may require long-term follow-up to determine presence of substance abuse or psychiatric abnormalities.

For the remaining patients, it is critical to distinguish POTS from IST because inappropriate treatment of suspected IST with sinus node ablation (when it is actually misdiagnosed POTS) will have a devastating effect. Treatment can be as simple as avoiding triggers of tachycardia and exercise training. Because tachycardia-induced cardiomyopathy develops rarely, the primary reason to treat IST is to improve symptoms. Caution is advised to limit aggressive treatment attempts in patients with IST because the cure often can be worse than the condition itself.