Inappropriate sinus tachycardia: a review

Inappropriate sinus tachycardia (IST) has been defined as a resting heart rate of > 100 beats per minute and an average 24-hour heart rate > 90 bpm with distressing symptoms resulting from the persistent tachycardia. IST is prevalent in 1% of the middle-aged population, mostly females. Rarely can elderly patients also present with IST. Possible mechanisms of IST include intrinsic sinus node abnormality, beta-adrenergic receptor stimulating autoanti-body,beta-adrenergicreceptorsupersensitivity,muscarinicreceptor autoantibody, or hyposensitivity, impaired baroreflex control, de-pressedefferentparasympathetic/vagalfunction,nociceptivestimu- lation, central autonomic overactivity, aberrant neurohumoral modulation, etc. Symptoms associated with IST are palpitations, chest pain, fatigue, shortness of breath, presyncope, and syncope. Despite these distressing symptoms, IST has not been associated with tachycardia-associated cardiomyopathy or increased major cardiovascular events. Various treatment options for patients with IST are ivabradine,beta-adrenergicblockers,calciumchannelblockers,psy-chiatric evaluation, and exercise training. Although, endocardial radiofrequency ablation targeting the sinus node has been used as a treatment modality for otherwise treatment-refractory IST, the results have been dismal. The other modalities used for refractory IST treatment are endocardial modification of the sinus node using radiofrequency energy, combined endo and epicardial ablation of the sinusnode,thoracoscopicepicardialablationofthesinusnode,sinus node sparing thoracoscopic and endocardial hybrid ablation. The goal of this review is to provide the readership with the pathophys-iologicalbasisofISTanditsmanagementoptions.


Introduction
Inappropriate sinus tachycardia (IST) is a clinical syndrome characterized by persistently increased resting heart rate (HR) and a further exaggerated increase with minimal physiologic stimuli. 2015 Heart Rhythm Society (HRS) expert consensus statement defines IST as a resting sinus HR of >100 beats per minute (bpm), an average 24-hour HR >90 bpm without any identifiable cause, and distressing symptoms resulting from the persistent tachycardia [1]. Some experts have divided IST patients into three groups based on the HR pattern (a) normal resting heart rate (<85 bpm) with an exaggerated increase in HR in response to minimal stimuli, (b) moderately increased resting HR (>85 bpm) with an exaggerated increase in HR in response to minimal stimuli and (c) markedly elevated resting HR with a graded response to physiologic stimuli [2].

Epidemiology
Epidemiological data regarding IST is scarce. A prospective, population-based case-control study found a prevalence of 1.16% (n = 7; Male:Female, 1:4) in 604 middle-aged subjects. The mean age of the IST patients was 47 ± 7 years [3].
In a single-center, retrospective study of Holter recordings, 63 patients (4.98%) out of 1265 patients were diagnosed with IST according to the Heart Rhythm Society (HRS) criteria [4]. The authors did not include 33 patients with a mean HR of ≥90 bpm and resting HR of <100 bpm in the IST cohort, which may have underestimated the true IST prevalence in the symptomatic population. The mean age of patients was 39.7 years, and 60% of the patients were females.
In a retrospective analysis of 305 IST patients, the mean age of patients was 33 years at the time of diagnosis, and 92.1% (n = 281) were females [5].
Although most patients are young females, IST has been diagnosed in elderly patients as well. Lopera et al. [6] have reported on four women in whom IST was diagnosed in the 6th or 7th decade of life. One of the main issues with their methodology was that they included an increase in HR of ≥25 bpm on standing from a supine position as an inclusion criterion which may indicate an overlap between IST and postural orthostatic tachycardia syndrome (POTS) [7].
Some reports indicate that a disproportionate number of IST patients are healthcare workers [8,9]. Two of the seven IST patients (29%) in the OPERA study were health- Fig. 1. Heart rate control via the autonomic nervous system. Sinus node activation is managed by cellular currents, including I KAch , I N aCa , I Kr , and L-type calcium channels, among others. Moreover, calcium released from the sarcoplasmic reticulum plays a role in the setting of the sinus rate. The parasympathetic system helps determine the rate at rest through acetylcholine and nitric oxide, and parasympathetic activation affects the muscarinic receptor (M2). If: funny current. I N aCa , sodium/calcium exchange current; I Kr , delayed rectifier potassium current; I KAch , inward-rectifier potassium channel. care workers [3]. The exact reason for this phenomenon is unknown, but one possibility is that the healthcare workers may be quick to recognize the tachycardia when it occurs and seek medical care for this.

Pathophysiology
The funny current (If) or the pacemaker current is a mixed Na + /K + inward current mediated by hyperpolarizationactivated cyclic nucleotide-gated (HCN) channels found in heart cells with pacemaking ability. The funny If current is activated during hyperpolarization and is responsible for spontaneous diastolic (phase 4) depolarization which leads to pacemaker cell depolarization. Sympathetic stimulation via beta-adrenergic activation increases the funny current by increasing cyclic adenosine monophosphate (cAMP), leading to an increased firing rate of pacemaker cells. Vagal stimulation leads to decreased pacemaker activity by decreasing cAMP levels. HCN channels most common in the human sinoatrial node are HCN4 [10] (Fig. 1).
Morillo et al. [11] found that in 6 IST patients, there was increased sinus node automaticity, beta-adrenergic hypersensitivity, and decreased response to vagal stimulation. Intrinsic heart rate in IST patients after autonomic blockade with propranolol and atropine was significantly higher, which means that patients with IST have an intrinsic sinus node abnormality despite adrenergic hypersensitivity and vagal hyporesponsiveness. IST patients also have a markedly reduced vagal efferent tone [12]. Wising in 1941 first described a familial form of IST that was labeled as familial, congenital sinus tachycardia [13]. A gain-of-function mutation (arginine-to-glutamine; R524Q) in the HCN4 gene has been reported in a family of IST patients. This mutation leads to an increased affinity of the HCN4 channels to cAMP, thus mimicking beta-adrenergic stimulation [14].
Chiale et al. [15] found circulating anti-beta-adrenergic IgG antibodies in 11 of 21 (52%) patients (21 females; mean age 37 years). These antibodies had a positive chronotropic effect by increasing cAMP levels which was abolished by propranolol in all but one patient. This study proved that the immunologic phenomenon might be responsible for IST in half of the IST patients, which still doesn't explain the pathogenesis of IST in a significant number of patients in which there may be other mechanisms responsible for IST. In this study, the chronotropic effect of anti-beta-adrenergic IgG antibodies could not be reversed by propranolol in one patient leading the authors to hypothesize that beta-adrenergic receptors may not be the only target of such antibodies.
Adenosine typically has a biphasic response on sinus node activity: an initial reduced sinus node firing rate followed by reflex sinus tachycardia. But in IST, both of these responses are impaired with or without pharmacologic autonomic blockade with propranolol and atropine. Interestingly, Still et al. [16] in their study also reported that transient second degree or third-degree atrioventricular block after adenosine administration was less frequent in IST patients in comparison to healthy controls leading the authors to pos- tulate that impaired function of acetylcholine-sensitive and adenosine-sensitive potassium channels (I KAch,Ado ) may be the cause of IST. These observations also suggest that autonomic system anomalies present in IST patients may not be the primary cause of the tachycardia.
IST has also been reported in a 53-year-old man who developed IST one year after receiving a bicaval heart transplant. Sympathetic reinnervation of the donor's heart was ruled out using I 123 metaiodobenzylguanidine (MIBG) scintigraphy, pointing out that IST can develop in a heart that has no autonomic innervation [17].
In a significant number of patients, a precipitating event initiating the tachycardia has been reported. The most common triggers identified in IST patients are pregnancy (7.9%), antecedent infectious illness (5.9%), emotional stress (3.6%) [5].
Multiple reports have documented IST after radiofrequency ablation (RFA) for various supraventricular tachycardias (SVT) [19][20][21][22]. The possible explanations for this phenomenon are autonomic modulation to the heart by ablation of vagal ganglia and increased awareness of heart rate after an ablation procedure. In atrioventricular nodal reentrant tachycardia (AVNRT) ablation procedures, one possibility remains that the patients were having symptoms of increased heart rate because of dual AV nodal physiology, which was ablated and were then labeled as AVNRT [5].
As the COVID-19 epidemic runs rampant across various nations, there is increasing evidence that one of the sequelae of COVID-19 infection is autonomic dysfunction as a component of the post-COVID syndrome [23]. Huang et al. [24] reported that at 6-months follow-up, 9% (154 out of 1655) of patients who had recovered from COVID-19 reported palpitations. Ståhlberg et al. [25] report that 25-50% of patients had palpitations or tachycardia persisting 12 weeks or longer, and they have proposed the term "post-COVID-19 tachycardia syndrome" for the persistent symptomatic tachycardia after COVID-19 illness. POTS and IST have been reported as a spectrum of this syndrome [23,26,27].

Clinical features and diagnosis
Palpitations are the most common symptom in around 90% of patients. Other symptoms include chest discomfort, fatigue, shortness of breath, presyncope, and syncope. Depression and anxiety each are found in a quarter of the patients with IST. Almost a quarter of patients have a documented arrhythmia other than IST, most commonly atrial tachycardia, followed by AVNRT and AF [5].
The occasional case reports of tachycardia-induced cardiomyopathy notwithstanding, the overall prognosis of IST is favorable. One of the reasons these patients do not develop cardiomyopathy is that the normal diurnal variation in HR is preserved in these patients [28].
IST is a diagnosis of exclusion. Evaluation should be aimed at ruling out secondary causes of sinus tachycardia, e.g., anemia, hyperthyroidism, heart failure, etc. Evaluation of an IST usually requires a 12-lead electrocardiogram (EKG), 24-hour Holter monitoring, echocardiography. The further non-invasive evaluation may require an exercise test to assess the severity of symptoms and diagnose patients who have normal resting heart rates, as already pointed out in the introduction section [1].
Tilt table testing is required to rule out the presence of POTS. In the study by Shabtaie et al. [5], 24% of patients were diagnosed as having POTS.
According to the HRS expert consensus statement [1], various tests for cardiac autonomic responses like Valsalva, heart rate variability, cold face test, and baroreflex sensitivity are not routinely indicated because of unproven clinical benefits.
An invasive cardiac electrophysiology study is indicated if the diagnosis is in doubt or another tachycardia mechanism is suspected [29].
IST and sinus node reentrant tachycardia have similar EKG findings. The two can be differentiated by initiation and termination with a premature atrial contraction, termination by adenosine, or various vagal maneuvers characteristic of sinus node reentrant tachycardia [30].

Management
Reassurance and avoidance of cardiac stimulants are an integral part of IST management [29].
Pharmacotherapy usually involves beta-blockers, ivabradine, and calcium channel blockers. Some of the other drugs that have been used in IST are flecainide, sotalol, fludrocortisone, midodrine, etc.
Beta-blockers are the most widely used drugs for IST, but the improvement in the symptoms is modest. In a retrospective analysis, only about 25% of patients reported improved symptoms, and 4% reported complete resolution of symptoms with beta-blockers [31].
Evidence of the benefit of nondihydropyridine calcium channel blockers in IST is limited but are nevertheless used. The overwhelming majority of IST patients report no improvement or worsening symptoms after using these agents [31].
Ivabradine reduces sinus node firing rate by inhibiting If current. It has the most evidence regarding its usage in IST. In a pooled analysis of 9 prospective studies involving 145 patients, ivabradine significantly reduced resting HR and peak HR, leads to significant improvement in symptoms, and is better tolerated [32].
An observational, non-randomized study with a 1-month follow-up compared ivabradine with metoprolol succinate. Ivabradine resulted in a similar reduction in HR, better symptomatic relief, increased exercise duration and maximal workload, and better safety profile [33].
In a prospective, open-label study involving 40 patients with a follow-up of 24 months, Annamaria et al. [34] compared ivabradine to bisoprolol. Ivabradine was superior to bisoprolol in reducing daytime and night-time mean HR, increasing exercise capacity, and improving quality of life, and as shown in previous studies, was tolerated better.
Ivabradine can be used along with beta-blockers or calcium channel blockers. A combination of ivabradine and metoprolol succinate was better than metoprolol monotherapy in an observational study of twenty IST patients who re-ceived metoprolol for 4 weeks followed by the combination therapy for another 4 weeks [35].
Caution is warranted in the co-administration of ivabradine, and calcium channel blockers as verapamil and diltiazem inhibit the CYP3A4 enzyme system, which metabolizes ivabradine [36].
Another non-pharmacological measure found effective in IST is exercise training. Exercise training and beta-blockers increase exercise capacity, reduce average HR, and improve symptoms and overall quality of life [37]. Management of accompanying depression and anxiety may lead to symptom amelioration [18].

Invasive
Many patients remain symptomatic even after using all the aforementioned treatment options, or their use is restricted because of the disabling adverse effects. Invasive treatment is reserved after the exhaustion of all the other treatment options.
Various invasive treatment options that have been reported are: (a) endocardial radiofrequency ablation (RFA) targeted at the sinus node.
(b) combined endo and epicardial ablation of the sinus node.
(c) thoracoscopic epicardial ablation of the sinus node. (d) sinus node sparing thoracoscopic and endocardial hybrid ablation.
The most commonly used treatment modality with available data to make an informed decision has been endocardial sinus node modification using radiofrequency energy.
In a systematic review of nine studies that included 153 patients, Rodríguez-Mañero et al. [38] reported acute procedural success in 90%. 86% of patients reported long-term improvement in symptoms. Various complications reported in 8.5% were: phrenic nerve injury, superior vena cava syndrome, arteriovenous fistula, retroperitoneal bleed, cardiac tamponade, right ventricular puncture, and pericarditis [38]. After a mean follow-up of 28.14 ± 12.64 months, 86% of patients reported improvement in symptoms, and 19.6% of patients had a recurrence. 15 patients (10%) underwent pacemaker implantation during the follow-up. The evidence regarding RFA based sinus node modification in IST so far (Table 1, Ref. [9,31,[39][40][41][42][43][44][45][46][47][48][49][50][51][52]) can be summarized as moderate acute procedural success, minimal longterm benefits, and an increased risk of complications. That is why the HRS expert consensus document [1] (Class III recommendation) and ESC guidelines [29] do not recommend RFA as a routine treatment for IST. It should be reserved for the most symptomatic patients in which all the available conservative therapeutic measures have failed.
Evidence suggests two distinct and dominant sinus nodes in human hearts: a superior sinus node near the SVC and an inferior sinus node near the IVC. So, a procedure for IST will lead to HR control only if sympathetic innervation to both these sinus nodes is interrupted [53].
This concept has led to sinus-node-sparing thoracoscopic isolation of SVC and IVC from the right atrium. This procedure involves thoracoscopic ablation at the SVC-RA junction (sparing the sinus node after identifying it by endocardial three-dimensional electroanatomic mapping), IVC-RA junction, and the third ablation line along crista terminalis connecting these two ablation lines (Fig. 3). In 39 consecutive IST patients, who underwent the hybrid procedure, the mean HR decreased from 119 ± 10 bpm before the procedure to 65 ± 13 bpm on the first day postablation and was 74 ± 9 bpm at 24 months follow-up. All patients stopped their rate-reducing drugs during the followup. The most common complication during the follow-up was pericarditis. None of the patients required pacemaker implantation, and none of the patients developed phrenic nerve injury.
In a multicenter, prospective registry, the hybrid ablation procedure was compared with RFA based endocardial sinus node modification in 100 IST patients. The patients' mean number of procedures was 1.02 in the hybrid group and 2.44 in the endocardial ablation group. Mean resting HR before the procedure was 122 and 121 bpm, respectively. Mean HR after the procedure, at 12 months follow-up, and after 6-minute walk test at 12 months was 61 vs. 82.9 bpm (p < 0.001), 72 vs. 88 bpm (p < 0.001), and 107 vs. 115 bpm (p = 0.01) [39].
78% of patients in the hybrid group could stop all of their rate-reducing drugs, while none of the patients in the endocardial RFA group was able to do so. Quality of life (QoL) scores showed a significant improvement in both groups, but the hybrid group had better QoL scores than the endocardial RFA group.
HRS expert consensus document [1] recommends Class III indication for surgical ablation (along with sinus node modification and sympathetic denervation) as a part of routine care for IST patients. Although unlikely to become a part of routine care, for patients with drug-refractory IST, hybrid ablation offers a safer and more effective treatment option than endocardial sinus node modification using radiofrequency energy.
Some of the other treatment options that have been utilized in drug-refractory IST are stellate ganglion block and cardiac sympathetic denervation [54], renal sympathetic denervation [55], surgical ablation of the sinus node [43], thoracoscopic epicardial ablation of the sinus node [42], surgical excision of the sinus node [56], partial cardiac denervation and sinus node modification via right thoracotomy [57].

Conclusions
IST is a clinical syndrome with distressing symptoms mainly affecting younger females, is challenging to treat, but has a favorable long-term prognosis. Ivabradine has shown better results and is tolerated better than other rate-reducing drugs. RFA aimed at sinus node modification has dismal results. Sinus node sparing thoracoscopic ablation aimed at isolation of sinus node has shown promising results.

Author contributions
MA, AH, AK were involved in literature search and drafting of the manuscript, BPG and KK approved the draft and were involved in final editions of the manuscript.

Ethics approval and consent to participate
Not applicable.