Academic Editor: Yoshiaki Kaneko
Inappropriate sinus tachycardia (IST) has been defined as a resting heart rate
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
Some experts have divided IST patients into three groups based on the HR pattern
(a) normal resting heart rate (
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
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 . The authors did not include 33 patients with a
mean HR of
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 .
Although most patients are young females, IST has been diagnosed in elderly
patients as well. Lopera et al.  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
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 healthcare workers . 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.
The funny current (If) or the pacemaker current is a mixed Na
Heart rate control via the autonomic nervous system. Sinus node
activation is managed by cellular currents, including I
Morillo et al.  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 .
Wising in 1941 first described a familial form of IST that was labeled as familial, congenital sinus tachycardia . 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 .
Chiale et al.  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.  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 postulate that
impaired function of acetylcholine-sensitive and adenosine-sensitive potassium
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
Other factors proposed for IST pathogenesis are beta-adrenergic receptor supersensitivity, muscarinic receptor abnormality, central and peripheral nociceptive effects, neurohormonal modulation, hypothalamic paraventricular nucleus stimulation, and non-muscarinic, non-adrenergic, vagally-mediated tachycardia  (Fig. 2).
Schematic of inappropriate sinus tachycardia pathogenesis. Please see the text for details.
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%) .
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 .
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 . Huang et al.  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.  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].
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 .
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 .
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 .
Tilt table testing is required to rule out the presence of POTS. In the study by Shabtaie et al. , 24% of patients were diagnosed as having POTS.
According to the HRS expert consensus statement , 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 .
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 .
Reassurance and avoidance of cardiac stimulants are an integral part of IST management .
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 .
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 .
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 .
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 .
In a prospective, open-label study involving 40 patients with a follow-up of 24 months, Annamaria et al.  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 received metoprolol for 4 weeks followed by the combination therapy for another 4 weeks .
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 .
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 . Management of accompanying depression and anxiety may lead to symptom amelioration .
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 the retrospective study by Shabtaie et al. , over a period of 20
years, 55 out of 305 IST patients underwent a sinus node modification procedure.
91% of the procedures were endocardial, and 9% were epicardial RFA procedures.
Within 6 months of the procedure, 58% of patients reported any improvement; 66%
didn’t report any long-term improvement even with multiple procedures (mean
procedures per patient: 1.8
In a systematic review of nine studies that included 153 patients,
Rodríguez-Mañero et al.  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 . After a mean follow-up of 28.14
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 long-term benefits, and an increased risk of complications. That is why the HRS expert consensus document  (Class III recommendation) and ESC guidelines  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.
|Study||Year||Number of patients||Type of study||Treatment strategy||Results||Remarks|
|Shabtaie et al. ||2021||55||Single-center retrospective||Endocardial RFA SNM (91%)||58% showed improvement in symptoms in 6 months||See text for details|
|case series||Epicardial RFA SNM (9%)||5% showed long-term (
|Lakkireddy et al. ||2021||100 (82 females)||Multicenter prospective||50: Hybrid strategy||Restoration of normal sinus rhythm and rate: 100% vs.||See text for details|
|registry||50: endocardial RFA||84%|
|78% vs. 0% of patients were able to stop their rate-reducing drugs|
|RFA group was associated with multiple repeat procedures and more adverse effects|
|Daher et al. ||2020||39 (37 females)||Single-center retrospective||Endocardial RFA based SNM||37 patients had symptom resolution after at least 1 SNM||13 patients required PPM implantation|
|case series||21 required
||2 patients had phrenic nerve injury|
|13 required postprocedure rate control medications||6 patients had postprocedure pericarditis|
|Reissmann et al. ||2020||3 (all females)||Single-center retrospective||Endocardial RFA based SNM||100% acute success rate.||1 required PPM implantation after SN ab-|
|case series||2 of the 3 patients had relief of symptoms after a mean FU of 424 days||lation|
|Aalaei-Andabili et al. ||2019||10 (8 females)||Single-center retrospective||Minimally invasive thoracoscopic||100% acute success rate||1 pericarditis|
|case series||surgery||2 IST recurrences after a median FU of 13 months||1 pulmonary embolism|
|All patients had recurred after at least 1||88% freedom from reintervention at 6 months||No PPM implantation|
|endocardial RFA based SNM||4 repeat interventions (3 endocardial RFA, 1 minimally invasive surgery)|
|Khiabani et al. ||2019||18 (16 females)||Single-center retrospective case series||Surgical isolation of sinus node||100% acute success rate||5 patients required PPM implantation on FU|
|15 patients had recurred after endocardial RFA based SNM||No IST recurrence in 17 patients after a mean FU of 11 years||2 patients required RFA for atrial flutter and AT|
|de Asmundis et al. ||2019||50 (41 females; 39||Single-center retrospective||Sinus node sparing hybrid thoracoscopic||Preablation HR in IST 119
||Pericarditis was the most common com-|
|IST, 11 POTS)||case series||ablation||HR on day 1 postablation 65
|After a mean FU of 28 months, 100% of patients had||No requirement of PPM during FU|
|significantly slower HR (74
||No phrenic nerve injury|
|All patients stopped rate-reducing medications during FU|
|Ibarra-Cortez et al. ||2015||13 (all females)||Single-center retrospective case series||Endocardial RFA based SNM.||100% acute success rate||1 pericardial bleeding which required surgery|
|Pericardial access in 10 patients for phrenic nerve preservation.||84.6% (11 out of 13) relief of symptoms after a mean FU of 811 days||1 PPM implantation|
|Jacobson et al. ||2014||5 (All females)||Single-center retrospective||Epicardial SN ablation in patients who||100% acute success rate||3 cases of pericarditis|
|case series||had failed an endocardial approach.||100% relief of symptoms after a FU of 30 months||1 case of RV puncture|
|3 patients already had a device implanted|
|Frankel et al. ||2012||33 (31 females)||Single-center retrospective case series||Endocardial RFA based SNM||6 patients (18%) had an IST recurrence after a mean FU of 2 years||Non-IST tachycardias were found in 42% before the SNM procedure (most common was AVNRT) and in 27% after the procedure (most common was AT)|
|4 patients required PPM implantation on FU|
|Takemoto et al. ||2011||6 (3 females)||Single-center case series||Endocardial RFA based SNM||SNM success 100%|
|1 patient had a recurrence after a mean FU of 29 months|
|Lin et al. ||2007||7 (6 females)||Single-center case series||Endocardial RFA based SNM||SNM success 100%||1 patient required PPM implantation|
|6 patients had no recurrence over a mean FU of 13 months|
|Marrouche et al. ||2002||39 (35 females)||Single-center case series||Endocardial RFA based SNM||SNM success 100%||1 SVC syndrome|
|21% had recurrence over a mean FU of 32 months||3 patients presented with atrial tachycar-|
|None of the patients required PPM implantation after the procedure||dia after the procedure|
|Man et al. ||2000||29 (26 females)||Single-center case series||Endocardial RFA based SNM||76% acute success||1 right diaphragmatic palsy|
|55% (16) free of symptoms after a mean FU of 32 months||6 patients received a PPM on FU (5 after AVNJ ablation)|
|Callans et al. ||1999||10 (9 females)||Single-center, retrospec-||Endocardial RFA based SNM||84% (11) acute success in 13 procedures||5 patients had a |
|tive case series, studied||3 (30%) recurrences||RA junction diameter|
|SVC obstruction post RFA for IST||No FU data||1 PPM implantation after SN ablation|
|Lee et al. ||1995||16 (15 females)||Single center case series||Endocardial RFA based SNM (n = 12)/SN||100% acute success||Right phrenic nerve palsy (n = 1, tran-|
|ablation (n = 4)||87% symptom relief at 20 months follow-up||sient)|
|2 recurrences||SVC syndrome (n = 1, transient)|
|4 patients were deemed to be as partial success on FU||3 patients received a PPM|
|2 patients developed ectopic atrial tachycardia||3 patients had already received a PPM after AVNJ ablation|
|AT, atrial tachycardia; AVNJ, atrioventricular node junction; AVNRT, atrioventricular nodal reentrant tachycardia; SN, sinus node; SNM, sinus node modification; FU, follow-up; PPM, permanent pacemaker.|
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 .
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).
Thoracoscopic sinus node sparing ablation strategy. Ablation lesions (red-colored oval circles and straight line) are created at SVC-RA junction, IVC-RA junction, and along crista terminalis by using a bipolar radiofrequency clamping device. If any, the gaps along the crista terminalis ablation line are endocardially ablated (yellow dots).
In 39 consecutive IST patients, who underwent the hybrid procedure, the mean HR
decreased from 119
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
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.
The hybrid procedure was associated with significantly more extended ICU stay (1 vs. 0.2 days) and acute pericarditis (92 vs. 48%). The endocardial RFA procedure was associated with a significantly longer non-ICU hospital stay (4.2 vs. 2.9 days), more rehospitalizations during the 12-month follow-up (54 vs. 6%), more right hemidiaphragm stunning (14 vs. 0%), and more permanent pacemaker implantations during the follow-up (50 vs. 4%).
HRS expert consensus document  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 , renal sympathetic denervation , surgical ablation of the sinus node , thoracoscopic epicardial ablation of the sinus node , surgical excision of the sinus node , partial cardiac denervation and sinus node modification via right thoracotomy .
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.
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.
We would like to express our gratitude to peer reviewers for their opinions and suggestions.
This research received no external funding.
The authors declare no conflict of interest. Dr. Kanjwal is the consultant for St Jude Medical and Bio sense webster.