Inappropriate sinus tachycardia (IST) is a clinical syndrome characterized by excessive resting heart rate (HR) or disproportional HR increase during exercise. The etiology of IST has not been fully elucidated and remains controversial. The aim of the present study was to assess autonomic function by means of noninvasive tests and commonly available electrocardiographic methods in a series of consecutive patients with symptomatic IST. Twenty-four patients (37 ± 12 years; 20 women) with IST were enrolled. Six cardiovascular reflex tests were performed: (1) HR variation during slow deep breathing, (2) 30-to-15 ratio during active standing, (3) blood pressure response to standing, (4) cold face test, (5) Valsalva maneuver, and (6) blood pressure response to sustained handgrip. Intrinsic HR was calculated and compared with HR after pharmacologic denervation. Additionally, spontaneous baroreflex sensitivity and 24-hour HR variability indices were analyzed. In IST patients, intrinsic HR was significantly higher compared with control subjects. Most cardiovascular autonomic tests revealed abnormal or borderline results, particularly those reflecting mainly parasympathetic function. The spontaneous baroreflex gain was significantly reduced in IST patients. After controlled orthostatic stress and during Valsalva maneuver, impaired baroreflex function was observed. The sympathovagal balance from HR variability was preserved, but altered activity in both bands of frequency domain analysis was recorded. In conclusion, IST is a heterogenic syndrome with enhanced sinus node automaticity modulated by complex alterations of autonomic tone.
The aim of the present study was to assess systematically autonomic function and balance by means of a simple battery of noninvasive tests and commonly available electrocardiographic methods in patients with highly symptomatic inappropriate sinus tachycardia (IST).
The study population consisted of consecutive white patients referred to the Autonomic Heart Dysfunction Laboratory due to highly symptomatic, persistent sinus tachycardia. Previous antiarrhythmic treatment was discontinued for at least 4 weeks. Subsequently, all patients were screened for IST according to current criteria. Those with a confirmed diagnosis of IST (heart rate ≥100 beats/min at rest in sitting position and/or an average heart rate ≥90 beats/min during 24-hour Holter monitoring) were considered to participate in the present study. Patients with symptoms or clinical criteria suggestive of postural orthostatic tachycardia syndrome, with secondary causes of tachycardia, or with diseases affecting autonomic function were not included. The severity of IST-related symptoms was assessed by European Heart Rhythm Association score. A cohort study was conducted with age- and gender-matched healthy controls (n = 24). None of the controls had clinical signs of autonomic dysfunction, and no study participant was being treated with drugs known to interfere with autonomic nervous function. Patient characteristics are depicted in Table 1 . Participants gave informed consent before enrollment in the study. The study protocol was approved by local ethics committee.
|Variable||Patients (n = 24)||Controls (n = 24)|
|Age (yrs)||36 ± 10||35 ± 9|
|Female gender||20 (83%)||20 (83%)|
|Height (m)||1.64 ± 0.07||1.66 ± 0.12|
|Weight (kg)||53.67 ± 9.89||54.55 ± 10.11|
|Body Mass Index (kg/m 2 )||20.11 ± 4.21||21.10 ± 5.11|
|Smoker||2 (8%)||3 (12.5%)|
|Exercise intolerance||12 (50%)|
|Chest discomfort||4 (17%)|
Autonomic tests were performed according to standard protocols using Finometer PRO (Finapres Medical Systems, Amsterdam, The Netherlands) for continuous noninvasive blood pressure measurement.
Six cardiovascular reflex tests were performed in the following order with 15 minutes of recovery time between recordings: (1) expiration-to-inspiration ratio of RR interval during slow deep breathing (heart rate variation), (2) maximum-to-minimum 30-to-15 ratio of RR intervals during active standing, (3) systolic blood pressure response to standing, (4) cold face test, (5) maximum-to-minimum ratio of RR intervals during Valsalva maneuver (Valsalva ratio), and (6) blood pressure response to sustained handgrip (handgrip ratio). Methodologies as well as databases of normal values for healthy individuals of these tests have been described in detail elsewhere. Normal, borderline, and abnormal values of the tests are summarized in Table 2 .
|Test reflecting mainly parasympathetic function|
|Heart rate response to Valsalva Manoeuvre (Valsalva ratio)||≥1.21||1.11–1.20||≤1.10|
|Heart rate variation (RRI) during deep||≥15||11–14||≤10|
|Breathing (6 breaths per minute)||bpm||bpm||bpm|
|Heart rate response to standing (30:15 ratio)||≥1.04||1.01–1.03||≤1.00|
|Tests reflecting mainly sympathetic function|
|Blood pressure response to standing (fall in systolic blood pressure – mmHg)||≤10||11–29||≥30|
|Blood pressure response to sustained handgrip (increase in diastolic blood pressure – mmHg)||≥16||11–15||≤10|
Before entry into the study, a resting surface 12-lead electrocardiogram (ECG) and 24-hour Holter monitoring (Medilog Darwin, Schiller, Switzerland) were recorded. The following parameters were calculated from 24-hour Holter monitoring: mean heart rate, maximum heart rate, and daytime mean heart rate (defined as a mean heart rate between 6:00 a.m. and 10:00 p.m. ). Additionally, to assess autonomic function and balance, heart rate variability indices were calculated from Holter recordings. The following time and frequency domain heart rate variability indices were analyzed: (1) mean RR interval, (2) the standard deviation from the mean of the normal RR interval, (3) the standard deviation of 5-minute mean standard deviations of RR interval, (4) the percentage of adjacent RR interval that differ by >50 milliseconds (pNN50), (5) the root mean square of successive RR differences, (6) low-frequency (LF, 0.04 to 0.15 Hz), (7) high frequency (HF, 0.15 to 0.4 Hz) power (ln[ms 2 ]), and (8) low-frequency/high-frequency ratio (LF/HF). Heart rate variability was also assessed from short-term ECG recordings in the supine and upright position.
Baroreflex sensitivity (BRS) was determined from spontaneous fluctuations of RR intervals and systolic blood pressure obtained from ECG and continuous blood pressure recordings in the supine position during 5 minutes of spontaneous breathing and 2 minutes of slow deep breathing (6 breaths/min). The BRS alpha-index was calculated as the square root of the ratio of the spectral powers of RR intervals and systolic blood pressure in the low-frequency range and high-frequency range. Transfer function was determined as the average of the systolic blood pressure-RR interval cross-spectrum divided by the systolic blood pressure spectrum in the frequency range of 0.04 to 0.15 Hz, when coherence exceeded 0.5.
Additionally, BRS calculated from the sequence method was assessed at supine rest and during Valsalva maneuver and orthostatic stress. Measures were performed from sequences in which the systolic blood pressure and the subsequent RR intervals (≥3 beats) changed concurrently at the minimum of 1 mm Hg or 5 milliseconds. The slopes of the regression lines between systolic blood pressure and RR intervals were calculated for valid sequences with correlation coefficients >0.8. The average value of the individual slopes was taken as BRS SEQ . Three Valsava maneuvers tests were performed, separated by 3-minute recovery periods. We used the slope method to assess baroreflex sensitivity during phase IV arterial pressure elevation. Mean value was expressed as BRS VM .
Intrinsic heart rate was assessed the day after the autonomic tests procedures. Predicted intrinsic heart rate was calculated according to Jose formula: intrinsic heart rate = 118.1 − (0.57 × age). Autonomic blockade was achieved by bolus injection of propranolol 0.2 mg/kg and atropine 0.04 mg/kg. Increased intrinsic heart rate was defined as an observed intrinsic heart rate >2 SD of the predicted intrinsic heart rate.
Statistical analysis was performed using Statistica software (version 9.0, StatSoft, Tulsa, Oklahoma). Continuous variables are expressed as mean ± SD, and categorical variables are presented as frequency (%). Because not all analyzed data had normal distribution (Shapiro-Wilk W test), the nonparametric analysis of variance Friedman test was used for multiple group comparison with subsequently nonparametric post hoc test. The significance of the relationship between the categorical variables were tested with chi-square Pearson and its modifications for 2×2 tables (Yates Correction and Fischer Exact Test). Values of p <0.05 were considered statistically significant.
Mean resting heart rate as measured from the 12-lead resting ECG was 114.4 ± 7.5 bpm in IST patients. Mean heart rate calculated from 24-hour Holter monitoring was 99.8 ± 8 bpm and mean daytime heart rate was 108.5 ± 8 bpm. The maximal heart rate during monitoring was 152 ± 12 bpm. Observed intrinsic heart rate was significantly increased in IST patients compared to controls (128 ± 14 vs 105 ± 12, p <0.001). Abnormal intrinsic heart rate was observed in 17 (71%) IST patients.
The prevalence of abnormal and borderline test results in relation to standard normal values was significantly higher in IST patients compared to controls. The incidence of tests results suggesting autonomic dysregulation was greater for tests reflecting mainly parasympathetic function. Sustained handgrip test was completed by only 9 (37.5%) patients compared to 15 (63%) normal subjects, mainly due to painful cannula site on their dominant hand. The prevalence of subsequent tests results are summarized in Table 3 .
|Valsalva ratio||8 (33%)||20 (83%) ∗||6 (25%)||4 (17%)||10 (42%)||0 (0%)|
|Deep breathing test|
|Heart rate variation (bpm)||6 (25%)||21 (86%) ∗||10 (42%)||2 (8%)||8 (33%)||1 (4%)|
|Heart rate response to standing|
|30:15 ratio||8 (33%)||19 (79%) ∗||2 (8%)||4 (17%)||14 (58%)||1 (4%)|
|Systolic blood pressure response to standing (mmHg)||14 (58%)||18 (75%)||4 (17%)||2 (8%)||6 (25%)||4 (17%)|
|Diastolic blood pressure response to sustained handgrip (mmHg) †||6 (67%)||9 (60%)||1 (11%)||5 (33%)||2 (22%)||1 (7%)|
Table 4 presents autonomic function assessment in patients with IST in comparison to controls. Significantly different results were observed for all tests assessing mainly parasympathetic tone: Valsalva ratio, heart rate variation, heart rate response to standing, and heart rate change during cold face test. Tests using blood pressure variation as a measure of sympathetic autonomic function, namely systolic blood pressure response to standing and increase of systolic blood pressure in cold face test did not reveal significant differences.
|Variable||Patients (n = 24)||Controls (n = 24)||p Value|
|Cardiovascular reflex tests|
|Valsalva ratio||1.87 ± 0.26||2.26 ± 0.29||<0.001|
|Deep breathing test|
|Heart rate variation (bpm)||15 ± 7||27 ± 9||<0.001|
|Heart rate response to standing|
|30:15 ratio||1.11 (0.25)||1.52 (0.22)||<0.001|
|Systolic blood pressure response to standing (mmHg)||4 ± 5||5 ± 4||NS|
|Diastolic blood pressure response to sustained handgrip (mmHg) ∗|
|Women||10 ± 7||14 ± 5||<0.05|
|Men||14 ± 5||16 ± 3||NS|
|Cold face test|
|Heart rate decreasing after 60s (bpm)||1.1 ± 0.5||7.1 ± 0.6||<0.001|
|Increase of systolic blood pressure after 60s (mmHg)||8.1 ± 3.1||11.1 ± 2.4||NS|
|BRS αLF||10.1 ± 1.3||16.3 ± 2.1||<0.001|
|BRS αHF||14.6 ± 1.7||26.8 ± 3.3||<0.001|
|BRS TF||9.8 ± 0.7||15.8 ± 1.4||<0.001|
|BRS SEQ||9.3 ± 2.1||21.8 ± 2.3||<0.001|
|BRS STAND||7.1 ± 1.7||9.3 ± 2.1||0.060|
|BRS VM||9.7 ± 0.9||17.3 ± 1.3||<0.001|
|Heart rate variability (24-h recordings)|
|Mean R-R interval (ms)||526 ± 32||822 ± 23||<0.001|
|SDNN (ms)||66 ± 22.2||143 ± 33.1||<0.001|
|SDANN (ms)||55 ± 42.1||133 ± 54.3||<0.001|
|RMSSD (ms)||12.1 ± 1.2||37.1 ± 2.1||<0.001|
|pNN50 (%)||4.2 ± 1.1||13.1 ± 3.1||<0.001|
|LFP (ln[ms 2 ])||4.0 ± 1.1||6.1 ± 1.1||<0.010|
|HFP (ln[ms 2 ])||3.7 ± 0.7||5.2 ± 1.2||<0.010|