|Year : 2019 | Volume
| Issue : 1 | Page : 26-33
Characteristics of dynamic electrocardiogram, heart rate variability, and electrophysiological study in a Chinese population with vasovagal syncope
Zhuzhi Wen, Chulian Fu, Yangxin Chen, Dengfeng Geng, Jingfeng Wang
Department of Cardiology, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangdong Province Key Laboratory of Arrhythmia and Electrophysiology, Guangzhou, Guangdong Province, China
|Date of Web Publication||25-Nov-2019|
Dr. Dengfeng Geng
Department of Cardiology, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou 510120, Guangdong Province
Dr. Jingfeng Wang
Department of Cardiology, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou 510120, Guangdong Province
Source of Support: None, Conflict of Interest: None
Background: Little is known about characteristics of dynamic electrocardiogram (DCG), heart rate (HR) variability (HRV), and invasive electrophysiological study (EPS) in the presence, pattern, and stage of vasovagal syncope (VVS) during head-up tilt test (HUTT). The present study aims to explore predictive value of these tests for HUTT outcomes with underlying mechanisms. Subjects and Methods: This retrospective study consecutively enrolled 519 patients with VVS from January 2007 to December 2017. Parameters of DCG, HRV, and EPS were evaluated according to the presence, pattern, and stage of syncope during HUTT. Results: Mixed pattern was the predominant subtype of VVS, and vasodepressor patients had a positive response earlier than in cardioinhibitory patients. Compared with negative group, positive group with mixed and cardioinhibitory patterns had significantly slower maximal HR and mean HR all day, at daytime, nighttime, and each hour point. No significance was observed in parameters of HRV between negative and positive groups. There was no significant difference in HR, spectral power components, and time-domain variables among syncopal patterns and syncopal stages. Positive group had longer durations of A-H interval, sinus node recovery time, Wenckebach point, and Wenckebach 2:1 point than negative group. There was a significant difference only in sinus node recovery time among syncopal patterns as well as A-H interval among syncopal stages. Conclusion: DCG-derived HR and EPS properties rather than 24-h HRV may be used to predict positive responses, but they could not predict syncopal patterns and syncopal stages.
Keywords: Dynamic electrocardiogram, electrophysiological study, head-up tilt test, heart rate variability, vasovagal syncope
|How to cite this article:|
Wen Z, Fu C, Chen Y, Geng D, Wang J. Characteristics of dynamic electrocardiogram, heart rate variability, and electrophysiological study in a Chinese population with vasovagal syncope. Int J Heart Rhythm 2019;4:26-33
|How to cite this URL:|
Wen Z, Fu C, Chen Y, Geng D, Wang J. Characteristics of dynamic electrocardiogram, heart rate variability, and electrophysiological study in a Chinese population with vasovagal syncope. Int J Heart Rhythm [serial online] 2019 [cited 2020 Sep 27];4:26-33. Available from: http://www.ijhronline.org/text.asp?2019/4/1/26/271664
| Introduction|| |
Vasovagal syncope (VVS) is the primary cause of syncope, accounting for more than half of syncope episodes in specialized clinical settings. Recurrent episodes of VVS, despite not increase the mortality for patients, can lead to impaired quality of life and even cause serious damage. However, the pathogenesis of VVS is complex and the exact mechanisms are not yet fully understood. It is of paramount importance to alarm the genesis of VVS and perform effective management to improve syncope-related injury and quality of life.
Head-up tilt test (HUTT) has been determined as a useful examination to evaluate patients with suspected VVS. HUTT is expensive for per diagnosis and somewhat time-consuming in busy clinical settings. However, it has not been confirmed that single measurement or combination is able to predict the HUTT resulting in advance precisely. Therefore, promising predictors rather than HUTT are being investigated to evaluate VVS.
Despite not as routinely recommended tests, dynamic electrocardiogram (DCG), heart rate (HR) variability (HRV) and electrophysiological study (EPS) have been performed to elucidate the underlying mechanisms involved in VVS. Up to date, few studies have focused on the characteristics of 24-hour DCG, 24-hour HRV, and invasive EPS in the appearance, pattern, and stage of syncope during HUTT in VVS patients. Therefore, the present study aims to explore syncopal characteristics in a Chinese population and further evaluate predictive value of 24-hour DCG, 24-hour HRV, and invasive EPS parameters for HUTT results in the population.
| Subjects and Methods|| |
Study population and data collection
The present study consecutively enrolled 519 patients aged 15–70 years, including 275 males and 244 females, admitted to the Department of Cardiology of Sun Yat-Sen Memorial Hospital between January 2007 and December 2017 for the complaint of syncope. All patients had been diagnosed as VVS through medical history, physical examination, HUTT, and other ancillary tests. Patients with potential cardiac syncope, neurological syncope, orthostatic hypotension, carotid sinus syndrome, or any medical condition that could cause syncope were excluded from the study.
Patients were investigated, assessed, and treated according to the usual institutional practice. The collection of data included demographic data, medical history, body measurements, routine laboratory tests, 18-lead electrocardiogram, 24-hour Holter electrocardiogram monitoring, echocardiography, computerized tomography, magnetic resonance imaging, and electroencephalogram. HUTTs, coronary artery angiograms, and EPS were performed for individuals with approved written informed consent. Investigations were in accordance with the Declaration of Helsinki, and all medical records were studied in anonymous manners. This is a retrospective study, and data collections have been approved by the medical records statistics and quality assessment center of our hospital. Our study did not involve obvious ethical issues; thus, we did not apply for approval by the Ethics Committee ahead of schedule.
Head-up tilt test
Other causes of syncope were excluded from the study before the HUTT was performed. After written consent signed and overnight fasting or 6 hours after a light meal, the modified HUTT was performed for patients in a comfortable and slightly darkened room equipped for cardiopulmonary resuscitation. Any vasoactive drug should be withheld for at least 5 half-life periods before the tilt test. The test was performed on an electrically adjustable tilt table (Siemens, Erlangen, Germany). At least 10 minutes before the beginning of the test, the antecubital intravenous line containing Ringer's solution was inserted into the right arm and was used for isoproterenol infusion. After 6-lead electrocardiogram and an external blood pressure recorder were prepared, HR was monitored throughout the test and cuff blood pressures were gained every 5 minutes or when syncope occurred. After an initial resting period of 10 minutes in the supine position, the table was then smoothly tilted to 70° for 10 minutes. Subsequently, in the absence of syncope or presyncope, the table was returned to supine position and increasing doses of isoproterenol at a rate of 1, 3, and 5 μg/min was gradually infused in three successive stages, respectively. Each stage consisted of 10 minutes in the tilted position and 5 minutes in the supine position between stages.
Positive response was defined as the development of syncope or presyncope associated with bradycardia (marked bradycardia <50 beats/min or ≥20% decrease in HR) or hypotension (systolic blood pressure ≤80 mmHg, diastolic blood pressure ≤50 mmHg, or ≥25% decrease in mean arterial pressure), or both. Negative response was defined as the completion of the protocol without symptoms, while patients had an HR exceeding 150 beats/min for at least 2 minutes under isoproterenol infusion or failed to complete the test for other symptoms were defined as intolerance response. Positive responses were further classified into three syncopal patterns, including cardioinhibitory pattern when isolated marked bradycardia occurred, vasodepressor pattern when isolated hypotension occurred, and mixed pattern when mild bradycardia accompanied by hypotension was observed at the time of syncope or presyncope. Positive responses were further divided into four syncopal stages, including basic stage (without isoproterenol infusion), low-dose isoproterenol stage (1 μg/min), medium-dose isoproterenol stage (3 μg/min), and high-dose isoproterenol stage (5 μg/min) according to the time when syncope occurred during HUTT.
Twenty-four-hour Holter electrocardiogram monitoring and heart rate variability
Seven-channel 24-hour Holter electrocardiogram monitoring (SEER Light; GE Medical Systems, Milwaukee, WI, USA) was performed for patients. The Holter system was attached on a workday morning and detached the next morning by a well-trained technician for participants. Patients were asked to keep a diary to record their daily activities, including the time when they went to bed and got up. The following parameters of the recorded electrocardiogram were evaluated, including the minimal HR, the maximal HR, mean HR over a whole day (24 hours), the mean HR in daytime (6:00–22:00), the mean HR at nighttime (22:00–6:00), and the mean HR at each hour point.
The parameters of HRV derived from 24-hour Holter monitoring including spectral power and time domain were automatically analyzed by the MARS Workstation of the same device (GE Medical Systems). Spectral power components included very low-frequency component (LF, 0.00–0.04 Hz), LF component (0.04–0.15 Hz), high-frequency component (HF, 0.15–0.40 Hz), wideband frequency component (0.00–1.71 Hz), and low- to high-frequency ratio (LF/HF ratio). The time-domain variables consisted of the mean of all coupling intervals between normal beats (mean NN), standard deviation of normal-to-normal RR intervals (SDNN), the SD of all the 5-minute mean NN intervals, average of the SDNN every 5-minute segments, the root-mean-square of the difference between successive RRs, and the proportion of adjacent normal RR intervals differing by greater than 50 ms.
Vasoactive drugs were withheld for at least five half-life periods before the test performed. Written informed consent was signed by each participant before the test underwent. Patients should be kept fasting at least 6 hours after a light meal. A standard protocol was applied by electrophysiologists for the evaluation of electrophysiologic parameters. Briefly, percutaneous puncture for femoral vein and/or subclavian vein was performed using the Seldinger method. The electrodes were placed in the high right atrium, right ventricular apex, and bundle of His and sometimes coronary sinus. Program stimulation protocols with S1S2, S1S2S3, and burst stimulation were performed at different rates. Standard 12-lead and intracardiac electrocardiogram were continuously recorded during the test to evaluate the electrophysiological properties of the heart. Parameters of A-H interval, H-V interval, sinus node recovery time, sinoatrial conduction time, Wenckebach point, and Wenckebach 2:1 point were measured in patients.
Continuous variables were presented as the mean ± SD and were compared by Student's t-test or one-way ANOVA with the least significant difference test post hoc test within subgroups. Categorical variables were presented as number and proportion (n, %); differences were tested for statistical significance with the chi-square test. General line model repeated measures were used to evaluate the distributions of mean HR at each hour during 24-hour Holter electrocardiogram monitoring. Two-tailed P < 0.05 was considered statistically significant. All statistical analyses were performed with the software package SPSS 16.0 for Windows (SPSS, Chicago, IL, USA).
| Results|| |
Demographic and clinical characteristics of patients
There were 519 patients with a mean age of 44 years enrolled into the study, of whom 378 patients underwent a HUTT (HUTT group) and 141 patients did not receive a HUTT (non-HUTT group) [Table 1]. HUTT group was significantly younger that non-HUTT group. Patients receiving the HUTT were also prone to accept invasive examinations, such as coronary artery angiogram and EPS. Two hundred and forty-four angiograms were performed for participants, but only 33 patients were revealed to have significant stenoses in coronary arteries in the study. Only a few patients with mild stroke were revealed, even if a high proportion of patients underwent computerized tomography or magnetic resonance imaging examinations. There was not any significant difference in the prevalence of coronary heart disease, stroke, hypertension, and diabetes mellitus between the two groups. Pacemaker therapy was almost performed for patients undergoing the HUTT, suggesting HUTT screening patients for treatment with a pacemaker. No significance was observed in syncope family history and psychiatric traits including insomnia, depression, anxiety, and somatization disorder, between HUTT and non-HUTT groups. Blood electrolyte, renal function, and HR as well as blood pressure at admission were assessed in the study [Table 2]. Except a litter higher in blood chlorine in HUTT group, there was no significant difference in blood potassium, sodium, creatinine, blood hemoglobin, as well as HR and blood pressure at admission between HUTT and non-HUTT groups.
|Table 1: Baseline demographics and clinical characteristics of the study population|
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Syncopal characteristics of the population
Mixed pattern was the predominant subtype of VVS according to the HUTT, which accounted for 47.5% of syncope presentations overall [Figure 1]a. Compared with younger patients, the prevalence of mixed and vasodepressor pattern was significantly higher in older patients, while younger patients trended to have a higher proportion of cardioinhibitory VVS. A larger number of positive episodes appeared at medium-dose stage overall and in both younger and older patients. However, there was no significant correlation between syncopal stages and age [Figure 1]b. No significant difference was observed in the presence of prodrome and syncope duration between HUTT and non-HUTT groups [Table 3]. Syncopal triggers were indistinguishable except for significance in pain in HUTT group. Patients had more syncope episodes were prone to accept the HUTT.
|Figure 1: Head-up tilt test results in population. (a) Syncopal subtypes based on tilt test. P =0.010 for mixed, cardioinhibitory, and vasodepressor groups. (b) Syncopal stages based on tilt test. P =0.810 for 1, 3, and 5 μg/min isoproterenol groups, respectively|
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Characteristics of heart rate during 24-hour Holter monitoring according to the head-up tilt test
Compared with negative response patients, patients with a positive response had significantly lower mean HR all over the day, in daytime, and at nighttime. Both minimal and maximal HR in positive patients was slower than those in negative response patients [Table 4]. When compared with negative group, significances of mean HR were revealed all day, at daytime, and nighttime in mixed and cardioinhibithory groups, but only at daytime and all over the day in vasodepressor group. However, there was no significance of minimal HR, maximal HR, and mean HR at a whole day, daytime, and nighttime, among syncopal subtypes. No significance of these parameters was demonstrated among syncopal stages [Table 5]. Patients with positive responses had lower mean HR than that in negative patients at each hour point, but no significance of mean HR at each hour point was revealed among syncopal patterns and stages [Figure 2].
|Table 4: Heart rate of 24-hour Holter monitoring according to tilt test results|
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|Table 5: Heart rate of 24-hour Holter electrocardiogram monitoring according to syncopal stages|
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|Figure 2: Holter monitoring-derived mean heart rate distributions at each hour point according to the head-up tilt test results. (a) Based on positive response, F=5.476, P=0.021, according to general line model repeated measures; (b) based on syncopal subtypes, F=2.053, P=0.132, according to general line model repeated measures; (c) based on syncopal stages, F=0.199, P=0.820, according to general line model repeated measures. IP=Isoproterenol|
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Characteristics of 24-hour heart rate variability according to head-up tilt test
There were no significant differences between spectral power components and time-domain variables between positive and negative response patients and among different syncopal patterns [Table 6]. Furthermore, there was not any significant difference in spectral power components and time-domain variables among syncopal stages [Table 7]. The parameters of HRV derived from 24-hour electrocardiogram monitoring provided no meaningful prediction for HUTT outcomes.
|Table 6: Twenty-four-hour heart rate variability according to head-up tilt test results|
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|Table 7: Parameters of heart rate variability according to syncopal stages|
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Characteristics of electrophysiological properties according to head-up tilt test
More than half of patients underwent EPS, and HUTT group trended to have more EPS performed than non-HUTT group [57.9% vs. 37.6%, P < 0.001; [Table 1]. As compared with negative response patients, patients with positive responses had significantly longer parameters of A-H interval, sinus node recovery time, Wenckebach point, and Wenckebach 2:1 point. Significant difference of parameters hereinbefore had also been revealed between negative group and syncopal subtypes, expect for A-H interval between negative and vasodepressor groups [Table 8]. There was a significant difference only in sinus node recovery time among three syncopal subtypes. Among syncopal stages, only H-V interval was found to have a significant difference, but there was not a trend according to isoproterenol dose [Table 9].
|Table 9: Electrophysiological parameters according to different syncopal stages|
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| Discussion|| |
Initiate diagnosis of VVS is usually based on detail medical history, physical examination, including supine and standing BP measurements as well as electrocardiogram. The HUTT as an orthostatic stress test has been widely considered as a useful tool to demonstrate the susceptibility of a vasovagal response to a positional change from supine to tilt position. If the diagnosis is unclear after initial evaluation, the HUTT can be useful for patients with suspected VVS., The present study demonstrated that HUTT group had a smaller mean age than that in non-HUTT group, suggesting that older patients might refuse to undergo the time-resuming and discomfortable HUTT. Pacemaker therapy was almost performed for patients underwent the HUTT, suggesting the HUTT screening patients for treatment with a pacemaker. Using adjunctive agents, such as isoproterenol infusion or sublingual nitroglycerin, may improve sensitivity but decrease specificity. It has been observed that results of HUTT with graded isoproterenol infusions can be duplicated in 90% of patients. Increasing doses of isoproterenol at a rate of 1, 3, and 5 μg/min was gradually infused in three successive stages in our present study. The appearance of positive response is more than 90% in our selected patients, and more than half of positive reactions occurred at a dose of 3 μg/min isoproterenol. Overall, mixed vasovagal response is the most common syncopal pattern, and younger patients had a higher cardioinhibitory response but a lower vasodepressive response than in older patients. The distribution of syncopal patterns is inconsistent with other study; differences in age and population selection might partly account for the phenomenon. It has been shown that patients who had more syncope episodes were prone to accept the HUTT. However, no significant difference was observed in the presence of prodrome and syncope duration between HUTT and non-HUTT groups, but patients with syncope induced by pain were less prone to undergo the HUTT.
Additional tests may be performed in the specific features that need further evaluation. Despite not as recommended examinations for causal diagnosis of syncope, both echocardiogram and angiography are sometimes indicated if cardiac disease, myocardial ischemia, or infarction is suspected in patients., Routine neurological testing, including electroencephalogram and computerized tomography or magnetic resonance imaging of the brain, is only indicated in the evaluation of patients with syncope in the presence of specific neurological features, suggestive of a seizure and focal neurological findings or head injury that need further evaluation., Our findings further demonstrated that coronary artery angiogram, computerized tomography, or magnetic resonance imaging has low diagnostic yield and very high cost per diagnosis. It is meaningful to avoid costly or invasive tests ordered in patients without a complete evaluation with simple methods. Therefore, how to improve syncope management remains a major challenge to reduce inappropriate admissions and overuse of these tests.
The indication of DCG monitoring is only when there is a high pretest probability of identifying an arrhythmia associated with syncope, since symptoms do not recur during electrocardiogram monitoring in most patients, and the true yield of DCG monitoring in syncope may be very low in an unselected population. Therefore, Holter monitoring in syncope may be of more value if symptoms are frequent, such as daily single or multiple episodes. However, few researches have focused on the role of mean HR during DCG monitoring in predicting HUTT results. In the exception of minimal HR, maximal HR and mean HR at daytime, nighttime, and a whole day were significant lower in positive patients than those in negative patients. Furthermore, the mean HR at each hour point was also lower in patients with a positive response as well. When compared with negative group, mixed and cardioinhibithory groups but not vasodepressor group had lower HR all the day, at daytime, and at nighttime. However, there were no significant differences of these parameters among syncopal patterns and syncopal stages. Our findings suggest that HR derived from DCG monitoring may be of value in predicting positivity of the HUTT in VVS patients, but not in discriminating syncopal types as well as syncopal stages. Further research is warranted to identify the role of mean HR of DCG monitoring in HUTT.
HRV is a well-established method used for noninvasive evaluation of autonomic nervous system activity and provides useful information to understand the pathogenesis of VVS. HRV parameters indicating parasympathetic effect were higher in patients with positive HUTT results than in patients with negative response,, suggesting that increased parasympathetic tonus is associated with a greater frequency of HUTT positivity in VVS patients. The parameters of HRV including spectral power and time domain were automatically evaluated in the present study, but no significant difference of these parameters was revealed between positive and negative response patients. It has been shown that patients with different syncopal pattern possess different HVR parameters, especially between patients with cardioinhibitory and vasodepressor response, suggesting heterogeneous properties in VVS population.,, On the contrary, there was not any significant difference of HRV parameters among syncopal subtypes in the present study, which is consistent with findings from the other study. Isoproterenol can provoke an early and persistent increase in parasympathetic nerve tone to enhance the vasovagal reaction during HUTT. However, increasing doses of isoproterenol were used in our HUTT protocol, but no significant difference of HRV parameters among patients with syncope occurred at different stages. The parameters of HRV during 24-hour electrocardiogram monitoring used for VVS evaluation are debated, and our findings provided no meaningful prediction of HRV for VVS outcomes.
Due to the development of noninvasive diagnostic methods, such as prolonged DCG monitoring, EPS is generally not useful in patients with syncope but without heart disease and palpitations. Positive results of EPS performed for syncope patients occurred predominantly in patients with structural heart disease. Clinical registry data have shown that only approximately 3% of patients with unexplained syncope evaluated by cardiologists undergo EPS. More than half of the patients underwent EPS, and patients received the HUTT trended to have more EPS performed than patients refused the HUTT in our study. Except for H-V interval and sinoatrial conduction time, significant differences of A-H interval, sinus node recovery time, Wenckebach point, and Wenckebach 2:1 point had been revealed between positive and negative patients. However, there was not any significant trend of these parameters among patients with different syncopal patterns and among syncopal stages. One study measured corrected sinus node recovery time and Wenckebach point using transesophageal atrial stimulation in children with VVS. The study revealed that Wenckebach point but not corrected sinus node recovery time differed significantly between positive and negative patients. These findings suggest increased autonomic tonus in favor of parasympathetic activity in positive patients. Our findings support that invasive EPS is more expensive and does not offer any valuable applications, such as shortening tilt-test time and indicating implantable pacemaker, thus would not be a routine method for VVS evaluation. Nevertheless, if specific clinical situations such as asymptomatic sinus bradycardia, bifascicular bundle branch blocked, or tachycardia suspected, EPS remains useful for the diagnosis.
| Conclusion|| |
Mixed response is the most common pattern in patients with VVS, and syncope occurs frequently at stage with a dose of 3 μg/min isoproterenol infusion. HR of DCG and parameters derived from EPS may be used to predict positive responses, but they could not predict what a syncopal pattern is and when syncope episodes would happen. HRV parameters do not provide any value information for HUTT results in advance. DCG, HRV, and invasive EPS could not predict the occurrence of syncope in advance during HUTT and provide no valuable information for therapeutic choice, and thus could not be used as routine tools for VVS evaluation. Cross-sectional, single-center nature, and fewer patients in negative response group represent important limitations of the present study. Then, not all patients have the HUTT, 24-hour DCG monitoring, HRV, and EPS done overall. Finally, the population is highly selected; thus, control groups from multiple centers will need to confirm our novel observations in the future.
Financial support and sponsorship
This work was supported by the PhD Start-up Program of Guangdong Province Natural Science Fund (2014A030310459) and Guangdong Natural Science Foundation Project (2018A030313531).
Conflicts of interest
There are no conflicts of interest.
Institutional review board statement
This study was performed in accordance with the Declaration of Helsinki. This is a retrospective study, and data collections have been approved by the medical records statistics and quality assessment center of our hostital. Our study did not involve obvious ethical issues, thus we did not apply for approval by the Ethics Committee ahead of schedule.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the forms, the patients have given their consent for their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9]