Available online at www.sciencedirect.com

ScienceDirect Journal of Electrocardiology 47 (2014) 374 – 382 www.jecgonline.com

Handheld ECG in analysis of arrhythmia and heart rate variability in children with Fontan circulation☆ Jenny Alenius Dahlqvist, MD, a,⁎ Marcus Karlsson, MSc, b Urban Wiklund, PhD, b Rolf Hörnsten, PhD, c Annika Rydberg, MD, PhD a a Department of Clinical Sciences, Umeå University, Sweden Department of Radiation Sciences, Biomedical Engineering, Umeå University, Sweden c Clinical Physiology, Heart Centre and Department of Surgical and Perioperative Sciences, Umeå University, Sweden b

Abstract

Background: Our aim was to evaluate the intermittent use of a handheld ECG system for detecting silent arrhythmias and cardiac autonomic dysfunction in children with univentricular hearts. Methods: Twenty-seven patients performed intermittent ECG recordings with handheld devices during a 14-day period. A manual arrhythmia analysis was performed. We analyzed heart rate variability (HRV) using scatter plots of all interbeat intervals (Poincaré plots) from the total observation period. Reference values of HRV indices were determined from Holter-ECGs in 41 healthy children. Results: One asymptomatic patient had frequent ventricular extra systoles. Another patient had episodes with supraventricular tachycardia (with concomitant palpitations). Seven patients showed reduced HRV. Conclusions: Asymptomatic arrhythmia was detected in one patient. The proposed method for pooling of intermittent recordings from handheld or similar devices may be used for detection of arrhythmias as well as for cardiac autonomic dysfunction. © 2014 Elsevier Inc. All rights reserved.

Keywords:

Handheld ECG; Arrhythmia; Heart rate variability; Fontan circulation

Introduction In Fontan surgery, the systemic venous blood return is redirected so the blood goes to the pulmonary arteries instead of being pumped through the ventricle. Since the introduction of this surgery [1], the technique has been modified and long-term results have steadily improved. However, arrhythmias and conduction abnormalities remain frequent complications. Known risk factors for arrhythmia in Fontan patients include older age at surgery, duration of follow-up after surgery, and worse NYHA (New York Heart Association) class symptoms. In addition, it has been suggested that autonomic nervous control plays an important role in the development of arrhythmias and that impaired cardiac autonomous nervous activity could be explained ☆ Sources of funding: Swedish Heart–Lung Foundation and Fundings according to Agreement on Medical Education and Research, Västerbotten County Council, Sweden. ⁎ Corresponding author at: Department of Clinical Sciences, Pediatrics, Umeå University, 901 85 Umeå, Sweden. E-mail address: [email protected]

0022-0736/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jelectrocard.2014.02.006

by surgery-related damage to cardiac autonomic nerves or their blood vessels. In contemporary materials with up to 15 years of follow-up time, the frequency of arrhythmia, mostly atrial re-entrant tachycardia, after Fontan operation is 4%–11% [2,3]. Due to significant hemodynamic abnormalities, a Fontan patient is more sensitive to recurrent atrial tachycardia. Persistent tachycardia is poorly tolerated in patients with single ventricle physiology and congestive heart failure may develop within 12–36 h [4,5]. In Fontan patients, the onset of the arrhythmia can be hard to recognize since symptoms may be vague; symptoms include fatigue, abdominal pain, nausea, edema, presyncope/ syncope and respiratory symptoms. The patient may not even experience any symptoms, i.e., present silent arrhythmias. In a recent study, Czosek et al. evaluated 24-h ECG monitoring in patients with congenital heart disease, including 84 recordings from 31 Fontan patients in the age group b 18 years. The pediatric Fontan patients were asymptomatic in the majority of the recordings (79%), but arrhythmia findings led to a change in management in 2% [6].

J.A. Dahlqvist et al. / Journal of Electrocardiology 47 (2014) 374–382

Arrhythmias tend to occur intermittently and may be hard to detect on conventional Holter recordings [7,8]. However, with the recent development of handheld devices to monitor ECG, home monitoring could be a viable option for detecting arrhythmias, allowing for both symptomrelated recordings and multiple shorter recordings of ECG over a longer period of time than possible with a Holter monitor. One of the first clinical applications for such a device was for detection of recurrent atrial fibrillation [9]. This device easily recognizes episodes of atrial fibrillation and can also detect other types of heart rate disturbances. Doliwa et al. compared the hand-held-ECG 10 s registration for 30 days to a 24-h ECG recording in a screening for asymptomatic atrial fibrillation in a population that had suffered from ischemic stroke, and concluded that the handheld-ECG system was significantly better than 24-h ECG [9]. However, as also pointed out by Czosek et al., systems for home monitoring need to be evaluated further in patients with congenital heart disease [6]. To find arrhythmias, patients are instructed to use the handheld ECG device both at fixed time points and when symptoms occur. The recordings are transmitted using a mobile phone connection, stored in a database and then reviewed manually. Considering that patients often perform a large number of short ECG recordings (10–30 s), the manual ECG analysis can be time consuming. Therefore, a tool is needed for efficient presentation of the heart rhythm that can assist the operator to detect signs of cardiac arrhythmia. The approach undertaken in our study is to use a graphical tool – Poincaré plot – to summarize the beat-tobeat fluctuations in heart rate occurring in all recordings in a single diagram. In these plots, the previous interbeat interval is plotted against the next one, which results in characteristic patterns for different types of normal and abnormal heart rate patterns. Poincaré plots are often based on data from 24-h ECG recordings, but they have also been applied to shorter recordings. In addition to being useful for detecting cardiac arrhythmia, they can be used to detect cardiac autonomic dysfunction [10,11]. In adults, reduced heart rate variability (HRV) implies a shift of the sympathovagal balance toward sympathetic predominance, and reduced vagal tone has been shown to precede onset of arrhythmia [12]. Furthermore, impaired autonomic nervous activity is associated with an increased risk of sudden cardiac death in patients with congenital heart disease [13]. We, and others have earlier shown that HRV is reduced in patients with Fontan circulation [14,15] and that HRV appears to be successively reduced over time after total cavopulmonary connection (TCPC) surgery [15]. Interestingly, in pediatric Fontan patients HRV changes can also be associated with and even precede development of arrhythmia [16]. Thus, identification of altered HRV in Fontan patients may indicate early signs of arrhythmia [16]. A potential limitation is that handheld ECG monitoring only can be performed during short-term intervals, whereas HRV parameters normally are determined over a 5-min or a 24-h period. However, the use of very short HRV recordings (10 s) has been evaluated in previous studies [17,18]. In this study we propose a strategy where HRV is analyzed based

375

on pooled data from all recordings that one subject performed with the handheld device. The aim was to evaluate the applicability of intermittent ECG recordings in a pediatric Fontan population. Our hypothesis was that silent arrhythmias and impaired autonomic function can be detected in Fontan patients using handheld ECG monitoring.

Materials and methods Written informed parent consent was obtained and the study was approved by the Regional Ethical Review Board, Umea University, Sweden. Study group Twenty-seven pediatric Fontan patients from the Northern part of Sweden were consecutively enrolled in the study. Forty-one healthy children in the same age range were included as controls. Medical record review The clinical records for the Fontan patients were reviewed for age, anatomical diagnosis, type of surgical repair, age at final surgery, medication, earlier findings or symptoms of arrhythmia, presence of a pacemaker, and echocardiographic findings. Ventricle morphology of the functional systemic ventricle was determined from preoperative echocardiography reports or surgical reports and was defined as dominant left ventricle (LV), dominant right ventricle (RV) or a dominant ventricle of non-defined morphology. Echocardiographic data included assessment of ventricular function and AV-valve regurgitation. Semi-quantitatively assessed ventricular function was graded on a scale from I to IV, where I was poor and IV was good. AV-valve regurgitation was graded on a scale from 0 to 3, where 0 was no, and 3 was assessed as large regurgitation. Standard 12-lead resting-ECG was obtained from patients’ medical records. Predominant rhythm was classified as sinus rhythm, supraventricular rhythm, and nodal or paced rhythm. Heartbeats were classified as normal, supraventricular extra systolic beats, or ventricular extra systolic beats. Bradycardia, tachycardia, and other arrhythmias were noted. Handheld intermittent ECG recordings The device used in the study for intermittent ECG recordings, Zenicor-ECG® (Zenicor Medical system AB, Stockholm, Sweden), consists of a small portable box. It has a display and two thumb sensors, providing for a bipolar extremity lead I (Fig. 1). The subjects were instructed to do ECG recordings for 14 days by putting their thumbs on the sensors for 30 s twice a day, once in the morning and once in the evening. The participants were told to perform extra recordings upon occurrence of symptoms such as palpitations, dizziness, nausea, presyncope/syncope, or any discomfort from the chest. They were also asked to perform at least one additional recording after exercise.

376

J.A. Dahlqvist et al. / Journal of Electrocardiology 47 (2014) 374–382

One operator inspected all ECG strips and performed the manual arrhythmia analysis using a web-based software. Heartbeats were classified as normal, supraventricular extra systolic beats, nodal beats, or ventricular extra systolic beats (VES). Bradycardia was defined as a heart rate less than the 5th percentile and tachycardia as more than 95th percentile for age. Detected symptomatic episodes were highlighted in the window showing the ECG: s. Fig. 1. A child using the hand-held ECG device.

Poincaré Plot analysis The 14 day time period was chosen since 81.2% of the total amount of detected atrial fibrillation in an adult population was detected within 14 days (and only 17.9 between 15 and 29 days [19]). In their study 10 s recordings were performed twice a day. One other reason for us to choose a two-week period, but 30 instead of 10 s was because monitoring would be more practicable, considering it concerns pediatric population. After having recorded each 30-s ECG, the subject was to push a send button to send the ECG to a database, using the built-in mobile phone. If the recording was prompted by symptoms the participant was to press an extra event button. The sampling rate was 500 Hz, and the ECG could optionally be low-pass filtered to reduce muscle interference and noise (50 Hz filtering). Moreover, the device could store up to 200 recordings in case of out of mobile network connection.

Another operator performed the Poincaré plot analysis. The two operators were blinded to each other’s results, i.e., the second operator performed the Poincaré plot analysis without knowing which patients presented with arrhythmia or had a pacemaker. The ECG data were exported from the database, and further analyzed using custom-developed software in Matlab (Mathworks Inc., Natick, MA). Since only the ECG could be exported, heartbeats were automatically detected and manually confirmed. As described above, the HRV analysis was performed based on Poincaré plots after pooling data from all 30-s episodes for each patient. Then each interbeat interval was plotted as a function of the previous interval as a scatter plot. A normal Poincaré pattern shows increasing variability with increasing RR interval and is displayed in the shape of a comet (see the right panel in Fig. 2). When the variability is low, a torpedo-shaped pattern is shown High HRV

1.8

1.8

1.6

1.6

RR−intervals(s)

RR−intervals(s)

Low HRV

1.4 1.2 1 0.8

1.4 1.2 1

0.8

0.6

0.6

0.4

0.4

0.2

0

100

200

300

400

500

600

700

800

900

0.2

0

100

200

300

Tid(s)

1.8

1.8

1.6

1.6

1.4

1.4

1.2 SD2 SD1

0.6

0.6

0.4

0.4 1

RR(n)

700

800

1.5

2

SD1

SD2

1 0.8

0.5

600

1.2

0.8

0.2

500

Poincare

RR(n+1)

RR(n+1)

Poincare

1

400

Tid(s)

0.2

0.5

1

1.5

2

RR(n)

Fig. 2. Recorded interbeat intervals from all 30-s sequences (top) and the corresponding patterns of Poincaré plots (bottom). Left: one patient with reduced HRV, torpedo shaped. Right: one patient with high HRV, comet shaped.

J.A. Dahlqvist et al. / Journal of Electrocardiology 47 (2014) 374–382

(see the left panel in Fig. 2). In the case of arrhythmia, the Poincaré plot of short HRV recordings presents more complex patterns, such as clusters of points in different regions. HRV was quantified by fitting an ellipse around the points, with SD1 as the short axis and SD2 as the long axis of the ellipse. SD1 represents the short-term (parasympathetic) and SD2 represents the long-term (sympathetic) variability. Results are presented as SD1, SD2, and the ratio SD1/SD2. The age-dependency in HRV was determined based on quadratic regression lines, based on data from controls from which z-scores were determined for patients. Reduced HRV was defined as a z-score less than − 2 and high HRV as a z-score more than + 2. Since the main focus of this study was to detect arrhythmias, the Poincaré plot analysis was first performed on the original series of interbeat intervals. Our custom-made software did not include any algorithm for automatic beat annotation, and therefore data included interbeat intervals between both normal and extrasystolic beats. Thus, the presence of arrhythmic beats results in the above-mentioned complex patterns and also relatively high scores of SD1. We also aimed to detect cardiac autonomic dysfunction. Therefore, the next step was to remove interbeat intervals that corresponded to extrasystolic beats, which otherwise precludes the assessment of autonomic function. In this study we applied a previously described algorithm for automatic removal of extrasystolic beats, where outliers in the series of interbeat intervals were detected and removed [20]. By this procedure interbeat intervals were removed if they differed more than 35% from the mean of the preceding and following value. Then, new Poincaré plot analysis and calculation of HRV scores were performed on the filtered data; this time focusing on the analysis of cardiac autonomic modulation. As an additional evaluation of the handheld ECG system, we performed simultaneous recordings of Holter ECG and handheld ECG in 10 subjects. Five patients and 5 healthy controls did a total of 41 recordings with the handheld ECG device, each one of 30-s duration. Every child contributed at least 3 recordings. HRV was quantified both in the recordings from the handheld ECG device and in the corresponding simultaneously recorded 30-s windows from the Holter monitor. The synchronization of the recordings was based on both the time when the recording was made, and by a cross-correlation analysis of the series of RR intervals from the two devices. To compare the recordings from the handheld-ECG device from the children with Fontan circulation with data from healthy children, we extracted ECG sequences from Holter recordings from 41 healthy children. To obtain data comparable to the day and night recordings made with the handheld ECG device, two segments were selected from the Holter ECG recordings: a morning reading taken between 08:00 and 10:00 and an evening reading taken between 17:00 and 19:00. From each of these periods, we randomly selected 15 non-overlapping 30-s segments. Then data from the 30 segments were pooled and SD1, SD2, and the ratio SD1/SD2 were calculated. Patients with a pacemaker, on β-blocking agents, or with very frequent

377

extra systoles were excluded from the HRV analysis comparing controls to patients. Statistical analysis SPSS software version 18.0 (SPSS, Chicago, IL) was used for statistical analysis. Continuous variables are presented as mean, range, and ± SD. Categorical variables are reported as a number or a percentage. Agreement between measures obtained from 24-ECG recordings and from the handheld ECG monitor was determined by a paired T-test. ANOVA with adjustment for age was used to compare patients to healthy controls. The level of statistical significance was defined as a p-value b 0.05.

Results Recordings were used from 27 patients, 10 girls and 17 boys, mean age 9.5 years (range 2.7–16.5) who underwent intermittent monitoring with a handheld ECG device. Age at surgery with TCPC was 2.4 ± 0.9 years (range 1.1–3.9). Postoperative follow-up time was 7.1 years (range 0.4–15.4). Thirteen patients (48 %) had a dominant LV; 12 patients (45%) had a dominant RV; and 2 patients (7 %) had a non-defined morphology of their systemic ventricle. Eight patients had hypoplastic left heart syndrome, six patients had tricuspid atresia, and four patients had pulmonary atresia with intact ventricular septum. Medications included diuretics (n = 18), acetylsalicylic acid (ASA) (n = 23), warfarin (n = 2), angiotensin converting enzyme (ACE) inhibitors (n = 11), sildenafil (n = 1), and beta-blocker (n = 2). Fifteen patients had multiple medications. Ventricular function was graded on a scale from I to IV and 18 patients (67%) showed a good ventricular function (grade IV) and 9 patients (33%) showed a grade III ventricular function. No patient had poor function. AV-regurgitation was graded on a scale from 1 to 4. Three patients (11%) had no regurgitation; 15 patients (58%) showed grade 1 regurgitation; and 8 patients (31%) showed grade 2 regurgitation. Larger regurgitations (grade 3 or 4) were not present. Data from one patient were missing. One patient (#25) had previously been diagnosed with supraventricular tachycardia and one patient (#26) with ventricular tachycardia. Two patients (#17 and #26) had implanted pacemakers: one had it because of sinus node dysfunction and the other because of beta-blocker-induced bradycardia due to treatment for frequent VES and ventricular tachycardia. Six patients had a history of symptoms that could indicate arrhythmia: five patients had experienced palpitations and 1 patient had experienced dizziness. No patient had a history of syncope. 12-lead resting-ECG The 12-lead resting-ECGs from the patients were analyzed. Twenty-two patients were in sinus rhythm; one in ectopic atrial rhythm (#13); two in nodal rhythm (#19, #25); and two in pacemaker rhythm (#17 and #26). One patient had VES (#26); no patient showed extra systoles.

378

J.A. Dahlqvist et al. / Journal of Electrocardiology 47 (2014) 374–382

Handheld intermittent ECG monitoring The 27 patients performed 22–43 (mean 27) recordings each, resulting in a total observation time of 11–22.5 (mean 13.5) min. The handheld ECG recordings were analyzed one at a time (using the Internet-based software), showing that 22 (82%) of the patients were in sinus rhythm. One patient had ectopic atrial rhythm (#13); one patient had nodal rhythm (#25); five had frequent nodal replacement beats; and two patients had intermittent pacemaker-induced rhythm (#17 and #26). In one patient who experienced palpitations, we identified a previously undiagnosed supraventricular tachycardia (#24) (Fig. 3). One patient showed frequent ventricular extra systoles in pairs and in bigeminia and was asymptomatic (#26). Thus we found one asymptomatic patient with arrhythmia in this group of patients. The analysis of the variation of heart rate during the 14-day period showed that 15 (58%) patients had sinustachycardia and 12 (46%) sinus-bradycardia at least once during the period. Comparison between intermittent handheld ECGs and Holter ECGs Five patients and five healthy volunteers performed simultaneous recordings with the handheld ECG device and a Holter monitor. Mean SD1 was 55.7 ms (SD 47.9 ms) and SD2 was 93.7 ms (SD 49.5 ms) in the recordings the Handheld device, whereas SD1 was vs. 56.1 ms (SD 48.2 ms) and SD2 was 93.7 ms (SD 48.1 ms) in the Holter recordings. No significant differences were found when comparing HRV data calculated from the two devices: mean difference was 0.32 ms (SD = 1.73 ms) for SD1, and 0.13 ms (SD 0.61 ms) for SD2 (p = 0.54 and p = 0.50, respectively). The Pearson correlation coefficient was 1.0 for both SD1 and SD2 (p b 0.001). HRV analysis Within the study-group we found different normal and abnormal Poincaré patterns. Fig. 2 shows typical Poincaré patterns found in patients with reduced HRV (torpedo pattern) and high HRV (comet pattern). Fig. 4 shows the complex patterns found in patients with pacemaker and VES and in a patient with frequent nodal beats. The different HRV parameters for all subjects are presented in Fig. 5. Quadratic regression lines were determined based on data from the healthy subjects. Four patients showed markedly reduced HRV, SD1 or SD2. Four patients had HRV parameters just above the 95% confidence

interval for controls. The children with Fontan circulation did not show any statistically significant differences in mean values of HRV parameters compared with the controls (p = 0.86 for SD1; p = 1.00 for SD2; and p = 0.54 for SD1/SD2). As shown in Fig. 5, three patients presented with marked changes in SD1 when comparing results based on the original interbeat intervals with results after removal of non-sinus beats by filtering: patient #24 had two episodes of supraventricular tachycardia and presented with low HRV even before filtration; HRV was further reduced after filtration. Patient #26, who had an implanted pacemaker, presented with frequent ventricular extra systoles and had high SD1 before filtration but normal SD1 after filtration, which confirms that the abnormally high SD1 was due to the frequent extra systoles. Patient #17, who had a pacemaker, presented with very low HRV that was further reduced after filtration. The patients discussed above all had an AV-regurgitation graded as grade 2 out of 4. Patient #17 had a good ventricular function (grade IV/IV) and patients #24 and #26 had grade III/IV ventricular function (Fig. 5). Table 1 presents a summary of data from individuals with findings of arrhythmia or markedly low/high HRV. Seven patients presented with reduced HRV in SD1, or SD2, or both: two of these patients had a pacemaker; three patients had nodal replacement beats, supraventricular tachycardia, or nodal rhythm; and the remaining two patients presented reduced HRV without any obvious explanation for this finding. High values of SD1 and SD2 were found in four individuals of whom two had frequent nodal replacement beats.

Discussion This study evaluates the applicability of using a handheld ECG device for intermittent monitoring in a pediatric Fontan population. It also presents an innovative approach to quantifying and summarizing all the obtained 30-s recordings in a single plot, with applications in detection of arrhythmia and of abnormalities in cardiac autonomic function. Furthermore, to the best of our knowledge, this is the first study using a handheld ambulatory ECG system to analyze HRV. Arrhythmia Early diagnosis of arrhythmia in the Fontan population is important because arrhythmia contributes to significant

Fig. 3. Supraventricular tachycardia detected in a handheld recording from a patient who suddenly experienced palpitations. The figure shows eight seconds of the ECG recording and the mean heart rate was 150 beats/min.

J.A. Dahlqvist et al. / Journal of Electrocardiology 47 (2014) 374–382

Episodes with nodal rhythm

1.8

1.8

1.6

1.6

RR−intervals(s)

1.4 1.2 1

0.8

1.4 1.2 1

0.8

0.6

0.6

0.4

0.4 100

RR(n+1)

0.2 0

200

300

400

500

600

700

800

900

0.2 0

100

200

Poincaré 1.8 1.6

1.4

1.4

SD1

SD2

1

0.6

0.6

0.4

0.4 1.5

2

RR(n)

700

800

SD2

1 0.8

1

SD1

600

1.2

0.8

0.5

500

Poincaré

1.6

0.2

400

Tid(s)

1.8

1.2

300

Tid(s)

RR(n+1)

RR−intervals(s)

Pacemaker

379

0.2

0.5

1

1.5

2

RR(n)

Fig. 4. Recorded interbeat intervals from all 30-s sequences (top) and the corresponding Poincaré plots with complex patterns (bottom) from one patient with pacemaker and VES (left panels) and one patient with frequent nodal beats (right panels).

risks: syncope, development of congestive heart failure, sudden death, and venous thromboembolism [4,5]. Arrhythmia in Fontan patients has also been reported to impair quality of life [21]. Lower functional status has been independently associated with the history of arrhythmia in this patient group [22]. The current standards of follow-up vary between different centers. We ourselves for example aim that each patient should perform a 24-h ECG every year. Holter monitoring is recommended by Wernovsky et al. as routine outpatient follow-up in asymptomatic and symptomatic patients with Fontan at least once every third year [5,23]. In this study of 27 Fontan patients we found one patient with a silent, asymptomatic arrhythmia (frequent VES). Based on our clinical observations, we had expected a higher occurrence. This finding could be due to improved long-term results because modifications of Fontan surgery methods have resulted in a lower frequency of arrhythmiacomplications than reported in earlier forms of Fontan surgery [2]. In addition, intermittent ECG monitoring revealed a significant arrhythmia (two episodes of supraventricular tachycardia) in one patient (#26). This patient had been complaining of palpitations for at least a year, but previous ECGs (resting 12-lead ECG and 24-h Holter monitoring) had not shown arrhythmia. Another patient had a previously diagnosed supraventricular tachycardia and was treated with β-blocking agents. Thus, the frequency of supraventricular tachycardia in this small study population of pediatric Fontan patients was 2/27 patients (7.4%). The total

frequency of arrhythmia in the group was 3/27 (11%). Our material is small, but the findings are in line with other larger studies of incidence of arrhythmia in a contemporary Fontan population [2].

Fig. 5. HRV data for intermittent handheld recordings in patients in relation to data from the healthy subjects before and after filtration. Lines indicate quadratic regression lines and 95% confidence intervals for HRV at different ages based on data from Holter ECG recordings in the healthy subjects (see text for details). Symbols indicate data from individual patients: • patients with sinus rhythm; + patients with arrhythmias; o pacemaker patients. The upper end of the lines shows the value before filtration and the symbol the value after filtration.

380

J.A. Dahlqvist et al. / Journal of Electrocardiology 47 (2014) 374–382

Table 1 HRV for patients with findings of arrhythmia, and for those with very low/ high HRV. Data are presented as z-scores of the parameters SD1 and SD2 before and after filtering, where values outside of the 95% confidence intervals for controls are marked with grey color (z N 2, or z b −2, respectively).

HRV HRV is normally used to study the autonomic nervous function of the sinus node, but HRV also mirrors the heart rate fluctuations caused by cardiac arrhythmia. Known risk factors for arrhythmia in Fontan patients include older age at surgery, duration of follow-up and worse NYHA class symptoms. In addition, autonomic nervous control may play an important role in the development of arrhythmias. The analytical tool used in this study – Poincaré diagrams – can be helpful in revealing autonomic dysfunction as well as subtle arrhythmias [10]. The arrhythmia analysis was based on the assessment of HRV with the original series of interbeat intervals (unfiltered data), and the changes in HRV after filtration. The Poincaré plot of the pooled data is very helpful to reveal arrhythmia if present in any of the 30 s registrations, since the presence of arrhythmia will generate complex patterns in the Poincaré plots (Fig. 4). High values of HRV (z-score N 2), and also a marked reduction after filtration, should always be interpreted carefully since this might reflect arrhythmia, e.g., correspond to frequent extra systoles. In particular SD2 is expected to become high if there are frequent nodal

replacement beats, which could be seen in one subject (#14). Five patients showed high HRV before filtration of data. One patient with high SD1 showed frequent extra systoles; after filtration the SD1 was normal. Another two of the patients with high HRV scores showed nodal replacement beats on the ECG, after the filtration the HRV remained high. This could reflect an early sign of sinus node dysfunction, a common complication after Fontan surgery [24]. The assessment of cardiac autonomic dysfunction is mainly based on the analysis of HRV using the filtered series of interbeat intervals, which requires arrhythmia-free data. Low HRV corresponds to reduced autonomic function. A pitfall with HRV analyses based on short recordings is that findings of low HRV could result from nodal rhythm, in the presence of a pacemaker, or because of temporary tachycardia with short R-R intervals, which also results in low HRV. Thus, low HRV does not necessarily represent any pathology— it could simply be due to exercise shortly before the monitoring or to anxiety or distress during the recording. However, if this pattern of low HRV is repeated in the majority of the recordings, this could warrant a further investigation by, for example, Holter-ECG monitoring, which could verify whether the low HRV was due to autonomic dysfunction. Low HRV (z-score b − 2) was seen in seven patients. As expected, the two patients with pacemakers had reduced HRV because of the low variability in the pacemaker-induced rhythm. Two patients had episodes of nodal rhythm. The patient with supraventricular tachycardia (#24) showed low HRV, which is partly due to the high heart rate during the tachycardia. But since the patient showed a reduced HRV after filtration and when all recordings were pooled, the findings could indicate a reduced autonomic function. At the time of the study, this patient had echocardiographic findings of grade 2 out of 4 AV-valve regurgitation and a grade III out of IV ventricular function. After one year of follow-up, this patient went into severe heart failure and was listed for a heart transplant. This may indicate that individuals with reduced HRV, even with milder echocardiographic findings, could benefit from careful follow-up. Another two patients had low HRV but there was no obvious explanation of the findings. In these cases longer recordings would have been helpful for revealing whether this low HRV was related to autonomous dysfunction or to other factors. While HRV is usually studied from 5 min up to 24 h recordings, the length of each recording taken with a handheld ECG device is only 30 s. A previous report shows that the mean from two or three 10-s recordings correlates well with 5-min recordings, regarding HRV findings [17]. The novel approach undertaken in this study was to collect several intermittent recordings and pool them. Although longer recordings are preferred for assessment of autonomic function based on analysis of HRV, short intermittent recordings done with handheld ECG devices could be used as a convenient method for detection of cardiac autonomic dysfunction. A marked beat-to-beat variability with a comet-shaped pattern of the heartbeats in a recording suggests preserved cardiac autonomous nervous function (Fig. 2), whereas absence of variability indicates

J.A. Dahlqvist et al. / Journal of Electrocardiology 47 (2014) 374–382

381

potential loss of cardiac autonomous nervous function and points to the need for longer recordings and more detailed HRV analyses.

reasons. Another limitation is that this device only takes ECG recordings through one lead, lead I, analysis of p-wave morphology is challenging.

ECG monitoring

Conclusions

In clinical practice, arrhythmia is usually diagnosed with either resting 12-lead ECG or ambulatory 24-h Holter ECG monitoring. Another option is intermittent patient- or eventactivated trans-telephonic monitors. It has been shown, in children, that trans-telephonic event recordings showed a statistically significantly better correlation of sensed symptoms with arrhythmias compared to Holter recordings [25]. Doliwa et al. compared intermittent 10 s recordings taken using a handheld, patient-activated ECG recording device during a 30-day period, to 24-h ambulatory continuous ECG recording taken during a single 24-h period, in patients with paroxysmal atrial fibrillation. They showed that hand-held ECG had a better diagnostic yield than 24-h ECG [9]. Since a device handheld ECG recorder is minimally intrusive, it offers a more convenient alternative to a Holter monitor, which is especially important in the pediatric population. In clinical practice, children from time to time object to Holter recording, but in this study the handheld monitoring seemed to be feasible and easy to handle. The feasibility of intermittent handheld monitoring is also supported by the fact that the children accepted to use this device during the complete study period, whereas many of them probably would have refused to wear a Holter during two weeks. Moreover, if symptoms are infrequent, conventional 24-h Holter ECGs can be inadequate when analyzing the ECGs of patients complaining of palpitations. Another limitation of the Holter system is frequent non-compliance of the patients [26]. In a large study of patients with palpitations and altered consciousness, the diagnostic utility of Holter monitoring was considered very limited, particularly in young patients [8]. In a study of a pediatric population of 30 patients with palpitations, where 24-h Holter monitoring showed no arrhythmia, a cardiac event device provided a diagnosis in all cases [7]. There are also disadvantages to using handheld ECG monitors and other types of post-event recorders: for example, if the device started recording because of symptoms, it would not have recorded the initiation of the arrhythmia, which might have provided a clue to the arrhythmic mechanism. Another disadvantage is that it does not record short arrhythmias that terminate before the thumbs are put on the device. In our study, which focused on the detection of silent arrhythmia and on HRV analysis, these disadvantages were not significant.

As we hypothesized, asymptomatic arrhythmia occurred during two weeks of intermittent ECG monitoring in patients with Fontan circulation, although we recorded fewer events than we expected. We also found reduced HRV in several subjects. Poincaré plot of pooled recordings is a useful tool in visualizing the abnormalities in heart rhythm. Thus, we conclude that intermittent handheld ECG recording can be a useful method for detection of arrhythmia as well as of cardiac autonomic dysfunction.

Limitations This is a small study of 27 patients. The prevalence of arrhythmia could be under- or overestimated. Our study design consisted of a two-week-long follow-up period where ECG registrations were performed intermittently, and since we did not perform a 14-day continuous ECG registration, there could be an underestimation of arrhythmia. The choice of a 14-day registration period was made because of practical

References [1] Fontan F, Baudet E. Surgical repair of tricuspid atresia. Thorax 1971;26:240–8. [2] Blaufox AD, Sleeper LA, Bradley DJ, et al. Functional status, heart rate, and rhythm abnormalities in 521 Fontan patients 6 to 18 years of age. J Thorac Cardiovasc Surg 2008;136:100–7. [3] Giannico S, Hammad F, Amodeo A, et al. Clinical outcome of 193 extracardiac Fontan patients: the first 15 years. J Am Coll Cardiol 2006;47:2065–73. [4] Deal BJ, Mavroudis C, Backer CL. Arrhythmia management in the Fontan patient. Pediatr Cardiol 2007;28:448–56. [5] Feinstein JA, Benson DW, Dubin AM, et al. Hypoplastic left heart syndrome: current considerations and expectations. J Am Coll Cardiol 2012;59:1–42. [6] Czosek RJ, Anderson J, Khoury PR, et al. Utility of ambulatory monitoring in patients with congenital heart disease. Am J Cardiol 2013;111:723–30. [7] Park MH, de Asmundis C, Chierchia GB, et al. First experience of monitoring with cardiac event recorder electrocardiography Omron system in childhood population for sporadic, potentially arrhythmiarelated symptoms. Europace 2011;13:1335–9. [8] Sulfi S, Balami D, Sekhri N, et al. Limited clinical utility of Holter monitoring in patients with palpitations or altered consciousness: analysis of 8973 recordings in 7394 patients. Ann Noninvasive Electrocardiol 2008;13:39–43. [9] Doliwa PS, Rosenqvist M, Frykman V. Paroxysmal atrial fibrillation with silent episodes: intermittent versus continuous monitoring. Scand Cardiovasc J 2012;46:144–8. [10] Wiklund U, Hornsten R, Karlsson M, et al. Abnormal heart rate variability and subtle atrial arrhythmia in patients with familial amyloidotic polyneuropathy. Ann Noninvasive Electrocardiol 2008;13:249–56. [11] Woo MA, Stevenson WG, Moser DK, et al. Patterns of beat-to-beat heart rate variability in advanced heart failure. Am Heart J 1992;123:704–10. [12] Huikuri HV, Perkiomaki JS, Maestri R, Pinna GD. Clinical impact of evaluation of cardiovascular control by novel methods of heart rate dynamics. Philos Trans A Math Phys Eng Sci 2009;367:1223–38. [13] Lammers A, Kaemmerer H, Hollweck R, et al. Impaired cardiac autonomic nervous activity predicts sudden cardiac death in patients with operated and unoperated congenital cardiac disease. J Thorac Cardiovasc Surg 2006;132:647–55. [14] Davos CH, Francis DP, Leenarts MF, et al. Global impairment of cardiac autonomic nervous activity late after the Fontan operation. Circulation 2003;108(Suppl 1):180–1855. [15] Dahlqvist JA, Karlsson M, Wiklund U, et al. Heart rate variability in children with Fontan circulation: lateral tunnel and extracardiac conduit. Pediatr Cardiol 2012;33:307–15. [16] Rydberg A, Karlsson M, Hornsten R, Wiklund U. Can analysis of heart rate variability predict arrhythmia in children with Fontan circulation? Pediatr Cardiol 2008;29:50–5. [17] Schroeder EB, Whitsel EA, Evans GW, et al. Repeatability of heart rate variability measures. J Electrocardiol 2004;37:163–72.

382

J.A. Dahlqvist et al. / Journal of Electrocardiology 47 (2014) 374–382

[18] Nussinovitch U, Elishkevitz KP, Katz K, et al. Reliability of ultra-short ECG indices for heart rate variability. Ann Noninvasive Electrocardiol 2011;16:117–22. [19] Hendrikx T, Hornsten R, Rosenqvist M, Sandstrom H. Screening for atrial fibrillation with baseline and intermittent ECG recording in an out-of-hospital population. BMC Cardiovasc Disord 2013;13:41. [20] Karlsson M, Hornsten R, Rydberg A, Wiklund U. Automatic filtering of outliers in RR intervals before analysis of heart rate variability in Holter recordings: a comparison with carefully edited data. Biomed Eng Online 2012;11:2. [21] van den Bosch AE, Roos-Hesselink JW, Van Domburg R, et al. Longterm outcome and quality of life in adult patients after the Fontan operation. Am J Cardiol 2004;93:1141–5.

[22] Longmuir PE, Russell JL, Corey M, et al. Factors associated with the physical activity level of children who have the Fontan procedure. Am Heart J 2011;161:411–7. [23] Wernovsky G, Rome JJ, Tabbutt S, et al. Guidelines for the outpatient management of complex congenital heart disease. Congenit Heart Dis 2006;1:10–26. [24] Cohen MI, Wernovsky G, Vetter VL, et al. Sinus node function after a systematically staged Fontan procedure. Circulation 1998;98:352–8. [25] Karpawich PP, Cavitt DL, Sugalski JS. Ambulatory arrhythmia screening in symptomatic children and young adults: comparative effectiveness of Holter and telephone event recordings. Pediatr Cardiol 1993;14:147–50. [26] Zimetbaum P, Goldman A. Ambulatory arrhythmia monitoring: choosing the right device. Circulation 2010;122:1629–36.