Using QRS loop descriptors to characterize the risk of sudden cardiac death in patients with structurally normal hearts.

The predictive value of non-invasive electrocardiographic examination findings for the risk of sudden cardiac death (SCD) in populations with structurally normal hearts remains unclear. This study aimed to investigate the characteristics of the QRS vectorcardiography of surface electrocardiography in patients with structurally normal hearts who experienced SCD. We consecutively enrolled patients who underwent vectorcardiography between March 2017 and December 2018 in a tertiary referral medical center. These patients didn't have structural heart diseases, histories of congestive heart failure, or reduced ejection fraction, and they were classified into SCD (with aborted SCD history and cerebral performance category score of 1) and control groups (with an intervention for atrioventricular node reentrant tachycardia and without SCD history). A total of 162 patients (mean age, 54.3±18.1 years; men, 75.9%), including 59 in the SCD group and 103 in the control group, underwent propensity analysis. The baseline demographic variables, underlying diseases, QRS loop descriptors (the percentage of the loop area, loop dispersion, and inter-lead QRS dispersion), and other electrocardiographic parameters were compared between the two groups. In the univariate and multivariate analyses, a smaller percentage of the loop area (odds ratio, 0.0003; 95% confidence interval, 0.00-0.02; p<0.001), more significant V4-5 dispersion (odds ratio, 1.04; 95% confidence interval, 1.02-1.07; p = 0.002), and longer QRS duration (odds ratio, 1.05; 95% confidence interval, 1.00-1.10; p = 0.04) were associated with SCD. In conclusion, the QRS loop descriptors of surface electrocardiography could be used as non-invasive markers to identify patients experiencing aborted SCD from a healthy population. A decreased percentage of loop area and elevated V4-5 QRS dispersion values assessed using vectorcardiography were associated with an increased risk of SCD in patients with structurally normal hearts.

1. Introduction

Sudden cardiac death (SCD) is a significant public health problem worldwide, accounting for approximately 12–20% of all deaths annually [1-3]. To avoid such tragedy, it is important to identify high-risk patients vulnerable to cardiac arrest. However, developing a good tool is exceptionally challenging because detailed information on these patients is usually limited [4]. Surveillance of these survivors might be another method to help gradually characterize high-risk patients. Echocardiography and electrocardiography (ECG) have been widely validated as classifiers for certain populations to detect low ejection fraction and structural abnormalities in high-risk patients. In a healthy population without structural heart disease screened by echocardiography or ECG, some anomalies might exist but are difficult to identify, especially electrical abnormalities susceptible to malignant arrhythmias. Although ventricular arrhythmias (VAs) were not frequently detected, a previous study has proposed that the majority of SCDs could probably result from malignant arrhythmias [5]. VAs and non-VAs were considered to be in the same pathophysiology cascade but occur at different time points. Malignant arrhythmias probably have already degenerated to asystole, or sinus rhythm has already been restored when there is no detectable VA in aborted SCD. Thus, identifying the abnormal substrates of the ventricle to define high-risk groups has become an important issue because these subtle discontinuities may induce VA leading to SCD [6].

Although surface ECG is commonly used to evaluate the repolarization derangement of the QRS complex during the cardiac cycle, subtle QRS changes may not be detected by visual inspection, particularly in patients with structurally normal hearts. With the aid of a vectorcardiogram derived from ECG, a tiny repolarization abnormality could be identified.

We hypothesized that the vectorcardiogram of the QRS complex of surface ECG could be used to characterize the risk of SCD in patients with structurally normal hearts.

2. Materials and methods

2.1. Study population

This retrospective study was performed in a tertiary referral medical center and was approved by the Institutional Review Board of Taipei Veterans General Hospital (IRB 2019-01-002C). All patients were aged 18 years or older. Oral and written informed consents were obtained from all participating adults or from the parents or legal guardians for incapacitated adults. The records and personal information of the patients were anonymized and de-identified before analysis. Reporting of the study conforms to the Strengthening the Reporting of Observational Studies in Epidemiology statement and the broader Enhancing the Quality and Transparency of Health Research guidelines [7].

This study consecutively enrolled patients who had histories of aborted SCD or palpitation that is due to atrioventricular node reentrant tachycardia (AVNRT) in our clinics and underwent vectorcardiography between March 2017 and December 2018. These patients didn’t have structural heart diseases (e.g., dyskinesia or hypertrophy of left ventricles), histories of congestive heart failure, or reduced ejection fraction (<50%) [8, 9], and the attribution to non-cardiac causes wasn’t favored in patients with a history of aborted SCD. A total of 315 patients were investigated. Patients who had a history of aborted SCD were classified into the case group; these patients had a cerebral performance category score of 1 at baseline. Conversely, patients with no history of SCD were classified into control group. SCD was defined as death from cardiac arrest occurring within 1 hour from symptom onset [10]. A shockable rhythm was presented as the initial rhythm or during resuscitation. Propensity score matching was performed to minimize the confounders. The cases and controls were matched at a 1:2 ratio using a 0.10 caliper for identical characteristics of age, sex, and histories of hypertension and coronary artery disease. Fifty-nine patients with a history of aborted SCD and one hundred three controls were included in the analysis (Fig 1).

Fig 1

Flow diagram demonstrating the number of patients enrolled.

During the study period, 315 patients were enrolled. The patients were then separated into two groups: with and without a history of aborted sudden cardiac death (SCD). Propensity analysis was performed to minimize the confounders, and the cases and controls were matched at a 1:2 ratio using a 0.10 caliper for identical characteristics of age, sex, and histories of hypertension and coronary artery disease. Ultimately, there were 59 patients with a history of aborted SCD and 103 control patients without a history of aborted SCD. (Abbreviations: Hx, history; LV, left ventricular; SCD, sudden cardiac death).

2.2. Morphological complexity of the 12-Lead QRS wave

The 12-Lead ECG was taken at a stable stage using LabSystem™ PRO (Boston Scientific, Boston, MA, USA) with a 1-min duration for QRS descriptor analysis. The QRS descriptors, including the percentage of the loop area (PL), loop dispersion (LD), and inter-lead QRS dispersion (IQRSD) are measured using the ECG vector in the constructed space spanned by the eigenvector of 12 lead ECG matrix. All collected variables, including disease history, risk factors, and comorbidities, were obtained from primary or secondary hospital discharge diagnoses and outpatient visits, and the information was confirmed via telephone interviews. Targeted co-morbidities, including hyperlipidemia, CKD, old CVA, prior CAD, were determined by using the International Classification of Diseases (ICD) 9 codes from the medical record at the time of examination. In addition to the index aborted SCD event, the number of other major arrhythmic events was also recorded, including sustained ventricular tachycardia, ventricular fibrillation, appropriate implantable cardioverter-defibrillator shocks, aborted cardiac arrest, and SCD. The ECG and echocardiographic parameters, including the heart rate, PR interval, QRS duration, corrected QT(QTc) interval, and left ventricular ejection fraction (LVEF), were also compared between the two groups.

2.3. ECG decomposition via principal component analysis (PCA)

The energy of the QRS complex was analyzed. An ECG matrix, X8xN, was used, and each row corresponded to standard ECG leads (I, II, V1, V2, V3, V4, V5, and V6). N represented the number of cases for each lead. Only 8 of the 12 leads were used because of algebraic interdependency to reconstruct an orthogonal-8-lead system via PCA in the signal space [11]. Nighty-nine percent of the ECG energy was calculated in the first three PCAs [12], and the vectors associated with the first three PCAs were incorporated to investigate and describe the spatiotemporal variations of the energy in the QRS complex. This method has been described in detail elsewhere [13].

2.4. QRS loop descriptors

The QRS loop in a two-dimensional plane was constructed by sampling the QRS complex of the first principal component as the x-coordinate and the corresponding data of the second principal component as the y-coordinate [12-14]. The minimum rectangle was created and accommodate the planar loop, and the rectangle was divided equally into N (N = 4900 in this study). PL was defined as the percentage of cells within the QRS loop, indicating the regularity of the loop. LD was defined as the total number of cells that were passed through by the loop [13, 14]. IQRSD was based on the angular difference between the reconstructed adjacent vectors obtained from QRS loop decomposition via PCA [12, 14], and it represented the dissimilarity of the shape between the QRS complexes of two ECG leads [13] (Fig 2, lower part), which could not be detected by visual inspection on surface ECG (Fig 2, upper part). IQRSDs and other parameters were compared between the two groups.

Fig 2

Representative examples showing the 12-lead surface electrocardiogram (ECG) and the reconstruction vectors.

The difference is subtle by visual inspection on surface ECG (upper part); however, a substantial difference is observed on the basis of the QRS descriptors (lower part). These examples show a lower PL in the patients with a history of aborted sudden cardiac death than in the controls. (Abbreviations: PL, percentage of the loop area).

2.5. Diagnosis of SCD

All patients with a history of aborted SCD were diagnosed in accordance with the diagnostic criteria. Arrhythmogenic right ventricular cardiomyopathy (ARVC) was diagnosed in accordance with the 2010 modified Task-Force criteria [15]. Brugada syndrome was diagnosed on the basis of documented spontaneous or flecainide-induced ECG changes [16, 17]. Long QT syndrome was diagnosed on the basis of the proposed diagnostic score [18]. An idiopathic etiology was considered when these abovementioned diseases were not identified.

2.6. Statistical analysis

All analyses were performed using the SPSS software (version 24.0, SPSS, Inc., Chicago, IL, USA) and R (version 3.6.3). The baseline characteristics of the patients were reported as means ± standard deviations for continuous variables and as percentages for categorical variables. The Chi-square test was performed to compare the categorical variables between the groups. The independent t-test was used to compare the continuous variables between the two groups, while the one-way ANOVA was used to compare the values between the three groups. Multivariate analysis was performed for variables with a p-value of <0.1 in the univariate analysis. Receiver operating characteristic (ROC) curve analysis was used to assess the values of the continuous variables for risk stratification, and optimal cutoff values were calculated sequentially according to the specificity and sensitivity. Statistical significance was set at p-value of <0.05.

3. Results

3.1. Baseline characteristics

The baseline characteristics of the patients in the SCD and control groups are shown in Table 1. A total of 315 patients (mean age, 51.9±17.4 years; men, 49.8%) were analyzed, of whom 72 were classified into the SCD group and 243 into the control group. The proportion of men was higher in the SCD group than in the control group (76.4% vs. 42.0%, p<0.01), and the SCD group was more likely to have hypertension (41.7% vs. 16.9%, p<0.01) and coronary artery disease (27.8% vs. 4.9%, p<0.01) than the control group. No statistically significant differences were observed in the other variables between them, including the prevalence of old cerebrovascular accident (1.4% vs. 2.5%, p = 0.59), diabetes mellitus (12.5% vs. 7.4%, p = 0.18), chronic kidney disease (5.6% vs. 2.1%, p = 0.18), hyperlipidemia (12.5% vs. 8.6%, p = 0.33), chronic obstructive pulmonary disease (4.2% vs. 2.1%, p = 0.32), malignancy (2.8% vs. 8.2%, p = 0.11), and smoking rate (1.4% vs. 1.6%, p = 0.88). Meanwhile, the two groups had a similar LVEF (55.2±4.6% vs. 57.8±4.4%, p = 0.52).

Table 1

Baseline characteristics of the patients with SCD or without SCD history.

	Total (N = 315)	Control group (N = 243)	SCD group (N = 72)	p valuea
Age-yr	51.9 ± 17.4	51.0 ± 17.4	55.6 ± 16.9	0.06
Male- No. (%)	157(49.8)	102(42.0)	55(76.4)	<0.01
Hypertension- No. (%)	71(22.5)	41(16.9)	30(41.7)	<0.01
Old CVA- No. (%)	7(2.2)	6(2.5)	1(1.4)	0.59
Diabetes mellitus- No. (%)	27(8.6)	18(7.4)	9(12.5)	0.18
Chronic kidney disease- No. (%)	9(2.9)	5(2.1)	4(5.6)	0.12
Hyperlipidemia- No. (%)	30(9.5)	21(8.6)	9(12.5)	0.33
COPD- No. (%)	8(2.5)	5(2.1)	3(4.2)	0.32
Coronary artery disease- No. (%)	32(10.2)	12(4.9)	20(27.8)	<0.01
Malignancy- No. (%)	22(7.0)	20(8.2)	2(2.8)	0.11
Smoking- No. (%)	5(1.6)	4(1.6)	1(1.4)	0.88
Echocardiogram
LVEF-%	57.8 ± 4.4	57.8 ± 4.4	55.2 ± 4.6	0.52
ECG parameters
Heart rate- beats/min	73.9 ± 12.6	74.3 ± 11.4	72.3 ± 16.2	0.34
PR interval- ms	154.8 ± 22.2	151.2 ± 20.8	171.1 ± 21.4	<0.01
QRS duration- ms	90.0 ± 10.0	88.9 ± 9.5	96.2 ± 10.3	<0.01
QTc- ms	438.4 ± 30.7	433.6 ± 23.1	455.7 ± 45.5	<0.01
Vectorcardiographic parameters
V1-2 dispersion- °	49.4 ± 23.7	49.3 ± 24.7	49.7 ± 20.5	0.89
V2-3 dispersion- °	54.5 ± 20.0	55.8 ± 20.0	50.6 ± 19.6	0.06
V3-4 dispersion- °	41.1 ± 17.4	39.9 ± 17.1	45.0 ± 17.8	0.03
V4-5 dispersion- °	30.2 ± 16.8	25.9 ± 13.2	43.4 ± 19.7	<0.01
V5-6 dispersion- °	25.9 ± 15.0	24.9 ± 14.1	28.9 ± 17.2	0.05
V6-I dispersion- °	67.7 ± 16.8	67.6 ± 17.7	67.9 ± 13.8	0.90
Loop dispersion- N	297.6 ± 20.4	296.6 ± 17.7	300.8 ± 27.0	0.22
Percentage of loop area- %	63.1 ± 11.3	65.5 ± 9.1	55.7 ± 14.1	<0.01

COPD, chronic obstructive pulmonary disease. CVA, cerebrovascular accident. ECG, electrocardiography. LVEF, left ventricular ejection fraction. QTc, corrected QT interval. SCD, sudden cardia death.

aP values were between SCD and control groups.

Surface ECG showed that the SCD group had a prolonged PR interval (171.1±21.4 ms vs. 151.2±20.8 ms, p<0.01), QRS duration (96.2±10.3 ms vs. 88.9±9.5 ms, p<0.01), and QTc interval (455.7±45.5 ms vs. 433.6±23.1 ms, p<0.01) compared with the control group. The heart rate was similar between the two groups (72.3±16.2 beats per min vs. 74.3±11.4 beats per min, p = 0.34).

Vectorcardiography showed that the SCD group had a lower PL (55.7±14.1% vs. 65.5±9.1%, p<0.01) but a similar LD (300.8±27.0 vs. 296.6±17.7, p = 0.22) compared to the control group. Further evaluation of IQRSD revealed that the SCD group had higher V4-5 dispersion (43.4±19.7° vs. 25.9±13.2°, p<0.01) and V3-4 dispersion values (45.0±17.8° vs. 39.9±17.1°, p = 0.03) than the control group. The other parameters of IQRSD showed no significant difference, including V1-2 dispersion (49.7±20.5° vs. 49.3±24.7°, p = 0.89), V2-3 dispersion (40.6±19.6° vs. 55.8±20.0°, p = 0.06), V5-6 dispersion (28.9±17.2° vs. 24.9±14.1°, p = 0.05), and V6-I dispersion (67.9±13.8° vs. 67.6±17.7°, p = 0.90) between the two groups.

3.2. Propensity score matching analysis

A total of 162 patients (mean age, 54.3±18.1 years; men, 75.9%) were enrolled in the 1:2 propensity score-matched cohort (Table 2). The baseline demographic characteristics, including age (53.7±18.5 years vs. 55.3±17.5 years, p = 0.59) and sex (men: 75.7% vs. 76.3%, p = 0.94), were similar between the two groups. The incidence of underlying diseases, including hypertension (32.0% vs. 39.0%, p = 0.37), old cerebrovascular accident (3.9% vs. 1.7%, p = 0.44), diabetes mellitus (13.6% vs. 6.8%, p = 0.18), chronic kidney disease (4.9% vs. 3.4%, p = 0.66), hyperlipidemia (12.6% vs. 11.9%, p = 0.89), chronic obstructive pulmonary disease (1.0% vs. 3.4%, p = 0.27), and coronary artery disease (10.7% vs. 18.6%, p = 0.15) showed no difference between them. VA was the initial presentation in 42.4% of the patients in the SCD group. The final diagnosis was Brugada syndrome in 8 patients, ARVC in 6 patients, long QT syndrome in 3 patients, and idiopathic etiology in 41 patients.

Table 2

Baseline characteristics of the propensity matched patients.

	Total (N = 162)	Control group (N = 103)	SCD group (N = 59)	p valuea
Age-yr	54.3 ± 18.1	53.7 ± 18.5	55.3 ± 17.5	0.59
Male- No. (%)	123(75.9)	78(75.7)	45(76.3)	0.94
Hypertension- No. (%)	56(34.6)	33(32.0)	23(39.0)	0.37
Old CVA- No. (%)	5(3.1)	4(3.9)	1(1.7)	0.44
Diabetes mellitus- No. (%)	18(11.1)	14(13.6)	4(6.8)	0.18
Chronic kidney disease- No. (%)	7(4.3)	5(4.9)	2(3.4)	0.66
Hyperlipidemia- No. (%)	20(12.3)	13(12.6)	7(11.9)	0.89
COPD- No. (%)	3(1.9)	1(1.0)	2(3.4)	0.27
Coronary artery disease- No. (%)	22(13.6)	11(10.7)	11(18.6)	0.15
Malignancy- No. (%)	9(5.6)	8(7.8)	1(1.7)	0.10
Smoking- No. (%)	3(1.9)	2(1.9)	1(1.7)	0.91
Echocardiogram
LVEF-%	58.0 ± 4.4	58.0 ± 4.3	58.0 ± 4.8	1.00
IVS- mm	8.3 ± 1.0	8.2 ± 1.0	8.4 ± 1.0	0.44
LVIDED- mm	48.2 ± 4.4	48.3 ± 4.4	48.2 ± 4.5	0.94
ECG parameters
Heart rate- beats/min	73.6 ± 13.5	74.5 ± 11.7	72.0 ± 16.2	0.30
PR interval- ms	162.0 ± 20.9	158.9 ± 19.4	169.1 ± 22.7	0.01
QRS duration- ms	91.3 ± 10.3	89.8 ± 9.9	95.7 ± 10.3	<0.01
QTc- ms	440.2 ± 35.9	431.6 ± 22.3	456.0 ± 6.5	<0.01
LVH- No.(%)	0	0	0	-
BBB- No.(%)	0	0	0	-
Pathological Q wave- No.(%)	0	0	0	-
TWI ≥ V2- No.(%)	4	2(1.9)	2(3.4)	0.46
Vectocardiographic parameters
V1-2 dispersion- °	49.0 ± 23.1	49.1 ± 24.8	48.7 ± 20.3	0.91
V2-3 dispersion- °	52.0 ± 19.7	52.04 ± 19.9	52.0 ± 19.5	0.99
V3-4 dispersion- °	43.5 ± 17.4	42.9 ± 17.0	44.5 ± 18.3	0.59
V4-5 dispersion- °	34.8 ± 17.6	28.9 ± 12.8	44.0 ± 20.2	<0.01
V5-6 dispersion- °	27.5 ± 16.1	26.6 ± 14.6	28.8 ± 18.3	0.42
V6-I dispersion- °	64.9 ± 18.2	63.7 ± 20.4	66.9 ± 13.9	0.28
Loop dispersion- N	297.8 ± 20.0	295.4 ± 12.2	301.6 ± 28.0	0.11
Percentage of loop area- %	62.0 ± 12.2	66.0 ± 8.8	55.0 ± 14.0	<0.01

BBB, bundle branch block. COPD, chronic obstructive pulmonary disease. CVA, cerebrovascular accident. ECG, electrocardiography. IVS, interventricular septum. LVIDED, left ventricular inner dimension at end diastole. LVEF, left ventricular ejection fraction. LVH, left ventricular hypertrophy by Sokolow–Lyon index >35 mm. QTc, corrected QT interval. SCD, sudden cardia death. TWI ≥ V2, T wave inversion beyond V1.

ap values were between SCD and control groups.

The SCD group had a prolonged PR interval (169.1±22.7 ms vs. 158.9±19.4 ms, p = 0.01), QRS duration (95.7±10.3 ms vs. 89.8±9.9 ms, p<0.01, Fig 3), and QTc interval (456.0±6.5 ms vs. 431.6±22.3 ms, p<0.01) compared with the control group. The heart rate (74.5±11.7 beats per min vs. 72.0±16.2 beats per min, p = 0.30) and LVEF (58.0±4.3% vs. 58.0±4.8%, p = 1.00) were similar between the two groups.

Fig 3

Comparison of the box plots derived from three variables in the two groups.

The sudden cardiac death (SCD) group had a significantly greater V4-5 dispersion (p<0.01, panel A), smaller percentage of the loop area (p<0.01, panel B), and longer QRS duration (p<0.01, panel C) than the control group. Boxes in the box plots start in the first quartile, end in the third quartile, and represent 50% of the central data. A line inside represents the median values. In these box plots, black dots present the distribution of the data, and empty dots exhibit the location of the outliers and line centrally. A data dot is said to be an outlier if it is greater than the third quartile of data plus 1.5 times the interquartile range (high outlier) or less than the first quartile of data minus 1.5 times the interquartile range (lower outlier). Therefore, upper lines represent the maximum value in the dataset without high outliers, and lower lines represent the minimum value in the dataset without lower outliers. (Abbreviations: SCD, sudden cardia death).

The PL was lower in the SCD group than in the control group (55.0±14.0% vs. 66.0±8.8%, p<0.01, Fig 3), while the LD was similar between the two groups (295.4±12.2 vs. 301.6±28.0, p = 0.11). IQRSD evaluation showed that the V4-5 dispersion value was higher in the SCD group than in the control group (44.0±20.2° vs. 28.9±12.8°, p<0.01, Fig 3). The other parameters of IQRSD, including V1-2 dispersion (49.1±24.8° vs. 48.7±20.3°, p = 0.91), V2-3 dispersion (52.04±19.9° vs. 42.0±19.5°, p = 0.99), V3-4 dispersion (42.9±17.0° vs. 44.5±18.3°, p = 0.59), V5-6 dispersion (26.6±14.6° vs. 28.8±18.3°, p = 0.42), and V6-I dispersion (63.7±20.4° vs. 66.9±13.9°, p = 0.28), were similar between the two groups.

Based on the findings shown in Fig 3A, there was no subject in the control group with a V4-5 dispersion value of >60°. To shed some light on the features of patients at risk for SCD, we demonstrated the baseline characteristics and ECG and echocardiographic findings of the patients with V4-5 dispersion values of >60° in S1 Table. We noticed that most of these patients were men (73.3%), and the mean age was 51 years. Histories of hypertension and coronary artery disease accounted for 33.3% of all cases. Regarding the etiologies of SCD, all the patients with a history of aborted SCD have received routine coronary angiography, and none of them have acute coronary syndrome. One case was Brugada syndrome (6.7%); one was ARVC (6.7%); and 13 were idiopathic (86.7%). In addition, there were no significant abnormalities in the ECG and echocardiographic parameters.

3.3. Multivariate analysis

The odds ratios (ORs) for SCD derived from the multivariate analysis are shown in Table 3. In model 1, the patients with a longer QRS duration (OR, 1.05; 95% confidence interval (CI), 1.00–1.10; p = 0.04) had a higher risk for SCD. In model 2, the patients with a smaller PL (OR, 0.0003; 95% CI, 0.00–0.02; p<0.01) and larger V4-5 dispersion (OR, 1.04; 95% CI, 1.02–1.07; p<0.01) had a higher risk for SCD. Moreover, we used ROC curve analysis to assess the values of the PL, V4-5 dispersion, and QRS duration for predicting SCD or non-SCD (S1 Fig), and the summary is shown in S2 Table. For predicting SCD, the area under the curve (AUC) for the V4-5 dispersion value was 0.73 (95% CI, 0.64–0.82, S1A Fig) with an optimal cut-off value of 37.7° (specificity, 75.3%; sensitivity, 67.8%; positive predictive value (PPV), 62.5%; negative predictive value (NPV), 78.4%); that for the QRS duration was 0.65 (95% CI, 0.55–0.76, S1B Fig), with an optimal cut-off value of 89.0 ms (specificity, 49.5%; sensitivity, 77.1%; PPV, 34.6%; NPV, 86.0%). For predicting non-SCD, the AUC for the PL was 0.76 (95% CI, 0.68–0.84, S1C Fig), with an optimal cut-off value of 62.6% (specificity, 67.8%; sensitivity, 81.7%; PPV, 80.0%; NPV, 70.2%).

Table 3

OR for aborted SCD history in univariate and multivariate logistic regression.

Model 1 *	Univariate logistic regression			Multivariate logistic regression
	OR	95% CI	p	OR	95% CI	p
PR interval	1.03	1.01–1.05	0.01	1.01	0.99–1.04	0.25
QTc	1.02	1.01–1.03	<0.01	1.01	0.99–1.03	0.24
QRSd	1.06	1.02–1.11	<0.01	1.05	1.00–1.10	0.04
Model 2 **	Univariate logistic regression			Multivariate logistic regression
	OR	95% CI	p	OR	95% CI	p
PR interval	1.03	1.01–1.05	0.01	1.02	0.99–1.04	0.18
QTc	1.02	1.01–1.03	<0.01	1.01	0.99–1.03	0.18
PL	0.0002	0.00–0.01	<0.01	0.0003	0.00–0.02	<0.01
V4-5 dispersion	1.06	1.03–1.08	<0.01	1.04	1.02–1.07	<0.01

CAD, coronary artery disease. CI, confidence interval. HTN, hypertension. OR, odds ratio. SCD, sudden cardiac death. PL, percentage of loop area. QRSd, QRS duration. QTc, corrected QT interval.

*Model 1 was adjusted by PR interval, QTc, QRSd.

**Model 2 was adjusted by PR interval, QTc, PL, and V4-5 dispersion.

In the SCD group, 28.9% of the patients had two SCD events, and 72.1% had only one event. To investigate the PL, V4-5 dispersion, and QRS duration values in relation to the SCD events, we further compared these parameters with regard to the SCD event numbers, and the results are shown in Fig 4. The PL of the patients with one event (57.4±13.3%) and two events (54.1±14.6%) was lower than that of the controls (66.0±8.8%) (p<0.01). The patients with one event (47.6±18.5°) and two events (41.7±19.5°) had higher V4-5 dispersion values than the controls (28.9±12.8°) (p<0.01). The QRS duration of the patients with one event (95.1±10.8 ms) was longer than that of the controls (89.8±9.9 ms). However, there was no significant difference in the QRS duration between the patients with two events (90.8±9.4 ms) and controls (p = 0.10).

Fig 4

Box plot of the comparison of percentage of the loop area (PL), V4-5 dispersion, and QRS duration in the different event number groups.

The comparisons were performed using one-way ANOVA. The x-axis represents the number of events, while the y-axis shows the units of the different values. A significant difference among the three groups was observed in the PL and V4-5 dispersion values (p<0.01). The QRS duration failed to demonstrate significance (p = 0.10). *The p-values are significant between the two groups. (Abbreviations: PL, loop area percentage).

3.4. Subgroup analysis within the SCD group

A subgroup analysis was performed to determine the future risk factors for SCD, as shown in S2 Fig. We found that sex (male sex: OR, 1.03; 95% CI, 0.49–2.18; female sex: OR, 0.97; 95% CI, 0.46–2.06) did not contribute to a higher SCD risk (p = 0.94).

There was also no difference in the SCD risk between the three age subgroups (p = 0.87): <55 years old (OR, 0.85; 95% CI, 0.44–1.63), between 55 and 65 years old (OR, 1.03; 95% CI, 0.51–2.10), and >65 years old (OR, 1.18; 95% CI, 0.58–2.38) and the two chronic kidney disease subgroups (p = 0.88) divided by serum creatinine levels of 2.5 mg/dL (≤2.5 mg/dL: OR, 0.58; 95% CI, 0.06–5.65; >2.5 mg/dL: OR, 0.87; 95% CI, 0.08–9.81).

The patients with an LVEF of 50–55% were more likely to have SCD (OR, 3.71; 95% CI, 1.29–10.62), while the patients with an LVEF of 55.1–60% (OR, 0.88; 95% CI, 0.44–1.74) and >60% (OR, 0.53; 95% CI, 0.23–1.23) had no increased risk for SCD.

In addition, the baseline demographic characteristics and studied parameters were also compared between the patients with and without shockable rhythms at initial presentation (S3 Table). There was no difference in the underlying diseases, vectorcardiographic parameters, and most ECG and echocardiographic parameters between the two groups. Only the PR interval was significantly longer in the shockable rhythm group than in the other group, which was probably attributed to the effect of multiple factors, including the heart rate.

4. Discussion

4.1. Main findings

In this study, surface ECG was used to create a vectorcardiogram, which could define the difference between patients with symptomatic AVNRT and patients with a history of aborted SCD. The main findings of this study are as follows: (1) In the patients with structurally normal hearts, increased QRS duration on ECG, decreased PL, and elevated V4-5 QRS dispersion values assessed on vectorcardiography were associated with an increased risk of SCD. These parameters were also associated with SCD independently of the presence of other ECG abnormalities in a multivariate model. Of note, approximately 20% of the SCD cases had V4-5 dispersion >60°, whereas none of the controls had V4-5 dispersion >60°. (2) the PL and V4-5 QRS dispersion values were correlated with the number of SCD events.

4.2. ECG findings in relation to SCD risk stratification

The majority of SCD cases occurred in the adults above 35 years of age, and nearly 50% of the events were attributed to VAs, although the actual incidence of VA in patients with a history of aborted SCD remains unknown because it inevitably progresses to unwitnessed asystole [5]. The predictive value of repolarization abnormalities in SCD has been evaluated by measuring the R-wave and T-wave dispersion in previous studies [19, 20]. One of the models was constructed on the basis of a 12-lead ECG to calculate the T-wave area dispersion of leads I, II, and V4 through V6. Patients with lower values are more vulnerable to SCD, which suggests that repolarization heterogeneity is implicated in SCD [20]. However, subtle abnormalities in depolarization are sometimes difficult to recognize on ECG only, especially in patients with structurally normal hearts. With the aid of vectorcardiograms derived from ECG, we can characterize the depolarization abnormalities in patients with a history of aborted SCD by investigating the energy of the QRS complex. We observed that decreased PL and elevated V4-5 QRS dispersion values assessed on vectorcardiography were associated with an increased risk of SCD in the patients with structurally normal hearts. Further studies are warranted to validate these observations in the future.

4.3. Role of the QRS loop descriptors in SCD

To our knowledge, this is the first time that QRS loop descriptors have been used to characterize aborted SCD. Our analysis showed that the patients with a smaller PL and more significant V4-5 dispersion were at risk for SCD. Moreover, a longer QRS duration was also related to the risk for SCD [21].

The PL indicates the regularity of the loop, and a smaller PL could result from asynchrony in the myocardial tissue and influence IQRSD [13]. Moreover, IQRSD refers to the similarity between adjacent leads. Hence, a highly heterogeneous substrate could result in a higher IQRSD value. Thus, it is reasonable that the PL of the patients with a history of SCD was small, and the IQRSD value was higher in the SCD group than in the control group in our study (Table 2).

The findings of the vectorcardiography analysis can be discussed from different perspectives. First, a previous study has proposed that QRS dispersion is related to the electrophysiological conduction of the myocardium; thus, more significant dispersion will lead to more VAs [22]. In our study, the SCD group had a lower regularity of the QRS loop descriptors than the control group. The irregularity property of the QRS loop descriptors represents the non-identical conductive features of the myocardium. It could introduce arrhythmogenic effects and even induce SCD.

Second, the concept of failed activation was proposed on the basis of a current-to-load mismatch in the depolarization phase. In studies of explanted human hearts and experimental mouse hearts, a depolarization disorder might result in VA or SCD [23]. Herein, tiny QRS abnormalities may not be detected on a 12-lead surface ECG (Fig 2). We used the QRS loop descriptors to substantially reveal the difference in the QRS complex between the two adjacent leads in a signal space and to show the main inconsistency and failed activation [12, 14]. In our study, the inter-lead dispersion of QRS might represent the dissimilarity of the energy of the QRS complexes from the two leads, and this is the angle between the two reconstructed vectors [13]. The more dissimilar they are, the large the angle will be. We found that V4-5 had significant dispersion in the SCD group compared with the control group. The significantly different dispersion within the precordial region might also indicate the main inconsistent activation of the precordial leads.

Finally, SCD primarily results from left ventricular disease [24]. However, in populations with structurally normal hearts, this risk is considerably difficult to identify. In our study, we used a high value of inter-lead dispersion to identify left ventricle disorder in the patients with a history of aborted SCD. Although this tool could not accurately identify the etiologies, it could still be a promising approach to point out the lethally subtle changes in cardiac repolarization.

4.4. Role of the QRS duration in SCD

It has been proposed that a wide QRS duration might contribute to SCD [25]. In our study, we found that the QRS duration in the SCD group was relatively longer than that in the control group (Tables 2 and 3), even though there were no structural heart disorders in these patients. Hence, for the general population with structurally normal hearts and longer QRS duration, potentially lethal events should still be considered.

4.5. Proportion of initial shockable rhythms in survivors

The proportion of VA (42.4%) among the survivors in this study was relatively low. According to the pooled dataset from the COSTA group, the percentage of patients presenting with VA among European patients who experienced out-of-hospital cardiac arrest (OHCA) has already reached 37–38% [26]. However, the differences between continents and ethnicities in these data probably need to be considered. A lower detection rate of a shockable rhythm at the initial presentation in Asia has been reported by Berdowski et al. [27]. In addition, real-world data from the THUNDER study based on the Taiwanese population also disclosed that the incidence of a shockable rhythm in patients who experienced OHCA was only 7.9% [3]. According to this registry, 17.8% of the patients with an initial shockable rhythm and 2.7% of those with an initial non-shockable rhythm would be able to survive to discharge, indicating that only 36% of all survivors who experienced OHCA had shockable rhythms at the initial presentation. Taken together, our results are similar to the real-world Taiwanese registry data and was consistent with other study data in relation to the difference among continents.

4.6. Limitations

Our study has several limitations. First, there is a possibility of selection bias and survivorship bias because only patients with a cerebral performance category score equal to 1 were enrolled. We had no access to the patients who didn’t survive the OHCA as well as the severely ill patients who were unable to undergo 1-min vectorcardiography owing to poor clinical status; therefore, the findings of our study were probably related to the survival of cardiac arrest instead of the risk of the cardiac arrest itself. In addition, the ECG parameters were collected and elaborated after the event; thus, the differences found in our study might also have a chance to be a result of these events. Second, the etiologies of SCD in the patients were heterogeneous. Forty-one patients had an idiopathic etiology; these patients need further evaluation in the future. Third, our hospital is a tertiary referral medical center in the Taipei metropolitan area, which encompasses a population of 6.6 million. Unfortunately, we did not have a detailed number of aborted SCD events in this area; thus, we could not precisely assess the proportion of patients included in this study. However, an estimation can be made according to a previous study conducted in central Taiwan with a population of 2.7 million [3]. In that study, there were 1629 patients who experienced OHCA in a year, of whom 3.9% survived. Hence, at a rough estimate, there were 285 patients with a history of aborted SCD in this region during the study period, of whom 25.3% were referred to our hospital. Fourth, we had limited access to the results of cardiac magnetic resonance imaging, genetic evaluation, and brain computed tomography angiography that might be routine examinations following SCD, especially when patients were referred to our clinic. Furthermore, the surface ECG parameters were recorded using LabSystem™ PRO (Boston Scientific, Boston, MA, USA). More studies are warranted for the application to more systems in the future.

5. Conclusions

The QRS loop descriptors and vectorcardiographic parameters derived from surface ECG could be used as non-invasive markers to identify patients at a high risk for SCD. Specifically, low PL and high V4-5 QRS dispersion values are associated with patients who had structurally normal hearts and experienced aborted SCD.

Receiver operating characteristic curve analysis of the parameters.

(A) The V4-5 dispersion value was a significant discriminant parameter in predicting sudden cardiac death(SCD), with an area under the curve(AUC) of 0.73 (95% confidence interval[CI], 0.64–0.82). (B) The QRS duration was a significant discriminant parameter in predicting SCD, with an AUC of 0.65(95% CI, 0.55–0.76). (C) The percentage of the loop area was a significant discriminant parameter in predicting non-SCD with an AUC of 0.76 (95% CI 0.68–0.84) (Abbreviation: AUC, area under the curve).

(TIF)

Click here for additional data file.

Subgroup analysis with a forest plot.

We performed a subgroup analysis to determine the risk factors in the two groups. We found that sex, age, and creatinine level did not significantly contribute to the incidence of SCD. Instead, we observed that the patients with a relatively low LVEF had a tendency to have a history of aborted SCD, although this was not significant. (Abbreviations: Cr, creatinine; LVEF, left ventricular ejection fraction; OR, odds ratio; QTc interval, corrected QT interval; SCD, sudden cardiac death).

(TIF)

Click here for additional data file.

Characteristics of the patients with a V4-5 dispersion value of >60°.

We used a cut-off value of >60° for V4-5 dispersion to characterize patients at risk for sudden cardiac death.

(DOCX)

Click here for additional data file.

ROC analysis of the parameters for predicting sudden death cardiac death(SCD) or non-SCD.

Receiver operating characteristic curve analysis was used to assess the values of the continuous variables for risk stratification, and optimal cutoff values were calculated sequentially according to the specificity and sensitivity.

(DOCX)

Click here for additional data file.

Baseline characteristics of the patients with a history of aborted sudden cardiac death with shockable and non-shockable rhythms.

There was no difference in the underlying diseases, vectorcardiographic parameters, and most ECG and echocardiographic parameters between the two groups. Only the PR interval was significantly longer in the shockable rhythm group than in the other group.

(DOCX)

Click here for additional data file.

6 Sep 2021

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Reviewer #1: Wu and colleagues provide an interesting study on the possible markers for sudden cardiac death in patients with structurally normal hearts found on the vectorcardiogram. PL and QRS dispersion were the main indicators of SCD on the vectorcardiogram.

The study is overall well performed, and the propensity matching appears to be solid, but there are some issues that I would like to see addressed.

Major issues:

Methods section, page 7, line 150

Were only patients with a presumed cardiac cause of SCD included, and e.g. patients with cardiac arrest due to pulmonary embolism or other non-cardiac causes excluded? I cannot find this in the in- or exclusion criteria.

Results section, page 10, line 201

The etiology of ventricular arrhythmic SCD and non-arrhythmic SCD are often very different. Why have the authors decided to lump together ventricular arrhythmia and non-VA SCD?

This is my main concern about this study. I would at least prefer to see a subgroup analysis of the studied parameters between VA and non-VA SCD.

Were there also patients who presented with non-shockable rhythms initially but who had shockable rhythms later on during resuscitation?

Also, the proportion of ventricular arrhythmia of these patients who have survived SCA is quite low, which is surprising considering the percentage of initial presentation VA is similar to the percentage provided here: ~37%

(e.g. Oving et al. Occurrence of shockable rhythm in out-of-hospital cardiac arrest over time: A report from the COSTA group. Resuscitation 2020 https://www.sciencedirect.com/science/article/pii/S0300957220301258),

but also the usually much higher rate of survival among SCA patients who present with VA.

(e.g. Berdowski et al. Global incidences of out-of-hospital cardiac arrest and survival rates: Systematic review of 67 prospective studies. Resuscitation. 2010 https://www.sciencedirect.com/science/article/abs/pii/S0300957210004326)

The authors later say "the real incidence of VA in SCD patients remained unknown because of inevitably progresses to unwitnessed systole", however, this does not explain the large difference between this study and others.

Can the authors provide details on why this relatively low percentage of VA/shockable rhythm survivors (or high percentage of non-shockable rhyhm survivors) has occurred?

Discussion section, page 17, line 331:

could the authors elaborate a bit more on the survivorship bias? There is a possibility that these findings relate to the survival of cardiac arrest and not to the risk of cardiac arrest itself.

Also, because these ECG's were collected after the event, the differences found may also be a result of the event itself and, for example, its associated cardiac ischaemia instead of a marker of sudden cardiac death. Overall, I think the conclusion that “low PL and high V4-5 QRS dispersion values were associated with increased SCD risks in patients with structurally normal hearts.” (Conclusion section, page 17, line 342-344) is too strong and should be rephrased into something like “were associated with patients who survived SCD”, since, based on this data we cannot say for certain it is also found in people who are at risk of SCD, but in whom SCD hasn’t occurred yet.

Minor issues:

Introduction section, page 3, line 52

Is there a more contemporary reference than this one from 1998?

Some words like "a", "the" and "are" are left out, or added unnecessarily. Although small, these words are important for the sentence structure and would improve the readability of the manuscript. For example page 3, line 57-62.

“In [a] healthy population without structural heart disease screened by echocardiography or ECG, some anomalies might exist but [are] hard to be identified, especially [[the (can be left out)]] electrical abnormalities susceptible to malignant arrhythmias. Although ventricular arrhythmias (VA) were not frequently detected, [a] previous study has proposed that the majority of SCD could probably result from malignant arrhythmias.”

In figure S1, the authors have written "chornic" instead of "chronic" kidney disease.

Reviewer #2: In the present manuscript Dr. Wu et al. present their findings regarding differences in electrocardiograms in subjects with aborted sudden cardiac death and other subjects. Their main findings are that longer QRS duration, more significant dispersion between lead V4 and V5 in principal component analysis, and smaller loop area percentage are present in subjects with aborted sudden cardiac death. Especially the finding of more dignificant dispersion seems interesting and is novel and worth publishing. However, there were some important concerns which should be considered first.

1. It is stated that the study included consecutive patients who underwent vectorcardiogram from March 2017 to December 2018, and patients with structural heart diseases, congestive heart failure, or reduced ejection fraction were excluded. A total of 315 patients were investigated and 72 of those patients had aborted SCD with good functional status. 27% in the aborted sudden cardiac death group had coronary artery disease, 8 Brugada syndrome, 6 ARVC, 3 LQTS, and the etiology was idiopathic in 41 patients.

The population studied (both cases and controls) appears to be highly selected. One would expect to see a higher proportion of subjects with aborted sudden cardiac death to have coronary artery disease, and a smaller proportion to be idiopathic. It would be of use to describe in more detail how the subjects were included (what was the indication to record vectorcardiography?). Then the reader could better think about the generalizability of the findings. Were the controls healthy volunteers, patients of an arrhythmia clinic without aborted sudden cardiac death, patients with syncope, or something else? How big proportion of patients with aborted sudden cardiac death in the area during the study period ended up in the study? Also, to assess the value of the of the electrocardiographic variables studied in risk stratification it would be of use to know the distribution of these variables in healthy subjects.

2. Before proposing new risk markers one should assess whether the new markers provide new information. Two of the three example electrocardiograms are clearly abnormal. Please report the prevalence of electrocardiographic LVH, bundle branch blocks, T wave inversions, and Q waves in both cases and controls. Also please provide detailed echocardiographic data in addition to left ventricular ejection fraction (at least wall thickness and LVEDD).

3. There are "empty" dots in the box plots (Figure 3.). Is there some kind of a problem with the data?

4. The most interesting part of the population is the subset with V4-V5 dispersion >60 as one can see in Figure 3. that such high dispersion was not present in any of the controls. Thus, the use of this (or higher) cutoff might prove useful in identifying subjects at risk of sudden cardiac death. Please provide the charactestics, other electrocardiographic findings, ECHO findings, and identified channelopaties and other diseases of this group also.

5. The construction of the propensity score is not reported in detail. Please see for example Althouse AD et al. Recommendations for Statistical Reporting in Cardiovascular Medicine: A Special Report From the American Heart Association. Circulation 2021 for recommendation about reporting.

6. Finally, the use of an expert scientific English editor would be beneficial to improve the readability of the manuscript.

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9 Oct 2021

We thank the academic editor and reviewers for the very useful comments. Those comments were very instructive and very helpful to this manuscript. You will find our response to your comments below.

Response to Journal Requirements

We would like to thank you for evaluating our manuscript and reminding us the valuable comments. Following your suggestion, we have modified manuscript in accordance with Journal Requirements.

1. Regarding the journal requirements: “please ensure that your manuscript meets PLOS ONE's style requirements.”

Thank you for this reminder very much. Following the guidance, we have ensured the manuscript meets PLOS ONE's style requirements accordingly.

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Thank you for these reminders very much. Following your guidance, we have ensured the additional details regarding participant consent has been provided in the section of Materials and methods in lines 78-81 on page 4 and online submission information.

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Thank you for your comments very much. Following your recommendation, we considered employing a professional scientific editing service, and we have provided a copy of the manuscript as a *supporting_information* file showing the changes by professional scientific editing service.

4. Regarding the comments: “we note that you have provided funding information that is not currently declared in your Funding Statement. However, funding information should not appear in the Acknowledgments section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form. Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Please include your amended statements within your cover letter; we will change the online submission form on your behalf.

Thank you for your comments very much. We have modified the section of Acknowledgments in line 420 on page 20 as follows: “none.” In addition, the amended Funding Statements have been provided in the cover letter, and thank you for changing the online submission form on my behalf.

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Thank you for your comments very much. We have ensured the correct grant numbers for the awards being provided in Funding Information and Financial Disclosure.

Response to Reviewer #1

We want to thank you for evaluating our manuscript and providing us with valuable comments. Following your suggestion, we have modified several parts of our manuscript accordingly.

1. Regarding the comment: "Were only patients with a presumed cardiac cause of SCD included, and e.g. patients with cardiac arrest due to pulmonary embolism or other non-cardiac causes excluded? I cannot find this in the in- or exclusion criteria."

Thank you for this comment very much. We only included the patients with a presumed cardiac cause of SCD because we aimed to identify the abnormal substrates of the ventricle that are difficult to access by electrocardiography and echocardiography to define high-risk patients vulnerable to SCD. Following your comment, we have modified the section of Methods by adding a sentence in line 88 on page 4 as follows: "patients with a history of aborted SCD due to non-cardiac causes were also excluded."

2. Regarding the comments: "The etiology of ventricular arrhythmic SCD and non-arrhythmic SCD are often very different. Why have the authors decided to lump together ventricular arrhythmia and non-VA SCD? This is my main concern about this study. I would at least prefer to see a subgroup analysis of the studied parameters between VA and non-VA SCD. Were there also patients who presented with non-shockable rhythms initially but who had shockable rhythms later on during resuscitation? Also, the proportion of ventricular arrhythmia of these patients who have survived SCA is quite low, which is surprising considering the percentage of initial presentation VA is similar to the percentage provided here: ~37% (e.g. Oving et al. Occurrence of shockable rhythm in out-of-hospital cardiac arrest over time: A report from the COSTA group. Resuscitation 2020 https://www.sciencedirect.com/science/article/pii/S0300957220301258), but also the usually much higher rate of survival among SCA patients who present with VA. (e.g. Berdowski et al. Global incidences of out-of-hospital cardiac arrest and survival rates: Systematic review of 67 prospective studies. Resuscitation. 2010 https://www.sciencedirect.com/science/article/abs/pii/S0300957210004326) The authors later say the real incidence of VA in SCD patients remained unknown because of inevitably progresses to unwitnessed asystole', however, this does not explain the large difference between this study and others. Can the authors provide details on why this relatively low percentage of VA/shockable rhythm survivors (or high percentage of non-shockable rhyhm survivors) has occurred?"

Thank you for this comment very much. Regarding the first question, the method we used to lump these 2 types of SCD together was based on the previous literature (Huikuri, et al. N Engl J Med 2001) in which the majority of SCD was proposed to result from malignant arrhythmias, although VAs were not frequently detected. VA and non-VA were considered to be in the same pathophysiology cascade but at different time points. Malignant arrhythmias probably have already degenerated to asystole, or sinus rhythm has already been restored when there is no detectable VA in aborted SCD. Therefore, we aimed to identify these abnormal substrates of the ventricle that are difficult to access by electrocardiography and echocardiography to define high-risk patients vulnerable to sudden cardiac death. In order to clarify this point of view, we have added the statements into the section of introduction in lines 61-64 on page 3 as follows: "VAs and non-VAs were considered to be in the same pathophysiology cascade but occur at different time points. Malignant arrhythmias probably have already degenerated to asystole, or sinus rhythm has already been restored when there is no detectable VA in aborted SCD."

Following your comment, we also added a subgroup analysis in the S3 Table to compare the studied parameters between patients with and without initial VAs(or shockable rhythms). There was no difference in the underlying diseases, vectorcardiographic parameters, and most ECG and echocardiographic parameters between the two groups. Only the PR interval was significantly longer in the shockable rhythm group than in the other group, which was probably attributed to the effect of multiple factors, including the heart rate. Given these results, we also added the statements in the section of Discussion in lines 303-308 on page 16 as follows: "in addition, the baseline demographic characteristics and studied parameters were also compared between the patients with and without shockable rhythms at initial presentation (S3 Table). There was no difference in the underlying diseases, vectorcardiographic parameters, and most ECG and echocardiographic parameters between the two groups. Only the PR interval was significantly longer in the shockable rhythm group than in the other group, which was probably attributed to the effect of multiple factors, including the heart rate."

As to the second question, the shockable rhythm in our study was defined as showing in the initial rhythm or during the resuscitation. Therefore, it is difficult to determine if patients presented non-shockable rhythms initially and had shockable rhythms later on during resuscitation. We have added the statements in the section of Methods to clarify this part in lines 93-94 on page 4 as follows: "a shockable rhythm was presented as the initial rhythm or during resuscitation."

Regarding the third question and the last part in this comment, we agreed with you that the proportion of VA (42.4%) among the survivors in this study was relatively low. According to the pooled dataset from the COSTA group, the percentage of patients presenting with VA among European patients who experienced out-of-hospital cardiac arrest (OHCA) has already reached 37–38%. However, the differences between continents and ethnicities in these data probably need to be considered. A lower detection rate of a shockable rhythm at the initial presentation in Asia has been reported by Berdowski et al (Berdowski, et al. Resuscitation 2010). In addition, real-world data from the THUNDER study (Lin, et al. Mayo Clin Proc 2017) based on the Taiwanese population also disclosed that the incidence of a shockable rhythm in patients who experienced OHCA was only 7.9%. According to this registry, 17.8% of the patients with an initial shockable rhythm and 2.7% of those with an initial non-shockable rhythm would be able to survive to discharge, indicating that only 36% of all survivors who experienced OHCA had shockable rhythms at the initial presentation. Taken together, our results are similar to the real-world Taiwanese registry data and was consistent with other study data in relation to the difference among continents. In order to elucidate this viewpoint, we have added the statements in the section of Discussion in lines 377-390 on page 19 as follows: "the proportion of VA (42.4%) among the survivors in this study was relatively low. According to the pooled dataset from the COSTA group, the percentage of patients presenting with VA among European patients who experienced out-of-hospital cardiac arrest (OHCA) has already reached 37–38%. However, the differences between continents and ethnicities in these data probably need to be considered. A lower detection rate of a shockable rhythm at the initial presentation in Asia has been reported by Berdowski et al. In addition, real-world data from the THUNDER study based on the Taiwanese population also disclosed that the incidence of a shockable rhythm in patients who experienced OHCA was only 7.9%. According to this registry, 17.8% of the patients with an initial shockable rhythm and 2.7% of those with an initial non-shockable rhythm would be able to survive to discharge, indicating that only 36% of all survivors who experienced OHCA had shockable rhythms at the initial presentation. Taken together, our results are similar to the real-world Taiwanese registry data and was consistent with other study data in relation to the difference among continents."

3. Regarding the comment: "could the authors elaborate a bit more on the survivorship bias(Discussion section, page 17, line 331)? There is a possibility that these findings relate to the survival of cardiac arrest and not to the risk of cardiac arrest itself. Also, because these ECG's were collected after the event, the differences found may also be a result of the event itself and, for example, its associated cardiac ischaemia instead of a marker of sudden cardiac death. Overall, I think the conclusion that “low PL and high V4-5 QRS dispersion values were associated with increased SCD risks in patients with structurally normal hearts.” (Conclusion section, page 17, line 342-344) is too strong and should be rephrased into something like “were associated with patients who survived SCD”, since, based on this data we cannot say for certain it is also found in people who are at risk of SCD, but in whom SCD hasn’t occurred yet."

Thank you for this comment very much. We agree with you that survivorship bias is probably associated with these findings of survival of cardiac arrest. It was also one of the limitations in our study because we had no assessment of those patients who didn't survive from OHCA. This comment is very precious, and we have discussed this in the section of Limitations in lines 392-399 on pages 19-20 as follows: "there is a possibility of selection bias and survivorship bias because only patients with a cerebral performance category score equal to 1 were enrolled. We had no access to the patients who didn't survive the OHCA as well as the severely ill patients who were unable to undergo 1-min vectorcardiography owing to poor clinical status; therefore, the findings of our study were probably related to the survival of cardiac arrest instead of the risk of the cardiac arrest itself. In addition, the ECG parameters were collected and elaborated after the event; thus, the differences found in our study might also have a chance to be a result of these events." We also agree with your valuable comment on the conclusion, and we have rephrased the statements in lines 416-417 on page 20 as follows: "low PL and high V4-5 QRS dispersion values are associated with patients who had structurally normal hearts and experienced aborted SCD."

4. Regarding the comment: "Is there a more contemporary reference than this one from 1998?"

Thank you for this comment very much. Following your comment, we have modified this statement and added more contemporary references in line 51 and page 3.

5. Regarding the comment: "Some words like "a", "the" and "are" are left out, or added unnecessarily. Although small, these words are important for the sentence structure and would improve the readability of the manuscript. For example page 3, line 57-62. “In [a] healthy population without structural heart disease screened by echocardiography or ECG, some anomalies might exist but [are] hard to be identified, especially [[the (can be left out)]] electrical abnormalities susceptible to malignant arrhythmias. Although ventricular arrhythmias (VA) were not frequently detected, [a] previous study has proposed that the majority of SCD could probably result from malignant arrhythmias.” In figure S2, the authors have written "chornic" instead of "chronic" kidney disease.

Thank you for this comment very much. We have modified these words in lines 57-61 on page 3 and S2 Fig accordingly.

Response to Reviewer #2

We want to thank you for evaluating our manuscript and providing us with valuable comments. Following your comments, we have modified several parts of our manuscript accordingly.

1. Regarding the comment: "the population studied (both cases and controls) appears to be highly selected. One would expect to see a higher proportion of subjects with aborted sudden cardiac death to have coronary artery disease, and a smaller proportion to be idiopathic. It would be of use to describe in more detail how the subjects were included (what was the indication to record vectorcardiography?). Then the reader could better think about the generalizability of the findings. Were the controls healthy volunteers, patients of an arrhythmia clinic without aborted sudden cardiac death, patients with syncope, or something else? How big proportion of patients with aborted sudden cardiac death in the area during the study period ended up in the study? Also, to assess the value of the of the electrocardiographic variables studied in risk stratification it would be of use to know the distribution of these variables in healthy subjects."

Thank you for these comments very much, and these questions are very important to help readers think about the generalizability of our findings. As to the first and second questions, our cases were enrolled to undergo vectorcardiography from the clinics during the study period, and all these patients had histories of either aborted SCD or palpitation. Following your comments, we have modified the statements in lines 84-86 on page 4 as follows: "this study consecutively enrolled patients who had histories of aborted SCD or palpitation in our clinics and undergo vectorcardiography between March 2017 and December 2018."

As to the third question, unfortunately, we didn't have a detailed number of aborted SCD in this area during the study period. However, an estimation can be made according to a previous study that was conducted in central Taiwan with a population of 2.7 million (Lin, et al. Mayo Clin Proc 2017). In that study, there were 1629 OHCA patients in a year, and 3.9% of these patients survived. Our hospital is a tertiary referral medical center in the Taipei metropolitan area that encompasses a population of 6.6 million. Hence, at a rough estimate, there were 285 patients with aborted SCD in this region during the study period, and 25.3% of these patients were referred to our hospital. Following your comment, we have added the statements in the section of Limitations in lines 401-408 on pages 20 as follows: "our hospital is a tertiary referral medical center in the Taipei metropolitan area, which encompasses a population of 6.6 million. Unfortunately, we did not have a detailed number of aborted SCD events in this area; thus, we could not precisely assess the proportion of patients included in this study. However, an estimation can be made according to a previous study conducted in central Taiwan with a population of 2.7 million. In that study, there were 1629 patients who experienced OHCA in a year, of whom 3.9% survived. Hence, at a rough estimate, there were 285 patients with a history of aborted SCD in this region during the study period, of whom 25.3% were referred to our hospital."

Following the last comment, we added S1 Fig and S2 Table to demonstrate using ROC curve analysis to elaborate the values of these parameters for risk stratification. We have added the statements in the section of Method in lines 167-169 on page 7 as follows: "receiver operating characteristic (ROC) curve analysis was used to assess the values of the continuous variables for risk stratification, and optimal cutoff values were calculated sequentially according to the specificity and sensitivity." We have also added descriptions for S1 Fig and S2 Table in the section of Results in line 259-268 on pages 13-14 as follows: "moreover, we used ROC curve analysis to assess the values of the PL, V4-5 dispersion, and QRS duration for predicting SCD or non-SCD (S1 Fig), and the summary is shown in S2 Table. For predicting SCD, the area under the curve (AUC) for the V4-5 dispersion value was 0.73 (95% CI, 0.64–0.82, S1A Fig) with an optimal cut-off value of 37.7° (specificity, 75.3%; sensitivity, 67.8%; positive predictive value (PPV), 62.5%; negative predictive value (NPV), 78.4%); that for the QRS duration was 0.65(95% CI, 0.55–0.76, S1B Fig), with an optimal cut-off value of 89 ms (specificity, 49.5%; sensitivity, 77.1%; PPV, 34.6%; NPV, 86.0%). For predicting non-SCD, the AUC for the PL was 0.76 (95% CI, 0.68–0.84, S1C Fig), with an optimal cut-off value of 62.6% (specificity, 67.8%; sensitivity, 81.7%; PPV, 80.0%; NPV, 70.2%)."

2. Regarding the comment: "before proposing new risk markers one should assess whether the new markers provide new information. Two of the three example electrocardiograms are clearly abnormal. Please report the prevalence of electrocardiographic LVH, bundle branch blocks, T wave inversions, and Q waves in both cases and controls. Also please provide detailed echocardiographic data in addition to left ventricular ejection fraction (at least wall thickness and LVEDD)."

Thank you for this comment very much. Following your comment, we have added the variables, including electrocardiographic LVH by Sokolow–Lyon index >35 mm, bundle branch block, T wave inversion beyond V1, pathologic Q waves, thickness of interventricular septum, and left ventricular inner dimension at end-diastole, in Table 2 and S3 Table.

3. Regarding the comment: "there are "empty" dots in the box plots (Figure 3.). Is there some kind of a problem with the data?"

Thank you for this comment very much. There are no problems with this data, and the empty dots in these box plots represent the location of outliers. In these box plots, the distribution of the data is disclosed by the black dots, and the empty dots exhibit the location of outliers and line centrally. According to the statistical definition, a data dot is said to be an outlier if it is greater than the third quartile of data plus 1.5 times the interquartile range (high outlier) or less than the first quartile of data minus 1.5 times the interquartile range (lower outlier). For instance, in the left panel of Fig 3B, there are 8 black dots that are outliers in this graph, so the empty dots are repotted to disclose the location of these outliers and line centrally. Therefore, upper lines represent the maximum value in the dataset without high outliers, and lower lines represent the minimum value in the dataset without lower outliers. Follow this comment, I have added the statements in the figure legend of Fig 3 to make it clear in lines 226-233 on page 12 as follows: "boxes in the box plots start in the first quartile, end in the third quartile, and represent 50% of the central data. A line inside represents the median values. In these box plots, black dots present the distribution of the data, and empty dots exhibit the location of the outliers and line centrally. A data dot is said to be an outlier if it is greater than the third quartile of data plus 1.5 times the interquartile range (high outlier) or less than the first quartile of data minus 1.5 times the interquartile range (lower outlier). Therefore, upper lines represent the maximum value in the dataset without high outliers, and lower lines represent the minimum value in the dataset without lower outliers."

4. Regarding the comment: "the most interesting part of the population is the subset with V4-V5 dispersion >60 as one can see in Figure 3. that such high dispersion was not present in any of the controls. Thus, the use of this (or higher) cutoff might prove useful in identifying subjects at risk of sudden cardiac death. Please provide the charactestics, other electrocardiographic findings, ECHO findings, and identified channelopaties and other diseases of this group also."

Thank you for this comment very much. Following your recommendation, we use a cut-off of V4-5 dispersion > 60° to characterize the patients at risk of SCD, and we have provided the characteristics, and electrocardiographic and echocardiogram findings in S1 Table. We have also added the statements in the section of Results in lines 244-252 on page 13 as follows: "based on the findings shown in Fig 3A, there was no subject in the control group with a V4-5 dispersion value of >60°. To shed some light on the features of patients at risk for SCD, we demonstrated the baseline characteristics and ECG and echocardiographic findings of the patients with V4-5 dispersion values of >60° in S1 Table. We noticed that most of these patients were men (73.3%), and the mean age was 51 years. Histories of hypertension and coronary artery disease accounted for 33.3% of all cases. Regarding the etiologies of SCD, one case was Brugada syndrome (6.7%); one was ARVC (6.7%); and 13 were idiopathic (86.7%). In addition, there were no significant abnormalities in the ECG and echocardiographic parameters."

5. Regarding the comment: "the construction of the propensity score is not reported in detail. Please see for example Althouse AD et al. Recommendations for Statistical Reporting in Cardiovascular Medicine: A Special Report From the American Heart Association. Circulation 2021 for recommendation about reporting."

Thank you for this comment very much. We have modified the description accordingly in lines 94-96 on pages 4 as follows: " propensity score matching was performed to minimize the confounders. The cases and controls were matched at a 1:2 ratio using a 0.10 caliper for identical characteristics of age, sex, and histories of hypertension and coronary artery disease."

6. Regarding the comment: "the use of an expert scientific English editor would be beneficial to improve the readability of the manuscript."

Thank you for this comment very much. We have employed a professional scientific editing service to copyedit our manuscript for language usage, spelling, and grammar accordingly. A copy of the manuscript was provided as a *supporting_information* file showing the changes by professional scientific editing service.

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26 Oct 2021

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Reviewer #2: The Authors have done a good work addressing the previous comments and the main findings of the study are still of interest. Still, some concerns remain.

1. The Title of the study should be reconsidered as vectorcardiographic loop assessment and QRS duration were also among the main findings.

2. The exact definition of structurally normal heart/structural heart disease should be provided. Which conditions/findings led to exclusion?

3. The authors state that the control subjects indication for vectorcardiography was palpitationsWere the patients admitted to vectorcardiogram for clinical reasons, or for the purposes of the present study? Thorough characterization of the control subjects is of great importance to enable accurate interpretation of the results, and their generalizability. In the flow chart it should be reported that how many subjects underwent vectorcardiography during the time period, and how many of those subjects were excluded due to structural heart disease/reduced ejection fraction, how many due to lacking echocardiographic/other data, how many did not give concent. Also, it would be of great importance to know about the control subjects in more detail (What were the diagnoses after examinations? VES? Atrial ectopy? NSVT? Were subjects with syncope included?).

4. The authors should report how the vectorcardiograms were recorted. Was Dower transform used or did they use specific Frank electrode placements?

5. Please state in the methods the definitions for hyperlipidemia, CKD, old CVA, and how the prevalence coronary artery disease was ascertained. Did the SCD cases undergo routine coronary angiography or CTA? What were the findings?

6. In Response 2 to Reviewer 1: ”VA and non-VA SCD included” but on row 93-94 ”A shockable rhythm was presented as the initial rhythm or during resuscitation.” What does this mean?

7. Why PL is not in Table 1? Also some characteristics are rather surprising as the prevalence of smoking, hyperlipidemia, and hypertension are really low, at least compared to Western cohorts. How were the presence of these conditions defined/ascertained? Also, it seem really surprising, that no subjects presented with LVH or BBB in the propensity matched analysis, and the number of subjects with T-wave inversions are really low, although one subject in in the example ECG:s almost fulfills Sokolow criteria, and two subjects present with pathological T inversions. Are these figures correct?

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30 Nov 2021

We thank the reviewer for the very useful comments. Those comments were very instructive and very helpful to this manuscript. You will find our response to your comments below.

Response to Reviewer #2

Thank you for evaluating our manuscript and providing us with valuable comments. Following your comments, we have modified several parts of our manuscript accordingly.

1. Regarding the comment: “The Title of the study should be reconsidered as vectorcardiographic loop assessment and QRS duration were also among the main findings.”

Thank you for this comment very much. Following your comment, we have revised the title of the article as follows: “Using QRS loop descriptors to characterize the risk of sudden cardiac death in patients with structurally normal hearts.”

2. Regarding the comment: “The exact definition of structurally normal heart/structural heart disease should be provided. Which conditions/findings led to exclusion?”

Thank you for this comment very much. Following your comment, we have revised the section of Methods in lines 86-90 on page 4 as follows: “these patients didn't have structural heart diseases(e.g., dyskinesia or hypertrophy of left ventricles), histories of congestive heart failure, or reduced ejection fraction (<50%), and the attribution to non-cardiac causes wasn't favored in patients with a history of aborted SCD. A total of 315 patients were investigated.”

3. Regarding the comments: “The authors state that the control subjects indication for vectorcardiography was palpitationsWere the patients admitted to vectorcardiogram for clinical reasons, or for the purposes of the present study? Thorough characterization of the control subjects is of great importance to enable accurate interpretation of the results, and their generalizability. In the flow chart it should be reported that how many subjects underwent vectorcardiography during the time period, and how many of those subjects were excluded due to structural heart disease/reduced ejection fraction, how many due to lacking echocardiographic/other data, how many did not give concent. Also, it would be of great importance to know about the control subjects in more detail (What were the diagnoses after examinations? VES? Atrial ectopy? NSVT? Were subjects with syncope included?).”

Thank you for these comments very much. These control subjects were diagnosed having atrioventricular node reentrant tachycardia after examination and were admitted for therapy, and the vectorcardiography was also applied when the patients agreed with it. Following your comment, we have revised the statements in lines 84-86 on page 5 as follows: “this study consecutively enrolled patients who had histories of aborted SCD or palpitation that is due to atrioventricular node reentrant tachycardia in our clinics and underwent vectorcardiography between March 2017 and December 2018.”

Regarding the comment on the flow chart, because we only focused on the patients who had histories of aborted SCD or palpitation that is due to atrioventricular node reentrant tachycardia in our clinics and underwent vectorcardiography between March 2017 and December 2018, it would be difficult to conclude the actual numbers of other situations. In order to clarify the concept of enrollment, we have removed the terms(e.g., exclusion and inclusion) to make it clear and modified it in the section of Abstract(lines 30-33 on page 2) and Methodology(lines 86-90 on page 4) as follows: “these patients didn't have structural heart diseases, histories of congestive heart failure, or reduced ejection fraction, and they were classified into SCD (with aborted SCD history and cerebral performance category score of 1) and control groups (without SCD history),” and “these patients didn't have structural heart diseases(e.g., dyskinesia or hypertrophy of left ventricles), histories of congestive heart failure, or reduced ejection fraction (<50%), and the attribution to non-cardiac causes wasn't favored in patients with a history of aborted SCD. A total of 315 patients were investigated.”

4. Regarding the comment: “The authors should report how the vectorcardiograms were recorted. Was Dower transform used or did they use specific Frank electrode placements?”

We thank the reviewer for the suggestion. Instead of using a spatial filter with fixed coefficients to construct three orthogonal leads (i.e., Frank's leads X, Y, and Z) from 12 leads ECG, we studied the spatial variation in the space defined by the singular vectors; all QRS loop descriptors (PL, LD, IQRSD) are measured using the ECG vector in the constructed space spanned by the eigenvector of the ECG matrix.

We also provide how to derive a 3D representation of the cardiac electrical activity from a singular vector in sections 2.3 and 2.4. However, to avoid misunderstanding, the title of section 2.2. was replaced as “Morphological complexity of the 12-Lead QRS wave”. We also made some modifications in section 2.2 in lines 110-114 on page 5 as follows: "the 12-Lead ECG was taken at a stable stage using LabSystemTM PRO (Boston Scientific, Boston, MA, USA) with a 1-min duration for QRS descriptor analysis. The QRS descriptors, including the percentage of the loop area (PL), loop dispersion (LD), and inter-lead QRS dispersion (IQRSD) are measured using the ECG vector in the constructed space spanned by the eigenvector of 12 lead ECG matrix.”

5. Regarding the comment: “Please state in the methods the definitions for hyperlipidemia, CKD, old CVA, and how the prevalence coronary artery disease was ascertained. Did the SCD cases undergo routine coronary angiography or CTA? What were the findings?”

Thank you for this comment very much. These targeted co-morbidities, including hyperlipidemia, CKD, old CVA, prior CAD, were determined by using the International Classification of Diseases (ICD) 9 codes from the medical record at the time of examination. Following your comment, we have stated it in the section of Methods in lines 117-119 on page 5 as follows: “Targeted co-morbidities, including hyperlipidemia, CKD, old CVA, prior CAD, were determined by using the International Classification of Diseases (ICD) 9 codes from the medical record at the time of examination.”

We agree with you that routine coronary angiography and CTA following SCD are required. In our study, all the patients with a history of aborted SCD have received routine coronary angiography, and none of them have acute coronary syndrome. We have added this statement in the section of Results in lines 253-254 on page 13 as follows: “all the patients with a history of aborted SCD have received routine coronary angiography, and none of them have acute coronary syndrome.” In addition, all these patients had a cerebral performance category score equal to 1. Unfortunately, we had limited access to the results of CT angiography, especially when patients were referred to our clinic. Following your comment, we have added this into the section of Limitation in lines 412-415 on page 20 as follows: “Patients with a history of aborted SCD in our study had a cerebral performance category score equal to 1. However, we had limited access to the results of CT angiography that might be a routine examination following SCD, especially when patients were referred to our clinic.”

6. Regarding the comment: “In Response 2 to Reviewer 1: “VA and non-VA SCD included” but on row 93-94 ”A shockable rhythm was presented as the initial rhythm or during resuscitation.” What does this mean?”

Thank you for this comment very much. There are separate questions in Response 2, and Reviewer 1 asked that “Were there also patients who presented with non-shockable rhythms initially but who had shockable rhythms later on during resuscitation?” In our study, our record for shockable rhythms(or VA) did not clearly mention whether the shockable rhythms were the initial rhythm or happened during the resuscitation. Therefore, we have to add a statement in the section of Methods to clarify this part in lines 93-94 on page 4 as follows: “a shockable rhythm was presented as the initial rhythm or during resuscitation.”

7. Regarding the comments: “Why PL is not in Table 1? Also some characteristics are rather surprising as the prevalence of smoking, hyperlipidemia, and hypertension are really low, at least compared to Western cohorts. How were the presence of these conditions defined/ascertained? Also, it seem really surprising, that no subjects presented with LVH or BBB in the propensity matched analysis, and the number of subjects with T-wave inversions are really low, although one subject in in the example ECG:s almost fulfills Sokolow criteria, and two subjects present with pathological T inversions. Are these figures correct?”

Thank you for these comments very much. For the first question, we do have the data of PL (Percentage of loop area) in Table 1, and it is at the bottom. In addition, we agree with you that the prevalence of smoking, hyperlipidemia, and hypertension was relatively low, and it was probably related to the selection and survivorship bias that we mentioned in the Section of limitation. Regarding the last part of the comments, it is reasonable that there were no LVH or BBB in the propensity-matched analysis because those patients probably have been excluded. For the last question, we have to say that these figures are correct, and we agreed with you that two of them had pathological T inversions. However, none of them fulfill Sokolow criteria, and we have modified Figure 2 to provide a scale to clarify this.

Submitted filename: response_to_reviewers_R2.docx

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13 Dec 2021

3 Jan 2022

We thank the reviewer for the very useful comments. Those comments were very instructive and very helpful to this manuscript. You will find our response to your comments below.

Response to Reviewer #2

Thank you for evaluating our manuscript and providing us with valuable comments. Following your comments, we have modified several parts of our manuscript accordingly.

1. Regarding the comment: “The present study compares ventorcardiographic ECG parameters between subjects with aborted SCD and subjects having palpitations due to AVNRT. Subjects with LV hypertrophy, reduced LVEF, regional LV wall motion abnormalities, and congestive heart failure were excluded. The authors use propensity score matching to create equal groups for comparisons according to age, sex, hypertension, and coronary artery disease. The main findings of the study are that mean QRS duration, V4-5 dispersion, and percentage of loop area were different between subjects with aborted SCD and symptomatic AVNRT. These parameters were also associated with SCD independently of the presence of other ECG abnormalities in a multivariate model. Of note, approximately 20% of the SCD cases had V4-5 dispersion >60, whereas none of the controls had V4-5 dispersion >60 and this is an interesting and important finding.”

Thank you for your valuable comments to emphasize the important issues of our study, and we have revised the sentence in the paragraph of main finding accordingly to enforce our points of view, in lines 317-319 on page 16 as follows: “In this study, surface ECG was used to create a vectorcardiogram, which could define the difference between patients with symptomatic AVNRT and patients with a history of aborted SCD.” In addition, we also added the sentence in the same paragraph in lines 322-324 on page 17 as follows: “these parameters were also associated with SCD independently of the presence of other ECG abnormalities in a multivariate model. Of note, approximately 20% of the SCD cases had V4-5 dispersion >60°, whereas none of the controls had V4-5 dispersion >60°.”

2. Regarding the comment: “The application of these results to clinical practice is cumbersome for numerous reasons. The distributions of QRS duration and percentage of loop area were largely overlapping between the cases and controls (despite statistically significant differences in the means), and most of the SCD cases also had V4-5 dispersion in the same range as the controls. Thus, if one tried to screen subjects with structurally normal hearts (generally a really low-risk population) to identify subjects at risk for SCD, only V4-5 dispersion >60 might be of use, and this marker would identify only 20% of cases.

The SCD cases in the present study are not very representative, as none of the cases had acute coronary syndrome (the most common trigger of SCD in the population), and generally no cases with DCM or HCM were included (all patients in the study had normal LVEF and LV wall thickness). However, it would be of great interest if the ECG parameters studied would be predictive of SCD in the aforementioned patient groups.

Therefore, channelopaties were identified in a large proportion of cases (8 Brugada, 6 ARVC, 3 LQTS) and there may have been even more cases as routine cardiac magnetic resonance imaging, or screening for gene mutations associated with these diseases were not routinely performed (at least according to the manuscript). However, as electrocardiograpic characteristics in these diseases (Brs, ARVC, LQTS) differ greatly, the prognostic significance of an electrocardiographic abnormality should be studied separately in each of these diseases.”

We are glad to receive these valuable comments very much. We admit that this study has several drawbacks for widely applying to the general population. As you have mentioned that V4-5 dispersion >60° only identified 20% of cases, but we could also assume that the significant dispersion is probably located at other places. With further analysis of vectorcardiography in subgroups, the subtle abnormalities are likely to be defined and localized.

Regarding the representativeness of our SCD cases, we agreed with you that the etiologies of our patients were not very common in the population. However, our patients referred from other medical centers usually met an unrevealed problem that causes SCD events. These events will probably occur again in the future; therefore, it is still of importance to investigate the possible etiologies underneath these patients and plan further work in electrophysiology.

Seventeen out of 58 patients (29.3%) have channelopathies, and we agreed with you that the electrocardiographic characteristics in these diseases differ greatly. Therefore, we will plan further separate studies to evaluate the prognostic significance of electrocardiographic abnormalities based on distinct conditions.

3. Regarding the comment: “In addition, the methodology used does not provide with an opportunity to assess wheter the electrocardiographic abnormalities detected in patients with aborted SCD were caused by the acute event.”

Thank you for this comment very much. We agree that the methodology does not provide an opportunity to assess whether the electrocardiographic abnormalities detected in patients with aborted SCD were caused by the acute events. We have modified the section of limitations in lines 405-407 on page 20 the clarify this as follows: “the ECG parameters were collected and elaborated after the event; thus, the differences found in our study might also have a chance to be a result of these events.”

4. Regarding the comment: “It should be made clear already in the abstract that the study compares ECGs of patients with aborted SCD and patients having an intervention for AVNRT.”

Thank you for this comment. We have revised the abstract accordingly in lines 30-34 on page 2 as follows: “These patients didn't have structural heart diseases, histories of congestive heart failure, or reduced ejection fraction, and they were classified into SCD (with aborted SCD history and cerebral performance category score of 1) and control groups (with an intervention for atrioventricular node reentrant tachycardia and without SCD history).”

5. Regarding the comment: “It should be mentioned in the limitations section, that no cardiac MRI or genetic data were used in the study.”

Thank you for this comment very much. We have revised the section of Limitation according in lines 417-419 on page 21 as follows: “we had limited access to the results of cardiac magnetic resonance imaging, genetic evaluation, and brain computed tomography angiography that might be routine examinations following SCD, especially when patients were referred to our clinic.”

6. Regarding the comment: “The link to supplemental material led to a Word document including a changes traced version of R1, and no supplemental tables and thus the supplemental tables could not be addressed.”

Thank you for this reminder. It could be something wrong with the link system, but we will upload them again.

Submitted filename: Response_to_reviewers_R3.docx

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31 Jan 2022

Using QRS loop descriptors to characterize the risk of sudden cardiac death in patients with structurally normal hearts

PONE-D-21-20744R3

Dear Dr. Lin,

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Reviewers' comments:

7 Feb 2022

PONE-D-21-20744R3

Using QRS loop descriptors to characterize the risk of sudden cardiac death in patients with structurally normal hearts

Dear Dr. Lin:

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