Deng C, et al.

Association of QTc Interval with Risk of Cardiovascular

Diseases and Related Vascular Traits: A Prospective and Longitudinal
Analysis. Global Heart. 2020; 15(1): 13. DOI: https://doi.org/10.5334/gh.533

ORIGINAL RESEARCH

Association of QTc Interval with Risk of

Cardiovascular Diseases and Related Vascular
Traits: A Prospective and Longitudinal Analysis
Chanjuan Deng, Jingya Niu, Liping Xuan, Wen Zhu, Huajie Dai, Zhiyun Zhao,
Mian Li, Jieli Lu, Yu Xu, Yuhong Chen, Weiqing Wang, Guang Ning, Yufang Bi,
Min Xu and Tiange Wang
Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and
Metabolic Diseases of the National Health Commission of the PR China, Shanghai Institute of Endocrine and Metabolic
Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, CH
Corresponding authors: Tiange Wang, MD, PhD ([email protected]); Min Xu, MD, PhD ([email protected]);
Yufang Bi, MD, PhD ([email protected])

Background: Prolonged heart rate corrected QT (QTc) interval was reported to be associated
with cardiovascular diseases (CVDs).
Objective: There exists little data on the association between QTc interval and cardiovascular
risk in Asian populations. We prospectively investigated the association of QTc interval with
CVDs and vascular traits in a large cohort of Chinese adults.
Methods: A total of 7,605 participants aged 40 years or older from a well-defined community
without CVDs at baseline were included and followed up for an average of 4.5 years. Associa-
tion of baseline QTc interval with incident CVDs was evaluated using Cox regression analysis.
Associations of QTc interval with brachial-ankle pulse wave velocity (baPWV), carotid intima-
media thickness (CIMT), and risk of microalbuminuria and peripheral arterial diseases (PAD) were
secondarily examined.
Results: Prolonged QTc interval (≥460 ms in women and ≥450 ms in men) was associated
with 51% higher risk of total major CVDs (hazard ratio [HR] = 1.51, 95% confidence interval
[CI] [1.20, 1.90]), particularly, 48% increased risk of stroke (95% CI [1.16, 1.88]). Prolonged
QTc interval was positively associated with baPWV (β = 38.10 cm/s, standard error [SE] =
8.04, P < 0.0001) and CIMT (β = 0.01 mm, SE = 0.01, P = 0.04). Prolonged QTc interval was
associated with increased risk of incident microalbuminuria (odds ratio [OR] = 1.65, 95% CI
[1.21, 2.24]) and PAD (2.49, 95% CI [1.35, 4.59]).
Conclusions: Prolonged QTc interval is positively and significantly associated with increased
risk of CVDs and related vascular traits in Chinese population.

Keywords: QTc interval; cardiovascular diseases; vascular traits

Introduction
Cardiovascular diseases (CVDs) are the leading cause of mortality worldwide, including developing countries
such as China, especially with the increasing rates of obesity and Type 2 diabetes, which are the two impor-
tant risk factors of CVDs [1, 2]. It is estimated that in China the number of patients suffering from CVDs is
up to 29 million, which will continue growing rapidly in the next 10 years [3]. It is of extreme importance to
discover more effective predictors to optimize screening or preventative measures for individuals susceptible
to CVDs.
The electrocardiogram (ECG) is a simple, noninvasive diagnostic test to detect functional and structural
abnormity of the heart with cardiac electricity activity. The latest recommendation from the American Heart
Association (AHA) and the American College of Cardiology Foundation (ACCF) emphasized the diagnostic
Art. 13, page 2 of 11 Deng et al: Association of QTc Interval with Risk of Cardiovascular
Diseases and Related Vascular Traits

value of ECG for CVDs in patients with hypertension and diabetes [4]. Of note, QT interval is a common ECG
index for diagnosis of ventricular arrhythmia by representing the whole process of electrical repolarization of
myocardium [5]. A number of studies have shown that heart rate corrected QT (QTc) interval is strongly asso-
ciated with the risk of CVDs in different populations [5–8]. For example, a longitudinal study in Americans
identified that QTc interval was an independent predictor of all-cause and cardiovascular mortality in diabetic
patients [5]. Another cohort study reported that prolonged QTc interval was associated with a significantly
increased risk of stroke in the general population [6]. In addition, QTc interval was demonstrated to improve
the accuracy of the personalized CVDs prognosis built on a conventional risk predicting model [9].
Recent studies demonstrated significantly longer QTc intervals of black people compared with those of
other races [10, 11], indicating a remarkable ethnic and racial variation. The existing studies mostly focused
on Western populations; whereas, few studies to date have explored the predictive value of QTc interval for
CVDs in East Asians. Furthermore, based on the positive association between prolonged QTc interval and
risk of sudden cardiac mortality [10], it is of much significance to detect the prolongation of QTc interval. As
such, validation of the association between QTc interval and risk of CVDs in the East Asian population is nec-
essary. Therefore, we performed a prospective analysis to assess the association of QTc interval with the risk
of CVDs in a well-defined community-based Chinese cohort; we further performed longitudinal analyses to
examine the associations of QTc interval with several CVD-related vascular traits, for instance, the repeated
measurements of brachial-ankle pulse wave velocity (baPWV), carotid intima-media thickness (CIMT), and
early indicators, urinary albumin excretion, and ankle-brachial index (ABI).

Methods
Study population
The prospective analysis was performed in a community-based cohort study that was initiated in 2010 at
baseline, Jiading District, Shanghai, China [12, 13]. Between March and August 2010, a total of 10,375 resi-
dents aged 40 years or older were recruited. For the primary analysis of the present study, we excluded 1,357
participants at baseline for the following reasons: 1) 355 had self-reported CVDs or missed data on CVDs;
2) 879 missed ECG measures; 3) 14 had a cardiac pacemaker placed; and 4) 109 took antiarrhythmic therapy
(procainamide, sotalol, flecainide, amiodarone, et al). From August 2014 to May 2015, all 9,018 participants
were invited to attend a follow-up visit. After excluding 1,413 individuals who failed to attend the follow-up
examination, 7,605 participants were followed up with for the primary analysis of association between QTc
interval and incident CVDs. For the secondary analysis, we further excluded 2,654 individuals with missing
or poor ECG data, 5 with a cardiac pacemaker, 27 using antiarrhythmic therapy at follow-up, and 667 with-
out complete vascular traits measurements, leaving 4,252 participants for the analysis. Details on the flow
chart of study participants are shown in Supplemental Figure 1.
The study protocol was approved by the Institutional Review Board of Ruijin Hospital, Shanghai Jiao Tong
University School of Medicine. Written informed consent was obtained from each participant.

Anthropometric Measurements
Participants were interviewed by trained personnel according to the standard questionnaire involving medi-
cal history, medication use, as well as lifestyle factors. The participant was defined as a current smoker if
he/she smoked one cigarette per day or seven per week regularly for at least six months. Physical activ-
ity was evaluated on the basis of the International Physical Activity Questionnaire (IPAQ) [14]. Metabolic
equivalent (MET) was calculated in minutes per week according to IPAQ, and the level of physical activity
was divided into three groups: mild (≤599 MET-min/week), moderate (600–2,999 MET-min/week), vigor-
ous (≥3000 MET-min/week) [15, 16]. Education attainment was categorized as high school or above and
less than high school. Body height and weight were measured by the same trained physicians. Body mass
index (BMI) was calculated as body weight in kilograms divided by height squared in meters (kg/m2). Systolic
blood pressure (SBP) and diastolic blood pressure (DBP) were measured with an automated electronic device
(OMRON Model HEM-752 FUZZY, Omron Company, Dalian, China) on the nondominant arm three times
consecutively with one-minute intervals after at least 10-minutes’ rest. The average value of the three meas-
urements was adopted in our analysis. Hypertension was defined as SBP ≥ 140 mmHg or DBP ≥ 90 mmHg
or physician-diagnosed hypertension and use of antihypertensive medications.

Laboratory Measurements
All participants underwent a 75-g oral glucose tolerance test (OGTT), and 0 and 2 hours blood samples were col-
lected. The fasting blood glucose (FBG) and 2-hour post-loading blood glucose (PBG) were measured using the
glucose oxidize method on an autoanalyzer (Modular P800; Roche, Basel, Switzerland). Diabetes was defined
Deng et al: Association of QTc Interval with Risk of Cardiovascular Art. 13, page 3 of 11
Diseases and Related Vascular Traits

as FPG ≥ 7.0 mmol/L or OGTT-2h PBG ≥ 11.1 mmol/L or self-reported physician-diagnosed diabetes and use of
anti-diabetic agents [17]. Fasting serum triglycerides (TG), total cholesterol (TC), high density lipoprotein cho-
lesterol (HDL-C), and low density lipoprotein cholesterol (LDL-C) were determined by the chemiluminescence
method using an autoanalyzer (Modular E170; Roche, Basel, Switzerland). Urinary albumin and creatinine con-
centrations were determined using the first void sterile urine sample in the early morning by rate nephelometry
(Beckman Coulter, Fullerton, CA) and alkaline nitroxanthic acid method, respectively [18]. Urinary albumin-to-
creatinine ratio (UACR) was calculated by dividing the urinary albumin concentrations by the urinary creatinine
concentrations and expressed in mg/g. Microalbuminuria was defined as 30 mg/g ≤ UACR < 300 mg/g [19].

ECG measures
Participants underwent resting ECG recording with a 12-lead electrocardiograph instrument (CAM14, GE,
US). The QT duration was determined from the start of the QRS complex until the end of the T-wave, meas-
ured and recorded by the electrocardiograph automatically. To adjust for heart rate, we used Bazett formula:
QTcBaz = QT (heart rate/60)1/2, where QTc value of ≥460 ms in women and ≥450 ms in men was considered
as prolonged QTc interval [20].

Ascertainment of outcomes and vascular traits

The primary outcome of the current analysis was the composite of incident fatal and nonfatal CVDs, includ-
ing cardiovascular mortality, myocardial infarction, and stroke. We collected the disease and mortality infor-
mation on vital status from the local municipal health authorities. For each deceased participant, the date
and mostly likely cause of mortality were obtained, and the length of follow-up was determined from the
date of first visit in 2010 to the date of mortality. For the other participants, the dates and types of major
events were recorded if they happened, and the lengths of follow-up were determined from the dates of first
visit in 2010 to the dates of second visit.
For the secondary analyses, the baPWV and ABI were measured by a fully automatic arteriosclerosis diag-
nosis device (Colin VP-1000, Model BP203RPE II, form PWV/ABI, Japan) with the participants after at least
10-minutes’ rest. Peripheral vascular disease (PAD) was defined as narrowing and obstruction of antegrade
flow of major systemic arteries [21], which was diagnosed as ABI < 0.9 or >1.4 at either side [22]. CIMT meas-
urements were performed using a high-resolution B-mode tomographic ultrasound system (Esaote Biomedica
SpA, Genoa, Italy) equipped with 7.5 MHz line transducer [23]. The same experienced physician measured
CIMT on the far wall of the right and left common carotid arteries, 1.5 cm proximal to the bifurcation.

Statistical Analysis
Baseline characteristics of the participants were described as the mean (standard deviation, SD) for continu-
ous variables that were normally distributed, the median (interquartile range) for continuous variables of
skew distribution, and the frequency (percentage) for categorical variables. Differences between participants
with normal QTc interval and those with prolonged QTc interval were examined by unpaired t (for continu-
ous variables) and chi-square (for categorical variables) tests.
Association between QTc interval and incident CVDs was assessed by multivariable Cox regression analysis
with QTc interval in per 1-SD increase, as well as prolonged versus normal QTc interval. Models of statistical
analysis were performed as follows: model 1, unadjusted; model 2, adjusted for age, sex; model 3, addition-
ally adjusted for BMI, education, current smoking, physical activity, diabetes, hypertension, TC, TG, HDL-C,
and LDL-C. We also performed stratified analyses by sex (men vs. women), age (≥median of 57.4 vs. <57.4
years), BMI (≥25 vs. <25 kg/m2), high school education or above (yes vs. no), current smoking (yes vs. no),
physical activity (mild vs. moderate vs. vigorous), diabetes (yes vs. no) and hypertension (yes vs. no). We
tested the multiplicative interactions of QTc interval with stratification factors.
Secondary analyses included 1) examining the association of QTc interval with repeated baPWV and CIMT
measurements by generalized estimating equations (GEE); 2) examining the association of QTc interval with
newly-developed microalbuminuria and PAD by multivariable logistic regression analysis.
Statistical significance was accepted at a two-sided P value <0.05. All analyses were performed using SAS
software, version 9.4 (SAS Institute, Cary, NC).

Results
The baseline characteristics of the study participants are shown in Table 1. At baseline, 1,137 of the
­participants (15%) had prolonged QTc interval. Compared with the participants who had normal QTc
­interval, those with prolonged QTc interval were much older and had higher BMI levels. The prevalence of
diabetes and hypertension were also higher in the group of prolonged QTc interval.
Art. 13, page 4 of 11 Deng et al: Association of QTc Interval with Risk of Cardiovascular
Diseases and Related Vascular Traits

Table 1: Baseline characteristics of the participants.

Characteristics Overall Normal QTc Prolonged P value

(n = 7605) interval QTc interval
(n = 6468) (n = 1137)
Men, n (%) 2861 (37.6) 2460 (38.0) 401 (35.3) 0.08
Age, years 58.1 (9.3) 57.6 (9.2) 61.1 (9.8) 0.001
Body mass index, kg/m2 25.2 (3.2) 25.1 (3.2) 25.7 (3.5) 0.002
High school education or above, n (%) 1552 (20.4) 1354 (20.9) 198 (17.4) 0.007
Current smoking, n (%) 1565 (21.2) 1368 (21.8) 197 (17.9) 0.004
Physical activity, mild/moderate/vigorous (%) 65.5/21.3/13.2 64.4/21.5/14.1 71.4/20.3/8.3 <0.0001
Systolic blood pressure, mmHg 141.1 (19.9) 139.8 (19.4) 148.7 (21.1) 0.0001
Diastolic blood pressure, mmHg 82.9 (10.4) 82.5 (10.1) 85.2(11.2) <0.0001
Fasting blood glucose, mmol/L 5.6 (1.5) 5.5 (1.4) 5.9 (2.0) <0.0001
OGTT-2h blood glucose, mmol/L 8.2 (4.3) 8.0 (4.1) 9.5 (5.2) <0.0001
Serum triglyceride, mmol/L 1.4 (1.0, 1.9) 1.3 (1.0, 1.9) 1.6 (1.1, 2.2) 0.11
Serum total cholesterol, mmol/L 5.4 (1.0) 5.3 (1.0) 5.5 (1.0) 0.50
Serum HDL cholesterol, mmol/L 1.3 (0.3) 1.3 (0.3) 1.3 (0.3) 0.27
Serum LDL cholesterol, mmol/L 3.2 (0.9) 3.2 (0.9) 3.2 (0.9) 0.81
Diabetes, n (%) 1359 (17.9) 1047 (16.2) 312 (27.4) <0.0001
Hypertension, n (%) 4565 (60.1) 3716 (57.5) 849 (74.7) <0.0001
Heart rate, bpm 76.3 (0.9) 76.2 (11.8) 76.7 (12.3) 0.36
QT interval, ms 387.2 (31.7) 383.1 (27.2) 410.4 (43.4) <0.0001
QTc interval, ms 432.7 (30.2) 424.6 (19.8) 479.3 (36.2) <0.0001
Data are presented as mean (SD), median (inter-quartile ranges), or proportions. Linear regression for continuous
v­ariables and Cochran Armitage trend chi-square test for categorical variables were applied to analyze the difference
according to whether prolonged QTc interval happen. OGTT: oral glucose tolerance test; HDL cholesterol: high density
lipoprotein cholesterol; LDL cholesterol: low density lipoprotein cholesterol; QTc interval: ­corrected QT for heart rate
using Bazett’s formula [QTc-Baz = QT (heart rate/60)1/2]; prolonged QTc interval: QTc interval ≥450 ms in men or QTc
interval ≥460 ms in women.

During an average of 4.5 years of follow-up, we documented 419 events of CVDs, including 385 cases of
non-fatal and fatal stroke and 36 cases of non-fatal and fatal myocardial infraction; of these cases, the num-
ber of cardiovascular mortality was 37. Participants may have experienced more than 1 CVD event.

Association of QTc interval with risk of incident CVDs

As shown in Table 2, compared with normal QTc interval, prolonged QTc interval was associated with a 51%
higher risk of incident CVDs (hazard ratio [HR] = 1.51, 95% confidence interval [CI]: [1.20, 1.90]; P = 0.0004);
and 48% increased risk of incident stroke (HR = 1.48, 95%CI [1.16, 1.88]; P = 0.002), after adjustments for
the potential confounding factors (Model 3). We did not find a significant association between prolonged
QTc interval and myocardial infarction (HR = 1.52, 95%CI [0.73, 3.17]; P = 0.26). The continuous variable
analyses with each 1-SD increase in QTc interval as an exposure were also performed. The results showed
similar trends but not significant association with CVDs or the specific CVD (Table 2).
Supplemental Figure 2 shows the multivariable-adjusted HRs for CVDs and stroke in relation to pro-
longed versus normal QTc interval, in subgroups stratified by sex (men vs. women), age (≥median of 57.4
vs. <57.4 years), BMI (≥25 vs. <25 kg/m2), high school education or above (yes vs. no), current smoking (yes
vs. no), physical activity (mild vs. moderate vs. vigorous), diabetes (yes vs. no), and hypertension (yes vs. no).
It is shown that prolonged QTc interval (vs. normal) was significantly associated with an increased risk of
CVDs across most subgroups, except for that in participants younger than median age of 57.4 years, current
smokers, those with high school education or above, moderate physical activity, and those without hyper-
tension (Supplemental Figure 2A). The interactions between QTc interval and stratification factors were
Deng et al: Association of QTc Interval with Risk of Cardiovascular Art. 13, page 5 of 11
Diseases and Related Vascular Traits

Table 2: Association between QTc interval and cardiovascular diseases, stroke, and myocardial infraction in
Chinese population.

Events Incidence rates QTc interval QTc interval

(n, %) (per 1000 PYs) (per 1-SD increase)* (prolonged† vs. normal)
HR (95% CI) P value HR (95% CI) P value
Cardiovascular diseases 419 (5.5) 12.0
Model 1 1.17 (1.09, 1.26) <0.0001 1.99 (1.60, 2.48) <0.0001
Model 2 1.09 (1.01,1.19) 0.04 1.62 (1.30, 2.03) <0.0001
Model 3 1.07 (0.98, 1.17) 0.13 1.51 (1.20, 1.90) 0.0004
Stroke 385 (5.1) 11.0
Model 1 1.16 (1.07, 1.25) 0.0002 1.92 (1.52, 2.42) <0.0001
Model 2 1.08 (0.99, 1.18) 0.09 1.57 (1.25, 1.99) 0.0001
Model 3 1.06 (0.97, 1.16) 0.23 1.48 (1.16, 1.88) 0.002
Myocardial infraction 36 (0.5) 1.0
Model 1 1.24 (1.00, 1.53) 0.048 2.50 (1.23, 5.07) 0.01
Model 2 1.20 (0.93, 1.53) 0.16 1.84 (0.89, 3.80) 0.10
Model 3 1.13 (0.86, 1.48) 0.37 1.52 (0.73, 3.17) 0.26
Data are presented as hazard ratio (HR) and 95% confidence interval (CI). *Corrected QT for heart rate using Bazett’s
­formula (QTc-Baz = QT [heart rate/60]1/2), 1-SD: standard deviation, 30.2 ms; †Prolonged QTc interval: QTc interval
≥ 450 ms in men or QTc interval ≥ 460 ms in women; PY: person years. Model 1, unadjusted; Model 2, adjusted for sex,
age; Model 3, further adjusted for BMI, education, current smoking, physical activity, diabetes, hypertension, serum
total cholesterol, triglycerides, HDL cholesterol and LDL cholesterol based on model 2. BMI: body mass index; HDL
cholesterol: high density lipoprotein cholesterol; LDL cholesterol: low density lipoprotein cholesterol.

not significant (all P > 0.05). Similar results were observed in the subgroup analysis when we analyzed the
association of prolonged QTc interval with stroke (Supplemental Figure 2B).

Association of QTc interval with vascular traits using repeated measurements

As shown in Table 3, the average value of baPWV was 1585 ± 345 cm/s at baseline and 1661 ± 344 cm/s
at follow-up. The corresponding value of CIMT was 0.6 ± 0.1 mm and 0.7 ± 0.2 mm. The repeated measures
analysis revealed that QTc interval was positively associated with the increase in baPWV and CIMT, after
adjustments for sex, age, BMI, current smoking, physical activity, education, diabetes, hypertension, TC,
TG, HDL-C, and LDL-C (baPWV: β = 0.56 cm/s, Standard error [SE] = 0.11, P < 0.0001; CIMT: β = 0.0001
mm, SE = 0.0001, P = 0.03). When we regarded QTc interval as a categorical variable, similar results were
shown (prolonged vs normal QTc interval: baPWV: β =38.10 cm/s, SE = 8.04, P < 0.0001; CIMT: β = 0.01 mm,
SE = 0.01, P = 0.04).

Association of QTc interval with early vascular diseases

When examining the association of baseline QTc interval with newly developed microalbuminuria and
PAD, we additionally excluded a corresponding 267 and 290 individuals because of suffering from the
respective disease at baseline in 2010. Figure 1 and Supplemental Table 1 show incidences of micro-
albuminuria and PAD according to subgroups, comparing the prolonged QTc interval group with the
normal QTc interval group. Compared with the group of normal QTc interval, the group of prolonged
QTc interval had higher incidences of microalbuminuria and PAD across all the subgroups (Figure 1).
In the multivariable logistic regression analysis, we found that prolonged QTc interval was associated
with an increased risk of newly developed microalbuminuria (odds ratio [OR] = 1.65, 95% CI [1.21, 2.24];
P = 0.002) and PAD (2.49, 95% CI [1.35, 4.59]; P = 0.004), after adjustments for sex, age, BMI, current
smoking, physical activity, education, diabetes, hypertension, TC, TG, HDL-C, and LDL-C. Incidences of
microalbuminuria and PAD comparing the prolonged QTc interval group with the normal QTc interval
group are shown in Supplemental Figure 3. Compared with the group of normal QTc interval, the group
of prolonged QTc interval had a higher incidence of microalbuminuria (10.7% vs. 5.9%, P < 0.0001) and
PAD (3.0% vs. 1.1%, P = 0.0004).
Art. 13, page 6 of 11 Deng et al: Association of QTc Interval with Risk of Cardiovascular
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Table 3: Association of QTc interval with vascular markers using repeated measurements.

Baseline Follow-up QTc interval QTc interval

(per 1-ms increase) (prolonged* vs. normal)
β (SE) P value β (SE) P value
baPWV, cm/s 1585 (345) 1661 (344) 0.56 (0.11) <0.0001 38.10 (8.04) <0.0001
CIMT, mm 0.6 (0.1) 0.7 (0.2) 0.0001 (0.0001) 0.03 0.01 (0.01) 0.04
Parameter estimates were computed from separate generalized estimating equation analysis model with each variable at
a time after adjustment for sex, age, BMI, current smoking, physical activity, education, diabetes, hypertension, serum
total cholesterol, triglycerides, HDL cholesterol and LDL cholesterol. * Prolonged QTc interval: QTc interval ≥ 450 ms
in men or QTc interval ≥ 460 ms in women; baPWV: brachial-ankle pulse wave velocity; CIMT: carotid intima-media
thickness; SE: standard error.

Figure 1: Incidences of microalbuminuria (A) and PAD (B) according to subgroups, comparing the pro-
longed QTc interval group with the normal QTc interval group. Prolonged QTc interval: QTc ­interval ≥ 450
ms in men or QTc interval ≥ 460 ms in women; PAD: peripheral arterial disease.
Deng et al: Association of QTc Interval with Risk of Cardiovascular Art. 13, page 7 of 11
Diseases and Related Vascular Traits

Discussion
In this cohort study in a general population aged 40 and above, prolonged QTc interval was significantly
associated with increased risks of incident CVDs and stroke. In addition, prolonged QTc interval was associ-
ated with the increases in baPWV, CIMT in repeated measurements analysis, and increased risks of newly
developed vascular diseases, microalbuminuria, and PAD.
The QT interval in the surface electrocardiogram is the total duration of ventricular depolarization and
repolarization [24]. As an electrophysiological disorder, prolonged QTc interval often occurs when ventricu-
lar repolarization is lengthened, consequently resulting in malignant ventricular arrhythmias [24, 25]. A
number of cohort studies have shown that prolonged QTc interval may act as a predictor for CVDs in Western
populations [11, 26]. However, the prevalence of QTc interval prolongation is not consistent in various eth-
nicities. For example, the prevalence of QTc interval prolongation is below 5% among Americans [27, 28] but
is up to 13.7% in Chinese [29], suggesting a higher presence of prolonged QTc interval in Chinese than those
in other populations. In our study based on participants aged 40 and above, the prevalence of prolonged
QTc interval was nearly 15%. It has been reported that there could be a great variation of QTc interval among
different ethnic populations caused by genetic risk factors [11, 30, 31]. A multi-ethnic study of Europeans
and Japanese found that 28% of acquired long QT syndrome subjects had mutations in congenital long QT
syndrome genes, which differed among races [32]. Although the evidence of QT-related genetic variation
in the Chinese population is scarce, the data from a Japanese population have shown a markedly higher
prevalence of genetic mutation carriers associated with prolonged QTc interval than in Western popula-
tions [32]. In accordance with previous studies, our findings confirmed the association of QTc interval with
CVDs by expanding the evidence to the general population but not only limited to the Type 2 diabetic
patients [5]. We did not detect a significant association between QTc interval and myocardial infarction in
the present study, which might be due to a relatively low incidence and less power to get a statistical signifi-
cance. In multivariable-adjusted stratification analysis, although the association of prolonged QTc interval
(vs. normal) with CVDs appeared to be more pronounced among non-current smokers than among current
smokers, the association pattern was consistent between current smokers and non-current smokers, con-
firmed by a nonsignificant interaction between QTc interval and smoking status (P for interaction = 0.86;
Supplementary Figure 2).
QTc interval has been reported as a novel risk factor for progression of albuminuria in patients with Type 2
diabetes [33]. Our study also verified the association between QTc interval and microalbuminuria in the gen-
eral population, which adjusted the confounding effect of Type 2 diabetes. Consistent with the Hisayama
Study among the general population of Japan [34], we found QTc interval prolongation was independently
associated with the increase of baPWV. We analyzed two repeated measurement data at both baseline and
follow-up to correct random error from measurements or population and to provide more reliable evidence
supporting the association. For the first time, we found that prolonged QTc interval was associated with
the increase in CIMT and an increased risk of PAD, indicating that QTc interval prolongation could reflect a
deterioration of vascular health condition.
The mechanisms underlying the observed associations of QTc interval with CVDs are not quite clear.
However, several physiological processes involved as reported before may help interpret the observed asso-
ciation of QTc interval with CVDs in the study. Inflammation, one of the well-established traditional cardio-
vascular risk factors, can cause widespread endothelial dysfunction, increase oxidative stress, and reduce
vascular nitric oxide (NO) bioavailability [35]. The decrease in the content of NO could inhibit the activity
of Ca2+-ATPase and K+/Na+-ATPase, thus leading to an increase of cytosolic free calcium and a delay of myo-
cardial repolarization [36]. In addition, periphery blood influx could be accelerated and the ventricular load
could be gradually increased as atherosclerosis were intensified by erosions of long-term cardiovascular
inflammations and oxidative stress [37]. In this notorious pathogenesis of CVDs, prolongation of the QTc
interval could be promoted by myocardial and electrophysiological remodeling [38].
The strengths of this study included a well-defined community-based cohort study, a relatively large
sample size, and repeated measurements to evaluate multiple early vascular traits, including baPWV, ABI,
CIMT, and urinary albumin excretion. In addition, we collected information on CVDs from local municipal
health authorities, which was sufficiently validated, and adjusted fully well-defined confounding factors to
reach a reliable conclusion. We also adopted multiple vascular measurements to comprehensively interpret
the underlying association of QTc interval with the conditions of vessels. Meanwhile, by GEE, we analyzed
repeated measurements at both baseline and follow-up to reduce random errors and to improve reliability
for the results. Based on the robust and consistent results, we could convincingly conclude that prolonged
QTc interval was associated with an increased risk of CVDs in a Chinese population.
Art. 13, page 8 of 11 Deng et al: Association of QTc Interval with Risk of Cardiovascular
Diseases and Related Vascular Traits

Study limitations
This study has several notable limitations. First, the Bazett formula, which we used in the study to calculate
heart rate corrected QT interval, may overcorrect the impact of heart rate when it is faster than 100 bpm
[39]. However, it has been validated and commonly used in clinical practice and epidemiological investiga-
tions [27]. Second, because we only had two measurements of QTc interval based on baseline and follow-up,
we could not assess the association between the variation of QTc interval during repeated follow-up periods
and the risk of CVDs, which required data from subsequent follow-ups. Third, our study was restricted to
middle-aged and elderly adults who were mostly Han Chinese, making it inappropriate to generalize our
conclusions to younger populations or other ethnic populations.

Conclusions
Our study demonstrated positive associations of QTc interval with CVDs and several vascular traits as well as
early vascular diseases. Given a high prevalence of prolongation of QTc interval in the Chinese population,
our findings suggest that the prolongation of QTc interval could be applied in the early identification and
prevention of CVDs in middle aged and elderly populations.

Additional Files
The additional files for this article can be found as follows:

• Supplemental Table 1. Incidences of microalbuminuria and PAD according to subgroups,

comparing the prolonged QTc interval group with the normal QTc interval group. URL: https://s3-
eu-west-1.amazonaws.com/ubiquity-partner-network/up/journal/gh/gh-15-1-533-s1.pdf
• Supplemental Figure 1. Flow chart of study population. URL: https://s3-eu-west-1.amazonaws.
com/ubiquity-partner-network/up/journal/gh/gh-15-1-533-s2.pdf
• Supplemental Figure 2. Hazard ratios and 95% confidence intervals of cardiovascular diseases
(A) and stroke (B) according to subgroups, comparing the prolonged QTc interval group with the
normal QTc interval group. URL: https://s3-eu-west-1.amazonaws.com/ubiquity-partner-network/
up/journal/gh/gh-15-1-533-s3.pdf
• Supplemental Figure 3. Incidences of microalbuminuria (A) and PAD (B) comparing the ­prolonged
QTc interval group with the normal QTc interval group. URL: https://s3-eu-west-1.amazonaws.com/
ubiquity-partner-network/up/journal/gh/gh-15-1-533-s4.pdf

Acknowledgements
We thank the field workers for their contribution and the participants for their cooperation.

Funding Information
This study was funded by National Key R&D Program of China (2018YFC1311705, 2018YFC1311800,
2016YFC1305600, and 2016YFC1304904), National Natural Science Foundation of China (81561128019,
81770842, and 81970706), Shanghai Pujiang Program (18PJ1409600), Shanghai Municipal Education Com-
mission–Gaofeng Clinical Medicine Grant Support from Shanghai Jiao Tong University School of Medicine
(20171901), and the Shanghai Science and Technology Commission (YDZX20173100004881).

Competing Interests
The authors have no competing interests to declare.

Author Contributions
• Chanjuan Deng and Jingya Niu contributed equally to this study
• Tiange Wang, Min Xu, and Yufang Bi equally supervised this study

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How to cite this article: Deng C, Niu J, Xuan L, Zhu W, Dai H, Zhao Z, Li M, Lu J, Xu Y, Chen Y, Wang W, Ning G,
Bi Y, Xu M, Wang T. Association of QTc Interval with Risk of Cardiovascular Diseases and Related Vascular Traits: A
Prospective and Longitudinal Analysis. Global Heart. 2020; 15(1): 13. DOI: https://doi.org/10.5334/gh.533

Submitted: 29 September 2019 Accepted: 07 January 2020 Published: 10 February 2020

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Global Heart is a peer-reviewed open access journal published by Ubiquity Press. OPEN ACCESS