- Academic Editor
†These authors contributed equally.
This is an open access article under the CC BY 4.0 license.
Background: Several studies have linked traumatic injury and
cardiovascular disease. However, few studies have investigated the associations
between traumatic injury and cardiovascular disease subtypes. We aimed to
prospectively examine the association between traumatic injury and the risk of
incident myocardial infarction (MI) and stroke. Methods: This study was
based on a prospective cohort study that included 13,973 patients who had been
hospitalized for traumatic injuries from 1980 to 2020. We randomly selected 4
uninjured participants from the cohort study for each patient as controls matched
by age (
Cardiovascular disease (CVD) is the leading cause of death worldwide [1], with myocardial infarction (MI) and stroke being the most prevalent and major causes of CVD-related mortality [2, 3]. Although behavioral and biological risk factors were mainly associated with developing CVD [4], recent studies have shown that traumatic injury may influence the risk of developing CVD [5, 6]. Traumatic injury is a major public health concern, with cases widely distributed among all age groups [7]. Injured patients tend to develop negative coping behaviors following injury, which can damage physical health. In fact, traumatic injury was associated with multiple behavioral CVD risk factors, such as smoking, substance abuse, and physical inactivity [8, 9]. The association between traumatic injury and CVD risk factors has prompted an increasing interest in exploring the association between traumatic injury and CVD-related health outcomes.
Several studies have linked traumatic injury to the surge in CVD events [10, 11]. A survey from Canada found spinal cord injury to be associated with significantly increased odds of CVD [12]. Similarly, a study from Hong Kong showed that the risk of CVD in patients with hip fractures increased by 27% more than in propensity score-matched controls [13]. Previous research has usually classified all cardiovascular disease events into one group and few studies have prospectively investigated the associations between traumatic injury and the subtypes of CVD events (MI and stroke). Therefore, the objective of this study was, in a prospective cohort study, to examine the associations between traumatic injury and the risk of incident MI and stroke.
This study was based on the Kailuan Study, a prospective cohort study conducted in the Kailuan community in Tangshan, China. The detailed study design and procedures have been described previously [14, 15]. Briefly, the Kailuan Study conducted the first health survey enrolling on-job and retired employees of the Kailuan Group from July 2006 to October 2007 [14, 15]. Participants responded to questionnaires and underwent health examinations in 11 local hospitals. Data on demographics, lifestyle, basic anthropometric measurement, and blood tests, were gathered and subsequently updated every 2 years. From July 2006 to October 2019, a total of 171,089 participants at least 18 years old were enrolled in the Kailuan Study.
In this study, individuals from the Kailuan study who had been hospitalized for
traumatic injuries from January 1980 to December 2020 were included. An expert
panel was made up of three experienced clinicians from the emergency department, orthopedics and general surgery checked the admission
and discharge lists annually from the 11 local hospitals and the social insurance records to ascertain these injured patients.
The panel defined injury severity (mild, moderate, and severe injury) according
to the injury conditions of patients at the time of admission. The classification
criteria were as follows. First, the mild injury was defined as no injury in the main sites and organs (e.g., brain,
thoracic cavity, and abdominal cavity) of the patient, mostly skin and soft
tissue injury or fracture of the distal limb. Second, the moderate injury was
defined as an injury to the main sites or organs of the patient with relatively
stable vital signs and no short-term life-threatening events (e.g., abdominal
organ injury and long bone fracture). Third, severe injury was defined as an
injury to the main sites or organs of the patient, if not a timely and effective
treatment, which can lead to death in a short time (e.g., severe bleeding and
several fractures of the skull vault). Patients with repeated injuries were
classified according to the heavier grade of injury [16]. We excluded
participants with missing information on age and sex and a history of MI or
stroke at enrolment in the Kailuan Study (Supplementary Fig. 1). For
each patient, four uninjured participants of the Kailuan Study were randomly
selected as controls matched by age (
This study followed the principles expressed in the Declaration of Helsinki. The ethics committee of Kailuan General Hospital approved the study protocol (Approval number: 2006-05). All participants provided written informed consent and did not receive financial compensation.
The outcome event in this study was the first incident of MI or stroke (no history of outcome events before the start of follow-up and for multiple occurrences of MI or stroke, follow-up ended at the first visit) during the follow-up period. All outcome events were identified according to the International Classification of Diseases 10th revision (ICD-10, MI: I21, I60 and I61; stroke: I63) [17]. Information on MI or stroke was obtained from the Hospital Discharge Register of 11 location hospitals and from the Municipal Social Insurance Institution, and updated annually during the follow-up period. Suspected cases of MI or stroke were identified by a review of annual discharge records by three experienced clinicians from the Department of Cardiology. The diagnosis of MI was determined by the patient’s clinical symptoms, electrocardiogram, and dynamic changes in myocardial enzymes, following the World Health Organization’s Multinational Monitoring of Trends and Determinants in Cardiovascular Disease criteria [18]. The diagnosis of stroke was based on neurological signs, clinical symptoms, and neuroimaging tests (including computed tomography and magnetic resonance imaging), in line with the World Health Organization criteria [19]. The information of all-cause mortality was from the municipal death registries. and checked annually against local residential records, with active survival confirmation through subdistrict offices.
Covariates in this study were gathered from the self-reported questionnaires (including age, sex, smoking and drinking status, physical activity, salt intake, and family history of MI and stroke), basic anthropometric measurements (including height, weight, systolic blood pressure [SBP], and diastolic blood pressure [DBP]), and blood tests (including fasting blood glucose [FBG], low-density lipoprotein cholesterol [LDL-c], high-density lipoprotein cholesterol [HDL-c] and triglycerides [TG]) [20, 21, 22, 23]. All covariates were collected when participants enrolled in the Kailuan Study.
Body mass index (BMI) is calculated by dividing weight (kg) by height squared (m
The blood tests at each health assessment were conducted after overnight fasting. The blood samples were analyzed using an auto-analyzer (Hitachi 747, Hitachi, Tokyo, Japan) at the central laboratory of Kailuan General Hospital [26].
The baseline characteristics were compared between injured patients and controls. Variance or the Kruskal-Wallis test was
used for continuous variables, and the chi-square test was used for categorical
variables. The incidence rate of MI and stroke per 1000 person-years was calculated by the total number of
incident cases divided by the total number of years of follow-up and multiplied
by 1000. Cox proportional hazards models were used to calculate the hazard ratio
(HR) and 95% confidence intervals (CI) of incident MI and stroke. Covariates
with p
Furthermore, two stratified analyses were conducted to determine the role of age at injury and sites of injury in the association between traumatic injury and incident MI or stroke. Patients with multiple injuries were classified based on the major site of injury. Each control was assigned a false age at injury and a site of injury similar to those of the matched injured patient. The likelihood ratio test was used to examine the interaction between traumatic injury and age at injury and sites of injury.
Several sensitivity analyses were conducted to test the robustness of our
findings. (1) The MI and stroke events incident within the first year of the
follow-up periods were excluded to minimize potential reverse causation. (2)
Injured patients who had been injured for
All analyses were performed using SAS (version 9.4, SAS Institute, Cary, NC,
USA). All statistical tests were two-sided, and p
The baseline characteristics of 13,973 injured patients and 55,892 controls were
shown in Table 1. In general, the mean age of participants was 52.3
Variables | Total | Uninjured | Injured | p value |
---|---|---|---|---|
(N = 69,865) | (N = 55,892) | (N = 13,973) | ||
Age, yrs | 52.3 |
52.3 |
52.3 |
0.989 |
Male | 66,690 (95.5) | 53,352 (95.5) | 13,338 (95.5) | 1.000 |
Active physical activity | 10,419 (14.9) | 8410 (15.0) | 2009 (14.4) | 0.047 |
Drinker | 13,956 (20.0) | 10,767 (19.3) | 3189 (22.8) | |
Smoker | 30,871 (44.2) | 24,597 (44.0) | 6274 (44.9) | 0.057 |
High salt intake | 7713 (11.0) | 6153 (11.0) | 1560 (11.2) | 0.600 |
Family history | 3138 (4.5) | 2364 (4.2) | 774 (5.5) | |
Obesity | 11,805 (16.9) | 9416 (16.8) | 2389 (17.1) | 0.480 |
TG, mmol/L | 1.8 |
1.8 |
1.7 |
0.004 |
FBG, mmol/L | 5.6 |
5.7 |
5.5 |
|
HDL-c, mmol/L | 1.5 (1.2–1.7) | 1.5 (1.2–1.7) | 1.5 (1.3–1.8) | |
LDL-c, mmol/L | 2.5 (2.0–3.0) | 2.5 (2.0–3.0) | 2.4 (1.9–3.0) | |
SBP, mmHg | 132.5 |
132.7 |
131.8 |
|
DBP, mmHg | 85.0 |
85.0 |
84.8 |
0.068 |
Data are presented as mean |
The median follow-up period for participants was 13.5 (8.6–14.1) years. During
the period, 1032 cases of MI and 4068 cases of stroke were identified. The
median time of developed as MI or stroke after injury was 5.68 (2.93–7.95) years
and 7.51 (4.14–10.10) years, respectively. Fig. 1 shows the incidence rates of
MI and stroke per 1000 person-years and the HR and 95% CI of incident MI and
stroke among injured patients. Patients with severe injury have a higher
incidence rate per 1000 person-years of MI and stroke (1.05 and 3.12 per 1000
person-years, respectively). After multivariable adjustment, we observed a
significant trend of increasing risks of MI and stroke with injury severity among
injured patients (p-trend = 0.0128 for MI and
Adjusted HR (95% CI) of incident MI and stroke for injured patients according to injury severity. Abbreviations: MI, myocardial infarction; PYrs, person-years; HR, hazard ratio; CI, confidence interval.
In the stratified analyses, injured patients and controls were classified into
four groups according to age at injury:
Age at injury | Uninjured controls | Injured patients | HR (95% CI) | |||
---|---|---|---|---|---|---|
Case/Total | Incident rate/1000 PYrs | Case/Total | Incident rate/1000 PYrs | |||
MI (p for interaction | ||||||
215/18,116 | 0.39 | 56/4529 | 0.34 | 0.73 (0.54–0.98) | ||
30–39 yrs | 236/16,908 | 0.49 | 65/4227 | 0.53 | 1.20 (0.91–1.58) | |
40–49 yrs | 260/15,652 | 0.64 | 62/3913 | 0.74 | 1.50 (1.13–1.99)** | |
104/5216 | 0.78 | 34/1304 | 1.60 | 2.58 (1.73–3.85)*** | ||
Stroke (p for interaction | ||||||
848/18,116 | 1.54 | 272/4529 | 1.64 | 0.88 (0.77–1.01) | ||
30–39 yrs | 906/16,908 | 1.90 | 257/4227 | 2.10 | 1.24 (1.08–1.43)* | |
40–49 yrs | 981/15,652 | 2.42 | 272/3913 | 3.27 | 1.95 (1.69–2.25)*** | |
424/5216 | 3.21 | 108/1304 | 5.17 | 2.24 (1.78–2.81)*** | ||
*p |
Sites of injury | Uninjured controls | Injured patients | HR (95% CI) | |||
---|---|---|---|---|---|---|
Case/Total | Incident rate/1000 PYrs | Case/Total | Incident rate/1000 PYrs | Case/Total | ||
MI (p for interaction = 0.0456) | ||||||
Head injury | 33/2496 | 0.48 | 10/624 | 0.59 | 1.30 (0.64–2.66) | |
Chest injury | 93/4832 | 0.71 | 31/1208 | 1.17 | 1.85 (1.22–2.80)** | |
Abdominal injury | 74/5004 | 0.53 | 23/1251 | 0.66 | 1.31 (0.82–2.10) | |
Extremities injury | 465/33,868 | 0.48 | 112/8467 | 0.45 | 0.95 (0.77–1.16) | |
Other injury | 150/9692 | 0.55 | 41/2423 | 0.59 | 1.09 (0.77–1.55) | |
Stroke (p for interaction | ||||||
Head injury | 145/2496 | 2.13 | 41/624 | 2.44 | 1.22 (0.86–1.73) | |
Chest injury | 337/4832 | 2.60 | 107/1208 | 4.10 | 1.82 (1.46–2.28)*** | |
Abdominal injury | 267/5004 | 1.93 | 80/1251 | 2.33 | 1.26 (0.98–1.62) | |
Extremities injury | 1,851/33,868 | 1.94 | 538/8467 | 2.19 | 1.12 (1.01–1.23)* | |
Other injury | 559/9692 | 2.06 | 143/2423 | 2.05 | 1.02 (0.85–1.22) | |
*p |
The result of sensitivity analyses excluding
MI and stroke events incident within the first year of follow-up (N = 69,443),
patients with traumatic injury who had been injured for
In this study, traumatic injury was associated with an increased risk of MI and stroke during a median follow-up period of 13.5 years. Notably, the risks of incident MI and stroke increased with injury severity. Additionally, patients with older age at injury or a chest injury have higher HRs of MI and stroke.
MI and stroke are the leading causes of mortality worldwide [29]. Chiang et al. [30] reported
a 29% increased risk of MI among 8758 patients with hip fractures during a
median follow-up period of 3.2 years. Variably, a significant association only
existed between severe traumatic injury and incident MI among patients during a
median follow-up period of 13.5 years. Some findings may explain the difference.
This finding may be due to decreasing risk of MI over time after traumatic injury
[5, 13]. The study showed that the risk of MI persists for
Furthermore, the association between traumatic injury and incident MI and stroke differed by age at injury and injury site. Age effects reflect the biological and
social processes of aging intrinsic to individuals [32]. Therefore, differences
in metabolic condition and recovery of injured patients exist at different ages
of injury. Clinical recovery was worse, and the burden of complications was
greater with the increasing age of injury [33]. Ismailov et al. [34]
reported that abdominal or pelvic traumatic injury was associated with a 65% and
93% increased risk of acute MI among patients with ages of
This study provides strong evidence linking traumatic injury with incident MI and
stroke. Although the pathogenesis underlying this association could not be elucidated, some mechanisms may explain this association. First, traumatic injury
triggers a range of host responses, including immune, endocrine, and inflammatory
responses [6]. Existing evidence suggests
that traumatic injury induces neuroendocrine activation of the
hypothalamic-pituitary-adrenal axis and the sympathetic nervous system as the
core [36]. However, these responses are consistently activated in injured
patients and result in impairment of metabolism and cardiovascular function [37, 38]. Traumatic injury produces an excess of pro-inflammatory mediators, leading
to systemic inflammatory responses [39]. A meta-analysis showed significantly
high levels of inflammatory markers, including C-reactive protein, interleukin-6,
and tumor necrosis factor-
This study had some limitations. First, mental conditions such as poor mood, depression, and anxiety in post-injury patients were not considered, all of which are associated with traumatic injury and could explain the study results. Second, we lack data on the recovery status of injured patients, and patients who have not fully recovered may be at greater risk for MI and stroke due to physical activity limitations than those who have fully recovered, which is more pronounced in patients with severe injuries, and therefore we may be underestimating the risk in these not fully recovered patients. Additionally, since the Kailuan Study was based predominantly on men and the incidence of traumatic injury is much higher in Chinese men than in women, the majority of participants in this study were men [46]. In the female subgroup, we did not find a significant association between traumatic injury and the incident of MI and stroke. The 95% CI of HR was wider, which may be related to fewer cases in women. Thus further studies with equal sex distribution are still warranted.
Traumatic injury was associated with an increased risk of MI and stroke. The incidence of traumatic injury is still surging, possibly translating into a high disease burden of MI and stroke in the future. Therefore, strategies for early identification and prevention of post-traumatic MI and stroke, which are essential for injured patients improving the quality of life, should be developed.
The data presented in this study are available on request from the corresponding author. The data are not publicly available due to privacy.
CC and SH designed the research study. TL, YL, and HF performed the research. SW, SC, JG and XLi participated in collecting the data and data management. XLiu and AW analyzed the data and wrote the manuscript. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript.
Informed consent was obtained from all subjects involved in the study. The study was conducted in accordance with the Declaration of Helsinki, and approved by the ethics committee of Kailuan General Hospital (Approval number: 2006-05).
The authors thank all the survey teams of the Kailuan study group for their contribution and the study participants who contributed their information.
This research was funded by the National Key R&D Program of China (grant numbers: 2021YFC260050401 and 2019YFC160630401).
The authors declare no conflict of interest.
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