Wei CC, Huang YQ, Yu CH. Relationship between longitudinal changes in lipid composition and ischemic stroke among hypertensive patients. World J Clin Cases 2025; 13(4): 95803 [PMID: 39917573 DOI: 10.12998/wjcc.v13.i4.95803]
Corresponding Author of This Article
Yu-Qing Huang, Doctor, Department of Cardiology, Guangdong Cardiovascular Institute, No. 106 Zhongshan 2nd Road, Yuexiu District, Guangzhou 510080, Guangdong Province, China. hyq513@126.com
Research Domain of This Article
Cardiac & Cardiovascular Systems
Article-Type of This Article
Retrospective Cohort Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Co-corresponding authors: Yu-Qing Huang and Cheng-Hong Yu.
Author contributions: Huang YQ acquired clinical data; Huang YQ and Yu CH have played important and indispensable roles in the design, data analysis, interpretation and manuscript preparation, conceptualized, designed, and supervised the whole process of the project, searched the literature, revised and submitted the early version of the manuscript, data re-analysis and re-interpretation, figure plotting, comprehensive literature search, preparation and submission of the current version of the revised manuscript; Wei CC, Huang YQ and Yu CH conceptualized and designed the research and wrote the paper; all of the authors read and approved the final version of the manuscript to be published.
Institutional review board statement: While all the pooled data in the present study was obtained from publicly available datasets that obtained relevant ethical approval and participant consent, the design and analysis of this study was also approved by the Ethics Committee of Guangdong Provincial People's Hospital (No. 2018292H).
Informed consent statement: We obtained relevant participant consent from participants.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: The data of this study were available upon request from the corresponding author of Huang YQ.
STROBE statement: The authors have read the STROBE Statement-checklist of items, and the manuscript was prepared and revised according to the STROBE Statement-checklist of items.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Yu-Qing Huang, Doctor, Department of Cardiology, Guangdong Cardiovascular Institute, No. 106 Zhongshan 2nd Road, Yuexiu District, Guangzhou 510080, Guangdong Province, China. hyq513@126.com
Received: April 19, 2024 Revised: September 10, 2024 Accepted: November 1, 2024 Published online: February 6, 2025 Processing time: 210 Days and 1.5 Hours
Abstract
BACKGROUND
Dyslipidemia was strongly linked to stroke, however the relationship between dyslipidemia and its components and ischemic stroke remained unexplained.
AIM
To investigate the link between longitudinal changes in lipid profiles and dyslipidemia and ischemic stroke in a hypertensive population.
METHODS
Between 2013 and 2014, 6094 hypertension individuals were included in this, and ischemic stroke cases were documented to the end of 2018. Longitudinal changes of lipid were stratified into four groups: (1) Normal was transformed into normal group; (2) Abnormal was transformed into normal group; (3) Normal was transformed into abnormal group; and (4) Abnormal was transformed into abnormal group. To examine the link between longitudinal changes in dyslipidemia along with its components and the risk of ischemic stroke, we utilized multivariate Cox proportional hazards models with hazard ratio (HR) and 95%CI.
RESULTS
The average age of the participants was 62.32 years ± 13.00 years, with 329 women making up 54.0% of the sample. Over the course of a mean follow-up of 4.8 years, 143 ischemic strokes happened. When normal was transformed into normal group was used as a reference, after full adjustments, the HR for dyslipidemia and ischemic stroke among abnormal was transformed into normal group, normal was transformed into abnormal group and abnormal was transformed into abnormal group were 1.089 (95%CI: 0.598-1.982; P = 0.779), 2.369 (95%CI: 1.424-3.941; P < 0.001) and 1.448 (95%CI: 1.002-2.298; P = 0.047) (P for trend was 0.233), respectively.
CONCLUSION
In individuals with hypertension, longitudinal shifts from normal to abnormal in dyslipidemia-particularly in total and low-density lipoprotein cholesterol-were significantly associated with the risk of ischemic stroke.
Core Tip: Longitudinal changes from normal to abnormal in total cholesterol was significantly related to the occurrence of ischemic stroke among hypertension. Longitudinal changes from normal to abnormal in low-density lipoprotein cholesterol was remarkably related to the occurrence of ischemic stroke among hypertension.
Citation: Wei CC, Huang YQ, Yu CH. Relationship between longitudinal changes in lipid composition and ischemic stroke among hypertensive patients. World J Clin Cases 2025; 13(4): 95803
Ischemic stroke was the primary cause of neurological morbidity and mortality, typically leading to disability or death worldwide[1]. A variety of modifiable risk factors, such as dyslipidemia including abnormal of total cholesterol (TC), triglycerides (TG), high density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol (LDL-C), and non-modifiable factors like age, influenced the condition known as ischemic stroke[2,3]. Dyslipidemia was a prevalent and preventable chronic illness that increased the risk of atherosclerosis, including stroke[4]. Many previous cohort studies and clinical trials have demonstrated that single measurements or baseline lipid levels were significantly associated with the onset of ischemic stroke[5-7]. However, the relationship between blood lipid changes and stroke remained unclear.
Notwithstanding the recent advances in the field's understanding of lipids, studies have indicated that there may be a strong correlation between lipid fluctuations or fluctuating states and atherosclerotic disorders like stroke[8-11]. Furthermore, lipid-lowering medication has been shown in meta-analyses to reduce the risk of ischaemic stroke occurrences in both primary and secondary prevention[12-14]. Crucially, lipid levels may alter as a result of improved lifestyle choices or medicinal interventions. As a result, measures of lipid profiles may differ at different times, and lipid status may also alter during the follow-up procedure. Although some previous studies focused on the relationship between lipid status at baseline and the variability or trajectory of numerous lipid parameters with ischemic stroke, the impact of longitudinal changes in lipid status over time on the development of ischemic stroke remained uncertain. Thus, the goal of this study was to investigate whether longitudinal changes in dyslipidemia status and each of the lipid profiles between two time points increase ischemic stroke risk in people with middle and old-age hypertension.
MATERIALS AND METHODS
Study population
This was a retrospective cohort study with all Liaobu community members between 2013 and 2014 in Guangdong Province, China. Previously, the design of this research concept was thoroughly documented[9,15]. A yearly medical examination comprising a standard physical examination, a questionnaire on cardiovascular risk factors, blood lipids, blood glucose, and renal function testing was provided to the Liaobu cohort population. In this research, individuals with hypertension who were at least eighteen years old were recruited and underwent two separate physical tests in 2013 and 2014. In 2013, there were 8141 hypertensive patients, and 9739 in 2014. Participants who had previously suffered a stroke were excluded. Participants with no data on blood pressure, blood lipids, or body mass index (BMI) were also eliminated. Finally, 6094 hypertensive subjects were analyzed (Figure 1). All participants gave written consent prior to research. The Institute of Guangdong Provincial People’s Hospital’s Ethics Committee approved this research protocol (No. 2018292H).
We drew fasting blood during physical examinations in 2013 and 2014 and utilized it to measure lipids and serum creatinine. The primary lipid profiles were composed of TG, HDL-C, LDL-C, and TC. The key criteria used to establish abnormal lipid profiles were TC ≥ 200 mg/dL, LDL-C ≥ 130 mg/dL, TG ≥ 150 mg/dL, and/or HDL-C ≤ 40 mg/dL[16]. The definition of dyslipidemia must meet at least one of the following criterions: (1) TC ≥ 200 mg/dL; (2) LDL-C ≥ 130 mg/dL; (3) TG ≥ 150 mg/dL; (4) HDL-C ≤ 40 mg/dL; (5) Taking lipid-lowering drugs; and (6) Have been diagnosed with dyslipidemia by a professional physician[16]. According to the results of the first and second blood lipid tests, four groups were created based on the longitudinal changes in lipid levels: (1) Normal was transformed into normal group; (2) Abnormal was transformed into normal group; (3) Normal was transformed into abnormal group; and (4) Abnormal was transformed into abnormal group.
Assessment of covariates
Staff members who have received training and certification gathered the questionnaires and exams for this study in a standard way. The primary covariates included lifestyle, past medication history, comorbid conditions, and demographic data. The primary demographic variables included were gender, place of birth, education and income level, and marital status. Stroke, diabetes, hypertension, dyslipidemia, and coronary heart disease were the most common comorbid conditions. Physical activity, smoking, and drinking alcohol were all lifestyle habits. Currently, the most commonly utilized medications were antihypertensive, hypoglycemic, and lipid-lowering. Standing height and body weight were also measured by expert investigators. BMI was calculated by dividing weight (kg) by height (m2). An electronic blood pressure monitor was adopted to assess blood pressure (OMRONHBP1100u; Omron Corporation, Tokyo, Japan). The estimated glomerular filtration rate (eGFR) was computed via a simplified algorithm based on diet change[17]. The diagnostic criteria for hypertension should satisfy at least one of the following: (1) Previously diagnosed by a specialist with hypertension according to self-reported; (2) Taking antihypertensive drugs currently; and (3) Average systolic/diastolic blood pressure ≥ 140/90 mmHg[18]. The definition of diabetes must meet at least one of the following criterions: (1) Fasting blood glucose of ≥ 7.0 mmoL/L (126 mg/dL); (2) Self-reported diabetes previously diagnosed by a specialist; (3) Taking with hypoglycemic medications currently; and (4) Hemoglobin A1C content of ≥ 6.5%[19].
Clinical outcome
Ischemic stroke was the outcome of this study and was followed up until the end of 2018. According to our previous studies[9,15], all ischemic stroke episodes were acquired through the local health insurance system. A neurologist evaluated an ischaemic stroke using cranial magnetic resonance imaging or computed tomography imaging images, as well as subjective complaints and physical symptoms. Every ischaemic stroke occurrence was confirmed by the Clinical Events Arbitration Board and the Data Safety Monitoring Board.
Statistical analysis
The mean ± SD was used to illustrate all continuous variables, whereas percentages or numbers were used to illustrate categorical variables. Using one-way analysis of variance for continuous variables, χ² tests for categorical variables, and, when appropriate, the Wilcoxon rank sum test for ordinal variables, baseline data from the various longitudinal changes of the dyslipidaemia groups were compared. To assess the relationship between longitudinal changes in dyslipidaemia and lipid profiles and ischaemic stroke, multivariate Cox proportional hazards models were used, with the normal was transformed into normal group serving as the reference. Crude and adjusted hazard ratio (HR) and 95%CI values were calculated. There was no covariate adjustment in model 1. Age and gender were modified in model 2. Further adjustment for smoking, drinking, physical activity, BMI, eGFR, systolic and diastolic blood pressure, and fasting blood glucose were made in model 3, which was based on model 2. Model 4 included further modifications for diabetes, lipid-lowering drugs, antihypertensive drugs, hypoglycemic medicines, and coronary heart disease based on model 3. Furthermore, standardized Kaplan-Meier curves were used to analyze survival, and the log-rank test was applied to evaluate changes in cumulative event rate caused by longitudinal modifications in lipid profiles and dyslipidemia. Statistical significance was defined as a two-sided at P < 0.05. R version 3.3.2 (R Foundation for Statistical Computing, Vienna, Austria) along with Statistical Package for the Social Sciences version 19.0 (Statistical Package for the Social Sciences, Chicago, Illinois, United States) were adopted for all statistical analyses.
RESULTS
Baseline characteristics
This study included 6094 hypertensive participants, with a mean age of 62.32 years ± 13.00 years and 3292 (54.0%) of them being women. A total of 143 (2.35%) patients were newly diagnosed with ischemic stroke over the 4.8-year mean follow-up period. Depending on whether they had had an ischemic stroke or not (n = 5951) or both (n = 143), the subjects were split into two groups. As summarized in Table 1, we discovered that patients with ischemic stroke tended to be older than participants without the condition, and they also had higher TC, systolic blood pressure, LDL-C, fasting blood glucose, and a larger percentage of antihypertensive medication use (all P < 0.05). However, no significant differences were seen between the two groups in terms of gender distribution, alcohol intake, smoking status, physical activity, BMI, TG, HDL-C, diastolic blood pressure, eGFR, or co-morbid history (all P > 0.05).
Table 1 Baseline characteristics of participants, n (%).
According to the results of the first and second examinations, study participants were divided into four groups based on changes in their lipid status, as shown in Table 2: (1) Normal was transformed into normal group, 1786 (29.31%); (2) Abnormal was transformed into normal group, 979 (16.06%); (3) Normal was transformed into abnormal group, 883 (14.49%); and (4) Abnormal was transformed into abnormal group, 2446 (40.14%), respectively. Between the four groups, there were no statistically significant variations in eGFR or history of coronary heart disease (all P > 0.05). All other baseline characteristics, however, showed significant differences between the four groups (all P < 0.05).
Table 2 Baseline characteristics among different in longitudinal changes of dyslipidemia groups, n (%).
Association of longitudinal changes in dyslipidemia with ischemic stroke
Of all 143 ischemic stroke events, there were 28 (1.57%), 18 (1.84%), 34 (3.85%), and 65 (2.58%) cases in normal was transformed into normal group, abnormal was transformed into normal group, normal was transformed into abnormal group and abnormal was transformed into abnormal group, respectively. Four groups with longitudinal changes in dyslipidemia had significantly different cumulative ischemic stroke occurrences, according to Kaplan-Meier curves (log rank P = 0.002) (Figure 2A). Furthermore, as indicated in Table 3, with the normal was transformed into normal group serving as a reference, in model 1 with none variables were adjusted, the HR for dyslipidemia and ischemic stroke among abnormal was transformed into normal group, normal was transformed into abnormal group and abnormal was transformed into abnormal group were 1.173 (95%CI: 0.648-2.120; P = 0.597), 2.486 (95%CI: 1.507-4.099; P < 0.001) and 1.654 (95%CI: 1.060-2.582; P = 0.026) (P for trend was 0.156), respectively. In model 4, after full adjustments, the HR for dyslipidemia and ischemic stroke among abnormal was transformed into normal group, normal was transformed into abnormal group and abnormal was transformed into abnormal group were 1.089 (95%CI: 0.598-1.982; P = 0.779), 2.369 (95%CI: 1.424-3.941; P < 0.001) and 1.448 (95%CI: 1.002-2.298; P = 0.047) (P for trend was 0.233), respectively.
Figure 2 Kaplan-Meier analysis for the incidence of ischemic stroke among groups.
A: Dyslipidemia; B: Total cholesterol; C: High density Lipoprotein-cholesterol; D: Low density lipoprotein-cholesterol; E: Triglycerides.
Table 3 Relationship between longitudinal changes of dyslipidemia with ischemic stroke.
Case/total
Model 1
Model 2
Model 3
Model 4
HR (95%CI)
P value
HR (95%CI)
P value
HR (95%CI)
P value
HR (95%CI)
P value
Normal was transformed into normal group
28/1786
Reference
Reference
Reference
Reference
Abnormal was transformed into normal group
18/979
1.173 (0.648-2.120)
0.597
1.255 (0.693-2.271)
0.452
1.157 (0.638-2.098)
0.631
1.089 (0.598-1.982)
0.779
Normal was transformed into abnormal group
34/883
2.486 (1.507-4.099)
< 0.001
2.692 (1.629-4.449)
< 0.001
2.531 (1.526-4.199)
< 0.001
2.369 (1.424-3.941)
< 0.001
Abnormal was transformed into abnormal group
63/2446
1.654 (1.060-2.582)
0.026
1.827 (1.168-2.859)
0.008
1.584 (1.005-2.497)
0.015
1.448 (1.002-2.298)
0.047
P for trend
0.156
0.168
0.182
0.233
Association of longitudinal changes in lipid profiles with ischemic stroke
As demonstrated in Supplementary Table 1, in model 4 with full adjustments, the HR for dyslipidemia and ischemic stroke among abnormal was transformed into normal group, normal was transformed into abnormal group and abnormal was transformed into abnormal group were 1.331 (95%CI: 0.667-2.658; P = 0.418), 1.554 (95%CI: 1.020-2.366; P = 0.040) and 1.360 (95%CI: 0.820-2.255; P = 0.234), respectively. According to survival analysis, there were 85 (2.07%), 9 (2.65%), 30 (3.17%), and 19 (2.72%) ischemic stroke occurrences in the abnormal was transformed into normal group, normal was transformed into abnormal group, and abnormal was transformed into abnormal group, respectively. Kaplan-Meier curves revealed no significant differences in cumulative ischemic stroke occurrences among four groups with longitudinal changes in TC (log rank P = 0.200) (Figure 2B), whereas similar results were seen in HDL-C (log rank P = 0.770) (Figure 2C). However, the Kaplan-Meier curves showed that there were differences in the cumulative occurrences of ischemic stroke among the four groups based on longitudinal changes in LDL-C (log rank P < 0.001) (Figure 2D) and TG (log rank P = 0.030) (Figure 2E), respectively.
Supplementary Table 2 illustrated that, after controlling for potential covariates, the longitudinal changes in HDL-C were not significantly associated with an increased risk of ischemic stroke (all P > 0.05). The same findings were observed in the group with longitudinal changes in TG (all P > 0.05) (Supplementary Table 3). Nevertheless, after full adjustments, the risk of ischemic stroke was significantly increased by longitudinal changes in LDL-C in the abnormal was transformed into normal group (HR = 4.640, 95%CI: 1.699-12.672; P = 0.003) and the normal was transformed into abnormal group (HR = 2.083, 95%CI: 1.347-3.220; P = 0.001), respectively, when participants in the normal was transformed into normal group were used as a reference (Supplementary Table 4).
DISCUSSION
This study has two primary findings: (1) Compared to those who were always normal, those with community hypertension whose blood lipids fluctuated between two time points from normal to abnormal, with persistent abnormalities remaining abnormal, were linked to a higher risk of ischemic stroke; and (2) Changes in TC from normal to abnormal and LDL-C from normal to abnormal were found to significantly enhance the risk of ischemic stroke, according to longitudinal lipid research.
The current investigation showed that the risk of ischemic stroke was significantly raised when blood lipid levels changed from normal to abnormal or from continuous abnormal conditions to normal, as compared to individuals with continuous normal blood lipid levels. These results showed that the risk of an ischemic stroke may be increased by both persistently low blood lipid levels and long-term blood lipid rise. Our data were similar to those in some previous studies. A Chinese population-based longitudinal cohort study discovered that the risk of cardiovascular illnesses (such as coronary heart disease and stroke) was significantly influenced by certain types of changes in lipid trajectories[20]. Additionally, the Framingham study demonstrated a correlation between atherosclerotic cardiovascular illnesses and higher trajectories of blood lipid contents throughout adulthood[21]. Furthermore, we discovered that whereas longitudinal changes in TG along with HDL-C levels were not significantly associated with ischemic stroke, longitudinal changes in TC along with LDL-C levels from normal to abnormal significantly raised the risk of ischemic stroke. A population-based cohort study made clear that a longer duration of elevated LDL-C variations was associated with a higher chance of developing atherosclerotic cardiovascular disease[22]. Liu et al[23] documented that cumulative exposure to elevated LDL-C was an independent risk factor of newly acquired atherosclerotic cardiovascular disease. Some previous investigations found an independent link between the risk of atherosclerotic cardiovascular disease events and prior cumulative exposure to high contents of LDL-C[24,25]. These findings demonstrated the effect of long-term lipid increase on stroke risk; however, additional studies were required to ascertain its practical implications.
At present, the precise processes underlying the association between long-term blood lipid alterations and ischemic stroke remain unknown. On the one hand, apolipoprotein E (APOE) polymorphisms were linked to longitudinal trends in blood lipids[26], and APOE was essential for lipid metabolism and transport, both of which were linked to stroke[27]. On the other hand, other cardiovascular and metabolic markers, such as blood pressure, fasting blood glucose, and body weight, may also change in tandem with a change in blood lipid from normal to abnormal. Changes in blood pressure, BMI, and fasting blood glucose have all been proven to be strongly associated with the start of cardiovascular and cerebrovascular disorders. Additionally, oxidative stress and other inflammatory processes were frequently present in conjunction with alterations in blood lipid levels[28]. Finally, a previous study has shown that alterations in LDL-C contents were independent determinants of subclinical atherosclerosis[29], and subclinical atherosclerosis was a window reflecting stroke[30].
This study was the first to discover in a large Chinese hypertensive cohort population that longitudinal changes in blood lipid concentrations from normal to abnormal or chronically abnormal could significantly increase the risk of ischemic stroke. However, some limitations should be acknowledged in the current study. First, the longitudinal changes in blood lipids in this study were acquired only by monitoring blood lipid levels twice, approximately one year apart, which did not adequately represent the longitudinal changes in blood lipids. Second, there were just a few incidents during the follow-up period, which may have influenced the research findings. Third, further subgroup analyses, including gender, obesity, diabetes, and use of cholesterol-lowering medicines, were not possible due to a lack of stroke events in specific lipid profile groups. Fourth, while adjusting for various ischaemic stroke risk variables, this study did not include uric acid or atrial fibrillation. Fifth, because the study's population consisted of hypertension individuals, the findings cannot be generalised to other groups. Sixth, longitudinal changes in other measures, such as BMI, blood pressure, and heart rate, were not investigated in this study. Finally, some of the baseline variables, such as smoking, drinking, past medical history, and medication history, were self-reported, resulting in memory bias.
CONCLUSION
In conclusion, this investigation demonstrated that longitudinal changes in blood lipids between two time periods were closely related to the occurrence of ischemic stroke, particularly when the contents of TC and LDL-C changed from normal to abnormal, potentially increasing the risk of ischemic stroke. This finding revealed that while managing blood lipids in hypertensive patients, it is important to emphasize not only the significance of cholesterol-lowering medication, but also the relevance of maintaining blood lipid stability. However, the particular processes of longitudinal changes in blood lipids and ischemic stroke remained unknown, and more researches were needed to explain the association between them in the future.
Footnotes
Provenance and peer review: Unsolicited article; Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Medicine, research and experimental
Country of origin: China
Peer-review report’s classification
Scientific Quality: Grade C
Novelty: Grade C
Creativity or Innovation: Grade C
Scientific Significance: Grade B
P-Reviewer: Yao Y S-Editor: Luo ML L-Editor: A P-Editor: Wang WB
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