Association between HDL levels and stroke outcomes in the Arab population

Low HDL levels are associated with an increased stroke incidence and worsened long-term outcomes. The aim of this study was to assess the relationship between HDL levels and long-term stroke outcomes in the Arab population. Patients admitted to the Qatar Stroke Database between 2014 and 2022 were included in the study and stratified into sex-specific HDL quartiles. Long-term outcomes included 90-Day modified Rankin Score (mRS), stroke recurrence, and post-stroke cardiovascular complications within 1 year of discharge. Multivariate binary logistic regression analyses were performed to identify the independent effect of HDL levels on short- and long-term outcomes. On multivariate binary logistic regression analyses, 1-year stroke recurrence was 2.24 times higher (p = 0.034) and MACE was 1.99 times higher (p = 0.009) in the low-HDL compared to the high-HDL group. Mortality at 1 year was 2.27-fold in the low-normal HDL group compared to the reference group (p = 0.049). Lower sex-specific HDL levels were independently associated with higher adjusted odds of 1-year post-stroke mortality, stroke recurrence, and MACE (p < 0.05). In patients who suffer a stroke, low HDL levels are associated with a higher risk of subsequent vascular complication.


Methods
The Qatar stroke database prospectively collects data on stroke patients admitted to the Hamad General Hospital (HGH), the only tertiary care hospital for stroke admissions in the State of Qatar.The details of the database have previously been published 4 .This is a retrospective cohort analysis of stroke patients from the database.All patients admitted with a stroke, including ischemic stroke, stroke mimics, transient ischemic attack (TIA) and intracranial hemorrhage admitted to Hamad General Hospital (HGH), Doha, Qatar between January 1, 2014 and December 04, 2021 were available for analysis.For the purpose of this study we included only Arab patients with a confirmed diagnosis of ischemic stroke.In order to better understand the relationship between HDL and stroke, we excluded patients with missing data on HDL levels.
Atrial fibrillation (AF) was diagnosed based on electrocardiographic findings on admission or on holter monitoring during hospitalization.Smoking was defined as current cigarette smoking.Diabetes was diagnosed according to the American Diabetes Association (ADA) and World Health Organization (WHO) recommendations and included patients with a previous diagnosis of diabetes mellitus (DM), on medication for DM or a HbA1c ≥ 6.5% and the diagnosis of pre-DM was based on a HbA1c of 5.7-6.4% as per 2015 ADA clinical practice recommendations 6 .Hypertension was defined as a previous systolic blood pressure ≥ 140 mm Hg or a diastolic blood pressure ≥ 90 mm Hg, or current treatment with antihypertensive drugs.Complications monitored and recorded included aspiration pneumonia, urinary tract infection, bedsores, deep venous thrombosis, and sepsis during hospitalization.
Inpatient outcome measures were National Institute of Health stroke scale (NIHSS) on admission, in-hospital mortality, Intensive are unit (ICU) admission, major complications, in-hospital interventions including thrombolysis and mechanical thrombectomy, and survivor-only hospital length of stay (LOS).Long-term outcome measures among survivors of index admission with adequate follow-up data available were mortality and modified Rankin Score (mRS) at 90 days of discharge, and stroke recurrence, post-stroke myocardial infarction (MI), post-stroke major cardiac adverse events (MACE), and post-stroke cardiac revascularization procedures within 1 year of discharge.To achieve this, the Cerner electronic medical systems were used to track patient admissions throughout the state of Qatar.
Descriptive results for all continuous variables were reported as mean ± standard deviation (SD) when normally distributed or as medians with interquartile ranges (IQR) when non-normally distributed.The distribution of continuous variables was assessed by applying Kolmogorov Smirnov tests prior to using statistical tools.Descriptive results for all categorical variables were reported as numbers and percentages.ANOVA test was used to compare normally distributed continuous variables between groups.Kruskall-Wallis h test was used to compare non-parametric continuous variables between groups.Chi-square or Fisher's exact test were used to compare categorical variables between groups where appropriate.
Multivariate binary logistic regression analyses were performed to determine the independent effect of sexspecific TG-HDL indices on outcomes: In-hospital mortality, in-hospital major complications, 1-year stroke recurrence, 1-year post-stroke MACE, 1-year post-stroke cardiac revascularization, 90-day mortality, and 1-year mortality.
Multivariate analyses adjusted for potential confounders, including patient demographics (age, sex), emergency department vitals (systolic blood pressure), comorbidities (diabetes, hypertension, dyslipidemia, coronary artery disease, atrial fibrillation, prior stroke history, obesity, smoking status), stroke severity, and in-hospital interventions (thrombolysis or thrombectomy).Covariates for multivariate analyses were chosen from an initial bivariate analysis as well as from prior literature demonstrating effect on stroke outcomes.Alpha was set at 5% and a p-value less than 0.05 was considered statistically significant.All statistical analyses were performed using IBM Statistical Product and Service Solutions (SPSS) version 28.All methods were carried out in accordance with relevant guidelines and regulations.Informed consent was obtained from all subjects and/or their legal guardian(s).The study was approved by the Committee for Human Ethics Research, Academic Health Service at HMC (MRC-01-20-1135).

Ethics statement
The study was approved by the Committee for Human Ethics Research, Academic Health Service at HMC (MRC-01-20-1135).
On univariate analyses, LOS was highest for the Low-HDL group compared to all the other groups (p = 0.045).There was no statistically significant difference in the rate of thrombolysis between the different sex-specific HDL quartiles, however, thrombectomy rates in the Low-HDL group were almost twice as that of the High-HDL group (p = 0.026).Similar rates were also observed for the 1-year stroke recurrence [6.1% vs. 2.9% (p = 0.014)] and 1-year post-stroke MACE [11.7% vs. 6.2% (p = 0.021)] between the low-HDL and high-HDL group.No statistically significant difference was observed between the sex-specific HDL quartiles for the 90-day and 1-year mortality, and for the 1-year post-stroke MI and cardiac revascularization procedures (Table 2).
On multivariate binary logistic regression analyses, risk adjusted odds ratio for 1-year stroke recurrence was 2.24 times higher (p = 0.034) and for MACE was 1.99 times higher (p = 0.009) in the low-HDL group compared to the high-HDL group.Mortality at 1 year was 2.27-fold in the low-normal HDL group compared to the reference group (p = 0.049).No difference in 90-Day Mortality between the different sex-specific HDL quartiles was observed (Table 3).

Discussion
Our study shows that a low HDL was associated with a 2.24-fold risk of 1-year stroke recurrence on multivariate binary logistic regression analysis in the Arab cohort.Several studies have previously shown an inverse relationship between lower HDL and an increased risk of stroke [7][8][9][10][11][12] .There is however limited data on the relationship between HDL and short and long-term post-stroke outcomes, especially in the Arab population where lipid abnormalities are very common.Mei et al. conducted a study on 1059 ischemic stroke patients in a Chinese population, and reported two-fold risk of recurrent stroke in the low-HDL group compared to the high HDL group 13 .A Vietnamese study identified low HDL as a significant recurrent ischemic stroke risk factor (OR 1.43; 95% CI 1.08-1.88) 14.The stroke prevention by aggressive reduction in cholesterol levels (SPARCL) trial similarly showed each 13.7 mg/dl increment in www.nature.com/scientificreports/HDL to be associated with a 13% reduction in ischemic stroke risk with reduction in MACE events reported as well 15 .Conversely, Park et al. analysed the Vitamin Intervention for Stroke Prevention (VISP) study database comprising of 3680 non-cardioembolic stroke patients followed up for up to 2 years, and was unable to demonstrate a significant association between baseline HDL-C and recurrent ischemic stroke in multi-variable cox analysis.However, the different outcome of this study may be attributed to not being able to adjust for metabolic syndrome due to unavailability of glucose levels 16 .The risk of MACE was 1.99 times higher in the low-HDL group when compared to the high-HDL group (p = 0.009).Major adverse cardiovascular events (MACE) are common in patients who suffer an acute ischemic stroke 4 , and our study corroborated these findings.This is similar to the report in a Brazilian cohort by Vitturi et al., who demonstrated an inverse association between low HDL-C levels and increased risk of MACE (OR 5.96, 1.66-21.39,p = 0.005), but not increased stroke recurrence 17 .There are other reports where the association was not established 18 .
Mortality at 1 year was however 2.27-fold higher in the low-normal HDL group compared to the reference group (p = 0.049).Perovic et al., observed in a small study of 52 patients that lower HDL at discharge was associated with significantly higher patient disability (Barthel index < 60), and mortality at 90-days 19 .Tian et al. had  20 .However, low HDL was also associated with almost twice as high thrombectomy rates as compared to high HDL on univariate analysis in our population.Bravi et al. had similar outcomes in an Italian cohort where endovascular thrombectomy (EVT) patients showed lower levels of non-HDL-C, compared to non-EVT patients   21 .Some reasons for our findings could be that low HDL-C has been shown to be associated with a significant increase in carotid plaque volume by ultrasound 22 , and increased infarct size 23 .Another explanation could be the inverse association of HDL levels with development of intracranial atherosclerotic stenosis (ICAS), severity of ICAS, and multi-vessel involvement of ICAS 24 .
Our findings can be attributed to the several mechanisms by which HDL protects against atherosclerosis.It transports cholesterol from the artery wall to the liver for excretion by the mechanism of reverse cholesterol transport.It blocks inflammation by acting as an anti-oxidant and it reduces thrombotic risk by inhibition of platelet activation and aggregation.HDL has been able to reduce neuronal damage after onset of ischemic stroke in both excitotoxic and MCA occlusion models of stroke 22 .Interestingly, Experimental IV infusion of HDL has shown neuroprotective effects by reducing lesion size 25 .Moreover, apolipoprotein A-1 (Apo A-1), which is a component of HDL, has been associated with a decrease of brain lesion size by 64% in a middle cerebral artery occlusion model 22 .HDL has also been shown to enhance insulin sensitivity and promote insulin secretion by pancreatic beta islet cells 24 .
A number of clinical trials that involved HDL-C raising strategies, including AIM-HIGH trial (niacin), ACCORD trial (fenofibrate), and ILLUMINATE trial (torcetrapib), however, failed to demonstrate any clinical benefits with the treatments 24 .A reasonable explanation why the treatment-induced increase in HDL does not result in positive results may be dysfunctional HDL, similar to the HDL patients with DM, CKD, or metabolic syndrome have.It has been proposed that this may lead to endothelial injury and promote atherosclerotic processes.Edzard Schwedhelm proposed calculating the 'biologically effective' HDL cholesterol level as a way to differentiate between regular and dysfunctional HDL 18 .Multiple observational studies have also found that HDL particle number and size may be better predictors of cardiovascular disease than HDL-C alone 11 .

Conclusion
Our study shows that lower sex-specific HDL levels were associated with worse 1-year post-stroke neurologic and also cardiovascular outcomes.This is the first reported corroboration of previously known associations between HDL levels and long-term stroke outcomes in the Arab population.Our findings highlight the importance of cardiovascular risk stratification after initial stroke occurrence.These interventions may play an even more important role in the Arab population where dyslipidemia is highly prevalent.The 90-Day mRS showed no difference between the different HDL quartiles but at the 1-year visit, a difference in mortality was observed.Supplementing the 90-Day clinic visit with 1-year and 5-year follow-up visits will lead to more accurate representation of post-stroke outcomes.

Figure 1 .
Figure 1.Kaplan meier curve for time to recurrent stroke.

Figure 2 .
Figure 2. Kaplan meier curve for 1-year post-stroke all cause mortality.

Table 4
lists a comparative analysis of the outcomes among different studies.Figures1, 2, 3

Table 1 .
Baseline Characteristics Stratified by Sex-Specific HDL Quartiles.TG triglyceride, HDL high density lipoprotein, M males, F females, SD standard deviation, BMI body mass index, CAD coronary artery disease, SBP systolic blood pressure, DBP diastolic blood pressure, RBS random blood sugar, HbA1C glycosylated hemoglobin, LDL low density lipoprotein, Chol cholesterol, NIHSS National Institutes on Health Stroke Severity Scale, TOAST trial of ORG 10,172 in Acute Stroke Treatment Classification.

Table 2 .
Univariate Analysis of Outcomes Stratified by Sex-Specific HDL Quartiles.HDL high-density lipoprotein, LOS length of stay, d days, y year, IQR interquartile range, ICU intensive care unit, MRS modified Rankin Scale, MACE major adverse cardiac event, MI myocardial infarction, M males, F females.Long-term outcomes and in-hospital LOS were assessed among survivors of index hospital admission.

Table 3 .
Multivariate Binary Logistic Regression Analysis of Outcomes Stratified by Sex-Specific HDL Quartiles.HDL high-density lipoprotein, LOS length of stay, d days, IQR interquartile range, ICU intensive care unit, MRS modified Rankin Scale, MACE major adverse cardiac event, MI myocardial infarction, aOR adjusted odds ratio, 95% CI 95% confidence interval, M males, F females.Multivariate analyses adjusted for patient demographics (age, sex, ethnicity), emergency department vitals (systolic blood pressure), comorbidities (diabetes, hypertension, dyslipidemia, coronary artery disease, atrial fibrillation, prior stroke history, obesity, smoking status), stroke severity, and in-hospital interventions (thrombolysis or thrombectomy).

Table 4 .
Comparison of Post-Stroke Outcomes in Different HDL Quartiles, previously published studies.MT mechanical thrombectomy, MACE major adverse cardiovascular events, CHD coronary heart disease, MI myocardial infarction, HDL-C high density lipoprotein cholesterol, C.I confidence interval, S.D standard deviation, H high, LN low-normal, L low, M male, F female.† Barthel Index = Marker of patient disability.
similar observations in 1568 Chinese ischemic stroke patients, in whom low HDL measured within 24 h of admission was associated with adverse patient outcomes (defined as NIHSS > 10 at discharge or death)