Association between serum triglycerides and stroke type, severity, and prognosis. Analysis in 6558 patients

Hypertriglyceridemia (HT) is frequently diagnosed in clinical practice, with a prevalence of ~10% worldwide [1]. The prevalence is higher in the USA (29.6%) and Europe (25.9%), which likely reflects the increase in obesity and diabetes [2]. In the Middle Eastern and South Asian population, the prevalence of HT has been estimated at 39.5% in men and 21.9% in women [3, 4]. Genetic, dietary and life-style factors contribute to the higher prevalence of HT in these populations [4]

HT is increasingly recognized as an important risk factor for both coronary artery disease (CAD) [1] and stroke [5]. Most previous studies have focused on Caucasian populations, and few have evaluated the effects of HT in the Middle-East/Asia where the incidence of stroke is higher than CAD [3]. A recent study in stroke patients from Japan showed that HT was associated with a higher incidence of intracranial atherosclerosis (ICAD) and an increase in major atherosclerotic cardiovascular events (MACE) during early follow-up [6]. South Asian and Middle Eastern populations may be particularly susceptible to the effects of HT and may manifests sequelae at a younger age [7], suggesting an urgent need for further research in this population.

Although HT contributes to the risk for stroke, several studies have reported an inverse relationship between the levels of serum triglycerides and the severity of symptoms of acute ischemic stroke [8]. This was initially reported from Glasgow in 2003 [9]. In a study of 1310 non-diabetic patients with acute stroke, increasing age, hyperglycemia and low triglycerides were associated with higher mortality. Similarly, another study with 863 ischemic stroke patients confirmed an associated between lower triglyceride levels and increased stroke severity [10]. These findings were confirmed in studies from Korea [1067 acute ischemic stroke patients] [11] and Greece [790 patients with acute ischemic stroke] [12]. Interestingly, a study of 121 patients from Zagreb showed that higher serum triglycerides was associated with a smaller volume of the ischemic stroke [13]. These are small studies that lack details on the relationship between HT and the type of stroke or long-term prognosis. There is no information on the effects of HT in the Asian or Arab population, where HT high and where stroke is more common than CAD [3].

The Qatar stroke database has prospectively collected data on all stroke admissions to the Hamad General Hospital (HGH) the main tertiary care hospital where ~95% of patients were acute stroke are admitted. The patient population is predominantly South Asian (52.8%) and Arab (32%). The database has over 15,000 patients and captures important details including risk factors, severity of symptoms, short-term fsuppland long-term prognosis [14‐19]. We have previously documented high rates of dyslipidemia in this population [15, 17, 19]. For the current analysis, we had the following objectives: i) to evaluate the effects of increasing levels of serum triglycerides on the age at presentation, severity of symptoms and the type of ischemic stroke, ii) to review the relationship between HT and short and long-term prognosis following acute ischemic stroke, and iii) to determine if these relationships are independent of diabetes, which is commonly associated with HT.

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 through December 04, 2021 were entered into the database and the information was available for analysis. For the purpose of this study we retrospectively evaluated data on patients with a confirmed diagnosis of ischemic stroke. The details of the stroke database have previously been published [14‐19]. In brief, HGH is a Joint Commission International accredited 600-bed hospital, where ~95% of all strokes in Qatar requiring hospital admission are admitted. The stroke program, also certified by the Joint Commission International, is equipped with all the necessary laboratory, neuro-radiological and neurosurgical facilities needed to manage acute stroke patients and has a 24-hour thrombolysis and thrombectomy services. All patients with a suspected diagnosis of acute stroke seen in the Emergency Department (ED) by the Stroke team to enable immediate decisions on thrombolysis and further management.

During the time period of analysis (January 2014-December 2021), there were 14,768 patients entered into the acute stroke database. After exclusion of patients with ICH (1549), TIAs (1413), stroke mimics (4302), and cerebral venous thrombosis (204), there were 7300 patients with a diagnosis of ischemic stroke. After excluding 742 patients in whom the data was not complete, we were left with 6558 patients for the study.

This study evaluates the effects of increasing levels of triglycerides on the severity of symptoms, stroke sub-types and the short and long-term prognosis. As diabetes is frequently seen in patients with high triglyceride values, we did additional analysis in patients without diabetes. An important feature of our study is the evaluation of the detrimental effects of HT in patients from the Middle Eastern and South Asia. In these populations, HT is very common and stroke and CAD presents at an earlier age [3, 4, 15, 23‐26].

In our study, there was correlation of higher triglyceride levels with having acute strokes. This was evident in patients with or without diabetes. Similar to previous observation [9‐13, 27‐30], we also noted that the severity of acute stroke in patients with HT was milder. We believe that this can be best explained by a higher incidence of acute SVD/lacunar strokes in the HT population. Previous studies, while concentrating on the severity of neurological symptoms, have not documented the ischemic stroke sub-types. The better outcome at 90-days follow-up in HT is also likely related to the higher rates of SVD/lacunar stroke. During a follow-up of one year, MACE events were significantly were higher in HT patients, suggesting a higher atherosclerosis risk.

Diabetes is a very common risk factor for stroke in the Middle Eastern and South East Asian population [4, 5, 24‐26, 31] and was seen in 56% of our patients and likely contributed to the younger age at onset of stroke. As diabetes is frequently associated with SVD, we also evaluated the relationship between triglyceride levels and stroke in patients with no diabetes. Similar to the total cohort, patients without diabetes also had strokes at a younger age, had milder symptoms and a significantly higher incidence of SVD/lacunar strokes. Whereas the 90- days outcome was better in patients with HT, the one-year MACE did not show any significant differences in patients with increasing triglyceride values.

Hypertriglyceridemia most commonly results from genetic factors or from consumption of food high fructose or fatty products. The higher prevalence in USA and Europe likely reflects the higher rates of obesity and diabetes [2]. Hypertriglyceridemia is seen more frequently in the Arab and South Asian population [4]. Triglycerides remain high in the South Asian individuals after they immigrate to UK and contribute to the higher risk of coronary artery disease [7]. Genetic and dietary factors account for most of the HT in this population. The effects of HT have been studied mostly in coronary artery disease and there is convincing evidence that rising levels of triglycerides leading to higher incidence of coronary and systemic atherosclerosis [32, 33].

The relationship between stroke and HT was studied in the Copenhagen City Heart Study. The study followed 13,956 city dwellers between 1976 and 2007. Stroke developed in 1529 individuals. The risk of stroke increased with increasing levels of triglyceride levels [34]. Similar trends have been noted from Asia-Pacific region, India, China, American Aboriginal population and Europe [1]. The increased risk for stroke remained after adjustment for age, body mass index, family history, systolic blood pressure, diabetes and obesity [34, 35].

Does HT contribute to an increase in small vessel disease? There is evidence that HT may increase asymptomatic small vessel disease in the population. Two observation studies from France reported on the cross-sectional association of lipid abnormalities and asymptomatic cerebral small vessel disease as measured on MRI. All subjects were free of coronary artery or cerebrovascular disease at the time of inclusion into the study. The 3C-Dijon study comprised of 1842 subjects and the Epidemiology of Vascular Aging Study compromised of 766 subjects. Increasing serum triglycerides was associated with an increasing burden of SVD. This was not evident with abnormalities in other lipids. The association of SVD and HT was attenuated but maintained after adjusting for other vascular risk factors or inflammatory markers [36]. The underlying mechanisms for the increase in asymptomatic SVD with HT are not fully understood. Triglycerides have pro-inflammatory properties [37]. These researchers speculated that the SVD may be related to triglyceride-induced chronic inflammation. An increase in triglycerides is associated with blood-brain dysfunction, which may contribute to the development of SVD [38]. Importantly, HT has also been shown to affect compliance of cerebral small vessels and may result in chronic white matter hypo-perfusion, which may lead to SVD [36, 39]. Given the increased prevalence of HT, especially in the South Asian and Middle Eastern population, the increase in the development of SVD requires further study. Treatment of HT with omaga-3 agent icosapent ethyl in a large phase-III trial was shown to significantly reduce the risk of CAD and stroke in actively treated patients and may be considered in patients with HT to reduce asymptomatic SVD, and the risk of recurrent stroke and heart disease [40].

Weir et al first reported the association between serum triglyceride levels and acute stroke in 2003 [9]. Paradoxically, lower levels of triglycerides were associated with poor outcome in acute stroke. The study involved 1310 non-diabetic acute stroke patients. Age, hyperglycemia and lower triglyceride levels independently predicted higher mortality [9]. A number of subsequent reports from across the globe have confirmed similar observations between serum triglycerides and stroke prognosis in patients with and without diabetes [10‐13, 27‐30]. In addition, imaging studies have shown that patients with HT have smaller size of ischemic infarction [13]. The better prognosis with HT in older patients reported from China was also likely related to higher rates of SVD [27]. In patients with HT, diabetes further increases small vessel disease and lacunar stroke [30]. Our study with 6558 ischemic stroke patients provides a comprehensive understanding of the relationship between acute stroke, HT and diabetes. The incidence of diabetes and HT was high in this population and the database allows for important conclusions that were not possible with previous studies. Our study shows that together with diabetes and hypertension, HT is an important contributor of acute SVD/lacunar stroke and required aggressive treatment to prevent recurrences.

There are limitations in our study. As this is a single center data, the design may limit the generalizability of findings. The study population is distinctive comprising mainly of Arab and Asian community, which limits generalizability of the results. Also, the retrospective analysis introduces the possibility of imprecise comorbidity data. Although the lipid levels were on fasting specimens following the acute stroke, these are a single-time measurement and may not accurately reflect HT. It is important to note that our study population is a predominantly young male expatriate and may not reflect cerebrovascular disease the general population. Finally, the association of HT to stroke outcome is limited predominantly to Arab and South East Asia populations. The effects cannot be genialized to other populations. The MACE follow-up was for one year, which may not be enough to evaluate the damaging effects of HT in this high-risk population.

In conclusion, we can make the following important observations from our study with more than 6550 patients. HT contributes to an increase in the percentage of patients with SVD/lacunar strokes. This is evident in patients with and without diabetes. The higher rates of SVD/lacunar strokes are most likely responsible for the milder symptoms and lower rates of medical complications in patients with HT and acute stroke. This is also the most likely reason for shorter hospital stay and higher rates of patients with higher rates of 90-days mRS of 0-2 in the HT group. Our study and the previous reports that HT is an important and perhaps under-recognized contributor to acute stroke. The increased SVD/lacunar stroke requires strategies that are targeted to this specific population [41].