Herein, we evaluated risk factors for early-onset IS among non-diabetic non-hypertensive patients. We found that IS patients exhibited elevated TG, HCY, WBC, ANC, SBP, and DBP levels, as well as lower HDL-C, TC, FT3, and FT4 levels relative to controls. Further analysis revealed that HCY and ANC levels were positively correlated with IS risk, whereas HDL-C and FT3 levels were negatively correlated with such risk.
Our findings are consistent with those of many other prior analyses which have detected negative correlations between HDL-C levels and IS incidence in young adults. Indeed, while low HDL-C has been linked to elevated IS risk in young populations, LDL-C, TG, and TC levels have been found to be unrelated to such risk [12–14]. These findings are not universal, however, as no significant relationship between HDL-C levels and IS was observed in the ARIC Study . Indeed, some studies have found HDL-C levels to be negatively correlated with vascular events and mortality among IS patients [16, 17], and one study found elevated HDL-C levels to be correlated with decreased IS severity in patients ≤ 50 years old, whereas no such relationship was observed among older patients . HDL-C is involved in reverse cholesterol transport, but also plays antithrombotic and anti‐inflammatory roles [19, 20]. In one systematic review, the risk of IS was found to decrease by 11–15% for every 10 mg/dL increase in HDL-C . HDL administration has also been found to be neuroprotective, as it is associated with reducing neutrophil recruitment and preserving the blood-brain barrier . Based on our data and these prior studies, we can hypothesize that HDL-C play a key role in mediating IS risk among younger patients, and that preventative efforts aimed at elevating serum HDL-C levels in younger adults may significantly decrease IS risk.
We also found that FT3 levels were negatively correlated with IS incidence among young adults. This is the first study to our knowledge to have reported such a relationship, as prior studies and meta-analysis have largely focused on correlations between low FT3 levels and severity/mortality among acute IS patients[23–27]. These prior studies have reported such a relationship even for low FT3 values within the standard reference range [28, 29]. One study, however, found that this relationship was age-dependent, such that TT3 and FT3 levels were unrelated to IS outcomes in patients < 65 years old, whereas TT3 levels were independently predictive of poor outcomes among older patients . In these prior studies, the average population ages ranged from 61.4–81.5 years [23–28], with the exception of one study with a median population age of 48 years . Serum TT3 and FT3 levels are lower among healthy older individuals , and FT3 levels decline over time . Age may, therefore, have the potential to confound the effect of FT3 on the cardiovascular system in older individuals, whereas lower FT3 levels in younger patients may be more clinically significant. As acute diseases can decrease the conversion of FT4 to FT3 , reductions in FT3 levels in acute IS patients may simply be indicative of disease rather than a driver of disease progression. Future research will be essential in order to confirm the mechanistic basis for the observed correlation.
We additionally found that HCY levels were positively correlated with early-onset IS risk. Hyperhomocysteinemia is well known to be associated with elevated IS risk . In line with our findings, many prior studies have confirmed elevated HCY levels to be associated with IS risk in younger patient populations [35–38], with this correlation being strongest in younger individuals . The risk of IS has been shown to be roughly two-fold higher in IS patients with high HCY levels relative to patients with low HCY levels [39, 40]. Huang et al. in contrast, determined a 20% reduction in HCY level to be linked with a 7% decrease in IS risk . HCY levels are also correlated with stroke severity, with a poorer prognosis [42, 43], and with stroke recurrence . A 3 µmol/L decrease in total HCY levels was associated with a 10% reduction in the risk of stroke recurrence . HCY may elevate the risk of IS incidence through mechanisms including the impairment of thrombolysis, thrombosis, enhanced H2O2 production, endothelial dysfunction, and increased LDL-C oxidation [46–48].
We also found ANC levels to be positively correlated with early-onset IS risk, in line with prior reports that ANC is an independent predictor of IS incidence and recurrence [49–51]. Other studies have also found elevated ANC values to be related to more severe stroke, poorer stroke outcomes, larger infarct volumes [52, 53], the presence of intracranial atherosclerotic stenosis , and unstable carotid plaques . Neutrophils can influence thrombosis and atherosclerosis, thereby modulating the risk of IS [56, 57]. Neutrophil activation can be reduced by elevated levels of HDL-C and consequent changes in pro-inflammatory cytokine production , partially explaining the beneficial impact of HDL-C levels in this context. Neutrophils are key markers of acute inflammation, and are among the first cells recruited following IS . Whether neutrophil accumulation is a response to stroke or a risk factor associated with IS incidence thus requires further investigation.
This study has multiple limitations. For one, we were not able to account for all possible risk factors pertaining to IS incidence (including nutrition, alcohol intake, and physical inactivity) in this patient population owing to a lack of complete data. Furthermore, we selected controls at random from among health patients, resulting in significant differences in rates of cigarette smoking between the case and control populations that may have significantly impacted the results of our analyses. This was also a retrospective single-center study with a small sample size, potentially biasing our results. Despite these limitations, we believe that these data represent a valuable first step towards understanding risk factors associated with early-onset IS incidence among non-hypertensive and non-diabetic patients.