Cardiovascular risk factors modulate the effect of brain imaging-derived phenotypes on ischaemic stroke risk

Abstract

Studies have shown that cardiovascular risk factors are closely related to the occurrence of stroke, especially ischaemic stroke, as they can lead to changes in brain structure and function. However, the role of cardiovascular risk factors-induced changes in brain structure and function in the development of ischaemic stroke has not been studied. The aim of this study is thus to explore the causal association among cardiovascular risk factors, brain phenotypes and ischaemic stroke by assessing Mendelian randomization. We used univariate Mendelian randomization to sequentially investigate the causal effects of the 12 most common cardiovascular risk factors on brain structure and 3935 brain imaging-derived phenotypes in the development of ischaemic stroke. We also examined the mediating effect of brain structure on blood pressure-induced ischaemic stroke using a multivariable Mendelian randomization test. We tested the reliability of our results using the Steiger test, heterogeneity test, horizontal pleiotropy test and leave-one-out method. We found that 8 of the 12 examined cardiovascular risk factors were associated with 538 brain imaging-derived phenotypes, and 9 of the 12 cardiovascular risk factors were associated with IS. The main cardiovascular risk factors associated with brain imaging-derived phenotypes and ischaemic stroke was blood pressure (systolic and diastolic), which can affect the occurrence of ischaemic stroke through 6 types of brain imaging-derived phenotypes. However, extrapolation of our findings to other ethnic groups is challenging, and the possibility of reverse causality cannot be completely ruled out. This study identifies the role of cardiovascular risk factors, especially blood pressure, in affecting brain structure and ischaemic stroke risk. The findings assist in early risk detection and enhance stroke prevention strategies, also hinting at non-vascular factors' involvement.

Keywords: Mendelian randomization; brain imaging-derived phenotypes; cardiovascular risk factors; ischaemic stroke.

Graphical Abstract

Figure 1

Overview of this study. There are three main steps in our study. First, we assessed the causal effects of 12 CRF measures on brain structure. Next, we used GWAS data to verify their impact on IS. Finally, we examined if brain structural changes mediate the effects of CRFs on IS risk. (DBP, diastolic blood pressure; SBP, systolic blood pressure; BMI, body mass index; TC, total cholesterol; TG, triglyceride; HDL, high-density lipoprotein; LDL, low-density lipoprotein; CpD, number of cigarettes smoked per day; FI, fasting insulin; HbA1c, glycosylated haemoglobin; L, left; R, right; rfMRI, resting-state functional MRI).

Figure 2

Upset Venn diagram of the results from univariate Mendelian analysis of 12 CRF and IDP. The rectangle on the left shows that DBP-related IDPs have the largest number of 449 IDPs. There were 195 IDPs affected by DBP alone, and 240 IDPs affected by both SBP and DBP. (DBP, diastolic blood pressure; SBP, systolic blood pressure; BMI, body mass index; TC, total cholesterol; TG, triglyceride; HDL, high-density lipoprotein; LDL, low-density lipoprotein; CpD, cigarettes per day).

Figure 3

Forest plot of univariate Mendelian randomization using the inverse variance weighted method for 12 cardiovascular risk factors in relation to IS. The results indicated that systolic and diastolic BP had the most significant causal effects. The x-axis is the OR (95% CI) and the y-axis is the different exposure. OR (95% CI), odds ratio (95% confidence interval).

Figure 4

Forest plot of univariate Mendelian randomization using the inverse variance weighted method for six brain imaging-derived phenotypes in relation to IS. The anterior limb of the internal capsule and the fronto-occipital tract exhibit negative effects on IS, while the posterior thalamic radiation and brain volume exhibit positive effects. The x-axis is the OR (95% CI) and the y-axis is the different exposure. (OR (95%CI), odds ratio (95% confidence interval); IDP, imaging derived phenotypes; dMRI, diffusion MRI; TBSS, tract-based spatial statistics; L1, axial diffusivity; L2, second Eigenvalue; MD, mean diffusivity; FA, fractional anisotropy; LP, lateral posterior nucleus; AV, anteroventral nucleus; lh/rh: left hemisphere/right hemisphere).

Figure 5

Pattern of brain structure. Brain structural patterns of white matter associated with cardiovascular risk factors and a significant effect on IS. (R, right; A, anterior; S, superior; P, posterior).