The current MR study demonstrated that a genetic predisposition to a higher genetically estimated SBP and DBP level was linked to heightened risks of CAD. These findings are significant, underscoring the impact of BP on the structural integrity of cerebral arteries. Therefore, for patients with high SBP and DBP, the occurrence of CAD can be partially prevented by drug intervention.
The CAD, spanning extracranial and intracranial segments, is defined by the formation of a hematoma within the cerebral artery wall. This condition significantly contributes to stroke occurrence in children, young adults, and middle-aged individuals[18–20]. Despite the thorough research and detailed extracranial CeAD descriptions, data concerning exclusively IAD is limited, which excludes the cervical part of the artery. Several factors contribute to the limited information available regarding IADs. Primarily, occurrences of IAD are rarer compared to CeAD[5, 21]. Secondly, individuals with CeAD often exhibit symptoms like headache, neck pain, and ischemic stroke, typically receiving care from neurologists. In contrast, those with IAD may experience subarachnoid hemorrhage, necessitating a broader range of specialists, including neurosurgeons and interventional neuroradiologists, in addition to neurologists. This multidisciplinary approach might result in a fragmented understanding of the disorder. Consequently, there is a lack of unanimous agreement regarding the diagnostic standards and best treatment practices for individuals with IADs. It is critically important to promptly recognize and address the reversible and changeable risk factors associated with IAD.
Two primary mechanisms are proposed to initiate CAD: an intimal tear allowing blood penetration into the artery wall and the vasa vasorum rupture, the small blood vessels supplying blood to the artery wall[22, 23]. The inner wall of the cerebral artery can be compromised when these two conditions occur simultaneously. The pathophysiological rationale behind the association linking elevated BP with a heightened risk of CAD could stem from the mechanical strain HTN imposes on the arterial walls. Over time, sustained high BP can weaken the arterial structure, leading to dissections. HTN can hasten the atherosclerotic deterioration of the artery, leading to increased vulnerability of the artery wall. This vulnerability manifests as intimal thickening, fibrosis, calcification, extracellular fatty acid deposition, and extracellular matrix (ECM) degradation. Accordingly, the artery wall elasticity is diminished, and the integrity of the connections between each elastic lamina within the artery wall structures is impaired[24]. Furthermore, HTN can lead to an intimal tear by exerting excess pressure on the artery wall. Also, HTN-induced macrophages can release proinflammatory cytokines and matrix metalloproteinases (MMP), degrading the ECM. Conversely, effective BP management may yield beneficial outcomes, preserving the elastic fibers, ensuring the aortic wall's stability, and supporting seamless molecular repair processes[25, 26]. This mechanism aligns with our findings and suggests that interventions to control BP could mitigate the risk of dissections.
There is undeniable evidence that HTN is a significant cardiovascular risk factor in ischemic stroke. While the link between BP and spontaneous CeAD (sCeAD) requires further investigation, preliminary findings do suggest a correlation between HTN and sCeAD, with odds ratios (ORs) reaching as high as 2.7 for certain sCeAD subtypes[4].
In the Italian Project on Stroke in Young Adults—Cervical Artery Dissection (IPSYS CeAD), individuals with spontaneous sCeAD displayed elevated prevalence rates of HTN (OR: 1.65), migraine (OR: 2.45) and vascular disease family history in first-degree relatives (OR: 1.69) relative to those without stroke[27]. These studies only focused on extracranial arterial dissection; there are no existing studies comparing potential risk factors between patients who have IAD and individuals without the condition who are healthy. In the limited research that has examined patients with CAD alongside those having IAD, the vascular risk factor prevalence was generally consistent across both groups. Nonetheless, one particular study indicated a greater incidence of HTN among IAD individuals. This observation could potentially be influenced by the comparative older age of the IAD group versus the controls in that study, with average ages being 48 and 37 years, respectively[28].
Our findings suggest that a genetically determined elevation in SBP by one standard deviation is linked with a threefold rise in the likelihood of CAD. Likewise, a one standard deviation rise in genetically determined DBP is linked with more than a twofold increase in the likelihood of this condition. The specific underlying mechanisms that account for the notably stronger correlation between BP and CAD still need to be identified. Le Grand et al. have elucidated the significant association between elevated SBP and DBP with CeAD, underscoring the importance of mean arterial pressure, which is closely tied to the resistance of small arteries[4]. This is further underscored by the significant correlation with DBP, where a 10 mm Hg elevation in DBP more than doubled CeAD risk. It is proposed that elevated SBP and reduced DBP are arterial stiffness indicators, which could serve as a protective mechanism against artery disease, potentially clarifying the less pronounced correlation between SBP and artery disease[29]. However, in our study, we found that SBP is more associated with CAD than DBP. One potential explanation lies in the structural disparities between intracranial arteries and the carotid artery. In intracranial arteries, there is a well-developed internal elastic lamina, minimal elastic fibers in the middle layer, limited adventitial tissue, and absent external elastic lamina. However, additional investigation should fully elucidate the mechanism driving the notably stronger association between SBP and CAD in comparison to DBP.
Our study's use of MR strengthens the causal inference between BP and CAD, reducing the likelihood that confounding factors have influenced our results. From a clinical perspective, we highlight the necessity for aggressive HTN management, especially for those with higher SBP, not only to prevent common cardiovascular diseases but also to reduce the risk of CAD. Public health strategies aimed at controlling BP population-wide could, therefore, significantly reduce the incidence of this condition.
Our study has some limitations. Initially, our investigation concentrated solely on individuals of European descent, and we combined data from both males and females in our analyses. This approach restricts our findings' applicability to non-European populations and to specific genders. Second, the influence of HTN treatment protocols on the emergence of dissection is noteworthy, but such details were absent in the initial GWAS data. Nonetheless, neither the MR-Egger analysis nor the funnel plots exhibited indications of directional pleiotropy. Thirdly, the sample size of the CAD GWAS is comparatively smaller than that of GWAS for risk factors, primarily because of the low CAD incidence rate. Subsequent investigations should prioritize replicating these findings in larger and more diverse populations. Additionally, exploring the efficacy of targeted BP-lowering interventions in mitigating CADs warrants further exploration.