THE ROLE OF INTIMA-MEDIA-THICKNESS, ANKLE-BRACHIAL-INDEX, AND INFLAMMATORY BIOCHEMICAL PARAMETERS FOR STROKE RISK PREDICTION: AN UPDATE SYSTEMATIC REVIEW

Background: Stroke is a leading cause of global mortality and morbidity. The capacity to precisely estimate a person's risk of having a stroke is critical for early intervention and prevention stretegies. Researchers are exploring novel predictors beyond traditional risk factors, such as Intima-Media Thickness (IMT), Ankle-Brachial Index (ABI), and inflammatory biochemical parameters, to accurately predict stroke risk. The aim: This study aims to determine the role of intima-media-thickness, ankle-brachial-index, and inflammatory biochemical parameters for stroke risk prediction. Methods: By comparing itself to the standards set by the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) 2020, this study was able to show that it met all of the requirements. So, the experts were able to make sure that the study was as up-to-date as it was possible to be. For this search approach, publications that came out between 2014 and 2024 were taken into account. Several different online reference sources, like Pubmed, SAGEPUB, and ScienceDirect, were used to do this. It was decided not to take into account review pieces, works that had already been published, or works that were only half done. Results: In the PubMed database, the results of our search brought up 1,004 articles, whereas the results of our search on SAGEPUB brought up 651 articles, and our search on ScienceDirect brought up 4,254 articles. In the end, we compiled 12 papers, 8 of which came from PubMed, 1 of which came from SAGEPUB, and 3 of which came from ScienceDirect. We included twelve research that met the criteria. Conclusion: In conclusion, the findings of our study strongly support that Carotid Intima-Media Thickness (CIMT) and Ankle-Brachial Index (ABI) hold significant promise as predictors of stroke risk. This can be helpful to improve stroke prevention and management strategies. However, further research is warranted to clarify the role of inflammatory biochemical parameters in the context of stroke risk prediction.


INTRODUCTION
Stroke is a neurological condition that is clinically described as an immediate, focal loss of function in the brain that is caused by vascular injury (hemorrhage, infarction) to the central nervous system. 1 Stroke remains one of the leading causes of mortality and morbidity worldwide, imposing a significant burden on healthcare systems and societal well-being.Stroke is currently the second greatest cause of mortality globally, with vascular diseases accounting for the majority of deaths.Together, ischemic heart disease and stroke claimed 15.2 million lives in 2015 (15-15.6 million).Two Hemorrhagic stroke accounts for a large share of the worldwide burden of stroke, as assessed by mortality and disability-adjusted life years (DALYs), even though ischemic strokes account for the majority of stroke cases.Hemorrhagic stroke mortality rates in low-and middle-income nations are as high as 80%. 2 The increasing global burden of stroke strongly implies that current primary preventive measures for cardiovascular disease and stroke are either underutilized or undereffective. 3The ability to accurately predict an individual's risk of experiencing a stroke is of paramount importance for early intervention and prevention strategies.2][3] This research delves into the intricate interplay between vascular health markers, specifically Intima-Media Thickness (IMT), Ankle-Brachial Index (ABI), and inflammatory biochemical parameters, in the context of stroke risk prediction.4][5] Additionally, inflammatory biomarkers such as Creactive protein (CRP), interleukins, and tumor necrosis factor-alpha (TNF-α) signify the inflammatory processes implicated in atherosclerosis and plaque instability, thereby contributing to stroke pathogenesis. 6,7derstanding the significance of these vascular and inflammatory markers in stroke risk assessment offers a promising avenue for enhancing predictive models and refining personalized medicine approaches.Through a comprehensive review and analysis of existing literature, this systematic review aims to determine the role of IMT, ABI, and inflammatory biomarkers for stroke risk prediction.

METHODS Protocol
By following the rules provided by Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) 2020, the author of this study made certain that it was up to par with the requirements.This is done to ensure that the conclusions drawn from the inquiry are accurate.

Criteria for Eligibility
For the purpose of this systematic review, we compare and contrast the role of intima-media-thickness, ankle-brachialindex, and inflammatory biochemical parameters for stroke risk prediction.As the primary purpose of this piece of writing, demonstrating the relevance of the difficulties that have been identified will take place throughout its entirety.
For researchers to take part in the study, they needed to fulfill the following requirements: 1) The paper needs to be written in English, and it needs to investigate the role of intima-media-thickness, ankle-brachial-index, and inflammatory biochemical parameters for stroke risk prediction.For the manuscript to be considered for publication, it needs to meet both of these requirements.2) The studied papers include several that were published after 2014, but before the period that this systematic review deems to be relevant.Examples of studies that are not permitted include editorials, submissions that do not have a DOI, review articles that have already been published, and entries that are essentially identical to journal papers that have already been published.

Data retrieval
After reading the abstract and the title of each study, the writers examined to determine whether or not the study satisfied the inclusion criteria.The writers then decided which previous research they wanted to utilize as sources for their article and selected those studies.After looking at several different research, which all seemed to point to the same trend, this conclusion was drawn.All submissions need to be written in English and can't be seen anywhere else.

Figure 1. Prisma Flow Diagram
Only those papers that were able to satisfy all of the inclusion criteria were taken into consideration for the systematic review.This reduces the number of results to only those that are pertinent to the search.We do not take into consideration the conclusions of any study that does not satisfy our requirements.After this, the findings of the research will be analysed in great detail.The following pieces of information were uncovered as a result of the inquiry that was carried out for the purpose of this study: names, authors, publication dates, location, study activities, and parameters.

Quality Assessment and Data Synthesis
Each author did their own study on the research that was included in the publication's title and abstract before deciding on which publications to explore further.The next step will be to evaluate all of the articles that are suitable for inclusion in the review because they match the criteria set forth for that purpose in the review.After that, we'll determine which articles to include in the review depending on the findings that we've uncovered.This criteria is utilized in the process of selecting papers for further assessment to simplify the process as much as feasible when selecting papers to evaluate.Which earlier investigations were carried out, and what elements of those studies made it appropriate to include them in the review, are being discussed here.

RESULT
In the PubMed database, the results of our search brought up 1,004 articles, whereas the results of our search on SAGEPUB brought up 651 articles, and our search on ScienceDirect brought up 4,254 articles.In the end, we compiled 12 papers, 8 of which came from PubMed, 1 of which came from SAGEPUB, and 3 of which came from ScienceDirect.We included twelve research that met the criteria.

Intima-Media-Thickness (IMT)
Six studies 8,10,[14][15][16]19 suggested that increase in carotid intima-media-thickness (CIMT) was significantly associated with a higher risk of stroke. Danaji, et al. (2023) 8 found that Atherosclerotic arteries are a risk factor for acute ischemic stroke (AIS) if their carotid intima-media-thickness (CIMT) value is less than 25% or greater than 1.0 mm.Sun, et al. (2020) 15 showed increase in mean cIMT was linked to a lower risk of first ischemic stroke (HR, 1.  19 showed that the prognostic value of IMT for AIS was still better than that of non-HDL-C and LDL-C.However, Gronewold, et al. (2014) 10 showed that CIMT had the lower predictive value compared with ABI.

Ankle-Brachial-Index (ABI)
Six studies [10][11][12][13]17,18 suggested that patients with a low ABI ≤0.9 had higher rates of stroke. Groneold, et al. (2014) 10 showed that the best prognostic value for stroke was found in ABI.Low ABI values are uncommon in the general population, despite the fact that ABI most significantly influenced stroke risk in the analyses above.Just 4.8% of participants in the HNR research had ABI values less than 0.9.Lee, et al. (2021) showed in univariate Cox regression analysis, compared to abnormal ABI levels, normal ABI levels were linked to a 96.5% lower incidence of IS (HR: 0.035, 95% CI: 0.009-0.145,p < 0.001).

DISCUSSION
The purpose of this research was to review studies published after January of 2014 and up to March of 2024 that investigated the role of intima-media-thickness, ankle-brachial-index, and inflammatory biochemical parameters for stroke risk prediction.With a substantial predictive value for both myocardial infarction and IS, cIMT has been shown to predict cardiovascular risk without the need for conventional cardiovascular risk variables. 20CIMT can be easily accessed by non-invasive B-mode ultrasound. 21The European Hypertension Guidelines and the European Prevention Guidelines both identify increased cIMT as an organ damage condition because it is seen by some to be a sign of subclinical atherosclerosis.But genetically and physiologically, cIMT differs from plaque load. 22Mean cIMT values have been suggested as a valuable technique for early detection of systemic atherosclerosis and cardiovascular event risk, including ischemic stroke, as well as a possible surrogate outcome in several clinical trials. 20Sahoo et al. found a greater mean CIMT (0.782 ± 0.19 mm) in stroke cases compared to controls (0.594 ± 0.98 mm; p < 0.0001), although in a group residing in south India.The difference was consistent in all age groups, as was found in our study. 21cording to our research, stroke cases with the identified comorbidities had higher CIMT values, and this difference was statistically significant.A prior study that looked at risk variables like smoking, diabetes, and hypertension found that there was a significant difference between the patient and control groups in the subgroup analysis.In a small group of ischemic stroke cases with age-matched controls, a study on Asian Indian stroke cases found a higher IMT with plaque grades in type II diabetes stroke patients. 20In the Rotterdam Study, 374 participants 55 years of age and older with a history of stroke or MI were followed for an average of 4.2 years in order to assess the impact of CIMT in predicting future CAD.We assessed these participants to see whether CIMT played a role in the novel MI prediction.The traditional risk indicators that were added to the CIMT readings were measured for prognostic value using receiver operating characteristic (ROC) curves.With respect to age and sex, the ROC area was 0.65 (95% CI: 0.62-0.69).Previous MI, stroke, diabetes mellitus, smoking, systolic and diastolic blood pressure, total cholesterol, and HDL cholesterol levels were risk variables that increased the ROC area from 0.65 to 0.72 (95% CI, 0.69-0.75).When CIMT was added to the previous model, the ROC area increased to 0.75 (95% CI, 0.72-0.78). 23nerjee et al. recently conducted a topical review in which they noted the high prevalence of multi-territory vascular illness in stroke patients and the significant impact this has on cardiovascular risk, particularly vascular death.The highrisk patients identified can be addressed with multiple tactics to limit the chance of recurrence, such as more aggressive treatment of concurrent vascular risk factors through different drug strategies or encouraging patient adherence in patients, possibly with the use of ABI. 24The ankle-brachial index (ABI), which is the ratio of a patient's systolic blood pressure recorded at their arm and ankle while they are in a supine position, is a cheap, non-invasive, and accurate technique for assessing patients who may have lower extremity peripheral artery disease (PAD). 25ABI screening may be helpful in identifying participants who are extremely high-risk for stroke events; nevertheless, the majority of research has concentrated on the association between low ABI and risk.A low ABI has a high 92.2%specificity in predicting future stroke outcomes, but a low 16.0% sensitivity. 26e Multi-Ethnic Study of Atherosclerosis (MESA) research revealed a stronger correlation between ABI<1.0 and composite endpoints such as stroke, coronary heart disease, and other vascular events, but not just with stroke.With a large cohort size of 14,839 participants, the Atherosclerosis Risk in Communities (ARIC) study found a strong correlation between ABI<0.80 and an increased 7-year risk of ischemic stroke (HR, 5.68 [95% CI, 2.77-11.66]);however, after controlling for major cardiovascular risk factors, the risk became statistically insignificant (HR, 1.93 [95% CI, 0.78-4.78]). 27Moreover, an ABI <0.9 has a strong association with stroke mortality and stroke recurrence during the followup period, after additional adjustment for a variety of risk factors. 25flammatory biomarkers, such as C-reactive protein (CRP), interleukins, and tumor necrosis factor-alpha (TNF-α), are implicated in the inflammatory processes underlying atherosclerosis and plaque instability, both critical contributors to stroke pathogenesis.Multiple studies have indicated that elevated levels of inflammatory biomarkers are associated with an increased risk of stroke.The findings suggest that inflammation plays a pivotal role in the development and progression of stroke, independent of traditional cardiovascular risk factors.The mechanisms by which inflammation contributes to stroke risk are multifaceted, including endothelial dysfunction, plaque rupture, and thrombosis.Inflammatory processes promote the formation and destabilization of atherosclerotic plaques, increasing the likelihood of embolic events and ischemic stroke.Additionally, inflammation can exacerbate cerebrovascular injury and impair neurological recovery following a stroke event. 6 Records identified from: Pubmed (n = 1004) SagePub (n = 651) Science Direct (n = 4254) Records removed before screening: • Duplicate records removed (n = 18) • Records marked as ineligible by automation tools (n = 0) • Records removed for other reasons (n = 0) Records screened: (n = 5891) Records excluded: Wrong publication date (n = 0) Wrong study design (n = 1965) Wrong intervention (n = 3912) Reports sought for retrieval (n = 12) Reports assessed for eligibility (n = 12) Reports not retrieved: (n = 5879) Reports excluded: (n = 0) Studies included in the review (n = 12) Reports of included studies (n = 12)

Table 1 . The literature included in this study Author Origin Method Sample Size Result
9onovan, et al. (2023)9showed that atherosclerotic cardiovascular disease was present in 26,266 (8%) of the UK Biobank individuals.The composite of ischemic stroke (1.04; 95% CI, 0.94 to 1.15; 5992 outcomes) did not show any correlation with genetically predicted FGF-23.Nonatherosclerotic cardiovascular disease was present in 12,652 (4%) of the UK Biobank individuals overall.Hemorrhagic stroke was not associated with genetically predicted FGF-23 (1.05; 95% CI, 0.88 to 1.27; 1745 outcomes).FGF-23, which was genetically predicted, did not correlate with an increased risk of ischemic stroke (0.82; 95% CI, 0.65 to 1.03).