European Journal of Cardiovascular Medicine

According to the World Health Organization (2021), cardiovascular diseases continue to be the main cause of death throughout the globe, accounting for around 18 million deaths annually. Chronic inflammation is a significant contributor to the pathophysiology of cardiovascular events and plays a role in developing these events. An increasing number of research suggests that biomarkers have the potential to one day be used as prediction tools for cardiovascular events such as myocardial infarction, stroke, and sudden cardiac death (1). C-reactive protein (CRP), fibrinogen, tumour necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6) are examples of molecular compounds that are created by the body during the inflammatory response throughout the process. According to Patoulias et al., these indications have been linked with both the beginning and the development of atherosclerosis (2).

According to Stefanadi et al., inflammation is a significant factor in the development of atherosclerosis, the creation of plaques, and the rupture of plaques, all of which may result in acute cardiovascular events (3). Within clinical settings, it is becoming clearer that these signs have the potential to be used to identify individuals who are more susceptible to cardiovascular events. Inflammatory biomarkers, when combined with recognized risk variables such as hypertension, cholesterol, and smoking status, provide doctors with a greater opportunity to improve risk categorization and identify patients who might potentially benefit from early intervention (4).

The fact that fibrinogen and other inflammatory markers play a substantial role in the development of cardiovascular disease is now well-known within the scientific community. Interleukin-6 and C-reactive protein are two examples of some biomarkers that fall within this category. When it comes to creating a thrombus in the setting of cardiovascular events, fibrinogen, a glycoprotein engaged in the coagulation cascade, is necessary. According to Ridker et al., an increase in fibrinogen levels is related to both an increase in blood viscosity and an increase in platelet aggregation. The formation of atherosclerotic plaques, as well as their rupture, are both impacted by both factors (5).

Consequently, fibrinogen plays a role in the pathophysiology of cardiovascular events and works as an indication of inflammation. It is important to note that fibrinogen serves a dual role in predicting the progression of illness, highlighting this substance's relevance. Because fibrinogen affects both inflammation and thrombosis, it is a useful biomarker for determining the chance of developing cardiovascular disease (6).

Even though cardiovascular events in clinical populations are extremely varied, established risk factors such as age, hypertension, and cholesterol levels cannot account for this heterogeneity. Researchers have been growing interest in investigating other components, such as inflammation, which might provide a more thorough knowledge of cardiovascular disease-associated risk. The introduction of inflammatory biomarkers into risk assessment models may be able to achieve an improvement in early diagnosis and preventive measures for persons who are at high risk (7).

In the context of cardiovascular events, this study aimed to investigate the potential predictive ability of inflammatory biomarkers, namely C-reactive protein and interleukin-6. In cardiology, the objective is to contribute to the growing body of research on biomarker-based risk assessment strategies.

Aim of the study

The goal of this study was to find out how to reliably predict cardiovascular events in high-risk groups using inflammatory biomarkers like C-reactive protein (CRP), interleukin-6 (IL-6), and fibrinogen (FIB).

Objective

To assess the relationship between levels of CRP, IL-6, and fibrinogen with the incidence of cardiovascular events with known cardiovascular risk factors.

During the investigation, a prospective cohort design was used. Researchers monitored 500 individuals aged 40-75 for five years to determine whether there was a connection between the levels of biomarkers present at the study's beginning. Hypertension, diabetes, and hyperlipidemia were all conditions that were present in their medical history; these conditions all contribute to an increased risk of cardiovascular disease.

Inclusion Criteria

The age range of the individuals who participated in this study had to be between 40 and 75 years old to be eligible to participate in the study. This is because cardiovascular disease is more common in those who are 40 and older. The cause of this phenomenon is therefore brought to light. Participants had to fulfil one of the following conditions: hypertension, type 2 diabetes mellitus, hyperlipidemia, or smoking history.  Participants had to be available for follow-up, provide written informed permission, and be willing to participate in the experiment for all five years. The only way for participants to participate in the research was if they had no major medical conditions that may have affected the outcomes.

Exclusion Criteria

The following criteria were used to exclude patients from the study:

• Individuals aged younger than 40 or older than 75 years.
• History of acute myocardial infarction, stroke, or coronary artery bypass surgery within the last 6 months.
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• Severe renal (stage IV or V chronic kidney disease) or hepatic dysfunction.
• Active inflammatory diseases (e.g., infections, autoimmune disorders).
• Inability or unwillingness to comply with study protocol, including follow-up visits.
• Use of immunosuppressive medications, steroids, or medications that significantly alter inflammatory biomarkers (e.g., NSAIDs) within 3 months prior to study initiation.
• Deaths unrelated to cardiovascular events during the follow-up period.
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Data Collection

Data collection consisted of the first assessment and the subsequent follow-up. At the time of participation, every member was required to undergo a comprehensive screening procedure. In addition to clinical data, medical history, and vital signs such as blood pressure, lipid profiles, and glucose levels, this method included gathering a wide range of vital indicators from the patient. These vital signs included the patient's age, gender, marital status, and employment status. While the participants were fasting for a certain amount of time, we employed high-sensitivity ELISA kits to determine the amounts of CRP, IL-6, and fibrinogen in their blood. During the five-year follow-up period, every participant was subjected to rigorous monitoring for the development of cardiovascular events. These events included myocardial infarction, stroke, and sudden cardiac death. The patient could accomplish this objective by attending their physician once a month and examining their medical records. The outcomes of diagnostic procedures and medical professionals' records were used to verify every incident.

Data Analysis

The statistical analysis tool was used to carry out the data analysis. Descriptive statistics were used to characterize the characteristics of the people, and this was done without regard to the individuals' quartiles concerning the baseline biomarkers' levels. While refining these models, several factors were considered, including but not limited to gender, age, smoking status, cholesterol levels, and diabetes. Given that the p-value is less than 0.05, it may be concluded that the variation in question is statistically significant. Kaplan-Meier survival curves were developed for the people who were classified according to biomarker values that were different from these. During the process of evaluating the data, the degree of correlation that exists between greater levels of biomarkers and the likelihood of experiencing cardiovascular events was taken into consideration.

Table 1: Baseline Characteristics of Study Participants

When comparing individuals in the lowest quartile (<2.0 mg/L) to those in the highest quartile (≥6.0 mg/L), Table 1 shows that there was an association between the highest quartile of CRP and being older, male, and have higher rates of hypertension and diabetes. This correlation was observed when comparing the two groups. There was a correlation between the elevated levels of CRP and LDL cholesterol that were seen in the subjects.

Table 2: Hazard Ratios for Cardiovascular Events According to Biomarker Quartiles

In Table 2, a higher level of C-reactive protein, interleukin-6, and fibrinogen was shown to be related to an increased risk of cardiovascular events. To clarify, persons in the highest quartile of CRP had a 2.50 (95% confidence interval: 1.60-3.90) greater risk of cardiovascular events than those in the lowest quartile. Interleukin-6 (IL-6) was related to a risk of 2.20 times higher than the risk associated with fibrinogen, with a risk of 1.85 times higher.

Table 3: Cardiovascular Event Incidence by Biomarker Quartile

Table 3 presents the incidence of cardiovascular events (including myocardial infarction, stroke, and sudden cardiac death) over the 5-year follow-up period, stratified by quartiles of inflammatory biomarkers (CRP, IL-6, and fibrinogen). The table shows that as the levels of each biomarker increase, so does the incidence of cardiovascular events. Specifically, participants in the highest quartile of CRP, IL-6, and fibrinogen had significantly higher event rates compared to those in the lowest quartile, with p-values indicating a statistically significant trend (p = 0.03 for CRP, p = 0.04 for IL-6, and p = 0.02 for fibrinogen). This suggests that elevated levels of these biomarkers are associated with an increased risk of cardiovascular events, supporting their potential role in predicting adverse outcomes.

Table 4: Cox Proportional Hazards Regression Analysis

Table 4 displays the results of the Cox proportional hazards regression analysis, which examines the relationship between baseline levels of inflammatory biomarkers (CRP, IL-6, and fibrinogen) and the risk of cardiovascular events over the 5-year follow-up period. The table shows the hazard ratios (HR) for each biomarker after adjusting for confounding factors such as age, sex, smoking status, cholesterol levels, and diabetes. Elevated levels of CRP, IL-6, and fibrinogen were all associated with an increased hazard of experiencing cardiovascular events. Specifically, for every unit increase in CRP, IL-6, and fibrinogen, the hazard of a cardiovascular event increased by 45%, 23%, and 31%, respectively. The statistical significance of these associations (p-values ≤ 0.05) supports the predictive value of these biomarkers in identifying individuals at higher risk for cardiovascular events.

This research indicated that patients with conventional cardiovascular risk factors had an increased risk of cardiovascular events when their levels of inflammatory biomarkers were greater. These biomarkers included C-reactive protein and interleukin-6. These results are consistent with prior findings concerning cardiovascular risk factors. Research conducted in the past has shown that systemic inflammation has a role in both the beginning stages of atherosclerosis and its progression. This conclusion aligns with the findings of those prior examinations (5).

Danesh et al., states that C-reactive protein, or CRP for short, is a recognized factor in inflammation, endothelium malfunction, and plaque instability. One trustworthy marker of cardiovascular events is the C-reactive protein (CRP) (8). This work demonstrates a considerable link between IL-6 and cardiovascular events, contributing to our knowledge of the function of inflammatory cytokines in the processes leading to atherosclerosis. Research suggests that IL-6 inhibition may be an effective strategy to lower the risk of cardiovascular events. The findings of the CANTOS investigation corroborate this conclusion, proving that the two sets of data are consistent (9).

Even though the research offers significant insights into the significance of inflammatory biomarkers for prognosis, it is important to point out that the study has several limitations. Considering that most of the people who participated in the cohort had a cardiovascular risk factor, it is possible that this research cannot be generalized to groups who have fewer risk factors or to those who do not have any symptoms. Due to the short duration of the follow-up period of five years, it is quite possible that long-term cardiovascular problems were overlooked. More studies with longer follow-up periods are thus required to evaluate the capability of these biomarkers to give helpful prognostic information over an extended length of time. The fact that genetic testing is not easily accessible is another issue from this study. Through genetic testing, we would be able to get a better understanding of the intricate relationship that exists between hereditary vulnerability and inflammatory indicators, which serve to increase the likelihood of cardiovascular disease and other disorders that are associated with it.

To conclude, inflammatory signs play a significant part in predicting cardiovascular events. This work contributes to the expanding body of data that establishes a connection between elevated C-reactive protein levels, interleukin-6, and fibrinogen and an increased risk of cardiovascular disease. It also highlights the possible use of these markers for risk stratification in clinical settings. With more research that utilizes bigger and more varied populations, longer follow-up periods, and genetic data, prediction models and tactics for preventing cardiovascular disease might be improved.

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