European Journal of Cardiovascular Medicine

Coronary Artery Disease (CAD) remains the leading cause of mortality worldwide, with inflammation recognized as a pivotal factor in its pathogenesis. The relationship between systemic inflammation and the severity of CAD has been a focus of numerous studies, as inflammation contributes to the initiation and progression of atherosclerotic plaques, leading to coronary artery obstruction.^1,2 Inflammatory markers, including C-reactive protein (CRP), interleukins (IL-6, IL-1β), tumor necrosis factor-alpha (TNF-α), and fibrinogen, have emerged as critical biomarkers in understanding the severity and prognosis of CAD.³

Several studies have shown a significant association between elevated levels of inflammatory markers and the extent of coronary artery stenosis, a key indicator of CAD severity. For instance, Reza Mohebi et al. (2022)⁴ demonstrated that CRP levels independently predict the risk of cardiovascular events, even in patients without overt cardiovascular disease. Peng Kong (2022)⁵ also emphasized that chronic low-grade inflammation plays a fundamental role in the development of atherosclerosis by promoting endothelial dysfunction, plaque formation, and thrombotic complications. These inflammatory responses contribute to the destabilization of plaques, making them more prone to rupture and causing acute coronary events.

In the Indian context, where CAD has become increasingly prevalent, particularly among the urban population, there is a need to explore how inflammatory markers correlate with the severity of the disease.⁶ Gupta et al. (2002)⁷ highlighted that the prevalence of CAD in India is rising, and inflammation has been identified as a key factor in the progression of CAD in the Indian population, where lifestyle factors such as diet, smoking, and physical inactivity contribute to both inflammation and cardiovascular risk.

Virendra Verma et al. (2024)⁸ further supported this by showing that higher levels of CRP and IL-6 were associated with more extensive coronary artery lesions in Indian CAD patients, with elevated inflammatory markers correlating with a higher risk of adverse outcomes, including myocardial infarction and sudden cardiac death.

This article aims to explore the association between inflammatory markers and the severity of coronary artery disease in patients, with a specific focus on their role as predictive biomarkers for disease progression. Understanding these associations could help in the early detection and personalized management of CAD, particularly in high-risk populations such as those in India.

This observational study was conducted at a tertiary care hospital over a period of two years, from 2023 to 2024, with a total of 128 patients diagnosed with coronary artery disease (CAD). The patients were categorized into two groups: those with high inflammatory marker levels (based on C-reactive protein (CRP), interleukin-6 (IL-6), and fibrinogen levels) and those with low inflammatory marker levels. Inclusion criteria were adult patients (aged 30-75 years) diagnosed with CAD through coronary angiography, presenting with either stable angina or acute coronary syndrome. Exclusion criteria included patients with a history of autoimmune diseases, active infections, cancer, or recent major surgeries, as these factors could potentially confound inflammatory marker levels.

Data collection involved a detailed review of the patients' medical records, including demographic information (age, gender, comorbidities), clinical presentation, and laboratory findings. Inflammatory markers (CRP, IL-6, fibrinogen) were measured at baseline, and coronary artery disease severity was assessed using coronary angiography. Severity was classified based on the number of affected coronary vessels and the degree of stenosis (mild, moderate, severe). Atherosclerotic burden was also quantified by the Gensini score, which evaluates the extent and severity of coronary artery involvement.

The study utilized descriptive and inferential statistical methods to analyze the data. The correlation between inflammatory markers and the severity of CAD was assessed using Pearson's correlation for continuous variables and chi-square tests for categorical variables. Multivariate logistic regression models were used to adjust for potential confounders, such as age, gender, diabetes, hypertension, smoking, and hyperlipidemia, in order to evaluate the independent association between inflammatory markers and CAD severity. The p-value threshold for statistical significance was set at 0.05.

This study aimed to identify the role of inflammatory biomarkers as potential predictors of CAD severity, with the goal of improving early diagnosis and personalized management of CAD, especially in high-risk populations. All patients provided informed consent, and the study was approved by the institutional review board (IRB) of the hospital.

Table 1: Demographic and Clinical Characteristics of Study Participants

Table 1 presents the demographic and clinical characteristics of the study participants, divided into two groups: high inflammation (n=64) and low inflammation (n=64). The mean age of participants in the high inflammation group was 58.2 ± 7.1 years, while in the low inflammation group it was slightly higher at 60.3 ± 6.9 years, but this difference was not statistically significant (p = 0.18). In terms of gender, 75.00% of the high inflammation group were male, compared to 71.88% in the low inflammation group, with no significant difference between the two groups (p = 0.58). Diabetes was present in 50.00% of the high inflammation group and 43.75% in the low inflammation group, but again, this difference was not significant (p = 0.35). The prevalence of hypertension was slightly higher in the high inflammation group (60.94%) compared to the low inflammation group (51.56%), but the difference was not statistically significant (p = 0.20). Finally, smoking was reported in 46.88% of the high inflammation group and 39.06% of the low inflammation group, with no significant difference between the groups (p = 0.29). Hyperlipidemia was observed in 62.50% of the high inflammation group and 57.81% of the low inflammation group, with no significant difference (p = 0.61). Overall, the two groups showed similar demographic and clinical characteristics, with no major differences observed in risk factors.

Table 2: Inflammatory Marker Levels in High vs. Low Inflammation Groups

Table 2 compares the levels of key inflammatory markers between the high inflammation group (n=64) and the low inflammation group (n=64). The levels of C-reactive protein (CRP) were significantly higher in the high inflammation group, with a mean of 15.2 ± 5.3 mg/L, compared to 3.1 ± 1.2 mg/L in the low inflammation group (p < 0.001).

Fig 1: Inflammatory Marker Levels

This substantial difference indicates that CRP, a known marker of systemic inflammation, is markedly elevated in individuals with high inflammation. Similarly, the interleukin-6 (IL-6) levels were significantly higher in the high inflammation group (11.4 ± 4.5 pg/mL) compared to the low inflammation group (2.8 ± 1.1 pg/mL), with a p-value of < 0.001. IL-6 is a pro-inflammatory cytokine, and its elevated levels in the high inflammation group further support the presence of a more pronounced inflammatory state. Additionally, fibrinogen levels were also higher in the high inflammation group (4.8 ± 0.9 g/L) compared to the low inflammation group (2.6 ± 0.8 g/L), with a p-value of < 0.001. Fibrinogen is an acute-phase reactant, and its higher levels reflect a stronger inflammatory response in the high inflammation group. Overall, these findings confirm that the high inflammation group exhibits significantly elevated levels of CRP, IL-6, and fibrinogen, suggesting a more pronounced inflammatory profile compared to the low inflammation group.

Table 3: CAD Severity Based on Coronary Artery Stenosis in High vs. Low Inflammation Groups

Table 3 compares the severity of coronary artery disease (CAD) based on coronary artery stenosis between the high inflammation group (n=64) and the low inflammation group (n=64). The proportion of participants with no significant stenosis was slightly higher in the low inflammation group (25.00%, 16/64) compared to the high inflammation group (20.31%, 13/64), though this difference was not statistically significant (p = 0.44). This suggests that a slightly higher percentage of participants in the low inflammation group had no significant coronary artery narrowing.

For 50-70% stenosis, both groups showed an identical percentage (40.63%, 26/64), indicating that the extent of moderate stenosis was the same across both groups. The p-value of 1.00 further confirms that there is no statistical difference in the frequency of moderate stenosis between the two groups.

Finally, greater than 70% stenosis was observed in 39.06% (25/64) of the high inflammation group and 34.38% (22/64) of the low inflammation group. Again, the difference was not statistically significant (p = 0.54), suggesting that the incidence of severe coronary artery stenosis did not differ significantly between the two groups.

Table 4: Inflammatory Markers and Coronary Artery Disease Severity (Gensini Score)

Table 4 compares the relationship between inflammatory markers and the severity of coronary artery disease (CAD) based on the Gensini score between the high inflammation group (n=64) and the low inflammation group (n=64). The mild CAD severity category (Gensini score 0-10) was observed in 18.75% (12/64) of the high inflammation group, while 31.25% (20/64) of the low inflammation group fell into this category. However, the difference between the groups was not statistically significant (p = 0.12), suggesting that the distribution of mild CAD severity was similar between the two groups.

Fig 2- : Inflammatory Markers and Coronary Artery Disease Severity

For moderate CAD severity (Gensini score 11-30), 40.63% (26/64) of the high inflammation group and 39.06% (25/64) of the low inflammation group were classified in this range. With a p-value of 0.92, the difference between the two groups was not significant, indicating that moderate CAD severity was similarly distributed across both groups.

Regarding severe CAD severity (Gensini score >30), 40.63% (26/64) of the high inflammation group had severe CAD, while 29.69% (19/64) of the low inflammation group were classified in this category. Although the high inflammation group had a slightly higher percentage, the difference was not statistically significant (p = 0.18), suggesting that the severity of CAD, as assessed by the Gensini score, did not significantly differ between the two groups.

Table 5: Correlation Between Inflammatory Markers and CAD Severity (Spearman's Rank Correlation)

Table 5 presents the correlation between inflammatory markers and coronary artery disease (CAD) severity, as assessed by Spearman's rank correlation. The CRP (C-reactive protein) levels showed a moderate positive correlation with CAD severity, with a Spearman's correlation coefficient (r) of 0.45 (p < 0.001). This indicates that as CRP levels increase, CAD severity also tends to increase, and the relationship is statistically significant. CRP, being a well-established inflammatory marker, aligns with previous studies suggesting its role in the pathogenesis and progression of CAD.

Similarly, IL-6 (interleukin-6) levels demonstrated a moderate positive correlation with CAD severity, with a correlation coefficient of 0.42 (p < 0.001). The statistically significant p-value indicates that higher IL-6 levels are associated with more severe CAD, further supporting IL-6’s role as a key pro-inflammatory cytokine in cardiovascular diseases.

For fibrinogen, the correlation with CAD severity was also positive, though slightly weaker, with a Spearman's correlation coefficient of 0.38 (p = 0.003). While fibrinogen is an acute-phase reactant and an indicator of systemic inflammation, its correlation with CAD severity was still statistically significant, suggesting its involvement in the inflammatory processes that contribute to atherosclerosis and CAD progression.

The results of this study provide valuable insights into the relationship between inflammatory markers and the severity of coronary artery disease (CAD) in patients, with a particular focus on the high and low inflammation groups. Our findings suggest that inflammatory markers such as CRP, IL-6, and fibrinogen are significantly elevated in patients with high inflammation and positively correlate with CAD severity, supporting their role in the pathogenesis of CAD. This is consistent with numerous studies that have established the critical role of inflammation in cardiovascular diseases, particularly in atherosclerosis and coronary artery disease.⁹

The high inflammation group had significantly higher levels of CRP, IL-6, and fibrinogen compared to the low inflammation group (p < 0.001 for all). These findings are in line with previous research showing that elevated levels of these markers are associated with increased cardiovascular risk. CRP, a marker of systemic inflammation, is widely recognized for its predictive value in CAD (S Visvanathan et al., 2007)¹⁰. Similarly, IL-6, a pro-inflammatory cytokine, is known to promote endothelial dysfunction, which plays a central role in the development and progression of atherosclerosis (A R Fatkhullina et al., 2017).¹¹ Fibrinogen, an acute-phase reactant, is involved in clot formation and is a known contributor to the development of coronary thrombus, further supporting the idea that inflammation is intricately linked to CAD pathogenesis.

Interestingly, despite the significant differences in inflammatory marker levels between the two groups, the severity of CAD based on coronary artery stenosis did not differ significantly between the high and low inflammation groups. Both groups showed a similar distribution of stenosis, with the majority of patients exhibiting either moderate (50-70% stenosis) or severe (>70% stenosis) coronary artery narrowing. These findings suggest that while inflammation is elevated in the high inflammation group, it may not directly translate into a higher degree of stenosis, or other factors may be contributing to CAD severity. This is in contrast to some studies that have shown a clear association between higher inflammatory markers and more severe coronary artery lesions (Epaminondas Zakynthinos et al., 2009)¹². It is possible that the relationship between inflammation and CAD severity is more complex and influenced by additional factors, such as genetic predisposition, lifestyle factors, or other comorbidities.

When assessing CAD severity based on the Gensini score, no significant differences were found between the high and low inflammation groups. Both groups had comparable distributions in terms of mild, moderate, and severe CAD severity. Although there was a slightly higher percentage of severe CAD cases in the high inflammation group, this difference was not statistically significant. These findings suggest that while high inflammation may be linked to the overall risk of CAD, it does not necessarily correlate with a more advanced stage of the disease, as assessed by the Gensini score. This observation aligns with some research indicating that inflammatory markers may be more predictive of CAD risk than its severity (Feyza Aksu et al., 2024)¹³.

The correlation analysis revealed a statistically significant positive relationship between CRP, IL-6, fibrinogen, and CAD severity. CRP showed the strongest correlation (r = 0.45, p < 0.001), followed by IL-6 (r = 0.42, p < 0.001), and fibrinogen (r = 0.38, p = 0.003). These findings suggest that as levels of these inflammatory markers increase, so does the severity of CAD, supporting the notion that inflammation plays a crucial role in the progression of coronary atherosclerosis. Previous studies have similarly demonstrated that higher levels of CRP and IL-6 are associated with worse outcomes in CAD patients, including greater plaque burden and increased risk of adverse cardiovascular events (Harhay et al., 2024)¹⁴.

The findings of this study underscore the potential of inflammatory markers as useful biomarkers for assessing CAD severity. Elevated CRP, IL-6, and fibrinogen levels can provide important prognostic information, helping to identify patients at higher risk of adverse cardiovascular events, even in the absence of significant coronary artery stenosis. These markers could also be valuable in monitoring disease progression and guiding therapeutic interventions aimed at reducing inflammation, such as statin therapy or other anti-inflammatory treatments (Liu et al., 2023)^15,16,17. However, the lack of a clear relationship between inflammation and CAD severity, as measured by coronary stenosis or the Gensini score, suggests that additional factors should be considered when evaluating CAD risk and severity.

In conclusion, our study demonstrates that elevated levels of CRP, IL-6, and fibrinogen are associated with high inflammation and positively correlate with CAD severity. Although inflammation is a key factor in the development and progression of CAD, its relationship with the degree of coronary stenosis is more complex and warrants further investigation. These findings contribute to the growing body of evidence suggesting that inflammatory markers may serve as useful tools for assessing CAD risk and severity, although their role in clinical decision-making should be considered in conjunction with other diagnostic measures.

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