1. Introduction
Cardiovascular diseases (CVDs) represent the leading cause of mortality globally, responsible for approximately 32% of all deaths annually.[1] In Iran, the burden of CVDs has been rising steadily, now accounting for nearly 43% of total deaths nationwide.[2] Among these, coronary artery diseases (CAD) stand out as the predominant contributor to both illness and death worldwide. Particularly in low- and middle-income countries, the incidence of CAD is escalating swiftly, posing a growing public health concern.[3] As medical and interventional therapies for CAD have improved, increasing numbers of patients now undergo coronary artery interventions such as percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG).[4] Individuals undergoing these interventions frequently experience significant psychological distress.[5,6] Indeed, the prevalence of anxiety and depression is notably elevated in these patients, and these psychological disorders are increasingly recognized as critical factors influencing cardiac prognosis, contributing to delayed recovery, reduced medication adherence, increased rates of rehospitalization, and heightened mortality risk.[7–9]
A growing body of evidence suggests that the pathophysiological relationship between psychological disorders and cardiovascular outcomes may be mediated through inflammatory pathways. Depression and anxiety are associated with activation of the hypothalamic-pituitary-adrenal (HPA) axis and increased production of pro-inflammatory cytokines. These mechanisms contribute to chronic low-grade inflammation, which is commonly observed in patients with CAD.[10–12] As a result, inflammatory biomarkers have been increasingly investigated as potential links between mental and physical health.
In particular, novel systemic inflammatory indices such as the Systemic Immune-Inflammation Index (SII) – calculated as (Platelet count × Neutrophil count)/ Lymphocyte count – and the Systemic Inflammatory Response Index (SIRI) calculated as (Neutrophil count × Monocyte count)/ Lymphocyte count have emerged as promising tools for capturing the balance between immune activation and suppression. These indices, calculated from simple blood cell counts, reflect systemic inflammation and have been associated with disease severity and prognosis in both cardiovascular disease and psychiatric disorders.[13–17]
Unlike patients with primary psychiatric disorders, patients with ACS are exposed to an acute inflammatory milieu caused by myocardial ischemia and tissue injury. Myocardial injury activates innate immune pathways and induces the release of inflammatory mediators, leading not only to local cardiac inflammation but also to a systemic inflammatory response involving circulating inflammatory cells and mediators. Therefore, systemic inflammatory indices in patients with ACS may reflect both the underlying inflammatory status and the acute cardiovascular event itself, which may limit the direct extrapolation of findings from psychiatric populations to ACS patients.[18–20]
Despite growing interest in these markers, limited research has focused on their association with psychological states in patients with ACS undergoing coronary angiography (CAG). Therefore, the present study aimed to investigate whether SII and SIRI were associated with the severity of anxiety and depression in patients with ACS undergoing CAG. We hypothesized that higher levels of SII and SIRI would be associated with greater severity of anxiety and depression in this population.
2. Material and methods
2.1. Study design and data collection
This single-center, retrospective cross-sectional study was conducted using data from the Coronary Artery Diseases Heshmat Registry (CADHER) at Dr Heshmat Hospital, affiliated with Guilan University of Medical Sciences (GUMS) in Rasht, Iran, between January 2022 and June 2023. The study included 1498 eligible participants (Fig. 1).
The study enrolled participants aged 20 and above who had been diagnosed with acute coronary syndrome (ACS) and admitted to the angiography unit. ACS diagnoses were made by a certified cardiologist, guided by the European Society of Cardiology’s 2019 guidelines for diagnosing and managing chronic coronary syndromes. Participants were primarily selected for CAG based on the presence of stable angina or atypical chest pain suggestive of ACS.
Upon hospital admission, participants were informed about the study’s objectives. Those who declined participation or follow-up were excluded.
2.2. Ethical statement
The study complied with the 2013 Declaration of Helsinki ethical standards. Further ethical clearance was granted by the GUMS Ethics Committee. The protocol received approval by the Institutional Review Board of the Cardiovascular Diseases Research Center at GUMS and the GUMS Ethics Committee (ethics code: IR.GUMS.REC.1404.417).
3. Demographic and clinical information
A team of 4 trained researchers conducted structured interviews to gather data. The collected information included participants’ age, gender, education level, smoking behavior, medical background such as a history of dyslipidemia (DLP), hypertension (HTN), diabetes mellitus (DM), heart failure (HF), family history of CVDs, and the type of coronary intervention received after CAG.
4. Coronary artery angiography
Upon admission, two cardiologists carried out a visual evaluation of atherosclerosis severity using the Judkins method via a femoral catheterization approach. The analysis of normal angiograms, defined as those showing no signs of coronary artery atherosclerosis, was performed by cardiologists who were blinded to the study objectives. In instances of diagnostic disagreement, a third interventional cardiologist, also blinded to the study data and laboratory findings, assessed the angiograms to establish the degree of stenosis.
5. Inflammatory index calculations
Venous blood was collected from each participant using standard phlebotomy techniques upon admission to the emergency ward. Blood samples were drawn into ethylenediaminetetraacetic acid (EDTA)-coated tubes to prevent coagulation. All samples were labeled and transported to the Dr Heshmat hospital laboratory under controlled conditions to ensure sample integrity.
The CBC with differential test included the measurement of key hematological parameters such as neutrophils, lymphocytes, platelets, and monocytes, and their results were obtained before the CAG procedure. SII was calculated as the product of neutrophil and platelet counts divided by lymphocyte count. Similarly, SIRI was determined by multiplying neutrophil and monocyte counts and dividing by lymphocyte count.[21]
6. Hospital anxiety and depression assessment
Patients’ psychological status regarding anxiety and depression was evaluated using the Hospital Anxiety and Depression Scale (HADS), as documented in the registry records. The HADS questionnaire consists of 14 items, with seven targeting anxiety symptoms (HADS-A) (items 1, 4, 5, 8, 9, 12, and 13) and 7 focused on depression symptoms (HADS-D) (items 2, 3, 6, 7, 10, 11, and 14). Each item was rated on a four-point scale ranging from 0 to 3.
Scores ranging from 8 to 10 are generally considered indicative of mild symptoms. Scores between 11 and 16 suggest a moderate level of anxiety or depression, while scores exceeding 16 reflect severe psychological distress.[22] Psychological data were obtained roughly 24 hours after blood sample collection.
7. Sample size calculation
Because this was a registry-based study, all eligible patients recorded during the study period were included in the analysis; therefore, no a priori sample size calculation was performed.
8. Statistical analysis
Quantitative variables are summarized by mean, standard deviation, or median and interquartile range, depending on their distribution. Qualitative variables are reported by frequency and percentage. To examine the independent association of each study variable (sociodemographic, comorbidities, clinical characteristics, etc.) with the severity of depression and anxiety, univariable analyses were conducted using Mann-Whitney U, Kruskal-Wallis, or Spearman correlation tests, as appropriate.
Variables demonstrating a significant association in the univariable analyses, along with clinically relevant variables identified as potential confounders, were subsequently entered into multivariable ordinal logistic regression models. Separate models were constructed for depression and anxiety severity. Multicollinearity among the independent variables was assessed using variance inflation factors (VIFs), with VIF values < 5 considered indicative of no substantial multicollinearity.
The proportional odds assumption was assessed using the test of parallel lines. Model fit was evaluated using the Pearson goodness-of-fit test. For the depression severity model, the Pearson goodness-of-fit test indicated adequate model fit (χ2 = 4132.66, df = 4115, P = .420).
Similarly, for the anxiety severity model, there was no evidence of lack of fit (χ2 = 4115.86, df = 4119, P = .511). The overall study population comprised 1498 participants. For the multivariable analyses, a complete-case approach was used, resulting in an analytic sample of 1377 patients for depression and 1378 for anxiety; about 7.5% were excluded because of missing values in the covariates included in the regression models.
Missing data were minimal for individual variables, with no variable having more than 5% missing observations; the highest proportion of missingness was observed for “Severity of coronary artery involvement” (5%). The difference between the number of participants with complete data for individual variables and the final regression sample reflects the cumulative effect of missing values across covariates included in the multivariable models. A two-sided P < .05 was considered statistically significant.
All analyses were performed using IBM SPSS Statistics, version 22.
9. Results
A total of 1498 patients were entered in the final analysis. The mean age of patients was 58.49 ± 11.14 years and 57.5% were male. The comparison of sociodemographic and clinical characteristics of patients based on depression and anxiety scores are summarized in Table 1.
Male patients showed higher anxiety and depression scores compared to females (P < .05). Depression scores varied significantly across education levels (P = .002). No significant differences were observed in anxiety or depression scores between smokers and nonsmokers.
Patients with HTN, DLP, and DM showed significantly lower anxiety scores (P < .05). Anxiety scores differed significantly across CAG outcomes (P = .004), with the highest scores in patients who were candidates for CABG. No significant differences were found in anxiety or depression scores across coronary artery involvement (P > .05).
9.1. Correlation between psychological scores and other variables
Table 2 presents the Spearman’s correlation coefficients between psychological scores and various biological and demographic variables. Although the correlations of anxiety with platelet count and BMI were small, they reached statistical significance (r = −0.065, P < .05 and r = −0.053, P < .05 respectively). Despite statistical significance, these correlations were very small and likely of limited clinical relevance, particularly given the large sample size.
No significant correlations were found between inflammatory indices (SII and SIRI) and either anxiety or depression scores, although weak positive or negative trends were noted (P > .05).
9.2. Ordinal logistic regression with depression severity
The proportional odds assumption for the depression severity model was evaluated using the test of parallel lines. The result was not statistically significant, indicating that the assumption was met (χ2 = 35.79, df = 26, P = .096).
Since gender, education, and a positive family history of CVDs were found to be statistically significant in the initial analysis, they were included in the regression model. Additionally, the severity of coronary artery involvement and the CAG results were incorporated as potential confounders due to their clinical and statistical relevance. Inflammatory indices, including SII and SIRI, did not demonstrate significant associations with depression severity (P = .878 and P = .390, respectively).
Only a positive family history of CVDs was significantly associated with depression severity (β = −0.280, P = .009). The severity of depression was lower in individuals with a family history of CVDs compared to those without such a history. Gender, educational level, and severity of coronary artery involvement (Patent, Mild, SVD, 2VD, 3VD) were not significantly related to depression severity (all P > .05).
Regarding CAG results, neither CABG (β = −0.155, P = .445) nor PCI (β = 0.006, P = .973) showed significant associations with depression severity (Table 3).
9.3. Ordinal logistic regression with anxiety severity
The test of parallel lines was also conducted for the anxiety severity model. The non result confirmed that the proportional odds assumption held for this model (χ2 = 33.66, df = 24, P = .091).
Since gender and comorbidities were found to be statistically significant in the initial analysis, they were included in the regression model. Additionally, the severity of coronary artery involvement and the CAG results were incorporated as potential confounders due to their clinical and statistical relevance. Inflammatory markers such as SII and SIRI did not show significant associations with anxiety severity (P = .590 and P = .690, respectively).
Similarly, comorbid conditions including DLP (P = .532), HTN (P = .961), and DM (P = .201) were not significantly related to anxiety severity. Gender was the only factor significantly associated with anxiety severity. Specifically, being male was positively associated with higher levels of anxiety (β = 0.853, P < .001), indicating that male participants were more likely to report greater anxiety severity compared to females.
Clinical variables related to coronary artery involvement severity did not show significant associations (all P > .05). Likewise, CAG results including CABG (β = 0.148, P = .454) and PCI (β = -0.098, P = .546) did not significantly predict anxiety severity (Table 4).
10. Discussion
The present study investigated the association between SII, SIRI, and the severity of anxiety and depression among patients with ACS undergoing CAG. The findings revealed no statistically significant associations between SII or SIRI and the severity of anxiety or depression. In the univariable analyses, male participants had higher anxiety and depression scores than female participants, while HTN, DLP, and DM were associated with lower anxiety scores.
Anxiety scores also differed significantly according to CAG results, with the highest scores observed among patients who were candidates for CABG. However, after adjustment for relevant covariates in the multivariable ordinal logistic regression model, gender was the only variable significantly associated with anxiety severity, whereas the associations of comorbidities and CAG results were no longer statistically significant. Similarly, none of the evaluated clinical variables, except a positive family history of CVDs, showed a significant association with depression severity in the adjusted model.
These findings highlight the importance of distinguishing unadjusted associations from independent associations after accounting for potential confounding factors.
In contrast with our findings, previous studies have suggested a potential association between systemic inflammatory indices and psychological disorders. Cui et al[23] reported that SII measured at hospital admission may be useful for assessing depression severity, highlighting its potential role as an accessible marker of systemic inflammation. Similarly, Bai et al[24] demonstrated that higher SII levels were associated with an increased risk of major depression, particularly among females and individuals aged 50 years or older.
Liu et al[25] also observed a positive association between SII and depressive symptoms in the general population, with a stronger relationship among individuals without CVDs. Moreover, in patients with tuberculosis, elevated SII levels were associated with anxiety and depression, suggesting that systemic immune dysregulation may contribute to psychological distress in chronic inflammatory conditions.[26] Elevated SII has also been associated with poststroke depression, further supporting a possible link between inflammation and psychological outcomes.[27]
In patients with coronary heart disease, Ju et al[28] demonstrated that SII may partially mediate the association between regular walking and depression, suggesting a potential role for systemic inflammation in the complex interaction between cardiovascular status, lifestyle behaviors, and psychological health. However, their findings were obtained in elderly patients with chronic coronary heart disease, which differs from our ACS population experiencing an acute inflammatory response. Furthermore, Zhou et al[29] reported a U-shaped association between SII and depression among adults with hypertension, suggesting that the relationship between systemic inflammation and psychological symptoms may not be simply linear.
Their findings indicate that both excessive inflammatory activation and altered immune balance may contribute to depressive symptoms, highlighting the complexity of inflammatory pathways involved in mental health. This nonlinear relationship may partly explain the inconsistent findings across studies, as differences in disease status, inflammatory burden, and patient characteristics may influence the association between SII/SIRI and psychological outcomes.
The discrepancy between our findings and previous reports may be explained by differences in study populations. Previous studies have mainly investigated psychiatric populations or individuals without acute cardiovascular events, whereas patients with ACS experience a distinct inflammatory state related to myocardial injury and acute ischemic stress. In patients with ACS, acute inflammatory activation caused by myocardial injury may have a stronger influence on circulating inflammatory markers than psychological factors, potentially attenuating the association between SII/SIRI and anxiety or depression severity.
Gender-related differences in the association between inflammatory markers and psychological symptoms remain unclear. In our study, male patients exhibited higher levels of anxiety and depression, although the underlying mechanisms remain uncertain. Previous studies have reported inconsistent findings regarding sex-specific inflammatory patterns.
Mommersteeg et al[30] found that women reported higher anxiety and depressive symptoms than men; however, HADS scores did not differ significantly between sexes. Women also showed higher hsCRP levels and lower monocyte and eosinophil counts, while the association between hsCRP and cognitive depressive symptoms was observed in men but not women. In contrast, our findings indicated higher rates of anxiety and depression among male participants.
Similarly, another study reported a stronger association between SII and depression risk in males, despite the generally higher prevalence of depression among females in the general population.[31] These differences may be related to variations in study populations, inflammatory conditions, and biological or psychosocial factors. However, in our study, no significant association was observed between SII/SIRI and psychological distress, suggesting that sex-related differences alone may not explain the relationship between systemic inflammation and anxiety or depression in patients with ACS.
Although the study included a relatively large sample, small associations may not have been detected. Therefore, the absence of statistically significant associations should not be interpreted as evidence that no relationship exists between systemic inflammatory indices and psychological distress.
Despite the strengths of this study, several limitations should be acknowledged. Conducting the study at a single hospital may limit the generalizability of findings to broader populations with different healthcare settings or demographic profiles. The study’s design captures data at one point in time, which restricts the ability to infer causality or assess changes in psychological or inflammatory markers over time.
Anxiety and depression were evaluated using the HADS questionnaire, which, while validated, is subject to reporting bias and may not capture clinical diagnoses with full accuracy. Residual confounding may have influenced our findings. Although several clinically relevant covariates were adjusted for, factors including socioeconomic status, medication use, lifestyle behaviors, psychosocial stressors, previous psychiatric history, and antidepressant use were not available in the database.
Other variables, such as CRP, were excluded due to a high rate of missing data (>30%). Because HADS was administered approximately 24 hours after admission, the measured anxiety and depression scores may partly reflect acute emotional responses to hospitalization or ACS rather than chronic psychological status.
11. Conclusion
Our findings suggest that SII and SIRI were not significantly associated with anxiety or depression severity among patients with ACS undergoing CAG. However, these results do not exclude the possibility of associations in other populations or clinical settings. Further longitudinal studies are needed to clarify the role of systemic inflammatory indices in psychological outcomes.
Acknowledgments
The authors would like to express their sincere gratitude to the Vice-Chancellor for Research and Technology of Guilan University of Medical Sciences for their valuable support and assistance. The authors also acknowledge the Cardiovascular Diseases Research Center of Guilan University of Medical Sciences for their support and contribution to this study.
Author contributions
Supervision: Amir Savarrakhsh, Yasaman Borghei.
Writing – review & editing: Amir Savarrakhsh.
Data curation: Bahare Gholami-Chaboki, Sadra Eghbali, Adele Isanazar.
Formal analysis: Bahare Gholami-Chaboki.
Methodology: Bahare Gholami-Chaboki, Sadra Eghbali.
Conceptualization: Fardin Mirbolouk, Yasaman Borghei.
Project administration: Yasaman Borghei.
Writing – original draft: Yasaman Borghei, Adele Isanazar.