European Journal of Cardiovascular Medicine

Cardiovascular diseases (CVD) remain the leading cause of global mortality, with an estimated 17.9 million deaths in 2019, accounting for 32% of all deaths worldwide (1). The majority of these deaths occur in low- and middle-income countries, driven by an epidemiological transition in risk factors and a rising prevalence of coronary artery disease (CAD) (2). This shift is linked to broader social, economic, and cultural changes such as globalization, urbanization, and population aging (3). India, too, is witnessing a disturbing increase in cardiovascular disease prevalence and mortality, with CAD being the most significant contributor. While much is known about traditional coronary risk factors—such as hypertension, diabetes, smoking, dyslipidemia, physical inactivity, and obesity—there is growing interest in non-traditional factors, primarily linked to inflammation and procoagulant states. These include C-reactive protein (CRP), fibrinogen, lipoprotein(a), BNP, calcium score, homocysteine, microalbuminuria, and ankle-brachial pressure index (ABPI). Studies have shown that hypogonadal males exhibit a higher prevalence of traditional coronary risk factors compared to those with normal testosterone levels (4,5). Low testosterone is notably associated with diabetes and metabolic syndrome, while androgen replacement has shown improvements in risk profiles and ischemic

symptoms in hypogonadal males, along with a reduction in the procoagulant state linked to atherosclerosis (6,7).

Despite global interest, literature on the relationship between testosterone levels and CAD remains limited, particularly in India. This study aims to explore the association between testosterone levels and the angiographic severity of CAD in middle-aged Indian men, also examining the relationship between testosterone and traditional coronary risk factors

AIMS & OBJECTIVES

The aim of this study was to estimate serum testosterone levels in middle-aged males and assess their correlation with the angiographic severity of coronary artery disease (CAD). Specifically, the objectives were to measure serum testosterone levels in this population, evaluate the relationship between these levels and the severity of CAD as determined by angiographic scoring, and examine the correlation between serum testosterone levels and the clinical profile, including traditional risk factors of CAD such as hypertension, diabetes, obesity, and dyslipidemia.

This prospective observational study was conducted on male patients aged 40-60 years, admitted for coronary angiography (CAG) at the Department of Cardiology, SVIMS, Tirupati. The inclusion criteria were male patients within this age range undergoing CAG, provided they met no exclusion criteria. Exclusion criteria included previous revascularization procedures, history of hypogonadism, prostate cancer with anti-androgen therapy, liver/renal dysfunction, recent or current infection, and a previous history of ischemic heart disease or CAD. After obtaining informed consent, detailed clinical profiles were recorded, including age, BMI, lifestyle, hypertension, diabetes, dyslipidemia, smoking, history of ischemic heart disease, and family history. Routine blood tests, fasting serum testosterone, SHBG, and calculation of free and bioavailable testosterone were performed. Post-CAG, the severity of CAD was assessed using angiographic scores (GENSINI and SYNTAX), and correlations between testosterone levels and CAD severity were analyzed.

Serum testosterone, SHBG, free testosterone, and bioavailable testosterone levels were measured using automated chemiluminescence methods (Beckman Coulter Access 2) in the endocrinology lab. Angiographic scoring was done by a cardiologist unaware of the biochemistry results to avoid bias. Sample size calculations were based on previous studies with a correlation coefficient of -0.513 between testosterone levels and angiographic scores. The data was analyzed using SPSS 26.0, with descriptive variables presented as means ± standard deviation and categorical data as percentages. The study population was divided into three groups based on the Gensini and Syntax scores: low, moderate, and high severity. The correlation between testosterone levels and angiographic severity was assessed using Pearson's correlation, and differences between groups were analyzed using ANOVA and post-hoc Bonferroni tests. Multiple linear regression was used to adjust for potential confounders such as age, BMI, smoking, hypertension, diabetes, and dyslipidemia to evaluate the independent association of testosterone with CAD severity.

RESULTS

In this study, 88 middle-aged male participants were enrolled, with a mean age of 51.3 ± 6.8 years. The population had a mean BMI of 26.4 ± 4.5 kg/m², mean ejection fraction of 43.0 ± 9.2%, and hemoglobin levels of 14.0 ± 1.6 g/dl. The study highlighted a high prevalence of coronary artery disease (CAD risk factors), with 48.9% of participants being smokers, 45.5% having diabetes, and 64.8% categorized as obese. Hypertension was present in 25.1%, and dyslipidemia in 27.3%. These participants were grouped based on the severity of CAD as assessed by the GENSINI and SYNTAX scores. While there were no significant differences in the prevalence of hypertension, diabetes, obesity, smoking, dyslipidemia, or peripheral artery disease among the groups based on these scores, the distribution of these risk factors varied across the severity subgroups.

The analysis also focused on the relationship between testosterone levels and CAD severity. However, serum total testosterone, SHBG, free testosterone, and bioavailable testosterone were not correlated with the severity of CAD, as indicated by both Pearson and Spearman correlation coefficients (r-values ranged from -0.122 to 0.097). The ANOVA tests revealed no significant variation in testosterone levels across the severity subgroups classified by the GENSINI and SYNTAX scores (p-values ranged from 0.582 to 0.987). Furthermore, multiple linear regression models showed that age, smoking, diabetes, and testosterone levels did not serve as independent predictors for the severity of CAD. These findings suggest that while traditional CAD risk factors were prevalent in this cohort, testosterone levels did not independently correlate with or predict the angiographic severity of coronary artery disease.

In this study, 88 middle-aged male participants were enrolled, with a mean age of 51.3 ± 6.8 years. The population had a mean BMI of 26.4 ± 4.5 kg/m², mean ejection fraction of 43.0 ± 9.2%, and hemoglobin levels of 14.0 ± 1.6 g/dl. The study highlighted a high prevalence of coronary artery disease (CAD risk factors), with 48.9% of participants being smokers, 45.5% having diabetes, and 64.8% categorized as obese. Hypertension was present in 25.1%, and dyslipidemia in 27.3%. These participants were grouped based on the severity of CAD as assessed by the GENSINI and SYNTAX scores. While there were no significant differences in the prevalence of hypertension, diabetes, obesity, smoking, dyslipidemia, or peripheral artery disease among the groups based on these scores, the distribution of these risk factors varied across the severity subgroups.

The analysis also focused on the relationship between testosterone levels and CAD severity. However, serum total testosterone, SHBG, free testosterone, and bioavailable testosterone were not correlated with the severity of CAD, as indicated by both Pearson and Spearman correlation coefficients (r-values ranged from -0.122 to 0.097). The ANOVA tests revealed no significant variation in testosterone levels across the severity subgroups classified by the GENSINI and SYNTAX scores (p-values ranged from 0.582 to 0.987). Furthermore, multiple linear regression models showed that age, smoking, diabetes, and testosterone levels did not serve as independent predictors for the severity of CAD. These findings suggest that while traditional CAD risk factors were prevalent in this cohort, testosterone levels did not independently correlate with or predict the angiographic severity of coronary artery disease.

Cardiovascular disease (CVD) is currently the leading cause of death worldwide, with coronary artery disease (CAD) being the most prominent contributor to this high mortality rate. This trend has been notably observed in both high-income and low- to middle-income countries, where an epidemiological shift has occurred in the risk factors and prevalence of CAD. India, in particular, has witnessed a disturbing rise in the prevalence and mortality associated with cardiovascular diseases, with CAD emerging as the most common and significant cause of death. This trend is compounded by the growing burden of traditional risk factors and a shift in lifestyle that heightens the risk of cardiovascular events.

Extensive research has focused on traditional coronary risk factors, such as hypertension, diabetes, smoking, and dyslipidemia, and their association with the severity of CAD. These risk factors form the basis of most existing cardiovascular risk assessment tools. However, validation studies of these tools indicate that they are not perfect, often overestimating or underestimating risk. Despite this, these tools remain central in predicting outcomes and guiding clinical practice.

Linear regression models have suggested that the behavioral risk factors alone do not fully explain the disproportionate burden of CAD in men. A significant number of CAD cases occur in individuals who do not exhibit traditional risk factors. This has sparked interest in examining non-traditional factors that may contribute to the development and progression of CAD. Among these, markers of inflammation and procoagulant or atherosclerotic burden have garnered attention. Notably, the prevalence of CAD in men is approximately three times higher than in women, and men tend to develop CAD roughly a decade earlier. These disparities are not entirely explained by the differences in traditional risk factor profiles, suggesting that sex hormones may play a role in the pathophysiology of cardiovascular diseases.

The role of sex hormones, particularly testosterone, in cardiovascular health is a subject of growing interest. While it is commonly believed that testosterone is harmful to the male heart, this view has been challenged by emerging research. Contrary to the assumption that higher testosterone levels contribute to a greater burden of coronary disease in men, several studies have demonstrated that men with CAD tend to have lower testosterone levels than those without CAD. The relationship between low testosterone levels and CAD remains unclear, with some proposing that low testosterone may accelerate the development of CAD, while others suggest that it could be a consequence of chronic illness.

Given the limited research on this topic in India, our study aimed to explore the correlation between serum testosterone levels, traditional coronary risk factors, and the severity of CAD as assessed by angiographic scores. This prospective observational study included 88 middle-aged men undergoing coronary angiography. The study outcomes were evaluated under three primary headings:

The average age of participants was 51.38 ± 6.82 years, and no statistically significant differences were found in the mean age across the angiographic severity groups (A, B, C) as per both the GENSINI and SYNTAX scores. The prevalence of hypertension in severe CAD cases (GENSINI group C) was 50%, compared to 31.8% in SYNTAX group C, though this was not statistically significant. Diabetes was found in 42.5% of those with severe CAD in the GENSINI group C, versus 15% in SYNTAX group C. The prevalence of obesity and dyslipidemia was also high in GENSINI groups B and C, but these differences were not statistically significant. Smoking was notably more prevalent in severe CAD patients, with 73.4% of those in GENSINI groups B and C being smokers. However, none of these traditional risk factors showed a statistically significant correlation with CAD severity in this study.

A weak negative correlation (r = -0.401) was observed between total testosterone levels and age, but this correlation was not statistically significant (p = 0.349). A similar weak negative correlation (r = -0.597) between bioavailable testosterone and total cholesterol levels was also found, though it did not reach statistical significance (p = 0.369).

Serum testosterone levels, including total testosterone (p = 0.739), SHBG (p = 0.887), free testosterone (p = 0.987), and bioavailable testosterone (p = 0.943), did not show significant variation across the subgroups A, B, and C according to the GENSINI score. Similarly, when analyzed by the SYNTAX score, no significant differences were found in testosterone levels across the severity groups (total testosterone p = 0.582, SHBG p = 0.740, free testosterone p = 0.606, bioavailable testosterone p = 0.722). Multiple linear regression analysis revealed that traditional coronary risk factors (age, hypertension, smoking, diabetes, dyslipidemia) and serum testosterone levels did not independently predict CAD severity, as assessed by angiographic scores.

In contrast to our findings, studies by English et al (8), have reported significant differences in testosterone levels between CAD patients and controls, although no significant correlation was found with increasing disease severity. Additionally, some studies have demonstrated an inverse relationship between testosterone levels and CAD severity, suggesting that hypogonadism or androgen deficiency may be associated with CAD in men (9,10). Similar findings were reported by Dobrzycki et al (11)., Zaho et al (12)., Rosano et al (13)., Hux et al (14)., Philips et al (15)., and Li et al(16)., all of whom observed a negative relationship between androgens and CAD.

In conclusion, while traditional risk factors remain critical in the assessment and management of CAD, our study found no significant correlation between serum testosterone levels and the severity of CAD. This highlights the complexity of cardiovascular disease, where multiple non-traditional factors, including sex hormones, may play a role, but their precise contribution remains unclear. Further research, particularly in the Indian context, is required to fully understand the interplay between testosterone and CAD.

LIMITATION OF THE STUDY

While the sample size in our study was calculated using appropriate statistical methods, it remains insufficient to definitively assess the association of traditional risk factors and serum testosterone levels as independent predictors of CAD severity. The division of patients into groups based on angiographic severity revealed significant differences in age, diabetes, hypertension, and other risk factors, which may have influenced the analysis of hormone levels and their relationship to CAD severity. Population bias is another consideration, as the analysis could have differed if the subgroups were completely homogeneous, although we made efforts to adjust for confounders using multiple linear regression. As this was a cross-sectional observational study, causal relationships between CAD severity and testosterone levels could not be established, and the patients were not followed for mortality outcomes. Longitudinal studies would provide more valuable insights in this regard.

In our study, we observed a high prevalence of traditional coronary risk factors such as hypertension, diabetes, obesity, dyslipidemia, and smoking in the moderate and severe CAD subgroups based on the GENSINI scoring. However, these findings were not statistically significant. We noted weak negative correlations between age and serum total testosterone, as well as between total cholesterol levels and bioavailable testosterone, though these were not statistically significant either. Multiple linear regression analysis indicated that traditional risk factors like age, hypertension, diabetes, smoking, dyslipidemia, obesity, and serum testosterone levels did not independently predict the severity of CAD in our study. A meta-analysis of previous research in this area revealed significant heterogeneity in study designs and outcomes. The question of whether low testosterone is a cause or consequence of CAD remains unresolved, with evidence supporting both perspectives. It is likely that testosterone plays a dual role, acting both as a potential causative factor and as a consequence of illness and frailty. Further research is necessary to explore the complex mechanisms behind this relationship, and future studies will undoubtedly deepen our understanding of the connection between testosterone and coronary artery disease, which remains an area of great interest.Top of Form

(Conflict of interest: The study was done with financial support of SVIMS Tirupathi. Grant No-SBAVP/ERPW/113/2020-21)

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