|Year : 2022 | Volume
| Issue : 4 | Page : 97-101
Premature coronary artery disease in young Indians: The hormonal triad of insulin, testosterone, and vitamin D
JR Vijaykumar Reddy, Rahul S Patil, Laxmi H Shetty, CN Manjunath
Department of Cardiology, Sri Jayadeva Institute of Cardiovascular Sciences and Research, Bengaluru, Karnataka, India
|Date of Submission||13-Sep-2022|
|Date of Decision||23-Sep-2022|
|Date of Acceptance||01-Nov-2022|
|Date of Web Publication||21-Jan-2023|
MD, DM Laxmi H Shetty
Department of Cardiology, Sri Jayadeva Institute of Cardiovascular Sciences and Research, Bengaluru - 560 069, Karnataka
Source of Support: None, Conflict of Interest: None
Background: Cardiovascular diseases (CVDs) are on the rise globally. India, in spite of housing the youngest population, has now been termed the CVD capital of the world. Several independent studies have shown association between low levels of Vitamin D, insulin resistance, and low testosterone levels and coronary artery disease (CAD). However, the presence of this hormonal triad in premature CAD patients in India has not been studied. Therefore, we aimed to explore the role of this hormonal triad in CAD in young Indians. Methods: This was a prospective, case–control, study conducted at a tertiary care center in India. Premature CAD patients were enrolled as cases and healthy individuals were enrolled as controls. Demographic, behavioral, anthropometric and body composition, physiological, and biochemical parameters were recorded/assayed as per standard protocols. Results: A total of 644 individuals were enrolled in the study. Among them, 344 belonged to the case group and 300 to the control group. The mean age did not differ significantly between cases (32.1 ± 5.6 years) and controls (32.5 ± 5.0 years). Significantly lower levels of Vitamin D levels (P = 0.01) and serum insulin (P < 0.001) were observed in the case group compared to the control group. In males, no significant difference was observed between the two groups in terms of serum testosterone level (P = 0.075). Conclusion: Higher fasting insulin levels may be a reliable indicator of premature CAD. Vitamin D levels may not reliably predict premature CAD because 70%–90% of Indians are deficient of Vitamin D. Testosterone levels in females, but not in males, may be a reliable predictor for the same. However, larger studies are required to validate these findings.
Keywords: Coronary artery disease, insulin, testosterone, Vitamin D, young adult
|How to cite this article:|
Vijaykumar Reddy J R, Patil RS, Shetty LH, Manjunath C N. Premature coronary artery disease in young Indians: The hormonal triad of insulin, testosterone, and vitamin D. J Clin Prev Cardiol 2022;11:97-101
|How to cite this URL:|
Vijaykumar Reddy J R, Patil RS, Shetty LH, Manjunath C N. Premature coronary artery disease in young Indians: The hormonal triad of insulin, testosterone, and vitamin D. J Clin Prev Cardiol [serial online] 2022 [cited 2023 Mar 29];11:97-101. Available from: https://www.jcpconline.org/text.asp?2022/11/4/97/368353
| Introduction|| |
According to the World Health Organization (WHO), cardiovascular diseases (CVDs) are the leading cause of death globally. A large portion of these deaths are from low- and middle-income countries and India accounts for one-fifth of them. Ironically, India is the youngest country in the world with around 66% of its population under the age of 35 years. Coronary artery disease (CAD) is the most common CVD, and its premature occurrence can result in death and disability in the prime years of life. CAD that develops before the age of 65 years in women and 55 years in men is referred to as premature CAD. Young-onset CAD is defined as CAD in patients under the age of 40 years and is the most severe type of premature CAD. The after effects are significant consequences for the patients, their families, and the country's health-care systems.
Asian Indians have a 20%–50% higher risk of CAD-related death than other populations. Several studies imply that metabolic, genetic, environmental, and social factors contribute to the greater risk. Despite regional variation, men are approximately three times more likely to develop CAD as compared to women, irrespective of ethnicity. Studies have found that insulin resistance (IR),, Vitamin D deficiency, and hypotestosteronemia or precisely, low levels of free testosterone,,, are significant contributors to the development of CAD.
Aforementioned studies, based on examining the individual impact of these factors on CAD patients, have been conducted in nonIndian patients. Due to the fundamental differences in the pathophysiology and clinical features of the CVD, guidelines derived from such studies cannot be generalized to the Indian population. Considering this, the current study aimed at collectively investigating the role of these hormones, namely, insulin, Vitamin D, and testosterone on the pathophysiology of premature CAD in Indian patients.
| Methods|| |
Study design and population
In this prospective, case-control, single-center study, 644 participants were recruited at a tertiary care center in India between March 2019 and March 2021. The study was approved by the institutional ethics committee and was conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from all participants before enrollment.
Systematic random sampling method was used. The control group consisted of age-matched participants from the general population with no history of CAD based on clinical presentation or detailed examination.
Patients aged ≤40 years, diagnosed with ischemic heart disease as evidenced by acute coronary syndrome, and chronic stable angina with evidence of CAD were included in the study. The study excluded patients having a history of chronic alcoholism, concomitant liver or kidney disease, acute or chronic infection, patients taking hypolipidemic drugs and oral contraceptives, and those on hormone replacement therapy.
Demographic (age and sex), behavioral (smoking and drinking), anthropometric and body composition (body mass index, waist and hip circumferences, and waist-to-hip circumference ratio), and physiological (blood pressure) parameters were recorded. Biochemical parameters (fasting glucose, total cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, insulin, and Vitamin D serum levels) were assayed as per standard protocol.
Statistical analyses were performed using Statistical Package for the Social Sciences version 20.0 (IBM, Chicago, IL, USA). Categorical variables were compared using Chi-square statistics, Fisher's exact test, and Student's t-test as applicable; one-way ANOVA was used for continuous variables.
| Results|| |
A total of 644 participants who satisfied the inclusion and exclusion criteria were registered for the study. Among the 644 participants, 344 were CAD patients (case) and 300 were healthy individuals (control). Baseline characteristics and risk exposure of cases and controls are given in [Table 1]. As shown in [Table 1], 98.6% of patients were aged <40 years. The most frequently observed age group was between 31 and 35 years; 134 (39.0%) patients from the case group and 123 (41.0%) individuals from the control group. Males were predominant in both groups: 229 out of 344 (86.9%) patients in the case group and 201 out of 300 (67%) individuals in the control group [Table 1].
|Table 1: Sample characteristics and risk factors for coronary artery disease|
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Risk factors such as diabetes (n = 30 [37.5%] vs. n = 5 [1.6%]), smoking (n = 138 [40.1%] vs. n = 16 [5.3%]), impaired glucose tolerance (n = 129 [37.5%] vs. n = 32 [10.7%]), family history of premature CAD (n = 35 [10.2%] vs. n = 0), and metabolic syndrome (n = 234 [68%] vs. n = 110 [36.7%]) were more prominent in the case group as compared to the control group. Prehypertension and hypertension were more prevalent in the case group (n = 187 [54%] and n = 30 [0.8%], respectively) than in the control group (n = 104 [34.7%] and n = 0, respectively).
As depicted in [Table 2], a significant difference was observed between the two groups in terms of waist-to-hip ratio (P < 0.001), fasting blood sugar (P < 0.001), glycated hemoglobin (P < 0.001), triglycerides level (P < 0.001), high-density lipoprotein (P = 0.006), Vitamin D level (P = 0.01), and fasting insulin level (P < 0.001). Although not significant, testosterone levels were lower in the case group (4.4 ± 11.3) as compared to the control group (8.9 ± 38.2) in males (P = 0.075). In the case of females, testosterone levels were significantly greater in the case group (1.2 ± 38.2) than in the control group (0.3 ± 0.8) (P = 0.038).
| Discussion|| |
As predicted by the WHO, India has become the global capital of CVDs. A higher prevalence of risk factors such as hypertension, diabetes, dyslipidemia, smoking, and obesity have contributed to this. Studies have shown that over 50% of all CAD mortalities in the Indian population occur in patients <50 years of age, and 25% of these cases belong to the below 40 age group. A prominent risk factor for CAD is male sex. Studies suggest that this may be attributed to the less-adaptive stress-coping mechanisms in males as compared to females. However, we cannot eliminate the fact that Indian females neglect their health due to family pressure and their symptoms are quite often overlooked. The proportion of male patients (86.9%) was much higher than the proportion of female patients (13.1%) in our study. The same skewness has been observed in the AMIYA study, the YOUTH registry, and various other studies., Asian men (9.7%) and women (4.4%) experience their first myocardial infarction below the age of 40 years. Studies suggest that this is 2–3.5 fold greater than the Western population. The mean age of patients in the current study was 32.1 ± 5.6 years, which is similar to other studies that had a mean age of 27 ± 2.8 years and 26 ± 3.9 years.
The present study found a higher prevalence of conventional risk factors such as smoking, hypertension, prehypertension, hypercholesterolemia, diabetes, and obesity in the case group than in the control group. A similar trend was observed by the Jaipur Heart Watch-2 study that found smoking, physical inactivity, hypertension, hypercholesterolemia, diabetes and obesity, truncal obesity, low- and high-density lipoprotein-cholesterol, and high triglycerides as risk factors for CAD in the urban Indian population. In the current study, impaired glucose tolerance and metabolic syndrome were common in the case group as compared to the control group. The history of familial premature CAD was 10.6% in the case group. This was comparable with the INTERHEART study which showed that family history was slightly more important in young patients (14.8%) compared to older patients (10.45%).
In 1973, Lund B et al. reported for the first time an association between serum Vitamin D levels and the risk of ischemic heart disease. The ideal Vitamin D range is between 20 and 40 ng/mL. We found that both groups in our study were Vitamin D deficient. Nonetheless, Vitamin D deficiency was significantly greater in CAD patients (14.8 ng/mL) as compared to controls (16.8 ng/mL). Therefore, we cannot establish a solid relationship between Vitamin D deficiency and CAD. Various studies from across India have found that up to 70%–90% of Indians have a deficiency of Vitamin D irrespective of their age, sex, or place of residence.,,
Evidence suggests that Vitamin D is associated with decreased risk of endothelial dysfunction, calcification, and arterial stiffness. Syal et al. found a higher prevalence of Vitamin D deficiency in angiographically proven CAD patients, but their study lacked a control group. They also found a correlation between the extent of the deficiency and the severity of CAD, which was not confirmed in our study. In contrast, the study conducted by Akhtar et al. on the association of serum Vitamin D levels in patients with CAD found no significant difference between patients (40.19 nmol/L) and healthy controls (34.06 nmol/L) (P = 0.08).
Hyperinsulinemia increases the risk of cardiovascular events mediated by an inflammatory prothrombotic state and by its direct effects on arterial walls. The cause of lipid abnormalities, a known risk factor for CAD, is mostly attributed to hyperinsulinemia. Lakka et al. and Yarnell et al. prospectively found an association between hyperinsulinemia and CVD. They suggested that hyperinsulinemia causes dyslipidemia, hypertension, and obesity, which increases the risk of CVD. CAD patients in our study showed significantly higher (P < 0.001) baseline fasting insulin levels (32.1 pmol/L) than the control group (14.4 pmol/L). Comparable to our findings, Lakka et al. found that serum insulin levels were directly associated with the risk of CVD (P = 0.006), acute coronary events (P = 0.04), and stroke (P = 0.02).
How testosterone affects the heart and blood vessels is well-known. Briefly, testosterone and the more potent dihydrotestosterone (DHT) bind to androgen receptors (AR). DHT-AR migrates as a complex into the nucleus and further dimerizes, associates with the coactivator proteins, and causing activation of genes which alter myocardial and vascular cell behavior. Serum testosterone concentrations are known to decrease with age. Some studies suggest that reduced testosterone is associated with premature CAD and an elevated risk of cardiovascular death regardless of age. There was no significant difference between the case group (4.4 nmol/L) and control group (8.6 nmol/L) with respect to serum testosterone levels in males (P = 0.075) in our study. This may be because the majority of our study sample was made up of young patients, many of whom were sexually active.
Comparable to our findings, Kabakci et al. found no significant difference in serum testosterone levels between male patients with CAD (4.0 g/ml) and healthy individuals (3.5 ng/mL) (P = 0.30). It was noteworthy that the females had testosterone levels significantly higher in the case group (1.2 nmol/L) versus the control group (0.3 nmol/L) (P = 0.038). However, larger studies in females are required to confirm this finding. Overall, we found higher deficiency of Vitamin D, hyperinsulinemia, and fairly normal levels of testosterone in CAD patients in the current study.
The findings of the current study must be evaluated in the context of the following limitations. First, being a single-center study, the results cannot be applied to the young Indian population in general. Second, the present study was observational. Thus, the correlation can only be hypothesized, but not established. Third, since both populations were deficient of Vitamin D, we could not establish a relationship between CAD and Vitamin D levels. Finally, we did not evaluate whether the extent of Vitamin D deficiency, IR, and testosterone levels correlated with the severity of stenosis in angiographic findings.
| Conclusion|| |
This study supports that hyperinsulinemia could help in identifying people at risk of premature CAD. Since both groups, cases and controls, were Vitamin D deficient, we could not establish a relationship between CAD and Vitamin D levels. Whether serum testosterone levels could be employed for the same depends on factors such as age, gender, and sexual activity, as seen in the current study. Further studies using a larger population may be required to validate our findings.
Financial support and sponsorship
Grant-in-aid for advanced scientific research By Rajiv Gandhi University of Health Sciences, Bangalore.
Conflicts of interest
There are no conflicts of interest.
| References|| |
Sreeniwas Kumar A, Sinha N. Cardiovascular disease in India: A 360 degree overview. Med J Armed Forces India 2020;76:1-3.
Enas EA, Mehta J. Malignant coronary artery disease in young Asian Indians: Thoughts on pathogenesis, prevention, and therapy. Coronary artery disease in Asian Indians (CADI) Study. Clin Cardiol 1995;18:131-5.
Karim MA, Majumder AA, Islam KQ, Alam MB, Paul ML, Islam MS, et al
. Risk factors and in-hospital outcome of acute ST segment elevation myocardial infarction in young Bangladeshi adults. BMC Cardiovasc Disord 2015;15:73.
Ardeshna DR, Bob-Manuel T, Nanda A, Sharma A, Skelton WP 4th
, Skelton M, et al
. Asian-Indians: A review of coronary artery disease in this understudied cohort in the United States. Ann Transl Med 2018;6:12.
Morris PD, Channer KS. Testosterone and cardiovascular disease in men. Asian J Androl 2012;14:428-35.
An X, Yu D, Zhang R, Zhu J, Du R, Shi Y, et al
. Insulin resistance predicts progression of de novo atherosclerotic plaques in patients with coronary heart disease: A one-year follow-up study. Cardiovasc Diabetol 2012;11:71.
Cho YR, Ann SH, Won KB, Park GM, Kim YG, Yang DH, et al.
Association between insulin resistance, hyperglycemia, and coronary artery disease according to the presence of diabetes. Sci Rep 2019;9:6129.
Verdoia M, Schaffer A, Sartori C, Barbieri L, Cassetti E, Marino P, et al
. Vitamin D deficiency is independently associated with the extent of coronary artery disease. Eur J Clin Invest 2014;44:634-42.
Shores MM, Smith NL, Forsberg CW, Anawalt BD, Matsumoto AM. Testosterone treatment and mortality in men with low testosterone levels. J Clin Endocrinol Metab 2012;97:2050-8.
Sharma R, Oni OA, Gupta K, Chen G, Sharma M, Dawn B, et al
. Normalization of testosterone level is associated with reduced incidence of myocardial infarction and mortality in men. Eur Heart J 2015;36:2706-15.
Badran HM, Soliman MA, Elmadbouh I, Ibrahim WA, El Masry SF. Relationship of coronary artery disease with testosterone level in young men undergoing coronary angiography. Menoufia Med J 2019;32:18. [Full text]
Krishnan MN. Coronary heart disease and risk factors in India – On the brink of an epidemic? Indian Heart J 2012;64:364-7.
Sharma R, Bhairappa S, Prasad S, Manjunath CN. Clinical characteristics, angiographic profile and in hospital mortality in acute coronary syndrome patients in south Indian population. Heart India 2014;2:65.
Weidner G. Why do men get more heart disease than women? An international perspective. J Am Coll Health 2000;48:291-4.
Sinha SK, Krishna V, Thakur R, Kumar A, Mishra V, Jha MJ, et al
. Acute myocardial infarction in very young adults: A clinical presentation, risk factors, hospital outcome index, and their angiographic characteristics in North India-AMIYA Study. ARYA Atheroscler 2017;13:79-87.
Shukla AN, Jayaram AA, Doshi D, Patel P, Shah K, Shinde A, et al
. The young myocardial infarction study of the Western Indians: YOUTH Registry. Glob Heart 2019;14:27-33.
Deshmukh PP, Singh MM, Deshpande MA, Rajput AS. Clinical and angiographic profile of very young adults presenting with first acute myocardial infarction: Data from a tertiary care center in Central India. Indian Heart J 2019;71:418-21.
Sharma M, Ganguly NK. Premature coronary artery disease in Indians and its associated risk factors. Vasc Health Risk Manag 2005;1:217-25.
Gupta R, Gupta VP, Sarna M, Bhatnagar S, Thanvi J, Sharma V, et al
. Prevalence of coronary heart disease and risk factors in an urban Indian population: Jaipur Heart Watch-2. Indian Heart J 2002;54:59-66.
Yusuf S, Hawken S, Ounpuu S, Dans T, Avezum A, Lanas F, et al.
Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): Case-control study. Lancet 2004;364:937-52.
Lund B, Badskjaer J, Lund B, Soerensen OH. Vitamin D and ischaemic heart disease. Horm Metab Res 1978;10:553-6.
Bhatt SP, Misra A, Sharma M, Guleria R, Pandey RM, Luthra K, et al
. Vitamin D insufficiency is associated with abdominal obesity in urban Asian Indians without diabetes in North India. Diabetes Technol Ther 2014;16:392-7.
Harinarayan CV, Sachan A, Reddy PA, Satish KM, Prasad UV, Srivani P. Vitamin D status and bone mineral density in women of reproductive and postmenopausal age groups: A cross-sectional study from south India. J Assoc Physicians India 2011;59:698-704.
Selvarajan S, Gunaseelan V, Anandabaskar N, Xavier AS, Srinivasamurthy S, Kamalanathan SK, et al
. Systematic review on Vitamin D level in apparently healthy Indian population and analysis of its associated factors. Indian J Endocrinol Metab 2017;21:765-75.
Al Mheid I, Quyyumi AA. Vitamin D and cardiovascular disease: Controversy unresolved. J Am Coll Cardiol 2017;70:89-100.
Syal SK, Kapoor A, Bhatia E, Sinha A, Kumar S, Tewari S, et al.
Vitamin D deficiency, coronary artery disease, and endothelial dysfunction: Observations from a coronary angiographic study in Indian patients. J Invasive Cardiol 2012;24:385-9.
Akhtar T, Aggarwal R, Jain SK. Serum Vitamin D Level in Patients with Coronary Artery Disease and Association with Sun Exposure: Experience from a Tertiary Care, Teaching Hospital in India. Adv Med 2019;2019:6823417. doi: 10.1155/2019/6823417. PMID: 30863784; PMCID: PMC6378067.
Kumar A, Patel DR, Wolski KE, Lincoff AM, Kashyap SR, Ruotolo G, et al
. Baseline fasting plasma insulin levels predict risk for major adverse cardiovascular events among patients with diabetes and high-risk vascular disease: Insights from the ACCELERATE trial. Diab Vasc Dis Res 2019;16:171-7.
DeFronzo RA. Insulin resistance, hyperinsulinemia, and coronary artery disease: A complex metabolic web. J Cardiovasc Pharmacol 1992;20 Suppl 11:S1-16.
Lakka TA, Lakka HM, Salonen JT. Hyperinsulinemia and the risk of coronary heart disease. N Engl J Med 1996;335:976-7.
Yarnell JW, Sweetnam PM, Marks V, Teale JD, Bolton CH. Insulin in ischaemic heart disease: Are associations explained by triglyceride concentrations? The caerphilly prospective study. Br Heart J 1994;71:293-6.
Lakka HM, Lakka TA, Tuomilehto J, Sivenius J, Salonen JT. Hyperinsulinemia and the risk of cardiovascular death and acute coronary and cerebrovascular events in men: The kuopio ischaemic heart disease risk factor study. Arch Intern Med 2000;160:1160-8.
Melmed S, Polonsky KS, Larsen PR, Kronenberg HM. Williams Textbook of Endocrinology E-Book. Amsterdam: Elsevier Health Sciences; 2015.
Khaw KT, Dowsett M, Folkerd E, Bingham S, Wareham N, Luben R, et al.
Endogenous testosterone and mortality due to all causes, cardiovascular disease, and cancer in men: European prospective investigation into cancer in Norfolk (EPIC-Norfolk) prospective population study. Circulation 2007;116:2694-701.
Kabakci G, Yildirir A, Can I, Unsal I, Erbas B. Relationship between endogenous sex hormone levels, lipoproteins and coronary atherosclerosis in men undergoing coronary angiography. Cardiology 1999;92:221-5.
[Table 1], [Table 2]