The Association of Hair Cortisol and Cardiometabolic Risk Factors in Cardiovascular Disease

Abstract

Hair cortisol is increasingly becoming a reliable measure of long-term cortisol concentration and is thought to be a suitable biomarker for chronic stress. Further, a growing amount of scientific literature links elevated hair cortisol concentration with well-known cardiometabolic risk factors such as hypertension, obesity, dyslipidemia, and diabetes. This has important implications for the prognosis, treatment, and prevention of cardiovascular disease. This review focuses on the association between increased hair cortisol and stress-related cardiometabolic risk factors for cardiovascular disease. While the evidence for the relationship between cardiometabolic risk and elevated hair cortisol is clear and compelling, the data is inconsistent. Further studies are needed to support the use of hair cortisol as a biomarker of cardiometabolic risk in cardiovascular disease.

1. Introduction

Cardiovascular disease (CVD) continues to be the primary cause of morbidity and mortality worldwide [1]. In 2019, approximately 17.9 million people died from CVDs, representing 32% of all global deaths [2]. Eighty-five percent of CVD deaths resulted from heart attack and stroke. These high numbers are especially concerning since most CVDs are preventable or modifiable by addressing behavioral risk factors, such as a sedentary lifestyle, unhealthy diet, tobacco use, and harmful use of alcohol [1, 2, 3]. Early detection is essential in eradicating or in beginning management of cardiovascular disease with counseling and medications.

Cardiometabolic risk (CMR) refers to the risk factors that increase the likelihood of experiencing cardiovascular events or developing metabolic disease [4]. Besides the traditional cardiovascular risk factors (age, gender, family history, hypertension, diabetes, and smoking), CMR factors include abdominal obesity, insulin resistance, inflammation, unhealthy eating habits, and a sedentary lifestyle (Figure 1). Several cross-sectional clinical studies have shown a positive association between cortisol and cardiometabolic risk factors. With stress being an integral part of modern life that has become a significant health problem [5, 6], the importance of biomarkers that can assist in the treatment of stress-related diseases should only increase. In particular, hair cortisol concentration (HCC) is gaining interest as a promising biomarker for cardiometabolic risk [7]. However, research investigating the direct association between HCC and cardiometabolic risk factors is still in its infancy, and more extensive prospective cohort studies are needed to gain further insight into the relationship between HCC, CMR, and the development of CVD. Unhealthy lifestyles such as physical inactivity, smoking, and excessive alcohol use also result in elevated cortisol levels and are associated with cardiometabolic risk and cardiovascular disease [4]. However, this review focuses on biological factors linked to high cortisol levels and stress that are activated through the hypothalamic-pituitary-adrenal (HPA) axis pathway, including hypertension, obesity, dyslipidemia, and diabetes.

Figure 1.

Factors contributing to cardiometabolic risk.

2. Laboratory determination of hair cortisol concentration (HCC)

Different laboratories use similar methods to measure HCC with minor variations in experimental procedures. Usually, the proximal 3 cm of hair which represents the last 3 months of cortisol production, is collected [8, 9]. Using the most proximal segments reduces the potential for a ‘wash-out effect’ which relates to a decline in cortisol levels in distal segments due to ultraviolet radiation and hair care practices [8]. The hair sample is carefully sectioned into segment lengths that approximate the period of interest, for example, cut into 1 cm fragments, or whole hair samples are used. Hair grows approximately 1 cm per month, so this is a convenient approximation of changes in HCC each month [9].

The hair is then either finely minced with scissors or pulverized with a ball mill. The mass of hair used for analysis varies between studies, with a range of 2.5–50 mg for ELISA and 1.25–20 mg for LCMS [10]. Next, the samples are incubated in a solvent such as methanol for a set period to extract the cortisol. The extraction medium is evaporated to dryness and the extracted cortisol is reconstituted in a solution such as phosphate-buffered saline or distilled water. HCC is typically measured using two types of analyses: immunoassays or mass spectrometry [9, 10]. Immunoassays used for the analysis include enzyme-linked immunosorbent assay (ELISA), immunoassay with chemiluminescence detection (CLIA), and radioimmunoassay (RIA). Alternatively, liquid chromatography-mass spectrometry (LCMS) is used to determine HCC. Typically, the inter- and intra-assay coefficients of variability (cvs) are reported to indicate variability between measurements using different plates or tests and between duplicate samples on the same plate, respectively [10].

As the clinical utilization of HCC increases, it is important to establish an international benchmark [8, 9, 11]. Russell et al. conducted a study comparing the cortisol testing protocols of four leading laboratories, which include four ELISA methods and two LCMS methods, by analyzing the same hair samples representing the low, intermediate, and high ranges of hair cortisol concentrations (HCC) [9]. This study showed significant positive correlations between the four different immunoassay methods, while the results for the LCMS methods were almost identical. Further, the study concluded that laboratories using immunoassays could use a correction factor to convert results into standard LCMS equivalents.

3. The role of long-term hair cortisol levels in CVD risk

Stress can be defined as any stimuli that can alter homeostasis and causes physical, emotional, or psychological strain. It impairs both physical and physiological health [6], resulting in a higher risk for obesity, type 2 diabetes mellitus, and cardiovascular diseases [5, 6]. Stress can be the result of psychosocial factors like anxiety, social isolation, and traumatic life events. Although some stress is beneficial and helps the body cope (e.g., with inflammation), excessive/prolonged stress can be harmful [12, 13, 14, 15]. The response to stress is mediated by the “stress hormone” cortisol, which is released in higher doses under an excessive amount of stress [12]. Cortisol is a lipid-soluble glucocorticoid hormone that regulates a wide range of basal processes throughout the body, including metabolism, and immune response, and, most importantly, it helps the body to respond to stress and to maintain homeostasis. Cortisol does this by increasing blood sugar through gluconeogenesis, suppressing the immune system, and increasing the metabolism of fat, glucose, protein, and carbohydrates [13]. The production of cortisol is housed in the cortex of the adrenal glands and then released into the bloodstream, which transports it throughout the body [12]. Cortisol is an end product of the Hypothalamic-Pituitary-Adrenal (HPA) axis; its secretion in response to biochemical stress may influence health and cognitive events [12, 13].

The hypothalamic-pituitary-adrenal (HPA) axis is a crucial stress response system in the human body [12]. The primary function of the HPA axis is to maintain homeostasis and facilitate successful adaption to the surrounding environment through an intricate cascade of hormonal reactions. The stress response initiates when a stressor triggers the hypothalamus, releasing corticotropin-releasing factor (CRF) and vasopressin (AVP). These hormones stimulate the production of adrenocorticotropic hormone (ACTH) from the pituitary gland, eliciting the release of glucocorticoids, most notably cortisol, from the adrenal glands (Figure 2). Chronic stress has been well-documented as increasing the risk of cardiovascular disease through sustained exposure to increased levels of endogenous cortisol [6, 13]. The elevation of plasma cortisol levels is one of the best-studied components of the stress response, and this hormone is one of the best indicators of acute stress in humans.

Figure 2.

The HPA axis response to stress resulting in elevated cortisol, increased cardiometabolic risk (CMR), and cardiovascular disease (CVD).

Elevated cortisol leads to downregulation of the glucocorticoid receptor and potently affects lipid and carbohydrate metabolism [6]. Repeated or chronic stress can result in HPA axis dysfunction and cortisol remaining at high levels [12]. Clinical and population studies have shown that excessive cortisol levels are associated with developing central adiposity, insulin resistance and hyperglycemia, hypertension, and dyslipidemia [14, 15]. Traditionally these studies measured cortisol levels in body fluids, including saliva, blood, and urine [16]. While blood and saliva samples provide a cortisol measurement of a single timepoint, urine reflects the total exposure to bioactive cortisol over 12 or 24 hours. In contrast, hair allows for retrospective assessment of long-term cortisol concentrations over weeks, months, and even years [11, 17], potentially providing a better measure of an individual’s long-term exposure to stress. HCC is increasingly important in establishing and providing significant insight into cardiovascular disease prognosis, diagnosis, and management [13]. Elevated cortisol has been shown to be associated with an increased risk of cardiovascular diseases (9). Also, several cross-sectional studies found positive associations of hair cortisol with adverse cardiometabolic outcomes, including higher systolic blood pressure [18], diabetes, metabolic syndrome [18], and adiposity [18, 19].

4. Association of hair cortisol with cardiometabolic risk factors

4.1 Hypertension

Hypertension is also known as high or raised blood pressure, in which the blood vessels have persistently raised pressure. A patient is diagnosed with hypertension when the systolic blood pressure (SBP) is above or equal to 140 mm Hg and/or diastolic blood pressure (DBP) is above or equal to 90 mm Hg [20]. If left unmanaged, hypertension can lead to a heart attack, an enlarged heart, and heart failure [21]. Hypertension can also result in kidney failure, blindness, rupture of blood vessels, and cognitive impairment. Hypertension is a critical public health and clinical condition affecting billions worldwide, including approximately the 2 million Americans diagnosed annually [22]. Hypertension is one of the most prevalent risk factors for almost all cardiovascular diseases [23].

Chronic psychosocial stress is believed to increase the risk of hypertension through sustained exposure to elevated cortisol levels [21]. Cortisol is essential for maintaining normal blood pressure but, in excess, produces hypertension [24]. In 2002, the Prospective Studies Collaboration published a meta-analysis based on 61 cohort studies showing that the risk of CVD increased steadily with progressively higher levels of baseline SBP and DBP; a 20 mm Hg higher level of SBP and a 10 mm Hg higher level of DBP resulted in a 2-fold higher BP-related absolute risk of CVD [25]. While research exploring an independent association between HCC and hypertension is still a new research area, several cross-sectional studies found a positive correlation between hair cortisol and hypertension [18, 21]. Still, the data on the relationship between blood pressure and hair cortisol level is inconsistent. While some studies reported a positive association between mean arterial or systolic blood pressure and HCC, other studies failed to demonstrate a relationship. In addition, Feller et al. found no association between prevalent hypertension and HCC and a negative relationship between objectively measured diastolic blood pressure and HCC. Hypertension prevalence was 2.23 times higher in participants with CVD [21].

4.2 Obesity

Cardiovascular disease (CVD) is one of the primary causes of increased morbidity and mortality in people with obesity [26, 27]. Obesity is defined as an excessive accumulation of body fat, with the amount of this excess fat being directly responsible for most obesity-associated health risks [27]. Although body mass index (BMI) is the established clinical measurement to estimate CVD risk associated with excess body weight, increasing evidence suggests that abdominal obesity, as assessed by the waist-hip ratio (WHR), could represent a better marker of CVD risk than BMI [28].

The incidence of obesity is increasing at a rapid and concerning rate in most regions worldwide, with direct consequences on the risk of developing several chronic diseases such as systemic hypertension [29] and type 2 diabetes [30]. More seriously, obesity usually occurs with a cluster of metabolic disturbances such as impaired glucose metabolism, atherogenic dyslipidemia, and hypertension, and obese individuals have an increased risk of CVD [26]. Interestingly, perceived societal stigma due to weight discrimination was shown to contribute to HCC [31], complicating the association of elevated cortisol with obesity. Still, HCC was associated with higher BMI in obese individuals (BMI > 30 kg/m2) compared to average weight (BMI: 18.5–24.9) and nonobese overweight (BMI: 25.0–29.9) people [19]. A meta-analysis confirmed the positive associations between HCC and stress-related anthropometric measures (BMI and WHR) and reported a 9.8% increase in HCC per 2.5 points BMI [18].

4.3 Dyslipidemia

Dyslipidemia is a common metabolic disorder and an established risk factor for cardiovascular disease [32]. The condition is characterized by high-risk lipid levels with an increased level of serum total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), or a decreased concentration of serum high-density lipoprotein cholesterol (HDL-C) [33]. Dyslipidemia is closely linked with obesity, a disease characterized by an adverse effect on lipoproteins a known cardiometabolic risk factor [34].

The relationship between hair cortisol with lipids varied considerably across studies. The MASHAD study, a prospective cohort population study, found that increased serum total cholesterol levels were positively associated with absolute CVD risk among men and women [33]. However, after adjusting for confounding factors, high serum TC only significantly increased the risk of myocardial infarction in men. Kuehl et al. reported a positive association between triglycerides and HCC [35]. Another study found a positive association between low-density lipoprotein cholesterol (LDL-C) and HCC [3]. Since dyslipidemia is one of the main cardiovascular risk factors, further research is needed to examine chronic cortisol exposure and its effect on lipid metabolism.

4.4 Diabetes

Cardiovascular diseases are the most common cause of morbidity and mortality among patients with diabetes mellitus [36]. More than 90% of people with diabetes mellitus suffer from type 2 diabetes (T2D), a disease characterized by hyperglycemia, insulin resistance, and impaired glucose tolerance [37]. T2D and CVD have several shared characteristics; both conditions increase with age, are associated with an adverse lipid profile, obesity, and a sedentary lifestyle, and lifestyle modifications of common risk factors can reduce the risk of both [38]. Generally, patients with T2D also display other comorbidities such as obesity, hypertension, and dyslipidemia, increasing the risk for CVD [36].

Recently the CAPTURE study, a study assessing the prevalence of established CVD and its management in adults with T2D across 13 countries and five continents, reported that CVD was prevalent in 34.8% of patients with T2D [39]. Elevated cortisol levels are consistently associated with glycated hemoglobin, the diagnostic measure of T2D [18, 40] or diabetes [41, 42, 43]. Manenschijn et al. reported that HCC is associated with CVD and diabetes [13]. Since CVD and T2D share so many characteristics, further study of HCC measurements could be interesting in trying to discriminate between the two diseases or show that they are inextricably linked.

5. Conclusion

The prevention and sensible management of cardiometabolic risk factors such as hypertension, obesity, dyslipidemia, and diabetes can markedly alter cardiovascular morbidity and mortality. Interestingly, cardiovascular risk is often associated with more than one cardiometabolic risk factor related to elevated cortisol levels. The metabolic syndrome describes this group of interrelated disorders such as insulin resistance, abdominal obesity, glucose intolerance, dyslipidemia, and hypertension [18]. HCC levels provide a measure of long-term exposure to chronic stress and have the potential as a suitable biomarker of CMR and contribute to the prevention, early diagnosis, treatment, and management of CVD. Hair cortisol measurements potentially reduce the variability associated with self-reported measures and provide a more robust view than the acute cortisol determinations in urine, saliva, and blood samples. While the evidence for the relationship between cardiometabolic risk and cortisol is clear and compelling, inconsistencies in the data must be addressed and understood.

A recent meta-analysis showed that adherence to several healthy lifestyle behaviors simultaneously reduced cardiovascular disease risk by 66% compared with adopting none or only one behavior [44]. However, no evidence exists that interventions that reduce cardiometabolic risk factors decrease hair cortisol levels in preventing or treating CVD [7]. More extensive studies are needed to ascertain the use of hair cortisol as an effective measure of stress reduction interventions. Also, further research is required to delineate whether HCC is a biomarker of CVD or CVD risk to utilize HCC in clinical settings effectively. Further insight into the mechanisms underlying increased cortisol exposure is necessary for the more effective implementation of cortisol-lowering therapies and potential new treatment targets.

Acknowledgments

I express my sincere gratitude to Francina (Riah) Van Wyk and Momar Milliones for their continued support.

Conflict of interest

The author declares no conflict of interest.