Atherosclerosis is a chronic inflammatory disease, triggered in response to endothelial injury occurring to the vessel wall. Although endothelium has regenerative characteristics, in presence of various cardiovascular risk factors (CVRFs), this natural healing process is hampered 1. It is known that conjoint effects of CVRFs lead to the development of premature atherosclerosis, and these factors may also contribute to premature graying and alopecia by interacting with follicular epithelium and resident stem cells similar to their effects on endothelium and circulating progenitor stem cells 2,3.
Biological age is an established risk factor of coronary artery disease (CAD) and is often associated with various dermatological changes. Earlier published reports have indicated that atherosclerosis and cutaneous markers such as alopecia and premature graying have common mechanism of actions such as impaired DNA repair, oxidative stress, inflammation, hormonal changes, and senescence of functional cells. Similar to vascular system, mammalian hair follicle system possesses distinct regenerative characteristics, where involved stem cells produce melanocyte, a coloring pigment at the base of follicle. Hence, premature graying of hair indicates initiation of the early degenerative changes in the system and is reported to show a relationship with CAD 4. Male pattern baldness, often known as androgenic alopecia (AGA), is also a proposed cutaneous marker of CAD risk by many 5. AGA is a typical pattern of gradual, progressive hair loss, beginning along the frontal hairline and on the vertex. For association of AGA with CAD, several mechanisms such as increased peripheral sensitivity to androgens, metabolic syndrome, insulin resistance, chronic inflammation, dyslipidemia, and hypertension have been proposed 6.
We herewith aim to study the overall prevalence and association of premature graying, AGA, and hair thinning with CAD in young Asian male patients and their predictability for CAD.
Patients and methods
In this prospective case–control study, we recruited 1380 individuals, of which 468 were patients with CAD (<40 years of age) who were admitted for various cardiac surgeries or procedures between the months of January 2014 and January 2016 in a super specialty hospital of Ahmedabad, Gujarat, India. The diagnosis of CAD was performed using angiography, and stenosis of at least 70% diameter was considered as significant. Age-matched young healthy male individuals (n=912), not having any major history of illness with normal coronary angiograms, were included as healthy control. Voluntary participation and written informed consent was obtained for all the participants. The study was reviewed and approved by the Institutional Ethics Committee (UNMICRC/CARDIO/2015/72). Basic demographic information, details of comorbidities, past medical history, individual income, smoking habit, and BMI were collected for all participants.
Diagnosis of androgenic alopecia, premature graying, and hair thinning
The diagnosis of the cutaneous markers in the study population was based on detailed history and clinical examinations. Hamilton-Norwood scale was used as a tool for grading of AGA (I–VII) in young male individuals 7. Patients were classified into various grades of premature graying as follows: 1 = pure black hair, 2 = black more than white, 3 = black equals white, 4 = white more than black, and 5 = pure white. The grades of AGA and premature graying for each patient were determined by two independent observers. Hair thinning was noted based on self-perceived thinning of hair reported by an individual in response to a questionnaire 8.
Cardiovascular risk factor assessment
The patients were evaluated for age, demographical properties, and the CVRFs. Hypertension was defined as the active use of antihypertensive drugs or documentation of blood pressure more than 140/90 mmHg. Diabetes mellitus was defined as fasting plasma glucose levels of more than 126 mg/dl or glucose level more than 200 mg/dl at any measurement or active use of antidiabetic treatment. Patients who were using tobacco products on admission to our hospital and those who quitted smoking within the past year were considered as smokers. The family history for CAD was defined as a history of CAD or sudden death in a first-degree relative before the age of 55 years for men and 65 years for women. C-reactive protein level and routine biochemistry including glucose and lipid levels were measured. Serum C-reactive protein was analyzed using a nephelometric technique.
The statistical calculations were performed using SPSS software, version 20.0 (SPSS Inc., Chicago, Illinois, USA). Quantitative data were expressed as mean±SD, whereas qualitative data were expressed as percentage. Univariate analysis of the continuous data was performed using Student’s t-test (paired or unpaired whichever is applicable), whereas χ 2-test was used for the categorical data. Logistic regression was used for estimation of independent risk factors for the factors with significant P value (<0.05) on univariate analysis.
The demographic and risk factor profile of CAD cases and control was compared and is presented in Table 1. Cases were more hypertensive (30.3 vs. 13.6%), obese (26.7 vs. 12%), and had a greater prevalence of lipid abnormalities (higher total cholesterol – 16.7 vs. 8.8%, P<0.0001; higher low-density lipoprotein – 7.3 vs. 2.2%, P<0.0001; and low high-density lipoprotein – 92.5 vs. 88.7%, P=0.0212) as compared with controls. Similarly, overall prevalence of hair thinning, premature graying, and AGA in CAD cases were 36.3, 49 and 50%, respectively, which was significantly higher as compared with control population (hair thinning – 14.6%, premature graying – 25.8%, and AGA – 27.4%).
The relationship of hair thinning, premature graying, and AGA with various risk factors is assessed and tabulated in Tables 2–4, respectively. Multiple linear regression analysis showed that diabetes, hypertension, habits of smoking and tobacco consumption, and various lipid abnormalities are independently associated with these cutaneous markers. SYNTAX score – an index of CAD complexity – was also found to be an independent associate of premature graying (P<0.0001) and AGA (P<0.0001) but not of hair thinning (P=0.737) (Table 5). Similarly, LVEF as assessed by Simpson’s method on echocardiography and degree of severity were also associated with these cutaneous markers. Adjusted odds ratio was calculated to investigate the independent risk of each factor for development of CAD (Table 6). AGA had the highest odds [(5.619, 95% confidence interval (CI): 4.025–7.845, P<0.0001], which was closely followed by premature graying (5.267, 95% CI: 3.716–7.466, P<0.0001), whereas hair thinning showed odds of 3.36 (95% CI: 2.452–4.621, P<0.0001). Risks exerted by various factor according to age are presented in Table 7. Premature graying and AGA had higher odds in young adult patients (30–40 years) as compared with younger population (20–30 years), whereas association of hair thinning was not influenced by age.
The current study results indicate that presence of cutaneous markers such as hair thinning, premature graying, and AGA are potential prognostic markers that could be effectively used in designing primary preventive strategies for effective management of CAD in Western Indians. Though these markers are nonmodifiable in nature, it could contribute significantly in risk stratification of the population in whom controlling of modifiable risk factors and periodic screening for CAD may be beneficial.
Several epidemiological evidences have indicated a positive association between CAD and AGA, where androgen levels are suggested to play a pivotal role. It is also known that men with baldness have higher levels of serum androgens, androgen receptors in scalp, and total and free testosterone 9–13. After adjusting the influence of other confounders, current study results postulate that the patients with AGA and premature graying have approximately five times higher risk of developing CAD at a younger age. This is in concordance with one of our earlier study where we found a significant association between vertex baldness (grades IV–VII) and CAD in young (<45 years) male patients with CAD, with an overall AGA incidence of 37.73% 5. It is documented that 50% of white men have some degree of baldness before the age of 50 years, and in this ethnic group, thinning of hair starts as early as age of 12 years 14. Similar to AGA, premature graying is also an indicator of accelerated ageing process which is associated with CVRFs through various interlinked pathways. Loss of hair pigmentation and atherosclerosis are known to share similar molecular and cellular mechanisms, and scalp ageing is known to predispose an individual to premature CAD. Pomerantz had reported that premature graying is more common in patients with CAD younger than 35 years and is subjected to various intrinsic and extrinsic factors such as smoking, ultraviolet rays, pollution, and lifestyle factors 15,16. In contrast to our findings, Sari et al. 17 reported lack of association between male pattern of baldness and severity of CAD; however, the study had few limitations: (i) smaller sample size and (ii) cross-sectional design of the study. The cumulative evidence from six different (three cohort and three case–control) studies was examined and presented as a meta-analysis by Yamada and colleagues. They found that vertex baldness, but not frontal baldness, is associated with an increased risk of coronary heart disease. They found that severity of the disease is directly related to the severity of vertex baldness 18.
The interplay between atherosclerosis, classical CVRFs, and cutaneous markers has been reported earlier, which is in concordance with our results where diabetes, hypertension, smoking, obesity, and various dyslipidemias were found to be associated with these markers. Sharma et al. 19 and El-Esawy and Abd El-Rahman 20 showed that severity of systolic blood pressure is well correlated with severity of alopecia. Park and colleagues evaluated this association in Asians where they aimed to investigate the relationship between Korean men with AGA and various CVRFs, considering life habits, type of hair loss, and sex. They found a direct relationship between AGA severity and increased incidences of CVRFs, namely, hypertension, diabetes, and smoking 21. Similarly, obesity was also shown to be a causative factor of AGA by Yang et al. 22. Higher circulating lipid levels, namely, total cholesterols, triglycerides, and low-density lipoproteins, are known to be risk factors for atherosclerotic plaque formation, which were found to increase with increased severity of AGA 23. Apart from this, it is also documented that smokers have greater severity of AGA as compared with nonsmokers, which could be explained by the smoking-induced deleterious effects on microvasculature of dermal hair papilla and redox and proteases imbalance in the hair follicular system. The toxicants present in the smoke may directly damage the follicle DNA also 24,25. Herewith we report that 50% of the male CAD population had premature graying of hair and AGA, which significantly correlated with high blood pressure, BMI, smoking, and lipid levels. Apart from these modifiable risk factors, family history also showed a strong association (P<0.0001) with hair thinning indicating a role of genetics in the entire phenomena. A variety of genetic and environmental factors are said to play a role in causing AGA. Androgen receptor gene, which is X-linked recessive, has been mentioned to be the cardinal prerequisite for balding, but other genes are also involved. Genetic sensitivity of hair follicles to dihydrotestosterone causes them to shrink when exposed to it 26. 5-alphareductase is responsible for converting free testosterone (a major circulating androgen in men) into dihydrotestosterone 27. Hair growth inhibitory factor-β, released from androgen-stimulated fibroblasts of the follicular dermal papilla, may cause hair growth inhibition, hair follicle miniaturization, and short lifespan, thereby preventing normal hair production 28. So, our findings suggest that cutaneous markers are common indicators of ageing, which may play a role as a biological age indicator. Similar to various biological age calculators such as Framingham vascular age calculator, a potentially useful scale for biological age having clinical usage may be introduced.
We herewith conclude that screening of young male patients with CAD for the presence of AGA, premature graying of hair, and thinning of hair facilitates identification of a subset of individuals who are at an increased risk for future acute CAD and who require more rigorous follow-up and treatment. Intensive monitoring of these patients and strict advocacy of exercise and lifestyle modification are necessary to reduce the incidence of premature CAD.
U.N. Mehta Institute of Cardiology and Research Center (affiliated to B.J. Medical College, Ahmedabad).
Conflicts of interest
There are no conflicts of interest.
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