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Updated meta-analysis of the relation between heart disease and androgenic alopecia or alopecia areata

Background The relationship between baldness and heart disease is still controversial. We performed an updated meta-analysis of observational studies to evaluate the relation between heart disease and androgenic alopecia or alopecia areata. Aims To evaluate the relation between heart disease and androgenic alopecia or alopecia areata. Methods Studies were identified by searching Medline and Embase up to October 20, 2017 without language restriction. Metaanalysis was performed by using a random-effects model. Results Nine studies were included in the meta-analysis (eight on androgenic alopecia and one on alopecia areata: 44,806 participants). Compared to men without baldness, men with androgenic alopecia had an increased risk of heart disease (relative risk (RR): 1.32, 95 per cent CI: 1.08 to 1.63, p=0.01, I 2 =25 per cent), and younger men (<55 or ≤60 years) showed a stronger association (RR: 1.44, 95 per cent CI: 1.11 to 1.86, p=0.01, I 2 =0 per cent). The positive relation depended on the severity of baldness and decreased in order of severe vertex (RR: 1.60, 95 per cent CI: 1.19 to 2.16, p=0.002), moderate vertex (RR: 1.41, 95 per cent CI: 1.22 to 1.64, p<0.001), mild vertex (RR: 1.18, 95 per cent CI: 1.05 to 1.33, p=0.007), and frontal baldness (RR: 1.10, 95 per cent CI: 0.92 to 1.32, p=0.28)). In contrast, there was no significant relation between alopecia areata and heart disease (RR: 0.91, 95 per cent CI: 0.60 to 1.39, p=0.66).


ABSTRACT Background
The relationship between baldness and heart disease is still controversial. We performed an updated meta-analysis of observational studies to evaluate the relation between heart disease and androgenic alopecia or alopecia areata.

Aims
To evaluate the relation between heart disease and androgenic alopecia or alopecia areata.

Methods
Studies were identified by searching Medline and Embase up to October 20, 2017 without language restriction. Metaanalysis was performed by using a random-effects model.

Results
Nine studies were included in the meta-analysis (eight on androgenic alopecia and one on alopecia areata: 44,806 participants).
Compared to men without baldness, men with androgenic alopecia had an increased risk of heart disease (relative risk (RR): 1.32, 95 per cent CI: 1.08 to 1.63, p=0.01, I 2 =25 per cent), and younger men (<55 or ≤60 years) showed a stronger association (RR: 1 Background "Hair loss" is a common clinical complaint that is a symptom of various disorders. The cause is easily diagnosed in many cases, such as in persons who present with classic male pattern hair loss or patchy hair loss due to alopecia areata. Androgenic alopecia, also called male pattern baldness, is the most common type of hair loss in men, and affects approximately 50 per cent of Caucasian men by age 50. It is characterized by progressive loss of terminal hairs on the scalp in a characteristic distribution. 1,2 Alopecia areata is a chronic autoimmune disorder targeting anagen hair follicles that causes non-scarring hair loss. It most commonly presents with discrete patches of alopecia on the scalp. However, other areas may also be affected, and patients may lose all scalp or body hair in severe cases. [3][4][5] Our previously published meta-analysis 6 showed a positive relationship between androgenic alopecia (male pattern baldness) and coronary heart disease. However, the relationship between alopecia areata and heart disease was not determined due to lack of suitable studies. Therefore, we performed an update of our systematic review and meta-analysis to assess the association of baldness (both androgenic alopecia and alopecia areata) with heart disease.

Search strategy
The detailed methods were described in our previous report. Medline and Embase were searched from 1 January 1950 to 20 October 2017 using the medical subject headings 'baldness' ('baldness' or 'hair loss' or 'alopecia') and 'heart disease' ('coronary heart disease' or 'cardiovascular disease' or 'coronary artery disease') to identify observational studies that estimated the association between baldness and heart disease. The reference lists of all studies thus identified were also reviewed.

Study selection
We performed initial screening based on the study titles or abstracts, while the second screening process involved a full-text review. Cohort studies and cross-sectional studies that assessed the association between androgenic alopecia (or alopecia areata) and heart disease were eligible for inclusion if the following criteria were met: (1) the full text of the report was published in English, (2) the relative risk (RR) (risk ratio, hazard ratio, or odds ratio) was reported with adjustment for possible covariates (e.g., age, smoking, family history of baldness, or family history of heart disease), (3) the presence and severity of baldness was reported, and (4) heart disease events were reported.

Definitions of baldness and heart disease
Androgenic alopecia and alopecia areata were defined according to the description in the study and/or based on terms used by the authors. We excluded studies on other types of baldness (e.g., scarring alopecia). Heart disease was defined as including all the following: coronary artery disease, myocardial infarction, angina pectoris, cardiomyopathy, and other types of ischemic heart disease.

Assessment of validity
To ascertain the validity of the eligible studies, quality was appraised with reference to the STROBE statement. In addition, the Newcastle-Ottawa Scale for assessing the quality of non-randomized studies in meta-analyses was used to quantify the validity of each study. 7,8 Data extraction Two investigators (MA and KH) independently reviewed each study to determine its eligibility, and then extracted and tabulated all of the relevant data. Disagreement was resolved by consensus. The following information was obtained from each study: first author, year of publication, type of study, country where the study was conducted, number of participants (all participants who participated in the study), heart disease events, method of assessing baldness, follow-up period, mean age, smoking, covariates for adjustment of analyses, and severity of baldness.

Statistical analysis
The pooled RR (adjusted for possible covariates) and its 95 per cent CI were calculated for the risk of heart disease events in each study by the DerSimonian-Laird random effect model weighted with inverse variance. 9 Cochrane's χ2 test and the I 2 test were performed to evaluate heterogeneity among the studies. 10 Possible publication bias was evaluated by creating a funnel plot of the effect size for each study versus the standard error (SE). Funnel plot asymmetry was assessed by the tests of Begg and Egger. 11,12 All analyses were performed with Stata V.14.0 software (StataCorp, College Station, Texas, USA) and p<0.05 was considered significant. Results are expressed as the mean with 95 per cent CI, unless otherwise indicated.

Results
We identified a total of 353 reports by searching the two databases. After further evaluation, nine studies fulfilled the criteria for the present meta-analysis (44,806 participants) ( Figure 1). [13][14][15][16][17][18][19][20][21] The nine studies included four cohort studies and five crosssectional studies, and their characteristics are summarized in Table 1. Eight studies investigated androgenic alopecia and one study assessed alopecia areata. Three studies used a modified Hamilton scale and one study used a simplified Hamilton scale. The RR of subjects with baldness for heart disease was adjusted for several coronary risk factors (age, smoking, diabetes, etc.) in each study, but the number of variables differed significantly among the studies.
All of the studies used in the present meta-analysis achieved at least six of nine points in the Newcastle-Ottawa quality assessment scale for observational studies.

Androgenic alopecia and heart disease
Analysis of the three cohort studies 13 (Figure 3).

Alopecia areata and heart disease
One study 21 (5,508 participants) was identified and it showed no significant relation between alopecia areata and heart disease (RR: 0.91, 95 per cent CI: 0.60 to 1.39, p=0.66) (Figure 4).

Publication bias
The funnel plot, Begg's test, and Egger's test were used to evaluate the influence of publication bias on the association between baldness and heart disease. The funnel plot did not show asymmetry, while Egger's test and Begg's test found no significant influence (data not shown).

Discussion
This up-dated meta-analysis demonstrated that androgenic alopecia was significantly associated with an increased risk of heart disease among men of all ages and particularly among younger men. In addition, the relationship between heart disease and androgenic alopecia was dependent on the severity of baldness. On the other hand, there was no significant relation between alopecia areata and heart disease, although only 1 relevant study was identified.
Meta-analysis showed a trend that people with severe baldness may be associated with higher risk of heart disease. Thus, the severity of baldness might have reflected the progression of atherosclerosis.
Several mechanisms could explain the positive association between androgenic alopecia and the risk of heart disease. Classical coronary risk factors might influence both conditions, making baldness a surrogate marker of atherosclerosis. Also, a positive association has been reported between androgenic alopecia and insulin resistance, 22 metabolic syndrome, 23 and hypertension. 24 As we stated, 6 mechanisms such as hyperinsulinemia/insulin resistance, 25 chronic inflammation, 26 and increased peripheral sensitivity to androgens 27 have also been suggested.
This meta-analysis had several limitations. While assessment of publication bias did not suggest that unpublished results had been missed, the analysis might have been underpowered due to the small numbers of studies. Also, between-study heterogeneity was significant for some factors, with differences of epidemiological characteristics or diagnostic criteria (for baldness and/or heart disease) probably contributing to heterogeneity.
The third limitation was incomplete information about medications that might have contributed to baldness. Fourth, the method of assessing baldness varied between studies, so we could not exclude other local (or systemic) causes of diffuse hair loss.

Conclusion
In summary, this meta-analysis showed that androgenic alopecia is associated with heart disease, but alopecia areata is not. Further research is warranted to investigate differences between androgenic alopecia and alopecia areata in the mechanisms underlying the association with heart disease.

PEER REVIEW
Not commissioned. Externally peer reviewed.

CONFLICTS OF INTEREST
The authors declare that they have no competing interests.