Earlobe Creases as a Marker of the Risk for Coronary Atherosclerosis Before Angiography in Elderly and Non-elderly Patients

Background The close relationship between earlobe creases (ELC) and the presence of coronary artery disease (CAD) has been reported. In addition, this study aimed to determine associations between ELC and the presence, extent, and severity of coronary atherosclerosis assessed by coronary angiography in non-elderly and elderly patients. Methods We assessed 1,086 consecutive patients with suspected CAD by coronary angiography. We defined severe CAD as Gensini scores > 20. Multiple logistic regression analysis was adjusted for age, sex, hypertension, diabetes mellitus, smoking status, lipid profiles, and body mass index (BMI) to assess the presence or absence of CAD, multivessel disease, and severe CAD in elderly (age ≥ 60 years) and non-elderly (age < 60 years) patients. Results ELC was a significantly positive determinant of CAD (odds ratio (OR) = 3.074, p < 0.001), multivessel disease (OR = 3.101, p < 0.001), and severe CAD (OR = 2.823, p < 0.001) in all patients. ELC was also a predictor of CAD, multivessel disease, and severe CAD not only in patients aged ≥ 60 years (OR = 3.095, p < 0.001; OR = 3.071, p < 0.001; OR = 2.761, p < 0.001, respectively) but also in those aged < 60 years (OR = 2.749, p = 0.035; OR = 2.634, p = 0.038; OR = 2.766, p = 0.006, respectively). Conclusions ELC was independently associated with the presence of CAD, multivessel disease, and severe CAD in both elderly and non-elderly patients who were assessed by coronary angiography.


Introduction
initially described the relationship between earlobe creases (ELC) and coronary artery disease (CAD). Some subsequent studies found a significant positive relationship between ELC and CAD [2,3], whereas others did not [4,5]; thus, conclusions have remained controversial. Moreover, a relationship between the angiographic severity of CAD and ELC has been implied [6,7] but not confirmed, and the increasing prevalence of ELC with aging and their clinical significance according to age is unclear.
The present study aimed to clarify the association between ELC and the presence, extent, and severity of CAD in non-elderly and elderly patients who were assessed by coronary angiography.

Participants
This study included a series of 1,086 consecutive patients (mean age: 66.1 ± 11.4 years; males: 826) who were assessed by coronary angiography at Saitama Medical Center, Saitama Medical University, located in Kawagoe City, Saitama Prefecture, Japan, between February 2009 and September 2012. The exclusion criteria comprised a history of coronary artery bypass grafts and percutaneous coronary intervention (PCI). Our institutional review board at Saitama Medical Center, Saitama Medical University (approval number: 1116) approved the study, and all patients provided written informed consent to participate.
The patients were divided into groups according to the presence or absence of ELC. The severity of coronary atherosclerosis was assessed using Gensini scores [8], and coronary risk factors such as age, sex, hypertension, dyslipidemia, diabetes mellitus, and smoking were identified from a review of the medical records of the patients. The effects of angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers (ACEI/ARB) and statins, as well as body mass index (BMI) and low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) levels, were also assessed.

Definitions
Body mass index was calculated as weight (kg) divided by height squared (m 2 ). Coronary artery disease was defined as >50% luminal narrowing of any main coronary artery on coronary angiograms. Multivessel disease was defined as >50% luminal narrowing in at least two of the left anterior descending, left circumflex, and right coronary arteries. Severe CAD was defined as Gensini scores ≥ 20 [9]. Dyslipidemia was defined as values of >220, >140, <40, and >150 mg/dL for total cholesterol, LDL-C, HDL-C, and triglycerides, respectively, or taking lipid-lowering medication. Smoking was defined as currently smoking or having stopped smoking <1 month before enrollment. Hypertension was defined as systolic or diastolic blood pressure > 140 and/or > 90 mmHg, respectively, or under medication with antihypertensive drugs. Diabetes was defined as a confirmed diagnosis of diabetes mellitus or under antidiabetic medication with insulin or oral hypoglycemic agents at enrollment.

Coronary angiography
We evaluated the severity of CAD using Gensini scores [8]. Severe CAD was defined as Gensini scores ≥ 20, which was equivalent to 90% stenosis at a proximal site in the left anterior descending coronary artery [9]. The patients were divided according to Gensini scores of ≥20 (severe CAD) and <20 (mild CAD).

ELC classification
Earlobe creases were generally assessed in patients while seated or supine if they were in an unstable clinical condition such as shock. Two trained observers who were blinded to the coronary angiographic findings graded ELC as absent (grade 0), superficial or not completely extending across the earlobe (grade 1), or clearcut creases extending across the earlobe (grade 2) [10]. Figure 1 illustrates a schema that outlines the grading of earlobe creases.

Statistics
All data were analyzed using the Statistical Package for the Social Sciences (SPSS) software version 22.0 (IBM SPSS Statistics, Armonk, NY, USA). Continuous variables are expressed as mean ± standard deviation (SD), and categorical variables are expressed as numbers (n) with frequency (%). Continuous and categorical variables were compared using unpaired t-tests and chi-square tests, respectively. Associations between ELC and coronary atherosclerosis such as CAD, multivessel disease, and severe CAD were assessed using multiple logistic regression analyses. Odds ratios (ORs) and 95% confidence intervals (CIs) for coronary atherosclerosis were calculated from the outcomes of multiple logistic regression models after adjustment for the potential confounders of age, sex, hypertension, diabetes mellitus, smoking status, LDL-C, HDL-C, and BMI. Table 1 shows the baseline characteristics of the patients. We found that 841 (77.4%) of them had ELC and 245 (22.5%) did not. The frequencies of gender, dyslipidemia, smoking, and plasma HDL-C values did not significantly differ between the two groups. However, patients with ELC were older (68.6 ± 9.3 versus 58.1 ± 13.2, p < 0.001) and had lower plasma LDL-C values (111.6 ± 34.7 versus 118.4 ± 33.2, p = 0.008) than those without ELC.

Discussion
We identified two important clinical issues. The presence of ELC was independently associated with the presence of CAD, multivessel disease, and severe CAD assessed by coronary angiography. The presence of ELC was a more powerful indicator of CAD than conventional coronary risk factors in both elderly patients and non-elderly patients who were assessed by coronary angiography.

Earlobe creases and the severity of coronary atherosclerosis
An association between ELC and coronary atherosclerosis has been identified in clinical [1][2][3][11][12][13] and necropsy [14][15][16] studies. A previous meta-analysis [12] has revealed a potential association between ELC and the presence of coronary artery disease, with an odds ratio of 3.3. Earlobe creases are also significantly related to atherosclerotic changes in the carotid artery [17] and the aorta [14]. Elliott et al. [6] followed up on patients admitted to a coronary care unit or who underwent cardiac catheterization and found an association between the number of creased ears and 10-year cardiac events.
The association between ELC and atherosclerosis was evaluated using various methods, including carotid ultrasonography [17], CT angiography [18], coronary angiography [9], and autopsy or necropsy [14][15][16]. To the best of our knowledge, only one study has identified an association between ELC and the severity of coronary atherosclerosis using CT angiography [18], and the present study is the first to demonstrate a relationship between ELC and the severity of CAD based on a semiquantitative scoring system for coronary angiography.

Clinical implications for elderly and non-elderly populations
The present findings identified ELC as the most powerful indicator of coronary atherosclerosis among elderly and non-elderly patients and that age, diabetes mellitus, and BMI (or obesity) were not significantly associated with coronary atherosclerosis in this population. Aging is one of the most important risk factors for many diseases, and it is generally considered to be significantly associated with atherosclerosis. Indeed, previous studies [3,19,20] have shown a relationship between age and CAD. However, one autopsy study [14] found no association between age and the extent of coronary aortic atherosclerosis, whereas ELC was significantly associated with both coronary and aortic atherosclerosis. Age was no longer considered a predictor of CAD in that population, whereas ELC remained a significant indicator of CAD.
The present study of a high-risk population with suspected CAD did not find any association between age and CAD but identified ELC as the most significant determinant of coronary atherosclerosis in both elderly and non-elderly populations. This finding is consistent with the outcomes of a previous meta-analysis [12]. Therefore, ELC could be a useful marker for the risk stratification of patients before coronary angiography regardless of age.

Mechanism and future
One explanation for an association between the myocardium and earlobe has been that both are supplied by the same end arteries, of which the origin is genetically determined. Shoenfeld et al. [21] found significant tears in the elastic fibers of biopsy specimens of earlobes from patients with ELC, and Higuchi et al. [10] found that patients with ELC had shorter telomeres. However, the precise mechanism of the association between ELC and CAD has not been clearly elucidated. Further investigation is needed to clarify the mechanism of this relationship.

Limitations
As a limitation of this study, it is important to note that it is a single-center, cross-sectional, and observational investigation, which differs significantly from a randomized controlled trial. The study included high-risk patients who underwent coronary angiography. In fact, 83.9% of the patients had significant CAD defined as >50% stenosis on coronary angiograms. Therefore, the present findings cannot be expanded to healthy or asymptomatic individuals. Race, family history of coronary artery disease, and other possible confounding factors were important variables but were not included in our study.

Conclusions
Earlobe creases were independently associated with the presence of CAD, multivessel disease, and severe CAD in elderly and non-elderly patients who were assessed by coronary angiography. Earlobe creases could serve as a useful marker for the risk stratification of patients before undergoing coronary angiography regardless of age.

Additional Information Disclosures
Human subjects: Consent was obtained or waived by all participants in this study. Saitama Medical Center, Saitama Medical University issued approval 1116. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.