Essay: Diagonal Earlobe Crease May Predict Early Atherosclerosis Without CVD: Evidence and Analysis



Diagonal Earlobe Crease May Predict Early Atherosclerosis Without Clinical Manifestation of Atherosclerotic Cardiovascular Disease

Introduction

Diagonal earlobe crease (DEL) is defined as diagonal fold or wrinkle of the ear lobe skin, extending from the tragus towards the ear lobe. DEL can be seen in patients with coronary artery disease (CAD) (1). This condition was first reported by Frank in 1973 (2) and was recognized as a simple cutaneous marker to identify patients with CAD. In some studies, intima-media thickness of the carotid artery was shown to be increased in patients with DEL, and it has been suggested that DEL is closely related to atherosclerosis (3,4).

Carotid artery intima-media thickness (cIMT), a widely-accepted radiological marker for atherosclerosis, reportedly predicts adverse cardiovascular events (5-7) and is closely linked to cardiovascular risk factors (8,9). Intima-media thickness (IMT) is a non-invasive, early marker of atherosclerosis; an increase in this measure may reflect an increase in cardiovascular risk (10). This is an independent predictor of CVD, and may be considered as a marker for the assessment of subclinical atherosclerosis (11).

Studies in adults have shown that the measurement of the cIMT represents an excellent marker of subclinical atherosclerosis (12,13). The carotid artery has been the target in these studies because it is located rather superficially on the neck and can be easily visualized by ultrasound. Autopsy studies, however, have shown that the first atherosclerotic lesions actually begin to develop in the abdominal aorta (14). Because it is now possible to visualize the abdominal aorta and accurately assess its wall thickness (aortic intimamedia thickness, aIMT), measuring aIMT might provide a better index of preclinical atherosclerosis in high-risk children than cIMT.

Although there have been a few studies on the association between ELC and cIMT (4,20), there is not any research directly examining the relevance between ELC and abdominal (aIMT) and common femoral intima-media thickness (fIMT). In our literature review, the relationship between ELC and abdominal aIMT and cfIMT has not been investigated yet. We aimed to investigate the association of ELC with early atherosclerosis in our study. For this purpose ; We aimed to investigate the relationship between abdominal aIMT that shows preclinical atherosclerozis among ELC present and ELC absent patients.

Method

Study Population

Asymptomatic subjects, who admitted to University of Health Sciences, Trabzon Ahi Evren Cardiovascular and Thoracic Surgery Research and Application Center Cardiology Clinic for assessment of cardiovascular risk profile for screening and primary prevention purposes, were systemically screened for presence of cutaneous markers of cardiovascular disease. Among subjects screened, 52 DEL cases were identified.  A propensity score matched 52 subjects, according to age and sex, were selected as a control group from the same population pool. DEL is defined as diagonal fold or wrinkle on the ear lobe skin, extending from the tragus towards the ear lobe (figure 1). Patients with DEL in both ear lobes were included in the DEL group.

Patients with moderate to severe valvular disease including prosthetic valves, and patients with congenital heart disease, bacterial endocarditis, hematological, oncological, or an inflammatory disorder; white blood cell (WBC) count >12000 mm3; hemoglobin level <10 g/dL; ejection fraction <40%, renal insufficiency, liver or thyroid dysfunction, thrombocytopenia or thrombocytosis, as well as those who had symptomatic vascular disease such as stroke, transient ischemia, coronary heart disease, congestive heart failure, or intermittent claudication, were excluded. After exclusion of patients who met above mentioned exclusion criteria, 104 patients (52 patients with DEL and 52 patients without DEL) were included in the study. Informed consent was obtained from each participant and the study was conducted in accordance with the Principles of Declaration of Helsinki. The study was approved by the local Ethics Committee.

History of hyperlipidemia (HL) , arterial hypertension (HT), diabetes mellitus (DM), smoking and family history of coronary artery disease (CAD), noted down all patients. Patients with known hypertension history, antihypertensive drug use history, the average measurement of systolic blood pressure ≥ 140 mmHg and / or diastolic blood pressure ≥ 90 mmHg at least twice from both arms, defined as hypertension. Patients with fasting blood glucose level of ≥126 mg/dl, history of DM and antidiabetic drug use were considered as type II DM. The patients who were on anti-hyperlipidemia therapy use and had a fasting total cholesterol level ≥200 mg/dl, a fasting low-density lipoprotein level ≥160 mg/dl, a fasting triglyceride level ≥200 mg/dl were considered as HL. History of CAD or sudden cardiac death in a first-degree relatives under the age of 55 years for men and 65 years for women were defined as family history of CAD.

IMT assessment

cIMT, abdominal aIMT and common fIMT was quantified by an Esaote Mylab 50 (Esaote Biomedica, Genova, Italy) device using a 7.5-MHz linear array imaging probe. The right and left common carotid artery were selected for the study. The patients were placed in supine position, with their heads turned away from the testing side and their necks mildly bended. Proximal and distal walls of the common carotid artery were aligned parallel to the transducer's axis, and its lumen was augmented in the longitudinal plane. The IMT was quantified at a site 1 cm proximal to the carotid bifurcation, by determining the distance from the border of arterial lumen and intima to the border between media and adventitia. A mean CIMT was obtained by averaging a total of four CIMT measurements taken from adjacent sites 1 cm apart. An experienced physician (A.K), who was unaware of the clinical and demographic data of the participants, performed all ultrasonography examinations.

Two images of the far wall IMT were obtained in the distal 10 mm of the abdominal aorta proximal to the iliac artery. For aorta images, aIMT was calculated as the mean thickness along the 10-mm length, and a mean IMT measure was then computed from the 2 images to obtain the overall aIMT value used for analysis.

Abdominal IMT ve Femoral IMT Esaote Mylab 50 (Esaote Biomedica, Genova, Italy) device using a 7.5-MHz linear array imaging probe

Statistical analyses

Data analysis was performed using SPSS (Statistical Package for Social Sciences) for Windows 19 (SPSS Inc. Chicago, IL, USA). The continuous variables were described as mean±SD or median (minimum–maximum), and the categorical variables were reported as frequency and percentage. Kolmogorov Smirnov test was used to evaluate normal distribution of numerical variables. Independent samples t test was used to compare normally distributed and Mann Whitney U test was used to compare non-normally distributed variables between the two groups. Quantitative data were analyzed using the Chi-square test. A correlation analysis was performed to assess the relationship between continuous variables and the analysis was interpreted using Spearman’s Rank correlation coefficient. The confidence interval was at 95 % and p values of < 0.05 were considered statistically significant.

Results

Istatistiksel olarak ELC absent ve ELC present grupların yaÅŸ, cinsiyet, BMI, hipertansyon, diabetes mellitus, dislipidemi, sigara içimi ve ailede CAD arasında anlamlı fark yoktu. Klinik ve demografik özellikler tablo 1 de gösterilmiÅŸtir. Ä°statistiksel olarak ELC present grubunda ELC absent grubuna göre , Carotid artery intima-media thickness ( CIMT) left, CIMT right, aortic intima media thickness ( AIMT), common femoral intima media thickness saÄŸ ve sol ( CFIMT left and right) arasında anlamlı fark izlendi ( AIMT ELC present 1,04±0,22 mm and ELC absent 0,87±0,15 mm p< 0,001 ; CIMT Left ELC present 0,52±0,12 mm and ELC absent 0,44±0,10mm ; CIMT Right,  ELC present 0,53±0,12mm and ELC absent 0,43±0,10 mm p<0,001 ; CFIMT Left ELC present 0,64±0,12 mm and ELC absent 0,54±0,13 mm ; CFIMT Right ELC present 0,63±0,11 mm and ELC absent 0,55±0,12mm p< 0,001 ) ( Figure 2)

Discussion

This is the first study that has investigated the relationship between ELC and abdominal aIMT and common fIMT in patients without clinical manifestation of CVD. The main finding of the our study is that ELC was significantly associated with cIMT, abdominal aIMT and common fIMT, independently of cardiovascular risk factors.

DEL is defined as diagonal fold or wrinkle on the ear lobe skin, extending from the tragus towards the ear lobe. In 1973, Frank first described that a bilateral or unilateral prominent ear crease in the lobule of the ear-lobe was present in a large proportion of his patients who had one or more risk factors for coronary heart disease. Several clinical studies have subsequently examined the association of the diagonal ear crease with coronary atherosclerotic heart disease [15–22]. A previous study also reported a correlation between DEL and carotid intima media thickness and epicardial fat thickness [23]. DEL was shown to be associated with vascular inflammation and oxidative stress [24], as well as cardio ankle vascular index (CAVI), which is a subclinical marker of atherosclerosis (25). In a postmortem autopsy study of 520 patients, DEL was strongly associated with CAD in both men and women [26]. Biz Çalışmamızda DEL in carotis, aortic ve common femoral IMT ile ilişkili olduğunu saptadık. DEL olanlarda common fIMT yüksek olması asemptomatik periferik arter hastalığını predicte edebilceğini düşündürür.. Levent Korkmaz ve arkadaşları yaptıkları bir çalışmada ELC nin asemptomatik periferik arter hastalığını predicte edebileceğini göstermiştir (27).

ELC ile CAD arasında ilişki altta yatan mekanizma tam belli olmamasına rağmen birçok çalışmada gösterilmiştir ve çeşitli mekanizmalar öne sürülmüştür. It was initially proposed that both the earlobe and heart are supplied by end arteries, without the possibility of collateral circulation, which could cause simultaneous rise in both DEL and CAD (28). Some researchers found degeneration of the elastin, tear in elastic fibers, and pre-arteriolar wall thickening in cases of DEL (29). Although atherosclerotic changes in the arterial wall could include smooth muscle cell proliferation and accumulation of collagen and proteoglycans, degeneration caused by changes in the collagen:elastin ratio may be the final common pathophysiological pathway of both atherosclerosis and DEL (30). Biz çalışmamızda daha önce Şükrü çelik ve arkadaşları ve Murat Ziyrek ve arkadaşlarının yaptıkları çalışmalarda olduğu gibi ELC olanlarda cIMT anlamlı olarak yüksek bulduk.

Ayrıca  literature taramalarımızda daha önce gösterilmemiÅŸ olan ELC ile aortic ve common fIMT arasında anlamlı iliÅŸki bulduk. Labropoulos et al measured abdominal aIMT using transcutaneous ultrasound in a group of adults and observed increased aIMTs in subjects with atherosclerosis (31). Autopsy studies have shown that the first atherosclerotic lesions actually begin to develop in the abdominal aorta (14). aIMT, erken dönem aterosklerozu göstermede cIMT dan daha iyi olduÄŸu tip 1 DM li çocuklarda gösterilmiÅŸtir.  Bizim çalışmamızda ELC olanlarda aIMT, ELC olamyanlara göre daha kalın ölçüldü. Bu bulgu ELC nin erken dönem eterosklerozu predicte edebileceÄŸini düşündürür. Bu çalışma bize ELC olanların erken dönem preclinik ateroskleroz açısından dikkatli olmamız gerktiÄŸini düşündürür.

Study limitations:

Several limitations of this study should be addressed. First, the most important limitation of this study was the small number of patients. As the study population consisted of patients who presented to our clinic, we can speculate that it would not reflect the general population. Çalışmada aortic IMT değerlendirilirken 7.5-MHz linear array imaging ultronografi probe kullanılmıtır.

Conclusion:

Çalışmamızda DEL olanlarda carotid, aortic ve common femoral IMT olmayanlara göre daha kalın olarak saptadık. DEL olanlarda özellikle subklinik aterokleroz açısından dikaktli olunmalıdır. DEL olanlarda aIMT yüksek olması erken dönem aterokleroz açısından dikkatli olunması gerektiğini düşündürür. Yine fIMT yüksek olması asemptomatik periferik arter hastalığı açısından dikkatli olmamız gerektiğini düşündürür.

References

1. Lichstein E, Chadda KD, Naik D, Gupta PK. Diagonal ear-lobe crease: prevalence and implications as a coronary risk factor. N Engl J Med 1974;290:615–6.

2.  Frank ST. Aural sign of coronary-artery disease. N Engl J Med 1973;289:327–8.

3. Shrestha I, Ohtsuki T, Takahashi T, Nomura E, Kohriyama T, Matsumoto M. Diagonal ear-lobe crease is correlated with atherosclerotic changes in carotid  arteries. Circ J 2009;73:1945–9.

4. Celik S, Erdog an T, Gedikli O, Kiris¸ A, Erem C. Diagonal ear-lobe crease is associated with carotid intima-media thickness in subjects free of clinical cardiovascular disease. Atherosclerosis 2007;192:428–31

5. Bots ML, Hoes AW, Kondstaal PJ, et al. Common carotid intima-media thickness and risk of stroke and myocardial infarction: the Rotterdam study. Circulation 1997;96:1432–7.

6. Chambless LE, Folsom AR, Clegg LX, et al. Carotid wall thickness is predictive of incident clinical stroke: the Atherosclerosis Risk in Communities (ARIC) study. Am J Epidemiol 2000;151: 478–87.

7. Longstreth Jr WT, Shemanski L, Lefkowitz D, et al. Asymptomatic internal carotid artery stenosis defined by ultrasound and the risk of subsequent stroke in the elderly The Cardiovascular Health Study. Stroke 1998;29:2371–6.

8. Celermajer DS. Noninvasive detection of atherosclerosis. N Engl J Med 1998;339:2014–5.

9. Davis PH, Dawson JD, Riley WA, et al. Carotid intimal-medial thickness is related to cardiovascular risk factors measured from childhood through middle age The Muscatine Study. Circulation 2001;104:2815–20.

10. Polak JF, Pencina MJ, Pencina KM, O’Donnell CJ, Wolf PA, D’Agostino RB.

Carotid-wall intima-media thickness and cardiovascular events. N Engl J Med.

2011;365(3):213-21.

11. Polak JF, Pencina MJ, O’Leary DH, D’Agostino RB. Common carotid artery

intima-media thickness progression as a predictor of stroke in multi-ethnic study

of atherosclerosis. Stroke. 2011;42(11):3017-21.

12. Salonen JT, Salonen R. Ultrasonographically assessed carotid morphology and the risk of coronary heart disease. Arterioscler Thromb. 1991;11: 1245–1249.

13. Bots ML, Hoes AW, Koudstaal PJ, et al. Common carotid intima-media thickness and risk of stroke and myocardial infarction: the Rotterdam Study. Circulation. 1997;96:1432–1437.

14. McGill HC, McMahan CA, Herderick EE, et al. Effects of coronary heart disease risk factors on atherosclerosis of selected regions of the aorta and right coronary artery: PDAY research group: Pathobiological Determinants of Atherosclerosis in Youth. Arterioscler Thromb Vasc Biol. 2000;20:836–845.

15. Frank ST. Aural sign of coronary-artery disease. N Engl J Med 1973;289:327–8.

16. Doering D, Ruhsenberger C, Phillips DS. Ear-lobe creases and heart disease. J Am Geriatr Soc 1977;25:183–5.

17. Kaukola S, Manninen V, Valle M, et al. Ear-lobe crease and coronary atherosclerosis. Lancet 1979;2:1377.

18. Lichstein E, Chadda KD, Naik D, et al. Diagonal ear-lobe crease: prevalence and implications as a coronary risk factor. N Engl J Med 1974;290:615–6.

19. Shoenfeld Y, Mor R, Weinberger A, et al. Diagonal ear lobe crease and coronary risk factors. J Am Geriatr Soc 1980;28:184–7.

20. Elliott WJ. Ear lobe crease and coronary artery disease 1000 patients and review of the literature. Am J Med 1983;75:1024–32.

21. Mehta J, Hamby RI. Diagonal ear-lobe crease as a coronary risk factor. N Engl J Med 1974;291:260.

22.Jorde LB, Williams RR, Hunt SC. Lack of association of diagonal earlobe crease with other cardiovascular risk factors. Western J Med 1984;140:220–3.

23. Ziyrek M, Şahin S, Özdemir E, Acar Z, Kahraman S. Diagonal earlobe crease associated with increased epicardial adipose tissue and carotid intima media thickness in subjects free of clinical cardiovascular disease.Turk Kardiyol Dern Ars. 2016 Sep;44(6):474-80.

24. Koyama T, Watanabe H, Ito H. he association of circulating inflammatory and oxidative stress biomarker levels with diagonal earlobe crease in patients with atherosclerotic diseases. J Cardiol. 2016 Apr;67(4):347-51.

25. Levent Korkmaz, Mustafa Tarık Ağaç, Hakan Erkan, et al: Association between Diagonal Earlobe Crease and Cardio-Ankle Vascular Index in Asymptomatic hypertensive Patients. Med Princ Pract 2013;22:530–534.

26. Edston E. The earlobe crease, coronary artery disease, and sudden cardiac death: an autopsy study of 520 individuals. Am J Forensic Med Pathol. 2006 Jun;27(2):129-33.

27. Korkmaz L, Ağaç MT, Acar Z, Erkan H. Earlobe crease may provide predictive information on asymptomatic peripheral arterial disease in patients clinically free of atherosclerotic vascular disease. Angiology. 2014 Apr;65(4):303-7

28. Friedlander AH, López-López J, Velasco-Ortega E. Diagonal ear lobe crease and atherosclerosis: a review of the medical literature and dental implications. Med Oral Patol Oral Cir Bucal 2012;17:153–9. Crossref

29. Wermut W, Jaszczenko S, Ruszel A. Ear lobe crease as a risk factor in coronary disease. Wiad Lek (in Polish) 1980;33:435– 38.

30. Zureik M, Temmar M, Adamopoulos C, Bureau JM, Courbon D, Thomas F, et al. Carotid plaques, but not common carotid intima-media thickness, are independently associated with aortic stiffness. J Hypertens 2002;20:85–93. Crossref

31. Labropoulos N, Zarge J, Mansour MA, et al. Compensatory arterial enlargement is a common pathobiologic response in early atherosclerosis. Am J Surg. 1998;176:140–143.