Frank’s Sign and Cardiovascular Risk: An Observational Descriptive Study

Title Page Title: Frank´s Sign and cardiovascular risk: an observational descriptive study. Authors: Lucía Fernández Ascariz1 (lucia.f[email protected]), Berta Rivas Mundiña1 ([email protected]), Eliane García Mato1 ([email protected]), Jacobo Limeres Posse1 (jacobo.[email protected]), Manuela Alonso Sampedro2,3 ([email protected]), Arturo Gónzalez Quintela ([email protected])4 Francisco Gude Sampedro5 (fr[email protected]), Pedro Diz Dios1 (pedro.[email protected]) . 1 Medical-Surgical Dentistry Research Group (OMEQUI), Health Research Institute of Santiago de Compostela (IDIS), University of Santiago de Compostela (USC), Santiago de Compostela, Spain. 2 Research Methods Group (RESMET), (IDIS), Santiago de Compostela, Spain. 3 Network for Research on Chronicity, Primary Care, and Health Promotion (RICAPPSISCIII). 4 Departments of Clinical Internal Medicine, Complejo Hospitalario Universitario de Santiago, Spain.REDIAPP “Network on Preventive Activities and Health Promotion”, Barcelona RD12/0007/, Spain. 5 Departments of Clinical Epidemiology, Complejo Hospitalario Universitario de Santiago, Spain.REDIAPP “Network on Preventive Activities and Health Promotion”, Barcelona, RD12/0007/, Spain. All of the authors participated in the preparation of the manuscript and the final version has been read and approved by all authors Correspondence: Berta Rivas Mundiña Department of Surgery and Medical-Surgical Specialties Faculty of Medicine and Denstistry, University of Santiago de Compostela c/ Entrerríos sn, 15782 Santiago de Compostela, Spain. Tel: +34 881812344, Fax: +34 981562226, E-mail: [email protected] Financial disclosure: This research project was supported by a grant from Spain’s Carlos III Institute of Health (Instituto de Salud Carlos III/ISCIII) (PI11/02219). Declarations of interest: None. Article type: Clinical Research study. Keywords Diagonal earlobe crease, Cardiovascular diseases, Cardiovascular risk scores. Abstract Purpose: To analyze the relationship between the diagonal earlobe crease (DELC) and the main indices of cardiovascular risk (CVR), considering the crease’s anatomical variations. Methods: The study group consisted of 1050 adults residing in A Estrada town (Spain). Participants underwent the following determinations: age, sex, body mass index, smoking habit, blood pressure, glycemia, glycated hemoglobin, total cholesterol, HDL- C, LDL-C, and cardiovascular events. CVR was calculated applying the Framingham- Anderson equation, the SCORE equation and the ASCVD risk calculator. Both earlobes were examined, recording DELC presence, length and depth, and presence of accessory creases. Results were analyzed by using chi-square test, Student’s t-test, ANOVA, Mann-Whitney or Kruskal-Wallis tests. To extract the functions of CVR, a script in R was created (https://cran.r-project.org/). Results: The estimated cardiovascular mortality risk was significantly higher in patients who presented DELC (p<0.001). According to the “European Guidelines on cardiovascular disease prevention”, some 76.1% of patients who showed no DELC had low CVR, this percentage decreasing significantly as the presence of the crease increased (64.4% for unilateral and 42.1% for bilateral; p<0.001). The number of individuals with moderate, high or very high CVR increased significantly as the presence of the crease increased (23.8% had no crease, 35.6% had unilateral creases, and 58% had bilateral creases; p<0.001). The mean CVR estimated was significantly higher for patients with higher DELC length scores (p<0.001), with higher DELC depth scores (p<0.001), and with accessory creases (p<0.001). Conclusions The DELC is independently associated with higher CVR values, especially when the crease is complete, bilateral, deep and has accessory creases. Introduction According to the World Health Organization, cardiovascular diseases (CVDs) represent the leading cause of death worldwide, with 17.9 million deaths each year, a third of which occur prematurely in individuals younger than 70 years (1). CVDs also involve significant morbidity and loss of quality of life, to the point where the disability-adjusted life years and years of life lost of patients with CVDs have doubled in the past 30 years (2). Of special interest, therefore, are prevention programs based on promoting healthy lifestyles and controlling potentially modifiable risk factors such as tobacco use, high systolic blood pressure, diabetes, high low-density lipoprotein cholesterol and obesity (2,3). Assuming that CVDs have a multifactorial etiology and in an attempt to jointly assess the risk factors, the calculation of the cardiovascular risk (CVR) was proposed and involves a series of mathematical functions that define the likelihood that an individual will present a cardiovascular episode, especially an acute coronary or stroke event within a specified period (4). The most widely used prediction indices for CVR are the Framingham-Anderson equation (5), the Systematic Coronary Risk Evaluation (SCORE) equation (6) and the Atherosclerotic Cardiovascular Disease Risk Score (ASCVD) (7). Although these CVR prediction indices are regularly applied in Europe and the U.S., it has been suggested that there is a need for developing specific indices for different countries and populations, because the risk assessment tools developed for one specific population often are inaccurate when applied to other populations (4). Although the ideal scenario would be the ability to estimate the CVR in all adults, this initiative depends on each country’s health policies and resources. It is therefore important to identify the most common physical signs related to atherosclerosis and CVD, such as xanthelasmas (8), corneal arcus (9), acanthosis nigricans (10) and obesity (11). In 1973, the United States pulmonologist Saunders T. Frank described the diagonal earlobe crease (DELC), which consists of an oblique line that travelled from the tragus to the pinna (Figure 1A, 1B), generally bilateral and clearly visible on inspection, shown by some of his patients with a history of angina pectoris, electrocardiographic ischemic changes or coronary artery disease confirmed angiographically (12). The author was therefore attributed with the initial report of an association between this physical sign, which was named after him, and coronary artery disease (13). This finding was immediately replicated in a clinical study published in 1974, in which a significant and independent statistical association was found between the presence of the DELC and coronary artery disease, with a prevalence of 47% in the cases and 30% in the controls (14). Since then, numerous published articles have confirmed that the DELC is an independent predictor of the onset of CVD and is closely associated with an increase in its prevalence, extent and severity (15-35), In most published studies, the sensitivity of DELC as a diagnostic tool for atherosclerosis was above 75% (27), and its specificity exceeded 85% (25). Only a minority of researchers suggested that the association between the DELC and atherosclerosis is not independent and is due to both entities being related to atherogenic risk factors such as hypertension (36), tobacco use (37), obesity (38), diabetes (39) and hypercholesterolemia (40). However, the histomorphological analysis of the DELC recently performed by our group revealed a redistribution of connective tissue and poor capillary density, which allows us to speculate that the DELC could represent an early indicator of peripheral microangiopathy (41). To date, we have found only 3 articles in the literature that studied the relationship between the DELC and the indices of CVR, without considering in any case the crease’s characteristics (29,42,43). Accordingly, this study’s main objective was to analyze the relationship between the DELC and the main indices of CVR, considering the crease’s anatomical variations. Material and Methods • Study group The study participants were selected within the framework of the “A Estrada Study of Glycation and Inflammation” (AEGIS), approved by the Clinical Research Ethics Committee of Galicia, Spain (CEIC2012-025). AEGIS is a populational study conducted in the northwest of Spain, in the municipality of A Estrada (Pontevedra) that, during recruitment, had 18,744 inhabitants older than 18 years. The sample selection was stratified by the following age groups (in years): 18–29, 30– 39, 40–49, 50–59, 60–69, 70–79 and older than 80. Using software, a random sample was generated of 500 individuals belonging to each age group, for a total of 3500 individuals. After excluding those who declined to participate, those who had died, those who did not respond, those who no longer lived in the municipality, those with no health coverage and those who did not meet the inclusion criteria due to presenting dementia, intellectual disability, severe cerebrovascular disease, cancer, terminal illness or inability to communicate, a study group was created with 1050 participants: 468 men (44.6%) and 582 women (55.4%), with a mean age of 52 ± 19.1 years. • Collection of demographic, medical and laboratory data Between November 2012 and March 2015, the participants attended the Health Center of A Estrada (Pontevedra) where they were evaluated by a team of previously trained and calibrated health practitioners (physician, nurse and dentist). Each participant underwent a clinical interview and a set of specific determinations that included the following: - Structured questionnaire with demographic and anthropometric data, recording the age and sex and calculating the body mass index (BMI). An individual was considered to not have excess weight with BMI values <25 kg/m2, to have excess weight with BMI ≥25 kg/m2 and <30 kg/m2 and to have obesity with BMI ≥30 kg/m2. - Smoking habit recording. An individual was considered to be a smoker if they consumed ≥1 cigarette a day or had stopped smoking less than 1 year ago. - Evaluation of mean blood pressure using an automatic WatchBP Office ABI device (Micro, Barcelona, Spain). An individual was considered to have hypertension if their systolic blood pressure was ≥140 mm Hg, if their diastolic blood pressure was ≥90 mm Hg or if they were undergoing antihypertensive drug therapy. - Measurement of serum glucose levels using the Accu-Chek Guide Me system (Roche, Barcelona, Spain) and of glycated hemoglobin (HbA1c) using the Arkray HA 8140 analyzer (Menarini Diagnostics, Barcelona, Spain). The HbA1c values were converted from the reference JDS/JSCC system (Japanese Diabetes Society/Japanese Society for Clinical Chemistry) to the standardized DCCT/NGSP system (Diabetes Control and Complications Trial/National Glycohemoglobin Standardization Program) (4). An individual was considered to have diabetes if they were undergoing hypoglycemic therapy or had fasting blood glucose levels ≥126 mg/dL or HbA1c levels ≥6.5%. - Measurement of serum levels of total cholesterol, HDL-C and LDL-C using standard commercial methods. An individual was considered to have hypercholesterolemia with serum cholesterol levels ≥250 mg/dL, LDL-C levels ≥130 mg/dL or if they were undergoing lipid-lowering therapy. - Cardiovascular events. We collected the participants’ history of ischemic heart disease and cerebrovascular disease. Additionally, each individual underwent a 12- lead electrocardiogram to mainly investigate the presence of a pathological Q wave. • Cardiovascular risk stratification Based on the recorded variables, we calculated the CVR applying 3 prediction indices: the Framingham-Anderson equation (5), the SCORE equation (6) and ASCVD (7). • Inspection of the diagonal earlobe crease We examined both earlobes, recording the variable “absence/presence of the DELC”. We categorized the length of each crease, considering as “full length” the oblique line that extends from the tragus to the posterior edge of the pinna. We established three categories: 1, extending <1/3 of the full length; 2, extending ≥1/3 and <2/3 of the full length; and 3, extending ≥2/3 of the full length. Based on these scores, we calculated the variable “total length”, the result of summing the values corresponding to the categories of the crease length for both ears. Thus, the total length achieved a score of 1 to 6. For the depth of the DELC based on its penetration into the skin, we attributed 2 categories: 1, superficial crease; and 2, deep crease (Figure 1A, 1B). We calculated the variable “total depth”, the result of summing the crease depth categories for both ears. Thus, the total depth achieved a score of 1 to 4. We analyzed the absence/presence of secondary or accessory creases in each lobe, considering this variable to be any additional crease to the main crease. The variables were measured by 2 trained and calibrated examiners. To check the reproducibility of the results, we repeated the measurements of 10 randomly selected cases one month after the first measurements, obtaining for all evaluated variables an intraclass correlation coefficient that varied between 0.89 and 0.99. • Statistical analysis The relationship between the 2 qualitative variables (e.g., presence/absence of accessory creases and male/female) was assessed using the chi-squared test. To study the influence of a qualitative variable (e.g., presence/absence of the DELC) on the mean values of a quantitative variable (e.g., estimated CVR), we used Student’s ttest and analysis of variance (ANOVA) or the nonparametric Mann-Whitney or Kruskal- Wallis tests, in the event of non-normal distributions. Values of p<0.05 were considered statistically significant. To extract the functions of CVR, we created a script in R (https://cran.r-project.org/). This software was also employed in the data analysis, as well as the SPSS program for Windows version 19 (SPSS Inc, Chicago, USA). Results • Description of the diagonal earlobe crease in the study population Of the 1050 individuals who participated in the study, the examination of both ears was completed in 1048 (2 patients could not be analyzed in one of the ears due to ablation or traumatic deformation of the lobe). The DELC was bilateral in 56.9% of the participants, unilateral in 8.3% and not detected in 34.9% of the cases. No predilection for any particular ear was observed; 59.2% of the sample presented a right ear crease and 59.3% presented a left ear crease. In 71.5% of the participants with creases, these occupied at least 2/3 of the full length in at least one ear; in 45.7%, the creases of both ears reached the maximum score. 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Cardiovascular risk estimated based on the presence of the diagonal earlobe crease ESTIMATION METHOD PRESENCE OF THE CREASE n ESTIMATED CARDIOVASCULAR RISK (%) Mean ± SD Median Range Framingham 0 238 5.4 ± 8.3 2.7 0.5–62.0 1 74 8.1 ± 9.2 4.2 0.8–42.7 2 424 14.0 ± 12.2 10.4 0.4–70.8 Total 736 10.6 ± 11.5 6.3 0.4–70.8 SCORE 0 108 0.6 ± 0.9 0.2 0.02–6.9 1 46 0.8 ± 1.0 0.5 0.0–5.1 2 260 1.4 ± 1.5 1 0.0–7.9 Total 413 1.1 ± 1.3 0.7 0.0–7.9 ASCVD 0 121 5.7 ± 1.0 1.7 0.1–49.9 1 55 8.3 ± 12.9 2.8 0.1–52.4 2 431 14.2 ± 14.0 9.4 0.2–73.6 Total 607 12.0 ± 13.7 6.5 0.1–73.6 n, number of individuals evaluated; DS, standard deviation; Framingham, Framingham-Anderson equation; SCORE, systematic coronary risk evaluation equation; ASCVD, atherosclerotic cardiovascular disease equation; 0, no crease; 1, unilateral crease; 2, bilateral crease. Table 2. Cardiovascular risk estimated according to the categorical classification for the SCORE index, depending on the presence of the diagonal earlobe crease ESTIMATED CARDIOVASCULAR RISK CATEGORY Diagonal earlobe crease Absent, n (%) Unilateral, n (%) Bilateral, n (%) Very high (n=41) 6 (5.5) 5 (11.1) 30 (11.5) High (n=49) 8 (7.3) 3 (6.7) 38 (14.7) Moderate (n=102) 12 (11) 8 (17.8) 82 (31.7) Low (n=221) 83 (76.2) 29 (64.4) 109 (42.1) SCORE, Systematic Coronary Risk Evaluation equation; n, number of individuals; %, percentage of individuals.