Association Between the Frank Sign and Cardiovascular Events Saleh Nazzal, MD; Arnon Blum, MD DISCLOSURES South Med J. 2018;111(8): Abstract Clinicians have attempted to find early preclinical physical diagnosis signs to detect vascular diseases at the preclinical stage and to prevent clinical deterioration in time. An interesting example of such signs is the Frank sign, which was first described by Dr Sonders T. Frank in 1973. Our goal was to summarize the clinical trials and observational studies that had examined the association between the Frank sign and cardiovascular diseases. Summarizing the 57 studies we found showed that this association could be used for early diagnosis of coronary and vascular diseases in the preclinical stage and that they were found in different populations around the world. Autopsy studies also found a strong association between the Frank sign and cardiovascular causes of death in both sexes. Cardiovascular causes of death included ischemic and hypertensive heart disease, calcific valvular stenosis, ruptured dissecting aneurysm of the thoracic aorta, and ruptured atheromatous aneurysm of the abdominal aorta. The Frank sign was correlated with increased intima-media thickness and stroke and was found in patients with peripheral vascular disease and with cardiovascular risk factors. The Frank sign could serve as a physical sign to help clinicians diagnose cardiovascular diseases. Introduction In the last decade physicians have learned to rely on advanced technology to detect subclinical stages of atherosclerosis. Cardiovascular diseases are among the most common causes of morbidity and mortality worldwide. They constitute approximately 31% of all deaths globally every year, or 17.5 million individuals annually.[1] Clinicians have attempted to find early preclinical physical diagnosis signs to detect vascular diseases at the preclinical stage and to prevent clinical deterioration in time.[2] There remains, however, great debate about the accuracy and reliability of such "natural" means. An interesting example is the Frank sign, which was first described by Dr Sonders T. Frank in 1973. It is a diagonal earlobe crease at a 45° angle, in varying depths, that starts from the tragus and extends to the edge of the auricle. Frank made a clinical observation that 19 of 20 patients with the crease had at least one of the known cardiovascular risk factors.[3] The Frank sign can be classified by the length of the crease. It is considered complete when it crosses the entire earlobe, whereas it is considered incomplete when it is visible only partly through the earlobe (Figure 1). The Frank sign also can be evaluated by its depth. Mild is graded when it is visible as a superficial wrinkling on the earlobe, moderate when it is seen as a sulcus with visible base, and severe when the sulcus is so deep that the base is not visible (Figure 2).[4] In addition, a stronger association between the Frank sign and coronary heart disease was found when the sign existed in both ears, not only in one ear.[5–7] Figure 1. The Frank sign classification according to length: complete (A) and incomplete (B). Figure 2. The Frank sign classification according to depth: (A) mild is graded when it is visible as a superficial wrinkling on the earlobe, (B) moderate is graded when it is seen as a sulcus with visible base, and (C) severe is graded when the sulcus is so deep that the base is not visible. The Frank sign has been documented in sculptures from the time of ancient Rome. The earliest work of art is believed to date to the Roman emperor Hadrian (76–138 CE; Figure 3); it was described by Patrakis, who found an association between the Frank sign in this ancient statue and the medical history of Hadrian, who experienced recurrent events of epistaxis and hypertension.[8] Recently, Charlier and Deo[9] identified bilateral earlobe creases in the 1880 death mask of French novelist Gustave Flaubert (1821–1880), who died at age 59 years from brain hemorrhagic stroke, and Galassi et al identified numerous instances of the Frank sign in Renaissance art.[10] Figure 3. Roman emperor Hadrian (76–138 CE). The arrow points to the Frank sign. Our goal was to summarize the clinical trials and observational studies that had examined the association between the physical sign, the Frank sign, and cardiovascular diseases. We searched PubMed and MEDLINE from 1973 to July 2017 using combinations of the following key words: earlobe crease, ear lobe crease, ear-lobe, crease, ear crease, ear creases, and Frank's sign. Randomized controlled trials, original papers, review articles, and case reports were included in the present review. We found 57 papers that summarized clinical observations and clinical retrospective and prospective studies that looked into this interesting association between a physical sign detected during a medical physical examination and the clinical events that follow. In a study that examined 215 Indian patients from different communities, the bilateral Frank sign was significantly associated in patients with documented coronary artery disease (CAD; P < 0.001). The prevalence of the Frank sign increased with advancing age. The combined presence of the Frank sign and ear canal hair represented a more sensitive index of CAD.[5,6] The association between the Frank sign and CAD was studied prospectively among 956 patients with ischemic heart disease who underwent coronary intervention. The Frank sign was associated with ischemic heart disease mainly in patients with more than four cardiovascular risk factors. An increased rate of cardiovascular complications was found following coronary intervention in patients who had a bilateral Frank sign.[7] The first controlled study that examined the relation between the Frank sign and cardiovascular disease found that 47% of 531 patients who had acute myocardial infarction also had the Frank sign (unilateral or bilateral), which is significantly greater than the 30% rate of the Frank sign observed among 305 age-matched control subjects with no clinical evidence of CAD (P < 0.001).[11] A Spanish study found that the association between the Frank sign and CAD was mainly positive and relevant among subjects between the ages of 30 and 60 years.[12] A prospective study that examined 222 patients with CAD found that the prevalence of the Frank sign among patients with coronary disease was significantly higher than those without (82% vs 38.5%). Patients with the Frank sign were prone to develop intraoperative cardiovascular complications (42.6% with vs 4.9% without) and postoperative cardiovascular complications (24.9% with vs 4.9% without).[13] Another prospective study of 286 patients with CAD who underwent coronary angiography because they demonstrated typical symptoms of angina pectoris found that of the 286 patients, 200 had critical stenosis in at least one coronary artery (>50% stenosis). There was a significant higher prevalence of the Frank sign in patients with CAD (72% vs 21%, P < 0.001). The Frank sign was detected in older patients and patients with an increased severity of coronary disease but not with other classic risk factors of coronary disease such as diabetes mellitus, hypertension, smoking, obesity, and hyperlipidemia.[14] Prospective cohort studies found that the Frank sign was associated with increased all-cause and cardiac morbidity and mortality. Patients with the Frank sign had more coronary events and were cautioned to reduce cardiac risk factors, even if they did not have any diagnostic evidence of CAD at the time of examination.[15] The Copenhagen City Heart Study tested the hypothesis that visible age-related signs may be associated with risk of coronary disease, myocardial infarction, and death independent of chronological age. Male pattern baldness, the Frank sign, and xanthelasmata predicted an increased risk of ischemic heart disease and myocardial infarction independent of chronological age and other well-known cardiovascular risk factors.[16] In a Brazilian study of 1464 patients, Tranchesi Júnior et al found that the Frank sign was present in 220 of 338 patients (65%) with CAD (>70% stenosis of ≥1 coronary artery documented by angiography) and that this prevalence was significantly greater compared with patients with the Frank sign but without coronary disease (28% of 1086 patients, P < 0.0001).[17] Both the Frank sign and CAD increased with advanced age (P < 0.0001 for both). This association remained statistically significant in all decades, except for patients older than 70 years. The presence of the Frank sign also was associated with the extent of coronary disease as measured by the number of narrowed major arteries (P = 0.015). The observed sensitivity of the sign for the diagnosis of coronary disease was 65%, with a specificity of 72%, a positive predictive value of 42%, and a negative predictive value of 87%. The Frank sign also was related to the severity of CAD. In stenosis in one to three coronary arteries, the prevalence of the Frank sign increased from 55% (when patients had 1-vessel CAD) to 78% (when patients had 3-vessel CAD, P = 0.015).[17] This association was found in different populations around the world; a significant association between the Frank sign and CAD was found in populations in Croatia,[18] Japan,[19] and Turkey.[20,21] In 2011 an Israeli review described the diagonal earlobe crease as an indicator of ischemic heart disease,[22] and similar results were found by a Chinese group 1 year later.[23] The association between CAD and the Frank sign was studied in 430 individuals without a history of coronary heart disease using coronary computed tomography. The Frank sign was present in 71% of the patients with documented CAD (a 50% stenosis at least in one of the coronary arteries). The prevalence of coronary significant lesions in 307 patients with the Frank sign was 77%, significantly greater compared with 55% of 123 patients without the Frank sign (P < 0.001). The sensitivity, specificity, and positive and negative predictive values for the Frank sign to diagnose any CAD were 78%, 43%, 77%, and 45%, respectively.[24] Adding the Frank sign to the cardiovascular risk assessment of patients with angina pectoris improved the prediction of CAD beyond the Diamond-Forrester classification

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