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\begin{document}

\title{Why we should be looking for ear lobe creases. A systematic review and
meta-analysis of diagonal ear lobe crease and coronary artery disease.}



\author[1]{Jonathan Curtis}%
\author[1]{Sophie Walford}%
\affil[1]{University Hospitals Coventry and Warwickshire NHS Trust}%


\vspace{-1em}



  
  \date{May 18, 2024}


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\selectlanguage{english}
\begin{abstract}
Objectives The association between diagonal ear lobe crease (DELC) and
cardiovascular disease was first suggested in 1973 although some studies
have attributed this to confounding cardiovascular factors. This review
looked to see if there is a significant association between DELC and
angiography-confirmed coronary artery disease (CAD) independent of other
risk factors. Design Systematic review and meta-analysis of selected
studies using the PRISMA checklist. Setting 12 different hospitals with
angiography in eight countries. Participants 4960 adult patients
undergoing coronary angiography. Main Outcome Measures *
Presence/absence of diagonal ear lobe crease * Diagnostic Odds Ratio *
Sensitivity/Specificity Results 12 studies were included in the
meta-analysis. Findings from our study suggest: * Patients with DELC
have a 4x increased likelihood of having CAD (OR 4.61
P\textless{}0.00001). * The relationship between DELC and CAD was
independent of age and all other conventional cardiovascular risk
factors. * Bilateral DELC has a stronger association with CAD than
unilateral DELC. * Presence of DELC has insufficient sensitivity /
specificity to be used as a diagnostic test for cardiovascular disease
but instead should be used as a risk marker. Conclusions We found that
DELC is associated with CAD independently of other known cardiovascular
risk factors including age. Histology studies indicate that
atherosclerosis is causing DELC and patients with DELC appear to have an
increased risk of CAD. It has insufficient sensitivity or specificity to
be used as a diagnostic test but should be used as a valuable risk
marker to be aware of whilst examining ears.%
\end{abstract}%



\sloppy


\textbf{Why we should be looking for ear lobe creases. A systematic
review and meta-analysis of diagonal ear lobe crease and coronary artery
disease.}

\textbf{Abstract}

Objectives

The association between diagonal ear lobe crease (DELC) and
cardiovascular disease was first suggested in 1973 although some studies
have attributed this to confounding cardiovascular factors. This review
looked to see if there is a significant association between the presence
of a DELC and angiography-confirmed coronary artery disease (CAD)
independent of other risk factors.

Design

Systematic review and meta-analysis of selected studies using the PRISMA
checklist.

Setting

12 different hospitals with angiography in eight different countries

Participants

4960 adult patients undergoing coronary angiography.

Main Outcome Measures

\begin{itemize}
\tightlist
\item
  Presence / absence of diagonal ear lobe crease
\item
  Diagnostic Odds Ratio
\item
  Sensitivity / Specificity
\end{itemize}

Results

12 studies were included in the meta-analysis. Findings from our study
suggest:

\begin{itemize}
\tightlist
\item
  Patients with DELC have a 4x increased likelihood of having CAD (OR
  4.61 P\textless{}0.00001).
\item
  The relationship between DELC and CAD was independent of age and all
  other conventional cardiovascular risk factors.
\item
  Bilateral DELC has a stronger association with CAD than unilateral
  DELC.
\item
  Presence of DELC has insufficient sensitivity / specificity to be used
  as a diagnostic test for cardiovascular disease but instead should be
  used as a risk marker.
\end{itemize}

Conclusions

We found that DELC is associated with CAD independently of other known
cardiovascular risk factors including age. Histology studies indicate
that atherosclerosis is causing DELC and patients with DELC appear to
have an increased risk of CAD. It has insufficient sensitivity or
specificity to be used as a diagnostic test but should be used as a
valuable risk marker to be aware of whilst examining ears.

\textbf{5 Key Points}

\begin{itemize}
\tightlist
\item
  The relationship between a diagonal ear lobe crease (DELC) and
  cardiovascular disease has been known about for over 45 years but some
  have suggested it is a result of a confounding factor and there have
  been no studies in otolaryngology publications.
\item
  We performed a PRISMA based systematic review and meta-analysis
  involving 12 studies and 4960 patients.
\item
  Findings from our study suggest:
\item
  Patients with DELC have a 4x increased likelihood of having Coronary
  Artery Disease (CAD) (OR 4.61 P\textless{}0.00001).
\item
  The relationship between DELC and CAD is independent of age and all
  other conventional cardiovascular risk factors and that bilateral DELC
  has a stronger association with CAD than unilateral DELC.
\item
  Presence of DELC has insufficient sensitivity / specificity to be used
  as a diagnostic test for cardiovascular disease but instead should be
  used as a risk marker.
\end{itemize}

\textbf{Key words:} Ear lobe crease, earlobe, Frank's sign, coronary
disease

\textbf{Figures}

Figure 1 -- Examples of diagonal ear lobe creases

Figure 2 -- Flow diagram of study selection process

Figure 3 - Forest Plot of Diagnostic Odds Ratios

Figure 4 -- Sensitivity and specificity of studies

Figure 5 - Receiver Operating Characteristic (ROC) Curve

\textbf{Introduction}

An association between a diagonal ear lobe crease (DELC) and
cardiovascular disease was first suggested by Sanders T. Frank in 1973
in the New England Journal of Medicine\textsuperscript{(1)}. Since then
there have been numerous further studies that have investigated the
association of `Frank's Sign' with carotid disease, cerebral vascular
disease and diabetic retinopathy. Whilst almost all of the studies since
then have found a correlation between DELC and cardiovascular disease,
there is disagreement on whether this is an independent association or
whether both of these are related to increasing age or other potential
confounding cardiovascular risk factors \textsuperscript{(2)}.

The purpose of this meta-analysis is therefore to determine if there is
a significant association between the presence of a diagonal ear lobe
crease (Fig. 1) and coronary artery disease (CAD) independent of other
risk factors. Although there have been other reviews that have looked
into this \textsuperscript{(3)}, these have included autopsy studies or
clinically diagnosed CAD and none have specifically looked at studies
solely using coronary angiography which is the gold standard for
confirming CAD\textsuperscript{(4-6)}. At the same time, although this
is an aural sign, there have been no studies in any otology journals and
no reports in any otolaryngology literature. We believe this is the
first literature review and meta-analysis that solely looks at patients
with DELC undergoing angiography and the first article about this topic
in an otology publication.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

\textbf{Figure 1: Examples of diagonal ear lobe creases}

\textbf{Methodology}

\emph{Protocol and Information Sources}

The Preferred Reporting Items for Systematic reviews and Meta-Analyses
(PRISMA) checklist\textsuperscript{(7)} was used to report this review.
The PUBMED database was searched on August 12\textsuperscript{th} 2020
using the following separate terms: ear lobe crease(s), earlobe
crease(s), Frank's sign.

\emph{Study selection, data collection and bias}

Retrieved studies were filtered on title and abstract and where there
was any doubt, the study was accepted to the next level. Only original
studies equal to or above OCEBM Level 4
evidence\textsuperscript{(8)}that reported on the presence of a diagonal
ear lobe crease in patients undergoing coronary angiography were
included. Selected studies were then assessed independently by both
authors for quality and bias using CASP checklists\textsuperscript{(9)}.
Differences were resolved by discussion. Objective data were extracted
from the studies and summarized into tables and meta-analysis was
performed using Revman 5.4\textsuperscript{(10)}.

\textbf{Results}

\emph{3.1 -- Study selection}

The search retrieved 355 individual studies that were filtered by
language, title and abstract leaving 21 original studies. Nine studies
were then excluded at full text, mostly for not reporting on patients
who had undergone coronary angiography although one study was excluded
for unclear results\textsuperscript{(2)} and another excluded for
reporting on the same patients as another study\textsuperscript{(11)}.
This left 12 original studies published between 1974 and 2017 included
in this review. Figure 2 shows the selection process.

\textbf{Hosted file}

\verb`image2.emf`  available at \url{https://authorea.com/users/379460/articles/495661-why-we-should-be-looking-for-ear-lobe-creases-a-systematic-review-and-meta-analysis-of-diagonal-ear-lobe-crease-and-coronary-artery-disease}

\textbf{Figure 2: Flow diagram of study selection process}

\emph{3.2 -- Study Characteristics}

Key characteristics of the 12 studies are included in Table 1 and
assessed quality of studies is shown in Appendix 1. All the studies were
case-control studies and cumulatively included 4960 patients (min 125
max 1424) across eight countries and it is unlikely that this involved
any duplicated patients due to the geographical and chronological spread
of the studies. For each study the case population was well described as
patients undergoing coronary angiography. Most studies reported
relatively consistent definitions of DELC. This was typically a deep
crease extending obliquely from the tragus towards the outer border of
the ear lobe although the distance varied from a third to complete. All
studies defined the presence of coronary artery disease as
\textgreater{}50\% stenosis of at least one major epicardial vessel,
except for three studies which used a threshold of \textgreater{}70\%
stenosis\textsuperscript{(6, 12, 13)}.

\emph{3.3 Risk of bias within studies}

Bias was mostly excluded from studies by the presence of DELC being
measured without knowing the cardiac history shortly before undergoing
angiography and with fairly consistent definitions of DELC and CAD. No
patients were lost to attrition however two studies\textsuperscript{(4,
6)} used non-cardiac patients as controls and it was assumed they had no
CAD without undergoing angiography. Other potential biases are mentioned
further in results.

\textbf{Hosted file}

\verb`image3.emf`  available at \url{https://authorea.com/users/379460/articles/495661-why-we-should-be-looking-for-ear-lobe-creases-a-systematic-review-and-meta-analysis-of-diagonal-ear-lobe-crease-and-coronary-artery-disease}

Table 1: Key characteristics of included studies

\emph{3.4 Overall results of studies}

All 12 studies were included in the pooled analysis. This included 2415
cases and 2545 controls. The pooled results (Figure 3) suggest that
patients with DELC have an increased likelihood of having coronary
artery disease. (OR= 4.61, 95\% CI: 3.17 to 9.60). There was significant
heterogeneity among studies (I\textsuperscript{2}=83\%,
P\textless{}0.00001) whilst test for overall effect, Z, was 8.01
(p\textless{}0.00001). Ten of the 12 studies found a significant
association between DELC and CAD. The two studies that found no
significance association \textsuperscript{(14, 15)} were poorer quality
studies which both attributed their findings to age without any
statistical analysis.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image4/image4}

\end{center}
\end{figure}

\textbf{Figure 3: Forest Plot of Diagnostic Odds Ratios}

\emph{3.4.1 -- Sensitivity and Specificity}

Sensitivity of DELC as a diagnostic test for CAD ranged from 0.26 to
0.90 and specificity ranged from 0.32 to 0.96 (Figure 4). This variance,
as demonstrated on the ROC curve (Figure 5), suggests that DELC by
itself is not suitable as a diagnostic test for CAD.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image5/image5}

\end{center}
\end{figure}

\textbf{Figure 4: Sensitivity and Specificity of Studies}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image6/image6}

\end{center}
\end{figure}

\textbf{Figure 5: Receiver Operating Characteristic (ROC) Curve}

\emph{3.4.2 - Bilateral vs Unilateral DELC}

Three studies investigated unilateral and bilateral DELC
separately\textsuperscript{(4, 16, 17)}, two studies just looked at
bilateral DELC\textsuperscript{(11, 13)}, two studies included both
unilateral and bilateral DELC combined \textsuperscript{(6, 18)} and in
five studies it was not clear which was used. Whilst this raises
concerns, it is noted that in the three studies which compared bilateral
and unilateral DELC, unilateral DELC was found to have either a reduced
association with CAD\textsuperscript{(17)} or no significant
association\textsuperscript{(4, 16)}. The breakdown is shown in Table 2.
It is therefore believed that in any studies that included unilateral
DELC with bilateral DELC, this would have had a diluting effect in the
odds ratio and association with CAD.

\textbf{Hosted file}

\verb`image7.emf`  available at \url{https://authorea.com/users/379460/articles/495661-why-we-should-be-looking-for-ear-lobe-creases-a-systematic-review-and-meta-analysis-of-diagonal-ear-lobe-crease-and-coronary-artery-disease}

\textbf{Table 2:} Breakdown of diagnostic odds ratio (DOR) for
unilateral vs bilateral DELC

\emph{3.4.3 Age}

In studies which reported a mean age there was good comparison between
case and control groups (Table 1). Ten of the studies looked at the
association with age either by looking at different age cohorts or by
performing multivariate regression analysis. Of these ten, four studies
looking at cohorts found a significant association between DELC and CAD
in all age brackets investigated\textsuperscript{(5, 6, 12, 18)} whilst
four\textsuperscript{(11, 13, 16, 17)} using multivariate regression
analysis found that DELC was independently and significantly associated
with CAD when compared with age. Only two studies\textsuperscript{(14,
15)} suggested that DELC was directly due to age and they provided no
statistical analysis to support their view. Of the four studies which
looked at different age cohorts, only one\textsuperscript{(6)} provided
enough detail to look at the diagnostic odds ratio for different 10 year
age cohorts. There was no obvious pattern with the ratios although the
DOR was greatest in the youngest cohort (\textless{}40yo) and smallest
in the oldest cohort (\textgreater{}70yo).

\emph{3.4.4 -- Gender}

It was noted that most studies which recorded gender had a disparate
gender ratio between the case and control groups (Table 1). This is
partly explained as female patients have a lower prevalence of coronary
artery disease and are therefore more likely to be in the control group
however only Kamal \emph{et al} gender matched each
group\textsuperscript{(4)}. Although there was a reported increased
prevalence of DELC and CAD in male patients in most studies, only one
study \textsuperscript{(17)} looked at the odds ratio for both genders
independently and found that women had a greater association between
DELC and CAD (Female OR 6.368 95\% CI 2.961 to 13.694 vs Male OR 5.420
95\% CI 2.804 to 10.477). No other studies reported results in
sufficient detail to allow comparison with this study.

\emph{3.4.5 - Ethnicity}

Only two studies looked at different ethnic populations separately
within their study. One\textsuperscript{(6)} found that DELC was more
prevalent in caucasian than non-caucasian populations but there was
still a significant association with CAD in both groups.
Another\textsuperscript{(12)} attempted to investigate this as well but
cases and controls were not well matched on gender and race and no
meaningful results were obtainable. Overall the twelve studies covered
multiple ethnic populations from around the globe and it is believed
that this suggests the findings are applicable to a wider population
although variations between ethnic groups can not be excluded.

\emph{3.4.6 -- Other cardiovascular risk factors}

Eight of the studies\textsuperscript{(5, 11, 13, 14, 16-19)} used
multivariate regression analysis to look at the relationship between
DELC and other conventional cardiovascular risk factors including
hypertension, hyperlipidaemia, smoking status, diabetes mellitus,
obesity and family history. Although four studies \textsuperscript{(11,
13, 17, 18)}, found a significant correlation between DELC and certain
risk factors such as age, male gender, hypertension and smoking status
this did not correspond with the presence of CAD. Instead all eight
studies found that DELC was independently and significantly associated
with CAD when compared against all conventional risk factors.

\emph{3.4.7 -- Severity of disease}

Four studies looked at the association between DELC and severity of CAD
as assessed by the number of stenosed coronary arteries. Of these,
two\textsuperscript{(16, 18)} found no significant association between
the number of diseased vessels and DELC but two\textsuperscript{(5,
6)}found that multi-vessel disease was more common in patients with
DELC.

\emph{3.5 Publication Bias}

No publication bias across studies was found especially as two of the
included studies\textsuperscript{(14, 15)} suggested that there was no
association between DELC and CAD.

\textbf{Discussion}

\emph{Summary of evidence}

This study investigated if there is a significant association between
the presence of a diagonal ear lobe crease (DELC) and coronary artery
disease (CAD) independent of age. By using the gold standard diagnosis
for CAD, angiography, we were able to provide a more objective analysis
than other reviews which have included autopsy studies and clinically
diagnosed heart disease\textsuperscript{(3)}. Our study found that
patients with DELC have an increased likelihood of having CAD. Also
despite some previous studies suggesting that DELC was simply a result
of age, all ten of the included studies that looked at this found that
the relationship between DELC and CAD was independent of age and all
other conventional cardiovascular risk factors.

We also looked to see if the diagnostic odds ratio varied between
different cohorts. In looking at different age groups, only one
study\textsuperscript{(6)} provided their findings for each age bracket
and although it found that the diagnostic odds ratio was greatest in the
youngest cohort, the population size of each cohort was relatively small
and it is difficult to assess the validity of this finding without other
studies. Similarly, only one study looked at different odds ratio
between genders and found that it was greater in women than men (OR
6.368 vs 5.420) however it is difficult to assess this effect overall in
our analysis as there was frequently a disparate gender ratio between
the case and control groups. Whilst this is due to poor recruitment, it
may partly be influenced by there being a reduced prevalence of CAD in
women and also some studies excluding patients with ear lobe piercings
causing an iatrogenic DELC. Other studies\textsuperscript{(20)} have
found no difference in the prevalence of DELC between males and females.

As the included studies spanned eight different countries it is believed
that the results are applicable to multiple ethnic populations. However
it is difficult to determine the impact of ethnicity especially as there
are few studies which look at the general prevalence of DELC in a
healthy population. Without knowing the generalised prevalence of DELC
and relationship with CAD in different populations it is difficult to
ascertain the impact of ethnicity.

Although this study found that patients with DELC have an increased
likelihood of having CAD, there was wide variance in the sensitivity and
specificity of DELC as a diagnostic test. This supports findings from
other studies that indicate DELC should only be used as a physical
marker not a diagnostic clinical test for CAD\textsuperscript{(12)}.

\emph{Pathophysiology}

At first there may not be any obvious link between coronary arteries and
ear lobes however a few papers shed some light on this issue. Autopsy
studies involving biopsies of ear lobes in patients with DELC found
thickening of arterial walls and tears in the
elastin\textsuperscript{(21)} and that both earlobe and myocardium are
supplied by end arteries without collateral
circulation\textsuperscript{(22)}. More recently
Stoyanov\textsuperscript{(23)} found that patients with DELC had diffuse
fibrosis of an arterial vessel located at the base of the ear lobe
crease and that this was associated with corresponding changes to
myocardial tissue. As with our study, Stoyanov \emph{et al} also found
that this correlation was independent of age. As has been suggested in
an earlier study\textsuperscript{(21)}, a reduced blood supply to the
ear lobe could cause destruction of the elastin which manifests as
creases in the ear lobe. It is feasible therefore that the same
atherosclerotic processes that causes narrowing of coronary arteries may
be causing a similar effect in the blood vessels supplying the ear lobe.

\textbf{Limitations}

There are three main limitations to this review. Firstly to include
sufficient studies we could not restrict the time period and the
selected studies ranged over forty years. However the methodology for
identifying DELC and CAD remained unchanged in that period and we
believe all included studies are relevant. Secondly, although studies
used fairly consistent definitions of DELC and CAD, there was some
variance especially in the length of the crease. Three studies also used
\textgreater{}70\% stenosis of at least one major epicardial vessel to
define CAD when the majority used 50\% but it is not possible to
determine the impact that had on their results. Studies also varied in
using unilateral or bilateral creases to define DELC, although it was
noted that including unilateral creases appeared to reduce the odds
ratio and therefore significant results were still considered valid.
Lastly some studies used non-cardiac patients as controls and it was
assumed that they had no coronary artery disease without undergoing
angiography. We recommend that, for consistency, further studies assess
bilateral DELC and use Shresta's\textsuperscript{(24)} definition of a
deep (\textgreater{}1mm) diagonal crease extending obliquely at least
two-thirds from the tragus towards the outer border of the ear. This
should be assessed by two examiners with the patient upright and
patients with ear piercings which could cause iatrogenic creases should
be excluded. Similarly CAD should be defined as \textgreater{}50\%
stenosis of at least one major epicardial vessel on angiography for both
case and control groups.

\textbf{Conclusion}

This review looked to see if there is a significant association between
the presence of a diagonal ear lobe crease (DELC) and coronary artery
disease (CAD). We found that DELC is associated with CAD independently
of other known cardiovascular risk factors including age and that
patients with DELC appear to have an increased risk of CAD (OR 4.61) and
this may be higher for patients with bilateral DELC. The variety of
groups included in the selected studies suggest that this finding is
relevant to the wider population. The sign does not have sufficient
specificity or sensitivity to be used as a diagnostic test but instead
it should be considered as a risk marker. For this reason we believe it
is an important quick sign for clinicians to be aware of particularly
those who more frequently examine ears. Histology studies have also
indicated a feasible mechanism for atherosclerosis to cause DELC and
explain this finding.

\textbf{Funding and Conflicts of Interest}

No funding was received for this review. The authors have no conflicts
of interest to disclose.

\textbf{Data sharing}

Data sharing is not applicable to this article as no new data were
created or analysed in this study.

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Histological Basis of Frank's Sign. Head and Neck Pathology. 2020.

24. Shrestha I, Ohtsuki T, Takahashi T, Nomura E, Kohriyama T, Matsumoto
M. Diagonal Ear-Lobe Crease is Correlated With Atherosclerotic Changes
in Carotid Arteries. Circulation Journal. 2009;advpub:0907230438-.

25. \emph{Evidence} CASPC\emph{AtESAt} , 2013,
http://www.casp-uk.net/find-appraise-act/appraising-the-evidence/. {[}

\textbf{Appendix 1: Assessed Quality of Studies using CASP
checklist\textsuperscript{(25)}}

\textbf{Hosted file}

\verb`image8.emf`  available at \url{https://authorea.com/users/379460/articles/495661-why-we-should-be-looking-for-ear-lobe-creases-a-systematic-review-and-meta-analysis-of-diagonal-ear-lobe-crease-and-coronary-artery-disease}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure1-DELC/Figure1-DELC}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure2-Flowchartofstudyselectionprocess/Figure2-Flowchartofstudyselectionprocess}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure3-Forestplot/Figure3-Forestplot}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-4---Sensitivity-and-Specificity/Figure-4---Sensitivity-and-Specificity}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure5-ROCCurve/Figure5-ROCCurve}

\end{center}
\end{figure}

\textbf{Hosted file}

\verb`Table1 - Key Study Characteristics.xlsx`  available at \url{https://authorea.com/users/379460/articles/495661-why-we-should-be-looking-for-ear-lobe-creases-a-systematic-review-and-meta-analysis-of-diagonal-ear-lobe-crease-and-coronary-artery-disease}

\textbf{Hosted file}

\verb`Table 2 - Unilateral vs bilateral DELC.xlsx`  available at \url{https://authorea.com/users/379460/articles/495661-why-we-should-be-looking-for-ear-lobe-creases-a-systematic-review-and-meta-analysis-of-diagonal-ear-lobe-crease-and-coronary-artery-disease}

\selectlanguage{english}
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