Received: 15 August 2017 Revised: 23 October 2017 Accepted: 25 October 2017

DOI: 10.1002/clc.22848

CLINICAL INVESTIGATIONS

Skin aging parameters: A window to heart block

Hisham Samir Roshdy1 | Mohammad Hassan Soliman1 | Ibtesam Ibrahim El-Dosouky1 |
Soheir Ghonemy2

1
Cardiology Department, Faculty of Medicine,
Zagazig University, Zagazig, Egypt
2
Dermatology and Venereology Department,
Faculty of Medicine, Zagazig University,
Zagazig, Egypt
Correspondence
Ibtesam Ibrahim El-Dosouky, MD, Cardiology
Department, Faculty of Medicine, Zagazig
University, Zagazig, 44519 Egypt
Email: ibtesamaldosoky@yahoo.com
Background: Skin acts as a mirror to the internal state of the body.
Hypothesis: We tried to find the relation between skin aging parameters and the incidence of
degenerative AV block.
Methods: This study included 97 patients divided into 2 groups; group D comprised 49 patients
with advanced-degree AV block, and group C comprised the 48 matched control group. All
were subjected to full history taking, thorough clinical examination, calculation of intrinsic skin
aging score, and resting 12-lead surface electrocardiography (ECG). ECG for all patients
assessed left ventricular end-systolic diameter, left ventricular end-diastolic diameter, ejection
fraction, left atrium (LA) diameter, aortic root diameter, mitral annular calcification, aortic scle-
rosis. Coronary angiography was also performed when indicated for patients in group D.
Results: Patients in group D had a higher percentages of uneven pigmentation, fine skin wrin-
kles, lax appearance, seborrheic keratosis, total score > 7 (38 [77.55%] vs 10 [20.83%]), mitral
annular calcification score of 33 (67.34%) vs 5 (10.41%), aortic sclerosis score of 21 (42.85%)
vs 4 (8.33%), and mean LA diameter of 39.98  5.52 vs 36.21  3 mm (P < 0.001). Total
score > 6 is the best cutoff value to predict advanced-degree heart block with 89.79% sensitiv-
ity and 64.58% specificity. Seborrheic keratosis was the strongest independent predictor.
Conclusions: Any population with a total intrinsic skin aging score of >6 is at high risk for
developing advanced-degree AV block and should undergo periodic ECG follow-up for early
detection of any conduction disturbance in the early asymptomatic stages to minimize sudden
cardiac death.

KEYWORDS

Aging Heart, Degenerative Heart Block, Skin Aging Parameters, Tissue Fibrosis

1 | I N T RO D UC T I O N assessment of skin aging. SCINEXA (SCore for INtrinsic and EXtrinsic

Skin acts as a mirror to the internal state of the body. Skin aging has
become an importance field due to the growth of the elderly popula-
tion and is a complex biological process that is classified as intrinsic
and extrinsic.1 Intrinsic skin aging is a natural aging phenomenon of
the skin that appears on the entire integument and is mainly caused
by the passage of time and genetic factors. Extrinsic skin aging is due
to environmental insults, such as ultraviolet radiation, smoking, pollu-
tion, and certain drugs such as corticosteroids, and is more pro-
nounced on areas of the body that are sun exposed.2,3
Clinical signs of skin aging are thinning of the skin with exagger-
ated expression lines, wrinkles, age spots, and actinic keratosis,
among others. There are many scoring systems used in the
skin Aging) is an easy-to-use clinical scoring system recently devel-
oped to differentiate between chronological (intrinsic) skin aging and
photo (extrinsic) skin aging. This score evaluates the intrinsic skin
aging with 5 items: uneven pigmentation, skin wrinkles, lax appear-
ance, reduced fat tissue, and benign skin neoplasm.4
With increasing age, atrioventricular (AV) conduction disorders
are inevitable. About 30% of people older than 65 years have AV
conduction or intraventricular conduction defects. PR interval
increases with increasing age caused by delayed conduction in the
atrioventricular node (AVN) and the proximal portion of the His
bundle.5
Mitral annular calcification (MAC) is associated with increased
frequency of conduction problems, and there is a high prevalence of

Clinical Cardiology. 2018;41:51–56. wileyonlinelibrary.com/journal/clc © 2017 Wiley Periodicals, Inc. 51

52
symptomatic bradyarrhythmias due to AVN and sinoatrial node dis-
6
ease in patients with MAC. However, no studies have evaluated the
relationship between skin-aging parameters and the incidence of
degenerative advanced-degree AV block. This study aimed to find
out the association between the intrinsic skin-aging score and degen-
erative variable degrees of advanced AV block and associated echo-
cardiographic features.
2 | METHODS
This retrospective study included 97 patients who were divided into
2 groups. Group D was the diseased group, with 49 consecutive
patients admitted to the cardiology department with advanced-
degree AV block based on electrocardiographic (ECG) data. Group C
was the control group, with 48 age- and gender-matched cardiac
patients from the outpatient clinic without evidence of heart block.
Both groups were in sinus rhythm.
Patients with drug-induced, surgically induced, or congenital AV
block; previous radiofrequency AV ablation; acute coronary syn-
drome; and ECG evidence of cardiac mass or bad echo window were
excluded from the study. Our institution's medical research and ethics
committee approved the study.
When irreversible advanced-degree AV block requiring perma-
nent pacemaker implantation was proven in the patient group, writ-
ten informed consent was obtained from all participants after
explanation of the procedure. Both groups were then subjected to
the procedures outlined below.
2.1 | Patient History and Clinical Examination
A full history was taken that included age, gender, diagnosis of diabe-
tes mellitus and hypertension, family history of advanced-degree AV
block needing permanent pacing, and drug history of digoxin,
β-blockers, calcium channel blockers, or antiarrhythmic drugs. Infor-
mation was obtained on the onset, course, and duration of the pre-
senting complaint (syncope, palpitation, low cardiac output
symptoms); chest pain; exposure to radiation; as well as history of
operation or ablation.
A thorough clinical examination was conducted including pulse,
blood pressure, and cardiac examination, as well as the calculation of
the intrinsic skin aging score under the supervision of a specialist
from the dermatology department.
The intrinsic skin aging score is comprised of 5 items. Each item
is assigned a score from 0 to 3 according to the severity (absent, mild,
moderate, or severe), except uneven pigmentation, in which a binary
scale “yes” (present = 3) or “no” (absent = 0) was used. These items
4
include uneven pigmentation, which are brownish pigmentations that
appear on the cheek with advanced age4; and fine skin wrinkles,
which are fine wrinkles that appear around the eyes and mouth with
advanced age.7 These were graded as follows: 0 = absent, 1 = just
appear on laughing, 2 = just seen in resting facial position and deepen
during laughing, 3 = high-grade wrinkles in resting facial position.
Lax appearance and reduced fat tissue were noted. Loss of elas-
ticity and reduced fat tissue lead to the lax appearance of facial skin
ROSHDY ET AL.
that appears as drooping or sagging (we examined the face).8 This
was graded as follows: 0 = absent, when no drooping at all;
1 = accentuation of the nasolabial folds; 2 = sagging at angles of the
mandible (jowls); and 3 = drooping of the submental region (turkey
neck deformity).
Evidence of a benign skin neoplasm, such as seborrheic keratosis,
which is a benign skin tumor that appears with aging on the face,
chest, shoulders, or back, was noted.9 It was graded as follows:
0 = no lesion at all, 1 = up to 10 lesions, 2 = from 11 up to 20 lesions,
3 = more than 20 lesions.
Resting 12-lead surface ECG data were recorded for each
patient, immediately after hospital admission, at a paper speed of
25 mm/s and amplification of 10 mm/mV.
Second-degree AV block (Mobitz type II, more than 2:1 block)
was defined when more than 1, but not all, atrial impulses failed to
reach the ventricles without prolongation of the PR interval, which
can be fixed or variable. Third-degree AV block was defined when no
atrial impulses were conducted to the ventricles, with AV dissociation
(independent atrial and ventricular rhythms), fixed R-R interval, fixed
P–P interval but variable PR interval,10 ECG was used also to exclude
myocardial ischemia.
Laboratory investigations were conducted to exclude other
causes of reversible heart block, mainly serum potassium level and
cardiac enzymes (troponin I and creatine kinase–myocardial band) to
exclude myocardial ischemia.
2.2 | Echocardiographic study
Transthoracic echocardiography was performed using the GE Vivid
E9 (GE Healthcare, Oslo, Norway) using a 2.5-MHz transducer. M-
mode and 2-dimensional echocardiographic assessment was per-
formed while the patient was in the supine or in the left lateral posi-
tion. Echocardiography was performed on all studied groups to
assess the following: left ventricular end-systolic diameter, left ven-
tricular end-diastolic diameter, ejection fraction, left atrium
(LA) diameter, aortic root diameter, presence or absence of mitral
annular calcification, and presence or absence of aortic sclerosis.
2.3 | Coronary angiography
Coronary angiography was done for patients suspected to have
unstable angina from their history of acute chest pain, ECG evidence
of ischemia, or echo evidence of segmental wall motion abnormalities
with negative cardiac enzymes according to 2014 European Society
of Cardiology guidelines for myocardial revascularization to rule out
ischemic heart disease as a cause of advanced-degree AV block.11
2.4 | Statistical analysis
Statistical analysis was performed using the Statistical Package for
Social Sciences version 16.0 (IBM, Armonk, NY). The differences
between groups were tested using the independent samples t test,
and homogeneity of variances was analyzed by the Levene test.
Results were expressed as mean  standard deviation. Categorical
data were presented as absolute numbers and percentages. χ2
ROSHDY ET AL. 53

analysis or Fisher exact test was used to compare these variables
when expected cell frequency was less than 5. As the SCINEXA
scores are considered qualitative data, we used Mood's median test.
The Mood's median score was 7. Diagnostic accuracy of the total
intrinsic skin aging score to predict advanced-degree heart block was
assessed by receiver operating characteristics (ROC) analysis, a total
score of >6 was the best cutoff value. Correlations between categori-
cal data were done using the Spearman correlation coefficient. Step-
wise logistic regression analysis was done to pick up the best
predictor and the cofactors of advanced-degree AV block. We calcu-
lated the regression coefficient for each parameter separately and for
the total. Significant difference was when P was <0.05.
3 | RESULTS
Demographic data of the studied groups are shown in Table 1. Group
D had 10 patients (20.4%) with second-degree Mobitz type II AV
block (more than 2:1 block), and 39 patients (79.6%) had third-degree
AV block.
Regarding the skin parameters, patients in group D had higher
percentages of uneven pigmentation (28 patients [57.14%] vs
10 [20.83%]), high-grade (score 3) fine skin wrinkles (24 patients
[48.98%] vs 9 [18.75%]), intermediate-grade (score 2) fine skin wrin-
kles (22 patients [44.9%] vs 19 [39.58%]), low grade (score 1) fine
skin wrinkles (3 patients [6.12%] vs 16 [33.33%]), score 3 lax appear-
ance and reduced fat tissue (14 patients [28.57%] vs 3 [6.25%]), score
2 lax appearance (30 patients [61.23%] vs 25 [52.08%]), score 1 lax
appearance (5 patients [10.20%] vs 20 [42.67%]), score 3 seborrheic
keratosis (1 patient [2.04%] vs 0 [0%]), score 2 seborrheic keratosis
(4 patients [8.16%] vs 0 [0%]), score 1 seborrheic keratosis
(39 patients [79.59%] vs 10 [20.83%]), score 0 seborrheic keratosis
(5 patients [10.20%] vs 38 [79.91%]) compared to group C
(P < 0.001) (Table 2).
As the scores are considered qualitative data, we used Mood's
median test. The Mood's median score was 7. There were 38 patients
(77.55%) in group D with a total score > 7 vs 10 patients (20.83%) in
group C (odds ratio = 13.12) (P < 0.001) (Table 2).
Mitral annular calcification was more prevalent in group D com-
pared to group C (33 patients [67.34%] vs 5 [10.41%], P < 0.001).
Aortic sclerosis was more prevalent in group D than in group C
(21 [42.85%] vs 4 [8.33%], P < 0.001). Mean LA diameter was higher
in group D compared to group C (39.98  5.52 mm vs
36.21  3 mm, P < 0.001) (Table 1).
There were significant positive correlations between the total
score of intrinsic skin aging and the presence of mitral annular calcifi-
cation (r = 0.355, P = 0.001), the presence of aortic sclerosis
(r = 0.308, P = 0.002), smoking (r = 0.381, P = 0.007), and ages of
the patients in group D (r = 0.675, P < 0.001 (Figure 1).
ROC analysis of the measured parameters of intrinsic skin aging
score revealed that a total score > 6 was the best cutoff value to pre-
dict the presence of advanced-degree heart block with 89.79% sensi-
tivity and 64.58% specificity (area under the curve = 0.838%,
P < 0.001) (Figure 2).
Stepwise regression analysis revealed that seborrheic keratosis
was the strongest independent factor that predicts the development
of advanced-degree AV block, with regression coefficient of 0.658
(P < 0.001). Mitral annular calcification, fine skin wrinkles, the age of
the patient, and uneven pigmentation were cofactors that predict
such problems, with a regression coefficient of 0.828 (P = 0.009).

TABLE 1 Demographic and echocardiographic data of the study

groups
Variables Group D, n = 49 Group C, n = 48 P Value TABLE 2 Skin parameters in the study groups
Age, y, mean  SD 69.02  9.04 68.96  8.64 0.92 Group D, Group C,
50–<60 n (%) 9 (18.4%) 8 (16.3%) 0.808 Variables n = 49 n = 48 P Value

60–<70 n (%) 16 (32.7%) 16 (32.7%) 1.00 Uneven pigmentation 28 (57.14%) 10 (20.83%) <0.001

70–<80 n (%) 16 (32.7%) 16 (32.7%) 1.00 Fine skin wrinkles <0.001

≥80 n (%) 8 (16.3%) 8 (16.3%) 1.00 3 24 (48.98%) 9 (18.75%)

Gender, m/f, n (%) 15/34 21/27 0.18 2 22 (44.90%) 19 (39.58%)

(30.6%/ (43.7%/ 1 3 (6.12%) 16 (33.33%)
69.4%) 56.3%)
0 0 (0.00%) 4 (8.34%)
Smoking, n (%) 15 (30.60 %) 07 (14.58 %) 0.059
Lax appearance <0.001
Hypertension, n (%) 24 (48.98 %) 16 (33.33%) 0.118
3 14 (28.57%) 3 (6.25%)
Diabetes mellitus, n (%) 15 (30.61 %) 20 (41.67%) 0.257
2 30 (61.23%) 25 (52.08%)
LVEDD, mm, mean  SD 52.33  5.19 52.35  5.24 0.979
1 5 (10.20%) 20 (42.67%)
LVESD, mm, mean  SD 34.55  4.65 34.63  4.67 0.938
0 0 0
EF, %, mean  SD 61.57  7.46 61.4  7.44 0.908
Seborrheic keratosis <0.001
IVS, mm, mean  SD 9.63  0.88 9.6  0.96 0.879
3 1 (2.04%) 0 (0.00%)
LA diameter, 39.98  5.52 36.21  3 <0.001
2 4 (8.16%) 0 (0.00%)
mm, mean  SD
1 39 (79.60%) 10 (20.50%)
Aortic diameter, 30.78  1.54 30.73  1.57 0.884
mm, mean  SD 0 5 (10.20%) 38 (79.50%)
Median of total score = 7 <0.001
Abbreviations: EF, ejection fraction; f, female; IVS, interventricular sep-
tum; LA, left atrium; LVEDD, left ventricular end diastolic diameter; >Median 38 (77.55%) 10 (20.83%)
LVESD, left ventricular end systolic diameter; m, male; SD, standard devi-
≤Median 11 (22.46%) 38 (79.17%)
ation; y, years.
54
FIGURE 1 Correlation between the ages of patients in group D and
the total score of intrinsic skin aging
FIGURE 2 Receiver operating characteristic (ROC) curve of the total
score of intrinsic skin aging
4 | DISCUSSION
Advanced degrees of AV block can cause sudden cardiac death.12
Early prediction of this problem can help in decreasing mortality.
Degenerative AV block is 1 of the degenerative diseases of the heart
13
associated with the aging process. Using skin as a mirror of the
heart can offer a noninvasive tool for early prediction of different
pathological problems.14 Mild cyanosis of the lips, cheeks, and malar
prominences, without clubbing of the fingers, is often seen in patients
15
with mitral stenosis. Can we use skin parameters to predict the
presence of heart block as we have used mitral facies to suspect the
presence of mitral stenosis? To the best of our knowledge, we are
the first to study the association between simple intrinsic skin aging
parameters, as they may better reflect the natural age of the body
and the heart tissues and degenerative advanced-degree AV block.
ROSHDY ET AL.
Carotid atherosclerosis is related to perceived age (associated with
higher degrees of facial pigmentation), and may be a better predictor of
mortality than chronological age.16 In our study, uneven pigmentation
was higher in those with advanced-degree heart block; the grades of
fine skin wrinkles were significantly higher in heart block group.
Our skin becomes stiff, thin, and flabby, with the development of
more wrinkles with advanced age, and all are related to fibrosis of the
skin, as elastic fibers are injured and collagen fibers are broken with the
passage of time. New collagen fibers are produced to replace broken
elastic fibers and broken collagen fibers.17 Tissue fibrosis due to pro-
gressive deposition of excessive collagen fibers has been observed in
most organs with aging, especially the heart. This results in hardening
and atrophy of that organ, secondary to loss of parenchyma cells and
the increase of collagen substance in tissues. Essential arterial hyperten-
sion, sinus node dysfunction, and degenerative AV block are examples
of cardiac complications that are caused by tissue fibrosis.18,19 In our
study, the grades of the lax appearance of the face and reduced fat tis-
sue, prevalence of seborrheic keratosis, and the total score of intrinsic
skin aging were significantly higher in the group of heart block. The best
cutoff value to predict advanced-degree heart block was 6.
The association between intrinsic skin aging and degenerative
advanced-degree AV block could be explained by the pathogenesis
background that may be incriminated in the development of both disor-
ders. Extensive evidence, derived from both clinical and experimental
studies, suggests that the aging heart undergoes fibrotic remodeling.
Advanced glycation end products (AGEs), which are developed by the
glycation and oxidation of different structural proteins, and play an
important role in age-dependent changes, were described in skin aging
and in organs such as the kidney, blood vessels, and the eye lenses.20–22
AGEs are important factors for assessing cardiac aging and fibrosis.23,24
Diminished expression of connective tissue growth factor (CTGF)
is responsible for the progressive loss of dermal collagen.25 There are
positive correlations between the levels of CTGF and cardiovascular
fibrotic diseases in the elderly population. Degenerative AV block is
1 of the diseases where fibrosis is a main pathological cause.26,27
We found that there was significant positive correlation between
the total skin aging score and the age, which is in agreement with
Farage et al.1 and Vierkötter et al.,4 and also with smoking in concor-
dance with Morita,28 who concluded that smoking is a risk factor of
premature skin aging. The total score of intrinsic skin aging had signif-
icant positive correlation with the presence of both aortic sclerosis
and mitral annular calcification, which were significantly higher in
those with advanced-degree AV block, in concordance with Nair
et al.6 The LA diameter had significant positive correlation with mitral
annular calcification, both of which were higher in the group of
advanced-degree AV block, which is in agreement with Abuelenin.29
Our study revealed that seborrheic keratosis was the strongest
independent predictor for the development of advanced-degree AV
block. Silver30 and Teraki et al31 stated that seborrheic keratosis is
the best biomarker of intrinsic skin aging.
4.1 | Study limitations
The study was retrospective study, so the ability of the score to pre-
dict the development of advanced-degree AV block is questionable.
ROSHDY ET AL.
The results were obtained from a single medical center. We did not
study extrinsic skin aging, which may be of added value. The cardiolo-
gist may be unable to adequately classify signs of intrinsic skin aging,
but the presence of seborrheic keratosis may be an ominous sign of
advanced-degree of AV block.
5 | CO NC LUSIO N
Our study confirms that anyone with a total intrinsic skin aging score
of more than 6 is at high risk for developing advanced-degree AV
block and should undergo periodic ECG follow-up for early detection
of any conduction disturbance in the early asymptomatic stages to
minimize sudden cardiac death. We advocate using mitral annular cal-
cification and aortic sclerosis as copredictors for the development of
advanced-degree AV block. A future prospective cohort study to test
the validity of the intrinsic skin aging score, mitral annular calcifica-
tion, and aortic sclerosis to predict the development of degenerative
advanced-degree AV block should be conducted. A future prospec-
tive cohort study to test the validity of extrinsic skin aging parame-
ters to ascertain if there is a relation to cardiac problems should also
be conducted, as well as training of cardiologists to recognize these
simple skin signs.
Acknowledgments
The authors thank all of their colleagues who helped them to fulfill
this work.
Conflicts of interest
The authors declare no potential conflicts of interest.
ORCID
Hisham Samir Roshdy http://orcid.org/0000-0002-0470-6065
Ibtesam Ibrahim El-Dosouky http://orcid.org/0000-0003-
4385-5458
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