Title
Beta adrenergic receptor blockers reduce the occurrence ofkeloids and hypertrophic scars after cardiac deviceimplantation: a single-institution case-control study(Dissertation_全文 )
Author(s) Enoshiri, Tatsuki
Citation 京都大学
Issue Date 2017-09-25
URL https://doi.org/10.14989/doctor.r13126
Right 許諾条件により本文は2018-05-13に公開; DOI:10.1097/PRS.0000000000003239
Type Thesis or Dissertation
Textversion ETD
Kyoto University
1
Plastic and Reconstructive Surgery Advance Online Article
DOI: 10.1097/PRS.0000000000003239
Beta adrenergic receptor blockers reduce the occurrence of keloids and
hypertrophic scars after cardiac device implantation: a single-institution
case-control study
Tatsuki Enoshiri, M.D. 1
Motoko Naitoh, M.D., Ph.D. 1
Satoko Yamawaki, M.D. 2
Atsushi Kawaguchi, Ph.D. 3
Rino Aya, M.D., Ph.D. 1
Kazuo Noda, M.D., Ph.D. 1
Yasuhiro Katayama, M.D. 1
Takahiro Doi, M.D., Ph.D. 4
Tetsuma Kawaji, M.D. 4
Shigehiko Suzuki, M.D., Ph.D. 1
1. Department of Plastic and Reconstructive Surgery, Graduate School of Medicine,
Kyoto University, Kyoto, Japan
2. Department of Plastic and Reconstructive Surgery, Fukui Red Cross Hospital, Fukui,
Japan
3. Section of Clinical Cooperation System, Center for Comprehensive Community
Medicine, Faculty of Medicine, Saga University, Saga, Japan
4. Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto
University, Kyoto, Japan
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Short running head
The first observational study by which the putative association between beta blocker
administration and reduced keloid or hypertrophic scar formation has been investigated
Correspondence to:
Tatsuki Enoshiri, M.D.
Department of Plastic and Reconstructive Surgery, Graduate school of Medicine, Kyoto
University, 54 Shogoin kawahara-cho, sakyou-ku, Kyoto, 606-8507, Japan
Fax: +81-75-751-4340. Tel: +81-75-751-3613
E-mail: [email protected]
Disclosure
All authors have no financial interest to declare in relation to the content of this article.
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INTRODUCTION
Keloids and hypertrophic scars typically result from an abnormal tissue response to
dermal injuries, and both are characterized by excessive proliferation of fibroblasts and
abnormal accumulation of extracellular matrix [1]. Both of these abnormal scars present
clinically as raised, red, itchy, and sometimes painful lesions. The two scar types differ
in that keloids, but not hypertrophic scars, extend beyond the margins of the original
wound and usually recur after surgical excision alone. Moreover, hypertrophic scars
usually disappear spontaneously within a few years, whereas keloids almost never
disappear [2] [3]. A number of methods to treat keloids have been devised. They include
the internal use of tranilast, intralesional steroid injection, compression with silicone
sheeting, and postsurgical irradiation. However, none of these interventions, either alone
or in combination, are sufficiently effective for keloids [4] [5] [6] [7].
Implantable cardiac devices such as artificial cardiac pacemaker (PM),
implantable cardioverter defibrillator (ICD), and cardiac resynchronization
therapy-pacemaker or -defibrillator (CRT-P or CRT-D, respectively) are used widely to
treat severe arrhythmia or heart failure [8]. Each device is usually implanted
subcutaneously around the sub-clavicular area. Some of these patients develop keloids
or hypertrophic scars at the incisions used for implantation [9] [10].
In the keloid outpatient clinic in our department, we became aware that patients
who had been administered β adrenergic receptor blockers (β blockers) tended to have
better postoperative scar formation than those who had not. Therefore, since studies on
the effect of β blockers on scar formation have not yet been reported, the present
case-control study was performed. In this study, patients with abnormal scars after
implantation of cardiac devices were compared with patients with normal scars in terms
of the frequency of β blocker treatment. Our hypothesis was that the patients with
abnormal scars would be less likely to be treated with β blockers than the controls with
normal scars.
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METHODS
Study design
This case-control study was conducted with the approval of the Ethics Review Board of
Kyoto University Graduate School of Medicine, Kyoto, Japan (approval number,
E2448). Informed consent to participate in the study was obtained from all patients
before the study commenced. The study was conducted according to the principles of
the Declaration of Helsinki.
Patient selection
Patients who had undergone implantation with PM, ICD, CRT-P, or CRT-D in Kyoto
University Hospital 7–23 months previously and went to the outpatient clinic of the
Department of Cardiovascular Medicine of the hospital for routine follow-up were
approached in May–October 2015 by plastic surgeons. The patients were not
consecutively enrolled because the plastic surgeons were not present at all hours in the
cardiology outpatient clinic. The implantations included both primary and exchange
operations. Patients were excluded if they had developed an infection at the
implantation incision site, had been administered β adrenergic receptor agonists after
device implantation, or refused or were unable to give consent. We also excluded
patients with a past history or family history of abnormal scars because there was a
greater likelihood they had undergone abnormal scar treatments, such as with
corticosteroids, Tranilast, or excisional surgery, than patients without such scars.
The eligible patients were divided into two groups: the cases, who had developed
abnormal scars at the implantation incision, and the controls, whose scars were normal.
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Primary and secondary study outcomes
The primary outcome was the rate of β blocker administration in the case and control
groups. β blocker administration was defined as treatment with β blockers that started
either before implantation or just after the date of implantation and continued until the
scars were scored with the Kyoto Scar Scale in the present study. The patients in the
non- β blocker group did not use a β blocker during the postoperative period. The β
blockers that were used by the patients in the present study were Carvedilol, Bisoprolol,
or Atenolol. The secondary outcome was the rate of antihypertensive medication
(calcium channel blockers, angiotensin-converting enzyme (ACE) inhibitors, and
angiotensin receptor blockers) in the two groups. This secondary outcome was selected
because there is some evidence that hypertension promotes keloid development [11] and
that antihypertensive treatments can reduce the progression of keloids [12] [13].
Implantation procedure
All patients underwent device implantation by cardiologists under general anesthesia in
the same manner: the devices were implanted subcutaneously around the sub-clavicular
area, after which the fat and dermal layers were sutured with 4-0 or 5-0 PDS II
absorbable surgical sutures (ETHICON, Somerville, New Jersey, USA).
Study protocol
After patients provided informed consent, their post-implantation scars were
photographed by a digital camera and the dimensions were measured (Fig. 1). The
patients were then asked about the subjective symptoms of the scars and their personal
and family histories of keloids or hypertrophic scars. Other clinical information was
collected from the medical records, including the primary disease that required cardiac
device implantation, the medications received before and during the study period, the
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blood pressure at the time of hospitalization and discharge and before and after
implantation surgery, and comorbidities.
Identification of abnormal and normal post-implantation incision scars
The Kyoto Scar Scale measures three objective symptoms, namely, redness, hardness,
and elevation, and two subjective symptoms, namely, itching and pain (Table 1). The
scores of the five symptoms are added together to yield the total score (Table 2) [2]. In
this study, three board-certified plastic surgeons who were blinded to patient details
assessed the digital photographs of the scars and diagnosed them as abnormal or normal
using one element of the Kyoto Scar Scale, namely, redness. This was because this is a
variable that can be measured objectively on the basis of photographs. In the present
study, all partially or totally red scars were deemed to be abnormal scars. All scars that
lacked redness were considered to be normal scars. If the judgements of the three
surgeons were not the same, the final diagnosis was based on the decision of the
majority. The patients were then divided into the abnormal and normal scar groups on
this basis. In addition, the total Kyoto Scar Scale score was calculated on the basis of all
objective and subjective symptoms, as reported by the patients when they visited the
clinic.
Classification of blood pressure
The blood pressure measurements at the time of hospitalization and discharge and
before and after implantation surgery were averaged and classified as optimal, normal,
high-normal, or grade I, II, or III hypertension on the basis of Japanese Society of
Hypertension (JSH) guidelines 2014 (Table 3).
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Statistical analyses
Continuous variables were expressed as mean±standard deviation if the distribution was
normal or as median (range) if the distribution was skewed. Categorical variables were
expressed as n (%). The abnormal scar cases and normal scar controls were compared in
terms of continuous variables (age, postoperative period, scar length, mean blood
pressure, and total Kyoto Scar Scale scores) using Wilcoxon rank sum test, and
categorical variables (sex, type of β blocker, number of implantation surgeries, type of
cardiac device, and use of hypertensive medication) using Fisher’s exact test. The cases
and controls were also compared in terms of the frequency of β blocker administration
using univariate and multivariate logistic regression, which yielded odds ratios (OR)
and 95% confidence intervals (CI). The multivariate logistic regression was adjusted for
age. All statistical analyses were performed using JMP Pro statistical software version
12 (SAS institute Inc., Cary, North Carolina, USA). Statistical significance was set at
p<0.05.
RESULTS
Subjects
Sixty patients were identified during the study period. Of these, 15 were excluded
because they had developed an infection at the implantation incision site after surgery
(n=1), they had a personal (n=9) or family (n=2) history of keloids or hypertrophic scars,
or they had been administered β adrenergic receptor agonists after device implantation
(n=3). The remaining 45 patients were included in this study. Of those, 12 had abnormal
scars, as defined by three plastic surgeons on the basis of scar redness. Thus, the study
consisted of 12 cases and 33 controls (Fig. 2).
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Characteristics of the case and control patients
Comparison of the case and control groups in terms of their demographic, clinical, and
scar characteristics showed that the cases were significantly younger in terms of age at
scar diagnosis (67.5±10.0 vs. 78.3±10.2 years; p=0.0020). The two groups did not differ
in terms of gender distribution, time since implantation, frequency with which PM, ICD,
or CRT-P/CRT-D were implanted, or mean scar length (Table 4). All implantation
surgeries were performed by one of five surgeons. The cases and controls did not differ
in terms of the frequencies with which each surgeon performed the surgery (data not
shown). They also did not differ in terms of the frequency of the two main primary
diseases that required cardiac device implantation, namely, atrio-ventricular block and
sick sinus syndrome. The two groups also did not differ significantly in terms of
representative comorbidities, namely, malignancy and diabetes mellitus (Table 4).
Various other complications, such as dyslipidemia, angina pectoris, respiratory disease,
and renal dysfunction, occurred in the two groups at similar frequencies (data not
shown). As expected, the cases had a significantly higher mean total Kyoto Scar Scale
score than the controls (2.50±1.78 vs. 0.03±0.17; p<0.001) (Table 4).
The case and control groups did not differ significantly in terms of the
frequency with which the β blocker was Carvedilol, Bisoprolol, or Atenolol (Table 5).
They also did not differ in terms of the frequency of patients who underwent cardiac
device implantation for the first time (50% vs. 72.7%) or the second, third, or fourth
time. The mean number of operations for the two groups was 1.92±1.08 and 1.42±0.75,
respectively (Table 6).
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Primary study outcome: frequencies of β blocker use
Overall postoperative period
The patients with abnormal scars tended to take β blockers less often than the controls
(25.0% vs. 45.5%), but this difference did not achieve statistical significance on
univariate logistic regression (OR=0.40; 95% CI=0.08–1.62; p=0.2058) or multivariate
logistic regression adjusted for age (OR=0.43; 95% CI=0.07–2.06; p=0.2992) (Table 7).
To assess whether the widely ranging duration after implantation (7–23
months) limited our ability to detect an association between abnormal scarring and low
use of β blockers, we performed the same analysis with our patients using narrower
durations after implantation.
Scar diagnosis 8–23, 9–23, 10–23, 11–23, or 12–23 months after device implantation
In 10 cases and 29 controls, the scars were diagnosed 8–23 months after implantation.
Of these, 1 (10.0%) and 13 (44.8%) took β blockers and this difference achieved
statistical significance on univariate logistic regression (OR=0.14; 95% CI=0.01–0.87;
p=0.0334) and multivariate logistic regression adjusted for age (OR=0.10; 95%
CI=0.000.83; p=0.0309). Similarly, in 9 cases and 29 controls, the scars were diagnosed
9–23 months after implantation. Of these, 1 (11.1%) and 13 (44.8%) took β blockers,
respectively. This difference also achieved statistical significance on univariate logistic
regression (OR=0.15; 95% CI=0.01–1.00; p=0.0499) and multivariate logistic
regression adjusted for age (OR=0.11; 95% CI=0.00–0.98; p=0.047).
These associations were no longer observed in patients whose scars were
diagnosed 10–23, 11–23, or 12–23 months after implantation, even though, in each
comparison, only one case took β blockers, whereas nearly half of the controls took β
blockers (Table 8).
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Secondary study outcome: frequencies of antihypertensive medication use
The two groups did not differ in terms of mean systolic blood pressure (125.2±6.6 vs.
125.6±15.3), but the abnormal scar patients had significantly lower diastolic blood
pressure (66.4±8.1 vs. 69.3±10.1; p=0.048). Neither group had patients with grade II or
III hypertension. The two groups did not differ significantly in terms of the frequency of
patients with optimal/normal blood pressure, high-normal blood pressure, or grade I
hypertension (Table 9). The two groups also did not differ in the frequency with which
they received calcium channel blockers and/or angiotensin receptor blockers, or ACE
inhibitors (Table 10).
DISCUSSION
To our knowledge, this is the first time the putative association between β blocker
administration and reduced keloid or hypertrophic scar formation has been investigated
by an observational study. Our results support the hypothesis that β blockers could
prevent or ameliorate keloids and hypertrophic scars after surgery: the patients who had
keloids or hypertrophic scars after cardiac device implantation tended to be less likely to
take β blockers than the control patients with normal scars. This difference achieved
statistical significance in patients whose scars were diagnosed 8–23 or 9–23 months
after surgery.
β blockers are classified into three subtypes on the basis of the adrenergic
receptor that they inhibit, namely, β1, β2, or β3. The β1 receptor mainly affects cardiac
function: it increases the power of myocardial contraction and cardiac output when it is
stimulated. When the β2 receptor is stimulated, it induces vasodilation of the peripheral
artery and bronchodilation. The β3 receptor relates to fat metabolism: when it is
stimulated, brown adipocytes combust free fatty acids [14]. Beta blockers antagonize
these effects. At present, β1 and β 2 adrenergic receptor antagonists are used clinically
as βblockers.
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Although β blockers are primarily used to manage cardiac arrhythmias and
angina pectoris, other indications have also arisen. Of particular interest for the present
study, Léauté-Labrèze et al. first reported in 2008 that the non-selective βblocker
propranolol improved infantile hemangiomas in their case series [15]. Thereafter, many
case studies showed that propranolol or other βblockers effectively treat infantile
hemangiomas [16] [17] [18]. This effect may relate to the fact that vasodilation and
vascular endothelial proliferation play an important role in vascular tumor growth.
These phenomena are promoted by β adrenergic receptor stimulation as it induces nitric
oxide synthesis by the vascular endothelium and therefore promotes vasodilation; it also
activates proangiogenic factors such as vascular endothelial cell growth factor (VEGF),
which induces vascular endothelial proliferation. βblockers are surmised to inhibit
infantile hemangioma proliferation by blocking these effects [19] [20].
These observations are pertinent for keloids because, like vascular tumors, the
fibroblasts in keloid lesions produce abundant amounts of VEGF [21] [22]. In addition,
Salem et al. reported that, when keloids are treated by intralesional steroid injection, the
VEGF levels in the lesions drop [23]. Thus, βblockers could theoretically prevent the
development or progression of keloids by suppressing their VEGF production. It is also
possible that βblockers inhibit keloid cell proliferation because β adrenergic receptor
stimulation activates extracellular signal-related kinase, which inhibits apoptosis and/or
accelerates inflammatory cell migration and cell proliferation [24] [25] [26].
In the present study, the patients received three types of βblockers, namely,
Carvedilol, Bisoprolol, and Atenolol. Carvedilol is an α-β adrenergic receptor blocker
that antagonizes β1 and β2 at a β1: β2 blocking ratio of 7:1 [27]. Both Bisoprolol and
Atenolol are selective β1 blockers with β1: β2 blocking ratios of 75:1 and 35:1,
respectively [28]. In the present study, the cases and controls did not differ in the
frequencies with which they were treated with the three βblocker types. Thus, the effect
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of βblockers on keloid development that we observed could not be attributed to a
specific βblocker.
We diagnosed the scars of our patients between 7 and 23 months after the
implantation. The most ideal time point for this diagnosis would have been 1 year after
surgery because even healthy scars can take up to 12 months to mature; moreover,
diagnosing scars much later may fail to detect hypertrophic scars, as these scars tend to
improve after several years [29]. Indeed, we found that the difference between the case
and control groups in terms of βblocker administration frequency only became
statistically significant when the postoperative duration range was 1–2 years after
cardiac device implantation. This may reflect the fact that the scars were generally
diagnosed at the appropriate time in those patient subgroups.
We assumed that multiple implantations at the same site of the body may
worsen the scar condition. However, the cases and controls did not differ significantly in
terms of the number of operations.
In this study, the controls had significantly higher mean diastolic blood
pressure than the cases. However, differences in systolic blood pressure or the frequency
of optimal/normal and high-normal blood pressure or grade I hypertension were not
observed. Arima et al. proposed that hypertension may be an aggravating factor for
keloids in their retrospective case series [11]. The discrepancy between our study and
theirs may reflect several differences between the studies. First, Arima et al. examined
patients who had true keloids, whereas we divided our participants into cases and
controls on the basis of scar redness alone. Thus, both keloids and hypertrophic scars
were included in our cases. Second, severe keloid cases may have been excluded from
our cohort because our exclusion criteria included a past history of abnormal scars.
Third, because all of our patients had severe cardiac disorders, their blood pressure was
being strictly managed by cardiologists at the time of the study. This may explain, at
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least in part, why the cases and controls did not differ markedly in terms of the
distribution of their blood pressures.
Several studies suggest that antihypertensive agents may influence wound
healing. First, the meta-analysis of Wang et al. concluded that verapamil, which is a
calcium channel blocker, can improve keloids and hypertrophic scars [12]. Moreover,
ACE and angiotensin II (Ang II) mediate adverse remodeling and fibrosis in diverse
organs such as cardiac muscle [30], kidney [31], and lung [32]. Notably, a recent study
showed that keloids and hypertrophic scars also have significantly higher ACE activities
than normal skin and normal wounds. They also express the Ang II type 1 (AT1)
receptor, which mediates the proliferation of various cells. Thus, ACE inhibitors and
AT1 receptor blockers may be able to prevent abnormal scar formation [13]. However,
our cases and controls did not differ significantly in terms of the use of calcium channel
blockers, ACE inhibitors, or AT1 receptor blockers. This suggests that, at least in our
study population, abnormal scar development did not associate with higher frequencies
of antihypertensive medication use.
This study has several limitations. First, it was a single-center case-control
study. The inherent tendency of case-control studies to selection bias may also have
been enhanced by the fact that the patients were not consecutively enrolled. However,
the fact that the cases and controls did not differ in terms of demographic and clinical
variables except age (which was employed as a confounding variable in the multivariate
analyses) may mitigate this possible bias. Second, the sample size was small. As a result,
the study may not have had sufficient power to clearly detect differences between the
cases and controls in terms of the βblocker administration rate. Third, the time after
implantation when the scars were diagnosed ranged rather widely (7–23 months).
However, it was not feasible to set the postoperative period more narrowly as this would
have strongly affected the sample size.
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CONCLUSION
Beta adrenergic receptor blockers may be an effective alternative modality for
preventing and treating keloids and hypertrophic scars. Large-scale prospective
multi-center studies that use histology to diagnose abnormal scarring and diagnose the
postoperative scars at the most suitable period are needed to confirm the effectiveness
of β blockers for keloids and hypertrophic scars.
ACKNOWLEDGMENTS
We appreciate Dr. Katsuhiro Yoshikawa, Dr. Kentaro Ueki, Dr. Kazuhiko Maeda, and
Dr. Yoshitaka Tanaka for help in interviewing the patients. We also wish to thank Ms.
Yoriko Suita for patient recruitment.
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FIGURE LEGENDS
Fig 1. Representative scars of the case (a and b) and control (c and d) patients.
(a) Patient no. 23. An 83-year-old man. Twenty-two months after his second cardiac
resynchronization therapy defibrillator implantation, all three plastic surgeons
diagnosed his scar as a red abnormal scar. The total Kyoto Scar Scale score was 5 (poor).
He had not taken β blockers after surgery. (b) Patient no. 46. A 68-year-old man.
Nineteen months after his first pacemaker implantation, all three plastic surgeons
diagnosed his scar as an abnormal scar. The total Kyoto Scar Scale score was 6 (poor).
He had not taken β blockers after surgery. (c) Patient no. 45. A 68-year-old woman.
Twelve months after her first cardiac resynchronization therapy defibrillator
implantation, all three plastic surgeons diagnosed the scar as a normal scar. The total
Kyoto Scar Scale score was 0 (excellent). She had been taking Carvedilol 5 mg/day
since implantation. (d) Patient no. 52. A 77-year-old woman. Ten months after her first
pacemaker implantation, all three plastic surgeons diagnosed the scar as a normal scar.
The total Kyoto Scar Scale score was 0 (excellent). She had been taking Bisoprolol 2.5
mg/day since implantation.
Fig 2. Flow diagram of subject enrollment.
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Table 1. The Kyoto Scar Scale that is used to score scars according to their
objective and subjective symptoms
Objective symptom Score
Redness
None 0
Partial 1
Whole 2
Hardness
None 0
Partial 1
Whole 2
Elevation
None 0
Partial 1
Whole 2
Subjective symptom Score
Itching
None 0
Any 1
Pain
None 0
Any 1
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Table 2. Total Kyoto Scar Scale scores
Score Evaluation
0 Excellent
1, 2 Good
3 Fair
4−8 Poor
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Table 3. Blood pressure classification in the Japanese Society of Hypertension
(JSH) guidelines 2014
Classification Blood pressure value
Optimal BP SBP < 120 and DBP < 80
Normal BP SBP = 120−129 and/or DBP = 80−84
High-normal BP SBP = 130–139 and/or DBP = 85−89
Grade I HT SBP = 140−159 and/or DBP = 90−99
Grade II HT SBP = 160−179 and/or DBP = 100−109
Grade III HT SBP > 180 and/or DBP >110
BP: blood pressure; DBP: diastolic blood pressure; HT: hypertension; SBP: systolic
blood pressure.
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Table 4. Demographic and clinical characteristics of the case and control groups
Characteristics Cases, n=12 Controls n=33 p-value
Male gender, n (%) 7 (58.3%) 16 (48.5%) 0.7381 (F)
Age, years, mean±SD
[median; range]
67.5±10.0
[68.5; 48−83]
78.3±10.2
[78.0; 45−95]
0.0020* (W)
Postoperative period, months, mean±SD
[median; range]
13.5±5.25
[13; 7−22]
14.9±4.99
[14; 7−23]
0.4100 (W)
PM, n (%) 9 (75.0%) 27 (81.8%) 0.6818 (F)
ICD, n (%) 2 (16.7%) 0 (0%) 0.0667 (F)
CRT-P or CRT-D, n (%) 1 (8.3%) 6 (18.2%) 0.6548 (F)
Primary disease
AVB 3 (25%) 14 (42.4%) 0.4880 (F)
SSS 3 (25%) 12 (36.4%) 0.7222 (F)
DCM 0 (0%) 3 (9.1%) NA
Brugada 2 (16.7%) 0 (0%) NA
VT 1 (8.3%) 1 (3.0%) NA
AF 1 (8.3%) 1 (3.0%) NA
AT 1(8.3%) 0 (0%) NA
CLBBB 1 (8.3%) 0 (0%) NA
HOCM 0 (0%) 1 (3.0%) NA
BTS 0 (0%) 1 (3.0%) NA
Comorbidities
Malignancy 2 (16.7%) 7 (21.2%) 1.0000 (F)
DM 5 (41.7%) 5 (15.2%) 0.1012(F)
Scar length, cm, mean±SD
[median; range]
4.42±0.60
[4.35; 3.8−6.0]
5.00±1.21
[5.00; 2.1−8.0]
0.1193 (W)
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Total Kyoto Scar Scale score, mean±SD
[median; range]
2.50±1.78
[2; 1−6]
0.03±0.17
[0; 0−1]
<0.001* (W)
AF: Atrial fibrillation; AT: Atrial tachycardia; AVB: Atrio-ventricular block; BTS:
Bradycardia-tachycardia syndrome; Brugada: Brugada syndrome; CLBBB: Complete
left bundle branch block; CRT-P or CRT-D: Cardiac resynchronization
therapy-pacemaker or -defibrillator; DCM: Dilated cardiomyopathy; DM: Diabetes
mellitus; HOCM: Hypertrophic obstructive cardiomyopathy; ICD: Implantable
cardioverter defibrillator; PM: Artificial cardiac pacemaker; SD: Standard deviation;
SSS: Sick sinus syndrome.
The p-values were determined by Fisher’s exact test (F) or Wilcoxon rank sum test (W).
*, statistically significant difference.
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Table 5. Frequency of use of specific � blockers by the cases and controls
Cases, n=12 Controls, n=33 OR (95% CI) p-value
Carvedilol 1 (8.3%) 6 (18.2%) 0.41 (0.04−3.80) 0.6548
Bisoprolol 1 (8.3%) 8 (24.2%) 0.28 (0.03−2.55) 0.4069
Atenolol 1 (8.3%) 1 (3.0%) 2.91 (0.17−50.55) 0.4667
The data are shown as n (%) unless otherwise indicated.
The p-values were determined using Fisher’s exact test.
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Table 6. Number of implantation surgeries in the cases and controls
Cases, n=12 Controls, n=33 p-value
First operation 6 (50%) 24 (72.7%) 0.1736 (F)
Multiple operations 6 (50%) 9 (27.3%) 0.1736 (F)
Second operation 2 (16.7%) 4 (12.1%) NA
Third operation 3 (25%) 5 (15.2%) NA
Fourth operation 1 (8.3%) 0 (0%) NA
No. of operations, mean±SD
[median; range]
1.92±1.08
[1.5; 1−4]
1.42±0.75
[1; 1−3]
0.1240 (W)
The data are expressed as n (%) unless otherwise indicated.
SD, standard deviation.
The p-values were determined by Fisher’s exact test (F) or Wilcoxon rank sum test (W).
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Table 7. Rates of � blocker administration in the cases and controls who underwent
implantation 7–23 months previously
Cases,
n=12
Controls,
n=33
Total,
n=45
OR
(Adjusted
for age)
95% CI
(Adjusted for
age)
p-value
(Adjusted
for age)
Received β
blocker
3 (25.0%) 15 (45.5%) 18
(40.0%)
0.40
(0.43)
0.08−1.62
(0.07−2.06)
0.2058
(0.2992)
Did not
receive β
blocker
9 (75.0%) 18 (54.5%) 27
(60.0%)
2.50
(2.33)
0.62−12.82
(0.48−14.31)
0.2058
(0.2992)
Total n 12 33 45
The data are expressed as n (%) unless otherwise indicated.
CI: Confidence interval; OR: Unadjusted odds ratio.
The p-values were determined using unadjusted logistic regression analysis and
multivariate logistic regression analysis adjusted for age.
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Table 8. Unadjusted logistic regression analysis of the rates of � blocker
administration in the cases and controls who underwent implantation 8–23, 9–23,
10–23, 11–23, and 12–23 months previously
Postoperative
period (mos.)
Cases who took β
blocker, n (%)
Controls who took
β blocker, n (%)
OR 95% CI p-value
8−23 1 (10.0%) 10 13 (44.8%) 29 0.14 0.01−0.87 0.0334*
9−23 1 (11.1%) 9 13 (44.8%) 29 0.15 0.01−1.00 0.0499*
10−23 1 (12.5%) 8 13 (46.4%) 28 0.16 0.01−1.10 0.0647
11−23 1 (12.5%) 8 12 (48.0%) 25 0.15 0.01−1.06 0.0576
12−23 1 (14.3%) 7 11 (45.8%) 24 0.20 0.01−1.40 0.1114
CI: Confidence interval; OR: Unadjusted odds ratio.
*Statistically significant odds ratio.
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Table 9. Blood pressure measurements of the cases and controls
BP measurement Cases, n=12 Controls, n=33 p-value
SBP, mgHg, mean±SD
[median; range] 125.2±6.6 [123; 116−133] 125.6±15.3 [129; 75−148]
0.68
DBP, mgHg, mean±SD
[median; range] 66.4±8.1 [65.5; 53−84] 69.3±10.1 [68; 49−88]
0.048*
Optimal/normal BP, n (%) 6 (50%) 17 (51.5%) 1.00
High-normal BP, n (%) 6 (50%) 11 (33.3%) 0.32
Grade I HT, n (%) 0 (0%) 5 (15.2%) 0.30
The p-values were determined using Wilcoxon rank sum test. *, statistically significant
differences.
BP: blood pressure; DBP: diastolic blood pressure; HT, hypertension; SBP: systolic
blood pressure.
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Table 10. Rates of antihypertensive medication use by the cases and controls
Antihypertensive
medication Cases, n=12 Controls, n=33
P-value
CCB 6 (50%) 15 (45.5%) 1.00
ACEI 1 (8.3%) 2 (6.1%) 1.00
ARB 5 (41.7%) 10 (30.3%) 0.50
CCB+ARB 4 (33.3%) 6 (18.2%) 0.42
No medication 4 (33.3%) 12 (36.4%) 1.00
The data are shown as n (%).
The p-values were determined using Fisher’s exact test.
ACEI: angiotensin-converting enzyme inhibitor; ARB: angiotensin receptor blocker;
CCB: calcium channel blocker.
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Figure 1
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Figure 2
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