Beta adrenergic receptor blockers reduce the occurrence of ......administration and reduced keloid or hypertrophic scar formation has been investigated Correspondence to: Tatsuki Enoshiri,

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

Copyright © American Society of Plastic Surgeons. All rights reserved.

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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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REFERENCES

1. Hu ZC, Tang B, Guo D, Zhang J, Liang YY, Ma D, et al. Expression of insulin-like

growth factor-1 receptor in keloid and hypertrophic scar. Clin Exp Dermatol. 2014

Oct;39(7):822-8.

2. Satoko Yamawaki, Motoko Naotoh, Toshihiro Ishiko, Gan Muneuchi, Shigehiko

Suzuki. Keloids can be forced into remission with surgical excision and radiation,

followed by adjuvant therapy. Ann Plast Surg. 2011 Oct;67(4):402-6.

3. Durani P, Bayat A. Levels of evidence for the treatment of keloid disease. J Plast

Reconstr Aesthet Surg. 2008;61(1):4-17.

4. Monstrey S, Middelkoop E, Vranckx JJ, Bassetto F, Ziegler UE, Meaume S, et al.

Updated scar management practical guidelines: non-invasive and invasive measures.

J Plast Reconstr Aesthet Surg. 2014 Aug;67(8):1017-25.

5. Arno AI, Gauglitz GG, Barret JP, Jeschke MG. Up-to-date approach to manage

keloids and hypertrophic scars: a useful guide. Burns. 2014 Nov;40(7):1255-66.

6. Jones CD, Guiot L, Samy M, Gorman M, Tehrani H. The Use of Chemotherapeutics

for the Treatment of Keloid Scars. Dermatol Reports. 2015 May 21;7(2):5880.

7. Ogawa R. The most current algorithms for the treatment and prevention of

hypertrophic scars and keloids. Plast Reconstr Surg. 2010 Feb;125(2):557-68.

8. Epstein AE, DiMarco JP, Ellenbogen KA, Estes NA 3rd, Freedman RA, Gettes LS,

et al. 2012 ACCF/AHA/HRS Focused Update Incorporated Into the

ACCF/AHA/HRS 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm

Abnormalities. J Am Coll Cardiol. 2013 Jan 22;61(3):e6-75.

9. Spencker S, Coban N, Koch L, Schirdewan A, Mueller D. Comparison of skin

adhesive and absorbable intracutaneous suture for the implantation of cardiac

rhythm devices. Europace. 2011 Mar;13(3):416-20.

10. Harding ME, Chinitz LA. Clinical considerations for allied professionals:

optimizing outcomes: surgical incision techniques and wound care in device


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implantation. Heart Rhythm. 2014 Apr;11(4):737-41.

11. Arima J, Huang C, Rosner B, Akashi S, Ogawa R. Hypertension: asystemic key to

understanding local keloid severity. Wound Repair Regen. 2015 Mar-Apr;

23(2):213-21.

12. Wang R, Mao Y, Zang Z, Li Z, Chen J, Cen Y. Role of verapamil in preventing and

treating hypertrophic scars and keloids. Int Wound J. 2015 May 12. Doi:

10.1111/iwj.12455.

13. Morihara K, Takai S, Takenaka H, Sakaguchi M, Okamoto Y, Morihara T, et al.

Cutaneous tissue angiotensin-converting enzyme may participate in pathologic scar

formation in human skin. J Am Acad Dermatol. 2006 Feb; 54(2):251-7.

14. Fredriksson JM1, Lindquist JM, Bronnikov GE, Nedergaard J. Norepinephrine

induces vascular endothelial growth factor gene expression in brown adipocytes

through a beta -adrenoreceptor/cAMP/protein kinase A pathway involving Src but

independently of Erk1/2. J Biol Chem. 2000 May 5;275(18):13802-11.

15. Léauté-Labrèze C, Dumas de la Roque E, Hubiche T, Boralevi F, Thambo JB, Taïeb

A. Propranolol for severe hemangiomas of infancy. N Engl J Med. 2008 Jun

12;358(24):2649-51.

16. Bigorre M, Van Kien AK, Valette H. Beta-blocking agent for treatment of infantile

hemangioma. Plast Reconstr Surg. 2009 Jun;123(6):195e-6e

17. Sans V, de la Roque ED, Berge J, Grenier N, Boralevi F, Mazereeuw-Hautier J, et al.

Propranolol for severe infantile hemangiomas: follow-up report. Pediatrics. 2009

Sep;124(3):e423-31.

18. Buckmiller LM, Munson PD, Dyamenahalli U, Dai Y, Richter GT. Propranolol for

infantile hemangiomas: early experience at a tertiary vascular anomalies center.

Laryngoscope. 2010 Apr;120(4):676-81.

19. Chisholm KM, Chang KW, Truong MT, Kwok S, West RB, Heerema-McKenney

AE. β-Adrenergic receptor expression in vascular tumors. Mod Pathol. 2012

Nov;25(11):1446-51.


ACCEPTED

15

20. Ji Y, Chen S, Li K, Xiao X, Zheng S, Xu T. The role of β-adrenergic receptor

signaling in the proliferation of hemangioma-derived endothelial cells. Cell Div.

2013 Jan 3;8(1):1.

21. Le AD, Zhang Q, Wu Y, Messadi DV, Akhondzadeh A, Nguyen AL, et al. Elevated

vascular endothelial growth factor in keloids: relevance to tissue fibrosis. Cells

Tissues Organs. 2004;176(1-3):87-94.

22. Gira AK, Brown LF, Washington CV, Cohen C, Arbiser JL. Keloids demonstrate

high-level epidermal expression of vascular endothelial growth factor. J Am Acad

Dermatol. 2004 Jun;50(6):850-3.

23. Salem A, Assaf M, Helmy A, Nofal A, Ibrahim S, Eldeeb F, et al. Role of vascular

endothelial growth factor in keloids: a clinicopathologic study. Int J Dermatol.2009

Oct;48(10):1071–7.

24. Stork PJ, Schmitt JM. Crosstalk between cAMP and MAP kinase signaling in the

regulation of cell proliferation. Trends Cell Biol. 2002 Jun;12(6):258-66.

25. Mebratu Y, Tesfaigzi Y. How ERK1/2 activation controls cell proliferation and cell

death: Is subcellular localization the answer? Cell Cycle. 2009 Apr 15;8(8):1168-75.

26. Ban K, Peng Z, Kozar RA. Inhibition of ERK1/2 worsens intestinal

ischemia/reperfusion injury. PLoS One. 2013 Sep 20;8(9):e76790.

27. Sponer G, Bartsch W, Strein K, Müller-Beckmann B, Böhm E. Pharmacological

profile of carvedilol as a beta-blocking agent with vasodilating and hypotensive

properties. J Cardiovasc Pharmacol. 1987 Mar;9(3):317-27.

28. Wellstein A, Palm D, Belz GG. Affinity and selectivity of beta-adrenoceptor

antagonists in vitro. J Cardiovasc Pharmacol. 1986;8 Suppl 11:S36-40.

29. Andriessen MP, Niessen FB, Van de Kerkhof PC, Schalkwijk J. Hypertrophic

scarring is associated with epidermal abnormalities: an immunohistochemical study.

J Pathol. 1998 Oct;186(2):192-200.

30. Schnee JM, Hsueh WA. Angiotensin II, adhesion, and cardiac fibrosis. Cardiovasc

Res. 2000 May;46(2):264-8.


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16

31. Sun Y, Zhang J, Zhang JQ, Ramires FJ. Local angiotensin II and transforming

growth factor-beta1 in renal fibrosis of rats. Hypertension. 2000

May;35(5):1078-84.

32. Marshall RP, McAnulty RJ, Laurent GJ. Angiotensin II is mitogenic for human lung

fibroblasts via activation of the type 1 receptor. Am J Respir Crit Care Med. 2000

Jun;161(6):1999-2004.


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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.


ACCEPTED

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.


ACCEPTED

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.


ACCEPTED

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