ISSN: 1735-7306journal.iha.org.ir/Files/Journal/issue_6.pdf · 1 Department of Interventional Cardiology, Rajaie cardiovascular, Medical and Research center, Iran University of Medical

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According to the ruling of the Medical Sciences Publications Commission No. 14313-80/10/1 and 36914-85/2/10 signed by the Minister of Health and Medical Education and the Head of the Medical Sciences Publications Commission of the Islamic Republic of Iran, this journal has been granted accreditation as a scientific-research journal. This Journal is indexed in the Scientific Information Database (WWW.SID.IR) and IMEMR and Index COPERNICUS, SCOPUS, CINAHL and Google Scholar.

ISSN: 1735-7306

http://www.sid.ir/

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OFFICIAL QUARTERLY PUBLICATION OF THE IRANIAN HEART ASSOCIATION

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Executive Board:

Chairman: Editor-in-Chief: Executive Manager: Feridoun Noohi, MD A. Hussein Tabatabaei, MD Majid Maleki, MD

Technical Editors: Associate Editors: Assistant Manager: Farshad Amouzadeh, MA Rasoul Azarfarin, MD Shahin Shrani, MD

Hooman Bakhshandeh, MD Shabnam Madadi, MD Reza Golpira, MD

Local Editorial Board: Abdi S. Gholampour Dehaki M. Maleki M. Peighambari M. M. Ahmadi H. Hagh Azali M. Mandegar M. H. Pezeshkian M.

Alizadeh Ghavidel A. R. Haghjoo M. Mehranpour M. Poorhosseini HR

Alizadeh Sani, Z Haj Sheikholeslami F. Mohagheghi A. Pourmoghaddas M. Aminian B. Haji Zeinali AM. Mohebbi A. Radpour M.

Arefi H. Hakim H. Mojtahedzadeh S. Sadeghi M.

Azarfarin R. Handjani A. M. Momtahen M. Sadeghpour Tabaee A. Azarnik H. Hashemi J. Mortezaeian H. Sadr Ameli M. A.

Baghezadeh A. Hashemian M. Mostafavi A. Sadeghpour A.

Baharestani B. Heidarpour A. Motamedi M. R. Sattarzadeh R. Bakhshankdeh H. Hosseini K. Nabavizadeh Rafsanjani F. Shahmohammadi A.

Bassiri H. Hosseini S. Navabi M. A. Shakibi J.

Bolourian A. Javidi D. Nazeri I. Shirani SH. Eslami M. Jebbeli M Nematipour E. Tabatabaei A. H.

Farasatkish R. Kalantar Motamedi M. H. Nikdoost F. Tabatabaei M. B.

Firouzabadi H. Karimi A. Nozari Y. Yousefi A.A. Firouzi A. Kazemi Saleh D. Ojaghi Haghigi S. Z. Youssefnia M. A.

Firouzi I. Kamal hedayat D. Noohi F. Vahedian J.

Ghaffari Nejad M. H. Kiavar M. Omrani G. Zavarehee A. Ghasemi M. Madadi Sh. Oraii S. Zand parsa A.F.

International Editorial Consultants:

Alipour M. USA Karim S. Indonesia Pavie A. France

Anderson D. UK Khaghani A. UK Qureshi S. A. UK Bagir R. USA Koolen J. Netherlands Razavi M. USA

Bellosillo A. Phillipines Kranig W. Germany Robin J. France

Davis W. UK Kusmana D. Indonesia Sadeghi A. USA Deutsch M. Austria M Samuel. India Samad A. Pakistan

Djavan S. Austria Malek J. USA Sheikh S. Pakistan

Domanig E. Austria Marco J. France Sheikhzadeh A. Germany Dorosti K. USA Mee R. USA Shenasa M. USA

Elliott M. UK Mirhoseini M. USA Siddiqui H. India

Estafanous F.G. USA Monga M. S. Pakistan Sloman G. Australia Foale R. UK Moosivand T. Canada Smith W. M. New Zealand

Gandjbakhch I. France Moten M. USA Tajik A. J. USA

Jahangiri M. UK Nagamia H. USA Tynan M. UK Jazayeri M.R. USA Otto A. Turkey Wolner E. Austria

Contributing Editors of This Issue:

Abdi S. Jebbeli M Mandegar M. H. Peighambari M. M.

Azarfarin, R. Kamal hedayat D. Mohebbi A. Sadr Ameli M. A. Bassiri H.A. Madadi, Sh. Noohi F. Shirani, Sh.

Hosseini S. Maleki M. Omrani G.R. Tabatabaei A. H.

Technical Typist: F. Ghomi

Secretary: A. Beheshti

Address: Iranian Heart Association: P.O. Box: 15745-1341, Tehran, I.R. Iran. Tel: (009821) 22048174, Fax: (009821)

22048174

E-mail: [email protected]

mailto:[email protected]

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EDITORIAL

In the Name of God, the Most Beneficent, the Most Merciful

Dear colleagues and friends,

We are delighted to present to you Volume 17, Number 3 (Fall, 2016) issue of The Iranian

Heart Journal, which contains some interesting new studies and case reports in the domains of

cardiovascular medicine and surgery from our colleagues across Iran.

The Iranian Heart Journal is indexed in the Scientific Information Database (WWW.SID.IR),

IMEMR, Index Copernicus, Scopus, and CINAHL, thereby facilitating access to published

literature. There is no doubt, however, that our journal requires your opinions, ideas, and

constructive criticism in order to accomplish its main objective of disseminating cutting-edge

medical knowledge.

As ever before, we continue to look forward to receiving your latest research and cases.

Yours truly,

A. Hussein Tabatabaei, MD F. Noohi, MD

Editor-in-Chief, Chairman,

The Iranian Heart Journal The Iranian Heart Journal

http://www.sid.ir/

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Volume 17, Number 3

Fall, 2016

CONTENTS:

Page

ORIGINAL ARTICLES: CLINICAL SCIENCE

Outcome of Primary PCI in ST-Segment-Elevation Myocardial Infarction

Seyedeh Samaneh Ahmadi, MD; Hamidreza Sanati, MD; Majid Hajikarimi, MD; Alireza

Hoghooghi Esfahani, MD; Somayeh Beikmohammadi, MD; Ehsan Khalilipur, MD;

Hooman Bakhshandeh, MD; Maryam Hajimolaali, MS; Mehdi Farzaneh, MD; Mehdi

Noori, MD

6-11

Association between Diastolic Function Parameters and MRI T2* Measurements in a

Sample of Iranian Patients with Major Thalassemia

Fatemeh Rajabipour, MD; Seyed Abdolhossein Tabatabaei, MD; Atoosa Mostafavi, MD;

Seyedeh Sahel Rasoulighasemlouei, MD; Siamak Khavandi, MD

12-17

Pre-Exposure to Normobaric Hyperoxia Has No Effect on Myocardial Injury Biomarkers

after Percutaneous Transluminal Coronary Angioplasty

Asghar Mohammadi, MS; Shahin Raoufi, MS; Mehrdad Namdari, MD; Amir Raoufi,

MD; Khatereh Anbari, MD; Shiba Tahzibi, BS; Mohammad Almasian, MA; Bahram

Rasoulian, MD, PhD

18-26

Measuring and Modeling the Viscoelastic Properties of the Human Saphenous Vein Using

the Pressure–Diameter Test

Morteza Darjani, Ali Esteki, S. Ahmad Hassantash

27-35

Echocardiographic and Clinical Factors Related to the False Results of the Exercise

Tolerance Test

Hakimeh Sadeghian, MD; Seyed Abdolhussein Tabatabaie, MD; Mahmmod Sheikh

Fathollahi, MD; Elham Hakki Kazazi, MD; Arezou Zoroufian, MD; Mahmood

Sahebjam, MD; Ali Mohammad Haji Zeinali, MD

36-45

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CONTENTS:

ORIGINAL ARTICLES: CLINICAL SCIENCE

Page

CASE REPORT

Right Ventricle Tumoral Mass in Acute Promyelocytic Leukemia (AML M3): Cardiac

Magnetic Resonance Findings

Farahnaz Nikdoust, MD; Zahra Alizadeh Sani, MD; Seyed Abdolhussein Tabatabaei, MD

46-50

Neonatal Tuberous Sclerosis Complex with Large and Multiple Cardiac Rhabdomyomas

Ramesh Bhat Y, MD; Leslie E Lewis, MD;

Jayashree P, MD; Prakashini K, MD;

Ranjan S, MD; Krishnananda N, MD

51-54

INSTRUCTIONS FOR AUTHORS 55-58

FORTHCOMING MEETINGS 59-61

SUBSCRIPTION FORM 62-63

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Outcome of Primary PCI in STEMI Ahmadi SS, et al.

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Original Article


Outcome of Primary PCI in ST-Segment-Elevation

Myocardial Infarction

Seyedeh Samaneh Ahmadi1, MD; Hamidreza Sanati

*1, MD; Majid Hajikarimi

1, MD;

Alireza Hoghooghi Esfahani1, MD; Somayeh Beikmohammadi

1, MD;

Ehsan Khalilipur1, MD; Hooman Bakhshandeh

1, MD;

Maryam Hajimolaali2, MS; Mehdi Farzaneh

1, MD; Mehdi Noori

1, MD

ABSTRACT

Background: We sought to assess the feasibility and outcome of primary percutaneous coronary

intervention (PCI) for ST-segment elevation myocardial infarction (STEMI).

Methods: Between April 2014 and April 2015, consecutive STEMI patients who underwent

primary PCI were prospectively enrolled in a primary PCI registry. The patients’

demographics, risk factors, procedural characteristics, and in-hospital and 6-month major

adverse cardiac events (MACE) were assessed.

Results: A total of 393 patients underwent primary PCI during this period. The mean age was

58±11 years and 80.6% were male. Additionally, 40.7% of the patients were hypertensive,

37.9% had dyslipidemia, 37.7% were smokers, and 29% had diabetes mellitus. Single-vessel

disease was found in 36.6% of the study population, 2-vessel disease in 30.5%, and

multivessel disease in 27.7%. At admission, 74.5% of the patients had TIMI grade 0 flow.

Following revascularization, 74.7% achieved TIMI grade 3 flow, 22% TIMI grade 2 flow,

and 1.8% TIMI grade 1 flow—whereas 1.5% had TIMI grade 0 flow. The predictors of the

TIMI flow grade after primary PCI included history of diabetes mellitus, lesion severity,

time elapsed from symptom onset to admission, and use of thrombectomy. Stent thrombosis

developed in 5.6% of the patients; it was more frequent among those receiving bare-metal

stents. The in-hospital and 6-month mortality rates were 5.9% and 2.3%, correspondingly.

In-hospital mortality was strongly related to the TIMI flow grade.

Conclusions: Our study demonstrated that the outcome of primary PCI was strongly related to the

postprocedural TIMI flow grade. Patients with lower TIMI flow grades postprocedurally

should receive special attention. (Iranian Heart Journal 2016; 17(3):6-11)

Keywords: ST-segment elevation myocardial infarction Primary PCI Thrombolysis in myocardial infarction (TIMI)

flow Major adverse cardiovascular events

1 Department of Interventional Cardiology, Rajaie cardiovascular, Medical and Research center, Iran University of Medical Sciences, Tehran, I.R.Iran. 2 Department of Education Rajaie cardiovascular, Medical and Research center, Iran University of Medical Sciences, Tehran, I.R.Iran.

Corresponding Author: Hamid Reza Sanati, MD; Rajaie cardiovascular, Medical and Research center, Iran University of Medical Sciences, Tehran, I.R.Iran.

E-mail: [email protected] Tel: 09123765828

Received: May 29, 2016 Accepted: August 20, 2016


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ver the past decade, cardiovascular

disease (CVD) has emerged as the

single most important cause of death

worldwide. In 2010, CVD accounted for

approximately 30% of all deaths and 11% of

all the disability-adjusted life years lost that

year.

Ischemic heart disease may be manifested

clinically as chronic stable angina or acute

coronary syndrome. The latter, in turn, can be

subdivided into ST-segment-elevation

myocardial infarction (STEMI), non-ST-

segment-elevation myocardial infarction

(NSTEMI), and unstable angina.

The clinical diagnosis of MI requires a

clinical syndrome indicative of myocardial

ischemia with some combination of evidence

of myocardial necrosis on biochemical, ECG,

or imaging modalities.

Despite advances in diagnosis and

management, STEMI remains a major public

health problem in the industrialized world and

is on the rise in developing countries. The

overall number of deaths from STEMI,

following a steady rise in the final decades of

the previous century, has stabilized over the

past decade. According to estimates from the

American Heart Association, the short-term

mortality rate of patients with STEMI ranges

from 5% to 6% during the initial

hospitalization and 7% to 18% at 1 year. The

rate of appropriate initiation of reperfusion

therapy varies widely, with up to 30% of

patients with STEMI eligible to receive

reperfusion therapy not receiving this

lifesaving treatment according to some

registries.1

The past 2 decades have witnessed dramatic

changes in the care of patients with STEMI.

Randomized controlled trials in the early

1990s showed that primary percutaneous

coronary intervention (PCI) was superior to

fibrinolytic therapy, and a 2003 meta-analysis

of 23 clinical trials firmly established primary

PCI as the preferred treatment for STEMI

patients.2 Primary PCI is generally the

preferred option provided that an experienced

operator and team can perform it in a timely

fashion. This approach has evolved from the

passage of a balloon catheter over a guide

wire to potent oral antiplatelet therapy,

multiple options for anticoagulants, coronary

stents, and thrombectomy. Missed

opportunities for improvement in the care of

STEMI include failure to deliver any form of

reperfusion therapy in approximately 20% of

patients and failure to minimize delays in

reperfusion because of inefficient systems of

care.1

The introduction of primary PCI has reduced

patient mortality and improved outcomes in

comparison with fibrinolysis, which was the

previous standard.3

The present paper reviews the outcome of

primary PCI in patients with STEMI.

METHODS

This is a single-center trial with a prospective

cross-sectional design of acute STEMI

patients undergoing primary PCI. Totally, 393

patients were initially evaluated between

April 2014 and April 2015. Patients were

considered eligible if they were >18 years of

age, with acute STEMI, and indication for

primary PCI based on clinical and ECG

characteristics. The exclusion criteria were

comprised of late comers (>24 hours from the

onset of chest pain), coronary anatomy or

mechanical complications of acute MI

requiring emergent surgery, failed

thrombolysis, and post CABG patients. The

institutional Ethics Committee of Rajaie

Cardiovascular, Medical, and Research Center

approved the trial design.

Procedural Protocol and Follow-Up

The clinical, laboratory, and procedural

characteristics of the studied patients were

collected and entered in a questionnaire.

The patients received 325 mg of aspirin and

600 mg of clopidogrel in the emergency

department. Coronary angiography and

primary PCI procedures were performed

according to the standard routines. The

intention to treat was for the culprit artery.

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Heparin was administered with the dose of

50–100 IU/kg to maintain an activated

clotting time >250–300 s depending on the

use of concomitant glycoprotein IIb/IIIa

inhibitors. Manual thrombectomy was carried

out in cases with large thrombus burden. Peak

cardiac troponin I (cTnI) and creatine-kinase

MB (CK-MB) levels were defined as the

highest amount obtained by serial (3 times)

enzyme check during the first 24 hours of

admission. A complete echocardiographic

study was performed on the patients the day

after primary PCI. The left ventricular

ejection fraction was estimated using the

Simpson equation in the 4-chamber view. All

the echocardiograms were performed by a

single attending physician to avoid

interobserver variability.

The patients were observed during the

hospitalization and a 6-month period.

Primary and Secondary End Points

The primary end points of this study were the

pre- and postprocedural epicardial blood flow

of the culprit artery measured as the

thrombolysis in myocardial infarction (TIMI)

flow, and the secondary end points were in-

hospital mortality and 6-month major adverse

cardiac events (MACE) (defined as death,

acute coronary event, target vessel

revascularization, and cerebrovascular

events).

RESULTS

A total of 393 patients were enrolled in the

present study. The mean age of the

participants was 58±11 years, and 317

(80.66%) of the patients were male.

The most common cardiovascular risk factor

was hypertension, observed in 160 (40.7%)

patients, followed by dyslipidemia, seen in

149 (37.9%) patients. Additionally, 148

(37.7%) patients were smokers, 114 (29%)

had diabetes mellitus, and 63 (16%) had a

positive family history of CVD.

The time elapsed from symptom onset to

admission was <2 hours in 71 (18%) patients,

between 2 and 6 hours in 140 (35.6%),

between 6 and 12 hours in 107 (27.2%), and

>12 hours in 75 (19.1%).

Figure 1. Time from symptom onset to admission

The prevalence of the different number of

diseased vessels among the study population

comprised single-vessel disease in 144

(36.6%) patients, 2-vessel disease in 120

(30.5%), and multivessel disease in 109

(27.7%). Left main lesion was observed in 12

patients.

The most common culprit lesion severity was

total occlusion, observed in 273 (69.4%)

patients, followed by 90–99% occlusive

lesion in 95 (24.1%), 70–90% occlusive

lesion in 19 (4.8%), and 50–70% occlusive

lesion in 1.

Type A coronary lesion was observed in 9

(2.2%) patients, type B in 78 (19.8%), and

type C in 252 (64.1%). Additionally,

significant calcification was seen in 33 (8.3%)

patients.

Figure 1. Procedural data

POBA, Plain old balloon angioplasty

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Figure 2. Pre and post PCI TIMI flow grades

PCI, Percutaneous coronary intervention; TIMI, Thrombolysis in myocardial infarction

The median of peak post-PCI troponin levels

among the patients was 9.97 (2.6–23.5), and

the median of peak post-PCI CK-MB levels

was 219 (91–350).

Figure 3. Prevalence of procedural complications

Figure 4. Post PCI complications

PCI, Percutaneous coronary intervention; TVR, Target vessel revascularization; CVA, Cerebrovascular accident; CIN, Contrast-induced nephropathy

The mean of the postprocedural left

ventricular ejection fraction was 36%. Mild

mitral regurgitation was observed in 322

(81.9%) patients and moderate mitral

regurgitation in 47 (11.9%); 24 (6.1%)

patients had no mitral regurgitation.

ST-resolution was seen in 278 (70.7%)

patients.

Q-wave formation was observed in 269

(64.8%) patients postprocedurally.

Figure 5. Six-month follow-up adverse events

ACS, Acute coronary syndrome; PCI, Percutaneous coronary intervention; CVA, Cerebrovascular accident

CONCLUSIONS

The present study was conducted on 393

patients (80.6% male) at a mean age of 58±11

years. Hypertension was detected in 40.7% of

the patients, dyslipidemia in 7.9%, and

diabetes mellitus in 29%. Smokers accounted

for 37.7% of the whole study population.

Single-vessel disease was found in 36.6%, 2-

vessel disease in 30.5%, and multivessel

disease in 27.7% of the study group. The

most common culprit lesion severity was total

occlusion, which was observed in 69.4% of

the patients with type C lesions.

Growing evidence suggests that a poor

coronary blood flow after primary PCI is

associated with unfavorable clinical

outcomes.4 In our study, 74.5% of the patients

had TIMI grade 0 flow at admission.

However, after revascularization, 74.7%

achieved TIMI grade 3 flow, 22% TIMI grade

2 flow, and 1.8% TIMI grade 1 flow—while

1.5% of the study population had TIMI grade

0 flow.

Our results revealed that the predictors of the

TIMI flow grade after primary PCI included a

history of diabetes mellitus, lesion severity,

time elapsed from symptom onset to

admission, and use of thrombectomy.

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Table 1. Relation between the TIMI flow grade and risk factors

TIMI<3 TIMI=3 P

Number 99 292 -

DM 39 (39.4%) 75 (25.7%) 0.009

Multivessel disease 61 (61.6%) 186 (63.7%) 0.710

Type of stenosis

0.367 Type A 3 (3%) 7 (2.4%)

Type B 33 (33.3%) 98 (33.6%)

Type C 63 (63.6%) 186 (64%)

Significant calcification 9 (9.1%) 24 (8.2%) 0.787

Thrombectomy 42 (32.4%) 71 (34.3%) 0.001

Lesion severity

0.05

50 – 70% 0 (0%) 1 (0.3%)

70 – 90% 2 (2%) 17 (5.9%)

90 – 99% 20 (20.4%) 75 (25.9%)

100 76 (77.6%) 197 (67.9%)

CP onset

0.008 < 6 h 39 (39.4%) 172 (58.9%)

> 6 h 60 (60.6%) 120 (41%)

TIMI, Thrombolysis in myocardial infarction; DM, Diabetes mellitus; CP, Chest pain

Adel Jamal et al.5 showed that the predictors

of the TIMI flow grade included diabetes

mellitus, symptom duration, Killip class,

thrombus burden, pre-dilation, total nature of

the occlusion, patency of the infarct-related

artery, multivessel disease, and length of

deployed stents.

In the hospital course after primary PCI,

14.4% of the patients had episodes of chest

pain and 5.6% developed stent thrombosis.

Early coronary stent thrombosis occurs most

frequently after primary PCI for STEMI, with

its specific risk factors including

postprocedurally discovered dissection,

undersizing and smaller stent diameters,

absence of glycoprotein IIb/IIIa therapy, and

use of drug-eluting stents.6

In our study, stent

thrombosis was more frequent in the patients

receiving bare-metal stents, and there was no

relation between stent thrombosis and history

of diabetes mellitus, kind of stenosis,

significant calcification, multivessel disease,

and postprocedurally discovered dissection.

Table 2. Relation between stent thrombosis and risk factors

No Yes P

None 369 22

Diabetes mellitus 109 (29.5%) 5 (22.7%) 0.495

Multivessel 235 (63.7%) 12 (54.5%) 0.388

Type of stenosis

0.562 Type A 10 (2.7%) 0

Type B 126 (34.1%) 5 (22.7%)

Type C 233 (63.1%) 17 (77.3%)

Significant calcification 31 (8.4%) 2 (9.1%) 0.910

Bare-metal stent 226 (61.7%) 14 (63.6%) 0.859

Drug-eluting stent 113 (30.9%) 2 (9.1%) 0.03

Dissection 8 (2.2%) 0 0.626

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A simple method for determining prognosis

after primary PCI is ST-segment-elevation

recovery.7

In the current study, ST-resolution was seen

in 70.7% of the patients and it provided strong

prognostic information regarding the clinical

outcomes.

Q-wave formation was observed in 64.8% of

our study population. The association

between the Q wave and the infarct size is

strongest when the classic Q-wave criteria are

employed. Q-wave regression is associated

with the largest improvement in the left

ventricular ejection fraction as assessed with

cardiac magnetic resonance imaging.8 ECG

information can be drawn upon for the

prediction of the clinical outcome.

After primary PCI, 81.9% of our patients had

mild and 11.9% moderate mitral

regurgitation, whereas 6.1% of the patients

had no mitral regurgitation. Ischemic mitral

regurgitation is a frequent finding after

primary PCI, and the regression of early

ischemic mitral regurgitation during a long-

term follow-up is uncommon. Since

moderate-to-severe ischemic mitral

regurgitation post primary PCI appears to be

correlated with worse outcomes, a close

follow-up is required.9

In the present study, the in-hospital and 6-

month mortality rates were 5.9% and 2.3%,

respectively. In-hospital mortality is strongly

related to the TIMI flow grade and high-risk

complications that develop during admission.

There were 23 in-hospital deaths in our study:

16 deaths among the patients with TIMI grade

<3 flow and 7 deaths among the patients with

TIMI grade 3 flow (P<0.001).

Accordingly, patients with high-risk

complications and lower TIMI flow grades

postprocedurally should receive special

attention.

REFERENCES

1. Braunwald; 2015

2. John E. Brush Jr, Improving ST-elevation-

Myocardial infarction care. Circulation 2012;

420-422

3. Diana Cooper, The use of primary PCI for the

treatment of STEMI. British journal of cardiac

nursing 2015

4. MD Juergen Kammler, MD Alexander Kypta,

MD Robert Hofmann et al, TIMI 3 flow after

primary angioplasty is an important predictor

for outcome in patients with acute myocardial

infarction. Spriger 2009

5. ADEL JAMAL, M.D.; MUHAMMAD

ABDUL QADER, M.D and MUSTAFA

ABDULMONEIM at al, Predictor of TIMI

Flow Grade after Primary PCI in cases of

Anterior STEMI. Med. J. cairo Univ., Vol. 80,

No. 1, December: 767-777, 2012

6. Heestermans AA, van Werkum JW, Zwart B

et al, Acute and subacute stent thrombosis

after primary percutaneous coronary

intervention for ST-segment elevation

myocardial infarction: Incidence, predictors

and clinical outcome. Pub Med 2010

Nov;8(11):2358-93

7. Christopher E. Buller, Yuling FU, Kennet W.

Mahaffey et al, ST-segment Recovery and

Outcome After Primary Percutaneous

Coronary Intervention for ST-Elevation

Myocardial Infarction. INTERNATIONAL

CARDIOLOGY 2008

8. Ronak Delewi MD ,George IJff MD , Tim

P.van de hoef MD et al, Pathological Q Waves

in Myocardial Infarction in Patients Treated

by Primary PCI. ELSEVIER 2012.

9. Jimmy MacHaalany, Olivler F Bertrand, Kim

o connor, Predictors and prognosis of early

ischemic mitral regurgitation in the era of

primary percutaneous coronary Intervention.

Springer 2014.

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Association between Diastolic Function Parameters and MRI T2* Measurements with Major Thalassemia Rajabipour F, et al.

12

Original Article Association between Diastolic Function Parameters and MRI T2* Measurements with Major Thalassemia Rajabipour F, et al.

Association between Diastolic Function Parameters and

MRI T2* Measurements in a Sample of Iranian Patients

with Major Thalassemia

Fatemeh Rajabipour1, MD; Seyed Abdolhossein Tabatabaei

2, MD;

Atoosa Mostafavi2*, MD; Seyedeh Sahel Rasoulighasemlouei

2, MD;

Siamak Khavandi2, MD

ABSTRACT

Background: The aim of the present study was to investigate the relationship between the

echocardiographic indices of diastolic dysfunction and MRI T2* measurements, indicating

myocardial iron loadings, in patients with thalassemia major and normal left ventricular

ejection fractions.

Methods: A series of consecutive patients with known thalassemia major under treatment with

regular blood transfusions and iron chelation therapy were enrolled in the current study

between July 2012 and June 2015 at Baharlou Hospital, Tehran, Iran. All the patients

underwent cardiac MRI with the measurement of T2* for the liver and heart,

echocardiographic examination with tissue Doppler assessment, and serum ferritin assay.

The correlation between diastolic function parameters and T2* measurements was assessed

using statistical software. Standard diastolic indices, comprising early (E) and late (A)

transmitral peak flow velocities and early deceleration time (DT), were recorded.

Results: The mean E/A, mean E/E′, and mean E′ were 2.09±0.54, 0.07±0.011, and 14±1.40 cm/s,

respectively. The mean deceleration time (dt) was 190.97±35.89. The average serum ferritin

level was 1498±783.08 ng/mL (range =212.7 to >3000 ng/mL). The mean cardiac T2*

derived from MRI was 26.58±7.54 ms. The frequencies of the different severities of

myocardial iron loading based on myocardial T2* were as follows: 44 (80%) normal, 4

(7.3%) mild, 2 (3.6%) moderate, and 5 (9.1%) severe. MRI T2* did not have a significant

correlation with E/A (r=0.091; P=0.508), E′ (r=0.130; P=0.345), E/E′ (r=0.005; P=0.971),

and dt (r=0.028; P=0.838). Hepatic iron loading based on the MRI T2* values also did not

have any correlation with the echocardiographic indices of left ventricular diastolic

dysfunction—namely E/A (r=0.151; P=0.270), E′ (r=0.034; P=0.804), E/E′ (r=0.083;

P=0.547), and dt (r=0.128; P=0.351).

Conclusions: None of the echocardiographic diastolic function parameters examined in this study

were found to be suitable for cardiac surveillance in transfusion-dependent patients affected

by thalassemia major. Longitudinal studies are needed to evaluate the utility of

echocardiographic and MRI parameters to predict cardiac events. At the moment, we cannot

recommend the replacement of cardiac MR and T2* measurements, indicating myocardial

iron loading, by Doppler echocardiography in patients with a normal systolic function.

(Iranian Heart Journal 2016; 17(3):12-17)

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Keywords: Diastolic dysfunction Thalassemia major Hemoglobin disorders Iron overload

1 Pediatric Department of Baharlou Hospital, Tehran University of Medical Sciences, Tehran, I. R. Iran. 2 Department of Cardiology, Shariati Hospital, Tehran University of Medical Sciences, Tehran, I.R. Iran.

*Corresponding Author: Atoosa Mostafavi, MD; Shariati Hospital, Tehran University of Medical Sciences, Tehran, I.R. Iran.


Received: January 20, 2016 Accepted: May 10, 2016

INTRODUCTION

β-thalassemia, first described by Cooley and

Lee, represents a group of autosomal

recessive hemoglobin disorders with the

impaired synthesis of β-globin chain. The

homozygous state, so called thalassemia

major, brings about severe anemia.1 Due to

numerous consanguineous marriages in Iran,

major thalassemia is more frequent than in

other developed countries—with about 14000

affected individuals mostly residing in the

northern and southern parts of the country.2

Patients suffering from major thalassemia

need regular blood transfusions to survive.

However, with the longer lifespan of these

patients, iron deposition throughout the

body—especially in the heart and endocrine

tissues—consequently forms a secondary

devastating condition.3 Myocardial iron

loading is the leading cause of death in

transfusion-dependent thalassemia patients.4

Cumulative and progressive deposition of iron

in the myocardium—albeit silent in the

beginning—could further cause systolic and

diastolic dysfunction, arrhythmias, and

congestive heart failure. These symptoms

usually present in the 2nd or 3rd decade of

life.5 Iron deposition-induced cardiomyopathy

in thalassemic patients can be reversible if the

diagnosis has been made early followed by

intensive chelation therapy.6 Previous

conventional studies such as ECG,

conventional echocardiography, and Holter

monitoring failed to help detect the cardiac

involvement in early stages.7 Recently,

cardiac magnetic resonance imaging (CMR)

has gained popularity in diagnosing

preclinical iron-overload cardiomyopathy in

transfusion-dependent thalassemia. Although

the MRI-derived relaxation time parameter,

T2*, has been shown to be associated with

left ventricular function,8 the availability and

cost of such MRI examinations have limited

the clinical impact of T2*—especially in less

developed countries. Thus, less expensive

diagnostic methods are more desirable. One

of these recently highlighted techniques is the

echocardiographic assessment of left

ventricular diastolic function, which might be

a more sensitive marker than systolic function

for detecting excess myocardial iron-induced

adverse effects. We, therefore, aimed to

investigate the correlation between the

echocardiographic indices of diastolic

function and myocardial T2* in a series of

Iranian patients with transfusion-dependent

thalassemia.

Study Population

Our subjects were a consecutive series of all

patients with thalassemia major who were

referred for cardiac function assessment and

underwent both echocardiography and CMR

between July 2012 and June 2015 at Baharlou

Hospital, Tehran, Iran. All the patients were

transfusion dependent and had been under

chelation therapy with deferoxamine from

childhood. Additionally, all the patients had

undergone regular ferritin assay to assess the

outcome of chelation therapy. None of the

patients had decreased left ventricular ejection

fractions at the time of imaging assessment.

MRI Techniques and Data Analysis

MRI examinations were routinely performed

within 10 days of transfusion. Iron in the

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myocardium was quantified by measuring

T2* (1/R2*), an MR relaxation parameter that

has been shown to vary inversely with tissue

iron concentrations.9 The MRI measurements

were performed using a 1.5-T clinical MRI

scanner (Philips Achieva, Philips Medical

System, Best, the Netherlands) and a torso

surface coil. ECG-gated CMR images were

obtained for T2*. Short-axis images were

prepared in different sequences, similar to the

technique described by Westwood et al.10

The

T2* and iron-load values were calculated

using “CMR Tools” software. Liver T2* was

also assessed similarly to myocardial values.

In the myocardium, the loading of iron was

categorized into 4 groups according to the

corresponding myocardial T2* as follows:

normal (>20 ms), mild (14–20 ms), moderate

(10–14 ms), and severe (<10 ms). In the liver,

hepatic iron loading was divided based on

both hepatic T2* (in ms) and mg of iron in

each gram of liver dry weight (mg/g/dw). The

4 groups were as follows: normal (>6.3 ms or

<2 mg/g/dw), mild (2.8–6.3 ms or 2–5

mg/g/dw), moderate (1.4–2.7 ms or 5–10

mg/g/dw), and severe (<1.4 ms or >10

mg/g/dw).

Echocardiography

Complete 2D, Doppler, and tissue-Doppler

echocardiography was performed. Left

ventricular end-diastolic and end-systolic

volumes were calculated using a modified

Simpson algorithm based on long- and short-

axis images, and the ejection fraction was

calculated. Left ventricular diastolic function

was assessed using the pulsed-Doppler

samples of the mitral inflow and pulsed-tissue

Doppler at the level of the lateral wall of the

mitral annulus. Standard diastolic indices,

comprising early (E) and late (A) transmitral

peak flow velocities and early deceleration

time (DT), were recorded. Deceleration time

was measured as the time between the peak E

velocity and the point where the velocity

returns to 0. The peak velocities (cm/s) of the

myocardial systolic wave and of the early (E′)

and late (A′) diastolic tissue Doppler signals

were measured, and the E/E′ ratio was

calculated.

Statistical Analysis

The correlations between myocardial and

hepatic T2* and the indices of left ventricular

systolic and diastolic functions were

calculated using the linear regression analysis.

A P value <0.05 was considered statistically

significant.

RESULTS

Patients

A total of 55 patients (27 male, mean age

=20.4±4.55 y, age range =4–27 y), who were

referred to our medical center, underwent

both echocardiography and MRI T2*

assessment. The average serum ferritin level

was 1498±783.08 ng/mL (range =212.7 to

>3000 ng/mL).

Echocardiographic Findings

There were 55 echocardiograms collected

over our study period. None of the subjects

had left ventricular ejection fractions <50%–

55%. The mean E/A, mean E/E′, and mean E′

were 2.09±0.54, 0.07±0.011, and 14±1.40

cm/s, correspondingly. The mean deceleration

time (dt) was 190.97±35.89.

MRI Findings

There were 55 CMR images obtained within 1

month of an echocardiogram. The mean

cardiac T2* derived from MRI was

26.58±7.54 ms, while the mean hepatic T2*

and the mean hepatic iron loading per grams

of liver dry weight were 4.32±2.76 ms and

4.59±2.14 mg/g/dw, respectively. The

frequencies of the different severities of

myocardial iron loading based on myocardial

T2* were as follows: 44 (80%) normal, 4

(7.3%) mild, 2 (3.6%) moderate, and 5 (9.1%)

severe. The frequencies of normal, mild, and

moderate amounts of liver iron loading based

on hepatic T2* were 8 (14.5%), 34 (61.8%),

and 12 (21.8%), respectively. However, in 1

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case, hepatic iron loading was severe (1.8%).

In addition, based on the presence of iron in

liver dry weight, the prevalence of normal,

mild, moderate, and severe hepatic iron

loading was similar.

Relationship between MRI and

Echocardiographic Findings

MRI T2* did not have a significant

correlation with E/A (r=0.091; P=0.508), E′

(r=0.130; P=0.345), E/E′ (r=0.005; P=0.971),

and dt (r=0.028; P=0.838). Hepatic iron

loading based on the MRI T2* values also did

not have any correlation with the

echocardiographic indices of left ventricular

diastolic dysfunction—namely E/A (r=0.151;

P=0.270), E′ (r=0.034; P=0.804), E/E′

(r=0.083; P=0.547), and dt (r=0.128;

P=0.351).

DISCUSSION

In the present study, we sought to investigate

the correlation between the echocardiographic

indices of diastolic function and myocardial

and hepatic T2*, which are allied to iron

loading in transfusion-dependent thalassemia

patients. We found that all the patients had

normal left ventricular ejection fractions. The

parameters of E/A, E′, E/E′, and the dt index

did not correlate with myocardial or hepatic

iron concentration (1/T2*).

The main role of a cardiac surveillance

program in patients with thalassemia major is

to prevent the development of cardiac

dysfunction and arrhythmia while avoiding

chelator-associated toxicities through the

optimal titration of iron chelator medications.

The systolic function, although being normal,

may rapidly deteriorate and is not adequately

sensitive; thus, a periodic monitoring of

systolic function is not satisfactory in this

setting.11

The fact that, in ischemic

cardiomyopathy, left ventricular diastolic

dysfunction precedes the onset of systolic

dysfunction has led some researchers to

assume that left ventricular diastolic function,

as an early marker of myocardial iron

overload, may be more sensitive and, thus,

serve as a guide for adjusting chelator

therapy. To assess left ventricular diastolic

function in thalassemia major, investigators

have developed several noninvasive

techniques in clinical practice. These include

the Doppler echocardiography of the

transmitral flow, tissue-Doppler imaging, and

radionuclide ventriculography.12–14

Although

in the absence of systolic dysfunction, the

abnormalities of diastolic function are often

noted—as was seen in our study—the clinical

significance of these abnormalities has yet to

be elucidated. The identification of patients at

greater risk for systolic dysfunction and heart

failure is the potential clinical usage of

subclinical diastolic functional abnormalities.

In transfusion-dependent patients, the

importance of diastolic function indices to

identify at-risk subjects for heart failure has

not been shown by others12–14

and is not

supported by our data. In the present study,

diastolic function indices, regardless of

systolic function, were abnormal in our series.

Investigating the correlation between diastolic

function parameters and myocardial MRI T2*

measurements would be another efficient

approach to assess the potential utility of

echocardiographic cardiac surveillance in

thalassemia major. In the literature, it has

been shown that myocardial T2* correlates

well with biopsy-derived iron levels in the

heart muscular tissue.15,16

However, we were

unable to detect a significant correlation

between the diastolic function parameters of

E/A, E′, E/E′, and dt and myocardial T2*—

suggesting that among our studied patients,

these parameters were a poor reflection of

myocardial iron concentration. There are only

a few other reports comparing

echocardiographic diastolic function indices

with myocardial T2*. Aessopos et al.17

studied the relationship between a variety of

parameters—including E, A, and E/A, but not

tissue-Doppler indices—and myocardial T2*.

The authors found statistically significant but

weak (r<0.5) correlations between A and E/A

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and T2*; these, however, lacked

discriminatory powers to identify patients

with myocardial iron overload but with a

normal systolic function. Vogel et al.13

found

that despite commonly seen anomalies in

tissue-Doppler measurements among

thalassemia patients with myocardial iron

overload, they were also present in 35% of the

patients with a normal T2*, which means that

this method was only 65% specific in the

setting of iron overload. Westwood et al.10

used MRI-derived ventricular volume-time

curves to measure early and atrial peak filling

rates and found that diastolic parameters were

weakly correlated with myocardial iron

loading. Leonardi et al.7 also failed to show a

significant correlation between myocardial

T2* measurements and the echocardiographic

parameters of diastolic function. In summary,

the above reports overall are consistent with

our findings in that abnormal diastolic

function indices are frequently seen in

patients with thalassemia major but have

unsatisfactory specificity to categorize

patients into low and high risk of iron

overload-induced cardiomyopathy.

Study Limitations

The essential limitation of our study is its

relatively small sample size, which decreases

its power to detect correlations between

echocardiographic diastolic parameters and

myocardial T2*. We could not assess the left

ventricular ejection fraction by CMR due to

high expenses and poor equipment, an issue

which was addressed in earlier related reports.

CONCLUSIONS

None of the echocardiographic diastolic

function parameters examined in the current

study was found to be suitable for cardiac

surveillance in transfusion-dependent patients

affected by thalassemia major. Longitudinal

studies are needed to evaluate the utility of

echocardiographic and MRI parameters to

predict cardiac events. At the moment, we

cannot recommend the replacement of CMR

and T2* measurements, indicating myocardial

iron loading, by Doppler echocardiography in

patients with a normal systolic function.

REFERENCES

1. Shamshirsaz AA, Bekheirnia MR, Kamgar M,

Pourzahedgilani N, Bouzari N, Habibzadeh

M, et al. Metabolic and endocrinologic

complications in beta-thalassemia major: a

multicenter study in Tehran. BMC Endocr

Disord. 2003 Aug 12;3(1):4.

2. Abolghasemi H, Amid A, Zeinali S, Radfar

MH, Eshghi P, Rahiminejad MS, et al.

Thalassemia in Iran: epidemiology,

prevention, and management. J Pediatr

Hematol Oncol. LWW; 2007;29(4):233–8.

3. Chen M-R, Ko H-S, Chao T-F, Liu H-C, Kuo

J-Y, Bulwer BE, et al. Relation of myocardial

systolic mechanics to serum ferritin level as a

prognosticator in thalassemia patients

undergoing repeated transfusion.

Echocardiography. 2015 Jan;32(1):79–88.

4. Kondur AK, Li T, Vaitkevicius P, Afonso L.

Quantification of myocardial iron overload by

cardiovascular magnetic resonance imaging

T2* and review of the literature. Clin Cardiol.

2009 Jun;32(6):E55–9.

5. Wood JC, Enriquez C, Ghugre N, Otto-

Duessel M, Aguilar M, Nelson MD, et al.

Physiology and pathophysiology of iron

cardiomyopathy in thalassemia. Ann N Y

Acad Sci. 2005 Jan;1054:386–95.

6. Davis BA, Porter JB. Long-term outcome of

continuous 24-hour deferoxamine infusion via

indwelling intravenous catheters in high-risk

beta-thalassemia. Blood. American Society of

Hematology; 2000 Feb 15;95(4):1229–36.

7. Leonardi B, Margossian R, Colan SD, Powell

AJ. Relationship of magnetic resonance

imaging estimation of myocardial iron to left

ventricular systolic and diastolic function in

thalassemia. JACC Cardiovasc Imaging. 2008

Sep;1(5):572–8.

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8. Anderson LJ, Holden S, Davis B, Prescott E,

Charrier CC, Bunce NH, et al. Cardiovascular

T2-star (T2*) magnetic resonance for the early

diagnosis of myocardial iron overload. Eur

Heart J. 2001 Dec;22(23):2171–9.

9. Wood JC, Otto-Duessel M, Aguilar M, Nick

H, Nelson MD, Coates TD, et al. Cardiac iron

determines cardiac T2*, T2, and T1 in the

gerbil model of iron cardiomyopathy.

Circulation. 2005 Jul 26;112(4):535–43.

10. Westwood M, Anderson LJ, Firmin DN,

Gatehouse PD, Charrier CC, Wonke B, et al.

A single breath-hold multiecho T2*

cardiovascular magnetic resonance technique

for diagnosis of myocardial iron overload. J

Magn Reson Imaging. 2003 Jul;18(1):33–9.

11. Felker GM, Thompson RE, Hare JM, Hruban

RH, Clemetson DE, Howard DL, et al.

Underlying Causes and Long-Term Survival

in Patients with Initially Unexplained

Cardiomyopathy. N Engl J Med.

Massachusetts Medical Society; 2000 Apr

13;342(15):1077–84.

12. Küçük NO, Aras G, Sipahi T, Ibiş E, Akar N,

Soylu A, et al. Evaluation of cardiac functions

in patients with thalassemia major. Ann Nucl

Med. 1999 Jun;13(3):175–9.

13. Vogel M, Anderson LJ, Holden S, Deanfield

JE, Pennell DJ, Walker JM. Tissue Doppler

echocardiography in patients with

thalassaemia detects early myocardial

dysfunction related to myocardial iron

overload. Eur Heart J. Eur Soc Cardiology;

2003;24(1):113–9.

14. Chrysohoou C, Greenberg M, Pitsavos C,

Panagiotakos DB, Ladis V, Barbetseas J, et al.

Diastolic Function in Young Patients with

Beta-Thalassemia Major: An

Echocardiographic Study. Echocardiography.

Wiley Online Library; 2006;23(1):38–44.

15. Ghugre NR, Enriquez CM, Gonzalez I,

Nelson MD, Coates TD, Wood JC. MRI

detects myocardial iron in the human heart.

Magn Reson Med. Wiley Online Library;

2006;56(3):681–6.

16. Mavrogeni SI, Markussis V, Kaklamanis L,

Tsiapras D, Paraskevaidis I, Karavolias G, et

al. A comparison of magnetic resonance

imaging and cardiac biopsy in the evaluation

of heart iron overload in patients with β-

thalassemia major. Eur J Haematol. Wiley

Online Library; 2005;75(3):241–7.

17. Aessopos A, Giakoumis A, Fragodimitri C,

Karabatsos F, Hatziliami A, Yousef J, et al.

Correlation of echocardiography parameters

with cardiac magnetic resonance imaging in

transfusion-dependent thalassaemia major.

Eur J Haematol. 2007 Jan;78(1):58–65.

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Oxygen pre-Exposure and Coronary Angioplasty Mohammadi A, et al.

18

Original Article Oxygen pre-Exposure and Coronary Angioplasty Mohammadi A, et al.

Pre-Exposure to Normobaric Hyperoxia Has No Effect on

Myocardial Injury Biomarkers after Percutaneous Transluminal

Coronary Angioplasty

Asghar Mohammadi1, MS; Shahin Raoufi

1, MS; Mehrdad Namdari

1*, MD;

Amir Raoufi1, MD; Khatereh Anbari

1, MD; Shiba Tahzibi

1, BS;

Mohammad Almasian1, MA; Bahram Rasoulian

2, MD, PhD

ABSTRACT

Background: It has been determined in animal models that hyperoxia-induced preconditioning

could reduce the ischemia/reperfusion injury of the heart tissue. Short-term ischemia and the

subsequent reperfusion occur unavoidably in coronary angioplasty. The purpose of the

present study was to determine the possible effects of oxygen pretreatment in inducing

preconditioning during percutaneous transluminal coronary angioplasty (PTCA).

Methods: Thirty-two patients, referred for elective angioplasty, were randomly divided into the

control group and the oxygen group. The subjects in the oxygen group were exposed to

normobaric oxygen (nearly 70% O2) via non-rebreathing masks for 1 hour at 12 and 2 hours

before PTCA. One hour after the last oxygen pre-exposure period, the patients underwent

PTCA (20 s of balloon inflation and 2 min of reperfusion). The chest pain score and cardiac

injury biomarkers were assessed 12 hours after coronary angioplasty. The biomarker data

and the chest pain scores were analyzed using the Mann–Whitney test and the Wilcoxon t-

test. Also, the ratio of patients with positive C-reactive protein results was compared

between the groups using the Fisher exact test.

Results: The troponin I and CKMB levels were elevated in both groups after angioplasty, but there

was no significant difference between the groups in this regard (P=0.23 and P=0.47,

respectively). The average pain score during balloon inflation in the oxygen group was

lower than that in the control group (2.8±1.2 vs. 4.11±1.21; P=0.008).

Conclusions: Two episodes of 1-hour pre-exposure to normobaric hyperoxia (nearly 70% O2) at 12

and 2 hours before PTCA had no significant effect on myocardial injury biomarkers,

troponin I, and CKMB. (Iranian Heart Journal 2016; 17(3):18-26)

Keywords: Chest pain Coronary angioplasty Hyperoxia Oxygen Preconditioning

1 Department of Cardiology, Madani Hospital, Lorestan University of Medical Sciences, Khorramabad, I.R. Iran. 2 Razi Herbal Medicines Research Center and Department of Physiology and Pharmacology, Lorestan University of Medical Sciences, Khorramabad,

I.R. Iran.

Corresponding Author: Mehrdad Namdari, MD; Madani Hospital, Lorestan University of Medical Sciences, Khorramabad, I.R. Iran.


Received: January 9, 2016 Accepted: June 14, 2016


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eart ischemia/reperfusion (I/R) not only

occurs after myocardial infarction but

also some degree of I/R may occur as a

result of elective procedures such as cardiac

surgery and coronary angioplasty.1 Ischemic

preconditioning (IPC) was originally

introduced by Murry et al.,2 who reported that

short periods of cardiac I/R in dogs increased

myocardial tolerance to more prolonged

subsequent ischemia and the consequent

reperfusion. Preconditioning consists of 2

windows of protection. The 1st window

begins immediately and the 2nd one

commences about 12 hours after ischemia.3

Many agents have been proven to induce

preconditioning or to be involved in IPC

mechanism; these include bradykinin,

adenosine, opioids, and reactive oxygen

species (ROS).4-7

Although excess amounts of

ROS produced during the reperfusion period

are involved in myocardial injury, a small

amount of ROS released during a short period

of ischemia or short term hyperoxic pre-

exposure can induce cardiac preconditioning,

while the cardioprotective effects of IPC are

canceled out by free radical scavengers.7-9

Additionally, many pharmacological agents

that generate ROS are able to reduce the

myocardial infarct size.8-10

Several animal

studies have shown that normobaric oxygen

pretreatment could reduce heart I/R injury.8-12

Moreover, it has been demonstrated in human

studies that hyperoxic pre-exposure improves

renal function in patients undergoing kidney

transplantation and that the administration of

hyperbaric oxygen improves myocardial

function after coronary artery bypass grafting

surgery (CABG).13,14

Percutaneous

transluminal coronary angioplasty (PTCA) is

a clinical setting with inevitable periods of I/R

and provides an excellent situation to assess

the effects of different possible protective

protocols in the human myocardium.15

Based

on previous animal studies on the effects of

oxygen pre-exposure on reducing cardiac I/R

injury and the role of ROS in the mechanism

of IPC, the present study for the 1st time

aimed to assess the effects of hyperoxic

preconditioning on heart injury biomarkers

and the chest pain score of patients

undergoing coronary angioplasty. It should be

noted that short-term hyperoxic pre-exposure

is a benign protocol, which leads only to a

sub-lethal increase in ROS production and

works as a possible inducer of cellular

endogenous defense mechanisms.

METHODS

Study Population

In this randomized clinical trial, 32 patients—

referred for elective PTCA—were randomly

divided into the oxygen group and the control

group. The study was carried out in Shahid

Madani Heart Hospital in Khorramabad, Iran,

between February 2013 and December 2014.

The study protocol was approved by the

Medical Ethics Research Committee of

Lorestan University of Medical Sciences.

First, the method of study was explained to

each patient and then a written informed

consent was obtained from each patient. All

the patients had stable angina when

undergoing coronary angioplasty. Patients

were included if they had isolated obstructive

lesions in at least 1 coronary artery branch

with ≥70% reductions in the luminal

diameter. Patients who had chronic

obstructive lung disease, exposure to oxygen

3 days prior to the commencement of PTCA,

episode(s) of chest pain 48 hours before

PTCA, Prinzmetal angina, or upper

respiratory infection were excluded from the

study. Both the control group and the oxygen

group consisted of 16 patients (10 men and 6

women, mean age =53±11 y and 53±9 y,

respectively). The mean ejection fraction

was 52±5% in the control group and

49±1% in the oxygen group. The last

episode of chest pain in all the patients

occurred 48 hours prior to PTCA.

Study Protocol

In this single-blinded randomized clinical

trial, each patient in the intervention (oxygen)

group was exposed to normobaric oxygen

twice (about 70% O2 in the inspired air) via a

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non-rebreathing mask at 12 and 2 hours

before PTCA. Each episode of oxygen

pretreatment lasted for 1 hour. One hour after

the last period of oxygen pre-exposure,

diagnostic angiography was performed and a

nonionic contrast agent (Visipaque GE,

Healthcare Ireland, osmolality: 320 mg/mL)

was administrated intravenously to each

patient. After diagnostic angiography, the

patients who had isolated obstructive lesions

in at least 1 coronary artery branch with ≥70%

reductions in the luminal diameter underwent

coronary angioplasty. The PTCA procedure

was performed via a routine technique using

the femoral approach. After prep and drape,

heparin (2000 IU) was administered

intravenously before coronary angioplasty.

Subsequently, the balloon was positioned

across the lesion and 1 session of balloon

inflation was done for 20 seconds. The stent

was thereafter inserted into the narrowed

coronary artery, and then there was a 2-

minute period of reperfusion. The balloon

inflation pressure ranged from 11 to 14 atm.

At the end of the procedure, the angioplasty

balloon was deflated and was withdrawn from

the stenotic site; and after 2 minutes, the

reperfusion study protocol was finished.

Similar procedures were carried out for the

control group patients, except that they were

not exposed to normobaric oxygen

pretreatment with oxygen masks. The

cardiologist who did the angiography and

angioplasty procedures was not aware of the

patients’ group and did not know whether the

patients had been subjected to oxygen

pretreatment or not.

Laboratory Measurements

Venous blood samples were obtained from

each patient before and 12 hours following

the PTCA procedure to measure troponin I

and CKMB levels and C-reactive protein

(CRP) as biomarkers of cardiac cell injury.

Troponin I and CKMB activities were

measured with standard kits (RAMP

Vancouver, Canada) using an auto-analyzer

and expressed as nanograms per milliliter

(ng/mL). Also, the level of highly sensitive C-

reactive protein (hs-CRP) was determined

with a standard kit (Enison, Iran) and

expressed as positive or negative. The normal

values of CKMB and cTnI were considered to

be ≤5 ng/mL and ≤0.1 ng/mL, respectively.

Assessment of Chest Pain At the end of balloon inflation, the severity of

chest pain was assessed with visual analog

scores by a nurse, who had no knowledge of

the patients’ group. The patients were asked

to indicate the severity of chest pain on a

scale of 0 (no pain) to 10 (severe pain).


The biomarker data are expressed as means ±

SDs. All the chest pain score data are shown

in the relevant figure, and the median has also

been presented. The data were analyzed with

SPSS, version 21, and the comparisons

between the groups were analyzed with the

Mann–Whitney test and the changes within

the groups were analyzed with the Wilcoxon

t-test. The ratio of cases with positive CRP

results was compared between the 2 groups

using the Fisher exact test. A P value <0.05

was considered statistically significant.

RESULTS

The demographic characteristics of the

control and oxygen groups are summarized in

Table 1. There were no statistically significant

differences between the 2 groups in terms of

the determined parameters. Angioplasty was

successfully performed in all the patients.

Chest Pain

The average pain score during balloon

inflation in the oxygen group was lower than

that in the control group (2.8±1.2 vs.

4.11±1.21; P=0.008). The chest pain score

data are depicted in Figure 1.

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Figure 1. Chest pain score at the end of balloon inflation in the control and oxygen groups. The chest pain score was higher in the control group than in the oxygen group. The line shows the median in each group. **, P=0.008

Cardiac Biomarkers

Troponin level: The troponin level changed

from 0.001±0.0001 ng/mL to 0.039±0.062

ng/mL in the oxygen group and from

0.0055±0.012 ng/mL to 0.061±0.21 ng/mL in

the control group. The changes were not

significant in either group (P=0.068 and

P=0.28, respectively). There were no

significant differences in the values of

troponin I between the 2 groups before and

after angioplasty (P=0.23) (Table 2).

CKMB level: The CKMB level changed from

1.44±1.18 ng/mL to 3.04±2.56 ng/mL in the

oxygen group and from 1.8±1.16 ng/mL to

3.78±3.61 ng/mL in the control group. The

changes were significant in both groups

(P=0.034 and P=0.017, respectively). There

were no significant differences in the values

of CKMB between the 2 groups before and

also after angioplasty (P=0.47) (Table 3).

CRP value: According to the Fisher exact

test, there was no significant difference in

terms of positivity between the 2 groups

(P=0.57) (Table 4).

Table 1. Demographic and clinical characteristics of the patients in the 2 groups

Variable Control Group

(n=16) Oxygen Group

(n=16)

Age (y) (mean± SD) 53±11 53±9

Gender, M/F 10/6 10/6

Hypertension, n 3 5

Smoking, n 5 5

Diabetes mellitus, n 3 9

Previous CABG , n 0 2

Previous PTCA , n 4 0

Left ventricular ejection fraction, %, (mean± SD) 52%±5 49%±1

Use of Long-acting nitrates, n 5 10

Use of β-blocker agents, n 9 8

Glibenclamide usage, n 3 7

Opioid usage, n 3 2

CABG, Coronary artery bypass graft surgery; PTCA, Percutaneous transluminal coronary angioplasty There were no statistically significant differences between the 2 groups in terms of the determined parameters.

Table 2. Serum troponin values before and after PTCA in the 2 groups

Group Value (Within each group)

Before PTCA (mean ± SD)

ng/mL

After PTCA (mean ± SD)

ng/mL P

Oxygen group 0.001±0.0001 0.039±0.062 0.068

Control group 0.0055±0.012 0.061±0.2 0.280

*P<0.05 significant PTC, Percutaneous transluminal coronary angioplasty

Table 3. Serum CKMB values before and after PTCA in the 2 groups

Group Value (Within each group)

Before PTCA (mean ± SD),

ng/mL

After PTCA (mean ± SD),

ng/mL P

Oxygen group 1.44±1.18 3.04±2.56 0.034

Control group 1.8±1.16 3.78±3.61 0.017

*P<0.05 PTC, Percutaneous transluminal coronary angioplasty

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Table 4. CRP changes following PTCA in the 2 groups

Group Positive CRP before PTCA

n (%)

Positive CRP after PTCA

n (%) P

Oxygen group 0(0%) 0(0%) >0.050

Control group 0(0%) 1(6.3%) 0/317

CRP, C-reactive protein; PTCA, Percutaneous transluminal coronary angioplasty

DISCUSSION

The results of the present study showed that 2

episodes of 1-hour pre-exposure to nearly

70% normobaric hyperoxia before PTCA had

no significant effect on the release of cardiac

injury biomarkers.

In some studies, cardiac biomarkers such as

troponin I and CKMB have been assessed

before and after angioplasty as the hallmarks

of cardiac cell injury.19,20

Of course, the

purpose of these studies was to determine the

relationship between biomarker changes after

PTCA and the patients’ outcome.21-23

Also in

a study, the beneficial effects of IPC during

PTCA on CKMB release were determined.24

Accordingly, in the present study, alongside

the chest pain score, cardiac biomarker

changes were measured as a sign of cardiac

cell injury to assess the possible

cardioprotective effects of hyperoxic pre-

exposure in coronary angioplasty. In addition

to oxygen, a number of pharmacological

agents like estrogen, nitroglycerine,

bradykinin, and enalaprilat have been shown

to be cardioprotective in patients undergoing

PTCA as determined by ST-segment changes,

echocardiographic findings, and severity of

chest pain.16-18

Oxygen therapy is a common

treatment for patients who experience

respiratory and/or cardiac failure, but oxygen

is a double-edged sword in this regard.

Hyperoxia worsens systolic myocardial

performance in healthy volunteers.25

It also

leads to the impairment of cardiac relaxation

and increased left ventricular filling pressures

in patients with and without congestive heart

failure.26

In addition, hyperoxia results in a

reduced cardiac output and increased

peripheral vascular resistance in patients with

acute myocardial infarction.27

Additionally, a

large number of studies have shown that

oxygen usage in normoxemic patients with

acute myocardial infarction has no beneficial

effects and that oxygen therapy is indicated

only in patients who are hypoxemic.28

Besides

these minor side effects of hyperoxia on

cardiovascular disease, atelectasis is a

pulmonary complication that occurs after a

short-term administration of high oxygen

fraction in the clinical setting. Of course, the

severity of atelectasis is much less

pronounced in patients who are pre-

oxygenated with 80% O2 as compared with

100% O2; and in patients breathing 60% O2,

atelectasis almost is not found.29

Oxygen

toxicity is the most important pulmonary

complication that occurs only after long-time

exposure and up to 24 hours for 80% O2 and 6

hours for 100% O2 is considered safe in

clinical practice.30

Moreover, it is well-known

that hyperoxia could also have beneficial

effects on patients because of its so-far

documented preconditioning-like effects on

the myocardium. For example, several

experimental studies have demonstrated that

the normobaric oxygen pretreatment of rats

reduces the infarct size and the incidence of

I/R-induced cardiac arrhythmias.11, 12, 31-33

Also, Sharifi et al.34

showed that hyperbaric

oxygen therapy was able to inhibit restenosis

after coronary angioplasty in patients who had

experienced acute myocardial infarction. On

the other hand, Karu et al.35

demonstrated that

pre-exposure to oxygen for 120 minutes

immediately before cardioplegia could not

significantly affect the release of troponin I

and CKMB after CABG. In another study,

Karu et al.36

again showed that 1 hour’s

oxygen pre-treatment, 30 minutes before

cardioplegia, did not have cardioprotective

effects against myocardial injury after CABG.

Although the hyperoxia protocol implemented

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in these studies was different, the results of

these studies were similar and no

cardioprotective effects were found for

hyperoxia. In our study, we tested 2 episodes

of 1-hour pre-treatment with oxygen, 12 and 2

hours before PTCA, to induce both early and

late phases of IPC; this protocol of hyperoxia,

however, did not significantly reduce

myocardial injury biomarkers (troponin I and

CKMB) after PTCA. Therefore, the results of

our study chime in with the results reported

by Karu et al. in cardiac surgery. In contrast,

Yogaratnam et al.13

used hyperbaric oxygen

preconditioning in patients undergoing CABG

and found lower levels of troponin in the

oxygen-pretreated group as a sign of less

damage to the cardiac cells. Moreover, the

authors reported that blood loss, blood

transfusion, and length of the intensive care

stay decreased in their intervention group. Of

course Yogarantam et al. used hyperbaric

rather than normobaric oxygen and this factor

probably can explain the difference of results

between these studies. There are possible

reasons that may explain the different results

of the studies by Karu et al. in CABG and our

study in PTCA: The hyperoxic pre-exposure

protocol (i.e., 1 or 2 episodes of 1 or 2 hours

of oxygen pretreatment) may not be sufficient

to activate intrinsic cardiac protective

pathways in humans. On the other hand,

inspiratory concentrations of oxygen are

another important factor in the induction of

preconditioning-like effects. For example,

Tähepõld et al.33

showed in their isolated

heart model study that 60 or 180 minutes of

≥80% O2 was able to reduce I/R-induced

infarct size in the rat heart and exposure to

95% O2, 80% O2, and 60% O2, but not 40%

O2, immediately before heart isolation

improved post-ischemic heart functional

parameters. Also, it has been shown in other

organs like the kidney that the protective

effects of hyperoxic pretreatment relate to the

oxygen exposure timing protocol.37

Animal

studies also have shown that there are

interspecies differences in terms of response

to pre-exposure to oxygen for the activation

of protective mechanisms. Therefore, further

studies are needed to determine the optimal

hyperoxia protocol (duration of exposure and

concentration of oxygen) in humans. It could

also be proposed that the preconditioning

phenomenon may not be induced by

hyperoxia in the human heart. This hypothesis

has already been considered in a study.36

However, thus far, there is not sufficient

evidence to support this idea. Another issue

examined in our study is that in contrast to

cardiac biomarkers, which exhibited no

significant changes between the 2 groups, the

chest pain scores decreased slightly in the

oxygen-pretreated group. Nonetheless, there

is a limitation that could affect the validity of

the chest pain score in our study. The duration

of balloon inflation was short (20 s), because

2 minutes of balloon inflation used in some

clinical studies16-18

was not approved by the

Medical Research Ethics Committee of

Lorestan University of Medical Sciences.

Thus, balloon inflation for a 20-second

duration was performed. This duration of

balloon inflation did not induce considerable

chest pain in all the patients.

In conclusion, 2 episodes of 1-hour pre-

exposure to normobaric hyperoxia (nearly

70% O2) at 12 and 2 hours before PTCA did

not induce cardioprotective effects in the

human heart as was determined by the

absence of significant differences in terms of

myocardial injury biomarkers, troponin I, and

CKMB between the oxygen-pretreated and

control groups. We suggest that further

studies be undertaken with a view to

determining the possible optimal oxygen

usage protocol before cardiac interventions to

activate preconditioning pathways in the

human heart.

Acknowledgments

The present study was supported by the Vice

Chancellorship for Research, Lorestan

University of Medical Sciences. The authors

would like to thank the staff of the CCU ward

in Shahid Madani Hospital.

http://ejcts.oxfordjournals.org/search?author1=P.+T%C3%A4hep%C3%B5ld&sortspec=date&submit=Submit

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C, Zilmer, M, Vaage J. Pretreating rats

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35. Karu I, Loit R, Zilmer K, Kairane C,

Paapstel A, Zilmer M, Starkopf J:

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Measuring and Modeling the Viscoelastic Properties of the Human Saphenous Vein Using the Pressure–Diameter Test Darjani M, et al.

27

Original Article


Measuring and Modeling the Viscoelastic Properties of the

Human Saphenous Vein Using the Pressure–Diameter Test

Morteza Darjani

1*, Ali Esteki

2, S. Ahmad Hassantash

3

ABSTRACT

Coronary artery bypass graft surgery is a customary therapy for vascular-related diseases, with

many thousands of such a surgical modality reported annually. In this surgery, the saphenous vein,

internal mammary artery, or radial artery is grafted in order to replace the coronary arteries. Using a

device designed in our own laboratory, we primarily sought to find a suitable model representing

the mechanical behavior of the human saphenous vein wall and then to assess its mechanical

properties. The most important feature of this device is its ability to simulate the physiological

conditions that exist inside the human body. We obtained 2 samples from the saphenous opening

and the medial epicondyle in patients with hypertension. After performing measurements at

frequencies near to the heart beat frequency and finding the loss and storage moduli for each

frequency, we found that—in the scanned frequency range—the Kelvin model was the best

approach to evaluating the viscoelastic behavior of the vessels. Our findings also indicated that the

elasticity and damping coefficients could be deemed equal along the length of the saphenous vein.

Accordingly, we would advise that heart surgeons not consider the changes in the mechanical

properties along the length of the saphenous vein at the time of transplantation. (Iranian Heart

Journal 2016; 17(3):27-35)

Keywords: Mechanical behavior Pressure–diameter test Viscoelastic modeling Soft tissue Saphenous vein

1Department of Biomedical Engineering, Science and Research Branch, Islamic Azad University, Tehran, I.R. Iran. 2 Department of Biomedical Engineering and Physics, Shahid Beheshti University of Medical Sciences, Tehran, I.R. Iran. 3Modares Hospital, Institute of Cardiovascular Research, Shahid Beheshti University of Medical Sciences, Tehran, I.R. Iran.

Corresponding Author: Morteza Darjani; Science and Research Branch, Islamic Azad University, Tehran, I.R. Iran.

E-mail:[email protected]; Tel: 09121572830

Received: November 29, 2015 Accepted: June 5, 2016

therosclerosis is a progressive and

gradual disease and is deemed the most

important health problem around the

globe. The disease occurs due to the

thickening of the coronary arteries. Annually,

in excess of 900 thousand deaths occur due to

cardiovascular diseases in the United States.

About three-quarters of these deaths are

related to coronary artery diseases.1 In Iran,

cardiovascular diseases, particularly coronary

artery diseases, have been introduced as the

1st and the most common cause of death in all

ages and in both sexes.2 These diseases of the

cardiovascular system are caused by damage

to arterial epithelial cells, which form the

innermost layer of vessels in the vicinity of

the blood flow.

All blood vessels comprise different

components such as smooth muscles, elastins,

collagens, fibroblasts, and ground

substances.3 Veins are structurally similar to

arteries but they have thinner walls, less

A

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28

elastic intermediate layers, and thicker

collagen external layers.4 In vessels with large

diameters, the mechanical properties are

essentially provided by the unique

viscoelastic properties of each component.

Where hypertension is the primary disease of

the middle layer of vessels (the tunica media),

atherosclerosis is the primary disease of the

inner layer (the tunica intima).5 In fact, the

latter constitutes the most frequent vascular

disorder overall. The risk factors for

atherosclerosis include hyperlipidemia,

smoking, diabetes mellitus, genetic

predisposition, social stress, sedentary

lifestyle, and hypertension.6 Specifically,

atherosclerotic plaques tend to occur at

locations with a complex geometry (e.g.,

along the outer section of a bifurcation), most

commonly in abdominal aortas, iliac arteries,

coronary arteries, femoral arteries, popliteal

arteries, carotid arteries, and cerebral arteries

(Fig. 1).

Figure 1. Some preferential locations of

atherosclerosis in blood vessels

Two different therapeutic methods, namely

stenting and coronary artery bypass graft

surgery (CABG), are usually considered for

atherosclerosis.7 Given the riskiness of these

methods, however, they are drawn upon only

in urgent cases of atherosclerosis, when the

drug therapy has failed. CABG is a common

treatment for vascular diseases and is done by

replacing the blocked coronary artery with a

saphenous vein, or an internal mammary

artery, or a radial artery.8 This surgical

modality is performed with the use of

autologous grafts thousands of times annually

the world over. There has, therefore, been

considerable incentive—not least among

biomechanical and biomaterial engineers—to

study the mechanical properties of the vessel

wall. Indeed, biomechanical engineers can

present the best part of the vessel for graft to

the surgeon by measuring the mechanical

properties of the replaced arteries in bypass

graft and comparing them with the

mechanical properties of the coronary artery.

Biomaterial engineers work on the

construction of artificial blood vessels and

prostheses; one of their major fields of

interest is to design and produce materials that

would match the mechanical behavior of

blood vessel walls.

The mechanical properties of the vessel wall

depend on the mechanical role of the passive

components (i.e., elastin and collagen fibers)

and the active components (i.e., smooth

muscle cells in the vessel). These components

determine the elastic, viscous, and inertial

properties of vessels. The inertial effect is

negligible due to the quasi-static assumption

of changes and slight accelerations.9

However, elastin and collagen fibers create

the elastic properties of a healthy vessel. The

modulus of the elasticity of the vessel wall

comes from the modulus of the elasticity of

elastin fibers and the modulus of the elasticity

of collagen fibers.10

The viscous properties of

vessels are due to the smooth muscle of the

vascular tissue.11

In the literature, there are 3 methods for

determining the mechanical properties of

blood vessels: the tensile test method,12

which

does not comply with the physiological

conditions of vessels in the body; in-vivo

method,13

which only determines the modulus

of elasticity; and pressure–diameter method,14

which is the most appropriate and the most

useful method. In the pressure–diameter test,

the exerted pressure in blood vessels is used.

In this test, the inflation (or the diameter) of

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the tested sample vessel is measured and the

pressure is recorded simultaneously. Then, the

mechanical properties of the vessel are

extracted using the ratio between pressure and

diameter at any point and the time delay

between these 2 signals. Using this method

for the human saphenous vein in patients with

hypertension and normotensive subjects with

coronary artery disease, Milesi et al.15

demonstrated that the vessels of the

hypertensive patients was stiffer than the

vessels of the normotensive subjects. Bia et

al.16-18

designed a simulator and conducted the

pressure–diameter test to examine the

dynamic properties of the vessel wall. The

authors drew upon the Kelvin model and

performed the test on 3 types of samples—

namely arteries, veins, and artificial

prostheses—and found that the elastic

modulus obtained from the arteries was

smaller than that of the veins and the artificial

prostheses. Additionally, they reported that

while the damping coefficient of the veins

was greater than that of the arteries, the

damping coefficient of the artificial

prostheses was lower than that of the arteries.

In their investigations, the pressure was

obtained by means of indirect testing and

using empirical relationships. However, in our

study, in addition to the direct measurement

of pressure and the elimination of errors

caused by empirical relationships, the main

innovation is the frequency change of the

pressure throughout the test. This frequency

change in the physiological range helps select

the best model for the dynamic behavior of

blood vessels.

METHODS

To obtain the mechanical properties of the

vessel wall tissue, we designed a device (the

pressure–diameter test device) to test blood

vessels (Fig. 2). The sample was installed

between 2 tubes (by means of silk suture

ligatures), such that one of them was fixed,

while the other one could be moved to and be

fixed at different locations. Inflation was

designed to replicate the pulsatility of the

physiological environment. The air pressure

was monitored by 2 pressure transducers,

located on both sides of the rigid cannula.

There being a small difference between the

measured pressure and the actual pressure

inside the center of the specimen, 2 pressure

transducers were used in the device, and the

pressure within the central length of the

sample was obtained using the average of

both sensors. Given the maximum matching

between the system of this device and the

physiological circulatory system, it provides a

reliable and appropriate environment to

achieve the mechanical properties of blood

vessels in operating conditions. Through the

application of pressure in a swinging manner

and use of a closed-loop control system in the

liquid with physiological properties, the

pressure inside the sample and the diameter

were recorded simultaneously by PC.

According to Figure 2, at point A, there was a

mechanism whereby the vessel could be

stretched manually. This stretch rate (2%) was

provided for pre-conditioning. The

measurement of the pre-conditioning was

done with a ruler mounted on the wall. The

liquid temperature of the container

surrounding the vessel was also adjustable; it

was set at a constant 37oC. According to the

physiological range, the frequency of the

applied pressure was adjustable from 0.1 to

10 Hz by a computer program. The data

acquisition frequency was adjusted at 50 Hz.

The capillaries were protected from possible

damage, when being transferred from the

hospital to the laboratory, by storage in a

container at 4oC. This is commonly

mentioned in the literature for the protection

of the properties of organs. Vessel removal

and the mechanical test lasted about 1.5

hours. We measured all excessive textures

(e.g., the fat) in the removed vessels and the

surroundings of the vessels before the test so

as to measure the diameter with a scaled band.

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Figure 2. Schematic depiction of the experimental set-up designed for monitoring the

pressure–diameter variations of blood vessels.

From 10 patients with hypertension, 2

samples were taken from the saphenous

opening (in the thigh area) and the medial

epicondyle (in the knee area) and sent to the

laboratory. Some information about the

patients is presented in Table 1. At the time of

removing the saphenous vein, the whole vein

from thigh to ankle was removed. Note also

that the author was provided with the parts

not having been used by the surgeon. In the

operating room, following vein removal,

heparin was injected into the vein to flush out

the blood. Additionally, the branch locations

were checked for bores, and the branches

were fastened with clips or surgical thread, if

needed.

Table 1. Characteristics of the studied cases Average Blood

Pressure (mm Hg) Weight

(kg) Age (y) Sex

15.7/9.5 79.219.3 55.86.7 Male: 6 Female: 4

In this experiment, for each sample,

frequencies with periods of 0.3, 0.4, 0.5, 0.6,

0.8, 1.0, 1.2, 1.4, 1.6, 1.8, and 2.0 seconds and

frequency ranges of 0.5–3.3 Hz or 30–200

bpm were applied. Thereafter, according to

the reference,14

E*, E1, and E2 were calculated

using the following equations:

max

max

E*

2

i e

2 2 2

e i

(R *R ) 12P

R R R

o

RR

In these equations, P was pressure, Ri was the

internal radius of the vessel, Re was the

external radius of the vessel, and R was the

average radius ) (. The storage (E1) and

loss (E2) moduli were obtained using the

following equations:

1E E*cos

2E E*sin

RESULTS

For 10 pairs of saphenous veins, obtained

from the subjects’ thighs and knees, the

diameter–pressure test was carried out using a

diastolic pressure of 89 mm Hg or a systolic

pressure of 158 mm Hg. The test was repeated

for each sample at 11 different frequencies.

To avoid the effect of waste tensions resulting

from the last loadings, we did not apply the

data of 5 sways at the beginning of the test.

The samples were obtained from the

saphenous veins of 48 men, hospitalized in

Shahid Modares Hospital to undergo CABG.

Figure 3 illustrates 4 states and demonstrates

the pressure–diameter diagram in which the

hysteresis loop is depicted. This diagram

proves the existence of damping elements and

the fitness of the viscoelastic model for

modeling the behavior of the saphenous vein.

It clearly shows that the energy loss level

increased with the applied frequency. The

loading and unloading stages of the dynamic

test are also marked in the diagram.

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Figure 3. Pressure–diameter hysteresis cycles, measured at different frequencies for a sample.

Figure 4 presents the diagram of the storage

and loss moduli with respect to the frequency

changes for the sample taken from the thigh

area. While the storage modulus (E1)

remained almost constant at 1101.466.8 mPa

along the frequency changes, the loss

modulus increased approximately linearly

(R2=0.87). The Kelvin viscoelastic model was

represented by a purely viscous damper and a

purely elastic spring connected in parallel.

The constancy of E1 and the direct

proportional change of E2 due to the

frequencies applied were necessary and

sufficient conditions for the confirmation of

the suitability of the Kelvin model for a

viscoelastic material.19

The slope of the fitted

line, which played the role of the damping

coefficient, η, in the Kelvin viscoelastic

model, was 4.13 mPa·s. Figure 5 reveals that

as regards the saphenous vein obtained from

the same subject’s knee, the SD for

E1=1029.8 mPa was 6.7% and η was 8.04

mPa·s.

Figure 4. Variations in the storage and loss moduli with respect to frequency for a saphenous opening sample.

Figure 5. Variations in the storage and loss moduli due to frequency for a sample taken from the knee area.

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Showing the pressure–diameter test results for

a sample pair of saphenous veins in the thigh

and knee areas, we verified the viscoelastic

behavior, fitness of the Kelvin viscoelastic

model for this sample, and linearity of the

material behavior. Table 2 presents the results

for the 10 tested pairs of saphenous veins.

Table 3 shows the means and SDs of the

properties the saphenous veins, obtained from

the thigh and knee areas. According to this

table, the average of η was 15.16 mPa·s in the

thigh area and 14.58 mPa·s in the knee area.

Similarly, the elastic coefficient, E, was about

722.44 mPa for the thigh area and 638.44

mPa for the knee area. Finally, the mean of

η/E was 0.021 mPa for the thigh are and 0.022

mPa for the knee area. In terms of these

means, the η and E values were higher for the

thigh.

Table 2. Obtained properties for 10 pairs of saphenous veins

Sample Number

Saphenous Opening (Thigh) Medial Epicondyle (Knee)

E (mPa) η (mPa·s) η/E (s) E (mPa) η (mPa·s) η/E (s)

1 477.4 16.2 0.034 421.9 13.1 0.031

2 369.8 10.4 0.028 303.3 7.7 0.025

3 1416.1 35.3 0.025 1063.7 29.2 0.027

4 275.8 5.5 0.020 265.3 4.6 0.017

5 1101.4 4.1 0.004 1029.8 8.0 0.008

6 440.7 9.8 0.022 425.8 6.2 0.015

7 579.5 8.3 0.014 527.9 11.9 0.023

8 789.9 17.5 0.022 741.3 22.1 0.030

9 668.1 15.1 0.023 628.3 15.8 0.025

10 1105.7 29.4 0.027 977.1 27.2 0.028

Table 3. Summary of the results for the saphenous ‎veins‎in‎the‎knee‎and‎thigh‎areas

Property Average SD Minimum Maximum

Saphenous opening (thigh)

η 15.16 10.16 4.10 35.30

E 722.4 374.6 275.8 1416.1

η/E 0.021 0.008 0.004 0.034

Medial epicondyle (knee)

η 14.58 8.82 4.60 29.20

E 638.4 301.0 265.3 1063.7

η/E 0.022 0.007 0.008 0.031

Table 3 shows that the η and E means were

lower for the knee than for the thigh.

Additionally, η/E was higher for the knee than

for the thigh. To statically study the

significance of these differences, we

employed the independent t-test (Table 4). A

comparison of η, E, and η/E showed no

significant differences between thigh and

knee vis-à-vis these indices (P>0.05). The

results, presented in Table 4, show that these

differences did not constitute statistical

significance.

Table 4. T-test‎results‎to‎compare‎thigh‎and‎knee‎on‎η,‎

E, and η/E

Property T Score df P

η 0.136 18 0.893

E 0.553 18 0.587

η/E -0.287 18 0.778

DISCUSSION

In the present study, 2 basic approaches were

considered to be more appropriate for testing.

In the related investigations,16-18

the

measurement of the flow rate was done to

calculate pressure at any moment using an

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33

empirical relationship. We created a new

design in the pressure–diameter test device

and measured pressure directly at any

moment. This approach eliminates some of

the errors that the use of empirical

relationships creates. Accordingly, the term

“pressure–diameter” fits our system in a more

realistic manner. In addition, most of the

previous studies were conducted using animal

vessels and there was a palpable need for

research on human vessels. Furthermore,

previous investigations conducted the test at a

constant frequency and extracted Kelvin

model coefficients without proving the

appropriateness of the model for the dynamic

behavior of the sample. Another question is

whether it is possible to consider the approach

adopted by the previous studies as the

“dynamic approach” without changing the

applied frequency. In the current study, all the

samples were placed under loading and

unloading conditions at different frequencies

within the physiological range so that

selection could be based on the viscoelastic

model frequency according to changes in the

loss and storage moduli. Then, the

coefficients of the model, including stiffness

and damping, were obtained.

Figure 2 shows that loss increased with a rise

in frequency. This proves that the loss in the

saphenous vein sample was a viscous loss.

The reason is that frequency can be regarded

as the representative of the term “speed”.

Viscous damping changes on the basis of

speed and not on the basis of Coulomb

damping. Each of the 4 modes illustrated in

Figure 2 is the representative of the tests

conducted at different frequencies. Using the

equations in Section 2, we obtained the

storage and loss moduli. Given that we

focused on the saphenous vein, we can

compare η and E based on the position of the

vein (i.e., thigh or knee). It is also deserving

of note that the coefficients of η and E vary

between people significantly. Indeed, it is

vitally important that this point be taken into

consideration in research on organs and vital

tissues. These variations are related to

patients’ features such as sex, age, smoking,

weight, and physical activities. Although it is

possible to arrive at such general conclusions

as increased roughness among smokers or

reduced tissue damping along with higher

age, the hypotheses raised should be

separately studied in depth in future studies.

We primarily sought to investigate the effects

of the location of the saphenous vein. Our

results revealed that the toughness coefficient

for the knee saphenous vein was smaller than

that for the thigh. Additionally, we found that

. Nevertheless, we

could not confirm the hypothesis of

because of the

high SD of and in

different people.

Krasinski et al.20

conducted a study on the

saphenous vein using the tensile stress–strain

test at a frequency of 1 Hz (Table 5). Their

results, despite the difference in the type of

the test applied, are concordant with ours

insofar as their η was almost equal to ours and

their E was approximately 60% of our value.

There were also some samples in which E

was almost similar to the value reported in

our paper.

Table 5. Values of the moduli of elasticity

and damping coefficients 20

E (mPa) η (mPa·s)

1235±76 13.2±0.97

CONCLUSIONS

The results of the present study demonstrated

that the saphenous vein walls behaved

viscoelasticly. All the tests revealed that there

was a loss between the applied pressure and

the diameter deviations in each sample. Most

importantly, the loss was directly related to

the increased frequency loading. Given that

loss results from viscose terms, the studied

vessel walls were a viscoelastic solid.

Furthermore, our results confirmed the

appropriateness of the Kelvin model in

explaining the dynamic behavior of the blood

vessels in the study time span. As the

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34

nonlinearity of tissue behaviors in expansive

areas has been proved in previous research,

the research results cannot be used for the

claimed areas whether for the pressure or the

applied frequency. Our findings also indicated

that the elasticity and dampness coefficients

could be deemed equal along the length of the

saphenous vein. Finally, cardiac surgeons are

advised not to take into account the changes

in the mechanical behavior along the length of

the saphenous vein at the time of

transplantation. In other words, it is not

possible mechanically to demonstrate that a

part of the saphenous vein is more desirable

for bypass surgery.

REFERENCES

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position and cardiovascular health, Ph.D.

Thesis, University of Michigan, 2008.

2. Fakhrzadeh H, Larijani B, Bandarian F, Adibi

H, Samavat T, Malekafzali H, Javadi HR,

Hojatzadeh E, The relationship between

ischemic heart disease and coronary risk

factors in population aged over 25 in Qazvin:

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3. Khan MG, Encyclopedia of Heart Diseases,

Academic Press, New York, pp. 118–121,

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4. Tanaka TT, Fung YC, Elastic and inelastic

properties of the canine aorta and their

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Bellenfant F, Barra J, Levenson J, Effects of

hypertension on viscoelasticity of carotid and

femoral arteries in humans, Hypertension

26:48–54, 1995.

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8. Bypass Surgery, Coronary Artery. American

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9. Argatov I, Mishuris G, Contact Mechanics of

Articular Cartilage Layers: Asymptotic

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Timi JRR, Comparative analysis of rupture

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bovine pericardium and great saphenous vein,

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11. Matthews PB, Azadani AN, Jhun CS, Ge L,

Guy TS, Guccione JM, Tseng EE,

Comparison of porcine pulmonary and aortic

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89:1981–1989, 2010.

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bovine veins, J. Mechanical Behavior of

Biomedical Materials 3:210–215, 2010.

13. Stephanis CG, Mourmouras DE,

Tsagadopoulos DG, On the elastic properties

of arteries. J Biomech 36:1727–1731, 2003.

14. Bia D, Armentano RL, Zocao Y, Barmak W,

Migliaro E, Cabrera Fisher EI, In vitro model

to study arterial wall dynamics through

pressure-diameter relationship analysis, Latin

Am Appl Res 35:217–224, 2005.

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Tommasi J, Gustavo JR, Grassi AO,

Mechanical properties of human saphenous

veins from normotensive and hypertensive

patientsm Ann Thorac Surg 66:455–461,

1998.

16. Valdez-Jasso D, Bia D, Zócalo Y, Armentano

RL, Haider M, Olufsen MS, Linear and

nonlinear viscoelastic modeling of aorta and

carotid pressure-area dynamics under in vivo

and ex vivo conditions, Ann. Biomed. Eng.

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17. Alvarez I, Viscoelastic and functional

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Armentano RL, Modeling the arterial wall

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Kaczmarek E, Krasińska B, Staniszewski R,

Pawlaczyk K, Stanisić M, Majewski P,

Majewski W, The influence of elastic

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Echocardiographic and Clinical Factors Related to the False Results of the Exercise Tolerance Test Sadeghian H, et al.

36

Original Article Echocardiographic and Clinical Factors Related to the False Results of the Exercise Tolerance Test Sadeghian H, et al.

Echocardiographic and Clinical Factors Related to

the False Results of the Exercise Tolerance Test

Hakimeh Sadeghian1, MD; Seyed Abdolhussein Tabatabaie*

2, MD;

Mahmmod Sheikh Fathollahi1, MD; Elham Hakki Kazazi

1, MD;

Arezou Zoroufian1, MD; Mahmood Sahebjam

1, MD;

Ali Mohammad Haji Zeinali1, MD

ABSTRACT

Background: We aimed to identify the clinical and echocardiographic factors related to false results

in the exercise tolerance test (ETT).

Methods: The present study included all patients who underwent transthoracic echocardiography

and the ETT, followed by coronary angiography, within 6 months prior to echocardiography

between March 2008 and March 2013. Clinical, 12-lead resting ECG, ETT, transthoracic

echocardiography, and coronary angiography data were extracted. The multivariable logistic

regression analysis was used to investigate the independent predictors of the false results of

the ETT.

Results: Totally, 4057 patients, who underwent transthoracic echocardiography, ETT, and

angiography, were enrolled. From 1132 patients with no significant coronary stenosis on

angiography, 979 (84%) had false-positive results in the ETT and 153 (14%) had true-

negative ETT results. In patients with significant coronary artery disease (CAD), there were

2728 (93%) true-positive and 197 (7%) false-negative ETT results. In our univariate

analysis, the patients with false ETT results were more likely to be female and younger than

the group with true ETT results. In our multivariable model, female gender increased and

right bundle branch block and dilated left ventricular diastolic internal dimension (LVID)

decreased the likelihood of a false-positive result in the ETT. The probability of a false-

negative result in the ETT was increased by resting ECG changes, hemiblocks, and dilated

LVID.

Conclusions: The diagnostic value of the ETT in patients with suspected CAD should be adjusted

according to sex, presence of resting ECG changes, CAD risk factors, and traditional

echocardiographic measurements. A dilated LV increases the risk of false-negative

results and decreases the likelihood of a false-positive result in the ETT. (Iranian Heart

Journal 2016; 17(3):36-45)

Keywords: Exercise tolerance test False positive False negative Echocardiography

1 Department of Cardiology, Tehran Heart Center, Tehran University of Medical Sciences, Tehran, I.R. Iran. 2 Department of Cardiology, Shariati Hospital, Tehran University of Medical Sciences, Tehran, I.R. Iran.

*Corresponding Author: Seyed Abdolhussein Tabatabaei, MD; Shariati Hospital, Tehran University of Medical Sciences, Tehran, I.R. Iran.


Received: February 20, 2016 Accepted: 15 July, 2016


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Echocardiographic and Clinical Factors Related to False Results of Exercise Tolerance Test Sadeghian H, et al.

37

he predictive power of normal as well

as abnormal exercise tolerance test

(ETT) results can provide us with a

very useful tool in the clinical management of

patients with coronary artery disease (CAD),

not least those with chest pain.1,2

As the ETT

results are considered a decisive factor in

performing angiography in patients with

suspected CAD,3 the false-positive results of

the ETT can impose invasive procedures on

patients with no obstruction in the coronary

artery and lead to inattention to patients with

false-negative ETT results. The

accompanying clinical and paraclinical factors

that increase the likelihood of false ETT

results require further evaluation with other

subsequent stress tests for a more precise

discrimination of patients in need of

angiography. In the previously published

studies, the accuracy of the ETT varies

broadly due to different factors such as

heterogeneity in the population

characteristics, methodological variations,

technical factors, data interpretation methods,

and drug consumption.4,5

The sensitivity, specificity, predictive value,

and accuracy of the ETT have been

accentuated in previous publications

abundantly.1,3,6,7

Nevertheless, to our

knowledge, there is no study to feed all

clinical and echocardiographic variations into

analysis as a whole. The purpose of the

present study was to identify the clinical and

echocardiographic factors that are strongly in

relation with false-positive ETT results on

normal angiograms and patients with CAD.

METHODS

From March 2008 up to March 2013, this

retrospective study recruited 4057 patients,

who underwent transthoracic

echocardiography, ETT, and angiography

within 6 months prior to echocardiography.

All the inclusion and exclusion criteria to

perform the ETT were in accordance with the

current guidelines.8

Patients with the Wolff–

Parkinson–White syndrome or a left

ventricular hypertrophy (LVH) pattern on

ECG or those using digoxin were excluded.

The study protocol was approved by our

institutional review board. All the patients

signed a consent form prior to angiography,

allowing the investigators of the hospital to

use their data for research purposes.

The ETT was performed in accordance with

the Bruce protocol—with continuous

monitoring of blood pressure, heart rate, and

12-lead ECG up to 5 minutes into recovery.

Drugs like β-blockers, calcium channel

blockers, and nitrates were discontinued 2

days before the test. From the ECG point of

view, ETTs with ≥1 mm horizontal or

downsloping ST-segment depression 0.08

seconds after the J point were interpreted as

positive. A nondiagnostic test result was

defined as an exercise ECG without ischemic

changes at a peak heart rate > 85% of the age-

predicted maximum rate.8 Patients with

nondiagnostic test results were excluded from

the present study.

Additionally, the patients’ clinical data—

comprising age, sex, symptoms, family

history of CAD (first-degree relatives with

CAD at age <55 y), current smoking (in the

past month), history of dyslipidemia (total

cholesterol >200 mg/dL or LDL ≥130 mg/dL

or HDL <30 mg/dL or TG >150 mg/dL or

taking lipid-lowering agents), hypertension

(repeated blood pressure >140/90 mm Hg or

under treatment with antihypertensive drugs),

and diabetes (repeated fasting glucose >126

mg/dL or controlled by diet, tablet, or

insulin)—were recorded systematically by

physicians at the time of clinic visit. In

sequence, paraclinical data such as 12-lead

resting ECG, ETT, and transthoracic

echocardiography were completed and

merged with the clinical data if any or all of

them were requested. 2D transthoracic

echocardiography was conducted using a

Vingmed-General Electric, Horten, Norway

machine. The patients were asked to lie in the

left lateral decubitus position, and

T

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echocardiography was conducted with a 3.5-

MHZ phased-array transducer. Measurements

were carried out in accordance with the

guidelines of the American Society of

Echocardiography.9 Finally, the databank was

completed with the results of coronary

angiography recorded by the treating

cardiologist. In the negative ETT cases,

eligibility for angiography was based on the

clinician’s assessment and the results of other

stress tests.

Within all the variables in the clinical

component of the database, we extracted age,

sex, family history of CAD, current smoking,

history of dyslipidemia, hypertension, and

diabetes. Additionally, we obtained ST-

segment or T-wave changes, existence of Q

wave, and conduction disorders such as right

bundle branch block, left bundle branch

block, and hemiblocks from the recorded

resting 12-lead ECG variables.


The data are presented as means ± SDs for the

continuous variables and frequencies (%) for

the categorical variables. The Pearson χ2

test

was used to compare the categorical variables,

and the Student t-test or the Mann–Whitney

test was employed to compare the continuous

variables between the study groups, as

required. Multivariable logistic regression

models with the backward selection method

for the factors associated with false, false-

positive, and false-negative ETT results were

constructed, and the associations between the

independent predictors and false, false-

positive, and false-negative ETT results in the

final models were expressed as ORs with 95%

CIs. Model calibration was estimated using

the Hosmer–Lemeshow goodness-of-fit

statistic. (A higher P implies that the model

fits the observed data better.) The variables

were incorporated into the multivariable

model if there was a P ≤ 0.15 in the univariate

analysis. A P <0.05 was considered

statistically significant. The statistical

analyses were conducted using SPSS, version

15 for Windows.

RESULTS

Of 45330 consecutive patients referred for

coronary angiography between March 2008

and March 2013, a total of 4057 patients met

our inclusion criteria and were enrolled in our

study. The mean age of the patients was 57.39

± 9.36 years. Sex distribution was 72% male

and 28% female. Based on the angiographic

results, 1132 (28%) patients had no or <50%

stenosis in coronary arteries and 2925 (72%)

had ≥50% stenosis of any coronary artery.

From the 4057 patients, who underwent the

ETT, 979 (24.1%) had false-positive, 2728

(67.2%) had true-positive, 197 (4.9%) had

false-negative, and 153 (3.8%) had true-

negative results.

Of the 1132 patients, who had no significant

coronary stenosis on angiography, 979

(86.5%) patients had false-positive results in

the ETT and 153 (13.5%) had true-negative

ETT results. In the CAD group, there were

2728 (93%) true-positive and 197 (7%) false-

negative ETT results. In the entire

population—according to the angiographic

results—2881 patients had true results and

1176 had false results in the ETT.

Table 1 depicts the clinical characteristics and

echocardiographic findings of the patients

with false ETT results in comparison to those

of the patients with true ETT results. In the

unadjusted analysis, the patients with false

ETT results were more likely to be female and

younger than those with true ETT results. All

the traditional CAD risk factors—namely

diabetes mellitus, smoking, hypertension,

dyslipidemia, and family history of CAD—

had a higher prevalence in the patients with

true ETT results. Moreover, the patients with

true ETT results had a significantly higher

frequency of resting ECG changes than those

with false ETT results.

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Table 1. Baseline clinical characteristics and echocardiographic findings of the total study population according to the ETT results

True Results

(n=2881)

False Results

(n=1176) P

Female 636(22.1) 489(41.6) <0.001

Age, mean ± SD 58.4±9.19 54.93±9.32 <0.001

BMI 27.39±3.92 27.91±4.12 <0.001

BSA 1.84±0.177 1.84±0.181 0.988

Symptomatic 2739(95.4) 1119(95.5) 0.953

Risk Factors

Family history of CAD 663(23.3) 239(20.7) 0.075

Hypertension 1248(43.5) 473(40.3) 0.061

Dyslipidemia 2333(81.4) 899(76.9) 0.001

Current smoker 599(20.8) 197(16.8) 0.003

Diabetes mellitus 821(28.5) 218(18.6) <0.001

ECG

Resting ECG changes 1146(40) 356(30.5) <0.001

Right bundle branch block 37(1.3) 19(1.6) 0.409

Left bundle branch block 31(1.1) 7(0.6) 0.156

Hemiblock 82(2.9) 35(3) 0.816

Echocardiography

Abnormal LA sizea 708(24.7) 283(24.1) 0.722

Abnormal LVIDdb 141(4.9) 77(6.6) 0.035

Abnormal IVSTc 1489(52) 589(50.4) 0.344

Abnormal PWTd 1426(49.9) 577(49.4) 0.753

LVMI, g/m2

97.45±27.49 92.69±27.36 <0.001

Left ventricular hypertrophye 768(27.3) 263(22.9) 0.004

Moderate or severe MR 128(4.4) 48(4.1) 0.607

Moderate or severe AI 48(1.7) 19(1.6) 0.909

Moderate or severe TR 59(2) 34(2.9) 0.105

*Categorical variables are presented as frequencies (percentages) and the continuous variables as means ± SDs. ETT, Exercise tolerance test; BMI, Body mass index; BSA, Body surface area; CAD, Coronary artery disease; LA, Left atrium; LVIDd, Left ventricular internal diastolic diameter; IVST, Interventricular septal thickness; PWT, Posterior wall thickness; LVMI, Left ventricular mass index (0.8*[(LVIDd + PWT + IVST)

3 – LVIDd

3] + 0.6)/body surface area); MR, Mitral regurgitation; AI,

Aortic insufficiency; TR, Tricuspid regurgitation a: male >4 cm, female >3.8 cm; b: male >5.9 cm, female >5.3 cm; c: male >1 cm, female >0.9 cm; d: male >1 cm, female >0.9 cm; e: male LVMI >115, female LVMI >95

One important interaction was found between

female gender and diabetes mellitus in

decreasing the likelihood of a false result in

the ETT. Among the conventional

echocardiographic measurements, dilated left

ventricular diastolic internal dimension

(LVID) was significantly more common in

the patients with false ETT results. The mean

of the left ventricular mass index (LVMI) in

the group with true ETT results was

significantly higher than that of the group

with false ETT results. Accordingly, left

ventricular hypertrophy (LVH) by

echocardiography was also more prevalent in

the group with true ETT results. In the

multivariate model, the contribution of the

above variables remained statistically

significant in the same pattern (Table 4).

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Table 2. Baseline clinical characteristics and echocardiographic findings of the patients with <50% stenosis on angiography according to the ETT results

True Negative (n=153)

False Positive (n=979)

P

Female 55(35.9)* 450(46) 0.021

Age, y 52.22±10.1 54.66±9.17 0.012

Symptomatic 147(96.1) 926(95) 0.557

BMI, kg/m2

29.22±4.99 27.94±4.15 0.003

BSA, m2

1.91±0.20 1.83±0.18 <0.001

Risk Factors

Family history of CAD 34(23.4) 182(18.9) 0.201

Hypertension 57(37.3) 379(38.8) 0.723

Dyslipidemia 116(76.3) 736(75.6) 0.857

Current smoker 20(13.1) 144(14.7) 0.593

Diabetes mellitus 24(15.7) 161(16.5) 0.809

ECG

Resting ECG changes 48(31.4) 225(23.1) 0.028

Right bundle branch block 9(5.9) 14(1.4) 0.001

Left bundle branch block 2(1.3) 7(0.7) 0.455

Hemiblock 5(3.3) 24(2.5) 0.562

Echocardiography


Abnormal LVIDdb 17(11.1) 52(5.3) 0.005

Abnormal IVSTc 76(49.7) 489(50.3) 0.893

Abnormal PWTd 69(45.4) 491(50.5) 0.24

LVMI, g/m2

94.79±34.1 90.95±26.35 0.279

Left ventricular hypertrophye 38(25.5) 212(22.1) 0.36


Moderate or severe AI 5(3.3) 15(1.5) 0.139

Moderate or severe TR 6(3.9) 30(3.1) 0.575

*Categorical variables are presented as frequencies (percentages) and the continuous variables as means ± SDs. ETT, Exercise tolerance test; BMI, Body mass index; BSA, Body surface area; LA, Left atrium; LVIDd, Left ventricular internal diastolic diameter; IVST, Interventricular septal thickness; PWT, Posterior wall thickness; LVMI, Left ventricular mass index (0.8*[(LVIDd + PWT + IVST)

3 – LVIDd

3] + 0.6)/body surface area); MR, Mitral regurgitation; AI, Aortic insufficiency; TR, Tricuspid regurgitation

a: male >4 cm, female >3.8 cm; b: male >5.9 cm, female >5.3 cm; c: male >1 cm, female >0.9 cm; d: male >1 cm, female >0.9cm; e: male LVMI >115 female LVMI >95

As the clinical and paraclinical conditions that

accompany a false ETT result may differ

between false-positive and false-negative ETT

results, we classified the patients into 2

groups based on their angiographic results:

patients with no stenosis or stenosis <50% on

the angiogram and patients with ≥50%

occlusion of any coronary artery. The results

of the univariate comparison between the

true-negative and false-positive ETT results

and true-positive and false-negative results of

the ETT in terms of clinical characteristics,

ECG findings, and echocardiographic

measurements are exhibited in Table 2 and

Table 3—respectively. There were

statistically significant differences between

the true-negative and false-positive ETT

results in female gender, resting ECG

changes, right bundle branch block, and

dilated LVID. After adjusting, female gender

increased and right bundle branch block and

dilated LVID decreased the likelihood of a

false-positive result in the ETT (Table 5). A

comparison of the true-positive and false-

negative ETT results indicated that the

probability of a false-negative result in the

ETT was increased by resting ECG changes,

hemiblocks, and dilated LVID (Table 6).

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Table 3. Baseline‎clinical‎characteristics‎and‎echocardiographic‎findings‎of‎the‎patients‎with‎≥50%‎

stenosis on angiography according to the ETT results

True Positive

(n=2728)

False Negative

(n=197) P

Female 581(21.3)* 39(19.8) 0.619

Age, mean ± SD 58.74±9.02 56.23±9.98 0.001

Symptomatic 2592(95.4) 193(98) 0.090

BMI 27.30±3.83 27.75±4.00 0.108

BSA 1.84±0.18 1.90±0.18 <0.001

Risk Factors

Family history of coronary artery disease 629(23.3) 57(29.7) 0.045

Hypertension 1191(43.8) 94(47.7) 0.288

Dyslipidemia 2217(81.7) 163(83.2) 0.605

Current smoker 579(21.3) 53(27) 0.059

Diabetes mellitus 797(29.2) 57(28.9) 0.928

ECG

Resting ECG changes 1098(40.4) 131(66.8) 0.001

Right bundle branch block 28(1) 5(2.5) 0.062

Left bundle branch block 29(1.1) 0 0.998

Hemiblock 77(2.8) 11(5.6) 0.033

Echocardiography


Abnormal LVIDdb 124(4.6) 25(12.7) <0.001

Abnormal IVSTc 1413(52.2) 100(51) 0.758

Abnormal PWTd 1357(50.2) 86(43.9) 0.087

LVMI, g/m2

97.6±27.08 101.44±30.57 0.276

LVHe 730(27.4) 51(26.7) 0.843


Moderate or severe AI 43(1.6) 4(2) 0.624

Moderate or severe TR 53(1.9) 4(2) 0.939

*Categorical variables are presented as frequencies (percentages) and the continuous variables as means ± SDs. ETT, Exercise tolerance test; BMI, Body mass index; BSA, Body surface area; LA, Left atrium; LVIDd, Left ventricular internal diastolic diameter; IVST, Interventricular septal thickness; PWT, Posterior wall thickness; LVMI, Left ventricular mass index; LVH, Left ventricular hypertrophy; MR, Mitral regurgitation; AI, Aortic insufficiency; TR, Tricuspid regurgitation a: male >4 cm, female >3.8 cm; b: male >5.9 cm, female >5.3 cm; c: male >1 cm, female >0.9 cm; d: male >1 cm, female >0.9 cm; e: male LVMI >115 female LVMI >95

Table 4. Association between the ETT false results and the clinical characteristics and echocardiographic findings

Total Population

(N=4058)

Univariate

OR (95% CI) P

Multivariable

OR (95% CI) P

Female 2.51 (2.72-2.906) <0.001 3.629 (2.986-4.410) <0.001

Age (y) 0.960 (0.953-0.967) <0.001 0.957 (0.949-0.966) <0.001

Family history of coronary artery disease 0.859 (0.727-1.015) 0.075 0.627 (0.521-0.755) <0.001

Hypertension 0.876 (0.763-1.006) 0.061 0.865 (0.738-1.014) 0.074

Dyslipidemia 0.761 (0.645-0.898) 0.001 0.696 (0.581-0.835) <0.001

Current smoker 0.766 (0.641-0.914) 0.003 0.802 (0.655-0.983) 0.033

Diabetes mellitus 0.571 (0.483-0.675) 0.001 0.677 (0.532-0.861) 0.001

Female with diabetes mellitus 0.500 (0.347-0.723) <0.001

Resting ECG changes 0.659 (0.570-0.762) <0.001 0.688 (0.586-0.806) <0.001

LVHa 0.792 (0.674-0.930) 0.004 0.769 (0.637-0.928) 0.006

Abnormal LVIDdb 0.812 (0.624-1.057) 0.035 1.451 (1.037-2.029) 0.030

ETT, Exercise tolerance test; LVH, Left ventricular hypertrophy; LVIDd, Left ventricular internal diastolic diameter a: male LVMI >115 female LVMI >95; b: male >5.9 cm, female >5.3 cm Area under the curve =69.8% (95% CI: 67.9 – 71.6%; P <0.001), P for Hosmer–Lemeshow goodness-of-fit statistic =0.383

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Table 5. Association between the ETT false-positive results and the clinical characteristics and echocardiographic findings in the patients with <50% stenosis on angiography

Total Population (N=1132) Univariate OR

(95% CI) P

Multivariable OR

(95% CI) P

Female 1.516 (1.065-2.158) 0.021 1.483 (1.027-2.142) 0.035

Age (y) 1.029 (1.01-1.048) 0.003 1.030 (1.011-1.049) 0.002

Resting ECG changes 0.659 (0.454-0.956) 0.028 0.717 (0.488-1.054) 0.09

Right bundle branch block 0.234 (0.099-0.55) 0.001 0.213 (0.087-0.522) 0.001

Abnormal LVIDda 0.7 (0.374-1.309) 0.005 0.455 (0.246-0.841) 0.012

ETT, Exercise tolerance test; LVIDd, Left ventricular internal diastolic diameter a: male >5.9 cm, female >5.3 cm Area under the curve =64.7% (95% CI: 59.8 – 69.5%; P <0.001), P for Hosmer–Lemeshow goodness-of-fit statistic =0.383

Table 6. Association of ETT false negative result with clinical characteristics and echocardiographic findings in patients‎with‎≥50%‎stenosis‎in‎angiography

Total population (n=2925) Univariable OR (95% CI)

p-value multivariable OR (95% CI)

p-value

Age 0.970 (0.954-0.986) <0.001 0.968 (0.952-0.984) <0.001

Resting ECG changes 2.968 (2.183-4.033) <0.001 2.600 (1.879-3.599) <0.001

Hemi block 2.028 (1.06-3.882) 0.033 2.032 (1.011-4.087) 0.047

Abnormal LVIDda 1.272 (0.785-2.061) <0.001 2.295 (1.377-3.824) 0.001

Abnormal PWTb 0.775 (0.579-1.038) 0.087 0.755 (0.558-1.022) 0.069

ECG: electrocardiogram, LVIDd: left ventricular internal dimension diastolic, PWT: posterior wall thickness a: male>5.9cm, female>5.3cm; b: male>1cm, female>0.9cm

DISCUSSION

The current study suggests that the utilization

of clinical characteristics, ECG findings, and

echocardiographic measurements could adjust

the discriminatory ability of the ETT in CAD

diagnosis.

Our results showed that female gender

increased the likelihood of a false ETT result

(both false-positive and false-negative) by

threefold. This finding supports the results of

the previous studies that reported a 36%

frequency of false ETT results in

women.5,7,10,11

It has been discussed that this

pattern can be in relation to the digitalis-like

effects of estrogen, higher vascular resistance

and increased oxygen demand, higher mean

pulmonary pressure with exercise, limited

vasodilator reserve, and decreased hematocrit

in women.12-14

It is recommended that for the

diagnosis of CAD in women, physicians

consider the patient’s age, existence of CAD

risk factors, and resting ECG changes and

make the decision to apply the ETT or other

stress tests such as myocardial perfusion scan

or stress echocardiography.

We found that resting ECG changes and

hemiblocks in ECG increased the likelihood

of a false-negative ETT result by more than

twofold in the patients with significant CAD

compared to those without these changes.

This can be due to the interference in the

interpretation of the ETT results. The majority

of the previous studies have published

conflicting results.15-17

Be that as it may, it

seems that in these conditions, it is logical to

classify patients according to the type and the

level of ECG changes.18,19

Since patients with

ST-T abnormalities have a higher prevalence

of CAD, severe CAD, LV dysfunction, and

higher cardiac mortality and morbidity than

those with normal resting ECG,19-22

the value

of further follow-up and other stress tests in

patients with suspected CAD with resting

ECG changes and negative ETT results is

demonstrably highlighted.

The new finding in our study is that the

probability of a false-negative ETT result was

doubled in the patients with significant CAD

and dilated LVID (males >5.9 cm and females

>5.3 cm) compared to those with significant

CAD and normal LVID. LV enlargement is

associated with both systolic and diastolic

dysfunction, giving rise to an increase in the

end-diastolic and end-systolic volumes. The

potassium shifting process, which is present

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in producing subendocardial current of injury

and ST depression on ECG, may be altered by

those changes and ischemic ST response is

likely to be reduced.23

Previous studies have argued that LVH

increases the probability of false-positive

results in the ETT.24,25

In our study, we did

not obtain this result. It may be argued that in

the previous studies, specific criteria

accounting for the diagnosis of LVH were

based on ECG and not on echocardiography.

As it has been revealed that the sensitivity of

ECG for ECG-defined LVH is only 6.9%,26

ECG is a poor screening test for detecting

LVH compared to echocardiography. To our

knowledge, there is no study to report the role

of echocardiographically defined LVH in the

false-positive results of the ETT. Further

studies are required to confirm our results.

Study Limitations

First and foremost among the limitations of

the present study is its retrospective design. In

addition, eligibility for angiography was

based on the clinician’s assessment in patients

with negative ETT results. Therefore,

coronary angiography was not performed on

all the subjects and the patients with true-

negative ETT results but without angiography

were excluded. Another weakness of note is

that although all the ETT examinations were

done according to the current guidelines of

the ACC/AHA, variables such as the Duke

treadmill score were not included in the

angiography registry—resulting in the

unavailability of such variables for reporting.

Moreover, because of the retrospective nature

of the study, echocardiographic findings

reported by different physicians were drawn

upon—which may have influenced the

results.

CONCLUSIONS

The diagnostic value of the ETT in patients

with suspected CAD should be adjusted

according to sex, presence of resting ECG

changes, CAD risk factors, and traditional

measurements on echocardiography. Based on

clinical, paraclinical, and echocardiographic

variables—other stress tests for the initial

assessment of patients with suspected CAD or

confirmation of the ETT results should be

considered. A dilated LV increases the risk of

false-negative results and decreases the

likelihood of a false-positive result in the

ETT.

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JS, Solomon SD, Spencer KT, Sutton MS,

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American Society of Echocardiographyʼs

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Bonow R, Eugene, Braunwald E. Braunwald’s

heart disease: a textbook of cardiovascular

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Zencka AE, Runco V. Significant sex

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AL, Tsialtas D, Vasini P, Visioli O.

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computer study. Cardiology. 1984; 71: 341-7.

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Stratbucker RA. The effect of baseline

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)

AML and Cardiac MRI Nikdoust F, et al.

46

Case Report AML and Cardiac MRI Nikdoust F, et al.

Right Ventricle Tumoral Mass in Acute Promyelocytic Leukemia

(AML M3): Cardiac Magnetic Resonance Findings

Farahnaz Nikdoust1, MD; Zahra Alizadeh Sani

2, MD;

Seyed Abdolhussein Tabatabaei1*, MD

ABSTRACT

Intracardiac masses found on 2D echocardiography in patients with leukemia can present diagnostic

challenges. A correct differentiation between thrombi, metastases, and infective vegetations is

important in the management of patients with leukemia.

We describe a 24-year-old male patient, who was diagnosed with acute myelogenous leukemia

(APL, AML M3). 2D transthoracic echocardiography showed 2 inhomogeneous highly mobile

masses (10×13 and 6×9 mm) in the right ventricle (RV). The masses were attached to the chordae

tendineae and exhibited movements compatible with the cardiac cycle. Cardiac magnetic resonance

imaging revealed 3 mobile masses in the RV attached to the RV trabeculations with isosignal

intensity on steady-state free precession sequence. There was no obvious evidence of mass invasion

or necrosis. On the last transesophageal echocardiography (6 months after the initial admission), the

mass did not exist anymore. At the time of paper compilation, the patient has no complaints and is

in remission.

This report underscores the importance of cardiac magnetic resonance imaging in differentiating

intracardiac thrombi from aggregations of tumoral cells in APL, AML M3. (Iranian Heart Journal

2016; 17(3):46-50)

Keywords: Right ventricle Mass Tumor Leukemia Cardiac magnetic resonance imaging

1 Department of Cardiology, Shariati Hospital, Tehran University of Medical Sciences, Tehran, I.R. Iran. 2 Department of MRI, Shahid Rajaie Cardiovascular, Medical, and Research Center, Iran University of Medical Sciences, Tehran, I.R. Iran.

Corresponding Authors: Seyed Abdolhussein Tabatabaei, MD; Shariati Hospital, Tehran University of Medical Sciences, Tehran, I.R. Iran.


Received: January 11, 2016 Accepted: July 4, 2016

ntracardiac masses are usually synonymous

with challenge. Generally speaking, such

masses are categorized into primary and

secondary ones. Primary cardiac tumors are

relatively rare, and about 80% of such

primary tumors are benign such as myxomas

and lipomas.1 Secondary or metastatic tumors

occur more commonly in the 6th and 7th

decades of life. With recent advances in the

treatment of primary tumors, cardiac

metastases have increased.2 Apart from the

tumors of the central nervous system, every

malignant tumor can metastasize to the heart.

Particularly, lung and breast tumors as well as

lymphomas and leukemia have been

implicated in the literature.2

One of the most important malignancies in

which intracardiac metastases have been

implicated is leukemia. Cardiac infiltrates

have been detected in the post-mortem

examinations of about 30% of patients who

died from leukemia.2 In fact, infiltrates in

I

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various locations such as the pericardium,

myocardium, and endocardium have been

noted in this entity.2

Acute myelogenous leukemia (AML)

encompasses a group of hematologic

malignancies affecting the precursor (blast)

cells of the myeloid lineage. These are

characterized by uncontrolled proliferation of

immature blast cells mainly in the bone

marrow, but also in the peripheral blood and

other tissues. Through histochemical,

immunological, and morphological findings,

AML is classified into different types. One of

these types is acute promyelocytic leukemia

(APL, AML M3). This type of AML has

somehow particular features that have

attracted the attention of many clinicians.

These include higher risks of disseminated

intravascular coagulation and increased risks

of coagulopathy manifested either as

thrombocytopenia or thrombosis.3

Intracardiac tumors in APL have been

reported in a limited number of case reports.4-

6 The differential diagnoses for intracardiac

masses in patients diagnosed with AML

include coincidental primary cardiac tumors,

infective vegetations because of the

malfunction of the immune system in

leukemia, or formation of thrombi due to

coagulation dysfunction as a result of

leukemia.4-6

A 4th possible differential may

be tumoral masses as a result of the

aggregation of tumoral leukemic cells inside a

cardiac chamber. All these conditions are rare.

In the reports indicated in the literature,4-6

all

masses were verified as thrombi resulting

from APL.

Apropos the diagnosis and follow-up of such

intracardiac lesions, 2D echocardiography has

been a useful diagnostic method in that it can

help with the diagnosis of the presence of an

intracardiac mass and with its follow-up.

Echocardiography can yield valuable

information about the location, appearance,

and mobility of such masses. However,

transthoracic echocardiography (TTE) alone

may not be a sufficient diagnostic tool in

differentiating between metastases from a

primary tumor and vegetations. Hence,

transesophageal echocardiography (TEE) or

other diagnostic imaging modalities and

clinical observations are usually necessary.7

In addition to 2D echocardiography, cardiac

magnetic resonance imaging (CMR) can be

drawn upon to diagnose these masses.6,8

Some

studies have claimed that CMR is superior to

both TTE and TEE in the detection and

evaluation of cardiac masses.1,9,10

A correct

diagnosis of any of the above-mentioned

conditions is, albeit difficult, crucial.

Differentiating between a thrombus and a

cardiac tumoral mass, based solely on echo

appearance, could be challenging.

We herein report our experience regarding a

patient, who had a confusing picture of an

intracardiac mass, and discuss his

echocardiographic findings and CMR images.

Case Presentation

The patient described here is a 24-year-old

man, who presented in September 2013 to

another hospital complaining of fever, chills,

coughs, and hemoptysis of 10 days’ duration.

He had no remarkable past medical history.

His temperature was 38°C, and his respiratory

rate was 18/min. His conjunctivae were pale.

Cardiac auscultation was normal. Lung

examination showed basilar rales. For the

exclusion of infective endocarditis, TTE was

done at that center: It ruled out infective

endocarditis but showed intracardiac masses.

In the patient’s complete blood count test,

leukocytosis (51300/micL), anemia

(hemoglobin =10.7g/dL), and thrombo-

cytopenia (61000/micL) were observed. The

patient was then referred to our tertiary

medical center for further evaluation. With

the clinical suspicion of hematologic

malignancies, we performed bone marrow

aspiration, which showed 80% blasts and

abnormal promyelocytes. Based on the bone

marrow studies, the diagnosis of APL, AML

M3 was made.

For the evaluation of the intracardiac masses

reported earlier, the patient underwent 2D

TTE, which showed 2 inhomogeneous highly

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mobile masses (10×13 and 6×9 mm) in the

right ventricle (RV). The masses were

attached to the chordae tendineae and had

movements compatible with the cardiac cycle.

Some densities were also observed in the RV.

The left ventricular ejection fraction was 60%

(Fig. 1).

Spiral chest computed tomography scan

demonstrated air space consolidation in both

lower lobes with a few paratracheal lymph

nodes with no pleural effusion. Lower limb

and pelvic Doppler ultrasound did not

demonstrate deep venous thrombosis. Since

cardiac biopsy was not possible, CMR was

performed: It showed 3 mobile masses (17×3,

4×4, and 6×4 mm) in the RV attached to the

RV trabeculations with isosignal intensity on

steady-state free precession (SSFP) sequence.

There was no obvious evidence of mass

invasion into the other cardiac or extracardiac

structures. On T1-weighted images with fat

suppression, there was no evidence of

significant fat components in the masses. The

mass was not enhanced with gadolinium. RV

size was normal (Fig. 2).

Figure 2. (A) Sine steady-state free

precession (SSFP) image shows small and round mobile right ventricular (RV) masses, which are attached to the RV trabeculations. (B) Short T1 inversion recovery (STIR) image shows an RV mass with isosignal intensity. (C) T1-weighted image shows an RV mass with isosignal intensity. (D) First-pass perfusion image in the SAX plane does not show Gadolinium enhancement.

Figure 1. Parasternal right ventricular inflow

view of transthoracic echocardiography shows 2 inhomogeneous highly mobile masses (10×13 and 6×9 mm) in the right ventricle attached to the chordae tendineae.

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Chemotherapy with arsenic and all-trans

retinoic acid (ATRA) was initiated along with

warfarin. Antibiotics (vancomycin and

gentamicin), started earlier for the

presumptive diagnosis of infective

endocarditis, were discontinued. After 1

month, repeated TTE showed a 50% decrease

in the size of the mass. The chemotherapy

was then continued for 4 more cycles with

arsenic and hydroxyurea. Warfarin has been

continued since the patient’s discharge from

the hospital. On the last TEE (6 months after

the initial admission), the mass did not exist

anymore. At the time of the compilation of

this paper, the patient has no complaints and

is in remission.

DISCUSSION

APL is a distinct subtype of AML. APL is

characterized by a balanced chromosomal

translocation between chromosomes 15 and

17, young age of the patients at the time of

diagnosis, and unique response to ATRA

treatment.6 It constitutes about 15% to 20% of

all cases of AML. Vegetations secondary to

infections caused by defective leukocyte

function, thrombus formation owing to

coagulopathy seen in AML, and tumoral

masses secondary to the aggregation of

tumoral leukemic cells are the differential

diagnoses regarding the intracardiac masses

seen in patients with AML.

Here, initially, echocardiography enabled us

to detect 2 intracardiac masses in the patient’s

RV. The approach to such masses can be

challenging. First, in light of consultation

with the hematology services, a diagnosis of

thrombus was high on our differential list.

Indeed, thrombi in APL have been reported

previously in the literature, with 10% of

patients with APL known to have thrombosis

upon admission.3-6

As regards our patient,

however, after a long-term follow-up and in

light of the CMR images, we are of the belief

that that this mass was likely an aggregate of

blastocysts and not a thrombus. Evidence

favoring the tumoral nature of the mass

secondary to AML is that the size of the

tumor decreased significantly by half after the

1st month of chemotherapy. This evidence

was further bolstered by CMR appearance.

And as for echocardiography, in case of a

mass, echo appearance will show central

necrosis and peripheral calcification, whereas

in case of a thrombus, echo appearance will

demonstrate clot lysis—which usually starts

from its periphery. Another finding that rules

out a thrombus here is that we did not find

deep vein thrombosis on Doppler studies. A

thrombus in the right heart usually is found in

the setting of embolization from a deep vein

thrombosis in the pelvis or lower extremities.4

Cahill et al.5 described a 29-year-old female

patient, who presented with sudden-onset

chest pain. Her ECG as well as cardiac

biomarkers showed myocardial infarction.

Echocardiogram revealed a mass at the left

ventricular apex. CMR demonstrated apical

scarring, suggestive of myocardial infarction

as well as apical thrombi in the left ventricle

and the RV. Early gadolinium image

differentiated the thrombus from the

myocardium. Diagnostic coronary

angiography did not reveal coronary artery

disease. The patient had elevated D-dimer,

dropping neutrophil count, and prolonged

prothrombin time and partial thromboplastin

time. Based on bone marrow biopsy, the

diagnosis of APL was made for the patient.

CMR of the patient showed that the mass was

isointense to the myocardium. The patient

received ATRA and idarubicin chemotherapy

and remained in remission at the last follow-

up after 2 months. Repeated CMR showed a

reduction but not the resolution of the cardiac

thrombus.

Potenza et al.6 described a 22-year-old male

patient, who presented with the initial

complaint of palpitation. 2D

echocardiography showed a mobile

heterogeneous bilobate mass in the RV. CMR

demonstrated a mass with heterogeneous

signal intensity on T1-weighted images with

no contrast enhancement. With leukopenia

found on laboratory investigations, bone

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marrow biopsy was done and it demonstrated

90% blasts. With the diagnosis of APL,

ATRA was ordered for the patient. Then, after

the recovery of the bone marrow, the mass

was removed surgically. Histological

examination showed amorphous eosinophilic

material with inflammatory cells, consistent

with thrombosis as a result of APL. The

patient remained in remission until the last

follow-up.

To the best of our knowledge, our report of an

APL patient with a tumoral mass—as

demonstrated by CMR and

echocardiography—is the 1st of its kind in the

literature. Our report highlights not only the

importance of the correct diagnosis of such

masses with the use of CMR but also the

advantages of CMR over 2D

echocardiography. Echocardiography was not

sufficiently informative in differentiating the

thrombus from the aggregation of tumoral

cells. It can be concluded that when faced

with a patient diagnosed with APL, clinicians

can draw upon CMR as a useful method to

differentiate between thrombi and tumoral

masses.

Disclosure: None.

REFERENCES

1. Narin B, Arman A, Arslan D, Simsek M,

Narin A. Assessment of cardiac masses:

magnetic resonance imaging versus

transthoracic echocardiography. Anadolu

kardiyoloji dergisi : AKD = the Anatolian

journal of cardiology. 2010;10(1):69-74.

2. Reynen K, Kockeritz U, Strasser RH.

Metastases to the heart. Annals of oncology :

official journal of the European Society for

Medical Oncology / ESMO. 2004;15(3):375-

81.

3. De Stefano V, Sora F, Rossi E, Chiusolo P,

Laurenti L, Fianchi L, et al. The risk of

thrombosis in patients with acute leukemia:

occurrence of thrombosis at diagnosis and

during treatment. Journal of thrombosis and

haemostasis : JTH. 2005;3(9):1985-92.

4. Nanjappa MC, Shankarappa RK, Kalpana SR,

Bhat P, Moorthy N. Intracardiac thrombi in

acute myeloid leukemia: an echocardiographic

and autopsy correlation. Echocardiography

(Mount Kisco, NY). 2010;27(1):E4-8.

5. Cahill TJ, Chowdhury O, Myerson SG,

Ormerod O, Herring N, Grimwade D, et al.

Myocardial infarction with intracardiac

thrombosis as the presentation of acute

promyelocytic leukemia: diagnosis and

follow-up by cardiac magnetic resonance

imaging. Circulation. 2011;123(10):e370-2.

6. Potenza L, Luppi M, Morselli M, Riva G,

Saviola A, Ferrari A, et al. Cardiac

involvement in malignancies. Case 2. Right

ventricular lesion as presenting feature of

acute promyelocytic leukemia. Journal of

clinical oncology : official journal of the

American Society of Clinical Oncology.

2004;22(13):2742-4.

7. Peters PJ, Reinhardt S. The echocardiographic

evaluation of intracardiac masses: a review.

Journal of the American Society of

Echocardiography : official publication of the

American Society of Echocardiography.

2006;19(2):230-40.

8. Torromeo C, Latagliata R, Avvisati G, Petti

MC, Mandelli F. Intraventricular thrombosis

during all-trans retinoic acid treatment in

acute promyelocytic leukemia. Leukemia.

2001;15(8):1311-3.

9. O'Donnell DH, Abbara S, Chaithiraphan V,

Yared K, Killeen RP, Cury RC, et al. Cardiac

tumors: optimal cardiac MR sequences and

spectrum of imaging appearances. AJR

American journal of roentgenology.

2009;193(2):377-87.

10. Gulati G, Sharma S, Kothari SS, Juneja R,

Saxena A, Talwar KK. Comparison of echo

and MRI in the imaging evaluation of

intracardiac masses. Cardiovascular and

interventional radiology. 2004;27(5):459-69.

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Neonatal Tuberous Sclerosis Complex Ramesh Bhat Y, et al.

51

Case Report Neonatal Tuberous Sclerosis Complex Ramesh Bhat Y, et al.

Neonatal Tuberous Sclerosis Complex with

Large and Multiple Cardiac Rhabdomyomas

Ramesh Bhat Y1, MD;

Leslie E Lewis

1, MD;

Jayashree P

1, MD;

Prakashini K2, MD;

Ranjan S

3, MD; Krishnananda N

3, MD

ABSTRACT

The tuberous sclerosis complex (TSC) is most commonly diagnosed around the age of 5 years.

Neonatal TSC is rare. The important neonatal manifestations include cardiac rhabdomyomas,

central nervous system abnormalities, and skin manifestations. We describe a neonate suffering

from the TSC with large and multiple cardiac rhabdomyomas. The largest rhabdomyoma measured

3.6 cm × 2 cm almost filling the right ventricle. The neonate did not have any symptoms. She

continued to remain asymptomatic until 8 months’ follow-up. (Iranian Heart Journal 2016;

17(3):51-54)

Keywords: Cardiac rhabdomyoma Neonate Tuberous sclerosis

1Department of Pediatrics, Kasturba Medical College, Manipal University, Manipal-576104, Udupi District, Karnataka, India. 2Department of Radiodiagnosis and Imaging, Kasturba Medical College, Manipal University, Manipal-576104, Udupi District,

Karnataka, India. 3Department of Cardiology, Kasturba Medical College, Manipal University, Manipal-576104, Udupi District, Karnataka, India.

Corresponding Author: Ramesh Bhat Y, MD; Kasturba Medical College, Manipal University, Manipal-576104, Udupi District,

Karnataka, India.


Received: January 20, 2016 Accepted: 11 June 2016

he tuberous sclerosis complex (TSC) is

an autosomal dominant neuroectodermal

disorder affecting multiple organ

systems.1-5

The disorder is diagnosed in

pediatric patients mostly at the age of 5 years

or later. Neonatal TSC is rare, with an

estimated incidence of 1 in 6000 to 12000 live

births.6 A 42-year retrospective review

identified only 70 fetal/neonatal TSC

patients.2 Cardiac rhabdomyomas (CRs) and

central nervous system (CNS) abnormalities

are the distinct manifestations in fetal or

neonatal cases. We describe a female neonate

suffering from the TSC with predominant and

distinct cardiac findings along with CNS and

skin findings.

Case Report

A term (40 wk) appropriate for gestational

age neonate born to a primigravida mother by

cesarean section and uneventful perinatal

history showed multiple hypopigmented ash

leaf macules on the right hypochondrium

(Fig. 1A), back, and right thigh (the largest

measuring 1 cm × 2.5 cm). The antenatal scan

at 22 weeks and fetal echocardiography at 28

weeks suggested a rhabdomyoma in the right

ventricle (RV). She weighed 3240 g with a

length of 50 cm and head circumferences of

35 cm. Her vital signs were normal.

Cardiovascular system examination revealed a

left-sided apex and a grade 3 systolic murmur

T

Tel:91

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at the lower left sternal border. Other

systemic examinations were normal.

Investigations revealed a normal complete

blood count and serum creatinine of 0.6

mg/dL. Echocardiography showed multiple

rhabdomyomas, with the largest measuring

3.6 cm × 2 cm almost filling the RV and

causing right ventricular outflow tract

(RVOT) obstruction. The pressure gradient

across the RVOT was 27 mm Hg.

Rhabdomyomas were also seen on the left

ventricular (LV) wall, apex, and papillary

muscle, and even extending to the pericardial

cavity (Fig. 1B). LV systolic function was

normal. There was a small patent ductus

arteriosus with a left-to-right shunt. ECG was

normal, and there was no conduction

disturbance. Magnetic resonance imaging

(MRI) of the brain showed well-defined,

multiple (>10) T1 hyperintense subependymal

nodules (Fig. 1C). Radial white matter bands

in both frontal lobes were present in addition.

There was no retinal hamartoma. Renal scans

and hearing evaluation were normal. The

baby was asymptomatic, feeding well, and

was discharged on phenytoin. At 4 months’

and 8 months’ follow up, she was

asymptomatic with normal growth and

development and the same echocardiographic

findings.

DISCUSSION

The TSC is characterized by pleomorphic

features involving the brain, kidneys, heart,

eyes, lungs, and skin.1-4

A mutation in either

the TSC1 gene or the TSC2 gene causes this

autosomal dominant disorder. The expression

of the disease varies substantially. A family

history of the TSC is present in only 7–37%

of newly diagnosed cases. About 60–70% of

the cases occur sporadically.6 In the present

case, the mother had asymptomatic TSC.

Although the penetrance is complete in the

TSC, the range of phenotypic changes such as

age at onset, disease severity, and different

signs and symptoms are highly variable.

Hence, diagnostic clinical criteria including

major and minor criteria have been proposed.7

Two major or 1 major and 2 minor features

confirm definite TSC. The fetal and neonatal

manifestations include mainly cardiac, CNS,

and skin manifestations. The present case had

these characteristic manifestations and met

the criteria for definite TSC. The major

presenting findings in the fetus include CR(s)

detected on routine antenatal sonography,

arrhythmias, cerebral lesions, hydrops, and

stillbirth, whereas the main signs initially in

the neonate include respiratory distress,

arrhythmias, murmurs, and cardiomegaly.2

CRs are the most common finding in the

fetal/neonatal TSC (up to 79%). CRs can be

detected by early prenatal scan or fetal

echocardiography as in the present case. CRs

can be multiple, more frequent on the left side

and in the ventricles, and usually measure 5–

15 mm in diameter. Multiple CRs can be the

sole manifestations of perinatal TSC as well.4

The neonatal echocardiography in the present

case showed multiple CRs and the 1 in the

RV was unusually large, even causing RVOT

obstruction. CRs are usually asymptomatic

and regress spontaneously, mostly within 6

years of life. Occasionally CRs may cause

cardiac failure (2–4%) and arrhythmias (9%)

depending on their size or location.1,2

LVOT

obstruction may lead to death.1 In a review of

33 CR cases, Sciacca et al.8 reported

significant obstruction in 12%, arrhythmia in

24.2%, and death in 1 neonate. The neonate

who died due to heart failure following birth

had enormous septal CRs. Despite having

unusually large and multiple CRs, the present

case was asymptomatic until 8 months’

follow-up. As CRs demonstrate benign

pathological characteristics and tend to

regress over time, a conservative approach is

preferable and useful in most cases. The

chance of spontaneous regression does not

depend on the initial size, number, or location

of rhabdomyomas. A spontaneous involution

of CRs was observed in 30 out of 31 TSC

cases in a study by Sciacca et al.8 As

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mutations in TSC genes result in increased

mammalian target of rapamycin (mTOR)

pathway activation leading to hamartomatous

lesions of the TSC, therapy with mTOR

inhibitors such as everolimus has been

suggested. The beneficial effects of

everolimus in a symptomatic neonate with

inoperable multiple CRs were reported by

Dogan V et al.9 Everolimus at a dose of 0.25

mg twice per day, 2 days per week for 3

months—maintaining the therapeutic levels

between 5 and 15 ng/mL—resulted in

dramatic improvement in hemodynamic

instability and significant reduction in the size

of most of the CRs in that neonate. Surgical

approach may only be considered when there

is critical obstruction or dysrhythmias.

The 2nd characteristic finding in the

fetal/neonatal TSC is subependymal nodules

on brain MRI.1,2,5,6

The present case had

multiple subependymal nodules and frontal

radial bands on brain MRI. The median

subependymal nodules may vary (4–

13/patient). A median of 13 nodules was

reported by Baron and Barkovich6 in neonates

and young infants with the TSC. The usual

percentage of patients with >10

subependymal nodules is 12%, but it could be

as high as 57%.6 The increased number of

nodules may be associated with greater

morbidity and mortality. White matter

anomalies and subependymal giant cell

astrocytomas (SGCA) are the other

characteristic MRI findings. For the detection

of these abnormalities on MRI, T1-weighted

sequences in 2 orthogonal planes, section

thickness ≤4 mm, and the gap as small as

possible (0.5–1 mm) have been suggested.

Nearly all patients with the TSC have 1 or

more of the skin lesions characteristic of the

disorder. The present case had multiple ash

leaf macules. Renal manifestations are rare in

neonates.2

The TSC is a progressive disorder. Hence, a

systematic follow-up of all cases is suggested;

it may include ophthalmology evaluations,

renal scans, electroencephalography,

echocardiography, and brain MRI.10

Some of

the recent research works being done on the

treatment of tuberous sclerosis using mTOR

inhibitors such as sirolimus and everolimus

are promising.9,11

Early mTOR inhibition in

patients with the TSC may prevent the

development of the TSC lesions and alter the

natural history of the disease. A significant

decrease in brain tumor volume and

prevention of facial angiofibromas and renal

angiomyolipomas by using everolimus over a

24-month period without significant side

effects have been reported.11

In conclusion, CRs of the TSC are mostly

silent, despite being large and multiple in

numbers. However, because of their rare but

serious consequences, they warrant follow-up

and may need an early treatment.

REFERENCES

1. Józwiak S, Kotulska K, Kasprzyk-Obara J,

Domanska-Pakiela D, Tomyn-Drabik M,

Roberts P et al (2006). Clinical and genotype

studies of cardiac tumors in 154 patients with

Tuberous Sclerosis Complex. Pediatrics

118:e1146.

Figure 1. A Hypopigmented ash leaf macule on the right

hypochondrium. B Echocardiography shows multiple

rhabdomyomas. C Multiple subependymal nodules in brain

magnetic resonance imaging.

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2. Isaacs H (2009). Perinatal (fetal and neonatal)

tuberous sclerosis: a review. Am J Perinatol

26(10):755-60.

3. Pipitone S, Mongiovi M, Grillo R, Gagliano

S, Sperandeo V(2002). Cardiac rhabdomyoma

in intrauterine life: clinical features and

natural history. A case series and review of

published reports. Ital Heart J 3(1):48-52.

4. Jozwiak S, Domanska-Pakiela D,

Kwiatkowski DJ, Kotulska K (2005). Multiple

cardiac rhabdomyomas as a sole symptom of

tuberous sclerosis complex: case report with

molecular confirmation. J Chid

Neurol 20(12):988-9.

5. Langer RD, van-Gorkom KN, Raupp P

(2008). Cerebral MRI findings in Neonatal

Tuberous Sclerosis. Iran J Radiol 5(1):25-9.

6. Baron Y, Barkovich AJ (1999). MR imaging

of Tuberous Sclerosis in neonates and young

infants. Am J Neuroradiol 20:907–916.

7. Roach ES, Gomez MR, Northrup H (1998).

Tuberous sclerosis complex consensus

conference: revised clinical diagnostic criteria.

J Child Neurol 13:624.

8. Sciacca P, Giacchi V, Mattia C, Greco F,

Smilari P, Betta P et al (2014).

Rhabdomyomas and Tuberous sclerosis

complex: our experience in 33 cases. BMC

Cardiovascular Disorders 14:66.

9. Dogan V, Yesil S, Kayal S, Beken S, Ozgur S,

Ertugrul I, et al (2014). Regression of

symptomatic multiple cardiac rhabdomyomas

associated with Tuberous Sclerosis Complex

in a newborn receiving Everolimus. J Trop

Pediatr, doi:10.1093/tropej/fmu056.

10. Roach ES, DiMario FJ, Kandt RS, Northrup H

(1999). Tuberous Sclerosis Consensus

Conference: Recommendations for Diagnostic

Evaluation. J Child Neurol 14:401-7.

11. Kotulska K, Borkowska J, Jozwiak S (2013).

Possible prevention of Tuberous Sclerosis

Complex lesions. Pediatrics132:e239.

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of funding and potential conflicting

interest, such as receiving funds or

fees by, or holding stocks and shares

in, an organization that may profit or

lose through the publication of the

paper. Declaring a competing interest

will not lead to the automatic rejection

of the paper.

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Ethical guidelines must be addressed

in the Materials and Methods section.

(1) Please state that informed consent

was obtained from all human adult

participants and from the parents or

legal guardians of minors. Include the

name of the appropriate institutional

review board that approved the

project. (2) Indicate in the text that the

maintenance and care of experimental

animals complies with National

Institutes of Health guidelines for the

humane use of laboratory animals, or

those of your institute or agency.

References should be identified by

using superscript numbers without

changing the font size (e.g.,1,2,3

). Do

not cite personal communications,

manuscripts in preparation, or

unpublished data. Type the references

double spaced on a separate sheet and

number consecutively in the order in

which they are mentioned in the text.

List all authors if 6 or fewer;

otherwise list the first 6 and add et al.

Style and punctuation of references

should conform to the Vancouver style

or the Index Medicus format as in the

examples below:

Journal articles:

1. Burt VL, Cutler JA, Higgins M, Horan

MJ, Labarthe D, Whelton P, et al.

Trends in the prevalence, awareness,

treatment and control of hypertension

in the adult US population.

Hypertension 1995; 26: 60-69.

Chapters in books:

2. Ross DN, Martelli V, Wain WH:

Allograft and autograft valves used for

aortic valve replacement. In: Ionescu

MI, (ed.). Tissue Heart Valves.

London: Butterworth, 1979: pp. 319-

29.

Tables should be typed double spaced

on separate sheets, each with a table

number and title above the table and

explanatory notes and legends below.

Tables should be self-explanatory and

the data should not be duplicated in

the text or figures. If tables provide

repetitive information, they will be

deleted.

Legends to illustrations should be

typed double spaced on a separate

sheet. Numbers should correspond to

the order in which they appear in the

text. Give the type of stain and

magnification power for

photomicrographs. Patients should not

be recognizable in illustrations unless

written consent is supplied.

Illustrations should be submitted

digitally (preferable), or in 3 sets of

glossy prints. High-quality laser

artwork is also acceptable, but

photocopies are not. Write the first

author’s last name, figure number, and

an arrow indicating the top of the

figure on the back of each illustration

in pencil. All illustrations will be

published in black and white unless

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color prints are specifically requested

by the author(s). The author must be

prepared to pay a fee for publication

of color photographs.

Reprints: Reprints can be ordered at

an extra charge. Contact the Editorial

Office for details.

Electronic manuscripts

All authors are strongly encouraged to

submit their manuscripts via e-mail using

Microsoft Office Word (2003 or afterward) in

order to allow more rapid editing and

preparation for publication. The author

should retain copies of all files as backup. E-

mails should bear the author’s name, short

title of the article, and operating system used.

All manuscripts and correspondences

should be submitted to:

Hussein Tabatabaei, M.D.

Editor-in-Chief

Iranian Heart Association Journal

P. O. Box: 15745-1341

Tehran 19974 Iran

Tel: (009821) 22048174

Fax: (009821) 22048174

E-mail: [email protected]


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Forthcoming Meetings

The 35th Annual International Symposium: Clinical Update in Anesthesiology, Surgery and Perioperative Medicine Sunday, January 15, 2017 to Friday, January 20, 2017 Marriott Resort Casa Magna Cancun Mexico See map: Google Maps Cardiac Tumour Conference – Cardiac Endocrine Tumours Thursday, January 19, 2017 University of Toronto Conference Centre 89 Chestnut Street Toronto Canada See map: Google Maps STS 53rd Annual Meeting and STS/AATS Tech-Con 2017 Saturday, January 21, 2017 to Wednesday, January 25, 2017 George R. Brown Convention Center Houston, TX United States See map: Google Maps 2017 STS and CTSNet Career Fair Sunday, January 22, 2017 to Tuesday, January 24, 2017 George R. Brown Convention Center Houston, TX United States See map: Google Maps Mitral Valve Meeting 2017 Sunday, February 5, 2017 to Tuesday, February 7, 2017 University Hospital Zurich (USZ) – Schulungszentrum Gloriastrasse 19 Zurich 8092 Switzerland See map: map.search.ch, Google Maps Name of Event Fundamentals in Cardiac Surgery: Part I Monday, February 6, 2017 to Friday, February 10, 2017 EACTS House Windsor United Kingdom See map: Google Maps 8th Advanced VATS Course Wednesday, February 8, 2017 to Thursday, February 9, 2017

St. James's University Hospital Leeds United Kingdom See map: Google Maps Hands-on Cardiac Morphology Wednesday, February 22, 2017 to Friday, February 24, 2017 Royal Brompton Hospital London United Kingdom See map: Google Maps AATS Grant Writing Workshop Friday, March 10, 2017 Doubletree Hotel Bethesda Bethesda , MD United States See map: Google Maps SCTS Annual Meeting & Cardiothoracic Forum 2017 Sunday, March 12, 2017 to Tuesday, March 14, 2017 Belfast Waterfront Centre Belfast United Kingdom See map: Google Maps ESTS Knowledge Track "Antalya Revisited in Prague" Monday, March 13, 2017 to Saturday, March 18, 2017 Lindner Hotel Prague Castle Strahovska 128 Prague Czech Republic See map: Google Maps 2nd International Conference on Cardiovascular Medicine and Cardiac Surgery Wednesday, March 15, 2017 Hilton London Docklands Riverside 265 Rotherhithe St. London SE16 5HW United Kingdom See map: Google Maps

Introduction to Aortic Surgery Thursday, March 16, 2017 to Saturday, March 18, 2017 EACTS House Windsor United Kingdom See map: Google Maps 35th Cardiovascular Surgical Symposium Saturday, March 18, 2017 to Saturday, March 25, 2017 Robinson Select Alpenrose Zürs Zürs am Arlberg

http://www.ctsnet.org/events/35th-annual-international-symposium-clinical-update-anesthesiology-surgery-and-perioperative



http://www.ctsnet.org/events/cardiac-tumour-conference-%E2%80%93-cardiac-endocrine-tumours

http://www.ctsnet.org/events/cardiac-tumour-conference-%E2%80%93-cardiac-endocrine-tumours

http://www.ctsnet.org/events/sts-53rd-annual-meeting-and-stsaats-tech-con-2017

http://www.ctsnet.org/events/sts-53rd-annual-meeting-and-stsaats-tech-con-2017

http://www.ctsnet.org/events/2017-sts-and-ctsnet-career-fair

http://www.ctsnet.org/events/mitral-valve-meeting-2017

http://map.search.ch/8092-Zurich/Gloriastrasse%2019

http://www.ctsnet.org/events/name-event-fundamentals-cardiac-surgery-part-i

http://www.ctsnet.org/events/name-event-fundamentals-cardiac-surgery-part-i

http://www.ctsnet.org/events/8th-advanced-vats-course

http://www.ctsnet.org/events/hands-cardiac-morphology-1

http://www.ctsnet.org/events/aats-grant-writing-workshop

http://www.ctsnet.org/events/scts-annual-meeting-cardiothoracic-forum-2017

http://www.ctsnet.org/events/ests-knowledge-track-antalya-revisited-prague

http://www.ctsnet.org/events/ests-knowledge-track-antalya-revisited-prague

http://www.ctsnet.org/events/2nd-international-conference-cardiovascular-medicine-and-cardiac-surgery

http://www.ctsnet.org/events/2nd-international-conference-cardiovascular-medicine-and-cardiac-surgery

http://www.ctsnet.org/events/introduction-aortic-surgery-0

http://www.ctsnet.org/events/35th-cardiovascular-surgical-symposium

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Austria See map: Google Maps Master Class on Aortic Valve Repair: A Step-by-Step Approach Wednesday, March 22, 2017 to Friday, March 24, 2017 L'Institut Mutualiste Montsouris (IMM) Paris France See map: Google Maps The 25th Annual Meeting of the Asian Society for Cardiovascular and Thoracic Surgery (ASCVTS 2017) Thursday, March 23, 2017 to Sunday, March 26, 2017 Coex Convention and Exhibition Center Seoul South Korea See map: Google Maps 13th International Congress of Update in Cardiology and Cardiovascular Surgery Thursday, March 23, 2017 to Sunday, March 26, 2017 Cesme Sheraton Convention Center Izmir Turkey See map: Google Maps Thoracic Surgery: Part I Monday, March 27, 2017 to Friday, March 31, 2017 EACTS House Windsor United Kingdom See map: Google Maps 23th Annual Conference of the Egyptian Society of Cardiothoracic Surgery Tuesday, April 4, 2017 to Thursday, April 6, 2017 Mena House Hotel, Giza, Egypt Cairo Egypt See map: Google Maps 32nd EACTA Annual Congress 2017 Wednesday, April 19, 2017 to Friday, April 21, 2017 Maritime Hotel Berlin Germany See map: Google Maps ESTS Skill Track Course "Elancourt in Copenhagen" Wednesday, April 19, 2017 to Friday, April 21, 2017 Denmark See map: Google Maps

AATS Mitral Conclave 2017 Thursday, April 27, 2017 to Friday, April 28, 2017 New York Hilton Midtown New York, NY United States See map: Google Maps AATS Centennial Saturday, April 29, 2017 to Wednesday, May 3, 2017 Boston Hynes Convention Center Boston, MA United States See map: Google Maps Massachusetts General Hospital Postgraduate Course in General Thoracic Surgery Thursday, May 25, 2017 to Friday, May 26, 2017 Royal Sonesta Hotel Cambridge, MA United States See map: Google Maps 25th European Conference on General Thoracic Surgery Sunday, May 28, 2017 to Wednesday, May 31, 2017 Congress Messe Innsbruck Austria See map: Google Maps Fundamentals in Cardiac Surgery: Part II Monday, June 5, 2017 to Friday, June 9, 2017 EACTS House Windsor United Kingdom See map: Google Maps Thoracic Surgery: Part II Monday, June 12, 2017 to Wednesday, June 14, 2017 EACTS House Windsor United Kingdom See map: Google Maps Ventricular Assist Device Co-ordinators Training Course Thursday, June 15, 2017 to Saturday, June 17, 2017 Deutsches Herzzentrum Berlin (German Heart Institute Berlin) Berlin Germany See map: Google Maps Magna Græcia AORtic Interventional Project® (MAORI) 5th Symposium Complex Diseases of Thoracic and Thoraco-Abdominal Aorta Tuesday, June 20, 2017 to Wednesday, June 21, 2017 University Campus “Salvatore Venuta” Italy Building H, Auditorium Room B, level 2

http://www.ctsnet.org/events/master-class-aortic-valve-repair-step-step-approach

http://www.ctsnet.org/events/master-class-aortic-valve-repair-step-step-approach

http://maps.google.fr/?q=L%27Institut+Mutualiste+Montsouris+%28IMM%29%2C+Paris%2C+%2C+fr

http://www.ctsnet.org/events/25th-annual-meeting-asian-society-cardiovascular-and-thoracic-surgery-ascvts-2017



http://www.ctsnet.org/events/13th-international-congress-update-cardiology-and-cardiovascular-surgery

http://www.ctsnet.org/events/13th-international-congress-update-cardiology-and-cardiovascular-surgery

http://www.ctsnet.org/events/thoracic-surgery-part-i-1

http://www.ctsnet.org/events/23th-annual-conference-egyptian-society-cardiothoracic-surgery

http://www.ctsnet.org/events/23th-annual-conference-egyptian-society-cardiothoracic-surgery

http://www.ctsnet.org/events/32nd-eacta-annual-congress-2017

http://www.ctsnet.org/events/ests-skill-track-course-elancourt-copenhagen

http://www.ctsnet.org/events/ests-skill-track-course-elancourt-copenhagen

http://www.ctsnet.org/events/aats-mitral-conclave-2017

http://www.ctsnet.org/events/aats-centennial

http://www.ctsnet.org/events/massachusetts-general-hospital-postgraduate-course-general-thoracic-surgery-1

http://www.ctsnet.org/events/massachusetts-general-hospital-postgraduate-course-general-thoracic-surgery-1

http://www.ctsnet.org/events/25th-european-conference-general-thoracic-surgery

http://www.ctsnet.org/events/25th-european-conference-general-thoracic-surgery

http://www.ctsnet.org/events/fundamentals-cardiac-surgery-part-ii-1

http://www.ctsnet.org/events/thoracic-surgery-part-ii-2

http://www.ctsnet.org/events/ventricular-assist-device-co-ordinators-training-course-1

http://www.ctsnet.org/events/ventricular-assist-device-co-ordinators-training-course-1

http://www.ctsnet.org/events/magna-gr%C3%A6cia-aortic-interventional-project%C2%AE-maori-5th-symposium-complex-diseases-thoracic-and



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Catanzaro Italy See map: Google Maps ASAIO 63rd Annual Conference Wednesday, June 21, 2017 to Saturday, June 24, 2017 Hyatt Regency Chicago Chicago, IL United States See map: Google Maps The New Orleans Conference - Las Vegas Edition Wednesday, June 28, 2017 to Saturday, July 1, 2017 The Four Seasons Resort Las Vegas, NV United States See map: Google Maps 27th Annual Congress of the World Society of Cardiovascular &Thoracic Surgeons Friday, September 1, 2017 to Sunday, September 3, 2017 The Palace Of Independence Astana Kazakhstan See map: Google Maps 2nd International Conference on Hypertension & Healthcare Monday, September 11, 2017 to Wednesday, September 13, 2017 Hyatt Place Amsterdam Airport Rijnlanderweg 800 Hoofddorp 2132 NN Amsterdam Netherlands

See map: Google Maps Annual Conference on Heart Diseases Monday, September 18, 2017 to Tuesday, September 19, 2017 Holiday Inn Toronto International Airport 970 Dixon Road Toronto, ON M9W 1J9 Canada See map: Google Maps 37th Annual Cardiothoracic Surgery Symposium Thursday, September 28, 2017 to Sunday, October 1, 2017 Westin San Diego Gaslamp Quarter San Diego, CA United States See map: Google Maps Fundamentals in Cardiac Surgery: Part III Monday, October 23, 2017 to Friday, October 27, 2017 EACTS House Windsor United Kingdom See map: Google Maps Thoracic Surgery: Part III Monday, December 4, 2017 to Wednesday, December 6, 2017 EACTS House Windsor United Kingdom See map: Google Maps

http://www.ctsnet.org/events/asaio-63rd-annual-conference

http://www.ctsnet.org/events/new-orleans-conference-las-vegas-edition

http://www.ctsnet.org/events/27th-annual-congress-world-society-cardiovascular-thoracic-surgeons

http://www.ctsnet.org/events/27th-annual-congress-world-society-cardiovascular-thoracic-surgeons

http://www.ctsnet.org/events/2nd-international-conference-hypertension-healthcare

http://www.ctsnet.org/events/2nd-international-conference-hypertension-healthcare

http://www.ctsnet.org/events/annual-conference-heart-diseases

http://www.ctsnet.org/events/37th-annual-cardiothoracic-surgery-symposium

http://www.ctsnet.org/events/fundamentals-cardiac-surgery-part-iii

http://www.ctsnet.org/events/thoracic-surgery-part-iii

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SUBSCRIPTION ORDER FORM

Please enter my subscription to The Iranian Heart Journal for 500 000 Rials for one year

(Four quarterly issues) beginning (Year)

ADDRESS: Please type or print clearly:

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Address:

Zip Code: City:

PAYMENT

Check enclosed Cheek or money order must be made to:

Iranian Heart Association

Account no: 6166/1, Mellat Bank, Rajaie Cardiovascular,

Medical and Research Center Branch, Tehran, Iran.

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Account no: 116AC252899, Mellat Bank, Mirdamad Branch

Tehran, Iran, Branch code 6507/8

P.O.Box: 15745-1341

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تهران :گيرنده مجلة قلب ايران

11731-1431صندوق پستي

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Documents

ISSN: 1735-7306journal.iha.org.ir/Files/Journal/issue_6.pdf · 1 Department of Interventional Cardiology, Rajaie cardiovascular, Medical and Research center, Iran University of Medical