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THE

JOURNAL OF

TEHRAN UNIVERSITY

HEART CENTER

Editor-in-Chief

Managing Editor

International Editors

Editorial Board

ABBASALI KARIMI, MD

ASSOCIATE PROFESSOR OF CARDIAC SURGERY

TEHRAN UNIVERSITY OF MEDICAL SCIENCES

SEYED HESAMEDDIN ABBASI, MD

TEHRAN HEART CENTER

TEHRAN UNIVERSITY OF MEDICAL SCIENCES

Zohair Yousef Al-halees, MD , FRCSC, FACS

King Faisal Heart Institute

Saudi Arabia

Hooshang Bolooki, MD, FRCS (C), FACS, FCCP

University of Miami, School of Medicine

U. S. A

Yadolah Dodge, PhD

University of Neuchâtel

Switzerland

Ali Dodge–Khatami, MD, PhD

University of Zürich

Switzerland

Iradj Gandjbakhch, MD

Hopital Pitie

France

Omer Isik, MD

Yeditepe University, School of Medicine

Turkey

Sami S. Kabbani, MD

Damascus University Cardiovascular Surgical Center

Syria

Kayvan Kamalvand, MD, FRCP, FACC

William Harvey Hospital

United Kingdom

Jean Marco, MD, FESC

Centre Cardio- Thoracique de Monaco

France

Ali Massumi, MD

Texas Heart Institute

U. S. A

Hossien Ahmadi, MDTehran Heart Center

Tehran University of Medical Sciences

Shahin Akhondzadeh, PhDRoozbeh Psychiatric Hospital

Carlos-A. Mestres, MD

University of Barcelona

Spain

Fred Morady, MD

University of Michigan

U. S. A

Mohammed T. Numan, MD

Hamad Medical Corporation

Qatar

Ahmand S. Omran, MD, FACC, FASE

King Abdulaziz Cardiac Center

Saudi Arabia

Fausto J. Pinto, MD, PhD, FESC, FACC, FASA, FSCAI, FASE

Lisbon University

Portugal

Mehrdad Rezaee, MD, PhD

Stanford University, School of Medicine

U. S. A

Gregory S. Thomas, MD, MPH, FACC, FACP, FASNC

University of California

U. S. A

Lee Samuel Wann, MD

Wisconsin Heart Hospital

U. S. A

Hein J. Wellens, MD

Cardiovascular Research Institute, Maastricht

The Netherlands

Douglas P. Zipes, MD

Indiana University, School of medicine

U. S. A


Mohammad Ali Boroumand, MD

Tehran Heart Center


Advisory Board

Ahmad Reza Dehpour, PhD

Department of Pharmacology


Abbasali Karimi, MD

Tehran Heart Center


Davood Kazemi Saleh, MD

Baghiatallah Hospital

Baghiatallah University of Medical Sciences

Majid Maleki, MD

Shaheed Rajaie Cardiovascular Medical Center

Iran University of Medical Sciences

Mehrab Marzban, MD

Tehran Heart Center


Mansor Moghadam, MD

Imam Khomeini Hospital


Sina Moradmand Badie, MD

Amir Alam Hospital


Seyed Mahmood Mirhoseini, MD, DSc, FACC, FAES

Tehran Heart Center


Seyed Rasoul Mirsharifi, MD



Ahmad Mohebi, MD



Mohammad-Hasan Namazi

Shaheed Modarres Hospital

Kiyomars Abbasi, MD

Tehran Heart Center


Seifollah Abdi, MD



Mohammad Alidoosti, MD

Tehran Heart Center


Alireza Amirzadegan, MD

Tehran Heart Center


Naser Aslanabadi, MD

Shaheed Madani Heart Hospital

Tabriz University of Medical Sciences

Sirous Darabian, MD

Tehran Heart Center


Gholamreza Davoodi, MD

Tehran Heart Center


Saeed Davoodi, MD

Tehran Heart Center

Shaheed beheshti University of Medical Sciences

Ebrahim Nematipour, MD

Tehran Heart Center


Rezayat Parvizi, MD



Masoud Pezeshkian



Hassan Radmehr, MD



Saeed Sadeghian, MD

Tehran Heart Center


Mojtaba Salarifar, MD

Tehran Heart Center


Nizal Sarraf –Zadegan, MD

Isfahan Cardiovascular Research Center

Isfahan University of Medical Sciences

Ahmad Yaminisharif, MD

Tehran Heart Center


Mohammad Reza Zafarghandi, MD

Sina Hospital


Aliakbar Zeinaloo, MD

Children Medical Center’s Hospital



Iraj Firoozi, MD



Seyed Khalil Foroozannia, MD

Afshar Haspital

Shaheed Sadoghi University of Medical Sciences

Armen Gasparyan MD, PhD

Yerevan State Medical University

Armenia

Ali Ghaemian, MD

Mazandaran Heart Center

Mazandaran University of Medical Sciences

Namvar Ghasemi Movahedi, MD

Tehran Heart Center


Abbas Ghiasi, MD

Tehran Heart Center


Seyed Ebrahim Kassaian, MD

Tehran Heart Center


Ali Kazemi Saeed, MD

Tehran Heart Center


Seyed Kianoosh Hoseini

Tehran Heart Center


Mohammad Jafar Hashemi, MD



Elise Langdon- Neuner

The editor of The Write Stuff (The Journal of The

European Medical Writers Association) Austria

Jalil Majd Ardekani, MD

Tehran Heart Center


Fardin Mirbolook, MD

Dr. Heshmat Hospital

Gilan University of Medical Sciences

Mehdi Najafi, MD

Tehran Heart Center


Younes Nozari, MD



Hamid Reza Pour Hosseini, MD

Tehran Heart Center


Hakimeh Sadeghian, MD

Tehran Heart Center


Mohammad Saheb Jam, MD & PT

Tehran Heart Center


Abbas Salehi Omran, MD

Tehran Heart Center


Mahmood Shabestari, MD

Imam Reza Hospital

Mashhad University of Medical Sciences

Shapour Shirani, MD

Tehran Heart Center


Abbas Soleimani, MD

Tehran Heart Center


Seyed Abdolhosein Tabatabaei, MD

Shariati Hospital


Murat Ugurlucan, MD

Department of Cardiac Surgery

Rostock University Medical Faculty

Arezou Zoroufian, MD

Tehran Heart Center


Statistical Consultant

Technical Editors

Office

Address

Mahmood Sheikh Fathollahi

Fatemeh Talebian

Fatemeh Esmaeili Darabi

The Journal of Tehran University Heart Center is indexed in EMBASE, CAB Abstracts, Global Health, Cinahl, Google

Scholar, DOAJ, Geneva Foundation for Medical Education and Research, Index Copernicus, Index Medicus for the

WHO Eastern Mediterranean Region (IMEMR), SID, Iranmedex and Magiran

North Kargar Street, Tehran Heart Center, Tehran, Iran 1411713138. Tel: +98 21 88029720. Fax: +98 21 88029702.

Web Site: http://jthc.tums.ac.ir. E-mail: [email protected]

Pedram Amouzadeh

ContentVolume: 3 Number: 4 Autumn 2008

The Journal of Tehran University Heart Center

Editorial

Review Article

Original Articles

Case Report

Letter To The Editor

Problems of Editing a Peer-Reviewed Biomedical Journal in a Developing CountryShaukat Ali Jawaid ...................................... ……………………………………..………………..………………………................................……..…... 187

Surgical Treatment of Atrial FibrillationKyomars Abbasi, Iman Abbasi, Naghmeh Moshtaghi ……………………..…………………………..…………….…….………..................................... 191

Congenital Left Ventricular Diverticulum Associated with ASD, VSD, and Epigastric HerniaAkbar Shahmohammadi, Nader Givtaj, Seyed mohammad Dalili, Rahman Ghaffari ………...………………………………..............................…......... 229

Nobel Prize in Physiology or Medicine for the Year 2007: Breakthrough in Pathophysiology and Experimental

Therapy of Cardiovascular and Other DiseasesMurat Ugurlucan, Armen Yuri Gasparyan, Hamid Darban …………………………………………………….................................…………………...... 233

Enhanced Myocardial Vascularity and Contractility by Novel FGF-1 Transgene in a Porcine Model of Chronic

Coronary OcclusionReza Forough, Matthew W. Miller, Milred Mattox, Wayne Dunlap, Andy Ambrus, Rola Barhoumi, Cristine L. Heaps, Janet L.Parker .......................... 197

Prosthetic Valve Endocarditis: Early Outcome following Medical or Surgical TreatmentAbbas Salehi Omran, Abbasali Karimi, Setareh Davoodi, Hossein Ahmadi, Namvar Movahedi, Mehrab Marzban, Banafsheh Alinejad, Neda Ghaffari

Marandi ................................................................................................................................................................................................................................. 205

Assessment of Regional Myocardial Displacement via Spectral Tissue Doppler Compared with Color Tissue

TrackingHassan Moladoust, Manijhe Mokhtari-Dizaji, Zahra Ojaghi-Haghighi …………………………..............................……..…………………………….... 209

Postoperative Mortality and Morbidity in Elderly Patients Undergoing Coronary Artery Bypass Graft SurgeryHassan Radmehr, Alireza Bakhshandeh, Mehrdad Salehi, Iraj Ghorbandaeipour, Amir Hossein Sadeghpoor Tabai, Mehdi Sanatkarfar, Ahmad Reza

Nasr ....................................................................................................................................................................................................................................... 215

Discrete Subvalvular Aortic Stenosis: Severity of Aortic Regurgitation and Rate of Recurrence at Midterm

Follow-Up after SurgeryHakimeh Sadeghian, Abbasali Karimi, Seyed Hosein Ahmadi, Masoumeh Lotfi-Tokaldany, Nader Fallah, Reihaneh Zavar, Seyed Hesameddin

Abbasi ….……...........................................................................................................................................................................................................……... 219

The Effect of Post Coronary Angiography Bed-Rest Time on Vascular ComplicationsRabiallah Farmanbar, Madjid Chinikar, Maryam Gozalian, Mojgan Baghaie, Zahra Atrkar Roshan, Mohamadtaghi Moghadamnia …….……………... 225


TEHRAN HEART CENTER

The Journal of Tehran University Heart Center 187

TEHRAN HEART CENTER

Editing a peer-reviewed medical journal in a developing

country can be a very stressful and frustrating job in view

of the enormous problems which an editor has to face.1

Authors’ failure to comply with instructions, financial

constraints, poor quality of manuscripts, duplicate submission,

slicing, plagiarism, poor quality of reviewers and their

non-availability, and untrained manpower including editorial

staff coupled with the desire to improve the quality and

standard of the journal and get it indexed in important

databases create such a vicious circle that an editor finds

himself/herself in a very challenging situation all the time.2

Editors are defined as those who are responsible and

accountable for determining the scientific contents of a peer-

reviewed biomedical journal. The International Committee

of Medical Journal Editors (ICMJE) defines a peer-reviewed

journal as one that has submitted most of its published

articles for review by experts who are not part of the

editorial staff (www.icmje.org). Editors are responsible

not only to authors but also to reviewers, readers, study

subjects, science and the publishers, hence they have to work

under a great deal of pressure. The pressure is magnified in

the absence of optimally trained and experienced editorial

staff. Editors are supposed to create such an equilibrium that

all the stake holders can be kept happy. It is indeed a very

difficult and onerous task.1 That is why Dr. H. Whitefield,

editor of the British Journal of Urology, is reported to have

remarked, “If you do not want to make friends, become

an editor.” Likewise, Sir Hugh Clegg, editor of the British

Medical Journal (BMJ) (1947-1965) is reported to have said,

“A medical editor has to be the keeper of the conscience of

a profession and if he/she tries to come up to this ideal, he/

she always be getting into trouble.” 3 “In general the only

people who love editors are their wives/husbands, children

and parents,” 4 says Dr. Harvey. This shows how difficult the

job of an editor is and particularly so in a developing country

working under financial as well as other constraints.

Some of the specific problems which editors have to face

include incomplete and incorrect references in manuscripts

submitted by authors; missing photos and illustrations;

missing Letter of Undertaking signed by all the authors,

which is supposed to confirm exclusive submission and

willingness to pay publication charges; withdrawal of

accepted manuscripts at the last minute disrupting publica-

tion schedule; failure to arrange publication charges in

time; failure to respond to queries by the authors promptly;

misplacement of manuscripts by the reviewers or need for

repeated reminders; ignorance on the part of the authors

as to how to convey the corrections to a PDF file sent for

proof reading; request for change of the authors; addition or

deletion of some of the authors’ names or change in their

order; and pressing for early publication, to mention but a few.

The fact that 25% of the world’s scientists are from

developing Third World countries but their contribution to

world medical literature is just 2% is highly disappointing

(Laporte RE. Proceedings of South Asian Cardiovascular

Research Methodology Workshop held at Aga Khan

University, Karachi. Pulse International Feb. 15th 2005.

Karachi. Pakistan.). One of the important reasons for

this is disregard for merit and the fact that medical

writing was until recently not taught in medical schools in

most of these countries and even now only a few of them have

set out in this direction. Research culture has been mostly

lacking; most often the research scientists never received

the respect and status which they deserved, and research

was also not a career which many thought of adopting. The

situation, however, is gradually changing.

Peer review is considered a central activity in improving

the quality of manuscripts, but this is a poorly understood

process which remains under intense scrutiny and controversy.

During discussion on the World Association of Medical

Editors (WAME) List serve recently, Dr. Godlee, editor of

BMJ, remarked, “Peer review is expensive, slow, subjective,

Editorial

Problems of Editing a Peer-Reviewed Biomedical

Journal in a Developing Country

Shaukat Ali Jawaid

*Corresponding Author: Shaukat Ali Jawaid, Managing Editor, Pakistan Journal of Medical Sciences, Karachi, Pakistan. Tel: +92 21 5688791. E mail:

[email protected].

Managing Editor, Pakistan Journal of Medical Sciences, Karachi, Pakistan.

188


biased, open to abuse, patchy at detecting important meth-

odological defects and almost useless at detecting fraud

and misconduct.” Dr. Farrokh Habibzadeh, secretary of

the WAME, participating in the discussion opined, “Many

experienced editors practically do not rely on the peer

reviewers to accept or reject articles. Reviewers are indeed

advisors and editors use their comments to improve the

quality of papers if they find they are publishable at all. It

is the editors who are fully responsible for the publication/

rejection of a manuscript. A good editor will use any means

available to improve the quality of his/her journal.”

If one looks at the ground realities, what happens is that

“non-availability of competent and qualified reviewers”

forces the small journals in most of the developing world to

open the gates too wide and use reviewers who might lack the

necessary knowledge (Morcos A. Publishing in developing

countries: problems and solutions. CBE Views 1999;22:198).”

Richard Smith, former editor of the BMJ, in his book

entitled “The Trouble with Medical Journals” remarks that

clinicians, researchers, editors, journalists and publishers

should all accept that medical journals have many problems

and thus need reform. During his twenty-five years at the

BMJ, Smith became aware of the complex problems in

medical editing and publishing. The situation becomes still

worse when there is a lack of evidence to guide on how to

conduct all this (Smith R. The trouble with medical jour-

nals.Royal Society of Medicine Press. London 2006.).

Currently (as of December 2007), 5,194 journals are indexed

by Medline. Other important databases include the Nether-

lands-based Excerpta Medica Database (EMBASE). Science

Citation Index Expanded (SCIE) by Thompson/ISI, more

commonly known for impact factor, covers 7,631 medical

journals which include fewer than 2% of the journals published

in the developing world (Morcos A. Publishing in developing

countries: problems and solutions. CBE Views 1999;22:198).

Directory of Open Access Journals (DOAJ) covers 3,680

journals. The Iran-based emrmedex database has included

one hundred ninety-five journals from the EMRO region.

The Eastern Mediterranean Association of Medical

Editors (EMAME) has also established its own database,

IMEMR Current Contents (Index Medicus for the World Health

Organization (WHO) Eastern Mediterranean Region), which

is being linked to Medline. Hence this requirement will also

be met to a great extent in the not too distant future, thanks to

the untiring efforts of Dr. Najib Shorbaji and his team at the

WHO EMRO (http://www.emro.who.int/HIS/VHSL/imemr.

htm).

Regulatory authorities in different countries are also trying

to monitor the standard and quality of biomedical journals

published in their respective countries. In Pakistan, there

are about fifty medical and dental journals recognized by

the Pakistan Medical and Dental Council, while about half a

dozen are recognized by the Higher Education Commission

of Pakistan. Among these, the number of the medical and

dental journals which practice peer review is less than ten.

The Ministry of Health in the Islamic Republic of Iran has

also constituted a committee of experts for the recognition

of biomedical journals, and authors are encouraged to

publish their manuscripts in those journals, which are either

indexed in Medline or covered by SCIE ISI/Thompson Web

of Sciences. Be that as it may, in most of the developing

countries, scholarly publishing still remains a cottage

industry.

The picture is not so gloomy, however, for in the face

of the difficulties and hardships, medical editors involved

in editing peer-reviewed biomedical journals in the

developing world have made a lot of progress. It is all the

more commendable since most of them had no formal

training in editing but had on-the-job training and most

of them are working part time. Apart from their clinical

responsibilities, most medical editors have taken upon this

additional responsibility and are trying their best to come

up to the expectations of readers, authors and reviewers.

Still, for a long time to come except for those biomedical

journals which are sponsored by various institutions and can

afford to have full time editors and other editorial staff,

most editors will have to be content with working in

honorary capacity. It will never be the financial

rewards but professional satisfaction which will keep them

moving. Once they are able to influence some

decisions at policymaking level, this should offer them the

immense satisfaction of having accomplished something.

It will be the editor who will have to finally decide which

of the manuscripts can be accepted for publication after

internal review and which are the manuscripts which need

to be submitted for external review. Keeping up with the

advances in technology, now going online, which is very

economical as compared to print publication, improves

the visibility of the journals tremendously and also serves

as a great source of manuscripts and potential regional

cooperation.5 Indexing in Medline Index Medicus is of course

considered an important yardstick of quality and

standard of a journal; not succeeding in that, however,

should not weaken an editor’s resolve to continue his/her

efforts to enhance the quality and standard of the journal.

With more and more medical journals going online with

full text manuscripts, Medline, in the opinion of some,

may not stay as relevant in the days to come (Laporte

RE. With availability of full text online medical journals

indexing in Medline is going to become irrelevant. Pulse

International Karachi. Pakistan 2005;6:1). Google Scholar,

which has turned out to be an excellent database for latest

references, is being increasingly used by researchers as it

covers a much larger number of manuscripts published in

biomedical journals available online. Hence, all efforts

should be directed at maintaining the online edition of the

journal, which enables the authors to have a much wider

readership.

Shaukat Ali Jawaid

TEHRAN HEART CENTER


What we need to do is to include subjects like medical

writing and research methodology in the undergraduate

curriculum, organize frequent courses, seminars, symposia

and workshops not only for authors but also for reviewers

and training of editors. This is something which the

Pakistan Medical Journalists Association (PMJA) has

undertaken in Pakistan for the last couple of years. It was

with the same objective that we organized the First National

Conference on Medical Editing in Rawalpindi in April 2007.

Proceedings of this conference were published and are now

freely accessible on the PMJA website (pmja.com). It offers

a great deal of useful material not only for authors and

reviewers but also for editors (Proceedings of First National

Conference on Medical Editing held in Pakistan in April

2007. Accessible free on www.pmja.com).

More recently, we have embarked upon planning a

series of workshops on medical editing and peer review in

collaboration with the Easter Mediterranean Association of

Medical Editors (EMAME), wherein the latter has provided

some technical assistance. We have organized three such

successful workshops and will be only too glad to share our

experience with the editors in the region.6 What we earnestly

require is a closer cooperation and collaboration between

research scientists and medical editors of the countries

in this region to share our knowledge and learn from one

another’s experience. It was with this objective in mind

that I myself recently visited various Islamic Republic of

Iran’s medical universities, namely Ahwaz, Tehran, Shaheed

Beheshti, Iran, and Isfahan, participated in their workshops

on medical writing and peer review, and had fruitful

discussions with their faculty members, all of which has

been a great learning experience for me.

References

1. Jawaid SA. Problems faced by Editors of Peer Reviewed

Medical Journals. Saudi Med J 2004;25:S21-25.

2. Jawaid SA, Jafary MH. Simultaneous submission and duplicate

publication: curse and a menace which needs to be checked. Pak J Med

Sci 2005;21:245-248.

3. Jawaid SA. What medicine and medical journal editing means to

me. Mens Sana Monographs 2006;4:62-77.

4. Harvey M. What medical journal editing means to me. In: Mens

Sana Monograph 2008;6:237-243.

5. Jafary MH, Jawaid SA. Online edition of a journal: a great source

of manuscripts and potential regional cooperation. Pak J Med Sci

2006;22:107-109.

6. Jawaid SA. Proceedings of workshop on medical editing and peer

review held at NICH and DUHS, Karachi. Pakistan. Pak J Med Sci

2008;24:637-641.

Problems of Editing a Peer-Reviewed Biomedical Journal in a Developing Country

190



TEHRAN HEART CENTER

Surgical Treatment of Atrial Fibrillation

Kyomars Abbasi, MD*, Iman Abbasi, MD, Naghmeh Moshtaghi, MD

Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran.

Review Article

Abstract

Introduction

which need surgical treatment. Various types of surgery including the traditional cut-sew operations and operations using

different energy sources are currently in use. In comparison with medical treatment, surgery is safe, effective, and has

reliable results.

J Teh Univ Heart Ctr 4 (2008) 191-196

*Corresponding Author: Kyomars Abbasi, Assistant Professor of Cardiac Surgery, Tehran University of Medical Sciences, Tehran Heart Center, Jalal

Al Ahmad & North Kargar Intersection, Tehran, Iran. 1411713138. Tel: +98 21 88029256. Fax: +98 21 88029256. E-mail: [email protected].

Keywords:

Atrial fibrillation (AF) is the most common cardiac

arrhythmia. It is estimated to occur in 3% of the general

population, and its likelihood increases significantly in the

elderly (Table 1). Far from being a harmless arrhythmia, AF

may beget major complications or even mortality.1-3

Table 1. Number of cases with atrial fibrillation per 100 persons

(examined in the Framingham study)

Age groups (y) Persons with atrial fibrillation (%)

50-59 0.5

60-69 1.8

70-79 4.8

80-89 8.8

AF may cause:

1. Palpitation, which leads to anxiety and

discomfort.

2. Decreased ventricular function due to the loss of

atrioventricular synchrony and, in its extreme, heart

failure.

3. Thrombus formation in consequence of the stasis

of the blood in the left atrium.

4. Risk of systemic thromboemboli.

According to the Framingham Heart Study,3 AF increases

the odds ratio for death 1.5 to 1.9 times and the risk of

embolic cerebrovascular accidents up to five times. The

pharmacotherapy of AF has proved disappointing because of:

1. Failure to reverse arrhythmia to normal sinus

rhythm in the majority of cases

2. Significant side effects of drugs

3. Need to long-term or even lifelong use of drugs

4. Exorbitant costs

5. Poor patient compliance

The AFFIRM Study (the Atrial Fibrillation Follow-up

Investigation of Rhythm Management) showed that rhythm

control in comparison to rate control offered no mortality

benefits. Given the limitations of drug treatment for AF,

192


other treatments based on percutaneous or surgical ablation

are now the focus of interest.4-6

Patients with permanent AF require anticoagulation

warfarin use, which is associated with major bleeding

complications up to 2-3% per year. This is another reason

for the interest in treatments that convert AF to normal

sinus rhythm.

Electrophysiological basis of atrial

The commencement and continuation of AF require

conditions which include:

1. A trigger that may be unifocal or mov ing or may be

permanent or paroxysmal

2. Change in the refractory period of the atrium

3. Change in the conduction velocity

4. Change in the atrial dimensions allowing the

continuation of AF

These conditions set off multiple macroreentrant circuits,

which give rise to irregular atrial activation. Pathological

conditions such as ischemia, inflammation, or increased

atrial size provide a basis for change in the refractory

period and conduction velocity; and once triggered, AF may

continue.

The role of the pulmonary veins in AF is very important.

The pulmonary veins contain no pacemaker tissue, but their

refractory period is longer than that of the nearby atrial

tissue. The anatomy of the pulmonary veins is highly

variable in humans, and some studies have shown that the

pulmonary veins are the trigger zone in more than 50%

of cases.7

The most useful classification suggested to date is that by

joint American Heart Association (AHA), American College

of Cardiology (ACC), and Heart Rhythm Society (HRS),

according to which AF may be:

1. Paroxysmal

2. Persistent

3. Permanent

Paroxysmal AF is recurrent AF (2 or 3 episodes) that

is self-terminating; persistent AF is AF that is not self-

terminating; and permanent AF is AF lasting more than 1 year

in which cardioversion fails or is not indicated at all (Figure 1).

All types of AF may be treated surgically. However,

persistent and permanent AFs comprise the bulk of the

cases and tend to be associated with important concomitant

cardiac pathologies such as coronary artery disease,

valvular heart disease, and congestive heart failure.

Surgical ablation is also applicable to AF without any

Kyomars Abbasi et al

associated pathology (lone AF).

Figure 1. Different patterns of atrial fibrillation (AF)

The basic points in the surgical treatment of AF are the

disruption of the pathways of AF wave conduction and

the isolation of the trigger zones while saving normal

atrioventricular conduction and effective atrial contraction.

These goals may be fulfilled via the traditional cut-and-sew

techniques or the use of different energy sources to create

similar lesions in the atrial wall.8

Cut-and-sew procedures

In the evolution of AF surgery, some historical operations

merit special mention. They may have been ineffective or

caused many complications or even mortalities, but they

provided the knowledge which is the basis of modern AF

surgery. The most salient of these operations are:

1. Left atrial isolation

2. Atrioventricular node ablation

3. Corridor procedure

4. Atrial transaction

5. Maze I and II operations

The only cut-and-sew operation still in use with

acceptable results is Maze III operation, named Cox/Maze

III operation in honor of its inventor (Figure 2).9

Cox/Maze III operation became the gold standard for the

surgical treatment of AF when it was reported that 97% of

the patients at late follow-up were free of AF. Since then,

although this procedure has yielded acceptable outcomes in

various institutions, it has failed to gain popularity due to

the complexity and technical challenges that it poses to the

average surgeon.

Recently, other types of cut-and-sew techniques have

been devised which involve different lines of incision

(radial incisions). Nonetheless, they are not popular and

long-term results are unavailable. Cox/Maze III operation is

the choice procedure for Huge LA (D>60 mm).

TEHRAN HEART CENTER



Figure 2. Cox/Maze III operation

SVC, Superior vena cava; IVC, Inferior vena cava

Procedures using alternative sources of energy

The medical industry has made major strides in

simplifying AF surgery and keeping it effective, so much so

that an average surgeon can now perform AF surgery. There

is presently a wide array of ablation devices available in a

surgeon’s armamentarium (Table 2).

MechanismTransmural

lesionClinical

experienceThrombo- genicityEnergy source

Table 2. Various energy sources for AF ablation

It is worthy of note, however, that any ablation device

should fulfill certain important conditions:

1. The lesion created by the device must be

transmural to provide bidirectional block.

2. It must be safe and not damaging to important

cardiac tissue or adjacent organs.

3. It must be simpler than cut-and-sew techniques.

4. It should be applicable via the epicardial or

endocardial route and have the potential to be usedvia

minimally invasive routes.

Different devices available in clinical practice utilize

different energy sources which include:

Cryothermy

Cryotherapy is a well-known method of arrhythmia

surgery and can create transmural lesions when applied

to the atrial tissue. It causes myocardial cell necrosis but

spares the collagen framework. The source may by N2O

(-60 to -89.5°C) or liquid argon (-185.7°C). Recently, a

laser-based cryothermal source has been introduced. It can

be applied via the endocardium or epicardium or even in

beating-heart surgery. Cryolesions are unique in that they

are non-disruptive to vital cardiac organs and skeleton,

and the likelihood of injury to the valves and the coronary

artery is low. Cryothermy is very safe for the adjacent or-

gans to the heart. The efficiency depends on the set of lesions

and the experience of the surgeon in creating transmural

lesions; the overall efficacy of the method is around

75-80%. Cox/Maze IV operation, which is a modifica-

tion of Cox/Maze III operation, uses alternative sources of

energy and is as effective as the standard Cox/Maze III

operation (95% long-term AF cure) (Figure 3).10-12

Radiofrequency

Radiofrequency is utilized to apply an alternative

current of 350 KHz to 1 MHz to the heart tissue. The

creation of a transmural lesion depends on the power of

radiofrequency, impedance of the tissue, and time of

application. Radiofrequency can create full thickes lesions

if applied long enough and can be used as a unipolar or

bipolar device (Figure 4). The dry mode now is not

available, and irrigation radiofrequency is currently the

device in use. Irrigation can decrease tissue charring and

nearby organ injury and at the same time increase the

depth of the atrial lesion. Radiofrequency is quick and safe,

easily fits minimally invasive surgery, and can be

applied via the epicardium or endocardium. It is, therefore,

the most popular energy source. The overall efficiency of

radiofrequency is around 60-80% in the long-term

cure of AF. Biatrial radiofrequency AF ablation

may cure AF in 85% of cases but is associated with

unacceptable rates of A-V block (up to 10%).13-16

Microwave

Microwave is a new source of energy that induces

vibration in water molecules and creates thermal en-

ergy. The energy band in ablation surgery is between 915

and 2450 MHz. Microwave does not char the tissue and

is able to create transmural lesions. When used in the

correct set of lesions, microwave can cure AF in 65-80% of

cases. In some studies, lesions created by microwave are not

Radiofrequency

Microwave

Cryothermal

Ultrasound

Laser

2 +

2-3 +

– / +

Unknown

2 +

Radiofrequency

current

Electromagnetic

waves (2.45GHz)

N2O or helium

Pressure waves

Photon absorption

2 +

2 +

2-3 +

4 +

1 +

4 +

1 +

3-4 +

1 +

1 +

194


transmural. Microwave can be applied via the pericardium

and in minimally invasive procedures.17-18

Figure 4. Left atrium lesion set in radiofrequency ablation of atrial fibrillation

Ultrasound

Ultrasound transducers with frequencies of 2 to 20 MHz

are now in use. Transducers convert the electrical energy

to mechanical waves, and the absorption of the mechanical

waves generates heat in the tissue. The depth of penetration

can be set. Ultrasound may be focused or unfocused. Clinical

experience with ultrasound is limited, but most studies have

Kyomars Abbasi et al

demonstrated that increasing the

epicardial fat has no effect on the creation of transmural lesions

(contrary to other energy sources). This is an advantage when

this source of energy is used epicardially. An overall

efficacy rate of up to 85% has been reported for this

alternative source of energy, but the general figure must

bearound 75-80%. The mean advantage of ultrasound is

that it is contact forgiving and can focus the waves on the

tissue.19

Laser

Laser is a monochromic coherent beam generating tissue

heating. The most popular laser for AF ablation is a diode la-

ser with a continuous low energy power. Animal studies have

shown transmural lesions, whereas clinical human studies are

small and mid- and long-term results are not available.20-21

Contraindication of AF ablation using alternative sources of energy

AF ablation is ineffective in the following conditions:

1. LA dimension more than 60 mm

2. Calcified LA wall

3. Very chronic AF (relative)

Figure 3. Cox/Maze IV operation

TEHRAN HEART CENTER



Conclusion

AF is an important, epidemic arrhythmia and is frequently

associated with major morbidity or even mortality.

The medical treatment of permanent AF is frustrating, and

lifelong anticoagulation is an additional problem.

Surgery opened a new horizon to the treatment of AF,

but the only cut-and-sew operation that stood the test of time

is Cox/Maze III operation with 97% long-term cure for AF.

Variations of Cox/Maze III operation that use alternative

sources of energy have yielded results that approximate to

the results of the standard operation. Due to the complexity

and time-consuming nature of the standard or Cryo-Maze

III operation, other energy sources are now available in

practice with long-term cure rates of around 70-85% and very

low complication rates.

AF ablation is a solid part of surgery of each

patient with AF rhythm. Cryoablation or radiofquencyre

ablation with various sets of lesions has acceptable results

and few complications. Let’s do it!!

Acknowledgment

The authors wish to thank Ms. Akhlaghi for typing the

manuscript and Ms. Raheleh Esmaeili Darabi for drawing

the figures.

References

1. Fuster V, Rydén LE, Asinger RW, Cannom DS, Crijns HJ, Frye

RL, Halperin JL, Kay GN, Klein WW, Lévy S, McNamara RL,

Prystowsky EN, Wann LS, Wyse DG, Gibbons RJ, Antman EM,

Alpert JS, Faxon DP, Fuster V, Gregoratos G, Hiratzka LF, Jacobs AK,

Russell RO, Smith SC Jr, Klein WW, Alonso-Garcia A, Blomström-

Lundqvist C, de Backer G, Flather M, Hradec J, Oto A, Parkhomenko A,

Silber S, Torbicki A; American college of cardiology/American heart

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trol and rhythm control in patients with recurrent

persistent atrial fibrillation. N Engl J Med 2002;347:1834-1840.

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patients. Prog Cardiovasc Dis 2005;48:29-40.

8. Cox JL. Intraoperative options for treating atrial fibrillation associated

with mitral valve disease. J Thorac Cardiovasc Surg 2001;122:212-215.

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use for the surgical ablation of atrial fibrillation. Semin Thorac

Cardiovasc Surg 2002;14:198-205.

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12. Watanabe H, Hayashi J, Aizawa Y. Myocardial infarction

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Thorac Cardiovasc Surg 2002;50:210-212.

13. Demazumder D, Mirotznik MS, Schwartzman D. Biophysics of

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trophysiol 2001;5:377-389.

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P, Müller KM, Laczkovics A. Saline-irrigated, cooled-tip

radiofrequency ablation is an effective technique to perform the maze

procedure. Ann Thorac Surg 2001;72:1090-1095.

15. Laczkovics A, Khargi K, Deneke T. Esophageal perforation

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2003;126:2119-2120.

16. Ruchat P, Schlaepfer J, Delabays A, Hurni M, Milne J, Von Segesser

LK. Left atrial radiofrequency compartmentalization for chronic atrial

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155-159.

17. Gillinov AM, Smedira NG, Cosgrove DM 3rd. Microwave

ablation of atrial fibrillation during mitral valve operations. Ann

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microwave energy in cardiac tissue ablation: from in vitro analyses to

clinical use. Ann Thorac Surg 2002;74:1500-1505.

19. Saliba W, Wilber D, Packer D, Marrouche N, Schweikert R,

Pisano E, Shewchik J, Bash D, Fanelli R, Potenza D, Santarelli P, Tchou

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201-206.

196



TEHRAN HEART CENTER

Enhanced Myocardial Vascularity and Contractility by Novel FGF-1

Transgene in a Porcine Model of Chronic Coronary Occlusion

Reza Forough, PhD1,2*, Matthew W. Miller, DVM3, Mildred Mattox, BS3, Wayne

Dunlap, MD2, Aandy Ambrus, PhD3, Rola Barhoumi, PhD3, Cristine L. Heaps, PhD3,

Janet L. Parker, PhD2,3

1Bellevue College, Science Division, Bellevue, Washington, USA.2College of Medicine, The Texas A&M University, USA.3College of Veterinary Medicine, The Texas A&M University, USA.

Abstract

Background: Angiogenesis gene therapy has long been sought as a novel alternative treatment for restoring the blood

factor-1 (FGF-1) is a promising candidate for developing a promising gene therapy protocol due to its multipotent ability

to stimulate endothelial cell (EC) growth, migration, and tube formation. Despite these advantages, however, FGF gene

angiogenic effect of FGF-1, we reasoned that constitutively synthesized minute quantities of this polypeptide hormone, when

empowered with the ability to escape the cellular constraint, could freely act in a paracrine/autocrine fashion on nearby

purpose.

Methods: We report the direct gene transfer of a retroviral-based mammalian expression vector encoding a secreted form

of FGF-1 (sp-FGF-1) for the purpose of therapeutic angiogenesis into the porcine myocardium subjected to the surgical

Results:

alone).

Importantly, an assessment of the cardiac function by echocardiography, performed 3 weeks after surgery, demonstrated

improved cardiac contractility due to increased left ventricular free wall contraction in the sp-FGF-1-treated animals only.

Conclusion: These results suggest that the intramyocardial delivery of our chimeric secretory FGF-1 gene can enhance

vascularity and improve cardiac contractility in a chronic ischemic heart. This protocol may serve useful for developing

reparative angiogenesis strategies aimed at improving the pumping function of the ischemic hearts in human patients.


*Corresponding Author: Reza Forough, Research Associate Professor of Medical Physiology, Department of Systems Biology & Translational Medicine

and Cardiovascular Research Institute, College of Medicine, The Texas A&M University System Health Science Center, College Station, TX 77843.

Tel: +1 425 5907235. Fax: +1 425 5644125. Email: [email protected].

Original Article

Received 29 May 2008; Accepted 30 September 2008

Keywords:

198

The Journal of Tehran University Heart Center Reza Forough et al

Introduction

Angiogenesis gene therapy is viewed as an alternative

treatment for patients with myocardial and peripheral

ischemia in whom conventional therapies including

antianginal medications, angioplasty, and bypass surgery have

failed. The goal of angiogenesis gene therapy is to improve

the blood flow to ischemic tissues through the induction of

neovascularization by angiogenic agents introduced by gene

transfer. Highly promising angiogenic factor candidates are

members of fibroblast growth factor (FGF) and vascular

endothelial growth factor (VEGF) families.1-6 However, a

major limitation to progress in developing useful angiogenesis

gene therapy protocols using FGF and VEGF has been the

inefficient delivery of the growth factors to ischemic target

sites in animal and human subjects.7 Efficient synthesis and

release of transgene in target tissues is largely determined

by the ability of host cells to express the transgene, choice

of vector, and route of delivery. To circumvent problems

associated with poor in vivo transfection, we developed

strategies for therapeutic angiogenesis in an ischemia-

induced pig heart model using a novel secreted form of

FGF-1 gene construct. For this study, we employed a

chimeric version of fibroblast growth factor-1 (sp-FGF-1),

composed of a secretory signal peptide (sp) attached to

the 5’-end of human FGF-1 gene construct, which was

previously shown to exhibit very strong angiogenic properties

both in cultured endothelial cells and in the developing chick

embryo.8,9

In the current study, we set out to test our hypothesis that

the direct in vivo gene transfer of sp-FGF-1 into ischemic

myocardium leads to increased synthesis and secretion of

recombinant FGF-1 protein, acting in autocrine/paracrine

modes to induce successful neovascularization and im-

proved cardiac pumping function. The ischemic pig heart

model used in this study is a progressive chronic coronary

artery occlusion (CCO) model,10-15 whereby an ameroid

occluder is surgically placed around the left

circumflex coronary artery (LCx) of a pig followed by

direct intramyocardial injections of sp-FGF-1 plasmid DNA

into the myocardium residing just distal to the occluder.

This model of CCO for sp-FGF-1 gene therapy was selected

because porcine and human hearts exhibit many similarities

in coronary and collateral physiology/anatomy.16 For

example, normal pigs and humans possess minimal innate

coronary collaterals; a sudden blockade of a major coronary

artery will typically induce infarction and possibly death.17

Although progressive chronic coronary artery stenosis/

occlusion will enhance the collateral development to ischemic

myocardium-at-risk, collateral development remains

limited and long-term phenotypic and physiologic changes

are observed in pigs that mimic those of human patients with

coronary artery disease and CCO. In light of the foregoing

discussions, we evaluated the potential application of a

novel secreted angiogenic factor FGF-1 (sp-FGF-1) for the

design of new angiogenic gene therapies aimed at repairing

damaged ischemia-induced porcine heart tissues.

Methods

We have previously described the construction and

angiogenic characteristics of sp-FGF-1.8-9 Briefly, the

human FGF-1 open reading frame (ORF) was isolated from

a human cDNA library using polymerase chain reaction

technique (PCR) and subcloned into the unique SalI and

EcoRI DNA restriction enzyme sites of the mammalian

expression vector pMEXneo. Subsequently, a 78-base pair

oligo (encoding 22 hydrophobic amino acids) corresponding

to the published signal-peptide sequence of one of the

secretory members of the FGF family known as FGF-

418,19 was joined in-frame to 5' end of the FGF-1 ORF in

the eukaryotic expression vector pMEXneo. We chose the

FGF-4 signal peptide sequence in our construct because in

its native form, FGF-4 is a member of the FGF family and

encodes a growth factor of 30-40% homology to FGF-1,

which is secreted outside the cell. In addition, the PCR

was used to add a Kozak sequence (CCACCATGG) to the

final construct for improving the efficiency of the

sp-FGF-1 protein synthesis.20 pMEXneo is a retroviral-based

vector driven by mouse sarcoma virus promoter (MSV-

LTR). It stably integrates into the host chromosome. In

addition, pMEXneo contains a gene encoding for neomycin

phosphotransferase, which allows the isolation of

stable transfectants.21 sp-FGF-1 final gene construct is

approximately 500 bp in length.

Yucatan miniature swine (25-45kg) were surgically

instrumented with an ameroid occluder on the proximal

LCx via a left lateral thoracotomy. Immediately following

occluder placements, two groups of pigs were used to

investigate the potential effects of sp-FGF-1 gene on

angiogenesis. One group (n=4) received myocardial

injections of pMexNeo vector alone, and the other group

(n=5) received injections of sp-FGF-1/pMexNeo plasmid-

each injection contained 25 µg of DNA in an equal volume

of TransIT in vivo transfection solution. There were four

total injection sites (100 µg total plasmid DNA/heart was

injected). The injection sites were (in relation to the right

edge of the occluder): 1 cm down, 1 cm distal and 1 cm down,

2 cm down, and 1 cm distal and 2 cm down.22 Two additional

sham-occluded pigs received no occluder and no injections.

Each pig was allowed 3 weeks to recover, during which time

the gradual closure of the LCx occurred. Echocardiography

was performed on the sp-FGF-1 (n=3), vector-control (n=1),

and sham (n=1) animals prior to surgery and 3 weeks after

surgery in order to compare the cardiac function before

and after the occlusion and also to compare the control and

FGF-treated pigs. The animals were then euthanized, and

TEHRAN HEART CENTER


Enhanced Myocardial Vascularity and Contractility ...

the myocardial tissue was sampled at injection sites as well

as the non-occluded, non-ischemic regions of each heart.

The samples were subdivided for freezing and immediate

histological sectioning for vessel analysis and future

biochemical/molecular studies. Additional tissues, including

liver, spleen, eye, and skin, were harvested for potential

angiogenic side-effects.

All the echocardiographic images were obtained with a

General Electric System Five echocardiograph using a 3.5

MHz transducer with harmonic imaging. The images were

recorded on optical disk and stored for later offline analysis

(EchoPac™ work station). Short-axis and long-axis images

were obtained with the transducer placed in contact with the

right hemithorax, positioned to optimize the standard tomo-

graphic planes. A digital loop consisting of at least three

cardiac cycles were recorded in the short axis at the level

of the papillary muscles (midventricle) and in the long axis

to obtain the maximal left ventricular dimension and allow

visualization of the mitral valve. Fractional shortening,

wall thickening percent, and endocardial excursion were

measured or calculated from m-mode recordings obtained

from the short-axis image. All the echocardiographic

analyses were performed by an independent observer blinded

to the treatment which the animals received. Segmental

contractions were compared in all the segments at all times

using the animal as its own control.

The pigs were anesthetized with and maintained on

isoflurane via endotracheal intubation. A carotid artery was

isolated, and a French soft-tipped coronary guiding catheter

was advanced into the aorta and then selectively into the

right and then left coronary ostium. Fluoroscopy contrast

was injected into the proximal coronary artery to visualize

the coronary vasculature and potential collateral arteries.

The injections were recorded on video and radiographic

film. Immediately upon the completion of the angiography

(approx. 45-60 min.), the animal was sacrificed and the heart

removed.

Total RNA was extracted from frozen heart tissues

containing the plasmid injected sites using Totally RNA Kit

™ (Ambion Inc., Austin, TX) according to the manufacturer’s

recommendations. The aliquots of each RNA sample were

subjected to Agilent bioanalyzer (Agilent Technologies,

New Castle, DE) to determine the integrity and quantity of

the isolated RNA.

For reverse transcription (RT), 1.0 µg of total RNA was

incubated with 0.25 µg of a random primers in the presence

of M-MLV enzyme (Invitrogen, Carlsbad, CA) at 37°C for

1h. For PCR, we designed the following sense and antisense

oligonucleotides corresponding to the sp-FGF-1 coding

frame: (sense primer) 5'-GTCCTGCTGGCCTTGCTG-3'

and (antisense primer) 5'-AAACAAGATTGCTTTCTG-

GCCAT-3'; for internal control, Oligonucleotide primers

corresponding to the regions of the house keeping gene

glyceraldehydes-6-phosphate dehydrogenase (GAPDH):

(sense primer) 5'-TTGTCAGCATGCCTCCTGCACC-3'

and (antisense primer) 5'-AACTGGTCCTCAGTGTAGC-

CTAG-3' were used. All the primers for this study were

synthesized by Integrated DNA Technologies, Inc.,

Coralville, IA. We successfully amplified sp-FGF-1

transgene and internal control GAPDH using the follow-

ing PCR condition: cycle one was 94°C for 1’, cycle 2 was

55°C for 2’, and cycle 3 was 72°C for 3’; thereafter, cycles

1 to 3 were repeated 34 times. An additional 7’ extension at

72°C was added at the end of the last cycle of the PCR. The

thermostable enzyme DyNAzyme EXT™ (MJ Research,

Inc.; Waltham, MA) was used for the PCR step. The PCR

products were resolved on a 1% agarose gel, ethidium

bromide stained, and photographed.

For factor VIII staining of endothelial cells, we used

the streptavidin-biotin/horseradish peroxidase method

(Vectastain Elite ABC Kit; Vector Laboratories Inc.;

Burlingame, CA) with 3,3’-diaminobenzidine (Histomark

DAB chromogen kit; KPL Inc., Gaithersburg, MD) as a

chromogen. The sections were deparaffinized in xylene and

rehydrated in graded alcohols, incubated in proteinase K

(DAKO Corp., Carpinteria, CA) for 3 minutes for antigen

retrieval. The sections were treated with 3% hydrogen

peroxide for 15 minutes in order to block their endogenous

peroxidase activity. Subsequently, the sections were incubated

with Universal Block (KPL Inc.), washed, and incubated

with normal serum blocking reagent using R.T.U. Vectastain

Elite ABC Kit (Vector Laboratories Inc.) to block the

nonspecific sites. Endothelial layers were identified by a

rabbit polyclonal antibody (Ab) to von Willebrand Factor

(vWF) (Cat#A0082; DAKO) (1:800). Negative controls

included the substitution of an unrelated Ab for vWF Ab.

Immunohistochemical staining of the blood vessels was

completed using the ABC Elite Kit according to the manu-

facturer’s recommendations of biotinylated secondary Ab

and ABC label reagent. Gill No.3 hematoxylin (Sigma Inc.;

St. Louis, MO) was used to counterstain the sections.

For the quantitation of vascularization, digital images

were taken at 40X per random fields, and vWF-positive

stains were counted using Version 6.0 Metamorph Software

(Universal Imaging Corp., Downingtown, PA). Picture

taking and quantitation of vascularization were performed

by an independent observer blinded to the treatment which

the animals received. Differences between the sp-FGF-1

and control groups were analyzed using an unpaired

two-tailed t-test at p<0.05 using GraphPad PRISM Version 4.0

(GraphPad Software, San Diego, CA).

Results

An evaluation at 21 days post-surgery by coronary an-

giography confirmed the formation of coronary stenosis and

the interruption of the blood flow, at and distal to the occlu-

200


sion site of the LCx, respectively (Figure 1). A comparison

of the intensities of the contrast dye within the LCx at sites

proximal and distal to the ameroid occluder demonstrates the

shutdown of the blood flow downstream to the occlusion/

stenosis (Figure 1). This is in agreement with the previous

observation that complete ameroid occlusion occurs around

17-20 days post-implantation in the porcine CCO model and

precedes the formation of ischemia within the left ventricular

tissue.23

Figure 1. Representative angiogram of a treated pig. Note the contrast dye

intensities distal and proximal to the occluder, demonstrating a successful

interruption of blood flow downstream the occluder device

Figure 2. sp-FGF-1 transgene expression in pig heart demonstrated by

reverse transcription (RT)-polymerase chain reaction technique (PCR) tech-

nique. Total RNA (1 µg) was extracted from the vector control (lane 1) or

sp-FGF-1 (lane 2) transfected heart tissues. RT products were PCR-ampli-

fied (30 cycles) using a pair of specific primers to sp-FGF-1 (upper panel)

and the house keeping gene glyceraldehydes-6-phosphate dehydrogenase

(GAPDH) (lower panel). PCR-amplified materials were resolved on an aga-

rose gel, stained with ethidium bromide, and photographed

Confirmation of sp-FGF-1 gene expression was also deter-

mined in the transfected porcine hearts. As described above,

immediately following the occluder placement, either 100

µg of the sp-FGF-1/pMEXneo or pMEXneo plasmid alone

was directly transfected into myocardia using lipid agents.

The plasmids were introduced into the exact same tissue

sites relative to the occluder position for each pig in order

to reduce variability in tissues that were later retrieved

from the sp-FGF-1 and control pigs for comparison of

their vascularity and the transgene expression. Sp-FGF-1

transgene expression was confirmed by RT-PCR, in which

the forward primer corresponded to the portion of the gene

encoding the signal peptide sequence and the reverse primer

corresponded to the DNA region encompassing the carboxyl

terminus of the FGF-1 (Figure 2). These primers were

designed to specifically recognize the sp-FGF-1 chimera but

not theendogenous porcine FGF-1 in the heart tissues.

These results document that 21 days following the

proposed gene therapy: 1) the ameroid occluder successfully

blocked the blood flow through the LCx to the myocardial

regions within the left ventricle and 2) direct intramyocar-

dially transfected sp-FGF-1 gene was expressed within the

tissues at the sites of the transgene injection.

Similar geographic sites were injected with the plasmid

constructs for two reasons. First, this reduces variability

in the innate vascularity, which may exist from region to

region of porcine hearts. Second, the injected sites were

carefully selected to encompass the border regions of the

ischemic zones in the left ventricle. This region is known to

exhibit active angiogenesis and collaterization in ischemic

conditions.17

sp-FGF-1/pMEXneo and pMEXneo vector-alone plasmids

were separately mixed with Trans IT In Vivo (Pan Vera

Inc.), a cationic liposome transfection reagent, and the

mixture was immediately used to directly transfect the

exposed myocardium.

Immunostaining of the transfected heart tissues for

vWF, an endothelial cell specific marker, followed by

the quantitation of vWF-positive stains at day 21 clearly

demonstrated a higher degree of angiogenesis in the sp-FGF-1

compared to vector-alone-transfected animals at the

injected sites. In this analysis, the number of vessels (vWF-

positive by immunostaining) in the plasmid injected sites

using a ‘point counting’ method confirmed the difference

to be statistically significant (sp-FGF-1: 45.79±2.056,

n=5; vector control: 37.42±1.71, n=4; p<0.05, unpaired

two-tailed t-test with Welch Correction). It revealed a 19%

increase in the vascularity of the myocardium of the sp-FGF-1

-treated hearts compared to the vector control (Figure 3).

These data indicate that a bolus intramyocardial injection

of 100 µg of the secreted form of FGF-1 DNA induces an

elevated number of blood vessels 21 days later at the

injected site in an ischemia-induced pig heart model.

Echocardiography was used to assess the cardiac function

in the sp-FGF-1 and control plasmid-treated porcine hearts.

Echocardiography using m-mode was performed (n=3,

sp-FGF-1/pMEXneo; n=2, pMEXneo); and n=1, sham) at

baseline (prior to surgery) and at 3 weeks after surgery in

TEHRAN HEART CENTER



Figure 3. Angiogenic effects of sp-FGF-1 gene construct (n=5) compared

to control vector-alone pigs (n=4) at the injected sites. Direct plasmid gene

delivery was accomplished. After 21 days, hearts were removed, sectioned,

immunostained using antibody specific to von Willebrand Factor, and their

blood vessel cross-sections (a total of 48 digital images collected from ran-

domly selected sites per treatment) were counted in a blind manner. The

asterisk indicates statistical difference (P<0.05)

order to evaluate the cardiac pumping function in the

vector-alone (control) and sp-FGF-treated pigs. Interest-

ingly, there were no significant baseline (prior to surgery)

variations based on echocardiographic analyses between the

pigs. In other words, it would be acceptable to calculate an

average baseline value by the echocardiographic analysis

of only a few randomly selected pigs prior to surgery and

use the obtained data in a generalized manner to represent

the baseline value for each individual animal in the study. In

addition, during the echocardiographic analysis, each

porcine heart was stressed by exposure to progressively

increasing heart rates using the dobutamine stress test

(similar to that used in human CAD testing). During the

stress test, increasing dobutamine doses of 5 µg/kg/min were

administered for five-minute periods increasing to 40 µg/

kg/min. Contractile function was assessed at each increased

level of heart rate. Interestingly, sp-FGF-1 had improved the

cardiac function compared to the control pigs both in resting

and stressed states. In fact, during the stress test when the

highest heart rate had been achieved, the sp-FGF-1-injected

pigs had no obvious ventricular dysfunction upon echocar-

diogram (percent thickening=100%). The control showed

a dramatic decrease in free wall contraction and shortening

(percent thickening=50%), which indicates profound region-

al myocardial systolic dysfunction (Figure 4). In summary, a

significant aspect of this observation is that the improvement

in the left ventricular function exhibited by the sp-FGF-1-

treated porcines still was measurable in the absence of the

dobutamine stress test, indicating a more profound stimulat-

ing effect of sp-FGF-1 on the ventricular pumping function.

Discussion

The objective of the current study was to assess a

Figure 4. Representative echocardiograms of sp-FGF-1 (Treated) and

vector-alone (Control) pigs. The final echocardiograms were performed

in order to determine if there was any left ventricular dysfunction. The

m-mode images show a two-dimensional view of the lumen of the left

ventricle. As the heart contracts, the walls of the interventricular septum

(IVS) and the posterior free wall (PW) of the left ventricle (LV) contract and

thicken to eject blood from the ventricle. The amount of contraction and

thickening, known as the percent thickening value, is a measure of regional

cardiac function. The sp-FGF-1-injected pigs (upper panel) had no obvious

ventricular dysfunction upon echocardiogram (percent thickening=100%;

please note the PW thickness). The control (lower panel) showed a dramatic

decrease in free wall contraction and shortening (percent thickening=50%;

please note the PW thickness), which indicates profound regional

myocardial systolic dysfunction

potentially new angiogenic gene therapy protocol for

the improvement of the cardiac function in the ischemic

porcine heart. We demonstrated that a direct intramyocardial

administration of a signal peptide-containing FGF-1 in a

porcine heart model of chronic coronary occlusion and

ischemia resulted in an approximately 19% increase in

the density of coronary vascularization when compared to

the control vector-alone injected hearts. Importantly, this

increased vascularity appears associated with improved

contractile function. Furthermore, our sp-FGF-1 gene

therapy in ischemic porcine heart appears to exert no overt

detrimental side effects in remote organs examined for the

presence of pathological signs.

202


Several previous investigators have attempted to stimulate

therapeutic angiogenesis using members of FGF family,24

delivered either as recombinant protein or DNA to the

ischemic tissues of end-stage cardiac patients or those of

animal models of chronic ischemia.25-29 Despite the fact that

other FGF-1 or FGF-2 angiogenesis therapy protocols appear

safe, a major challenge to their use has been an unequivocal

demonstration of a clinical improvement in the magnitude of

the cardiac function following FGF therapy.30

We sought to improve on the FGF therapy protocol by

making the FGF-1 gene construct a more potent angiogenic

factor through the addition of a signal peptide for the

secretion to its amino terminus. Although in vivo transfection

efficiency is generally poor, we reasoned that the secreted

FGF, albeit inefficient transfection, could readily promote

angiogenesis due to its autocrine/paracrine functions in

nearby sites. We employed naked plasmid DNA as the

vector of choice for introducing sp-FGF-1 gene into

porcine hearts rather than the use of a more efficient

adenoviral vector. This choice was made because adenoviral

vectors sustain short-term expression of the foreign gene

and also stimulate a vigorous immune response in the host,

which results in a progressive loss of the recombinant

virus.31 However, in order to improve transfection

efficiency, we chose to introduce the transgene via a direct

intramyocardial route. This selection was based on the

observations of others that the administration of a set

of selected foreign genes through either intravenous

(intracoronary), pericardial, or intramyocardial injection

into the porcine hearts, yielded the highest efficiency of

gene transfection and expression when the myocardium was

directly targeted (Laham RJ, Rezaee M, Garcia L, Post M,

Sellke FW, Baim DS, Simons M. Tissue and myocardial

distribution of intracoronary, intravenous, intrapericardial, and

intramyocardial 125I-labeled basic fibroblast growth factor

(bFGF) favor intramyocardial delivery. J AM Coll Cardiol

1999;35:10A). Indeed, our RT-PCR analysis using a set of

primers corresponding to different exons of the sp-FGF-1

chimera (sense primer encoding the signal peptide and the

antisense primer encoding the C-termius of the FGF-1)

demonstrated efficient and sustained sp-FGF-1 gene

expression at 21 days post-transfection.

An important observation of this study was that the

sp-FGF-1-injected pigs had no obvious ventricular dys-

function upon echocardiogram (percent thickening=100%).

In contrast, the control heart (vector alone) showed a

dramatic decrease in free wall contraction and shortening

(percent thickening=50%), which indicates profound regional

myocardial systolic dysfunction. Furthermore, the

performance of the sp-FGF-1-injected pigs during the

dobutamine stress test was improved relative to the pigs in

the control group.

Conclusion

Although coronary artery bypass graft surgery and

coronary angioplasty are often highly effective in restoring

coronary artery function, many conditions are not

treatable in this way and some patients are not candidates

for surgery. Such refractory conditions may be responsive

to newly developed and novel angiogenic therapies. Our

findings suggest the value of further consideration of the

selective therapeutic use of sp-FGF-1, wherein the

angiogenic effects of sp-FGF-1 could allow reparative

revascularization of ischemic regions of the myocardium-

at-risk downstream to a coronary artery stenosis/occlusion,

as well as protection and/or recovery from ischemia-induced

systolic contractile dysfunction in the setting of chronic

coronary artery disease.

Acknowledgement

This work was supported by The Texas A&M University

System HSC Funds (RF) and NIH grant HL64931 (JLP).

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3. Horvath KA, Doukas J, Lu CY, Belkind N, Greene R, Pierce GF,

Fullerton DA. Myocardial functional recovery after fibroblast growth

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Mayskiy M, Isner JM. Gene therapy with vascular endothelial growth

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Symes JF, Isner JM. Left ventricular electromechanical mapping to

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373-381.

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strategies to achieve therapeutic myocardial angiogenesis. Circulation

2000;101:454-458.

8. Partridge CR, Hawker JR Jr, Forough R. Overexpression of a se-

cretory form of FGF-1 promotes MMP-1-mediated endothelial cell mi-

TEHRAN HEART CENTER


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9. Forough R, Wang X, Martinez-Lemus LA, Thomas D, Sun Z,

Motamed K, Parker JL, Meininger GA. Cell-based and direct gene

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Angiogenesis 2003;6:47-54.

10. Roth DM, Maruoka Y, Rogers J, White FC, Longhurst JC, Bloor

CM. Development of coronary collateral circulation in left circumflex

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11. Roth DM, White FC, Nichols ML, Dobbs SL, Longhurst JC,

Bloor CM. Effect of long-term exercise on regional myocardial

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12. Griffin KL, Woodman CR, Price EM, Laughlin MH, Parker JL.

Endothelium-mediated relaxation of porcine collateral-dependent

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Sarcoplasmic reticulum Ca(2+) uptake is impaired in coronary smooth

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204



TEHRAN HEART CENTER

Prosthetic Valve Endocarditis: Early Outcome following

Medical or Surgical Treatment

Abbas Salehi Omran, MD1*, Abbasali Karimi, MD1, Setareh Davoodi, MD2,

Hossein Ahmadi, MD1, Namvar Movahedi, MD1, Mehrab Marzban, MD1,

Banafsheh Alinejad, MD1, Neda Ghaffari Marandi, MD1

1Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran.2Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran.

Abstract

Introduction

Prosthetic valve endocarditis (PVE) remains a serious

complication of cardiac valve replacement despite

improvements in prostheses types, surgical techniques,

and infection control measures. PVE is an endovascular,

microbial infection occurring on parts of the valve prosthesis

Background: Prosthetic valve endocarditis (PVE) is an important cause of morbidity and mortality associated with heart

valve replacement surgery. The aim of the present study was to describe the early outcome of treatment in patients with PVE

in a single center.

Methods: The data of all the episodes of PVE registered at our institution between 2002 and 2007 were collected and

-

ria). The analysis included a detailed study of hospital records. The continuous variables were expressed as mean±standard

deviation, and the discrete variables were presented as percentages.

Results: Thirteen patients with PVE were diagnosed and treated at our center during the study period. In all the cases,

mechanical prostheses were utilized. The patients’ mean age was 46.9±12.8 years. Women made up 53.8% of all the cases.

Early PVE was detected in 6 (46.2%) patients, and late PVE occurred in 7 (53.8 %). Eleven (84.6%) patients were treated

with intravenous antimicrobial therapy, and the other two (15.4%) required surgical removal and replacement of the infected

prosthesis in addition to antibiotic therapy. Blood cultures became positive in 46.2% of the patients. Mortality rate was

15.4% (2 patients).

Conclusion: It seems that in selected cases with PVE, i.e. in those who remain clinically stable and respond well to

antimicrobial therapy, a cure could be achieved by antimicrobial treatment alone with acceptable morbidity and mortality

risk.


*Corresponding Author: Abbas Salehi Omran, Assistant Professor of Cardiac Surgery, Tehran Heart Center, North Kargar Street, Tehran, Iran.

1411713138. Tel and Fax: + 98 21 88029256. Email: [email protected].

Keywords:

Original Article

Received 10 June 2008; Accepted 10 September 2008

or on reconstructed native heart valves.1 PVE occurs in 3%

to 6% of recipients of substitute valves. Infection is generally

categorized into early (usually less than 60 days postoperative)

and late (greater than 60 days post- implantation).2 The risk

of infection of the prosthetic material shows a bimodal

distribution pattern, with an early peak during the first 6

postoperative weeks and likelihood of approximately 3%

206


during the first postoperative year. The incidence of late

PVE ranges between 0.1 and 2.3 per 100 patient-years.3

Endocarditis developing on prosthetic valves accounts for

15 to 32% of all cases of infectious endocarditis.4 Advanc-

es in the management of PVE include a lesser incidence of

early-onset infections, improvements in diagnosis by means

of transesophagial echocardiography, and better outcome

associated with combined medical/surgical treatment.4

The traditional approach to the management of this

condition has been early surgery, and superior results

have been demonstrated with surgical treatment compared

with antibiotics alone.

However, while early surgery is indicated in patients

with hemodynamic compromise, there is evidence that in

selected cases treatment with antibiotics alone provides

equivalent results.5,6 To describe the outcome of patients

treated either with antibiotics alone or surgery, we

conducted this retrospective study and reviewed all

cases of PVE in our center between 2002 and 2007.

Methods

Thirteen patients who had undergone cardiac valve

replacement and were admitted with a definite clinical

diagnosis of PVE between February 2002 and March

2007 were included in this study. In one patient, PVE

diagnosis was not supported by echocardiography

and blood culture; he was, therefore, excluded from

the study. All the thirteen cases fulfilled the Duke

criteria7 for definite endocarditis. Clinical information was

obtained using a detailed review of hospital clinical records.

No, Number; PVE, Prosthetic valve endocarditis; F, Female; M, Male

No. Age (y) Sex Treatment type Blood culture OutcomeInvolved

valve type

Time of PVE after

surgery (month)

Table 1. Patient’s characteristics and antimicrobial regimen

1

2

3

4

5

6

7

8

9

10

11

12

13

36

33

61

51

37

60

52

63

28

38

67

41

43

M

M

F

F

M

M

F

M

F

F

F

F

M

mitral

aortic

aortic

aortic

aortic

mitral

mitral

mitral

mitral

mitral

mitral

mitral

mitral

2.27

0.83

0.33

9.33

3.7

0.33

0.43

1.03

0.13

3.47

17.03

120.0

4.0

Medical

Medical

Medical

Medical

Surgical

Medical

Medical

Medical

Medical

Medical

Medical

Medical

Surgical

Survived

Survived

Expired

Survived

Survived

Survived

Survived

Survived

Survived

Survived

Expired

Survived

Survived

Staphylococcus Epidermidis

Staphylococcus Epidermidis

Negative

Kelebceiella Oxytoka

Bacillus gram negative HACECK

Negative

Negative

Staphylococcus Aurous

Negative

Negative

Negative

Negative

Pseudomonas Aeroginosa

The following information was collected from the

medical records: age, gender, coexisting comorbidities

(diabetes mellitus, ischemic cardiomyopathy, malignancy,

Abbas Salehi Omran et al

and chronic renal failure), clinical signs and symptoms,

microorganisms isolated from cultures, echocardiographic

findings, medical or surgical treatment, and short-term or

in-hospital outcome. Cases were considered early PVE when

they occurred within 60 days after valve replacement and

late PVE when occurring later.

This investigation was approved by the Ethics Committee

of our institution. Because of the retrospective nature of

the study, requirement for informed consent was waived.

Data analysis was performed using SPSS version 13.0

package. The continuous variables were expressed as

mean±standard deviation, and the discrete variables were

presented as percentages.

Results

Thirteen cases fulfilled the Duke criteria for definite

endocarditis. Overall, seventeen valves were replaced

with mechanical prosthetic valves in these 13 patients.

Endocarditis occurred at an average of 12.5±32.5 months

(range=0.13 to 120 months) after valve replacement. The

patients’ mean age was 46.9±12.8 years (range=28 to 67

years) at the time of PVE diagnosis. Women made up 53.8%

of all the cases. Two (15.4%) patients had diabetes mellitus,

and 5 (38.5%) had hypertension. The history of renal

dysfunction and intravenous drug use was not

positive in any patient. No other comorbidity was found in

the study group.

The mitral valve was affected in 9 (69.2%) patients

and the aortic valve in 4 (30.8%). There was no multiple

value involvement. Positive echocardiographic findings for

infective endocarditis were found in the transesophageal

echocardiograms of all the cases.

Six (46.2%) patients presented with early PVE, while late

TEHRAN HEART CENTER


Prosthetic Valve Endocarditis: Early Outcome following Medical or Surgical Treatment

PVE occurred in 7 (53.8 %) cases. Eleven (84.6%) patients

were treated with antimicrobial therapy alone for 6 weeks,

and two (15.4%) patients required the surgical removal

and replacement of the infected prosthesis in addition to

antibiotic therapy (Table 1). The blood cultures were

positive in 6 (46.2 %) patients: (in 2 cases of early and 4

cases of late endocarditis). All the cultures fulfilled the Duck

criteria.The results of the blood cultures were as follows:

staphylococcus epidermidis in 2 (one in early and one in

late PVE), staphylococcus aurous in 1 (early PVE), gram-

negative bacilli HACECK in 1 (late PVE), klebceiella-

oxytoka in one (late PVE), and pseudomonas aeroginosa in

another (late PVE).

For all the patients in the medically treated group (11

patients), treatment was commenced on admission and

continued intravenously for six weeks. The initial choice of

antibiotics was according to the existing guidelines8 for PVE

treatment. For those with positive blood cultures, treatment

was modified by consulting with an infectious disease

specialist. In those who underwent surgery (2 patients),

antibiotics were also initially commenced on admission. An

inappropriate response to medical therapy (persisting fever

or heart failure due to severe prosthetic valve dysfunction)

led to surgical treatment. Aortic homograft in combination

with antibiotics was utilized just in one case who had heart

failure and continuing sepsis with a blood culture positive

for gram-negative microorganism (klebceiella-oxytoka) in

addition to severe aortic valve insufficiency and

paravalvular leakage.

Two (15.4%) patients (one in early and one in late PVE)

who were managed by antibiotics alone died during hospital-

ization due to multiorgan failure.

Discussion

Prosthetic heart valves, utilized for the management of

valvular heart disease, have been in use since the

mid-1960s. Today, more than 2 million individuals

have received a cardiovascular prosthetic device in the

United States and worldwide, and more than a quarter of a

million prosthetic heart valves are implanted annually.9

In the emerging years of heart valve replacement surgery,

the incidence of bacterial endocarditis after cardiac

operations was as high as 10%.3 PVE is now a rare

condition with a frequency ranging from 1% to 3% within

the first postoperative year;10 it is associated with high

morbidity and mortality rates of between 10 and 59% 6

and with a 10-year survival rate of 50%.11

In our study, 11/13 (84.6%) of the PVE cases occurred

within the first year after surgery. The mortality rate was

15.4% in the patients with antimicrobial treatment due

to multiorgan failure. According to Dominguez et al.,12

the early mortality of PVE was 20%. Akowuah et al.5

reported 29% mortality among their antibiotic group.

The most appropriate treatment approach to PVE, either

medical or surgical, is still under discussion. Whereas

surgery is the treatment of choice for PVE

according to some authors, others think that

antibiotics may be sufficient for some patients.13

The superiority of surgical treatment over antibiotic

treatment alone was shown in the Wang et al. study.14 However,

antibiotics play a major role in the treatment of PVE. Some

studies have confirmed that selected patients with PVE

who remain clinically stable or show improvement on

antibiotic treatment can be treated successfully with

antibiotics alone.5,6,15

Indications for valve replacement in early PVE include

the presence of mild heart failure with evidence of valve

obstruction caused by vegetations or a regurgitant mur-

mur and staphylococcal endocarditis with any degree of

heart failure. In late PVE (more than 2 months after the

initial operation), advanced degree of heart failure, emboli,

continuing sepsis, and staphylococcal organism are

indications for valve surgery.16 Multidrug- resistant

gram-negative bacilli infection is another PVE surgical

indication.10

Staphylococci are more prevalent in both early and late

PVE compared with endocarditis of the native valves.6

Although the blood cultures became positive in less than half

of our cases, 50% of them were caused by staphylococci in

both early and late PVE. PVE caused by staphylococcal or-

ganism is one of the indications for surgery; be that as it

may, in all of our three cases conservative treatment with

antimicrobial agents was successful and there was no

requirement for surgery.

Vancomycin was utilized in 11/13 (84.6%) of our

cases, and there was no resistance against it in patients

with a positive blood culture or in culture-negative ones.

The retrospective methodology of the present study along

with the small number of patients with PVE was our notable

limitation. Another limitation was the short duration of

follow-up, which was confined to the duration of

admission in contrast to other studies with long-term

follow-up periods.

Conclusion

In conclusion, according our study with this sample size,

it seems that patients with prosthetic valve endocarditis

without left heart failure and echocardiographic evidence

of the presence of large abscesses could be managed by

antimicrobial treatment alone with acceptable morbidity

and mortality risks. In this study, we reported cases of PVE

(some with early PVE) in which medical therapy without

surgical intervention was able to control the infection. This

result raises the question about the necessity of surgery in

208


all cases of PVE. It seems that in selected cases, i.e. those

who remain clinically stable and show a good response

to antimicrobial therapy, a cure by medical treatment

can be achieved. Nevertheless, it is advisable that more

experiments with more cases and long-term follow-up be

conducted for a better management of these patients.

Acknowledgment

This study has been approved by Institutional

Review Board and Ethics Committee of Tehran Heart

Center, Tehran University of Medical Sciences.

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TEHRAN HEART CENTER

Assessment of Regional Myocardial Displacement via Spectral

Tissue Doppler Compared with Color Tissue Tracking

Hassan Moladoust, phD1, Manijhe Mokhtari-Dizaji, PhD1*, Zahra Ojaghi-Haghighi, MD2

1Department of Medical Physics, Tarbiat Modares University, Tehran, Iran.2Shaheed Rajaie Heart Center, Iran University of Medical Sciences, Tehran, Iran.

Original Article

Received 6 August 2008; Accepted 18 October 2008

Abstract

Introduction

Background:

of the myocardial function. In the current systems, tissue tracking or displacement curves are generated from color tissue

Doppler data through the instantaneous temporal integral of velocity-time curves.

Methods: The purpose of the present study was to assess regional myocardial displacement via spectral TDI. Maximum

myocardial velocities were extracted from spectral pulsed tissue Doppler images using a developed computer program

and were integrated throughout the cardiac cycle. Spectral tissue Doppler echocardiography was performed to evaluate

longitudinal and radial functions in 20 healthy men, and the calculated end-systolic displacements were subsequently

compared with the displacements measured from the same areas via color tissue tracking.

Results:

Conclusion:

displacement using spectral TDI, which can be used in a wider range of equipment than is currently possible.

J Teh Univ Heart Ctr 4 (2008)209-214

*Corresponding Author: Manijhe Mokhtari-Dizaji, Associate Professor of Medical Physics, Department of Medical Physics, Tarbiat Modares

University, Jalal Ale-Ahmad Ave, Tehran, Iran. 1411713116. Tel: 98-21-82883893. Fax: 98-21-88006544. E-mail: [email protected].

Keywords:

Tissue Doppler imaging (TDI), a new method in echocar-

diography for analyzing segmental myocardial function,

demonstrates the velocity of a myocardium segment toward

or away from the transducer.1 Recent advances in science have

ushered in new refinements such as tissue tracking, which has

been validated by various studies. Tissue tracking curves are

generated from tissue Doppler data through the instantaneous

temporal integral of velocity-time curves.2-5 This is displayed

as the distance of motion or displacement along the Doppler

axis throughout the cardiac cycle. Tissue tracking allows an

assessment of the systolic displacement of different

myocardial regions, visualized by a graded display of

seven-color bands indicating the different distances of the

systolic myocardial motion amplitude and tissue tracking

curves.6,7

Spectral tissue Doppler velocities are obtained using

pulsed Doppler, a method that provides a spectrum of

velocities for each point at a time so that the maximum

velocity can be chosen by measuring the outer border of

the modal display. On the other hand, color tissue Doppler

210


usesthe autocorrelation analysis when computing myocardial

velocity, and can only compute one velocity for each

sample volume at a time; this velocity is the mean

of all velocity components found within the sample

volume.8 McCulloch et al. reported that color Doppler

myocardial velocities underestimated spectral tissue Doppler

velocities and such differences might result in interpretive

errors. Since tissue tracking curves are generated

from color tissue Doppler data, underestimating color

Doppler may lead to underestimating tissue tracking data.9

The present study suggests a computerized method for the

evaluation of myocardial displacement using spectral TDI.

This method relies on the computation of the area under

the maximum velocity recordings, from which displace-

ment measurement can be performed throughout the cardiac

cycle.

Methods

Twenty healthy men between 29 and 50 years of age were

included in the study. All of them had a normal physical

examination, electrocardiograms, and echocardiography;

and none of them had a history of cardiovascular disease,

angina, hypertension, diabetes, and medication. Informed

consent was obtained from all the subjects prior to their

inclusion in the study.

Echocardiographic acquisition: Spectral and color tissue

Doppler imaging: All the echocardiography studies were

conducted with a Vivid 7 digital ultrasound scanner (GE,

Milwaukee, WI, USA), equipped with an ergonomically-

designed M3S transthoracic sector transducer with harmonic

capability. The images were acquired with the subjects at rest

and lying in the lateral decubitus position with data acquisition

at end-expiration. Two-dimensional electrocardiograms

were superimposed on the images. Standard two-

dimensional echocardiography was performed on all the

participants, and their ejection fractions were measured

using Simpson>s biplane method. TDI was performed using

standard transthoracic apical two- and four-chamber views

and also para-sternal short axis view in the base and mid

levels according to the guidelines of the American Society

of Echocardiography.10 For the apical views, care was taken

to obtain the data by limiting the angle of interrogation in

an attempt to align at as low a degree as possible to the

longitudinal motion. For the para-sternal short axis views,

care was taken to keep the anteroseptal and posterior left

ventricular wall segments perpendicular to the ultrasound

beam so that it would be aligned at zero degrees to ra-

dial motion. Color Doppler myocardial imaging (CDMI)

and spectral pulsed TDI were performed by adjusting the

signal filters until they reached a Nyquist limit of 16 cm/s

and by using the minimum optimal Doppler gain settings to

minimize the spectral broadening of the Doppler signals.

The CDMI raw data were recorded at a depth of 16 cm,

frequency of 2.4 MHz, and frame rates of higher than 150

frames per second throughout two cardiac cycles and were

stored digitally in a cine-loop format on the memory of the

scanner. Off-line analysis was performed using quantitative

analysis software so as to obtain the regional myocardial

velocity. The digital 8-mm sample volume was placed within

the myocardium wall thickness at the basal and middle

segments of the interventricular septum and anterior walls

in the apical views and also the basal and middle levels

of the posterior wall in the para-sternal short axis views,11

and the tissue velocity curves were subsequently acquired

(Figure 1A). The integrals of the tissue velocity curves

were thereafter calculated to create tissue tracking curves12

(Figure 1B), and end-systolic displacements were measured

for the two cardiac cycles.

A

B

Figure 1. Tissue Doppler imaging and velocity curves throughout two car-

diac cycles from the base and mid segments of the septum wall in the four-

chamber view (A) and displacement curves (color tissue tracking) calcu-

lated by integrating the velocity curves (B)

Spectral TDI was performed using an 8-mm pulsed

Doppler sample volume, placed in the same locations as

those for CDMI. The spectral TDI and CDMI patterns were

characterized by isovolumic contraction and ejection phase

(with positive polarity) during systole; and they were

characterized during diastole by isovolumic relaxation, early

diastolic (with negative polarity), and late atrial contraction

velocities (with negative polarity), respectively13 (Figure 1A

and Figure 2A). The spectral tissue Doppler images were

saved and were transferred to a personal computer for off-

Hassan Moladoust et al

TEHRAN HEART CENTER


Assessment of Regional Myocardial Displacement via ...

line analysis via a program written in the Matlab software

version 7.0.1 (Math Software Co., Matwork, USA) for evaluat-

ing regional myocardial displacement throughout the cardiac

cycle. The outer borders or envelopes of the velocity

spectrums were extracted automatically via this program

based on color purity and were integrated by Simpson>s rule

to create displacement curves. The curves were afterward

employed to measure the myocardial displacements at end-

systole, which were then compared with the displacements

measured from the same areas via color tissue tracking.

A block diagram of the program and the related images is

presented in Figure 2.

Figure 2. Block diagram of the presented method for the assessment of

myocardial displacement using maximum spectral tissue Doppler data

Simpson,s rule is well known for anyone attempting

to work out a digitized signal. This method, instead of

approximating function y=f(x) with straight line segments,

can approximate with parabolas (Figure 3) before the area

under the parabolas can be integrated. In Simpson,s rule, the

integral,a

b

f(x)d(x) is approximated by:14

)42...424(3

123210 nnn yyyyyyyh

S

This approximation is based on a regular partition

of [a, b] of size n, where n is even and h=(b-a)/n.

The area under the Doppler velocity curve represents the

time velocity integral (TVI) and is equal to the area enclosed

by the Doppler velocity profile during one ejection period.15

A method for the verification is to process the images of

the spectral tissue Doppler with known TVI and assess the

accuracy of the program by comparison. For this reason,

we applied our program not only to the 70 spectral tissue

Doppler images but also to the end-systolic TVI,

determined manually by an expert echocardiologist. The

results of the two methods were compared by correlation

and the Bland-Altman16 analysis.

All the data were expressed as mean±standard

deviation (SD), and the comparisons between the differenc-

eswere made using the paired samples t-test. Results were

considered significant when the probability value was <0.05.

Figure 3. Simpson,s rule by approximating function y=f(x) with parabolas

and integrating the area under the parabolas. For i=0 to n, (xi, yi) shows

coordinate of points

The correlation and Bland-Altman analysis with the 95%

limit of agreement (i.e. mean difference±1.96 SD of the dif-

ference) were calculated to assess the relationships between

the end-systolic displacements of the manual TVI and the

presented methods and also to assess the relationships be-

tween the myocardial end-systolic displacements with the

spectral and color tissue tracking methods. Intraobserver

and interobserver variabilities were defined as differences

between the two measurements and were expressed as a

percentage error of the means. All the statistical analyses

were performed using the SPSS software package (SPSS

Inc. Chicago, IL, USA).

Results

The mean age of the participants was 43±9 years old. Their

resting heart rates and echocardiographic ejection fractions

varied between 62 and 79 beats per minute (mean=71±6

bpm) and 55 and 60% (mean=57.4±2.4%), respectively.

The statistical analyses showed no significant difference

in terms of the end-systolic displacement between the

results of the proposed program and manually traced TVI

by an expert echocardiologist at 95% confidence level

(p=NS). There was an excellent correlation between the

results of the proposed program and the TVI acquired from 70

segments, comprised of 35 base segments (10 interven-

tricular septum base, 13 anterior base, and 12 posterior

wall base segments) and 35 mid segments (10 interven-

tricular septum mid, 13 anterior mid, and 12 posterior wall

mid segments). The coefficient correlation, correlation

significance, and regression equation were r=0.99, p<0.001

and y=-0.122+1.004x, respectively (Figure 4A). For the

Bland-Altman analysis, the difference between the two

methods was plotted against the average of both observa-

tions. The Bland-Altman analysis revealed that there was no

significant bias of 0.06 mm with the SD mean differences of

±0.38 mm in the evaluated segments between the end-systolic

displacements using the proposed program and TVI (Figure 4B).

212


Figure 4. The correlation of the two end-systolic displacements that

resulted from integrating the spectral tissue Doppler images acquired using the

proposed program and manually traced time velocity integral (TVI),

respectively (A) and the Bland-Altman graphs with 95% limit of

agreement (B). The middle line indicates the average difference between

the two methods, whereas the outer lines represent 1.96 SD or the 95% limit

of agreement.

The results of the end-systolic displacements of the

interventricular septum (18 base and 18 mid

segments) and anterior (18 base and 16 mid segments)

walls from the longitudinal assessment and posterior wall

segments (18 base and 18 mid segments) from the

radial assessment using the spectral and color TDI

(spectral and color tissue tracking) are presented in

Table 1. There were significant differences between the two

methods at 95% confidence level in all the segments

(p<0.001).

The statistical analyses showed a significant correlation

between the displacements acquired using the spectral

and color tissue tracking methods obtained from the 106

segments, comprising 54 base and 52 mid segments

of the interventricular septum and anterior and poste-

riorwalls (r=0.79, p<0.01 and regression equation was

y=9.041+0.813x) (Figure 5A). According to the Bland-

Altman analysis, the significant arithmetic mean was 7.34

mm with SD mean differences of ±2.24 mm in all the

Table 1. End-systolic displacement (Mean±SD): Spectral tissue tracking

versus color tissue tracking

Septal base

Septal mid

Anterior base

Anterior mid

Total base

Total mid

Short axis base

Short axis mid

20.98±2.27

14.33±1.66

17.59±1.88

13.79±2.41

19.57±2.40

14.06±2.06

17.16±1.54

14.73±1.26

11.94±1.26

7.92±1.19

12.21±1.44

7.17±1.19

11.98±1.28

7.54±1.23

9.13±1.30

6.88±0.93

<0.001

<0.001

<0.001

<0.001

<0.001

<0.001

<0.001

<0.001

Sample site Spectral TT (mm) Color TT (mm) P-value

Spectral TT, Spectral tissue tracking; Color TT, Color tissue tracking; Total

base, Mean values calculated from total base segments in longitudinal

assessments; Total mid, Mean values calculated from total mid segments in

longitudinal assessments

evaluated segments (Figure 5B). The intraobserver and

interobserver variabilities for the proposed method were

found to be 3.4% and 4.3%, respectively; and there was no

significant difference between the two measurements used

for these calculations.

Figure 5. The correlation of the two end-systolic displacements using the

spectral and color tissue tracking from the 106 base and mid evaluated

segments combined (A) and the Bland-Altman graphs with 95% limit of

agreement (B). The middle line indicates the average difference between

the two methods, whereas the outer lines represent 1.96 SD or the 95% limit

of agreement


TEHRAN HEART CENTER


Assessment of Regional Myocardial Displacement via ...

Discussion

The color tissue tracking modality offers the

possibility of gaining supplementary information on the

myocardial function, and efforts have been made to

utilize the imaging capability of the technique qualitatively in

various clinical situations including dilated cardiomyopathy,

left bundle branch block, myocardial ischemia, and cardiac

resynchronized therapy studies.17-21 We herein presented a

computerized approach for the evaluation of myocardial

displacement using spectral TDI. The method relies on the

computation of the area under the maximum spectral tissue

Doppler recordings, from which displacement measure-

ment was made using the described program (Figure 2).

In this program, we employed Simpson’s rule in order to

calculate the area under the curve. What is very important in the

present context is the error in Simpson’s rule, which is

proportional to the fourth power of the subintervals.

Simpson’s rule, therefore, renders exact values for

polynomial functions.14 A practical capability in the

presented method is the ability to measure myocardial

displacement using the echo systems supplemented to

spectral pulsed TDI, which can be used in a wider range

of equipment than is currently possible. We verified

accuracy by manually tracing the TVI of the spectral tissue

Doppler images throughout the cardiac cycle and comparing

the end-systolic displacements resulting from the methods.

This study was part of another one in which our aim was

to carry out a longitudinal assessment of the myocardium

in the left anterior descending artery at-risk regions. In

this study, consequently, we chose the anterior and septum

wall segments for longitudinal assessments as well as the

posterior wall segments for radial assessments,

because spectral Doppler signals are clearer than are the

anteroseptal wall segments. The results of the color tissue

tracking for the total base and mid segments (Table1) may be

comparable with the myocardial displacement values of the

mid and base segments, already defined in healthy individu-

als by Borges et al.22 (11.98±1.28 mm in our study versus

12.5±2.02 mm for base and 7.54±1.23 mm in our study

versus 8.5±1.99 mm for mid segments). We could not

compare the presented spectral tissue tracking findings with the

previous ones because they have not been reported previously.

The Doppler-based methods prevailed at the clinical stage,

although these methods suffer from inherent limitations.

TDI is a Doppler technique and, therefore, the limitations

of Doppler measurements must also be applied to this

method. First, one of the most important limitations of

Doppler measurements is their angle dependence.23-25 Storaa

et al. investigated the impact of angular error in the apical

two- and four-chamber views on measured velocities in a

clinical setting. They sought to find out how large an

angular mismatch could be accepted and their results showed

that angular mismatch of up to 15 or 20 degrees gave

acceptable velocity estimates and that the misalignment was

very low in the mid segments.23 In our study, even though

we tried to perform accurate recordings of myocardial

velocities by adequate alignment between the ultrasound

beam and the main vector direction of wall motion, the angle

errors for the anterior and septum base segments were almost

12±3 degrees and 6±2 degrees, respectively. Second, TDI

has been widely used to quantify the regional myocardial

function by measuring tissue velocities. However, the regional

Doppler tissue velocities, consisting of spectral and color tissue

Doppler methods in one area, are affected by the motion of the

adjacent regions as well as the whole heart translational motion,

which has been posed as a limitation of these techniques.22,26,27

We studied only healthy persons in the present study; it is

important that the diagnostic capacity of such an analysis be

evaluated for the detection or discrimination of significant

heart disease. The work reported here should be considered

the first step of the tissue tracking process using spectral

TDI, and it could form the basis for further advances. We are

currently exploring ways to utilize the data of the spectral

TDI so as to perform such analyses more objectively and

rapidly. The present findings have not been reported previ-

ously and may have some clinical relevance for assessing con-

ventional or stress echocardiography by quantitative means.

Conclusions

It can be concluded from our experience that our

proposed approach has the ability to assess regional

myocardial displacement using spectral tissue Doppler

images. Even though there was a significant difference

between color and spectral tissue tracking, there was a good

correlation between them. The differences between the

presented method and the color tissue tracking method were

predictable because as we mentioned in the introduction

section, color tissue Doppler uses the autocorrelation

analysis and the computed velocity is the mean of all the

velocity components found within the sample volume,9

whereas the spectral tissue tracking method described

here uses the maximum component found within the sample

volume.

Acknowledgments

The study protocol was approved by the ethics committees

of Tarbiat Modares University and Shaheed Rajaie Heart

Center. We wish to thank Prof. F. Noohi, Dr. A. Khajavi, Dr.

M. Esmaielzadeh, Dr N. Samiei, Dr. A.Sadeghpour, Dr. M.

Parsaei, and Dr. A. Mirdamadi for their valuable technical

assistance. Thanks are also due to H. Grailu for computer

programming assistance, T. Zarrin-Peikar, Mrs. Rajaei, and

214


E. Rajabi for subject recruitment and all the people who

contributed to the completion of this research.

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TEHRAN HEART CENTER

Postoperative Mortality and Morbidity in Elderly Patients

Undergoing Coronary Artery Bypass Graft Surgery

Hassan Radmehr, MD*, Alireza Bakhshandeh, MD, Mehrdad Salehi, MD,

Iraj Ghorbandaeipour, MD, Amir Hossein Sadeghpoor Tabai, MD, Mehdi Sanatkarfar,

MD, Ahmad Reza Nasr, MD

Imam Khomeini Medical Center, Tehran University of Medical Sciences, Tehran, Iran.

Abstract

Introduction

The provision of care for an increasing number of

elderly persons, who are liable to be afflicted with

a higher incidence of illnesses and complicated

psychosocial sequels thereof, accounts for the

extraordinary burden on traditional health care systems.

Geriatric medicine is an interdisciplinary approach to

the management of sickness and disability and to health

promotion and disease prevention in the elderly that

involves gerontology (the study of normal aging and the

Background: Elderly patients (>75 years) have constituted the fastest growing portion of the coronary artery bypass graft-

ing (CABG) patient population over the last two decades. Of the goals that surgical care for the elderly pursues, cure may

The present study sought to examine the postoperative course and events in elderly patients undergoing CABG with or

without other procedures and to compare the results with those in younger patients.

Methods: Demographic, mortality, morbidity, and resource utilization data were collected from the records of the patients

undergoing CABG between January 2005 and July 2007 in Imam Khomeini Medical Center, Tehran, Iran.

Results:

Conclusion:

of postoperative renal failure, neurological complications, and in-hospital mortality.


*Corresponding Author: Hassan Radmehr, Associate Professor of Cardiac Surgery, Tehran University of Medical Sciences, Imam Khomeini Hospital

Complex, Tehran, Iran. Tel: +98 21 61192791. Fax: +98 21 66581595. Email: [email protected].

Keywords:

Original Article

Received 24 June 2008; Accepted 26 October 2008

process of growing old as differentiated from disease effects).

Aging is concomitant with a decline in the physiological

function of all organ systems, although the magnitude of this

deterioration varies among organs and individuals. Surgical

care for the elderly may be unable to bring about a cure, but

palliation and comfort are indubitably goals worth seeking.

Coronary artery bypass grafting (CABG) has long since

proved its efficiency in alleviating the symptoms of angina,

improving the quality of life, and increasing the longevity

of coronary artery disease patients.1 Elderly patients have

comprised the fastest growing section of CABG

216


patient population over the last two decades.2 As was

stated above, advanced age is associated with diminished

physiological reserve and increased comorbidity, including

diabetes, chronic obstructive pulmonary disease (COPD),

and peripheral vascular disease.3

The evolution of CABG via cardiopulmonary bypass

(CPB) ushered in continuous reductions in morbidity and

mortality rates. Be that as it may, since CPB was allied

with the induction of a pro–inflammatory state with several

adverse consequences;4 off-pump CABG has emerged as a

less invasive technique of myocardial revascularization in

more recent years.

It is deserving of note, however, that many authors have

of late argued that because of the high risk that they pose,

elderly patients can benefit from myocardial revascular-

ization without CPB.5-7 Indeed, several publications have

reported the surgical results of off-pump CABG in this

age group. Unfortunately, most of these reports are

retrospective and non-randomized, precluding a

rigorous demonstration of the usefulness of this technique.

We sought to examine time to extubation, packed RBC

transfusion, Intensive Care Unit (ICU) length of stay, and

preoperative and postoperative lengths of stay in an elderly

group of patients undergoing CABG with or without other

procedures and to compare the results with those in a

younger group of patients. We also evaluated the differences

in the postoperative morbidity and mortality rates between

the two groups.

Methods

This retrospective study was conducted in 2095 patients,

comprising 132 elderly and 1963 non-elderly persons,

between January 2005 and July 2007 in Imam Khomeini

Medical Center, Tehran, Iran. Extubation time, blood

transfusion, ICU length of stay, renal dysfunction, neurological

complication, myocardial infarction, supraventricular

arrhythmia, and early mortality (in 30 days) were

considered as the main variables. The demographic,

mortality, morbidity, and resource utilization data of the

patients were collected from the domestic database of the

patients in our institution during the foregoing period.

For the analysis of the descriptive statistics and

categorical variables, the Chi-square or Fisher

exact test was used as appropriate. The level of statis-

tical significance was set at a p-value <0.05. All the

statistical analyses were performed with SPSS Software.

Results

In this study 132 out of the 2095 patients were

elderly. The mortality rate was 9% in the elderly group and

Hassan Radmehr et al

2.8% in the non-elderly group.

The elderly patients had a significantly higher

incidence of peripheral vascular disease, COPD, congestive

heart ailure, and left main disease than did the non-elderly

subjects. Moreover, by comparison with the younger group, the

elderly patients weighed significantly less and had lower

preoperative hematocrit. The clinical and demographic

variables were correlated with age 75 years or older.

Multivariate linear and logistic regression models were

constructed to show the combined effects of age and

comorbid conditions on the outcomes.

The results are summarized in Tables 1 to 6.

Variable Elderly Non-elderly

Table 1. Patients’ preoperative characteristics

NYHA, New York heart association classification; EF, Ejection fraction

Mean age (y)

Gender

Male

Female

NYHA (1/2/3/4)

Diseased coronary artery

Associated condition

EF > 50%

EF 30-50%

EF <30%

75±5

71( 53.7% )

61(46.3% )

19/63/50/0

3±0.7

MR++: 46

MR+++: 18

TR++: 3

TR+++: 2

27(20.4%)

53(40.1%)

52(39.5%)

58±12

1155 (55.1%)

940 (44.9%)

146/981/836/0

3±0.5

MR++: 186

MR+++: 377

TR++: 31

TR+++: 9

478(22.8%)

934(44.6%)

683(32.6%)

Procedure Number

Table 2. Type of accomplished procedures

CABG, Coronary artery bypass grafting; MVR, Mitral valve replacement;

MVr, Mitral valve repair; TVr, Tricuspid valve repair; AVR, Aortic valve

replacement

CABG alone

MVR+CABG

MVr+CABG

MVR+TVr+CABG

MVr+TVr+CABG

Bentall+CABG

AVR+MVR+CABG

AVR+CABG

1623(77.4%)

48(2.29%)

309(14.7%)

14(0.66%)

22(1.05%)

23(1.09%)

44(2.1%)

52(2.48%)

Procedure Elderly Non-elderly

Table 3. Associated procedures in elderly and non-elderly patients

MVR, Mitral valve replacement; MVr, Mitral valve repair; TVr, Tricuspid

valve repair; AVR, Aortic valve replacement

MVR

MVr

MVR + TVr

MVr + TVr

Bentall

AVR + MVR

AVR

46(2.34%)

283(14.4%)

13(0.66%)

20(1.01%)

19(0.96%)

39(1.98%)

45(2.29%)

2(1.5%)

26(19.6%)

1(0.75%)

2(1.5%)

4(3%)

5(3.7%)

7(5.3%)

TEHRAN HEART CENTER


Postoperative Mortality and Morbidity in Elderly ...

Variable Elderly Non-elderly P value

Table 4. Preoperative variables in elderly and non-elderly patients

Smoking

Systemic hypertension

Diabetes mellitus

Old myocardial infarction

Renal dysfunction

Left main disease

Congestive heart failure

Chronic obstructive pulmonary disease

Peripheral vascular disease

0.31

0.23

0.26

0.07

0.08

<0.01

<0.01

0.03

<0.01

34(25.7%)

72(54.5%)

40(30.3%)

19(14.3%)

4(3%)

24(18.1%)

21(15.9%)

25(18.9%)

18(13.6%)

486(24.7%)

950(48.3%)

556(28.3%)

204(10.3%)

55(2.8%)

165(8.4%)

169(8.6%)

235(11.9%)

167(8.5%)

ICU, Intensive care unit

Variable Elderly Non-elderly P value

Table 5. Postoperative variables in elderly and non-elderly patients

Extubation time (h)

Blood transfusion

ICU length of stay (d)

Postoperative length of stay (d)

Renal dysfunction

Neurological complication

Myocardial infarction

Supraventricular arrhythmia

Early mortality (in 30 days)

<0.01

<0.01

<0.01

<0.01

<0.01

<0.01

0.08

0.32

<0.01

9.3

87.8%

2.1

6.8

24.4%

9.8%

6%

18.9%

9%

6.3

58.5%

1.4

3.4

10.5%

2.6%

4.6%

15.9%

2.8%

CABG, Coronary artery bypass grafting; MVR, Mitral valve replacement;

MVr, Mitral valve repair; TVr, Tricuspid valve repair; AVR, Aortic valve

replacement

Procedure elderly non-elderly P value

Table 6. Associated procedures with CABG

MVR

MVr

MVR+TVr

MVr+TVr

Bentall

AVR+MVR

AVR

>0.05

>0.05

>0.05

>0.05

<0.05

>0.05

>0.05

2(1.5%)

26(19.6%)

1(0.75%)

2(1.5%)

4(3%)

5(3.7%)

7(5.3%)

46(2.34%)

283(14.4%)

13(0.66%)

20(1.01%)

19(0.9%)

39(1.9%)

45(2.29%)

Discussion

The last two decades have seen a rapid rise in the number

of elderly patients candidated for CABG.2 Diminished phys-

iological reserve and increased comorbidity seem to be part

and parcel of advanced age. The elderly comprise only 12%

of the population of the United States of America, yet they

account for over 40% of over-the-counter drug users and 30%

of the health budget. Certainly, many other countries around

the globe are no strangers to this scenario as the elderly are

prone to a significantly higher incidence of peripheral vascular

disease, COPD, congestive heart failure, and left main

disease.3

The elderly patients recruited in the present study weighed

significantly less and had lower preoperative hematocrit

than did the younger group. As Table4 demonstrates, the

respective extubation time in the elderly and non-elderly

groups was 9.3 and 6.3 hours. In addition, 87.8% of the

elderly, as opposed to 58.5% of the non-elderly persons,

required blood transfusion. Whereas the elderly patients

stayed in the ICU for 2.1 days, the younger patients spent

an average of 1.4 days there. Hospital length of stay was

6.8 days for the elderly patients compared to 3.4 days for

the non-elderly ones. Renal dysfunction was observed in

24.4% and 10.5% of the elderly and non-elderly groups,

respectively. From the total study population, 9.8% of the

elderly and 2.6% of the non-elderly patients developed

neurological complications during their course of admission.

Early in-hospital mortality was seen in 9% of the elderly,

while it was observed in only 2.8% of the non-elderly

subjects. Statistical analysis also showed a meaningful

difference between these variables, which was discussed

above.The results of the present study demonstrated that in the

elderly patients, the mean time from the end of

surgery to endotracheal extubation, need to blood

transfusion, mean ICU length of stay, mean postop-

erative length of stay, postoperative renal failure, and

neurological complications were clearly higher than those

in the non-elderly group. Furthermore, early hospital

mortality rate was significantly higher in the elderly group.

The most salient limitation of the present study is its

retrospective design; further prospective multicenter studies

are, therefore, required to shed more light on this particular

topic in the future.

Conclusion

In conclusion, age 75 years or older was significantly

associated with an adverse outcome and was an independent

predictor of increased postoperative mortality and morbid-

ity after CABG. Given the higher morbidity and mortality

rates among the elderly, it seems advisable that non-surgical

procedures or less invasive ones such as off-pump CABG be

considered for this age group in fragile health. Opting for

surgery in this age group should not be made liberally, and

the overall condition of this group of patients should be

balanced with indications for surgery, which are noted in

academic textbooks.

Acknowledgment

This study was approved and supported by Tehran

University of Medical Sciences. The authors wish to thank

Miss Zargarn, the secretary, for her contributions to this

study.

218


References

Hassan Radmehr et al

1. Edwards FH, Clark RE, Schwartz M. Coronary artery bypass

grafting: the society of thoracic surgeons national database

experience. Ann Thorac Surg 1994;57:12-19.

2. Curtis JJ, Walls Jt, Boley TM, Schmaltz RA, Demmy TL,

Salam N. Coronary revascularization in the elderly: determinants of

operative mortality. Ann Thorac Surg 1994;58:1069-1072.

3. Hirose H, Amano A, Yoshida S, Takanashi A, Nagano N,

Kohmoto T. Coronary artery bypass grafting in the elderly. Chest

2000;117:1262-1270.

4. Edmuds LH. Inflammatory response to CPB. Ann Thorac Surg

1998;66:S12-16.

5. Hirose H, Amano A, Takahashi A. Off-pump coronary artery

bypass grafting for elderly patients. Ann Thorac Surg 2001;72:

2013-2019.

6. Boyd WD, Desai ND, Del Rizzo DF, Novick RJ, McKenzie

FN, Menkis AH. Off-pump surgery decreases postoperative

complications and resource utilization in the elderly. Ann Thorac Surg

1999;68:1490-1493.

7. Plomondon ME, Cleveland JC, Ludwig ST. Off-pump coronary

artery bypass is associated with improved risk adjusted outcomes. Ann

Thorac Surg 2001;72:114-119.


TEHRAN HEART CENTER

Discrete Subvalvular Aortic Stenosis: Severity of Aortic

Regurgitation and Rate of Recurrence at Midterm Follow-Up

after Surgery

Hakimeh Sadeghian, MD*, Abbasali Karimi, MD, Seyed Hosein Ahmadi, MD,

Masoumeh Lotfi-Tokaldany, MD, Nader Fallah, PhD, Reihaneh Zavar, MD,

Seyed Hesameddin Abbasi, MD

Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran.

Original Article

Received 29 July 2008 ; Accepted 16 September 2008

Abstract

Introduction

Background: Discrete subaortic stenosis (DSS) is a progressive condition. Controversy still rumbles on as to whether the

subaortic membrane causes aortic regurgitation (AR) and whether membrane resection reduces AR severity. We investigated

changes in AR severity and obstruction recurrence after surgery in DSS patients.

Methods: Twenty patients were evaluated before and after surgery for DSS (mean follow-up time: 13.60±9.61 months).

The patients were evaluated via transthoracic echocardiography and transesophageal echocardiography, if necessary. The

Results: The mean age of the patients was 28.55±15.23 years, and 35% of them were male. LVOT-PG decreased from a

mean of 80.83±42.72 mmHg preoperatively to 19.14±14.03 mmHg postoperatively and to 25.47±16.10 at follow-up. AR was

Conclusion: Our results indicated no relationship between AR severity and LVOT-PG and the patient’s age. Patient selec-

tion for surgery can, therefore, be carried out on the basis of LVOT-PG or AR severity separately. Subaortic resection may

not the presence of the AR is an indication for surgery.


*Corresponding Author:Hakimeh Sadeghian, Assistant Professor of Cardiology, Department of Echocardiography, Tehran Heart Center, North Kargar

Street, Tehran, Iran. 1411713138. Tel: +98 21 88029257. Fax: +98 21 88029256. E-mail: [email protected].

Keywords:

Discrete subaortic stenosis (DSS) is more com-

mon in childhood, but it is also a relatively

frequent heart disease in adult patients with a prevalence of

6.5% of all adult congenital heart diseases.1

Fixed subaortic stenosis is responsible for up to 20%

of the left ventricular outflow tract (LVOT) obstructions

requiring intervention.2 It generally occurs in one of

two forms.The less common form is secondary to

circumferential fibromuscular tunnels, but it more

commonly results from a discrete membrane immediately

below the aortic valve.3

Traditionally, it has been difficult to differentiate DSS

from the valvular aortic stenosis; today, however, we may

reliably determine a subaortic membrane masked by a

hypertrophied and prominent ventricular septum using

220

The Journal of Tehran University Heart Center Hakimeh Sadeghian et al

transthoracic echocardiography (TTE) and transesophageal

echocardiography (TEE) techniques.4,5

The treatment and prognosis of subaortic stenosis have

been studied sufficiently in children, whereas there is a

dearth of data in the adult patient population.1 It has been

reported that aortic regurgitation (AR) secondary to DSS

is common, is usually hemodynamically insignificant in

childhood, tends to be progressive, and is related to the

degree of LVOT obstruction.2,6,7 Some investigators have

stressed that in contrast to children, adult patients with fixed

subaortic stenosis have a high incidence of significant AR.2

There is a paucity of information to support the benefits of an

early surgical intervention on the basis of LVOT gradient in

patients with a progressive obstruction.

The main purpose of this study was to determine whether

AR severity is related to the severity of LVOT obstruction

and the patient’s age and whether the severity of AR

decreases after the surgical resection of the membrane.

Methods

All the patients with DSS who underwent surgical

treatment between March 2002 and January 2006 at

Tehran Heart Center, a hospital dedicated to heart diseases in

the capital of Iran, Tehran, were evaluated prospectively. The

study was approved by the institutional ethics committee.

DSS was diagnosed when a fixed subvalvular obstruction

causing a subaortic flow acceleration was detected by TTE

(Figure1) and TEE, if necessary. TTE was performed for all

the patients preoperatively, postoperatively, and at follow-

up. Data on the patients’ age, sex, previous cardiac surgery,

coexisting cardiac anomalies (if any), symptoms, electrocar-

diography, echocardiography, and cardiac catheterization (if

needed) were collected.

Figure 1. Transthoracic echocardiogram of discrete subaortic stenosis. There is a membrane below aortic valve which is attached to septum. There is another attachment to anterior mitral leaflet (arrow)

TTE (either the apical, parasternal, or suprasternal

approach) was utilized to assess the left ventricular outflow

tract peak gradient (LVOT-PG), presence of membrane, and

degree of AR. If there was any doubt about the presence

of a membrane, TEE was performed. Angiography and

catheterization were applied for those over the age of 35

years. AR was evaluated according to the appearance of

the regurgitation jet by Doppler; and it was categorized as

mild, moderate, and severe (Table 1) in accordance with the

American Society of Echocardiography Guidelines.8

Table 1. Quantitative evaluation of aortic regurgitation severity (American

Society of Echocardiography Guidelines)

Parameter Mild Severe

Jet width/LVOT

Vena contracta (cm)

Pressure half-time (ms)

Regurgitant volume (ml/beat)

Regurgitant fraction (%)

Regurgitant orifice area (cm²)

<25%

<0.3

>500

<30

<30

<0.1

>0.6

<200

LVOT, Left ventricular outflow tract

Indications for surgery tend to vary; nonetheless, they nor-

angiographic evidence of progressive AR,2 and coexisting

cardiac lesions that require surgery. All the operations were

performed by the expert cardiac surgeons at the department

of cardiac surgery in Tehran Heart Center. In line with tech-

niques usually favored for subaortic resection, an oblique

aortotomy was made and extended into the non-coronary

sinus. The aortic valve was thereafter retracted carefully to

reveal the subaortic membrane. Both the obstructing discrete

membrane and the adjacent hypertrophied muscle (when

indicated) were subsequently excised circumferentially

as completely as possible. All the operations were carried

out with great care to avoid injury to the conduction tissue

between the right and non-coronary aortic cusps and the

anterior leaflet of the mitral valve.

At least one TTE examination was performed for all

the patients during hospitalization after surgery. The

patients underwent second TTE at the first visit after being

discharged. The changes in LVOT-PG and AR severity as

well as the recurrence of the membrane were evaluated

in both postoperative and follow-up examinations. The

recurrence was determined in terms of the presence of the

membrane during the follow-up.

The numerical variables were presented as mean±SD, and

the categorized variables were summarized by percentages.

The continuous variables were compared using the Student’s

t-test or the nonparametric Mann-Whitney U test whenev-

er the data did not appear to have normal distributions. A

The changes in the continuous variables before surgery,

after surgery, and at follow-up were compared through the

TEHRAN HEART CENTER


Discrete Subvalvular Aortic Stenosis: ...

repeated measures ANOVA, followed by the Wilcoxon

Signed Rank test (considering the Bonferroni method to

age and AR severity were analyzed using the Spearman

correlation coefficient. The Friedman test and Kendall tau

rank correlation test for trend were also used in further

analyses.

Results

A total of 20 patients diagnosed with DSS who under-

went membrane resection were identified. The patients’

mean age was 28.55±15.23 years (range 5 to 64). The

group comprised 7 (35%) males and 13 (65%) females.

One of the patients had previously undergone the resec-

tion of the subaortic membrane and had to have redo

surgery for the recurrence of the membrane with a significant

gradient. The mean follow-up time was 13.60±9.61 months.

Seventeen (85%) patients were symptomatic: 10

(50%) had dyspnea, 3 (15%) had chest pain, 2 (10) had

palpitation, and 2 (10%) had mixed complaints. For the

remaining 3 patients (15%), who were without symptoms,

diagnosis was made using echocardiography for an evalu-

ation of cardiac murmur. The number of the patients with

concomitant congenital heart disease was 3 (15%): ventric-

ular septal defect in 1 (5%) and bicuspid aortic valve in 2

(10%). None of the patients had endocarditis preoperatively.

Of the 20 patients in the study group, 5 (25%) had no AR

preoperatively, whereas AR was identified in 15 (75%)

patients: mild in 8 (40%) and moderate in 7 (35%). None

of the patients had severe AR. There was no significant

correlation between the patient’s age and AR severity

(rs=0.099, P=0.677). The follow-up TTE showed that while

40% of the patients had no AR, 40% had mild and 20% had

moderate AR (Figure 2). Of the patients who had moderate AR

before surgery; 42.9% remained unchanged, 28.6% had mild

AR, and 28.6% had no AR.

Figure 2. Aortic regurgitation (AR) changes in postoperative and follow-up transthoracic echocardiographies

Among the cases having preoperative mild AR; 75%

showed no changes, 12.5% had no AR, and 12.5%

progressed to moderate AR in the follow-up evaluations.

The patients with no preoperative AR showed no

regurgitation of the aortic valve at follow-up. AR sever-

ity was reduced after membrane resection; this change,

however, was not significant. The correlation between

AR severity and the distance of the membrane from the

aortic valve was not significant (rs=-0.126, P=0.56).

The preoperative TTE showed a mean LVOT-PG of

80.83±42.72 mmHg. The mean LVOT-PG decreased

substantially to 19.14±14.03 postoperatively and to

25.47±16.10 mmHg at follow-up (P<0.001) compared to that

of preoperation. Early after surgery, LVOT-PG was less than

10 mmHg in only 30% of the patients, while 70% had still

LVOT-PG >10 mmHg. At follow-up, 20% of the patients had

LVOT-PG <10 mmHg.

There was no significant correlation between preoperative

LVOT-PG and the incidence and severity of preoperative

AR, and nor was there any association between preoperative

LVOT-PG and the size of the membrane or the distance of

the membrane from the aortic valve (rs=0.270, P=0.24 and

rs=0.185, P=0.39, respectively). Membrane recurrence was

detected in 5 (25%) patients at follow-up. The residual

gradient in these patients ranged from 5 to 20 mmHg (mean

12.20±7.26 mmHg) in early postoperative and from 16 to

41 mmHg (mean 27.96±10.46 mmHg) in follow-up TTE.

At follow-up, the increase in LVOT-PG was significant

in the patients with recurrence by comparison with those

without it (P=0.03); none of them required reoperation

(LVOT-PG <50 mmHg and less than moderate AR). Table

2 depicts a comparison of LVOT-PG postoperatively and at

follow-up between the patients with and without recurrence.

The severity of LVOT obstruction did not have a significant

influence on membrane recurrence after surgery.

Table 2. Comparison of LVOT PG (mmHg) post operatively and at

follow up between patients with and without recurrence

With recurrence Without recurrence P value

Postoperative

At follow up

Changes of LVOT PG

12.20±7.26

24.64±17.82

1.72±10.72

22.99±17.08

27.96±10.46

15.76±12.06

NS

NS

0.02

LVOT PG, Left ventricular outflow tract peak gradient; NS, Not

significant

Discussion

DSS is a progressive cardiac abnormality which leads

to LVOT obstruction by the subvalvular fibromuscular

tissue. The main cause of obstruction is still a matter of

debate, but there are various theories about the causes of

DSS and it seems that the disease is multifactorial. It has

been demonstrated that DSS is a pathological complex

and that endocardial abnormality is a part of this complex

begetting membrane development.9

De Vries and colleagues reported AR in 30% of their

patients at the time of diagnosis, which increased to 54%

222

The Journal of Tehran University Heart Center Hakimeh Sadeghian et al

during a mean follow-up interval of 3.7 years.2 We found

AR in 75% of our patients, and there was no significant

correlation between the presence or severity of AR and the

mean age of the patients.

There has been a great deal of research into the changes in

AR severity after surgery; still, the role of surgery and the time

of intervention in this regard are unclear. The retrospective

nature of the available reports and the heterogeneity

of the lesion, together with its unpredictable natural

history, are probably responsible for this uncertainty. Several

series have reported the progression of AR despite surgery.

Be that as it may, some with similar postoperative follow-

up evaluations have demonstrated little change, and others

have concluded that early surgery decreases the incidence of

AR at late follow-up.2 In addition, much as AR can progress

despite a postoperative reduction in LVOT obstruction, the

worsening of AR in DSS can be slowed or stopped with

an adequate resection of the membrane.3,9 In our study, AR

severity was reduced after surgery in some patients; the

reduction, however, was not statistically significant.

Some studies10 have shown that patients with a lower

preoperative systolic gradient have less significant late

postoperative regurgitation and that early operation with

adequate resection can preserve the integrity of the aortic

valve to avoid later valve replacement. By contrast, other

series have asserted that surgery does not have a beneficial

impact on AR because both the incidence and severity of AR

increase after surgery.1,6

Some researchers maintain that there is a relationship

between the severity of LVOT obstruction and AR in children

and adults1,11,12 and that secondary aortic valve damage can

be prevented if surgery is performed when LVOT mean

gradient rises to more than 30 mmHg.10 Our results did

not show a significant correlation between LVOT-PG and

the severity of AR before surgery. If future studies confirm

our findings, there will be no more fear of the progression

of AR with an increase in LVOT gradient, and the cut-off

point for surgery could, as a result, rise. It is noteworthy

that LVOT-PG remained more than 10 mmHg in 70%

and 80% of our patients postoperatively and at follow-up,

respectively.

The proportion of patients having symptoms varies from

series to series. Rayburn and colleagues3 confirmed

that 70% of their cases had no symptoms. Darcin and

associates11 reported that 61.9% of their patients were

asymptomatic. The majority of our patients were noted

to be symptomatic (85%), the most common symptom

being dyspnea (50%). This finding is probably due to

the fact that the mean preoperative LVOT-PG in our

cases was relatively higher than that in the previous series:

80.83±42.67 mmHg in our patients vs. 63.39±7.63 mmHg

in the cases reported by Rayburn et al.3 and 59.23±35.38

mmHg11 in the patients of Darcin and his colleagues.

The recurrent LVOT obstruction requiring reoperation is

at a rate of 4.8% to 30% in previous studies11,12 Serraf et al.

believed that recurrence and reoperation were significantly

influenced by previous repair and by the quality of the ini-

tial relief of subaortic stenosis.13 We observed a 25% recur-

rence rate, which chimes in with previous findings in the

literature.

Conclusion

The findings of this study revealed that an increased

LVOT-PG did not influence AR severity significantly.

In addition, AR severity had no correlation with age;

consequently, patient selection for surgery can be carried

out on the basis of LVOT-PG or AR severity separately. The

infrequent occurrence of the disease requires longer-term

studies and longer follow-up periods with more patients if

more light is to be shed on the course of postoperative DSS

and a cut-off point for surgery.

Acknowledgement

This study was supported by Tehran Heart Center,

affiliated with Tehran University of Medical Sciences. The

authors wish to thank all the staff of the Research

Department of Tehran Heart Center whoparticipated in

gathering and processing the data.

References

1- Oliver JM, Gonzalez A, Gallego P, Sanchez-Recalde

A, Benito F, Mesa JM. Discrete subaortic stenosis in adults:

increased prevalence and slow rate of progression of the

obstruction and Aortic regurgitation. JACC 2001;38:835-842.

2- Neutze JM, Louise Calder A, Gentles TL, Wilson NJ. Aortic

stenosis. In: Moller JH, Hoffman JIE, eds. Pediatric cardiovascu-

lar medicine. 1st ed. Philadelphia: Churchill Livingstone; 2000. p.

511-551.

3- Rayburn T, Netherland E, Heath J. Discrete membranous

subaortic stenosis: improved results after resection and myectomy.

Ann Thorac Surg 1997;64:105-109.

4- Movsowitz C, Jacobs LE, Eisenberg S, Movsowitz HD,

Kotler MN. Discrete subaortic valvular stenosis: the clinical

utility and limitations of transesophageal echocardiography.

Echocardiography 1993;10:485-487.

5- Cabrera A, Galdeano JM, Zumalde J, Mondragon F,

Cabrera J, Pilar J, Pastor E. Fixed subaortic stenosis: the

value of cross-sectional echocardiography in evaluating

different anatomical patterns. Int J Cardiol 1989;24:151-157.

6- Rohlicek CV, Font del Pino S, Hosking M, Miro J, Côté JM,

Finley J. Natural history and surgical outcomes for isolated discrete

subaortic stenosis in children. Heart 1999;82:708-713.

7- Rizzoli G, Tiso E, Mazzucco A. Discrete subaortic

stenosis: operative age and gradient as predictors of late valve incom-

petence. J Thorac Cardiovasc Surg 1993;106:95-104.

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Discrete Subvalvular Aortic Stenosis: ...

8- Otto CM. Valvular regorgitation. In: Otto OM, ed. Textbook of

clinical echocardiography. 3rd ed. Philadelphia: Elsevier Saunders;

2004. p. 315-354.

9- Parry J, Kovalcihin p, Kenji Suda, McElhinney B, Silverman H,

Mohan Reddy V, Hanley L. Resection of subaortic stenosis; can a more ag-

gressive approach be justified. Eur J Cardiothorac Surg 1999;15:631-638.

10- Coleman M, Smallhorn F, McCrindle W, Williams G, Free-

dom M. Postoperative follow-up of fibromuscular subaortic stenosis.

JACC 1994;24:1553-1564.

11- Darcin T, Yagdi T, Atay Y, Engin C, Levent E, Buket S,

Alayunt A. Discrete subaortic stenosis: surgical outcomes and

follow-up results. Tex Heart Inst J 2003;30:286-292.

12- Wright GB, Keane JF, Nadas AS, Bernhard WF,

Castaneda AR. Fixed subaortic stenosis in the young: medical and

surgical course in 83 patients. Am J Cardiol 1983:52:830-835.

13- Serraf A, Zoghby J, Lacour-Gyet F, Houel R, Belli E,

Galletti L, Planche C. Surgical treatment of subaortic stenosis: a

seventeen-year experience. J Thorac Cardiovasc Surg 1999;117:

669-678.

224



TEHRAN HEART CENTER

Original Article

The Effect of Post Coronary Angiography Bed-Rest Time on

Vascular Complications

Rabiallah Farmanbar, MSc1, Madjid Chinikar, MD2, Maryam Gozalian, MSc3*, Mojgan

Baghaie, MSc1, Zahra Atrkar Roshan, MSc2, Mohamadtaghi Moghadamnia, MSc1

1College of Nursing and Midwifery, Guilan University of Medical Sciences, Rasht, Iran. 2Cardiology Department, Guilan University of Medical Sciences, Rasht, Iran.3Valiasr Teaching Hospital, Zanjan University of Medical Sciences, Zanjan, Iran.

Abstract

Introduction

Coronary artery disease is one of the leading causes of

death in the world.1,2 Coronary angiography is a routine

diagnostic procedure indicated for the assessment and

evaluation of cardiac diseases such as coronary artery

Background: Coronary angiography is frequently applied for diagnostic purposes in patients with coronary artery disease.

Be that as it may, there is still no consensus about the optimal time for the ambulation of patients following femoral arterial

puncture. We sought to compare 6 hours of complete bed rest and 2 hours of complete bed rest in patients after angiogra-

phy.

Methods: This randomized quasi–experimental study was performed in 120 patients candidated for coronary angiography.

The patients were divided into experimental and control groups randomly. Primarily demographic data were obtained from

both groups before intervention was carried out for them. The arterial sheath was removed immediately after the procedure.

Hemostasis was achieved by manual compression and maintained with sandbags. Early ambulation was attempted after two

hours of supine bed rest following sheath removal. The incidence of bleeding and insertion site complications was

documented at 24 hours and subsequently at 30 days post-procedure.

Results:

index, catheter size, total procedure duration, total hemostasis time, history of anticoagulant drug use, and coagulation tests

before angiography. Pre-ambulation bleeding occurred in 2 patients in each of the two groups. Post-ambulation bleeding

occurred in 2 patients in the control group and 1 in the experimental group. Whereas there was no incidence of large pre-am-

bulation hematoma in the control group, there was one case in the experimental group. There was no case of post-ambulation

hematoma, however, in either group, and nor was there any late bleeding or vascular complication.

Conclusion: Ambulation 2 hours after angiography via the femoral site is feasible and safe with the same incidence of

insertion site complication as that of 6 hours of bed rest. Therefore, an early ambulation protocol can shorten hospital stay

J Teh Univ Heart Ctr 4(2008) 225-228

*Corresponding Author: Maryam Gozalian, Zanjan University of Medical Sciences, Valiasr Teaching Hospital, End of Sheikhfazlloahenoori

Highway, Zanjan, Iran. Tel: +98 241 7123299. Fax: +98 241 7270751. Email: [email protected].

Keywords:

Received 12 August 2008; Accepted 26 October 2008

disease and valvular disease.2

Nowadays, a femoral coronary artery catheter is com-

monly used for this invasive procedure. It is, however,

associated with a risk of such complications as bleeding and

hematoma at the femoral arterial puncture site.3 The poten-

tial of these complications has been traditionally reduced

226


by restricting the patient to at least 6 hours of bed rest after

angiography.1 This practice is based on empirical reason-

ing and tradition and is associated with discomfort for the

patient.4

Several studies support reducing the duration of bed

rest to 2 or 3 hours for the outpatients who have diagnostic

coronary angiography.4-7 There were no studies in the

existing literature to examine bed-rest times following any

cardiac catheterization in Iran when this trial was designed.

The purpose of the current trial was to test the hypothesis

that reducing time-to-ambulation from 6 hours to 2 hours

would not increase post-angiography vascular complications.

Methods

The study was conducted from November 2006 to

February 2006 in the post-angiography wards of two

hospitals in Rasht (Heshmat Teaching Hospital and

Arya Hospital). All the patients of one interventionist (to

control the complications related to the operator’s experience)

presenting for cardiac angiography to the hospitals were

considered for study participation if a femoral arterial

approach was planned. The study protocol was approved

by the Ethics Committee of Guilan University of Medical

Sciences, and written informed consent was obtained from

all the patients. Single puncture of the femoral artery was

an inclusion criterion; and renal failure, chronic obstructive

pulmonary disease, known pre-procedure bleeding disorder,

and patient transfer to the ICU after angiography comprised

the exclusion criteria.

The patients were randomized to a period of either 2 hours

(experimental group) or 6 hours (control group) of bed rest

after sheath removal. Upon the completion of angiography,

the patients were transferred to the post-angiography ward,

where the arterial sheaths were removed immediately by

experienced nurses and hemostasis was achieved by the

manual compression of the puncture site. The minimal time of

compression was 10 minutes. A transparent dressing was

applied on the puncture site in order to control bleeding and

hematoma and to augment the visibility of the puncture site.

Two sandbags (each weighing 2.5 kg) were used to remind

the patient not to move the affected leg during the supine

position of bed rest. One of the sandbags was removed after one

hour of bed rest, and the second was lifted before ambulation.

The patients’ vital signs, pedal pulses, and puncture

site were checked prior to sheath removal, every 15 min-

utes after hemostasis for 1 hour, every 30 minutes for 1

hour, and thereafter every 1 hour until ambulation. After

ambulation, they were checked every 15 minutes for 1 hour.

The final assessment for the presence of any complication

was made at discharge, i.e. the day after angiography.

Bleeding was defined as any bleeding that required

renewed compression. Hematoma formation was defined

Rabiallah Farmanbar et al

as small (a palpable mass <5×5 cm) and large (a palpable

mass >5×5 cm), and late complications were determined by

the ultrasound appearance of false aneurysms or fistulas.

These complications were checked for 24 hours on

patient follow-up by one nurse. At 30 days, the

patients were visited by there physicians and were checked

for late complications via ultrasound.

The data were analyzed using the Statistical Package

for Social Sciences (SPSS, version 13). The Chi square,

t- test, and Fisher Exact test were employed to determine any

significant differences between the two groups.

Results

During the study period, 120 patients, who had met the

inclusion criteria, were randomized to two groups of 2 hours

(n=60) and 6 hours (n=60) of bed rest.

There were no statistically significant differences in terms

of gender, age, body mass index, catheter size, total proce-

dure duration, total hemostasis time, history of anticoagu-

lant drug use, and coagulation tests between the two groups

pre-angiography. The results are summarized in Table 1.

Table 2 depicts the incidence of vascular complications.

BMI, Body mass index; PT, Prothrombin time; PTT, Partial

thromboplastin time

experimental(n=60) control(n=60) P value

Table 1. Patient characteristics

Age (y)

Male

BMI (kg/m2)

PT (sec)

PT activity (%)

INR

PTT (sec)

Platelet count

Procedural time (min)

Time to hemostasis (min)

7 French sheath usage

Use of oral antiplatelet

60.17±11.50

61.7 %

27.08±4.11

12.63±0.54

98.64±4.26

1.01±0.04

31.9 ±3.17

210433±69498

15.63±4.43

17.6±3.25

96.7 %

90%

59.9±10.15

58.3 %

28.04±4.29

12.73±0.49

99.27±2.22

1.08±0.02

31.43±3.04

221066±62870

15.45±4.64

17.85±3.16

93.3 %

91.6%

0.51

0.70

0.25

0.31

0.30

0.40

0.41

0.38

0.54

0.93

0.40

0.91

VariableP value

Experimental

(2 hours)

Control

(6 hours)

Table 2. Vascular complications

Bleeding before ambulation

Small hematoma before ambulation

Large hematoma before ambulation

Post-ambulation bleeding

(until 24 hours)

Post-ambulation hematoma

(until 24 hours)

Late vascular complication

(after 30 days)

2 (3.3%)

1 (1.7%)

1 (1.7%)

1 (1.7%)

0

0

2 (3.3%)

1 (1.7%)

0

2 (3.3%)

0

0

0.69

0.75

0.50

0.50

-

-

TEHRAN HEART CENTER


The Effect of Post Coronary Angiography Bed-Rest Time on Vascular Complications

Pre-ambulation bleeding occurred in 2 (3.3%)

patients in both groups. In addition, post-ambulation

bleeding occurred in 1 (1.7%) patient in the experimental

group and 2 (3.3%) patients in the control group.

Small pre-ambulation hematoma (a palpable mass

< 5×5 cm) occurred in 1 (1.7%) patient in both groups,

while large pre-ambulation hematoma (a palpable

mass > 5×5 cm) was observed in 1 (1.7%) patient in the

experimental group. There were no hematomas (small or

large) after ambulation in either group. Also, there was

no late bleeding or vascular complications such as a false

aneurysm or arteriovenous fistula at 30 days’ follow-up.

The incidence of vascular complications before and after

ambulation did not differ significantly between the experi-

mental and control groups (Fisher Exact test=not significant).

Discussion

The results of the present study, the first report of early

post-angiography ambulation in Iran, show that early

ambulation (two hours) after coronary angiography is

safe and not associated with an increased risk of vascular

complications compared to 6 hours of bed rest. Our results

chime in with those of many previously published studies

by investigators such as Alarcan et al.,8 Wangs et al.,9

Tagney, Lackie,10 and Tengiz et al.,11 demonstrating the safety

of early ambulation after diagnostic and therapeutic cardiac

catheterizations.

Rosenstein et al.5 found similar complication rates after

6 French diagnostic heart catheterizations among patients

who commenced ambulation 2 hours after sheath removal

compared to those who did so 6 hours after the removal

of the sheath. Koch et al.4 demonstrated the safety of

early ambulation in patients who underwent percutaneous

coronary angioplasty with 6 French sheaths and low-dose

heparin. Gianakos et al.12 in a pilot study also showed that 2

hours of bed rest by comparison with 4 hours of bed rest after

electrophysiological procedures could be safe. They showed

that the incidence of bleeding did not differ significantly

between the two groups. Vlasic et al.13 reported that the

patients undergoing femoral arterial puncture for coronary

interventional procedures could safely ambulate 2 hours

after the hemostasis of the puncture site.

Conclusion

In light of the findings of the present study, we would

posit that the institutional standard of requiring 6 hours of

bed rest after coronary angiography via the femoral artery

could be reduced to 2 hours safely. The reduction of time-to-

ambulation may add to the patient’s comfort, although it is

primarily pursued for economic and logistic reasons in many

centers confronted with increasing numbers of patients and

restricted hospital facilities.

Acknowledgments

This study was approved by Guilan University of Medical

Sciences and the Ethics Committee thereof. We hereby wish

to express our gratitude for their invaluable support.

References

1- Dressler D. Management of patients with coronary vascular

disorders. In: Smeltzer SC, Bare BG, Hinkle JL, Cheever KH, eds.

Brunner and Suddarth’s textbook of medical surgical nursing. 11th ed.

philadelphia: Lippincott Williams and Wilkins; 2007. p. 858-913.

2- Popma JJ. Coronary angiography and intravascular

ultrasound imaging. In: Zipes DP, Libby P, Bonow RO,

Braunwald E, eds. Braunwald’s heart disease: a textbook of

cardiovascular medicine. 7th ed. philadelphia: Elsevier; 2005. p. 423-455.

3- Parkosewich JA. Assessment of cardiovascular function. In: Smelt-

zer SC, Bare BG, Hinkle JL, Cheever KH, eds. Brunner and Suddarth’s

textbook of medical surgical nursing. 11th ed. philadelphia: Lippincott

Williams and Wilkins; 2007. p. 780-821.

4- Koch KT, Piek JJ, Winter RJde, Mulder K, Schotborgh CE, Tijssen

JGP, Lie KI. Two hour ambulation after coronary angioplasty and stent-

ing with 6F guiding catheters and low dose heparin. Heart 1999;81:53-56.

5- Rosenstein G, Cafri C, Weinstein JM, Yroslavtsev S,

Abuful A, Ilia R, Fuchs S. Simple clinical risk stratification and

the safety of ambulation two hour after 6 french diagnostic heart

catheterization. J Invasive Cardiology 2004;16:126-128.

6- Pamela J, Lisa A, Christine M, Amy L. Evaluation of nursing care

after diagnostic coronary angiography. Am J Crit Care 2001;10:330-340.

7- Pollard SD, Munks K, Wales C, Crossman DC, Cum-

berland DC, Oakley GDG, Gunn J. Position and mobilisa-

tion post-angiography study (PAMPAS): a comparison of

4.5 hours and 2.5 hours bed-rest. Heart 2003;89:447-448.

8- Alarcan EZ, Cecena F, Ashar R, Patel R, Poppel SV, Carlson

R. Safety of elective -including “high risk”-percutaneous coronary

interventions without on-site cardiac surgery. Am Heart J 2004;148:

676-683.

9- Wangs SL, Redeker NS, Moreyra AE, Diamond

MR. Comparison of comfort and local complications

after cardiac catheterization. Clin Nurs Res 2001;10:29-39.

10- Tagney J, lackie D. Bed-rest post femoral arterial sheath

removal-What is safe practice? A clinical audit. Nurs Crit Care

2005;10:167-173.

11- Tengiz I, Ercan E, Bozdemir H, Durmaz O, Gurgun C, Nalbantgil I.

Six hour ambulation after elective coronary angioplasty and stenting with

7F guiding catheters and low dose heparin. Kardiol Pol 2003;58:93-97.

12- Giannakos S, Keeling AW, Haines D, Haugh

K. Time in bed after electrophysiological procedures

(TIBS IV): a pilot study. Am J Crit Care 2004;13:56-58.

13- Vlasic W, Almond D, Massel D. Reducing bed rest following

arterial puncture for coronary interventional procedures-impact on

vascular complication: The BAC Trial. J Invasive cardiol 2001;13:788-792.

228



TEHRAN HEART CENTER

Congenital Left Ventricular Diverticulum Associated with ASD,

VSD, and Epigastric Hernia

Akbar Shahmohammadi, MD, Nader Givtaj, MD, Seyed Mohammad Dalili, MD*,

Rahman Ghaffari, MD

Shaheed Rajaie Cardiovascular Medical and Research Center, Tehran, Iran.

Received 4 December 2007; Accepted 6 August 2008

Case Report

Abstract

Introduction

Congenital left ventricular apical diverticulum is a very

uncommon cardiac malformation.1-5 It is always

associated with midline thoraco-abdominal defects and other

heart malformations.1,2,6 All patients with a

midline thoraco-abdominal defect and a pulsatile mass

should be evaluated carefully to rule out this anomaly. In

symptomatic patients, medical and surgical treatment can

relieve symptoms and prevent further complications.1,7

Case report

A 10-month-old girl referred to us for cardiac evaluation

before surgical repair of epigastric hernia. The cause of refer-

ral was heart murmur and cardiomegaly, which were found

in routine physical examination and chest roentgenogram,

Congenital left ventricular diverticulum is a rare cardiac malformation. Two categories of congenital ventricular diverticu-

with midline thoraco-abdominal defects and other heart malformations. Non-apical diverticula are always isolated defects.

Diagnosis is established by imaging studies such as echocardiography, magnetic resonance imaging, or left ventricular

angiography. Mode of treatment has to be individually tailored and depends on clinical presentation, accompanying

abnormalities, and possible complications.

We report a 10-month-old girl with left ventricular apical diverticulum, large atrial septal defect, two small muscular

ventricular septal defects, and pulmonary hypertension, associated with epigastric hernia. This patient underwent total sur-

gical repair for intra-cardiac defects as well as diverticular resection.

*Corresponding Author: Seyed Mohammad Dalili, Assistant Professor of Pediatric Cardiology, Department of Pediatric Cardiology, Shaheed Rajaie

Cardiovascular Center, Vali Asr Ave, Tehran, Iran. Tel: +98 21 23922509. Fax: +98 21 22663312. E-mail: [email protected].

Keywords:

respectively.

The patient, weighing 6.5 kg, had normal

facies and a normal developmental history.

A relatively large hernia was clearly apparent in the

epigastric region with a pulsatile mass upon it (Figure 1).

A heavy cardiac impulse was felt at the left side of the

anterior chest wall at the normal site. There was an approxi-

mately 3-cm distance between the point of the maximal car-

diac impulse and the pulsatile mass. There were no other

pulsations or thrills.

Cardiac auscultation revealed a widely split second heart

sound with an accentuated pulmonary component. A holo-

systolic murmur, grade 3/6, was heard along the left sternal

border, as well as an ejectional murmur, grade 2/6, at the

upper left sternal border.

Electrocardiography showed a sinus rhythm with a heart

rate of 120, right axis deviation, and right ventricular hyper-

trophy.


230


Figure 1. Simple photograph of the patient in supine position. Note the

eminency on the epigastric region (arrow)

Chest roentgenogram revealed moderate cardiomegaly, prominent pulmonary artery shadow, and increased pulmonary vascular markings. There was no other structural finding in the anteroposterior and lateral films (Figure 2).

A

BFigure 2. Chest X-ray of the patient. A, anteroposterior view; B, lateral

view. Cardiomegaly and increased pulmonary vascular markings are seen

in both images, but the diverticulum is not seen directly

Akbar Shahmohammadi et al

Two-dimensional echocardiography revealed a relatively

large secundum type atrial septal defect (ASD), 2 small

muscular ventricular septal defects (VSDs), and a dilated

pulmonary trunk. A long outgrowth (diverticulum) was

also detected in the left ventricular apex with simultaneous

contractions (Figure 3). The thoracic and abdominal aorta

seemed normal without any abnormal dilatation. A Doppler

color examination showed left-to-right flow across the atrial

and ventricular septal defects. There was no significant flow

gradient through the diverticulum origin.

Figure 3. Two dimensional and color Doppler echocardiograms of the

patient. A, large large atrial septal defect (ASD) and relatively enlarged left

atrium (LA) are seen in subcostal coronal view. B, two small muscular

ventricular septal defect (VSDs) (arrows) are seen in apical five- chamber

view. C, an apical outgrowth (diverticulum) is seen in modified four-cham-

ber view (arrow). D, non-turbulent antegrade-retrograde flow is seen in the

diverticulum by color Doppler imaging (arrow)

Cardiac catheterization and angiography was performed to

delineate the exact anatomy and measure the

pulmonary artery pressure and pulmonary vascular resis-

tance.

Pulmonary systolic pressure was as high as 60 mmHg

when aortic pressure was 80 mmHg. Left-to-right shunt was

estimated at approximately 2:1.

The left ventricle angiogram in the lateral projection clear-

ly illustrated the diverticulum (Figure 4). ASD and VSDs

were detected in their special views. The diverticulum had

synchronal contractions with the left ventricle.

Because of the high pulmonary artery pressure and heart

failure, total surgical repair (closure of ASD and VSDs and

diverticulectomy) was recommended.

TEHRAN HEART CENTER


Congenital Left Ventricular Diverticulum Associated with ASD, VSD, and Epigastric Hernia

Figure 4. Left ventricle angiogram of the patient

AO, Aorta; LV, Left ventricle; D, Diverticulum

Under general anesthesia and via median sternotomy, car-

dio-pulmonary bypass (CPB) was established and the heart

was arrested with cold crystalloid cardioplagin

administration. The diverticulum was herniated into the

abdominal wall through a relatively small diaphragmatic

defect (Figure 5 A). The diverticulum was released from

the surrounding tissues and resected (Figure 5 B, C). The

ventricular septal defects were thereafter repaired via right

ventriculotomy. The atrial septal defect was closed via right

atriotomy without patch usage. The patient was weaned from

CPB by using a temporary pacemaker.

After surgery, the patient was transferred to the

pediatric ICU. However, the patient continued to have

complete heart block, which persisted after 10 days, l

eading to the insertion of a permanent pacemaker. The

patient is healthy otherwise with a good ejection fraction. Figure 5. Surgical diverticular resection

Discussion

Congenital left ventricular diverticulum is a rare

cardiac malformation.1-5 It appears to be a developmental

anomaly, starting in the 4th embryonic week.1 Although this

anomaly may exist alone, associated cardiac, vascular, or

thoraco-abdominal abnormalities are present in some

cases.1,2

Diagnosis can be made after the exclusion of the ventricular

aneurysm, coronary artery disease, local or systemic inflam-

mation, or traumatic causes as well as cardiomyopathies.1,2,8

Clinically, most congenital left ventricular diverticula are

asymptomatic, but some of them may causesystemic embo-

lization, heart failure, valvular regurgitation, ventricular wall

rupture, ventricular tachycardia, or sudden cardiac death.1

Diagnosis is established by imaging studies such as echocar-

diography, magnetic resonance imaging, or left ventricular

angiography.1,9,10

232


Two categories of congenital ventricular diverticu-

lum could be identified with respect to their localization:

apical and non-apical. Apical diverticula are always

associated with midline thoraco-abdominal defects and other

heart malformations. Non-apical diverticula are always

isolated defects.

Ventricular diverticula could be differentiated from

ventricular aneurysms by echocardiography and

angiography.1,8 Diverticula are characterized by synchronal

contractility, but aneurysms are akinetic with paradoxical

systolic motion. The outcome is different in these two types

of outpouchings: congenital ventricular aneurysms are

associated with adverse outcomes, whereas the prognosis for

congenital ventricular diverticula is good.1

All patients with a midline thoraco-abdominal defect and

a pulsatile mass should be evaluated carefully to rule out

ventricular apical diverticulum. Otherwise, it may compli-

cate surgical options for repairing the thoraco-abdominal

defects. Patients with cardiac diverticulum should be

evaluated for other associated intracardiac and extracardiac

lesions.1,2,6

Mode of treatment has to be individually tailored and

depends on clinical presentation, accompanying abnormali-

ties, and possible complications. Because of the usually

benign course of congenital left ventricular diverticula, most

of them can be managed conservatively. Treatment options

for high-risk cases include surgery, anticoagulant therapy,

and management of arrhythmias.

Different surgical approaches have been recommended

for the treatment of apical diverticula.7 Irrespective of the

method, however, the surgeon should be aware of surgical

complications such as complete heart block as well as other

well-known complications.

Acknowledgment

We wish to thank Mr. A. Abdi, for the high quality

intraoperative photographs. Thanks are also due to

the pediatric catheterization laboratory staff of Shaheed

Rajaei Cardiovascular Medical and Research Center for their

cooperation.

References

1- Ohlow MA, Secknus MA, Geller JC, von Korn H, Lauer B.

Congenital left ventricular aneurysms and diverticula. Pathophysiology,

clinical relevance, and treatment. Med Klin 2007;102:358-365.

2- Pradhan M, Dalal A, Kapoor A, Kumar S, Manisha R. Fetal left

ventricular diverticulum presenting as dysrhythmia: diagnosis and man-

agement. Fetal Diagn Ther 2007;23:10-14.

3- Ohlow MA. Congenital left ventricular aneurysms and diverticula:

definition, pathophysiology, clinical relevance and treatment. Cardiol-

ogy 2006;106:63-72.

4- El Kettani NE, Dafiri R. Isolated congenital left ventricular diver-

ticulum: report of a paediatric case. J Radiol 2006;87:56-58.

5- Pitol R, Cardoso Cde O, Cardoso CR, Gomes Mde F, Schvartz-

man P. Congenital ventricular diverticulum associated with ventricular

tachycardia. Arq Bras Cardiol 2005;84:173-175.

6- Sakabe K, Fukuda N, Fukuda Y, Wakayama K, Nada T,

Morishita S, Shinohara H, Tamura Y. Isolated congenital left ventricu-

lar diverticulum in an elderly patient that was identified because of an

incidental finding during a complete medical checkup. Int J Cardiol

2008;125:e30-33.

7- Rastan AJ, Walther T, Daehnert I, Mohr FW, Kostelka M. Left

ventricular diverticulum repair in a newborn. Thorac Cardiovasc Surg

2007;55:61-64.

8- Yazici M, Demircan S, Durna K, Yasar E Left ventricular

diverticulum in two adult patients. Int Heart J. 2005;46:161-165.

9- Russo G, Sarais C, Corbetti F, Ramondo A, Daliento L. Imag-

ing for the diagnosis of an unusual case of left ventricular aneurysm.

Cardiovasc Intervent Radiol 2005;28:254-255.

10- Ghersin E, Kerner A, Gruberg L, Bar-El Y, Abadi S, Engel A. Left

ventricular pseudoaneurysm or diverticulum: differential diagnosis and

dynamic evaluation by catheter left ventriculography and ECG-gated

multidetector CT. Br J Radiol 2007;80:e209-211.

Akbar Shahmohammadi et al


TEHRAN HEART CENTER

Nobel Prize in Physiology or Medicine for the Year 2007:

Breakthrough in Pathophysiology and Experimental Therapy

of Cardiovascular and Other Diseases

Murat Ugurlucan, MD1, FASA, Armen Yuri Gasparyan, MD, PhD2, Hamid Darban, PhD,

CCP3*

1Rostock University Medical Faculty, Department of Cardiac Surgery, Rostock, Germany.2Yerevan State Medical University, Armenia. 3King Faisal Heart Institute, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia.

Received 20 August 2008; Accepted 26 August 2008

Letter To The Editor

In the year 2007, Professor of Human Genetics and

Biology Mario Capecchi from University of Utah, USA,

Professor of Mammalian Genetics Martin J. Evans from

School of Biosciences, Cardiff University, Wales, UK, and

Professor of Pathology and Laboratory Medicine Oliver

Smithies from University of North Carolina, USA shared the

Nobel Prize in Physiology or Medicine for developing a way

to eliminate or “knockout” specific genes in mice.1,2 Joint

efforts of these distinguished scientists allowed the creation

of a variety of animal models to study pathophysiology and

experimental therapy of mono- and polygenic human

diseases, including cardiovascular diseases.

The scientists employed specific gene modifications in

embryonic stem cells in mice. Exchange of DNA sequences

within chromosome pairs increases genetic variations in the

population. It takes place by a process called homologous

recombination. Mario Capecchi and Oliver Smithies

proposed that homologous recombination could be used to

modify genes in mammalian cells. Capecchi demonstrated

that homologous recombination could occur between

introduced DNA and chromosomes. He showed that defective

genes might be repaired by homologous recombination with

the incoming DNA. Smithies tried to repair mutated genes

in human cells. He postulated that certain inherited blood

diseases could be cured by treating mutations in bone marrow

stem cells. He discovered that endogenous genes could be

targeted. This suggested that genes could be accessible for

modification by homologous recombination.

On the other hand, the cell types initially studied

by Capecchi and Smithies could not be used to create

gene-targeted animals. For this purpose, another cell type

which could give rise to germ cells was required. In other

words, inherited DNA modifications were necessitated.

Martin Evans worked with mouse embryonal carcinoma

*Corresponding Author: Hamid Darban, Academic Director, Clinical Perfusion Program, King Faisal Heart Institute, King Faisal Specialist

Hospital & Research Center. P.O.Box: 3354 MBC 16. Riyadh 11211, Saudi Arabia. Tel: +96 614647272. Fax: +96 614427482. Mobile: + 96 6505291848.

Email: [email protected].

cells. Although these cells originate from tumors, they have

the capacity to differentiate into a variety of cell types. He

suggested using embryonal carcinoma cells as vehicles to

introduce genetic material into the mouse germ lines. His

early attempts had been unsuccessful because embryonal

carcinoma cells carried abnormal chromosomes which

prevented their contribution to germ cell formation. On the

other hand, Evans searched for alternatives and discovered

that cells with normal chromosomes obtained from mouse

embryos could be cultivated. These cells were embryonic

stem cells.

The next step was to investigate the contribution of

embryonic stem cells to the germ line. Embryos of one

mouse strain were injected with embryonic stem cells from

another mouse strain. Then, these mosaic embryos were

carried by surrogate mothers and delivered. The mosaic

offspring was grown and subsequently mated. The presence

of embryonic stem cell-derived genes was investigated in

the 2nd generation and they were present in the newborns. It

gave rise to the understanding of gene inheritance according

to Mendel’s laws. In his further experiments, Evans modified

the embryonic stem cells, using retroviruses capable of

integrating their genes into chromosomes. Evans used

embryonic stem cells to generate porter mice carrying new

genetic material.

In 1986, the first gene-targeted embryonic stem cells were

created. Capecchi and Smithies demonstrated that genes

can be targeted by homologous recombination in cultured

cells. The first reports on homologous recombination in

embryonic stem cells used to generate gene-targeted mice

were published in 1989. Since then, the number of knockout

mouse strains has increased drastically. Gene targeting

became a highly challenging issue, and it is now possible

to introduce mutations that can be activated at specific time

234


points or in specific cells or organs.

Importantly, gene targeting is a basis for understanding

the role of genes in mammalian fetal development. Capec-

chi clarified the role of genes involved in mammalian or-

gan development and indicated possible causes of several

congenital malformations. Evans applied gene targeting in

several experimental models of human diseases, particularly

cystic fibrosis, and tested effects of gene therapy. Smith-

ies used gene targeting to develop mouse models for cystic

fibrosis, thalassemia, diabetes, cardiac fibrosis and hyper-

trophy, hypertension, and atherosclerosis.3-5 He provided a

genetic basis for the so-called inflammatory theory of ath-

erosclerosis by targeting genes encoding apolipoprotein E. It

was shown that apoE-knockout homozygous mice could still

spontaneously develop atherosclerosis in the absence of high

fat and cholesterol diet. In a series of experiments, Smithies

targeted candidate genes of hypertension coding

angiotensinogen, aldosterone synthase, and atrial natriuretic

peptide and clarified many hemodynamic and metabolic

mechanisms of essential hypertension. In genetically modi-

fied mice lacking natriuretic peptide receptor A, the scientist

developed a model of hypertension that expressed cardiac

hypertrophy and sudden cardiac death. Thus, he proved that mul-

tifactorial cardiovascular diseases can be explored by studying

knockout mice.

In conclusion, gene targeting in mice has been a major

focus in most fields of medicine over the past decades. It

is obvious that a better understanding of genes function

throughout the whole life cycle, starting from embryonic

stage, will provide clues for the treatment of a variety of

human diseases with a complex pathophysiology and

gradually progressive course (e.g. essential hypertension).

Specific gene modification in mice has great implications

for studying the effects of numerous biomarkers, particularly

those involved in atherogenesis, endothelial dysfunction,

and heart failure (e.g. C reactive protein, natriuretic peptide,

angiotensin II, etc.). Although most experimental achievements

of the past decades are not immediately applicable to

clinical practice, one should appreciate beginning of an era

of studies aimed at the clarification of genotype-phenotype

associations in humans based on our understanding of

experimental models of diseases.

References

Murat Ugurlucan et al

1. Manis JP. Knock out, knock in, knock down--genetically manipu-

lated mice and the Nobel Prize. N Engl J Med 2007;357:2426-2429.

2. Vogel G. Nobel Prizes. A knockout award in medicine. Science

2007;318:178-179.

3. Smithies O, Maeda N. Gene targeting approaches to complex ge-

netic diseases: atherosclerosis and essential hypertension. Proc Natl

Acad Sci USA 1995;92:5266-5272.

4. Smithies O. Many little things: one geneticist’s view of complex

diseases. Nat Rev Genet 2005;6:419-425.

5. Pandya K, Cowhig J, Brackhan J, Kim HS, Hagaman J, Rojas M,

Carter CW Jr, Mao L, Rockman HA, Maeda N, Smithies O. Discordant

on/off switching of gene expression in myocytes during cardiac hyper-

trophy in vivo. Proc Natl Acad Sci USA 2008;105:13063-13068.

TEHRAN HEART CENTER


236


INTERNATIONAL CARDIOVASCULAR SURGERY

MEETINGS CALENDER (2008-2009)

Congress Time-Location Address

The Second Asia-Pacific Congress of Pediatric

Cardiology and Cardiac Surgery

61st Congress of the French Society for

Thoracic and Cardiovascular Surgery

THE NEW ORLEANS CONFERENCE

Practices in Cardiac Surgery and

Extracorporeal Technologies

EACTS Academy: European School for

Cardio-Thoracic Surgery, Cardiac Course

level B

Bypass, Balloons and Circulatory Support

IVth Biennial Conference of the Polish Society of Car-

diothoracic Surgeons

XIX National Congress of the Spanish

Society for Thoracic - Cardiovascular Surgery

(SECTCV)

World Summit on Pediatric and Congenital Heart Surgery Services, Education and

Cardiac Care in Children and Adults with Congenital Heart Disease

27-30 May 2008Jeju, Korea (South)

4- 8 June 2008Versailles, France

5-7 June 2008New Orleans, LA United States

9-14 June 2008Bergamo, Italy

9 June 2008London, United Kingdom

12-14 June 2008Warsaw, Poland

19-21 June 2008

19-21 June 2008Montreal, PQ Canada

Website: http://www.pccs2008.com

Website: http://www.fstcvs.org

Website: http://theneworleasconference.

com/index.htm

Website: http://school.eacts.org/

Website: http://www.rcseng.ac.uk/

education/courses/specialty/

cardiosurgery.html

Website: http://www.kardiotorakokon-

gres2008.pl

Website:http://19congresosectcv.

unicongress.org/

Website: http://www.wspchs.org/

TEHRAN HEART CENTER


Blood Conservation In Cardiac Surgery - Can We

Achieve A Consensus?

The 8th Symposium on Aortic and Mitral Reconstructive

Surgery

APACVS 9th Annual Summer Educational Meeting

Eurasian Workshop on Valve Repair

The Fourth Annual STS Legislative Advocacy Workshop

Cardiac Surgical Unit Advanced Life Support

ROCKY XVIII - Rocky Mountain Valve

Symposium - Managing the Aortic Root:

Current Therapies and Controversies

Terms and Techniques In Aortic Surgery For Trainees

Canadian Association of Thoracic

Surgeons - 11th Annual Meeting

2008 Heart Valve Summit – Case-Based

Review: Medical and Surgical Management

2nd Meeting Towards Safer Repeat Cardiac and Tho-

racic Surgery - Hosted by The Heart Hospital, London

International Meeting on Aortic Aneurysms

ESTS School of Thoracic Surgery (Practical course in

the laboratory)

Birmingham Review Course In Cardiothoracic Surgery

20 June 2008London, United Kingdom

20-21 June 2008Brussels Belgium

30 June-2 July 2008Kailua Kona, HI United States

11-13 July 2008Parumala, Kerala India

13-15 July 2008Washington, DC United States

24-26 July 2008Penright, Cumbria United King-

dom

24-25 July 2008Missoula, MT United States

22-24 September 2008Liverpool, Merseyside UK

11-14 September 2008Halifax, NS Canada

18 - 20 September 2008Chicago, IL United States

19 September 2008London United Kingdom

19-20 September 2008Liège Belgium

25-26 September 2008Elanacourt France

2-5 October 2008Bordesley East, Birmingham UK

Website: http://www.rsm.ac.uk/academ/

cae102.php

Website: http://www.valvesymposium.org

Website: http://www.apacvs.net

Website: http://www.frontierlifeline.com

Website: http://www.sts.org/sections/

governmentrelations/Legislative

%20Advocacy%20Workshop/index.html

Website: http://csu-als.com/

Website: http://www.rockymountainvalves-

ymposium.org/

Website: http://www.mpoullis.com/courses.

htm

Website: http://www.canats.org/

Website: http://www.acc.org/education/

programs/

brochures/heartvalvesummit_08.htm

Website: [email protected]

Website: http://www.chuliege-imaa.be/

Website: http://www.estsschool.org

Website: http://www.birminghamreview-

course.com


238


American College of Surgeons annual Clinical Congress

Meeting

EACTS Academy: European School for Cardio-Tho-

racic Surgery , Thoracic Course level C

Annual Meeting of the Swedish Association for Cardio-

thoracic Surgery

10th National Congress of the Turkish

Cardiovascular Surgery Society

8th National Scientific Conference of Chinese Society

for Thoracic and Cardiovascular Surgery

Fifty-Fifth Southern Thoracic Surgical Association

Annual Meeting

XXIV National Meeting of the Italian Society for

Cardiac Surgery

EACTS Academy: European School for Cardio-Tho-racic Surgery , Cardiac Course level C

13th Congress on Cardio-Thoracic Surgery

EACTS Academy: Advanced Techniques in Adult

Cardiac Surgery

Cardiac Surgical Unit Advanced Life Support

EACTS Academy: Cardio-Thoracic Surgery and Re-

generative Medicine

2nd Meeting Towards Safer Repeat Cardiac and Tho-

racic Surgery - Hosted by The Heart Hospital, London

ICR 2008: Integrated Cardiovascular Repair - Work-

shop 4th Interdisciplinary Workshop for Interventional

Cardiologists, Cardiac Surgeons and Cardiac

Intervention Teams

10-14 October 2008San Francisco, CA United States

13-18 October 2008Bergamo Italy

16 - 18 October 2008Lund Sweden

17-21 October 2008Cesme, Izmir Turkey

29 October-2 November 2008Chengdu China

6-8 November 2008Austin, TX United States

8 - 11 November 2008Rome Italy

10-15 November 2008Bergamo Italy

15 November 2008Woluwe, Brussels Belgium

20-22 November 2008Krakow Poland

27-29 November 2008Penright, Cumbria United

Kingdom

28-29 November 2008Bern Switzerland

19 September 2008London United Kingdom

4-6 December 2008Innsbruck Austria

Website: http://www.facs.org/

Website: http://school.eacts.org

Website: http://www.sacts.org

Website: http://www.tkdcd2008.org

Website: http://www.cstcvs.com

Website: http://www.stsa.org

Website: http://www.sicch.org/

Website: http://school.eacts.org

Website: http://www.bacts.org

Website: http://courses.eacts.org/sections/

Cardiac/AdvTechCar/index.html

Website: http://csu-als.com/

Website: http://www.acc.org/education/

programs/

brochures/heartvalvesummit_08.htm


CT/CTRegen/index.html

Website: http://www.icrworkshop.at/


TEHRAN HEART CENTER


Aortic Surgery and Anesthesia “How to do it”

7th Biennial International Conference - Pakistan Society

of Cardiovascular & Thoracic Surgeons

45th Annual Meeting of The Society of Thoracic

Surgeons

EACTS Academy: Cardiac and Thoracic Robotic

Surgery

58th International Congress of the European Society for

Cardiovascular Surgery

Advance Cardiac Techniques in Surgery - The Seventh in the Series - Surgical and Interventional Therapies for

Heart Valve Diseases, Left Ventricluar Failure, Aortic Arch Aneurysms and Atrial Fibrillation

Emgergency in Cardiovascular Surgery: An

Integrated Approach

11-13 December 2008Milan Italy

18-21 December 2008Peshawar Pakistan

26-28 January 2009San Francisco, CA United States

4-7 February 2009Strasbourg France

1-4 May 2009Warsaw Poland

6-7 May 2009New York, NY United States

18-23 May 2009Erice.Sicily Italy

Website: http://www.aorticsurgery.it

Website: http://www.7bic.org

Website: http://www.sts.org


CT/RobSurg/index.html

Website: http://www.escvs.org

Website: http://www.promedicacme.com/

Website: http://www.ccsem.infn.it


240


INTERNATIONAL CARDIOVASCULAR MEETING

AND CONGRESSES CALENDER (2008-2009)

Annual Meeting of the Hungarian Society of Cardiology

Euro PCR 2008

American Society of Hypertension 23rd Annual Scientific

Meeting and Exposition

Advanced Cardiac Life Support

XVI World Congress of Cardiology

Cardiology Essentials and Case Studies

6th Euro CMR 2008

2nd Annual Sights and Sounds of Echocardiography in the

Heart of the Big Apple

Annual meeting of the Working Group on Myocardial Function - “The influence of specific risk factors

on myocardial function. “

Cardiovascular CT at Concord

Advanced Cardiac Life Support: 2 day

16th Annual Congress of the Czech Society of Cardiology

Title City Start Date End Date

Balatonfüred,

Hungary

Barcelona,

Spain

New Orleans,

United States

Tampa, FL,

United States

Buenos Aires,

Argentina

Civitavecchia, Italy

Lisbon, Potugal

New York,

United States

Anacapri, Italy

Sydney, NSW,

Australia

Tampa, FL,

United States

Brno

Czech

7 May 2008

13 May 2008

13 May 2008

15 May 2008

18 May 2008

21 May 2008

22 May 2008

22 May 2008

23 May 2008

23 May 2008

23 May 2008

24 May 2008

10 May 2008

16 May 2008

17 May 2008

15 May 2008

21 May 2008

2 June 2008

24 May 2008

25 May 2008

25 May 2008

25 May 2008

24 May 2008

27 May 2008

TEHRAN HEART CENTER


IV International Symposium of Hypertension HTA 2008 and II

International WorkShop of Vascular Risk

The 2nd Asia-Pacific Congress of Pediatric Cardiology and

Cardiac Surgery

Annual Congress of the Swiss Society of Cardiology

Annual Meeting of the Austrian Society of Cardiology

European Section Meeting of the International Society for

Heart Research

Emory Symposium on Coronary Atherosclerosis (ESCAPE)

Annual Meeting of the Norwegian Society of Cardiology

Certification Examination for Competency in Cardiac Rhythm

Device Therapy for the Physician Preparation Course

Cardiovascular & Neurovascular Emergencies:

Optimal Diagnostic & Treatment Strategies

3C, Curso Cardiovascular de Caracas

XXXIX Annual Congress of the Italian Association of Hospital

Cardiologists (ANMCO)

Annual Meeting of the British Cardiovascular Society

Cardiovascular Imaging: SPECT, PET & CT

Duke Cardiovascular Research Symposium

18th International Symposium on Adult Congenital

Heart Disease 2008

Advanced Cardiac Life Support: 2 day

The New Orleans Conference: Practices in Cardiac Surgery and

Extracorporeal Technologies

16th Annual Meeting of the Alpe Adria Association

of Cardiology

2nd Annual Pulmonary Hypertension Symposium

Innovations in Treatment of Cardiac Structural Disease: The

Mediterranean Meeting

The Annual Scientific Sessions of the American Society of

Echocardiography - ASE 2008

Ultrasound Techniques in Vascular Emergencies / 5°corso di

Ecografia Vascolare in Emergenza

Santa Clara, Cuba

Jeju Island, Korea,

Berne, Switzerland

Salzburg, Austria

Athens, Greece

Amelia Island,

United States

Bergen, Norway

Dallas, TX,

United States

Washington,

United States

Caracas, Venezuela

Firenze, Italy

Manchester, UK

New Haven,

United States

Durham, NC,

United States

Toronto, Canada

Keywest, FL,

United States

New Orleans,

United States

Portoroz, Slovenia

Westport, CT,

United States

Pittsburgh,

United States

Toronto, Canada

Florence, Italy

26 May 2008

27 May 2008

28 May 2008

28 May 2008

28 May 2008

28 May 2008

29 May 2008

30 May 2008

30 May 2008

30 May 2008

30 May 2008

2 June 2008

3 June 2008

3 June 2008

4 June 2008

4 June 2008

5 June 2008

5 June 2008

6 June 2008

6 June 2008

7 June 2008

9 June 2008

29 May 2008

30 May 2008

30 May 2008

31 May 2008

31 May 2008

28 June 2008

31 May 2008

1 June 2008

30 May 2008

31 May 2008

2 June 2008

5 June 2008

3 June 2008

6 June 2008

7 June 2008

5 June 2008

7 June 2008

7 June 2008

6 June 2008

7 June 2008

11 June 2008

12 June 2008


242


5th Tunisian-European Congress on Cardiology Practice (Les 5 èmes Journées Tuniso Européennes de Cardiologie Pra-

tique) pratique

Cardiovascular Diseases Symposium

European Meeting on Hypertension 2008

Heart Failure 2008 Congress

CARDIOSTIM - 16th world congress in Cardiac

Electrophysiology and Cardiac Techniques

9th International Fetal Cardiology Symposium

10th National Congress on Cardiovascular Update

Current Topics in Noninvasive Cardiovascular Imaging

H.E.A.R.T UK 22nd Annual Conference

4th Asian Interventional Cardiovascular Therapeutics

ICI - Imaging in Cardiovascular Interventions

20th International Congress on Thrombosis

CSI - 11th International Congress Congenital and

Structural Interventions

14th Annual Scientific Session of the Society of

Geriatric Cardiology

The 1st World Congress on Controversies in Cardiovascular

Disease Diagnosis, Treatment and Interventions (C-Care)

14th World Congress on Heart Disease, International Academy

of Cardiology Annual Scientific Sessions 2008

Heart Failure 2008

2nd International Congress of Egyptian Cerebro-Cardio-Vascu-lar Association (ECCVA) in Collaboration with

World Stroke Organization (WSO)

14th World Congress on Heart Disease International Academy of

Cardiology Annual Scientific Sessions 2008

Cardiology & Infectious Disease

Success with Failure: New Strategies for the Evaluation and

Treatment of Congestive Heart Failure

22nd Annual Echocardiographic Symposium at Vail

Hammam, Tunisia

Iowa City, IA,

United States

Berlin, Germany

Milan, Italy

Nice, France

Nice, France

Tehran, Iran

San Diego, CA,

United States

Hatfield, UK

Bangkok, Thailand

Frankfurt, Germany

Athens, Greece

Frankfurt, Germany

Washington,

United States

Berlin, Germany

Toronto, Canada

Amelia Island,

United States

Alexandria, Egypt

Toronto, ON, Canada

Oslo, Norway

Whistler, BC, Canada

Vail, CO,

United States

12 June 2008

13 June 2008

14 June 2008

14 June 2008

18 June 2008

19 June 2008

21 June 2008

22 June 2008

25 June 2008

25 June 2008

28 June 2008

25 June 2008

26 June 2008

27 June 2008

3 July 2008

16 July 2008

17 July 2008

23 July 2008

26 July 2008

28 July 2008

3 August 2008

11 August 2008

14 June 2008

13 June 2008

19 June 2008

17 June 2008

21 June 2008

21 June 2008

25 June 2008

27 June 2008

27 June 2008

27 June 2008

28 June 2008

28 June 2008

28 June 2008

29 June 2008

6 July 2008

29 July 2008

20 July 2008

25 July 2008

29 July 2008

9 August 2008

6 August 2008

14 August 2008


TEHRAN HEART CENTER


17th International Cardiovascular Symposium

Echocardiography: The Fundamentals

The Baltic Summer School 2008: Basic and Clinical Aspects of

Cardiac Arrhythmias

ESC Congress 2008

Controversies and Advances in the Treatment of

Cardiovascular Disease: The Eighth in the Series

Intraoperative Echocardiography in the 21st Century

19th Annual Coronary Interventions

Mayo Cardiovascular Review Course for Cardiology

Boards and Recertification

VIVA 2008 (Vascular InterVentional Advances) ? The National

Education Course for Vascular Intervention and Medicine

12th International Congress of the Polish Cardiac Society

National Congress of the Latvian Society of Cardiology

6th Advanced Symposium on Congenital Heart

Disease in the Adult

AICT 2008: Athens Interventional Cardiovascular Therapeutics

3rd Georgian Congress of Cardiology

XIII Annual Congress of the Slovak Society of Cardiology

National Congress of the Society of Cardiology

of the Russian Federation

Annual Meeting of the Spanish Society of Cardiology 2008 (El

Congreso de las Enfermedades Cardiovasculares SEC 2008)

Irish Cardiac Society Annual Scientific Meeting 2008

Rheumatology & Cardiovascular Medicine

Venice, Italy

Philadelphia,

United States

Copenhagen,

Denmark

Munich, Germany

Beverly Hills,

United States

Atlanta, GA,

United States

San Diego, CA,

United States

Rochester,

United States

Las Vegas,

United States

Poznan, Spain

Riga, Latvia

Thessaloniki, Greece

Athens, Greece

Tbilisi, Georgia

Bratislave, Slovakia

Moscow, Russia

Bilbao, Spain

Galway, Ireland

Istanbul, Turkey

12 August 2008

13 August 2008

17 August 2008

30 August 2008

4 September 2008

4 September 2008

7 September 2008

20 September 2008

22 September 2008

25 September 2008

26 September 2008

26 September 2008

26 September2008

30 September 2008

5 October 2008

7 October 2008

9 October 2008

10 October 2008

11 October 2008

14 August 2008

15 August 2008

29 August 2008

3 September 2008

5 September 2008

7 September 2008

19 September 2008

25 September 2008

26 September 2008

27 September 2008

27 September 2008

27 September 2008

27 September 2008

1 October 2008

7 October 2008

9 October 2008

11 October 2008

11 October 2008

25 October 2008


244


Information for AuthorsThe first three consecutive issues of ''The Journal of Tehran University Heart Center'' were published under the title of ''The Journal of Tehran Heart Cen-

ter'' with ISSN: 1735-5370. From the fourth issue onward, however, the journal has been entitled ''The Journal of Tehran University Heart Center'' with

ISSN:1735-8620.

“The Journal of Tehran University Heart Center” aims to publish the highest quality material, both clinical and scientific, on all aspects of Cardiovascular

Medicine. It includes articles related to research findings, technical evaluations, and reviews. In addition, it provides a forum for the exchange of informa-

tion on all aspects of Cardiovascular Medicine, including educational issues. “The journal of Tehran University Heart Center” is an international, English

language, peer reviewed journal concerned with Cardiovascular Medicine. It is an official journal of the Tehran University Heart Center and is published

quarterly. Papers submitted to this journal which do not adhere to the Instructions for Authors will be returned for appropriate revision to be in line with the

Instructions for Authors. They may then be resubmitted. Submission of an article implies that the work described has not been published previously (except

in the form of an abstract or as part of a published lecture or academic thesis), that it is not under consideration for publication elsewhere , that its publica-

tion is approved by all Authors and tacitly or explicitly by the responsible authorities where the work was carried out, and that, if accepted , it will not be

published elsewhere in the same form, in English or in any other language, without the written consent of the publisher. .

Four double spaced copies on 8 1/2 × 11 in. paper should be sent to:

Dr. A. Karimi,

Editor in Chief,

“The Journal of Tehran University Heart Center”,

Tehran Heart Center,

North Kargar Street,

Tehran, Iran

1411713138

Photocopies or good reproductions of illustrations are acceptable only on the spare copies. Included also should be a set of the electronic files of the manu-

script on floppy – disk or CD-ROM. For preparation of electronic files, see the instructions herein below.

Also, manuscripts can be submitted electronically via the journal’s website: http://jthc.tums.ac.ir. On-line submission allows the manuscript to be handled in

electronic forms throughout the review process.

All manuscripts correctly submitted to will first be reviewed by the Editors. Some manuscripts will be returned to authors at this stage if the paper is deemed

inappropriate for publication in “The Journal of Tehran University Heart Center”, if the paper does not meet submission requirements, or if the paper is not

deemed to have a sufficiently high priority. All papers considered suitable by the Editors to progress futher in the review process will undergo appropriate

peer review and all papers provisionally accepted for publication will undergo a detailed statistical review.

All submitted manuscripts must not exceed 5000 words, including References, Figure Legends and Tables. The number of Tables, Figures and References

The Journal of Tehran University Heart Center” accepts the following categories of articles:”

Guest Editorial

Original Article

Clinical and pre-clinical papers based on either normal subjects or patients and the result of cardiovascular pre-clinical research will be

Considered for publication provided they have an obvious clinical relevance.

Brief communication

Case report

Review Article

“The Journal of Tehran University Heart Center” publishes a limited number of scholarly, comprehensive reviews whose aims are to summarize

and critically evaluate research in the field addressed and identify future implications. Reviews should not exceed 5000 words.

Letter to editor

Letters to the editor must not exceed 500 words and should focus on a specific article published in “The Journal of Tehran University Heart Center” within

the preceding 12 weeks. No original data may be included. Authors will receive pre-publication proofs, and the authors of the article cited invited to reply.

Scope of the journal

Article Categories

Submission of manuscripts

Review of manuscripts Review of manuscripts

Preparation of manuscripts

TEHRAN HEART CENTER


Original articles should be divided into the following sections: (1) Title page, (2) Abstract and Keywords, (3) Introduction, (4) Methods, (5) Results, (6)

Discussion, (7) Conclusion, (8) Acknowledgements, (9) References, (10) Figure legends, (11) Tables, (12) Figures.

Prepare your manuscript text using a word processing package. Submissions of text in the form of PDF files are not permitted. Manuscripts should be double

–spaced, including text, tables, legends and references. Number each page. Please avoid footnotes; use instead, and as sparingly as possible, parenthesis

within brackets. Enter text in the style and order of the Journal. Type references in the correct order and style of the journal. Type unjustified, without hy-

phenation, except for compound words. Type headings in the style of the journal. Use the TAB key once for paragraph indents. Where possible use Times

New Roman for the text font and Symbol for the Greek and special characters. Use the word processing formatting features to indicate Bold, Italic, Greek,

Maths, Superscript and subscript characters. Clearly identify unusual symbols and Greek letters. Differentiate between the letter o and zero, and the letters I

and i and the number 1. Mark the approximate position of each figure and table. Check the final copy of your paper carefully, as any spelling mistakes and

errors may be translated into the typeset version.

The title page should include the following: (1) the title, (2) the name (s) of authors and their highest degree ( no more than 12 authors are acceptable), (3)

the institution (s) where work was performed, (4) institution, and location of all authors, (5) the address, telephone number, fax number and e-mail address

of the corresponding author.

All abstracts may not contain more than 250 words and should also be submitted as a separate file. The abstract should be formatted with the following

heading: (1) Background, (2) Methods, (3) Results, (4) Conclusion.

A maximum of six Keywords may be submitted.

The review process will not begin until all figures are received. Figures should be limited to the number necessary for clarity and must not duplicate data

given in tables or in the text. They must be suitable for high quality reproduction and should be submitted in the desired final printed size so that reduction

can be avoided. Figures should be no larger than 125 (height)×180 (width) mm (5×7 inches) and should be submitted in a separate file from that of the

manuscript.

Figures should be saved in TIFF format at a resolution of at least 300 pixels per inch at the final printed size for colour figures and photographs, and 1200

pixels per inch for black and white line drawings. Although some other formats can be translated into TIFF format by the publisher, the conversion may alter

the tones, resolution and contrast of the image. Digital colour art should be submitted in CMYK rather than RGB format, as the printing process requires

colours to be separated into CMYK and this conversion can alter the intensity and brightness of colours. Therefore authors should be satisfied with the

colours in CMYK (both on screen and when printed) before submission. Please also keep in mind that colours can appear differently on different screens

and printers. Failure to follow these guides could result in complications and delays.

Photographs: Photographs should be of sufficiently high quality with respect to detail, contrast and fineness of grain to withstand the inevitable loss of

contrast and detail inherent in the printing process. Please indicate the magnification by a rule on the photograph. Colour figures: There is a special charge

for the inclusion of colour figures. Figure legends: These should be on a separate, numbered manuscript sheet grouped under the heading “Legends” on a

separate sheet of the manuscript after the References. Define all symbols and abbreviations used in the figure. All abbreviations and should be redefined in

the legend.

Section of the manuscripts

General format

Title page

Abstract

Figures

should be appropriate to the manuscript content and should not be excessive. Authors should comply with the manuscript formatting and the ethical conven-

tions of the “Uniform Requirements for Manuscripts Submitted to Biomedical Journals” issued by the International Committee of Medical Journal Editors

( http://www.icmje.org ).

Style and spelling

Authors whose first language is not English are requested to have their manuscripts checked carefully before submission. This will help expedite the review

process and avoid confusion. Abbreviations of standard SI units of measurement only should be used.

Declaration of Helsinki

The Authors should state that their study complies with the Declaration of Helsinki that the locally appointed ethics committee has approved the research

protocol and that informed consent has been obtained from the subjects (or their guardians).

Clinical trials

Authors should comply with the clinical trial registration statement from the ICMJE. More information can be found at www.icmje.org. Clinical trial reports

should also comply with the Consolidated Standards of Reporting Trials (CONSORT) and include a flow diagram presenting the enrollment, intervention

allocation, follow-up, and data analysis with number of subjects for each (www.consort-statement.org). Please also refer specifically to the CONSORT

Checklist of items to include when reporting a randomized clinical trial.

246


Tables should be typed with double spacing, but minimizing redundant space and each should be placed on a separate sheet. Tables should be submitted,

wherever possible, in portraits, as opposed to landscape, layout. Each Table should be numbered in sequence using Arabic numerals. Tables should also have

a title above and an explanatory footnote below. All abbreviations and should be redefined in the Footnote.

All sources of funding and support, and substantive contributions of individuals, should be noted in the Acknowledgements, positioned before the list of

references.

Number references sequentially and use Arabic number in superscript to cite the reference in the text. All references should be compiled at the end of the

article in the Vancouver style. Complete information should be given for each reference including the title of the article, abbreviated journal title and page

numbers. All authors should be listed. Personal communications; manuscripts in preparation and other unpublished data should not be cited in the reference

list but may be mentioned in parentheses in the text. Authors should get permission from the source to cite unpublished data. Titles of journals should be

abbreviated in accordance with Index Medicus (see list printed annually in the January issue of Index Medicus). If a journal is not listed in Index Medicus

then its name should be written out in full.

Article citation example:

Journal citation example: 1. Schroeder S, Baumbach A, Mahrholdt H. The impact of untreated coronary dissections on the acute and long-term outcome

after intravascular ultrasound guided PTCA. Eur Heart J 2000;21:137-145.

Chapter citation example: 2. Nichols WW, O’Rourke MF. Aging, high blood pressure and disease in humans. In: Arnold E, ed. McDonald’s Blood Flow

in Arteries: Theoretical, Experimental and Clinical Principles. 3rd ed. London/Melbourne/Auckland: Lea and Febiger; 1990. p. 398-420.

Webpage citation example: 3. Panteghini M. Recommendations on use of biochemical markers in acute coronary syndrome: IFCC proposals. eJIFCC 14.

http://www.ifcc.org/ejifcc/vol14no2/1402062003014n.htm (28 May 2004). Where the date in parenthesis refers to the access date.

All manuscripts selected for publication will be reviewed for the appropriateness and accuracy of the statistical methods used and the interpretation of statis-

tical results. All papers submitted should provide in their Methods section a subsection detailing the statistical methods , including the specific method used

to summarize the data , the methods used to test their hypothesis testing and (if any) the level of significance used for hypothesis testing.

At submission, the editors require authors to disclose any financial association that might pose a conflict of interest in connection with the submitted article.

All sources of funding for the work should be acknowledged in a footnote on the title page and in the Acknowledgements within the manuscript, as should

all the institutional affiliations of the authors (including corporate appointments). Other kinds of associations, such as consultancies, stock ownership or

other equity interest or patent – licensing arrangements should be disclosed to the editors in the cover letter at the time of the of submission. If no conflict

of interest exists, please state this in the cover letter.

Page proofs will be sent to the corresponding author. Please provide an e-mail address to enable page proofs to be sent as PDF files via e-mail. These should

be checked thoroughly for any possible changes or typographic errors. Significant alterations instigated at this stage by the author will be charged to the

author. It is the intention of the Editor to review, correct and publish your article as quickly as possible. To achieve this it is important that all of your

corrections are returned to us in one all – inclusive mail or fax. Subsequent additional corrections will not be possible, so please ensure that your first com-

munication is complete.

Tables

Acknowledgements

Reference format

Statistics

Proofs

TEHRAN HEART CENTER

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Hospital or Organization:

Date of subscription:

Full mail address:

P.O.BOX: Tell: Fax:

E-mail:

The annual Subscription and postage rate: 100/000 Rials for Iran and US $ 100 including postage for other countries.

Please liquidate the total amount of Subscription and postal charges into:

Bank: Refah Branch Code: 1232 Account: Tehran Heart Center Account Number: 200001.28

and send the original Bank slip along with Duly completed form of Subscription to the following address:


North Karegar Street,

Tehran, Iran : 1411713138

88029702 21 +98

FAX: +98 21 88029702

E-mail: [email protected]

TEHRAN HEART CENTER

Subscription Form

The Journal of Tehran University Heart CenterNew Subscription: Continuation of Subscription:

Surname:

First Name:

Hospital or Organization:

Date of subscription:

Full mail address:

P.O.BOX: Tell: Fax:

E-mail:

The annual Subscription and postage rate: 100/000 Rials for Iran and US $ 100 including postage for other countries.

Please liquidate the total amount of Subscription and postal charges into:

Bank: Refah Branch Code: 1232 Account: Tehran Heart Center Account Number: 200001.28

and send the original Bank slip along with Duly completed form of Subscription to the following address:


North Karegar Street,

Tehran, Iran : 1411713138

88029702 21 +98

FAX: +98 21 88029702

E-mail: [email protected]

TEHRAN HEART CENTER

248


TEHRAN HEART CENTER


250


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