AHA/ACCF/ESC scientific statement
The role of endomyocardial biopsy in the management
of cardiovascular disease
A Scientific Statement from the American Heart Association, the
American College of Cardiology, and the European Society of
Cardiology
Endorsed by the Heart Failure Society of America and the Heart
Failure Association of the European Society of Cardiology
Leslie T. Cooper, MD, FAHA, FACC; Kenneth L. Baughman, MD, FAHA, FACC; Arthur M. Feldman,
MD, PhD, FAHA, FACC; Andrea Frustaci, MD; Mariell Jessup, MD, FAHA, FACC; Uwe Kuhl, MD;
Glenn N. Levine, MD, FAHA, FACC; Jagat Narula, MD, PhD, FAHA; Randall C. Starling, MD, MPH;
Jeffrey Towbin, MD, FAHA, FACC; and Renu Virmani, MD, FACC
Online publish-ahead-of-print 24 October 2007
KEYWORDS
Scientific statements; Biopsy; Transplantation; Heart failure; Cardiomyopathy; Myocarditis
The role of endomyocardial biopsy (EMB) in the diagnosis
and treatment of adult and pediatric cardiovascular
disease remains controversial, and the practice varies
widely even among cardiovascular centers of excellence. A
need for EMB exists because specific myocardial disorders
that have unique prognoses and treatment are seldom
diagnosed by noninvasive testing.1 Informed clinical decision
making that weighs the risks of EMB against the incremental
diagnostic, prognostic, and therapeutic value of the procedure
is especially challenging for nonspecialists because the rel-
evant published literature is usually cited according to specific
cardiac diseases,which are only diagnosed after EMB.To define
The American Heart Association makes every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside relationship or a
personal, professional, or business interest of a member of the writing panel. Specifically, all members of the writing group are required to complete and submit a
Disclosure Questionnaire showing all such relationships that might be perceived as real or potential conflicts of interest.
This document was approved by the American Heart Association Science Advisory and Coordinating Committee on July 2, 2007; the American College of
Cardiology Foundation Board of Trustees on May 21, 2007; and the European Society of Cardiology Committee for Practice Guidelines on April 3, 2007.
When this document is cited, the American Heart Association, the American College of Cardiology Foundation, and the European Society of Cardiology request
that the following citation format be used: Cooper LT, Baughman K, Feldman AM, Frustaci A, Jessup M, Kuhl U, Levine GN, Narula J, Starling RC, Towbin J, Virmani R.
The role of endomyocardial biopsy in themanagement of cardiovascular disease: a scientific statement from the American Heart Association, the American College of
Cardiology, and the European Society of Cardiology. Eur Heart J 2007;28:3076–3093. doi:10.1093/eurheartj/ehm456.
This article has been copublished in the Journal of the American College of Cardiology and Circulation.
Copies: This document is available on the World Wide Web sites of the American Heart Association (my.americanheart.org), the American College of Cardiology
(www.acc.org), and the European Society of Cardiology (www.escardio.org). Bulk reprints are available from Oxford University Press by contacting Special Sales
(special.sales@oxfordjournals.org), Journals Division, Oxford University Press, Great Clarendon Street, Oxford, OX2 6DP, UK. Phone þ44 (0) 1865 353827, Fax
þ44 (0) 1865 353774, Work Mobile þ44 07841322925. A single reprint is also available by calling 800-242-8721 (US only) or writing to the American Heart Associ-
ation, Public Information, 7272 Greenville Ave, Dallas, TX 75231-4596. Ask for reprint No. 71-0421. To purchase Circulation reprints, call 843-216-2533 or e-mail
kelle.ramsay@wolterskluwer.com.
Permissions: Multiple copies, modification, alteration, enhancement, and/or distribution of this document are not permitted without the express permission of
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http://www.oxfordjournals.org/access_purchase/rights_permissions.html) or visit the Web site located at http://www.americanheart.org/presenter.
jhtml?identifier=4431.
The content of this scientific statement has been published for personal and educational use only. No commercial use is authorized. No part of this document
may be translated or reproduced in any form without written permission from the ESC. Permission can be obtained upon submission of a written request to Oxford
University Press, the publisher of the European Heart Journal and the party authorized to handle such permissions on behalf of the ESC.
Disclaimer. The scientific statement represents the views of the ESC, which were arrived at after careful consideration of the available evidence at the time
they were written. Health professionals are encouraged to take them fully into account when exercising their clinical judgement. The document does not,
however, override the individual responsibility of health professionals to make appropriate decisions in the circumstances of the individual patients, in consul-
tation with that patient, and where appropriate and necessary the patient’s guardian or carer. It is also the health professional’s responsibility to verify the rules
and regulations applicable to drugs and devices at the time of prescription.
& The European Society of Cardiology, the American Heart Association, Inc, and the American College of Cardiology Foundation 2007.
All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org
European Heart Journal (2007) 28, 3076–3093
doi:10.1093/eurheartj/ehm456
the current role of EMB in the management of cardiovascular
disease, a multidisciplinary group of experts in cardiomyopa-
thies and cardiovascular pathologywas convened by the Amer-
ican Heart Association (AHA), the American College of
Cardiology (ACC), and the European Society of Cardiology
(ESC). The present Writing Group was charged with reviewing
the published literature on the role of EMB in cardiovascular
diseases, summarizing this information, andmaking useful rec-
ommendations for clinical practice with classifications of rec-
ommendations and levels of evidence.
The Writing Group identified 14 clinical scenarios in which
the incremental diagnostic, prognostic, and therapeutic
value of EMB could be estimated and compared with the pro-
cedural risks. The recommendations contained in the present
joint Scientific Statement are derived from a comprehensive
review of the published literature on specific cardiomyopa-
thies, arrhythmias, and cardiac tumors and are categorized
according to presenting clinical syndrome rather than patho-
logically confirmed disease. The ultimate intent of this docu-
ment is to provide an understanding of the range of
acceptable approaches for the use of EMB while recognizing
that individual patient care decisions depend on factors not
well reflected in the published literature, such as local avail-
ability of specialized facilities, cardiovascular pathology
expertise, andoperator experience. TheuseofEMB in thepost-
transplantation setting is beyond the scope of this document.
This ScientificStatementwasapproved forpublicationby the
governing bodies of the American Heart Association, the Amer-
icanCollege of Cardiology, and theEuropeanSociety of Cardiol-
ogy and has been officially endorsed by the Heart Failure
Society of America and the Heart Failure Association of the
European Society of Cardiology.
The classifications of recommendations used in this docu-
ment are
† Class I: conditions for which there is evidence or there is
general agreement that a given procedure is beneficial,
useful, and effective;
† Class II: conditions for which there is conflicting evidence
and/or a divergence of opinion about the usefulness/
efficacy of a procedure or treatment;
† Class IIa: conditions for which the weight of evidence/
opinion is in favor of usefulness/efficacy;
† Class IIb: conditions for which usefulness/efficacy is less
well established by evidence/opinion; and
† Class III: conditions for which there is evidence and/or
general agreement that a procedure/treatment is not
useful/effective and in some cases may be harmful.
The levels of evidence are
† Level A (highest): multiple randomized clinical trials;
† Level B (intermediate): limited number of randomized
trials, nonrandomized studies, and registries; and
† Level C (lowest): primarily expert consensus.
Technique and risks of EMB
The first nonsurgical techniques for heart biopsy were
reported in 1958.2 In the 1960s the safety of heart biopsy
improved, with vascular access through the right external
or internal jugular vein, sampling of the right interventricu-
lar septum, and designation of the heart borders by right
heart catheterization before biopsy.3 Sakakibara and
Konno4 introduced the use of a flexible bioptome with shar-
pened cusps that allowed EMB by a pinching as opposed to a
cutting technique. Caves et al.5 modified the Konno biopsy
forceps (Stanford Caves-Shulz bioptome) to allow percuta-
neous biopsies through the right internal jugular vein with
only local anesthesia and rapid tissue removal. The reusable
Stanford-Caves bioptome and its subsequent modifications
became the standard device for EMB for approximately 2
decades.6,7 Single-use bioptomes and sheaths allow access
through the right and left jugular or subclavian veins, right
and left femoral veins, and right and left femoral arteries
and may be associated with lower risk of pyrogen reaction
and transmission of infection than reusable bioptomes.
The right internal jugular vein is themost common percuta-
neous access site for right ventricular EMB in the United
States. In Germany and Italy, the femoral vein is commonly
used for percutaneous access.8 Sonographic techniques to
identify the location, size, and respirophasic variation in
size of the internal jugular vein decrease the duration of the
procedure and complications.9,10 Monitoring should include
electrocardiographic rhythm, blood pressure, and pulse oxi-
metry. The subclavian vein also may be used occasionally.
The femoral artery may be used as a percutaneous access
site for left ventricular biopsy.11,12 This approach requires
insertion of a preformed sheath to maintain arterial
patency. All arterial sheaths must be maintained under con-
stant pressurized infusion to avoid embolic events. Aspirin or
other antiplatelet agents may be used in addition to heparin
during left heart biopsy procedures to decrease the risk of
systemic embolization. No comparative studies exist on
which to base a recommendation for left versus right ventri-
cular biopsy; however, left ventricular biopsy has been used
in case series to define cardiomyopathic processes limited to
the left ventricle.13
EMB usually is performed safely under fluoroscopic gui-
dance. Fluoroscopy is generally better than 2-dimensional
echocardiography to guide EMB because it provides more
information to the operator about the course of the bioptome
and site of biopsy.14,15 The echocardiographic technique
without fluoroscopy has been used primarily to biopsy intra-
cardiac masses. Some operators use fluoroscopy and echocar-
diography in combination to enhance entry into the right
ventricle and direction of the bioptome. Noninvasive com-
puted tomography (CT) or cardiac magnetic resonance
(CMR) imaging may be of value in patients scheduled for
EMB. CTscanning may be used to assess the angle of the intra-
ventricular septum relative to the superior vena cava or
inferior vena cava. Knowledge of this angle may lessen the
risk of inadvertent biopsy of the right ventricular free wall
during a fluoroscopically directed biopsy. In addition, CMR
detection of a focal disease process may identify the area
of the left or right ventricle that would be most likely to
demonstrate the underlying pathological process.13,16 Three-
dimensional echocardiography may enhance visualization and
reduce the reliance on radiographic imaging in the future.17
The risks of EMB may be divided into those that are acute
and those that are delayed. Immediate risks of biopsy
include perforation with pericardial tamponade, ventricular
or supraventricular arrhythmias, heart block, pneu-
mothorax, puncture of central arteries, pulmonary emboli-
zation, nerve paresis, venous hematoma, damage to the
tricuspid valve, and creation of arterial venous fistula
AHA/ACCF/ESC scientific statement 3077
within the heart. The risks of EMB likely vary with the
experience of the operator, clinical status of the patient,
presence or absence of left bundle-branch block, access
site, and possibly bioptome. The use of a long sheath that
crosses the tricuspid valve may decrease the risk of
bioptome-induced tricuspid valve trauma. Delayed compli-
cations include access site bleeding, damage to the tricuspid
valve, pericardial tamponade, and deep venous thrombosis.
Most complications are known from case reports, and there-
fore the precise frequency of these events is not known.
The data on EMB risks are derived from several single-
center experiences and registries that have been reported
in the literature. Fowles andMason18 reported an overall com-
plication rate of ,1% in .4000 biopsies performed in trans-
plantation and cardiomyopathy patients, including 4 with
tamponade (0.14%), 3 pneumothorax, 3 atrial fibrillation, 1
ventricular arrhythmia, and 3 focal neurological compli-
cations.18 Olsen, in an unpublished series referenced by
Fowles and Mason,18 reported an overall complication rate
of 1.55% in 3097 cardiomyopathy patients biopsied in
Europe. Sekiguchi and Take19 reported a 1.17% complication
rate in a worldwide questionnaire of 6739 patients, including
perforation in 28 patients (0.42%) and death in 2 patients
(0.03%). Deckers et al.20 prospectively recorded compli-
cations from 546 consecutive right heart biopsy procedures
in patients with new-onset unexplained cardiomyopathy.
These are the most reliable data in the literature;20 the com-
plication rates of sheath insertion and biopsy procedure were
reported as 2.7% and 3.3%, as noted in Table 1.
The death rate associated with EMB is a result of perfor-
ation with pericardial tamponade.20 Patients with increased
right ventricular systolic pressures, bleeding diathesis,
recent receipt of heparin, or right ventricular enlargement
seem to be at higher risk. Echocardiography is used to
confirm myocardial perforation and should be done in any
patient in whom the operator believes perforation may
have occurred, even without cardiovascular collapse,
before central venous access is removed or the patient
leaves the catheterization laboratory. Immediate pericardio-
centesis and the capability to surgically evacuate the pericar-
dial space should be available at centers that perform EMB.
Careful attention to technique can minimize procedural
risks. The risk of pneumothorax can be minimized by
taking a relatively high internal jugular approach and avoid-
ing the immediate supra-clavicular location. Patients with
preexistent left bundle-branch block may develop complete
heart block when any catheter is placed into the right ven-
tricle and presses against the intraventricular septum.20 If
this occurs, the bioptome and/or sheath must be removed,
and the patient may require temporary ventricular pacing.
Rarely, the heart block may be permanent. Lidocaine in
the jugular venous and carotid sheath may result in Horner
syndrome, vocal paresis, and, infrequently, weakness of
the diaphragm. These complications last only for the dur-
ation of the lidocaine effect, unless permanent damage
has been done by trauma from the needle itself.
The risks of EMB depend on the clinical state of the
patient, the experience of the operator, and the availability
of expertise in cardiac pathology. If a patient with an indi-
cation for EMB presents at a medical center where expertise
in EMB and cardiac pathology is unavailable, transfer of the
patient to a medical center with such experience should be
seriously considered. Additionally, patients with cardiogenic
shock or unstable ventricular arrhythmias may require the
care of specialists in medical and surgical management of
heart failure, including ventricular assist device placement
and potentially heart transplantation.
Analysis of EMB tissue
EMB processing
Samples should be obtained from .1 region of the right ven-
tricular septum. The number of samples obtained should
range from 5 to 10, depending on the studies to be per-
formed, and each sample should be 1 to 2 mm3 in size.
The sample must be handled carefully to minimize artifacts
and transferred from the bioptome to fixative (10% neutral
buffered formalin) by use of a sterile needle and not with
forceps.21,22 The fixative should be at room temperature
to prevent contraction band artifacts.23
The clinical reason for the biopsy determines how many
samples are removed and how they are fixed. In general,
at least 4 to 5 samples are submitted for light microscopic
examination, but more may be submitted for transmission
electron microscopy if the clinical question is anthracycline
cardiotoxicity.22,24,25 Transmission electron microscopy may
also be helpful for the assessment of suspected infiltrative
disorders such as amyloidosis, glycogen storage diseases,
lysosomal storage diseases, and occasionally viral myocarditis.
For transmission electron microscopy, pieces are fixed in 4%
glutaraldehyde at room temperature at the time of EMB.22
Oneormorepiecesmaybe frozen formolecular studies, immu-
nofluorescence, or immunohistochemistry that may be
required for suspected myocarditis, storage diseases, tumor
typing, amyloid classification, or viral genome analysis.26
Pieces of myocardium can be snap-frozen in OCT-embedding
medium and stored at 2808F for immunohistochemical or
liquid nitrogen molecular studies. Flash-freezing is suitable
for culture, polymerase chain reaction (PCR), or reverse tran-
scriptasePCR (rtPCR) for the identificationof viruses, butflash-
freezing is not ideal for standard histological preparation
because of ice crystal artifacts and cell culture.
Light microscopic examination and stains
For routine light microscopy examination, EMB tissue is
embedded in paraffin, and serial sections are obtained and
sequentially numbered.23 For suspected myocarditis, many
laboratories will stain every third piece for hematoxylin
Table 1 Risks associated with endomyocardial biopsy in
546 procedures
Overall 33 complications (6%)
Sheath insertion 15 (2.7%)
12 (2.0%) arterial puncture during local anesthesia
2 (0.4%) vasovagal reaction
1 (0.2%) prolonged venous oozing after sheath removal
Biopsy procedure 18 (3.3%)
6 (1.1%) arrhythmia
5 (1.0%) conduction abnormalities
4 (0.7%) possible perforation (pain)
3 (0.5%) definite perforation (pericardial fluid)
2 of 3 patients with definite perforation died
Data derived from Deckers et al.20
AHA/ACCF/ESC scientific statement3078
and eosin and the middle 2 pieces for Movat or elastic tri-
chrome stain to visualize collagen and elastic tissue. Many
laboratories also routinely stain 1 slide for iron on men
and all postmenopausal women, regardless of the indication
for EMB.23 Congo red staining may be performed on 10- to
15-mm sections to rule out amyloidosis. The remaining
slides are usually preserved for immunohistochemistry.
Molecular biological detection of viral genomes
Recent advances in quantitative (qPCR) and qualitative
(nested PCR) molecular techniques can detect fewer than
10 gene copies of viral pathogens in the myocardium. These
highly sensitive techniques provide both challenges and
opportunities. The clinical impact on prognosis and treatment
largely depends on establishing a standardized set of diagnos-
tic methods. PCR analysis for viral genomes can yield false
results if
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