Professional Documents
Culture Documents
doi:10.1093/eurheartj/ehm456
AHA/ACCF/ESC scientific statement
KEYWORDS
Scientific statements; Biopsy; Transplantation; Heart failure; Cardiomyopathy; Myocarditis
The role of endomyocardial biopsy (EMB) in the diagnosis diagnosed by noninvasive testing.1 Informed clinical decision
and treatment of adult and pediatric cardiovascular making that weighs the risks of EMB against the incremental
disease remains controversial, and the practice varies diagnostic, prognostic, and therapeutic value of the procedure
widely even among cardiovascular centers of excellence. A is especially challenging for nonspecialists because the rel-
need for EMB exists because specific myocardial disorders evant published literature is usually cited according to specific
that have unique prognoses and treatment are seldom 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 the management 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
the European Society of Cardiology or the American Heart Association. Please direct requests to journals.permissions@oxfordjournals.org (Web site located at
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
AHA/ACCF/ESC scientific statement 3077
the current role of EMB in the management of cardiovascular heart catheterization before biopsy.3 Sakakibara and
disease, a multidisciplinary group of experts in cardiomyopa- Konno4 introduced the use of a flexible bioptome with shar-
thies and cardiovascular pathology was convened by the Amer- pened cusps that allowed EMB by a pinching as opposed to a
ican Heart Association (AHA), the American College of cutting technique. Caves et al. 5 modified the Konno biopsy
Cardiology (ACC), and the European Society of Cardiology forceps (Stanford Caves-Shulz bioptome) to allow percuta-
(ESC). The present Writing Group was charged with reviewing neous biopsies through the right internal jugular vein with
the published literature on the role of EMB in cardiovascular only local anesthesia and rapid tissue removal. The reusable
diseases, summarizing this information, and making useful rec- Stanford-Caves bioptome and its subsequent modifications
ommendations for clinical practice with classifications of rec- became the standard device for EMB for approximately 2
ommendations and levels of evidence. decades.6,7 Single-use bioptomes and sheaths allow access
The Writing Group identified 14 clinical scenarios in which through the right and left jugular or subclavian veins, right
the incremental diagnostic, prognostic, and therapeutic and left femoral veins, and right and left femoral arteries
value of EMB could be estimated and compared with the pro- and may be associated with lower risk of pyrogen reaction
cedural risks. The recommendations contained in the present and transmission of infection than reusable bioptomes.
within the heart. The risks of EMB likely vary with the heart block when any catheter is placed into the right ven-
experience of the operator, clinical status of the patient, tricle and presses against the intraventricular septum.20 If
presence or absence of left bundle-branch block, access this occurs, the bioptome and/or sheath must be removed,
site, and possibly bioptome. The use of a long sheath that and the patient may require temporary ventricular pacing.
crosses the tricuspid valve may decrease the risk of Rarely, the heart block may be permanent. Lidocaine in
bioptome-induced tricuspid valve trauma. Delayed compli- the jugular venous and carotid sheath may result in Horner
cations include access site bleeding, damage to the tricuspid syndrome, vocal paresis, and, infrequently, weakness of
valve, pericardial tamponade, and deep venous thrombosis. the diaphragm. These complications last only for the dur-
Most complications are known from case reports, and there- ation of the lidocaine effect, unless permanent damage
fore the precise frequency of these events is not known. has been done by trauma from the needle itself.
The data on EMB risks are derived from several single- The risks of EMB depend on the clinical state of the
center experiences and registries that have been reported patient, the experience of the operator, and the availability
in the literature. Fowles and Mason18 reported an overall com- of expertise in cardiac pathology. If a patient with an indi-
plication rate of ,1% in .4000 biopsies performed in trans- cation for EMB presents at a medical center where expertise
and eosin and the middle 2 pieces for Movat or elastic tri- When should EMB be performed?
chrome stain to visualize collagen and elastic tissue. Many
laboratories also routinely stain 1 slide for iron on men Most publications on the use of EMB are only accessible through
and all postmenopausal women, regardless of the indication multiple literature searches by specific pathological diseases,
for EMB.23 Congo red staining may be performed on 10- to such as lymphocytic myocarditis or giant cell myocarditis
15-mm sections to rule out amyloidosis. The remaining (GCM). The Writing Group recognized that a major obstacle
slides are usually preserved for immunohistochemistry. to the clinical use of these data is that decisions to proceed
with EMB are made on the basis of clinical presentations, not
of pathological diagnoses, which are known only after the pro-
Molecular biological detection of viral genomes cedure. To create a set of clinically useful recommendations,
Recent advances in quantitative (qPCR) and qualitative the writing group members extracted and synthesized the
(nested PCR) molecular techniques can detect fewer than presenting scenarios from pathology-focused publications in
10 gene copies of viral pathogens in the myocardium. These which EMB was used to obtain tissue. The novel result of this
highly sensitive techniques provide both challenges and effort is a set of distinct clinical scenarios from which a practi-
in the randomized trials of acute myocarditis and cardiomyo- sensitivity of EMB for GCM is 80% to 85% in subjects who sub-
pathy.44,45 Therefore, there are too few data on immunosup- sequently die or undergo heart transplantation.52 In the
pressive treatment of fulminant myocarditis in the adult setting of anticipated mechanical circulatory device
population to assess the efficacy or safety of intravenous support, a pathological diagnosis of GCM may lead to use of
immunoglobulin or corticosteroids in this disorder. However, a biventricular device because of the likelihood of progressive
if other causes of heart failure (such as coronary artery right ventricular failure. Thus, EMB may provide unique and
disease) are excluded, EMB can provide unique prognostic clinically meaningful information and should be performed
information and exclude clinically more aggressive disorders. in the setting of unexplained, new-onset heart failure of ,2
GCM and necrotizing eosinophilic myocarditis may present weeks’ duration associated with a normal-sized or dilated
with a fulminant clinical course, but unlike fulminant lym- left ventricle in addition to hemodynamic compromise.
phocytic myocarditis, both disorders have a poor progno-
sis.46 Necrotizing eosinophilic myocarditis is a rare
condition known only from small case series and case
Clinical Scenario 2
reports. The prognosis is poor, with most cases diagnosed EMB should be performed in the setting of unexplained
at autopsy.47 This form of eosinophilic heart disease is new-onset heart failure of 2 weeks’ to 3 months’ duration
characterized by an acute onset and rapid progression of associated with a dilated left ventricle and new ventricu-
hemodynamic compromise. Histologically, necrotizing eosi- lar arrhythmias, Mobitz type II second- or third-degree
nophilic myocarditis may be identified by a diffuse inflam- atrioventricular (AV) heart block, or failure to respond
matory infiltrate with predominant eosinophils associated to usual care within 1 to 2 weeks. Class of Recommen-
with extensive myocyte necrosis.48 Necrotizing eosinophilic dation I, Level of Evidence B.
myocarditis differs from typical hypersensitivity myocarditis Although most cases of acute DCM are relatively mild and
(HSM) in that the lesions are diffuse rather than perivascular resolve with few short-term sequelae, certain signs and symp-
and interstitial, and myocyte necrosis is prominent. A histo- toms predict GCM, a disorder with a mean transplantation-
logical diagnosis on EMB alters prognosis and would lead to free survival duration of only 5.5 months.46 GCM is associated
immunosuppressive treatment. with a variety of autoimmune disorders, thymoma,53 and drug
Therapy with combinations of immunosuppressive agents hypersensitivity.54 At presentation, ventricular tachycardia is
has been associated with improved outcome in GCM and present in 15% of cases, complete heart block in 5%, and an
necrotizing eosinophilic myocarditis.46,49 The sensitivity of acute coronary syndrome in 6%–rates higher than are typically
EMB for lymphocytic myocarditis is variable and depends on seen in noninflammatory DCM. In follow-up, 29% of GCM
the duration of illness. In subjects with symptom duration patients developed ventricular tachycardia and 15% devel-
of ,4 weeks, up to 89% may have lymphocytic myocarditis,50 oped AV block (8% complete).55 Thus, clinical clues to
but generally the yield is lower, between 10% and 35% depend- suggest GCM and prompt an EMB include association with
ing on the “gold standard” used.1,51 In contrast, the other autoimmune disorders or thymoma, failure to respond
AHA/ACCF/ESC scientific statement 3081
to usual care, and the presence of complete heart block or Even though the diagnostic rate of the EMB in cardiac sar-
ventricular tachycardia. coidosis is low, a histological distinction between cardiac sar-
Patients with acute heart failure due to GCM respond well to coidosis and GCM (both of which have giant cells) is important
heart transplantation. Alternatively, treatment with combi- for therapeutic decisions and prognosis. The rate of
nation immunosuppression may improve transplantation-free transplantation-free survival at 1 year is significantly worse
survival duration compared with patients with GCM not receiv- in patients diagnosed by EMB with idiopathic GCM than in
ing immunosuppressive treatment. Patients treated without patients with cardiac sarcoidosis (21.9% versus 69.8%; P ,
immunosuppressive therapy had a median transplantation- 0.0001).61 Reports differ as to whether survival rate in
free survival duration of 3.0 months, compared with a cardiac sarcoidosis is similar to or worse than in DCM.1,58,66
12.3-month (P ¼ 0.003) median transplantation-free survival Sarcoidosis may respond to treatment with corticoster-
duration for patients treated with cyclosporine-based immu- oids. Rate of survival was better in those who received cor-
nosuppression. Therefore, a diagnosis of GCM will affect prog- ticosteroids than in those who received usual care (64%
nosis and treatment. A comparison of survival between versus 40%; P ¼ 0.048) in one retrospective study.67 Small
patients in the multicenter Giant Cell Myocarditis Registry case series and case reports also suggest that corticosteroids
heart failure associated with a DCM of any duration associated heart failure and on echocardiogram is found to have
with suspected allergic reaction in addition to eosinophilia. normal or decreased volume of both ventricles, biatrial
enlargement, normal or minimally increased wall thickness
Clinical scenario 5 with no valvular abnormality, or normal or near-normal
systolic function with impaired diastolic filling, for
EMB is reasonable in the setting of unexplained heart failure
example, restrictive physiology. As shown in Table 3, this
associated with suspected anthracycline cardiomyopathy.
category of cardiomyopathy has been further classified into
Class of Recommendation IIa, Level of Evidence C.
noninfiltrative processes, infiltrative disorders, and storage
Certain chemotherapeutic agents, particularly anthracy-
diseases that cause characteristic ventricular filling abnorm-
clines, are known to be cardiotoxic, particularly at higher
alities, as well as the endomyocardial diseases that have
cumulative doses. Although cardiotoxicity may be monitored
many of the same clinical manifestations.87 Thus, a variety
by several modalities, including echocardiographic or radio-
of pathological processes may result in restrictive cardio-
nuclide angiography assessment of EF, fractional shortening,
myopathy, although the cause often remains unknown.
or parameters of diastolic dysfunction, these modalities are
More importantly, the clinical and hemodynamic features
immunosuppressive regimen consisting of either prednisone serum iron and HFE gene mutation. In the event that findings
and azathioprine or prednisone and cyclosporine.44 The are equivocal and the possibility of cardiac hemochromato-
average symptom duration before treatment was 4 weeks, sis still exists, EMB can be useful for diagnosis and to guide
and the primary end point was the change in EF after 28 treatment. Iron deposition is seen within the sarcoplasm.120
weeks. The average EF and the median transplantation-free Treatment with phlebotomy or iron chelation therapy can
survival duration were similar in the immunosuppression reverse the ventricular dysfunction.121
and conventional therapy groups. The risk of death or trans- On the basis of these reports, the Writing Group recog-
plantation was 56% at 4 years. Similarly, in the Immunoglobu- nizes that divergent evidence exists with regard to the
lin for Myocarditis and Acute Cardiomyopathy (IMAC-1) trial utility of EMB in this clinical scenario. The Writing Group
of intravenous immunoglobulin for acute nonischemic DCM, recommends that EMB may be considered in the setting of
at 2 years the risk of death or transplantation was 12%. unexplained heart failure of .3 months’ duration associated
Sixteen percent of patients in the IMAC-1 study had border- with a dilated left ventricle, without new ventricular
line or active myocarditis.45 Grogan et al. 114 compared the arrhythmias, or Mobitz type II second- or third-degree AV
prognosis of patients with acute DCM with and without myo- heart block, that responds to usual care within 1 to 2
ARVD/C, an inherited or sporadic form of right and left patients, granulomatous myocarditis in 2 patients, and
ventricular cardiomyopathy, is estimated to occur in small-vessel vasculitis in 1 patient. In another series of 14
1:5000 persons. The disorder involves predominantly the patients with high-grade ventricular arrhythmias and no
right ventricle, with progressive loss of myocytes that are structural heart disease, EMB was normal in 6 patients and
replaced by fibrofatty tissue, resulting in ventricular dys- demonstrated nonspecific abnormalities, predominantly
function and tachyarrhythmias, typically monomorphic ven- fibrosis, in the other patients. In this series, abnormal
tricular tachycardia.128–130 Noninvasive tests, including biopsy findings did not correlate with induced arrhythmias
echocardiography, right ventricular angiography, cardiac or prognosis. No specific treatable diagnoses were revealed
CMR, and cardiac CT imaging, often establishes the diagno- by biopsy in this series.139 In a third case series, EMB in 12
sis. In a study of the use of CMR in 40 patients with AVRD/C patients with serious ventricular arrhythmias and structu-
and 20 normal subjects, the sensitivity of fat infiltration, rally normal hearts demonstrated nonspecific abnormalities
right ventricular enlargement, and regional right ventricular in 11 patients and acute lymphocytic myocarditis in 1
dysfunction for diagnosing ARVD/C was 84%, 68%, and 78%, patient.140 Vignola et al. 141 reported that in 12 patients
and specificity was 79%, 96%, and 94%, respectively.131 with high-grade ventricular arrhythmias and without overt
Table 4 Findings in reports of endomyocardial biopsy in patients with primary (idiopathic) arrhythmias and conduction abnormalities
Strain et al. 157 1983 Ventricular 18 16 of 18 patients (89%) with abnormal findings
tachycardia or Nonspecific myocellular hypertrophy, interstitial
ventricular and perivascular fibrosis, and vascular sclerosis in 9
fibrillation of 18 patients, subacute inflammatory myocarditis
in 3 of 18 patients, diffuse abnormalities of the
intramyocardial arteries in 2 of 18 patients, and
changes consistent with ARVD/C in 2 of 18 patients
Vignola et al. 141 1984 Malignant ventricular 12 ‘Clinically unsuspected myocarditis’ in 6 of 12 cases
arrhythmias and ‘early cardiomyopathy’ in 3 of 12 cases
clinically unsuspected myocarditis, the value of this finding disorganization, interstitial mononuclear cells, and endocar-
in clinical decision making remains controversial. The detec- dial lesions were only seen in those biopsy specimens from
tion of active myocarditis in a patient with malignant ventri- patients with sick sinus syndrome. No mention is made of
cular arrhythmia might theoretically lead to a decision to how these findings might have related to clinical manage-
defer implantation of a defibrillator until the myocarditis ment.148 On the basis of these reports, the Writing Group
has subsided, but such an approach is more theoretical recommends that EMB not be performed in the setting of
than tested. Eighteen years ago, Mason and O’Connell136 unexplained atrial fibrillation.
classified the indication for EMB in unexplained, life-
threatening ventricular tachyarrhythmias as “uncertain,”
and it seems there has been little published literature EMB as a research tool
since to change this classification. Therefore, the Writing In addition to its clinical roles, EMB may be used to better
Group recommends that EMB may be considered in the understand the cellular and molecular pathophysiology of
setting of unexplained ventricular arrhythmias only in cardiovascular disease. For example, the development of
exceptional cases in which the perceived likelihood of
Writing group Employment Research Other research Speakers’ bureau/ Expert Ownership Consultant/advisory board Other
member grant support honoraria witness interest
Leslie T. Cooper Mayo Clinic None None None None None None None
Kenneth Brigham and Women’s Hospital NIH† None None None None None None
L. Baughman
Arthur Feldman Thomas Jefferson University None None None None None None None
Hospital
Andrea Frustaci La Sapienza University None None None None None None None
Mariell Jessup University of Pennsylvania None None AstraZeneca*; Medtronic*; None None ACORN*; Medtronic*; None
ACORN*; GlaxoSmithKline*; Ventracor*
GlaxoSmithKline*
Uwe Kuhl Charite University None None None None None None None
Glenn N. Levine Baylor College of Medicine None None Sanofi-Aventis*; Medicines None None None None
Company*
Jagat Narula University of California, Irvine None None GlaxoSmithKline† None None None None
Randall C. Starling Cleveland Clinic Foundation NIH† Novartis*; None None None Acorn Cardiovascular Inc*; None
Orquis*; Cardiomems*; Myocor*;
Johnson & Medtronic*; World Heart*
Johnson*
Jeffrey Towbin Baylor College of Medicine None None None None None None None
Renu Virmani CV Path None None None None None Medtronic†; Guidant†; Abbott None
Laboratories†; W.L. Gore†;
CryoVascular Systems, Inc†;
Volcano Therapeutics Inc†;
Precient Medical†; Medicon†;
Cardiomind, Inc†; Direct Flow†;
Reviewer Employment Research Other research Speakers’ bureau/ honoraria Expert Ownership Consultant/ advisory Other
grant support witness interest board
Mazen Abu-Fadel Ponca City Medical Center None None None None None None None
Jeffrey Anderson LDS Hospital None None None None None None None
Eloisa Arbustini I.R.C.C.S. Policlinico San Matteo, None None None None None None None
Pavia, Italy
Eric Bates University of Michigan None None None None None None None
Fred Bove Temple University Penn Dept of None None None None Insight Telehealth None
Health Systems*
Rihal Charanjit Mayo Clinic None None None None None None None
G. William Dec Massachusetts General Hospital None None None None None None None
Jose Diez Baylor College of Medicine None None None None None Sanofi-Aventis* None
Mark Eisenberg McGill University None None None None None None None
Gerasimos Evangelismos Hospital, Athens, None None None None None None None
Filippatos Greece
Robert Harrington Duke University None None None None None None None
Mark Hlatky Stanford University None None None None None None None
Maryl Johnson University of Wisconsin None None None None None None None
Jay Mason Covance Central Diagnostics None None None None None None None
Walter Paulus VU University Medical Center, None None None None None None None
Netherlands
Richard Schofield University of Florida None None AstraZeneca*; AtCor Medical*; None None Pfizer None
Novartis*; Pfizer*; Scios*
Udo Sechtem Robert-Bosch-Medical Center, None None None None None None None
Stuttgart, Germany
Ajay Shah King’s College London None None None None None None None
Samuel Beth Israel Deaconess Medical None None None None None None None
J. Shubrooks, Jr Center
This table represents the relationships of reviewers that may be perceived as actual or reasonably perceived conflicts of interest as reported on the Disclosure Questionnaire, which all reviewers are required to com-
plete and submit. A relationship is considered to be “significant” if (a) the person receives $10 000 or more during any 12-month period, or 5% or more of the person’s gross income; or (b) the person owns 5% or more of the
voting stock or share of the entity, or owns $10 000 or more of the fair market value of the entity. A relationship is considered to be “modest” if it is less than “significant” under the preceding definition.
*Modest.
†
Significant.
3089
3090 AHA/ACCF/ESC scientific statement
References 25. Torti FM, Bristow MR, Howes AE, Aston D, Stockdale FE, Carter SK,
Kohler M, Brown BW Jr, Billingham ME. Reduced cardiotoxicity of doxor-
1. Felker GM, Thompson RE, Hare JM, Hruban RH, Clemetson DE, ubicin delivered on a weekly schedule: assessment by endomyocardial
Howard DL, Baughman KL, Kasper EK. Underlying causes and long-term biopsy. Ann Intern Med. 1983;99:745–749.
survival in patients with initially unexplained cardiomyopathy. N Engl J 26. Veinot JP. Diagnostic endomyocardial biopsy pathology: general biopsy
Med. 2000;342:1077–1084. considerations, and its use for myocarditis and cardiomyopathy: a
2. Weinberg M, Fell EH, Lynfield J. Diagnostic biopsy of the pericardium review. Can J Cardiol. 2002;18:55–65.
and myocardium. AMA Arch Surg. 1958;76:825–829. 27. Jin O, Sole MJ, Butany JW, Chia WK, McLaughlin PR, Liu P, Liew CC.
3. Bulloch RT, Murphy ML, Pearce MB. Intracardiac needle biopsy of the Detection of enterovirus RNA in myocardial biopsies from patients
ventricular septum. Am J Cardiol. 1965;16:227–233. with myocarditis and cardiomyopathy using gene amplification by poly-
4. Sakakibara S, Konno S. Endomyocardial biopsy. Jpn Heart J. 1962;3: merase chain reaction. Circulation. 1990;82:8–16.
537–543. 28. Grasso M, Arbustini E, Silini E, Diegoli M, Percivalle E, Ratti G,
5. Caves PK, Stinson EB, Graham AF, Billingham ME, Grehl TM, Bramerio M, Gavazzi A, Vigano M, Milanesi G. Search for Coxsackievirus
Shumway NE. Percutaneous transvenous endomyocardial biopsy. JAMA. B3 RNA in idiopathic dilated cardiomyopathy using gene amplification by
1973;225:288–291. polymerase chain reaction. Am J Cardiol. 1992;69:658–664.
6. Richardson PJ. King’s endomyocardial bioptome. Lancet. 1974;1: 29. Weiss LM, Movahed LA, Billingham ME, Cleary ML. Detection of Coxsack-
42. Amabile N, Fraisse A, Bouvenot J, Chetaille P, Ovaert C. Outcome of myocarditis: concepts through a study employing endomyocardial
acute fulminant myocarditis in children. Heart. 2006;92:1269–1273. biopsy, I: sarcoidosis. Jpn Circ J. 1980;44:249–263.
43. Felker GM, Boehmer JP, Hruban RH, Hutchins GM, Kasper EK, 65. Schulz-Menger J, Wassmuth R, Abdel-Aty H, Siegel I, Franke A, Dietz R,
Baughman KL, Hare JM. Echocardiographic findings in fulminant and Friedrich MG. Patterns of myocardial inflammation and scarring in sar-
acute myocarditis. J Am Coll Cardiol. 2000;36:227–232. coidosis as assessed by cardiovascular magnetic resonance. Heart.
44. Mason JW, O’Connell JB, Herskowitz A, Rose NR, McManus BM, 2006;92:399–400.
Billingham ME, Moon TE. A clinical trial of immunosuppressive therapy 66. Ardehali H, Howard DL, Hariri A, Qasim A, Hare JM, Baughman KL,
for myocarditis. The Myocarditis Treatment Trial Investigators. N Engl Kasper EK. A positive endomyocardial biopsy result for sarcoid is associ-
J Med. 1995;333:269–275. ated with poor prognosis in patients with initially unexplained cardio-
45. McNamara DM, Holubkov R, Starling RC, Dec GW, Loh E, Torre-Amione G, myopathy. Am Heart J. 2005;150:459–463.
Gass A, Janosko K, Tokarczyk T, Kessler P, Mann DL, Feldman AM. Con- 67. Takada K, Ina Y, Yamamoto M, Satoh T, Morishita M. Prognosis after pace-
trolled trial of intravenous immune globulin in recent-onset dilated car- maker implantation in cardiac sarcoidosis in Japan: clinical evaluation
diomyopathy. Circulation. 2001;103:2254–2259. of corticosteroid therapy. Sarcoidosis. 1994;11:113–117.
46. Cooper LT Jr, Berry GJ, Shabetai R. Idiopathic giant-cell myocarditis: 68. Bellhassen B, Pines A, Laniado S. Failure of corticosteroids to prevent
natural history and treatment. Multicenter Giant Cell Myocarditis induction of ventricular tachycardia in sarcoidosis. Chest. 1989;95:
Study Group Investigators. N Engl J Med. 1997;336:1860–1866. 918–920.
Etten RA, Alroy J, Durand JB, Force T. Cardiotoxicity of the cancer 110. Shirali GS, Ni J, Chinnock RE, Johnston JK, Rosenthal GL, Bowles NE,
therapeutic agent imatinib mesylate. Nat Med. 2006;12:908–916. Towbin JA. Association of viral genome with graft loss in children
86. Feldman AM, Lorell BH, Reis SE. Trastuzumab in the treatment of meta- after cardiac transplantation. N Engl J Med. 2001;344:1498–1503.
static breast cancer: anticancer therapy versus cardiotoxicity. Circula- 111. Dec GW. Introduction to clinical myocarditis. In: Cooper LT, ed. Myocar-
tion. 2000;102:272–274. ditis From Bench to Bedside. Totowa, NJ: Humana Press; 2003:257–281.
87. Kushwaha SS, Fallon JT, Fuster V. Restrictive cardiomyopathy. N Engl J 112. Aretz HT, Billingham ME, Edwards WD, Factor SM, Fallon JT, Fenoglio JJ
Med. 1997;336:267–276. Jr, Olsen EG, Schoen FJ. Myocarditis: a histopathologic definition and
88. Asher CR, Klein AL. Diastolic heart failure: restrictive cardiomyopathy, classification. Am J Cardiovasc Pathol. 1987;1:3–14.
constrictive pericarditis, and cardiac tamponade: clinical and echocar- 113. Baughman KL. Diagnosis of myocarditis: death of Dallas criteria. Circula-
diographic evaluation. Cardiol Rev. 2002;10:218–229. tion. 2006;113:593–595.
89. Yazdani K, Maraj S, Amanullah AM. Differentiating constrictive pericar- 114. Grogan M, Redfield MM, Bailey KR, Reeder GS, Gersh BJ, Edwards WD,
ditis from restrictive cardiomyopathy. Rev Cardiovasc Med. 2005;6: Rodeheffer RJ. Long-term outcome of patients with biopsy-proved myo-
61–71. carditis: comparison with idiopathic dilated cardiomyopathy. J Am Coll
90. Alter P, Grimm W, Tontsch D, Maisch B. Diagnosis of primary cardiac lym- Cardiol. 1995;26:80–84.
phoma by endomyocardial biopsy. Am J Med. 2001;110:593–594. 115. Wojnicz R, Nowalany-Kozielska E, Wojciechowska C, Glanowska G,
91. Iwaki T, Kanaya H, Namura M, Ikeda M, Uno Y, Terashima N, Ohka T, Wilczewski P, Niklewski T, Zembala M, Polonski L, Rozek MM,
129. Basso C, Thiene G. Adipositas cordis, fatty infiltration of the right ven- supraventricular tachycardia. Pacing Clin Electrophysiol. 1988;11:
tricle, and arrhythmogenic right ventricular cardiomyopathy: just a 1154–1167.
matter of fat? Cardiovasc Pathol. 2005;14:37–41. 146. Uemura A, Morimoto S, Hiramitsu S, Hishida H. Endomyocardial biopsy
130. Hulot JS, Jouven X, Empana JP, Frank R, Fontaine G. Natural history and findings in 50 patients with idiopathic atrioventricular block: presence
risk stratification of arrhythmogenic right ventricular dysplasia/cardio- of myocarditis. Jpn Heart J. 2001;42:691–700.
myopathy. Circulation. 2004;110:1879–1884. 147. Frustaci A, Caldarulo M, Buffon A, Bellocci F, Fenici R, Melina D. Cardiac
131. Tandri H, Castillo E, Ferrari VA, Nasir K, Dalal D, Bomma C, Calkins H, biopsy in patients with “primary” atrial fibrillation: histologic evidence
Bluemke DA. Magnetic resonance imaging of arrhythmogenic right ven- of occult myocardial diseases. Chest. 1991;100:303–306.
tricular dysplasia: sensitivity, specificity, and observer variability of fat 148. Uemura A, Morimoto S, Hiramitsu S, Ohtsuki M, Kato S, Kato Y,
detection versus functional analysis of the right ventricle. J Am Coll Sugiura A, Miyagishima K, Hishida H. Right ventricular endomyocardial
Cardiol. 2006;48:2277–2284. biopsy findings in 25 patients with sick sinus syndrome. Jpn Heart J.
132. Wichter T, Hindricks G, Lerch H, Bartenstein P, Borggrefe M, Schober O, 2004;45:73–80.
Breithardt G. Regional myocardial sympathetic dysinnervation in 149. Feldman AM, Ray PE, Silan CM, Mercer JA, Minobe W, Bristow MR. Selec-
arrhythmogenic right ventricular cardiomyopathy: an analysis using tive gene expression in failing human heart: quantification of
123I-meta-iodobenzylguanidine scintigraphy. Circulation. 1994;89: steady-state levels of messenger RNA in endomyocardial biopsies using
667–683. the polymerase chain reaction. Circulation. 1991;83:1866–1872.
133. Chimenti C, Pieroni M, Maseri A, Frustaci A. Histologic findings in 150. Ladenson PW, Sherman SI, Baughman KL, Ray PE, Feldman AM. Revers-