Case 1 -
Giant Cell Myocarditis
Gayle L. Winters
Brigham and Women's Hospital
Click on each slide thumbnail image for an enlarged view
A 51 year-old female nurse presented with a three-week history of fatigue and dyspnea on exertion.
The symptoms were progressive and led to significant limitation in her activities of daily living, such
that by the day of admission she was unable to climb a single flight of stairs. She also reported
occasional burning chest discomfort that did not radiate and had no clear association with exertion, as
well as some brief palpitations. Her past medical history (including risk factors for coronary artery
disease) was entirely negative and she took no regular medications. She did not smoke or use illicit
drugs, consumed alcohol only occasionally, and denied any high-risk sexual behaviors. She had no history
of travel outside the US and there were no notable occupational or environmental exposures.
On physical examination, she appeared well. She was afebrile with a blood pressure of 88/60 mm Hg,
pulse 90 beats per minute, and respiratory rate 20 breaths per minute. Cardiac examination revealed a
regular gallop rhythm with audible left-sided third and fourth heart sounds. Admitting laboratory
studies were non-contributory. ECG revealed left axis deviation, poor R wave progression, 2-3 mm ST
segment elevations in leads V2, V3, and 2-3 mm ST segment depressions in leads V5 and V6. Emergent
left-sided cardiac catheterization revealed a right dominant circulation with clean coronary vessels
except for a 20-30% stenosis in the left anterior descending artery. There was global hypokinesis.
Transthoracic echocardiography showed a mildly enlarged left ventricle with global hypokinesis and a left
ventricular ejection fraction of 15-20%.
The day of admission, the patient became severely hypotensive and developed sustained monomorphic
ventricular tachycardia requiring direct-current cardioversion. Urgent right heart catheterization with
endomyocardial biopsy was performed (Slide A). She remained hemodynamically
unstable and required placement of an intra-aortic balloon pump. Urgent transplant evaluation was
undertaken. Two days after her biopsy a Thoratec BiVAD was inserted for cardiogenic shock and recurrent
ventricular tachyarrhythmias. Her condition stabilized and she awaited transplantation in the hospital.
Approximately two months after her initial presentation, she underwent heart transplantation and her
explanted heart became available for examination (Slide B).
Case 1 - Figure 1 -
(Endomyocardial Biopsy): Low power view of four endomyocardial biopsy samples. There is extensive and diffuse replacement of myocardium by an inflammatory process.
Case 1 - Figure 2 -
(Endomyocardial Biopsy): Intermediate power of extensive inflammatory infiltrate containing giant cells. There is extensive myocyte damage.
Case 1 - Figure 3 -
(Endomyocardial Biopsy): High power view showing polymorphous nature of infiltrate, including lymphocytes, histiocytes, plasma cells and eosinophils.
Case 1 - Figure 4 -
(Endomyocardial Biopsy): High power of multinucleated giant cells.
Case 1 - Figure 5 -
(LVAD Core): Intermediate power of diffuse mixed inflammatory infiltrate with multinucleated giant cells and extensive myocyte damage.
Case 1 - Figure 6 -
(LVAD Core): High power of mixed inflammatory infiltrate with multinucleated giant cells and myocyte damage.
Case 1 - Figure 7 -
(Explanted Heart): Four-chamber cut of 310 gm explanted heart with LVAD cannula in left ventricular apex. There is biventricular dilation and a partially organized thrombus in the right atrium. The mitral valve is mildly myxomatous and there is no fusion (post-LVAD) of the aortic valve cusps. The coronary arteries contained only minimal (nonocclusive) atherosclerosis.
Case 1 - Figure 8 -
(Explanted Heart): There is mild mottling of the interventricular septal myocardium (left). Histology of the myocardium (H&E and Trichrome) reveals extensive fibrosis in a non-coronary distribution (right, top and bottom).
Case 1 - Figure 9 -
(Explanted Heart): Scattered giant cells are present within areas of fibrosis.
Case 1 - Figure 10 -
(Explanted Heart): There are multiple foci of residual active inflammation consisting of a mixed infiltrate with giant cells and myocyte damage.
The endomyocardial biopsy and the LVAD apical core revealed similar findings and illustrate the acute
phase of giant cell myocarditis. There was extensive, diffuse replacement of the myocardium by a mixed
inflammatory infiltrate composed of lymphocytes, histiocytes, plasma cells, and eosinophils. Numerous
multinucleated giant cells were admixed with the other cells in the inflammatory infiltrate, particularly
at the margin of necrotic zones of myocardium, but true granulomas were absent. No organisms or foreign
bodies could be demonstrated. There was widespread geographic myocardial necrosis.
The explanted heart obtained approximately two months after the initial biopsy illustrates the healing
phase of giant cell myocarditis. Large areas of fibrosis were present, containing a sparser inflammatory
infiltrate and occasional giant cells. Active myocyte necrosis was less evident when compared with the
Myocarditis has been defined as a non-ischemic inflammation of the myocardium characterized by an
inflammatory infiltrate and associated myocyte necrosis
. Although the cause of myocarditis
in a specific case is often idiopathic or unknown, the type of inflammation may provide a clue to the
. Lymphocytic myocarditis is most often associated with viral infection (also
autoimmunity, polymyositis, sarcoidosis, Lyme disease and drug toxicity). Eosinophilic myocarditis is
often the result of drug hypersensitivity (also parasitic infestations, hypereosinophilic syndrome,
asthmatic bronchitis, and restrictive cardiomyopathy). Neutrophilic or mixed inflammation is associated
with general infection, myocardial infarction, and drug toxicity. Giant cells may be present in giant
cell myocarditis and sarcoidosis (also infection, foreign body reaction, rheumatic disease, rheumatoid
disease, thymoma, systemic lupus erythematosus, dermatomyositis, thyroiditis, orbital myositis,
pernicious anemia, ulcerative colitis, and drug hypersensitivity).
The main differential diagnosis in this case, however, is between giant cell myocarditis and
. The histologic features of cardiac sarcoid are similar to those of
extracardiac sarcoid and consist of well-formed non-necrotizing granulomas within the myocardium. Giant
cells are usually present in association with the granulomas. Unlike giant cell myocarditis, myocyte
necrosis is typically absent and eosinophils are rare. Sarcoid granulomas may involve the endocardium
(valves), epicardium, and may surround and extend into the adventitia and media of intramural coronary
arteries. In addition, the clinical presentation of giant cell myocarditis is often fulminant cardiac
failure whereas sarcoid often presents with ventricular arrhythmias and other conduction disturbances.
Diagnosis: Giant Cell Myocarditis
Giant cell myocarditis is a relatively rare condition of unclear etiology. In some patients there
appears to be an association with immunologic abnormalities such as active rheumatic disease, thymoma
with or without myasthenia gravis
lymphoma , systemic lupus erythematosus,
dermatomyositis, thyroiditis, orbital myositis
anemia , or
. In most patients, however, it likely occurs in association with an
infective myocarditis, likely viral, in the setting of altered immunity. However, numerous attempts to
identify an infective agent have not been successful.
Pathogens have traditionally been identified by growing them in culture from samples of infected
tissue or staining the infected tissue with special histochemical and immunoperoxidase stains. These
methods, however, do not identify all pathogens. Even molecular methods such as polymerase chain
reaction (PCR) require comparisons to known DNA sequences. New methods in molecular diagnostics, in
association with the recently completed Human Genome Project, may allow for identification of as yet
undetected and possibly novel infectious agents. In order for such techniques to become practical,
technology is being developed that allows DNA sequencing to be both faster and cheaper.
DNA sequencing can be carried out on a sample of diseased tissue. Using a technique called
"computational subtraction"  computers compare the sample DNA with the sequence of DNA
derived from the human genome project. When the comparison is done, sequences with similarity to the
human genome are subtracted out. The remaining sequences, therefore, are of non-human origin. These
non-human sequences include (1) sequences from known pathogenic and commensal organisms, (2) new
microbial sequences, (3) sequences representing experimental contamination, and (4) transcripts from
unsequenced regions of the human genome. DNA from such organisms as hepatitis B and C viruses, human
papillomaviruses, cytomegalovirus, Kaposi's sarcoma herpesvirus, and Epstein-Barr virus have been
successfully identified from human tissue using this technique.
While still a research tool, computational subtraction holds great promise for many diseases of
unknown origin with proposed infectious etiologies, including rheumatoid arthritis, Type 1 diabetes,
atherosclerosis, sarcoidosis, lupus, multiple sclerosis, and some types of cancer. Another potential
application is in identifying emerging infectious diseases – such as HIV and Ebola which were unknown
until recent decades.
Samples from the patient's left ventricular apical core and explanted heart were submitted for
computational subtraction analysis.
Clinical Presentation and Course:
Because giant cell myocarditis is a rare condition, little was known about the natural history or
response to therapy. The largest reported series consists of 63 patients from 36 medical
centers . The authors found giant cell myocarditis to be a disease of relatively young (mean
age 43 years), previously healthy adults with no gender predilection. Patients typically presented
within 3 weeks of symptoms and the majority (75%) presented with symptoms of congestive heart failure,
followed by ventricular arrhythmias (14%), complete heart block (5%), and symptoms resembling acute
myocardial infarction (6%). Nineteen percent of patients had associated autoimmune conditions.
Sustained, refractory ventricular tachycardia developed in half of patients during the course of their
illness and, in general, patients had a fulminant course. The rate of death or cardiac transplantation
was 89% with a median survival of 5.5 months from the onset of symptoms to the time of death or
transplantation. Occasional, prolonged survival, up to 10 years, has been reported . Of
note, survival of patients with giant cell myocarditis is significantly worse than those with lymphocytic
myocarditis. A comparison of survival between patients with giant cell myocarditis and patients from the
Myocarditis Treatment Trial (lymphocytic myocarditis)  showed that approximately 50% of
patients with lymphocytic myocarditis were alive without cardiac transplant at 5 years vs 10% of patients
with giant cell myocarditis.
Role of Endomyocardial Biopsy:
According to the ACC/AHA 2005 Guideline Update for the diagnosis and management of chromic heart
failure in the adult, endomyocardial biopsy can be useful in patients presenting with heart failure when
a specific diagnosis is suspected that would influence therapy . One study which looked
specifically at endomyocardial biopsy for giant cell myocarditis in a referral population compared with
the histology of apical cores, explanted hearts or autopsies found a sensitivity of 80-85% .
This sensitivity is far higher than in lymphocytic myocarditis which is <10%. It should be noted that
the patients with giant cell myocarditis presented relatively early in their disease and had fulminant
heart failure. Unlike fulminant lymphocytic myocarditis, patients with fulminant cardiac failure caused
by giant cell myocarditis may respond to certain immunosuppressive agents. Therefore, endomyocardial
biopsy may be used selectively to distinguish fulminant heart failure caused by giant cell myocarditis
from other causes in which prognosis may differ.
Immunosuppressive Therapy and Cardiac Transplantation:
In the series of 63 patients with giant cell myocarditis who did not undergo cardiac transplantation,
those treated with corticosteroids and cyclosporine, azathioprine, or both therapies survived longer
(average 12 months) as compared with those who received no immunosuppressive therapy (average 3 months).
This is, however, non-randomized data. A randomized, open-label giant cell myocarditis treatment trial
has recently been completed .
In view of the poor prognosis, cardiac transplantation remains the best possibility for long-term
survival . Giant cell myocarditis is known to recur in the transplanted
and was identified by post-transplant endomyocardial biopsy in 26% of
patients. Routine anti-T cell immunosuppression for rejection is usually enough to control disease
recurrence. When giant cell myocarditis does recur in the allograft, it is usually mild and responds
well to a transient increase in immunosuppression. The outcome of patients with giant cell myocarditis
who undergo transplantation has clearly been better than that of patients who do not undergo
Giant cell myocarditis is a rare disorder that is distinct from lymphocytic myocarditis both in
clinical presentation and prognosis. Treatment must be immediate and aggressive and may be aided by
definite diagnosis by endomyocardial biopsy. Immunosuppression and/or early transplantation are viable
treatment options. Advances in molecular diagnostic techniques may identify a causative agent allowing
for targeted therapy, rather than therapy aimed only at the clinical symptoms.
- Aretz HT, Billingham ME, Edwards WD et al: Myocarditis: A histopathologic definition and classification. Am J Cardiovasc Pathol 1:3, 1987.
- Aretz HT: Myocarditis: The Dallas criteria. Hum Pathol 18:619, 1987.
- Aretz HT: Myocarditis: The Dallas classification. p. 246. In Virmani R, Atkinson JB, Fenoglio JJ (eds): Cardiovascular Pathology, WB Saunders, Philadelphia, 1991.
- Hauck AJ, Edwards ED: Histopathologic Examination of Tissues Obtained by Endomyocardial Biopsy. p.95. In Fowles RE (ed): Cardiac Biopsy, Futura, Mount Kisco, 1992.
- Winters GL, McManus BM: Myocarditis. P. 256. In Silver MD, Gotlieb AI, and Schoen FJ (eds): Cardiovascular Pathology, Churchill Livingstone, New York , 2001.
- Davies MJ, Pomerance A, Teare RD: Idiopathic giant cell myocarditis - a distinctive clinico-pathological entity. Br Heart J 37:192, 1975.
- Litovsky SH, Burke AP, Virmani R: Giant cell myocarditis: An entity distinct from sarcoidosis characterized by multiphasic myocyte destruction by cytotoxic T cells and histiocytic giant cells. Mod Pathol 9:1126, 1996.
- Okura Y, Dec GW, Hare JM et al: A clinical and histopathologic comparison of cardiac sarcoidosis and idiopathic giant cell myocarditis. J Am Coll Cardiol 41:322, 2003.
- Langston JD, Wagman GF, Dickenman RC: Granulomatous myocarditis and myositis associated with thymoma. Arch Pathol 68:367, 1959.
- Burke JS, Medline NM, Katz A: Giant cell myocarditis and myositis, associated with thymoma and myesthenia gravis. Arch Pathol 88:359, 1969.
- de Jongste MJ, Oosterhuis HJ, Lie KI: Intractable ventricular tachycardia in a patient with giant cell myocarditis, thymoma and myasthenia gravis. Int J Cardiol 13:374, 1986.
- Butany JW, McAuley P, Bergeron C, MacLaughlin P: Giant cell myocarditis and myositis associated with thymoma and leprosy. Can J Cardiol 7:141, 1991.
- Hales SA, Theaker JM, Gatter KC: Giant cell myocarditis associated with lymphoma: An immunocytochemical study. J Clin Pathol 40:1310, 1987.
- Klein BR, Hedges TR III, Dayal Y, Adelman LS: Orbital myositis and giant cell myocarditis. Neurology 39:988, 1989.
- Leib ML, Odel JG, Cooney MJ: Orbital polymyositis and giant cell myocarditis. Ophthalmology 101:950, 1994.
- Kloin JE: Pernicious anemia and giant cell myocarditis. Am J Med 78:355, 1985.
- McKeon J, Haagsma B, Bett JH, Boyle CM: Fatal giant cell myocarditis after colectomy for ulcerative colitis. Am Heart J 111:1208, 1986.
- Ariza A, Lopez D, Mate JL et al: Giant cell myocarditis: Monocytic immunophenotype of giant cells in a case associated with ulcerative colitis. Hum Pathol l26:121, 1995.
- Humbert P, Faivre R, Fellman D et al: Giant cell myocarditis: An autoimmune disease? Am Heart J 115:485, 1988.
- Weber G, Shendure J, Tanenbaum M, Church GM, Meyerson M: Identification of foreign gene sequences by transcript filtering against the human genome. Nat Genet 30:141, 2002.
- Cooper LT, Berry GJ, Shabetai R: Idiopathic giant cell myocarditis - natural history and treatment. N Engl J Med 336:1860, 1997.
- Ren H, Poston RS, Hruban RH et al: Long survival with giant cell myocarditis. Mod Pathol 6:402, 1993.
- Mason JW, O'Connell JB, Herskowitz A et al: A clinical trial of immunosuppressive therapy for myocarditis. N Engl J Med 333:269, 1995.
- Hunt SA, Abraham WT, Chin MH et al: ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult: a report of the American College of Cardiology/American Heart Association task force on practice guidelines developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: endorsed by the Heart Rhythm Society. Circulation 112:e154-235, 2005.
- Shields RC, Tazelaar HD, Berry GJ, Cooper LT Jr.: The role of right ventricular endomyocardial biopsy for idiopathic giant cell myocarditis. J Card Fail 8:74, 2002.
- Cooper L: The giant cell myocarditis treatment trial and registry: design and methods. J Heart Failure 6:133, 2000.
- Cooper LT, Berry GJ, Rizeq M, Schroeder JS: Giant cell myocarditis. J Heart Lung Transplant 14:394, 1995.
- Kong G, Madden B, Spyrou N et al: Response of recurrent giant cell myocarditis in a transplanted heart to intensive immunosuppression. Eur Heart J 12:554, 1991.
- Gries W, Farkas D, Winters GL, Costanzo-Nordin MR: Giant cell myocarditis: First report of disease recurrence in the transplanted heart. J Heart Lung Transplant 11:370, 1992.
- Grant SCD: Recurrent giant cell myocarditis after transplantation. J Heart Lung Transplant 12:155, 1993.