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Sudden Cardiac Death Caused by
an Uncommon Disease
Julie Y. Li, MD and Robin R. McGoey, MD
CASE REPORT
A 57-year-old female, found dead lying supine in bed, was transferred to the autopsy service for an unrestricted autopsy to be performed under the authorization by the coroner. Medical history was unknown.
At the time of autopsy, an implantable cardioverter-defibrillator (ICD) was identified in the subcutaneous
tissues of the left subclavicular chest, with distal leads terminating in a small amount of fibrous tissue within
the right auricular appendage and along the medial wall of the right ventricle. The heart was enlarged at
430gm (312 ±78) and cross sections were notable for left ventricular hypertrophy at 1.9cm (1.0-1.5cm) and for
dilatation of the right ventricular chamber on initial apical cross section. All cross sections, from cardiac
apex to subvalvular base, showed broad patches of white-yellow myocardial discoloration, without obvious hemorrhage, along the free wall of the left ventricle, the free wall of the right ventricle, and within
the anterior interventricular septum (Figure 1). Additional notable findings at autopsy included a vena
caval filter devoid of thromboembolic material, a patent foramen ovale (0.7cm) and microscopic plexogenic
arteriopathy, low grade, consistent with pulmonary hypertension within the intrapulmonary vasculature.
Histology from the discolored patches of myocardium is seen in Figure 2. Special stains for microorgansims
(periodic acid-Schiff, Gomori methanamine silver, and Fite) were all negative.
What is the most likely underlying disease process in this case and
what was the most likely immediate cause of death?
Answer is on p. 107
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Journal of the Louisiana State Medical Society
Figure 1: Gross image of the heart at autopsy demonstrating the broad patches of white-yellow
myocardial pallor in the free wall of the left ventricle, the free wall of the right ventricle, and
within the interventricular septum.
Figure 2: Microscopic image of the heart at autopsy demonstrating the noncaseating granulomatous inflammation with giant cell formation (hematoxylin and eosin, 40x). Similar findings
were seen in the epicardium, the left ventricle, the right ventricle, and within the interventricular
septum.
106 J La State Med Soc VOL 167 March/April 2015
PATHOLOGY DIAGNOSIS:
Cardiac sarcoidosis (CS); fatal arrhythmia
DISCUSSION
Sarcoidosis is a chronic inflammatory disease characterized by the presence of noncaseating epithelioid granulomas
in tissue. Infectious, other environmental, and genetic factors
have all been implicated in the pathogenesis of sarcoid, but
the precise etiology remains obscure other than to suggest
an aberrant immunological reaction to an unidentified antigenic trigger.1 Although sarcoidosis has been described
for more than 150 years, its propensity to involve cardiac
muscle was not recognized until 1929.2 Cardiac involvement
in sarcoid is being reported more frequently and is thought
to carry a frequency of between 20-30 percent of all cases if
microscopic analysis is performed on myocardium.3
Patients with sarcoidosis are often young to middle
age adults. Women are more often affected than men; and
American Blacks carry a 3-4 fold greater risk when compared
to American whites. The annual incidence in American
Blacks is estimated at approximately 35 cases per 100,000.2
The pathologic hallmark of sarcoidosis is the presence of
granulomatous inflammation without central caseous necrosis. Granulomas are frequently found in high number
and are loosely formed with abundant multi nucleated
giant cells. A variety of inclusions can be found within the
cytoplasm of the giant cells including the stellate asteroid
bodies and concentric calcifications known as schaumann
bodies. Though neither inclusion is pathognomonic for
sarcoidosis, their presence can be helpful in suggesting the
condition.4 Granulomas can form in virtually any organ
system but are most common in lymph nodes, skin, liver,
the gastrointestinal tract, eyes and the nervous system.2
Cardiac Sarcoid (CS) is a rare but potentially fatal condition that presents in a variety of ways including sudden
death. CS can affect any part of the heart including the
conduction system and thus presents with a wide array of
clinical manifestations. Within the myocardium of the heart,
the predominant sites are, in decreasing order of frequency,
the left ventricular free wall and papillary muscles, the basal
aspect of the interventricular septum, the right ventricular
free wall and the atrial walls. Complete heart block is the
most common finding in patients with clinically evident CS
and is reported in up to 30 percent of patients. Other clinical
manifestations include re-entrant tachyarrhythmias including ventricular tachycardia in nearly one-quarter of cases
and supraventricular arrhythmias in 15-17 percent.5-6 CS
is thought to impart a poor clinical prognosis on patients,
and is believed to account for as many as 25 percent of all
deaths from sarcoidosis in the US. In Japan, CS is reported
as the leading contributor to mortality in up to 85 percent of
cases. In fatal CS, the most common reported terminal event
is sudden cardiac death due to arrhythmia; with the second
most common fatal event being progressive congestive heart
failure in one-quarter of cases.2 In one retrospective study of
41 autopsy cases of CS, the cause of death in over 60 percent
was ultimately classified as sudden cardiac death due to the
precipitating mechanism of presumed arrhythmia. In these
cases of sudden death, the authors determined the pattern
of the CS distribution within the heart was more likely to
involve the epicardium and the interventricular septum.7
Because of the potential life-threatening nature of CS,
early diagnosis is critical. The antemortem diagnosis remains
challenging with only 40 percent of those proven to have
CS at autopsy ever showing clinical signs before death. Just
recently, the first expert committee was convened to write a
consensus statement on the diagnosis and management of
CS, from which two diagnostic pathways were developed
(Table 1). The authors also suggested a screening protocol
for those with known extracardiac sarcoidosis that included
not only a detailed clinical history for cardiac symptoms, but
also a 12-lead electrocardiogram and an echocardiogram.8-9
Therapy for CS is not standardized but corticosteroid
therapy is the current mainstay. Additional therapies may
be considered in select patients including antiarrhythmics,
additional immunosuppressive drugs, implantable cardioverter-defibrillator devices, cardiac surgery and heart transplantation.6,10 The prognosis in CS is not precisely known
but sudden cardiac death despite a functioning implantable
cardioverter-defibrillator (ICD) is well described and has
been previously documented in 28 percent of 320 deaths
occurring in a series of ventricular tachycardia/ventricular
fibrillation (VT/VF) patients who were treated with ICD.11
The case presented here of sudden death in the context
of multiple myocardial noncaseating granuloma along with
features of pulmonary hypertension and antemortem cardiac compromise evidenced by the presence of an ICD are
all classic features of CS. Of note, the autopsy did not reveal
any significant lymphadenopathy. However, histologic
evidence of sarcoidosis was also found along the pulmonary
subpleural lymphatic channels. Though the most likely
underlying disease and immediate cause of death in this
case are CS and a fatal arrhythmia, respectively, the absolute
certainty of the diagnosis is limited by both the paucity of
antemortem clinical information, as well as the fact that
sarcoidosis is frequently a diagnosis of exclusion. Granulomatous inflammation is a nonspecific histopathologic finding that is not pathognomonic for sarcoidosis. Myocardial
granulomas are relatively rare and generate a rather limited
differential diagnosis that includes myocarditis, metabolic
disorders, foreign body reactions, tuberculosis or fungal
infection and CS. But, the absence of any microorganisms on
special staining, the noncaseating nature of the granuloma,
the lack of polarizable material, the lack of eosinophils and
the absence of myocyte cell necrosis, as well as the distribution of the granulomas along the epicardium, within
both ventricular free walls and within the interventricular
septum, all strongly support the diagnosis of CS.
In conclusion, CS is a rare but potentially fatal condition that may present with a wide range of clinical manifestations including congestive heart failure, conduction
abnormalities, and sudden cardiac death. Because of the
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Table 1: Two Diagnostic Pathways for Establishing Cardiac Sarcoidosis (CS)8-9
1.
2.
Noncaseating granulomas in myocardial tissue with no alternative cause identified (including organismal stains if
applicable)
Noncaseating granulomas in other, extracardiac organ systems, and the presence of one or more of the following
cardiac findings so long as other causes for the cardiac manifestations have been reasonably excluded:
a.
Corticosteroid and/or immunosuppressant responsive cardiomyopathy or heart block
b.
Unexplained reduced LVEF (<40%)
c.
Unexplained sustained VT
d.
Mobitz type II second-degree heart block or third-degree heart block
e.
Patchy uptake on dedicated cardiac PET
f.
Late gadolinium enhancement on cardiovascular MR
g.
Positive gallium uptake
LVEF: left ventricular ejection fraction
VT: ventricular tachycardia
PET: positron emission tomography
MR: magnetic resonance
potential life-threatening complications, a deliberate and
algorithmic approach to screening all sarcoidosis patients
for cardiac involvement has been recently proposed. The
autopsy case presented here, though limited by the incompletely available antemortem clinical information, also
serves to support the current call for additional emphasis
on interdisciplinary, multicenter collaborations to further
advance knowledge about CS including the creation of a
prospective patient database.8-9
REFERENCES
1. Chen ES, Moller, DR. Etiology of sarcoidosis. Clin Chest Med.
2008;29:365-377.
2. Doughan A, Willams B. Cardiac sarcoidosis. Heart. 2006;92:282-288.
3. Silverman KJ, Hutchins GM and Bulkley BH. Cardiac sarcoid: a
clinicopathologic study of 84 unselected patients with systemic
sarcoidosis. Circulation. 1978;58(6):1204-1211.
4. Hsu RM, Connors AF and Tomashefski JF. Histologic, microbiologic,
and clinical correlates of the diagnosis of sarcoidosis by
transbronchial biopsy. Arch Pathol Lab Med. 1996; 120(4):364-368.
5. Roberts WC, McAllister HA, Ferrans VJ. Sarcoidosis of the heart.
A clinicopathologic study of 35 necropsy patients (group 1) and
review of 78 previously described necropsy patients (group 11).
Am J Med. 1977;63:(1):86-108.
6. Kim JS, Judson MA, Donnino R, et al. Cardiac sarcoidosis. Am Heart
J. 2009;157:(1):9-21.
7. Tavora F, Cresswell N, Li L, et al. Comparison of necropsy findings in
patients with sarcoidosis dying suddenly from cardiac sarcoidosis
versus dying suddenly from other causes. Am J Cardiol. 2009
August;104:(4):571-577.
108 J La State Med Soc VOL 167 March/April 2015
8. Kron J, Ellenbogen K. Cardiac sarcoidosis: Contemporary Review. J
Cardiovasc Electrophysiol. 2015;26:104-109.
9. Birnie DHS, Bogun F, Cooper J, et al. HRS expert consensus statement
on the diagnosis and management of arrhythmias associated with
cardiac sarcoidosis. Heart Rhythm. 2014;11:1305-1323.
10. Baughman R, Costabel U, Bois R. Treatment of sarcoidosis. Clin
Chest Med. 2008; 29: 533-548.
11. Mitchell LB, Pineda EA, Titus JL et al. Sudden death in patients
with implantable cardioverter defibrillators. J Am Coll Cardiol.
2002;39:(8):1323-1328.
Dr. Li is a first year pathology resident and Dr. McGoey is an
Associate Professor of Pathology and Residency Program Director in
the Department of Pathology at Louisiana State University School of
Medicine in New Orleans, LA.
Acknowledgements: The authors would like to gratefully
acknowledge the support of the Orleans Parish Coroner’s Office:
Dr. Jeffrey Rouse and Chief Investigator Brian Lapeyrolerie for
providing the case material for this report.