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Dilated Form of Endocardial Fibroelastosis as a Result of
Deficiency in Respiratory-Chain Complexes I and IV
Domenico Corradi, MD; Bertrand Tchana, MD; Dylan Miller, MD; Laura Manotti, MD;
Roberta Maestri, BSc, PhD; Davide Martorana, BSc; Sergio Callegari, MD; Valentina Allegri, MD;
Nicola Carano, MD; Aldo Agnetti, MD; Umberto Squarcia, MD
A
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2-month-old girl with poor appetite and failure to thrive
was admitted because of pallor, dyspnea, and
tachycardia with periodic gallop rhythm. Chest x-ray (Figure
1) showed cardiomegaly, and echocardiography (Figure 2)
revealed left ventricular dilation (diastolic diameter, 41.5 mm
[normal, ⬍23 mm]), decreased contractility, and mild to
moderate mitral valve insufficiency. ECG (Figure 3) showed
sinus rhythm with left bundle-branch block and repolarization
abnormalities. These findings were compatible with severe
dilated cardiomyopathy. Polymerase chain reaction of the
serum failed to detect any cardiotropic virus genomes. There
was lactic acidosis. On frozen striated muscle, the mitochondrial respiratory chain function was tested and found to have
decreased activities of complexes I (NADH coenzyme Q
reductase, 9.1 nmol/min per milligram [normal, 13 to 24])
Figure 2. Transthoracic echocardiography performed at the
same age displaying severe left ventricular (LV) chamber dilation. RV indicates right ventricle; LA, left atrium; and Ao, aorta.
and IV (cytochrome-c oxidase, 103 nmol/min per milligram
[normal, 120 to 220]). Therapy with oxygen, digoxin, captopril, and furosemide was initiated. Despite this, her cardiovascular function continued to worsen; she was readmitted at
10 months of age for decompensated heart failure and died 8
days later. Her family history revealed 1 brother who had died
suddenly at the age of 3 months (no autopsy was performed).
Autopsy confirmed cardiac enlargement with severe left
ventricular chamber dilation (Figure 4A); the endocardium
was whitish and extremely thickened (Figure 4B). Histopathologically, there was significant endocardial fibroelastosis (Figure 5A and 5B). The left ventricular subendocardial
myocardium displayed diffuse myocyte vacuolization (Figure
5C) with foci of necrosis and fibrosis (Figure 5A). Ultrastructurally, the myocyte vacuoles corresponded to severe loss of
sarcomeres (myolysis) with accumulation of abundant mitochondria (Figure 5D).
Figure 1. Chest x-ray obtained at age 2 months showing significant enlargement of the cardiac profile.
From the Department of Pathology and Laboratory Medicine, Section of Pathology (D.C., L.M., R.M.), and Department of Pediatrics, Pediatric
Cardiology Unit (B.T., V.A., N.C., A.A., U.S.), University of Parma, Parma, Italy; Department of Laboratory Medicine and Pathology, Division of
Anatomic Pathology, Mayo Clinic, Rochester, Minn (D.M.); Department of Clinical Medicine, Nephrology, and Health Science, Section of Genetics,
University of Parma, Parma, Italy (D.M.); and Division of Cardiology, Fidenza Hospital, Fidenza, Italy (S.C.).
Correspondence to Domenico Corradi, MD, Department of Pathology and Laboratory Medicine, Section of Pathology, University of Parma, Via
Gramsci 14, 43100 Parma, Italy. E-mail [email protected]
(Circulation. 2009;120:e38-e40.)
© 2009 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org
DOI: 10.1161/CIRCULATIONAHA.108.840660
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Corradi et al
Dilated Form of Endocardial Fibroelastosis
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Figure 3. ECG obtained at first admission to the hospital showing left bundle-branch block and repolarization abnormalities.
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Endocardial fibroelastosis is a nonspecific reaction to
endocardial stress and injury leading to elaboration of elastinrich extracellular matrix, which is particularly prominent in
the growing heart. Endocardial fibroelastosis often accompanies abnormal increases in mural tension (provoked by
chamber dilation) or markedly elevated intracavitary pressure. Inadequate subendocardial blood flow and lymphatic
obstruction are additional pathogenetic mechanisms that have
been proposed in this process.1 In this patient, respiratorychain enzyme analysis revealed deficiencies in oxidative
phosphorylation complexes I and IV, which strongly suggest
a pathogenic mitochondrial DNA (mtDNA) mutation.
The progressive myolysis and growing number of nonfunctioning myocytes putatively induced left ventricular dilation.
The resulting stresses placed on the endothelium had led to a
dramatic increase in endocardial elastic fiber matrix, ostensibly in an attempt to hinder further chamber dilatation and
allow for dynamic and reversible expansion during the
cardiac cycle.2 Apart from 1 brother who had died prematurely of unknown causes, there were no family members
with signs of metabolic disease.
Mitochondria possess their own DNA (mtDNA), which
contains 37 different genes. Twenty-four of these are needed
for transfer RNAs and ribosomal RNAs, and there are 13 for
4 respiratory chain multisubunit complexes (I, III, IV, V).
Because in every organelle there are ⬇900 different proteins,
the great majority of these gene products are encoded by
nuclear DNA.3 As a consequence, primary mitochondrial
defects may be subdivided into disorders involving mtDNA
(following the rules of mitochondrial genetics) and disorders
due to nuclear DNA defects (which obey Mendel’s laws). In
particular, mitochondrial genetics differs from the mendelian
in 3 main peculiarities: (1) There is a maternal inheritance; (2)
mutations affect only a fraction of mtDNAs (heteroplasmy);
in addition to depending on the anatomic site, the clinical
expression of these disorders will also depend on the proportion of mutated to wild-type mtDNAs within cells (threshold
effect); and (3) the random subdivision of mitochondria
during mitotic cell division can modify the proportion of
mutated mtDNA within the daughter cells (mitotic segregation), and a “bottleneck” between egg-cell and embryo allows
only a fraction of mtDNAs to become part of the fetal cells,
very likely in order to filter out mutations and minimize
heteroplasmy.3,4
In the presence of a respiratory chain defect, complex I
isolated deficiency is the most frequent one, followed by a
combined deficiency of complexes I, III, or IV.4 A mtDNA
mutation may affect either specific proteins belonging to the
respiratory chain apparatus or the entire mitochondrial protein synthesis (when involving transfer RNA, ribosomal
RNA, or as a result of giant deletions).3
Mitochondrial cardiomyopathies can genetically be subdivided into sporadic, mendelian-inherited, and maternally
inherited disorders.1 Sporadic cardiomyopathy may be encountered in the Kearns-Sayre syndrome, which is caused by
mtDNA deletions or duplication. It is invariably characterized
by early onset (before age 20 years), external ophthalmoplegia, and pigmentary retinopathy; ataxia, short stature, and
hearing loss may be additional symptoms. When present,
cardiac involvement consists of conduction defects (prolonged intraventricular conduction and atrioventricular
blocks, probably as a result of preferential accumulation of
mutated mtDNA in the conduction system myocytes) and,
only as a later event, impaired myocardial contractility.5,6
Figure 4. A, Autopsy heart specimen, cut
along a midventricular short-axis plane,
showing severe left ventricular chamber
(LV) dilation with right ventricular (RV)
compression. Bar⫽4.5 cm. B, A highermagnification view of the left ventricular
wall, with significant whitish endocardial
thickening (asterisk) with partial obliteration of the trabeculae. Bar⫽2 cm.
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Circulation
August 11, 2009
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Figure 5. A, Low-power photomicrograph
showing the histopathological appearance
of the endocardium (E) and areas of interstitial fibrosis (arrowheads). Hematoxylineosin stain; magnification ⫻4; bar⫽750
␮m. B, Low-power photomicrograph
showing that the endocardium (E) is
thickened and mainly composed of elastic
fibers (dark color). Weigert elastic fiber
stain; magnification ⫻10; bar⫽300 ␮m. C,
High-power photomicrograph of the subendocardial myocardium with severe
cytoplasmic vacuolization (arrowhead).
Hematoxylin-eosin stain; magnification
⫻40; bar⫽100 ␮m. D, On electron
microscopy, a binucleated myocyte
shows a severe loss of myofibrils (arrow)
and a cytoplasmic accumulation of mitochondria (arrowhead). N indicates
nucleus; RC, red cell. Magnification
⫻2800; bar⫽10 ␮m.
Mendelian inheritance in mitochondrial cardiomyopathies
is an infrequent event in which the genetic change affects the
nuclear DNA and, only secondarily, the mtDNA as multiple
deletions. An example of this is the reported autosomal
dominant chronic progressive external ophthalmoplegia associated with dilated cardiomyopathy and multiple mtDNA
deletions.5
Maternally inherited mutations represent the most frequent
category of mitochondrial cardiomyopathies whose cause is
an mtDNA point mutation in almost all the cases. More than
50 different point mutations have been associated with
various clinical disorders (mainly affecting heart, brain, and
skeletal muscle).5 MELAS syndrome (mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes)
can become manifest with cardiac involvement (as hypertrophic cardiomyopathy or, less frequently, Wolf-ParkinsonWhite syndrome) in 20% to 30% of cases. Another wellknown maternally inherited disorder is the MERRF syndrome
(myoclonic epilepsy with ragged red fibers), in which, in
addition to presenting with myopathy, ataxia, and deafness,
approximately one third of the patients show cardiomegaly
and ventricular arrhythmic episodes.5
From the pathological standpoint, very frequently, mitochondrial cardiomyopathy becomes manifest as a left ventricular concentric hypertrophy with, in isolated cases, an evolution into a dilated form that is only rarely associated with
endocardial fibroelastosis.1,7 Unfortunately, preclinical specific signatures of mitochondrial cardiomyopathy are scarce.
In general, clinical suspicion for neonatal mitochondrial
disorders with cardiomyopathy should arise in the presence of
deafness, failure to thrive, lactic acidosis, and cardiomegaly
with increasing signs of failure and/or arrhythmia, all of these
sometimes within the spectrum of a multisystem presentation
(mainly nervous system or skeletal muscle) and often with a
clear maternal inheritance.8 In the presence of nonspecific
signs of dilated cardiomyopathy in children, a large spectrum
of tests must be performed to narrow the differential diagnosis between mitochondrial and other metabolic diseases (eg,
fatty acid oxidation defects). Blood and muscle samples
should also be kept for genetic tests and biochemical/
morphological studies including those for mitochondrial diseases. In addition, clinical gene-based screening is strongly
recommended in patients’ family members to provide either
early cardiomyopathy diagnosis or personalized evaluation of
risk assessment.4
Disclosures
None.
References
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Dilated Form of Endocardial Fibroelastosis as a Result of Deficiency in Respiratory-Chain
Complexes I and IV
Domenico Corradi, Bertrand Tchana, Dylan Miller, Laura Manotti, Roberta Maestri, Davide
Martorana, Sergio Callegari, Valentina Allegri, Nicola Carano, Aldo Agnetti and Umberto
Squarcia
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Circulation. 2009;120:e38-e40
doi: 10.1161/CIRCULATIONAHA.108.840660
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2009 American Heart Association, Inc. All rights reserved.
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