Full text of DOI:10.1038/labinvest.3780404

0
023-6837/02/8202-117$03.00/0
LABORATORY INVESTIGATION
Vol. 82, No. 2, p. 117, 2002
Copyright © 2002 by The United States and Canadian Academy of Pathology, Inc.
Printed in U.S.A.
RESIDENT
REVIEW
SERIES
Isolated Noncompaction of the Ventricular
Myocardium: Clinical and Molecular Aspects of a
Rare Cardiomyopathy
Eduardo Zambrano, Stephen J. Marshalko, C. Carl Jaffe, and Pei Hui
Departments of Pathology (EZ, PH) and Cardiology (SJM, CCJ), Yale University School of Medicine,
New Haven, Connecticut
solated noncompaction of the ventricular myocar-
dium (INVM) is a rare congenital heart disease that
16-year-old son, who has no manifestations of cardiac
disease.
I
results from an abnormal arrest in endomyocardial
embryogenesis. It is characterized by the presence of
prominent ventricular myocardial trabeculations and
deep intertrabecular recesses, in the absence of other
structural heart defects. INVM was initially described
in the pediatric population (Chin et al, 1990), but it has
also been recognized more recently in adults (Oechs-
lin et al, 2000; Ritter et al, 1997). We present a case of
a 35-year-old woman with clinical and echocardio-
graphic features of INVM who underwent cardiac
transplantation in our institution. The literature on
cardiac embryogenesis and development, with an
emphasis on the different genetic factors that lead to
noncompaction of the ventricular myocardium, is also
reviewed.
Both transthoracic and transesophageal echocar-
diograms performed 2 weeks before surgery revealed
a severe reduction in the patient’s left ventricular
systolic function with an asymmetric pattern of hyper-
trophy of the left ventricular myocardium, localized to
the anterior and anterolateral segments. Prominent
trabeculations with deep intertrabecular recesses
were also identified in these regions of hypertrophy
(Fig. 1). The patient’s congestive heart failure pro-
gressed despite pharmacotherapy, and the patient
underwent orthotopic heart transplantation 12 years
after the onset of symptoms. Recovery after trans-
plantation has been uneventful.
Gross and Microscopic Findings
Case Presentation
The explanted heart weighed 420 g. It had been
transected at the level of the atria, the aorta, and the
pulmonary artery as part of the transplantation surgi-
cal procedure. The epicardial surface was grossly
unremarkable. The coronary arteries and the remain-
ing segments of the great vessels had a normal
anatomic distribution. The tricuspid, pulmonary, mi-
tral, and aortic valve circumferences measured 15, 8,
Clinical History
A 35-year-old woman of Hispanic descent was
evaluated at our institution for progressive signs and
symptoms of heart failure. The patient was asymptom-
atic until age 23 years, when she began to experience
intermittent episodes of shortness of breath, chest
pain, and syncope. Her past medical history was
negative for illegal drugs, alcohol, or tobacco con-
sumption, systemic hypertension, or diabetes melli-
tus. Family history was negative for congenital heart
diseases, with none of the patient’s parents or 22
siblings, including a nonidentical twin sister, present-
ing a similar clinical picture. The patient also has a
10, and 7 cm, respectively. Serial sectioning from the
apex toward the base of the ventricles revealed a
thickened left ventricular wall, measuring 25 mm in
greatest thickness. The left ventricular myocardium
showed prominent trabeculations, with intertrabecular
recesses invaginating deeply into the outer one-third
of the myocardium (Fig. 2A). The right ventricular wall
and the interventricular septum measured 15 mm and
20 mm, respectively. Multiple histologic sections were
taken and stained with hematoxylin/eosin, Klatskin’s
trichrome, and elastin stains. Marked interstitial fibro-
sis with compensatory hypertrophy of the myocytes
was present in the left ventricular myocardium. The
endocardium was thickened by fibrous tissue, but no
Received November 15, 2001.
Address reprint requests to: Dr. Eduardo Zambrano, Department of Pathol-
ogy Yale University School of Medicine, East Pavilion Room 2-614, 20 York
St., P.O. Box 208023, New Haven, Connecticut 06520-8023. E-mail:
eduardo.zambrano@yale.edu
Laboratory Investigation • February 2002 • Volume 82 • Number 2 117

Zambrano et al
tion, with persistence of multiple prominent ventricular
trabeculations and deep intertrabecular recesses.
INVM typically involves the left ventricular myocar-
dium. However, in less than one-half of patients, right
ventricular noncompaction may also be present (Hook
et al, 1996; Ritter et al, 1997).
The clinical manifestations are not specific and may
include heart failure resulting from systolic and dia-
stolic ventricular dysfunction, conduction abnormali-
ties, and cardioembolic events from thrombus forma-
tion within intertrabecular recesses (Ritter et al, 1997).
Cardiac manifestations may range from complete ab-
sence of symptoms to severe cardiac disability lead-
ing to heart transplantation or death (Agmon et al,
1999; Ichida et al, 1999).
Currently, echocardiography is the diagnostic mo-
dality of choice for INVM (Agmon et al, 1999). Echo-
cardiographic criteria for INVM, in the absence of
significant heart lesions, include a thin, compacted
epicardial and an extremely thickened endocardial
layer with prominent trabeculations and deep re-
cesses (Oechslin et al, 2000). Although INVM is a
congenital myocardial disorder, the onset of symp-
toms is commonly delayed until adulthood, possibly
secondary to progressive ventricular dysfunction. The
mechanism of systolic dysfunction is not entirely clear,
but it is most likely due to chronic ischemia caused by
a mismatch of blood demand and supply to the
multiple prominent myocardial trabeculae (Agmon et
al, 1999; Junga et al, 1999). Similarly, the causes and
electrophysiologic mechanisms of arrhythmias are still
unknown. However, grossly irregular branching and
connection of myocardial fascicles, isometric contrac-
tions with increased wall stress, and localized coro-
nary perfusion impairment can all induce disorganized
or delayed activation, and have been implicated as
potential causes for arrhythmias in cases of INVM
(Buonanno et al, 2000).
The prognosis of INVM is variable and may range
from a prolonged asymptomatic course to a fulminant
course of progressive heart failure leading to heart
transplantation or death (Agmon et al, 1999; Ritter et
al, 1997). Only seven cases of INVM treated by heart
transplantation have been previously reported in the
literature (Conraads et al, 2001).
Figure 1.
Transthoracic echocardiogram. A, Apical four chamber, and B, parasternal
short axis views demonstrating the prominent trabeculations and deep
intertrabecular recesses localized to the regions of hypertrophy in the mid and
apical anterior and anterolateral segments. Transesophageal echocardiogram.
C, Short axis view further depicting the trabeculations and intertrabecular
recesses in the anterior and anterolateral segments.
Cardiac Embryogenesis and Development
Cardiac embryogenesis and development involve
precisely regulated molecular and embryogenetic
events, triggered by specific signaling molecules and
mediated by tissue-specific transcription factors. Car-
diomyocytes originate in the anterior lateral mesoderm
soon after gastrulation, in response to protein factors
secreted from the adjacent endoderm. These cardio-
genic signals, which include cerberus and bone mor-
phogenetic proteins, activate the expression of the
homeobox gene tinman in flies and the related gene
Nkx2.5 in vertebrates. These factors cooperate with
zinc-finger transcription factors of the GATA family to
activate cardiac gene expression, including the Mef2
gene, which encodes a transcription factor that con-
fibroelastosis was identified. The right ventricle
showed moderate myocardial hypertrophy. Prominent
myocardial trabeculations with deep intertrabecular
recesses, and overlying endocardium thickened by
fibrous tissue were also evident microscopically (Fig.
2, B–D).
Review of the Literature
Isolated Noncompaction of the Ventricular Myocardium
INVM, also designated “spongy myocardium” or
“persistent embryonic myocardium,” results from an
arrest in the normal process of myocardial compac-
1
18 Laboratory Investigation • February 2002 • Volume 82 • Number 2

Isolated Noncompaction of the Ventricular Myocardium
Figure 2.
A, Gross photograph of the explanted heart showing prominent myocardial trabeculations and deep recesses in the left ventricular wall. Multifocal areas of fibrosis
are also evident. A section has been taken from the interventricular septum. B, Low-power view of histologic section showing a deep myocardial recess in close
proximity to the epicardial adipose tissue (hematoxylin and eosin stain; Original magnification, ϫ40). C, Low-power view of histologic section showing multiple
trabeculations and myocardial projections, with extensive fibrosis (Klatskin trichrome stain; original magnification, ϫ10). D, Low-power view of histologic section
showing a thickened endocardium overlying the myocardial recesses, with areas of patchy fibrosis (Klatskin stain; original magnification, ϫ40).
trols cardiac muscle cell differentiation. The Mef2
transcription factor activates the expression of genes
encoding cardiac muscle-specific proteins (such as
cardiac actin, atrial natriuretic factor, and the alpha
myosin heavy chain) (Gilbert, 2000; Srivastava and
Olson, 2000).
that form the conduction system of the heart, in
response to endothelin-1 (ET-1) (Srivastava and Ol-
son, 2000).
At this stage, before the development of the coro-
nary circulation, the human embryonic myocardium
consists of a “spongy” meshwork of interwoven myo-
cardial fibers forming trabeculae with deep intertrabe-
cular recesses (Dusek et al, 1975). The intertrabecular
recesses communicate with the left ventricular cavity,
and blood is supplied to the myocardium through the
intertrabecular spaces. Neuregulin growth factors se-
creted from the endocardium, and the local expres-
sion of the myocardial receptors ErbB2 and ErbB4, are
required for the development of these trabeculae.
Other angiogenic factors expressed in the endocar-
dium, such as vascular endothelial growth factor and
angiopoietin-1, may also play a role in the process of
ventricular trabeculation (Srivastava and Olson, 2000).
After this, during weeks 5 to 8 of human fetal life, the
ventricular myocardium undergoes gradual compac-
tion, with transformation of the relatively large intertra-
becular spaces into capillaries, and the large spaces
After their specification, myocytes migrate along the
ventral midline of the embryo. As they migrate, the
cells begin to express N-cadherin and differentiate
into an epithelium. A small population of these cells
then down-regulates N-cadherin and dissociate from
the epithelium to form the endocardium. The epithelial
cells, in turn, will form the myocardium. The myocar-
dium and endocardium eventually fuse together into a
single beating cardiac tube, at 3 weeks of human
gestational life (Gilbert, 2000). The linear heart tube
undergoes segmentation along the anterior-posterior
axis into precursors of the aortic sac, conotroncus,
ventricles, and atria, with different patterns of gene
expression in each of these chambers. In addition, a
subset of ventricular cardiomyocytes surrounding the
developing coronary arteries differentiates into cells
Laboratory Investigation • February 2002 • Volume 82 • Number 2 119

Zambrano et al
within the trabecular meshwork flatten or disappear.
The process of compaction of the ventricular myocar-
dium normally progresses from epicardium to endo-
cardium and from the base of the heart toward the
apex. At the same time, while the process of ventric-
ular myocardium compaction occurs, the coronary
vessels are formed and the coronary circulation is
established (Agmon et al, 1999).
other proteins that intervene in muscular contraction and
in maintaining the structural integrity of tissues (Mizuno
et al, 2001). In addition, a distal 5q deletion, del(5)(q35.1-
q35.5), was described in a girl with a complex heart
malformation including ventricular myocardial noncom-
paction. This deletion includes the locus for the cardiac-
specific homeobox gene CSX, suggesting that in some
instances ventricular myocardial noncompaction can be
caused by haploinsufficiency of CSX (Pauli et al, 1999).
Figure 3 summarizes the different factors that intervene
in cardiac embryogenesis, and the process of ventricular
myocardial trabeculation and compaction.
Given that most familial cases of INVM are X-linked
and that no relatives in the patient’s extensive family
present a similar clinical picture, the case under dis-
cussion most likely represents a sporadic form of the
disease. As previously stated, no genes responsible
for the sporadic forms of INVM have yet been
identified.
Genetics of INVM
INVM results from an arrest in the normal process of
myocardial compaction, with persistence of multiple
prominent ventricular trabeculations. It is a distinctive
clinical entity with a heterogeneous genetic back-
ground. Both sporadic and familial forms of INVM
have been described (Agmon et al, 1999; Bleyl et al,
1997a; Chin et al, 1990; Kurosaki et al, 1999; Matsuda
et al, 1999). Although male predominance is the rule in
familial cases of INVM, both sexes are affected in the
sporadic forms of the disease. Nevertheless, whereas
the genes responsible for some familial forms have
been identified (Bleyl et al, 1997b; Ichida et al, 2001)
those for the sporadic forms of INVM have not yet
been characterized.
Genetic linkage analysis has revealed that muta-
tions in the gene G4.5 on the Xq28 chromosomal
region are responsible for some familial cases of INVM
Conclusion
In the past few years, our understanding of the mo-
lecular factors involved in the embryogenesis and
development of the human heart has increased re-
markably. As a result of this, abnormalities of specific
genes and their products are now known to be re-
sponsible for different types of congenital heart dis-
eases once thought to have multifactorial etiologies
(
Bleyl et al, 1997a; Ichida et al, 2001). These cases of
X-linked INVM are allelic with Barth syndrome (MIM
02060) (Bleyl et al, 1997b), which is characterized by
(Chin, 1998; London, 1998; Seidman et al, 1998; and
Table 1). On many occasions, these developmental
cardiopathies result from single gene point mutations
that disrupt their normal function in cardiac specifica-
tion and morphogenesis. The consequences of these
mutations vary widely, not only because of the specific
3
dilated cardiomyopathy, short stature, skeletal myop-
athy, neutropenia, and abnormal mitochondria. Inter-
estingly, molecular studies have linked together what
were formerly considered different conditions and
have shown that the G4.5 gene is also responsible for
X-linked endocardial fibroelastosis (MIM 305300), and
severe X-linked cardiomyopathy (MIM 300069)
(
D’Adamo et al, 1997). In addition, this locus is in
proximity to other genes associated with systemic
myopathies that are commonly accompanied by var-
ious cardiomyopathies and arrhythmias, such as
Emery-Dreifuss muscular dystrophy (MIM 310300)
and myotubular myopathy (MIM 31040) (Bleyl et al,
1997a). The function of the G4.5 gene protein prod-
ucts, called tafazzins, is currently unknown (Bione et
al, 1996; Cantlay et al, 1999). However, gene sequenc-
ing has revealed nucleotide homology to a highly
conserved superclass of acyltransferases. It is there-
fore predicted that a glycerophospholipid is most
likely the missing end product (Barth et al, 1999).
Some cases of INVM have been found to be associ-
ated with certain genetic syndromes (Mandel et al, 2001;
Wong and Bofinger, 1997). Other forms of nonventricular
myocardial compaction associated with additional types
of congenital heart diseases have also been described.
Recently, a transition C3T mutation was identified in the
␣
-dystrobrevin gene in one family with such type of
congenital heart disease (Ichida et al, 2001). The
-dystrobrevin gene has been localized to chromosome
8q12 (Sadoulet-Puccio et al, 1997). It encodes for an
␣
1
Figure 3.
intracellular protein that interacts with dystrophin and
Protein factors at different stages of cardiac development.
1
20 Laboratory Investigation • February 2002 • Volume 82 • Number 2

Isolated Noncompaction of the Ventricular Myocardium
Table 1. Human Genes Implicated in Cardiac Defects
Gene Locus
Protein type
Cardiac defect
NKX2.5
5q34
Transcription factor
Atrial septal defect, cardiac
conduction abnormalities,
tetralogy of Fallot
Atrial septal defect, ventricular
septal defect,
TBX5
12q24
Transcription factor
Holt-Oram syndrome
Pulmonary stenosis, tetralogy
of Fallot, Alagille syndrome
Patent ductus arteriosus,
Char syndrome
JAGGED-1
TFAP2B
Elastin
20p12
6p12
Signaling molecule
Transcription factor
Connective tissue
Connective tissue
Connective tissue
7q11
Supravalvular aortic stenosis,
William’s syndrome
Fibrillin
15q21
2q31
Aortic aneurysm,
Marfan’s syndrome
Type III collagen
Aortic aneurysm,
Ehlers-Danlos syndrome
type IV
Unknown
22q11
Multiple genes
DiGeorge syndrome, Tetralogy
of Fallot, conotruncal and
aortic arch defects
HERG
7q35–q36
Potassium channel
Long QT syndrome,
Brugada syndrome
SCN5A
3p21
Sodium channel
Potassium channel
Potassium channel
Sarcomere protein
Sarcomere protein
Sarcomere protein
Sarcomere protein
Unknown
Long QT syndrome
KVLQT1
11p15
21q22
1q32
Long QT syndrome
KCNE2
Long QT syndrome
Cardiac troponin T
Hypertrophic cardiomyopathy
Hypertrophic cardiomyopathy
Hypertrophic cardiomyopathy
Hypertrophic cardiomyopathy
Hypertrophic cardiomyopathy,
Wolf-Parkinson-White
syndrome
Cardiac myosin binding protein C 11q1
Cardiac ␤-myosin heavy chain
14q1
15q2
7q3
␣
-tropomyosin
Unknown
G4.5
Xq28
Tafazzins (function unknown)
Emerin (function unknown)
Barth syndrome, INVM,
endocardial fibroelastosis,
dilated cardiomyopathy
Emery-Dreifuss syndrome,
dilated cardiomyopathy
Emerin
Xq28
Xp21
Dystrophin
Membrane-cytoskeleton system Duchenne syndrome,
in striated muscle
Becker syndrome,
dilated cardiomyopathy
␣-dystrobrevin
18q12
Membrane-cytoskeleton system Noncompaction of ventricular
in striated muscle
Unknown
myocardium
Dilated cardiomyopathies
Others
1p1–1q1, 1q24,
3
p25–p22, 9q13
genetic alteration they produce, but probably also
because of the influence of modifier genes, environ-
mental factors, and genetic polymorphisms that de-
termine the severity, type, and age of onset of con-
genital heart disease. Unraveling the molecular factors
that interplay in cardiac embryogenesis and develop-
ment has important implications not only for under-
standing congenital heart diseases, but also for the
potential of genetically reprogramming noncardiac
cells to be used in cardiac regeneration or cell
replacement.
References
Agmon Y, Connolly HM, Olson LJ, Khandheria BK, and
Seward JB (1999). Noncompaction of the ventricular myo-
cardium. J Am Soc Echocardiogr 12:859–863.
Barth PG, Wanders RJ, Vreken P, Janssen EA, Lam J, and
Baas F (1999). X-linked cardioskeletal myopathy and neutro-
penia (Barth syndrome) (MIM 302060). J Inherit Metab Dis
22:555–567.
Bione S, D’Adamo P, Maestrini E, Gedeon AK, Bolhuis PA,
and Toniolo D (1996). A novel X-linked gene, G4.5, is respon-
sible for Barth syndrome. Nat Genet 12:385–389.
Acknowledgement
Bleyl SB, Mumford BR, Brown-Harrison MC, Pagotto LT,
Carey JC, Pysher TJ, Ward K, and Chin TK (1997a). Xq28-
linked noncompaction of the left ventricular myocardium:
We thank Dr. Shulan Tian for her initial assistance
with this case.
Laboratory Investigation • February 2002 • Volume 82 • Number 2 121

Zambrano et al
Prenatal diagnosis and pathologic analysis of affected indi-
viduals. Am J Med Genet 72:257–265.
Junga G, Kneifel S, Von Smekal A, Steinert H, and Bauersfeld
U (1999). Myocardial ischaemia in children with isolated
ventricular non-compaction. Eur Heart J 20:910–916.
Bleyl SB, Mumford BR, Thompson V, Carey JC, Pysher TJ,
Chin TK, and Ward K (1997b). Neonatal, lethal noncompac-
tion of the left ventricular myocardium is allelic with Barth
syndrome. Am J Hum Genet 61:868–872.
Kurosaki K, Ikeda U, Hojo Y, Fujikawa H, Katsuki T, and
Shimada K (1999). Familial isolated noncompaction of the left
ventricular myocardium. Cardiology 91:69–72.
Buonanno C, Variola A, Dander B, Gabaldo S, and Marafioti
V (2000). Isolated noncompaction of the myocardium: An
exceedingly rare cardiomyopathy. A case report. Ital Heart J
London B (1998). Cardiac arrhythmias. In: Rosenzweig A and
Jameson LJ, editors. Principles of molecular medicine, 1st
ed. Totowa, New Jersey: Humana Press, 157–160.
1
:301–305.
Mandel K, Grunebaum E, and Benson L (2001). Noncompac-
tion of the myocardium associated with Roifman syndrome.
Cardiol Young 11:240–243.
Cantlay AM, Shokrollahi K, Allen JT, Lunt PW, Newbury-Ecob
RA, and Steward CG (1999). Genetic analysis of the G4.5
gene in families with suspected Barth syndrome. J Pediatr
Matsuda M, Tsukahara M, Kondoh O, and Mito H (1999).
Familial isolated noncompaction of ventricular myocardium.
J Hum Genet 44:126–128.
135:311–315.
Chin AJ (1998). Congenital heart disease. In: Rosenzweig A
and Jameson LJ, editors. Principles of Molecular Medicine,
Mizuno Y, Thompson TG, Guyon JR, Lidov HG, Brosius M,
Imamura M, Ozawa E, Watkins SC, and Kunkel LM (2001).
Desmuslin, an intermediate filament protein that interacts
with alpha-dystrobrevin and desmin. PNAS 98:6156–6161.
1
st ed. Totowa, New Jersey: Humana Press, 117–125.
Chin TK, Perloff JK, Williams RG, Jue K, and Mohrmann R
1990). Isolated noncompaction of left ventricular myocar-
(
dium. A study of eight cases. Circulation 82:507–513.
Oechslin EN, Jost CH, Rojas JR, Kaufmann PA, and Jenni R
(2000). Long-term follow-up of 34 adults with isolated left
ventricular noncompaction: A distinct cardiomyopathy with
poor prognosis. J Am Coll Cardiol 36:493–500.
Conraads V, Paelinck B, Vorlat A, Goethals M, Jacobs W, and
Vrints C (2001). Isolated non-compaction of the left ventricle:
A rare indication for transplantation. J Heart Lung Transplant
2
0:904–907.
Pauli RM, Scheib-Wixted S, Cripe L, Izumo S, and Sekhon
GS (1999). Ventricular noncompaction and distal chromo-
some 5q deletion. Am J Med Genet 85:419–423.
D’Adamo P, Fassone L, Gedeon A, Janssen EA, Bione S,
Bolhuis PA, Barth PG, Wilson M, Haan E, Orstavik KH, Patton
MA, Green AJ, Zammarchi E, Donati MA, and Toniolo D
Ritter M, Oechslin E, Sutsch G, Attenhofer C, Schneider J,
and Jenni R (1997). Isolated noncompaction of the myocar-
dium in adults. Mayo Clin Proc 72:26–31.
(
1997). The X-linked gene G4.5 is responsible for different
infantile dilated cardiomyopathies. Am J Hum Genet 61:862–
67.
8
Sadoulet-Puccio HM, Feener CA, Schaid DJ, Thibodeau SN,
Michels VV, and Kunkel LM (1997). The genomic organization
of human dystrobrevin. Neurogenetics 1:37–42.
Dusek J, Ostadal B, and Duskova M (1975). Postnatal per-
sistence of spongy myocardium with embryonic blood sup-
ply. Arch Pathol Lab Med 99:312–317.
Seidman CE, MacRae C, and Seidman JG (1998). Inherited
cardiomyopathies. In: Rosenzweig A and Jameson LJ, edi-
tors. Principles of molecular medicine, 1st ed. Totowa, New
Jersey: Humana Press, 127–132.
Gilbert SF (2000). Developmental biology, 6th ed. Sunder-
land, Massachusetts: Sinauer Associates, Inc., 471–477.
Hook S, Ratliff NB, Rosenkranz E, and Sterba R (1996).
Isolated noncompaction of the ventricular myocardium. Pe-
diatr Cardiol 17:43–45.
Srivastava D and Olson EN (2000). A genetic blueprint for
cardiac development. Nature 407:221–226.
Ichida F, Hamamichi Y, Miyawaki T, Ono Y, Kamiya T, Akagi
T, Hamada H, Hirose O, Isobe T, Yamada K, Kurotobi S, Mito
H, Miyake T, Murakami Y, Nishi T, Shinohara M, Seguchi M,
Tashiro S, and Tomimatsu H (1999). Clinical features of
isolated noncompaction of the ventricular myocardium:
Long-term clinical course, hemodynamic properties, and
genetic background. J Am Coll Cardiol 34:233–240.
Wong JA and Bofinger MK (1997). Noncompaction of the
ventricular myocardium in Melnick-Needles syndrome. Am J
Med Genet 71:72–75.
Ichida F, Tsubata S, Bowles KR, Haneda N, Uese K,
Miyawaki T, Dreyer WJ, Messina J, Li H, Bowles NE, and
Towbin JA (2001). Novel gene mutations in patients with left
ventricular noncompaction or Barth syndrome. Circulation
103:1256–1263.
1
22 Laboratory Investigation • February 2002 • Volume 82 • Number 2