AJR 2001; 176:575-581
© American Roentgen Ray Society
The Molecular Genetic Revolution in Congenital Heart Disease
Raymond W. Sze1,2 and
Katherine E. Yutzey3
1
Department of Radiology, Children's Hospital Medical Center, 3333 Burnet Ave.,
Cincinnati, OH 45229-3039.
2
Present address: Department of Radiology, Children's Hospital & Regional
Medical Center, 4800 Sand Point Way N.E., CH-69, Seattle, WA 98105.
3
Department of Pediatrics, Division of Molecular Cardiovascular Biology,
Children's Hospital Research Foundation, Cincinnati, OH 45229-3039.
Received June 30, 2000;
accepted after revision September 6, 2000.
Presented at the annual meeting of the American Roentgen Ray Society,
Washington, DC, May 2000.
R. W. Sze is a 2000-2001 American Roentgen Ray Society Scholar.
K.E. Yutzey is supported by grants from the National Institutes of Health
and the American Heart Society, Ohio Valley affiliate.
Address correspondence to R. W. Sze.
Introduction
Extraordinary advances have been made in understanding the molecular basis
of cardiovascular disease. In adult cardiology, gene therapy to trigger
myocardial neoangiogenesis for ischemic heart disease may replace current
therapies [1]. However, it is
in congenital heart disease that fundamental changes in our approach to
understanding and ultimately to treating cardiac disease are occurring. Our
colleagues in cardiology and cardiothoracic surgery have recognized the
bench-to-bedside importance of molecular genetic research, and one needs to
only glance through their journals to see the prominence with which these
insights are featured in their research and clinical articles.
The four overarching organizations of the radiology community have recently
agreed to reemphasize cardiac imaging in training, practice, and research.
Courses and workshops in cardiac imaging have featured prominently in recent
national conferences. What have been typically and appropriately emphasized
are basic cardiac anatomy and physiology and MR imaging techniques. What has
been neglected thus far is any mention of the molecular genetic approach to
cardiac disease. If the radiology community wishes to be an active player in
the diagnosis and treatment of congenital heart disease, then clearly the
language and research that form the foundation and concepts of its future must
be understood.
In this review, several fundamental concepts in molecular developmental
biology will be introduced by contrasting the classic, descriptive embryologic
approach to cardiac looping with the molecular genetic approach. Clinical
applications of molecular genetic research will be described using the
abnormalities that result from deletions in chromosome 22q11 and familial
hypertrophic cardiomyopathy syndromes as examples. Finally, opportunities for
radiologists and the radiology community to contribute to developmental
research will be described. As will be emphasized throughout this article,
modifications of traditional imaging techniques and the advancing science of
molecular imaging will have a critical role in assembling the seemingly
separate genetic pieces of the developmental puzzle into a unified and
coherent whole.
Molecular Foundations of Congenital Heart Disease
Classic descriptive embryology teaches us that the primitive heart tube is
formed by fusion of the lateral endocardial tubes
[2]. Bulges and constrictions
of the primitive heart tube mark future chambers, and as the heart tube
elongates, it loops to the right. Cardiac looping marks the first break in
left-right symmetry of the developing embryo. However, the mechanisms that
control looping have been poorly understood. Of importance is that excised
hearts from experimental animals have an intrinsic ability to loop; looping
occurs even when the heart tube is isolated from the pericardium, the cardiac
jelly, and the hemodynamic effects of blood flow.
During the past 3-5 years, molecular developmental biologists have made
exciting progress in elucidating the mechanisms that control cardiac looping
and development [3]. Asymmetric
gene expression in the primitive heart tube provides important clues and
markers for normal and abnormal looping
(Fig. 1). Abnormal cardiac
looping likely contributes to many developmental cardiac anomalies. Mutations
in genes with a variety of functions in early heart development have been
associated with human congenital heart disease
[4]. The broad spectrum of
genetic mutations that can lead to congenital disease underscores the
importance of accurate early diagnosis of these developmental anomalies.
View larger version (33K):
[in this window]
[in a new window]
[as a PowerPoint slide]
|
Fig. 1. —Drawing shows asymmetric gene expression in cardiac looping.
Paracrine signaling molecules (A) are secreted by cells into their
surroundings, affecting neighboring cells. Transcription factors bind to DNA
(B) and regulate transcription of DNA sequences (genes) into messenger RNA;
note helix-loop-helix motif. Extracellular matrix proteins (C) are
macromolecules that serve as support structure of cells.
|
|
Paracrine Signaling Molecules
Paracrine signaling molecules are secreted by cells into their
surroundings, with effects on target cells in close proximity
(Fig. 1). This is in contrast
to endocrine signaling, in which molecules are secreted into the blood stream
with effects on distant target cells. An example of paracrine signaling in a
nondevelopmental context is the transmission of nerve impulses via
neurotransmitters across synapses. BMP4 (bone morphogenetic protein 4) is a
paracrine signaling molecule expressed in the primitive heart tube of the
zebrafish. The shift in expression from radially symmetric to left-predominant
marks the first break in left-right symmetry of the developing heart
[5]. In mutant animals with
asymmetric or right-sided expression of BMP4, cardiac looping is
randomized.
Transcription Factors
Transcription factors are proteins that bind to DNA and regulate the
transcription of DNA to messenger RNA (Fig.
1). In embryonic chicks and mice, two muscle-specific
transcription factors, dHAND and eHAND, are asymmetrically expressed in the
right and left ventricles, respectively. Loss of dHAND expression leads to
arrest of cardiac development at the looping stage
[6]. Based on these studies,
dHAND has been hypothesized to have a critical role in heart chamber
development.
Extracellular Matrix Proteins
Extracellular matrix proteins are macromolecules secreted by cells that
serve as scaffolding for developing cells
(Fig. 1). These proteins may
separate developing groups of cells, direct cell migration, and even induce
differentiation in adjacent cells. The extracellular matrix protein JB3 is
asymmetrically expressed on the right side of the primitive heart tube, and
flectin and hLAMP1 are asymmetrically expressed on the left. When
extracellular matrix protein expression is experimentally disrupted, such as
in vitamin A-deficient quail hearts, looping is arrested
[7].
Mutations in human genes encoding for paracrine signaling molecules,
transcription factors, and extracellular matrix proteins have been associated
with a variety of syndromes with congenital cardiovascular defects. An example
of a paracrine signaling mechanism linked to congenital heart disease in
humans is Alagille syndrome
[8]. Deletions in the
jagged1 gene, which encodes a signaling molecule in the Notch
pathway, have been identified in patients with this syndrome. Mutations in the
transcription factor genes NKX2.5 and TBX5
(Fig. 1) have been associated
with a variety of congenital cardiac malformations in humans
[9,10,11].
Marfan syndrome, which includes cardiovascular defects, is the result of
mutations in the gene encoding the extracellular matrix protein fibrillin
[12]. In each case in which
the genetic cause of cardiovascular disease has been identified, there is
variable penetrance and the genotype is not predictive of the phenotype.
Therefore, the development of improved imaging techniques is critical for the
treatment of individuals with identified mutations in genes that can cause
cardiac disease.
Classic embryology deals with "what"; molecular developmental
biology attempts to explain "how" and "why." However,
the reductionist strategy of dissecting the individual genes associated with
heart development must then be redirected toward understanding the precise
effects of these genes in isolation and in concert. Just because a gene is
present during a developmental event does not prove its importance, nor does
it explain its function. Techniques to visualize the developing organ will be
critical to establishing causal relationships between gene and gene products
and their actual contribution to embryogenesis.
Clinical Applications
CATCH-22
CATCH-22 is the acronym for Cardiac defects, Abnormal facies, Thymic
hypoplasia, Cleft palate, and Hypocalcemia from deletions in chromosome 22
[4]
(Fig. 2). The cardiac defects
involve abnormalities of conotruncal development, such as persistent truncus
arteriosus, tetralogy of Fallot, and interrupted aortic arch. The association
of conotruncal cardiac lesions and abnormalities of third and fourth
pharyngeal pouch derivatives was first recognized in the Di-George syndrome
[13]. Two other syndromes, the
velocardiofacial [14] and
conotruncal anomaly face syndromes
[15], were recognized as
similar but were considered distinct because of different patterns of facial
dysmorphism and distribution of cardiac anomalies. Recent cytogenetic and
molecular studies, however, revealed microdeletions in the same specific
region of chromosome 22 (22q11) (Fig.
2) in 80-95% of patients. Furthermore, genotyping of nonsyndromic
patients with isolated conotruncal cardiac lesions revealed that between 20%
and 30% of these patients had deletions in the identical chromosomal region.
Likely, 10% of patient's requiring surgery for congenital heart disease have
abnormalities in this specific genetic neighborhood
[4].
View larger version (35K):
[in this window]
[in a new window]
[as a PowerPoint slide]
|
Fig. 2. —Drawing shows cardiac defects, abnormal facies, thymic
hypoplasia, cleft palate, and hypocalcemia from deletions in chromosome 22
(CATCH-22). 22q11 locus (A), DiGeorge-critical segment, is located on long arm
of chromosome 22. Neural crest migration (B) is shown by stippled arrows,
which depict migrational routes of neural crest cells to various primordia
affected in CATCH-22. Clinical manifestations of CATCH-22 (C), including
facial dysmorphism, hypocalcemia, immunodeficiency resulting from absence of
parathyroid and thymic development, and congenital heart and aortic arch
diseases, are illustrated.
|
|
DiGeorge [16] was first to
propose perturbation of the third and fourth pharyngeal pouches as an
underlying mechanism for the syndrome that he had first described. CATCH-22 is
currently understood as a defect of neural crest migration and development.
The neural crest is the pleuripotential cell population, sometimes referred to
as the fourth germ cell layer, that arises from the lateral margins of the
neural plate (Fig. 2). These
cells detach from the neural plate during neurulation, migrate throughout the
body, and differentiate into structures as diverse as the dermal bones of the
skull, adrenal medulla, dorsal root and chain ganglia, and melanocytes of the
skin. In the developing cardiovasculature, neural crest contributes to the
truncoconal septum and the aortic arch
(Fig. 2); ablation of the
neural crest in experimental chicken embryos re-creates the phenotype of
DiGeorge syndrome.
Current research is focused on determining which gene or genes within the
22q11 region are responsible for perturbing neural crest development and
causing the CATCH-22 syndrome. Researchers hope to create a mouse model of the
22q11 deletion, but a major obstacle will be recognizing and understanding the
development of this structural heart disease in experimental embryos and
animals. High-resolution imaging techniques to study the morphology of the
developing heart in transgenic animals, most commonly the mouse, could be
critical to the success of these efforts. In the future, identification of
early morphologic indicators of aortic arch anomalies could translate into the
clinic with more accurate prenatal diagnoses in fetuses at genetic risk for
cardiovascular disease.
Familial Hypertrophic Cardiomyopathy
Familial hypertrophic cardiomyopathy is defined as ventricular wall
thickening without a cause for increased cardiac mass
[17]. The estimated prevalence
is 0.2%, but it may be higher (patients who meet sonographic diagnostic
criteria can be asymptomatic). Familial hypertrophic cardiomyopathy is the
most common cause of sudden death in young adults
[18]. The severity and
anatomic manifestations of disease are variable. Recent molecular genetic
research reveals that familial hypertrophic cardiomyopathy is not one disease
with multiple manifestations but, instead, is multiple diseases of the
contractile proteins of the myocardium or sarcomere
(Fig. 3). To date, mutations of
eight distinct proteins have been implicated in familial hypertrophic
cardiomyopathy [19].
View larger version (39K):
[in this window]
[in a new window]
[as a PowerPoint slide]
|
Fig. 3. —Drawing illustrates sacromeric protein mutations, which cause
hypertrophic cardiomyopathy. Sarcomere (A) is basic unit of myocardial
contraction. Magnified view of region shown in inset (B) depicts individual
protein components of thick and thin filaments of sarcomere. Morphology and
prognosis (C) of various hypertrophic cardiomyopathies due to mutations of
specific sarcomeric contractile proteins are shown. LV = left ventricle.
|
|
Clinical studies of patients with familial hypertrophic cardiomyopathy and
experimental studies of transgenic mouse models of familial hypertrophic
cardiomyopathy have provided insight into this disease. Mutations of the
myosin light chain are associated with the mid-cavitary form of hypertophic
cardiomyopathy. Mutations of the ß-myosin heavy chain cause a high risk
of sudden death (Fig. 3).
Beyond gene-specific morphology and prognosis is the hope for gene-specific
treatment. Investigators recognized that certain sarcomeric mutations lead to
increased intracellular calcium with the subsequent activation of the enzyme
calcineurin. Calcineurin triggers a molecular cascade ultimately leading to
abnormal transcription of cardiac proteins. In a dramatic experiment, mice
with certain sarcomeric mutations were treated with cyclosporin, a calcineurin
inhibitor [20]. Treated mice
had normal hearts. Genetically identical but untreated littermates developed
severe hypertrophic cardiomyopathy, myofibrillar disarray histologically, and
early development of congestive failure (Fig.
4A,4B).
View larger version (94K):
[in this window]
[in a new window]
[as a PowerPoint slide]
|
Fig. 4A. —Prevention of cardiac hypertrophy in transgenic mice by
calcineurin inhibition. Heart specimens were taken from genetically identical
mice (tropomodulin-overexpressing transgenic). Images were digitized with
slide scanner and then enlarged using software (Photoshop; Adobe Systems,
Mountain View, CA). rv = right ventricle, lv = left ventricle. (Reprinted with
permission from [20])
Histologic specimen from untreated mouse shows characteristic cardiomyopathy
that develops by 24 days after birth. (H and E)
|
|
View larger version (98K):
[in this window]
[in a new window]
[as a PowerPoint slide]
|
Fig. 4B. —Prevention of cardiac hypertrophy in transgenic mice by
calcineurin inhibition. Heart specimens were taken from genetically identical
mice (tropomodulin-overexpressing transgenic). Images were digitized with
slide scanner and then enlarged using software (Photoshop; Adobe Systems,
Mountain View, CA). rv = right ventricle, lv = left ventricle. (Reprinted with
permission from [20])
Histologic specimen from mouse treated with cyclosporin reveals normal heart.
(H and E)
|
|
The clinical syndromes of CATCH-22 and familial hypertrophic cardiomyopathy
exemplify fundamental changes in clinical understanding and eventual
management of congenital heart disease. In CATCH-22, multiple syndromes based
on historical description are unified by a common chromosomal defect; in
familial hypertrophic cardiomyopathy, a single disease with an inexplicable
variety of clinical manifestations is found to be multiple distinct
abnormalities of the fundamental contractile unit of the heart. The molecular
etiologic classification will eventually replace classifications based on
historical descriptions, and further research will lead to gene-specific
diagnosis, prognosis, and treatment of congenital heart disease.
Imaging Applications and Opportunities
Traditional Imaging
The molecular revolution will provide important opportunities for the
radiology community to contribute to basic science and clinical research. As
has been emphasized throughout this article, the success of the reductionist
approach in dissecting out the genes associated with development must be
counterbalanced by the realization that identification of the molecular pieces
(genes) of a puzzle does not solve the puzzle. Even if a gene or gene product
is temporally and spatially related to a developmental event, it is not
certain that it plays an important role in that event. The power of current
genotyping techniques must be complemented by tools to study the dynamic
anatomy and function of the developing organism. It is in the determination of
the outward physical manifestation of a gene or gene product, or phenotype,
that the radiologic sciences stand to make tremendous contributions to the
understanding of developmental biology.
Molecular cardiovascular biology presents several challenges. The mouse is
the most common experimental animal because of its well-characterized genome,
comparability with the human heart, and relatively low breeding and
maintenance costs. However, its small size and rapid heart rate (basal heart
rate of 550-620 beats per minute) make anatomic and physiologic
characterization extremely difficult
[21,
22].
MR microscopy (MR imaging on super high-field magnets with resolution on
the 10- to 100-µ scale) has been applied to studying the vasculature in
fixed embryos [23] and embryos
in utero [24]. Our laboratory
has reported a high-resolution three-dimensional MR microscopic technique for
morphometric analysis of a transgenic mouse model of dilated cardiomyopathy.
The technique allowed calculation of atrial and ventricular chamber volumes,
and the isotropic voxel acquisition allowed volumetric postprocessing and
display [25] (Fig.
5A,5B,5C,5D).
Gated MR images of transgenic mice have also been obtained, with good
correlation of cardiac output and stroke volume calculations with an invasive
thermodilution technique [26].
Continued refinement of coils, contrast agents, and pulse sequences may
ultimately provide developmental biologists with a much-needed assay: a
high-resolution, noninvasive, in utero tool that can be used repeatedly to
study the precise sequence of events involved in normal and abnormal
development.
View larger version (163K):
[in this window]
[in a new window]
[as a PowerPoint slide]
|
Fig. 5A. —Three-dimensional T1-weighted gradient-echo MR images (TR/TE,
50/5; flip angle 45°; isotropic; 150-mm voxels) of heart; chambers were
perfused with gadolinium gelatin solution before scanning. (Reprinted with
permission from [25]) Normal
mouse heart showing direct-acquisition horizontal long-axis section (A)
and postprocessed volumetric rendering of isolated atria and ventricles
(B).
|
|
View larger version (96K):
[in this window]
[in a new window]
[as a PowerPoint slide]
|
Fig. 5B. —Three-dimensional T1-weighted gradient-echo MR images (TR/TE,
50/5; flip angle 45°; isotropic; 150-mm voxels) of heart; chambers were
perfused with gadolinium gelatin solution before scanning. (Reprinted with
permission from [25]) Normal
mouse heart showing direct-acquisition horizontal long-axis section (A)
and postprocessed volumetric rendering of isolated atria and ventricles
(B).
|
|
View larger version (152K):
[in this window]
[in a new window]
[as a PowerPoint slide]
|
Fig. 5C. —Three-dimensional T1-weighted gradient-echo MR images (TR/TE,
50/5; flip angle 45°; isotropic; 150-mm voxels) of heart; chambers were
perfused with gadolinium gelatin solution before scanning. (Reprinted with
permission from [25]) Heart of
transgenic mouse model (overexpression of myosin light chain) of dilated
cardiomyopathy showing direct acquisition horizontal long-axis section
(C) and postprocessed volumetric rendering of isolated atria and
ventricles (D). Note attenuated ventricular walls and enlarged chamber
volumes in cardiomyopathy model.
|
|
View larger version (84K):
[in this window]
[in a new window]
[as a PowerPoint slide]
|
Fig. 5D. —Three-dimensional T1-weighted gradient-echo MR images (TR/TE,
50/5; flip angle 45°; isotropic; 150-mm voxels) of heart; chambers were
perfused with gadolinium gelatin solution before scanning. (Reprinted with
permission from [25]) Heart of
transgenic mouse model (overexpression of myosin light chain) of dilated
cardiomyopathy showing direct acquisition horizontal long-axis section
(C) and postprocessed volumetric rendering of isolated atria and
ventricles (D). Note attenuated ventricular walls and enlarged chamber
volumes in cardiomyopathy model.
|
|
Molecular Imaging
Molecular imaging seeks specific molecules as the source of imaging
contrast, as opposed to traditional imaging, which targets nonspecific
physical and physiologic properties
[27]. Challenges include the
creation of specific molecular probes, systems to deliver the probe to the
area of interest, strategies to amplify the typically pico- to nanomolar
concentration signal, and high-resolution and high-sensitivity imaging
systems. Although most current molecular imaging research is focused on tumor
imaging, techniques developed should be equally applicable to answering
developmental questions.
Of particular interest is the recent report of MR imaging visualization of
gene expression in living Xenopus laevis tadpoles
[28]. Investigators designed a
gadolinium enhancement technique that capitalizes on the enzyme
ß-galactosidase, the workhorse of in vitro staining for gene expression
in developmental biology. The gadolinium contrast is shielded from water until
it encounters ß-galactosidase, at which time the protective cage is
opened. The unpaired electrons then interact with the protons in water to
cause signal enhancement (Fig.
6). The technique should be applicable to studying developmental
questions such as the anatomic location and timing of genes believed to be
involved in developmental processes.
View larger version (36K):
[in this window]
[in a new window]
[as a PowerPoint slide]
|
Fig. 6. —MR imaging detection of ß-galactosidase messenger RNA
expression in living Xenopus laevis tadpoles. Gadolinium is initially
enclosed in chemical cage. When cage encounters enzyme ß-galactosidase,
protective gate is cleaved open, exposing gadolinium (purple) to water and
causing signal enhancement. ß-galactosidase messenger RNA expression is
seen in eye (e), cement gland (c), brachial arches (b), and somites (s).
(Reprinted with permission from
[27])
|
|
Apoptosis, or programmed cell death, is a critical process in cardiac
development. It is thought to be involved in the fusion of the endocardial
tubes, remodeling of the muscular septum, and sculpting of the cardiac valves,
among other things. Investigators have recently described an in vivo nuclear
medicine technique to study apoptosis in transplant rejection. The technique
involves radiolabeling annexin V, a protein that binds to phosphatidylserine,
a membrane protein externalized during the early execution phase of apoptosis
[29]. Although these
investigators have concentrated on noninvasive cardiac and liver transplant
rejection detection (Fig.
7A,7B,7C,7D),
the availability of an in vivo method to study apoptosis in the developing
fetus has potential promise in clarifying the precise role of this
developmental event in normal and abnormal organogenesis.
View larger version (76K):
[in this window]
[in a new window]
[as a PowerPoint slide]
|
Fig. 7A. —Noninvasive monitoring of acute cardiac transplant rejection
and response to immunosuppression using radiolabeled annexin V in 12-week-old
male Sprague-Dawley rats. Cardiac allograft was anastomosed to abdominal aorta
and inferior vena cava. Immunosuppression was initiated on postoperative day
5. (Courtesy of Blankenberg F, Palo Alto, CA) Prone anterior nuclear imaging
scan shows no evidence of rejection on postoperative day 1.
|
|
View larger version (74K):
[in this window]
[in a new window]
[as a PowerPoint slide]
|
Fig. 7B. —Noninvasive monitoring of acute cardiac transplant rejection
and response to immunosuppression using radiolabeled annexin V in 12-week-old
male Sprague-Dawley rats. Cardiac allograft was anastomosed to abdominal aorta
and inferior vena cava. Immunosuppression was initiated on postoperative day
5. (Courtesy of Blankenberg F, Palo Alto, CA) Serial anterior acquisition
obtained on postoperative day 4 shows apoptotic acute rejection and increased
radiolabeled annexin V uptake (arrow). Immunosuppression was
initiated on postoperative day 5.
|
|
View larger version (81K):
[in this window]
[in a new window]
[as a PowerPoint slide]
|
Fig. 7C. —Noninvasive monitoring of acute cardiac transplant rejection
and response to immunosuppression using radiolabeled annexin V in 12-week-old
male Sprague-Dawley rats. Cardiac allograft was anastomosed to abdominal aorta
and inferior vena cava. Immunosuppression was initiated on postoperative day
5. (Courtesy of Blankenberg F, Palo Alto, CA) Prone anterior nuclear imaging
scan shows evidence of mild rejection on postoperative day 10.
|
|
View larger version (72K):
[in this window]
[in a new window]
[as a PowerPoint slide]
|
Fig. 7D. —Noninvasive monitoring of acute cardiac transplant rejection
and response to immunosuppression using radiolabeled annexin V in 12-week-old
male Sprague-Dawley rats. Cardiac allograft was anastomosed to abdominal aorta
and inferior vena cava. Immunosuppression was initiated on postoperative day
5. (Courtesy of Blankenberg F, Palo Alto, CA) Prone anterior nuclear imaging
scan shows no evidence of rejection on postoperative day 18; diminished
radionuclide activity represents response to therapy.
|
|
Conclusion
The concerted effort by the radiology community to reemphasize cardiac
imaging in both training and practice will advance cardiovascular diagnosis
and treatment and will ultimately benefit patients with congenital and
acquired diseases of the heart and great vessels. It is critical that
radiologists who plan to be involved in the care of patients with congenital
heart disease realize that molecular genetic research is fundamentally
changing our approach to and understanding of these malformations.
Insights obtained through chromosomal studies of patients and through
genetic manipulation of experimental animals already have clinical
applications. The recently described CATCH-22 syndrome unifies conotruncal
cardiac lesions with and without other anomalies of neural crest development
under deletions of a single chromosomal locus, and familial hypertrophic
cardiomyopathy is now understood to be multiple distinct diseases of the
sarcomere. Insights gained from basic science research may eventually allow
gene-specific diagnosis, prognosis, and treatment. The sequencing of the human
genome undoubtedly will result in the identification of additional genes
associated with developmental defects in the cardiovascular system
[11]. The cardiology community
is rapidly adopting the molecular approach to congenital heart disease, and
radiologists who intend to be a part of the future of congenital heart disease
must be able to understand and speak its language.
The molecular revolution offers important opportunities for the radiology
community to participate in basic science and clinical research. As basic
science researchers discover more and more genes associated with cardiac
development, it becomes increasingly clear that the specific role of most of
these genes in isolation and in concert is largely unknown. A fundamental
problem is the lack of techniques to determine the precise morphologic
consequences of a genetic perturbation. The molecular developmental
reductionists have made rapid strides in identifying the pieces, or genes, of
the cardiac developmental puzzle. The radiology community now has the
opportunity, through modification of traditional imaging methods and through
pioneering molecular imaging techniques, to help put the pieces together.
Acknowledgments
We thank Glenn Miñano for preparation of
the illustrations and Nikki Turner for secretarial assistance.
References
-
Rosengart TK, Lee LY, Patel SR, et al. Angiogenesis gene therapy:
phase I assessment of direct intramyocardial administration of an adenovirus
vector expressing VEGF121 cDNA to individuals with clinically significant
severe coronary artery disease. Circulation
1999;100:468
-474[Abstract/Free Full Text]
-
Larsen W. Human embryology, 2nd ed. New
York: Churchill Livingstone, 1997:153
-159
-
Majumder K, Overbeek PA. Left-right asymmetry and cardiac looping.
In: Harvey R, Rosenthal N, eds. Heart development. San
Diego: Academic Press, 1998:391
-402
-
Payne RM, Johnson MC, Grant JW, Strauss AW. Toward a molecular
understanding of congenital heart disease. Circulation
1995;91:494
-504[Abstract/Free Full Text]
-
Chen JN, van Eeden FJ, Warren KS, et al. Leftright pattern of
cardiac BMP4 may drive asymmetry of the heart in zebrafish.
Development
1997;124:4373
-4382[Abstract]
-
Srivastava D, Cserjesi P, Olson EN. A subclass of bHLH proteins
required for cardiac morphogenesis. Science
1995;270:1995
-1999[Abstract/Free Full Text]
-
Tsuda T, Philp N, Zile MH, Linask KK. Left-right asymmetric
localization of flectin in the extracellular matrix during heart looping.
Dev Biol
1996;173:39
-50[Medline]
-
Li L, Krantz ID, Deng Y, et al. Alagille syndrome is caused by
mutations in human Jagged1, which encodes a ligand for Notch1.Nat Genet
1997;16:243
-251[Medline]
-
Basson CT, Bachinsky DR, Lin RC, et al. Mutations in human
TBX5 cause limb and cardiac malformations in Holt Oram syndrome.
Nat Genet
1997;15:30
-35[Medline]
-
Li QY, Newbury-Ecob RA, Terrett JA, et al. Holt-Oram syndrome is
caused by mutations in TBX5, a member of the Brachyury (T) gene
family. Nat Genet
1997;15:21
-29[Medline]
-
Schott JJ, Benson DW, Basson CT, et al. Congenital heart disease
caused by mutations in the transcription factor Nkx2.5.
Science
1998;281:108
-111[Abstract/Free Full Text]
-
Dietz HC, Cutting GR, Pyeritz RE, et al. Marfan syndrome caused by
a recurrent de novo missense mutation in the fibrillin gene.
Nature
1991;352:337
-339[Medline]
-
Van Mierop LHS, Kutsche LM. Cardiovascular anomalies in DiGeorge
syndrome and importance of neural crest as a possible pathogenetic factor.
Am J Cardiol
1986;58:133
-137[Medline]
-
Young D, Shprintzen RJ, Goldberg RB. Cardiac malformations in the
velocardiofacial syndrome. Am J Cardiol
1980;46:643
-648[Medline]
-
Burn J, Takao A, Wilson D, et al. Conotrancal anomaly face syndrome
is associated with a deletion within chromosome 22q11. J Med
Genet 1993;30:822
-824[Abstract]
-
DiGeorge AM. Discussion on a new concept of the cellular basis of
immunology. J Pediatr
1965;67:907
-908
-
Fananapazir L. Advances in molecular genetics and management of
hypertrophic cardiomyopathy. JAMA
1999;281:1746
-1752[Free Full Text]
-
Driscoll DJ, Edwards WD. Sudden unexpected death in children and
adolescents. J Am Coll Cardiol
1985;5:118B
-131B
-
Bonne G, Carrier L, Richard P, Hainque B, Schwartz K. Familial
hypertrophic cardiomyopathy: from mutations to functional defects.
Circ Res
1998;83:580
-593[Abstract/Free Full Text]
-
Sussman MA, Lim HW, Gude N, et al. Prevention of cardiac
hypertrophy in mice by calcineurin inhibition. Science
1998;281:1690
-1693[Abstract/Free Full Text]
-
James JF, Hewett TE, Robbins J. Cardiac physiology in transgenic
mice. Circ Res
1998;82:407
-415[Abstract/Free Full Text]
-
Kass DA, Hare JM, Georgakopoulos D. Murine cardiac function: a
cautionary tail. Circ Res
1998;82:519
-522[Free Full Text]
-
Smith BR, Johnson GA, Groman EV, Linney E. Magnetic resonance
microscopy of mouse embryos. Proc Natl Acad Sci U S A
1994;91:3530
-3533[Abstract/Free Full Text]
-
Smith BR, Shattuck MD, Hedlund LW, Johnson GA. Time-course imaging
of rat embryos in utero with magnetic resonance microscopy. Magn
Reson Med 1998;39:673
-677[Medline]
-
Sze RW, Chan C, Dardzinski BJ, et al. Three-dimensional MR
microscopy of a transgenic mouse model of dilated cardiomyopathy.
Pediatr Radiol
2001;31:55
-61[Medline]
-
Franco F, Dubois SK, Peshock RM, Shohet RV. Magnetic resonance
imaging accurately estimates LV mass in a transgenic mouse model of cardiac
hypertrophy. Am J Physiol
1998;274:H679
-H683
-
Weissleder R. Molecular imaging: exploring the next frontier.
Radiology
1999;212:609
-614[Free Full Text]
-
Louie AY, Huber MM, Ahrens ET, et al. In vivo visualization of gene
expression using magnetic resonance imaging. Nat
Biotechnol 2000;18:321
-325[Medline]
-
Blankenberg FG, Strauss HW. Non-invasive diagnosis of acute heart-
or lung-transplant rejection using radiolabeled annexin V. Pediatr
Radiol 1999;29:299
-305[Medline]
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
Top
Introduction
Molecular Foundations of...
