The Molecular Genetic Revolution in Congenital Heart Disease

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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.

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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.

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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.

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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.

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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)

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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)

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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).

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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).

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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.

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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.

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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])

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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.

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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.

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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.

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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.

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