in 1928, maude abbott proposed that aortic dilatation and ......to clinical humility than aneurysm...
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In 1928, Maude Abbott proposed that aortic dilatation and dissection in congenital heart disease were caused by medial structural abnormalities. (Am Heart J 1928, 3:381).
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Niwa K, Perloff JK, Bhuta S, Laks H. Structural Abnormalities of Great Arterial Walls in Congenital Heart
Disease. Circulation. 2001;103: 393-400
An Early Step
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BACKGROUND
• Great arterial dilatation is common in congenital heart disease.
• Dilatation is often out of proportion to hemodynamic and morphogenetic expectations.
• Relatively little attention has been paid to the prevalence, degree and pathogenesis of the structural abnormalities of dilated great arterial walls in CHD.
Ahmanson/UCLA Adult Congenital Heart Disease Center
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BACKGROUND
Light and electron microscopic studies were performed in neonates through older adults on over 100 surgically excised biopsy specimens of the ascending aorta, para-coarctation aorta, truncus arteriosus, and pulmonary trunk, supplemented by 20 necropsy specimens.
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Controls
Aortic Root • Positive controls: Marfan syndrome • Negative controls: Trileaflet calcific AS; CABG; transplant donor Pulmonary Trunk • Negative controls: CABG
Ahmanson/UCLA Adult Congenital Heart Disease Center
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Constituents of Arterial Media—Functional Roles
1) Smooth Muscle Cells – Contraction and relaxation (vasomotion). 2) Extracellular Matrix: a) Elastic Fibers – Phasic distension and recoil (pulsatile flow). b) Collagen and Ground Substance – Static strength (rigidity).
Ahmanson/UCLA Adult Congenital Heart Disease Center
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In 1930, Jakob Erdheim described
“medionecrosis aortae idiopathica cystica.” However, Erdheim’s medial necrosis is seldom encountered, and his “cystica” are noncystic medial faults.
Cystic Medial Necrosis
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Circulation 1957 Victor A. McKusick Association of Aortic Valvular Disease
and Cystic Medial Necrosis of the Ascending Aorta
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Microscopic Analyses
• Light Microscopy — Superior for quantitative structural analysis of smooth muscle, elastic fibers, collagen, and ground substance.
• Electron Microscopy — Superior for qualitative sub-structural analysis of smooth muscle, elastic fibers and collagen.
Ahmanson/UCLA Adult Congenital Heart Disease Center
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Variables That Alter the Structure of
Ascending Aortic Media
• Pregnancy • Aging • Systemic hypertension • Mechanical stress
Ahmanson/UCLA Adult Congenital Heart Disease Center
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Normal Gestational Changes in Aortic Media
Fragmentation of elastic fibers Decrease in ground substance
Hypertrophy/hyperplasia of smooth muscle cells
It is not known whether these gestational changes normalize after pregnancy.
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Non-gravid
Gravid
Aortic Media
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Aging Fragmentation of aortic medial elastic fibers.
Decrease in smooth muscle cells. Increase in collagen and ground substance,
especially in the thoracic aorta.
Ahmanson/UCLA Adult Congenital Heart Disease Center
Systemic Hypertension Abnormalities of aortic medial elastin and collagen are significantly more prevalent than in
normotensive subjects.
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Wall Stress Longitudinal wall stress is an
additional risk factor for ascending aortic dissection.
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The Structural Integrity of Great Arterial Walls
Matrix is a dynamic structure that is central to the control of vascular remodeling, and that depends on the actions of proteolytic enzymes and their inhibitors.
If the structural integrity and physical properties of medial arterial matrix are not maintained, pulsatile mechanical stress will cause mural attenuation.
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Principal Constituents of Arterial Media—Functional Roles
1) Smooth Muscle Cells – Contraction and relaxation (vasomotion). 2) Extracellular Matrix: a) Elastic Fibers – Phasic distension and recoil (pulsatile flow). b) Collagen and Ground Substance – Static strength (rigidity).
Ahmanson/UCLA Adult Congenital Heart Disease Center
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Ahmanson/UCLA Adult Congenital Heart Disease Center
• Elastic Fibers Synthesized by fibroblasts and smooth muscle cells. An elastin core is surrounded by a sheath of microfibrils composed of the glycoprotein fibrillin.
• Collagen Thick connective tissue fibers. • Ground substance — A hydrated gel composed of
glycosaminoglycans (mucopolysaccharides), proteoglycans, and adhesive glycoproteins in which elastic fibers and collagen are imbedded.
Extracellular Matrix
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Structural Integrity of Great Arterial Walls
The matrix is a dynamic structure that plays a central role in vascular remodeling that in turn depends on proteolytic enzymes and their inhibitors. If the structural integrity and physical properties of medial arterial matrix are not maintained, pulsatile mechanical stress will cause mural attenuation.
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Matrix Metalloproteinases
The important role of matrix in maintaining arterial wall integrity. Do proteolytic enzymes (MMP’s) play pathogenetic roles in the medial abnormalities of dilated great arteries in congenital heart disease?
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Matrix Metalloproteinases in Congenital Heart Disease
The UCLA Adult Congenital Heart Disease Center in collaboration with Dr Luyi Sen’s laboratory is characterizing protein expression levels of MMP’s utilizing quantitative western blot and zymographic analysis of surgically excised specimens of great arterial walls from the same spectrum of patients studied with light and electron microscopy.
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Metallothionein
A metal-bonding protein that regulates
metaloproteinases, and is upregulated in
response to oxidative stress. Upregulation in the ascending aorta
may play an important role in aneurysm formation above a
bicuspid aortic valve.
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Morphologic Grading System
Normal— Elastic fibers are closely packed in orderly parallel arrays. . Grade 1 — Mild fragmentation of elastic fibers, mild increase in collagen. Grade 2 —Disruption and fragmentation of elastic fibers, loss of smooth muscle cells, greater increase in collagen. Grade 3— Virtual loss of elastic fibers and smooth muscle cells. Appreciable increase in collagen and ground substance.
Ahmanson/UCLA Adult Congenital Heart Disease Center
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Ahmanson/UCLA Adult Congenital Heart Disease Center
Light Microscopy
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Ahmanson/UCLA Adult Congenital Heart Disease Center
Light Microscopy contd.
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Ahmanson/UCLA Adult Congenital Heart Disease Center
Light Microscopy
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Ahmanson/UCLA Adult Congenital Heart Disease Center
Electron Microscopy
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Ahmanson/UCLA Adult Congenital Heart Disease Center
sinuses
ST junction
Asc aorta
Aortic Root Areas of Interest
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The presence of a bicuspid aortic valve appears to indicate, at least in a portion of the cases in which it occurs, a tendency for spontaneous rupture.
Ahmanson/UCLA Adult Congenital Heart Disease Center
Maude Abbott 1928
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Abraham Lincoln 1863 photograph
Blurred left foot was a
clue of the aortic regurgitation of
Marfan syndrome
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Marfan Syndrome
The Fibrillin-1 Protein Fibrillin-1 is a modular protein encoded by
the large (230-kb) FBN1 gene that contains 65 coding exons.
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There is no disease more conducive to clinical humility than aneurysm of
the aorta. William Osler
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Ascending Aortic Aneurysm Pectus excavatum deformity
Main Pulmonary artery Left atrium
Superior Vena Cava
Descending aorta
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Ascending aortic aneurysm
Distal ascending aorta Cranial
Caudal
Right Left
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Turner Syndrome Ascending Aortic Aneurysm
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DeBakey, at age 97, underwent an operation that he pioneered---
repair of an ascending aortic aneurysm.
Michael DeBakey
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Ahmanson/UCLA Adult Congenital Heart Disease Center
The Bicuspid Aortic Valve
Aortic root dilatation
Medial structural abnormalities
Aortic dissection
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Normal Aortic Media BAV Aortic Media
Fibrilin-1 microfibrils tether smooth muscle cells to the elastin/collagen matrix
Deficient microfibrils result in smooth muscle cell detachment, matrix disruption and cell death
Fedak et al, Circulation 2002
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Discrete Sub AS Discrete Supravalve AS
The Aortic Root Is Not Dilated
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Ahmanson/UCLA Adult Congenital Heart Disease Center
Restrictive Ventricular Septal Defect Age 6 Years
Ascending Aortic Dilatation
Ascending Aortic Media
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Ahmanson/UCLA Adult Congenital Heart Disease Center
Fallot’s Tetralogy Age 8 Years
Ascending Aortic Dilatation
Ascending Aortic Media
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Fallot’s Tetralogy Ascending Aortic Dilatation
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Fallot’s Tetralogy Dilated Aortic Root/AR. Age 52 Years
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Ahmanson/UCLA Adult Congenital Heart Disease Center
Marfan
VSD
Bicuspid Aortic Valve
Fallot
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Sinus of Valsalva Aneurysm
…the essential lesion is a defect in continuity of the media of the aortic root. Mayo Clin Proc 1956
…a developmental error involving
differentiation of tissues at the base of the aorta. Am Heart J 1960
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Ahmanson/UCLA Adult Congenital Heart Disease Center
Coarctation of the Aorta An Experiment of Nature
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Ahmanson/UCLA Adult Congenital Heart Disease Center
Coarctation of the Aorta
Para-coarctation Aorta Para-coarctation Media
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Ahmanson/UCLA Adult Congenital Heart Disease Center
Coarctation of the Aorta
Resection With End-to-End Anastomosis
Patch Graft
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Coarctation With Bicuspid Aortic Valve
In coarctation, a relatively rigid ascending aorta caused by increased collagen and decreased smooth muscle tends to persist after repair, and exerts an adverse effect on the coexisting medial abnormalities of a bicuspid aortic valve.
Ahmanson/UCLA Adult Congenital Heart Disease Center
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Coarctation The Neonatal Ascending Aorta
Elastic properties of the ascending aorta are inherently abnormal in
coarctation. This inborn fault remains unchanged after successful
operation. Vogt et al. Circulation June 2005
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Bicuspid Aortic Valve Morphology
Fusion of the right and non- coronary cusps (R-N) is significantly associated with cuspal abnormalities (aortic stenosis and regurgitation). Fusion of the right and left coronary cusps (R-L) is significantly associated with coarctation of the aorta.
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Ahmanson/UCLA Adult Congenital Heart Disease Center
D-TGA Arterial Switch The Suture Line
Ascending Aorta Ascending Aortic Media
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Ahmanson/UCLA Adult Congenital Heart Disease Center
Arterial Switch
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Neonatal Ductal Aneurysm
Ductal Aneurysm Media
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Ahmanson/UCLA Adult Congenital Heart Disease Center
Neonatal Truncus Arteriosus
The Truncal Media
The Truncus
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Ahmanson/UCLA Adult Congenital Heart Disease Center
Eisenmenger Truncus Arteriosus Age 52 Years
Truncal Media
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Mobile Pulmonary Valve Stenosis
Dysplastic Pulmonary Valve Stenosis
The Pulmonary Trunk
Dilated Non-dilated
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Ahmanson/UCLA Adult Congenital Heart Disease Center
Pulmonary Valve Stenosis
PT
Pulmonary Trunk Media
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Ahmanson/UCLA Adult Congenital Heart Disease Center
Ostium Primum ASD
Left-to-Right Shunt
Pulmonary Trunk Media
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Ahmanson/UCLA Adult Congenital Heart Disease Center
Eisenmenger VSD Age 42 Years
Aortic Dissection Aortic Media
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Ahmanson/UCLA Adult Congenital Heart Disease Center
Fallot’s Tetralogy Absent Pulmonary Valve
Aneurysmal Proximal Pulmonary Arteries
Severe Pulmonary Regurgitation
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Ahmanson/UCLA Adult Congenital Heart Disease Center
Fallot’s Tetralogy Absent Pulmonary Valve
Severe PR Media Pulmonary Trunk
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Fallot’s Tetralogy Transannular Patch Severe Pulmonary Regurgitation
Mild Pulmonary Artery Dilatation
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Eisenmenger ASD Aneurysmal Pulmonary Trunk
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Ahmanson/UCLA Adult Congenital Heart Disease Center
Eisenmenger VSD Aneurysmal Pulmonary Trunk
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Ahmanson/UCLA Adult Congenital Heart Disease Center
Fallot’s Tetralogy, Potts Shunt, PVD Ruptured Pulmonary Trunk
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CONCLUSIONS Medial structural abnormalities of great
arterial smooth muscle, elastic fibers, collagen and ground substance are present in a wide variety of congenital heart diseases from neonates to older adults.
Ascending Aortic Media Abnormalities predispose to dilatation, aneurysm
formation and rupture, and are potential surgical risks.
Ahmanson/UCLA Adult Congenital Heart Disease Center
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Pulmonary Trunk In patients with mobile pulmonary valve
stenosis and Fallot’s tetralogy with absent pulmonary valve, medial abnormalities of the pulmonary trunk predispose to dilatation and aneurysm formation. Hypertensive proximal pulmonary arteries may be aneurysmal and may rupture or thrombose.
Ahmanson/UCLA Adult Congenital Heart Disease Center
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PIVOTAL QUESTIONS 1) Are great arterial medial abnormalities in congenital
heart disease inherent or acquired? 2) Does congenital heart disease play an etiologic or
facilitating role? 3) If the medial abnormalities are in part inherent, to
what extent are they genetically determined?
Ahmanson/UCLA Adult Congenital Heart Disease Center
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In 1928, Maude Abbott proposed that aortic dilatation and dissection in congenital heart
disease were caused by medial structural abnormalities.
(Am Heart J 1928)
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“The presence of a bicuspid aortic valve appears to indicate, at least in a portion of the cases in which it occurs, a tendency for spontaneous rupture.”
Maude Abbott 1928
Ahmanson/UCLA Adult Congenital Heart Disease Center
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Fibrillin-1
Inadequate fibrillin-1 expression during valvulogenesis disrupts normal aortic cusp formation, and can result in a bicuspid aortic valve.
Inadequate fibrillin-1 expression in the contiguous ascending aortic media results in mural attenuation, dilation and dissection.
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Metallothionein
In the presence of a bicuspid aortic valve, there is a genetically determined defect in the cellular microenvironment of the ascending aortic wall
characterized in part by decreased expression of metallothionein.
This metal binding protein may regulate the response of aortic smooth muscle cells to
oxidative stress, to MMP expression, and to tissue homeostasis of aortic extracellular
matrix.
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Normal Aortic Media BAV Aortic Media
Fibrilin-1 microfibrils tether smooth muscle cells to the elastin/collagen matrix
Deficient microfibrils result in smooth muscle cell detachment, matrix disruption and cell death
Fedak et al, Circulation 2002;106:900-904
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Ahmanson/UCLA Adult Congenital Heart Disease Center
The Bicuspid Aortic Valve
Ascending Aortic
dilatation. Medial structural
abnormalities. Aortic dissection.
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Ahmanson/UCLA Adult Congenital Heart Disease Center
Restrictive Ventricular Septal Defect Age 6 Years
Ascending Aortic Dilatation
Ascending Aortic Media
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Ahmanson/UCLA Adult Congenital Heart Disease Center
Fallot’s Tetralogy Age 8 Years
Ascending Aortic Dilatation
Ascending Aortic Media
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Fallot’s Tetralogy Dilated Aortic Root/AR Age 52 Years
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Ahmanson/UCLA Adult Congenital Heart Disease Center
Coarctation of the Aorta An Experiment of Nature
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Ahmanson/UCLA Adult Congenital Heart Disease Center
Coarctation of the Aorta
Para-coarctation Aorta Para-coarctation Media
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Ahmanson/UCLA Adult Congenital Heart Disease Center
Neonatal Truncus Arteriosus
The Truncal Media
The Truncus
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Ahmanson/UCLA Adult Congenital Heart Disease Center
Eisenmenger VSD Age 42 Years
Aortic Dissection Aortic Media
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Conclusions Abnormalities of great arterial medial smooth
muscle, elastin, collagen and ground substance occur in a wide variety of congenital heart diseases from neonates to older adults.
These ascending aortic medial abnormalities predispose to dilatation, aneurysm formation and rupture, and are potential cardiac surgical risks.
Ahmanson/UCLA Adult Congenital Heart Disease Center
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Pivotal Questions
1) Are great arterial medial abnormalities in congenital heart disease intrinsic or acquired?
2) Does congenital heart disease play an etiologic or a facilitating role?
3) If the medial abnormalities are intrinsic, to what extent are they genetically determined?
Ahmanson/UCLA Adult Congenital Heart Disease Center
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A Variation on the theme.
From great arterial walls to coronary
arterial walls.
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Dilatation Exceeds the Response from
Endothelial Vasodilators
Gross Morphology Dilated tortuous extra-mural coronary arteries. Histology
Loss of medial smooth muscle. Increase in medial collagen. Duplication of the internal elastic lamina.
Coronary Arterial Walls in Cyanotic Congenital Heart Disease
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Ahmanson/UCLA Adult Congenital Heart Disease Center
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Thank You
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Luetic Aortic Eneurysm
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PO Fallot Severe PR Aneurysmal Dilatation
Proximal Pulmonary Arteries
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Matrix Metalloproteinases
A group of zinc dependent proteolytic enzymes that function in the resorption of extracellular matrices. Nine MMP’s have been identified, cloned and sequenced. A family of naturally occurring inhibitors
coexist with MMP’s.
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Luetic fusiform aneurysm of ascending aorta