Upload
fatima-hazlewood
View
220
Download
1
Tags:
Embed Size (px)
Citation preview
Vascular Calcification
Kristina Boström, MD, PhDCardiology, UCLA
Case Presentation
74 y o Caucasian female, with hypertension and critical aortic stenosis.
One year prior to presentation, aortic valve replacement had been attempted but was aborted due to severe aortic calcification, so called “porcelain aorta”.
Now increasing symptoms of shortness of breath with exertion and chest pain, with recurrent hospital admissions for congestive heart failure.
Echocardiogram: LVEF >60% with concentric left ventricular hypertrophy and diastolic dysfunction.Mild mitral regurgitation.Moderate tricuspid regurgitation.
Cardiac Catheterization: Normal systolic function. Non-obstructive coronary disease.
CT Chest: “Uniform, smooth calcification of the ascending aorta extending from the root to the origin of great vessels, with trivial atherosclerotic calcifications of the descending aorta. The appearance of the ascending aorta is
reminiscent of aortic graft.”Extensive aortic valve calcification and moderate mitral valve calcification.
Circumferential Calcification in the Ascending Aorta
Left Ventricular Apical Conduit to Descending Thoracic Aorta
• Calcification can be characterized by the anatomical location.• There are more than one type of vascular calcification.• We are unable to efficiently treat vascular calcification.• Vascular calcification may cause clinical complications.
This Case Illustrates ….
Anatomical location AorticCoronaryPeripheral arteriesHeart valve
Vascular layer Intima Media Adventitia Heart valve
Association with disease AtherosclerosisMönckeberg’s (Media Sclerosis)DiabetesRenal Failure
Vascular Calcification Differs in:
Intima
Media
Adventitia
Heart valves
AtherosclerosisRenal FailureDiabetes
Mönckeberg’s (Media sclerosis)Renal FailureDiabetes
Atherosclerosis
Diabetes
Vascular Calcification Is Associated with Vascular Disease:
Sangiorgi et al. JACC 1998
Intimal Calcification - Atherosclerosis
CLINICAL IMPLICATIONS OF INTIMAL CALCIFICATION
Coronary Arteries• Correlated with Coronary Artery Disease and atherosclerotic plaque burden.• Associated with Sudden Cardiac Death• Promotes dissection following angioplasty
Calcified, Atherosclerotic Coronary Artery
Calcification
Intima
Media
Webpath
Rupture at Edge of Calcified Lesion
In Vitro
In Vivo - after angioplasty
Mechanical stress analysis of a rigid inclusion in distensible material: a model of atherosclerotic calcification and plaque vulnerability. Hoshino et al. Am J Physiol 2009
Coronary Calcification
Detected by Electron Beam CT (EBCT) - “Heart Scans”
Coronary Calcification - EBCT
A negative EBCT test is associated with a low risk of a cardiovascular event in the next 2 to 5 years.
A positive EBCT confirms the presence of a coronary atherosclerotic plaque.
The greater the amount of calcium, the greater the likelihood of occlusive CAD, but there is not a 1-to-1 relationship, and findings may not be site specific.
The total amount of calcium correlates best with
the total amount of atherosclerotic plaque, although the true "plaque burden" is underestimated
Medial Calcification
Atherosclerotic Plaques
(Mönckeberg’s media sclerosis, elastocalcinosis)
WebpathPrice et al. ATVB 2000
VASCULAR MEDIAL CALCIFICATION
Arteriosclerosis associated with aging, diabetes, and end stage renal disease
CLINICAL IMPLICATIONS OF VASCULAR MEDIAL CALCIFICATION
Aorta• Correlates with increased ischemic episodes in peripheral vascular disease (PVD)
Peripheral Arteries• Strong marker for future cardiac events, PVD, and lower extremity amputations in diabetics• Prognostic marker for all-cause and cardiovascular mortality in dialysis patients
Causes increased aortic stiffness, pulse pressure, left ventricular hypertrophy and cardiovascular mortality
Medial Calcification in Arteries of Dialysis Patients
30-700 fold increase in cardiovascular mortality risk in dialysis patients compared to the general population.
Decreased survival in end stage renal disease patient with intimal and medial vascular calcification
Moe et al. Kidney Int. 2002
Heart Valve Calcification
Senile Aortic Stenosis CalcifiedBioprosthetic Valve
Normal Aortic Valve
CLINICAL IMPLICATIONS OF VALVE CALCIFICATION
• Major cause of failure in native valves
• Major cause of failure in bioprosthetic valves
• Highly prevalent in patients with end stage renal failure
Mechanisms of Vascular Calcification
Normal Vessels Don’t Mineralize
ActiveInducers
ActiveInhibitors
Dhore et al. ATVB 2001
Inhibitors
Promotors
Both Inhibitors and Promotors of Calcification in Atherosclerotic Plaques
VASCULAR CALCIFICATION
DISTURBED Ca/Pi BALANCEHyperphosphatemiaHypercalcemia
Ca x Pi
INDUCING FACTORSPiLipidsInflammatory cytokinesOthers
INDUCTION OF BONE FORMATIONVascular bone and cartilage-like cells
Apoptotic bodies
CELL DEATH
LOSS OF INHIBITIONPyrophosphateMGPOPNFetuin/alpha2-HS glycoproteinOthers
CIRCULATING NUCLEATIONAL COMPLEXES
BisphosphonatesOPG
Bone Remodeling
Matrix Vesicles
Major Theories of Vascular Calcification
Adapted from Speer & Giachelli, Cardiovasc Path 2004
VASCULAR CALCIFICATION
DISTURBED Ca/Pi BALANCEHyperphosphatemiaHypercalcemia
Ca x Pi
INDUCING FACTORSPiLipidsInflammatory cytokinesOthers
INDUCTION OF BONE FORMATIONVascular bone and cartilage-like cells
Apoptotic bodies
CELL DEATH
LOSS OF INHIBITIONPyrophosphateMGPOPNFetuin/alpha2-HS glycoproteinOthers
CIRCULATING NUCLEATIONAL COMPLEXES
BisphosphonatesOPG
Bone Remodeling
Matrix Vesicles
Major Theories of Vascular Calcification
Adapted from Speer & Giachelli, Cardiovasc Path 2004
GENERALIZED INFANTILE ARTERIAL CALCIFICATION
• Rare human genetic disorder; early lethal• Vascular medial calcification leading to a stenosing, fibroproliferative arterial process• Characterized by deficiency in extracellular pyrophosphate (PPi), due to a deficiency in PPi-generating nucleoside triphosphate pyrophosphohydrolase plasma membrane 1 enzyme (PC-1, ENPP1).
Levine et al. Circulation 2001
Long-axis image of aorta and aortic arch
Inhibitor of Bone Morphogenetic Proteins (BMP)(Zebboudj 2002, Yao 2006)
Dependent on Vitamin K for correct gamma-carboxylation of glutamates (Gla-modifications) and anti-calcific activity
(Murshed 2004)
Dependent on specific proline and Gla-residues for BMP binding (Yao 2008)
MGP loss of function mutations in humans cause Keutel syndrome (Keutel 1971, Munroe 1999)
Matrix Gla Protein (MGP)
Vascular Calcification in MGP Null Mice
Luo et al. Science 1997
Aortic media
Wild type
Aortic media
MGP null
• Potent inducers of bone formation
• Inflammatory mediators induced in vascular endothelium by abnormal oscillatory flow (Sorescu et al. 2004)
• Promotes hypertension and atherogenesis in mice(Miriyala et al. 2006, Jo et al. - in prep.)
• MGP reduces formation of atherosclerotic plaques and lesions calcification
(Yao et al. - in revision)
BONE MORPHOGENETIC PROTEINS (BMP)
Warfarin / Coumadin Use:
• Inhibits MGP gamma-carboxylation, induces vascular calcification in growing rats (Price 1998, Essalihi 2003, Schurgers 2007)
• Correlated with increased coronary and valve calcification (Schurgers 2004, Koos 2005)
• Associated with calcific uremic arteriolopathy in dialysis patients
(Coates 1998, Piccoli 2002)
Fetuin, 2 Hermann-Schmid Glycoprotein (AHSG)
• Made in the liver• Inhibitor of spontaneous hydroxyapatite (HA) formation from supersaturated calcium- and phosphate containing solutions• Fetuin null mice have decreased serum HA inhibitory activity and increased soft tissue calcification
(Jahnen-Dechent 1997, Schafer 2003)
Westenfeld et al. Trends Cardiovasc Med 2007
Normal mouse after phosphate challenge
Fetuin-deficient mouse after phosphate challenge
• Acidic phosphoprotein found in bone and teeth
• Inhibitor of apatite crystal growth
• Promotes osteoclast function
OSTEOPONTIN
Osteopontin Deficiency Worsens Calcification in MGP Null Mice
Speer MY et al. 2002
VASCULAR CALCIFICATION
DISTURBED Ca/Pi BALANCEHyperphosphatemiaHypercalcemia
Ca x Pi
INDUCING FACTORSPiLipidsInflammatory cytokinesOthers
INDUCTION OF BONE FORMATIONVascular bone and cartilage-like cells
Apoptotic bodies
CELL DEATH
LOSS OF INHIBITIONMGPOPNFetuin/alpha2-HS glycoproteinPyrophosphateOthers
CIRCULATING NUCLEATIONAL COMPLEXES
BisphosphonatesOPG
Bone Remodeling
Matrix Vesicles
Major Theories of Vascular Calcification
Adapted from Speer & Giachelli, Cardiovasc Path 2004
Ectopic Calcification in Atherosclerotic Plaqes
Rattazzi et al. ATVB 2005
Chondrocytes in Mouse Atherosclerotic Lesions
Mineral Precipitation Cell Differentiation
Ca2+ PO42-
CaPO4 mineral precipitation
osteoid(matrix)
matrix vesicles
hydroxyapatite
Ca2+ PO42-
CaPO4 mineral precipitation
“Active” inhibitor
osteoblast-like cell
• Pericytes
• Mesenchymal stem cells
• Multipotent cells from the adventitia
• Resident cells in the media or intima
• Trans-differentiated SMC(Synthetic vs contractile phenotype)
Potential Origins of Osteoblast-like Cells in the Artery Wall
Calcifying Vascular Cells (CVC)
CONDENSATION CALCIFIEDNODULES
UNDIFFERENTIATED
Bone Related Factors in Calcified Artery Wall
BMP-2 and -4Cbfa1OsterixCollagen IAlkaline PhosphataseOsteocalcinHydroxyapatite
OsteopontinMatrix GLA protein (MGP)Osteoprotegerin… and others …..
Dhore et al. ATVB 2001
Both Inhibitors and Promotors of Calcification in Plaques
VASCULAR CALCIFICATION
DISTURBED Ca/Pi BALANCEHyperphosphatemiaHypercalcemia
Ca x Pi
INDUCING FACTORSPiLipidsInflammatory cytokinesOthers
INDUCTION OF BONE FORMATIONVascular bone and cartilage-like cells
Apoptotic bodies
CELL DEATH
LOSS OF INHIBITIONMGPOPNFetuin/alpha2-HS glycoproteinPyrophosphateOthers
CIRCULATING NUCLEATIONAL COMPLEXES
BisphosphonatesOPG
Bone Remodeling
Matrix Vesicles
Major Theories of Vascular Calcification
Adapted from Speer & Giachelli, Cardiovasc Path 2004
(Despite serum Ca x P at or near solubility product)Normal Vessels Don’t Mineralize
ActiveInducers
ActiveInhibitors
Intima
Media
Adventitia
Heart valves
AtherosclerosisRenal FailureDiabetes
Mönckeberg’s (Media sclerosis)Renal FailureDiabetes
Atherosclerosis
Diabetes
Already above precipitation point at certain placesRenal failure may increase Ca x P product further
Hyperphosphatemia:Major independent risk factor for vascular calcification and cardiovascular mortality in dialysis patients
(Block 1998, 2004, Goodman 2000, Shigematsu 2003, Young 2005)
Calcium x Phosphate Product
Type III sodium-dependent phosphate co-transporters (Pit-1, Pit-2)Blockage of these transporters leads to phosphate induced SMC mineralization Pit-1 can be induced by BMP-2
Pi/Ca
Contractile SMC
Osteochondrogenic cellSM-MHCSM22alphaSM-alpha actinDesmin
Cbfa1OPNOsteocalcinAlk Phos
Phosphate-Induced Changes in SMC Differentiation
Wada et al. Circ Res 1999
Calcified Vascular Smooth Muscle Cells
VASCULAR CALCIFICATION
DISTURBED Ca/Pi BALANCEHyperphosphatemiaHypercalcemia
Ca x Pi
INDUCING FACTORSPiLipidsInflammatory cytokinesOthers
INDUCTION OF BONE FORMATIONVascular bone and cartilage-like cells
Apoptotic bodies
CELL DEATH
LOSS OF INHIBITIONMGPOPNFetuin/alpha2-HS glycoproteinPyrophosphateOthers
CIRCULATING NUCLEATIONAL COMPLEXES
BisphosphonatesOPG
Bone Remodeling
Matrix Vesicles
Major Theories of Vascular Calcification
Degenerative Joint Diseases are “Crystal diseases”where synovial fibroblasts have an inflammatory response to the crystals.
Connection between Vascular Calcification and Bone
Aortic Calcification and Osteoporosis Frequently Coexist
Similarities to Bone:Bone ProteinsOsteoblast-like CellsOsteoclast-like Cells
“The paradox of arterial calcification in osteoporotic patients”
Parhami et al. ATVB 1997
Oxidized lipids or other agents may be mediating the effect.
Mody et al. J Nucl Card 2003
Resorptive osteoclast-like cells are found in calcified atherosclerotic lesions. (Tintut et al. 2002)
Maybe derived from blood monocytes
Osteoclast-like cell with multiple nuclei
OPG is a secreted protein that inhibits osteoclast formationOPG deficient mice have osteoporosis and arterial (medial) calcification
OPG Null Mouse
Bucay et al. Genes & Development 1998
Osteoprotegerin (OPG)
Bone Resorption in the Skeleton Often Coexists with Bone Formation in the Vasculature
Panizo et al., Circ Res 2009Alexander, Circ Res 2009
The Size of Vascular Calcification May Matter!
VASCULAR CALCIFICATION AND INFLAMMATION
Dhore et al. ATVB 2001 Engelse et al.2001
Large Chunks Small BCP Crystals
BCP = Basic calcium phosphate
Degenerative Joint Diseases are “Crystal diseases”where synovial fibroblasts have an inflammatory response to the crystals.
The ingestion of BCP crystals by human monocyte-derived macrophages generates a pro-inflammatory response.
Nadra et al. Circ Res 2005
BCP Crystals Induces Pro-Inflammatory Factors in Macrophages
TNF-alpha
Nadra et al. Circ Res 2005
TNF-alpha Increases Calcification in Calcifying Vascular Cells (CVC)
Tintut et al. Circ 2000
Large calcified areas may be less pro-inflammatory.
How dangerous is the calcification we find on EBCT?
Mouse models for vascular calcification
Genes Associated with Ectopic Calcification in Mice
MUTATION PHENOTYPE
Matrix Gla Protein Arterial, valve and cartilage calcification
Fetuin Decreased serum HA inhibitory activity
Osteopontin Increased calcification of implanted bioprosthetic valves
Fibrillin Vascular calcification, aortic stenosis
Osteoprotegerin Osteoporosis, vascular calcification
FGF23 Hyperphosphatemia, vascular calcification
PC-1/Enpp1/NPP1 Vascular and articular cartilage calcification(nucleotide pyrophosphatase)
Ank (pyrophosphate transporter) Articular cartilage calcification, soft tissue calcification
ß-glucosidase (klotho) Vascular calcification, rapid aging
Carbonic Anhydrase II Calcification of small arteries
Smad6 Valve calcification
Desmin Neonatal cardiomyopahty with calcificationAriall
Mouse Models Illustrate the Diversity of Vascular CalcificationMGP knockout
OPG knockout
Smad6 knockout
Carbonic anhydrase II deficient
Fibrillin-1 deficient
Fat-fed ApoE (or LDLR) knockout mice
Warfarin treated ratVitD/Ca
Vascular calcification is heterogeneous and is
triggered through multiple mechanisms