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					Vascular Calcification
   Kristina Boström, MD, PhD
        Cardiology, 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
        This Case Illustrates ….

• 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.
      Vascular Calcification Differs in:
Anatomical location        Aortic
                           Coronary
                           Peripheral arteries
                           Heart valve

Vascular layer             Intima
                           Media
                           Adventitia
                           Heart valve

Association with disease   Atherosclerosis
                           Mönckeberg’s (Media Sclerosis)
                           Diabetes
                           Renal Failure
Vascular Calcification Is Associated with Vascular Disease:


        Intima              Atherosclerosis
                            Renal Failure
                            Diabetes


        Media               Mönckeberg’s (Media sclerosis)
                            Renal Failure
                            Diabetes


        Adventitia          Diabetes



        Heart valves        Atherosclerosis
Intimal Calcification - Atherosclerosis




    Sangiorgi et al. JACC 1998
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

                                                   Media



 Calcified, Atherosclerotic      Intima
 Coronary Artery

                                              Calcification



                     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
Atherosclerotic     Medial
   Plaques        Calcification
VASCULAR MEDIAL CALCIFICATION
(Mönckeberg’s media sclerosis, elastocalcinosis)

                           Arteriosclerosis associated
                           with aging, diabetes, and end
                           stage renal disease




                           Webpath
                           Price et al. ATVB 2000
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




Normal Aortic Valve   Senile Aortic Stenosis   Calcified
                                               Bioprosthetic 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

 Active
Inducers



                                 Active
                               Inhibitors
Both Inhibitors and Promotors of Calcification
          in Atherosclerotic Plaques




 Inhibitors




 Promotors



                             Dhore et al. ATVB 2001
Major Theories of Vascular Calcification
                                   DISTURBED Ca/Pi BALANCE
                                   Hyperphosphatemia
                                   Hypercalcemia                         INDUCING FACTORS
                                                                         Pi
  LOSS OF INHIBITION
                                                                         Lipids
  Pyrophosphate
                                                                         Inflammatory cytokines
  MGP
                                           Ca x Pi                       Others
  OPN
  Fetuin/alpha2-HS glycoprotein
  Others
                                                                         INDUCTION OF
                                                                         BONE FORMATION
                             VASCULAR CALCIFICATION                      Vascular bone and
                                                                         cartilage-like cells



              CIRCULATING                                                 Matrix Vesicles
              NUCLEATIONAL
              COMPLEXES
                                                     Apoptotic bodies
                         Bisphosphonates
                         OPG

  Bone Remodeling                                          CELL DEATH

                                              Adapted from Speer & Giachelli, Cardiovasc Path 2004
Major Theories of Vascular Calcification
                                   DISTURBED Ca/Pi BALANCE
                                   Hyperphosphatemia
                                   Hypercalcemia                         INDUCING FACTORS
                                                                         Pi
  LOSS OF INHIBITION
                                                                         Lipids
  Pyrophosphate
                                                                         Inflammatory cytokines
  MGP
                                           Ca x Pi                       Others
  OPN
  Fetuin/alpha2-HS glycoprotein
  Others
                                                                         INDUCTION OF
                                                                         BONE FORMATION
                             VASCULAR CALCIFICATION                      Vascular bone and
                                                                         cartilage-like cells



              CIRCULATING                                                 Matrix Vesicles
              NUCLEATIONAL
              COMPLEXES
                                                     Apoptotic bodies
                         Bisphosphonates
                         OPG

  Bone Remodeling                                          CELL DEATH
                                              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).




       Long-axis image of
       aorta and aortic arch




       Levine et al. Circulation 2001
          Matrix Gla Protein (MGP)

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)
Vascular Calcification in MGP Null Mice




                           Aortic
 MGP null                  media




 Wild type

                            Aortic
                            media



                                     Luo et al. Science 1997
   BONE MORPHOGENETIC PROTEINS (BMP)


• 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)
  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)




     Normal mouse after
     phosphate challenge




Fetuin-deficient mouse
after phosphate challenge

                                    Westenfeld et al. Trends Cardiovasc Med 2007
  OSTEOPONTIN

• Acidic phosphoprotein found in bone and teeth

• Inhibitor of apatite crystal growth

• Promotes osteoclast function
Osteopontin Deficiency Worsens Calcification
             in MGP Null Mice




                                      Speer MY et al. 2002
Major Theories of Vascular Calcification
                                   DISTURBED Ca/Pi BALANCE
                                   Hyperphosphatemia
                                   Hypercalcemia                         INDUCING FACTORS
                                                                         Pi
  LOSS OF INHIBITION
                                                                         Lipids
  MGP
                                                                         Inflammatory cytokines
  OPN
                                           Ca x Pi                       Others
  Fetuin/alpha2-HS glycoprotein
  Pyrophosphate
  Others
                                                                         INDUCTION OF
                                                                         BONE FORMATION
                             VASCULAR CALCIFICATION                      Vascular bone and
                                                                         cartilage-like cells



              CIRCULATING                                                 Matrix Vesicles
              NUCLEATIONAL
              COMPLEXES
                                                     Apoptotic bodies
                         Bisphosphonates
                         OPG

  Bone Remodeling                                          CELL DEATH
                                              Adapted from Speer & Giachelli, Cardiovasc Path 2004
Ectopic Calcification in Atherosclerotic Plaqes
Chondrocytes in Mouse Atherosclerotic Lesions




                       Rattazzi et al. ATVB 2005
 Mineral Precipitation          Cell Differentiation

                              osteoblast-like cell
Ca2+      PO42-
                                                     matrix
                                                     vesicles

 CaPO4 mineral
  precipitation


         “Active” inhibitor
                                  osteoid
                                  (matrix)
          Ca2+       PO42-



            CaPO4 mineral              hydroxyapatite
             precipitation
Potential Origins of Osteoblast-like Cells in the Artery Wall

       • Pericytes

       • Mesenchymal stem cells

       • Multipotent cells from the adventitia

       • Resident cells in the media or intima

       • Trans-differentiated SMC
             (Synthetic vs contractile phenotype)
          Calcifying Vascular Cells (CVC)




UNDIFFERENTIATED   CONDENSATION        CALCIFIED
                                       NODULES
Bone Related Factors in Calcified Artery Wall

            BMP-2 and -4
            Cbfa1
            Osterix
            Collagen I
            Alkaline Phosphatase
            Osteocalcin
            Hydroxyapatite

            Osteopontin
            Matrix GLA protein (MGP)
            Osteoprotegerin
            … and others …..
Both Inhibitors and Promotors of Calcification in Plaques




                                 Dhore et al. ATVB 2001
Major Theories of Vascular Calcification
                                   DISTURBED Ca/Pi BALANCE
                                   Hyperphosphatemia
                                   Hypercalcemia                         INDUCING FACTORS
                                                                         Pi
  LOSS OF INHIBITION
                                                                         Lipids
  MGP
                                                                         Inflammatory cytokines
  OPN
                                           Ca x Pi                       Others
  Fetuin/alpha2-HS glycoprotein
  Pyrophosphate
  Others
                                                                         INDUCTION OF
                                                                         BONE FORMATION
                             VASCULAR CALCIFICATION                      Vascular bone and
                                                                         cartilage-like cells



              CIRCULATING                                                 Matrix Vesicles
              NUCLEATIONAL
              COMPLEXES
                                                     Apoptotic bodies
                         Bisphosphonates
                         OPG

  Bone Remodeling                                          CELL DEATH
                                              Adapted from Speer & Giachelli, Cardiovasc Path 2004
   Normal Vessels Don’t Mineralize
  (Despite serum Ca x P at or near solubility product)


 Active
Inducers



                                                 Active
                                               Inhibitors
Intima         Atherosclerosis
               Renal Failure
               Diabetes


Media          Mönckeberg’s (Media sclerosis)
               Renal Failure
               Diabetes


Adventitia     Diabetes



Heart valves   Atherosclerosis
        Calcium x Phosphate Product

     Already above precipitation point at certain places
     Renal 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)
Phosphate-Induced Changes in SMC Differentiation

                                  Pi/Ca




     Contractile SMC
      SM-MHC
      SM22alpha                                     Osteochondrogenic cell
      SM-alpha actin                                      Cbfa1
      Desmin                                              OPN
                                                          Osteocalcin
                                                          Alk Phos


 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
Calcified Vascular Smooth Muscle Cells




                        Wada et al. Circ Res 1999
Major Theories of Vascular Calcification
                                   DISTURBED Ca/Pi BALANCE
                                   Hyperphosphatemia
                                   Hypercalcemia                        INDUCING FACTORS
                                                                        Pi
  LOSS OF INHIBITION
                                                                        Lipids
  MGP
                                                                        Inflammatory cytokines
  OPN
                                           Ca x Pi                      Others
  Fetuin/alpha2-HS glycoprotein
  Pyrophosphate
  Others
                                                                        INDUCTION OF
                                                                        BONE FORMATION
                             VASCULAR CALCIFICATION                     Vascular bone and
                                                                        cartilage-like cells



              CIRCULATING                                               Matrix Vesicles
              NUCLEATIONAL
              COMPLEXES
                                                     Apoptotic bodies
                         Bisphosphonates
                         OPG

  Bone Remodeling                                         CELL DEATH
Degenerative Joint Diseases are
         Connection between
“Crystal diseases”
    Vascular Calcification and Bone
where synovial fibroblasts have an
inflammatory response to the crystals.
Aortic Calcification and Osteoporosis Frequently Coexist
              Similarities to Bone:
                     Bone Proteins
                     Osteoblast-like Cells
                     Osteoclast-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
Osteoprotegerin (OPG)
OPG is a secreted protein that inhibits osteoclast formation
OPG deficient mice have osteoporosis and arterial (medial)
calcification




                     OPG Null Mouse


                       Bucay et al. Genes & Development 1998
Bone Resorption in the Skeleton Often Coexists with Bone
             Formation in the Vasculature




                                    Panizo et al., Circ Res 2009
                                    Alexander, Circ Res 2009
   VASCULAR CALCIFICATION
      AND INFLAMMATION


The Size of Vascular Calcification
          May Matter!
Large Chunks                      Small BCP Crystals




     Dhore et al. ATVB 2001                    Engelse et al.2001



                              BCP = Basic calcium phosphate
Degenerative Joint Diseases are
“Crystal diseases”
where synovial fibroblasts have an
inflammatory response to the crystals.
                Nadra et al. Circ Res 2005


The ingestion of BCP crystals by human
monocyte-derived macrophages generates a
pro-inflammatory response.
 BCP Crystals Induces Pro-Inflammatory Factors in Macrophages




                 TNF-alpha




TNF-alpha Increases Calcification in Calcifying Vascular Cells (CVC)




                                                    Nadra et al. Circ Res 2005
                                                        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 Calcification
   MGP knockout                                   Fibrillin-1 deficient


                        Fat-fed ApoE (or
                      LDLR) knockout mice




                                            Carbonic anhydrase II deficient
    OPG knockout




                                                  Warfarin treated rat
                                                       VitD/Ca
   Smad6 knockout
  Vascular calcification is
   heterogeneous and is
triggered through multiple
       mechanisms

				
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