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Vascular Calcification Kristina Boström, MD, PhD Cardiology, UCLA.

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Presentation on theme: "Vascular Calcification Kristina Boström, MD, PhD Cardiology, UCLA."— Presentation transcript:

1 Vascular Calcification Kristina Boström, MD, PhD Cardiology, UCLA

2 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.

3 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.

4 Circumferential Calcification in the Ascending Aorta

5 Left Ventricular Apical Conduit to Descending Thoracic Aorta

6 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 ….

7 Anatomical locationAortic Coronary Peripheral arteries Heart valve Vascular layerIntima Media Adventitia Heart valve Association with disease Atherosclerosis Mönckeberg’s (Media Sclerosis) Diabetes Renal Failure Vascular Calcification Differs in:

8 Intima Media Adventitia Heart valves Atherosclerosis Renal Failure Diabetes Mönckeberg’s (Media sclerosis) Renal Failure Diabetes Atherosclerosis Diabetes Vascular Calcification Is Associated with Vascular Disease:

9 Sangiorgi et al. JACC 1998 Intimal Calcification - Atherosclerosis

10 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

11 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

12 Coronary Calcification Detected by Electron Beam CT (EBCT) - “Heart Scans”

13 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

14 Medial Calcification Atherosclerotic Plaques

15 (Mönckeberg’s media sclerosis, elastocalcinosis) Webpath Price et al. ATVB 2000 VASCULAR MEDIAL CALCIFICATION Arteriosclerosis associated with aging, diabetes, and end stage renal disease

16 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

17 Medial Calcification in Arteries of Dialysis Patients 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

18 Heart Valve Calcification Senile Aortic Stenosis Calcified Bioprosthetic Valve Normal Aortic Valve

19 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

20 Mechanisms of Vascular Calcification

21 Normal Vessels Don’t Mineralize Active Inducers Active Inhibitors

22 Dhore et al. ATVB 2001 Inhibitors Promotors Both Inhibitors and Promotors of Calcification in Atherosclerotic Plaques

23 VASCULAR CALCIFICATION DISTURBED Ca/Pi BALANCE Hyperphosphatemia Hypercalcemia Ca x Pi INDUCING FACTORS Pi Lipids Inflammatory cytokines Others INDUCTION OF BONE FORMATION Vascular bone and cartilage-like cells Apoptotic bodies CELL DEATH LOSS OF INHIBITION Pyrophosphate MGP OPN Fetuin/alpha2-HS glycoprotein Others CIRCULATING NUCLEATIONAL COMPLEXES Bisphosphonates OPG Bone Remodeling Matrix Vesicles Major Theories of Vascular Calcification Adapted from Speer & Giachelli, Cardiovasc Path 2004

24 VASCULAR CALCIFICATION DISTURBED Ca/Pi BALANCE Hyperphosphatemia Hypercalcemia Ca x Pi INDUCING FACTORS Pi Lipids Inflammatory cytokines Others INDUCTION OF BONE FORMATION Vascular bone and cartilage-like cells Apoptotic bodies CELL DEATH LOSS OF INHIBITION Pyrophosphate MGP OPN Fetuin/alpha2-HS glycoprotein Others CIRCULATING NUCLEATIONAL COMPLEXES Bisphosphonates OPG Bone Remodeling Matrix Vesicles Major Theories of Vascular Calcification Adapted from Speer & Giachelli, Cardiovasc Path 2004

25 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

26 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)

27 Vascular Calcification in MGP Null Mice Luo et al. Science 1997 Aortic media Wild type Aortic media MGP null

28 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)

29 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)

30 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

31 Acidic phosphoprotein found in bone and teeth Inhibitor of apatite crystal growth Promotes osteoclast function OSTEOPONTIN

32 Osteopontin Deficiency Worsens Calcification in MGP Null Mice Speer MY et al. 2002

33 VASCULAR CALCIFICATION DISTURBED Ca/Pi BALANCE Hyperphosphatemia Hypercalcemia Ca x Pi INDUCING FACTORS Pi Lipids Inflammatory cytokines Others INDUCTION OF BONE FORMATION Vascular bone and cartilage-like cells Apoptotic bodies CELL DEATH LOSS OF INHIBITION MGP OPN Fetuin/alpha2-HS glycoprotein Pyrophosphate Others CIRCULATING NUCLEATIONAL COMPLEXES Bisphosphonates OPG Bone Remodeling Matrix Vesicles Major Theories of Vascular Calcification Adapted from Speer & Giachelli, Cardiovasc Path 2004

34 Ectopic Calcification in Atherosclerotic Plaqes

35 Rattazzi et al. ATVB 2005 Chondrocytes in Mouse Atherosclerotic Lesions

36 Mineral Precipitation Cell Differentiation Ca 2+ PO 4 2- CaPO 4 mineral precipitation osteoid (matrix) matrix vesicles hydroxyapatite Ca 2+ PO 4 2- CaPO 4 mineral precipitation “Active” inhibitor osteoblast-like cell

37 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

38 Calcifying Vascular Cells (CVC) CONDENSATION CALCIFIED NODULES UNDIFFERENTIATED

39 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 …..

40 Dhore et al. ATVB 2001 Both Inhibitors and Promotors of Calcification in Plaques

41 VASCULAR CALCIFICATION DISTURBED Ca/Pi BALANCE Hyperphosphatemia Hypercalcemia Ca x Pi INDUCING FACTORS Pi Lipids Inflammatory cytokines Others INDUCTION OF BONE FORMATION Vascular bone and cartilage-like cells Apoptotic bodies CELL DEATH LOSS OF INHIBITION MGP OPN Fetuin/alpha2-HS glycoprotein Pyrophosphate Others CIRCULATING NUCLEATIONAL COMPLEXES Bisphosphonates OPG Bone Remodeling Matrix Vesicles Major Theories of Vascular Calcification Adapted from Speer & Giachelli, Cardiovasc Path 2004

42 (Despite serum Ca x P at or near solubility product) Normal Vessels Don’t Mineralize Active Inducers Active Inhibitors

43 Intima Media Adventitia Heart valves Atherosclerosis Renal Failure Diabetes Mönckeberg’s (Media sclerosis) Renal Failure Diabetes Atherosclerosis Diabetes

44 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) Calcium x Phosphate Product

45 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 cell SM-MHC SM22alpha SM-alpha actin Desmin Cbfa1 OPN Osteocalcin Alk Phos Phosphate-Induced Changes in SMC Differentiation

46 Wada et al. Circ Res 1999 Calcified Vascular Smooth Muscle Cells

47 VASCULAR CALCIFICATION DISTURBED Ca/Pi BALANCE Hyperphosphatemia Hypercalcemia Ca x Pi INDUCING FACTORS Pi Lipids Inflammatory cytokines Others INDUCTION OF BONE FORMATION Vascular bone and cartilage-like cells Apoptotic bodies CELL DEATH LOSS OF INHIBITION MGP OPN Fetuin/alpha2-HS glycoprotein Pyrophosphate Others CIRCULATING NUCLEATIONAL COMPLEXES Bisphosphonates OPG Bone Remodeling Matrix Vesicles Major Theories of Vascular Calcification

48 Degenerative Joint Diseases are “Crystal diseases” where synovial fibroblasts have an inflammatory response to the crystals. Connection between Vascular Calcification and Bone

49 Aortic Calcification and Osteoporosis Frequently Coexist

50 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.

51 Mody et al. J Nucl Card 2003

52 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

53 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 Osteoprotegerin (OPG)

54 Bone Resorption in the Skeleton Often Coexists with Bone Formation in the Vasculature Panizo et al., Circ Res 2009 Alexander, Circ Res 2009

55 The Size of Vascular Calcification May Matter! VASCULAR CALCIFICATION AND INFLAMMATION

56 Dhore et al. ATVB 2001Engelse et al.2001 Large ChunksSmall BCP Crystals BCP = Basic calcium phosphate

57 Degenerative Joint Diseases are “Crystal diseases” where synovial fibroblasts have an inflammatory response to the crystals.

58 The ingestion of BCP crystals by human monocyte-derived macrophages generates a pro-inflammatory response. Nadra et al. Circ Res 2005

59 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

60 Large calcified areas may be less pro-inflammatory. How dangerous is the calcification we find on EBCT?

61 Mouse models for vascular calcification

62 Genes Associated with Ectopic Calcification in Mice MUTATIONPHENOTYPE Matrix Gla Protein Arterial, valve and cartilage calcification FetuinDecreased serum HA inhibitory activity OsteopontinIncreased calcification of implanted bioprosthetic valves FibrillinVascular calcification, aortic stenosis OsteoprotegerinOsteoporosis, vascular calcification FGF23Hyperphosphatemia, vascular calcification PC-1/Enpp1/NPP1Vascular and articular cartilage calcification (nucleotide pyrophosphatase) Ank (pyrophosphate transporter)Articular cartilage calcification, soft tissue calcification ß-glucosidase (klotho)Vascular calcification, rapid aging Carbonic Anhydrase IICalcification of small arteries Smad6Valve calcification DesminNeonatal cardiomyopahty with calcificationAriall

63 Mouse Models Illustrate the Diversity of Vascular Calcification MGP knockout OPG knockout Smad6 knockout Carbonic anhydrase II deficient Fibrillin-1 deficient Fat-fed ApoE (or LDLR) knockout mice Warfarin treated rat VitD/Ca

64 Vascular calcification is heterogeneous and is triggered through multiple mechanisms


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