arterial calcification and arterial stiffness alberto avolio department of biomedical sciences...
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Arterial Calcification and
Arterial Stiffness
Alberto Avolio
Department of Biomedical SciencesFaculty of Medicine and Health SciencesMacquarie UniversitySydney, Australia
Sydney, Australia.
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Faculty of Medicine and Health Sciences Macquarie University, Sydney, Australia
Arterial Calcification
Can arterial calcification be a treatment target for arterial stiffness ?
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Arterial Calcification
• Intimal calcification
• Medial calcification
Faculty of Medicine and Health Sciences Macquarie University, Sydney, Australia
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Persy V and D’Hasse P. Trends in Molecular Medicine, 2009; 15(9): 405-416
Faculty of Medicine and Health Sciences Macquarie University, Sydney, Australia
INTIMAL and MEDIAL Calcification
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Arterial Calcification
• Mechanisms for deposition of calcium in arteries are similar to mechanisms for bone formation.
Faculty of Medicine and Health Sciences Macquarie University, Sydney, Australia
• The vasculature - second most calcified structure in humans after the skeleton
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Arterial Calcification
1500 Benivieni &Falopio ..“degeneration of arteries into bone”
1863 Virchow Described vascular changes as “ossification” (rather than ‘calcification’)
1906 Buntin Demonstration of bone marrow in sclerotic aorta
Santos et al, Clin Med Insights: Endocrinol Diabetes 2012;5:47-54
Faculty of Medicine and Health Sciences Macquarie University, Sydney, Australia
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Faculty of Medicine and Health Sciences Macquarie University, Sydney, Australia
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Pathways and mediators involved in vascular calcification and the calcification paradox
Persy V and D’Hasse P. Trends in Molecular Medicine, 2009; 15(9): 405-416
Faculty of Medicine and Health Sciences Macquarie University, Sydney, Australia
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FINDNGS:
Association between increased arterial stiffness (PWV) and arterial calcification (detected by CT) - explained by a common genetic etiology - independent of noncalcified atheromatous plaque - independent of bone mineral density
Faculty of Medicine and Health Sciences Macquarie University, Sydney, Australia
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Atkinson J et al Am J Physiol 1994;266:H540-547
Carotid Artery Compliance
Control
VDN
Faculty of Medicine and Health Sciences Macquarie University, Sydney, Australia
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13012512011511010510095908580757065
mmHg
Pres1
2
6
767.15767.20767.25767.30767.35767.40767.45767.50767.55
ECG
(PE, 50ug/min; SNP, 10ug/min)
a b
a
bPPA
LPWV
t
tTransducer 2
Transducer 1
Catheter 1
Catheter 2
Drug infusion
Aortic Pulse Wave Velocity in Rat Models
Faculty of Medicine and Health Sciences Macquarie University, Sydney, Australia
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Sodium nitroprussidephynelephrine
P1, m
mH
gP2
, mm
Hg
HR,
bpm
PWV,
m/s
ec
Time, sec
Aortic Pulse Wave Velocity in Rat Models
Faculty of Medicine and Health Sciences Macquarie University, Sydney, Australia
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Thoracic Aorta Abdominal Aorta
Calcification
Calcification
Aortic Pulse Wave Velocity in Rat Models
Aortic calcificaton induced by Nicotine and Vitamin D
Faculty of Medicine and Health Sciences Macquarie University, Sydney, Australia
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Wall Area
Elastic Modulus
Wall Stress
Faculty of Medicine and Health Sciences Macquarie University, Sydney, Australia
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Thoracic Aorta Abdominal Aorta
: (a,b) Wall stress (106dyne/cm2), (c,d) elastic modulus (106dyne/cm2) and (e,f) elastic modulus/wall stress of the thoracic (a,c,e) and abdominal (b,d,f) aorta in WKY (white column), VDN (grey column) and SHR (black column). * P<0.05.
Faculty of Medicine and Health Sciences Macquarie University, Sydney, Australia
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Ng K, Hildreth CM, Phillips JK, Avolio AP Aortic stiffness is associated with vascular calcification and remodeling in a chronic kidney disease rat model.
Am J Physiol Renal Physiol 2011; 300: F1431–F1436
Arterial calcification and stiffness
Chronic Kidney Disease Rat Model (*)
Faculty of Medicine and Health Sciences Macquarie University, Sydney, Australia
(*) Rat model: Lewis Polycystic Kidney (LPK) ]
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Faculty of Medicine and Health Sciences Macquarie University, Sydney, Australia
Ng K et al. Am J Physiol Renal Physiol 2011; 300: F1431–F1436
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LKP• Increased isobaric pulse wave velocity ~ 30%• Increased aortic calcification ~ 600%• Decreased elastin lamella density • Decreased interlamellar elastin• Increased smooth muscle cell density• Reduced size of smooth muscle cell nucleus
Lewis Polycystic Kidney (LPK) Disease Rat Model
Faculty of Medicine and Health Sciences Macquarie University, Sydney, Australia
Ng K et al. Am J Physiol Renal Physiol 2011; 300: F1431–F1436
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Ng K, Hildreth CM, Avolio AP, Phillips JK.
Angiotensin converting enzyme inhibitor limits pulse-wave velocity and aortic calcification in a rat model of cystic renal disease.
Am J Physiol Renal Physiol 2011; 301: F959–F966
Arterial calcification and stiffness - Treatment
Blunted by ACE inhibition (Perindopril)
Faculty of Medicine and Health Sciences Macquarie University, Sydney, Australia
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Faculty of Medicine and Health Sciences Macquarie University, Sydney, Australia
Ng K et al. Am J Physiol Renal Physiol 2011; 301: F959–F966
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Faculty of Medicine and Health Sciences Macquarie University, Sydney, Australia
Ng K et al. Am J Physiol Renal Physiol 2011; 301: F959–F966
Control Perindopril
Wall Area
Calcification Wall Stiffness
Effect of ACE Inhibition
Elastin density
[ treatment 6-12 weeks ]
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ACEi and pressure–dependent PWV in LKP rat aorta
30 %
~ 70 mmHg
Faculty of Medicine and Health Sciences Macquarie University, Sydney, Australia
Ng K et al. Am J Physiol Renal Physiol 2011; 301: F959–F966
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Arterial calcification and stiffness
Affected by Renin-Angiotensin System?
Vascular calcification inhibited by preventing vascular osteogenesis
Faculty of Medicine and Health Sciences Macquarie University, Sydney, Australia
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Faculty of Medicine and Health Sciences Macquarie University, Sydney, Australia
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Faculty of Medicine and Health Sciences Macquarie University, Sydney, Australia
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Faculty of Medicine and Health Sciences Macquarie University, Sydney, Australia
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Atkinson J. J Appl Physiol 2008;105:1643-1651
Faculty of Medicine and Health Sciences Macquarie University, Sydney, Australia
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Avolio A. Arterial Stiffness . Pulse 2013;1:14-28
Faculty of Medicine and Health Sciences Macquarie University, Sydney, Australia
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NO-related Mechanisms of Arterial Stiffness
D. Berkowitz, Jonhs Hopkins University
Faculty of Medicine and Health Sciences Macquarie University, Sydney, Australia
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D. Berkowitz, Jonhs Hopkins University
Studies of NOS and TG2 in knockout mice models
TG2 activity
Pulse Wave Velocity
Arterial Compliance
Faculty of Medicine and Health Sciences Macquarie University, Sydney, Australia
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Faculty of Medicine and Health Sciences Macquarie University, Sydney, Australia
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Studies of NOS and TG2 in aging rat models
D. Berkowitz, Jonhs Hopkins University
TG2 activity
E : endothelium
TG2 S-Nitrosylation
Reduction of PWV with TG2 Inhibitor
Faculty of Medicine and Health Sciences Macquarie University, Sydney, Australia
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Increase of TG2 activity with age in human aorta
Faculty of Medicine and Health Sciences Macquarie University, Sydney, Australia
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1. Arterial Calcification
2. Nitric Oxide and alteration of extracellular matrix
Two mechanisms of cellular and molecular factors of arterial stiffness :
Faculty of Medicine and Health Sciences Macquarie University, Sydney, Australia
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1. Arterial Calcification
2. Nitric Oxide and alteration of extracellular matrix
Two mechanisms of cellular and molecular factors of arterial stiffness :
Question: Any possible connection ?
Faculty of Medicine and Health Sciences Macquarie University, Sydney, Australia
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1. Arterial Calcification
2. Nitric Oxide and alteration of extracellular matrix
Two mechanisms of cellular and molecular factors of arterial stiffness :
Answer: Tissue transglutaminase (TG2) ?
Faculty of Medicine and Health Sciences Macquarie University, Sydney, Australia
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Johnson KA et al , Circ Res, 2008;102:529-537
Faculty of Medicine and Health Sciences Macquarie University, Sydney, Australia
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Johnson KA et al , Circ Res, 2008;102:529-537
Faculty of Medicine and Health Sciences Macquarie University, Sydney, Australia
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Van Bavel E , Bakker E , Circ Res, 2008;102:507-509
Faculty of Medicine and Health Sciences Macquarie University, Sydney, Australia
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Vascular Effects of BiophosphonatesBiophosphonates used in treating osteoporosis; act on body’s source of hydroxyapatite - skeleton
Santos LL et al, Vascular effects of bisphosphonates-a systematic review. Clin Med Insights Endocrinol Diabetes. 2012;5:47-54
Faculty of Medicine and Health Sciences Macquarie University, Sydney, Australia
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ConclusionCan arterial calcification be a treatment target for arterial stiffness ?
Experimental data aimed at uncovering basic mechanisms of arterial calcification and arterial stiffness indicates potential pathways.
Faculty of Medicine and Health Sciences Macquarie University, Sydney, Australia