Arterial Calcification and

Arterial Stiffness

Alberto Avolio

Department of Biomedical SciencesFaculty of Medicine and Health SciencesMacquarie UniversitySydney, Australia

Sydney, Australia.

alberto.avolio@mq.ed.au

Faculty of Medicine and Health Sciences Macquarie University, Sydney, Australia

Arterial Calcification

Can arterial calcification be a treatment target for arterial stiffness ?

Arterial Calcification

• Intimal calcification

• Medial calcification

Faculty of Medicine and Health Sciences Macquarie University, Sydney, Australia

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

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

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

Faculty of Medicine and Health Sciences Macquarie University, Sydney, Australia

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

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

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

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

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

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

Wall Area

Elastic Modulus

Wall Stress

Faculty of Medicine and Health Sciences Macquarie University, Sydney, Australia

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

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) ]

Faculty of Medicine and Health Sciences Macquarie University, Sydney, Australia

Ng K et al. Am J Physiol Renal Physiol 2011; 300: F1431–F1436

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

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

Faculty of Medicine and Health Sciences Macquarie University, Sydney, Australia

Ng K et al. Am J Physiol Renal Physiol 2011; 301: F959–F966

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 ]

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

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

Faculty of Medicine and Health Sciences Macquarie University, Sydney, Australia

Faculty of Medicine and Health Sciences Macquarie University, Sydney, Australia

Faculty of Medicine and Health Sciences Macquarie University, Sydney, Australia

Atkinson J. J Appl Physiol 2008;105:1643-1651

Faculty of Medicine and Health Sciences Macquarie University, Sydney, Australia

Avolio A. Arterial Stiffness . Pulse 2013;1:14-28

Faculty of Medicine and Health Sciences Macquarie University, Sydney, Australia

NO-related Mechanisms of Arterial Stiffness

D. Berkowitz, Jonhs Hopkins University

Faculty of Medicine and Health Sciences Macquarie University, Sydney, Australia

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

Faculty of Medicine and Health Sciences Macquarie University, Sydney, Australia

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

Increase of TG2 activity with age in human aorta

Faculty of Medicine and Health Sciences Macquarie University, Sydney, Australia

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

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

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

Johnson KA et al , Circ Res, 2008;102:529-537

Faculty of Medicine and Health Sciences Macquarie University, Sydney, Australia

Johnson KA et al , Circ Res, 2008;102:529-537

Faculty of Medicine and Health Sciences Macquarie University, Sydney, Australia

Van Bavel E , Bakker E , Circ Res, 2008;102:507-509

Faculty of Medicine and Health Sciences Macquarie University, Sydney, Australia

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

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