Arterial Calcification and Arterial Stiffness Alberto Avolio Department of Biomedical Sciences Faculty of Medicine and Health Sciences Macquarie University Sydney, Australia Sydney, Australia.

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): 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” 1863VirchowDescribed vascular changes as “ossification” (rather than ‘calcification’) 1906BuntinDemonstration 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

Pathways and mediators involved in vascular calcification and the calcification paradox Persy V and D’Hasse P. Trends in Molecular Medicine, 2009; 15(9): 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:H Carotid Artery Compliance Control VDN Faculty of Medicine and Health Sciences Macquarie University, Sydney, Australia

mmHg Pres ECG (PE, 50ug/min; SNP, 10ug/min) a b Transducer 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 nitroprusside phynelephrine P1, mmHg P2, mmHg HR, bpm PWV, m/sec Time, sec Aortic Pulse Wave Velocity in Rat Models Faculty of Medicine and Health Sciences Macquarie University, Sydney, Australia

Thoracic Aorta Abdominal Aorta 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 (10 6 dyne/cm 2 ), (c,d) elastic modulus (10 6 dyne/cm 2 ) 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

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 ControlPerindopril 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

Atkinson J. J Appl Physiol 2008;105: 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

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

Johnson KA et al, Circ Res, 2008;102: Faculty of Medicine and Health Sciences Macquarie University, Sydney, Australia

Van Bavel E, Bakker E, Circ Res, 2008;102: Faculty of Medicine and Health Sciences Macquarie University, Sydney, Australia

Vascular Effects of Biophosphonates Biophosphonates 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

Conclusion Can 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