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3 VASCULAR AGING PLAN 1.Introduction 2.Normal vascular anatomy and physiology 3.What is vascular aging ? 4.What causes it ? 5.How to diagnose it ?

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Presentation on theme: "3 VASCULAR AGING PLAN 1.Introduction 2.Normal vascular anatomy and physiology 3.What is vascular aging ? 4.What causes it ? 5.How to diagnose it ?"— Presentation transcript:

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3 3 VASCULAR AGING

4 PLAN 1.Introduction 2.Normal vascular anatomy and physiology 3.What is vascular aging ? 4.What causes it ? 5.How to diagnose it ? 6.How to treat and prevent it ? 7.Take away

5 Aging : What matters? 45 yr IT professional Arteries are 70 yr old 70 yr Athlete Arteries are 45 yr old Chronological age is different from biological age

6 Atherothrombosis Significantly Shortens Life Analysis of data from the Framingham Heart Study. Peeters A, et al. Eur Heart J. 2002;23: Atherothrombosis reduces life expectancy by around 8-12 years in patients aged over 60 years 1 Average Remaining Life Expectancy at Age 60 (Men) Healthy Years History of AMI -9.2 years History of Cardiovascular Disease -7.4 years History of Stroke -12 years

7 Vascular age  Vascular age is the apparent age of the blood vessels, particularly the arteries when compared to what is normal for the healthy population  Vascular age is affected by genetic predisposition, lifestyle choices and other factors

8 PLAN 1.Introduction 2.Normal vascular anatomy and physiology 3.What is vascular aging? 4.What causes it? 5.How to diagnose it? 6.How to treat and prevent it? 7.Takeaways

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10 THE ARTERIAL SYSTEM  These are the main conducting vessels carrying blood away from the heart  Can be muscular or elastic. There is a gradual transition between these two types

11 Elastic Arteries  Are characterised by a predominance of elastin in the tunica media and little smooth muscle  Are found just downstream from the heart  Undergo expansion with each systole of the heart  On relaxation of the heart the elastic recoil of the wall helps propel blood through the blood vessels  Include the aorta, pulmonary, common carotid and other major vessels

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13 Muscular Arteries  These are medium sized to smaller arteries  Are characterised by a predominance of smooth muscle cells in the tunica media  Make up the main distributing branches of the arterial tree, eg. the femoral, radial, coronary and cerebral arteries  Remember, there is a gradual transition between elastic and muscular arteries.

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15 AORTA ARTERIES ARTERIOLES ELASTIC MUSCULAR

16 Systole Normal Arterial Pulsation Diastole Systole  Increases vascular afterload with a propensity to develop LVH  Decreases coronary perfusion pressure  Increases myocardial oxygen demand and subendocardial ischemia  Increases flow turbulence, endothelial dysfunction and atherogenesis  Increases in pulsatile strain and chance of plaque rupture  All recognized by a wide brachial artery pulse pressure in the elderly Young compliant arteries : Normal PW velocity (8 m/sec) Elderly stiff arteries with ISH : Increased PW velocity (12 m/sec) (1) Ventricular-Vascular coupling (2)  coronary blood flow (1) Ventricular-vascular mismatch (2) The reflected wave increases or “augments” central SBP during late systole: CushionConduit Forward wave Reflected Wave

17 Pulsatile flow to Continuous flow- Cushion effect

18 Conduit function – Role of Endothelium Tunica adventitia Tunica media Tunica intima Endothelium Subendothelial connective tissue Internal elastic membrane Smooth muscle cells Elastic/collagen fibers External elastic membrane

19 Normal Endothelium Regulates vascular tone and produces The endothelium is the gatekeeper of the vasculature and a major regulator of vascular tone and hemostasis It Provides a smooth, non-thrombogenic surface and a selectively permeability barrier between the circulation and the vessel wall. Adapted from Ormolgul and Dzau, J Vasc Med Biol., 1991, , Pepine, C., et. al., “Vascular Health as as Therapeutic Target in Cardiovascular Disease,” VBW, University of Florida, 1998 Atomic force micrograph frpm Barbara et al, Am J Physiol [Heart Care Physiol.], 1995; 266: H1765-H1772 Endogenous vasodilators and vasoconstrictors. Growth promoting and growth inhibiting factors. Anticoagulants and Procoagulants. Retards platelet and leucocyte adhesion Inhibits VSMC migration & proliferation Barrier to LDL, degrade VLDL & chylotriglyceride

20 Normal Arterial Function  Cushion function – mainly by Aorta; prevents transmission of systolic pressure to the periphery, slows systolic velocity and maintains continuous flow in distributing arteries and arterioles  Conduit function – Mainly by arteries and their endothelium ; prevents atheroma, plaque, thrombus formation to provide continuous and uninterrupted blood flow to the organs

21 PLAN 1.Introduction 2.Normal vascular anatomy and physiology 3.What is the mechanism of vascular aging ? 4.What causes it ? 5.How to diagnose it ? 6.How to treat and prevent it ? 7.Takeaways

22 Mechanism  Loss or reduction of Cushion and Conduit functions of the blood vessels

23 NORMAL SIZE NORMAL RELAXATION YOUNGOLD DILATED STIFF

24 Systole Aortic Stiffening and Early Wave Reflection Diastole Systole Young compliant arteries : Normal PW velocity (8 m/sec) Elderly stiff arteries with ISH : Increased PW velocity (12 m/sec) (1) Ventricular-Vascular coupling (2)  coronary blood flow (1) Ventricular-vascular mismatch (2) The reflected wave increases or “augments” central SBP during late systole:

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26 LV systolic,diastolic dysfunction Abnormal cushion function

27 Abnormal Conduit Function Abnormal Endothelium Dysfunction  LDL-C HypertensionDiabetesSmoking Oxidative stress Angiotensin II  Homocysteine Oestrogendeficiency Endothelial dysfunction sets the stage for atherosclerosis Formation of superoxide anion with inactivation of NO & stimulation of vascular oxidase system  platelet and leucocyte adhesion VSMC migration & proliferation  LDL deposition  lipid clearance Adapted from Ormolgul and Dzau, J Vasc Med Biol., 1991, Griendling, K. et.al., “Oxidative Stress and Cardiovascular Disease,”Circulation, 1007; 96: Atomic force micrograph frpm Barbara et al, Am J Physiol [Heart Care Physiol.], 1995; 266: H1765-H1772

28 The Evolution of Atherosclerosis Foam Cells Fatty Streak Intermediate Lesion Atheroma Fibrous Plaque Complicated Lesion/Rupture Endothelial Dysfunction From 1st Decade From 3rd Decade From 4th Decade Growth Mainly by Lipid Accumulation Smooth Muscle & Collagen Smooth Muscle & Collagen Thrombosis, Hematoma Thrombosis, Hematoma Adapted From Stary HC et al. Circulation. 1995;92:

29 Abnormal cushion function Abnormal conduit function VASCULAR AGING

30 PLAN 1.Introduction 2.Normal vascular anatomy and physiology 3.What is the mechanism of vascular aging ? 4.What causes it ? 5.How to diagnose it ? 6.How to treat and prevent it ? 7.Takeaways

31 Midsegment obesity FAMILY HISTORY

32 LARGE ARTERIES HYPERGLYCEMIA,OTHER RF A G E S PROTEIN GLYCATION IN VESSEL WALL LESS DISTENSIBLE COLLAGEN LOSS OF ARTERIAL COMPLIANCE HIGH SYSTOLIC BP LOW DIASTOLIC BP HIGH PULSE PRESSURE ATHEROMA

33 Factors contributing to Abnormal conduit function PAI-1 Endothelial dysfunction Proteolysis  NO +  Local mediators +  Tissue ACE, Angiotensin II VCAM, ICAM, Cytokines- NF-kB EndothelinGrowth factors, matrix  LDL-C HypertensionDiabetesSmoking Oxidative stress Angiotensin II  Homocysteine Thrombosis Plaque rupture InflammationVasoconstriction Vascular lesion and remodelling Clinical Sequelae Gibbons GH, Dzau VJ, New England J Med,1994; 330:

34 ATHERO- ARTERIO- SCLEROSIS SCLEROSIS (Increased vascular stiffness Decreased vascular compliance)  Focal, Occlusive  Intimal disease  Inflammatory  Endothelial dysfunction  Related to LDL cholesterol oxidation  “Inside-out”  Sensitive to A II and other substances  Diffuse, Dilatory  Medial disease  Fibrotic (elastin breakdown, collagen increase)  Adventitial and medial hypertrophy  Related to age and BP  “Outside-in”  Sensitive to A II and other substances

35 PLAN 1.Introduction 2.Normal vascular anatomy and physiology 3.What is the mechanism of vascular aging ? 4.What causes it ? 5.How to diagnose it ? 6.How to treat and prevent it ? 7.Takeaways

36 (CUSHION)(CONDUIT)

37 PULSE WAVE FORM ANALYSIS- TONOMETRY

38 MAP TONOMETRY-PULSE WAVE FORM ANALYSIS

39 NORMAL CUSHION EFFECT Normal systolic,diastolic And pulse pressure ABNORMAL CUSHION EFFECT High systolic,low Diastolic and high Pulse pressure Identification of Arterial Aging

40 CAD Death Rate per 10,000 Person-years <70 < Diastolic BP (mmHg) Systolic BP (mmHg) Neaton et al. Arch Intern Med 1992; 152: Effect of SBP and DBP on Age-Adjusted CAD Mortality: MRFIT High systolic and low diastolic pressure is dangerous

41 PULSE WAVE VELOCITY

42 What is Central Aortic Pressure ?  Blood pressure in the aorta, closer to the vital organs Central aortic pressure Peripheral brachial pressure

43 RISK FACTORS AND MARKERS  RISK FACTORS  PREDICT DISEASE  DM,DUR.  LIPIDS  HBP  SMOKING  MET SYN  MENTAL STRESS  FAMILY HISTORY  RISK MARKERS  INDICATE PRESENCE  MICROALB.,ED,CKD, FMD  CIMT, AB INDEX,PW VELOCITY  MSCT, STRESS TEST  Hs CRP  ECHO – DD,E/E’

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45 INDIVIDUAL ASSESSMENT FOR EARLY VASCULAR AGING (EVA)? AT 30 YRS RISK FACTOR AND RISK MARKER ASSESSMENT RISK FACTORS + RISK MARKERS + ALREADY EVA + RISK FACTORS + RISK MARKERS -- LIKELY TO DEVELOP EVA RISK FACTORS – RISK MARKERS -- PREVENT EVA

46 PLAN 1.Introduction 2.Normal vascular anatomy and physiology 3.What is the mechanism of vascular aging ? 4.What causes it ? 5.How to diagnose it ? 6.How to treat and prevent it ? 7.Takeaways

47 To reverse and prevent vascular aging  Life style modification – Diet/ Exercise / Good habits / Mental relaxation  Block Renin- Angiotensin system  Control Blood pressure  Reduce Lipids  Control Blood sugar

48 Y Y Y Y Y Y Y Y ACE Angiotensin II LDL endothelial damage oxLDL/eLDL lumen subintima + + ACE Macrophages + Ang II media Foam-cells smooth muscle cells + Growth factors Cytokines Local Angiotensin System in Macrophages and Role in Atherosclerosis Ang II oxidative stress differentiation (activation) Mod. from Diaz et al., N Engl J Med 337 (1997) ACE adhesion- molecules infiltration fatty streak, plaque endothelium circulating monocytes ACE

49 ACE I OR ARB? WHICH ACEI,ARB?

50 LIFE Charm TELMISARTAN

51 Distribution of ACE: Renin-Angiotensin Systems (III) Mod. from Dzau V, Arch Intern Med 153 (1993) R A S local (tissue) 10%90% Acute and short-term effects cardiovascular/ renal homeostasis Long-term effects local "organ adaptation" renal-independent activation circulating (plasma)

52 VSMC-Contraction VSMC-Growth VSMC-Migration Platelet aggregation PAI-1 t-PA Putative role of 10 mg ramipril: Potential Pharmacological Actions of ACE Inhibitors in Atherosclerosis RAS (Plasma-ACE) RAS (Plaque-ACE) Metalloproteinases (fibrous cap of plaque) Plaque rupture Ramipril adapt. from Dzau et al., Drugs 47 (1994) VSMC = vascular smooth muscle cells Angiotensin II Bradykinin NO Matrix-Stability Blood pressure in hypertension Collagen Elastin etc. Other targets? (CUSHION) (CONDUIT)

53 ACE I

54 Total CV events and procedures Number at risk Amlodipine  perindopril Atenolol  thiazide Years Amlodipine  perindopril (No. of events 1362) Atenolol  thiazide (No. of events 1602) HR = 0.84 (0.78­0.90) p <

55 55 Effects of Statins and ACE Inhibitors Agostino Faggiotto et al,Hypertension. 1999;34[part 2]:

56 State-of-the-art therapy (incl. ASA, Amlo, Statins) Deactivated PlaqueActivated Plaque ACE activity in plaques ACE activity in plaques Antiatherosclerotic Effect of ACE Inhibitors in the Vasculature (HOPE) Scheme of "plaque deactivation": ACE activity in plaques State-of-the-art therapy+ACE inhibitor (e.g. 10 mg Ramipril)

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59 So, to reverse and prevent Vascular Aging  Life style modification  Block RAS-ACEI (Ramipril, Perindopril-Max. tolerated dose)  Control BP- Calcium blockers  Amlodepin  Control lipids- Statins  Control sugar – emerging drugs  DPP4 inhibitors  Logical combination of above

60 PLAN 1.Introduction 2.Normal vascular anatomy and physiology 3.What is the mechanism of vascular aging? 4.What causes it? 5.How to diagnose it? 6.How to treat and prevent it? 7.Takeaways

61 Vascular Age - Approach Reverse Vascular aging

62 KEEPING THE ARTERIES YOUNGER

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