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VASCULAR AGING 3 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 Aging : What matters? 45 yr IT professional Arteries are 70 yr old Chronological age is different from biological age 70 yr Athlete Arteries are 45 yr old Atherothrombosis Significantly Shortens Life Atherothrombosis reduces life expectancy by around 8-12 years in patients aged over 60 years1 Average Remaining Life Expectancy at Age 60 (Men) 20 -7.4 years Years 16 12 -9.2 years -12 years 8 4 0 Healthy History of History Cardiovascular Disease of AMI Analysis of data from the Framingham Heart Study. Peeters A, et al. Eur Heart J. 2002;23:458-466. History of Stroke 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 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 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 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 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. ARTERIES ARTERIOLES AORTA ELASTIC MUSCULAR Normal Arterial Pulsation Young compliant arteries : Normal PW velocity (8 m/sec) Diastole Systole (1) Ventricular-Vascular coupling (2) coronary blood flow Cushion Conduit Elderly stiff arteries with ISH : Increased PW velocity (12 m/sec) Systole Forward wave Reflected (1) Ventricular-vascular mismatch Wave central SBP during late systole: (2) The reflected wave increases or “augments” 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 Pulsatile flow to Continuous flow- Cushion effect Conduit function – Role of Endothelium Tunica adventitia Tunica media Tunica intima Endothelium Subendothelial connective tissue Internal elastic membrane Smooth muscle cells Elastic/collagen Normal Endothelium 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. Regulates vascular tone and produces • Endogenous vasodilators and vasoconstrictors. • Growth promoting and growth inhibiting factors. • Anticoagulants and Procoagulants. Retards platelet and leucocyte adhesion Inhibits VSMC migration & proliferation Adapted from Ormolgul and Dzau, J Vasc Med Biol., 1991, 282-301, 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 Barrier to LDL, degrade VLDL & chylotriglyceride 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 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 Mechanism Loss or reduction of Cushion and Conduit functions of the blood vessels YOUNG NORMAL SIZE NORMAL RELAXATION OLD DILATED STIFF Aortic Stiffening and Early Wave Reflection Young compliant arteries : Normal PW velocity (8 m/sec) Systole Diastole (1) Ventricular-Vascular coupling (2) coronary blood flow Elderly stiff arteries with ISH : Increased PW velocity (12 m/sec) Systole (1) Ventricular-vascular mismatch (2) The reflected wave increases or “augments” central SBP during late systole: Abnormal cushion function LV systolic,diastolic dysfunction Abnormal Conduit Function Abnormal Endothelium LDL-C Hypertension Endothelial dysfunction sets the stage for atherosclerosis Angiotensin II Homocysteine Diabetes Smoking Oxidative stress Oestrogen deficiency Dysfunction 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, 282-301 Griendling, K. et.al., “Oxidative Stress and Cardiovascular Disease,”Circulation, 1007; 96: 3264-3265. Atomic force micrograph frpm Barbara et al, Am J Physiol [Heart Care Physiol.], 1995; 266: H1765-H1772 The Evolution of Atherosclerosis Foam Cells Fatty Streak Intermediate Lesion Atheroma Fibrous Plaque Complicated Lesion/Rupture Endothelial Dysfunction From 1st Decade From 3rd Decade Growth Mainly by Lipid Accumulation Adapted From Stary HC et al. Circulation. 1995;92:1355-1374 From 4th Decade Smooth Muscle Thrombosis, & Collagen Hematoma Abnormal conduit function Abnormal cushion function VASCULAR AGING 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 Midsegment obesity FAMILY HISTORY LARGE ARTERIES HYPERGLYCEMIA,OTHER RF AGES PROTEIN GLYCATION IN VESSEL WALL ATHEROMA LESS DISTENSIBLE COLLAGEN HIGH SYSTOLIC BP LOSS OF ARTERIAL COMPLIANCE LOW DIASTOLIC BP HIGH PULSE PRESSURE Factors contributing to Abnormal conduit function LDL-C Hypertension Angiotensin II Homocysteine Diabetes Smoking Oxidative stress Endothelial dysfunction NO + Local mediators + Tissue ACE, Angiotensin II PAI-1 VCAM, ICAM, Cytokines- NF-kB Thrombosis Inflammation Endothelin Growth factors, matrix Vasoconstriction Proteolysis Vascular lesion and remodelling Plaque rupture Clinical Sequelae Gibbons GH, Dzau VJ, New England J Med,1994; 330: 1431-1438 ATHEROSCLEROSIS ARTERIOSCLEROSIS Focal, Occlusive Intimal disease Inflammatory Endothelial dysfunction Related to LDL cholesterol oxidation “Inside-out” Sensitive to A II and other substances (Increased vascular stiffness Decreased vascular compliance) 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 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 (CUSHION) (CONDUIT) PULSE WAVE FORM ANALYSISTONOMETRY TONOMETRY-PULSE WAVE FORM ANALYSIS MAP Identification of Arterial Aging ABNORMAL CUSHION EFFECT NORMAL CUSHION EFFECT Normal systolic,diastolic And pulse pressure High systolic,low Diastolic and high Pulse pressure Effect of SBP and DBP on Age-Adjusted CAD Mortality: MRFIT CAD Death Rate per 10,000 Person-years 80.6 48.3 43.8 37.4 31.0 25.8 38.1 34.7 25.3 24.6 25.2 24.9 23.8 16.9 20.6 10.3 13.9 11.8 100+ 90-99 80-89 Diastolic BP (mmHg) 12.6 12.8 8.8 75-79 High systolic and low diastolic pressure is dangerous 8.5 70-74 11.8 9.2 <70 160+ 140-159 120-139 Systolic BP <120 (mmHg) PULSE WAVE VELOCITY What is Central Aortic Pressure ? Blood pressure in the aorta, closer to the vital organs Central aortic pressure Peripheral brachial pressure 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’ 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 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 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 Local Angiotensin System in Macrophages and Role in Atherosclerosis circulating monocytes ACE ACE Y Y Y adhesion- Y molecules endothelial damage + Angiotensin II LDL + Y infiltration + ACE smooth muscle cells Y Y Y endothelium oxidative stress oxLDL/eLDL subintima differentiation (activation) Macrophages lumen fatty streak, plaque ACE Ang II Mod. from Diaz et al., N Engl J Med 337 (1997) ACE Ang II Foam-cells + Growth factors Cytokines media ACE I OR ARB? WHICH ACEI,ARB? Evidence base in diabetic subjects Surrogate vascular structure & function trials Post MI patients High risk without LVF Stroke ACEIs ARBs TELMISARTAN (SECURE) NIL (AIRE,TRACE,SAVE) (HOPE/MICRO HOPE) (HOPE, PROGRESS) Preventing Heart failure Heart failure Diabetes & hypertension Renal disease (OPTIMAAL) NIL (SCOPE) LIFE ? (HOPE) (CONSENSUS, SOLVD,HOPE) (CAPP,ABCD, FACET) (LEWIS II) NIL (ELITE II,Val-HeFT) Charm (LIFE) (IDNT,RENAAL,IRMA2) Renin-Angiotensin Systems (III) Distribution of ACE: 10% RAS 90% circulating (plasma) local (tissue) Acute and short-term effects cardiovascular/ renal homeostasis Long-term effects Mod. from Dzau V, Arch Intern Med 153 (1993) local "organ adaptation" renal-independent activation Potential Pharmacological Actions of ACE Inhibitors in Atherosclerosis Putative role of 10 mg ramipril: in hypertension RAS (Plasma-ACE) RAS (Plaque-ACE) Ramipril Metalloproteinases (fibrous cap of plaque) Other targets? VSMC = vascular smooth muscle cells adapt. from Dzau et al., Drugs 47 (1994) Angiotensin II Bradykinin NO Collagen Elastin etc. Blood pressure VSMC-Contraction VSMC-Growth VSMC-Migration Platelet aggregation PAI-1 t-PA Matrix-Stability (CUSHION) Plaque rupture (CONDUIT) ACE I Total CV events and procedures 18.0 Atenolol thiazide (No. of events 1602) 16.0 14.0 12.0 Amlodipine perindopril (No. of events 1362) 10.0 8.0 6.0 4.0 HR = 0.84 (0.780.90) p < 0.0001 2.0 0.0 Number at risk Amlodipine perindopril Atenolol thiazide 0.0 1.0 2.0 3.0 4.0 5.0 9639 9618 9277 9210 8957 8848 8646 8465 8353 8121 7207 6977 Years Effects of Statins and ACE Inhibitors Agostino Faggiotto et al,Hypertension. 1999;34[part 2]:987-996. 55 Antiatherosclerotic Effect of ACE Inhibitors in the Vasculature (HOPE) Scheme of "plaque deactivation": ACE activity in plaques State-of-the-art therapy State-of-the-art therapy+ACE inhibitor (incl. ASA, Amlo, Statins) (e.g. 10 mg Ramipril) ACE activity in plaques Activated Plaque ACE activity in plaques Deactivated Plaque 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 drugsDPP4 inhibitors Logical combination of above 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 Vascular Age - Approach Reverse Vascular aging KEEPING THE ARTERIES YOUNGER