MODULE 3 CHAPTER 1D

3

VASCULAR AGING

PLAN1. 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 professionalArteries are 70 yr old

70 yr Athlete Arteries are 45 yr old

Chronological age is different from biological age

Atherothrombosis Significantly Shortens Life

Analysis of data from the Framingham Heart Study.Peeters A, et al. Eur Heart J. 2002;23:458-466.

Atherothrombosis reduces life expectancy by around 8-12 years in patients aged over 60 years1

Average Remaining Life Expectancy at Age 60 (Men)

0

4

8

12

16

20

Healthy

Yea

rs

History of AMI

-9.2 years

History of Cardiovascular Disease

-7.4 years

History of Stroke

-12 years

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.

AORTA

ARTERIESARTERIOLES

ELASTIC

MUSCULAR

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:

Cushion Conduit

Forwardwave

Reflected Wave

Pulsatile flow to Continuous flow- Cushion effect

Conduit function – Role of Endothelium

Tunica adventitia

Tunica media

Tunica intimaEndothelium

Subendothelial

connective tissue

Internal elastic

membrane

Smooth muscle cells

Elastic/collagen

fibers

External elastic

membrane

Normal Endothelium

Regulates vascular tone and produces

The endothelium is the gatekeeper of the vasculature and a major regulator of vascular tone and hemostasisIt 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, 282-301,Pepine, C., et. al., “Vascular Health as as Therapeutic Target in Cardiovascular Disease,” VBW , University of Florida, 1998Atomic 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

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

PLAN1.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

NORMAL SIZENORMAL RELAXATION

YOUNG OLD

DILATEDSTIFF

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:

LV systolic,diastolic dysfunction

Abnormal cushion function

Abnormal Conduit FunctionAbnormal Endothelium

Dysfunction

LDL-C Hypertension Diabetes Smoking

Oxidative stress

Angiotensin II Homocysteine

Oestrogen deficiency

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, 282-301Griendling, 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 AtherosclerosisThe Evolution of Atherosclerosis

FoamCells

FattyStreak

IntermediateLesion Atheroma

FibrousPlaque

ComplicatedLesion/Rupture

Endothelial DysfunctionEndothelial Dysfunction

From 1st DecadeFrom 1st Decade From 3rd DecadeFrom 3rd Decade From 4th DecadeFrom 4th Decade

Growth Mainly by Lipid AccumulationGrowth Mainly by Lipid Accumulation Smooth Muscle& Collagen

Smooth Muscle& Collagen

Thrombosis,Hematoma

Thrombosis,Hematoma

Adapted From Stary HC et al. Circulation. 1995;92:1355-1374Adapted From Stary HC et al. Circulation. 1995;92:1355-1374

Abnormal cushionfunction

Abnormal conduitfunction

VASCULARAGING

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

INTERHEART: THE EFFECT OF MODIFIABLE FACTORS ON RISK FOR MI

Midsegment obesity FAMILY HISTORY

LARGE ARTERIES

HYPERGLYCEMIA,OTHER RF

A G E S

PROTEIN GLYCATIONIN VESSEL WALL

LESS DISTENSIBLE COLLAGEN

LOSS OF ARTERIALCOMPLIANCE

HIGH SYSTOLIC BP

LOW DIASTOLIC BP

HIGH PULSE PRESSURE

ATHEROMA

Factors contributing to Abnormal conduit function

PAI-1

Endothelial dysfunction

Proteolysis

NO + Local mediators + Tissue ACE, Angiotensin II

VCAM, ICAM, Cytokines- NF-kB

Endothelin Growth factors, matrix

LDL-C Hypertension Diabetes Smoking

Oxidative stress

Angiotensin II Homocysteine

Thrombosis Plaque rupture

Inflammation Vasoconstriction Vascular lesion and remodelling

Clinical Sequelae

Gibbons GH, Dzau VJ, New England J Med,1994; 330: 1431-1438

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

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 ANALYSIS- TONOMETRY

MAP

TONOMETRY-PULSE WAVE FORM ANALYSIS

NORMAL CUSHION EFFECT

Normal systolic,diastolicAnd pulse pressure

ABNORMAL CUSHION EFFECT

High systolic,lowDiastolic and highPulse pressure

Identification of Arterial Aging

CAD Death Rate per 10,000 Person-years

100+ 90-99 80-89 75-79 70-74 <70<120

120-139140-159160+

Diastolic BP (mmHg)

Systolic BP (mmHg)

20.610.3 11.8 8.8 8.5 9.2

11.812.612.813.9

24.6 25.3 25.2 24.9

16.923.8

31.025.8

34.743.8

38.1

80.6

37.4

48.3

Neaton et al. Arch Intern Med 1992; 152:56-64.

Effect of SBP and DBP onAge-Adjusted CAD Mortality: MRFIT

High systolic and low diastolic pressure is dangerous

PULSE WAVE VELOCITY

What is Central Aortic Pressure ? Blood pressure in the aorta, closer to the vital organs

Central aorticpressure

Peripheral brachialpressure

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

YYYYY Y Y Y

ACE

ACE

Angiotensin II LDL

endothelialdamage oxLDL/eLDL

lumen

subintima

+ +

ACEMacrophages

+

Ang II media

Foam-cells

smooth muscle cells + Growth factorsCytokines

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

circulatingmonocytes

ACE

ACE I OR ARB?WHICH ACEI,ARB?

Surrogate vascular structure & function trials (SECURE) NIL

Post MI patients (AIRE,TRACE,SAVE) (OPTIMAAL)

High risk without LVF (HOPE/MICRO HOPE) NIL

Stroke (HOPE, PROGRESS) (SCOPE)

Preventing Heart failure (HOPE) NIL

Heart failure ?(CONSENSUS, SOLVD,HOPE) (ELITE II,Val-HeFT)

Diabetes & hypertension (CAPP,ABCD, FACET) (LIFE)

Renal disease (LEWIS II) (IDNT,RENAAL,IRMA2)

Evidence base in diabetic subjectsEvidence base in diabetic subjects

ACEIs ARBs

LIFE

Charm

TELMISARTAN

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 effectscardiovascular/

renal homeostasis

Long-term effectslocal "organ adaptation"

renal-independent activation

circulating (plasma)

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 pressurein hypertension

Collagen Elastin etc.

Other targets?(CUSHION)

(CONDUIT)

ACE I

Total CV events and procedures

Number at riskAmlodipine perindopril 9639 9277 8957 8646 8353 7207Atenolol thiazide 9618 9210 8848 8465 8121 6977

0.0 1.0 2.0 3.0 4.0 5.0 Years0.0

2.0

4.0

6.0

8.0

10.0

12.0

14.0

16.0

18.0

Amlodipine perindopril(No. of events 1362)

Atenolol thiazide(No. of events 1602)

HR = 0.84 (0.78 0.90)p < 0.0001

55

Effects of Statins and ACE Inhibitors

Agostino Faggiotto et al,Hypertension. 1999;34[part 2]:987-996.

State-of-the-art therapy

(incl. ASA, Amlo, Statins)

Deactivated Plaque

Activated Plaque

ACE activityin plaques

ACE activityin plaques

Antiatherosclerotic Effect of ACE Inhibitors in the Vasculature (HOPE)

Scheme of "plaque deactivation":

ACE activityin plaques

State-of-the-art therapy+ACE

inhibitor(e.g. 10 mg Ramipril)

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

ReverseVascular aging

KEEPING THE ARTERIES YOUNGER

END OF MODULE 3 CHAPTER 1D