2. MODULE 3 CHAPTER 1D

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
Atherothrombosis reduces life expectancy by around years in patients aged over 60 years1
Average Remaining Life Expectancy at Age 60 (Men) 20
-7.4 years 16
-9.2 years
-12 years
Years 12
A recent analysis of the data from the Framingham Heart Study was conducted to determine the impact of cardiovascular disease on life expectancy1. The study used 40 years of data collected on 5,070 patients who did not have cardiovascular disease (CVD) upon study entry. In this analysis, CVD was defined as coronary heart disease (ie, myocardial infarction (MI), angina pectoris, coronary insufficiency), cerebrovascular disease (ie, stroke, transient ischemic attack), congestive heart failure, and intermittent claudication. This definition of CVD covers all the manifestations of atherothrombosis; therefore the conclusions should directly relate to atherothrombosis.
According to this analysis, more than 60% of men and women over 40 years of age will develop atherothrombotic disease at some point in their lives. For patients greater than 50 years of age, the development of atherothrombotic disease reduces life expectancy by 8 to 12 years.
A 60-year-old man without atherothrombotic disease can expect to live to age 80, whereas the same person who has a history of acute MI can expect to live only an additional 10.8 years. A 60-year-old man with a history of stroke or congestive heart failure has a life expectancy of 7.98 years or 4.0 years, respectively. Although not shown on the slide, the life expectancy of a woman with CVD is slightly longer than that of a man, but life expectancy is still significantly shorter in the presence of CVD when compared with the life expectancy of a healthy woman.1 8 4
Healthy
History of
Cardiovascular Disease
History of AMI
History of Stroke
Analysis of data from the Framingham Heart Study.
Peeters A, et al. Eur Heart J. 2002;23:
References
Peeters A, Manus AA, Willekens F, et al. A cardiovascular life history. Eur Heart J. 2002;23:

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

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

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.

15. ARTERIES
ARTERIOLES
AORTA
ELASTIC
MUSCULAR

16. 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)
Forward
wave
Systole
Reflected
Wave
(1) Ventricular-vascular mismatch
(2) The reflected wave increases or “augments” central SBP during late 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

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
The normal artery has three distinct layers: the intima is the innermost layer and is composed of a single layer of endothelial cells on the luminal surface; the media is a tube of vascular smooth muscle cells (VSMCs) and their extracellular matrix; and the adventitia, the outer protective layer, is made of loose connective tissue that holds the blood vessels and nerves that supply the artery itself.1
The endothelial cells of the intima have a number of important functions: forming a nonthrombotic, nonadherent surface; acting as a semipermeable membrane; synthesizing and releasing chemical mediators; maintaining the basement membrane; and modifying lipoproteins as they cross into the artery wall.2
The VSMCs of the media contract and relax to alter the lumen diameter of the vessel in response to a variety of circulating and local stimuli, regulating vascular tone, blood flow, and blood pressure. This is caused by the production of a number of vasoactive substances, including prostaglandins, endothelin, and nitric oxide (NO).1
As the next slides reveal, LDL cholesterol is a central culprit in disrupting the normal homeostasis of the artery and its lumen, setting the stage for vascular occlusion, ischemia, and infarction.
References
Weissberg PL. Atherosclerosis involves more than just lipids: Plaque dynamics. Eur Heart J. 1999;1(suppl T):T13-T18.
Ross R. The pathogenesis of atherosclerosis: A perspective for the 1990s. Nature. 1993;362:

19. 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.
The endothelium is a major regulator of vascular tone and hemostasis lining the myocardium and every vascular channel in the body.
Rather than simply being a smooth, non-thrombogenic surface functioning as a selectively permeability barrier between the circulation and the vessel wall, the endothelium is also very metabolically active and is actually a regulatory organ, involved in processes that crucially affect –
hemostasis,
vascular contractility,
cellular proliferation, and
inflammation.
It produces a lot of things -.
Endogenous vasodilators and vasoconstrictors.
Growth promoting and growth inhibiting factors.
Anticoagulants and Procoagulants.
It modulates vascular smooth muscle cell migration and proliferation, and.
It also modulates the behavior of macrophages and monocytes, acts as a barrier to LDL and degrades VLDL.
If there is an alteration in the normal endothelial function, there is an imbalance of activities and problems occur with respect to vascular disease, leading to an abnormal endothelium, also called as endothelial dysfunction.
Retards platelet and leucocyte adhesion
Inhibits VSMC migration & proliferation
Barrier to LDL, degrade VLDL & chylotriglyceride
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

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. YOUNG
OLD
NORMAL SIZE
NORMAL RELAXATION
DILATED
STIFF

24. 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:

26. LV systolic,diastolic dysfunction
Abnormal cushion function
LV systolic,diastolic dysfunction

27. Abnormal Conduit Function Abnormal Endothelium
LDL-C
Hypertension
Angiotensin II
Homocysteine
Diabetes
Smoking
Endothelial dysfunction sets the stage for atherosclerosis
Oxidative stress
Oestrogen
deficiency
Dysfunction
Whenever the endothelium is diseased or damaged, vasodilative responsiveness is reduced. In fact, it is replaced by hyperresponsiveness to contractile stimuli. This phenomenon of Increased Oxidative Stress can be caused by various stressors that can impair the functional integrity of the endothelium such as:
Hypercholesterolemia
Hypertension
Hyperhomocysteinemia
Cigarette smoking
Diabetes mellitus and
Estrogen Deficiency in women
The Response of the Vasculature to Oxidative Stress is to mediate the release of reactive oxygen species (ROS) and cause an imbalance between the vasoactive substances secreted by the endothelium leading to problems called as endothelial dysfunction. Endothelial dysfunction primarly occurs due to:
Formation of superoxide anion which leads to inactivation of NO and consequent endothelial dysfunction
Stimulation of vascular oxidase system (NADH/NADPH oxidase) by Ang II
Vascular SMC proliferation, e.g. in hypertension and restenosis, leading to vascular remodeling and hypertrophy
Increased LDL oxidation and deposition with decreased lipid clearance causing an inflammatory response, leading to atherogenesis.
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. Growth Mainly by Lipid Accumulation
The Evolution of Atherosclerosis
Foam
Cells
Fatty
Streak
Intermediate
Lesion
Fibrous
Plaque
Complicated
Lesion/Rupture
Atheroma
Endothelial Dysfunction
From 1st Decade
From 3rd Decade
From 4th Decade
Growth Mainly by Lipid Accumulation
Smooth Muscle
& Collagen
Thrombosis,
Hematoma
Adapted From Stary HC et al. Circulation. 1995;92:

29. Abnormal conduit
function
Abnormal cushion
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. INTERHEART: the Effect of Modifiable Factors on Risk for MI
FAMILY HISTORY
Midsegment obesity
INTERHEART is a global study that focuses on the importance of various coronary artery disease (CHD) risk factors worldwide. This analysis involved 15,152 patients with a first acute myocardial infarction (MI) and 14,820 age- and sex-matched asymptomatic control subjects drawn from 262 centers in 52 countries in Asia, Europe, the Middle East, Africa, Australia, and North and South America. The goal of the analysis was to determine the effect of specific modifiable factors on risk for MI.
In this analysis, DM emerged as one of the 5 factors most strongly associated with the occurrence of MI, with an odds ratio (OR) of 2.37 (99% CI ), and was more strongly associated with MI than hypertension (OR 1.91, 99% CI ). The strongest risk factor was an elevated ratio of apolipoprotein (Apo) B to Apo A-1; an Apo B/Apo A-1 ratio of 5/1 had an OR of 3.25 (99% CI ). Co-occurrence of risk factors had a cumulative effect, with an OR of for the combination of current smoking, DM, and hypertension.
Yusuf S, Hawken S, Ôunpuu S, et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet. 2004;364:

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

33. 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
Endothelin
Growth factors, matrix
Proteolysis
In the past, coronary heart disease was thought of as essentially a disorder of "clogged pipes."
However, the fact that more than half of all MIs occur in persons with less than 50% stenosis in the involved coronary artery has prompted recognition that susceptible plaques and arterial hypercontractility due to endothelial dysfunction are the culpable underlying pathologies.
This flow chart will clearly show how endothelial dysfunction is responsible for causing various clinical sequelae including coronary artery disease.
What is essential here is to find out the most important factor responsible for all this.
The cause is clearly due to unopposed AII and increased PAI levels.
Thrombosis
Inflammation
Vasoconstriction
Vascular lesion and remodelling
Plaque rupture
Clinical Sequelae
Gibbons GH, Dzau VJ, New England J Med,1994; 330:

34. ATHERO-. ARTERIO- SCLEROSIS. SCLEROSIS. (Increased vascular stiffness
ATHERO ARTERIO- SCLEROSIS SCLEROSIS (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
Focal, Occlusive
Intimal disease
Inflammatory
Endothelial dysfunction
Related to LDL cholesterol oxidation
“Inside-out”
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. TONOMETRY-PULSE WAVE FORM ANALYSIS
MAP

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

40. Effect of SBP and DBP on Age-Adjusted CAD Mortality: MRFIT
CAD Death Rate per 10,000 Person-years
100+
90-99
80-89
75-79
70-74
<70
<120
160+
Diastolic BP (mmHg)
Systolic BP (mmHg)
20.6
10.3
11.8
8.8
8.5
9.2
12.6
12.8
13.9
24.6
25.3
25.2
24.9
16.9
23.8
31.0
25.8
34.7
43.8
38.1
80.6
37.4
48.3
Neaton et al. Arch Intern Med 1992; 152:56-64.
Multiple Risk Factor Intervention Trial (MRFIT)
Diastolic rates at systolic <140 mm Hg
Systolic rates at diastolic <90 mm Hg
Systolic blood pressure (SBP) and diastolic blood pressure (DBP) have been shown to correlate strongly with coronary artery disease (CAD) mortality. The combined effect of SBP and DBP on age-adjusted CAD mortality is shown on this slide. These data, from a cohort of men screened for the Multiple Risk Factor Intervention Trial (MRFIT) and followed for an average of 12 years, show that SBP is actually a stronger predictor of death from CAD than DBP.
High systolic and low diastolic pressure is dangerous
Source:
Neaton JD and Wentworth D for the Multiple Risk Factor Intervention Trial (MRFIT) Research Group. Serum cholesterol, blood pressure, cigarette smoking, and death from coronary heart disease. Arch Intern Med 1992; 152:56-64.

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
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’

45. INDIVIDUAL ASSESSMENT FOR EARLY VASCULAR AGING (EVA)? AT 30 YRS
RISK FACTOR AND RISK MARKER ASSESSMENT
RISK FACTORS +
RISK MARKERS +
RISK FACTORS +
RISK MARKERS --
RISK FACTORS –
RISK MARKERS --
ALREADY EVA +
LIKELY TO DEVELOP EVA
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. Local Angiotensin System in Macrophages and Role in Atherosclerosis
circulating
monocytes
ACE
LDL
lumen
ACE
Angiotensin II + + Y Y Y Y Y Y Y Y
adhesion-
molecules
infiltration
endothelium +
endothelial
damage
oxidative stress
ACE
oxLDL/eLDL
subintima
differentiation
(activation)
fatty streak, plaque
ACE
ACE
Macrophages
Foam-cells
smooth muscle cells +
Growth factors
Ang II
Ang II
Cytokines
media
Mod. from Diaz et al., N Engl J Med 337 (1997)

49. ACE I OR ARB?
WHICH ACEI,ARB?

50. TELMISARTAN
LIFE
Charm

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

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

53. ACE I

54. 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 <
2.0
0.0
0.0
1.0
2.0
3.0
4.0
5.0
Years
Number at risk
Amlodipine  perindopril
Atenolol  thiazide

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

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

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

63. END OF MODULE 3 CHAPTER 1D