Premature

Vascular Senescence

연세대학교 심장혈관병원

심장내과

박 성 하

• Chief Complaint2년간 코골이 및 수면 중 무호흡으로2006년 5월 이비인후과 내원

• Past History:• DM (-) Pulmonary tuberculosis (-) Hepatitis (-)

• Hypertension:

2002년 진단받고 Tenormin 12.5mg bid,

Norvasc 5mg bid, Atacand 8mg bid 복용 중

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• Review of System and Physical examination:• Easy fatigability

• Height 168cm, Weight 93kg, BMI 33.0kg/m2

• BP 130/80mmHg, PR 72/min

• Enlogated uvula, Redundant posterior pillar

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• LAB:• CBC 7250/16.1/256,000

• Glucose AC 90 mg/dL

• AST/ALT 46/40 IU/L

• BUN/Cr 9.9/0.8 mg/dL

• Uric acid 9.1 mg/dL

• Total Cholesterol 147mg/dL

• Triglyceride 197 mg/dL

• HDL 34 mg/dL

• LDL 74mg/dL

• hs-CRP 3.9mg/L

M/38 #3873129

Polysomnography Apnea/Hyperpnea index 132.2

Vascular changes with agingVascular changes

Arterial wall thickness(intima-media) Increase

Subendothelial collagen Increase

Elastin Decrease

Elastin fragmentation Increase

Proteoglycan Increase

MMP activity Increase

VSMC proliferation Increase

Arterial distensibility Decrease

Pulse wave velocity Increase

Endothelial NO release Decrease

Inflammatory markers/mediators Increase

Transforming growth factor-β Increase

SOD activity Decrease

Ferrari AU et al. J Appl Physiol 2003;95:2591-2597

Najjar SS et al. Hypertension 2005;46:454-462

Young normal aorta

Old stiff aorta

Resistance

artery

Young normal aorta

Resistance

artery

Old stiff aorta

PWV and cardiovascular

mortality in the elderly

According to quartiles of PWV

Sutton-Tyrell K et al. Circulation 2005;111:3384-90

PWV and cardiovascular

events in ESRD

Blacher J et al. Circulation 1999;99:2434-9

Pathogenesis of

arterial stiffness

Zieman SJ et al. Arterioscler Thromb Vasc Biol 2005;25:932-43

Variability of arterial stiffness

Najjar SS et al. Hypertension 2005;46:454-462

What factors are

associated with

increased arterial

stiffness?

Aging is associated with

increased oxidative stress

Oudot A et al. Free Radical Biol & Med 2006;40:2214-2222

Relationship between Age and baPWV

baPWV（cm/sec)

male female

age

Ｙ＝13Ｘ＋716

Ｒ＝0.59

20 40 60 80

4000

3000

2000

1000

0

Ｙ＝15Ｘ＋499

Ｒ＝0.71

20 40 60 80

4000

3000

2000

1000

0

Benetos A et al. Circulation 2002;105:1202-1207

Hypercholesterolemia and AIx

Wilkinson IB et al. J Am Coll Cardiol 2002;39:1005-11

Diabetes and

central arterial stiffness

Normal glucose metabolism

Impaired glucose metabolism

Type 2 diabetes

Carotid-femoral transit time(ms)

48

49

50

51

52

53

54

55

56

57

31

31.5

32

32.5

33

33.5

Aortic augmentation index(%)

Schram MT. Hypertension 2004;43:176-81

Metabolic syndrome

and arterial stiffness

Li S et al. Atherosclerosis 2005;180:349-54

Angiotensin II- induced Aortic wall thickening

Vehicle infused Angiotensin II infused

Descending Thoracic aorta in uninephrectomized

C57BL/6J mice after 8 weeks of treatment

Weisberg AD et al. Arterioscler Thromb Vasc Biol 2005;25:365-371

Aldosterone and arterial stiffness

940

960

980

1000

1020

1040

1060

A/R ratio ≥ 20 A/R ratio < 20

hfPWV

(cm/sec)P = 0.010

Park S, Chung N et al. J Hypertens 2007;25(6):1279-1283

CRP and arterial stiffness

920

940

960

980

1000

1020

1040

1060

1st tertile 2nd tertile 3rd tertile

hfPWV

(cm/sec)P = 0.003

Kim JS, Park S, Chung N et al. Atherosclerosis 2007;192:401-406

Circulation 2006;114:1185-1192

Etiology of arterial stiffness

Aging

Dyslipidemia

Blood pressure

Diabetes

Insulin resistance

Inflammation

RAAS

Genetic factors?

Unknown proteins?

Cytokines

Adipokines

Conclusion

Age associated increase in arterial stiffness

may be accelerated by interaction of multiple

cardiovascular risk factors

Specific interventions at reducing fibrosis(TGF-

β), AGE cross linkage(Alagebrium), protein

breakdown(MMP), inflammation(MCP-1) and

reactive oxygen species formation are

promising deserving of further investigation