Arterial stiffness

ƒDefinition and pathophysiology of arterial stiffness

ƒAssociation of arterial stiffness with cardiovascular disease

ƒTreatment of arterial stiffness

Arterial stiffness

Arteriosclerosis is

= The hardening of the arteries

In 1906 : Arteriosclerosis is an accompaniment of old age, and is the expression of the natural wear and tear to which the tubes are subjected.

“A man is only as old as his arteries”.

Physiological arteriosclerosis depends upon the quality of arterial tissue (vital rubber) which the individual has inherited and upon the amount

of wear and tear to which he has subjected it.

William Osler in The Principles & Practice of Medicine, NY

Historic Information on PWV

Aortic stiffness

Young adults Older adults

Treatment of Hypertension in the Elderly

박 성 하

연세대학교 의과대학 심장혈관병원 심장내과

Pathogenesis of arterial stiffness

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

Index of arterial stiffness Index of arterial stiffness

ƒ Compliance

= ∆D / ∆P ( cm/mmHg )

Absolute diamenter (or area) change for a pressure increment

ƒ Distensibility

= ∆D / ∆P•Dbaseline( mmHg^-1 )

Relative diameter (or area) change for a pressure increment

ƒ Young’s Elastic Modulus

= ∆P•D/ ∆DXh(mmHg/cm)

ƒ Beta index(Stiffness index)

= Ln(Ps/Pd)/ [(Ds-Dd)/Dd]

ƒ Pulse wave velocity(cfPWV, baPWV)

= Distance / ∆Time delay ^{( cm/sec )} Speed of travel of the pulse along an arterial segment

Local Stiffness

What is Pulse Wave Velocity?

Young normal aorta

Old stiff aorta

Resistance artery

Young normal aorta

Resistance artery

Old stiff aorta

Resistance artery

Young normal aorta

Resistance artery

Old stiff aorta Young normal aorta Old stiff aorta

Pressure during systole is a major determinant of myocardial O2 requirement

Pressure during diastole is a major determinant of CBF

Efficient arterial system

Inefficient arterial system

Pulse Wave Velocity (PWV)

is mainly determined by:

the elastic and geometric properties of the arterial wall

Higher velocity = higher stiffness

= lower distensibility

= lower compliance

^m/sec

A B

D

Pulse Wave Velocity

ƒ

PWV = D / ∆T

Augmentation index = P2-P1 Pulse pressure

Pulse wave shape in normal and stiff aorta

Young adults Older adults

60 80 100 120 140 160

What factors are associated with increased arterial stiffness?

Change Of Blood Pressure With Age (NHANES - Black Women)

Blood Pressure (mm Hg)

Age 60

80 100 120 140 160

20 30 40 50 60 70

Systolic Diastolic

Burt VL et al. Hypertension, 1995;25:305-13

Relationship between Age and 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

Increased blood pressure is associated with increased

aortic stiffness

Increased aortic pressure

Increased recruitment of stiff collagens

Systolic Blood Pressure related changes of baPWV in different age group

Yamashina A et al, Hypertension

Yamashina A et al, HypertensionResRes, 2003;26:801, 2003;26:801--0606

Comparison of aortic pulse-wave velocity between urban and rural normal subjects

Avolio AP et al. Circulation 1985

Significant association with high salt intake

Smoking and arterial stiffness

Mahmud A et al. Hypertension 2003;41:183-7

Hypercholesterolemia and AIx

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

Diabetes and central arterial stiffness

48 49 50 51 52 53 54 55 56 57

Normal glucose metabolism Impaired glucose metabolism Type 2 diabetes

Carotid-femoral transit time(ms) 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

1300 1350 1400 1450 1500 1550

1st quartile HOMA=0.85

2nd quartile HOMA=1.48

3rd quartile HOMA=2.09

4th quartile HOMA=3.47 1401 ± 156

1427 ± 208

1488 ± 235 1545 ± 258

Insulin Resistance and arterial stiffness

Seo HS, Park S et al. Hypertens Res 2005;28:945-951

N=285

1300 1350 1400 1450 1500 1550

1st quartile Log hs-CRP

=0.436

2nd quartile Log hs-CRP

=-0.156

3rd quartile Log hs-CRP

=-0.304

4th quartile Log hs-CRP

=-0.798 1341 ± 156

1479 ± 247 1510 ± 234

1516 ± 249 (cm/sec)

hs CRP and arterial stiffness

N=292

Kim JS Park S Atherosclerosis Revision

ƒDefinition and pathophysiology of arterial stiffness

ƒAssociation of arterial stiffness with cardiovascular disease

ƒTreatment of arterial stiffness

Arterial stiffness

Factors associated with wave reflection and pressure augmentation

ƒ

Arterial stiffness

ƒ

Site of branching points

ƒ

Systemic vascular resistance

Pulse pressure and Risk for CVD

⇑ Pulse Pressure

⇑ SBP

⇓ DBP

⇑ Metabolic need LVH

⇓ Coronary perfusion

Myocardial ischemia Mechanical

fatigue Arteriosclerosis ⇑ Aortic

stiffness

Arterial stiffness and systolic hypertension is a normal aging process. You don’t need to treat it

Arterial stiffness in an independent risk factor For adverse cardiovascular prognosis

Recent change in paradigm Arterial Stiffness

ƒ

SBP as a more informative CV risk factor in patients older than 50 years

ƒ

PP is an independent marker of CV risk

ƒ

In subjects > 50 years of age, arterial stiffness becomes the main determinant of increased SBP and PP

Relationship between 10-year cardiovascular risk and

carotid-femoral PWV in hypertensive patients

Blacher J,. Hypertension 1999; 33:1111-1117

Ten-yearCV risk (ratio)

r=0.495 P<0.0001

4 18 25

1.0

0 0.2 0.4 0.6 0.8

12 6

Aortic PWV(m/s)

Arterial stiffness and coronary events in hypertensives

1 2

3 1

2 3 0%

5%

10%

15%

Tertile of PWV

Tertile of FRS

% events

Boutouyrie P et al. Hypertension 2002;39:10-15

Blacher et al. Arch Intern Med. 2000;160

Pulse Pressure Predicts Risk Best In Older Hypertensives

A Meta-Analysis

2-Year Risk Of End Point

Systolic Blood Pressure (mm Hg)

Diastolic Pressure (mm Hg) EWPHE (N=840)

Syst-Eur (N=4695) Syst-China (N=2394)

Pulse pressure and CHD

Franklin SS et al. Circulation 1999;100:354-60

SBP-associated risks:MRFIT

*Men aged 35-57 years followed for a mean of 12 years.

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

Risk of CHD with SBP

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

Risk of cardiovascular events with elevated SBP

≥1.5 Coronary artery disease

=1.6 Myocardial infarction

≥1.8 Peripheral vascular disease

≥1.5 Heart failure

≥2.7 Stroke

≥2.8 Kidney failure (ESRD)

Relative risk Disease

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

Misconceptions about isolated systolic hypertension

Because the blood vessels are hard the systolic BP cannot be decreased

It is too late: the patients are too old to benefit from BP lowering

What’s the role of arterial stiffening in

HF?

ƒ

"the amount of energy expended by the heart … has been shown to be

proportional to the pressure developed

… hence the amount of energy that the heart has to expend per beat, other things being equal, varies with the elasticity of the arterial system".

J.C. Bramwell and A.V. Hill, Velocity of transmission of the pulse wave and elasticity of arteries. Lancet 1 (1922), pp. 891–892

Trigger for HF in patients with diastolic dysfunction

ƒ Altered load

ƒPreload

ƒAfterload

ƒ Neurohormonal change

Ventricular/Vascular interaction

Ventricular-Vascular Interaction

ƒ

Increase in ventricular stiffness with age occurs in tandem with large artery stiffness

1. Interaction of heart and vascular load 2. Intrinsic changes in heart itself

3. Comorbidities that impact both system: DM, HT, Renal disease, Neurohormonal stress

Kass DA et al. Hypertension. 2005;46:185-93

Work load on the heart

Mean BP (SVR)

Pulsatile pressure reflection

Ventriculo-Vascular interaction

Gates PE et al. European Heart Journal. 2003;24:2213 Gates PE et al. European Heart Journal. 2003;24:2213--2020

PW thickness/LVEDD

The etiology of DHF

ƒ

Hypertension

ƒ Hypertension

ƒ

Hypertension

ƒ Hypertension

ƒ

Hypertension

ƒ

Hypertension

ƒ

Hypertension

Effects of Therapy in Elderly Hypertensive Patients

SHEP STOP-HTN MRC

(1991) ( 1991) (1992)

ƒMean BP

at entry (mm Hg) 170/77 195/102 185/91 174/85

ƒRelative difference in rate between treated and placebo groups

ƒStroke –33* –47* –25* –42*

ƒCAD –27* –13† –19 –30

ƒCHF –55* –51* –29

ƒAll CVD –32* –40* –17* –31*

*Statistically significant

†Myocardial infarction; sudden deaths reduced from 13 to 4

SYSTEUR SYSTEUR (1997) (1997)

ƒ

The goal of drug treatment of HTN is to prevent CV complications

ƒ

Totality of the BP curve, not simply 2 specific and arbitrary points, should be considered to act mechanically on the arterial wall and therefore should be used to propose an adequate definition of high BP

Hundley WG et al. JACC 2001

Hundley WG et al. JACC 2001

Arterial stiffening Therapeutic implication

ƒ

Early return of wave reflection by arterial stiffening causes diastolic dysfunction, either directly by raising late systolic pressure or indirectly by causing LVH and ischemia

ƒ

Diastolic dysfunction should be relieved by

reducing or delaying wave reflection (ACEI,

ARB, CCB and nitrates)

ƒDefinition and pathophysiology of arterial stiffness

ƒAssociation of arterial stiffness with cardiovascular disease

ƒTreatment of arterial stiffness

Arterial stiffness Treatment of ISH

ƒ Benefit proven

ƒ Thiazide diuretics, Calcium antagonist

ƒ More data required

ƒ ACE inhibitors, AT₁blockers

ƒ Theoretically desirable

ƒ Spironolactone (aldosterone antagonist)

ƒ Nitrates (NO generator)

ƒ Experimental

ƒ - Alagebrium chloride: AGE cross linkage breaker

Systolic Hypertension in the Elderly Program (SHEP) – with Chlorthalidone

SHEP Cooperative Research Group. JAMA. 1991

Systolic Hypertension in Europe (Syst-Eur) – with Nitrendipine

Staessen JA et al. Lancet. 1997

SHEP and Syst-Eur: Risk reduction in elevated SBP and DM

Toumilehto J et al. N Engl J Med. 1999; Curb JD et al. JAMA. 1996

SHEP and Syst-Eur: Risk reduction in elevated SBP and non-DM

Toumilehto J et al. N Engl J Med. 1999; Curb JD et al. JAMA. 1996

SHEP 14-Year Follow-up: Death or Nonfatal Cardiovascular Event Rates

Sutton-Tyrrell et al. Arch Intern Med. 2003;163:2728-2731.

Kaplan-Meier Estimate (%)

100 90 80 70 60 50 40 30 20 10 0

Time Since Study Entry (years) 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

Placebo group (n=133) Active group (n=135) Normotensive control group (n=187)

SHEP Closeout

65%

79%

58%

47%

35%

P<.001

Can you reduce arterial

stiffness through medications?

PWV and BP control

Moderate BP control: < 140/90

Intensive BP control < 130/85

Ichihara A et al. Am J Hypertens. 2003;16:959-65 Länne T. Ultrasound in Medicine and Biology 1992;18:451-7

Drugs that may actively decrease the central aortic compliance, destiffening, are required to reduce central aortic pressure effectively

ƒ

Antifibrotic: ACEI, ARB, Spironolactone

ƒ

Endothelial function improvement: Statins

ƒ

Cleavage of AGE cross linkage: Alagebrium

Drugs on central augmentation

-12 -10 -8 -6 -4 -2 0 2 4 6

ACE

inhibitors CCBs

Aortic PP decrease AI(%) decrease

Beta

Blockers Diuretics

Morgan T et al. Am J Hypertens. 2004;17:118-23

CAFÉ Study Design

R 1 2 3 4 5 ASCOT (Years)

0 1 2 3 4 CAFÉ (Years)

36% 67% 87% 100%

• >70% of ASCOT patients at 5 study centers were recruited

• 80% of patients had more than 1 tonometry measurement

• Average 3.4 tonometry measurements/patients

• Average follow up after first tonomedtry measurement was 3 years 5 CAFÉ

Study centers UK & Ireland

Pulse Wave Analysis

Sensor

Artery

Bone

Brachial Blood Pressure

140

70 Radial

140

70 Central Aortic

Transfer function

CAFÉ Study Design

2199 subjects recruited From 5 UK ASCOT centers 128 excluded due to heart rate

irregularitylpoor waverforms

2073 evaluate For tonometry

1042 received Amlodipine-based regimen

4 subjects incomplete information, 1 alive at last visit 2 withdrawn

consent, 1 lost to follow up

1031 received Amlodipine-based regimen

1042 assessed on an intension to-treat basis 1038 complete Information (997 alive, 41dead)

4 subjects incomplete information, 1 alive at last visit 2 withdrawn

consent, 1 lost to follow up

1031 assessed on an intension to-treat basis 1038 complete Information (997 alive, 41dead)

Hemodynamic Data

Difference

(Atenolo- Statistics

Parameter Atenolol Amlodipine Amlodipine) t-test(P) Brachial SBP 133 133.2 0.7 0.2 (mm Hg) (133, 134.7) (132.5, 133.8) (-0.4, 1.7) Brachial DBP 78.6 76.9

(mm Hg) (78.1, 79.1) (76.4, 77.4) (0.9, 2.4) Brachial PP 55.3 56.2 -0.9 .06 (mm Hg) (54.6, 56) (55.6, 56.9) (-1.9, 0) Heart rate 58.6 69.3 -10.7 <.0001 (BPM) (58, 59.2) (68.6, 69.9) (-11.5, -9.8)

1.6 <.0001

Brachial and Central Aortic Pulse Pressure by Treatment Arm

Time (Years)

Atenolol 86 243 324 356 445 372 462 270 339 128 85 1031 Amlodipine 88 248 329 369 475 406 508 278 390 126 101 1042

38 43 48 53 58

0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6

mm Hg

AUC 56.2 55.3

46.4 P=.06

43.4 P<.0001

Amlodipine Atenolol

Central PP

Diff Mean (AUC) =3(2.1, 3.9) mm Hg Brachial SBP

Diff Mean (AUC)= -0.9 (-1.9,0)mm Hg

Augmentation Index (%) by Treatment Arm

Time (Years)

Atenolol 86 243 324 356 445 372 462 270 339 128 85 1031 Amlodipine 88 248 329 369 475 406 508 278 390 126 101 1042

15 20 25 30 35 40

0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6 AUC

Amlodipine Atenolol

25.3 31.9

Diff Mean (AUC) = -6.5(5.8,7.3) mm Hg P<.0001

Alx(%)

Impact of Blood Pressure and Central Aortic Hemodynamics on Clinical Outcomes in the CAFÉ Study (Hazard/10 mm Hg)

Updated Cox proportional hazard model for the composite endpoint, unadjusted

Factor X² P HR CI

Peripheral PP 21.0 <.0001 1.21 1.12-1.30 Central PP 17.8 <.0001 1.20 1.11-1.30 Augmentation 7.10 .008 1.22 1.06-1.4 P₁height 19.0 <.0001 1.37 1.20-1.54

• Atenolol-based therapy was associated with higher Central aortic systolic pressure and higher central aortic pulse pressure, despite similar brachial pressures, when compared with amlodipine-based therapy

• Central aortic outgoing pressure wave(P1 height) was lower with atenolol-based therapy vs amlodipine-based therapy

• Pulse wave augmentation and the percentage of the central aortic pressure wave attributable to wave reflection was increased by atenolol-based therapy compared with amolodipine-based thearpy

Result Summary

• Despite similar brachial systolic blood pressure, Amlodipine + perindopril-based treatment was more effective than

atenolol+thiazide-based treatment at lowering central aortic systolic blood pressure and central aortic pulse pressure

CAFÉ Study Conclusion (1)

• Branchial blood pressure overestimated the hemodynamic benefit of atenolol+thiazide-based treatment and underestimated the benefit of amlodipine+perindopril-based treatment on central aortic pressures and hemodynamics

• Central aortic pressure may be an important independent determinant of clinical outcomes

• Results of the CAFÉ study suggest that the “central aortic blood pressure hypothesis” is a plausible mechanism to explain the better clinical outcomes for hypertensive patients treated with amlodipine+perindopril-based therapy in ASCOT

CAFÉ Study Conclusion (2)

Antifibrotic effects of ACE blockade

0.0 2.0 4.0 6.0 8.0 10.0 12.0

Placebo Indapamide Perindopril Perindopril Indapamide+

Safar ME. Cardiovascular Research 2000;46:269-76 (% collagen density)

Angiotensin Receptor Blocker in Isolated Systolic Hypertension and LVH (LIFE)

Kjeldsen SE et al. JAMA. 2002;288:1491-1498

Aldosterone and systemic compliance

Blacher J et al. Am J Hypertens. 1997;10:1326-34

Large artery compliance and statins

0.32 0.34 0.36 0.38 0.4 0.42 0.44

Placebo Atorvastatin 80mg Large arterial compliance(ml/mmHg)

ISH: 3 months cross over design(N=22)

Ferrier KE et al. J Am Coll Cardiol. 2002;39:1020-5

Isosorbide mononitrate on BP and pulse wave in systolic hypertension

Stokes GS, et al. Journal of Hypertension 1999, 17:1767

Non pharmacologic Therapy

ƒ Aerobic exercise

ƒ Cessation of smoking

ƒ Weight reduction

ƒ Low sodium diet

ƒ Isoflavone

Laurent S et al. Am J Hypertens. 2002;15:453-8

Alagebrium chloride and arterial stiffess

0 0.05

0.1 0.15 0.2 0.25 0.3

Diabetic 1 week 3 weeks

Carotid artery compliance in streptozocin induced rats

Carotid artery compliance(10-3Xmm2/mmHg)

Aronson D. J Hypertens 2003;21:3-12

△ PWV(cm/sec)

N = 93

-80 -60 -40 -20 0 20 40

-70

+25

P < 0.05

Alagebrium 210mg Control

Kass DA et al. Circulation 2001;104:1464-70

Conclusion

ƒ Arterial stiffness is the major determinant of systolic blood pressure and pulse pressure

ƒ Arterial stiffness itself is an independent risk factor for cardiovascular events

ƒ Treatment may reduce arterial stiffness resulting in reduction of cardiovascular events

ƒ Novel drugs that may reduce arterial stiffness

through AGE cross linkage breakage and

antifibrotic mechanisms are being investigated