Protective adaptation theory and hemorheological intervention · 2015. 7. 7. · Enhancing Effect of Taxol in Solid Tumor 0 500 1000 1500 2000 2500 3000 3500 4000 17 20 23 27 30 34

Figure - 1

Protective adaptation theory

and hemorheological intervention

조영일 (Y. Cho) and Ken Kensey, M.D.

Drexel University, Philadelphia, PA

Rheologics, Inc, Exton, PA

Nov. 24, 2006

Figure - 2

How did I start biofluid research?

NASA-JPL: Space Medicine (1981-85)

Cardiovascular De-conditioning Program of astronauts

Coronary cast

from human cadaver Femoral cast

Figure - 3

Drexel University - Hemorheology(1985-present) Collaboration with Dr. Kensey


Figure - 4

Protective adaptation theory 자기보호반응이론

Aorta Aorta

Arterial wall

Elastic artery

Stretched in systole

Stiff aorta

No expansion in systole

60-70% Blood stored

Arteriosclerosis (Arterial Remodeling)

When aortic wall is over-stretched,

The elastic fiber in the aortic wall broken-torn, resulting in rupture: fatigue injury

Aorta transforms to stiff wall to protect its structural integrity.

Cushioning effect

Guyton 10th ed

Figure - 5

Mohrman-Heller 1991

Cause of fatigue injury?

Blood pressure, Contractility of the heart

LV

Vascular

Tone

Increased

Time

PressuredP/dt - CHF

P(t)

dP/dt

A

B

Beta blocker relaxes LV, thus slowing the heart rate.

ACE inhibitor dilates blood vessels.

Figure - 6

• When aorta loses compliance,

• Aorta cannot absorb the impulse from

pulsatile blood flow.

• The arteries after aorta (such as

coronary and carotid) must absorb the

impulse, transforming to stiff arteries.

• The arteries after ……..

• The arteries after ……..


Figure - 7

Protective adaptation theory 자기보호반응이론

왜 관상동맥과 경동맥이 다른 동맥들 보다 더 많은 문제를 갖게되는지를 생각해 보자.

대동맥이 탄력성을 잃게 되면 심장에서 뿜어 나오는 박동성 유동의 에너지를 더 이상흡수하지 못하게 된다. 이런 상황이 오면 그 다음에 있는 관상동맥과 경동맥에 이 박동성에너지가 충격처럼 몰려오게 된다. 그 결과 이 두 동맥들이 매 사이클 마다 팽창과 수축을반복하면서 전에는 대동맥이 했던 에너지 흡수의 임무를 하게 된다. 결국 관상동맥과 경동맥근육의 구조에도 점차 피로상처가 나타나면서 경화현상이 생긴다.

특히 분지에서의 유동은 전보다 더 나쁜 상태로 바뀌게 되어 내피세포에 상처가 생기면서점차 분지혈관이 막히게 된다. 다시 말하면 대동맥이 탄력을 잃게 되면 대동맥 다음에 있는동맥들에게 에너지 흡수의 역할이 넘어가서 이들 동맥들에게 경화현상이 나타나는 것이다.

또 이들 동맥들이 경화되었을 때 더 멀리 있는 동맥들, 예를 들어 다리에 있는 대퇴동맥에에너지의 충격이 가해져 대퇴동맥에 문제가 생기기 시작하여 다리부분에 혈액의 공급이부족해 지기 시작하는 것이다. 이와 같은 동맥경화 과정을 자기보호반응 Protective adaptive

response의 하나로 볼 수 있다.

Figure - 8

Effect of increased stiffness on pressure pulse

Normal

pressure pulse

Normal pulse wave velocity

Normal pulse wave velocity

Increased pulse wave velocity

Slightly

deformed pulse

Severely

Deformed pulse

Aortic compliance reduced slightly

Normal PVR

Aortic compliance reduced severely

Increased PVR

[O'Rourke, Safar, and Dzau, 1993].

BAD effect on bifurcation flow,

starting atherosclerotic plaque

Figure - 9

O”Rouke-vasodilation 1993

Effect of occlusion on pressure pulse

Aortic coarctation

Injurious

Blood flow

Not-Injurious

Blood flow

BAD effect on bifurcation flow,

starting atherosclerotic plaque

Figure - 10Malek et al. JAMA 1999, p.2035

Atherosclerosis Why do occlusions occur at branch vessels?

Low shear, flow disturbance: BAD hemorheology

Figure - 11

The fact that we can do coronary bypass surgery

means that the artery after blocked bifurcation is clean.

Figure - 12

1 2

34

5

z

P(z)

1 2

34

5

z

P(z)

Pressure variation

In a straight tube

Pressure jump

Due to branch flow

ProximalDistal

Poiseuille

law

Branch

Why does atherosclerosis occur mostly at bifurcation ?

– Bernoulli principle

Disturbed flow

Turbulence

Recirculating flow

Low shear

Figure - 13

Atherosclerosis (죽상동맥경화)

Response-to-injury theory (E-cell injury)

Inflammation hypothesis (Peter Libby)

Origins of injury and inflammation?

Hemorheological origin and intervention

Figure - 14

Benefit of Blood donation:

It reduces the risk of acute MI.

9.8%

0.7%0

2

4

6

8

10

12

Blood Donors Non-Donors

Acu

te m

yo

card

ial

infa

rcti

on

(%

)

N = 2,682

Mean follow up

= 5.5 y

P<0.001

Corrected for Other Major Risk Factors

Data indicates 90% reduction in MI rate for blood donors

Tuomainen TP, et al. BMJ. 1997;314:793 Kuopio IHD Study.

Figure - 15

4,000 Publications

Linking Blood viscosity with Cardiovascular Risk Factors

Diabetes, Linderkamp (1999)

Lipoproteins, Koenig (1991)

Blood Pressure, Smith (1992); Wannamethee (1994)

LDL, Lowe (1992); Crowley (1994); Sloop (1997)

Smoking, Levenson (1997)

Aging, Ajmani (1998), Kameneva (1999)

Obesity and Exercise, Caroll, (2000)

Diet, Fanari (1993)

Gender, Fowkes (1994), Lee (1998)

Aging, Lowe (1980)

Blood Pressure, Letcher (1983)

Obesity and Exercise, Ernst (1986)

Diabetes, Solerte (1987)Aging, Dintenfass (1989)

Smoking, Lowe (1980)

Smoking, Dintenfass (1975)

Smoking, Feher (1990)

1975 1980 1985 1990 1995 2000

Figure - 16

Atherosclerotic

Risk Factors

Cholesterol

Obesity

Smoking

Hypertension

Diabetes

Hyperhomocysteine

Age

Gender

Stress

All these

factors

elevate

WBV

Highest

Correlation with

CVD

In spite of 4,000 studies, blood viscosity has

not entered the main stream medicine yet.

Figure - 17

Hypothesis:

Elevated viscosity increases atherosclerotic process.

Elevated Viscosity

Increased residence time

LDL accumulation,

platelet and RBC aggregation and

WBC adhesion - Inflammation

Atherosclerosis

Low shear

Low shear

Figure - 18

When hypertension can not be

controlled by drugs - German story

Commercial flight pilots lose flight licenses

if they cannot maintain normal BP.

Repeated small phlebotomy (100 ml per week) reduced blood pressure

in 10 weeks for 4,000 commercial pilots.

Blood viscosity

Johann Schnitzer, Hypertension Cause and Cure, 2000

4

128

d

LQP

Figure - 19

Benefit of reduced blood viscosity for angina patient

Dintenfass; Ernst; Lowe; Koenig; Clinical Hemorheology

Blood Viscosity (cP)

Shear rate (1/s)

Normal

Patients

with chest pain

20

50

4

3001 10

Log-log scale

Repeated

small phlebotomy Increased blood viscosity

reduces coronary flow.

Figure - 20Honig-1988

Why does blood viscosity increase at low shear?

RBC aggregation

Plasma proteins

(Fibrinogen, IMG)

Cholesterol

Triglycerides

Hematocrit

RBC deformability

Plasma viscosity

centipoise

Figure - 21

Fung tissues

Hardened erythrocytes without fibrinogen

Blood

viscosity


Yield stress (항복응력) of blood

influences disturbed flow at bifurcation.


Hemorheological origin of atherosclerosis

Viscous

cycle

AT BIFURCATION

Figure - 24

Hemorheological parameters

Whole blood viscosity, yield stress

Erythrocyte aggregation rate (ESR)

Erythrocyte deformability

Thrombotic rate (PT, aPTT, not enough)

Figure - 25

A new scanning capillary tube viscometer - Rheolog

Blood

enters

Figure - 26

Capillary tube

Diameter > 800 m

LED Array

CCD

Computer data acquisition system

CCD

21-gauge needle for venipuncture

Rheolog – viscometer from Rheologics, Inc.

Figure - 27

At t = 0At t =

th

Disposable capillary tube of Rheolog

Figure - 28

Blood

Capillary tube

Fluid falls

Fluid rises

1

2

Riser columns

Pressure drop and flow rate

from single measurement of h(t)

)()( 21 ththgP

Calculate Shear stress

dt

)t(dh)t(vr

Calculate Shear rate

QL

Pd

128

4

Conceptually

Figure - 29

Calculation of blood viscosity using Casson model

Yield stress

included Due to surface

tension

stc

hgtPtghVPtghVP +

++

++ )()(2

1)(

2

12

2221

211

.

Casson model and yield stress

gtt ky +

yttg ,0.

ytt

Entrance effect; unsteady effect are negligible.

Figure - 30

Measurements of height variations from Rheolog

Figure - 31

Output of Rheolog device

Figure - 32

Blood Clots in deep vein

Hemorheology: Thrombotic rate measurement

Figure - 33

Drug delivery:

Enhancing Effect of Taxol in Solid Tumor

0

500

1000

1500

2000

2500

3000

3500

4000

17 20 23 27 30 34 37 41 44 48 51 55 58 62 65

Control

Taxol

Taxol + Visc.low.

Days

Tumor growth

Lowering WBV during chemotherapy in a solid tumor

animal model reduced tumor growth.

Figure - 34

L : Inertia of bloodRs : Peripheral Resistance

LV Aorta

C1 : Proximal ComplianceC2 : Distal Compliance

P1 : Proximal Blood PressureP1 : Proximal Blood Pressure

L : Inertia of bloodL : Inertia of bloodRs : Peripheral ResistanceRs : Peripheral Resistance

LV Aorta

C1 : Proximal ComplianceC1 : Proximal ComplianceC2 : Distal Compliance

P2 : Distal Blood PressureP2 : Distal Blood Pressure

Hypothetical arterial system

Qin Q1

Qin-Q1

Q2

Q1-Q2

C1 C2 Rs

P1 P2L

eq3 eq2

eq1

L : Inertia of bloodRs : Peripheral Resistance

LV Aorta

C1 : Proximal ComplianceC2 : Distal Compliance

P1 : Proximal Blood PressureP1 : Proximal Blood Pressure


LV Aorta


P2 : Distal Blood PressureP2 : Distal Blood Pressure



LV Aorta


P1 : Proximal Blood PressureP1 : Proximal Blood PressureP1 : Proximal Blood PressureP1 : Proximal Blood Pressure


LV Aorta


P2 : Distal Blood PressureP2 : Distal Blood PressureP2 : Distal Blood PressureP2 : Distal Blood Pressure


Qin Q1

Qin-Q1

Q2

Q1-Q2

C1 C2 Rs

P1 P2L

eq3 eq2

eq1

Qin Q1

Qin-Q1

Q2

Q1-Q2

C1 C2 Rs

P1 P2L

eq3 eq2

eq1

Work of the Heart, Compliances, PVR calculation methods

Blood viscosity

of patient.

Navier-Stokes

Equation used

Pressure pulse

of patient

Figure - 35

Modified Windkessel Modeling

Pressure and flow rate relations

)()()(

)( 21

1 tRtQdt

tdQLtP s+

dtC

tQtQ

dt

tdQLtP

+

2

2111

)()()()(

dtC

tQtQtP

in

1

11

)()()(

Goal is to estimate, using P(t) and blood viscosity

WOH (Work of the heart)

C1, C2 (proximal and distal compliances)

PVR (peripheral vascular resistance)

Eq.(1)

Eq.(2)

Eq.(3)

Figure - 36

0.00

0.50

1.00

1.50

2.00

2.50

3.00

100

120

140

160

180

200

220

240

260

Systolic blood pressure (mmHg)

WOH (W)

Work of the heart

Normal

CHF develops

Figure - 37

Summary

• Protective adaptation theory

Proximal and distal compliances, PVR,

PWV, Work of the heart

• Site-specific atherosclerosis at bifurcation

• Hemorheological intervention

Reducing blood viscosity

Reducing thrombogenic potential (LMWH)

Documents

Protective adaptation theory and hemorheological intervention · 2015. 7. 7. · Enhancing Effect of Taxol in Solid Tumor 0 500 1000 1500 2000 2500 3000 3500 4000 17 20 23 27 30 34