Underlying mechanisms for radi tidiation-id d di linduced ......radi tidiation-id d di linduced...

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Underlying mechanisms for di ti id d di l radiation-induced cardiovascular and cerebrovascular damage Fiona Stewart Saske Hoving, Nicola Russell, Sylvia Heeneman, Mat Daemen

Transcript of Underlying mechanisms for radi tidiation-id d di linduced ......radi tidiation-id d di linduced...

Underlying mechanisms for di ti i d d di lradiation-induced cardiovascular and cerebrovascular damage

Fiona Stewarto a Ste a tSaske Hoving, Nicola Russell, Sylvia Heeneman,

Mat Daemen

Radiation as an independent risk factor for cardio- and cerebro-vascular disease in cancercardio and cerebro vascular disease in cancer

patients

• Early breast cancer: RR fatal CVD RT vs no RT; EBCT = 1.3

• Testicular cancer:Testicular cancer:SIR 1.17 fatal and non-fatal CVD

• Hodgkin’s disease: RR fatal CVD 2-7; higher risks for childrenRR fatal CVD 2 7; higher risks for children RR stroke 4.3

• H&N cancer patients:RR stroke 2.1-5.6

• Pediatric cranial RT>30 Gy:leukemia RR stroke 5.9brain tumor RR stroke 38

Increased risk of stroke after radiotherapy for H&N cancer: NKI cohort (n = 367; 50-66 Gy)

15

e (%

)

RR of stroke 5.6

10

sk o

f str

oke

RR for FU >10 years = 10.1

5

mul

ativ

e ris

155 100

0Ti ft k i di ti ( )

Cum

Dorresteijn et al JCO 2002

Time after neck irradiation (years)

Increased risk of congestive heart failure after radiotherapy for breast cancer (40 50 Gy to IMC)radiotherapy for breast cancer (40-50 Gy to IMC)

1970-79 Mean heart dose

Chest wall/ R breast 3 GyChest wall/ L Breast 7 GyIMC + R chest 11 GyIMC L h t 15 GIMC+ L chest 15 Gy

1980-86Chest wall/ R breast 1.5 GyChest wall/ L Breast 5 GyChest wall/ L Breast 5 GyIMC + R chest 9 GyIMC+ L chest 13 Gy

Hooning et al JNCI 2007

Left direct internal mammary field – 6MVL ft t i

Right coronary artery

Left anterior descending coronary artery50

454035

25

Circumflex coronary artery

Typical doseBeam energyField arrangement

Mean dose (Gy)Target

Circ RCALADHeart

16141

675

25237

17153

50 Gy in 25 50 Gy in 25 50 Gy in 25

6MVCo-60Elec 10 Mev

Direct anteriorLeft IMC

107231350 Gy in 25250 kv

Taylor et al. IJROBP (2007)

Increased risk of vascular diseases in life span study of A bomb survivorsspan study of A-bomb survivors

Preston et al Rad Res 2003

1 0

Dose response for fatal CVD after RTSchultz Hector & Trott 2007

0.8

1.0

Heart diseaseERRSv 0.17

Peptic ulcer RT Carr 2005

Breast cancer RT Darby 2005, EBCT 2000*

Schultz Hector & Trott 2007

0.6

Sv90% CI 0.08; 0.26

P = 0.001

ve R

isk

*

y ,

0.4

ss R

elat

iv

**

0 0

0.2

Exce

s

0.0 0.5 1.0 1.5 2.0 2.5

0.0

C l D (S )A i t ff ti dColon Dose (Sv)Approximate average effective dose to heart (Gy)

Clinical manifestations and pathogenesis of radiation induced vascular damageradiation induced vascular damage

• Endothelial cells: expression of thrombotic and inflammatoryEndothelial cells: expression of thrombotic and inflammatory cytokines, proliferation, cell loss (days)

• Myocardial capillary network: obstruction microvessels, d d ill d it f i d f t h i di ldecreased capillary density, perfusion defects, hypoxia, myocardial degeneration and fibrosis (weeks)

• Medium sized vessels: intimal thickening, perivascular fibrosis (weeks)

• Pericardium: pericarditis (early inflammatory response) (months)

• M di d d t li f ti l d f t ( th )• Myocardium: reduced systolic function, valve defects (months)

• Coronary/carotid arteries: atherosclerosis, stenosis, coronary artery disease, stroke/myocardial infarct (years)y y (y )

Radiation induced prothrombotic changes in microvessels

Endothelial cell damage

Increased vWF

Exposed subendotheliumCell detachmentReduceded PGI2

Reduced ADPase

R d d TM

Inflammatory cytokines

Platelet aggregation

Thrombus formation

Reduced TM

Vascular occlusion

Ischemic organ failuresc e c o ga a u e

Microvascular damage in irradiated cancer patients: telangiectasia

Irradiated human bowel Irradiated human chest wall

patients: telangiectasia

Irradiated human rectum Irradiated rat spinal cord

Progression of telangiectasia in irradiated cancer patientscancer patients

Breast cancer Prostate cancer

Dose response

Turesson & Notter 1986Prostate cancerWachter et al 2001

35 frV90 >57%

30 fr

25 f

LatencyV90 <57%

25 fr

20 fr

Time from treatment (months) Time from treatment (months)

Microvascular damage in irradiated rat heartde

x (%

)La

belin

g in

d

Time from irradiation (days)

ityC

apill

ary

dens

• Reduced expression of alkaline phosphatase and increased EC proliferation

C

Time from irradiation (days)

Lauk & Trott IJRB 1990

p p p p

• Precedes reduced capillary density and myocardial degeneration

Heart damage in rats after local irradiation (20 Gy/1 year)

Myocardial degeneration and interstitial fibrosis Perivascular fibrosis

(20 Gy/1 year)

• Progressive myocardial degeneration and fibrosis follows reduced

J. Kruse 2002

capillary density

Heart damage in rats after local irradiation (20 Gy/1 year)(20 Gy/1 year)

• Decreased cardiac output (to p (50% control) parallels focal myocardial degeneration

• Further reduction in CO only• Further reduction in CO only seen immediately before congestive heart failure

• Compensatory mechanisms (upregulation of cardiac β-adrenergic receptors) maintain steady state for many weekssteady state for many weeks

Schultz-Hector et al. Rad Res 1992

Step 2SPECT/CT and ultrasound imaging of irradiated mouse hearts

8

100 Gy16 Gy

*hear

t (%

)

mouse hearts

2

4

6 *

d vo

lum

e of

the

00 weeks 20 weeks

Blo

od

0.080 Gy

m3 ) 25

0 Gy

min

)

0.04

0.0616 Gy

*

tolic

vol

ume

(cm

10

15

20 16 Gy

*

outp

ut (c

m3 /m

• 22 % decrease in blood volume (p = 0 03)

0.00

0.02

End

dias

t

0

5C

ardi

ac o

Stewart, Seemann, Visser, unpublished

• 22 % decrease in blood volume (p = 0.03)

• 32 % decrease in EDV (p <0.001); 19% decrease in CO (p = 0.042)

Prospective evaluation of perfusion defects in patients after RT for left sided breast cancerpatients after RT for left sided breast cancer

FU time Wall motion abnormalities Wall motion abnormalities(months) No perfusion defects With perfusion defects

6 4/53 (7.5%) 8/20 (40%*)12 2/39 (5.1%) 2/16 (12.5%)

24 0/14 (0%) 3/11 (27.3%*)

• Progressive increase in perfusion defects, most prevalent when >5%

Marks et al. IJROBP 2005

LV included in RT field• Wall motion abnormalities in LV correlated with perfusion defects

Diastolic dysfunction after mediastinal RT for Hodgkin’s lymphoma

Heidenreich et al. AHJ 2005Hodgkin s lymphoma

• High prevalence of diastolic dysfuntion in asymptomatic patients

• Associated with stress induced ischemia (wall motion and perfusion defects; 28% vs 11%) and worse cardiac event free survival

• Diastolic dysfunction probably result of microvascular thrombosis and ischemia leading to fibrosis

Initiation of age-related atherosclerosis

M t

LDLTransmigration

Rolling StickingMonocyte

Vessel lumen

Endothelial cells

Adhesion molecules

LDLMCP-1E-selectin VCAM-1

ICAM-1 Intima

HDL HDLmo cu s

Oxidized LDL

Cytokines

HDL

Foam cellGrowth factors

Metalloproteinases

Cell proliferationMatrix degradation

HDL promote cholesterol efflux

Progression of age-related atherosclerosisLibby, Nature 2002

IntimaMedia SMCsSMCs

AdventitiaNormal artery

ECs

Stabilized

Early atheroma

Stabilized advanced plaque

Thrombosis of ruptured plaque

Vulnerable initial plaque

Increased IMT in carotid artery after il t l k i di tiIMT differences measured using

D l lt d

unilateral neck irradiation

Duplex ultrasound0 Gy 50-66 Gy

IMT 0.83 mm vs 1.13 mm* (FU >10 yrs: 0.68 mm vs 1.35 mm)

Other prospective studies show increased rate of progression of IMT and p p p gstenosis in irradiated carotid arteries

Dorresteijn et al EJC 2005

Characterization of radiation damage in mid sized arteries of H&N cancer patientssized arteries of H&N cancer patients

Russell, Hoving et al. R&O in press

RT (n = 25)

Control(n = 45)

Age (years) 54 ± 12 57 ± 10

• Resection material from patients undergoing reconstructive surgery

Smoking (pack

)

26 ± 18 32 ± 23

g y

• Irradiated branch of carotid (50-70 Gy) and unirradiated

years)FU (years) 4 ± 7 -

donor artery (radial) from same patient

• U i di t d k (f i l) Dose (Gy) 66 ± 7 -

BMI 25 ± 7 24 ± 4

• Unirradiated neck (facial) and radial artery from other surgical patients

Increased IMT after radiotherapy inneck artery of H&N cancer patients

neck/facial

y p

radial

Russell, Hoving et al. R&O in press

0.20

0.25

T ca

rotid P=0.018 P=0.121

2

3

/radi

al

0.05

0.10

0.15

Mea

n IM

T

1

2IM

T ca

rotid

0 Gy (n=45) 65 Gy (n=25)0.00

0 Gy (n=36) 65 Gy (n=18)0

I

Study design: irradiation of mouse carotid arteries in ApoE / micecarotid arteries in ApoE-/- mice

(wild type mice have very low levels of LDL and are resistant to atherosclerosis)

1.5 cm

100% 2.0 cm

8-10%

<4%100 50

% of full dose

0

% of full dose

Increased incidence of early fatty streaks in irradiated arteries of ApoE / mice

Hoving et al IJROBP 2008

irradiated arteries of ApoE-/- mice

Follow-up time 0 Gy 14 Gy

1 week 0/10 0/101 week 0/10 0/10

4 weeks 0/9 4/9 *

Analysis of plaques in ApoE-/- miceAnalysis of plaques in ApoE / mice

Initial lesion Advanced lesion

• Macrophage rich

50 µm 100 µm

• Necrotic lipid core

• No fibrous cap • Fibrous cap

Increased numbers of carotid lesions after irradiation

Stewart et al, AJP 2006Hoving et al IJROBP 2008

6

7

**

**Total

4

5

*Initial

Hoving et al IJROBP 2008

3

4

5* *

er o

f les

ions

2

3

4 **

*

er o

f les

ions

0

1

2

3

Num

be

1

2

Num

be0

20 x0 Gy

20 x2 Gy

M- 22 wk M- 34 wk

20 x0 Gy

20 x2 Gy

0 Gy 8 Gy 14 Gy

F- 30 wk

0 Gy 14 Gy

M- 28-34 wk

020 x0 Gy

20 x2 Gy

M- 22 wk M- 34 wk

20 x0 Gy

20 x2 Gy

0 Gy 8 Gy 14 Gy

F- 30 wk

0 Gy 14 Gy

M- 28-34 wk

• Increased total plaque area in carotid arteries of irradiated miceIncreased total plaque area in carotid arteries of irradiated mice• Increased thrombotic features in plaque of irradiated arteries• No “out of field” effects

Interaction between hypercholesterolemia d di tiand radiation

8 Gy / HFD (C57Bl6 mice)8 Gy / HFD (C57Bl6 mice)

Tribble et al 19998 Gy / chow

Thrombotic phenotype of lesions in irradiated tid t icarotid arteries

Stewart et al. AJP 2006

Decreased collagen content in irradiated advanced lesionsadvanced lesions

Hoving et al IJROBP 2008

60

30

40

50

*llage

n

10

20

30

*% C

ol

0

34 wk20x0 Gy 20x2 Gy

22 wk

20x0 Gy 20x2 Gy

Is it possible to inhibit the pdevelopment or progression of di ti i d d th l i ?radiation-induced atherosclerosis?

Involvement of oxidative stress in di ti i d d th l iradiation induced athrosclerosis

8 Gy 0 Gy

• Two-fold lower lesion area in irradiated SOD-transgenic mice

• Singlet O2 in irradiated aortaSinglet O2 in irradiated aorta reduced in SOD-transgenics

SOD-TGCont Cont SOD-TG

Tribble et al 1999

Intervention strategies: study designIntervention strategies: study design

Platelet aggregation

Hoving et al unpublished

• Irradiation of carotid arteries

• 4 or 30 weeks follow up

Platelet aggregation

20

25ControlASA high

Ohm

)

p

• Control chow

• ASA (300 mg/kg/day) 5

10

15

Am

plitu

de (O

ohm

)

• NO-ASA (60 mg/kg/day)

• Clopidogrel (20 mg/kg/day)20

25ControlClopidogrelAtorvastatin)

0 *

Am

plitu

de (o

• Atorvastatin (15 mg/kg/day)

10

15

*

Am

plitu

de (O

hm)

Am

0

5

A

Expression of ICAM-1, VCAM-1 and TM 4 weeks after irradiation (position 0)(p )

70

80

%) Control 14 Gy

Hoving et al unpublished

50

60

70

ICA

M-1

/CD

31 (%

yNO-ASA 14 GyASA high 14 GyICAM-1

0.040

70

80

1 (%

)

40

50

60 *

VCA

M-1

/CD

31

VCAM-1

0.0

60

70

80

lin/C

D31

(%)

1O-1

Average ± SEM0.030

40

50 *

Thro

mbo

mod

ulTM

Effect of (NO-)ASA on atherosclerosisHoving et al unpublished

6

8Control 0 GyNO-ASA 0 GyASA high 0 Gy

ns

NO-ASA reduced # lesions in unirradiated ApoE-/- mice

4

6

*m

ber o

f les

ion

N d ti i l ft RT b t ASA i d d l t bili ti0

2

Num

10

ns

50

*

No reduction in plaque after RT but ASA induced plaque stabilizationControlNO-ASAASA high

4

6

8

mbe

r of l

esio

n

20

30

40%

Col

lage

n

0

2Num

0

10

%

Effect of Clopidogrel or Atorvastatin on atherosclerosis in ApoE-/- micep

Unirradiated Irradiated

Hoving et al unpublished

0.75

1.00 ControlClopidogrelAtorvastatin

a (m

m2 ) 1.00

1.25 ControlClopidogrelAtorvastatin

a (m

m2 )

0.25

0.50 *

al p

laqu

e ar

ea

0 25

0.50

0.75

tal p

laqu

e ar

eaClopidogrel

0.00

0.25

Tot

0.00

0.25

Tot

Clopidogrel• Reduced total plaque area in unirradiated mice• No effect on plaque area, phenotype or collagen content in irradiated miceAtorvastatinAtorvastatin• No effect on number of lesions, plaque area or phenotype or collagen content

Summary

• Inflammatory and thrombotic changes in microvasculature precede radiation induced myocardial degeneration fibrosisprecede radiation induced myocardial degeneration, fibrosis and cardiac damage

• Perfusion defects common in asymptomatic patients at 2 years y p p yafter RT >5% LV; associated with stress induced ischemia and subsequent cardiac events

• Irradiation of large vessels in combination with high cholesterol initiates and potentiates atherosclerosis

• L i i i di t d t i i fl t d l t bl• Lesions in irradiated arteries more inflammatory and less stable than “age related” lesions

• Anti-platelet and anti-inflammatory drugs less effective againstAnti platelet and anti inflammatory drugs less effective against radiation induced than age related atherosclerosis