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