Underlying mechanisms for. and cerebrovascular damage. Saske Hoving, Nicola Russell, Sylvia Heeneman, Mat Daemen

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1 Underlying mechanisms for radiation-induced i d d cardiovascular and cerebrovascular damage Fiona Stewart t Saske Hoving, Nicola Russell, Sylvia Heeneman, Mat Daemen

2 Radiation as an independent risk factor for cardio- and cerebro-vascular disease in cancer patients Early breast cancer: RR fatal CVD RT vs no RT; EBCT = 1.3 Testicular cancer: SIR 1.17 fatal and non-fatal CVD Hodgkin s disease: RR fatal CVD 2-7; higher risks for children RR stroke 4.3 H&N cancer patients: RR stroke Pediatric cranial RT>30 Gy: leukemia RR stroke 5.9 brain tumor RR stroke 38

3 Increased risk of stroke after radiotherapy for H&N cancer: NKI cohort (n = 367; Gy) 15 Cum mulative ris sk of stroke (%) RR of stroke 5.6 RR for FU >10 years = Time after neck irradiation (years) Dorresteijn et al JCO 2002

4 Increased risk of congestive heart failure after radiotherapy for breast cancer (40-50 Gy to IMC) Mean heart dose Chest wall/ R breast 3 Gy Chest wall/ L Breast 7 Gy IMC + R chest 11 Gy IMC+ L chest 15 Gy Chest wall/ R breast Chest wall/ L Breast IMC + R chest IMC+ L chest 1.5 Gy 5 Gy 9 Gy 13 Gy Hooning et al JNCI 2007

Left direct internal mammary field 6MV Right

descending coronary artery Circumflex coronary

Typical dose Heart Mean dose (Gy) LAD RCA Circ

250 kv 50 Gy in 25 50 Gy in 25 50 Gy in 25 50 Gy

5 Left direct internal mammary field 6MV Right coronary artery Left anterior descending coronary artery Circumflex coronary artery Target Field arrangement Beam energy Typical dose Heart Mean dose (Gy) LAD RCA Circ Left IMC Direct anterior 6MV Co-60 Elec 10 Mev 250 kv 50 Gy in Gy in Gy in Gy in Taylor et al. IJROBP (2007)

6 Increased risk of vascular diseases in life span study of A-bomb survivors Preston et al Rad Res 2003

7 Dose response for fatal CVD after RT Schultz Hector & Trott 2007 Exces ss Relativ ve Risk * Peptic Heart ulcer disease RT Carr 2005 Breast ERRcancer 0.17 Sv RT Darby 2005, EBCT % CI 0.08; 0.26 P = * * Approximate Colon average Dose effective (Sv) dose to heart (Gy)

8 Clinical manifestations and pathogenesis of radiation induced vascular damage Endothelial cells: expression of thrombotic and inflammatory cytokines, proliferation, cell loss (days) Myocardial capillary network: obstruction microvessels, decreased d capillary density, perfusion defects, hypoxia, myocardial degeneration and fibrosis (weeks) Medium sized vessels: intimal thickening, perivascular fibrosis (weeks) Pericardium: pericarditis (early inflammatory response) (months) Myocardium: reduced d systolic function, valve defects (months) Coronary/carotid arteries: atherosclerosis, stenosis, coronary artery disease, stroke/myocardial infarct (years)

9 Radiation induced prothrombotic changes in microvessels Endothelial cell damage Increased vwf Reduceded PGI 2 Reduced ADPase Reduced d TM Inflammatory cytokines Platelet aggregation Thrombus formation Vascular occlusion Ischemic coga organ failure ue Cell detachment Exposed subendothelium

10 Microvascular damage in irradiated cancer patients: telangiectasia Irradiated human bowel Irradiated human chest wall Irradiated human rectum Irradiated rat spinal cord

11 Progression of telangiectasia in irradiated cancer patients Breast cancer Turesson & Notter 1986 Prostate cancer Wachter et al 2001 Dose response 35 fr V 90 >57% 30 fr Latency 25 fr V 90 <57% 20 fr Time from treatment (months) Time from treatment (months)

Microvascular damage in irradiated rat heart dex

increased EC proliferation Precedes reduced

12 Microvascular damage in irradiated rat heart dex (%) Labeling ind Time from irradiation (days) Capillary density Time from irradiation (days) Reduced expression of alkaline phosphatase p and increased EC proliferation Precedes reduced capillary density and myocardial degeneration Lauk & Trott IJRB 1990

13 Heart damage in rats after local irradiation (20 Gy/1 year) Myocardial degeneration and interstitial fibrosis Perivascular fibrosis Progressive myocardial degeneration and fibrosis follows reduced capillary density J. Kruse 2002

14 Heart damage in rats after local irradiation (20 Gy/1 year) Decreased cardiac output (to 50% control) parallels focal myocardial degeneration Further reduction in CO only seen immediately before congestive heart failure Compensatory mechanisms (upregulation of cardiac β- adrenergic receptors) maintain steady state for many weeks Schultz-Hector et al. Rad Res 1992

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

weeks End diast tolic volume (cm 3 ) 0.08 0.06 0.04 0.02 0.

16 Gy 22 % decrease in blood volume (p = 0.

15 Step 2 SPECT/CT and ultrasound imaging of irradiated mouse hearts heart (%) Blood volume of the 10 0 Gy 16 Gy 8 6 * weeks 20 weeks End diast tolic volume (cm 3 ) * 0 Gy 16 Gy Cardiac output (cm 3 /m min) * 0 Gy 16 Gy 22 % decrease in blood volume (p = 0.03) 03) 32 % decrease in EDV (p <0.001); 19% decrease in CO (p = 0.042) Stewart, Seemann, Visser, unpublished

16 Prospective evaluation of perfusion defects in patients 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% LV included in RT field Wall motion abnormalities in LV correlated with perfusion defects Marks et al. IJROBP 2005

17 Diastolic dysfunction after mediastinal RT for Hodgkin s lymphoma Heidenreich et al. AHJ 2005 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

18 Initiation of age-related atherosclerosis Monocyte Rolling Sticking LDL Vessel lumen Transmigration Endothelial cells HDL E-selectin Adhesion molecules VCAM-1 ICAM-1 MCP-1 LDL HDL Intima Oxidized LDL Cytokines Foam cell Growth factors Metalloproteinases HDL promote cholesterol efflux Cell proliferation Matrix degradation

19 Progression of age-related atherosclerosis Libby, Nature 2002 Intima Media SMCs Normal artery ECs Adventitia Early atheroma Stabilized advanced plaque Vulnerable initial plaque Thrombosis of ruptured plaque

20 Increased IMT in carotid artery after unilateral l neck irradiation IMT differences measured using 0 Gy Duplex ultrasound Gy IMT 0.83 mm vs 1.13 mm* (FU >10 yrs: 0.68 mm vs 1.35 mm) Other prospective p studies show increased rate of progression of IMT and stenosis in irradiated carotid arteries Dorresteijn et al EJC 2005

21 Characterization of radiation damage in mid sized arteries of H&N cancer patients Russell, Hoving et al. R&O in press Resection material from patients undergoing reconstructive surgery Irradiated branch of carotid (50-70 Gy) and unirradiated donor artery (radial) from same patient RT (n = 25) Control (n = 45) Age (years) 54 ± ± 10 Smoking 26 ± ± 23 (pack years) FU (years) 4 ± 7 - Unirradiated d neck (facial) Dose (Gy) 66 ± 7 - and radial artery from other surgical patients BMI 25 ± 7 24 ± 4

22 Increased IMT after radiotherapy in neck artery of H&N cancer patients Russell, Hoving et al. R&O in press neck/facial radial Mean IMT carotid P=0.018 /radial IMT carotid P= Gy (n=45) 65 Gy (n=25) I 0 0 Gy (n=36) 65 Gy (n=18)

23 Study design: irradiation of mouse carotid 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% % of full dose 0 <4%

24 Increased incidence of early fatty streaks in irradiated arteries of ApoE-/- mice Hoving et al IJROBP 2008 Follow-up time 0 Gy 14 Gy 1week 0/10 0/10 4 weeks 0/9 4/9 *

25 Analysis of plaques in ApoE -/- mice Initial lesion Advanced lesion 50 µm 100 µm Macrophage rich No fibrous cap Necrotic lipid core Fibrous cap

26 Increased numbers of carotid lesions after irradiation Stewart et al, AJP 2006 Hoving et al IJROBP 2008 Numbe er of lesions Total * * * * Numbe er of lesions 5 Initial 4 * * * 0 20 x 20 x 20 x 20 x 0 Gy 2 Gy 0 Gy 2 Gy M- 22 wk M- 34 wk 0 Gy 14 Gy M wk 0 Gy 8 Gy 14 Gy F- 30 wk 0 20 x 0 Gy 20 x 2 Gy 20 x 0 Gy 20 x 2 Gy M- 22 wk M- 34 wk 0 Gy 14 Gy M wk 0 Gy 8 Gy 14 Gy F- 30 wk Increased total plaque area in carotid arteries of irradiated mice Increased total plaque area in carotid arteries of irradiated mice Increased thrombotic features in plaque of irradiated arteries No out of field effects

27 Interaction between hypercholesterolemia and radiation 8 Gy / HFD (C57Bl6 mice) 8 Gy / chow Tribble et al 1999

28 Thrombotic phenotype of lesions in irradiated carotid arteries Stewart et al. AJP 2006

29 Decreased collagen content in irradiated advanced lesions Hoving et al IJROBP % Col llagen * * 0 20x0 Gy 20x2 Gy 20x0 Gy 20x2 Gy 22 wk 34 wk

30 Is it possible to inhibit the development or progression of radiation-induced i d d atherosclerosis?

31 Involvement of oxidative stress in radiation induced d athrosclerosis 8 Gy 0 Gy Two-fold lower lesion area in irradiated SOD-transgenic mice Singlet O 2 in irradiated aorta reduced in SOD-transgenics Cont SOD-TG Cont SOD-TG Tribble et al 1999

32 Intervention strategies: study design Hoving et al unpublished 25 Irradiation of carotid arteries 20 4 or 30 weeks follow up 15 Control chow 10 ASA (300 mg/kg/day) 5 NO-ASA (60 mg/kg/day) 25 Clopidogrel (20 mg/kg/day) 20 Atorvastatin (15 mg/kg/day) ohm) Amplitude (O Ohm) A mplitude (o Am ) Amplitude (Ohm) Platelet aggregation 0 * Control Clopidogrel Atorvastatin * Control ASA high 0

33 Expression of ICAM-1, VCAM-1 and TM 4 weeks after irradiation (position 0) Hoving et al unpublished 80 ICAM-1 ICAM-1/CD31 (% %) Control 14 Gy NO-ASA 14 Gy ASA high 14 Gy VCAM-1 VCAM-1/CD31 1 (%) * TM Thrombomodul lin/cd31 (%) * O -1 Average ± SEM

34 Effect of (NO-)ASA on atherosclerosis Num mber of lesion ns 8 6 Hoving et al unpublished NO-ASA reduced # lesions in unirradiated ApoE-/- mice 4 2 * Control 0 Gy NO-ASA 0 Gy ASA high 0 Gy Num mber of lesion ns 0 No reduction in plaque after RT but ASA induced d plaque stabilization ti Control NO-ASA 10 ASA high % Collagen * 0 0

35 Effect of Clopidogrel or Atorvastatin on atherosclerosis in ApoE-/- mice Hoving et al unpublished al plaque area a (mm 2 ) Tot Unirradiated Control Clopidogrel Atorvastatin 0.50 * 0.00 Tot tal plaque area a (mm 2 ) Irradiated Control Clopidogrel Atorvastatin Clopidogrel Reduced total plaque area in unirradiated mice No effect on plaque area, phenotype or collagen content in irradiated mice Atorvastatin No effect on number of lesions, plaque area or phenotype or collagen content

36 Summary Inflammatory and thrombotic changes in microvasculature precede radiation induced myocardial degeneration, fibrosis and cardiac damage Perfusion defects common in asymptomatic patients at 2 years after 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 Lesions in irradiated d arteries more inflammatory and less stable than age related lesions Anti-platelet and anti-inflammatory inflammatory drugs less effective against radiation induced than age related atherosclerosis

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