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Risk of cardiovascular diseases after Hodgkin lymphoma treatment van Nimwegen, F.A.

2016

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van Nimwegen, F. A. (2016). Risk of cardiovascular diseases after Hodgkin lymphoma treatment.

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Chapter 2

ĂƌĚŝŽǀĂƐĐƵůĂƌĚŝƐĞĂƐĞĂŌĞƌ,ŽĚŐŬŝŶůLJŵƉŚŽŵĂ

ƚƌĞĂƚŵĞŶƚʹϰϬLJĞĂƌĚŝƐĞĂƐĞƌŝƐŬ

:DŝŶƚĞƌŶĂůŵĞĚŝĐŝŶĞϮϬϭϱ͖ϭϳϱ;ϲͿ͗ϭϬϬϳͲϭϬϭϳ

ŌĞƌĂŵĞĚŝĂŶĨŽůůŽǁͲƵƉŽĨϮϬ͘ϯLJĞĂƌƐ;ƌĂŶŐĞ͗ϱͲϰϳLJĞĂƌƐͿ͕ǁĞŝĚĞŶƟĮĞĚϭ͕ϳϭϯĐĂƌĚŝŽǀĂƐĐƵůĂƌ ĞǀĞŶƚƐŝŶϳϵϳƉĂƟĞŶƚƐ͖ϰϭϬƉĂƟĞŶƚƐ;ϱϭ͘ϰйͿĚĞǀĞůŽƉĞĚϮĞǀĞŶƚƐŽƌŵŽƌĞ͘dŚĞŵŽƐƚĨƌĞƋƵĞŶƚůLJ ŽĐĐƵƌƌŝŶŐĐĂƌĚŝŽǀĂƐĐƵůĂƌĚŝƐĞĂƐĞǁĂƐ,͕ǁŝƚŚϰϬϭƉĂƟĞŶƚƐĚĞǀĞůŽƉŝŶŐ,ĂƐƚŚĞŝƌĮƌƐƚ ĞǀĞŶƚ;^ƵƉƉůĞŵĞŶƚĂůƚĂďůĞϭͿ͕ĨŽůůŽǁĞĚďLJs,;ϯϳϰĞǀĞŶƚƐͿĂŶĚ,&;ϭϰϬĞǀĞŶƚƐͿ͘ƚŽƚĂůŽĨ ϭ͕ϯϮϭĐĂƌĚŝŽǀĂƐĐƵůĂƌĞǀĞŶƚƐ;ϳϳ͘ϭйͿĐŽƵůĚďĞŐƌĂĚĞĚ͘KĨƚŚĞs,Ɛ͕ϰϮϵ;ϲϳ͘ϬйͿǁĞƌĞŐƌĂĚĞϮ ŽƌŚŝŐŚĞƌ͕ĂŶĚϮϰϯ;ϯϴ͘ϬйͿǁĞƌĞŐƌĂĚĞϯŽƌŚŝŐŚĞƌ͘KĨ,&Ɛ͕ϭϰϬ;ϳϳ͘ϬйͿǁĞƌĞŐƌĂĚĞϯŽƌŚŝŐŚĞƌ ;^ƵƉƉůĞŵĞŶƚĂůƚĂďůĞϭͿ͘DĞĚŝĂŶŝŶƚĞƌǀĂůƐďĞƚǁĞĞŶ,>ƚƌĞĂƚŵĞŶƚĂŶĚĮƌƐƚĞǀĞŶƚƐǁĞƌĞϭϴ͕Ϯϰ ĂŶĚϭϵLJĞĂƌƐĨŽƌ,͕s,ĂŶĚ,&͕ƌĞƐƉĞĐƟǀĞůLJ͘ ŽŵƉĂƌŝƐŽŶǁŝƚŚƚŚĞŐĞŶĞƌĂůƉŽƉƵůĂƟŽŶ ^ƵƌǀŝǀŽƌƐŽĨ,>ŚĂĚĂϯ͘ϮͲĨŽůĚŝŶĐƌĞĂƐĞĚ^/Z;ϵϱй/͗ϯ͘ϬͲϯ͘ϱͿŽĨĚĞǀĞůŽƉŝŶŐĂ,ĂŶĚĂϲ͘ϴͲ ĨŽůĚŝŶĐƌĞĂƐĞĚ^/Z;ϵϱй/͗ϱ͘ϵͲϳ͘ϲͿŽĨĚĞǀĞůŽƉŝŶŐ,&ĐŽŵƉĂƌĞĚǁŝƚŚƚŚĞŐĞŶĞƌĂůƉŽƉƵůĂƟŽŶ͕ ĐŽƌƌĞƐƉŽŶĚŝŶŐƚŽϳϬĂŶĚϱϴĞdžĐĞƐƐĐĂƐĞƐŽĨ,ĂŶĚ,&ƉĞƌϭϬ͕ϬϬϬƉĞƌƐŽŶͲLJĞĂƌƐ͕ƌĞƐƉĞĐƟǀĞůLJ ;dĂďůĞϮͿ͘tŚĞŶŽŶůLJĐŽŶƐŝĚĞƌŝŶŐĮƌƐƚ,Žƌ,&ĞǀĞŶƚƐ͕^/ZƐǁĞƌĞƐƵďƐƚĂŶƟĂůůLJĞůĞǀĂƚĞĚĂƐ ǁĞůů;^ƵƉƉůĞŵĞŶƚĂůƚĂďůĞϮͿ͘ ůƚŚŽƵŐŚ ^/ZƐ ǁĞƌĞ ƐŝŐŶŝĮĐĂŶƚůLJ ŝŶĐƌĞĂƐĞĚ ĨŽƌ Ăůů ĂŐĞ ĐĂƚĞŐŽƌŝĞƐ͕ ƉĂƟĞŶƚƐ ƚƌĞĂƚĞĚ Ăƚ Ă LJŽƵŶŐĞƌĂŐĞŚĂĚŚŝŐŚĞƌ^/ZƐƚŚĂŶƉĂƟĞŶƚƐƚƌĞĂƚĞĚĨŽƌ,>ĂďŽǀĞƚŚĞĂŐĞŽĨϯϱLJĞĂƌƐ͘WĂƟĞŶƚƐ ƚƌĞĂƚĞĚďĞĨŽƌĞϮϱLJĞĂƌƐŽĨĂŐĞĞdžƉĞƌŝĞŶĐĞĚĂϰ͘ϲͲƚŽϳ͘ϱͲĨŽůĚŝŶĐƌĞĂƐĞĚƌŝƐŬŽĨ,ĂŶĚĂϭϬ͘ϵͲ ƚŽϰϬ͘ϱͲĨŽůĚŝŶĐƌĞĂƐĞĚ^/ZŽĨ,&ĚĞƉĞŶĚŝŶŐŽŶƚŚĞŝƌĂƩĂŝŶĞĚĂŐĞ;ƉĨŽƌƚƌĞŶĚĂĐƌŽƐƐĂƩĂŝŶĞĚ ĂŐĞĐĂƚĞŐŽƌŝĞƐ͗фϬ͘ϬϬϭĂŶĚфϬ͘ϬϬϭ͕ƌĞƐƉĞĐƟǀĞůLJͿ͘WĂƟĞŶƚƐƚƌĞĂƚĞĚĂƚϯϱƚŽϱϬLJĞĂƌƐŽĨĂŐĞ ĞdžƉĞƌŝĞŶĐĞĚĂϮ͘ϬͲƚŽϮ͘ϯͲĨŽůĚŝŶĐƌĞĂƐĞĚƌŝƐŬŽĨ,ĂŶĚϯ͘ϭͲƚŽϱ͘ϮͲĨŽůĚŝŶĐƌĞĂƐĞĚƌŝƐŬŽĨ,&͕ ĚĞƉĞŶĚŝŶŐŽŶƚŚĞŝƌĂƩĂŝŶĞĚĂŐĞ;ƉĨŽƌƚƌĞŶĚĂĐƌŽƐƐĂƩĂŝŶĞĚĂŐĞĐĂƚĞŐŽƌŝĞƐ͗Ϭ͘ϭϲϴĂŶĚϬ͘ϭϰϳ͕ ƌĞƐƉĞĐƟǀĞůLJͿ;dĂďůĞϮͿ͘dŚĞƌŝƐŬƐŽĨ,ĂŶĚ,&ƌĞŵĂŝŶĞĚƐŝŐŶŝĮĐĂŶƚůLJŝŶĐƌĞĂƐĞĚďĞLJŽŶĚϯϱ LJĞĂƌƐĂŌĞƌ,>ƚƌĞĂƚŵĞŶƚ;^/Z͗ϯ͘ϵ͕ϵϱй/͗Ϯ͘ϲͲϱ͘ϲĂŶĚ^/Z͗ϱ͘ϴ͕ϵϱй/͗ϯ͘ϴͲϴ͘ϱ͕ƌĞƐƉĞĐƟǀĞůLJͿ͕ ƌĞƐƵůƟŶŐŝŶŚŝŐŚĂďƐŽůƵƚĞĞdžĐĞƐƐƌŝƐŬƐŽĨϰϳϱĂŶĚϯϴϮƉĞƌϭϬ͕ϬϬϬƉĞƌƐŽŶͲLJĞĂƌƐ͕ƌĞƐƉĞĐƟǀĞůLJ ;dĂďůĞϮĂŶĚ^ƵƉƉůĞŵĞŶƚĂůĮŐƵƌĞϭͿ͘tŚĞŶŽŶůLJĐŽŶƐŝĚĞƌŝŶŐĮƌƐƚ,ĂŶĚ,&ĞǀĞŶƚƐ͕ƚŚĞ^/Z ĨŽƌ,ƌĞŵĂŝŶĞĚƐŝŐŶŝĮĐĂŶƚůLJŝŶĐƌĞĂƐĞĚƵƉƚŽшϯϬLJĞĂƌƐĂŌĞƌ,>ƚƌĞĂƚŵĞŶƚ͕ĐŽŵƉĂƌĞĚǁŝƚŚ ƚŚĞ ŐĞŶĞƌĂů ƉŽƉƵůĂƟŽŶ ;^ƵƉƉůĞŵĞŶƚĂů ƚĂďůĞ Ϯ ĂŶĚ ^ƵƉƉůĞŵĞŶƚĂů ĮŐƵƌĞ ϮͿ͘ dŚĞ ^/Z ĨŽƌ ,& ƌĞŵĂŝŶĞĚĞůĞǀĂƚĞĚĂƐǁĞůů͕ĂůƚŚŽƵŐŚŶŽƚƐƚĂƟƐƟĐĂůůLJƐŝŐŶŝĮĐĂŶƚůLJƐŽĨƌŽŵŵŽƌĞƚŚĂŶϯϬLJĞĂƌƐ ĂŌĞƌ,>ƚƌĞĂƚŵĞŶƚ͘

Within cohort comparisons

2

&ŽƌƚLJͲLJĞĂƌĐƵŵƵůĂƟǀĞŝŶĐŝĚĞŶĐĞƐĨŽƌ,ĂŶĚs,ĂƐĮƌƐƚĞǀĞŶƚƐǁĞƌĞϮϮ͘ϵй;ϵϱй/͗ϮϬ͘ϳͲ Ϯϱ͘ϭͿ͕ĂŶĚϮϱ͘ϵй;ϵϱй/͗Ϯϯ͘ϰͲϮϴ͘ϱͿ͕ƌĞƐƉĞĐƟǀĞůLJ;&ŝŐƵƌĞϭͿ͘,&ŵŽƐƚĨƌĞƋƵĞŶƚůLJŽĐĐƵƌƌĞĚ ĂƐĂƐƵďƐĞƋƵĞŶƚĞǀĞŶƚ͖ƚŚĞĐƵŵƵůĂƟǀĞŝŶĐŝĚĞŶĐĞŽĨ,&ĂƐĂĮƌƐƚĞǀĞŶƚǁĂƐŽŶůLJϴ͘ϭй;ϵϱй/͗ ϲ͘ϳͲϵ͘ϳͿ ĂŌĞƌ ϰϬ LJĞĂƌƐ͕ ǁŚĞƌĞĂƐ ƚŚĞ ϰϬͲLJĞĂƌ ĐƵŵƵůĂƟǀĞ ŝŶĐŝĚĞŶĐĞ ĨŽƌ ĂŶLJ ,& ǁĂƐ Ϯϰ͘ϴй ;ϵϱй/͗Ϯϭ͘ϰͲϮϴ͘ϰͿϰϬLJĞĂƌƐĂŌĞƌ,>ƚƌĞĂƚŵĞŶƚ͘ 0 5 10 15 20 25 30 35 40 45 50 55 60

Cumulative incidence of cardiovascular diseases (%)

604 (22) 492 (39) 364 (47) 180 (39) 46 (9) 14 (2) 1

No mediastinal radiotherapy and no anthracyclines

1448(48)1269(75)1097(102)848(119)552(123)273 (58) 119

Anthracyclines, but no mediastinal radiotherapy

169 (3) 139 (10) 105 (8) 59 (3) 13 (1) 6 (0) 1

Mediastinal radiotherapy, but no anthracyclines

302 (6) 270 (5) 249 (11) 208 (11) 158 (3) 110 (5) 55

Mediastinal radiotherapy and anthracyclines

Number at risk

0 5 10 15 20 25 30 35 40

Time since treatment (years)

Mediastinal radiotherapy and anthracyclines Mediastinal radiotherapy, but no anthracyclines Anthracyclines, but no mediastinal radiotherapy No mediastinal radiotherapy and no anthracyclines

0.0 10.0 20.0 30.0 40.0 50.0 60.0

Cumulative incidence of cardiovascular diseases (%) _{0 5 10 15 20 25 30 35 40 45}

Time since treatment (years)

all CHD all VHD all HF

first CHD first VHD first HF

Cumulative incidence of all and first cardiovascular diseases

Figure 1:ƵŵƵůĂƟǀĞ/ŶĐŝĚĞŶĐĞŽĨĐĂƌĚŝŽǀĂƐĐƵůĂƌĚŝƐĞĂƐĞƐǁŝƚŚĚĞĂƚŚŽĨĂŶLJĐĂƵƐĞĂƐĐŽŵƉĞƟŶŐƌŝƐŬ

A

2

0.0 10.0 20.0 30.0 40.0 50.0

Cumulative incidence of any cardiovascular disease (%

)

0 10 20 30 40 50 60 70 80 90

Attained age (years)

<25 years at HL treatment ï\HDUVDW+/WUHDWPHQW ï\HDUVDW+/WUHDWPHQW 0.0 10.0 20.0 30.0 40.0 50.0

Cumulative incidence of first CHD (%

)

0 10 20 30 40 50 60 70 80 90

Attained age (years)

<25 years at HL treatment ï\HDUVDW+/WUHDWPHQW ï\HDUVDW+/WUHDWPHQW 0.0 10.0 20.0 30.0 40.0 50.0

Cumulative incidence of first VHD (%

)

0 10 20 30 40 50 60 70 80 90

Attained age (years)

<25 years at HL treatment ï\HDUVDW+/WUHDWPHQW ï\HDUVDW+/WUHDWPHQW 0.0 10.0 20.0 30.0 40.0 50.0

Cumulative incidence of first HF (%)

0 10 20 30 40 50 60 70 80 90

Attained age (years)

^ƵƉƉůĞŵĞŶƚĂůŵĂƚĞƌŝĂůƐ

Supplemental Table 1:ĞƐĐƌŝƉƟŽŶĂŶĚŐƌĂĚŝŶŐŽĨs

CHD VHD HF

MI AP CMP CHF

E;йͿ E;йͿ E;йͿ E;йͿ E;йͿ

dŽƚĂůŶƵŵďĞƌŽĨĞǀĞŶƚƐ 305 314 796 75 223 EƵŵďĞƌŽĨĮƌƐƚĞǀĞŶƚƐۮ _{201 200 374 38 102} EƵŵďĞƌŽĨƉĂƟĞŶƚƐǁŝƚŚĞǀĞŶƚ 255 314 511 75 223 Grade* ϭ n.a. 14 (5) 211 (26) 1 (1) 3 (1) Ϯ n.a. 180 (57) ¥ _{186 (23) 8 (11) 30 (13)} ϯ 201 (66)Τ _{n.a. 86 (11) 30 (40) 68 (31)} ϰ 57 (19) n.a. 149 (19) 1 (1) 4 (2) ϱ 47 (15) n.a. 8 (1) 5 (7) 32 (14) ƵŶŬŶŽǁŶ n.a. 120 (38) 156 (20) 30 (40) 86 (39) ,͗ ĐŽƌŽŶĂƌLJ ŚĞĂƌƚ ĚŝƐĞĂƐĞ͖ D/͗ ĂĐƵƚĞ ŵLJŽĐĂƌĚŝĂů ŝŶĨĂƌĐƟŽŶ͖ W͗ ĂŶŐŝŶĂ ƉĞĐƚŽƌŝƐ͖ s,͗ ǀĂůǀƵůĂƌ ŚĞĂƌƚ ĚŝƐĞĂƐĞ͖ ,&͗ŚĞĂƌƚĨĂŝůƵƌĞ͖DW͗ĐĂƌĚŝŽŵLJŽƉĂƚŚLJ͖,&͗ĐŽŶŐĞƐƟǀĞŚĞĂƌƚĨĂŝůƵƌĞ ΎŐƌĂĚŝŶŐĂĐĐŽƌĚŝŶŐƚŽĂĚĂƉƚĞĚǀĞƌƐŝŽŶŽĨdǀϰ͘Ϭ;ƐĞĞ^ƵƉƉůĞŵĞŶƚĂůdĞdžƚϭͿ͖ŐƌĂĚĞϭсĂƐLJŵƉƚŽŵĂƟĐ͖ŐƌĂĚĞϮс ĐůŝŶŝĐĂůůLJƌĞůĞǀĂŶƚ͖ŐƌĂĚĞϯсŵŽĚĞƌĂƚĞ͖ŐƌĂĚĞϰсƐĞǀĞƌĞ͖ŐƌĂĚĞϱсĐŽŶƐĞƋƵĞŶƟĂůĚĞĂƚŚ͘ǀĞŶƚƐǁĞƌĞŐƌĂĚĞĚďLJ&ǀE͕ MS and two trained research assistants

Τ_{ĚŝƐƟŶĐƟŽŶďĞƚǁĞĞŶŐƌĂĚĞϯĂŶĚϰĐŽƵůĚŶŽƚďĞŵĂĚĞĨŽƌϭϱϮƉĂƟĞŶƚƐ͕ƐŽƚŚĞƐĞĞǀĞŶƚƐǁĞƌĞĐŽŶƐĞƌǀĂƟǀĞůLJŐƌĂĚĞĚ}

with grade 3.

¥_{ŽĨǁŚŝĐŚϭϯϴƌĞƋƵŝƌĞĚWdŽƌ'}

Supplemental Table 3:ZŝƐŬŽĨĂŶLJĐĂƌĚŝŽǀĂƐĐƵůĂƌĞǀĞŶƚĨŽůůŽǁŝŶŐ,ŽĚŐŬŝŶůLJŵƉŚŽŵĂƚƌĞĂƚŵĞŶƚ ůůĞǀĞŶƚƐ CHD VHD HF # of events: 480 512 270 hŶŝǀĂƌŝĂƚĞŵŽĚĞůƐ HR ;ϵϱй/Ϳ HR ;ϵϱй/Ϳ HR ;ϵϱй/Ϳ DĞĚŝĂƐƟŶĂůZd;LJĞƐǀƐŶŽͿ 2.2 (1.6-2.9) 4.8* (3.3 -7.0) 3.3* (2.1-5.3) DĞĚŝĂƐƟŶĂůZdĚŽƐĞ;ƉƌĞƐĐƌŝďĞĚͿ

EŽŵĞĚŝĂƐƟŶĂůZd 1.0 (ref) 1.0 (ref) 1.0 (ref)

ϭͲϮϵ'LJ 1.1 (0.5-2.4) 3.1* (1.5-6.4) 2.6* (1.03-6.5) ϯϬͲϯϱ'LJ 2.4* (1.6-3.5) 4.6* (2.9-7.2) 3.6* (2.1-6.4)

шϯϲ'LJ 2.3* (1.7-3.2) 5.8* (3.9-8.5) 4.7* (2.9-7.6) ŶƚŚƌĂĐLJĐůŝŶĞͲĐŽŶƚĂŝŶŝŶŐd;LJĞƐǀƐŶŽͿ 1.17 (0.9-1.5) 2.0* (1.6-2.5) 1.9* (1.4-2.6) ŶƚŚƌĂĐLJĐůŝŶĞĚŽƐĞ

EŽĂŶƚŚƌĂĐLJĐůŝŶĞͲĐŽŶƚĂŝŶŝŶŐd 1.0 (ref) 1.0 (ref) 1.0 (ref) ϯϱͲϮϬϬŵŐͬŵϮ _{1.2 (0.8-1.9) 1.2 (0.7-1.9) 1.5 (0.8-2.7)} ϮϭϬͲϯϮϱŵŐͬŵϮ _{1.1 (0.9-1.5) 2.2* (1.7-2.9) 1.9* (1.3-2.7)} ϯϱϬͲϴϴϬŵŐͬŵϮ _{1.0 (0.6-1.8) 2.7* (1.7-4.3) 2.7* (1.5-4.8)} ^Ğdž;ĨĞŵĂůĞǀƐŵĂůĞͿ 0.5* (0.4-0.6) 1.2* (1.03-1.5) 0.8 (0.7-1.1) ǀĞƌƐŵŽŬŝŶŐ;LJĞƐǀƐŶŽͿ 1.6* (1.3-1.9) 1.1 (0.9-1.3) 1.3 (1.0-1.6) DŽĚĞůϭΤ DĞĚŝĂƐƟŶĂůZd;LJĞƐǀƐŶŽͿ 2.9* (2.2-4.0) 5.2* (3.6-7.6) 3.9* (2.4-6.3) DŽĚĞůϮΤ DĞĚŝĂƐƟŶĂůZdĚŽƐĞ

EŽŵĞĚŝĂƐƟŶĂůZd 1.0 (ref) 1.0 (ref) 1.0 (ref)

ϭͲϮϵ'LJ 1.3 (0.6-2.9) 2.9* (1.4-6.1) 2.6* (1.0-6.6) ϯϬͲϯϱ'LJ 2.9* (2.0-4.3) 5.1* (3.3-8.0) 4.1* (2.4-7.2) шϯϲ'LJ 3.0* (2.1-4.1) 6.3* (4.2-9.3) 5.3* (3.3-8.7) DŽĚĞůϯ¥ ŶƚŚƌĂĐLJĐůŝŶĞͲĐŽŶƚĂŝŶŝŶŐd;LJĞƐǀƐŶŽͿ 1.0 (0.8-1.3) 1.6* (1.2-2.0) 1.9* (1.4-2.7) DŽĚĞůϰ¥ ŶƚŚƌĂĐLJĐůŝŶĞĚŽƐĞ

Ϭ Ϯ ϰ ϲ ϴ ϭ ϭ 0 2 4 6 8 10 12 CHD HF CHD HF CHD HF CHD HF CHD HF CHD HF CHD HF 5-9 10-14 15-19 20-24 25-29 30-34 •35 Sta nda rd ize d Inc iden c e R a tio

Follow-up time (years)

0 50 100 150 200 250 300 350 400 CHD HF CHD HF CHD HF CHD HF CHD HF CHD HF CHD HF 5-9 10-14 15-19 20-24 25-29 30-34 •35 A b so lu te E xcess Ri sk

Follow-up time (years)

Supplemental Figure 1:^ƚĂŶĚĂƌĚŝnjĞĚ/ŶĐŝĚĞŶĐĞZĂƟŽƐĂŶĚďƐŽůƵƚĞdžĐĞƐƐZŝƐŬƐĨŽƌĂŶLJ,ĂŶĚ,&ďLJĨŽůůŽǁͲƵƉ

period

A

2

Ϭ ϭ Ϯ ϯ ϰ ϱ ϲ ϳ ϴ ϵ ϭϬ 0 1 2 3 4 5 6 7 8 9 10 CHD HF CHD HF CHD HF CHD HF CHD HF CHD HF CHD HF 5-9 10-14 15-19 20-24 25-29 30-34 •35 S tand ar d ize d Inc iden ce R atio

Follow-up time (years)

0 20 40 60 80 100 120 140 CHD HF CHD HF CHD HF CHD HF CHD HF CHD HF CHD HF 5-9 10-14 15-19 20-24 25-29 30-34 •35 A b so lu te Excess R isk

Follow-up time (years)

Supplemental Figure 2:^ƚĂŶĚĂƌĚŝnjĞĚ/ŶĐŝĚĞŶĐĞZĂƟŽƐĂŶĚďƐŽůƵƚĞdžĐĞƐƐZŝƐŬƐŽĨĮƌƐƚ,ĂŶĚ,&ďLJĨŽůůŽǁͲƵƉ

period

A

0.0 10.0 20.0 30.0 40.0 50.0 60.0 Cumulative incidence of CVDs (%) 0 5 10 15 20 25 30 35 40 45

Time since treatment (years)

No mediastinal RT Mediastinal RT 1985-1995 Cumulative incidence of CVDs 0.0 10.0 20.0 30.0 40.0 50.0 60.0 Cumulative incidence of CVDs (%) 0 5 10 15 20 25 30 35 40 45

Time since treatment (years)

No mediastinal RT Mediastinal RT 1975-1984 Cumulative incidence of CVDs 0.0 10.0 20.0 30.0 40.0 50.0 60.0 Cumulative incidence of CVDs (%) 0 5 10 15 20 25 30 35 40 45

Time since treatment (years)

2

Supplemental Text 1: 'ƌĂĚŝŶŐĐƌŝƚĞƌŝĂďĂƐĞĚŽŶdǀϰ͘Ϭ ŽƌŽŶĂƌLJ,ĞĂƌƚŝƐĞĂƐĞ;ĂŶŐŝŶĂƉĞĐƚŽƌŝƐĂŶĚŵLJŽĐĂƌĚŝĂůŝŶĨĂƌĐƟŽŶͿ͗ Ͳ 'ƌĂĚĞϭʹZĞĐŽƌĚƐĚŽŶŽƚĐŽŶĮƌŵƚŚĞĚŝĂŐŶŽƐŝƐŽĨĐŽƌŽŶĂƌLJĂƌƚĞƌLJĚŝƐĞĂƐĞ͘dŚŝƐŐƌŽƵƉ ǁŝůůŝŶĐůƵĚĞƉĂƟĞŶƚƐǁŝƚŚĐůŝŶŝĐĂůĚŝĂŐŶŽƐŝƐŽĨĂŶŐŝŶĂƉĞĐƚŽƌŝƐďƵƚŶŽŽƚŚĞƌƐƵƉƉŽƌƟŶŐ ŝŶĨŽƌŵĂƟŽŶ Ͳ 'ƌĂĚĞϮʹŽƌŽŶĂƌLJĂƌƚĞƌLJĚŝƐĞĂƐĞĐŽŶĮƌŵĞĚďLJĂŶŐŝŽŐƌĂŵ;ďƵƚŶŽĂĐƵƚĞŵLJŽĐĂƌĚŝĂů ŝŶĨĂƌĐƟŽŶ Žƌ ƌĞǀĂƐĐƵůĂƌŝnjĂƟŽŶͿ͘ WƌŽďĂďůĞ ĐŽƌŽŶĂƌLJ ĂƌƚĞƌLJ ĚŝƐĞĂƐĞ ĂƐ ĞǀŝĚĞŶĐĞĚ ďLJ ŝƐĐŚĂĞŵŝĐ ' ĐŚĂŶŐĞƐ ;ƚƌĂŶƐŝĞŶƚ ^dͲƐĞŐŵĞŶƚ ĚĞƉƌĞƐƐŝŽŶ ĂŶĚ Žƌ dͲǁĂǀĞ ŇĂƩĞŶŝŶŐͬ ŝŶǀĞƌƐŝŽŶͿ͕ ŝŵĂŐŝŶŐ ƐƚƵĚŝĞƐ ;Ğ͘Ő͘ ƉŽƐŝƟǀĞ ƐƚƌĞƐƐ ƚĞƐƚͿ Žƌ ŽƚŚĞƌ ŝŶĚŝƌĞĐƚ ĞǀŝĚĞŶĐĞ ;Ğ͘Ő͘ ůĞƩĞƌƐĂŶĚĚƌƵŐƚƌĞĂƚŵĞŶƚͿ Ͳ 'ƌĂĚĞϯʹǀŝĚĞŶĐĞŽĨŶŽŶͲĨĂƚĂůD/͗'͕ůĂďŽƌĂƚŽƌLJ͕ŝŵĂŐŝŶŐƌĞƉŽƌƚ;ĂŶŐŝŽŐƌĂŵ͕ĞĐŚŽ͕ Dh'Ϳ͕ŚĂĞŵŽĚLJŶĂŵŝĐĂůůLJƐƚĂďůĞ Ͳ 'ƌĂĚĞ ϰ ʹ Ɛ ŐƌĂĚĞ ϯ͕ ďƵƚ ŚĂĞŵŽĚLJŶĂŵŝĐĂůůLJ ƵŶƐƚĂďůĞ Žƌ ǁŝƚŚ ůŝĨĞͲƚŚƌĞĂƚĞŶŝŶŐ ĐŽŶƐĞƋƵĞŶĐĞƐ;Ğ͘Ő͘ƐĞǀĞƌĞŚLJƉŽƚĞŶƐŝŽŶ͕ŚĞĂƌƚĨĂŝůƵƌĞŽƌǀĞŶƚƌŝĐƵůĂƌĮďƌŝůůĂƟŽŶƌĞƋƵŝƌŝŶŐ ĞŵĞƌŐĞŶĐLJƌĞƐƵƐĐŝƚĂƟŽŶŽƌŝŶŽƚƌŽƉŝĐͬďĂůůŽŽŶƉƵŵƉƐƵƉƉŽƌƚͿ͘ŽƌŽŶĂƌLJƌĞǀĂƐĐƵůĂƌŝnjĂƟŽŶ ;ĐŽƌŽŶĂƌLJĂƌƚĞƌLJďLJƉĂƐƐŐƌĂŌŽƌĂŶŐŝŽƉůĂƐƚLJͬƐƚĞŶƟŶŐͿ sĂůǀƵůĂƌŝƐĞĂƐĞ͗ Ͳ 'ƌĂĚĞϭʹƐLJŵƉƚŽŵĂƟĐǀĂůǀƵůĂƌƚŚŝĐŬĞŶŝŶŐǁŝƚŚŽƌǁŝƚŚŽƵƚŵŝůĚǀĂůǀƵůĂƌƌĞŐƵƌŐŝƚĂƟŽŶ ŽƌƐƚĞŶŽƐŝƐĂƐĂƐƐĞƐƐĞĚďLJŝŵĂŐŝŶŐ;ŽƌĐĂƚŚĞƚĞƌŝnjĂƟŽŶͿ Ͳ 'ƌĂĚĞ Ϯ ʹ ƐLJŵƉƚŽŵĂƟĐ͖ ŵŽĚĞƌĂƚĞ ƌĞŐƵƌŐŝƚĂƟŽŶ Žƌ ƐƚĞŶŽƐŝƐ ďLJ ŝŵĂŐŝŶŐ ;Žƌ ĐĂƚŚĞƚĞƌŝnjĂƟŽŶͿ Ͳ 'ƌĂĚĞϯʹ^LJŵƉƚŽŵĂƟĐ͖ƐĞǀĞƌĞƌĞŐƵƌŐŝƚĂƟŽŶŽƌƐƚĞŶŽƐŝƐďLJŝŵĂŐŝŶŐ;ŽƌĐĂƚŚĞƚĞƌŝnjĂƟŽŶͿ͖ ^LJŵƉƚŽŵƐĐŽŶƚƌŽůůĞĚǁŝƚŚŵĞĚŝĐĂůŝŶƚĞƌǀĞŶƟŽŶ Ͳ 'ƌĂĚĞ ϰ ʹ >ŝĨĞͲƚŚƌĞĂƚĞŶŝŶŐ ĐŽŶƐĞƋƵĞŶĐĞƐ͖ ^ƵƌŐŝĐĂů ŝŶƚĞƌǀĞŶƟŽŶ ŝŶĚŝĐĂƚĞĚ ;Ğ͘Ő͕͘ ǀĂůǀĞ ƌĞƉůĂĐĞŵĞŶƚ͕ǀĂůǀƵůŽƉůĂƐƚLJͿ

Cardiomyopathy and Heart Failure:

2

EŽƚĞƐŽŶŐƌĂĚŝŶŐ ŽƌŽŶĂƌLJ,ĞĂƌƚŝƐĞĂƐĞ;ĂŶŐŝŶĂƉĞĐƚŽƌŝƐĂŶĚŵLJŽĐĂƌĚŝĂůŝŶĨĂƌĐƟŽŶͿ͗ Ͳ ^ŽŵĞĚŝƐĐƵƐƐŝŽŶŵĂLJďĞƌĞƋƵŝƌĞĚƚŽĚŝƐƟŶŐƵŝƐŚŐƌĂĚĞϯͲϰŵLJŽĐĂƌĚŝĂůŝŶĨĂƌĐƟŽŶŽŶƚŚĞ ďĂƐŝƐŽĨŚĞŵŽĚLJŶĂŵŝĐŝŶƐƚĂďŝůŝƚLJŽƌůŝĨĞͲƚŚƌĞĂƚĞŶŝŶŐĐŽŶƐĞƋƵĞŶĐĞƐ͕ŝĨƵŶĐĞƌƚĂŝŶŵĂŬĞĂ ŶŽƚĞŽĨƚŚĞƵŶĐĞƌƚĂŝŶƚLJĨŽƌůĂƚĞƌƌĞǀŝĞǁĂŶĚƌĞĐŽƌĚƚŚĞĚŝĂŐŶŽƐŝƐĂƐŐƌĂĚĞϯ Ͳ WƌŽŐƌĞƐƐŝŽŶƚŽŐƌĂĚĞϰŽŶƚŚĞďĂƐŝƐŽĨƌĞǀĂƐĐƵůĂƌŝnjĂƟŽŶƐŚŽƵůĚďĞĚĂƚĞĚĂĐĐŽƌĚŝŶŐƚŽ ƚŚĞĚĂƚĞŽĨƚŚĞŝŶƚĞƌǀĞŶƟŽŶ sĂůǀƵůĂƌŝƐĞĂƐĞ͗ Ͳ dŚĞ ŵŽƐƚ ŝŵƉŽƌƚĂŶƚ ŝŶǀĞƐƟŐĂƟŽŶ ĨŽƌ ƚŚĞ ŐƌĂĚŝŶŐ ŽĨ ǀĂůǀƵůĂƌ ĚŝƐĞĂƐĞ ǁŝůů ďĞ echocardiograms - ĐŚŽĐĂƌĚŝŽŐƌĂŵƌĞƉŽƌƚƐĐŽŶǀĞŶƟŽŶĂůůLJƌĞĐŽƌĚǀĂůǀƵůĂƌůĞƐŝŽŶƐĂƐ͚ŵŝůĚ͕͚͛ŵŽĚĞƌĂƚĞ͛Žƌ ͚ƐĞǀĞƌĞ͛ǁŚŝĐŚƐŚŽƵůĚĂůůŽǁŐƌĂĚŝŶŐϭͲϯ - >ĞƐŝŽŶƐƌĞƉŽƌƚĞĚũƵƐƚĂƐ͚ƚƌŝǀŝĂů͛ƐŚŽƵůĚŶŽƚďĞƌĞĐŽƌĚĞĚ - WƌŽŐƌĞƐƐŝŽŶ ƚŽ ŐƌĂĚĞ ϰ ;ƌĞƋƵŝƌŝŶŐ ǀĂůǀƵůĂƌ ƌĞƉůĂĐĞŵĞŶƚ Žƌ ƌĞƉĂŝƌͿ ƐŚŽƵůĚ ďĞ ĚĂƚĞĚ ĂĐĐŽƌĚŝŶŐƚŽƚŚĞĚĂƚĞŽĨƐƵƌŐĞƌLJ

Cardiomyopathy and Heart Failure: