1. 50 year old man with history of Hodgkin Lymphoma as a child, treated with mediastinal radiation, now presenting with severe heart failure

2. At autopsy, we found Dense fibrous adhesions between chest wall, heart, and left lung Pericardial effusion (425 ml, straw-colored) Left pleural effusion (325 ml, straw-colored) Ascites (1.5 liters) Splenomegaly Pulmonary and hepatic congestion

3. Gross Findings, Cardiovascular System Severe atherosclerosis of the thoracic aorta, mild disease in the abdominal aorta. Marked calcifications of the mitral valve. Functional mechanical aortic valve. Marked calcification of the pulmonary artery wall.

4. Coronary Vasculature –Native Vessels: Severe coronary artery disease. RCA: 75-100%, proximal, 50-75% at the ostium LCx: 75-100%, proximal –Graft Vessels: Patent.

5. Contraction-band Necrosis Left VentricleRight Ventricle

6. Patchy interstitial fibrosis

7. Pulmonary congestion and hemorrhage Congested vessels Hemorrhage

8. Hemosiderin-laden macrophages

9. Bone marrow embolus

10. Hepatic congestion and mild fatty change Congested Sinusoids Fat in hepatocytes

11. Red neurons in hippocampus

12. Ionizing radiation causes acute endothelial damage and inflammation throughout the wall of blood vessels. Depending on where the radiation exposure occurs, virtually any artery can be affected; clinical symptoms may occur >10 years after exposure with the morphology of accelerated atherosclerosis.

13. Survivors of Hodgkin Lymphoma are at increased risk of various health problems Increased risk of second cancers Increased risk of cardiovascular disease: accelerated coronary artery disease, valvular disease, pericardial disease, conduction abnormalities, contractile dysfunction, exp if anthracyclines used in conjunction with radiation

14. Late cardiotoxicity after treatment for Hodgkin lymphoma. Aleman et al. Blood 2007; 109: 1878-1886. Assessed cardiovascular disease incidence in 1474 survivors of Hodgkin lymphoma. After median follow-up of 18.7 years, found risks of MI and CHF to be increased by 3.6 and 4.9 fold, respectively. Mediastinal radiotherapy also increased the risks of angina and valvular disorders (2 - 7 fold)

15. Valvular dysfunction and carotid, subclavian, and coronary artery disease in survivors of Hodgkin lymphoma treated with radiation therapy. Hull et al. JAMA 2003; 290: 2831 Studied 415 patients treated from 1962 to 1998, whose radiation fields included the heart or carotid or subclavian arteries and had at >2 years follow-up (median, 11.2 years). Vascular disease often found >10 years after treatment and valvular disease often >20 years after treatment.

16. 10.4% of patients develop coronary artery disease after a median of 9 years post radiation. CAD more common in patients with a median age at diagnosis above the mean (25 years). 6.2% of patients develop significant valvular disease after a median of 22 years post radiation. Aortic stenosis was most common valvular abnormality, mitral insufficiency was second most common. Valvular dysfunction more common in patients who were younger than the mean at diagnosis. Many (47% with AS) require valve replacement surgery.

17. Radiation-associated cardiovascular disease. Adams et al. Crit Rev Oncol/Hematol 2003; 45: 55-75. Thorough review of all cardiovascular complications of radiation therapy. Emphasizes that risk increases with length of time since exposure, and that all structures of the heart including pericardium, myocardium, valves, conduction system, and coronary arteries can be damaged by radiation.

18. Cardiovascular disease is currently a major cause of mortality for patients treated with radiation for Hodgkin lymphoma, following second malignancies and Hodgkin itself. Recognition of the potential cardiotoxicity of mediastinal radiation has led to improved techniques that are reducing the risk, but are unlikely to eliminate it completely.