CardioNerds (Dr. Patrick Azcarate, Dr. Teodora Donisan, and Amit Goyal) discuss Radiation-Associated Cardiovascular Disease (RACD) with Dr. Eric Yang, cardio-oncologist, assistant professor of medicine, and associate fellowship program director at UCLA. RACD is a consequence of radiation treatment for various mediastinal tumors (breast, lung, lymphoma). It is the second most common cause of morbidity and mortality in patients treated with mediastinal radiation for cancer. While novel techniques decrease radiation exposure during cancer treatment, the incidence is expected to increase because of historical practices and delayed onset of symptoms. The prevalence of RACD is difficult to estimate given under-recognition. Additionally, most of the data comes from patients treated with radiation techniques from decades ago. In this discussion we review every nook and cranny of RACD to help guide you the next time you see a patient with a history of chest radiation. Review this CardioNerds Case Report of radiation associated cardiovascular disease for more: Episode #169. Chest pain in a Young Man – “A Gray (Gy) Area” – UC San Diego. Audio editing by CardioNerds Academy Intern, student doctor Yousif Arif. This episode is supported by a grant from Pfizer Inc. This CardioNerds Cardio-Oncology series is a multi-institutional collaboration made possible by contributions of stellar fellow leads and expert faculty from several programs, led by series co-chairs, Dr. Giselle Suero Abreu, Dr. Dinu Balanescu, and Dr. Teodora Donisan. Pearls • Notes • References • Production Team CardioNerds Cardio-Oncology PageCardioNerds Episode PageCardioNerds AcademyCardionerds Healy Honor Roll CardioNerds Journal ClubSubscribe to The Heartbeat Newsletter!Check out CardioNerds SWAG!Become a CardioNerds Patron! Pearls and Quotes - Radiation-Associated cardiovascular disease Due to the legacy effect, the incidence of RACD will continue to increase in the next few years. When treating patients with a history of mediastinal radiation, we should remember to ask: How much radiation was given? Could the heart have been exposed? Radiation can affect every part of the heart by causing coronary artery disease (CAD), valvulopathy, myocardial disease, conduction disease, and pericardial disease. Exposure to ~25-30 Gy or more significantly increases the risk but RACD can occur at lower doses. Try to delay surgery as much as possible and do all you can in one operation to avoid re-operation in the future. For revascularization, percutaneous coronary intervention (PCI) is typically preferred over coronary artery bypass grafting (CABG) but the choice should be individualized in consultation with a multidisciplinary heart team experienced in the management of RACD. In general, for aortic valve disease, transcatheter replacement is recommended over surgical aortic valve replacement. For mitral valve disease, surgical replacement is recommended over repair. Every decision should be made with a heart team approach and made unique to that specific patient. Show notes - Radiation-Associated cardiovascular disease Notes were drafted by Dr. Patrick Azkarate. 1. Understand the pathophysiology of RACD Ionizing radiation has the potential to damage DNA. Both normal cells and cancer cells get damaged, but cancer has less effective DNA repair mechanisms and therefore malignant cells are more vulnerable to radiation therapy. After radiation causes acute damage, this sets off an inflammatory cascade leading to myofibroblast activation, fibrosis and collagen deposition, and subsequent stiffening of the myocardium and vessels. 2. What may increase one’s risk of developing RACD? Young age (30 Gy) or high dose of radiation fractions (2 Gy/day) Anterior or left chest radiation (breast cancer, lung cancer, lymphoma) Pre-existing cardiovascular disease Tumor in or next to the heart Concomitant chemotherapy (e.g. anthracyclines) 3. What are some techniques being used to reduce radiation exposure? Shielding Respiratory gating techniques (e.g. deep inspiratory breath-hold, activated breathing control) Smaller repeated fractions Narrow tangential beams Proton therapy 4. What are prevention and screening strategies for RACD? Annual history and physical examinationTreat pre-existing conditionsScreen for RACD (myocardial, valvular, pericardial, CAD, or conduction system disease)5 years post-exposure, screen for CAD and consider stress test every 2 years10 years post-exposure, screen for valvular heart disease with an echocardiogram every 2 years1 5. Discuss diagnosis and management of specific complications of RACD CAD The risk of radiation induced CAD (RICAD) is 7.5% per Grey Unit (Gy). The risk is roughly constant, begins several years after exposure, and persists for at least 2-3 decades (50% of excess ischemic events occurring 10 years after RT).2 Radiation causes inflammatory plaque with high collagen and fibrin content, similar to accelerated atherosclerosis. Angiographic characteristics: Ostial or proximal Anterior and central (predominantly affecting the left anterior descending and the right coronary arteries) Severe, diffuse Long, smooth, concentric, and tubular Treatment: CABG vs PCI While there are no head-to-head trials comparing CABG vs PCI in patients with RICAD, it is known that compared to the general population, following CABG they have worse outcomes (increased risk of wound dehiscence, infection, graft failure, and death).3 The data for PCI is mixed but most recently have shown that patients with RICAD undergoing PCI have similar outcomes compared to patients without radiation exposure.4 Unless there is an additional indication for surgery, PCI for chronic CAD usually preferred. If multi-vessel CAD or higher Syntax score (≥ 22) consider CABG. Other considerations might guide percutaneous vs surgical revascularization Porcelain aorta Fibrotic bypass grafts (internal mammary artery) in the radiation field Multi-valvular disease Valvular disease Radiation causes progressive valve thickening and calcification leading to valve leaflet retraction, followed by regurgitation and then stenosis. Patients usually become symptomatic 1-2 decades after radiation exposure (later than CAD). Prevalence of aortic regurgitation (AR) at 10 years is 4% and at 20 years is 60%. The prevalence of aortic stenosis (AS) at 10 years 0% but at 20 years: 16% Mitral regurgitation (MR) and AR are the most common and occur due to leaflet retraction. These ultimately progress to stenosis. MR is the most common reason for surgery. Echocardiogram is done to evaluate the valves. Surrounding structures may show calcification, such as the annulus, subvalvular apparatus, or aorta-mitral curtain (a hallmark of previous heart irradiation which is associated with mortality in patients undergoing cardiac surgery). Management decisions are complex, depends on the valvular lesion(s) involved, and should be guided by a heart team approach. For aortic valve disease, TAVR is preferred over SAVR (unless there is another indication for surgery or there is excess risk for coronary obstruction or annular rupture). If SAVR is pursued, usually try to replace all valves (even if one is just mild to moderate) to avoid re-operation. For the mitral valve, data is mixed between surgical vs transcatheter approaches. In general, if surgery is indicated then the valve is replaced and not repaired (irradiated valve tissue is fibrotic and calcified) Given increased risk of reoperation, mechanical prostheses may be appealing, especially for younger patients. If there are contraindications to anticoagulation, then a bioprosthesis should be used. General cardiothoracic surgery principles in patients with RACD Worse long-term outcomes compared to age and sex-matched controls undergoing similar procedures Reoperation portends significantly higher risk compared to non-RACD patients Delay surgical intervention as long as possible Address all issues with a complete operation the first time Surgical planning may involve cardiac magnetic resonance imaging (CMR) to look for fibrosis, computer tomography (CT) to identify calcified structures (intra- and extra-cardiac), transthoracic echocardiogram (TTE), right and left heart catheterization to evaluate for restriction vs constriction, coronary angiogram. Myocardial disease In terms of pathophysiology, radiation causes an acute inflammatory cascade, then a pro-fibrotic milieu which leads to myocardial fibrosis and reduced microvascular proliferation and density. RACD-related myocardial dysfunction is defined as 10% decrease in LVEF to a value

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