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. 

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

Pearls • Notes • References • Production Team

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1. Due to the legacy effect, the incidence of RACD will continue to increase in the next few years.
   
2. When treating patients with a history of mediastinal radiation, we should remember to ask:     
   
   1. How much radiation was given?
      
   2. Could the heart have been exposed?
      
   
   
3. Radiation can affect every part of the heart by causing coronary artery disease (CAD), valvulopathy, myocardial disease, conduction disease, and pericardial disease.
   
4. Exposure to ~25-30 Gy or more significantly increases the risk but RACD can occur at lower doses.
   
5. Try to delay surgery as much as possible and do all you can in one operation to avoid re-operation in the future.
   
6. 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.
   
7. 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.
   

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 (<50 years-old) at the time of radiation
  
• High cumulative dose (>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 <50% confirmed by repeated imaging 2-3 weeks after the first diagnostic study or heart failure with preserved ejection fraction (HFpEF)
  
• HFpEF is more common than heart failure with reduced ejection fraction (HFrEF).
  
• Risk of myocardial disease increases with total radiation dose, fraction size, and volume of heart in the radiotherapy field.
  
• Benefit of heart failure pharmacotherapy in subclinical myocardial dysfunction remains unknown, however guideline directed medical therapy is recommended.
  
• While transplant is not broadly recommended due to poor outcomes and high risk of recurrent malignancy, this remains a consideration.
   
  

Conduction system disease

• The conduction system can sustain direct damage from radiation or can be affected by ischemia or fibrosis.
  
• 75% of long-term survivors who received mediastinal radiation have conduction defects on electrocardiogram (ECG).
  
• Acutely, we can see transient, nonspecific repolarization abnormalities.
  
• Long-term, patients may develop right bundle branch block (anteriorly located).
  
• High risk for ectopy, supraventricular ventricular tachycardia, ventricular tachycardia, and non-specific T-wave and ST-segment ECG changes.
  
• Inappropriate sinus tachycardia is a sign of extensive RACD.
  
• There are no specific treatments in RACD patients and providers should treat according to guidelines.
  
• Radiation and Devices
  
• Radiation can impair healing after device implantation
  
• Devices can malfunction
  
• Manufacturers advise that the lifetime dose a device can take is 5 Gray (this is when circuit board can start to malfunction)
  
• It is recommended to interrogate device before and after radiation therapy
  

Pericardial disease

• Radiation causes pericardial thickening, calcification, and fibrosis with subsequent constriction and effusion.
  
• It can be hard to diagnose constriction since many patients may have concomitant restrictive physiology.
  
• Patients may present with pericarditis, pericardial effusion, chronic pericardial disease, or cardiac tamponade.
  
• TTE, CT, and CMR are helpful to identify pericardial thickening, enhancement and septal shift.
  
• When in doubt, simultaneous right and left heart catheterization can help with the diagnosis.
  
• To treat constriction, we can try anti-inflammatory therapy first (in case of reversibility), then standard of care.
  

1. Desai MY, Windecker S, Lancellotti P, et al. Prevention, Diagnosis, and Management of Radiation-Associated Cardiac Disease: JACC Scientific Expert Panel. J Am Coll Cardiol. 2019;74(7):905-927. doi:10.1016/j.jacc.2019.07.006
   
2. Darby SC, Ewertz M, McGale P, et al. Risk of ischemic heart disease in women after radiotherapy for breast cancer. N Engl J Med. 2013;368(11):987-998. doi:10.1056/NEJMoa1209825
   
3. Wu W, Masri A, Popovic ZB, et al. Long-term survival of patients with radiation heart disease undergoing cardiac surgery: a cohort study. Circulation 2013;127:1476–85.
   
4. Liang JJ, Sio TT, Slusser JP, et al. Outcomes after percutaneous coronary intervention with stents in patients treated with thoracic external beam radiation for cancer. J Am Coll Cardiol Intv 2014;7:1412–20.
   
5. Heidenreich PA, Hancock SL, Lee BK, et al. Asymptomatic cardiac disease following mediastinal irradiation. J Am Coll Cardiol 2003;42:743–9.