CardioNerds (Amit Goyal and Daniel Ambinder) join Dr. Patrick Azcarate and Dr. Antoinette Birs from the University of California San Diego along with a guest host Dr. Christine Shen from Scripps Health for a hike along Torrey Pines. They discuss a case of a 30-year-old man with a history of malignant thymoma status post two partial lung resections and radiation for pleural/pulmonary metastasis, as well as a history of myasthenia gravis on rituximab, and Ig deficiency on IVIG presents with progressive exertional chest pain. We focus on the differential diagnosis of patients with a history of chest radiation exposure and dive into the complex management and surveillance for patients with radiation associated cardiac disease (RACD). The E-CPR is provided by Dr. Milind Desai (multimodality cardiovascular imaging expert, Director of Clinical Operations, Director of Center for HCM, Medical Director for Center for Aortic Diseases, and Medical Director for Center for Radiation Heart Disease at the Cleveland Clinic).

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Disclosures: None
Jump to: Pearls – Notes – References

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Episode Teaching
Pearls – Heart Failure with Autism Spectrum Disorder

1. Radiation-associated cardiac disease (RACD) is a heterogeneous disease that can manifest several years, or decades following radiation exposure to the chest and is associated with high morbidity and mortality. Given the non-specific or vague symptoms, one of the greatest challenges for this patient population may be diagnosing RACD which requires high clinical suspicion.
     
   
2. In patients with a history of chest radiation, we should remember to ask three important questions: 1. What was the total dose of radiation given? 2. How long ago was radiation therapy administered? 3. Was the heart exposed?
   
3. A cumulative dose of >30 Gray (Gy) chest radiation significantly increases the risk of RACD long-term, but cardiac damage can occur at even lower doses. 
   
4. Effects from chest radiation can take years to become clinically detectable. Screening for radiation induced coronary artery disease with stress testing should start 5 years following XRT and in low-risk patients (without risk factors for typical coronary artery disease) and continue at 5-year intervals, and 2-year intervals in high-risk patients. Valvular heart disease surveillance should begin 10 years post XRT and can be accomplished with echocardiogram. 
   
5. Regarding revascularization planning, a Heart Team approach is recommended. However, percutaneous intervention is preferred over bypass surgery in most cases.
   

Notes – Heart Failure with Autism Spectrum Disorder

1. What is Radiation-Associated Cardiac disease (RACD)?

A spectrum of disease that can affect any part of the heart and typically develops anywhere from 5 to 20 years after radiation. It may present with non-specific or vague symptoms. Manifestations include myocarditis, pericarditis (typically early in the course) and well as long term sequela such as myocardial fibrosis, valvular heart disease (regurgitation or stenosis), pericardial disease, vasculopathy (CAD), conduction system disease. Radiation may impact any tissue of the heart:

• Vascular: microvascular, coronary artery disease, macrovascular (ascending aorta)
  

• Valvular: has a longer latency ~10-20 years with the left sided valves being more commonly affected; Aorto-mitral curtain thickening/calcification is a hallmark of previous heart radiation and associated with higher mortality 
  

• Conduction: Sick sinus syndrome, AV nodal block, atrial fibrillaiton; infra-nodal conduction disease and RBBB are common.
  

• Myocardial: fibrosis in the myocardium leading to HFpEF, or HFrEF; XRT + anthracycline is thought to be synergistic.
  

• Pericardial: chronic pericardial inflammation, scarring, calcification, restrictive physiology. Constrictive pericarditis from radiation has a particularly poor prognosis given often concurrent myocardial involvement.
  

2. What is the Pathophysiology of RACD?

The severity of disease is related to total radiation dose, fraction size and volume of the heart in the radiotherapy field. The resulting cell damage leads to activation of the acute inflammatory cascade and pro-fibrotic milieu.

3. What are the additional risk factors for RACD?

• Therapy-related risk factors:
  
  • Net dosage (dependent on cancer type and tumor site) > 30Gy received by the heart.
    
  • Proximity to heart to the radiation field.
    
  • Concomitant chemotherapy – anthracyclines may particularly have a radiation sensitizing effect, thereby increasing the risk of RACD.
    
  
  
• Patient-related risk factors:
  
  • Life expectancy – younger age at the time of radiation and a good cancer prognosis, as these patients may have more time to manifest the longer-term sequelae of RACD.
    
  • Presence of traditional cardiovascular risk factors
    
  
  

4. How common is RACD? 

• RACD is most often seen in those receiving chest radiation for breast cancer (particularly left sided), Hodgkin Lymphoma, lung cancer and esophageal cancers.
  
• There is a distinct population presenting with latent symptoms from treatment with wide-field radiation of Hodgkin lymphoma that was more commonly practiced 20-40 years ago.
  
• Prevalence of radiation associated cardiomyopathy is ~10% based on population studies although difficult to determine given the heterogeneity of presentation and under-recognition. 
  
  • Valvular abnormalities in 7-39% at 10 years, 12-60% at 20 years 
    
    • Mitral and aortic valves are most affected; symptoms arise 1-2 decades after radiation and later than CAD; AR in 60% vs 4% at 20 years vs 10 years post treatment. 
      
    • Aorto-mitral curtain thickening/calcification is a hallmark of previous heart irradiation, and its extent is strongly associated with mortality in subjects undergoing cardiac surgery. 
      
    
    
  • Radiation induced coronary vasculopathy has a prevalence of 85%. 
    
  
  

5. What is Radiation induced coronary artery disease (RICAD)?  

• Pathophysiology: inflammatory plaque, with accumulation of myofibroblasts, resulting in intimal proliferation with aggregation of lipid-rich macrophages; high collagen and fibrin content like accelerated atherosclerosis; doses of > 0.50 Gy can initiate atherosclerosis and affects micro and macro vasculature.
  
• Angiographically: Ostial or proximal epicardial coronary lesions of the anterior and central vessels are most common (left main trunk, proximal LAD, mid diagonal, or RCA) given the location of the heart in the chest.
  
• Lesions are often severe, proximal, and diffuse. They are typically long, smooth, concentric, and tubular and may require intravascular ultrasound (IVUS) for diagnosis as they can appear normal on coronary angiography (lumenography).
  

6. What are different types of radiation?  

• 3D vs Intensity modulated radiation therapy (IMRT): both are x-ray-based radiation
  
• Proton therapy: Unlike x-rays which go all the way through the body, protons are charged and can go to a specified depth causing less scatter radiation
  

7. What techniques may be used to reduce cardiac exposure to the radiotherapy field?

• ABC device, breathing techniques such as deep inspiratory breath hold (DIBH) which pulls the heart more inferiorly in the chest and allows treatment of the upper mediastinum with less cardiac exposure, shielding 
  

8. What are the surveillance recommendations? 

• The risk of RACD is 7.5% per Grey Unit (Gy) and is constant, beginning several years after exposure and persists for at least 2-3 decades (>50% of excess ischemic events occurring >10 years after RT). Those who will receive >30 Gy may warrant cardiology consultation prior to treatment
  
  • Screening for CAD: 5 years after radiation exposure
    
  • Screening for valvular disease: 10 years after exposure with 5-year surveillance intervals 
    
  
  

9. What is the recommended approach for revascularization for RICAD?

• PCI is generally preferred if feasible over bypass given chest radiation as this patient group has increased risk of complications from bypass surgery related to severely calcified aorta, possible radiation injury to the IMAs, restrictive lung disease, difficulty weaning patient from a ventilator, and lack of intra-thoracic lymphatics 
  

References – Heart Failure with Autism Spectrum Disorder

1. Desai MY, Jellis CL, Kotecha R, Johnston DR, Griffin BP. Radiation-Associated Cardiac Disease: A Practical Approach to Diagnosis and Management. JACC Cardiovasc Imaging. 2018 Aug;11(8):1132-1149. doi: 10.1016/j.jcmg.2018.04.028. PMID: 30092970. https://www.jacc.org/doi/abs/10.1016/j.jcmg.2018.04.028
   

• Desai MY, Windecker S, Lancellotti P, Bax JJ, Griffin BP, Cahlon O, Johnston DR. Prevention, Diagnosis, and Management of Radiation-Associated Cardiac Disease: JACC Scientific Expert Panel. J Am Coll Cardiol. 2019 Aug 20;74(7):905-927. doi: 10.1016/j.jacc.2019.07.006. https://www.jacc.org/doi/full/10.1016/j.jacc.2019.07.006
  

• Cuomo JR, Javaheri SP, Sharma GK, Kapoor D, Berman AE, Weintraub NL. How to prevent and manage radiation-induced coronary artery disease. Heart. 2018 Oct;104(20):1647-1653. doi: 10.1136/heartjnl-2017-312123. Epub 2018 May 15. PMID: 29764968; PMCID: PMC6381836. https://heart.bmj.com/content/104/20/1647.long
  

• Wu W., Masri A., Popovic Z.B.et al. : “Long-term survival of patients with radiation heart disease undergoing cardiac surgery: a cohort study”. Circulation 2013; 127: 1476. https://www.ahajournals.org/doi/epub/10.1161/CIRCULATIONAHA.113.001435
  

CardioNerds Case Report Production Team

• 
  Karan Desai, MD
  
  
• 
  Amit Goyal, MD
  
  
• 
  Daniel Ambinder, MD