Radiation Induced Coronary Artery Disease

Article Author:
Kristen Brown
Article Editor:
John Richards
Updated:
1/17/2019 8:30:27 AM
PubMed Link:
Radiation Induced Coronary Artery Disease

Introduction

Radiation-induced coronary artery disease (RICAD) is the second most common cause of morbidity and mortality in mainly oncology patients treated with radiation therapy (RT). With increased rates of oncologic treatment, the rates of RICAD are increasing in parallel. This article will discuss in detail the etiology of RICAD, epidemiology, clinical presentation, evaluation, screening recommendations, treatment options, differential diagnosis, and complications.

Etiology

RICAD primarily is caused by prior mediastinal radiation exposure or therapy. Radiation exposure can be natural or iatrogenic. Most natural exposure does not result in high levels of radiation at a single time, and sources of this type of exposure include radon gas in the ground seeping into basements and crawlspaces, [1] and cosmic rays from sun exposure and high altitude. More often patients are exposed to radiation through medical imaging or therapy, which explains the high incidence of RICAD in post-RT patients.  Risk of RICAD increases with frequency and duration of radiation exposure, regardless of source.

Epidemiology

RICAD is one of the most feared complications of radiation exposure to the chest. The most common conditions associated with RICAD are breast cancer (BC) and Hodgkin's Lymphoma (HL). HL survivors treated with radiation therapy have a 2.5 times higher risk of coronary artery disease (CAD), whereas BC patients only have 0.25 times higher risk.[2] [3] [4] [5] [6] The reason for this is HL patients receive a higher dose of RT than BC patients, which represents a dose-dependent effect on the development of RICAD. [7]  Even though BC CAD rates are lower, the incidence of CAD increases linearly with time. [8] Interestingly, radiation exposure to the chest at younger ages portends a lower risk of RICAD compared to older populations. Initially, the incidence of RICAD following left-sided RT was higher than right-sided RT. However, more recently there have been reports of higher rates of RICAD following right-sided RT, specifically involving the right coronary artery. [9] [10] 

Pathophysiology

The pathophysiology of RICAD is poorly understood. One prevailing theory is that it is caused by both microvascular and macrovascular endothelial damage in coronary arteries. [11] Radiation particles (ions) cause the initial cellular injury initiating a proinflammatory state. The NF-kB pathway has been considered one factor leading to long-term oxidative stress. [7] Endothelial injury also results in loss of endothelium-derived vasodilators resulting in vasoconstriction. Thrombomodulin, a pro-thrombotic factor, combined with endothelial injury results in a pro-thrombotic vasoconstrictive state with hemostasis. Fibrosis then begins at the microvascular level with progression to larger vessels and predisposes to plaque formation. [12] Occlusion and/or compromised coronary arterial blood flow may result in myocardial ischemia and infarction.

Histopathology

The coronary arteries are particularly vulnerable to RT of the chest. These arteries consist of three wall layers (tunica intima, media, and adventitia) of which only the tunica intima comprises the endothelium. [13] Endothelial cells respond to RT in a variety of ways. Depending on the radiation dose, cells can develop a range of problems from DNA breakage to apoptosis. [14]  On a histologic level, RT results in a variety of tissue damage, such as cellular loss, an influx of inflammatory cells and markers, and fibrin plaques in advanced disease-causing partial or complete occlusion.

History and Physical

The classic presentation of RICAD is typical chest pain in a young patient that has been formerly exposed to thoracic RT and has no risk factors for CAD. [15] Patients can also present in pulmonary edema, acute heart failure, or valvular disease with a new heart murmur. There may be decades between initial exposure to RT and symptoms of RICAD. Women and the elderly commonly present with atypical chest pain. The two most distinguishing characteristics that separate RICAD from acute coronary syndrome (ACS) is the age at presentation and history of RT. As with the history, the physical exam findings found in RICAD patients can be very similar to ACS. Hypertension and tachycardia may be present. The classic Levine sign, a clenched hand held over the chest, can also be seen in these patients as with ACS. RICAD patients may have dyspnea, lower extremity edema, bi-basilar pulmonary crackles, and jugular venous distension. Even with a history and physical, it can be challenging to identify the etiology of chest pain as RT can affect all exposed thoracic tissues resulting in irritation and/or inflammation, including the pericardium, lung parenchyma, pleura, esophagus, and other structures of the chest.

Evaluation

Evaluation is similar to that for ACS. For patients with chest pain, obtain an electrocardiogram, troponin, B-type natriuretic peptide (BNP), D-dimer, and echocardiogram.  If low risk for obstructive CAD, consider a cardiac stress test. If high risk, coronary angiography is indicated. [7] Of note, RICAD affects the region of radiation exposure. Right-sided radiation exposure mainly affects the right coronary artery, whereas left-sided exposure mostly affects the left main and anterior descending artery. 

Treatment / Management

Treatment of RICAD is similar to ACS, which includes pharmacotherapy, percutaneous coronary intervention (PCI), and surgical revascularization. In animal models, captopril [16] and simvastatin [17] decreased the effects of a radiation-induced injury. There is also evidence to support colchicine as prophylactic therapy for RICAD. [18] In addition to treating RICAD, it is important to include regular surveillance for radiation-induced injury to the heart and other mediastinal structures. [7] Annual evaluations and risk factor modification are recommended. Laboratory tests to be monitored include troponin, BNP, and C-reactive protein. The American Society of Echocardiography and European Association of Cardiovascular Imaging recommend a pre-radiation echocardiogram and a repeat in 10 years followed by 5-year intervals. [19]

Differential Diagnosis

The differential for RICAD is similar to the differential list for ACS as both present the same. A list of potential but not all-inclusive differential diagnosis are listed below:

  • Acute coronary syndrome
  • Acute pericarditis
  • Pulmonary embolism
  • Coronary vasospasm
  • Cardiac syndrome X
  • Pulmonary disease
  • Costochondritis
  • Kawasaki disease
  • Myocarditis
  • Esophagitis

Prognosis

RICAD has a good prognosis with current medical therapy.

Complications

Complications of RICAD are similar to CAD with a few added extras list below:

  • Myocardial ischemia/infarction
  • Dysrhythmia
  • Valvular disease
  • Aortic disease
  • Aortic dissection
  • Heart failure
  • Sudden cardiac death

Consultations

It is recommended that a Cardiology consult be placed.

Deterrence and Patient Education

Patient education starts with the initial discussion prior to the initiation of RT. After informed discussion, patients should be allowed the option to defer or dismiss RT. Other options for treatment should be offered. Sources of natural radiation exposure may also be discussed.

Pearls and Other Issues

The workup and diagnosis of RICAD is identical to that for CAD and ACS. [7]

Enhancing Healthcare Team Outcomes

RICAD may be overlooked as a potential diagnosis. As healthcare providers, it is essential to arrive at the appropriate diagnosis. Including a multi-disciplinary team approach can sometimes aid in narrowing the diagnosis. Members should include but are not limited to the Primary Care Physician, Cardiologist, Oncologist, nurse, and family members.


References

[1] Raghunathan D,Khilji MI,Hassan SA,Yusuf SW, Radiation-Induced Cardiovascular Disease. Current atherosclerosis reports. 2017 May;     [PubMed PMID: 28315200]
[2] Andersen R,Wethal T,Günther A,Fosså A,Edvardsen T,Fosså SD,Kjekshus J, Relation of coronary artery calcium score to premature coronary artery disease in survivors >15 years of Hodgkin's lymphoma. The American journal of cardiology. 2010 Jan 15;     [PubMed PMID: 20102909]
[3] van Nimwegen FA,Schaapveld M,Cutter DJ,Janus CP,Krol AD,Hauptmann M,Kooijman K,Roesink J,van der Maazen R,Darby SC,Aleman BM,van Leeuwen FE, Radiation Dose-Response Relationship for Risk of Coronary Heart Disease in Survivors of Hodgkin Lymphoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2016 Jan 20;     [PubMed PMID: 26573075]
[4] Darby SC,Ewertz M,McGale P,Bennet AM,Blom-Goldman U,Brønnum D,Correa C,Cutter D,Gagliardi G,Gigante B,Jensen MB,Nisbet A,Peto R,Rahimi K,Taylor C,Hall P, Risk of ischemic heart disease in women after radiotherapy for breast cancer. The New England journal of medicine. 2013 Mar 14;     [PubMed PMID: 23484825]
[5] van Leeuwen-Segarceanu EM,Bos WJ,Dorresteijn LD,Rensing BJ,der Heyden JA,Vogels OJ,Biesma DH, Screening Hodgkin lymphoma survivors for radiotherapy induced cardiovascular disease. Cancer treatment reviews. 2011 Aug;     [PubMed PMID: 21333452]
[6] Dunsmore LD,LoPonte MA,Dunsmore RA, Radiation-induced coronary artery disease. Journal of the American College of Cardiology. 1986 Jul;     [PubMed PMID: 3711522]
[7] DeZorzi C, Radiation-Induced Coronary Artery Disease and Its Treatment: A Quick Review of Current Evidence. Cardiology research and practice. 2018;     [PubMed PMID: 30410795]
[8] Takx RAP,Vliegenthart R,Schoepf UJ,Pilz LR,Schoenberg SO,Morris PB,Henzler T,Apfaltrer P, Coronary artery calcium in breast cancer survivors after radiation therapy. The international journal of cardiovascular imaging. 2017 Sep;     [PubMed PMID: 28342038]
[9] Rehammar JC,Jensen MB,McGale P,Lorenzen EL,Taylor C,Darby SC,Videbæk L,Wang Z,Ewertz M, Risk of heart disease in relation to radiotherapy and chemotherapy with anthracyclines among 19,464 breast cancer patients in Denmark, 1977-2005. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology. 2017 May;     [PubMed PMID: 28365142]
[10] Altınok A,Askeroğlu O,Doyuran M,Çağlar M,Cantürk E,Erol C,Beşe N, Dosimetric evaluation of right coronary artery in radiotherapy for breast cancer. Medical dosimetry : official journal of the American Association of Medical Dosimetrists. 2018 Aug 28;     [PubMed PMID: 30170990]
[11] Venkatesulu BP,Mahadevan LS,Aliru ML,Yang X,Bodd MH,Singh PK,Yusuf SW,Abe JI,Krishnan S, Radiation-Induced Endothelial Vascular Injury: A Review of Possible Mechanisms. JACC. Basic to translational science. 2018 Aug;     [PubMed PMID: 30175280]
[12] Armanious MA,Mohammadi H,Khodor S,Oliver DE,Johnstone PA,Fradley MG, Cardiovascular effects of radiation therapy. Current problems in cancer. 2018 Jul;     [PubMed PMID: 30006103]
[13] Virmani R,Farb A,Carter AJ,Jones RM, Comparative pathology: radiation-induced coronary artery disease in man and animals. Seminars in interventional cardiology : SIIC. 1998 Sep-Dec;     [PubMed PMID: 10406688]
[14] Rak J,Chomicz L,Wiczk J,Westphal K,Zdrowowicz M,Wityk P,Żyndul M,Makurat S,Golon Ł, Mechanisms of Damage to DNA Labeled with Electrophilic Nucleobases Induced by Ionizing or UV Radiation. The journal of physical chemistry. B. 2015 Jul 2;     [PubMed PMID: 26061614]
[15] Ruiz CR,Mesa-Pabón M,Soto K,Román JH,López-Candales A, Radiation-Induced Coronary Artery Disease in Young Patients. Heart views : the official journal of the Gulf Heart Association. 2018 Jan-Mar;     [PubMed PMID: 29876028]
[16] Wei J,Xu H,Liu Y,Li B,Zhou F, Effect of captopril on radiation-induced TGF-β1 secretion in EA.Hy926 human umbilical vein endothelial cells. Oncotarget. 2017 Mar 28;     [PubMed PMID: 28209920]
[17] Wilkinson EL,Sidaway JE,Cross MJ, Statin regulated ERK5 stimulates tight junction formation and reduces permeability in human cardiac endothelial cells. Journal of cellular physiology. 2018 Jan;     [PubMed PMID: 28639275]
[18] O'Herron T,Lafferty J, Prophylactic use of colchicine in preventing radiation induced coronary artery disease. Medical hypotheses. 2018 Feb;     [PubMed PMID: 29406998]
[19] Lee PJ,Mallik R, Cardiovascular effects of radiation therapy: practical approach to radiation therapy-induced heart disease. Cardiology in review. 2005 Mar-Apr;     [PubMed PMID: 15705258]