Radiation-Induced Vascular Disease-A State-of-the-Art Review

Abstract

Since the 1990s, there has been a steady increase in the number of cancer survivors to an estimated 17 million in 2019 in the US alone. Radiation therapy today is applied to a variety of malignancies and over 50% of cancer patients. The effects of ionizing radiation on cardiac structure and function, so-called radiation-induced heart disease (RIHD), have been extensively studied. We review the available published data on the mechanisms and manifestations of RIHD, with a focus on vascular disease, as well as proposed strategies for its prevention, screening, diagnosis, and management.

Keywords: cancer; cardio-oncology; coronary artery disease; peripheral arterial disease; radiation therapy.

Figure 1

Ionizing radiation causes cell death, both parenchymal and vascular, by multiple mechanisms. Historically, the direct cytotoxicity of radiation was the first identified pathway leading to tissue injury. More recently, another pathway involving inflammation has been identified. A third pathway has been studied in the last few years that implicates the innate immune response including bone marrow-derived cells (BMDC) and both M1, and M2 macrophage (MΦ) in resultant tissue damage. Arrows represent influence of one mechanism on another and suggest potential targets for interfering with the process. Cell death and tissue injury result in accelerated atherosclerosis over 1 to 2 decades that may also result in parenchymal injury to the myocardium and the valves resulting in fibrosis [Modified from (8)].

Figure 2

(A,B) Histologic section of the left circumflex coronary artery from a 67-year-old patient who received radiation therapy for carcinoma of the lung 7 years prior to sudden death. Low power view (A) demonstrates severe adventitial fibrosis (*) and focally extensive destruction of the media (arrowheads) with intimal plaque (p) causing 75% luminal narrowing. The plaque consists mostly of necrotic core that is rich in cholesterol clefts. Note a markedly thickened adventitia (*) at high power (B) with medial destruction (arrowheads) [Reproduced with permission from (9)]. (C,D) Right coronary artery from a 62-year old man with mediastinal radiation therapy for Hodgkin's disease 25 years antemortem. At autopsy, there was 70% lumen area narrowing (C) with intraplaque hemorrhage (arrow), marked adventitial fibrosis (*), and focal destruction of the arterial media (arrowheads). The boxed in area in (A) is shown at higher magnification in (B); note medial disruption (arrowheads) and replacement by smooth muscle cells in a collagenous matrix [Reproduced with permission from (14)].

Figure 3

Case presentation 1 (A,B) 53-year-old with unstable angina who received mantle radiation 45 years ago for Hodgkin's lymphoma. Severe ostial RCA (arrow) stenosis (A) successfully treated with PCI (B). Case presentation 2 (C,D) 33-year-old with class III angina who received radiation 7 years ago for thymic carcinoma. Severe diffuse LAD disease (arrow) successfully treated with PCI. Case presentation 3 (E,F) 75-year-old with severe symptomatic aortic stenosis who received extensive mantle radiation for esophageal cancer 15 years ago. Diffuse obstructive atherosclerosis involving the ostial left main (E, black arrow), the obtuse marginal (OM) branch (E, white arrow) and chronic totally occluded right coronary artery \(RCA) (F, arrow). The patient was managed with transcatheter aortic valve replacement (TAVR) and PCI of the left main and the OM.

Figure 4

Recommended screening for patients with RICAD. RICAD, radiation-induced coronary artery disease; RT, radiation therapy; CCTA, coronary computed tomography angiography; TTE, transthoracic echocardiogram.