Radiation-Induced Coronary Artery Disease in Young Patients.

Exposure to radiotherapy has been shown to accelerate myocardial damage or injury to the cardiac vasculature. Accelerated coronary artery disease (CAD) is one of the main manifestations of cardiac disease in patients who undergo mediastinal radiation therapy. We present the cases of three young patients who developed severe CAD secondary to remote mediastinal radiotherapy.

INTRODUCTION

Heart disease and cancer are the two most common causes of death in the world. Radiotherapy has led to the successful treatment of multiple malignancies, often leading to a definite cure. Therefore, it is imperative to recognize subsequent cardiovascular disease secondary to cancer treatment. With improving survival rates, delayed cardiac complications have been recognized, with one of the most severe being radiation-induced coronary artery disease (RICAD).

CASE PRESENTATIONS

Case 1

We present the case of a 31-year-old woman with a history of Hodgkin's lymphoma who presented to our institution with a 1-week history of oppressive chest discomfort and dyspnea associated with minimal exertion. Eight years before evaluation, she underwent a successful therapy of her lymphoma with 34 courses of radiation. She had no family history of premature CAD. Physical examination was remarkable for signs of congestive heart failure. A transthoracic echocardiogram revealed a moderate left ventricular systolic dysfunction with a left ventricular ejection fraction (EF) of 35%. Left heart catheterization was performed and revealed a critical 99% occluded proximal left main coronary artery [Figure 1]. She underwent subsequent coronary artery bypass grafting with improvement of symptoms and is currently doing well.

Figure 1

Proximal left main coronary artery 99% occlusion in Case 1

Case 2

A 25-year-old man presented to our institution with a 1-year history of progressive dyspnea with exertion. He had received multiple courses of radiation 9 years before our evaluation for a spinal tumor. He had multiple hospitalizations throughout the year for bronchopneumonia and bronchial asthma exacerbations. He had no family history of premature CAD. On echocardiography, a mildly reduced left ventricular systolic function with estimated EF of 40% was identified as well as moderate aortic insufficiency with severe calcification of the aortic and mitral valves. Cardiac catheterization revealed 99% stenosis of the left main coronary artery [Figure 2]. The patient underwent coronary bypass grafting, but unfortunately died due to intraoperative complications.

Figure 2

Left main coronary artery 99% occlusion in Case 2

Case 3

A 30-year-old man with a history of Hodgkin's lymphoma presented with oppressive chest pain 10 h before arrival. He had received radiation therapy for the successful treatment of lymphoma about 15 years before presentation. Electrocardiogram (ECG) was remarkable for anterior ST-segment elevations. Left heart catheterization performed showed total occlusion of the proximal left anterior descending (LAD) artery and 90% occlusion at the proximal right coronary artery (RCA). The patient underwent emergent percutaneous transluminal coronary angioplasty with stent placement at the LAD and subsequent staged RCA stenting.

DISCUSSION

Accelerated CAD is one of the main manifestations of cardiac disease in patients treated with mediastinal radiation therapy.[1] In fact, RICAD is a major contributor to cardiovascular mortality in cancer survivors. The presence of traditional cardiovascular risk factors significantly increases the incidence of RICAD.[2] This RICAD risk persists long after the initial exposure to radiation. Specifically, in some cases of patients treated with radiation for Hodgkin's lymphoma, RICAD risk can appear up to four decades after therapy.[3]

From a mechanistic point of view, individuals exposed to radiation may exhibit myocardial damage or endothelial injury. The extent of damage depends on both radiation dose and the irradiated volume.[4] In terms of RICAD, arterial narrowing generally occurs proximally in the affected vessel and often involves the coronary ostia.[5] The pathogenesis of RICAD involves several common pathways including microvascular damage, inflammation, and fibrosis; however, exact mechanisms are poorly understood.

RICAD may present as early as 5 years following treatment.[678] Recent expert consensus recommends baseline resting echocardiographic evaluation in all patients before initiating radiotherapy, with repeat testing 5 years after therapy for higher risk patients. Its value, however, is limited to resting wall-motion abnormalities.

In asymptomatic patients, moderate-to-severe hypokinesia has been found in up to 17% of survivors with Hodgkin's disease treated with mediastinal irradiation (approximately 35 Gy).[9] However, a hypokinetic ventricular region is not necessarily characteristic of the presence of CAD, but could reflect, to some extent, myocardial disease process.

In these patients, it might be reasonable to consider noninvasive stress imaging. Due to its higher specificity compared with exercise, ECG, stress echocardiography, or stress cardiac magnetic resonance (CMR) is preferred. Heidenreich et al., using stress echocardiography, reported a 2.7% prevalence of severe three-vessel or left main CAD, and a 7.5% prevalence of coronary stenosis >50%.[9] In this study, positive predictive values of 80% and 87% were reported for detection of 70% and 50% coronary stenosis, respectively.[9] Furthermore, after a median of 6.5-year follow-up, 23 patients developed symptomatic CAD, including 10 who sustained an acute myocardial infarction.[10] The risk of a cardiac event after screening was related to, among other things, the presence of resting wall-motion abnormalities on echocardiography and ischemia on stress testing.

Hodgkin's lymphoma patients were studied after 20 years' postexposure to radiotherapy using CMR, and pathologic findings were seen in approximately 70% of patients.[11] CMR may be used as a screening measure, but due to the postexposure length in the study, the number of patients, and the failure to follow-up on patient's morbidity and mortality, further studies are needed to determine its value on screening.

Although coronary computerized tomography (CT) angiography and calcium scores are useful tools for evaluation of RICAD, complementary physiologic tests might be necessary in selected patients. Larger studies are needed to better define the role of coronary CT angiography and calcium scores and to establish an algorithm for evaluation and treatment of these patients.[12] Furthermore, clinical worry of excessive and cumulative radiation may further prevent widespread screening using CT.

Concerning nuclear imaging, inducible perfusion abnormalities have not necessarily correlated with significant CAD, which may make perfusion single-photon emission computer tomography less reliable for screening RICAD.[1013]

CONCLUSION

In summary, subclinical cardiac damage is known to occur in a significant number of cancer survivors. Although modification in radiation protocols remains as an important measure in diminishing RICAD, special attention is required when following young patients as they are at high risk of developing cardiac and coronary manifestations from radiation therapy. Though the role of routine stress test and imaging in identifying high risk patients or predicting future cardiovascular events remains to be determined, physicians must be aware of these complications and individualize diagnostic and treatment options accordingly.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.