Author + information
- Published online August 6, 2018.
- Frank A. Flachskampf, MD, PhD∗ ()
- Department of Medical Sciences, Uppsala University, Clinical Physiology and Cardiology, Akademiska Sjukhuset, Uppsala, Sweden
- ↵∗Address for correspondence:
Dr. Frank A. Flachskampf, Department of Medical Sciences, Uppsala University, Clinical Physiology and Cardiology, Akademiska Sjukhuset, 751 85 Uppsala, Sweden.
Patients with cancer are at increased risk from cardiovascular disease (1). Although much current attention focuses on the early recognition of heart failure in patients with cancer undergoing chemotherapy, we face also an increasing number of long-term cancer survivors who have late cardiovascular sequelae of prior cancer therapies. Survivors of Hodgkin disease treated by chemotherapy and radiation have been shown to have a 4- to 6-fold higher risk of cardiovascular disease than the general population (2). This includes excess coronary artery disease, heart failure, valve disease, and others. Breast cancer survivors who have undergone irradiation endure an increased risk from ischemic heart disease compared with the general population that is proportional to the radiation dose (3); they also have higher ischemic risk than breast cancer survivors who have not undergone irradiation (4). A restrictive cardiomyopathy-like left ventricular dysfunction with diastolic dysfunction, largely preserved ejection fraction, and reduced longitudinal strain has been described in Hodgkin lymphoma survivors after chest radiation, independent of concomitant anthracycline therapy (5,6). Valve disease has received less attention than other post-radiation sequelae. Fibrosis and calcification of the mitral and aortic valves, especially at the leaflet base and the “aorto-mitral curtain” (7), have been noted. In a recent retrospective study of Hodgkin disease survivors with and without prior chest radiation, 6 of 49 (12%) patients who underwent radiation developed moderate or severe aortic regurgitation, mitral regurgitation, or aortic stenosis, whereas only 1 of 29 patients without prior chest radiation developed more than mild aortic stenosis, and 1 more than mild aortic regurgitation (8). This patient group is plagued by a high mortality and presents unique challenges in surveillance and in balancing risks and benefits of treatment (9).
The study of Donnellan et al. (10), in this issue of iJACC sheds light on the thorny questions of presentation, progress, and outcome of aortic stenosis in survivors of chest radiotherapy. In a retrospective, longitudinal study, the authors identified 81 patients seen between 2001 and 2015 at the Cleveland Clinic who had had previous chest radiation and were diagnosed with initially asymptomatic, moderate aortic stenosis (area: 1.0 to 1.5 cm2). Chest radiation treatment, with doses between 40 and 60 Gy, had been delivered on average 22 years before the initial echocardiogram, mostly to treat lymphoma or breast cancer; about one-third had also received chemotherapy. They were included in the study group if they had at least 2 serial echocardiograms with a minimal interval of 1 year. Furthermore, the 81 patients were compared with an age- and sex-matched group of 162 patients with asymptomatic moderate aortic stenosis of similar aortic valve area and gradient who had not had previous chest radiation. Follow-up (mean duration, 6.6 years) was obtained in both groups regarding aortic valve replacement (AVR) and survival, with an attempt to classify cause of death from chart review as “cardiopulmonary,” which included sudden cardiac death, or not cardiopulmonary, which included recurrent malignancy or noncardiac organ failure. This somewhat unorthodox deviation from the typical division into cardiac and noncardiac seems justifiable given the frequent uncertainty in post-radiation patients as to “true” cause of death when cardiac problems (e.g., heart failure) coexist with pulmonary fibrosis or recurrent pleural effusions.
The following 5 important findings of the study deserve emphasis:
1. The post-radiation patients had a very low mortality from malignancy; just 1 of 81 died of a recurrent malignancy. It would therefore have been wrong to deny or delay treatment of aortic stenosis on the grounds that recurrence of malignancy might be expected.
2. Surprisingly, the progression rate of aortic stenosis, evaluated by valve area and gradient, did not differ substantially in the 2 groups. At slightly <0.1 cm2/year, they were well in the range known from “ordinary” moderate-to-severe aortic stenosis progression (11). Both started at baseline with valve areas very close to the “severe” range (mean 1.05 and 1.04 cm2). Post-radiation patients developed throughout the serial evaluation slightly lower areas with slightly lower gradients, mediated by (significantly) lower stroke volumes when compared with nonradiation control subjects. Ejection fraction was not different and largely normal in both groups. Thus, post-radiation patients seem to develop preferentially a low-flow, low-gradient type of aortic stenosis with preserved ejection fraction, which might be ascribed to the radiation-induced restrictive left ventricular functional impairment (5,6) and may contribute to their worse prognosis. However, progression of aortic stenosis was not accelerated in these patients and it may be inferred that the underlying radiation-related mechanisms leading to valve stenosis may be operative mainly at earlier stages.
3. Post-radiation patients were more likely to develop symptoms, developed them earlier, and underwent AVR more often than the control group without prior radiation (80% vs. 50%, respectively). Dyspnea was the leading symptom in the vast majority of patients undergoing AVR, with similar frequency in both groups. It can be expected, though, that dyspnea developed earlier and to a higher degree in post-radiation patients, since radiation profoundly affects lung function, as documented by substantially decreased baseline pulmonary function indexes in this group. Of interest, coronary artery disease, which is a known sequela of radiation, was only modestly more often documented in the post-radiation group than in the control group (62% vs. 49%, respectively; p = 0.05), and angina was a rare symptom in both groups. Further, excluding patients with known obstructive coronary artery disease from the analysis did not fundamentally change the results of the study: prior radiation was associated with higher mortality and AVR with lower mortality. This is important because coronary artery disease is known to affect patients with Hodgkin lymphoma after radiation (2) and might explain by itself the higher mortality of post-radiation patients. The ambiguity of the endpoint “cardiopulmonary death” in the present study, however, ultimately makes it uncertain how many deaths were due to coronary artery disease.
4. In spite of equivalent aortic stenosis progression, the mortality in the post-radiation group was 4-fold higher (32 of 81) than in the no-radiation group (17 of 162). The difficulty of thoracic surgery after chest radiation is well recognized (9,12). The same authors have earlier published data on AVR in patients with and without previous chest radiation (13) confirming substantially higher in-hospital and 6-year mortality in the first group. Whether this increased operative risk might be mitigated by transcatheter intervention is not known, but appears likely and worth exploring.
5. On the other hand, AVR did confer a survival benefit not only in “ordinary” aortic stenosis patients reaching the stage of severity and symptoms calling for intervention, but also in the post-radiation patients; however, as said, at a higher cost of morbidity and mortality. Of course, this study did not compare outcomes of intervention versus conservative therapy in a prospective, controlled fashion, and therefore, possibly, the patients not receiving operative therapy were sicker from the outset and found not to be good surgical candidates.
In summary, the study of Donnellan et al. (10) offers important data on the course and the outcomes of aortic stenosis in late survivors of chest radiation. The analysis is naturally limited by the retrospective and selective nature of the study and other difficulties arising from the complex morbidity of the patients, in particular the uncertainty regarding cause of death in many patients. Nevertheless, the study is a valuable and welcome contribution to the management of these particularly complex and fragile patients.
↵∗ Editorials published in JACC: Cardiovascular Imaging reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Imaging or the American College of Cardiology.
Dr. Flachskampf has reported that he has no relationships relevant to the contents of this paper to disclose.
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