Summary
The number of studies demonstrating that right ventricular structure, function and mechanics are valuable predictors of cardiovascular and total morbidity and mortality in patients with a wide range of cardiovascular conditions is constantly increasing. Most studies that evaluated the influence of radiotherapy on the heart focused on left ventricular remodelling, which is why current guidelines only recommend detailed assessment of the left ventricle. Data regarding right ventricular changes in cancer patients treated with radiotherapy are scarce. Given that radiotherapy more often induces late cardiac impairment – unlike chemotherapy-induced cardiotoxicity, which is usually acute – it is quite reasonable to follow these patients echocardiographically for a long time (even for 20 years after initiation of radiotherapy). Investigations that have followed cancer survivors for at least 10 years after radiotherapy agree that right ventricular structure, systolic/diastolic function and mechanics are significantly impaired. The mechanisms of radiation-induced right ventricular remodelling are still unclear, but it is thought that fibrosis is the dominant factor in myocardial remodelling and vascular changes. Many factors may contribute to right ventricular impairment during and after radiotherapy: cumulative radiation dose; dose per treatment; delivery technique; radiation target (chest and mediastinum); and co-morbidities. In this review, we aim to provide a comprehensive overview of the potential mechanisms of radiation-induced right ventricular remodelling, and to summarize clinical studies involving radiotherapy-treated cancer patients.
Résumé
Les études ayant rapporté une valeur prédictive forte de la dysfonction ventriculaire droite sur la morbi-mortalité sont en nombre croissant dans la littérature. La majorité des études évaluant l’influence de la radiothérapie sur la fonction cardiaque ont été focalisées sur le remodelage ventriculaire gauche, raison pour laquelle les recommandations actuelles recommandent une évaluation détaillée des dimensions et de la fonction ventriculaire gauche. Les données concernant l’impact d’une radiothérapie chez des patients porteurs d’un cancer sur la fonction ventriculaire droite sont peu nombreuses. En prenant en considération le fait que la radiothérapie induit plus souvent une cardiotoxicité tardive, comparativement à la toxicité aiguë induite par les chimiothérapies anti-cancéreuses, il est raisonnable d’évaluer de façon prospective par échocardiographie au long cours les patients ayant eu une radiothérapie, jusqu’à 20 ans après ce traitement. Les études ayant évalué et suivi des patients porteurs d’un cancer ayant une ancienneté > 2 ans au décours de la radiothérapie concluent tant la structure que la fonction systolique et diastolique ventriculaire droite ainsi que la mécanique ventriculaire droite sont altérées de façon significative au décours d’une radiothérapie. Les mécanismes du remodelage ventriculaire droit induits par la radiothérapie sont inconnus mais il est considéré que la fibrose est le facteur prédominant du remodelage myocardique et des modifications vasculaires. De nombreux facteurs pourraient contribuer à l’altération du ventricule droit pendant et au décours d’une radiothérapie : la dose cumulée, la dose utilisée, les techniques d’administration, la cible de la radiation thorax ou médiastin, ainsi que les comorbidités sont autant de facteurs mis en avant dans les différentes études. Cette revue générale apporte un éclairage sur les mécanismes potentiels du remodelage ventriculaire droit induits par une radiothérapie et résume les études cliniques dans ce domaine.
Background
The number of patients with cancer is increasing each year. However, the modern therapeutic approach, which includes sophisticated chemotherapeutic agents and radiotherapy, has improved survival significantly in these patients. It is estimated that more than 50% of modern anticancer protocols involve radiotherapy. The effect of radiation on different tissues and organs that were not the target of radiotherapy has been recognized for more than 60 years, and it is well known that this effect depends on total amount of radiation, dose per treatment, delivery technique, tissue type and co-morbidities . Radiotherapy-induced heart disease (RIHD) typically occurs in patients with Hodgkin’s disease, breast cancer (particularly the left breast), lung cancer and other mediastinal malignancies (e.g. oesophageal carcinoma) who have undergone radiotherapy as part of their anticancer treatment. RIHD is associated with vascular, valvular, pericardial, conduction and myocardial damage. The changes in RIHD vary from mild (asymptomatic cardiac impairment) to severe (severe valve disease or symptomatic heart failure).
The mechanisms that are responsible for radiotherapy-induced heart remodelling (i.e. cardiomyopathy, valvulopathy and coronary artery disease) are still unclear. It is known that a cumulative radiotherapy dose of > 30 Gy, irrespective of cancer type, is related to cardiac damage . Given that the contemporary radiotherapy dose for breast cancer is 45–50 Gy , and for Hodgkin’s lymphoma is 35 Gy , it is clear why cardiac assessment should be a mandatory part of the routine evaluation of patients with cancer. Furthermore, the majority of patients with cancer are treated not only with radiotherapy, but also with chemotherapy, which is known to be a strong independent predictor of adverse cardiac remodelling, further increasing the necessity for careful cardiac assessment of patients with cancer.
The primary focus of investigations into RIHD has been the left ventricle (LV) , which is why current guidelines regarding cancer treatment and cardiovascular toxicity concentrate mainly on left ventricular (LV) assessment .
Data regarding radiotherapy-induced right ventricular (RV) remodelling are scarce and, in most studies, patients were also treated with chemotherapy, which makes the assessment of isolated radiotherapy-induced RV remodelling more difficult . For a long time, the right ventricle (RV) has been considered as a dispensable cardiac chamber that does not contribute significantly to overall cardiac function. However, the number of investigations showing the substantial influence of RV structure, function and mechanics on cardiovascular and total morbidity and mortality is constantly increasing .
The purpose of this review is to summarize current knowledge regarding radiotherapy-induced RV structural, functional and mechanical remodelling, and the potential mechanisms that lead to this condition.
Potential mechanisms of radiotherapy-induced RV remodelling
The RV is anatomically positioned superficially in the mediastinum, right behind the sternum and ribs, which makes it very exposed to radiotherapy. A recent study showed that although the global RV was exposed to a lower radiation dosage than the LV (2.85 vs 4.37 Gy), the RV free wall was actually exposed to a higher dosage than the LV (4.61 vs 4.37 Gy) in women with left-sided breast cancer . Furthermore, the RV was significantly more exposed to radiation than the LV in patients with right-sided breast cancer (0.45 vs 0.11 Gy). In theory, direct exposure to radiation should not be responsible for radiotherapy-induced RV changes, because cardiomyocytes are well differentiated and relatively radioresistant cells . However, radiotherapy has an impact on the RV myocardium, and it may be that the indirect effects of radiotherapy are more responsible for myocardial remodelling.
The mechanisms that induce RV remodelling during and after radiotherapy are not fully understood. There are several hypotheses that could connect radiotherapy and RV remodelling: microvascular and macrovascular ischaemia; myocardial fibrosis; accelerated atherosclerosis; endothelial dysfunction; and oxidative stress.
The first step in the cascade that results in RV remodelling could be radiotherapy-induced endothelial injury within heart blood capillaries that causes inflammation and activation of macrophages and monocytes, resulting in the secretion of cytokines and growth factors, including tumour necrosis factor, monocyte chemotactic factors, interleukins 1, 6 and 8, transforming growth factor beta, insulin-like growth factor and platelet-derived growth factor . Endothelial damage also induces activation of the coagulation mechanism, with consequent fibrin deposition. All of these changes provoke endothelial cell proliferation and, finally, obstruction of microcirculation. Activation of matrix metalloproteinases induces the degradation of the endothelial basement membrane, which allows accumulation of proinflammatory cells at the sites of tissue injury.
During the advanced stage, progressive obstruction of microcirculation and thrombi formation result in ischaemia and consequent myocyte death, which further induces the replacement of cardiac tissue by fibrotic tissue, and may be responsible for cardiac dysfunction and even heart failure . Furthermore, chronic oxidative stress, with continuous production of free radicals, increases the risk of late development of atherosclerotic disease.
The examination of myocardial and pericardial tissue in animal studies has demonstrated an increased number of inflammatory cells and fibroblasts, and a significantly enlarged extracellular matrix (involving collagen, proteoglycans and fibronectin) .
The existence of inflammation and fibrosis was described in patients who received radiotherapy for oesophageal cancer (median total dose, 66 Gy [60–70 Gy]) . The authors detected late gadolinium enhancement in 12 of the 24 patients. Late gadolinium enhancement was found in 15.38% of myocardial segments that received 40 Gy and in 21.21% of myocardial segments that received 60 Gy, whereas it was absent from segments that were out of the radiation fields . An autopsy study of normal heart tissue compared with LV tissue in patients with post-radiation pericarditis showed a significant increase in total tissue collagen in the LV tissue of irradiated hearts compared with non-irradiated hearts, which is consistent with long-standing cardiac fibrosis .
Additional evidence that radiotherapy provokes myocardial damage was the significant increase in cardiac injury markers, such as troponin and pro-B-type natriuretic peptide, in chemotherapy-naive cancer patients who received radiotherapy .
Post-radiation pericardial disease and the development of constrictive pericarditis are exceptionally significant in RV remodelling because of the unfavourable influence of thickened pericardium on the RV – a thin-walled cardiac chamber that works under relatively low pulmonary circulation pressure . In these conditions, pericarditis initially causes the deterioration of RV diastolic function, increases the RV filling pressure and affects RV systolic function over the course of the disease. Given that pericarditis occurs in 7–20% of cancer patients treated with radiotherapy , one should not neglect this mechanism in the development of radiotherapy-induced RV remodelling.
Another important factor that should not be ignored is radiotherapy-induced lung damage. On the one hand, radiotherapy-induced fibrosis does not spare the lungs, and causes interstitial pulmonary fibrosis; on the other hand, radiotherapy-induced endothelial damage and inflammation also occur in the pulmonary microcirculation. Both mechanisms could induce an increase in pulmonary resistance and pulmonary wedge pressure, which may elevate pulmonary pressure and ultimately induce or worsen RV remodelling.
Chemotherapy-induced cardiotoxicity can manifest only a few weeks after initiation of chemotherapeutic agents, whereas RIHD usually occurs much later – commonly 5–10 years after radiotherapy. Acute radiation effects are usually subtle, which is challenging for evaluation, and are clinically less relevant; they should be suspected and evaluated in patients with cardiovascular symptoms soon after radiotherapy. The late RIHD manifestations that are clinically evident typically develop several years after radiotherapy.
RV remodelling
The RV consists of three segments: the inflow tract, the outflow tract and the trabeculated muscular apex. Because of its complex shape, its geometry and its position in the chest, assessment of RV structure and function is not an easy task with the imaging techniques that we use in routine clinical circumstances ; this primarily refers to two-dimensional echocardiography, which is currently the most readily available imaging technique . The gold standard for the evaluation of the RV still remains cardiac magnetic resonance imaging . Three-dimensional echocardiography provides results that are comparable with cardiac magnetic resonance imaging, but it has been used insufficiently for the evaluation of RIHD so far.
As was underlined in the previous section, fibrosis is a dominant factor for both myocardial remodelling and vascular changes in RIHD. Although previous investigations mainly focused on the LV, there is no reason why this would not also be valid for the RV.
A limited number of studies have investigated RV structure, function and mechanics in cancer patients treated with radiotherapy. In the next sections, we seek to summarize the results of this research. An overview of existing data on the influence of radiotherapy on RV remodelling is provided in Table 1 .
| Reference | Sample size ( n ) | Age a (years) | Duration of follow-up b | Cancer type | Imaging technique | RV systolic function | RV diastolic function | RV mechanics |
|---|---|---|---|---|---|---|---|---|
| Tuohinen et al. | 49 | 63 ± 6 | 20–70 days c | Left-sided breast | Echocardiography | Impaired | Unchanged | Not evaluated |
| Tuohinen et al. | 78 | 63 ± 7 | 39 ± 13 days c | Left- and right-sided breast | Echocardiography | Impaired | Unchanged | Impaired |
| Murbraech et al. | 274 | 56 ± 12 | 13 ± 6 years d | Lymphoma | Echocardiography | Impaired | Not evaluated | Impaired |
| Christiansen et al. | 246 | 48 ± 20 | 21.7 years d | Lymphoma and leukaemia | Echocardiography | Impaired | Impaired | Impaired |
| Skyttä et al. | 58 | 63 ± 6 | 2–3 weeks | Left-sided breast | Echocardiography | Unchanged | Unchanged | Not evaluated |
| Skyttä et al. | 60 | 63 ± 6 | 3–5 weeks | Left-sided breast | Echocardiography | Impaired | Unchanged | Not evaluated |
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
