The Right Heart in Patients with Cancer. A Scientific Statement of the Heart Failure Association (HFA) of the ESC and the ESC Council of Cardio-Oncology

Abstract

Cardio-oncology guidelines, position statements and clinical trials have focused on the cardiotoxic effects of cancer therapies upon the left ventricle.1, 2 However, cancer therapies, including chemotherapy, targeted therapies, immunotherapies and radiation therapy (RT) may also have detrimental effects on the right heart (RH). These effects may manifest as right ventricular (RV) dysfunction, pulmonary hypertension (PH), pericardial disease and valvular abnormalities. The prevalence and clinical significance of RH involvement in patients treated with cancer therapies are being increasingly recognized,3 as these conditions can significantly impact treatment decisions, prognosis, and overall patient outcomes.4 In this scientific statement, we aim to discuss the impact of cancer therapies on the RH and explore the importance of RH assessment in patients with cancer. We discuss the prevalence and the mechanisms of RV dysfunction in cancer patients, the challenges and limitations of traditional imaging modalities, and the role of multimodality imaging in evaluating the RH. The integration of RH assessment into cardio-oncology practice will aid healthcare professionals to proactively manage cardiovascular (CV) complications, optimize cancer treatment strategies, and potentially improve clinical outcomes. Right ventricular dysfunction may pre-exist in cancer patients at diagnosis or it may be exacerbated by or may develop de novo due to cardiotoxic cancer therapy (anti-neoplastic medications and RT) or due to direct CV complications of the cancer itself (e.g. PH, venous thromboembolism [VTE] and pulmonary embolism [PE], primary or metastatic cardiac tumours, pericardial involvement, or endocarditis). Carcinoid heart disease (CHD) and amyloidosis are special entities where RH involvement is crucial (Figure 1). There is no universal definition of cancer therapy-related RV toxicity (CTR-RVT). Based on the current literature, the recent universal definition of heart failure5 and the 2022 European Society of Cardiology (ESC) guidelines on cardio-oncology,2 CTR-RVT can be divided into asymptomatic RV dysfunction and symptomatic RV failure, analogous to the concept of cancer therapy-related cardiac dysfunction (CTRCD) for the left ventricle (LV). In this document, we propose the following definitions (Table 1). Asymptomatic RV dysfunction refers to the presence of impaired RV function without overt clinical symptoms or signs, where a subclinical alteration in RV performance can be detected by transthoracic echocardiography (TTE). It can be defined as new relative decline in RV free wall longitudinal strain (RV FWLS) by >15% from the baseline value without significant change of the standard two-dimensional (2D)-echocardiographically assessed parameters (tricuspid annular plane systolic excursion [TAPSE], RV fractional area change [FAC], RV myocardial performance index [MPI], RV S′ or three-dimensional [3D]-assessed RV ejection fraction [RVEF]). Symptomatic RV failure can be defined as a condition where symptoms and/or signs of RV failure, such as dyspnoea, exercise intolerance, peripheral oedema, are caused by a structural and/or functional abnormality of the RH. Although there are some data based on RV systolic function assessment by RVEF either by 3D echocardiography6-9 or by cardiac magnetic resonance (CMR),10-14 this parameter is not included in the definition of asymptomatic RV dysfunction since 3D echocardiography and CMR are not widely available for the surveillance of asymptomatic cancer patients. Clearly, more work is needed to validate these criteria for the diagnosis of RV cardiotoxicity. Several cancer therapies may cause RV dysfunction through a number of different mechanisms including direct myocardial toxicity, myocarditis, myocardial ischaemia and/or increased afterload (systemic or pulmonary). Several studies have reported RV dysfunction in cancer patients and survivors, but the number of patients in these studies is relatively small and the methods and cut-off values vary significantly. Most of the studies focus on anthracycline-induced cardiotoxicity,6, 7, 9, 10, 15-27 some evaluate breast cancer patients receiving trastuzumab with or without anthracyclines,11, 28-36 and only a few address the impact of complex chemotherapeutic regimens.37, 38 Reports of immune checkpoint inhibitor-induced RV dysfunction39 or myocarditis involving the RV apart from the LV40 or restricted to the RV41, 42 have remained rare. Results on the effect of chemotherapy on RV diameters and volumes have been conflicting with some studies supporting RV remodelling,7, 10, 11, 23 while others do not identify significant changes.9, 15, 19, 29, 33, 43 This is similar to the results concerning RV systolic function. While some studies do not report significant changes,15-17, 28, 29, 33, 37 others reveal consistent decreases in RV FAC,9, 19, 22, 23, 25, 26 TAPSE9, 19, 26, 43 and RVEF.7, 11, 43 On the contrary, RV longitudinal strain (RVLS) was decreased by chemotherapy in almost all studies6, 7, 9, 16-23, 25, 27, 29, 35 with the most consistent results for RV FWLS. The timing of RV dysfunction compared to LV dysfunction is another topic of debate; most19, 22, 29, 34, 35 but not all studies have shown concurrent biventricular insult. Importantly, RV dysfunction expressed by the change in RVLS seems to predict LV cardiotoxicity in some trials.9, 10, 23, 37 Lastly, the effect of anthracyclines on the RV seems to be dose-dependent similar to LV toxicity.9, 17, 21, 25 The effects of anti-cancer therapies known to also cause CTRCD, including vascular endothelial growth factor (VEGF) inhibitors, epidermal growth factor receptor (EGFR) inhibitors, Bruton tyrosine kinase inhibitors and proteasome inhibitors, on RV function specifically, remain unknown. The effects of RT on the RH chambers have been insufficiently investigated.3, 44, 45 It is well known that the anatomical position of heart structures, tumour localization and radiation dose exposure dictate which cardiac chamber(s) will be most affected.46 Even though the RV is anatomically positioned more anteriorly and, therefore potentially, more exposed to superficial radiation targeting the chest wall or breast tissue, the majority of studies have focused on left-sided RT effects.47, 48 Moreover, pericardial disease, especially constriction, can significantly influence presentations and measurements. Tissue fibrosis related to micro- and macro-vascular injury is the most important cause for cardiac impairment in radiation-induced heart disease. Microvascular injury induces myocardial and pericardial fibrosis, as well as reduced capillary density. These alterations are related to LV and RV remodelling, including diastolic and systolic dysfunction, as well as pericardial effusion and fibrosis that can possibly lead to constriction. Macrovascular injury is related to accelerated coronary artery atherosclerosis. The effects of RT on RV systolic function depend on several factors including: the location of the cancer, the total dose of the radiation delivered, the mean dose to the heart and specifically to the RH, the combination of RT with antineoplastic drug therapy and the duration of the follow-up. The most consistent data about RV systolic function assessed by echocardiography involve TAPSE, which has been shown to be reduced in patients with left-sided breast cancer receiving RT49 or RT and hormonal therapy (aromatase inhibitors)50 or RT and chemotherapy,44 in patients with haematological malignancies, oesophageal cancer, central lung cancer and thymoma.45, 51 The changes of RV FAC, tricuspid valve (TV) S′ and RVEF are inconsistent.3, 44, 49, 51 A growing body of evidence shows that RV LS and particularly RV FWLS, are early markers of RT-induced RV damage.3, 51-53 The combination of RT with chemotherapy has an additive effect on RT-induced RV strain changes.3, 51 A study with stage III non-small cell lung cancer patients revealed the independent predictive value of RV FWLS at baseline and its change after anti-cancer therapy on 6-month all-cause mortality52 and the researchers proposed a percentage change of RV FWLS of 10.1% as clinically significant. Data for RV strain changes in breast cancer patients from CMR also report a deterioration in RV mechanics soon after completion of RT.53 Notably, the decline in RV LS appears to be primarily attributed to a reduction in apical strain. Pericardial disease in cancer patients manifesting as RH failure may be due to constrictive pericarditis or pericardial effusion. Pericardial effusions may occur in up to 15% of cancer patients secondary to direct invasion, metastasis, or cancer treatment.54 Gradual accumulation of fluid in the pericardial sac can compress the thin-walled RV manifesting as acute RH failure.55 This occurs due to external restriction of diastolic biventricular filling and elevated systemic and pulmonary venous pressures.56 Diagnosis of RH failure in this context is made initially by echocardiography which may reveal signs of dissociation of intrathoracic and intracardiac pressures and haemodynamic compromise.57 CMR can accurately assess pericardial thickness, tumour infiltration and inflammation along with ventricular interdependence.58 Cardiac computed tomography (CCT) can also determine pericardial thickness and visualize multiple tumour planes.59, 60 RH catheterization (RHC), which is the gold-standard diagnostic test, may be needed to make an invasive diagnosis of pericardial constriction, if non-invasive tests are inconclusive.61 Management of acute pericarditis is in line with the 2015 ESC guidelines for the diagnosis and management of pericardial disease61 and if secondary to immune checkpoint inhibitors then follow the 2022 ESC guidelines on cardio-oncology.2 Surgical window may be considered for effusions inaccessible to percutaneous drainage or in cases of recurrent effusion.2 Cancer and cancer therapies are predisposing factors for the development of VTE.62 VTE is 4–7 times more frequent in cancer patients63 and PE is the most critical complication associated with significant and The of PE in cancer patients from to The of PE has been associated with central and malignancies, as well as with and The of due to PE is reported in oesophageal cancer factors for development of VTE in cancer patients can be or cancer, especially if and cancer cancer patients with computed tomography for PE are have a body index and are have a percentage of chest or as of PE and are to with PE and RH strain at 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