In cardio-oncology, research and clinical monitoring of cardiotoxicity with anthracycline and trastuzumab treatment has focused primarily on asymptomatic reductions in left ventricular ejection fraction (LVEF), so-called "cancer therapy-related cardiac dysfunction," or heart failure with reduced ejection fraction (HFrEF). However, it is increasingly recognized that many cancer therapies can have adverse cardiovascular effects—myocardial, vascular, and metabolic—that may predispose patients to HFpEF. In addition, many patients with cancer may be at risk of HFpEF due to comorbid cardiovascular risk factors or cancer-related cardiometabolic effects. HFpEF has not been a commonly collected outcome in oncology clinical trials, and thus the exact incidence and relative risk compared with noncancer controls, as well as among various anti-cancer therapies, remain unknown. Although future research is needed to understand the incidence of HFpEF in cancer survivors, providers should be aware now that many cancer therapies may increase the risk of HFrEF and HFpEF (Figure 1).

Figure 1: Conceptual Model of Multiple Risk Factors for HFpEF After Cancer Treatment

Anthracycline therapy is known to cause left ventricular systolic dysfunction and HFrEF. Anthracyclines are associated with increased aortic stiffness¹ and diastolic dysfunction,² suggesting that anthracycline therapy may also increase the risk of HFpEF. In several cohort studies, significant changes in echocardiographic measures of diastolic function have been seen with modern breast cancer therapy, particularly in those treated with anthracycline therapy.^2,3 In a single-center study, the development of diastolic dysfunction has been reported in over 50% of patients treated with anthracycline chemotherapy within the first year of treatment.² Using data from SEER-Medicare, breast cancer survivors 66 years of age and older had increased risk of heart failure (HF) compared with noncancer controls.⁴ Although outcome research using claims-based dataset is unable to distinguish between HFpEF and HFrEF, older women are at increased risk for both. Further research is needed to better understand the clinical impact of these changes in vascular and diastolic function; however, we should be aware that cardiotoxicity after anthracycline therapy may present as HFpEF.

Radiation therapy causes microvascular endothelial damage, capillary loss, inflammation, and fibrosis and can affect all the layers of the heart. Late cardiovascular effects of radiation therapy are myriad and include coronary artery disease, constrictive pericarditis, valvular stenosis or regurgitation, arrhythmias, restrictive cardiomyopathy, HFpEF, and HFrEF. In a population-based case-control study, higher mean radiation dose to the heart was associated with higher odds of HFpEF development after breast cancer treatment, suggesting that radiation with the heart in the treatment field increases the risk of HFpEF.⁵

Hematopoietic cell transplant is associated with increased risk of HF and atherosclerotic cardiovascular events.⁶ Both pre- and post-transplant cancer treatment and pre- and post-transplant cardiac risk factors and comorbidities increase the risk of HF.

Monoclonal antibodies and small molecule tyrosine kinase inhibitors (TKIs) directed against VEGF commonly cause hypertension and may increase the risk of cardiomyopathy and HF, although the phenotype of HFrEF versus HFpEF has not been well characterized in cancer clinical trial reporting.⁷ The anti-VEGF TKI sunitinib was found to increase vascular stiffness, and changes in vascular function were associated with changes in diastolic function, suggesting that patients treated with VEGF inhibitors may be at increased risk for HFpEF.⁸

The proteasome inhibitor carfilzomib has been associated with higher rates of HF in randomized trials of carfilzomib versus alternative therapy in relapsed or refractory multiple myeloma as well as prospective cohort studies.^9,10 In studies with cardiac imaging data available, the majority of HF events have been consistent with HFpEF rather than HFrEF.¹⁰ Patients with multiple myeloma may be at higher risk for HF due to the following:

• Highly prevalent cardiac risk factors
• Prevalent cardiac and renal disease
• Coexisting amyloidosis involving the heart in a subset of patients
• Therapies such as steroids and proteasome inhibitors that may increase the risk of HF events in at-risk individuals

TKIs active against the BCR-ABL fusion protein that are used for chronic myeloid leukemia—especially ponatinib, nilotinib, and dasatinib—are associated with increased risk of atherosclerotic vascular events including myocardial infarction, stroke, and peripheral arterial disease due in part to the effects of these agents on endothelial cell function. Although less commonly reported than peripheral vascular events, increased risk of HF also appears to be associated with these agents.^11,12 Further studies are needed to understand the mechanism of HF with these agents. In addition, dasatinib is associated with pulmonary hypertension and pleural and pericardial effusions, which may present like HFpEF and should be considered.

Immune checkpoint inhibitors are increasingly used for many cancers and, in addition to myriad immune-mediated adverse events, can cause a fulminant myocarditis. Immune checkpoint inhibitor myocarditis may present with chest pain, arrhythmias, HF, cardiogenic shock, or sudden death. Although left ventricular systolic dysfunction may be present in some cases, data from an international registry have shown that the majority of patients with immune checkpoint inhibitor-associated myocarditis had preserved LVEF at the time of presentation. The LVEF is often normal, but global longitudinal strain is often abnormal and may be a prognostic marker of poor outcomes.¹³ Early administration of high-dose glucocorticoids in cases of suspected immune checkpoint inhibitor-associated myocarditis appears to be associated with lower risk of major adverse cardiac events.¹⁴

Cardiopulmonary exercise testing in individuals with newly diagnosed breast cancer shows markedly reduced peak exercise oxygen consumption compared with age- and gender-matched controls even prior to cancer therapy.¹⁵ Reduced cardiopulmonary fitness has also been seen in other adult cancers at the time of diagnosis and in survivors of childhood cancer years after cancer treatment.¹⁶ Structured exercise interventions have been shown to improve cardiopulmonary fitness after cancer treatment.¹⁷ Aggressive risk factor modification focusing on optimal control of cardiovascular risk factors, particularly hypertension and diabetes, and encouraging regular physical activity in the cancer population may help to mitigate some of the cardiovascular effects of cancer and cancer therapy.

As in the general population, treatable and reversible etiologies such as amyloidosis and endocrinopathies should be considered. In addition, patients on active treatment should be evaluated for potential contribution of the therapy to the HF syndrome. Management of HFpEF in patients receiving cancer treatment is generally similar to management of HFpEF in the noncancer population, including diuretics as needed, control of risk factors, and evaluation and management of coronary artery disease and atrial arrhythmias. Finally, for patients treated with chest radiation, constrictive pericarditis should be considered in addition to coronary artery disease, valvular disease, and restrictive cardiomyopathy.

References

1. Chaosuwannakit N, D'Agostino R Jr, Hamilton CA, et al. Aortic stiffness increases upon receipt of anthracycline chemotherapy. J Clin Oncol 2010;28:166-72.
2. Upshaw JN, Finkelman B, Hubbard RA, et al. Comprehensive Assessment of Changes in Left Ventricular Diastolic Function With Contemporary Breast Cancer Therapy. JACC Cardiovasc Imaging 2020;13:198-210.
3. Nagiub M, Nixon JV, Kontos MC. Ability of Nonstrain Diastolic Parameters to Predict Doxorubicin-Induced Cardiomyopathy: A Systematic Review With Meta-Analysis. Cardiol Rev 2018;26:29-34.
4. Pinder MC, Duan Z, Goodwin JS, Hortobagyi GN, Giordano SH. Congestive heart failure in older women treated with adjuvant anthracycline chemotherapy for breast cancer. J Clin Oncol 2007;25:3808-15.
5. Saiki H, Petersen IA, Scott CG, et al. Risk of Heart Failure With Preserved Ejection Fraction in Older Women After Contemporary Radiotherapy for Breast Cancer. Circulation 2017;135:1388-96.
6. Armenian SH, Sun CL, Shannon T, et al. Incidence and predictors of congestive heart failure after autologous hematopoietic cell transplantation. Blood 2011;118:6023-9.
7. Abdel-Qadir H, Ethier JL, Lee DS, Thavendiranathan P, Amir E. Cardiovascular toxicity of angiogenesis inhibitors in treatment of malignancy: A systematic review and meta-analysis. Cancer Treat Rev 2017;53:120-7.
8. Catino AB, Hubbard RA, Chirinos JA, et al. Longitudinal Assessment of Vascular Function With Sunitinib in Patients With Metastatic Renal Cell Carcinoma. Circ Heart Fail 2018;11:e004408.
9. Rahman MR, Ball S, Paz P, et al. Heart Failure with Carfilzomib in Patients with Multiple Myeloma: A Meta-analysis of Randomized Controlled Trials. J Card Fail 2020;Jul 24:[Epub ahead of print].
10. Cornell RF, Ky B, Weiss BM, et al. Prospective Study of Cardiac Events During Proteasome Inhibitor Therapy for Relapsed Multiple Myeloma. J Clin Oncol 2019;37:1946-55.
11. Cirmi S, El Abd A, Letinier L, Navarra M, Salvo F. Cardiovascular Toxicity of Tyrosine Kinase Inhibitors Used in Chronic Myeloid Leukemia: An Analysis of the FDA Adverse Event Reporting System Database (FAERS). Cancers (Basel) 2020;12:826.
12. Dorer DJ, Knickerbocker RK, Baccarani M, et al. Impact of dose intensity of ponatinib on selected adverse events: Multivariate analyses from a pooled population of clinical trial patients. Leuk Res 2016;48:84-91.
13. Awadalla M, Mahmood SS, Groarke JD, et al. Global Longitudinal Strain and Cardiac Events in Patients With Immune Checkpoint Inhibitor-Related Myocarditis. J Am Coll Cardiol 2020;75:467-78.
14. Mahmood SS, Fradley MG, Cohen JV, et al. Myocarditis in Patients Treated With Immune Checkpoint Inhibitors. J Am Coll Cardiol 2018;71:1755-64.
15. Jones LW, Courneya KS, Mackey JR, et al. Cardiopulmonary function and age-related decline across the breast cancer survivorship continuum. J Clin Oncol 2012;30:2530-7.
16. Christiansen JR, Kanellopoulos A, Lund MB, et al. Impaired exercise capacity and left ventricular function in long-term adult survivors of childhood acute lymphoblastic leukemia. Pediatr Blood Cancer 2015;62:1437-43.
17. Scott JM, Zabor EC, Schwitzer E, et al. Efficacy of Exercise Therapy on Cardiorespiratory Fitness in Patients With Cancer: A Systematic Review and Meta-Analysis. J Clin Oncol 2018;36:2297-305.

Clinical Topics: Cardio-Oncology, Heart Failure and Cardiomyopathies, Atherosclerotic Disease (CAD/PAD), Acute Heart Failure

Keywords: Cardio-oncology, Cardiotoxicity, Heart Failure, Proteasome Inhibitors, Stroke Volume, Risk Factors, Coronary Artery Disease, Anthracyclines, Glucocorticoids, Vascular Endothelial Growth Factor A

< Back to Listings