Author + information
- Received October 12, 2018
- Revision received June 20, 2019
- Accepted July 8, 2019
- Published online September 18, 2019.
- Jenica N. Upshaw, MD, MSa,
- Brian Finkelman, MD, PhDb,
- Rebecca A. Hubbard, PhDc,
- Amanda M. Smith, MAd,
- Hari K. Narayan, MDe,
- Linzi Arndt, BAd,
- Susan Domchek, MDf,
- Angela DeMichele, MDf,
- Kevin Fox, MDf,
- Payal Shah, MDf,
- Amy Clark, MDf,
- Angela Bradbury, MDf,
- Jennifer Matro, MDf,
- Srinath Adusumalli, MD, MScd,
- Joseph R. Carver, MDd,f and
- Bonnie Ky, MD, MSCEc,d,f,∗ ()
- aDepartment of Medicine, Division of Cardiology, Tufts Medical Center, Medford, Massachusetts
- bDepartment of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
- cDepartment of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
- dDepartment of Medicine, Division of Cardiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
- eDepartment of Pediatrics, Division of Cardiology, Rady Children’s Hospital San Diego, The University of California San Diego, San Diego, California
- fAbramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
- ↵∗Address for Correspondence:
Dr. Bonnie Ky, University of Pennsylvania School of Medicine, Smilow Center for Translational Research, 3400 Civic Center Boulevard, 11-105, Philadelphia, Pennsylvania 19104.
Objectives This study determined the effects of doxorubicin and/or trastuzumab on diastolic function and the relationship between diastolic function and systolic dysfunction.
Background Doxorubicin and trastuzumab can result in left ventricular ejection fraction (LVEF) declines. However, the effects of these therapies on diastolic function remain incompletely defined.
Methods In a rigorously phenotyped, longitudinal cohort study of 362 breast cancer participants treated with doxorubicin, doxorubicin followed by trastuzumab, or trastuzumb alone, changes in diastolic function were evaluated using linear models estimated via generalized estimating equations. Associations between baseline and changes in diastolic function with LVEF and longitudinal strain were also determined using generalized estimating equations. The Kaplan-Meier estimator derived the proportion of participants who experienced incident diastolic dysfunction. Cox proportional hazards models estimated the associations between participant characteristics and diastolic dysfunction risk, and between diastolic function and cancer therapy−related cardiac dysfunction risk, defined by an LVEF decline of ≥10% to <50%.
Results Over a median of 2.1 years (interquartile range [IQR]: 1.3 to 4.2 years), participants treated with doxorubicin or doxorubicin followed by trastuzumab demonstrated a persistent worsening in diastolic function, with reductions in the E/A ratio, lateral and septal e′ velocities, and increases in E/e′ (p < 0.01). These changes were not observed with trastuzumab alone. Incident abnormal diastolic function grade occurred in 60% at 1 year, 70% by 2 years, and 80% by 3 years. Abnormal diastolic function grade was associated with a subsequent decrease in LVEF (−2.1%; 95% confidence intervals [CI]: −3.1 to −1.2; p < 0.001) and worsening in longitudinal strain (0.6%; 95% CI: 0.1 to 1.1; p = 0.013) over time. Changes in E/e′ ratio were modestly associated with worsening longitudinal strain (0.1%; 95% CI: 0.0 to 0.2; p = 0.022).
Conclusions A modest, persistent worsening of diastolic function is observed with contemporary breast cancer therapy. Abnormal and worsening diastolic dysfunction is associated with a small risk of subsequent systolic dysfunction. (Cardiotoxicity of Cancer Therapy [CCT]; NCT01173341)
Dr. Ky is supported by the National, Heart, Lung, and Blood Institute (R01-HL118018 and K23-HL095661), a McCabe Fellow Award, and an American Cancer Society Institutional Research Grant (78-002-30). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Received October 12, 2018.
- Revision received June 20, 2019.
- Accepted July 8, 2019.
- 2019 American College of Cardiology Foundation
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