Jenica N Upshaw1, Brian Finkelman2, Rebecca A Hubbard3, Amanda M Smith4, Hari K Narayan5, Linzi Arndt4, Susan Domchek6, Angela DeMichele6, Kevin Fox6, Payal Shah6, Amy Clark6, Angela Bradbury6, Jennifer Matro6, Srinath Adusumalli4, Joseph R Carver7, Bonnie Ky8. 1. Department of Medicine, Division of Cardiology, Tufts Medical Center, Medford, Massachusetts. 2. Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois. 3. Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania. 4. Department of Medicine, Division of Cardiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania. 5. Department of Pediatrics, Division of Cardiology, Rady Children's Hospital San Diego, The University of California San Diego, San Diego, California. 6. Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania. 7. Department of Medicine, Division of Cardiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania; Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania. 8. Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania; Department of Medicine, Division of Cardiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania; Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address: bonnie.ky@pennmedicine.upenn.edu.
Abstract
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 trastuzumab 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).
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 cancerparticipants treated with doxorubicin, doxorubicin followed by trastuzumab, or trastuzumab 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).
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