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).

中文翻译：

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现代乳腺癌治疗对左心室舒张功能变化的综合评估。


目的 本研究确定阿霉素和/或曲妥珠单抗对舒张功能的影响以及舒张功能与收缩功能障碍之间的关系。背景阿霉素和曲妥珠单抗可导致左心室射血分数（LVEF）下降。然而，这些疗法对舒张功能的影响仍未完全确定。方法 在一项严格表型的纵向队列研究中，对 362 名乳腺癌受试者进行了阿霉素治疗、阿霉素随后曲妥珠单抗治疗或单独曲妥珠单抗治疗，使用通过广义估计方程估计的线性模型来评估舒张功能的变化。还使用广义估计方程确定基线和舒张功能变化与 LVEF 和纵向应变之间的关联。 Kaplan-Meier 估计器得出了发生舒张功能障碍的参与者的比例。 Cox 比例风险模型评估了参与者特征与舒张功能障碍风险之间的关联，以及舒张功能与癌症治疗相关的心功能障碍风险之间的关联，定义为 LVEF 下降 ≥10% 至 <50%。结果 在中位 2.1 年（四分位距 [IQR]：1.3 至 4.2 年）中，接受多柔比星或多柔比星随后曲妥珠单抗治疗的参与者表现出舒张功能持续恶化，E/A 比值、横向和间隔 e 降低。 ' 速度和 E/e 增加' (p < 0.01)。单独使用曲妥珠单抗未观察到这些变化。舒张功能等级异常的发生率在 1 年时发生率为 60%，在 2 年时发生率为 70%，在 3 年时发生率为 80%。舒张功能等级异常与随后的 LVEF 下降（-2.1%； 95% 置信区间 [CI]：-3.1 至 -1.2； p < 0.001)，并且纵向应变随时间恶化(0.6%；95% CI：0.1 至 1.1；p = 0.013)。 E/e' 比的变化与纵向应变恶化有一定的相关性（0.1%；95% CI：0.0 至 0.2；p = 0.022）。结论 在当代乳腺癌治疗中观察到舒张功能适度持续恶化。异常和恶化的舒张功能障碍与随后发生收缩功能障碍的小风险相关。 （癌症治疗的心脏毒性[CCT]；NCT01173341）。