For patients treating breast cancer, using doxorubicin and/or trastuzumab as a therapy was associated with abnormal or worsening diastolic function, according to study results  published in the Journal of the American College of Cardiology: Cardiovascular Imaging.

The aim of the Cardiotoxicity of Cancer Therapy study was to assess the longitudinal changes on echocardiographic measures of diastolic function resulting from doxorubicin and/or trastuzumab treatment and if these changes affect systolic dysfunction. Patients with breast cancer currently undergoing treatment with doxorubicin, trastuzumab, or doxorubicin followed by trastuzumab were eligible for this study.

A baseline transthoracic echocardiogram and ≥1 follow-up echocardiogram were required. Researchers collected cancer-related clinical variables, such as clinical stage, hormone receptor status, and surgical therapy, from a chart review and gathered clinical characteristics, such as hypertension, diabetes, hyperlipidemia, tobacco use, and body mass index, through patient or provider reports or a chart review. They used the echocardiography images to determine mitral valve peak E- and A-wave velocities, mitral annular e’ velocities, left atrial volume indexes, mitral valve deceleration times, isovolumic relaxation times, and peak tricuspid regurgitation systolic jet velocities.


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Of the 362 patients included in this study, 70% were white, median age was 49 (interquartile range, 41-57) years, median body mass index was 26 (interquartile range, 23.4-31,4) kg/m², 32% had hypertension, 21% had hyperlipidemia, 9% had diabetes, and 38% currently use or have used tobacco products. For treatment, 61% used doxorubicin without trastuzumab, 23% used trastuzumab without doxorubicin, 17% used doxorubicin followed by trastuzumab, and 65% also underwent radiation therapy.

At baseline, 24% of patients had abnormal diastolic function grade 1, 1.1% had abnormal diastolic function grade 2, 0.6% had abnormal diastolic function grade 3, 7% had indeterminate diastolic function, and 14% were unable to be categorized according to tachycardia, mitral inflow merging, or arrhythmias.

Longitudinally, the doxorubicin cohort experienced a modest decrease in E/A ratio, the doxorubicin-followed-by-trastuzumab cohort experienced an increase followed by a decrease in E/A ratio, and the trastuzumab cohort did not experience a significant change. The doxorubicin cohort and the doxorubicin-followed-by-trastuzumab cohort experienced reductions in lateral e’ and septal e’ and increases in E/e’ ratio. At a 3-year follow-up, all 3 cohorts experienced a decrease in left atrial volume, and overall, 11% of patients developed a tricuspid regurgitation velocity >280 cm/s.

Researchers indicated that 60% of the patients had abnormal diastolic function at 1 year of treatment, 70% of the patients had abnormal diastolic function at 2 years of treatment, and 80% of the patients had abnormal diastolic function at 3 years of treatment.

Using multivariable model analyses, there was an inverse association between radiation and diastolic dysfunction (P =.001), and being black (P =.007) or a current tobacco user (P =.022) increased the hazard of developing diastolic dysfunction. After a maximum follow-up time of 6.5 years, 14% of the doxorubicin cohort, 15% of the trastuzumab cohort, or 32% of the doxorubicin-followed-by-trastuzumab cohort experienced cancer therapeutics-related cardiac dysfunction.

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Researchers observed an association between baseline abnormal diastolic function and a decline in left ventricular ejection fraction (P <.001) that worsened over time. They noted a worsening in diastolic function related to  a 1.4% decrease in left ventricular ejection fraction (P =.006) and an increase in cancer therapeutics–related cardiac dysfunction (P =.028).

Limitations of this study included the small effect size over a relatively short follow-up time frame, the possibility of uncontrolled confounding variables, the potential impact radiation therapy has on cardiac substructures, not including serum biomarkers in data collection, and not correcting for multiple comparisons during analysis.

The researchers concluded that “there are significant changes in diastolic function parameters over time with modern breast cancer therapy, and abnormal or worsening diastolic function precedes systolic dysfunction.”

Reference

Upshaw JN, Finkelman B, Hubbard RA, et al. Comprehensive assessment of changes in left ventricular diastolic function with contemporary breast cancer therapy [published online September 18]. J Am Coll Cardio. doi:10.1016/j.jcmg.2019.07.018