Central Illustration
The literature describing the effects of cardiotoxic cancer therapies have focused primarily on left ventricular (LV) function, with a paucity of data on the right ventricle (RV). To fill this knowledge gap, we evaluated the longitudinal changes in echocardiographic RV systolic function measures and determined whether these changes were associated with LV systolic dysfunction or heart failure (HF) symptoms in women with breast cancer.
The Penn CCT (Cardiotoxicity of Cancer Therapy; NCT01173341) is a prospective longitudinal cohort study of women with breast cancer treated with doxorubicin and/or trastuzumab at the University of Pennsylvania (Philadelphia, Pennsylvania). The study design has been previously described.1 Echocardiography was performed at standardized time intervals during treatment and annually, and digitally archived.1 In blinded analysis, a measure of global RV systolic function, fractional area change (FAC), and measures of the longitudinal function of the basal RV, tricuspid annular plane systolic excursion (TAPSE), and tricuspid lateral annular systolic velocity (S′), were quantified by an expert sonographer at the Penn Center for Quantitative Echocardiography.2 Intraobserver coefficient of variation was 5.2% for FAC, 1.9% for TAPSE, and 5.4% for S′. The study was approved by the University of Pennsylvania institutional review board. All participants provided written informed consent.
Baseline-adjusted mean changes in RV systolic function measures were estimated according to treatment group (doxorubicin [Dox], trastuzumab [Tras], or sequential Dox and Tras [Dox+Tras]). Repeated measures linear regression via generalized estimating equations was used to estimate longitudinal changes. The cumulative incidence of RV systolic dysfunction, defined as FAC <35%, was estimated using competing risks methods accounting for death (n = 21) as a competing event.2 Among those who developed RV systolic dysfunction, the cumulative incidence of FAC recovery was similarly evaluated. Concurrent and subsequent associations between RV systolic function changes and LV ejection fraction (LVEF) changes or HF symptoms, measured using the MD Anderson Symptom Inventory–HF (MDASI-HF), were evaluated using generalized estimating equations. Models adjusted for age, hypertension, baseline values of the exposure, and outcome under consideration, and time since treatment initiation with its effect allowed to vary across treatment groups. Analyses were conducted using R version 3.4.0 (R Foundation for Statistical Computing).
A total of 348 participants with quantifiable RV function measures at baseline and at least 1 follow-up contributing 1,675 echocardiograms were included. The median age was 49 years (IQR: 41-58 years); 70% were White. The majority (59%) received Dox; 22% received Tras; and 19% received Dox+Tras.
Over a median follow-up of 2 years (IQR: 1-3 years), we observed modest, early declines in FAC from baseline with Dox and Dox+Tras. At 1 year, the estimated mean absolute changes in FAC in the Dox and Dox+Tras groups were −2.0% (95% CI: −3.0 to −0.9; P < 0.001) and −2.3% (95% CI: −3.6 to −0.9; P = 0.001), respectively (Figure 1A). This was followed by recovery at 3 years, with estimated mean changes from baseline at 3 years of 1.5% (95% CI: 0%-2.9%; P = 0.052) with Dox and 1.1% (95% CI: −0.3% to 2.6%; P = 0.124) with Dox+Tras. Furthermore, 22% (95% CI: 15%-29%) developed incident RV systolic dysfunction. All these participants demonstrated recovery with a subsequent FAC ≥35% at a median of 0.7 years (95% CI: 0.5-1.0 years) from time of dysfunction (Figure 1B). A comparable pattern of change was observed for TAPSE. At 1 year, the mean absolute changes in TAPSE in the Dox and Dox+Tras groups were −0.18 cm (95% CI: −0.22 to −0.13 cm; P < 0.001) and −0.12 cm (95% CI: −0.18 to −0.06 cm; P < 0.001), respectively. This was followed by partial recovery at 3 years. By contrast, changes in FAC and TAPSE were less pronounced in the Tras group, with none being statistically significant. Across all 3 treatment groups, modest declines in S′ were observed with a nadir at 2 years. At 2 years, S′ declined by 1.1 cm/s (95% CI: −1.4 to −0.7 cm/s; P < 0.001), 0.9 cm/s (95% CI: −1.3 to −0.5 cm/s; P < 0.001), and 0.9 cm/s (95% CI: −1.3 to −0.5 cm/s; P < 0.001) in the Dox, Tras, and Dox+Tras groups, respectively. This was followed by partial recovery at 3 years.
Figure 1.
Longitudinal Changes in FAC During and After Cancer Therapy
(A) Estimates of mean change (95% CI) in fractional area change (FAC) from baseline according to treatment group; (B) the cumulative incidence, among those developing right ventricular (RV) systolic dysfunction, of FAC recovery from time of dysfunction. Dox = doxorubicin; Tras = trastuzumab.
Change in S′ showed a statistically, but not clinically, significant association with concurrent change in LVEF. Each 1 cm/s decrease in S′ was associated with a 0.2% (95% CI: −0.4% to −0.1%; P = 0.007) absolute worsening in LVEF. No other associations were observed between RV systolic function and LVEF or MDASI-HF score (data not shown).
In the largest prospective cohort study to date, we define the long-term trajectory of RV systolic function changes in 348 women with breast cancer. Our findings provide definitive evidence to support that only modest, largely reversible changes in RV systolic function occurred with Dox. There was no significant, consistent effect on RV function with Tras. RV systolic function changes were not strongly associated with changes in LV systolic function or HF symptoms. Altogether, our findings provide insight into the lack of significant impact of modern breast cancer therapy on RV systolic function and highlight differences in the effects of cancer therapy on the RV compared with LV function.
Animal models have demonstrated that Dox induces significant increases in reactive oxygen species in the LV, but not RV.3 This might suggest that the RV is less vulnerable to injury than the LV. It has been hypothesized that the RV might be less susceptible to injury due to a lower oxygen demand, greater oxygen extraction reserve, contraction against low resistance, and better oxygen supply with perfusion during both systole and diastole. Our findings motivate additional mechanistic studies to confirm these hypotheses.
The study has limitations. We lacked sensitive imaging measures, including RV longitudinal and free wall strain, although this is an area of future investigation. However, the parameters that we describe are widely used and available, enhancing the generalizability of our findings, in contrast to RV strain.
In conclusion, our findings support the lack of a clinically significant population-level effect of Dox and/or Tras on RV systolic function in breast cancer. Additional translational studies are needed to further understand the mechanistic basis of our findings.
Footnotes
This work was supported by National Heart, Lung, and Blood Institute (NHLBI) R01-HL118018 (Dr Ky), McCabe Fellow Award (Dr Ky), American Cancer Society Institutional Research Grant -78-002-30 (Dr Ky), American Heart Association Transformational Grant, National Institutes of Health (NIH) R21 HL150723, NIH R21 HL157886, and NHLBI K23-HL095661 (Dr Ky). Dr Getz’s research effort is supported in part by NHLBI K01-HL143153. The authors have reported that they have no relationships relevant to the contents of this paper to disclose. Federico M. Asch, MD, served as Guest Associate Editor for this paper. Kathryn J. Ruddy, MD, MPH, served as Guest Editor-in-Chief for this paper.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center.
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