Anthracyclines are established cardiotoxic agents; however, the exact extent and time course of such cardiotoxicity has not been appraised in detail. We aimed to exploit serial measurements of standard and tissue Doppler imaging (TDI) echocardiographic parameters collected in a prospective clinical trial to clarify the outlook of cardiac function during and long after anthracycline chemotherapy. Women enrolled in a randomized trial focusing on liposomal doxorubicin-based chemotherapy for breast cancer and providing ≥4 separate echocardiographic assessments were included. Repeat-measure nonparametric analyses were used to appraise changes over time in the standard and tissue Doppler imaging echocardiographic parameters. A total of 39 patients with serial imaging evaluations were enrolled. Significant temporal changes were found for the left ventricular ejection fraction and diastolic parameters, despite different temporal trends. Specifically, the left ventricular ejection fraction exhibited a V -shaped trend, decreasing initially from 63% to 61% but then recovering to 64% (p <0.001), with a similar trend in the TDI E/Em ratio (p = 0.011). In contrast, persistent impairments typical of an L -shaped trend were found for the E wave (p = 0.006), TDI lateral Em wave (p = 0.001), and TDI septal Em wave (p = 0.001). In conclusion, subclinical temporal changes in the standard and TDI echocardiographic parameters after anthracycline chemotherapy showed a distinctive pattern of transient impairment followed by full recovery of the left ventricular ejection fraction versus a persistent impairment of the diastolic parameters, which must be taken into account in the everyday treatment of such patients.
The efficacy of anthracycline chemotherapy is limited by their cardiotoxicity, with clinically overt hemodynamic instability occurring acutely or, more frequently, after months or years. Although the acute effects are largely reversible, late effects will manifest as impaired left ventricular (LV) function, a reduction in exercise capacity, and progressive onset of heart failure (HF). Several mechanisms have been proposed, with cardiomyocyte loss considered the key point in progressive myocardial dysfunction. The optimal preventive strategy would be simple monitoring of high-sensitivity early predictors of late HF; however, the best method has not yet been identified. Troponins and B-natriuretic peptide (or its equivalent markers, such as N-terminal probrain natriuretic peptide) might be useful early biomarkers. Echocardiography can offer a low-cost, highly diffused, imaging method to evaluate LV function, and different cardiac performance indexes have been proposed. However, the exact extent and time course of such cardiotoxicity has not been appraised in detail. Preclinical identification of LV dysfunction is crucial, because early therapy will allow complete recovery of LV function. The aim of the present study was to exploit serial measurements of 2-dimensional, Doppler, and tissue Doppler imaging (TDI) echocardiographic parameters collected within the context of a prospective clinical trial to clarify the outlook of systolic and diastolic LV function during and after anthracycline chemotherapy.
Methods
A total of 39 women enrolled in a randomized trial comparing a liposomal doxorubicin-based versus an epirubicin-based chemotherapy regimen for breast cancer and providing ≥4 separate echocardiographic assessments were included in the present ancillary analysis. The details of the Liposomal doxorubicin-Investigational chemotherapy–Tissue Doppler imaging Evaluation (LITE) randomized clinical trial have been previously published. Anthracyclines were given in combination regimens according to international standards with cyclophosphamide, docetaxel, and 5-fluorouracil. The patients received epirubicin or doxorubicin every third week. All patients underwent at baseline, after the end of treatment, and at 6, 12, and 18 to 24 months of follow-up, a comprehensive clinical evaluation, including 12-lead electrocardiography and standard and TDI transthoracic echocardiography, as previously described. The local ethics committee approved the present study and each patient gave written, informed consent.
All echocardiographic evaluations were performed with the patient in the left lateral decubitus position, using a commercially available imaging system (IE33, Philips, Andover, Massachusetts) equipped with an S5, 1 to 5-MHz, phased-array probe. Each patient underwent standard M-mode, 2-dimensional, and Doppler echocardiographic studies at baseline, at the end of chemotherapy, at the mid-term (12 months), and at the long-term follow-up point (24 months). M-mode images of the left ventricle were obtained in the parasternal long-axis view, and the LV end-diastolic and end-systolic diameters were measured just below the mitral valve leaflets tips after alignment of the cursor perpendicular to the LV wall, according to the American Society of Echocardiography guidelines. The LV end-diastolic and end-systolic volumes were calculated using the biplane modified Simpson rule in the 4- and 2-chamber apical views, and the LV ejection fraction (LVEF) was derived from these volumes. Apical-view Doppler echocardiography was used to measure the transmitral peak flow velocities: the mitral peak E velocity at rapid ventricular filling and mitral peak A velocity at atrial contraction, their ratio (E/A), and the E wave deceleration time at the mitral tips. Pulsed TDI was used to measure the early and late diastolic velocities at the lateral and medial corner of the mitral annulus (Em and Am, respectively), their ratio (Em/Am), the peak early diastolic filling and Em (E/Em), and the peak systolic velocity (S wave) at both corners. The right ventricular peak systolic velocity was obtained placing the sample volume at the lateral corner of the tricuspid annulus. All parameters were measured during 3 consecutive cycles (selected according to image quality) and averaged.
Continuous variables are reported as the median (first to third quartile) and categorical variables as numbers (percentages). Repeat-measure nonparametric analyses were used to appraise the changes over time in the standard and tissue Doppler imaging echocardiographic parameters. Friedman and Wilcoxon nonparametric tests were used to test for differences between groups for continuous variables and chi-square tests for categorical variables. Statistical significance was set at the 2-tailed 0.05 level, and the reported p values are unadjusted for multiple testing. Computations were performed with Statistical Package for Social Sciences, version 20 (IBM, Armonk, New York).
Results
The study population characteristics and cumulative doses per cycles and per patient are listed in Table 1 . During the follow-up period, 1 death (3%) occurred and 3 patients developed (8%) cancer recurrence. No woman had signs of HF nor began treatment with angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or β blockers during the study period. The echocardiographic data at baseline, the end of chemotherapy, and mid- and long-term follow-up are listed in Table 2 . Before starting chemotherapy, all patients had basically normal echocardiographic findings, with a normal LVEF, no E/E′ ratio >15, and nonsevere valvular pathologic features. In 5 patients, an E/A ratio <1 was recorded. The results of an inferential analysis of the temporal changes in the echocardiographic parameters are listed in Table 3 .
| Variable | Value |
|---|---|
| Age (yrs) | |
| Median | 49 |
| First to third quartile | 40–53 |
| Family history of cardiac disease | 13 (33) |
| Hypertension ∗ | 7 (18) |
| Hypercholesterolemia † | 15 (39) |
| Diabetes mellitus | 6 (15) |
| Current or former smoking | 13 (34) |
| Body surface area (m 2 ) | |
| Median | 1.69 |
| First to third quartile | 1.60–1.80 |
| Body mass index (kg/m 2 ) | |
| Median | 23.2 |
| First to third quartile | 21.4–26.1 |
| Baseline ST-T electrocardiographic changes | 7 (18) |
| Baseline medical therapy | |
| Angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers | 4 (11) |
| β Blockers | 6 (15) |
| Statins | 2 (5) |
| Cumulative doses per cycle (mg/m 2 ) | |
| 5-Fluorouracil | |
| Median | 820 |
| First to third quartile | 775–885 |
| Anthracyclines | |
| Median | 100 |
| First to third quartile | 85–162 |
| Cyclophosphamide | |
| Median | 850 |
| First to third quartile | 800–945 |
| Docetaxel | |
| Median | 128 |
| First to third quartile | 120–142 |
| Cumulative doses per patient (mg/m 2 ) | |
| 5-Fluorouracil | |
| Median | 4,920 |
| First to third quartile | 4,650–5,310 |
| Anthracyclines | |
| Median | 600 |
| First to third quartile | 507–972 |
| Cyclophosphamide | |
| Median | 4,920 |
| First to third quartile | 4,740–5,550 |
| Docetaxel | |
| Median | 765 |
| First to third quartile | 720–851 |
| Cancer death during follow-up | 1 (3) |
| Cancer recurrence during follow-up | 3 (8) |
∗ Systolic blood pressure >140 mm Hg or diastolic blood pressure >90 mm Hg.
| Variable | Baseline (n = 39) | End of Chemotherapy (n = 39) | Mid-Term Follow-Up (n = 39) | Long-Term Follow-Up (n = 39) |
|---|---|---|---|---|
| Interval from echocardiogram and beginning of chemotherapy (mo) | — | 4.3 (3.9–4.8) | 11.2 (10.3–12.5) | 22.4 (17.0–31.1) |
| Standard echocardiography | ||||
| LVEF (%) | 63 (61–66) | 61 (57–63) | 63 (60–67) | 64 (61–69) |
| End-diastolic diameter (mm) | 46 (43–49) | 46 (44–48) | 46 (42–48) | 46 (43–50) |
| End-systolic diameter (mm) | 28 (26–30) | 29 (26–31) | 29 (25–31) | 28 (25–30) |
| E wave (cm/s) | 84 (67–92) | 68 (58–89) | 70 (62–70) | 72 (64–86) |
| A wave (cm/s) | 61 (55–73) | 65 (55–78) | 62 (53–70) | 62 (53–76) |
| Deceleration time (ms) | 210 (180–230) | 210 (163–230) | 200 (188–230) | 210 (200–250) |
| TDI | ||||
| Lateral wall Em wave (cm/s) | 16 (13–18) | 13 (11–15) | 12 (11–15) | 14 (10–15) |
| Lateral wall Am wave (cm/s) | 9 (7–11) | 9 (8–11) | 9 (8–10) | 9 (7–10) |
| Septal Em wave (cm/s) | 11 (10–13) | 9 (7–11) | 9 (7–11) | 9 (7–11) |
| Septal Am wave (cm/s) | 9 (7–10) | 9 (8–11) | 9 (7–10) | 9 (7–10) |
| Mean E wave (cm/s) | 13 (11–15) | 11 (9–13) | 11 (9–13) | 12 (9–13) |
| Lateral wall S wave (cm/s) | 10 (8–12) | 9 (8–11) | 10 (9–11) | 10 (9–12) |
| Septal S wave (cm/s) | 8 (7–9) | 8 (7–9) | 8 (7–9) | 8 (7–9) |
| Right ventricular S wave (cm/s) | 13 (11–15) | 13 (12–15) | 13 (11–14) | 14 (12–15) |
| Ratio | ||||
| E/A | ||||
| <1.0 | 5 (13) | 15 (39) | 12 (31) | 5 (13) |
| 1.0–2.0 | 32 (82) | 24 (61) | 25 (64) | 33 (85) |
| >2.0 | 2 (5) | 0 | 2 (5) | 1 (3) |
| Lateral wall Em/Am | ||||
| <1.0 | 4 (10) | 8 (21) | 7 (18) | 4 (10) |
| 1.0–2.0 | 23 (59) | 26 (67) | 24 (62) | 26 (67) |
| >2.0 | 12 (31) | 5 (13) | 8 (21) | 9 (23) |
| Septal Em/Am | ||||
| <1.0 | 8 (21) | 19 (49) | 16 (41) | 12 (31) |
| 1.0–2.0 | 22 (56) | 15 (38) | 18 (46) | 25 (64) |
| >2.0 | 9 (23) | 5 (13) | 5 (13) | 2 (5) |
| E/lateral wall Em | 5.6 (4.4–6.7) | 6.5 (5.4–8.0) | 5.8 (4.8–7.1) | 5.5 (4.7–7.2) |
| E/septal wall Em | 8.3 (5.9–9.3) | 7.7 (6.2–9.8) | 8.3 (6.4–9.9) | 8.4 (6.4–9.9) |
| E/mean Em | 6.5 (5.3–7.8) | 5.5 (4.5–7.2) | 6.7 (5.9–8.2) | 6.7 (5.5–8.1) |
| Variable | Overall p Value | Baseline vs End of Chemotherapy | Baseline vs Mid-Term | Baseline vs Long-Term | End of Chemotherapy vs Mid-Term | End of Chemotherapy vs Long-Term | Mid-Term vs Long-Term |
|---|---|---|---|---|---|---|---|
| Standard echocardiography | |||||||
| LVEF | 0.001 | <0.001 | 0.676 | 0.897 | 0.021 | <0.001 | 0.071 |
| End-diastolic diameter | 0.645 | — | — | — | — | — | — |
| End-systolic diameter | 0.434 | — | — | — | — | — | — |
| E wave | 0.006 | 0.003 | 0.001 | 0.013 | 0.777 | 0.406 | 0.647 |
| A wave | 0.150 | — | — | — | — | — | — |
| Deceleration time | 0.057 | — | — | — | — | — | — |
| TDI | |||||||
| Lateral wall Em wave | 0.001 | <0.001 | <0.001 | 0.001 | 0.717 | 0.788 | 0.822 |
| Lateral wall Am wave | 0.532 | — | — | — | — | — | — |
| Septal Em wave | 0.001 | — | — | — | — | — | — |
| Septal Am wave | 0.124 | — | — | — | — | — | — |
| Mean E wave | <0.001 | <0.001 | <0.001 | <0.001 | 0.889 | 0.971 | 0.922 |
| Lateral wall S wave | 0.470 | — | — | — | — | — | — |
| Septal S wave | 0.917 | — | — | — | — | — | — |
| Right ventricular S wave | 0.156 | — | — | — | — | — | — |
| Ratios | |||||||
| E/A | 0.047 | 0.017 | 0.154 | 0.839 | 0.308 | 0.024 | 0.115 |
| Lateral wall Em/Am | 0.489 | — | — | — | — | — | — |
| Septal Em/Am | 0.049 | 0.031 | 0.121 | 0.066 | 0.767 | 0.068 | 0.223 |
| E/lateral wall Em | 0.006 | <0.001 | 0.922 | 0.139 | 0.003 | 0.007 | 0.814 |
| E/septal wall Em | 0.658 | — | — | — | — | — | — |
| E/mean Em | 0.011 | 0.018 | 0.893 | 0.118 | 0.009 | <0.001 | 0.799 |
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