In the present study, we report that in patients treated with a combination of anthracyclines and trastuzumab, an early decrease in myocardial strain or elevation in plasma troponin as detected with a high-sensitivity assay predicts the later occurrence of cardiotoxicity. Subsequent cardiotoxicity is not clearly predicted by early changes in the LVEF or NT-proBNP level.
Patients enrolled in our study experienced decreases in the LVEF of similar magnitude as those reported previously in patients treated with anthracyclines and trastuzumab.4–6
Peak systolic radial, longitudinal, and circumferential strain decreased before any LVEF decrease. Similarly, in 13 children and in 16 women treated with anthracyclines, investigators reported decreases in peak systolic longitudinal and radial strain during the treatment.7,8
In contrast, echocardiograms obtained before and after trastuzumab therapy did not reveal a decrease in myocardial strain.9
Although we reported that in a mouse model of anthracycline-induced cardiotoxicity, myocardial strain rate predicted later decrease in the LVEF and subsequent mortality,10
the value of an early measurement of myocardial strain in humans for the prediction of later cardiotoxicity has not been reported.
Several factors may explain the increased sensitivity of strain compared to the LVEF in the detection of early cardiotoxicity found in our patients. As suggested by our findings, it is conceivable that the chemotherapy-induced cardiotoxicity has a regional pattern; the function of some myocardial segments may compensate for others, leading to a preserved LVEF, at least in the early stages. Another possible contributing factor to the higher sensitivity of strain compared to the LVEF may be variability. Strain measurement involves the averaging of the automated measurement of multiple segments, whereas LVEF assessment involves a tracing leading to 1 measurement. The variability (especially in the longitudinal dimension) may therefore be lower for strain than for the LVEF, particularly in patients with suboptimal images.
Using a high-sensitivity assay, we found that troponin I was elevated at 3 months of treatment in 28% of patients, suggesting that myocardial damage is frequent in chemotherapy-treated patients. Whereas Cardinale et al11
detected elevated troponin in 33% of patients after high doses of anthracyclines, more recent studies report less frequent troponin elevation and no value in predicting the decrease in LVEF after anthracyclines.12,13
In the present study, 1 sample obtained at 3 months of treatment was able to detect later LVEF decrease in 6 of 9 patients. Reconciling the results of previous studies, it is necessary to point out that the assay used in this study possesses an analytic precision that allows resolution of very small elevations in troponin I.
Neither the baseline value nor the change in NT-proBNP between 0 and 3 months was predictive of later decrease in the LVEF. Patients decreased their mitral annular velocities (E′) throughout the treatment (p = 0.004). This decrease was not accompanied by a decrease in the ratio of transmitral early peak velocity to early mitral annular velocity (E/E′) and may reflect subtle diastolic abnormalities rather than changes in filling pressures. This decrease was significant at the earliest time point (3 months) and is consistent with the early diastolic abnormalities reported in earlier studies.14–16
The follow-up period of the patients was 6 months; longer periods of follow-up will be necessary to determine whether the decrease of longitudinal strain or the increase in troponin is predictive of later cardiac events. The estimated sensitivity and specificity should also only be considered preliminary estimates considering the small number of patients.
The clinical implications of the present study are important. The reported findings demonstrate that myocardial strain and troponin, 2 noninvasive, easily performed measurements, recognize subtle myocardial alterations and predict later decrease in the LVEF in patients receiving anthracyclines and trastuzumab. The negative predictive value of the 2 tests allows the confident exclusion of cardiotoxicity detected by LVEF assessment 3 months later. Patients who do not have decreases of >10% in their peak systolic longitudinal strain or elevated hsTnI levels have a 3% probability of decreases in their LVEFs 3 months after the evaluation. In contrast, patients who either demonstrate decreases in longitudinal strain or elevations in hsTnI have a ninefold increase in risk for cardiotoxicity at 6 months compared to those with no changes in either of these markers. The presence of these predictive markers does not mandate cessation of a potentially lifesaving anticancer therapy. Rather, myocardial strain and hsTnI measurements may help target patients who could benefit from closer cardiac monitoring, earlier initiation of cardioprotective medical therapy, or less cardiotoxic novel tyrosine kinase inhibitors and anticancer drugs.