Left atrial longitudinal strain as a predictor of Cancer therapeutics-related cardiac dysfunction in patients with breast Cancer

With the improvements in early detection and therapeutic advances including chemotherapy, cancer survival rates have been gradually improved [1]. In contrary to these improvement in cancer survival, cancer therapeutics-related cardiac dysfunction (CTRCD) became a major concern, and it affects considerable portion of patients who underwent chemotherapy. Various chemotherapeutic agents, have been reported to have higher risk of CTRCD [2], and patients with human epidermal growth factor receptor II (HER2)-positive breast cancer are particularly at high risk, since many of them receive anthracycline, anti-microtubule agents, and trastuzumab-based chemotherapy with or without radiation therapy, which are all known to have high risk of CTRCD. Echocardiography is the most widely used imaging modality in the evaluation of CTRCD, for its wide availability, no exposure to radiation or contrast agents, relatively low cost, and its ability to evaluate hemodynamic state of the heart. Conventionally, left ventricular ejection fraction (LVEF) has been broadly used as a diagnostic criterion [2], and recent studies have suggested that LV global longitudinal strain (GLS) is a useful parameter in detecting subclinical myocardial damage and thus can be used as a predictor of upcoming CTRCD [3]. The usefulness of other echocardiographic parameters such as isovolumic relaxation time, peak early velocity (E), peak atrial velocity (A) of pulsed wave mitral doppler flow, E/A ratio, E deceleration time [4, 5] or early diastolic mitral annular velocity (e’) were also evaluated in the prediction of upcoming CTRCD, but these parameters have not shown consistent clinical significance or usefulness to predict upcoming CTRCD.

Recently, left atrial (LA) GLS using 2-dimensional (2D) speckle-tracking echocardiography has been suggested as a method to represent LA functional state. It is a new promising approach for LA mechanics and electromechanical coupling [6], and it showed good correlation with pulmonary capillary wedge pressure, even better than E/e’ ratio in advanced heart failure (HF) [7]. However, the clinical significance of LA strain measurement in the prediction of upcoming CTRCD in patients with breast cancer has been poorly studied. Therefore, the authors investigated the usefulness of peak LA longitudinal strain (PALS) in the prediction of upcoming CTRCD after additional trastuzumab therapy in HER2-positive breast cancer patients who did not develop CTRCD after chemotherapy.

The authors investigated the clinical significance of LA strain analysis in the prediction of future CTRCD after additional trastuzumab therapy in patients with HER2-positive breast cancer who did not develop CTRCD after standard chemotherapy, and the present study demonstrated several clinically important findings. First, CTRCD was not uncommon (18.1%) after additional trastuzumab therapy, even in patients who did not develop CTRCD after chemotherapy for breast cancer. Second, after the completion of chemotherapy, conventional echocardiographic parameters were not changed, but PALS and LVGLS were significantly decreased. Therefore, it is suggested that PALS and/or LVGLS changes can be used as a more sensitive marker for cardiac injury after chemotherapy. Third, PALS decline after chemotherapy could predict upcoming CTRCD with better sensitivity and specificity than LVGLS. Therefore, serial measurement of PALS can be used as a useful parameter in the prediction of future CTRCD in patients with breast cancer.

Anthracycline, cyclophosphamide, taxane, and trastuzumab-based chemotherapy is an important and highly effective chemotherapeutic regimen in HER2-positive breast cancer patients, both increasing survival duration of metastatic breast cancer and decreasing cancer recurrence and death after proper surgical treatment [12]. However, both agents carry a significant risk of cardiotoxicity: about 15–30% of patients treated with an anthracycline and trastuzumab are reported to experience CTRCD, and the risk is especially high when anthracycline and trastuzumab are administered concurrently [13, 14].

To date, the most widely accepted diagnostic criterion of CTRCD is based on LVEF. But its utility for early detection or prediction of CTRCD is somewhat limited by its relatively low reproducibility [3], and relatively low sensitivity to detect subclinical cardiotoxicity [4]. As LVGLS is well known to be able to detect subclinical LV dysfunction before evident LV dysfunction develops, recently LVGLS has been used to define and predict future CTRCD [10, 15]. LVGLS has shown a good sensitivity (65–86%) and a good specificity (73–95%) for predicting subsequent declines in LVEF or HF [16], and the finding was reproduced in our results.

Diastolic dysfunction and increase in LV filling pressure occur in earlier stages of various forms of HF. Comprehensive evaluation of diastolic function, using conventional parameters is also recommended, and some previous studies reported early changes of diastolic functional parameters [17, 18]. However, in a more recent study, e’ value showed only insignificant changes between patients with CTRCD and ones without it [19], and similar tendency was observed in our results. Also, until today, none of conventional parameters of diastolic function have been proven to be well correlated with further LV dysfunction. But in the present study, parameters which are known to better reflect diastolic dysfunction and increased in LV filling pressure, such as E/e’ ratio and changes in PALS showed significant impairment in CTRCD group, suggesting presence of diastolic dysfunction in hearts affected by CTRCD. To our best knowledge the present study is the first one to demonstrate it, and also to demonstrate value of PALS in prediction of CTRCD. As LVGLS does, PALS can comprehensively analyze global myocardial function of the LA, and it may reflect impairment of mechanical function of LA muscle before general structural changes of the LA such as LA enlargement by chronic elevation of LV filling pressure occurs.

In this study, the patients who did not experience CTRCD also experienced continuous impairment of PALS, although degree of the change was smaller than the patients with CTRCD. In some previous reports, impairment of LVGLS was observed in patients undergoing breast cancer treatment with trastuzumab, suggesting presence of subclinical cardiac dysfunction in those patients [20]. Our results can be suggesting ‘more subclinical and earlier’ LV dysfunction and subsequent LA dysfunction, or can be suggesting myocardial dysfunction of the LA itself in breast cancer patients undergoing chemotherapy and/or HER2-targeted therapy, irrespective of presence of evident CTRCD. Whether impairment of PALS is only secondary to LV dysfunction, or due to LA myocardial dysfunction itself should be defined in further studies. But until today, we believe impairment of PALS is not a single change and is related to subclinical LV dysfunction and subsequent diastolic dysfunction, since other studies have shown its close correlation with LV filling pressure [7] and in our results PALS shown significant negative correlation with E/e’ ratio, which is already known to be a good surrogate marker of LV filling pressure.

One possible explanation about why diastolic parameters have not shown consistent and serial changes in cardio-oncology setting to date is because many patients with cancer suffer from disability to have enough oral intake, and they are frequently under a lot of fluid therapy, especially for chemotherapy. We tried to minimize their effect in this study, by checking echocardiography when the patients were at the outpatient setting and free of any intravenous fluid therapy at least for the day of echocardiography. Also, presence of ‘gray zone’ in prediction of LV filling pressure [7] could have masked subtle changes of diastolic function in cancer patients, which could be revealed with other fine modalities such as PALS. And as volumetric analyses of the LA can be easily confounded by measurement errors, conventional parameters of diastolic function might not reflect subclinical changes in diastolic function and the LA function, in patients undergoing chemotherapy.

In many other forms of chronic and progressive HF, LA volume is not necessarily normalized despite reduction of LV filling pressure, by irreversible damage and remodeling process. However, PALS seems to be improved by reduction of LV filling pressure [21], suggesting potential role of PALS as a more sensitive monitoring tool of diastolic dysfunction, and a predictive factor of further LV dysfunction as we demonstrated in this study. Still, we do not know whether impaired PALS is restored before or after reverse remodeling and functional recovery of the LV with cessation of trastuzumab and/or guideline-directed HF management. Although whether LV functional recovery is truly reversible or not is still controversial, myocardial dysfunction by trastuzumab is generally considered as a reversible one (type II cardiotoxicity) and global LV function is frequently improved after cessation of trastuzumab. And it is anticipated that we could observe further changes in both LA and LV function and define prognostic utility of PALS and reversibility of LA structure and function with cessation of trastuzumab and medical HF management.

This study has some limitations. First, as shown in Fig. 1, many patients were excluded in the analysis because of inadequate echocardiography follow up schedule because of retrospective nature of this study. Second, some patients were also excluded for poor speckle tracking in LVGLS or in LA GLS. Measuring LA GLS by speckle tracking has several technical limitations: far field location of the LA, dropping-out of several portions (especially the interatrial septum) of the LA wall, and thin LA wall thickness makes it difficult to precisely track the LA. Third, although reference values are being reported recently [10, 22], general application is not so easy yet because of intervendor variabilities and absence of standardized measurement method: to our best knowledge, the vast majority of studies using LA GLS required manual definition of LA borders and region of interest, limiting wide use of it in real practice. Fourth, though we tried to minimize effect of volume loading condition on strain parameters by checking echocardiography when the patients were free of intravenous fluid therapy, such effect could not be fully eliminated when other loading conditions (dehydration, excessive salt and water intake, etc) are present, without other informations such as serum pro-brain natriuretic peptide level. And, since this study is a single center study, our results need to be validated in multicenter studies later.

In conclusion, this study demonstrated that functional changes of the LA as measured by PALS and functional changes of the LV as measured by LVGLS precede before developing overt CTRCD defined by changes of LVEF. Also, serial changes of PALS showed even better sensitivity and specificity, compared with that of LVGLS. Therefore, the serial measurement of PALS can be used as a useful parameter in the prediction of future CTRCD. As serial changes of the LA in patients undergoing chemotherapy is not clearly defined yet, reversibility of LA structure and function with cessation of trastuzumab and medical HF management should be defined, and further studies are required.