Dynamics and prognostic role of galectin-3 in patients with advanced heart failure, during left ventricular assist device support and following heart transplantation

Galectin-3 levels with LVAD support

That galectin-3 levels may initially decrease after LVAD implantation but were significantly increased at explantation offers interesting insight into the pathologic changes that occur with mechanical support. Evidence regarding changes in fibrosis following LVAD implantation have been conflicting [17]. Our group previously demonstrated decreased ECM turnover with reduced levels of circulating and myocardial metalloproteinases following LVAD placement [18]. Similarly, others have shown decreased myocardial collagen content in LVAD-supported patients [19, 20]. However, others have shown an increase in collagen deposition and an associated increase in myocardial stiffness [10, 21, 22].

Only one recent study analyzed changes in galectin-3 levels in patients undergoing LVAD implantation. Milting et al. found that 30 days post-implantation, ECM turnover defined by changes in levels of matrix metalloproteinases and their tissue inhibitors increased, but galectin-3 levels remained the same [23]. Our average length of LVAD treatment of 277 days is longer than in the study by Milting et al., which may explain why we were able to detect an increase in galectin-3 levels.

The dynamics of galectin-3 levels following LVAD implantation may be indicative of the complicated changes in myocardial structure and fibrosis, and further studies are necessary to more clearly elucidate these fluctuations in galectin-3 levels. Because galectin-3 is secreted in response to mechanical stress, decreased expression shortly after device implantation may be explained by ventricular unloading. However, elevated levels at explantation may indicate that prolonged mechanical support leads to an increase in inflammation and cardiac fibrosis. This is consistent with the results of Maybaum et al., who found that although LVEF significantly improved after LVAD implantation in almost all patients, longer duration of LVAD support appeared to deleteriously affect LV function [24]. Pathologic studies should be conducted to correlate galectin-3 levels with the amount of fibrosis as well as cardiac macrophage content and activation. The specific signals for increasing fibrosis after LVAD placement have not yet been fully elucidated, but the identification and reversal of this pro-fibrotic signal could assist to better define the potential of temporary LVAD placement as a “bridge to recovery” intervention in certain patients with advanced HF.

Adding to the value of galectin-3 is its potential use as a predictor of poor outcome in patients with HF. Van Kimmenade et al. found galectin-3 levels to be prognostic of adverse outcomes over 60 days [5]. Galectin-3 has also been shown to be an independent predictor of mortality in patients with NYHA class III-IV HF and in the general population, with levels 25.9 ng/ml shown to be predictive of a rapid progression of HF [3, 6, 7]. Adding to these findings, galectin-3 levels were predictive of survival in our cohort of patients undergoing LVAD placement, with plasma levels greater than 30 ng/ml at the time of implantation associated with greater mortality. Of note, although patients with galectin-3 levels 30 ng/ml were of similar age, NYHA Class, and had similar duration of HF and BNP levels than those with galectin-3 levels 30 ng//ml, patients with higher galectin-3 levels did have higher creatinine levels. It is possible, therefore, that some of the increased risk seen was due to impaired renal function. However, another study found that levels were a univariate but not independent risk factor for death in patients undergoing LVAD implantation [25]. These results indicate that this predictive value may be applicable to the subset of HF patients undergoing LVAD implantation, providing important prognostic information that may be used for patient selection and for stratifying high-risk patients.