The protein galectin-3 (Gal-3) is part of a family of lectins involved in inflammation and fibrosis in relation to the heart and vascular system,1 as well as other organs, including the kidneys, liver, and pancreas.2 Clinical interest in serum Gal-3 has recently increased because it shows potential as a useful biomarker in patients with cardiovascular disease.3 Patients with heart failure (HF) show particularly high Gal-3 serum levels,4 which are significantly correlated with all-cause mortality and cardiovascular mortality in this population.5

Heart transplant (HT) is the therapy of choice for patients with advanced HF, offering excellent postoperative survival and quality of life.6 Chronic inflammation and interstitial fibrosis,7 together with ischemia, cellular hypertrophy and increased wall stiffness, are major determinants of long-term myocardial remodeling of the transplanted heart graft. The association of serum Gal-3 with the first 2 processes supports the exploration of the potential clinical usefulness of this biomarker in heart HT recipients.

In a single-center study, Coromilas et al.8 reported significantly decreased Gal-3 serum levels following HT, and noted that persistently elevated serum Gal-3 levels after HT correlated with a higher occurrence of coronary allograft vasculopathy (CAV). In contrast, Grupper et al.9 found that Gal-3 serum levels did not significantly change after HT, nor were they significantly correlated with the intensity of myocardial Gal-3 expression, the grade of cardiomyocyte hypertrophy, or fibrosis of the graft. Rather, these authors stated that Gal-3 serum levels were strongly influenced by renal function. Franeková et al.10 observed a significant correlation between Gal-3 serum levels, as assessed 10 days after HT, and reduced left ventricular ejection fraction 1 year after the intervention; however, no association between this biomarker and survival was found in this study.

The aim of our study was to analyze the trend of Gal-3 serum levels over the first year after HT, and to explore its potential prognostic value as a biomarker in HT recipients.

The major finding of this study is that serum levels of Gal-3, a known marker of inflammation, fibrosis, and adverse outcomes in patients with HF, showed a steady decreasing trend during the first year after HT. This decline likely reflected a progressive reversal of the preoperative state of HF after transplant. Moreover, this is the first study to support the prognostic value of serum Gal-3 in HT recipients. Within our cohort, patients who exhibited persistently elevated Gal-3 levels at the end of the first year after transplant showed significantly worse clinical outcomes over subsequent long-term follow-up.

Our results showing a declining trend of Gal-3 serum levels after HT differed from the findings of Grupper et al.9 In their study, they determined Gal-3 serum levels before and after HT among 62 patients with advanced HF at the Mayo Clinic. Although the mean pretransplant Gal-3 serum levels were consistent with those described in our population (20.3 ng/mL in the American study vs 19.1 ng/mL in our study), they did not observe a significant postoperative decrease. They concluded that serum Gal-3 levels strongly depend on the development of posttransplant renal function, and questioned the usefulness of this biomarker in HT recipients. Another study examined 85 stable HT recipients and reported mean posttransplant Gal-3 serum levels of 17.8 ng/mL, which were similar to the mean value determined in a parallel cohort of 55 patients with stable HF but were significantly lower than for a parallel cohort of 63 patients with severe HF.8

The discrepancy between our results and the findings of Grupper et al.9 are likely due to differences in the populations examined, as well as the different time-points for Gal-3 serum level measurement following HT. In the American study,9 there was a high prevalence of restrictive cardiomyopathy among HT candidates, probably because it was conducted in a large referral center for this specific cardiac disorder. In addition, there was wide interindividual variability in the interval from HT to serum Gal-3 measurement, with an IQR of 54-767 days. In contrast, we performed measurements at fixed time-points for all participants throughout the first year after transplant. This was an important difference, since a newly implanted heart graft has a progressive rather than an immediate effect with regards to normalizing hemodynamics and reversing the pathophysiological disturbances and end-organ dysfunction inherent to the preoperative, sometimes long-standing, systemic HF state. Moreover, in the early post-HT stages, recipients may show substantial systemic inflammatory activity caused by several triggers, such as surgical aggression, organ cold ischemia, blood transfusions, infection, and host-to-graft immune responses. Consistent with these arguments, our present findings did not indicate that Gal-3 serum levels immediately declined following HT. Compared with preoperative values, a significant decrease in Gal-3 serum level was first detected at 6 months post-HT.

Our results identified several clinical variables that were associated with posttransplant Gal-3 serum levels. Similar to previous reports,3,9,13 serum Gal-3 was inversely correlated with glomerular filtration rate, likely due to decreased biomarker clearance in patients with renal dysfunction. Post-HT Gal-3 serum levels were positively correlated with high right atrial pressure, a sensitive marker of heart graft dysfunction and a major determinant of cardio-renal syndrome.14 The use of mycophenolate mofetil was associated with lower posttransplant Gal-3 serum levels, which was consistent with the beneficial effects of this therapy on immune tolerance, graft function, and overall survival of HT recipients.15 We also found that lower donor age was associated with increased posttransplant serum Gal-3, which we could not explain. By contrast, previous studies have consistently shown that heart grafts from younger donors are less prone to failure than those from older donors.

The present study supports the strong prognostic value of serum Gal-3 in HT recipients. Patients with 1-year posttransplant Gal-3 serum levels above the reference limit of 17.8 ng/mL exhibited > 3-times the risk of all-cause death or hospitalization due to graft failure (ie, symptomatic HF caused by graft dysfunction) over subsequent long-term follow-up. This independent association between posttransplant serum Gal-3 and long-term clinical outcomes remained significant even after extensive multivariable adjustment for several clinical characteristics, including renal function.

Our findings are consistent with the previously reported prognostic value of serum Gal-3 in several subsets of patients with cardiovascular disease, especially among patients with HF.4,5 However, there remains a need for further examination of the possible reasons why persistently elevated Gal-3 serum levels are associated with increased risk of death and graft failure in HT recipients. Gal-3 serum level has been proposed as a cardiac biomarker based on its direct correlation with the grade of inflammation and, more importantly, fibrosis of cardiac tissue.1–3,16 Thus, it could be hypothesized that persistently elevated serum Gal-3 after HT may be a sensitive indicator of subtle subclinical structural changes in the heart graft reflected in the host immunological responses. In our study, the 1-year posttransplant Gal-3 levels were not significantly associated with the presence of cellular rejection or CAV at the same time point. However, this might be a reflection of the low sensitivity of the diagnostic tests used to detect graft rejection and CAV, endomyocardial biopsies and coronary angiography. Indeed, Coromilas et al.8 previously found that higher posttransplant Gal-3 serum levels were significantly associated with CAV occurrence.

Prior reports have questioned the clinical usefulness of serum Gal-3 as a cardiac biomarker due to its relative lack of specificity and its dependence on other biological variables, mainly renal function.8,11 In this respect, Gal-3 serum levels might reflect the grade of inflammation and fibrosis at biological levels other than the cardiovascular system, such as in the kidneys, liver, or pancreas.1 Notably, significantly increased serum Gal-3 has also been described in patients with some types of cancer.17 In patients with chronic HF, Gal-3 serum levels correlate with the severity of end-organ dysfunction. Therefore, persistent serum Gal-3 elevation after HT may at least partly result from the inability of the newly implanted heart graft to reverse the systemic pathophysiological abnormalities inherent in the preexisting HF syndrome. Notably, in our study, serum Gal-3 predicted all-cause mortality more accurately than graft failure, arguing against its specificity as a cardiac biomarker.

This study has several limitations. First, it was an observational study for which clinical data were collected retrospectively; therefore, the results are subject to potential selection, information, and confusion biases. Second, although the total study population included 122 HT recipients, banked serum samples for Gal-3 measurement were only available from 99 to 105 patients, depending on the time point. Third, CAV and acute rejection were detected based on endomyocardial biopsies and coronary angiographies, respectively, which were scheduled according to the standard clinical follow-up protocol of our center. We did not routinely use other more sensitive methods, such as intravascular ultrasound, which might have resulted in a significant number of false-negative diagnoses in our study. Fourth, there is presently a lack of information regarding the posttransplant dynamics of other clinically relevant biomarkers, such as NT-pro-BNP, and a comparison was not part of this study. Finally, we recognize that our statistical approach to the predictive accuracy of serum Gal-3 levels in HT recipients has limited value, and it should be confirmed through external validation in a larger, prospective cohort.

The results of this study demonstrate than Gal-3 serum levels steadily decreased over the first year after HT, with a significant reduction beyond 6 months posttransplant. Furthermore, HT recipients with persistently elevated Gal-3 serum levels at 1-year posttransplant exhibited lower graft failure-free survival during subsequent long-term follow-up. Remarkably, Gal-3 serum levels correlated better with the risk of all-cause mortality than with the risk of graft-related events, CAV, rejection, or hospitalization due to HF; this finding suggest that it might be considered as a systemic rather than a cardiac specific biomarker. Future prospective multi-institutional studies are warranted to clarify the value of serum Gal-3 as a biomarker in the routine clinical management of HT recipients.

This study was funded by the Project N° PI12/02670, integrated in the National Plan for Scientific Research, Development and Technological Innovation 2008-2011 and funded by the ISCIII (Instituto de Salud Carlos III) General Subdirection of Assessment and Promotion for Research-ERDF (European Regional Development Fund) “A way of making Europe”.

None declared.