Galectin-3 and fibulin-1 in systolic heart failure

The primary findings of the present study were that plasma Gal-3 and fibulin-1 levels were elevated in HFrEF patients with abnormal glucose metabolism compared to HFrEF patients with NGT. The impact of impaired glucose metabolism on both Gal-3 and fibulin-1 levels was underlined by an independent association with increasing HbA1c. However, increased Gal-3 and fibulin-1 levels were not associated with the reduced contractile reserve observed among diabetic HFrEF patients.

Median Gal-3 level was 16.0 ng/mL, which is similar to findings in comparable HFrEF populations and clearly increased compared to healthy subjects [17, 18]. The mean fibulin-1 level in our HF population was 57?±?16 ?g/mL, which is slightly higher than the mean level observed in a DM population (46?±?1.3 ?g/mL [19]). Fibulin-1 is a novel biomarker and high concentrations have primarily been reported in patients with aortic stenosis and DM compared to a level of 5.6 (4.1–8.4) ?g/mL reported in healthy men [11, 20, 21].

The current results suggest that glucose metabolism is associated with circulating Gal-3 concentrations in HF, as elevated levels were found in patients with DM and an association with increasing HbA1c was demonstrated. The observations were supported by two previous studies reporting increased concentrations in patients with type 2 DM [18, 21]. However, we found a significant impact of renal function on plasma Gal-3 levels suggesting that other parameters, such as DM complications like diabetic nephropathy were more predictive of Gal-3 levels in HFrEF patients.

With regard to fibulin-1 we found elevated concentrations among patients with IGT and DM compared to NGT and a positive association with HbA1c, which corresponds with previous findings among type 2 DM reporting elevated circulating levels and of an up-regulation of fibulin-1 in the arterial walls [19, 22].

To our knowledge, the present study is the first to evaluate the relation between circulating Gal-3 and fibulin-1 levels and cardiac function evaluated by LDDE. Galectin-3 was not associated with LV contractile reserve and LVEF during low dose dobutamine infusion after adjusting for relevant confounders, especially eGFR. The present study demonstrated that impaired renal function was a strong and independent predictor of elevated Gal-3 levels, which is in line with previous studies in patients with DM and in a community cohort [8, 23]. The elimination of Gal-3 has to our best knowledge not been described, but the present findings indicate a renal component. The gold standard for evaluation of myocardial fibrosis requires an endomyocardial biopsy, which is a high-risk procedure. Cardiac magnetic resonance imaging (CMR) is another method that seems to provide a good estimate of myocardial fibrosis [24, 25]. However, it is technically difficult to perform CMR in patients with AF and devices; which are highly prevalent in HFrEF patients. Furthermore, the association between cardiac fibrosis estimated by CMR and Gal-3 levels is not well described. In patients with previous myocardial infarction Gal-3 was moderately associated with LVEF and infarct size [26]. We report no association of the biomarkers Gal-3 with IHD. A proposed mechanism could be that former MI in our HFrEF patients are not associated with persisting increased activity of the fibrotic tissue and thereby secretion to the circulation of these biomarkers.

Myocardial fibrosis evaluated by histomorphometry and LV contractile reserve seems associated in patients with dilated cardiomyopathy [5]. In patients with acute decompensated HF, the PRIDE study reported a relationship between Gal-3 and resting echocardiographic parameters related to diastolic function [27]. In the current cohort of patients with chronic HFrEF we found no independent association with parameters related to diastolic function (data not shown).

We found no association between fibulin-1 levels and LV contractile reserve, while univariable associations were demonstrated between fibulin-1 and resting parameters LVEF and S’. However, no association was shown in the multivariable analyses. This is partly in accordance with data from patients with aorta stenosis, where fibulin-1 levels were related with S’, but not with LVEF [10]. Furthermore, we demonstrated a moderate, inverse association with eGFR which could blunt a potential weaker association with LV contractile reserve.