Introduction: Heart failure (HF) biomarkers dominate clinical research but their relation with structural and functional cardiac changes remains elusive and their tissue origin unknown. Therefore, we investigated HF biomarkers in multiple organs in three HF mouse models.
Methods: Galectin-3 (Gal-3), Growth Differentiation Factor-15 (GDF-15), Tissue Inhibitor of Matrix Metalloproteinases-1 (TIMP-1) and Endostatin were investigated up to 8 weeks post myocardial infarction (MI) and 4 and 8 weeks post transverse aortic constriction (TAC), both resulting in HF with reduced ejection fraction (HFrEF). HF with preserved ejection fraction (HFpEF) was generated by high fat diet for 16 weeks and angiotensin II (AngII) infusion during the last 4 weeks. Control mice were sham operated. Magnetic resonance imaging (MRI) and hemodynamic pressure measurements were recorded. Protein and mRNA levels were analyzed in left ventricle (LV), liver, kidney, lung, fat and blood plasma.
Results: Gal-3, GDF-15 and TIMP-1 LV gene expression and protein levels were increased in HFrEF and showed significant relations with LV remodeling and inverse relations with LV ejection fraction (LVEF). However, plasma levels were not elevated after TAC and 8 weeks post-MI despite low LVEF. Gal-3 and TIMP-1 plasma levels increased briefly after MI concomitant with a transient increase in LV expression. TIMP-1 and GDF-15 plasma levels did increase in some mice after TAC, which correlated with increased lung expression and congestion. Gal-3, GDF15 and TIMP1 plasma levels were increased in HFpEF, but obesity alone also resulted in increased plasma levels. This strongly correlated with elevated expression in adipose tissue irrespective of LV function. Obesity is therefore also a strong determinant for Gal-3, GDF15 and TIMP1 plasma levels. Plasma Endostatin increased with AngII infusion independent of obesity.
Conclusion: The heart minimally contributes to Gal-3, GDF-15 and TIMP-1 plasma levels, even if LV expression is elevated during cardiac stress. Increased plasma levels in HF most likely reflect production in other tissues. This explains why these biomarkers are strong predictors for death and adverse outcome not only in HF patients, but also in other patients and the general population.