Plasma levels of heart failure biomarkers are primarily a reflection of extracardiac production

Abstract

Plasma heart failure (HF) biomarkers, like natriuretic peptides, are important in diagnosis, prognosis and HF treatment. Several novel HF biomarkers have been identified, including Gal-3, GDF-15 and TIMP-1, but their clinical potential remains vague. Here we investigated plasma biomarker levels in relation to tissue expression and structural and functional cardiac changes.Methods: Cardiac remodeling, cardiac function, and plasma and tissue biomarker levels were investigated in mice after myocardial infarction induced by temporal and permanent LAD ligation (tLAD and pLAD). In addition, a pressure overload model induced by transverse aortic constriction (TAC) and an obese/hypertensive HFpEF-like mouse model were investigated.Results: Plasma levels of ANP and its cardiac expression were strictly associated with cardiac remodeling and function. Gal-3, GDF-15 and TIMP-1 cardiac expressions were also related to cardiac remodeling and function, but not their plasma levels. Only directly after myocardial infarction could elevated plasma levels of Gal-3 and TIMP-1 be detected. Eight weeks after infarction, plasma levels were not elevated despite enhanced cardiac expression and low EF (18.3±3.3%, pLAD). Plasma levels of TIMP-1 and GDF-15 were elevated after TAC, but this also correlated with increased lung expression and congestion. In obese-hypertensive mice, elevated plasma levels of Gal-3, GDF-15 and TIMP1 were associated with increased adipose tissue expression and not with cardiac function.Conclusions: The Gal-3, GDF-15 and TIMP-1 plasma pool levels are hardly influenced by dynamic changes in cardiac expression. These biomarkers are not specific for indices of cardiac remodeling, but predominantly reflect stress in other affected tissues and hence provide health information beyond the heart.

Towards better definition, quantification and treatment of fibrosis in heart failure. A scientific roadmap by the Committee of Translational Research of the Heart Failure Association (HFA) of the European Society of Cardiology

“…This may be explained because in heart failure patients, several other organs undergo fibrotic changes as well: liver, lungs, kidneys, and vessels. A recent article by Du and colleagues showed that galectin‐3, growth differentiation factor‐15, and TIMP‐1 plasma levels do not reflect myocardial fibrosis in mouse models of post‐MI heart failure, hypertensive heart failure, and HFpEF . Instead, production in extracardiac tissues such as fatty and lung tissue had much greater impact on plasma levels of these markers.…”

“…A recent article by Du and colleagues showed that galectin-3, growth differentiation factor-15, and TIMP-1 plasma levels do not reflect myocardial fibrosis in mouse models of post-MI heart failure, hypertensive heart failure, and HFpEF. 53 Instead, production in extracardiac tissues such as fatty and lung tissue had much greater impact on plasma levels of these markers. So ideally, we would need a marker that is specific for cardiac fibrosis, or at the very least, adequately reflects changes in myocardial fibrosis.…”

Multi-level transcriptome sequencing identifies COL1A1 as a candidate marker in human heart failure progression

“…Based on the previous studies, plasma biomarkers can offer great promise to further dissect the underlying disease processes, which are important in diagnosis, prognosis, and HF treatment [45,46]. Thus, we attempted to investigate whether the COL1A1 content in plasma would be used as a biomarker for HF progression.…”

The influence of atrial fibrillation on the levels of NT-proBNP versus GDF-15 in patients with heart failure

“…These data suggest that in patients with HF, after adjustment for clinical confounders, the levels of NT-proBNP, but not GDF-15, are significantly influenced by the presence of AF at time of measurement. GDF-15 is mainly produced in non-cardiac and peripheral tissues, such as endothelial cells and adipocytes, and we recently showed that the levels of GDF-15 in mice are 2-to 60-fold higher in the liver, lungs and kidney than in the cardiac muscle [19]. Therefore, this marker reflects changes in many organs, not just in the cardiac ventricles and atria, and might therefore be less likely to be load-dependent as compared with NT-proBNP.…”