Relationship of Circulating Matrix Biomarkers to Myocardial Matrix Metabolism in Advanced Heart Failure

Aims: Interstitial fibrosis is a key component of myocardial remodelling in heart failure (HF). Many studies have measured peripheral blood levels of procollagens and matrix metalloproteinases (MMPs), as a surrogate for myocardial matrix metabolism, particularly to evaluate the effect of interventions and their prognostic relevance. However, the relationship between peripheral biomarker levels and actual cardiac turnover in HF is not known. We aimed to determine whether peripheral levels of relevant biomarkers reflect cardiac release in patients with advanced HF.

Methods And Results: We determined whether the failing human heart releases collagen precursors [procollagen I N-terminal peptide (PINP) and procollagen III N-terminal peptide (PIIINP)], or key matrix metalloproteinases (MMP9) and MMP inhibitors [tissue inhibitor of metalloproteinase 1 (TIMP1)] by performing transcardiac blood sampling in healthy controls (n = 9) and in patients with advanced HF (n = 18, left ventricular ejection fraction 22 ± 2%). HF patients had higher arterial levels of PIIINP compared with controls (7.0 ± 0.7 vs. 4.0 ± 0.2 µg/L, P < 0.001). PIIINP was closely correlated with the pulmonary capillary wedge pressure (r = 0.54, P = 0.01) and the estimated glomerular filtration rate (r = -0.50, P = 0.01). Transcardiac blood sampling demonstrated that there was no net release of either PINP or PIIINP in controls or HF patients. The transcardiac MMP9 gradient was significantly lower in HF patients (P < 0.05), and was negatively correlated with left ventricular mass (r = -0.51, P = 0.01).

Conclusions: Our study shows that the concentration of circulating levels of PINP, PIIINP, MMP9, and TIMP1 do not accurately reflect cardiac turnover. This study highlights the importance of performing transcardiac blood sampling to validate the utility of emerging cardiac biomarkers.