Increased turnover of extracellular matrix proteins is seen in many different diseases and is an underlying and driving feature of pathogenesis. An increased ratio of formation over degradation of extracellular matrix proteins, such as collagens, leads to accumulation of proteins in the tissues, ultimately impairing organ function. Understanding how this balance is regulated is key to providing deeper insight into high extracellular matrix turnover diseases. Type XXVIII collagen is a novel collagen with limited information available in relation to expression, tissue prevalence and clinical implication. We generated a novel, technically robust ELISA to measure a C-terminal fragment of type XXVIII collagen in plasma and serum (PRO-C28). PRO-C28 was found to be significantly elevated in circulation in patients with heart failure with preserved ejection fraction (HFpEF) and in patients with lung cancer. Additionally, PRO-C28 correlated significantly to NT-proBNP levels in HFpEF patients. PRO-C28 levels were elevated in diseases characterized by high ECM-turnover. This suggests that type XXVIII collagen may play a role in fibroproliferative disorders in the heart and the lungs.