Biomarkers to Predict the Response to Cardiac Resynchronization Therapy

Ward Heggermont; Angelo Auricchio; Marc Vanderheyden


Europace. 2019;21(11):1609-1620. 

In This Article

The Extracellular Matrix

One of the most important features of a beneficial CRT response, especially in the super-responders to CRT, is impactful reverse remodelling of the left ventricle. This process involves significant improvement of contractile function, thickening of the walls to again-physiological properties, and a decrease of the LVESV.[24] A systematic review on extracellular matrix biomarkers has been published recently.[25] N-terminal propeptides of type I and type III procollagens (PINP and PIIINP), type I collagen telopeptide (ICTP), and matrix metalloproteinase 1 (MMP-1) were measured in a subpopulation of the CARE-HF trial patient group (260 patients). In a multivariate model, these markers did not predict a CRT response, although some of them were associated with long-term cardiovascular outcomes.[13,26] Similar findings were obtained for MMP-1 and tissue inhibitor of metalloproteinase 1 (TIMP-I) in a pilot study involving 42 patients.[27] In another small pilot study (n = 27 ischaemic cardiomyopathy patients of which only 15 receiving CRT), MMP-9, TIMP-1, ICTP, and carboxyterminal propeptide of type 1 procollagen (PICP) were determined before and 12 weeks after CRT implantation.[28] With respect to cardiac function parameters, the MMP-9/TIMP-1 ratio correlated positively with LVEF, but the meaning of these findings is still unclear as the patient groups are very small. In the Osmancik paper,[22] discussed earlier, tissue growth factor (TGF)-β1—a stimulator of fibrosis development—significantly decreased in CRT responders, whereas in non-responders, TGF-β1 significantly increased. In this study, TGF-β1 was a significant predictor of death during follow-up. Also osteopontin, a matrix glycoprotein required for the activation of fibroblasts upon TGF-β1 stimulation, is altered in patients who show signs of CRT-induced reverse remodelling: plasma osteopontin, higher in HF patients compared to healthy controls, decreased in CRT responders, and even increased in non-responders (pilot trial involving only 12 CRT patients).[29]