Exploring collagen remodeling and regulation as prognosis biomarkers in stable heart failure.

We assessed the predictive ability of circulating biomarkers involved in collagen synthesis (procollagen type I N-terminal propeptide [PINP], and procollagen type III N-terminal propeptide [PIIINP], collagen degradation (c-terminal telopeptide of collagen type I [CTx] and mediators of cardiac fibrosis (Galectin-3 and soluble suppression of tumorigenicity 2 protein or sST2) as prognosis markers in 182 subjects with chronic heart failure (HF). In univariate analysis, all markers predicted mortality (except for PINP). A multivariate baseline model was fitted including variables potentially associated with mortality in HF patients. The baseline regression model included age, clinical data and biomarkers. We created four models from the baseline model augmented with the levels of hs-cTnT, CRP and NT-proBNP (model 1), CTx/PIIINP ratio, sST2 and Galectine-3 (model 2), NT-proBNP and sST2 (model 3) and NT-proBNP, CTx/PIIINP ratio and sST2 (model 4), to test whether these biomarkers have an incremental value for predicting mortality. After the addition of all biomarkers to the baseline model, age, CTx/PIIINP ratio and sST2 remained significant predictors. By contrast, Galectin-3 was not significantly associated with mortality. A multimarker strategy, demonstrated that the greatest prognostic improvement was attained with the combined addition of CTx/PIIINP ratio and sST2 highlighting the potential role of fibrosis pathways in risk stratification.

Cardiac mGluR1 metabotropic receptors in cardioprotection.

AIMS: In a previous study using a genome-wide microarray strategy, we identified metabotropic glutamate receptor 1 (mGluR1) as a putative cardioprotective candidate in ischaemic postconditioning (PostC). In the present study, we investigated the role of cardiac mGluR1 receptors during cardioprotection against myocardial ischaemia-reperfusion injury in the mouse myocardium. METHODS AND RESULTS: mGluR1 activation by glutamate administered 5 min before reperfusion in C57Bl/6 mice subjected to a myocardial ischaemia protocol strongly decreased both infarct size and DNA fragmentation measured at 24 h reperfusion. This cardioprotective effect was mimicked by the mGluR1 agonist, DHPG (10 µM), and abolished when glutamate was coinjected with the mGluR1 antagonist YM298198 (100 nM). Wortmannin (100 nM), an inhibitor of PI3-kinase, was able to prevent glutamate-induced cardioprotection. A glutamate bolus at the onset of reperfusion failed to protect the heart of mGluR1 knockout mice subjected to a myocardial ischaemia-reperfusion protocol, although PostC still protected the mGluR1 KO mice. Glutamate-treatment improved post-infarction functional recovery as evidenced by an echocardiographic study performed 15 days after treatment and by a histological evaluation of fibrosis 21 days post-treatment. Interestingly, restoration of functional mGluR1s by a PostC stimulus was evidenced at the transcriptional level. Since mGluR1s were localized at the surface membrane of cardiomyocytes, they might contribute to the cardioprotective effect of ischaemic PostC as other Gq-coupled receptors. CONCLUSION: This study provides the first demonstration that mGluR1 activation at the onset of reperfusion induces cardioprotection and might represent a putative strategy to prevent ischaemia-reperfusion injury.