Biomarkers of left ventricular remodeling after myocardial post-infarction and heart failure – PHOSTNT

Our objective is to validate the level of phosphorylation of troponin T as biomarker. An ELISA assay was developed using specific monoclonal antibodies against the phosphorylated troponin T and one antibody recognizing troponin T independently of the site of phosphorylation. This ELISA will be tested in normal populations to determine a “normal” value of phosphorylated troponin T. Then, we will quantify the level of phosphorylated TnT in the different populations of patients presenting left ventricular remodeling (REVE and REVE 2 studies) or suffering from heart failure (PTHF, INCA and COLLAG4 studies). The data will be correlated and adjusted with other conventional cardiac markers. The last step will be the demonstration of the relevance of this new biomarker, the phosphorylated form of troponin T, as diagnostic or pronostic marker in patients presenting heart failure.

Monoclonal antibodies specific of the phosphorylated form of troponin T are available.
The characteristics and biological samples of patients presenting left ventricular remodeling (REVE and REVE 2 studies) or suffering from heart failure (PTHF, INCA and COLLAG4 studies). We obtained agreement to access of samlples from healthy population, cad, without cardiovascular events (Stanislas cohort).
We have characterized REVE2 patients for cardiac conventional markers.
Another patent was filed with Inserm-Transfert.

Our objective is the validation of the level of phosphorylated troponin T as diagnostic and pronostic factor of left ventricular remodeling and of heart failure patients
A specific ELISA assay of the phosphorylated form of troponin T should allow to develop a diagnostic kit in which societies developing kits used at hospital should be interested.

Two papers have been published: one in Am J Cardiol (2012) which showed that the « ideal » biomarker associated to left ventricular remodeling was not yet identified and the second in Int J Cardiol (2013) that the levels of miR-133a and miR-423-5p are not associated to left ventricular remodeling.

Each year in France, 150,000 persons die from cardiovascular diseases, which are one of the major causes of mortality. Furthermore, each year 120,000 persons suffer from myocardial infarction (MI) while nearly 500,000 patients suffer of heart failure (HF). Left ventricular (LV) remodeling after MI is observed in 30% of patients despite modern therapeutic management. The discovery of circulating biomarkers as a signature of LV remodeling and HF allows for the development of biological tests that can be used for early diagnosis and risk stratification. The concept that biological markers may achieve this goal is an attractive one, because it is a non invasive, widely available, non operator-dependent, and relatively inexpensive method. Our aim is therefore to demonstrate that our new biomarker may help to predict : 1) LV remodeling in post-MI patients; and, 2) the severity and outcome of patients with chronic HF (systolic HF and with preserved ejection fraction). Previous experiments using an experimental model of MI in rats and phosphoproteomic technology, allowed us to discover a potential biomarker of LV remodeling: consisting of a decrease of phosphorylated troponin T (TnT) both in the heart and plasma of MI rats. We found in patients with high LV remodeling after MI, the same decrease of phosphorylated TnT compared to patients with no LV remodeling. Our objective is the validation and qualification of phosphorylated TnT as biomarker. For that purpose, an ELISA assay was developed using specific monoclonal antibodies against the phosphorylated TnT. This ELISA will be tested for its sensitivity and specificity in normal populations to determine a “normal” value of phosphorylated TnT. Then, we will quantify the level of phosphorylated TnT in the different populations of patients presenting LV remodeling (REVE and REVE 2 studies) or suffering from HF (PTHF, INCA and COLLAG4studies). The data will be correlated and adjusted with other conventional cardiac markers. Our purpose is the validation of the phosphorylated level of TnT as diagnostic, prognostic factors of LV remodeling and HF patients.
The strength of the collaboration of the three partners is that they possess complementary expertise in proteomics and in clinical studies dedicated to recruitment of patients with a precise and clear phenotype of LV remodeling post-MI and HF. Our purpose is to validate an ELISA kit to quantify the phosphorylated level of TnT as diagnostic, pronostic factors of LV remodeling and HF patients. The former ANR project granted (LREVMODEL (ANR-05-PCOD-021)) between the same three partners was fruitful with several publications and a patent (WO 2010/133655 A1) et and allowed the discovery of our potential biomarker.