Translating biomarkers from animal models to the clinic: validating assays in healthy volunteers.

Heart failure (HF) is a leading cause of hospitalization and mortality. It is a
common health problem particularly in the elderly. Existing biomarkers can only
be used to monitor progression of HF and they cannot predict the disease before
clinical symptoms become apparent.
Research over the last decades has provided strong evidence of inflammatory
activity as an important pathway in early phase of HF. Seminal clinical data
found raised plasma levels of cytokines in HF patients and subsequent animal
experiments suggested that certain anti-inflammatory therapies may be
beneficial.
The specific role of cytokines and chemokines is not yet dissected, but it is
generally acknowledged that they play an important role in the cardiac
remodeling and disease progression, particularly during early phases.
Therefore our research group has investigated in animal models that develop
left ventricle (LV) remodeling in response to pressure overload (TAC:
transverse aortic constriction) or permanent myocardial infarction (MI) to
identify the inflammatory mediators involved. The results indicate that in TAC
mice a strong increase in circulating levels of at least 4 biomarkers take
place. Interestingly, two out of these four molecules have never been described
in literature as heart failure related. We identified that the same 4
biomarkers are elevated in serum of MI rats. The cardiac origin of these
analytes was confirmed by analyzing homogenates of remote cardiac tissue,
obtained from the septum. As a positive control, we demonstrate the presence of
TIMP-1, a circulating inhibitor of matrix metalloproteinases, in both serum and
tissue obtained from the infarct area of rat hearts.
The new potential biomarkers are offering advantages over the existing
biomarkers used in the clinic: BNP and NT-proBNP. Indeed, the natriuretic
peptides are detectable only when the disease has been already established.
Thus, the new putative biomarkers may be helpful in the early diagnosis and
prognosis of HF.

The aim of our study is to identify the same 4 circulating analytes identified
in the animal models in human subjects. An additional task will be to measure
the basal levels and the inter-individual variability.

15 males and 15 females according to the inclusion/exclusion criteria will be
selected.
Each human subject will undergo a short questionnaire of 10 minutes to exclude
significant disease and will give blood via venipuncture 2 times a day (one in
the morning and one in the afternoon). At each session 15ml of blood will be
withdrawn.

Inconvenience of blood sampling and spending time in our outpatient department.