Processed BNP Molecular Forms As A New Generation Biomarker In Cardiovascular Disease

B-type natriuretic peptide (BNP), a clinical biomarker for cardiovascular disease (CVD), is secreted by cardiac tissue in response to neurohormonal stresses. However, BNP is processed in circulation by peptidases to produce molecular forms. Clinical BNP measurements associate with prognosis in CVD, but associations with molecular forms are not known. This thesis investigated the prognostic role of three major circulating BNP molecular forms (5-32, 4-32 and 3-32) in patients with CVD. BNP molecular forms were measured in plasma using an immuno-capture method followed by matrix-assisted laser desorption/ionisation-time of flight-mass spectrometry (MALDI-ToF-MS) analysis. Circulating levels were investigated for associations with adverse events and compared to clinical measurements for prognosis and risk stratification. BNP molecular forms independently predicted adverse events in patients with acute hospitalisations of heart failure (HF) (n=904) and myocardial infarction (MI) (n=1078), and predict death in chronic HF (n=1127). Prognostic ability was comparable with conventional BNP measurements for mortality from 6 months up to 3 years. Of the molecular forms, BNP 5-32 showed superior prediction qualities, indicating its utility in prognosis. Decision tree analysis showed the potential of BNP 5-32 as a secondary marker in MI after Global Registry of Acute Coronary Events (GRACE) scoring in identifying low-risk patients at 6 months. Serial measurements of BNP 5-32 showed that patients with elevated levels at follow-up were associated with worse outcomes. The results presented in this thesis, for the first time, demonstrate that BNP molecular forms provide beneficial prognostic information for outcome in CVD patients in a comparative or superior manner to current clinical protocols. In the personalised medicine era, measurement of specific BNP forms may provide additive information in CVD and improve risk stratification. The niche for these molecular forms remains to be elucidated and further research is warranted for clinical translation.