4 DISCUSSION
4.9 Specific diagnosis of cardiovascular diseases with BNP metabolites
The early diagnosis of cardiovascular pathologies through the general practitioner before the manifestation of a cardiac event or in the clinical setting, when heart failure is often already present, is pivotal. A variety of biomarkers have been utilized during the last decades to make diagnosis faster and more efficient349-351. However, the limitation of many tests determining biomarkers including the conventional BNP-test is their lack in the differentiation between specific cardiovascular diseases220, 352,
353.
Many cardiovascular diseases have in common that gene and protein expression is altered, which in turn is depending on the specific pathology. It was found that gene expression is altered during heart failure. Heidecker et al. found forty-six genes that are overexpressed in patients with heart failure having a good outcome compared to patients with heart failure having a poor outcome354. Alexander et al. found the concentration of sixty-one metabolites significantly different between patients with primary dilated cardiomyopathy and control individuals355, indicating that also levels of peptidases generating these metabolites are altered. Viral infection (e.g., parvovirus) or nonviral infection (e.g. Chagas disease) might lead to an altered peptidase expression. For example it was found that mRNA levels of ECE-1 are
elevated in Chagas Disease356. Furthermore higher activity of ECE-1 is associated with pulmonary arterial hypertension357. Meprin is markedly downregulated in chronic renal dysfunction358, whereby renal dysfunction is often associated with cardiac dysfunction359. NEP expression associates with cardiometabolic risk and plasma levels of NEP increase with obesity, a disease which is frequently accompanied by cardiac pathologies360. Circulating levels of DPPIV, the peptidase generating the human BNP3-32, is associated with left ventricular dysfunction.
This up or down-regulation of peptidases due to specific cardiovascular diseases will subsequently also change the concentrations of their substrates and products, e.g.
that of BNP1-32 and BNP metabolites. An up-regulation of e.g. ECE-1 would increase concentrations of BNP1-30 a down-regulation of Meprin A would decrease levels of BNP7-32. Besides altered generation it might also be that metabolite-degradation is specifically altered in a disease. It was for example shown in patients with idiopathic cardiomyopathy, that degradation of natriuretic peptides is markedly changed even in early stages of the disease361. Thus, the composition of the BNP pool is depending on the generation or degradation of BNP metabolites. Generation and degradation is in turn depending on enzymes whose expression level or activity is potentially altered during the development and etiopathology of a distinct cardiovascular diseases. It can therefore be hypothesized that patients with specific cardiovascular diseases have specific BNP metabolite profiles. The collection of such BNP metabolite profiles for every cardiovascular disease including different stages of the disease would allow the establishment of a database, which could be used for a rapid and specific diagnosis once the BNP metabolite profile of a patient has been assessed. In contrast to that, a conventional BNP assays will only determine the concentration of the whole BNP pool in a patients’ blood sample. Thus, increases in levels of the BNP pool allow the discrimination between healthy and diseased patients. If BNP levels of a patient are above a certain cut-off level the patient will have to undergo more examinations to specify the cardiovascular disease. Applying a BNP-test being able to distinguish between the different BNP metabolites and to quantify them opens the avenue for a more specific diagnosis of heart diseases and might even make further clinical assessment unnecessary. Taking metabolite-specific antibodies as a basis of this test, such an assay would only require a blood sample for the analysis. Such a non-invasive test would be usable in the clinic, e.g. emergency room, but might also be helpful in a pre-clinical setting e.g. in the physician's office.
The compilation of a BNP metabolite profile as a standard method during medical check-ups could contribute to risk stratification and early diagnosis of developing diseases, since a significant proportion of cardiovascular pathologies have a genetic background or develop without symptoms. For instance, a coronary artery disease might be present for years with symptoms occurring only late in the etiology, however, peptidase and metabolite levels might be already changed in an early onset.
Just as well, the determination of BNP metabolite profiles during the individual treatment of a patient with a cardiovascular disease could be used for the monitoring of etiopathology and guidance of therapy. Thus, the collection of BNP metabolite profiles throughout the life span of patients could contribute to the health status of the individual. An overview about the possible usage of the compilation of a BNP metabolite profile in the diagnosis and risk stratification of cardiovascular diseases has been pictured in Figure 55.
patient 1
0
pg/ml
A new strategy in the diagnosis of cardiovascular diseases
patients
Conventional BNP-test (quantification of the BNP pool)
patient 2 BNP metabolite profile
-x2 1 BNPx
-x4 3 BNPx
-x6 5 BNPx
-x8 7 BNPx
-x10 9 BNPx 0
pg/ml
patient 3 BNP metabolite profile
-x2 1 BNPx
-x4 3 BNPx
-x6 5 BNPx
-x8 7 BNPx
-x10 9 BNPx 0
pg/ml
Healthybut development of coronary artery disease
Compilation of a BNP metabolite profile
quantification of different BNP metabolites (BNPx-x)
patient 2
0
pg/ml
patient 3
0
pg/ml
healthy heart failure borderline
patient 1 BNP metabolite profile
-x2 1 BNPx
-x4 3 BNPx
-x6 5 BNPx
-x8 7 BNPx
-x10 9 BNPx 0
pg/ml
heart failure through dilated cardiomyopathy
Intrinsic cardiomyopathy cutoff
Figure 55: Comparison of two diagnostic strategies for the determination of BNP in patients. The upper part of the figure shows the quantification of the whole BNP pool with a conventional BNP-test.
The lower part shows a new strategy for the diagnosis of specific cardiovascular diseases by identifying and quantifying BNP metabolites leading to a compilation of a specific BNP metabolite profile for each patient. Abbreviations: B-type natriuretic peptide (BNP), B-type natriuretic peptide metabolites (BNPx-x)