Résumé
The history of hypertension research is sweet sour. Huge advances have been marred by the persistence of huge black boxes. The term primary hypertension epitomizes the issue: the underlying causes and pathophysiology of most cases of hypertension remain undefined. Furthermore, guideline panels are unable to agree on desirable target blood pressure values, and it may be the time to think about the cure of hypertension rather than just the control of blood pressure. The quote attributed to Einstein, “Insanity: doing the same thing over and over again and expecting different results” may provide some clues. It is likely that the next large conceptual leaps in our understanding of hypertension are based on the application of a novel technology not previously used for this purpose. In this regard, scientific advances depend to a large extent on technological advances that make them possible.1 Hypothesis-based approaches must rely on current knowledge, and we are aware that this is limited. Systems biology provides a nonbiased approach that recognizes the current limitations of our understanding of hypertension. Gajjala et al2 have used plasma proteomics to identify in a nonbiased manner potential molecular determinants that allowed the development of a model capable to discriminate between hypertensive and normotensive individuals. There are 2 main potential clinical consequences of these studies: the use of the proteomics panel as a biomarker and the identification of putative contributors to the pathophysiology of hypertension. As a biomarker of hypertension, the panel cannot, by definition, outperform a cheap and easy to use, noninvasive approach: measurement of blood pressure. So further studies are needed to explore whether the proteomics model may predict outcomes, response to therapy, define risk categories, or even more important, predict the development of clinical hypertension. In addition, as the authors point out, the identified molecular determinants, corresponding to 15 proteins and 1 amino acid, may be the starting point for further studies to clarify the molecular pathophysiology of hypertension.2 Interestingly, the concentrations of fragments corresponding to 11 proteins and tryptophan were decreased in hypertension, whereas those corresponding to 4 proteins (osteocalcin, PRUNE, RAB13, and sarcolipin) were increased. A bioinformatics analysis could not integrate in a single pathway all the identified features. This may represent the involvement of multiple different pathways, current limitations in understanding the potential interconnections between these features or the presence of red herrings. Moreover, despite the statistical association with hypertension, it is currently unknown whether these features may contribute to the pathophysiology of hypertension or are the consequence of hypertension, its complications, associated comorbidities, or therapy. The identified fragments correspond to proteins diverse in their primary location (intracellular or extracellular), as well as in their known functions (enzymes, ion channels, transcription factors, and others). The authors are correct in avoiding any speculation on the potential relationship or function of these peptides in the hypertension context. The possibilities are too wide at this point. A first step would be to validate the findings in a similar hypertensive population. Functional in vivo studies are then required to assess causality.