Proteomics-based Development of Biomarkers in Cardiovascular Disease

Cardiovascular disease remains a paramount focus of basic science and clinical investigation throughout the developed world, although the demographics have changed considerably in the later half of the 20th century. Atherosclerotic cardiovascular disease, especially ischemic heart disease, has emerged as the major concern, while rheumatic fever and its cardiac sequelae have been superseded by congenital heart disease. Understanding these disease states and their perturbations requires clarification of mechanistic changes in organ phenotype over time, the influence of genetic variations, and the effects of pharmacologic, surgical, and interventional treatment. These requirements have been addressed, in part, by genetic, biochemical, and system approaches. It is clear, however, that knowledge of the DNA sequence, although essential, is not sufficient. A more meaningful understanding of gene expression can be achieved through characterization of the products of that expression, the proteins that are the essential biological determinants of disease phenotype. The ultimate phenotype of cell, organ, and organism is reflected in the instantaneous proteomic profile; similarly changes in human states of health are the result of changes in the proteomes of individual patients over time in response to endogenous and/or external stimuli. The advent of novel proteomic approaches to investigate the complexity of human illness promises to shed new light on the pathogenesis of a broad range of cardiovascular diseases. These inferences are multifaceted and include the commonly recognized role of proteomics in characterizing biomarkers and biosignatures for the prognosis and diagnosis of disease, the capability of these technologies of revealing information regarding functional subproteomes of organelles and networks in the heart and vasculature, and the importance of proteomics in defining changes in these functional subproteomes to guide future therapy. The central focus of this review is to discuss the importance of proteomics as a non-biased tool for protein discovery. We explore the role of proteomics for hypothesis-driven research into cellular organelle status, and we discuss how this approach facilitates an understanding of the function of the cell in normal and diseased states. Lastly we present a review of proteomics as a tool for biomarker development and lay out a vision for how this technology promises to facilitate distinct biomarker development.