Toward metabolomic signatures of cardiovascular disease.

Small biochemicals are the end result of all the regulatory complexity present in a cell, tissue, or organism, including transcriptional regulation, translational regulation, and posttranslational modifications. Metabolic changes are thus the most proximal reporters of the body’s response to a disease process or drug therapy. In 1971, Robinson and coworkers1 conceived the core idea that information-rich data reflecting the functional status of a complex biological system resides in the quantitative and qualitative pattern of metabolites in body fluids. In the same year, Horning and Horning2 first used the term metabolic profiling to describe the output of a gas chromatogram from a patient sample. This new approach to the quantitative metabolic profiling of large numbers of small molecules in biofluids was ultimately termed “metabonomics” by Nicholson et al3 and “metabolomics” by others. Article see p 207 Two core technologies are used to perform metabolic profiling: nuclear magnetic resonance and tandem mass spectrometry (MS/MS), as previously reviewed in Circulation: Cardiovascular Genetics. 4 Nuclear magnetic resonance requires relatively little sample preparation and is nondestructive, allowing for subsequent structural analyses. However, the method tends to have low sensitivity and can detect only highly abundant analytes. Tandem mass spectrometry (MS/MS), coupled with liquid chromatography, on the other hand, has much higher sensitivity for small molecules and is also applicable to a wide range of biological fluids (including serum, plasma, and urine). Recent advances in MS technology now enable researchers to determine analyte masses with such high precision and accuracy that metabolites can be identified unambiguously even in complex fluids. These technologies can be used to characterize biological samples either in a targeted manner or in a pattern discovery manner. In the former, the investigator targets a predefined …