In the past decade, great strides have been made to improve proteome coverage, from how protein samples are extracted to mass spectrometry instrumentation. To perform proteomics analysis, it follows that the proteins must be effectively extracted and released from biological samples. This is typically achieved via mechanical homogenization or chemical surfactants. Protein solubilization techniques in early proteomics protocols were at times ineffectual in extracting hydrophobic or membrane proteins, which often aggregated out of the sample and led to their non-detection. Development in this area in recent years have led to commercially available, mass spectrometry compatible surfactants [9], size exclusion filter-mediated buffer exchange techniques [10], as well as empirically refined experimental protocols that are optimized for the analysis of various cardiac subproteomes [11]; all of which serve to expand the portion of the proteome that is open to mass spectrometry exploration. The incompleteness of proteolytic digestion was once found to be a limiting factor of the maximal peptide coverage of the experiment and contribute to batch-to-batch variations. The use of optimized proteolysis protocols including double lys-C/trypsin proteolysis is gaining traction [1].