Integrated Omic Analysis of a Guinea Pig Model of Heart Failure and Sudden Cardiac Death. J Proteome Res. 2016 Sep 2;15(9):3009-28. doi: 10.1021/acs.jproteome.6b00149. PMID: 27399916
in which we examined the transcriptome, proteome and metabolome of heart failure progression in a modified pressure-overload guinea pig model that uniquely recapitulates both the transition from compensated hypertrophy to end-stage heart failure, but also clinically relevant sudden cardiac death. The model was developed by Dr. Ting Liu and Dr. Brian O’Rourke, Professor of Medicine and Vice-Chair for Basic and Translational Research in the Department of Medicine at Johns Hopkins. This paper represents the culmination of a broad collaboration between cardiac physiologists and biochemists, MS specialists, bioinformaticists and statisticians and commercial partners.
The goal was more than to simply extensively phenotype a new model of heart failure. Rather, we used the latest inferential pathway and upstream regulator analyses to garner new insights into likely gene-regulatory programs at work both early in hypertrophy and upon cardiac decompensation. We also wanted to showcase the value of multi-omic integration. The transcriptome provided the greatest depth of coverage particularly for proteomically-recalcitrant proteins like ion channels and other integral membrane proteins. But the proteins are the ultimate executors of cardiac function and for nearly 3000 of them, the correlation between protein and transcript changes in heart failure was fairly weak and were sometimes diametrically opposed, suggesting substantial post-transcriptional regulation. By integrating the proteome and metabolome we were also able to identify putative bottlenecks in metabolism.
Along with Dr. O’Rourke and collaborators, we have laid out the multi-omic landscape of hypertrophy and heart failure and have distilled a few essential take home messages. Moreover, our hope is that this study will serve as a resource for the research community. Along with the article, we have included an expansive online supplement that contains reader-friendly tables of analyses, as well as raw MS2 signal intensities for those who wish mine the data further.