Researchers Daniel Martin, PhD, Debbie Seifert and Suneel Apte, MBBS, DPhil, all from the Department of Biomedical Engineering—with support from Belinda Willard, PhD, of the Proteomics and Metabolomics Core, and clinical collaborators from the Heart, Vascular & Thoracic and Pathology & Laboratory Medicine Institutes—have identified prospective novel biomarkers that may aid physicians in diagnosing infective endocarditis, a serious infection of the heart valves characterized by vegetations that form on the inner walls of the heart.
Importantly, this study, published in JCI Insight, is the first to use high-resolution mass spectrometry to characterize in detail the complete proteomes (all proteins within a cell or tissue) of patient-derived vegetations, offering important insights not just into potential disease biomarkers, but also into disease pathogenesis and how vegetations vary by causal bacteria.
A need for better diagnositcs
Most healthy people can efficiently clear bacteria that enters their bloodstream. People with preexisting conditions, or those who have implanted cardiac devices or a history of intravenous drug use, however, cannot do so as easily. As a result, bacteria may persist and form colonies on the interior surface of the heart valves. While the immune system attempts to wall these off, vegetations develop over time from the frequent cycles of bacterial colonization and immune response.
These growths can cause damage, scarring and leaking in the valves, and can also cause abscesses and emboli. In many cases, patients need potentially risky surgery for infective endocarditis to prevent emboli or to repair vegetation-related valve damage. It currently can be difficult and time-consuming to diagnose infective endocarditis, thus underscoring the need for diagnostic biomarkers that could aid in early detection and treatment.
Proteomics reveals pathogen-specific signatures
The team—which also included James Witten, MD, Eugene Blackstone, MD, and Gosta Pettersson, MD, PhD, from the Heart, Vascular & Thoracic Institute, and Carmela Tan, MD, and E. Rene Rodriguez, MD, of the Pathology & Laboratory Medicine Institute—studied vegetations from eight patients (four male and four female) who had infective endocarditis. They used mass spectrometry to sequence and compare the proteomes of vegetations from patients infected with Staphylococcus aureus bacteria versus those infected with other bacterial species.
Their analysis revealed that while many proteins were shared between vegetations, there were subtle differences that depended on the pathogen causing the infection. “We saw, for example, that peptides from circulation proteins, such as fibrin, were found in every vegetation,” said Dr. Martin, a postdoctoral fellow in Dr. Apte’s lab, and first author on the study. “But a specific fibronectin and C3 complement peptide, which has never been previously identified in human serum, was also seen in every vegetation in equal or higher quantities to that of the circulatory proteins. This makes these peptides excellent candidates as biomarkers.”
In addition, the team identified widespread protein breakdown within vegetations. This may explain the frequent tendency for small pieces of vegetation to break off and travel to distant sites via the bloodstream, where they may block blood supply and cause new bacterial infections.
It is important to note that more studies will be necessary to validate these peptides as biomarkers of infective endocarditis. Nevertheless, the team is excited that this proteomics study has offered early insights into both biomarkers and disease pathogenesis.
The study was supported by the Allen Distinguished Investigator Program, a joint initiative between The Paul G. Allen Frontiers Group and the American Heart Association.