Imaging Probe Allows Noninvasive Detection of Heart-Valve Infection

The investigators revealed how the presence of Staphylococcus aureus-associated endocarditis in a mouse model was revealed by positron emission tomography (PET) imaging with a radiolabeled version of a protein involved in a process that typically conceals infecting bacteria from the immune system.

“Our probe was able to sense whether S. aureus was present in abnormal growths that hinder the normal function of heart valves,” said Matthias Nahrendorf, MD, PhD, of the Massachusetts General Hospital (MGH; Boston, MA, USA) Center for Systems Biology, a co-lead author of the study, which was published August 2011 in advance online edition of the journal Nature Medicine. “It has been very difficult to identify the bacteria involved in endocarditis, but a precise diagnosis is important to steering well-adjusted antibiotic therapy.”

An infection of the tissue lining the heart valves, endocarditis is characterized by growths called vegetations comprised of clotting components such as platelets and fibrin along with infecting microorganisms. Endocarditis caused by S. aureus is the most dangerous, with a mortality rate of from 25 to nearly 50%, but diagnosis can be difficult since symptoms such as fever and heart murmur are vague and blood tests may not detect the involved bacteria. Without appropriate antibiotic therapy, S. aureus endocarditis can progress rapidly, damaging or destroying heart valves.

S. aureus bacteria initiate the growth of vegetations by secreting staphylocoagulase, an enzyme that sets off the clotting cascade. This process involves a protein called prothrombin, which is part of a pathway leading to the deposition of fibrin, a primary component of blood clots. The clotting process enlarges the vegetation, anchors it to the heart valve, and serves to conceal the bacteria from immune cells in the bloodstream.

To develop an imaging-based approach to diagnosing S. aureus endocarditis, the MGH investigators first investigated the molecular process by which staphylocoagulase sets off the clotting cascade, finding that one staphylocoagulase molecule interacts with at least four molecules of fibrin or its predecessor molecule fibrinogen in a complex that binds to a growing vegetation. Because prothrombin is an essential intermediary in the staphylocoagulase/fibrin interaction, the researchers investigated whether labeled versions of prothrombin could accurately detect S. aureus endocarditis in mice.

After initial experiments confirmed that an optical imaging technology called fluorescence molecular tomography -computed tomography (FMT-CT) could detect a fluorescence-labeled version of prothombin deposited into S. aureus-induced vegetations, the researchers showed that a radiolabeled version of prothombin enabled the detection of S. aureus vegetations with combined PET-CT imaging, an approach that could be used in human patients after additional development and FDA approval.

“An approach like this could help clinicians detect the presence of endocarditis, determine its severity and whether it is caused by S. aureus, and track the effectiveness of antibiotics or other treatments,” said Dr. Nahrendorf, also a co-corresponding author of the Nature Medicine article and an assistant professor of radiology at Harvard Medical School (Boston, MA, USA). “We are working to improve the PET reporter probe with streamlined chemistry and a more mainstream PET isotope to make it a better candidate for eventual testing in patients.”

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