In the current study, the team analyzed tissue from the hearts of patients with end-stage heart failure and from deceased healthy heart donors. The 14 sites the researchers identified are sites where troponin I binds with phosphate, a process known as phosphorylation. Phosphate can activate or deactivate many enzymes, thus altering the function of a protein and, in the case of heart failure, ignite disease. The six newly identified sites represent new "hot spots" involved in heart contraction, the researchers say, and could be used as diagnostic markers or a target for treatment to restore function. The Hopkins researchers found that in some sections of the molecule, phosphorylation ratcheted up the dimmer switch, while ratcheting it down in other sections, but it invariably led to muscle dysfunction.
"Our goal would be to zero in on these new sites, gauge risk of heart failure and, hopefully, restore heart muscle function," Van Eyk says.
Heart failure is a complex progressive disorder, and while cardiac pacemakers can restore or "resynchronize" heart function in many people, about one-third of patients do not improve even with pacemaker therapy in addition to standard medication treatments.
"This is a devastating disorder for which we desperately need new and less invasive therapies," says senior investigator Anne Murphy, M.D., a cardiologist at Johns Hopkins Children's Center.
In their analysis, the researchers used a novel technique, called multiple-reaction monitoring (MRM), which pinpoints the exact locations along the protein's molecule where faulty signaling occurs and disrupts heart muscle function. MRM is an ultra-sensitive type of mass spectrometry that measures the exact size and chemical composition of protein fragments. Phosphorylated protein fragments have different molecular weights than non-phosphorylat
|Contact: Ekaterina Pesheva|
Johns Hopkins Medicine