TROPONIN-I PHOSPHORYLATION IN THE NORMAL AND FAILING ADULT HUMAN HEART

Background In the failing human heart myofibrillar calcium sensitivity of tension development is greater and maximal myofibrillar ATPase act ivity is less than in the normal heart. Phosphorylation of the cardiac troponin I (cTnI)-specific NH2-terminus decreases myofilament sensiti vity to calcium, while phosphorylation of other cTnI sites decreases m aximal myofibrillar ATPase activity. Methods and Results We examined c TnI phosphorylation in left ventricular myocardium collected from fail ing hearts at the time of transplant (n=20) and normal hearts from tra uma victims (n=24). The relative amounts of actin, tropomyosin, and Tn I did not differ between failing and normal myocardium. Using Western blot analysis with a monoclonal antibody (MAb) that recognizes the str iated muscle TnI isoforms, we confirmed that the adult human heart exp resses only cTnI. A cTnI-specific MAb recognized two bands of cTnI, de signated cTnI(1) and cTnI(2), while a MAb whose epitope is located in the cTnI-specific NH2-terminus recognized only cTnI(1). Alkaline phosp hatase decreased the relative amount of cTnI(1), while protein kinase A and protein kinase C increased cTnI(1). The percentage of cTnI made up of cTnI(1), the phosphorylated form of TnI, is greater in the norma l than the failing human heart (P<.001). Conclusions This phosphorylat ion difference could underlie the reported greater myofibrillar calciu m sensitivity of failing myocardium. The functional consequence of thi s difference may be an adaptive or maladaptive response to the lower a nd longer calcium concentration transient of the failing heart, eg, en hancing force development or producing ventricular diastolic dysfuncti on.