Abstract 11366: Plasma Myosin Binding Protein-C Fragments and S-Glutathionylation in Diastolic Heart Failure
Heart failure with preserved ejection fraction (HFpEF) known as diastolic heart failure is increasing in prevalence and incidence, but there are no specific treatments nor diagnostic biomarkers known. Accumulated evidence indicates that increased oxidative stress and reduced nitric oxide (NO) bioavailability contribute to impaired relaxation and elevated diastolic myofilament tension. Recently, we reported that that impaired relaxation is associated with nitric oxide synthase (NOS) uncoupling that results in oxidative modification of cardiac myosin binding protein C (MyBP-C), induces slowed myofilament cross-bridge kinetics, and leads to diastolic dysfunction. We investigated whether serum S-glutathionylated MyBP-C could be a biomarker for diastolic dysfunction. Initially, we used a well established mouse model of isolated diastolic dysfunction as a result of mild hypertension induced in deoxycorticosterone acetate (DOCA)-salt water treated mice. Furthermore, we investigated S-glutathionylated MyBP-C levels in human plasma from HFpEF and healthy control patients. Plasma levels of intact (144kDa) and fragments (75 and 25 kDa) of MyBP-C were significantly increased in DOCA-salt mice. Immunoprecipitation with glutathione and MyBP-C-specific antibodies showed that the 75 kD glutathionylated MyBP-C degradation product was significantly increased in DOCA-salt mice (3.7 ± 0.6-fold, P=0.011). Human plasma from both HFpEF showed elevated MyBP-C and S-total glutathionylated MyBP-C fragments compared to healthy control group (4.2 ± 1.4-fold, N=12, P<0.05). Elevated plasma cardiac-specific S-glutathionylation of MyBP-C may be a useful biomarker of HFpEF, diastolic heart failure.
- © 2012 by American Heart Association, Inc.