Abstract 3806: Augmented Creatine Kinase Expression Attenuates the Decline in In Vivo Energetics and Contractile Function in Pressure-Overload Hearts
Purpose: The creatine kinase (CK) reaction is the primary energy reserve of the heart and a rapid ATP source for the contractile elements. In patients and animal models, pressure-overload results in impaired creatine kinase (CK) energy metabolism, the development of left ventricular hypertrophy (LVH), and eventual systolic dysfunction. To determine whether impaired CK energy metabolism contributes mechanistically to the development of systolic dysfunction in LVH, the muscle isoform of CK (CKM) was overexpressed in mouse hearts before induction of chronic pressure-overload and the anatomic and contractile consequences quantified.
Methods: Hearts were transduced by intra-aortic delivery of adeno-associated vector (AAV) encoding either reporter β-galactosidase (β-gal) or CK-M. One week later, pressure-overload was induced by thoracic aorta constriction (TAC). LV mass (LVM) and ejection fraction (EF) were measured by in vivo MRI and cardiac creatine phosphate/ATP (PCr/ATP) by 31P MR spectroscopy at 3 and 6 weeks (wks) after TAC.
Results: TAC+β-gal resulted in a doubling of LVM, a 42% decrease in mean EF, and a 44% decrease in PCr/ATP after 6 wks (Table⇓, mean±SD). In contrast, cardiac PCr/ATP was higher, LVM lower, and EF higher at 3 and 6 wks in TAC+CKM than in TAC+β-gal hearts (p<05 for all). In addition, EF correlated with PCr/ATP at 6 wks (EF= 55.0[PCr/ATP]-23.2, r2=0.59).
Conclusions: In a mouse model of pressure-overload LVH, progressive declines in in vivo energetics and contractile function are observed akin to those previously reported in human LVH. CK-M over-expression, achieved by AAV-CKM transduction prior to TAC, attenuates the decline in energetics, preserves ejection fraction, and limits LVH. These serial data provide the first direct causal evidence that reduced CK energetics contribute to the contractile dysfunction of pressure-overload LVH and support the hypothesis that the failing LVH heart is energy starved as it relates to CK energy metabolism.
This research has received full or partial funding support from the American Heart Association, AHA Mid-Atlantic Affiliate (Maryland, North Carolina, South Carolina, Virginia & Washington, DC).