Abstract 14219: Chronic Cyclosporine Treatment Preserves Mitochondrial Energetics but does not Improve Cardiomyocyte Contractile Function or Calcium Handling in a Translational Mini-Swine Model of Heart Failure With Preserved Ejection Fraction
Conventional treatments have not reduced mortality for heart failure with preserved ejection fraction (HFpEF) patients, highlighting the critical need for novel treatment options in this HF sub-group. Our lab recently characterized a translational mini-swine model of HFpEF, in which impaired relaxation during early diastole and diminished contractile reserve was associated with mitochondrial dysfunction characterized by increased mitochondrial permeability transition (MPT). Early diastolic function is ATP and Ca2+-dependent, thus, we hypothesized a reduced, non-immunosuppressive dose of cyclosporine (CsA; inhibiting only cyclophilin D, a key component of the MPT pore, and not calcineurin) would improve individual cardiomyocyte function and Ca2+ handling via improved myocardial energetics. Individual LV cardiomyocytes were isolated from aortic-banded mini-swine divided into three groups; control non-banded (CON; n=3, 20 cells), HFpEF non-treated (HF; n=5, 20 cells), and HFpEF treated with CsA (HF-CsA; 2 mg/kg/day for 14 wks; n=5, 15-25 cells). Ca2+ transients and contractile properties were monitored in fluo-4-loaded myocytes electrically stimulated at frequencies of 0.25, 0.5, & 1.0 Hz. CsA attenuated functional uncoupling of the respiratory chain and ATP synthesis seen in the HF group evident by a significant reduction in Complex-I dependent respiration. However, Ca2+ transient amplitude (F/Fo) was reduced and time to peak Ca2+ release increased in HF and HF-CsA groups compared to CON at all pacing frequencies, indicative of impaired Ca2+ handling. Recovery of the Ca2+ transient (i.e. tau) increased in HF and HF-CsA at 1 Hz, consistent with impaired diastolic function common in HFpEF. Cardiomyocyte shortening and shortening rate were decreased in HF and HF-CsA groups, and decreased LV systolic rotation rate and longitudinal transverse displacement (measured via 2-D speckle tracking) demonstrate functional coherence of whole heart and cellular contractile data. In conclusion, attenuation of mitochondrial dysfunction following CsA treatment did not improve cardiomyocyte Ca2+ handling of contractile function, suggesting preservation of myocardial energetics alone is not sufficient to improve myocardial function in HFpEF.
- © 2013 by American Heart Association, Inc.