title: A new twist on an old idea part 2: cyclosporine preserves normal mitochondrial but not cardiomyocyte function in mini-swine with compensated heart failure.
abstract: We recently developed a clinically relevant mini-swine model of heart failure with preserved ejection fraction (HFpEF), in which diastolic dysfunction was associated with increased mitochondrial permeability transition (MPT). Early diastolic function is ATP and Ca(2+)-dependent, thus, we hypothesized chronic low doses of cyclosporine (CsA) would preserve mitochondrial function via inhibition of MPT and subsequently maintain normal cardiomyocyte Ca(2+) handling and contractile characteristics. Left ventricular cardiomyocytes were isolated from aortic-banded Yucatan mini-swine divided into three groups; control nonbanded (CON), HFpEF nontreated (HF), and HFpEF treated with CsA (HF-CsA). CsA mitigated the deterioration of mitochondrial function observed in HF animals, including functional uncoupling of Complex I-dependent mitochondrial respiration and increased susceptibility to MPT. Attenuation of mitochondrial dysfunction in the HF-CsA group was not associated with commensurate improvement in cardiomyocyte Ca(2+) handling or contractility. Ca(2+) transient amplitude was reduced and transient time to peak and recovery (tau) prolonged in HF and HF-CsA groups compared to CON. Alterations in Ca(2+) transient parameters observed in the HF and HF-CsA groups were associated with decreased cardiomyocyte shortening and shortening rate. Cellular function was consistent with impaired in vivo systolic and diastolic whole heart function. A significant systemic hypertensive response to CsA was observed in HF-CsA animals, and may have played a role in the accelerated the development of heart failure at both the whole heart and cellular levels. Given the significant detriment to cardiac function observed in response to CsA, our findings suggest chronic CsA treatment is not a viable therapeutic option for HFpEF.
authors: Department of Biomedical Science, University of Missouri- Columbia, 1600 E. RollinsW160 Veterinary Medicine, Columbia, Missouri.
authors: Jessica A
authors: JA
authors: Hiemstra
authors: Department of Biomedical Science, University of Missouri- Columbia, 1600 E. RollinsW160 Veterinary Medicine, Columbia, Missouri Dalton Cardiovascular Research Center, University of Missouri- Columbia, 1600 E. RollinsW160 Veterinary Medicine, Columbia, Missouri.
authors: Manuel
authors: M
authors: Gutiérrez-Aguilar
authors: Department of Biomedical Science, University of Missouri- Columbia, 1600 E. RollinsW160 Veterinary Medicine, Columbia, Missouri Dalton Cardiovascular Research Center, University of Missouri- Columbia, 1600 E. RollinsW160 Veterinary Medicine, Columbia, Missouri.
authors: Kurt D
authors: KD
authors: Marshall
authors: Department of Biomedical Science, University of Missouri- Columbia, 1600 E. RollinsW160 Veterinary Medicine, Columbia, Missouri Dalton Cardiovascular Research Center, University of Missouri- Columbia, 1600 E. RollinsW160 Veterinary Medicine, Columbia, Missouri.
authors: Kyle S
authors: KS
authors: McCommis
authors: Department of Biomedical Science, University of Missouri- Columbia, 1600 E. RollinsW160 Veterinary Medicine, Columbia, Missouri.
authors: Pamela J
authors: PJ
authors: Zgoda
authors: Department of Biomedical Science, University of Missouri- Columbia, 1600 E. RollinsW160 Veterinary Medicine, Columbia, Missouri.
authors: Noelany
authors: N
authors: Cruz-Rivera
authors: Department of Kinesiology, University of Georgia, Athens, Georgia.
authors: Nathan T
authors: NT
authors: Jenkins
authors: Dalton Cardiovascular Research Center, University of Missouri- Columbia, 1600 E. RollinsW160 Veterinary Medicine, Columbia, Missouri Department of Medical Pharmacology and Physiology, University of Missouri- Columbia, 1600 E. RollinsW160 Veterinary Medicine, Columbia, Missouri.
authors: Maike
authors: M
authors: Krenz
authors: Department of Medical Pharmacology and Physiology, University of Missouri- Columbia, 1600 E. RollinsW160 Veterinary Medicine, Columbia, Missouri.
authors: Timothy L
authors: TL
authors: Domeier
authors: Department of Biomedical Science, University of Missouri- Columbia, 1600 E. RollinsW160 Veterinary Medicine, Columbia, Missouri Dalton Cardiovascular Research Center, University of Missouri- Columbia, 1600 E. RollinsW160 Veterinary Medicine, Columbia, Missouri.
authors: Christopher P
authors: CP
authors: Baines
authors: Department of Biomedical Science, University of Missouri- Columbia, 1600 E. RollinsW160 Veterinary Medicine, Columbia, Missouri.
authors: Craig A
authors: CA
authors: Emter
keywords: Calcium; HFpEF; cardiomyocyte; cyclosporine; mitochondria