1. Analysis of Metabolic Remodeling in Compensated Left Ventricular Hypertrophy and Heart FailureClinical Perspective
by Takao Kato, Shinichiro Niizuma, Yasutaka Inuzuka, Tsuneaki Kawashima, Junji Okuda, Yodo Tamaki, Yoshitaka Iwanaga, Michiko Narazaki, Tetsuya Matsuda, Tomoyoshi Soga, Toru Kita, Takeshi Kimura, and Tetsuo Shioi
Circ Heart Fail
Volume 3(3):
May 18, 2010
Copyright © American Heart Association, Inc. All rights reserved.

2. Analysis of cardiac energy metabolism in DS with LVH or CHF
Analysis of cardiac energy metabolism in DS with LVH or CHF. A, Representative images of echocardiography.
Analysis of cardiac energy metabolism in DS with LVH or CHF. A, Representative images of echocardiography. DS rats that were fed an HS diet developed hypertension, showing concentric LVH at 11 weeks (W) of age. The rats eventually developed CHF with systolic dysfunction at ≈17 weeks of age. DS rats that were fed an LS diet were used as controls. B, PCr/ATP decreased by 12% in LVH rats and 42% in CHF rats compared with control rats; n=8–16 for each group. C, Representative images of myocardial uptake of 18FDG. D, Uptake of 18FDG increased by 1.4-fold in LVH rats and 2.4 fold in CHF rats compared with control rats. E, Representative images of myocardial uptake of 125I-9MPA. F, Uptake of 125I-9MPA did not change in LVH rats but decreased by 36% in CHF rats; n=6–12. *P<0.05 vs control rats. †P<0.05 vs CHF.
Takao Kato et al. Circ Heart Fail. 2010;3:
Copyright © American Heart Association, Inc. All rights reserved.

3. Expression of molecules related to energy metabolism during the transition from LVH to CHF. A, Gene expression related to cardiac energy metabolism was measured by quantitative reverse transcription–polymerase chain reaction. 18S rRNA was used as an internal control.
Expression of molecules related to energy metabolism during the transition from LVH to CHF. A, Gene expression related to cardiac energy metabolism was measured by quantitative reverse transcription–polymerase chain reaction. 18S rRNA was used as an internal control. B and C, The levels of proteins related to energy metabolism were examined by Western blotting and quantified by densitometry. Hypoxia-inducible factor-1α, peroxisome proliferator–activated receptor-γ coactivator-1-α, and peroxisome proliferator–activated receptor-α were examined in nuclear extracts. Total cell lysate was used for other proteins. The mean value for control rats was expressed as 1 unit. *P<0.05 vs control rats. †P<0.05 vs LVH rats.
Takao Kato et al. Circ Heart Fail. 2010;3:
Copyright © American Heart Association, Inc. All rights reserved.

4. Effects of DCA on CHF rats.
Effects of DCA on CHF rats. A, Administration of DCA or vehicle to DS rats with LVH started from 11 weeks (W) of age. DCA improved the survival of CHF rats. B, Representative images of echocardiography, showing that DCA improved systolic cardiac function. C, DCA attenuated the increase in the plasma concentrations of brain natriuretic peptides at the CHF stage. D, CHF rats showed increased heart weight and lung weight per body weight, and DCA ameliorated the increase. E, PDH activity was unchanged at the LVH or CHF stage and was increased by DCA. Representative images and quantification by densitometry. The mean value for control rats was expressed as 1 unit. F, Plasma lactate and pyruvate levels. *P<0.05 vs control rats with vehicle or DCA. †P<0.05 vs vehicle-treated rats on the same diet. n=5–8 for each group.
Takao Kato et al. Circ Heart Fail. 2010;3:
Copyright © American Heart Association, Inc. All rights reserved.

5. Effects of DCA on myocardial energy reserve and substrate utilization.
Effects of DCA on myocardial energy reserve and substrate utilization. A, Chronic DCA administration increased cardiac PCr/ATP in both control and CHF rats. B and C, DCA increased 18FDG uptake in normal rats but did not change 125I-9MPA uptake. DCA tended to decrease 18FDG uptake and increase 125I-9MPA uptake in CHF rats. The increase of 18FDG/125I-9MPA in CHF rats was significantly reduced by DCA. *P<0.05 vs control rats with vehicle or DCA. †P<0.05 vs vehicle-treated rats on the same diet. n=6–10 for LS diet and n=16–19 for HS diet. D, Short-term DCA administration increased 18FDG uptake in control and LVH rats. *P<0.05 vs control rats. †P=0.07 vs vehicle-treated LVH rats; n=6–8.
Takao Kato et al. Circ Heart Fail. 2010;3:
Copyright © American Heart Association, Inc. All rights reserved.

6. Effects of DCA on myocardial gene expression.
Effects of DCA on myocardial gene expression. The gene expression related to energy metabolism was compared between control and CHF rats (left column). Red indicates increase and blue indicates decrease compared with control rats. The gene expression was also compared between CHF and CHF+DCA (right column). Red indicates increase and blue indicates decrease compared with CHF rats.
Takao Kato et al. Circ Heart Fail. 2010;3:
Copyright © American Heart Association, Inc. All rights reserved.

7. Metabolomic profile of the transition from LVH to CHF
Metabolomic profile of the transition from LVH to CHF. A, Metabolites of glycolysis and the TCA cycle.
Metabolomic profile of the transition from LVH to CHF. A, Metabolites of glycolysis and the TCA cycle. B, Metabolites of PPP. *P<0.05 vs control rats. †P<0.05 vs LVH rats. #P<0.05 vs CHF rats.
Takao Kato et al. Circ Heart Fail. 2010;3:
Copyright © American Heart Association, Inc. All rights reserved.

8. G6PD was activated at the CHF stage or by DCA
G6PD was activated at the CHF stage or by DCA. A, Gene and protein expressions of G6PD did not differ between the groups.
G6PD was activated at the CHF stage or by DCA. A, Gene and protein expressions of G6PD did not differ between the groups. The G6PD activity was increased at the CHF stage or by DCA. The mean value for control rats was defined as 1 unit; n=6–8 for each group. *P<0.05 vs control rats with vehicle or DCA. †P<0.05 vs vehicle-treated rats on the same diet. #P<0.05 vs LVH rats. B, DHEA sulfate decreased G6PD activity and NADPH/NADP+ in rats administered DCA; n=5. *P<0.05 vs rats without DCA. †P<0.05 vs rats without DHEA sulfate. C, Myocardial TBARS did not change at the LVH stage but increased at the CHF stage. DCA decreased TBARS of CHF rats; n=6–8. *P<0.05 vs control rats with vehicle or DCA. †P<0.05 vs vehicle-treated rats on the same diet. D, 4-Hydroxy-2-nonenal–modified protein was increased in CHF rats, and the increase was attenuated by DCA. A representative blot is shown, and GAPDH was used as a loading control.
Takao Kato et al. Circ Heart Fail. 2010;3:
Copyright © American Heart Association, Inc. All rights reserved.

9. DCA attenuated myocyte cell death in a PPP-dependent manner.
DCA attenuated myocyte cell death in a PPP-dependent manner. A, DCA attenuated H2O2-induced cardiomyocyte death in a dose-dependent manner up to 2 mmol/L. The mean value of the group without treatment was expressed as 1 unit. *P<0.05 vs cardiomyocytes without H2O2. †P<0.05 vs H2O2-treated cardiomyocytes without DCA. B, Inhibition of PPP suppressed the protective effect of DCA in cultured myocytes. Three, 10, 30, or 100 μmol/L of DHEA was used; 10, 100, or 300 μmol/L or 1 mmol/L of 6-aminonicotinamide (6AN) was used. *P<0.05 vs H2O2-treated cardiomyocytes without an inhibitor. †P<0.05 vs H2O2-treated cardiomyocytes without DCA. C, DCA increased G6PD activity, and the increase was suppressed by an inhibitor or siRNA. *P<0.05 vs cardiomyocytes without DCA. †P<0.05 vs cardiomyocytes without G6PD inhibition. D and E, DCA increased NADPH/NADP+ and GSH/GSSG, and these changes were suppressed by inhibiting G6PD. F, TBARS were increased by H2O2, and the increase was attenuated by DCA in cultured myocytes. The effect of DCA was suppressed by G6PD inhibitors. *P<0.05 vs cardiomyocytes without H2O2. †P<0.05 vs cardiomyocytes without DCA. #P<0.05 vs cardiomyocytes without inhibitor; n=9–18 samples for each group.
Takao Kato et al. Circ Heart Fail. 2010;3:
Copyright © American Heart Association, Inc. All rights reserved.