Nic heart failure.Chronic Heart Failure Study: Total Creatine and Adenine Nucleotide PoolsIndividual phosphocreatine, ATP, ADP and AMP levels cannot be reliably measured in the mouse heart in this experimental model, since measurements mainly reflect degradation during sample collection and preparation. However, the sum of these components are biochemically meaningful. Total creatine levels were lower by 15 in MI mice compared to sham (p,0.01) (Table 2) with a similar 13 reduction observed in group MI+R (p,0.05). However, infarcted CrT-OE mice maintained significantly higher creatine levels compared to sham (p,0.001) despite a 10 decrease in myocardial creatine concentration with development of heart failure (p,0.05). In all 3 infarcted groups, TAN pool was decreased by 8 to 12 (and with no significant difference among infarcted groups), but compared to sham, this only reached statistical significance in group MI+C+R (Table 2). There was no relationship between LV TAN or total creatine levels and ejection 79831-76-8 fraction in the infarcted mice (Figure 4). In contrast, a strong correlation between infarct size and ejection fraction was observed irrespective of genotype or ribose treatment (r2 = 0.63, p,0.0001).DiscussionThis is the first study to assess the effect of ribose administration in chronic left-sided heart failure. We show that oral ribose is palatable and bioavailable and that reduced TAN pool is a feature of murine heart failure, albeit to a lesser extent than in larger mammals. However, ribose treatment was ineffective at preventing this decline, and neither ribose on its own, nor in combination with elevated creatine, altered the pattern of adverse cardiac remodelling and LV dysfunction characteristic of the failing heart.Influence of Species on Adenine Nucleotides and Creatine in the Failing HeartIn the infarcted mouse heart, we observed a consistent decrease in TAN pool by 8?4 . This is a small change compared to other species and therefore did not always reach significance. Decreases of up to 50?0 have been measured in the failing rat heart [10] and in patients with end-stage heart failure at the time of cardiac transplant [9], while in the dog pacing model the decrease in TAN A196 closely followed progression of heart failure to reach 21 after 8 weeks [3]. This has similarities to the modest reduction in creatine levels in the failing mouse heart, 11?6 compared to 25?6 commonly observed in humans and other species [31]. In this context it could be argued that the mouse is not the ideal species in which to study these effects. However, key parameters such asRibose Treatment in Chronic Murine Heart FailureFigure 2. Left ventricular morphology and function derived from MRI 8 weeks post myocardial infarction. Group S are untreated wildtype sham-operated mice; Group MI are untreated wild-type infarcted mice; Group MI+R are wild-type infarcted mice treated with ribose; Group MI+C+R are infarcted creatine transporter overexpressing mice treated with ribose. Infarcted groups were matched for infarct size (A). Left ventricular remodelling and function was measured by cine-MRI (B ). Data are reported as mean 6 23977191 SD. *** denotes p,0.001 (1-way ANOVA with Bonferroni’s correction). doi:10.1371/journal.pone.0066461.gTable 2. Morphometry and myocardial biochemistry 8 weeks after myocardial infarction.S (n = 16) Body weight (g) LV weight (mg) by MRI LV/BW (6103) Lung weight/BW (6103) Total Creatine (nmol/mg prot) Total adenine nucleotides (nm.Nic heart failure.Chronic Heart Failure Study: Total Creatine and Adenine Nucleotide PoolsIndividual phosphocreatine, ATP, ADP and AMP levels cannot be reliably measured in the mouse heart in this experimental model, since measurements mainly reflect degradation during sample collection and preparation. However, the sum of these components are biochemically meaningful. Total creatine levels were lower by 15 in MI mice compared to sham (p,0.01) (Table 2) with a similar 13 reduction observed in group MI+R (p,0.05). However, infarcted CrT-OE mice maintained significantly higher creatine levels compared to sham (p,0.001) despite a 10 decrease in myocardial creatine concentration with development of heart failure (p,0.05). In all 3 infarcted groups, TAN pool was decreased by 8 to 12 (and with no significant difference among infarcted groups), but compared to sham, this only reached statistical significance in group MI+C+R (Table 2). There was no relationship between LV TAN or total creatine levels and ejection fraction in the infarcted mice (Figure 4). In contrast, a strong correlation between infarct size and ejection fraction was observed irrespective of genotype or ribose treatment (r2 = 0.63, p,0.0001).DiscussionThis is the first study to assess the effect of ribose administration in chronic left-sided heart failure. We show that oral ribose is palatable and bioavailable and that reduced TAN pool is a feature of murine heart failure, albeit to a lesser extent than in larger mammals. However, ribose treatment was ineffective at preventing this decline, and neither ribose on its own, nor in combination with elevated creatine, altered the pattern of adverse cardiac remodelling and LV dysfunction characteristic of the failing heart.Influence of Species on Adenine Nucleotides and Creatine in the Failing HeartIn the infarcted mouse heart, we observed a consistent decrease in TAN pool by 8?4 . This is a small change compared to other species and therefore did not always reach significance. Decreases of up to 50?0 have been measured in the failing rat heart [10] and in patients with end-stage heart failure at the time of cardiac transplant [9], while in the dog pacing model the decrease in TAN closely followed progression of heart failure to reach 21 after 8 weeks [3]. This has similarities to the modest reduction in creatine levels in the failing mouse heart, 11?6 compared to 25?6 commonly observed in humans and other species [31]. In this context it could be argued that the mouse is not the ideal species in which to study these effects. However, key parameters such asRibose Treatment in Chronic Murine Heart FailureFigure 2. Left ventricular morphology and function derived from MRI 8 weeks post myocardial infarction. Group S are untreated wildtype sham-operated mice; Group MI are untreated wild-type infarcted mice; Group MI+R are wild-type infarcted mice treated with ribose; Group MI+C+R are infarcted creatine transporter overexpressing mice treated with ribose. Infarcted groups were matched for infarct size (A). Left ventricular remodelling and function was measured by cine-MRI (B ). Data are reported as mean 6 23977191 SD. *** denotes p,0.001 (1-way ANOVA with Bonferroni’s correction). doi:10.1371/journal.pone.0066461.gTable 2. Morphometry and myocardial biochemistry 8 weeks after myocardial infarction.S (n = 16) Body weight (g) LV weight (mg) by MRI LV/BW (6103) Lung weight/BW (6103) Total Creatine (nmol/mg prot) Total adenine nucleotides (nm.
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