Metabolic Modulation: A New Therapeutic Target in Treatment of Heart Failure

Palaniswamy, Chandrasekar; Mellana, William Michael; Selvaraj, Dhana Rekha; Mohan, Diwakar

doi:10.1097/mjt.0b013e3181d70453

Cited by 23 publications

(16 citation statements)

References 38 publications

(28 reference statements)

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“…These therapies include drugs which either inhibit or downregulate the enzymes associated with beta-oxidation [242, 248, 253, 254]. Alternatively, glucose and pyruvate oxidation can be increased directly.…”

Section: Major Diseases Characterized By Aberant Pyruvate Metabolismmentioning

confidence: 99%

Regulation of pyruvate metabolism and human disease

Gray

Tompkins

Taylor

2013

Cell. Mol. Life Sci.

666

595

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Pyruvate is a keystone molecule critical for numerous aspects of eukaryotic and human metabolism. Pyruvate is the end-product of glycolysis, is derived from additional sources in the cellular cytoplasm, and is ultimately destined for transport into mitochondria as a master fuel input undergirding citric acid cycle carbon flux. In mitochondria, pyruvate drives ATP production by oxidative phosphorylation and multiple biosynthetic pathways intersecting the citric acid cycle. Mitochondrial pyruvate metabolism is regulated by many enzymes, including the recently discovered mitochondria pyruvate carrier, pyruvate dehydrogenase, and pyruvate carboxylase, to modulate overall pyruvate carbon flux. Mutations in any of the genes encoding for proteins regulating pyruvate metabolism may lead to disease. Numerous cases have been described. Aberrant pyruvate metabolism plays an especially prominent role in cancer, heart failure, and neurodegeneration. Because most major diseases involve aberrant metabolism, understanding and exploiting pyruvate carbon flux may yield novel treatments that enhance human health.

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Section: Major Diseases Characterized By Aberant Pyruvate Metabolismmentioning

confidence: 99%

Regulation of pyruvate metabolism and human disease

Gray

Tompkins

Taylor

2013

Cell. Mol. Life Sci.

666

595

View full text Add to dashboard Cite

show abstract

“…Myocardial energy metabolism may be normal in the early stages of HF, but as failure progresses, mitochondrial oxidative metabolism is reduced, and glycolysis is increased with the downregulation of glucose and fatty acid oxidation 4. In particular, evidence suggests that with HF, a shift of metabolism away from a preference for fatty acid towards more carbohydrate oxidation can improve contractile function, thus slowing the progression of HF and improving prognosis in patients with HF 5…”

mentioning

confidence: 99%

Trimetazidine: a meta-analysis of randomised controlled trials in heart failure

Gao

Ning

Niu

et al. 2010

Heart

167

105

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Objective To explore whether trimetazidine could improve symptoms, cardiac functions and clinical outcomes in patients with heart failure (HF). Methods A systematic literature search was conducted to identify randomised controlled trials (RCT) of trimetazidine for HF between 1966 and May 2010 in Pubmed, the Cochrane Central Registry of Clinical Trials and EMBASE. Reports of trials were sought that compared trimetazidine with placebo control for chronic HF in adults, with outcomes including all-cause mortality, hospitalisation, cardiovascular events, changes in cardiac function parameters and exercise capacity. Results 17 trials with data for 955 patients were identified by the literature search. Trimetazidine therapy was associated with a significant improvement in left ventricular ejection fraction in patients with both ischaemic (weighted mean difference (WMD) with placebo 7.37%; 95% CI 6.05 to 8.70; p<0.01) and non-ischaemic HF (WMD 8.72%; 95% CI 5.51 to 11.92; p<0.01). With trimetazidine therapy, left ventricular end-systolic volume was significantly reduced (WMD 10.37 ml; 95% CI 15.46 to 5.29; p<0.01) and New York Heart Association classification was improved (WMD 0.41; 95% CI 0.51 to 0.31; p<0.01) as was exercise duration (WMD, 30.26 s; 95% CI 8.77 to 51.75; p<0.01). More importantly, trimetazidine had a significant protective effect for all-cause mortality (RR 0.29; 95% CI 0.17 to 0.49; p<0.00001) and cardiovascular events and hospitalisation (RR 0.42; 95% CI 0.30 to 0.58; p<0.00001). Conclusion Trimetazidine might be an effective strategy for treating HF. More studies, especially larger multicentre RCT, are warranted to clarify the effect of trimetazidine on HF.With more than 5 million prevalent cases and nearly 1 million hospital discharges yearly, heart failure (HF) represents a rapidly growing therapeutic challenge for healthcare providers.

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“…Free fatty acid oxidation results in higher adenosine triphosphate production per molecule compared with carbohydrate substrates; however, utilization of free fatty acid as the primary energy fuel requires greater amount of oxygen consumption (Palaniswamy et al, 2011). In HFpEF, the chronically increased beta-adrenoreceptor stimulation and the insulinresistance promote the utilization of non-carbohydrate substrates for …”

Section: Introductionmentioning

confidence: 99%