Shenmai Injection Improves Energy Metabolism in Patients With Heart Failure: A Randomized Controlled Trial

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.

Acute heart failure (AHF) is one of the most common diagnoses assigned to emergency department (ED) patients who are hospitalized. Despite its high prevalence in the emergency setting, the diagnosis of AHF in ED patients with undifferentiated dyspnea can be challenging.

The nuclear receptors peroxisome proliferator-activated receptor-alpha (PPARalpha) and retinoid X receptor alpha (RXRalpha) stimulate the expression of key enzymes of free fatty acid (FFA) oxidation. We tested the hypothesis that the altered metabolic phenotype of the failing heart involves changes in the protein expression of PPARalpha and RXRalpha. Cardiac substrate uptake and oxidation were measured in 8 conscious, chronically instrumented dogs with decompensated pacing-induced heart failure and in 8 normal dogs by infusing 3 isotopically labeled substrates: 3H-oleate, 14C-glucose, and 13C-lactate. Although myocardial O2 consumption was not different between the 2 groups, the rate of oxidation of FFA was lower (2.8+/-0.6 versus 4.7+/-0.3 micromol x min(-1) x 100g(-1)) and of glucose was higher (4.6+/-1.0 versus 1.8+/-0.5 micromol x min(-1) x 100g(-1)) in failing compared with normal hearts (P<0.05). The rates of lactate uptake and lactate output were not significantly different between the 2 groups. In left ventricular tissue from failing hearts, the activity of 2 key enzymes of FFA oxidation was significantly reduced: carnitine palmitoyl transferase-I (0.54+/-0.04 versus 0.66+/-0.04 micromol x min(-1) x g(-1)) and medium chain acyl-coenzyme A dehydrogenase (MCAD; 1.8+/-0.1 versus 2.9+/-0.3 micromol x min(-1) x g(-1)). Consistently, the protein expression of MCAD and of RXRalpha were significantly reduced by 38% in failing hearts, but the expression of PPARalpha was not different. Moreover, there were significant correlations between the expression of RXRalpha and the expression and activity of MCAD. Our results provide the first evidence for a link between the reduced expression of RXRalpha and the switch in metabolic phenotype in severe heart failure.