Figure 1:

A simplified schematic drawing of molecular pathways for the metabolism of energy-providing substrates in the heart. Metabolic reactions are traced with labeled tracer analogs which are taken into the myocardium and retained, while tracer substrates such as ¹¹C-compounds are taken up, metabolized, and release as ¹¹CO₂. For glucose and fatty acid metabolism tracer analogs and/or tracers may be used (red star), while tracers are used for lactate, acetate, amino acids, and ketone body metabolism (blue star). Sustained metabolic or neurohumoral stress leads to altered glucose and fatty acid metabolism. Fatty acid-mediated inhibition of glucose utilization stems from the allosteric effects of metabolites whose concentration rise in response to increased β-oxidation. At the same time, the activity of phosphofructokinase (PFK), which catalyzes the rate-limiting step in glycolysis, is inhibited by citrate. The resulting increase in glucose 6-phosphate (G6P) levels in turn inhibits the activity of hexokinase (HK), and rates of glucose uptake are decreased. Increased flux of glucose through the pyruvate dehydrogenase (PDH) complex inhibits β-oxidation through an increase in cytosolic malonyl-CoA, which acts as an inhibitor of the carnitine palmitoyltransferase 1 (CPT1) reaction (green). The accumulation of fatty acid metabolites such as diacylglycerol, fatty acyl-CoA, and ceramides leads to the activation of novel PKC isoforms and to the inhibitory phosphorylation of insulin receptor substrates (IRSs) (purple). Additionally, the accumulation of G6P activates mTORC1, resulting in increased protein synthesis and ER stress. Consequently, the heart hypertrophies (increased protein synthesis), and eventually fails. As energy demand outstrips energy supply, contractile dysfunction ensues, induced by altered calcium metabolism from oxidative stress and ER stress. Note that metabolic remodeling precedes, triggers, and sustains structural and functional remodeling. Abbreviations used: AMPK: 5′AMP-activated protein kinase. HK: Hexokinase-II. LVH: Left ventricular hypertrophy. HFpEF: Heart Failure with preserved Ejection Fraction. HFrEF: Heart Failure with reduced Ejection Fraction.