Myocardial Metabolism

Energy for Myocardial Contraction

ATP concentration constant, even during stress; 2% from glycolysis, 98% from TCA (from pyruvate or FFA)

creatine phosphokinase (ATP from ADP, converting creatine phosphate to creatine)—rapid buffer

rate of production of ATP and contractile work are intimately related (each affects other)

based upon absorption after normal fast, 60-100% energy from FFA, 0-20% each from lactate and glucose
regulation based upon: arterial substrate/hormone levels, coronary flow, inotropic state, nutrition

2/3 ATP for contraction, 1/3 for everything else (mostly ion pump, especially diastolic Ca⁺⁺SR ATPase)

Fatty Acids – rate of uptake determined by plasma fatty acid concentration

80% taken up is immediately oxidized for energy
mitochondrial transport: CATI (carnitine palmitoyltransferase), carnitine:acylcarnitine translocase, CATII

CAT1 regulated—inhibited by MalCoA (from acetylCoA carboxylation by AcCoA carboxolase (ACC))

Carbohydrate – three sources of glucose

(1) extracellular glucose uptake regulated by transmembrane gradient and GLUT1/GLUT4 activity

insulin/ischemia: receptors from intracellular microsomal vesicles to membrane
glucose phosphorylated by hexokinase (itself activated by insulin)
analyze: glucose analogs 2-deoxyglucose, fluorodeoxyglucose (FDG) (noninvasive-radiolabel, PET)

(2) extracellular lactate—source of most of pyruvate used later in TCA; 80-100% is immediately used
(3) glycogen: concentration controlled by feeding state (G6P concentration and glycogen synthase activity)

glycogen synthase—activated by insulin
glycogen phosphorylase—activated by phosphorylase kinase (activated by Ca⁺⁺, PKA, and AMP)
high glycogen if high insulin/glucose/lactate/FFA (before surgery), low if ischemia or extra work

glycolysis—controlled by PFK1 activity and concentration of G6P, PFK, and NAD⁺

PFK1 inhibited by acidosis, citrate and ATP; stimulated by AMP, Ca⁺⁺, and fructose-2,6dP (from PFK2)

NAD+ to NADH by glyceraldehyde-3P dehydrogenase (rate limiting when lots of work or ischemia)

probably mostly for SR Ca⁺⁺ ATPase (inhibit glycolysis = impair relaxation, and enzymes coupled to SR)

pyruvate dehydrogenase complex

rate limiting, regulated primarily by phosphorylation (to inhibit) and conc. of reactants/products

phosphetase activated by Ca⁺⁺ and Mg⁺⁺; kinase inhib. by pyruvate and ADP, activated by AcCoA&NADH

Fatty Acid vs. Carbohydrate Metabolism

fatty acid oxidation inhibits glucose/lactate uptake and glycolysis (citrate inhibits PFK1)

AcCoA and NADH activate PDH kinase (inhibiting PDH) and may inhibit unphosphorylated PDH directly

high cytosolic AcCoA levels will produce high MalCoA, which inhibits fatty acid oxidation

Effects of Plasma Substrate and Insulin Levels

regulation of myocardial glucose and lactate oxidation

highly dependent upon FFA concentration (product inhibition on PDH and glycolysis)
dependent upon plasma lactate concentration only when lactate is very high (after exercise)
not dependent upon plasma glucose concentration

effect of plasma insulin

stimulates glucose transport into cardiomyocytes (GLUT1/4, hexokinase)
inhibits lipolysis in adipocytes, lowering plasma FFA levels leads to more glycolysis
stimulates glycogen synthase (unclear mechanism—perhaps because more glucose?)

Effects of Mechanical Workload – mechanical power output of the left ventricle directly correlates to:

rate of ATP hydrolysis/resynthesis, and myocardial O₂ consumption (MVO₂) since most ATP from TCA
increases in glucose, lactate and FFA uptake, and decrease in myocardial glycogen stores