PHYSIOLOGY OF CARDIAC MUSCLE 



sulinization upon the threshold for glucose. Ungar 

 et al. (242) and Goodale & Hackel (81) and their 

 colleagues have shown that the threshold for glucose 

 extraction is markedly elevated in diabetes in man 

 and in dogs, and that insulin treatment reduces it 

 toward normal. In addition, Hackel (92a) has shown 

 that insulinization of normal dogs causes a marked 

 reduction in the threshold for glucose extraction to 

 10 ± 3 mg per cent. It would appear that the cardiac 

 muscle cell membrane behaves like other muscles 

 toward glucose and insulin. Above their respective 

 thresholds, pyruvate, lactate, and glucose are re- 

 moved in proportion to arterial concentration. The 

 regression lines for lactate and pyruvate are linear in 

 the ranges studied, and that for glucose curvilinear 

 as shown in figure 20, approaching a maximum ex- 

 traction of about 20 mg per cent at levels of 250 mg 

 per cent. The earlier view of Evans (68) that lactate 

 was the primary food of the isolated heart was due 

 to his use of blood from fasted exsanguinated animals 

 for the perfusion medium. In such blood the lactate 

 levels are high and the glucose levels are low. 



Cardiac muscle glycogen, which appears to be de- 

 rived principally from blood glucose, is maintained 

 at very stable levels under normal conditions of car- 

 diac work, even in the presence of hypoglycemia (53). 

 Only with complete anoxia (102), excessive stimula- 

 tion by epinephrine (29), or excess thyroxin (6) does 

 cardiac muscle glycogen decrease. When depleted 

 experimentally in the dog by epinephrine injections, 

 it is replaced readily by blood glucose but not so 

 effectively by blood lactate or pyruvate (30). Interest- 

 ingly enough, cardiac glycogen may rise under certain 

 conditions of metabolic stress accompanied by ketosis, 

 such as severe starvation and diabetic acidosis. This 

 occurs, presumably, because of the preferential oxida- 

 tion of ketone bodies JDy the heart with a sparing of 

 carbohydrate (129). 



The state of nutrition of the organism influences 

 markedly the kind of substrate used for energy pro- 

 duction by the heart. With fasting, the heart shifts 

 from the predominant utilization of carbohydrate to 

 the almost exclusive utilization of fatty acids as a 

 source of energy. Under postprandial conditions or 

 after gluco.se infusions, the myocardium of both dog 

 (81) and man (22) utilizes mainly glucose, lactate, 

 and pyruvate as a source of energy, and the myo- 

 cardial respiratory quotient approaches i.o. After 

 an overnight fast, the pattern of metabolism shifts 

 to a greater dependence upon fatty acids and the 

 myocardial respiratory quotient drops to aljout 0.80. 

 Bing and associates (2 1 ), using a titrimetric method 

 for total fattv acids in arterial and coronary sinus 



TABLE I . EJfect oj Feeding and Fasting Upon 

 Myocardial Substrate Utilization in Man 



Condition Fed Fasted 



A-V difference 



O2 ml % 10.80 1 1 .50 



CBH* mM C — 3/liter I .49 0.51 



NEFAf mM C-i6/liter o.oi 0.12 



% O2 utilization accounted for by: 



CBH 92 30 



NEFA 5 58 



* CBH— Carbohydrate. f NEFA— Nonesterified fatty 



acids. 



blood, established that the human myocardium dur- 

 ing fasting could derive up to 67 per cent of its energy 

 from the oxidation of fatty acids. More recently 

 Gordon & Cherkes (84) have reported that the source 

 of these fatty acids for myocardial oxidation is the 

 nonesterified fatty acid (NEFA) fraction of the plasma 

 which is albumin-bound (57). By coronary sinus 

 catheterization of healthy postabsorptive subjects, 

 these workers found that from 25 to 70 per cent of 

 the myocardial oxygen usage could be accounted for 

 by the uptake of NEFA. With prolonged fasting and 

 diabetes mellitus, the uptake of carbohydrate by the 

 heart is further depressed with a decrease in the ex- 

 traction coefficients for glucose, pyruvate, and lactate 

 (82) the myocardial respiratory quotient drops to 

 0.70, and the heart depends almost solely upon fatty 

 acids and ketones for energy (242). 



The shifts in usage of substrate by the human heart 

 under conditions of feeding and overnight fasting 

 are shown in table i . During such transitions the 

 uptake of total "carbohydrate" and NEFA vary 

 reciprocally and correlate well with the observed 

 respiratory quotients (193). Carbohydrate appears 

 to be the preferred substrate if it is available and the 

 animal is in the "fed" state, and is thus the "active" 

 determinant of the fuel mixture taken up by the 

 heart. The highly variable pattern of NEFA uptake 

 in relation to NEFA level in arterial blood suggests 

 that it is the "passive" partner. Under ordinary con- 

 ditions, plasma amino acids do not contribute sig- 

 nificantly to the energy production of the heart (21). 



With regard to the uptake of oxygen, it has been 

 found by Goodale et al. (82) that the coronary arterio- 

 venous differences for oxygen in man vary linearly 

 with arterial oxygen content through the range from 

 mild anemia to marked polvcvthemia, as shown in 

 figure 21. It is somewhat remarkable that the uptake 

 of this "substrate" is also dependent upon arterial 

 level, considering the fact that the source of demand 

 for coronary arterial oxygen is the rate at which cyto- 

 chrome o.xidase is being reduced within the myocardial 



