The purpose of this study was to investigate myocardial substrate utilization during moderate intensity exercise in humans. Coronary sinus and arterial catheters were inserted in nine healthy trained male subjects (mean age, 25±6 (SD) years). Dual carbon-labeled isotopes were infused, and substrate oxidation was quantitated by measuring myocardial production of "CO2. Supine cycle ergometer exercise was performed at 40% of the subject's maximal 02 uptake.With exercise there was a significant increase in the arterial lactate level (P < 0.05). A highly significant positive correlation was observed between the lactate level and the isotopic lactate extraction (r = 0.93; P < 0.001). The myocardial isotopic lactate uptake increased from 34.9±6.5 gmol/min at rest to 120.4±36.5 Mmol/min at 5 min of exercise (P < 0.005). The 14CO2 data demonstrated that 100.4±3.5% of the lactate extracted as determined by isotopic analysis underwent oxidative decarboxylation.Myocardial glucose uptake also increased significantly with exercise (P < 0.04). The [l4Cjglucose data showed that only 26.0±8.5% of the glucose extracted underwent immediate oxidation at rest, and during exercise the percentage being oxidized increased to 52.6±7.3% (P < 0.01). This study demonstrates for the first time in humans an increase in myocardial oxidation of exogenous glucose and lactate during moderate intensity exercise.

Free fatty acids are considered to be the major energy source for the myocardium. To investigate the metabolic fate of this substrate in humans, 24 subjects underwent coronary sinus and arterial catheterization. 13 subjects were healthy volunteers and 11 subjects had symptoms of ischemic heart disease. I1-14CIoleate or 11-'4Cipalmitate bound to albumin was infused at a constant rate of 25 1Ci/h. Oxidation was determined by measuring the '4C02 production. The data demonstrated that a high percentage (84±17%) of the palmitate and oleate extracted by the myocardium underwent rapid oxidation. A highly significant correlation was present between the arterial level and the amount oxidized (r = 0.82, P < 0.001 for palmitate; r = 0.77, P < 0.001 for oleate). The isotope extraction ratio was greater than the chemical extraction ratio. This difference of 6±2 nmol/ml of blood in the young normal subjects was significantly less than the 12±4 nmol/ml observed in the ischemic heart disease patients (P < 0.001).

Lactate metabolism was studied in six normal males using a primed continuous infusion of lactate tracer during continuous graded supine cycle ergometer exercise. Subjects exercised at 49, 98, 147, and 196 W for 6 min at each work load. Blood was sampled from the brachial artery, the iliac vein, and the brachial vein. Arteriovenous differences were determined for chemical lactate concentration and L-[1-14C]-lactate. Tracer-measured lactate extraction was determined from the decrease in lactate radioactivity per volume of blood perfusing the tissue bed. Net lactate release was determined from the change in lactate concentration across the tissue bed. Total lactate release was taken as the sum of tracer-measured lactate extraction and net (chemical) release. At rest the arms and legs showed tracer-measured lactate extraction, as determined from the isotope extraction, despite net chemical release. Exercise elicited an increase in both net lactate release and tracer-measured lactate extraction by the legs. For the legs the total lactate release (net lactate release + tracer-measured lactate extraction) was roughly equal to twice the net lactate release under all conditions. The tracer-measured lactate extraction by the exercising legs was positively correlated to arterial lactate concentration (r = 0.81, P less than 0.001) at the lower two power outputs. The arms showed net lactate extraction during exercise, which was correlated to the arterial concentration (r = 0.86). The results demonstrate that exercising skeletal muscle extracts a significant amount of lactate during net lactate release and that the working skeletal muscle appears to be a major site of blood lactate removal during exercise.

To investigate the relationships between oxygen consumption (VO2) and the rates of systemic lactate appearance (Ra) and disappearance (Rd), six healthy males were studied at rest and during continuous graded exercise using a primed continuous infusion of lactate tracer. Subjects exercised for 6 min at 300, 600, 900, and 1,200 kg . m . min-1. L-(+)-[1-14C]lactate was infused intravenously, and arterial samples were drawn at rest and every 2 min throughout the exercise period. Ra and Rd were calculated using nonsteady-state equations. At rest Ra and Rd were 14.4 +/- 1.8 and 15.1 +/- 2.2 mumol . kg-1 . min-1, respectively. Near steady-state values were observed toward the end of the first two work loads. Ra and Rd values were 32.8 +/- 2.3 and 37.4 +/- 1.3 mumol . kg-1 . min-1 during min 5 and 6 at 300 kg . m . min-1 and were 59.1 +/- 2.6 and 55.4 +/- 2.3 mumol . kg-1 . min-1 during min 5 and 6 at 600 kg . m . min-1. Ra was significantly greater than Rd at both 900 and 1,200 kg . m . min-1. Ra and Rd averaged 145.4 +/- 10.5 and 110.2 +/- 5.6 mumol . kg-1 . min-1, respectively, during the last 2 min at 900 kg . m . min-1, and 309.4 +/- 20.8 and 169.7 +/- 10.6 mumol . kg-1 . min-1, respectively, at 1,200 kg . m . min-1.(ABSTRACT TRUNCATED AT 250 WORDS)

SUMMARY Myocardial blood flow has been recognized to be heterogeneous in patients with coronary artery disease. Traditional arterial-coronary sinus sampling methods cannot demonstrate comparable heterogeneity of myocardial metabolism. In this study we used a tracer technique to investigate possible heterogeneity of myocardial lactate metabolism. Twenty-one patients with symptoms of ischemic heart disease were studied. We injected "C-i-lactate intravenously as a constant infusion after a priming dose. Coronary sinus and arterial samples were obtained for chemical and radioisotopic analyses. At rest, myocardial lactate extraction by chemical analysis was 24.6 ± 8.5% (mean ± SD). By radioisotopic analysis, the lactate extraction was 41.0 ± 10.2% (p < 0.001). Thus, certain areas of the myocardium were releasing lactate despite global net extraction of lactate. In the 12 patients with significant left main or both left anterior descending (LAD) and left circumflex (LCX) lesions, the calculated amount of lactate released at rest was 0.136 ± 0.045 ,umol/ml of blood (mean + SD). In contrast, the amount released in the six patients with a significant lesion in only the LAD or LCX was 0.076 ± 0.019 jgmol/ml, and in the three patients without left coronary arterial lesions it was 0.039 ± 0.004 4mol/ml.Using a tracer method, myocardial lactate metabolism was demonstrated to be heterogeneous at rest in patients with ischemic heart disease. A significant amount of lactate can be released by the myocardium at a time when chemical arterial-coronary sinus analysis indicates global myocardial extraction. The amount of lactate released appears to be related to the severity of the coronary artery disease.IT HAS LONG BEEN SUSPECTED that patients with functionally significant coronary artery disease have marked heterogeneity of myocardial blood flow. Significant differences in regional myocardial blood flow in patients with coronary artery disease have been demonstrated at rest.1 More recently, transient defects have been found in resting thallium-201 myocardial scintigrams in patients with severe coronary lesions.2 These findings indicate that coronary perfusion is not uniform in these patients at rest. As myocardial oxygen extraction is close to maximal during normal perfusion at rest,3 a decrease in perfusion may produce regional disturbances or heterogeneity of myocardial metabolism.Even in animals with normal coronary arteries, several investigators have found heterogeneity in myocardial blood flow.4'6 In addition, a transmural myocardial gradient of certain glycolytic enzymes and substrate stores has been shown in experimental animals.7`9 Both nonuniformity of blood flow and differences from epicardium to endocardium in substrate concentrations are consistent with the hypothesis that myocardial metabolism is heterogeneous. Traditional chemical analysis of arterial and coronary sinus blood samples cannot detect such a heterogeneous state of metabolism. The purpose of this study was to determine if heterogeneity of myocardial lac...