Myocardial tissue metabolism

In a recent study [69] myocardial tissue metabolism has been measured by calorimetry in experimental hyperthyroidism in rats. It is known that hyperthyroidism is associated with increased myocardial aerobic metabolism and accelerated heart function, but it is unknown whether there is also an increase of anaerobic metabolism. Myocardial heat production, oxygen consumption and ATP content have been measured in a group of rats treated for 2 weeks with triiodothyronine. The results were compared with the corresponding values obtained from control rats who were administered saline. Tissue slices, about 5 mg, from the apical region of the heart were prepared immediately for measurement of heat production and oxygen consumption, whereas separate specimen were frozen in liquid nitrogen for ATP analysis. 

Complex 65 (Cardiolite), 99mTc(I)-sestamibi, is used for myocardial perfusion imaging. It was designed on the basis that lipophilic cationic complexes behave as potassium mimics and are taken up by the myocardium (281). The sequential metabolism of the six methoxy groups of 65 to hydroxyl groups in the liver leads to formation of 99mTc complexes with greater hydrophilicity which are not retained in myocardial tissues (282). 

Fig. 1. Two-compartment model to describe the metabolism of oxygen-derived free radicals in myocardial tissue. This figure depicts the progressive reduction of intracellular oxygen during the cycle of ischemia and reperfusion. Inhibitors of radical metabolism are shown in dashed boxes. Radical spin traps are shown in closed boxes.

The future of PET appears promising. Improved tomographic scanners, development of new radiopharmaceuticals, and improved understanding of substrate metabolism and its relationship to myocardial tissue viability will provide new dimensions to assess and evaluate myocardial function. Research enterprises are developing agents to label receptors as a tool to determine cardiovascular physiology and how altered receptor function, biochemical abnormalities, substrate metabolism, or other as yet unrecognized abnormahties impair cardiac function. 

Since fatty acids are the primary substrate for aerobic metabolism within the heart, they are also of interest as potentially useful tracers of myocardial perfusion (12-18). This class of compounds labeled with the positron emitter is being used with specially designed positron imaging (ECT) systems to quantitatively measure the regional distribution of myocardial blood flow in three dimensions (12,13,14). Carbon-11 labeled palmitic acid is also being evaluated as a tracer for studies of myocardial metabolism. Likewise, the o-iodofatty acids, which are structural analogs of the physiologic substrates, have been shown to be taken up by myocardial tissue in proportion to blood flow (15). Iodine-123 labeled 16-iodo-9-hexadecenoic acid (18,17) and 17-iodo-heptadeca-noic acid (18) have been used in conjunction with conventional scintillation cameras for in vivo studies in humans. In all cases with this class of compounds, turnover of the label within the tissue is related to some aspect of metabolism (17,18). 

It is apparent that a great amount of preliminary work of this type in animals is needed to probe and clarify the behavior of labeled substrates in physiologic models of normal and disease states. The recently discovered role of amino acids in protecting ischemic myocardial tissue from the deleterious eflFects of hypoxia (76) is an example of the type of processes that may be at work but whose eflFects on the metabolism of myocardial tissue are not yet fully understood. 

For over one hundred years it has been recognized that a parallelism exists between tissue metabolic activity and blood flow. In the case of the heart, this relationship was clearly demonstrated by Eckenhoff et al (1947) who observed a good correlation between myocardial oxygen consumption (MVO2) and coronary blood flow (CBF) under basal conditions and with several different experimental interventions that increased cardiac oxygen utilization. This correlation is of course not unexpected since the oxygen content of coronary venous blood is quite small and enhanced oxygen requirements must be met chiefly by an increase in CBF. 

Gallagher BM, Ansari A, Atkins H, et al (1977) Radiopharmaceuticals XXVn. 18F-labeled 2-deoxy-2-fluoro-d-glucose as a radiopharmaceutical for measuring regional myocardial glucose metabolism in vivo tissue distribution and imaging studies in animals. J Nucl Med 18 990-6. 

The hypothesis that a negative energy balance in the myocardial tissue might be the cause of the heart dysfunction in diabetes was tested in a calorimetric study [88], where heat production rate was measured in myocardial tissue of rats with streptozotocin-induced diabetes. Lower P values were found in heart muscle of diabetic rats as compared to the corresponding values in healthy rats (see Table 18). These results give support to the hypothesis that a derangement of myocardial metabolism is present in diabetes mellitus, independent of coronary disea.se. 

Congestive heart failure (CHF) due to ischemic heart disease is a very common clinical situation, particularly in the elderly group of patients. It is however unclear how the myocardial cells behave metabolically when decreased blood flow in the myocardial tissue develops as a result of stenosis, or obstruction of coronary vessels, eventually leading to myocardial infarction. Myocardial metabolism was studied by microcalorimetry and oxygen consumption measurement in tissue from rats with CHF after a myocardial infarction, induced by ligation of the left coronary artery [89]. 

Acidosis occurs during cardiac arrest because of decreased blood flow and inadequate ventilation. Chest compressions generate only about 20% to 30% of normal cardiac output, leading to inadequate organ perfusion, tissue hypoxia, and metabolic acidosis. Furthermore, the lack of ventilation causes retention of carbon dioxide, leading to respiratory acidosis. The combined acidosis reduces myocardial contractility and may cause arrhythmias because of a lower fibrillation threshold. 

Much of the research on myocardial viability has focused on measuring pathological changes, cellular metabolism, or myocardial contractility without defining how much of the myocardium is involved, its relation to LV systolic function, and clinical outcomes. PET currently provides the best answer to the following questions (a) How much myocardium is scarred or viable as a percent of the zone at risk distal to a stenosis and as a percent of the whole heart (b) What amount of viable tissue justifies revascularization ... 

Sobel BE, Geltman EM, Tiefenbrunn AJ, Jaffe AS, Spadaro JJ, Jr., Ter-Pogossian MM et al. Improvement of regional myocardial metabolism after coronary thrombolysis induced with tissue-type plasminogen activator or streptokinase. Circulation 1984 69 983-990... 

Methoxyflurane (Penthmne) is the most potent inhala-tional agent available, but its high solubility in tissues limits its use as an induction anesthetic. Its pharmacological properties are similar to those of halothane with some notable exceptions. For example, since methoxyflurane does not depress cardiovascular reflexes, its direct myocardial depressant effect is partially offset by reflex tachycardia, so arterial blood pressure is better maintained. Also, the oxidative metabolism of methoxyflurane results in the production of oxalic acid and fluoride concentrations that approach the threshold of causing renal tubular dysfunction. Concern for nephrotoxicity has greatly restricted the use of methoxyflurane. 

In heart diseases like hypertension, heart failure, ischemia, and hypertrophic cardiomyopathy (HCM) as well as dilated cardiomyopathies (DCM), total myocardial jS-AR density is reduced [90-94], A selective reduction of p -ARs without change of P2-AR density is often observed in the failing human heart [89], Therefore, there is a clinical need for the noninvasive assessment of p-AR density in vivo. PET is capable of assessing receptor concentrations in vivo, provided that a radioligand radiolabeled with a positron emitter specifically and selectively binds to the target receptor, and metabolism of the radiotracer does not occur in target tissue. 

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