Results of clinical and experimental animal studies have shown that unusually high levels of catecholamines in the blood cause a variety of morphological and functional changes in the heart (1, 18, 22, 25, 28). The endogenous stores of adenine triphosphate and creatine phosphate are depleted (8, 25, 26) and mitochondrial structure-function is impaired (7, 15). Intracellular increase in calcium has been considered to be a determinant factor in this as well as in variety of other models of heart cell damage (8, 21). In this regard catecholamine-induced cardiomyopathy, has been shown to be accompanied by a significant increase in the myocardial calcium content (8,15) indicating changes in the membrane permeability. Strong evidence for the alterations in the permeability of sarcolemma due to isoproterenol treatment was provided by the intracellular diffusion of horseradish peroxidase, an extracellular protein tracer, following the drug injection (19).

Potential Oxidative Pathways of Catecholamines in the Formation of Lipid Peroxides and Genesis of Heart Disease

This study was performed to elucidate the localization at the cellular level of technetium-99m phosphorus ((99m)Tc-P) radiopharmaceuticals in acute myocardial infarcts and the mechanisms responsible for (99m)Tc-P uptake in acute myocardial infarcts and other tissues. In 20 dogs with proximal left anterior descending coronary arterial ligation for 1-3 days, elevated calcium levels were measured at all sites of increased (99m)Tc-P uptake (acute myocardial infarcts, necrotic thoracotomy muscle, lactating breast, and normal bone); however, a consistent linear relationship between (99m)Tc-P and calcium levels was not observed. A strong correlation (r = 0.95 and 0.99, n = 2 dogs) was demonstrated between levels of (3)H-diphosphonate and (99m)Tc-P in infarcted myocardium. Autoradiographic studies with (3)H-diphosphonate revealed extensive labeling in the infarct periphery which contained necrotic muscle cells with features of severe calcium overloading, including widespread hypercontraction as well as more selective formation of mitochondrial calcific deposits. Autoradiography also demonstrated labeling of a small population of damaged border zone muscle cells which exhibited prominent accumulation of lipid droplets and focal, early mitochondrial calcification. Cell fractionation studies revealed major localization of both (99m)Tc-P and calcium in the soluble supernate and membrane-debris fractions of infarcted myocardium and less than 2% of total (99m)Tc-P and calcium in the mitochondrial fractions; however, electron microscopic examination showed that mitochondria with calcific deposits were not preserved in the mitochondrial fractions. In vitro studies evaluating the role of serum protein binding on tissue uptake of (99m)Tc-P agents demonstrated that, in spite of significant complexing with serum proteins, serum (99m)Tc-P activity retained the ability to adsorp to calcium hydroxyapatite and amorphous calcium phosphate. In vivo studies showed that concentration of human serum albumin (labeled with iodine-131) in infarcted myocardium reached a maximum of only 3.8 times normal after a circulation time of 96 h, whereas (99m)Tc-P uptake was at least 10 times normal after a circulation time as short as 1 h. It is concluded that: (a) (99m)Tc-P uptake in acutely infarcted myocardium, and possibly other types of soft tissue damage, is limited to necrotic and severely injured cells; (b) concentration of (99m)Tc-P results from selective adsorption of (99m)Tc-P with various forms of tissue calcium stores, including amorphous calcium phosphate, crystalline hydroxyapatite, and calcium complexed with myofibrils and other macromolecules, possibly supplemented by calcium-independent complexing with organic macromolecules; and (c) lack of a linear relationship between (99m)Tc-P and tissue calcium levels mainly results from local differences in composition and physicochemical properties of tissue calcium stores and from local variations in levels of blood flow for delivery of (99m)Tc-P agents.

/pdf/sites-and-mechanisms-of-localization-of-technetium-99m-4vg0i5p8dk.pdf

Sites and Mechanisms of Localization of Technetium-99m Phosphorus Radiopharmaceuticals in Acute Myocardial Infarcts and other Tissues

Experimental catecholamine-induced myocardial necrosis I. morphology, quantification and regional distribution of acute contraction band lesions

Various stressful stimuli are known to activate the sympathetic nervous system to release catecholamines and the hypothalamic–pituitary–adrenal axis to release glucocorticoids in the circulation. Although initial actions of both catecholamines and glucocorticoids are beneficial for the function of the cardiovascular system, their delayed effects on the heart are deleterious. Glucocorticoids not only increase plasma levels of catecholamines by inhibiting their extraneuronal uptake, but they have also been shown to induce supersensitivity to catecholamines in the heart by upregulating different components of the β-adrenoceptor signal transduction system. Low concentrations of catecholamines stimulate the heart by promoting Ca2+ movements, whereas excessive amounts of catecholamines produce cardiac dysfunction by inducing intracellular Ca2+ overload in cardiomyocytes. Several studies have shown, however, that under stressful conditions high concentrations of catecholamines become oxidized to form aminolutins...

Role of the excessive amounts of circulating catecholamines and glucocorticoids in stress-induced heart disease.

To obtain insight into the mechanism(s) responsible for the direct visualization of acute myocardial infarcts by myocardial scintigraphy with technetium-99m stannous pyrophosphate (99mTc-PYP), scintigraphic and morphologic studies were performed in 22 dogs subjected to occlusion of the proximal left anterior descending coronary artery (LAD). Grossly visible myocardial infarcts occurred in ten of 11 dogs with LAD occlusion for one day, five with LAD occlusion for two days, two with LAD occlusion for seven days and two with LAD occlusion for 13 days. Rare, microscopic foci of necrosis were observed in one dog with LAD occlusion for one day, and no lesions were present in two dogs subjected to temporary LAD occlusion for eight minutes and reflow for 24 hours. In the latter three dogs, 99mTc-PYP myocardial scintigrams were negative. In the 19 dogs with gross infarcts, 99mTc-PYP myocardial scintigrams were strongly positive at one and two days after LAD occlusion, much less positive at seven days and faintly positive at 13 days after occlusion. Positive myocardial scintigrams in most showed "doughnut" patterns, with marked peripheral concentration of radioactivity around central zones of much lower activity. On histologic examination, the one and two-day-old infarcts exhibited subendocardially located central zones and surrounding peripheral zones, both of which showed distinctive histopathological and histochemical features, including the selective occurrence in the peripheral zones of calcified muscle cells with ultrastructurally demonstrable apatite-like crystals in mitochondria. Selective occurrence of high tissue levels of 99mTc-PYP radioactivity also was demonstrated in the peripheral zones of four infarcts. Hearts with older infarcts (seven and 13 days) showed progressive replacement of necrotic myocardium by granulation tissue and progressive reduction in calcium deposits in the areas of damage. The data obtained in this study establish a temporal and topographical relationship between calcium accumulation in acute myocardial infarcts and 99mTc-PYP uptake responsible for scintigraphic detection of the lesions with this radionuclide in dogs subjected to proximal LAD occlusion.

Morphologic correlates of technetium-99m stannous pyrophosphate imaging of acute myocardial infarcts in dogs.

Pathogenesis of isoproterenol-induced myocardial alterations: functional and morphological correlates.

Studies with extracellular fine structural diffusion protein tracers, horseradish peroxidase and ferritin, were carried out on catecholamine-induced cardiac muscle cell injury. Epinephrine, norepinephrine, and isoproterenol were administered in a dose of 4- 6 mug/100g body weight by continuous intravenous infusion. For follow-up studies, isoproterenol was also given subcutaneously in a dose of 8.5 mg/100 g body weight as a single injection. In contrast to saline-infused controls and following epinephrine infusion, where these tracers always remained extracellular, norepinephrine- and isoproterenol-infused animals exhibited alteration of sarcoplasmic membrane permeability to macromolecules in the early stage of evolution preceding fine structural changes of cardiac muscle cells. This was reflected by the intrasarcoplasmic presence of peroxidase in some cardiac muscle cells which otherwise showed no ultrastructural alteration. Deposition upon and selective binding of the extracellular protein tracer, peroxidase, to intact myofilament was also a characteristic early change that may affect the contraction-relaxation mechanism of the myofilaments and may contribute to the evolution of necrobiotic alteration. In structurally altered cells, peroxidase showed similar affinity to contraction bands and fragmented myofilaments. Furthermore, these studies disclosed different sensitivities of various membrane components of the cardiac muscle cell. While in the early pahse of cell damage no peroxidase could be detected in various intrasarcoplasmic compartments, with increasing severity of the lesion the external and internal mitochondrial membranes as well as the sarcoplasmic reticulum were also affected. When the large molecular tracer, ferritin, was used, the sequence of events in altered cardiac muscle cells followed that outlined for peroxidase. However, free ferritin molecules could not be demonstrated in the sarcoplasm of cardiac muscle cells which exhibited normal ultrastructure.

Membrane permeability alterations as manifestation of early cardiac muscle cell injury.

Coronary artery ligation with or without reperfusion was carried out in Wistar rats to study the role of coronary microcirculatory factors and membrane permeability alteration of cardiac muscle cell in the evolution of cardiac muscle cell injury by using the fine structural extracellular protein tracer, horseradish peroxidase (HRP). The findings were compared with those obtained in noncoronarogenic myocardial injury models following administration of norepinephrine, a pressor, and isoproterenol, a depressor catecholamine. Following left coronary artery ligation lastingfor 10 and 20 minutes, some of the collaterals in the ischemic zone were perused by the tracer, but the numer of patent capillaries decreased during 60-min ligation. The inhomogeneous involvement of cardiac muscle cells in ischemic injury correlated well with these microcirculatory findings. In comparison to permanent ischemia, an abrupt deterioration of the cardiac muscle cell alteration occured after reperfusion with influx of HRP into the damaged cells. The binding of tracer to myofilaments was, however, a later event as compared to that seen in the catecholamine models. The latter observation implies that, in addition to microcirculatory factors, direct cardiac muscle cell stimulation should also be considered in the evolution of noncoronarogenic myocardial injury.

Coronary microcirculatory factors and cardiac muscle cell injury.

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Pathogenesis of isoproterenol-induced myocardial alterations: functional and morphological correlates.

Membrane permeability alterations as manifestation of early cardiac muscle cell injury.

Coronary microcirculatory factors and cardiac muscle cell injury.