Biomedical subjects

C R Malloy

Publications and source records attributed to C R Malloy.

At least 91 records · Page 5Linked to original sources

PubMed1989

Effect of ischemia on NMR detection of phosphorylated metabolites in the intact rat heart.

Phosphorus NMR spectroscopy is an important technique for the investigation of metabolism in tissues and intact organisms (including man). However, quantitation of the signals from an NMR experiment is difficult because it is not known from which regions of a cell metabolites are detected. It is generally believed that only metabolites free in the cytosol are observed. In this study a comparison of concentration measurements obtained by NMR and after freeze extraction was made in the normoxic and ischemic rat heart. The influence of ischemia was examined because of its potential effect on the level of phosphate metabolites in various compartments. The same fraction of ATP always appears visible to NMR, whereas inorganic phosphate is largely NMR invisible until after a period of ischemia and the phosphomonoesters are only partially observed early in ischemia.

Adenosine Monophosphate↗

PubMed1989

Transcardiac serotonin concentration is increased in selected patients with limiting angina and complex coronary lesion morphology.

Serotonin is released by activated platelets and may act as a mediator to initiate or sustain certain unstable syndromes of ischemic heart disease in humans. To determine whether or not serotonin concentration increases across the coronary bed in patients with severe, limiting angina, we measured central aortic and coronary sinus serotonin concentrations by a sensitive radioenzymatic assay in 39 patients with coronary artery disease and 13 patients with minimal or no coronary artery lesions as detected by arteriography. Although no difference existed in the mean aortic or coronary sinus serotonin concentrations between these two groups, elevated coronary sinus serotonin concentrations were detected in 23% of those with coronary artery disease. The coronary sinus and aortic serotonin concentration difference was greater in patients with significant coronary artery disease (0.6 +/- 6.62 ng/ml) compared with patients without significant coronary artery disease (-5.6 +/- 10.32 ng/ml) (mean +/- SD) (p less than 0.05). Further analysis revealed that patients with eccentric, irregular coronary artery lesions or intraluminal filling defects had a significantly elevated coronary sinus and aortic serotonin difference (3.1 +/- 5.54 ng/ml) compared with those with smooth concentric lesions (-1.9 +/- 6.61 ng/ml) (p less than 0.02). These data suggest that serotonin is released into the coronary circulation of some patients with coronary artery disease, especially those with frequent angina and complex coronary lesions. Although serotonin may be released in some patients with coronary artery disease, the specific pathophysiologic role of serotonin in the development or perpetuation of certain coronary syndromes in humans remains to be determined.

Aged↗

PubMed1988

Propionate metabolism in the rat heart by 13C n.m.r. spectroscopy.

High-resolution 13C n.m.r. spectroscopy has been used to examine propionate metabolism in the perfused rat heart. A number of tricarboxylic acid (TCA) cycle intermediates are observable by 13C n.m.r. in hearts perfused with mixtures of pyruvate and propionate. When the enriched 13C-labelled nucleus originates with pyruvate, the resonances of the intermediates appear as multiplets due to formation of multiply-enriched 13C-labelled isotopomers, whereas when the 13C-labelled nucleus originates with propionate, these same intermediates appear as singlets in the 13C spectrum since entry of propionate into the TCA cycle occurs via succinyl-CoA. An analysis of the isotopomer populations in hearts perfused with [3-13C]pyruvate plus unlabelled propionate indicates that about 27% of the total pyruvate pool available to the heart is derived directly from unlabelled propionate. This was substantiated by perfusing a heart for 2 h with [3-13C]propionate as the only available exogenous substrate. Under these conditions, all of the propionate consumed by the heart, as measured by conventional chemical analysis, ultimately entered the oxidative pathway as [2-13C] or [3-13C]pyruvate. This is consistent with entry of propionate into the TCA cycle intermediate pools as succinyl-CoA and concomitant disposal of malate to pyruvate via the malic enzyme. 13C resonances arising from enriched methylmalonate and propionylcarnitine are also detected in hearts perfused with [3-13C] or [1-13C]propionate which suggests that 13C n.m.r. may be useful as a non-invasive probe in vivo of metabolic abnormalities involving the propionate pathway, such as methylmalonic aciduria or propionic acidaemia.

Animals↗

PubMed1988

Evaluation of carbon flux and substrate selection through alternate pathways involving the citric acid cycle of the heart by 13C NMR spectroscopy.

A previous 13C NMR technique (Malloy, C. R., Sherry, A.D., and Jeffrey, F.M.H. (1987) FEBS Lett. 212, 58-62) for measuring the relative flux of molecules through the oxidative versus anaplerotic pathways involving the citric acid cycle of the rat heart has been extended to include a complete analysis of the entire glutamate 13C spectrum. Although still simple in practice, this more sophisticated model allows an evaluation of 13C fractional enrichment of molecules entering both the oxidative and anaplerotic pathways under steady-state conditions. The method was used to analyze 13C NMR spectra of intact hearts or their acid extracts during utilization of 13C-enriched pyruvate, propionate, acetate, or various combinations thereof. [2-13C]Pyruvate was used to prove that steady-state flux of pyruvate through pyruvate carboxylase is significant during co-perfusion of pyruvate and acetate, and we demonstrate for the first time that a nine-line 13C multiplet may be detected in an intact, beating heart. Acetate or pyruvate alone provided about 86% of the acetyl-CoA; in combination, about 65% of the acetyl-CoA was derived from acetate, about 30% was derived from pyruvate, and the remainder from endogenous sources. Propionate reduced the contribution of exogenous acetate to acetyl-CoA to 77% and also reduced the oxidation of endogenous substrates. Equations are presented which allow this same analysis on multiply labeled substrates, making this technique extremely powerful for the evaluation of substrate selection and relative metabolic flux through anaplerotic and oxidative pathways in the intact heart.

Acetates↗

PubMed1988

Clinical and hemodynamic characteristics of patients with inducible pulsus alternans.

Pulsus alternans can be found in some patients with abnormal left ventricular function and also can develop after spontaneous premature beats. The purposes of this study were to: (1) determine the inducibility of pulsus alternans in a series of patients referred for routine cardiac catheterization and (2) define the clinical and hemodynamic characteristics of those who develop pulsus alternans. In 104 patients referred for right and left heart catheterization, atrial premature beats and rapid atrial pacing were used to try to provoke pulsus alternans. The 29 patients who developed pulsus alternans in response to these maneuvers were older (63 +/- 6 vs 59 +/- 10 years, p less than 0.01) and had a greater incidence of valvular heart disease (45% vs 23%, p less than 0.01) and congestive heart failure (38% vs 17%, p less than 0.05). Aortic stenosis was the most prevalent valve lesion found. Those who developed pulsus alternans in response to pacing were further characterized by higher left ventricular systolic (143 +/- 42 vs 121 +/- 23 mm Hg, p less than 0.02) and end-diastolic pressures (17 +/- 9 vs 13 +/- 6 mm Hg, p less than 0.05), higher pulmonary artery systolic pressure (35 +/- 14 vs 29 +/- 11 mm Hg, p less than 0.04), and lower left ventricular ejection fractions (0.42 +/- 0.13 vs 0.53 +/- 0.14, p less than 0.001). Eight patients (28%) with inducible pulsus alternans had a normal left ventricular ejection fraction (greater than 0.50) and left ventricular end-diastolic pressure (less than 13 mm Hg).(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗

PubMed1988

Gadolinium-DTPA-enhanced nuclear magnetic resonance imaging of reperfused myocardium: identification of the myocardial bed at risk.

Gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA)-enhanced nuclear magnetic resonance (NMR) imaging can be useful in the identification of reperfused myocardium. However, the effects of dose and the time of administration and the relation of the extent of the region of enhancement to the myocardial bed at risk have not been evaluated. In this study, dogs were given Gd-DTPA (0.1 mM/kg body weight [n = 21] or 0.34 mM/kg [n = 7]) or saline solution (n = 5) after various periods of occlusion and reperfusion. Twenty-five dogs were killed after 1 or 2 h of reperfusion and the excised hearts were imaged. Images were analyzed for presence, intensity and extent of a region of increased signal. All images in dogs given Gd-DTPA had easily identifiable regions of increased signal in the distribution of the reperfused myocardial bed. Analysis of the extent of these regions in spin-echo images of excised hearts when Gd-DTPA was administered after 5 min of reperfusion demonstrated a correlation coefficient of 0.72 with the bed at risk as determined postmortem with a dye perfusion technique. These images consistently overestimated the infarct size. Signal intensity of the reperfused myocardium increased to a maximum of 1.67 times control (p less than 0.05) in spin-lattice relaxation time (T1)-weighted sequences as the dose of Gd-DTPA increased. This was due to a higher concentration of Gd-DTPA in the reperfused myocardium with resultant shortening of the T1 relaxation time. When Gd-DTPA was given after 90 min of reperfusion, NMR images did not identify the bed at risk.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1987

Carbon flux through citric acid cycle pathways in perfused heart by 13C NMR spectroscopy.

Mathematical models of the TCA cycle derived previously for 14C tracer studies have been extended to 13C NMR to measure the 13C fractional enrichment of [2-13C]acetyl-CoA entering the cycle and the relative activities of the oxidative versus anaplerotic pathways. The analysis is based upon the steady-state enrichment of 13C into the glutamate carbons. Hearts perfused with [2-13C]acetate show low but significant activity of the anaplerotic pathways. Activation of two different anaplerotic pathways is demonstrated by addition of unlabeled propionate or pyruvate to hearts perfused with [2-13C]acetate. In each case, the amount of [2-13C]acetate being oxidized and the relative carbon flux through anaplerotic versus oxidative pathways are evaluated.

Acetates↗

PubMed1987

Analysis of spin-echo rephasing with pulsatile flow in 2D FT magnetic resonance imaging.

The effects of pulsatile flow on spin phases in spin-echo magnetic resonance imaging are considered. General expressions for the spin phases of the first four echoes are derived in terms of the Fourier coefficients of flow. These expressions are valid for any time-dependent acceleration and, hence, are not restricted to constant acceleration. The derived expressions are then theoretically evaluated for aortic flow and examined at different points in the cardiac cycle. Our results show that rephasing may occur at certain points in the cardiac cycle for either even or odd echoes depending upon the particular Fourier coefficients of the velocity function and the spin-echo delay time. However, even-echo rephasing is not always necessarily valid. Furthermore, the possibility of determining the flow velocities in the body with an appropriate series of imaging studies is also discussed.

Aorta↗

PubMed1987

Even-echo rephasing and constant velocity flow.

It has been shown previously that for constant magnetic field gradients, constant velocity flow leads to even-echo rephasing for all echo delay times. We show that for flow which is not pluglike, even-echo rephasing also occurs for the pulsed readout gradients used in magnetic resonance imaging if and only if the gradients begin at the time the 90 degrees pulse is applied. We also show for these gradients that even-echo rephasing for all echo delay times in the case of nonpluglike flow implies a constant flow velocity at the point considered. Furthermore, it suffices to assume the vanishing of the spin-echo phase for any even echo, since the vanishing of any even echo for all echo delay times implies that all other even echoes also vanish identically. The odd echoes are then all equal to each other and proportional to the flow velocity. If acceleration is present, it may then be seen that for nonpluglike flow, even-echo rephasing may only be present for some but not all echo delay times. However, for the typical slice selection gradients used in magnetic resonance imaging or for usual readout gradients starting after the 90 degrees pulse is applied, it is shown that for constant velocity flow the even-echo phases do not vanish identically. Hence, rephasing cannot always occur for nonpluglike flow in either of these situations. Furthermore, the spin-echo phases are proportional to the flow velocity.(ABSTRACT TRUNCATED AT 250 WORDS)

Humans↗

PubMed1987

Nuclear magnetic resonance imaging in Marfan's syndrome.

Detection and evaluation of aortic root and other cardiovascular abnormalities in patients with Marfan's syndrome are important in determining appropriate therapy and preventing premature mortality. To evaluate the role of nuclear magnetic resonance imaging (NMR) in this syndrome, 10 patients were evaluated using a 0.35 tesla commercial nuclear magnetic resonance imaging system. Findings from these studies were compared with data from other noninvasive tests as well as surgical follow-up. Results from these examinations indicate that NMR-derived measurements of aortic root diameter agree closely with echocardiographic measurements. In addition, NMR provides more complete anatomic detail than does echocardiography and can be utilized to assess and follow up virtually all patients with this syndrome.

Adolescent↗

PubMed1987

Plasma serotonin concentrations: validation of a sampling technique using long catheters.

Serotonin is released by activated platelets and may promote platelet aggregation and epicardial coronary artery constriction in animal models. Serotonin may have similar effects in humans and, thus may be a mediator of certain ischemic syndromes. However, the role of serotonin in human ischemic heart disease has not been studied. Since evaluation of transcardiac serotonin metabolism requires that blood samples be obtained through long catheters, it is possible that artifactual changes in serotonin concentration could occur because of platelet activation in the catheters themselves. Accordingly, to determine if serotonin could be measured through long catheters without artifactual changes, the authors obtained paired blood samples by gentle aspiration through a large bore steel needle and a 100-cm polyurethane catheter placed in the femoral vein of 13 patients. All samples were processed to obtain platelet-poor plasma and then analyzed by a sensitive radioenzymatic assay. Blood sampling through long catheters did not cause a systematic alteration in plasma serotonin concentration. Mean serotonin concentration from the femoral vein through a needle was 22.3 +/- 26.55 ng/ml (mean +/- standard deviation), and that obtained through a long catheter was 20.0 +/- 26.29 ng/ml (p = 0.34). The authors conclude that carefully obtaining blood samples through long catheters does not significantly alter the plasma serotonin concentration and thus the accurate measurement of transcardiac serotonin concentrations is possible using these methods.

Blood Platelets↗

PubMed1987

Influence of intracellular acidosis on contractile function in the working rat heart.

The decrease in myocardial contractility during ischemia, hypoxia, and extracellular acidosis has been attributed to intracellular acidosis. Previous studies of the relationship between pH and contractile state have utilized respiratory or metabolic acidosis to alter intracellular pH. We developed a model in the working perfused rat heart to study the effects of intracellular acidosis with normal external pH and optimal O2 delivery. Intracellular pH and high-energy phosphates were monitored by 31P nuclear magnetic resonance spectroscopy. Hearts were perfused to a steady state with a medium containing 10 mM NH4Cl (extracellular pH, 7.4). The subsequent washout of NH3 from the cytosol generated a slight acidosis (from intracellular pH 7.0 to 6.8) which was associated with little change in the determinants of O2 consumption (rate-pressure product) and O2 delivery (coronary flow). Acidosis induced a substantial decrease in aortic flow and stroke volume which was associated with little change in peak systolic pressure. Results were qualitatively similar at different external [Ca2+] (1.75, 2.5, 3.15 mM) and preload (12 or 21 cmH2O) but were most prominent at the lowest external [Ca2+] and left atrial pressure. In contrast to this model of isolated intracellular acidosis, hearts subject to a respiratory (extracellular plus intracellular) acidosis showed a marked reduction in pressure development. It was concluded that 1) for the same intracellular acidosis the influence on tension development was more pronounced with a combined extra- and intracellular acidosis than with an isolated intracellular acidosis, and 2) stroke volume at constant preload was impaired by intracellular acidosis even though changes in developed pressure were minimal. These observations suggest that isolated intracellular acidosis has adverse effects on diastolic compliance and/or relaxation.

Acid-Base Equilibrium↗

PubMed1987

Direct determination of the attenuation coefficient for radionuclide volume measurements.

Correcting for the attenuation of photons between the cardiac chambers and chest surface is crucial for accurate nongeometric ventricular volume determinations from equilibrium radionuclide angiograms. Previous techniques have assumed that the attenuation coefficient of water for 99mTc (0.15/cm) should be used for this correction. In this study, this assumption was tested directly by measuring attenuation of the activity of a radioactive source within the right and left cardiac chambers. The balloon of a flow-directed catheter, filled with 99mTc, was used as a source and its depth within the body was measured with biplane fluoroscopy. In ten patients, a total of 36 measurements of attenuation were made. With linear regression analysis, the overall calculated attenuation coefficient, mu, was 0.12/cm (standard error of slope = 0.01, R = 0.93). Although the mean value of mu varied from 0.08 to 0.13 for four different intracardiac locations these differences were not significant. These direct measurements indicate that the attenuation of photons in the heart is not equivalent to that of water and suggest that an attenuation coefficient of 0.12/cm should be used in analyzing ventricular activity.

Adult↗

PubMed1986

Detection and localization of recent myocardial infarction by magnetic resonance imaging.

The potential of magnetic resonance imaging (MRI) to detect and localize acute myocardial infarction (AMI) in 27 patients a mean interval of 15 days after AMI was evaluated. Eighteen asymptomatic volunteers were also studied to determine the specificity of the observations. The diagnosis of AMI was established by conventional criteria; the infarct was localized by electrocardiography in all patients, technetium pyrophosphate scintigraphy in 19 and necropsy in 1 patient. MRI detected increased myocardial signal intensity in 88%, cavitary signal in 74% and regional wall thinning in 67% of the patients. At least 1 of these 3 features was seen in the area of the infarct in each patient. The sensitivity of these MRI observations was not influenced by location of the infarct or presence of Q waves. Asymptomatic volunteers also had increased myocardial signal in 83%, cavitary signal in 94% and wall thinning in 11% of cases. Some patients had these findings in myocardial segments not suspected of being involved by recent or remote AMI. It is concluded that AMI can be detected by MRI performed an average of 15 days after infarction. However, the hearts of normal volunteers and apparently normal myocardial segments of patients with AMI may have the MRI findings previously associated with AMI. Of these findings, wall thinning was the most predictive of and specific for AMI.

Adult↗

PubMed1986

Improved in vivo magnetic resonance imaging of acute myocardial infarction after intravenous paramagnetic contrast agent administration.

Gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA), a paramagnetic relaxation agent, has been used in vitro to improve the detection of acute myocardial infarction (MI) by magnetic resonance imaging (MRI). In this study, the ability of Gd-DTPA to improve in vivo magnetic resonance imaging of MI was examined. Ten dogs with MI caused by left anterior descending coronary artery ligation were imaged 1 to 5 days after infarction. Imaging was performed before and for 2 hours after intravenous administration of 0.34 mmol/kg Gd-DTPA. One to 2 days after MI, Gd-DTPA improved visualization of the infarct in 3 of 4 dogs. This effect was more prominent in dogs imaged 4 to 5 days after MI, when 6 of 6 dogs showed substantially improved infarct definition after Gd-DTPA. At both times the intensity ratio, an objective measure of contrast between infarcted and normal tissue that is defined by the ratio of image intensity of infarcted area to that of noninfarcted area, was significantly better after Gd-DTPA administration. The intensity ratio at 24 to 48 hours after infarction was 1.4 +/- 0.2 (mean +/- standard deviation) before Gd-DTPA, and 1.7 +/- 0.6 after Gd-DTPA (p = 0.03). The intensity ratio at 4 to 5 days after infarction was 1.5 +/- 0.3 before Gd-DTPA, and 1.8 +/- 0.5 after Gd-DTPA (p less than 0.001). Thus, Gd-DTPA administration improves in vivo visualization of MI by MRI.

Animals↗

PubMed1986

The metabolic state of the rat liver in vivo measured by 31P-NMR spectroscopy.

Previous 31P nuclear magnetic resonance (NMR) studies have measured the concentrations of phosphates, free Mg2+, pH and flux through enzyme-catalyzed reactions in a variety of tissues. A surgically-implanted coil has been developed to measure these parameters in the rat liver in vivo, and to assess the effect of external perturbations on the concentrations and physiological environment of phosphorus metabolities in the liver. The sensitive volume and optimal pulse were determined for the coil, which was insulated to exclude signal from surrounding tissues. The metabolic stability of the liver during acquisition of spectra was demonstrated by normal values for [Pi], [ATP], [lactate], and [pyruvate] in livers which were freeze-clamped immediately after completion of the NMR experiment. The stability was also confirmed by constant values for intracellular pH (7.2), free [Mg2+] (0.7 mM), and NMR detectable [Pi]/[ATP]. The sensitivity of the 31P-NMR spectrum of the liver in vivo to the physiological state of the animals was illustrated by comparing spectra from fed and 48 h fasted rats. The major qualitative differences were an increase in the pyridine nucleotide/adenine nucleotide ratio, and a small, but consistent shift in the frequency of the composite phosphomonoester peak. The spin-lattice relaxation time of each major phosphate resonance was measured in vivo using a modified homospoil saturation recovery pulse sequence; the T1 of ATP gamma-phosphate was 0.17 s. Selective saturation experiments did not detect magnetization transfer between the ATP gamma-phosphate and inorganic phosphate.

Adenine Nucleotides↗

PubMed1986

Effect of fasting and acute ethanol administration on the energy state of in vivo liver as measured by 31P-NMR spectroscopy.

The effects of 48 h fasting, administration of ethanol or 2,4-dinitrophenol, on the phosphorus-containing metabolites in liver in vivo have been determined utilizing 31P nuclear magnetic resonance spectroscopy. These measurements were combined with determinations of metabolite concentrations in livers which were freeze-clamped immediately after the NMR measurements were completed. Administration of sub-lethal amounts of dinitrophenol dramatically decreased ATP and increased Pi concentrations in liver in vivo as indicated by a 2.7-fold increase in the NMR-derived [Pi]/[ATP] ratio. Ethanol administration to fed animals increased the NMR-derived [Pi]/[ATP] ratio 27%; in contrast, the same amount of ethanol administered to fasted animals decreased the NMR-derived [Pi]/[ATP] ratio 30%. The NMR visible Pi and ADP represent about 50% and 15% of the total Pi and ADP, respectively. The phosphorylation potentials calculated from the NMR visible Pi and ADP were an order of magnitude higher than those obtained from metabolite concentrations in freeze-clamped tissue. There was no apparent correlation between the phosphorylation potentials derived from either the NMR spectral analyses or from metabolite concentrations and the hepatic [NAD+]/[NADH] ratio. The chemical shift of Pi indicated that ethanol administration elicited a decrease in pH of 0.1 unit in liver in vivo. Hepatic free [Mg2+] was increased 21% in fasted animals, but was unaffected by ethanol administration.

Acetoacetates↗

PubMed1986

A new technique for cannulation of the coronary sinus from the femoral vein.

Previous techniques for cannulation of the coronary sinus have required entry into the right atrium from the superior vena cava. We describe a new technique for cannulation of the coronary sinus from the femoral vein using a standard, unmodified Simmons II catheter. This method was successful in 97% of the patients attempted. The method for using this catheter from the femoral route is described.

Cardiac Catheterization↗