Hyperornithinemia, hyperammonemia, homocitrullinuria (HHH) syndrome: presentation as acute liver disease with coagulopathy.
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Amino Acid Metabolism, Inborn Errors↗
Biomedical subjects
G Jasmin
Publications and source records attributed to G Jasmin.
[Ca2+]i transients in the cardiomyopathic hamster heart.
Intracellular [Ca2+] transients were studied in isolated hearts of healthy and cardiomyopathic hamsters in late failure perfused with glucose or pyruvate. Hearts of healthy hamsters developed similar pressures when perfused with either glucose or pyruvate, and [Ca2+]i transients were comparable in amplitude when perfused with either substrate. On the other hand, hearts of cardiomyopathic hamsters in late failure developed normal pressure when perfused with pyruvate but developed depressed pressure (50%) when perfused with glucose. The amplitude of [Ca2+]i transients fell severely and was associated with a high diastolic [Ca2+]i in cardiomyopathic hamster hearts when the perfusate was switched from pyruvate to glucose. The high phosphomonoester sugars as evidenced by 31P nuclear magnetic resonance studies and the depressed oxygen consumption in the cardiomyopathic hamster hearts perfused with glucose reflect an inhibition in glycolysis and a subsequent decrease in mitochondrial activity. Without an adequate delivery of substrate to the mitochondria in the cardiomyopathic hamster, the myocardium is no longer capable of maintaining its [Ca2+]i homeostasis.
Animals↗
A tetrodotoxin- and Mn2(+)-insensitive Na+ current in Duchenne muscular dystrophy.
Muscle myotube cultures were obtained from normal and Duchenne muscular dystrophy (DMD) biopsies by using an explant technique. The current-voltage (I/V) curve of the whole sodium (Na+) current (INa) in normal myotubes was similar to that obtained from DMD myotubes. However, the inactivation curve of the whole INa was different in normal myotubes when compared to that obtained from DMD myotubes. Addition of 10(-4) M tetrodotoxin (TTX, a fast INa blocker) decreased the whole INa in both preparations. The inorganic calcium (Ca2+) blocker manganese (Mn2+) completely blocked the remaining TTX-resistant INa of normal myotubes and decreased this current in DMD myotubes leaving behind a TTX- and Mn2(+)-insensitive INa that was insensitive to the Ca2+ blocker desmetoxyverapamil ((-)D888). The slow inward barium current (IBa) of both normal and DMD myotubes was blocked by Mn2+ and (-)D888. However the kinetics of the slow channel in normal myotubes was different from that of DMD myotubes. This study demonstrates the presence of a TTX- and Mn2(+)-insensitive INa in DMD myotubes. This channel may contribute to the increase of intracellular Na+ [( Na]i) in DMD and allow Ca2+ to enter the cells through the Na(+)-Ca2+ exchanger, thus contributing to calcium loading.
Adolescent↗
Immuno-electron microscopy of atrial natriuretic factor secretory pathways in atria and ventricles of control and cardiomyopathic hamsters with heart failure.
The secretory pathways of atrial natriuretic factor have been investigated in atrial and ventricular cardiocytes of control and cardiomyopathic Syrian hamsters in severe congestive heart failure with four antibodies: a monoclonal antibody (2H2) against rat synthetic atrial natriuretic factor (101-126), which is directed against region 101-103 of rat atrial natriuretic factor (99-126), and polyclonal, affinity-purified antibodies produced in rabbits against synthetic C-terminal atrial natriuretic factor (101-126), synthetic N-terminal atrial natriuretic factor (11-37) or the putative cleavage site of atrial natriuretic factor (98-99): atrial natriuretic factor (94-103). Application of the immunogold technique on thin frozen sections (immunocryoultramicrotomy) revealed an identical picture with the four antibodies. In atria of both control and cardiomyopathic hamsters where atrial natriuretic factor secretion is regulated, the atrial natriuretic factor propeptide travels, uncleaved, from the Golgi complex to immature and mature secretory granules. In ventricles of control hamsters, where secretion is constitutive, the atrial natriuretic factor propeptide travels from the Golgi complex to secretory vesicles. In the ventricles of hamsters with severe congestive heart failure, the Golgi complex is larger, secretory vesicles more abundant and a few secretory granules are present in approximately 20% of cardiocytes. Here again, the peptide travels uncleaved in all these pathways. These results reveal the pathways of secretion of atrial natriuretic factor in atrial and ventricular cardiocytes and indicate that the propeptide is not cleaved intracellularly.
Animals↗
Dobutamine potentiates amrinone's beneficial effects in moderate but not in advanced heart failure. 31P-MRS in isolated hamster hearts.
There is controversy as to whether potent inotropic agents are beneficial or detrimental in moderate to severe heart failure. Accordingly, we studied the effects of amrinone, amrinone plus dobutamine, and dobutamine alone on mechanical performance, myocardial oxygen consumption, and high energy phosphate metabolism in different stages of congestive heart failure in the cardiomyopathic Syrian hamster. In hearts with moderate heart failure, administration of amrinone, amrinone plus dobutamine, and dobutamine alone increased developed pressure significantly, whereas the phosphorylation potential increased significantly only with amrinone and amrinone plus dobutamine. In hearts with advanced heart failure, administration of amrinone and amrinone plus dobutamine increased developed pressure significantly, whereas dobutamine alone had no effect. The phosphorylation potential improved significantly only with amrinone. Thus, amrinone improved mechanical performance and mitochondrial activity in both heart failure states. Dobutamine potentiated amrinone's beneficial effects in moderate heart failure, but negated the positive inotropic effect of amrinone in advanced heart failure. Therefore, hearts responded differently to potent inotropic agents depending on the severity of heart failure.
Amrinone↗
The effect of dobutamine on myocardial performance and high-energy phosphate metabolism at different stages of heart failure in cardiomyopathic hamsters: a 31P MRS study.
Dobutamine has been shown to exert disparate clinical effects in patients with cardiomyopathy and heart failure. This study evaluated the effects of dobutamine on hemodynamics and energetics in isolated, perfused myopathic hamster hearts at a moderate and advanced stage of heart failure. Biochemical changes were correlated with left ventricular developed pressure, coronary flow, and myocardial oxygen consumption. During dobutamine treatment left ventricular developed pressure increased in the control and moderate heart failure group 28.0 +/- 1.0% and 114.2 +/- 11.6%, respectively. Myocardial oxygen consumption increased 50.1 +/- 9.1% and 45.5 +/- 16.0%, respectively. There were no significant changes of left ventricular developed pressure and myocardial oxygen consumption in the advanced heart failure group. Inorganic phosphate (Pi) increased in the control group from 6.8 +/- 0.5 to 11.4 +/- 1.2 mmol (p less than 0.005) and in the advanced heart failure group from 10.4 +/- 1.1 to 15.3 +/- 1.2 mmol (p less than 0.01). Phosphocreatine (PCr) and beta-ATP (adenosine triphosphate) decreased in the control group from 12.2 +/- 0.4 to 8.7 +/- 0.7 mmol (p less than 0.001) and 10.4 +/- 0.8 to 7.7 +/- 0.7 mmol (p less than 0.02), respectively. PCr/Pi ratio, reflecting mitochondrial function, fell in the control and advanced heart failure group from 1.84 +/- 0.14 to 0.84 +/- 0.14 (p less than 0.02) and 0.81 +/- 0.16 to 0.37 +/- 0.08 (p less than 0.03), respectively. Thus in cardiomyopathic hamsters dobutamine improved mechanical performance and thermodynamic efficiency in moderate stages of heart failure by improving mitochondrial activity, but did not improve mechanical performance in an advanced stage of heart failure. These experiments provide into the disparate clinical effects of dobutamine at various stages of heart failure.
Adenosine Triphosphate↗
Ventricles as a major site of atrial natriuretic factor synthesis and release in cardiomyopathic hamsters with heart failure.
The aim of the present study was to correlate in cardiomyopathic hamsters with congestive heart failure the levels of atrial and ventricular atrial natriuretic factor (ANF) messenger RNA (mRNA) with immunoreactive ANF (IR-ANF) plasma levels and the relative amount of IR-ANF released by the whole heart versus isolated ventricles in the Langendorff preparation. High-performance liquid chromatography analysis of the forms of ANF present in plasma and in the Langendorff effluent of whole heart versus isolated ventricles was also performed. As previously found for cardiac IR-ANF, the levels of ANF mRNA decreased gradually in atria and increased in an analogous fashion in ventricles with the severity of congestive heart failure. Plasma IR-ANF levels (C-terminal) were more elevated in moderate than in severe congestive heart failure, as were the IR-ANF levels in the Langendorff effluent of the whole heart. On the contrary, the effluent of isolated ventricles from animals in severe heart failure yielded more IR-ANF than that from hamsters in moderate heart failure. Thus, while the isolated ventricles from controls contributed 35.8% of IR-ANF released by the whole heart, ventricles from hamsters in moderate heart failure contributed 17.5%, and those from hamsters in severe heart failure contributed 73.9%. These results indicate that atrial cardiocytes contribute more IR-ANF than their ventricular counterpart in moderate heart failure and that ventricles are a major source of plasma IR-ANF in severe heart failure. Analysis of IR-ANF from plasma and the Langendorff effluent from whole hearts and isolated ventricles revealed that the ventricles are the major source of the propeptide (and of its cleaved products) found in the circulation of cardiomyopathic hamsters. These results suggest that ANF synthesis and secretion do not increase conjointly in atria but do increase in ventricles during congestive heart failure.
Animals↗
Increased left ventricular diastolic stiffness in the early phase of hereditary cardiomyopathy.
Isolated hearts from normal and cardiomyopathic hamsters (160 to 180 days of age) were perfused through the aorta and assessed by echocardiographic and 31P-NMR (nuclear magnetic resonance) techniques. A decreased left ventricular systolic pressure in cardiomyopathic hamsters was associated with diminished cardiac size and left ventricular wall thickness. However, the ratio of inner/outer cross-sectional area and estimated left ventricular volume at any given left ventricular weight was significantly higher, indicating relative left ventricular chamber enlargement in cardiomyopathic hamsters. Left ventricular volumes were increased with an intraventricular balloon. Gradual inflation of the balloon resulted in increments of left ventricular systolic and developed stress that rose to the same values in both groups. At this point, the normalized stress-strain relationship was approximately two times steeper for cardiomyopathic hamsters, while at lower strain values the diastolic stress in cardiomyopathic hamsters was less than in controls, possibly due to cardiac dilatation. Almost the same degree of dilatation was induced in control hearts by the acute addition of 1% alcohol, but it was not followed by increased diastolic stiffness. Examination of hearts by 31P-NMR techniques revealed a decreased phosphocreatine/inorganic phosphate (PCr/Pi) ratio in the cardiomyopathic hamsters that progressed further with balloon inflation and was associated with a relative fall in PCr and adenosine triphosphate (ATP) content. Results suggest increased diastolic stiffness in cardiomyopathic hamsters, which was not seen in acute cardiac depression with alcohol. Diastolic volume overload with increased wall stress is probably the major factor contributing to increased diastolic stiffness early in the cardiomyopathy.
Adenosine Triphosphate↗
Improvement in myocardial performance without a decrease in high-energy phosphate metabolites after isoproterenol in Syrian cardiomyopathic hamsters.
To determine the effect of isoproterenol on cardiac energetics and function in an animal preparation of cardiomyopathy, we studied Langendorff perfused hearts from Syrian cardiomyopathic hamsters. High-energy phosphate metabolites (phosphocreatine [PCr], ATP, inorganic phosphate [Pi]) and intracellular pH (pHi) were measured by 31P nuclear magnetic resonance spectroscopy and correlated with left ventricular developed pressure, coronary flow, and O2 consumption before and during a 10(-6)M infusion of isoproterenol. Total intracellular calcium was also determined by atomic absorption spectroscopy with the use of potassium ethylenediamine tetra-acetate cobaltate as a marker for extracellular space. In cardiomyopathic hamsters, isoproterenol infusion increased mean developed pressure by 300% (p less than .005 compared with control; n = 5), O2 consumption eightfold (p less than .0005), and PCr by 40% (p less than .05). PCr/Pi ratio, which is analogous to phosphorylation potential, improved 100% (p = .05). In normal hamsters, isoproterenol infusion resulted in an 83% increase in developed pressure (p less than .001) and a 25% increase in O2 consumption (NS). However, mean PCr and PCr/Pi decreased by 30% and 50%, respectively (p less than .05 for both), during isoproterenol infusion. pHi decreased in normal animals (p less than .01), but tended to improve in diseased animals (NS) during isoproterenol infusion. Freeze-clamp measurements of phosphate metabolites correlated well with the nuclear magnetic resonance data. Intracellular calcium increased from 0.0102 +/- 0.002 to 0.144 +/- 0.030 mumol/ml heart water in normal hamsters during isoproterenol infusion. Cardiomyopathic hamsters had a markedly elevated baseline calcium content of 60.82 +/- 5.85 mumol/ml heart water due to the presence of dystrophic calcification.(ABSTRACT TRUNCATED AT 250 WORDS)
Adenosine Triphosphate↗
Histochemistry of ventricular heavy-chain myosins in cardiomyopathic Syrian hamsters treated with D-600.
Monoclonal antibodies (MAb) have been used to study the distribution of ventricular heavy-chain (HC) myosins in cardiomyopathic UM-X7.1 Syrian hamsters. The Ab were identified as alpha and beta anti-HC myosins because of their ability to cross-react with ventricular V1 and V3 myosins, respectively. Cryostat frozen sections from the midventricle region of normal and myopathic hearts were processed for demonstration of these isomyosins by indirect immunofluorescence. In myopathic hearts, there was a shift of predominant alpha myosin toward the beta isoform with the time course of the hamster cardiomyopathy. A D-600 treatment while preventing cardiac necrotic lesions had little or no effect on the beta isomyosin conversion. It is inferred that the isomyosin shift during the progression of the hamster cardiomyopathy is unrelated to the necrotizing process and merely reflects the hypokynetism of the cardiomyocytes.
Animals↗
ANF in experimental congestive heart failure.
The plasma and cardiac levels of immunoreactive (IR) atrial natriuretic factor (ANF) were measured during the entire lifespan of cardiomyopathic hamsters, which eventually develop spontaneous congestive heart failure, and were correlated with immunohistochemical, ultrastructural, and immunocytochemical changes in the secretory apparatus of atrial and ventricular cardiocytes. Plasma IR-ANF rose in the early stages of the disease, reached a maximum in moderate heart failure, and declined thereafter but remained above control values. The peptide decreased constantly in the atria during the evolution of the disease but increased markedly in the ventricles. Its highest levels were found in the inner half of the left ventricle. In atrial cardiocytes, the size and complexity of the Golgi complex increased with the progression of the disease, whereas the number, size, and IR-ANF content (as assessed by the immunogold technique) of secretory granules decreased constantly. In ventricular cardiocytes, the size of the Golgi complex increased, and typical secretory granules were present in approximately 20% of these cells, regardless of their localization in the myocardium. The results suggest that stimulation of ANF secretion in atrial cardiocytes leads to a dissociation between synthesis and release, the latter being maximal according to ultrastructural and immunocytochemical criteria. In ventricular cardiocytes, the same stimulation culminates in increased synthesis and the possibility of release via two pathways: one constitutive, the other regulated. Thus, the elevated plasma levels of IR-ANF in congestive heart failure may be derived from secretion by both atrial and ventricular cardiocytes.
Animals↗
Catecholamine, dopamine-beta-hydroxylase and atrial natriuretic factor content in separate heart chambers of cardiomyopathic hamsters.
Since previous investigations have suggested a relationship between atrial natriuretic factor (ANF) and dopamine-beta-hydroxylation, cardiomyopathic hamsters were studied for atrial and ventricular catecholamine (CA) and dopamine-beta-hydroxylase (D beta H) content as correlates to a parallel finding of markedly decreased atrial but increased ventricular ANF concentrations in these animals. It was noted that, with progressive cardiomyopathy, the reduced tissue norepinephrine (NE) content paralleled the declining D beta H activity in the atria. In the ventricles, however, the progressively-decreasing NE content was associated with an increase of D beta H. These data indicate that the NE depletion is mediated by different mechanisms in the ventricles and atria. They do not support a simple relationship between NE depletion and tissue D beta H activity or between the latter and tissue ANF concentrations.
Animals↗
Sarcolemmal phospholipid N-methylation in genetically determined hamster cardiomyopathy.
The heart sarcolemmal phosphatidylethanolamine N-methylation in UM-X7.1 strain of cardiomyopathic hamsters was examined by using 0.055, 10 and 150 microM S-adenosyl-L-(methyl-3H) methionine as methyl donor for sites I, II and III, respectively. In comparison with control values, methylation activities at site I was increased in 40, 120 and 250 days old cardiomyopathic hamsters. On the other hand, methylation activities at sites II and III in 120 and 250 days old cardiomyopathic animals were depressed without any change in the 40 days old group. The alterations in N-methylation activities were associated with kinetic changes in apparent Vmax values without any changes in the apparent Km. These results indicate a defect in the phospholipid N-methylation process in heart sarcolemma during the development of genetically determined cardiomyopathy.
Aging↗
Influence of heart rate on metabolic and hemodynamic parameters in the Syrian hamster cardiomyopathy.
The effect of varying heart rate in 155- to 170-day-old isolated, perfused cardiomyopathic Syrian hamster hearts was evaluated by 31P nuclear magnetic resonance spectroscopy. At a low paced heart rate of 170 bpm, cardiomyopathic hearts did not differ from normal hearts except for a lower developed left ventricular pressure. As pacing rate was increased progressively to 270/min, cardiomyopathic hearts showed prolongation of contraction, which led to a pronounced rise in diastolic pressure as the interstimulus interval shortened. This was accompanied by a marked decrease in energy-rich phosphorus compounds. By contrast, increasing heart rate in normal hearts did not change left ventricular pressure and caused only a mild reduction in energy-rich phosphorus compounds. Intracellular pH of cardiomyopathic animals paced at 270 bpm was significantly lower than in normal animals. Thus, indices reflecting mitochondrial function of 155- to 170-day-old cardiomyopathic hamsters appear adequate at low heart rate. Increasing the heart rate unmasks latent mitochondrial dysfunction.
Adenosine Triphosphate↗
Effects of altered coronary perfusion pressure on function and metabolism of normal and cardiomyopathic hamster hearts.
The effects of a sudden decrease in coronary perfusion pressure from 140 to 0 cmH2O for a 10-second interval were analyzed in normal and cardiomyopathic hamster hearts to determine whether cardiomyopathy would affect the relationship between altered coronary perfusion pressure and left ventricular geometry, wall thickness, myocardial hydrodynamics, and hemodynamics. In normal hamsters, an acute reduction in coronary perfusion pressure resulted in a decrease in left ventricular short axis epicardial cross-sectional area, base to apex length, diastolic wall thickness, myocardial water content and developed pressure. In cardiomyopathic hamsters all results induced by lowering the hydrostatic pressure of the perfusing medium were the same except that diastolic wall thickness failed to decline, indicating a decrease in intramyocardial elasticity in dilated cardiomyopathy. In parallel studies, hearts were freeze clamped at end-diastole and high energy phosphates and energy metabolites analyzed. In both normal and cardiomyopathic hamsters no significant changes were observed in ATP, PCr, or Pi levels at 10 s following the decrease in perfusion pressure. However, during the abrupt decrease in coronary perfusion pressure adenosine increased and cAMP decreased in both groups of animals. The erectile effect of altered coronary perfusion pressure is partially attenuated in the cardiomyopathic hamster in which no change in diastolic wall thickness occurs during an abrupt change in the hydrodynamics of the heart.
Animals↗
Cardiac and plasma atrial natriuretic factor in experimental congestive heart failure.
The cardiac and plasma levels of immunoreactive (IR-) atrial natriuretic factor (ANF) in cardiomyopathic hamsters with moderate and severe congestive heart failure were measured, compared with those of controls, and correlated by HPLC analysis of IR-ANF in atria, ventricles, and plasma and with the ultrastructure of atrial and ventricular cells. Congestive heart failure in the hamster produced a significant increase in plasma IR-ANF, a significant decrease in atrial IR-ANF, and a marked increase in ventricular IR-ANF. The HPLC pattern of IR-ANF was of the high mol wt type in atria and ventricles of control and cardiomyopathic animals. High mol wt forms of ANF appeared in the plasma of animals with severe congestive heart failure, but not in controls. Severe congestive heart failure produced a tremendous increase in the size of the Golgi complex, with a decrease in the number and size of secretory granules in atrial cardiocytes. Ventricular cardiocytes also showed a less marked increase in the size of the Golgi complex. Secretory-like granules indistinguishable from lysosomes were present in about 1% of ventricular cardiocytes of control hamsters; in hamsters with severe congestive heart failure, secretory granules, identical to those of atrial cardiocytes, were present in greater number in about 20% of ventricular cardiocytes. Immunocytochemistry (immunogold technique) revealed that secretory granules containing IR-ANF are not present in control ventricular cardiocytes but are localized in relatively large number in about 20% of ventricular cardiocytes in hamsters with severe congestive heart failure. These results suggest that the increased IR-ANF levels (including the high mol wt forms) in animals with congestive heart failure may come from hypersecretion of both atrial and ventricular cardiocytes.
Animals↗
Pathogens in children with severe combined immune deficiency disease or AIDS.
We evaluated the frequency and severity of illnesses caused by various microbial pathogens in 15 children with severe combined immune deficiency disease (SCID) and 8 with acquired immune deficiency syndrome (AIDS). There were 35 viral, 23 bacterial, 19 mycotic and 13 parasitic infections. Nineteen of the 23 patients died of infection; Pneumocystis carinii pneumonia, giant-cell pneumonia due to paramyxoviruses and various disseminated viral infections were responsible for most deaths in both groups. The emerging role of paramyxoviruses was illustrated by the fact that they were responsible for giant-cell pneumonia in seven patients. Viral enteric infections were frequent in both groups. The variety of infectious microorganisms and the severity of resulting illnesses in the patients with AIDS were similar to those in the patients with SCID.
Acquired Immunodeficiency Syndrome↗
Cardiomyopathic and healthy acidotic hamster hearts: mitochondrial activity may regulate cardiac performance.
A 50% decrease in adenine nucleotides and a 60% decrease in adenosine triphosphate concentration was found in glucose perfused myopathic Syrian hamster heart (240 days old) whereas there was an 18% decrease and 40% decrease respectively in acidotic healthy Syrian hamster heart re-equilibrated with a physiological medium. Correspondingly, there was a 60% decrease in cardiac performance with both models. Developed pressure fell when the phosphorylation potential decreased to less than or equal to 2; however, the heart recovered if mitochondrial activity was activated. If a substrate such as pyruvate or ribose was used with either model cardiac performance returned to near normal, although adenine nucleotide and adenosine triphosphate concentrations were further depressed. With glucose as substrate cardiomyopathic hearts, healthy acidotic hearts, and healthy acidotic hearts re-equilibrated with glucose as substrate had low pyruvate concentrations; limited availability of pyruvate depressed mitochondrial activity. Like the myopathic hearts the re-equilibrated acidotic hearts had high myocardial pyruvate concentrations, above normal ratios of phosphocreatine to creatine, and near normal oxygen consumption, developed pressure, dP/dt, and cyclic adenosine monophosphate concentrations when re-equilibrated with a medium containing pyruvate or ribose as substrate, although adenosine triphosphate and adenine nucleotide concentrations were severely depressed. When adenosine triphosphate values fell from 24 to 2 mumol X g-1 dry weight in the pyruvate or ribose perfused and normal functioning heart the heart stopped beating with no progressive fall in performance before termination of the metabolic processes.
Acidosis↗