Functional and metabolic evaluation of the hypertrophied heart using MRI and 31P-MRS

Most patients with cystic fibrosis require oral administration of pancreatic enzymes to treat pancreatic insufficiency. Recent use of higher-strength enzyme preparations in large doses has been found to be associated with fibrotic strictures of the colon. We report a case of pancolonic fibrosis due to pancreatic enzyme use.     

Peptide growth factors in normal and hypertrophied bladder

The pharmacokinetics of oral zidovudine in HIV-infected children and adults are reported. Fourty-six patients were investigated. For data analysis three groups of similar size were formed: young children 4 months-4 years, n = 15 (group 1), older children up to 13 years, n = 16 (group 2) and young adults, n = 15 (group 3). After a single oral dose repeated blood samples were taken 1/2 hourly during a period of 4 hours and zidovudine concentrations in plasma were determined by high performance liquid chromatography. For better comparison of dose dependent parameters peak concentrations (Cmax) and the area under the time-concentration curves (AUC) were normalized either to the dose/body weight (bw) or the dose/body surface area (bs), respectively. Time to reach peak concentrations and mean terminal elimination half-life times (t1/2 beta = 63.4 +/- 47.6, 74.9 +/- 54.9 and 56.9 +/- 16.4 min in group 1, 2 and 3, respectively, mean +/- SD) were not significantly different between the three groups. With normalization to dose/bw young children in comparison to adults had significantly lower Cmax (2.7 +/- 1.3 vs. 4.6 +/- 2.4 mumol/l, p = 0.016) and AUC (226 +/- 108 vs. 373 +/- 224 mumol.min/l, p = 0.038). Group 2 gave intermediate values. However, with normalization to dose/bs differences in Cmax (6.5 +/- 3.3, 7.3 +/- 4.2 and 6.8 +/- 3.6 mumol/l, in group 1, 2, and 3, respectively) and AUC (563 +/- 313, 691 +/- 351 and 555 +/- 342 mumol.min/l, in group 1, 2 and 3) were not significant between the three groups. It is likely that changes in body water content with age may account for most of these differences observed. In conclusion, a similar pharmacokinetic profile was found in children older than 3 months as compared to older children or adults.     

Number of glomeruli in normal and hypertrophied kidneys of mice and guinea-pigs

1. In mice and guinea-pigs, the number of glomeruli was counted in kidneys during normal growth and in hypertrophy induced by unilateral nephrectomy. 2. In mice, the number of glomeruli increased sharply during the first 2 weeks in life, and more slowly afterwards. Unilateral nephrectomy, when performed during this period of natural increase, induced the formation of supplementary nephrons in the contralateral kidney. 3. In guinea-pigs, the number of glomeruli was almost complete at birth. No evidence of a supplementary increase in the number of nephrons was found in hypertrophied kidneys following unilateral nephrectomy. 4. These results, together wit previous data obtained in the rat, suggest that the ability to induce new nephrons after unilateral nephrectomy in different species would depend more on the state of kidney maturity at birth than on differences in the renal mechanisms which lead to hypertrophy.     

Cardiac function during graded bicycle exercise: Doppler-echocardiographic findings in normal subjects and heart transplant recipients

Orthotopic heart transplantation results in altered atrial anatomy and denervation of the donor heart. To assess the impact of these sequelae on left ventricular filling and systolic performance, 16 heart transplant recipients and 10 normal controls were evaluated by Doppler echocardiography at rest and during graded bicycle exercise. Global and regional systolic ventricular allograft function was normal at rest and during exercise. Resting Doppler profiles demonstrated diminished atrial contribution to ventricular filling in transplant recipients. The response to dynamic exercise was different in both groups; controls increased heart rate, while mitral time-velocity integral was unchanged. Heart transplant recipients, in contrast, showed a blunted heart rate response and increased time-velocity integral. Atrial contribution to ventricular filling was not augmented during exercise as in normal controls. Alterations in transmitral flow profiles in heart transplant recipients do not necessarily reflect ventricular myocardial damage, but may be related to impaired atrial function.     

Contribution of glycogen and exogenous glucose to glucose metabolism during ischemia in the hypertrophied rat heart

Although hypertrophied hearts have increased rates of glycolysis under aerobic conditions, it is controversial as to whether glucose metabolism during ischemia is altered in the hypertrophied heart. Because endogenous glycogen stores are a key source of glucose during ischemia, we developed a protocol to label the glycogen pool in hearts with either [3H]glucose or [14C]glucose, allowing for direct measurement of both glycogen and exogenous glucose metabolism during ischemia. Cardiac hypertrophy was produced in rats by banding the abdominal aorta for an 8-week period. Isolated hearts from aortic-banded and sham-operated rats were initially perfused under substrate-free conditions to decrease glycogen content to 40% of the initial pool size. Resynthesis and radiolabeling of the glycogen pool with [3H]glucose or [14C]glucose were accomplished in working hearts by perfusion for a 60-minute period with 11 mmol/L [3H]glucose or [14C]glucose, 0.5 mmol/L lactate, 1.2 mmol/L palmitate, and 100 mumol/mL insulin. Although glycolytic rates during the aerobic perfusion were significantly greater in hypertrophied hearts compared with control hearts, glycolytic rates from exogenous glucose were not different during low-flow ischemia. The contribution of glucose from glycogen was also not different in hypertrophied hearts compared with control hearts during ischemia (1314 +/- 665 versus 776 +/- 310 nmol.min-1.g dry wt-1, respectively). Glucose oxidation rates decreased during ischemia but were not different between the two groups. However, in both hypertrophied and control hearts, the ratio of glucose oxidation to glycolysis was greater for glucose originating from glycogen than from exogenous glucose. Our data demonstrate that glycogen is a significant source of glucose during low-flow ischemia, but the data do not differ between hypertrophied and control hearts.     

MRI of the heart: morphological and functional aspects

The performances of cardiac magnetic resonance imaging have been recently improved by the possibility of obtaining functional information by means of gradient echo sequences. Cavity volumetry and wall thickness and mass measurements are now possible. Ultrarapid sequences are useful for the analysis of myocardial perfusion and methods for measuring blood flow and temporal labelling of the ventricular wall open up new prospects for functional evaluation of the heart. In clinical practice, MRI can be useful for the exploration of cardiac parietal and intracavitary masses, constrictive pericarditis, hypertrophic and restrictive cardiomyopathy and cardiac malformations. Assessment of valvular and coronary heart disease is based on new techniques and is currently under evaluation.     

Cardiac surgical implications of calcium dyshomeostasis in the heart

The prevalence of coronary artery disease renders myocardial ischemia a leading cause of morbidity and mortality. Both cardiac bypass operations and cardiac transplantation cause myocardial ischemia and reperfusion injury. Intracellular calcium transport and regulation are of paramount importance in both normal and pathologic myocardial states. Calcium regulation is integral to nearly every myocyte function, from early development to senescence. Normal intracellular calcium-mediated excitation-contraction coupling and abnormal patterns of calcium regulation leading to systolic/diastolic dysfunction are now therapeutically accessible to the cardiac surgeon. Additionally, altered Ca2+ transport protein gene expression is a mechanism of myocardial dysfunction. Therapeutic strategies involve receptor-mediated transduction of signals to intracellular metabolic sites. Evidence implicates protein kinase C as well as a potential therapeutic role for Ca2+. The potential for pharmacologic access to this protective state has abundant clinical appeal. The protective state (cardiac "preconditioning") is transient but is amenable as therapy against operation-related ischemic events.     

Effects of angiotensin II on inotropy and intracellular Ca2+ handling in normal and hypertrophied rat myocardium

The direct inotropic effect of angiotensin II on the myocardium is still controversial and little information exists as to its potential modification by heart disorders. Therefore, this study performed simultaneous measurements of isometric force and intracellular Ca2+ concentrations ([Ca2+]i) in left ventricular papillary muscles from sham-operated and aortic-banded rats at 10 weeks post-surgery. Angiotensin II (10(-6) M) induced a reduction of peak systolic [Ca2+]i (0.56 +/- 0.03 to 0.48 +/- 0.04 microM; P<0.05) and a parallel but insignificant diminution of developed tension (10.5 +/- 1.3 to 9.6 +/- 0.8 mN/mm2) in normal papillary muscles from sham-operated animals. Hypertrophied papillary muscles from aortic-banded rats demonstrated a significant decline in both peak systolic [Ca2+]i (0.51 +/- 0.02 to 0.44 +/- 0.01 microM; P<0.05) and developed tension (8.4 +/- 1.1 to 6.8 +/- 1.7 mN/mm2; P<0.05) after addition of angiotensin II. The time courses of the mechanical contraction and the intracellular Ca2+ signal were prolonged by angiotension II in both groups. Isoproterenol dose-dependently increased developed tension and peak systolic [Ca2+]i in papillary muscles from sham-operated rats. In contrast, the positive inotropic response to isoproterenol was markedly reduced in hypertrophied muscles despite a seemingly unimpaired increase in peak systolic [Ca2+]i. Pretreatment with angiotensin II (10(-6) M) resulted in a significant attenuation of the systolic [Ca2+]i response to isoproterenol stimulation in both normal and hypertrophied papillary muscles. Neither the bradykinin B2 antagonist icatibent (10(-6) M) nor the nitric oxide (NO) inhibitor L-NMMA (10(-6) M) abolished the depressant effects of angiotension II. Thus, ANG II induces a parallel decline of the mechanical performance and Ca2+ availability in rat myocardium. These effects are more distinct in hypertrophied than in normal muscle and become accentuated during beta-adrenergic stimulation. The underlying mechanism is not associated with the NO pathway but might involve a negative functional coupling between the angiotensin and beta-adrenergic-receptor complex.     

Potassium metabolism in the normal and ischemic heart cell

Potassium is an important electrolyte in heart cells and has the greatest membrane permeability in the unexcited state. Hence it is responsible for th generation of the resting membrane potential. Clinical disorders of conduction and impulse formation occur within physiological values of serum potassium. Potassium is indirectly involved in excitation-contraction coupling, and its relation to intracellular calcium metabolism is reviewed. While potassium movements within the cell are metabolic-dependent, it is also true that the activity of metabolic pathways is affected by changes in potassium concentration. During anoxia and ischemia, sodium and calcium are gained by the myocyte, and potassium and magnesium are lost by the cell. At the same time, the action potential duration is abbreviated, the slope of the action potential downstroke (phase 2) is increased, and the resting membrane potential may be reduced. A relationship between disturbances in intracellular potassium and ischemic arrhythmias appears likely.     

Direct gene transfer into the mouse heart

Direct injection of plasmid DNA into the myocardium of several species has been shown to be useful for studying cardiac gene expression. However, despite a better understanding of mouse genetics and the availability of several disease models in mice, gene injection with plasmid DNA into the mouse heart has not been reported. In this study, we demonstrate a simple and reproducible method for gene transfer into the mouse heart via direct injection of plasmid DNA. A firefly luciferase gene, driven by the RSV promoter, was used to quantitatively determine the spatial and temporal characteristics of gene transfer. Luciferase gene expression was stable for 8 weeks and showed a dose-dependent response over a range of 0.3-3 micrograms of input DNA. Inter-animal variability was low and gene expression was restricted to the left ventricle, near the site of injection. This method was also demonstrated to be suitable for detecting the expression of structural genes under the control of cellular promoters. Immunohistochemistry was used to detect the expression of an epitope-tagged myosin heavy chain driven by a rat alpha-myosin heavy chain promoter. Thus, naked DNA injection into the mouse heart results in a highly reproducible expression of constructs with either viral or cellular promoters. It is a relatively inexpensive and efficient means of studying cardiac gene regulation in vivo and a useful tool for screening the potential transgenes before generating transgenic mice.     

Contribution of MRI in the evaluation of ischemic heart diseases

The high spatial and temporal resolution of MRI provides accurate identification of left ventricular endocardial and epicardial contours. Cine-MRI allows reliable and reproducible measurements of end-systolic and end-diastolic volumes, ejection fraction and left ventricular mass. These measurements are not based on any geometrical hypothesis and so remain valid in presence of ventricular deformation as observed after myocardial infarctions. The value of cine-MRI has been demonstrated in ischaemic heart disease for the study of regional left ventricular function, by analysis of left ventricular segmental function and systolic thickening of the myocardial walls. Cine-MRI may also be performed during pharmacological stress. In coronary patients without ventricular dysfunction at rest, stress cine-MRI enables detection of segmental wall motion abnormalities or reduction of systolic thickening in potentially ischaemic territories. Cine-MRI may contribute to be study of myocardial viability. Regional myocardial perfusion may also be assessed using the rapid sequences of imaging and contrast agents opacifying the intravascular compartment. In coronary patient, underperfused regions may there by be detected. The most rapid imaging techniques enable visualisation of the proximal segments of the coronary arteries and the measurement of blood velocity in the coronary arteries and the calculation of coronary reserve. Simultaneous analysis under basal conditions and after pharmacological stress of global and segmental left ventricular function and of myocardial perfusion, associated with the possibility of imaging the proximal coronary arteries and of measuring the velocity of coronary flow, makes MRI a complete non-invasive method of evaluating patients with ischaemic heart disease.     

Cytosol androgen binding in submandibular gland and kidney of the normal mouse and the mouse with testicular feminization

The nature of maltose- and trehalose-induced electrical potential increments across everted small intestines of toads were investigated. A Michaelis-Menten-like relation was seen between the amplitude of PD increments (deltaPD) and the mucosal concentration of disaccharides over a wide range of concentration, but, at a higher concentration range, Lineweaver-Burk type plot of data always deviated from the linear line for the low and moderate concentration range. The extrapolation of the linear segment of the plots intercepted the ordinate at the same point as that of the line for the glucose-induced potential increments. Both the disaccharide- and the glucose-evoked potentials were not additive and were equally sensitive to phlorizin. Tris depressed the disaccharide-evoked potentials to about the same extent as that of inhibition of enzyme activities. The amplitude and time course of the disaccharide-induced potentials, however, could not be accounted for by the mucosal concentration of liberated glucose. These qualitative and quantitative characteristics were explained properly on the basis of a simple well-type local pool for liberated glucose assumed to exist at the brush border. In conclusion, a close functional linkage between brush border membrane disaccharidase activities and the electrogenic hexose transport is well reflected in the disaccharide-evoked potentials in the small intestine.     

Expression of fas antigen in the normal mouse brain

In this paper, the first of a series dealing with the development of a methodology for assessing quality of ambulatory care, a sample of 270 outpatients from the same health center were presented with a list of 12 questions. Although different versions of the questionnaire were tested, we found a high degree of agreement between the results. The findings indicate that the parameter "satisfaction" lends itself readily to measurement, thus becoming a useful instrument for guiding active intervention.     

Radioprotection of normal and malignant tissue in the mouse by diethylaminoreserpine

The protective effect of pre-irradiation injections of diethylaminoreserpine (DL-152) for normal and malignant tissues in the mouse has been investigated. Dose modifying factors (DMFs) obtained for normal tissue ranged from 1.0 for bone marrow CFUs to more than 1.8 for skin. The DMFs for two transplantable tumours investigated were 1.0 for the EMT6 adenocarcinoma and 1.70 for the KHT fibrosarcoma (at a surviving fraction of 0.1. Acutely hypoxic KHT tumours were protected to a slightly lesser extent than were aerated tumours. For the KHT tumour, the number of clonogenic cells recovered from non-irradiated tumours one hour after DL-152 injection was reduced to 60 per cent of the number covered fro saline-injected controls, while, if DL-152 injected mice were acutely hypoxic at the time of sacrifice, the number of clonogenic cells was further reduced. The survival of non-irradiated EMT6 tumour cells was unaffected by DL-152 injection prior to sacrifice.     

MRI for physiology and function in congenital heart disease: functional assessment of the heart preoperatively and postoperatively

We used patch-clamp recording techniques to investigate the contribution of GABA to baseline membrane properties in cultured embryonic rat hippocampal neurons. Almost all of the neurons recorded with Cl--filled pipettes and clamped at negative potentials exhibited baselines that were noticeably noisy, with microscopic fluctuations superimposed on the macroscopic holding current. A gentle steam of saline applied to the neuronal surface rapidly and reversibly reduced the baseline current and fluctuations, both of which were completely eliminated by bicuculline. Fluctuation analysis showed that the variance in the baseline current signal was exponentially distributed with estimated kinetics comparable to those activated by submicromolar concentrations of exogenous GABA. The kinetics of Cl- channels activated by endogenous GABA displayed a potential sensitivity comparable to those activated by exogenous GABA. Non-neuronal cells stably transfected with alpha1 and gamma2 GABAA receptor subunits exhibited little baseline current variance when recorded with Cl--filled pipettes. Addition of micromolar GABA to the extracellular saline or to the pipette solution induced a saline- and bicuculline-sensitive baseline current signal comparable to that recorded in hippocampal neurons. Thus, both intra- and extracellular sources of GABA could contribute to the baseline properties recorded in these cultured neurons.     

Beta-adrenergic signal transduction in the failing and hypertrophied myocardium

A strong sympathetic activation has been observed in heart failure and is the cause of beta-adrenergic desensitization in this condition. On the receptor level there is downregulation of beta1-adrenergic receptors and uncoupling of beta2-adrenoceptors. The latter mechanism has been related to an increased activity and gene expression of beta-adrenoceptor kinase in failing myocardium, leading to phosphorylation and uncoupling of receptors. beta3-Adrenoceptors mediate negative inotropic effects, but alterations in these receptors are not known. In addition, an increase in inhibitory G protein alpha subunits (Gi alpha) has been suggested to be causally linked to adenylyl cyclase desensitization in heart failure. In contrast, the catalytic subunit of adenylyl cyclase, stimulatory G protein alpha and betagamma subunits, have been observed to be unchanged. Recent evidence shows that increases in Gi alpha also depress adenylyl cyclase in compensated cardiac hypertrophy both in monogenic and polygenic and in secondary hypertension. These increases of Gi alpha can suppress adenylyl cyclase in the absence of beta-adrenergic receptor downregulation. Since cardiac hypertrophy in pressure overload is a strong predictor of cardiac failure, these observations indicate that adenylyl cyclase desensitization by Gi alpha may be a pathophysiologically relevant mechanism contributing to the progression from compensated cardiac hypertrophy to heart failure.