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Biomedical subjects

J Schaper

Publications and source records attributed to J Schaper.

At least 109 records · Page 6Linked to original sources
PubMed1994

Changes in gene expression following short coronary occlusions studied in porcine hearts with run-on assays.

OBJECTIVE: Brief coronary occlusions cause upregulation of expression in a wide variety of genes. These changes in tissue mRNA concentration could have been produced by transcriptional or post-transcriptional events. The aim of this study was to discriminate between increased transcription and changes in mRNA stability using run-on assays with isolated myocyte nuclei. METHODS: Myocyte nuclei isolated from ischaemic/reperfused and normal myocardium were incubated with labelled ribonucleotides. The radioactive RNA was then hybridised with specific cDNA probes and slot blots were autoradiographed. RESULTS: There was increased transcriptional activity for the proto-oncogenes c-myc, c-jun, jun-B, and jun-D. There were marked increases in transcriptional activity for sarcoplasmic Ca(2+)-ATPase, calmodulin, phospholamban, and calsequestrin. Strong transcriptional activity was found for the ubiquitin and heat shock protein (hsp27, hsp70) genes, and for PAI-1 and GAPDH. The transcription for the beta myosin heavy chain gene was not altered. CONCLUSIONS: Changes in the tissue concentration of mRNA species following brief coronary occlusion and reperfusion are most often the result of altered transcriptional activity. Increased c-fos mRNA concentrations observed in earlier studies cannot be explained by transcriptional activity of myocytes during reperfusion. Calmodulin is strongly transcribed but tissue concentration stays constant. The overall pattern of gene expression is indicative of damage at the molecular level, and calcium binding proteins (among perhaps many others) are in need of repair.

Adenosine Triphosphate↗
PubMed1994

Effects of a new Na+/H+ antiporter inhibitor on postischemic reperfusion in pig heart.

We investigated the effects of a new compound (3-methylsulfonyl-4-piperidinobenzoyl) guanidine hydrochloride (HOE 694) known to inhibit the Na+/H+ exchanger in a porcine model of ischemia/reperfusion. Ischemia was induced by coronary occlusion (twice for 10 min, with a 30-min reperfusion interval) followed by a 4-h reperfusion period. Treated animals (n = 8) received HOE 694 as a bolus (7 mg/kg) 20 min before ischemia and subsequently as a continuous infusion (0.07 mg/kg) throughout the experiment. Control pigs (n = 11) received vehicle. Regional wall function (percentage of segment shortening, % SS) of the treated animals was significantly improved as compared with that of controls after the 4-h reperfusion period (74.1 +/- 2.5 vs. 50.9 +/- 5.4, p < 0.005). Ventricular fibrillation (VF) could be prevented completely in treated pigs but occurred in 9 of 11 control animals (p < 0.001). Ultrastructural changes after ischemia and reperfusion were moderate and slightly abnormal in controls but much milder and completely recovered in the treated group, respectively. The tissue content of high-energy phosphates did not show a significant difference between groups. Inhibition of the sarcolemmal Na+/H+ antiporter with HOC 694 is antiarrhythmic and diminishes myocardial ischemic cell injury by preventing Na+ overload.

Adenine Nucleotides↗
PubMed1994

Expression of extracellular matrix proteins and the role of fibroblasts and macrophages in repair processes in ischemic porcine myocardium.

In the experimental model of coronary microembolization in pig hearts, the processes of wound healing and scar formation were studied. Methods employed were: electron microscopy, immunohistochemistry using monoclonal antibodies (against fibronectin, laminin, collagen I, III, and VI, chondroitin sulfate, and vimentin), and in situ hybridization with radioactively labeled RNA (histones, fibronectin) or cDNA (acidic fibroblast growth factor) probes. The following time course for expression of various proteins and their mRNAs was established: Mitotic activity was significant at 3 d as well as expression of fibronectin mRNA. Cellularity comprising blood borne cells and macrophages was high. At 7 d, fibronectin, laminin and collagen VI accumulation were pronounced, vimentin positive cells were numerous. At 4 weeks, collagen expression was prominent, but interstitial cells were still present. It is concluded that healing after myocardial necrosis passes through the classical phases of wound healing, i.e., granulation tissue formation and final scar formation. Different extracellular matrix proteins show a differing time course of expression, tumor necrosis factor-alpha (TNF-alpha) and acidic fibroblast growth factor (aFGF) produced by macrophages may be involved in inflammatory processes and angiogenesis. Scar formation is not yet completed at 4 weeks after injury.

Animals↗
PubMed1994

Altered nucleus/cytoplasm relationship and degenerative structural changes in human dilated cardiomyopathy.

We investigated systematically the structure of the myocardium obtained from patients with dilated cardiomyopathy undergoing transplantation because of intractable heart failure. Hearts were explanted at the time of surgery from 12 patients (10 men and 2 women, aged 31-57 years, ejection fraction < 20%) and numerous samples were taken for light and electron microscopy. Biopsies from the left ventricle of 8 patients during operations for atrial septal defect served as control tissue. The most obvious qualitative findings were focal hypertrophy and atrophy of myocytes, enlargement and bizarre shape of nuclei, lack of contractile material and occurrence of numerous small mitochondria. On a quantitative level, the nuclear density was reduced (18%, p < 0.05) but the nuclear profile area was significantly increased (85%, p < 0.001). Thus the nucleus/cytoplasm relationship was altered. The volume density of the contractile filaments was decreased (25%, p < 0.001), but the mitochondrial volume density was unchanged. There was an increase in cell width (39%, p < 0.01) and of the connective tissue content (= fibrosis) (112%, p < 0.001). It is suggested that the nuclear abnormalities may be the primary event in the pathogenesis of dilated cardiomyopathy. These may then lead to a reduced transcriptional rate which most probably is the cause of the lack of myofilaments and other degenerative changes. The deterioration of the structural quality of the hypertrophied myocytes results finally in atrophy and fibrosis and may be the structural correlate of functional disturbances in dilated cardiomyopathy.

Adult↗
PubMed1994

Platelet-activating factor plays an important role in reperfusion injury in myocardium. Efficacy of platelet-activating factor receptor antagonist (CV-3988) as compared with leukocyte-depleted reperfusion.

Although platelet-activating factor has been implicated in the pathogenesis of neutrophil-induced reperfusion injury, it has other mechanisms of direct deleterious hemodynamic effect. In this study we evaluated the definitive role of platelet-activating factor in myocardial reperfusion injury. Porcine hearts that underwent 60 minutes of normothermic ischemia with cardioplegia and 60 minutes of reperfusion under cardiopulmonary bypass were divided into three groups according to the methods of 15 minutes of controlled reperfusion: whole blood reperfusion group (n = 6), leukocyte-depleted reperfusion group (n = 6), and platelet-activating factor receptor antagonist (CV-3988) group (n = 6). At 60 minutes of reperfusion, the percentage of recovery of maximum slope of the pressure-volume relationship measured with intraventricular balloon, malondialdehyde value in coronary sinus blood, tissue adenosine triphosphate, and percentage of spontaneous defibrillation were evaluated. The receptor antagonist group showed significantly better recovery of maximum slope of the pressure-volume relationship than did the whole blood reperfusion group. Moreover, the receptor antagonist group showed significantly less release of malondialdehyde in the coronary sinus, higher values of adenosine triphosphate in the myocardium, and a higher percentage of spontaneous defibrillation than did the whole blood reperfusion group. On the other hand, the leukocyte-depleted reperfusion group showed no significant differences of maximum slope of the pressure-volume relationship, malondialdehyde, adenosine triphosphate, or spontaneous defibrillation as compared with the whole blood group. These results suggest that platelet-activating factor receptor antagonist attenuated severe damage in whole blood reperfusion of the myocardium as compared with leukocyte-depleted reperfusion, which also suggests that platelet-activating factor may play a more important role in myocardial reperfusion injury than do neutrophils.

Animals↗
PubMed1994

[Doppler and echocardiography parameters in detection of acute graft rejection after heart transplantation].

Due to the invasive nature of myocardial biopsies, a complication rate of up to 2.5%, and the limitations, e.g., at focal distribution of rejection, there is a continuous need for reliable, non-invasive parameters in recognizing moderate (grade 2) and severe (grade 3) acute cardiac allograft rejections in patients treated with cyclosporine A. 64 biopsies of 20 patients with previous heart transplantations in the past 3 weeks to 36 months (mean 11 months) were compared prospectively to Doppler and echocardiographic results. Parameters of systolic function such as percent fractional shortening (FS) and systolic wall thickness of the posterior wall (SWT) remained without significant changes at grade 2 and grade 3 rejections. The same is valid for relaxation parameters such as maximum velocity of posterior wall reduction (PTR), the time interval of endsystole to maximum velocity of posterior wall reduction (tES-PTR), and the isovolumic relaxation time (IVRT). Left-ventricular filling parameters such as maximum early diastolic flow velocity (VEmax) increased significantly from 73.3 +/- 15.2 cm/s in the rejection-free interval (grade 0) to 103.9 +/- 15.0 cm/s at grade 2 rejection and 101.1 +/- 9.2 cm/s at grade 3 rejection (both p < 0.001). A sensitivity of 50% and a negative predictive value of 77% are, however, too low to diagnose or exclude a moderate or severe acute rejection in the individual case.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗
PubMed1993

University of Wisconsin versus St. Thomas' Hospital solution for human donor heart preservation.

Prolongation of the safe period of ischemia of the heart is an efficient way to overcome donor organ shortage, as demonstrated in renal and hepatic transplantation. We present the results of a prospective, randomized study comparing preservation with University of Wisconsin solution (UWS) versus St. Thomas' Hospital solution (STS) in clinical heart transplantation. A total of 39 patients were enrolled in the study (n = 20 for UWS and n = 19 for STS). Hemodynamic, electron microscopic, and biochemical evaluation did not reveal any significant differences in postoperative myocardial performance. Only the number of intraoperative defibrillations (0.82 for UWS versus 1.7 for STS) and the rhythm stability after reperfusion (13/20 UWS hearts versus 6/19 STS hearts in sinus rhythm) were significantly different. Heart preservation with UWS and STS appears to be of comparable efficacy at mean ischemic times of less than 4 hours.

Adenosine↗
PubMed1992

Myocardial dystrophin immunolocalization at sarcolemma and transverse tubules.

Using monoclonal antibodies against two different regions of the helical rod part of dystrophin, we have localized dystrophin on both plasma membrane and transverse tubules in cardiac muscle of man and several animal species. The staining persisted after experimental ischaemia, and was observed in long-standing heart disease. No immunostaining was seen at the intercalated discs. In skeletal muscle the same two antibodies stained only the plasma membrane.

Animals↗
PubMed1992

The extracellular matrix in the failing human heart.

The composition of the extracellular matrix was investigated in eight human hearts explanted at the time of transplantation surgery because of endstage cardiomyopathy. All patients showed clinical signs of heart failure. The tissue was investigated by electron microscopy and immunofluorescence microscopy using monoclonal antibodies against collagen I, III, VI, and IV, fibronectin, laminin, and vimentin. All matrix proteins occurred in increased amounts in the extracellular space separating the myocardial cells by septa of enlarged thickness. Laminin and collagen IV surrounded myocardial and endothelial cells as layers of increased thickness. Vimentin localization was normal in individual cells, but occurred more often and corresponded to the numerous fibroblasts as observed by electron microscopy. It is concluded that an excessive deposition of extracellular matrix material in addition to myocyte degeneration (as reported previously (9)) are the structural correlates of cardiac failure.

Cardiomyopathy, Dilated↗
PubMed1992

Human fetal heart development after mid-term: morphometry and ultrastructural study.

A total of 44 normally developed human fetal hearts aged from 17 to 40 weeks gestation were provided for routine ultrastructural and morphometric studies. For morphometric analysis, the maximal thicknesses of the anterior, lateral and posterior wall of both ventricles and that of interventricular septum were measured and the left-to-right thickness ratios calculated. The cross-sectional areas of both ventricles in the plane of the greatest heart diameter were measured with computerized image analysis system. Data were analyzed using linear regression and one-way analysis of variance. Myofibril formation occurred by attachment of thin filaments into amorphous Z materials which were presented in sarcolemmal plaques, sarcoplasmic condensations, desmosomes and in Z lines. From these Z centers, myofibrils radiated many directions and branched and anastomosed with further development. This pattern of myofibrillar development continued throughout the whole fetal period. A transverse tubule system was clearly evident in later fetal development. It occurred by invagination of sarcolemma into myocardial cells and formation of subsarcolemmal caveolae. Mitochondria, well-developed Golgi complexes, glycogen granules and well-developed microvessels were found throughout the whole fetal period. Binucleated myocytes appeared by 32 weeks gestation and this suggests that myocyte hyperplasia may cease before birth in humans. The growth of both ventricular walls, the interventricular septum and that of both ventricular cross-sectional areas showed linear regression, and the left-to-right wall thickness ratios were nearly constant. Also, there were no differences in morphometric data between the left and right ventricles. In conclusion, development of the myocyte is an ongoing process which may be continued in the post-natal period in humans, and our statistical results do not support the theory of the right ventricular dominance during the fetal period.

Cell Differentiation↗
PubMed1992

Ultrastructural quantitation of mitochondria and myofilaments in cardiac muscle from 10 different animal species including man.

The ultrastructural quantitative composition of normal myocardial cells has been studied in 10 different species: man, dog, pig, cat, rabbit, ferret, guinea-pig, rat, mouse, and bat. Volume densities of mitochondria, myofibrils, and cytoplasm were determined using morphometry. It was found that the content of mitochondria differs in various species ranging between 22.0-37.0%. It is a very specific and constant value for any particular species, the smallest having the highest content. A close correlation exists between the mitochondrial volume density, heart rate and the rate of basal oxygen consumption in any group of animals. The myofibrillar volume density shows no species variability. It was about 60.0% in all species. It is concluded that the mitochondrial volume density is a good indicator of the oxidative capacity of cardiac muscle and that the species specific normal ultrastructural myocyte composition should be a useful baseline in pathophysiological studies of the heart in various animals.

Actin Cytoskeleton↗
PubMed1992

Ramipril prevents left ventricular hypertrophy with myocardial fibrosis without blood pressure reduction: a one year study in rats.

1. Angiotensin converting enzyme (ACE)-inhibitors have been demonstrated to be effective in the treatment of cardiac hypertrophy when used in antihypertensive doses. The aim of our one year study with an ACE-inhibitor in rats was to separate local cardiac effects produced by a non-antihypertensive dose from those on systemic blood pressure when an antihypertensive dose was used. 2. Rats made hypertensive by aortic banding were subjected to chronic oral treatment for one year with an antihypertensive dose of the ACE inhibitor, ramipril 1 mg kg-1 daily, (RA 1 mg) or received a low dose of 10 micrograms kg-1 daily (RA 10 micrograms) which did not affect high blood pressure. 3. Chronic treatment with the ACE-inhibitor prevented left ventricular hypertrophy in the antihypertensive rats as did the low dose which had no effects on blood pressure. Similar effects were observed on myocardial fibrosis. Plasma ACE activity was inhibited in the RA 1 mg but not in the RA 10 micrograms group although conversion of angiotensin (Ang) I to Ang II in isolated aortic strips was suppressed in both treated groups. Plasma catecholamines were increased in the untreated control group, but treatment with either dose of ramipril normalized the values. The myocardial phosphocreatine to ATP ratio (an indicator of the energy state in the heart) was reduced in the vehicle control group whereas the hearts from treated animals showed a normal ratio comparable to hearts from sham-operated animals. 4. After one year, five animals were separated from each group, treatment withdrawn, and housed for additional six months. In the RA 1 mg group, blood pressure did not reach the value of the control vehicle group and surprisingly, left ventricular hypertrophy and myocardial fibrosis did not recur in animals during withdrawal of treatment.5. These data show that long term ACE inhibitor treatment with ramipril in antihypertensive and non-antihypertensive doses prevented cardiac hypertrophy and myocardial fibrosis. This protective effect was still present after 6 months treatment withdrawal.

Adenosine Triphosphate↗
PubMed1992

The extracellular matrix in human cardiac tissue. Part II: Vimentin, laminin, and fibronectin.

In continuation of our previous work describing the localization of the collagens type I, III, VI, and IV the present study describes the localization of vimentin, laminin, and fibronectin in human myocardium obtained as left ventricular needle biopsies during cardiac surgery. Myocardium from normal pigs served for comparison. Monoclonal antibodies against the various proteins were used on frozen sections, labeled with fluorescein and viewed in the fluorescence microscope. Vimentin, the intermediate filament of mesenchymal cells, is present in fibroblasts, fibrocytes, and endothelial cells. Laminin is observed in the basal membrane of myocytes, smooth muscle and endothelial cells. The staining intensity for the B1-chain is higher in and around myocytes as compared with the B2-chain antibody, but more blood vessels were stained with the latter. The antibody against the A-chain only stained the basal lamina of vascular cells but not that of myocytes. Fibronectin was localized homogeneously throughout the extracellular space as matrix material in which the cellular elements and the various other proteins such as collagens are embedded. Intracellular staining in myocytes (T-tubules) was commonly observed. Both parts of this study show the distribution of extracellular proteins in normal human cardiac tissue and are intended to be the basis for investigations of pathological changes in diseased human myocardium.

Animals↗
PubMed1991

Impairment of the myocardial ultrastructure and changes of the cytoskeleton in dilated cardiomyopathy.

This study was designed to determine the morphological correlate of chronic heart failure. Myocardial tissue from eight patients undergoing transplantation surgery because of end-stage dilated cardiomyopathy was investigated by electron microscopy and immunocytochemistry using monoclonal antibodies against elements of the cytoskeleton: desmin, tubulin, vinculin, and vimentin. The tissue showed hypertrophy, atrophy of myocytes, and an increased amount of fibrosis. Ultrastructural changes consisted of enlargement and varying shape of nuclei, numerous very small mitochondria, proliferation of T tubules, and accumulation of lipid droplets and glycogen. The most obvious ultrastructural alteration was the decrease of myofilaments, ranging from rarefication to complete absence of sarcomeres in cells filled with unspecified cytoplasm. Immunocytochemistry showed that desmin was localized at the Z lines. In diseased myocardium, the amount of desmin was increased, but it was disorderly arranged. Tubulin formed a fine network throughout the myocytes and was significantly increased in cardiomyopathic hearts. Vinculin, a protein closely associated with the cytoskeleton, occurred not only at the sarcolemma and the intercalated disc but also within the myocardial cells. Ultrastructural changes and alterations of the cytoskeleton were severe in about one third of all cells. About one third of all cells showed moderately severe changes, and the remaining cells were normal. Vimentin was present in the interstitial cells and was increased in relation to the increase of fibrosis. We conclude that the increase of fibrosis, the degeneration of hypertrophied myocardial cells, and the alterations of the cytoskeleton are the morphological correlates of reduced myocardial function in chronic heart failure.

Antibodies, Monoclonal↗
PubMed1991

Coronary capillaries in patients with congestive cardiomyopathy or angina pectoris with patent main coronary arteries. Ultrastructural morphometry of endomyocardial biopsy samples.

BACKGROUND: The coronary microvasculature may be abnormal even in the presence of angiographically normal epicardial arteries. Abnormalities of small coronary vessels have been invoked as a cause of angina. METHODS AND RESULTS: To quantitatively evaluate the morphology of capillaries in patients with idiopathic dilated cardiomyopathy (DCM) or the syndrome of angina and small vessel disease (SVD), we performed electron microscopic morphometry of capillaries in right ventricular biopsy samples taken from 32 patients. Ten had angina, normal epicardial coronary arteries, and evidence for SVD; 12 had DCM; and 10 had normal hearts. In patients with DCM, the ratio of microvessels to myocytes was not different than that of controls (0.49 +/- 0.06 versus 0.51 +/- 0.05). Mean cross-sectional areas of the capillaries (lumen plus wall) and lumen were significantly greater than those of controls (45.3 +/- 15.1 versus 22.7 +/- 8.3 micron 2, p less than 0.001; 17.6 +/- 6.9 versus 11.6 +/- 6.2 micron 2, p less than 0.05, respectively). Fibrous content of the myocardium, as assessed by quantitative light microscopy, was significantly increased (16.3 +/- 3.3% versus 5.0 +/- 2.4%, p less than 0.001). In contrast, in patients with SVD, the capillary-to-myocyte ratio was reduced (0.33 +/- 0.08, p less than 0.001). Although mean cross-sectional areas of the entire capillary (32.4 +/- 19.7 micron 2) and the lumen (8.9 +/- 7.8 micron 2) were not statistically different than those of controls, there was an absence of capillaries less than 15 micron 2 in cross-sectional area, and the frequency distribution of the lumen area was skewed to the left. Swollen endothelial cells frequently encroached upon the lumen. There was a mild increase in fibrous content (9.5 +/- 3.7%, p less than 0.05). CONCLUSIONS: Enlarged capillaries and a normal ratio of capillaries to myocytes appear to be features of DCM. Of the patients with SVD, there was both a relative lack of capillaries and capillary lumen narrowing from swollen endothelium. These changes may induce ischemia and angina and may result in mild fibrosis.

Adult↗
PubMed1991

Effect of increasing degrees of ischemic injury on myocardial oxidative metabolism early after reperfusion in isolated rat hearts.

The present investigation studied the effect of increasing severities of ischemic injury on recovery of oxidative metabolism after reperfusion in isolated rat hearts perfused retrogradely with erythrocyte-containing medium. Hearts subjected to 60 minutes of low-flow ischemia (5% of control perfusion) exhibited delayed but sustained recovery of left ventricular pressure development during reperfusion and preservation of ultrastructure delineated with electron microscopy. Immediately after reperfusion, myocardial oxygen consumption returned to control values, well before left ventricular pressure development recovered. Early after reperfusion release of 14CO2 from [1-14C]palmitate was reduced (-53%, p less than 0.01). Conversely, release of 14CO2 from [U-14C]glucose was increased (+131%, p less than 0.05). After 60 minutes of reperfusion 14CO2 release had completely returned to normal for both labeled substrates. Pulse-labeling experiments indicated that during transient depression of [1-14C]palmitate oxidation more tracer was incorporated into myocardial lipid esters, primarily triglycerides. In contrast to hearts subjected to low-flow ischemia, hearts subjected to 60 minutes of no-flow ischemia exhibited poor recovery of contractile function during the reperfusion period. Electron microscopic examination of reperfused hearts showed advanced myocyte damage consistent with irreversible injury. Interestingly, myocardial oxygen consumption in this group also recovered to control values. The substrate pattern during the early reperfusion period was similar to that of hearts subjected to low-flow ischemia. After 120 minutes of no-flow ischemia, recovery of oxidative metabolism was virtually absent. The results indicate a pronounced dissociation between recovery of oxidative metabolism and of contractile function in reperfused myocardium. The oxidative metabolic rate was disproportionately high compared with contractile function, not only in reversibly "stunned" hearts, but also in severely damaged hearts exhibiting signs of irreversible injury.

Acetates↗
PubMed1991

The extracellular matrix in human myocardium: Part I: Collagens I, III, IV, and VI.

The composition of the extracellular matrix in normal human myocardium obtained at open-heart surgery was investigated using monoclonal antibodies against the collagens I, III, IV, and VI, and fluorescence microscopy. The aim of the study was to provide information on normal myocardium that could be used in the evaluation of pathological changes. Porcine myocardium was used for comparison, and both tissues showed a perfect agreement of the results, apart from collagen IV. This was negative in pig myocardium, due to the species specificity of the antibody. Collagens I and III were localized in the extracellular space as either coarse or fine fibrillar structures; the cellular elements of the interstitium, except for the endothelial cells, were also stained. Labeling for collagen VI was much finer than for the other collagens, and was present throughout the interstitium. Collagen IV stained the basement membranes of myocytes and capillary endothelial cells, and also labeled the T-tubular system in the myocytes. The second part of this communication will describe the localization of fibronectin, laminin and vimentin in normal human myocardium.

Animals↗