A bidomain model based BEM-FEM coupling formulation for anisotropic cardiac tissue.

A hybrid boundary element method (BEM)/finite element method (FEM) approach is proposed in order to properly consider the anisotropic properties of the cardiac muscle in the magneto- and electrocardiographic forward problem. Within the anisotropic myocardium a bidomain model based FEM formulation is applied. In the surrounding isotropic volume conductor the BEM is adopted. Coupling is enabled by requesting continuity of the electric potential and the normal of the current density across the boundary of the heart. Here, the BEM part is coupled as an equivalent finite element to the finite element stiffness matrix, thus preserving in part its sparse property. First, continuous convergence of the coupling scheme is shown for a spherical model comparing the computed results to an analytic reference solution. Then, the method is extended to the depolarization phase in a fibrous model of a dog ventricle. A precomputed activation sequence obtained using a fine mesh of the heart was downsampled and used to calculate body surface potentials and extracorporal magnetic fields considering the anisotropic bidomain conductivities. Results are compared to those obtained by neglecting in part or totally (oblique or uniform dipole layer model) anisotropic properties. The relatively large errors computed indicate that the cardiac muscle is one of the major torso inhomogeneities.

Analytical validation of the BEM--application of the BEM to the electrocardiographic forward and inverse problem.

The objective of this study is to analytically validate a boundary element (BE) formulation for the relationship between the transmembrane potential on the heart's surface and the potential on the body surface applying a concentric spherical test geometry. The relative difference (reldif) between the potential on the outer sphere of the test geometry computed analytically and numerically is determined by 3.59% for the coarse discretization (48 BEs) and by 0.46% in the case of the finer subdivision (192 BEs). In the inverse problem, the transmembrane potential on the inner sphere is estimated numerically from the electric potential on the outer sphere by using a minimum-norm least-square approach. The relative differences found are 20.2% when no measurement noise is added and 26.4% in the presence of 2% additional Gaussian noise. The BE formulation is also applied to real world data for solving the electrocardiographic inverse problem. A normal volunteer's inhomogeneous thorax (outer thorax surface, surfaces of the lungs, epicardial heart surface) is modelled by 424 BEs. The same inverse method is then applied in order to reconstruct the transmembrane potential on the epicardium from the measured body surface potential (BSP) data during normal ventricular depolarisation.

Magnetic source imaging in the human heart: estimating cardiac electrical sources from simulated and measured magnetocardiogram data.

The estimation of pseudo primary current dipoles on a 2D-manifold in the atrial and ventricular myocardium and septum, and of the transmembrane potential on the endocardium and epicardium, from the magnetic heart field is investigated. The human thorax surrounding the heart is modelled by an inhomogeneous boundary element volume conductor model, including the outer thorax surface and the surfaces of the lungs. The influence of the blood mass is neglected. In the inverse problem Tikhonov's regularisation is applied. The regularisation parameter is determined by the L-curve method. An algorithm for iterative improvement is applied to estimate the pseudo primary current dipoles. Synthetic magnetic field and electric potential data are generated using a cellular automaton model of the entire human heart. Real world magnetic field data for a normal subject are analysed to demonstrate the practicability and effectiveness of the presented method.

A simulation study on magnetic source imaging with a realistic model of the entire human heart.

A computer model study on magnetic source imaging from magnetocardiographic data is presented using a cellular automaton model of the entire human heart in the so-called forward problem. A homogeneous boundary element (BE) torso is built up from real magnetic resonance imaging (MRI) cross-sections. The heart model, which has a realistic anatomical shape, is positioned inside the BE torso. In the forward problem the spread of excitation is simulated by applying a modified Huygen's propagation principle. The magnetocardiogram (MCG) and electrocardiogram (ECG) can then be computed following the bidomain theory. From the simulated MCG data, pseudo primary current dipole (PPCD) estimation within the electrically active tissue is performed. The reconstruction space is defined as a surface in the middle of the atrial and ventricular myocardium and septum. The observation space consists of two mutually perpendicular planes closely above the torso surface on the frontal and the left lateral side, respectively. An iterative minimum-norm approach is applied in order to reconstruct PPCD distributions. The errors in PPCD estimation arising from noisy data and regularization algorithms are investigated in more detail.

Stress effects on hormonal growth factors in tobacco tissues indicated by special changes in the isoelectric peroxidase patterns.

The isoelectric peroxidase patterns of tobacco tissue cultures allow us to draw inferences to cell elongation and cell division because certain zones in acid pH ranges respond to the influence of auxines and gibberellins (promoting cell elongation) and others respond to the influence of cytokinins (promoting cell division). Stress, due to the absence of phosphate and presence of lead in the medium, causes characteristic changes in the intensity of these sensitive zones in peroxidase patterns. It may be deduced that the increase and decrease of these zones correspond to stimulation and inhibition of cell elongation and cell division, respectively. Cell elongation remains almost unaltered by lack of phosphate but is markedly inhibited by lead, while cell division is enhanced. However, stress brings about a reduction of dry weight. Reactions to stress can be observed earlier in patterns of peroxidase than in growth.

Influence of the acyl-coenzyme A:cholesterol--acyltransferase inhibitor octimibate on cholesterol transport in rat mesenteric lymph.

The effect of the new inhibitor of acyl-coenzyme A:cholesterol-acyltransferase, octimibate (sodium 8-[1,4,5-triphenyl-1H-imidazole-2yl)-oxy)octanoate), on the cholesterol transport in rat mesenteric lymph was evaluated. During intraduodenal infusion of a triglyceride-phospholipid emulsion, volume and triglyceride concentration of lymph collected from a mesenteric lymph fistula remained constant in control and treated rats. After addition of 3.75 mg 3H-cholesterol/h to the intraduodenal infusion, cholesterol content of lymph increased to about double the basic concentration in control rats. Yet there was no significant change of lymph cholesterol in treated animals, which had received 40 mg octimibate followed by ca. 120 mg/24 h x kg body weight octimibate added to the intraduodenal infusion. Up to 35% of the infused dose of 3H-cholesterol were recovered in lymph of control rats, in contrast to only 23% in lymph of treated rats. It is concluded that the inhibition of the intestinal acyl-coenzyme A:cholesterol-acyltransferase by octimibate may prevent the increase of cholesterol in mesenteric lymph induced by dietary cholesterol.

[Diagnosis of very early arteriosclerosis vascular changes using Duplex sonography]. / Die Diagnose sehr früher arteriosklerotischer Gefässwandveränderungen mit Hilfe der Duplexsonographie.

The technical evolution of ultrasonic equipment provides a high resolution imaging analysis of the vessel wall and thereby offers new possibilities in diagnosing very early atherosclerotic changes. The typical B-mode image in human and animal arteries shows parallel wall contures enclosing a hypoechoic space. In this study in Vitro- and in Vivo-experiments in rabbit aortas document the distance between these contures correlating histologically with a high cholesterol diet caused a broadening of the hypoechoic space in the rabbit aortic vessel wall. The data demonstrate that high resolution Duplex Sonography is a usefull noninvasive approach for the detection of very early atherosclerotic changes in arterial vessel walls in a stage before plaques can be identified.

Antiatherosclerotic and antihyperlipidemic effects of octimibate sodium in rabbits.

Octimibate sodium (8-[(1,4,5-triphenyl-1H-imidazol-2-yl)oxy]octanoic acid, sodium salt; NAT 04-152) was investigated for its antihyperlipidemic and antiatherosclerotic activities in New Zealand White rabbits. Hypercholesterolemia and atherosclerosis were induced by feeding a diet containing 0.3% cholesterol for 8 weeks. In addition, repeated injections of bovine serum albumin (BSA) were used to enhance the experimental atherosclerosis. Octimibate sodium, 10.0 and 30.0 mg/kg p.o., reduced both the increase in serum cholesterol levels and the aortic plaque-formation (by about 50% in the higher dose group) as compared to control animals. Serum triglyceride levels were not influenced. Biochemical and histological examinations of the aortas showed reduced cholesterol contents in the higher dose group and a dose-dependent inhibition of pathological changes in the aortas.

Prolonged infusion of prostacyclin in patients with advanced stages of peripheral vascular disease: a placebo-controlled cross-over study.

Twelve patients (age 33-77 years, mean age 68.4 years) with peripheral vascular disease (PVD) stage III-IV received continuous intravenous infusions of 5 ng prostacyclin (PGI2)/kg/min and physiological saline for 7 days. The administration was randomized and double-blind with an interval of 7 days between the infusions. During PGI2 infusion systolic blood pressure fell significantly from 147.8 +/- 4.8 mm Hg to 140.6 +/- 4.0 mm Hg (P less than 0.01) and returned to 144.5 +/- 4.9 mm Hg post infusion. Transcutaneous pO2 (tcpO2) measured on the instep of the affected limb increased significantly by 8.9 +/- 3.8 Torr during PGI2 infusion and remained elevated during the subsequent week. A significant reduction of pain was observed from the 5th day of PGI2 infusion, lasting for at least the following observation period. Platelet cAMP increased from 18.8 +/- 1.5 pmol/10(8) platelets to 24.7 +/- 1.6 pmol/10(8) platelets on the 3rd day of PGI2 infusion (P less than 0.01). Spontaneous platelet aggregation was also significantly reduced during PGI2 infusion. However, 7 days after the infusion thromboxane B2 (TXB2) in plasma and spontaneous platelet aggregation significantly increased in comparison with the preinfusion values, indicating a rebound phenomenon. The clinical outcome was favorable in 9 of 12 patients, was unchanged in two patients, while progressing to limb amputation in one patient.

Cardioprotective actions of pentoxifylline in an animal model of acute myocardial ischaemia.

The action of pentoxifylline on some of the consequences of acute myocardial ischaemia was studied in cats in vivo. Occlusion of the left anterior descending coronary artery (LAD) for 5 h resulted in a significant elevation in the ST-segment of the ECG, a reduction in free platelet count in right atrial blood and a loss of creatine phosphokinase (CK) and cathepsin D activities in homogenates of the severely ischaemic myocardium as compared to non-ischaemic myocardium. Intravenous infusions of pentoxifylline (0.30 mg kg-1 min-1 for 1 h and 0.15 mg kg-1 min-1 for the remainder of the 5 h observation period, starting 0.5 h after LAD occlusion) significantly reduced the loss of enzymes from the ischaemic myocardium, prevented any further increase in the ST-segment and restored the platelet count to its control level. There were no significant changes in plasma immunoreactive 6-oxo-prostaglandin F1 alpha (6-oxo-PGF1 alpha) and thromboxane B2 (TXB2), although a tendency for a reduction in TXB2 levels was observed. Pentoxifylline seems to affect, beneficially, the myocardium in this animal model of acute myocardial ischaemia. The reason for this cardioprotective action remains to be elucidated. It is, however, noteworthy that the overall profile of action of pentoxifylline resembles that of PGI2 administration in this model.

The effects of molsidomine and its metabolite SIN-1 on coronary vessel tone, platelet aggregation, and eicosanoid formation in vitro--inhibition of 12-HPETE biosynthesis.

We studied the action of the biologically active metabolite of molsidomine, N-morpholino-N-nitrosoamino-acetonitrile (SIN), on eicosanoid formation and functional behavior of bovine coronary arteries and human platelets in vitro. Glyceryltrinitrate (GTN) and prostaglandin (PG) I2 were used as reference compounds. SIN dose-dependently inhibited the thrombin-, collagen-, and primary ADP-induced platelet aggregation. The IC50 was in the range of 0.1-0.8 mumol/L. At these concentrations SIN also inhibited thromboxane formation, but did not influence the PGI2 biosynthesis of coronary vessels. Molsidomine itself was inactive. GTN stimulated vascular PGI2 formation, but did not modify the platelet aggregation at comparable concentrations. A particularly interesting finding was the dose-dependent and apparently complete inhibition of formation of the hydroperoxide of 12L-hydroxy-5,8,10,14-eicosatetraenoic acid (12-HPETE) in human platelets by SIN. The IC50 amounted to 1.7 +/- 0.4 mumol/L and was in the same range as with 5,8,11,14-eicosatetraynoic acid (2.0 +/- 0.3 mumol/L). Although the results may not suggest a common mechanism of the antiaggregatory action of GTN and SIN, they provide no evidence of a similar or dissimilar mechanism of action in vascular smooth muscle.

RCS from human platelets: is it only thromboxane?

To determine if inhibition of a rabbit aorta contracting substance (RCS) corresponds to inhibition of thromboxane synthetase human washed platelets were stimulated with thrombin. RCS formation was bioassayed on rabbit aorta strips in Tyrode solution containing selective blocking agents and thromboxane (TX)B2 in the same probes by specific radioimmunoassay. Dazoxiben inhibited the formation of TXB2 but not of RCS, whereas indomethacin inhibited both RCS and TX formation. The data indicate that the rabbit aorta cannot be used alone to predict inhibition of TX formation with specific TX synthetase inhibitors.

Evidence for high affinity prostacyclin binding sites in vascular tissue: radioligand studies with a chemically stable analogue.

Prostacyclin-specific binding sites are described in the muscularis of pig aorta using [3H]ZK 36374, a chemically stable prostacyclin analogue, as radioligand. Under standard incubation conditions [300 micrograms membrane protein in 350 microliter Tris buffer (50 mmoles/l., pH 7.4) containing 3 mM Ca2+ at 37 degrees for 10 min] both association and dissociation were complete within 30 sec, thus not allowing the determination of association or dissociation rate constants. The Scatchard plot was upward convex, whereas the Hill plot was linear, having a slope of 1.9. The equilibrium dissociation constant (KD) was 22.4 nmoles/l. and the specific binding was saturated at 360 fmoles [3H]ZK 36374/mg protein. The reversibility of binding was demonstrated by displacement of bound ligand with ZK 36374, its 5-(Z)-stereoisomer (ZK 36375), PGI2 and PGE1, but not with PGF2 alpha. The data suggest high affinity binding sites for ZK 36374 in the smooth muscle cells of pig aorta for which PGI2 may be the physiological ligand. They also demonstrate a possible co-operativity with two molecules binding simultaneously to two interacting sites.

[Iodine deficiency in Salzburg in spite of iodized table salt prophylaxis]. / Jodmangel in Salzburg trotz Jodsalzprophylaxe.

Urinary iodine excretion was determined in 293 medical technical and nursing students in hospitals of the province Salzburg. The average urinary iodine excretion amounted to 46.6 +/- 18 micrograms iodine per gram creatinine. 67.6% of the students showed a deficiency of iodine II, whilst 98.3% had a deficiency of iodine I according to WHO criteria. Urinary iodine levels and natriuria are closely correlated, indicating that iodized table salt probably constitutes the most important source of iodine. 73 of the students had a palpable giotre, 10 of these being nodular. Our investigations, together with those of Innsbruck, Graz and Vienna, demonstrate the existence of generalized iodine deficiency in spite of iodized salt prophylaxis, which has been legally enforced in all of Austria since 1963. Iodized table salt prophylaxis has, thus, led to a drastic decrease in goitres in children, but is not sufficient to eliminate iodine deficiency in adults. An increased level of iodization of table salt, as has been put into force in Switzerland, must be called for in Austria, too.

Effects of PGI2 and PGI analogues on cAMP levels in cultured endothelial and smooth muscle cells derived from bovine arteries.

PGI2 increased cAMP levels in cultured endothelial cells derived from bovine aortas in the presence of isobutylmethylxanthine (IBMX). Stable PGI analogues were more effective, while PGE1 was without effect. In cultured smooth muscle cells from bovine aortas, PGI2, pGE1 and the stable PGI analogues dose-dependently increased cAMP levels in the absence and presence of IBMX. The data confirm the stimulatory effect of PGI2 on cAMP content in bovine coronary artery rings and suggest that the effect is mainly due to the stimulatory action of PGI2 on cAMP in smooth muscle cells.