Integrative Models for Understanding the Structural Basis of Regional Mechanical Dysfunction in Ischemic Myocardium

Myocardial ischemia and many other cardiac pathologies are associated with regional ventricular dysfunction. Since the distributions of stress and material properties cannot be measured directly in intact myocardium, understanding how regional alterations in myocardial strain or segment function are related to underlying cellular dysfunction must be deduced from theoretical models. Here, we describe how anatomically detailed, three-dimensional computational models can be used in conjunction with experimental or clinical studies to elucidate the structural basis of regional dysfunction in acutely ischemic and ischemic-reperfused (stunned) myocardium in vivo. Integrative experimental and computational analysis shows that: (1) in acutely ischemic myocardium, the transition from abnormal systolic strain in the ischemic region to normal shortening in adjacent, normally perfused tissue is governed primarily by systolic blood pressure and regional fiber orientation rather than the geometry of the perfusion boundary; and (2) in stunned myocardium, the degree of reperfusion injury to the contractile apparatus may be uniform across the wall thickness despite observations that the extent of ischemia and the impairment of regional strain during reperfusion are both significantly greater in the subendocardium. © 2000 Biomedical Engineering Society. PAC00: 8719Hh, 8719Uv, 8719Ff, 8719Rr, 8710+e     

Coronary blood flow in rats native to simulated high altitude and in rats exposed to it later in life

Summary In rats exposed to a simulated high altitude of 3500 m for their whole prenatal and postnatal life a severe cardiac hypertrophy develops. In rats born and first staying 5 weeks at sea level and then being exposed to simulated high altitude, only a unilateral right cardiac hypertrophy occurs. In both groups nutritional coronary blood flow was estimated in left ventricle, right ventricle, and septum and was compared with control animals of similar age. Coronary blood flow was measured at hypoxia in all groups. At first cardiac output was determined by the Fick principle, then⁸⁶Rb was applied and the animals were killed after 55 sec. Activity of⁸⁶Rb was measured in both cardiac ventricles and septum and the fractional uptake was calculated. According to Sapirstein (1956, 1958) the distribution of⁸⁶Rb follows the distribution of cardiac output and from both these data the nutritional blood flow to the parts of the heart may be estimated.Cardiac output was similar in rats exposed to simulated high altitude later in life (newcomers) and in control animals, but it was significantly lower in rats born in the low pressure chamber (natives).Fractions of cardiac output supplying cardiac ventricles and septum in rats from both hypoxic groups were significantly higher than in control animals. In the natives they were significantly higher than in the newcomers. The fractions of cardiac output in both newcomers and natives remained significantly higher than those of the control animals, also when calculated per gram of heart tissue.Nutritional coronary blood flow (in ml/min) was higher in both ventricles and septum of the newcomers and in the right ventricle of the natives, and lower in the septum of the natives, when compared with control animals. Coronary blood flow per gram of heart tissue (in ml/min·g) was significantly higher in all cardiac parts of the newcomers, but it was about the same in all cardiac parts of the natives when compared with controls.The importance of observed changes concerning myocardial tissue oxygenation is analyzed by using Krogh's cylindrical tissue model.Presented in part at the XXVIth International Congress of Physiological Sciences, New Delhi, India, October 20–26, 1974.     

Comparative investigation of the effects of metoprolol, propranolol, practolol, and verapamil in the acute phase of experimental myocardial infarction

Summary Myocardial infarction in rats was produced by ligation of the left coronary artery. To ensure exact comparison of drug effects, the extent of the myocardial zone excluded from the coronary circulation was determined in each animal, and the experimental data were related to it. For this purpose, the hearts were perfused with Evans blue, and after the photometric determination of the dye content of the hearts the percentage of ischemic myocardium was calculated. With metoprolol, propranolol, and verapamil a significant increase of the survival times was obtained (min/% of non-ischemic myocardium). Metoprolol and propranolol also significantly increased the survival rates. None of the-blockers exerted an antiarrhythmic effect. The arrhythmias were prevented by higher doses of the calcium antagonist verapamil which, however, decreased the survival times. All-blocking agents delayed the typical elevation of the ST-segment in the electrocardiogram, and reduced the increase of the activity of the serum creatine kinase. Propranolol and metoprolol antagonized the blood pH decrease obtained after coronary occlusion. Results concerning heart rate, and arterial and central venous pressures are also reported. — The findings with metoprolol, especially, indicate that the essential mechanism in the therapeutic action of-blockers is their ability to block the cardiac ₁-receptors.Supported by the Deutsche Forschungsgemeinschaft     

Transient effects of norepinephrine on myocardial oxygen balance

Summary In conscious dogs with experimental atrioventricular block and with ventricles paced at constant rate the effects of norepinephrine (NE) and isoproterenol (ISO) on coronary flow, coronary resistance, and myocardial O₂-balance were investigated. Myocardial O₂-s balance, as estimated from continuous measurement of coronary venous O₂-s saturation, was used for the discrimination of coronary dilation induced either directly by vascular -adrenoreceptor stimulation or indirectly by increased myocardial metabolism.Following bolus injection of NE (0.3 g/kg) or ISO (0.1 g/kg) into the pulmonary artery, coronary venous O₂-s saturation increased from a control of 25±2% O₂-s saturation (mean±S.D.) transiently to 51±5 and 62±5% O₂-s saturation respectively. After ₁-adrenoreceptor blockade these increases were reduced to 33±4 and 41±3% O₂-s saturation, respectively. The remaining increase after NE was abolished when atropine was given in addition to ₁-b blockade. After ₁+2-adrenoreceptor blockade neither NE nor ISO injection had an effect on coronary venous O₂ saturation. After ₁-b blockade was superimposed on ganglionic blockade NE injection led to a decrease in coronary venous O₂-s saturation indicating a ratent -a activity of NE.NE seems to act directly via ₁-a adrenoreceptors, since no differences were observed in the time courses of changes in coronary venous O₂-s saturation after left atrial injection of NE when compared to adenosine.It is concluded that circulating NE like ISO is able to improve myocardial oxygen balance by a direct vasodilating effect on canine coronary vessels mediated by vascular ₁-adrenoreceptors.     

Effect of alpha adrenergic receptor stimulation on integrated systemic venous bed

Summary In 29 mongrel dogs, venous return was completely drained from the caval veins to an oxygenator and returned to the femoral arteries with a roller pump at a constant perfusion rate. Blood pressures in both caval veins were kept constant by an automatic control system. The oxygenator weight was recorded and showed changes of the intracorporeal blood volume, i. e. of systemic venous blood volume since allowance was made for parallel changes in arterial blood volume.Xylometazolin (5–20 g/kg) and norepinephrine (2–8 g/kg), both infused within 3 min, decreased systemic venous blood volume by up to 7 ml/kg. After denervation of arterial pressoreceptors, nearly similar results were obtained. After beta receptor blockade with prindolol (600 g/kg), the effects on venous system were unchanged. After alpha receptor blockade with phentolamin (2500 g/kg), all effects were abolished. Phentolamin as such increased venous volume by 3 ml/kg.It is concluded that stimulation of venous alpha receptors effects predominantly a constriction of the systemic venous bed and hereby must increase venous return and cardiac output.     

The effects of intraportl infusions of glucagon on the hepatic arterial and portal venous vascular beds of the dog: Inhibition of hepatic arterial vasoconstrictor responses to noradrenaline

The sympathetically-innervated hepatic arterial and portal venous vascular beds of the dog were perfused simultaneously in situ. Glucagon was infused into the hepatic portal vein (1–10 g/min); it caused increases in hepatic portal vascular resistance and tended to reduce the hepatic arterial vascular resistance. Extrahepatic effects of intraportal infusions of glucagon included increases in superior mesenteric blood flow and heart rate and falls in systemic arterial pressure.A test dose of noradrenaline (10 g) injected into either the hepatic artery or the portal vein caused both hepatic arterial and portal venous vasoconstriction. The hepatic arterial constrictor responses to noradrenaline were antagonized intraportal infusions of glucagon. In contrast, intraportal glucagon did not antagonize the portal constrictor responses to intraarterial or intraportal noradrenaline.Elevated portal blood glucagon concentrations may protect the hepatic arterial blood flow from vasoconstriction due to elevated systemic levels of vasoactive substances including catecholamines.     

Activation of atrial muscarinic K+ channels by low concentrations ofβγ subunits of rat brain G protein

Effects of G protein subunits from rat brain on cardiac K⁺ channel was examined in single atrial cells of guinea-pig, using patch clamp techniques. We found that 10 pM concentration of rat brain subunits preparation could activate the atrial muscarine receptor-gated K⁺ channel (I_K.ACh). Neither the detergent, CHAPS, used to suspend nor the boiled preparation activated I_K.ACh. Furthermore, preincubation of subunits preparation in Mg²⁺-free solution, which easily inactivated -GTP-S, did not affect -activation of I_K.ACh. We concluded, therefore, that subunits themselves can activate I_K.ACh.Supported by the grants from the Ministry of Education, Culture and Science of Japan and from the Calcium Signal Workshop on Cardiovascular Systems     

On the existence of a lyotropic and osmotic type of collagen swelling produced by representative electrolytes and anelectrolytes

Summary The influence of NaI, NaCl, urea, glucose and sucrose on venous tissue volume were studied with regard to osmotic (electrostatic and dehydrating) and lyotropic effects. NaI leads to the highest volume increase and to the extreme irreversibility of this change. The tested anelectrolytes cause a decrease of tissue volume over the whole range of concentration with the exception that, beyond 1.0 osM, urea causes an increase. The large reversibility of this increase is pointed out. A strict discrimination between osmotic and lyotropic volume change is questioned.     

Streptococcus milleri group: Renewed interest in an elusive pathogen

The following review examines the bacteriological characteristics, epidemiology, pathogenicity and antimicrobial susceptibility of the Streptococcus milleri group. Streptococcus milleri group is a term for a large group of streptococci which includesStreptococcus intermedius, Streptococcus constellatus andStreptococcus anginosus. Usually considered commensals, these organisms are often associated with various pyogenic infections including cardiac, abdominal, skin and central nervous system infections. Organisms of the Streptococcus milleri group are often unrecognized pathogens due to the lack of uniformity in classifications and difficulties in microbiological identification. Penicillin G, cephalosporins, clindamycin and vancomycin all possess activity against these streptococci. Use of agents with poor activity may promote infections with Streptococcus milleri group and allow it to exhibit its pathogenicity. An understanding of these organisms may aid in their recognition and proper treatment.     

On the regulation of the expressed L-type calcium channel by cAMP-dependent phosphorylation

The Ca²⁺ channel subunits _1C-a and _1C-b were stably expressed in Chinese hamster ovary (CHO) and human embryonic kidney (HEK) 293 cells. The peak Ba²⁺ current (I _Ba) of these cells was not affected significantly by internal dialysis with 0.1 mM cAMP-dependent protein kinase inhibitor peptide (mPKI), 25 M cAMP-dependent protein kinase catalytic subunit (PKA), or a combination of 25 M PKA and 1 M okadaic acid. The activity of the _1C-b channel subunit expressed stably in HEK 293 cells was depressed by 1 M H 89 and was not increased by superfusion with 5 M forskolin plus 20 M isobutylmethylxanthine (IBMX). The _1C-a·₂·₂/ complex was transiently expressed in HEK 293 cells; it was inhibited by internal dialysis of the cells with 1 M H 89, but was not affected by internal dialysis with mPKI, PKA or microcystin. Internal dialysis of cells expressing the _1C-a·₂·₂/ channel with 10 M PKA did not induce facilitation after a 150-ms prepulse to +50 mV. The Ca²⁺ current (I _Ca) of cardiac myocytes increased threefold during internal dialysis with 5 M PKA or 25 M microcystin and during external superfusion with 0.1 M isoproterenol or 5 M forskolin plus 50 M IBMX. These results indicate that the L-type Ca²⁺ channel expressed is not modulated by cAMP-dependent phosphorylation to the same extent as in native cardiac myocytes.     

The Stress–Strain Behavior of Coronary Stent Struts is Size Dependent

Coronary stents are used to re-establish the vascular lumen and flow conditions within the coronary arteries; the typical thickness of a stent strut is 100 m, and average grain sizes of approximately 25 m exist in stainless steel stents. The purpose of this study is to investigate the effect of strut size on the stress strain behavior of 316 L stainless steel. Other materials have shown a size dependence at the micron size scale; however, at present there are no studies that show a material property size dependence in coronary stents. Electropolished stainless steel stent struts within the size range of 60–500 m were tensile tested. The results showed that within the size range of coronary stent struts a size dependent stress–strain relationship is required to describe the material. Finite element models of the final phase of fracture, i.e., void growth models, explained partially the reason for this size effect. This study demonstrated that a size based stress–strain relationship must be used to describe the tensile behavior material of 316 L stainless steel at the size scale of coronary stent struts. © 2003 Biomedical Engineering Society. PAC2003: 8719Rr, 8780Rb, 8719Uv     

Structural Model of the Muscle Spindle

A model of the muscle spindle was developed based on its anatomical structure. The model contains three intrafusal fibers (bag1, bag2, and chain), two efferents (dynamic efferent to the bag1 fiber and static efferent to bag2 and chain fibers), and two afferents [primary (Ia) and secondary (II)]. As in the real muscle spindle, the spindle model, under the modulation of efferents, responds to the extrafusal muscle fiber length. Both outputs (Ia and II afferents) of the model were compared extensively with published data, under both sinusoidal stretch (with different stretch amplitudes and frequencies) and ramp and hold stretch (with different stretch amplitudes and velocities) in three different fusimotor activation conditions (dynamic stimulation, static stimulation, and without stimulation). Model Ia afferent responses fit the published data well with active gamma input, but less well in the passive state. Model II afferent responses also fit the published data, although less quantitative data were available for comparison. The model correctly predicted the fractional power dependence of the primary and secondary ending responses on stretch velocity. The current model provides a powerful tool for simulation studies of neuromusculoskeletal systems, and demonstrates the feasibility of using a structural approach to model complex neurophysiological systems. © 2002 Biomedical Engineering Society. PAC02: 8719Ff, 8719La, 8719St     

Ventilatory,circulatory, endocrine,and renal effects of almitrine infusion in man: a contribution to high altitude physiology

Summary Diuresis at altitude was thought to be the result of chemoreceptor stimulation leading to a reduction of cardiac volume overload. This hypothesis was tested in ten young, healthy subjects by infusion of almitrine (0.5 mg · kg^–1 body mass within 30 min) assuming analogous sites of action, i.e. arterial chemoreceptors and pulmonary vessels, for almitrine as for hypoxic hypoxia. The results show that almitrine increases ventilation, heart rate, systolic blood pressure, central venous pressure and natriuresis, but fails to increase significantly atrial natriuretic peptide plasma concentration and diuresis. It is concluded: (1) that almitrine has similar sites of action as hypoxic hypoxia at about 5000 m, (2) that natriuresis during arterial chemoreceptor stimulation might reduce cardiac volume overload, (3) that the volume excretion hypothesis, in particular the pathways from the cardiac volume overload to the water diuresis, need, for an understanding of the hypoxia-induced diuresis, further direct investigations at altitude.This study was supported in part by Stiftung für wissenschaftliche Forschung an der Universität Zürich, by Theodor and Ida Herzog-Egli-Stiftung, Zürich, and by the Swiss National Science Foundation (Grant No. 3.495-0.86)     

Das sog. Endokardmyxom

Summary Three cardiac Myxomas were studied by light-, immuno-fluorescence and electron microscopy. Acid mucopolysaccharides of the tumour were isolated chromatographically. The surfaces of the myxomas were papillary in two cases and smooth in one. The smooth surfaced tumour recurred six months after primary resection; histological specimens were more cellular than those of the papillary tumors and showed nuclear polymorphism and mitoses. The cells of two papillary tumours were identified as endocardial by electron microscopy, however, the cells of the smooth surfaced tumour were typical myofibroblasts. In both types of myxomas the cells were rich on cytoplasmic filament that contained acto-myosin. Biochemical investigation failed to reveal any difference between the acid mucopolysaccharide pattern of the two tumour types; isolated mucopolysaccharides being typical for embryonal mesenchymal tissue.The authors agree with Albertini (1963), that cardiac myxoma is a misnomer for two different typical endocardial tumours: a true endothelioma and a special fibroma (myofibroma or myofibrosarcoma).

     

Lability in the responses of cells in the auditory cortex of squirrel monkeys to species-specific vocalizations

Summary The activity of 28 cells located mainly in the secondary auditory cortex (A II) of awake squirrel-monkeys, was extracellularly recorded for periods of up to 6 h. Seven different species-specific vocalizations, which were repeatedly presented to the monkey, were used as auditory stimuli. Twenty-six cells responded, at least once, to one or more vocalizations; 22 cells revealed some change in their response (pattern or strength) to at least one vocalization (change in response). Twenty-one cells exhibited a change in the number and/or type of vocalization to which they responded during the recording period (change in selectivity). At some time during the recording period all the responding cells exhibited a change in response and/or a change in selectivity (change in responsiveness). A change in response of a cell to a vocalization did not necessarily exclude a change in selectivity, associated with the same vocalization, later in time and vice-versa. A change in responsiveness to one vocalization was not necessarily correlated with changes in responsiveness to other vocalizations.     

Synoviocytes in chronic synovitis in situ and cytokine stimulated synovial cells in vitro neo-express α1, α3 and α5 chains of β1 integrins

The expression of the 1 integrins was examined immunohistochemically in synoviocytes from normal synovial membrane and from chronic synovitis of different aetiology and intensity. Normal synoviocytes were 61-positive but lacked 1 through 5. In mild inflammation type A synoviocytes neo-expressed 1, 3, and 5 chains. In severe inflammation both type A and B synoviocytes expressed 3, 4, 5, and 6 chains. The effects of inflammatory cytokines, as single agents or in combination, on the 1 integrin expression in cultured normal synoviocytes was determined by immunocytochemistry and flow cytometry. The 1 chain, while absent in unstimulated synoviocytes, was induced by interleukin-1 (IL-1), tumour necrosis factor- (TNF-), and interferon- (INF-). This effect was enhanced by combining IL-1 and TNF-. Expression of the 3 chain was up-regulated by IL-1 and, more intensely, by IFN-. Transforming growth factor (TGF-) inhibited the up-regulating effect of IL-1 and antagonized the effect of IFN- on 3 chain expression. Expression of the 5 chain was up-regulated significantly by co-stimulation through IL-1 together with TGF- or TNF-. Thus, the 1 integrin profile of cytokine activated synoviocytes in vitro resembled that of synoviocytes in synovitis in situ. These data suggest that IL-1, TNF-, IFN-, and TGF- are likely to be among the effectors regulating 1 integrin expression in synoviocytes in vivo.     

Effect of the degree of myocardial hypertrophy associated with an experimental heart defect on the resistance to altitude hypoxia

Summary Experimental coarctation of the abdominal aorta with constriction of its lumen to one-third of the original diameter was created in 18 albino rats. Four months later various degrees of myocardial hypertrophy developed in the animals with a relative weight of the heart ranging from 0.0033 to 0.0069. In elevation in the barochamber, the altitude ceiling of the animals with a relative cardiac weight below 0.0040, did not differ from the normal one. The altitude ceiling proved to be considerably decreased in animals with a relative cardiac weight of over 0.0040. Analysis of ECG recorded during the elevation demonstrated that in the animals with a considerable myocardial hypertrophy reduced resistance to the acute high altitude hypoxia depended on the reduction of the functional resistance of the heart.(Presented by Active Member AMN SSSR V. V. Parin) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 55, No. 5, pp. 37–40, May, 1963     

Volumetric assessment of the capillary filtration coefficient in the cat small intestine

The capillary filtration coefficient of the cat small intestine was measured in four ways; the conventional measurement was compared with the zero time extrapolation technique, and with two methods designed to assess the end of the blood volume shift due to venous pressure elevation. If the capillary filtration coefficient (CFC) was determined using small elevations of venous pressure (10 mm Hg or less), there was good agreement between the techniques. Larger elevations of venous pressure resulted in apparent overestimates of CFC measured by the conventional technique, probably because of increased smearing of the blood volume shift into the component of the response measured as the CFC. In general, larger elevations of venous pressure gave smaller CFC's, and using venous pressure elevations of 10 mm Hg or less, the CFC was greater if the final elevated venous pressure was 10 mm Hg than if it was 20 or 30 mm Hg. Changes in CFC due to noradrenaline and isoprenaline (about 15 ng/ml arterial blood concentration) were in agreement when small venous pressure elevations were used and CFC measured in three different ways.     

A comparative study of skeletal and cardiac tropomyosins

Summary The subunit composition, the thiol group content and the biological activities of cardiac tropomyosin (TM) of various animal species were compared. Cardiac TM from small animals such as rabbit, guinea-pig, rat and dog contain 2 SH/mole and were resolved into one band on SDS and acid urea electrophoresis and into two bands on alkaline urea electrophoresis. Chicken cardiac TM likewise gave one band and it contains 4 SH/mole. In contrast pig, sheep and human cardiac TM contain respectively 2.6, 2.4, and 2.4 SH/mole and were resolved into two bands and on the different electrophoresis systems used, with a : ratio respectively of I:4.2, I:4.6, I:4.8. The -TM components from sheep skeletal and pig and sheep cardiac muscles were more positively charged than the rabbit skeletal -TM component, as shown in alkaline urea electrophoresis system. The and combinations of dimers found for skeletal muscle by other authors, were also found for cardiac pig TM.All the TM have the same effect on the Ca²⁺-stimulated ATPase activity of desensitized actomyosin (DAM) and on the Mg²⁺-stimulated ATPase activity of DAM with troponin-complex.This work suggests that the subunits of the TM from skeletal and cardiac muscles are heterogenous in their M.W. and their charges and that in the heart as well as in skeletal muscle a relationship seems to exist between the amount of the component and the speed of contraction of the muscle: a higher amount of this component was found in the bulky hearts which are also those which contract slower.     

Modulation of Nav1.5 by β1- and β3-subunit co-expression in mammalian cells

Cardiac sodium channels (Na_v1.5) comprise a pore-forming -subunit and auxiliary -subunits that modulate channel function. In the heart, 1 is expressed throughout the atria and ventricles, whilst 3 is present only in the ventricles and Purkinje fibers. In view of this expression pattern, we determined the effects of 3 and 1 co-expression alone, and in combination, on Na_v1.5 stably expressed in Chinese hamster ovary cells. The current/voltage relationship was shifted –5 mV with either 1 or 3 co-expression alone and –10 mV with co-expression of both 1 and 3. In addition, 3 and 1/3 co-expression accelerated macroscopic current decay. There were significant hyperpolarizing shifts in equilibrium gating relationships with co-expression of 1 and 3 alone and in combination. Co-expression of 1/3 together resulted in a greater hyperpolarizing shift in channel availability, and an increase in the slopes of equilibrium gating relationships. Co-expression of 3 and 1/3, but not 1, slowed recovery from inactivation at –90 mV. Development of inactivation at –70 and –50 mV was accelerated by -subunit co-expression alone and in combination. -Subunit co-expression also reduced the late Na current measured at 200 ms. In conclusion, -subunits modulate Na_v1.5 gating with important differences between co-expression of 1 and 3 alone and 1/3 together.