Effects of acute changes in load and inotropic state on the exponential rate of fiber shortening and other indices of myocardial contractility in the anesthetized intact dog

The effects of an acute increase in preload, afterload, and inotropic state on several indices of left ventricular contractility were studied in 20 anesthetized intact dogs. The behaviour of the exponential rate of fiber shortening (ERFS), a newly described index, which is based on the instantaneous fiber length--time relationship through ejection, was compared with other classical ejection and isovolumic indices of left ventricular contractility. Acute volume overload by dextran 40 infusion produced a significant increase in preload as reflected by a 103% (p less than 0.01) increase in left ventricular end-diastolic pressure and a 121% (p less than 0.001) increase in end-diastolic circumferential wall stress. There was also a smaller but significant increase (p less than 0.05) of heart rate (30%) and of peak systolic circumferential wall stress (24%). None of the left ventricular contractility indices showed any significant change. Acute pressure overload, produced mechanically by an aortic balloon, increased the afterload significantly as reflected by a 33% (p less than 0.05) rise of end-systolic circumferential wall stress and a 43% (p less than 0.001) increase in systemic resistance. Stroke volume decreased significantly by 23% (p less than 0.05). All ejection indices, including ERFS, were significantly diminished by 30-37%; all isovolumic indices showed no significant changes. Positive inotropic intervention was induced by dopamine infusion, which caused a significant 28% (p less than 0.05) increase in cardiac output. End-diastolic and end-systolic circumferential wall stress were significantly diminished. All indices of left ventricular contractility increased significantly and ERFS showed the quantitatively greatest change.(ABSTRACT TRUNCATED AT 250 WORDS)     

Computer analysis of ventricular pressure recordings: evaluation of myocardial contractility on the dog heart in situ]

The contractile indices Vmax (maximum shortening velocity of the contractile element) and ARPD (power averaged rate of power density generation) which have been shown to be unaffected by alterations in preload and afterload were computed from isovolumic left ventricular pressure data of dogs. The two indices were tested for their ability to detect changes in contractility induced by a positive inotropic drug (Isoprenalin). Whereas a good correlation was found between ARPD and Vmax (coefficient of correlation 0,895) the index ARPD was more sensitive to augmentation of myocardial contractility; also because it is simpler to obtain computationally and more appropriate for the intact heart from a theoretical point of view. ARPD should be useful especially for quantification of acute changes in myocardial contractility.     

The role of vagus nerves in different changes of the right atrial pressure following intravenous injection of pressor vasoactive drugs

In acute experiments on anesthetized cats, intravenous injection of the norepinephrine and angiotensin caused different changes of right atrial pressure in intact animals (decreasing--I group, of animals, and increasing--II group). After right and left vagus nerves had been cut, the right atrial pressure in the I group of animals decreased, but its changes were lesser than in intact animals due to slowing down of the increase of the right ventricular myocardial contractility and venous return. The latter was the result of severe diminution of the increase of the superior vena cava flow compared with the intact animals, meanwhile the value of the inferior vena cava flow did not change. In the II group animals after vagotomy and intravenous injection of the noripinephrine and angiotensin the sign of the right atrial pressure became negative, i. e. the direction of its shifts changed to the opposite, compared with intact animals. In this case, the changes of the sign of the right atrial pressure was caused by the removal of the reflectory inhibitory vagal influences on the heart, because the values of the right ventricular myocardial contractility and venous return were the same as in intact animals of the group, due to decreasing of the value of the superior vena cava flow and increasing of the shifts of the inferior vena cava flow. The vagotomy alone caused also different changes (decreasing or increasing) of right atrial pressure following increasing of the right ventricular myocardial contractility, meanwhile the changes of the venous return were insignificant. Direct electrical stimulation of both the right and the left vagus nerves caused the increasing of the right atrial pressure and decreasing of the right ventricular myocardial contractility and venous return. Thus we concluded, that different changes of the right atrial pressure in animals following intravenous injection of the pressor vasoactive drugs could be the result of different manifestations of the vagal afferent impulsation, which has influence on the sympathetic tonic discharges on the vessels of the regions of the superior and inferior vena cava, and the vagal reflectory inhibitory influences on the heart.     

Left ventricular shape-based contractility index

This study develops contractility indices in terms of the left ventricular (LV) ellipsoidal geometrical shape-factor. The contractility index (CONT1) is given by the maximum value dsigma(*)/dt wherein sigma(*)=sigma/P, sigma is the wall stress, and sigma(*) is expressed in terms of the shape factor S (the ratio of the minor axis and major axis, B/A, of the instantaneous LV ellipsoidal model). Another contractility index (CONT2) is also developed based on how far apart the in vivo S at the start of ejection is from its optimized value, CONT2=(S(se)-S(se)(op))/S(se)(op), where S(se) refers to the value of S at the start of ejection, S(se)(op) is the derived optimal value of S(se) for which sigma* is maximum. The values of S(=B/A) were calculated from cineventriculographically monitored LV volume, myocardial volume and wall-thickness. Then both the contractility indices were evaluated in normal subjects, as well as in patients with mild heart failure and in patients with severe heart failure. The normal values of CONT1 and CONT2 are 8.75+/-2.30s(-1) and 0.09+/-0.07, respectively. CONT1 decreased in patients with mild and severe heart failures to 5.78+/-1.30 and 3.90+/-1.30, respectively. CONT2 increased in patients with mild and severe heart failures to 0.11+/-0.09 and 0.23+/-0.12, respectively. This implies that a non-optimal and less ellipsoidal shape is associated with decreased contractility (and poor systolic function) of the LV. CONT1 and CONT2 are useful as non-invasively determinable quantitative indices of LV contractility, to distinguish between normal and pathologic LVs.     

Functional modulation of cardiac form through regionally confined cell shape changes

Developing organs acquire a specific three-dimensional form that ensures their normal function. Cardiac function, for example, depends upon properly shaped chambers that emerge from a primitive heart tube. The cellular mechanisms that control chamber shape are not yet understood. Here, we demonstrate that chamber morphology develops via changes in cell morphology, and we determine key regulatory influences on this process. Focusing on the development of the ventricular chamber in zebrafish, we show that cardiomyocyte cell shape changes underlie the formation of characteristic chamber curvatures. In particular, cardiomyocyte elongation occurs within a confined area that forms the ventricular outer curvature. Because cardiac contractility and blood flow begin before chambers emerge, cardiac function has the potential to influence chamber curvature formation. Employing zebrafish mutants with functional deficiencies, we find that blood flow and contractility independently regulate cell shape changes in the emerging ventricle. Reduction of circulation limits the extent of cardiomyocyte elongation; in contrast, disruption of sarcomere formation releases limitations on cardiomyocyte dimensions. Thus, the acquisition of normal cardiomyocyte morphology requires a balance between extrinsic and intrinsic physical forces. Together, these data establish regionally confined cell shape change as a cellular mechanism for chamber emergence and as a link in the relationship between form and function during organ morphogenesis.     

A comparative assessment of the effect of Omnipaque and Verografin on ECG indices and myocardial contractility in patients with unstable angina during coronary ventriculography

Altogether 30 patients with unstable angina (UA) were examined. In 15 patients omnipaque was used during coronography and ventriculography (VG), in the rest of 15 patients--verografin at common dosages. A study was made of the changes in the indices of central hemodynamics and myocardial contractility resulting from the action of these radiopaque media during VG, and of ECG changes during coronography. VG with verografin was accompanied by more noticeable disorders of left ventricular contractility, an increase in myocardial oxygen consumption; coronography with omnipaque was characterized by later ECG changes, less noticeable disorders of intraventricular conductivity. It is advisable that coronaroventriculography in patients with UA should be performed using a new group of radiopaque media, in particular omnipaque.     

Functional, structural, and chemical changes in myosin associated with hydrogen peroxide treatment of skeletal muscle fibers

To understand the molecular mechanism of oxidation-induced inhibition of muscle contractility, we have studied the effects of hydrogen peroxide on permeabilized rabbit psoas muscle fibers, focusing on changes in myosin purified from these fibers. Oxidation by 5 mM peroxide decreased fiber contractility (isometric force and shortening velocity) without significant changes in the enzymatic activity of myofibrils and isolated myosin. The inhibitory effects were reversed by treating fibers with dithiothreitol. Oxidation by 50 mM peroxide had a more pronounced and irreversible inhibitory effect on fiber contractility and also affected enzymatic activity of myofibrils, myosin, and actomyosin. Peroxide treatment also affected regulation of contractility, resulting in fiber activation in the absence of calcium. Electron paramagnetic resonance of spin-labeled myosin in muscle fibers showed that oxidation increased the fraction of myosin heads in the strong-binding structural state under relaxing conditions (low calcium) but had no effect under activating conditions (high calcium). This change in the distribution of structural states of myosin provides a plausible explanation for the observed changes in both contractile and regulatory functions. Mass spectroscopy analysis showed that 50 mM but not 5 mM peroxide induced oxidative modifications in both isoforms of the essential light chains and in the heavy chain of myosin subfragment 1 by targeting multiple methionine residues. We conclude that 1) inhibition of muscle fiber contractility via oxidation of myosin occurs at high but not low concentrations of peroxide and 2) the inhibitory effects of oxidation suggest a critical and previously unknown role of methionines in myosin function.     

Transitional and coastal waters ecological status assessment: advances and challenges resulting from implementing the European Water Framework Directive

The derivation, performance, sensitivity and inherent uncertainty of ecological quality indicators have become major topics in developing tools for the management of marine, transitional and coastal waters. In reviewing the advances in these waters, related to an ecological status assessment, we show the future challenges to be addressed within the European Water Framework Directive (WFD). Using new analyses carried out under the research project ‘Water Bodies in Europe: Integrative Systems to Assess Ecological status and Recovery’, we provide a complete set of assessments for the biological quality elements (BQEs) (phytoplankton, macroalgae-seagrasses, macroinvertebrates and fish) to be assessed, as well as the validation of existing indicators and multimetric indices and, in some cases, the development of new assessment indices. We show that these indices respond differently to different human pressures and they each have challenges in defining reference conditions against which future changes are judged. In investigating good ecological potential, as the response to heavily modified water bodies, we show that there are flaws in the Directive, not least in its definitions. Our analyses have also focussed on uncertainty in using the indices and we emphasise the problems of defining ecological class boundaries based on indices which themselves may be combined indices (multimetrics). The analysis shows that some of those multimetrics are redundant and/or are inter-correlated and thus may reduce the sensitivity in defining ecological class boundaries. If this is related to the drivers-pressures-state change-impacts-response approach then there are lessons for management measures aimed at achieving good ecological status and even the potential for legal challenges to decisions based on uncertain indices under the WFD. Hence, we conclude the continued need for advances in assessing pressures and gradients, and defining reference conditions for state change, index development, impact assessment and the validation of indices for each BQE.     

Dynamics of the Indices of Electrohippocampogram Recorded from Rats under Conditions of Long-Lasting Stress: Effects of Modulators of Synaptic Transmission

We studied the effects of modulation of the activity of noradrenergic and GABA-ergic cerebral transmitter systems on the hippocampal electrical activity in rats during long-lasting (21 weeks) stress induced by a zooconflict situation. The background field electrical activity of the hippocampus (electrohippocampogram, EHcG) was recorded from control and stressed rats in the state of residual ketamine-barbiturate anesthesia. We used injections of the following modulators of central neurotransmission: amitriptyline, aminazine, and carbamazepine, which are extensively used in clinics for intensification of the activity of the antistress GABA system based on the influence of these agents on the monoaminergic cerebral systems. Under such conditions, we found the two-phase dynamics of spectral powers of EHcG components. In the first phase, where changes in the excitatory influences on central neurons prevailed, the total power of EHcG oscillations and spectral powers of its components were significantly lower with respect to the control, while in the second phase we observed rapid increases in the above indices, which probably resulted from parallel hyperactivation of both excitatory and inhibitory (GABA-ergic) elements of neuronal networks of the hippocampus. In rats forming the groups for comparison (control animals and stressed ones with no injections of synaptic modulators), changes in the powers of EHcG oscillations during the 21-week-long experiment waves were three-phase; in the latter animal group, the above characteristics differed from each other mostly quantitatively. Such changes in stressed rats with respect to the control ones could reflect modulation of the mediator/hormonal influences on hippocampal neurons during three phases of the stress reaction of the organism.     

Alpha 1-adrenergic stimulation increases the Vmax of isolated myocardial papillary muscles.

alpha-Adrenergic agonists have been shown to increase the tension developed by myocardial muscle. However, their effects on the maximum velocity of unloaded muscle shortening (Vmax) have not been rigorously examined. In this study, the contractile effects of the alpha-adrenergic agonist phenylephrine were examined in the presence of propranolol in papillary muscles of two species, the dog and the rabbit. In rabbit papillary muscles studied at physiological calcium concentrations (1.25 mM), phenylephrine increased all indices of contractility (Vmax, tension, and maximum rate of tension developed (dT/dt)) starting at 10(-8) M. The percent increase in Vmax (121 +/- 8%) was less than that of tension (188 +/- 20%, p less than 0.05) and dT/dt (262 +/- 35%, p less than 0.01). These findings occurred at both 29 and 35 degrees C and were inhibited by adding 10(-5) M prazosin. Increasing extracellular calcium concentration from 1.25 to 15 mM caused changes in twitch configuration that were significantly different from those of phenylephrine. Calcium increased all indices of contractility more than did phenylephrine. This was particularly true for dT/dt (502 +/- 82 vs. 262 +/- 35% for phenylephrine, p less than 0.01). Nonetheless, the ratio of increase in tension to increase in Vmax under both experimental conditions was similar (the increase in Vmax was 64% of that of tension with phenylephrine and 69% with increased calcium). At 1.25 mM calcium, the increase in contractility caused by phenylephrine was much smaller in dog myocardium as compared with rabbit myocardium. Rather, the effects of phenylephrine on dog myocardium studied at 1.25 mM calcium resembled that of rabbit myocardium studied at 15 mM calcium.(ABSTRACT TRUNCATED AT 250 WORDS)     

Characteristics of bovine early puerperal uterine contractility recorded under farm conditions

A non-invasive, digital technique was used to measure and quantify intrauterine pressure (IUP) changes in early postpartum dairy cows kept under farm conditions in order to document physiological changes in uterine contractility after uncomplicated calvings. In addition, possible relationships between characteristics of uterine contractility and blood ionized calcium (Ca(2+))-concentrations were investigated. Recordings of uterine contractility were made by using a transcervically inserted open tip catheter in 12 healthy cows during their first 48h after calving. The IUP recording technique appeared easily applicable under farm conditions. Although mean frequency (FREQ), amplitude (AMP) and area under the curve (AUC) of the myometrial contractions significantly decreased due to time, untreated early postpartum cows showed a high variability in characteristics of uterine contractility. There was no correlation between blood Ca2+ -concentrations and any of the contractility parameters.     

Comparison of UTCI to selected thermal indices

Over the past century more than 100 indices have been developed and used to assess bioclimatic conditions for human beings. The majority of these indices are used sporadically or for specific purposes. Some are based on generalized results of measurements (wind chill, cooling power, wet bulb temperature) and some on the empirically observed reactions of the human body to thermal stress (physiological strain, effective temperature). Those indices that are based on human heat balance considerations are referred to as "rational indices". Several simple human heat balance models are known and are used in research and practice. This paper presents a comparative analysis of the newly developed Universal Thermal Climate Index (UTCI), and some of the more prevalent thermal indices. The analysis is based on three groups of data: global data-set, synoptic datasets from Europe, and local scale data from special measurement campaigns of COST Action 730. We found the present indices to express bioclimatic conditions reasonably only under specific meteorological situations, while the UTCI represents specific climates, weather, and locations much better. Furthermore, similar to the human body, the UTCI is very sensitive to changes in ambient stimuli: temperature, solar radiation, wind and humidity. UTCI depicts temporal variability of thermal conditions better than other indices. The UTCI scale is able to express even slight differences in the intensity of meteorological stimuli.     

Exploiting differential effects of actomyosin contractility to control cell sorting among breast cancer cells

In order to gain a greater understanding of the factors that drive spatial organization in multicellular aggregates of cancer cells, we investigate the segregation patterns of 6 breast cell lines of varying degree of mesenchymal character during formation of mixed aggregates. Cell sorting is considered in the context of available adhesion proteins and cellular contractility. It is found that the primary compaction mediator (cadherins or integrins) for a given cell type in isolation plays an important role in compaction speed, which in turn is the major factor dictating preference for interior or exterior position within mixed aggregates. In particular, cadherin-deficient, invasion-competent cells tend to position towards the outside of aggregates, facilitating access to extracellular matrix. Reducing actomyosin contractility is found to have a differential effect on spheroid formation depending on compaction mechanism. Inhibition of contractility has a significant stabilizing effect on cell-cell adhesions in integrin-driven aggregation and a mildly destabilizing effect in cadherin-based aggregation. This differential response is exploited to statically control aggregate organization and dynamically rearrange cells in pre-formed aggregates. Sequestration of invasive cells in the interior of spheroids provides a physical barrier that reduces invasion in three-dimensional culture, revealing a potential strategy for containment of invasive cell types.     

Non-invasive evaluation of systolic and diastolic functions of the left ventricle in newborn infants

To assess possible changes in myocardial contractile function and relaxation occurring after mild perinatal asphyxia, maximal blood pressure and M-mode echocardiograms should be registered simultaneously in 32 normal term newborns (group 1) and in 22 term asphyxiated newborns (group II). The slope of end-systolic pressure-dimension relation (ESPDR) was used as a reliable index for evaluation of the myocardial contractility. The slope of ESPDR and some indices of ventricular relaxation decreased in newborns from group II. It is suggested that ESPDR and parameters of left ventricular relaxation and filling can serve as early and sensitive indices of hypoxic myocardial damage.     

EPH/EPHRIN regulates cellular organization by actomyosin contractility effects on cell contacts

EPH/EPHRIN signaling is essential to many aspects of tissue self-organization and morphogenesis, but little is known about how EPH/EPHRIN signaling regulates cell mechanics during these processes. Here, we use a series of approaches to examine how EPH/EPHRIN signaling drives cellular self-organization. Contact angle measurements reveal that EPH/EPHRIN signaling decreases the stability of heterotypic cell:cell contacts through increased cortical actomyosin contractility. We find that EPH/EPHRIN-driven cell segregation depends on actomyosin contractility but occurs independently of directed cell migration and without changes in cell adhesion. Atomic force microscopy and live cell imaging of myosin localization support that EPH/EPHRIN signaling results in increased cortical tension. Interestingly, actomyosin contractility also nonautonomously drives increased EPHB2:EPHB2 homotypic contacts. Finally, we demonstrate that changes in tissue organization are driven by minimization of heterotypic contacts through actomyosin contractility in cell aggregates and by mouse genetics experiments. These data elucidate the biomechanical mechanisms driving EPH/EPHRIN-based cell segregation wherein differences in interfacial tension, regulated by actomyosin contractility, govern cellular self-organization.     

Projected timing of perceivable changes in climate extremes for terrestrial and marine ecosystems

Human and natural systems have adapted to and evolved within historical climatic conditions. Anthropogenic climate change has the potential to alter these conditions such that onset of unprecedented climatic extremes will outpace evolutionary and adaptive capabilities. To assess whether and when future climate extremes exceed their historical windows of variability within impact‐relevant socioeconomic, geopolitical, and ecological domains, we investigate the timing of perceivable changes (time of emergence; TOE) for 18 magnitude‐, frequency‐, and severity‐based extreme temperature (10) and precipitation (8) indices using both multimodel and single‐model multirealization ensembles. Under a high‐emission scenario, we find that the signal of frequency‐ and severity‐based temperature extremes is projected to rise above historical noise earliest in midlatitudes, whereas magnitude‐based temperature extremes emerge first in low and high latitudes. Precipitation extremes demonstrate different emergence patterns, with severity‐based indices first emerging over midlatitudes, and magnitude‐ and frequency‐based indices emerging earliest in low and high latitudes. Applied to impact‐relevant domains, simulated TOE patterns suggest (a) unprecedented consecutive dry day occurrence in >50% of 14 terrestrial biomes and 12 marine realms prior to 2100, (b) earlier perceivable changes in climate extremes in countries with lower per capita GDP, and (c) emergence of severe and frequent heat extremes well‐before 2030 for the 590 most populous urban centers. Elucidating extreme‐metric and domain‐type TOE heterogeneities highlights the challenges adaptation planners face in confronting the consequences of elevated twenty‐first century radiative forcing.     

Characteristics of the active lymph pump in bovine prenodal mesenteric lymphatics

BACKGROUND: The functional characteristics of the bovine mesenteric postnodal lymphatics are well-described. However there are no reports of pumping characteristics of the bovine mesenteric prenodal lymphatics. We propose that the prenodal lymphatics have adapted to the local conditions of lymph flow and are functioning differently than the postnodal vessels. METHODS AND RESULTS: To evaluate pumping in bovine prenodal mesenteric lymphatics, we observed their contractility in response to the changes in transmural pressure and imposed flow. Lymphatics (diameter approximately 460 microm) were isolated, cannulated, and pressurized. Lymphatic diameters were traced from video records; the lymphatic tone index, contraction amplitude and frequency, lymphatic pump indices were calculated. Increasing transmural pressure from 3 to 6 cm H2O produced a strong inotropic response, but did not induce a significant chronotropic response. Pumping reached its maximum at transmural pressures 6-9 cm H2O and was not significantly depressed up to 15 cm H2O, whereas pumping in postnodal lymphatics is typically depressed at transmural pressures higher than 10 cm H2O. Bovine prenodal mesenteric lymphatics also demonstrated very low sensitivity to the increases in imposed flow. CONCLUSIONS: We concluded that the functional heterogeneity exists on the intraregional levels in lymphatic nets.     

Transforming growth factor-beta and platelet-derived growth factor synergistically stimulate contraction by testicular peritubular cells in culture in serum-free medium

We report investigations on factors influencing contractility by testicular peritubular cells (PC) maintained in culture in a three-dimensional collagen gel system, and the behavior of PC in culture on a two-dimensional system. At low and moderate cell densities, PC embedded in collagen gels in serum-free Eagle's minimal essential medium (MEM) have a lesser degree of contractility than PC in culture in MEM containing calf serum. The contractility by PC, measured by determining changes in diameter of the collagen gel, was increased by addition of transforming growth factor-beta (TGF-beta) to serum-free MEM, and this was further enhanced by supplementing the medium with platelet-derived growth factor (PDGF). In the absence of TGF-beta, however, PDGF had no detectable effects on PC contractility. Other growth factors examined (epidermal growth factor, insulin, and fibroblast growth factor) did not influence the degree of contractility of PC in serum-free MEM in the presence or absence of TGF-beta. PC maintained in MEM supplemented with platelet-poor serum (PPS) have a lesser degree of contractility than their counterparts in MEM containing 2.5% calf serum. The addition of TGF-beta and PDGF to PPS-supplemented MEM restored contractility by PC to a level comparable to that observed by PC in MEM containing complete serum. The addition of nonpurified bovine serum albumin (BSA) to MEM greatly increased PC contractility. By contrast, highly purified BSA had no such effect, suggesting that one or more components adsorbed to the impure BSA was implicated. Polyclonal antibody against fibronectin did not influence the contractility of PC in collagen gels in the presence or absence of serum. Antiserum against TGF-beta partially blocked the enhancement of contractility of PC in MEM containing non-purified BSA. In PC plated on top of a collagen gel lattice, the attachment, spreading, and cell shape were greatly influenced by the presence of TGF-beta and PDGF, both singly and together. Data presented are interpreted to indicate that effects elicited by serum on the properties of PC in culture, and on the contractility of PC, can be attributed in part to the combined influences of TGF-beta and PDGF in serum.     

Comparative studies on effects of estrogens and progesterone on the contractility of isolated uterine horns of rats

The effect of estrogens on the myometrial contractility of 70 isolated uterine horns of rats was investigated; 40 of the rats had been treated with progesterone and 30 with estrogen. Contractions were recorded isotonically in solutions with extracellular potassium concentration of 2.5 to 40 mM. The contractility of the myometrium of rats treated with estrogens was observed to be similar to the optimum contractility during labor, with the characteristic high amplitude of tension, low initial tension, and good coordination of contractions. The contractility of the uterine horns treated with progesterone was almost 1/2 lower and showed worse coordination of contractions. The difference between progesterone and estrogen is expressed through the quantitatively and qualitatively different influences on the motor function of the uterus.