Remote ischaemic conditioning: defining critical criteria for success-report from the 11th Hatter Cardiovascular Workshop.

The Hatter Cardiovascular Institute biennial workshop, originally scheduled for April 2020 but postponed for 2 years due to the Covid pandemic, was organised to debate and discuss the future of Remote Ischaemic Conditioning (RIC). This evolved from the large multicentre CONDI-2-ERIC-PPCI outcome study which demonstrated no additional benefit when using RIC in the setting of ST-elevation myocardial infarction (STEMI). The workshop discussed how conditioning has led to a significant and fundamental understanding of the mechanisms preventing cell death following ischaemia and reperfusion, and the key target cyto-protective pathways recruited by protective interventions, such as RIC. However, the obvious need to translate this protection to the clinical setting has not materialised largely due to the disconnect between preclinical and clinical studies. Discussion points included how to adapt preclinical animal studies to mirror the patient presenting with an acute myocardial infarction, as well as how to refine patient selection in clinical studies to account for co-morbidities and ongoing therapy. These latter scenarios can modify cytoprotective signalling and need to be taken into account to allow for a more robust outcome when powered appropriately. The workshop also discussed the potential for RIC in other disease settings including ischaemic stroke, cardio-oncology and COVID-19. The workshop, therefore, put forward specific classifications which could help identify so-called responders vs. non-responders in both the preclinical and clinical settings.

A simulation study of CS2 solutions in two related ionic liquids with dications and monocations.

Atomistic simulations of solutions of CS2 in an ionic liquid, [ C 8 ( C 1 im ) 2 ] [ NTf 2 ] 2 , with a divalent cation and in the corresponding ionic liquid with a monovalent cation, [C4C1im][NTf2], were carried out. The low-frequency librational density of states of the CS2 was of particular interest in view of recent optical heterodyne-detected Raman-induced Kerr effect spectroscopy (OHD-RIKES). Compared to the monocation ionic liquid, the maximum shifts to higher frequencies in the dication ionic liquid under ambient conditions, but was found to be significantly pressure-dependent. CS2 molecules lie above and below the plane of the imidazolium rings and found to be close to the butyl tails of the monocation. The diffusion rates and embedding energies of solvent ions and CS2 in the two ionic liquids were measured.

Molecular dynamics simulation of the behaviour of water in nano-confined ionic liquid-water mixtures.

This work describes the behaviour of water molecules in 1-butyl-3-methylimidazolium tetrafluoroborate ionic liquid under nanoconfinement, between graphene sheets. By means of molecular dynamics simulations, the adsorption of water molecules at the graphene surface is studied. A depletion of water molecules in the vicinity of the neutral and negatively charged graphene surfaces, and their adsorption at the positively charged surface are observed in line with the preferential hydration of the ionic liquid anions. The findings are appropriately described using a two-level statistical model. The confinement effect on the structure and dynamics of the mixtures is thoroughly analyzed using the density and the potential of mean force profiles, as well as by the vibrational densities of the states of water molecules near the graphene surface. The orientation of water molecules and the water-induced structural transitions in the layer closest to the graphene surface are also discussed.

9th Hatter Biannual Meeting: position document on ischaemia/reperfusion injury, conditioning and the ten commandments of cardioprotection.

In the 30 years since the original description of ischaemic preconditioning, understanding of the pathophysiology of ischaemia/reperfusion injury and concepts of cardioprotection have been revolutionised. In the same period of time, management of patients with coronary artery disease has also been transformed: coronary artery and valve surgery are now deemed routine with generally excellent outcomes, and the management of acute coronary syndromes has seen decade on decade reductions in cardiovascular mortality. Nonetheless, despite these improvements, cardiovascular disease and ischaemic heart disease in particular, remain the leading cause of death and a significant cause of long-term morbidity (with a concomitant increase in the incidence of heart failure) worldwide. The need for effective cardioprotective strategies has never been so pressing. However, despite unequivocal evidence of the existence of ischaemia/reperfusion in animal models providing a robust rationale for study in man, recent phase 3 clinical trials studying a variety of cardioprotective strategies in cardiac surgery and acute ST-elevation myocardial infarction have provided mixed results. The investigators meeting at the Hatter Cardiovascular Institute workshop describe the challenge of translating strong pre-clinical data into effective clinical intervention strategies in patients in whom effective medical therapy is already altering the pathophysiology of ischaemia/reperfusion injury-and lay out a clearly defined framework for future basic and clinical research to improve the chances of successful translation of strong pre-clinical interventions in man.

Predicting cavity formation free energy: how far is the Gaussian approximation valid?

We examine the range of validity of the Gaussian model for various water-like liquids whose intermolecular potentials differ from SPC/E water, to provide insight into the temperature dependence of the hydrophobic effect for small hard sphere solutes. We find that low compressibility liquids that have more close-packed network structures show much larger deviations from Gaussian fluctuations for low or zero occupancies relative to more compressible fluids with more open networks. Water appears to be a unique molecular fluid in possessing equilibrium density fluctuations that are faithfully described by the Gaussian theory. We ascribe this success to the fact, shown here, that the orientational correlations near a small hard sphere solute involve remarkably little reorganization from the bulk, which is a consequence of water's low solvent reorganization enthalpy and entropy.

Probing the neutral graphene-ionic liquid interface: insights from molecular dynamics simulations.

We study basic mechanisms of the interfacial layer formation at the neutral graphite monolayer (graphene)-ionic liquid (1,3-dimethylimidazolium chloride, [dmim][Cl]) interface by fully atomistic molecular dynamics simulations. We probe the interface area by a spherical probe varying the charge (-1e, 0, +1e) as well as the size of the probe (diameter 0.50 nm and 0.38 nm). The molecular modelling results suggest that: there is a significant enrichment of ionic liquid cations at the surface. This cationic layer attracts Cl(-) anions that leads to the formation of several distinct ionic liquid layers at the surface. There is strong asymmetry in cationic/anionic probe interactions with the graphene wall due to the preferential adsorption of the ionic liquid cations at the graphene surface. The high density of ionic liquid cations at the interface adds an additional high energy barrier for the cationic probe to come to the wall compared to the anionic probe. Qualitatively the results from probes with diameter 0.50 nm and 0.38 nm are similar although the smaller probe can approach closer to the wall. We discuss the simulation results in light of available experimental data on the interfacial structure in ionic liquids.

Electrode screening by ionic liquids.

In this work we are concerned with the short-range screening provided by the ionic liquid dimethylimidazolium chloride near a charged wall. We study the free energy profiles (or potentials of mean force) for charged and neutral solutes as a function of distance from a charged wall. Four different wall charge densities are used in addition to a wall with zero charge. The highest magnitude of the charge densities is ±1 e nm(-2) which is close to the maximum limit of charge densities accessible in experiments, while the intermediate charges ±0.5 e nm(-2) are in the range of densities typically used in most of the experimental studies. Positively and negatively charged solutes of approximately the size of a BF ion and a Cl(-) ion are used as probes. We find that the ionic liquid provides excellent electrostatic screening at a distance of 1-2 nm. The free energy profiles show minima which are due to layering in the ionic liquid near the electrodes. This indicates that the solute ions tend to displace ionic liquid ions in the layers when approaching the electrode. The important role of non-electrostatic forces is demonstrated by the oscillations in the free energy profiles of uncharged solutes as a function of distance from the wall.

Hydrogen bond strength and network structure effects on hydration of non-polar molecules.

We measure the solvation free energy, Δµ*, for hard spheres and Lennard-Jones particles in a number of artificial liquids made from modified water models. These liquids have reduced hydrogen bond strengths or altered bond angles. By measuring Δµ* for a number of state points at P = 1 bar and different temperatures, we obtain solvation entropies and enthalpies, which are related to the temperature dependence of the solubilities. By resolving the solvation entropy into the sum of the direct solute-solvent interaction and a term depending on the solvent reorganisation enthalpy we show that, although the hydrophobic effect in water at 300 K arises mainly from the small molecular size, its temperature dependence is anomalously low because the reorganisation enthalpy of liquid water is unusually small. We attribute this to the strong tetrahedral network which results from both the molecular geometry and the hydrogen bond strength.

Screening of pairs of ions dissolved in ionic liquids.

The properties of pairs of solute ions in the ionic liquid, dimethylimidazolium chloride or [dmim][Cl], are studied as a function of their separation. The potential of mean force curves show that there is only a small stabilisation of ion pairs with opposite charges followed by a barrier to separation. Ion pairs with the same charge are also stabilised by solvent screening due to induced polarisation of the solvent. In both cases screening is essentially complete outside the first shell, but is large even when there is no solvent between the ions. Charge distributions in the solvation shells around ion pairs are shown and the results interpreted with the aid of a simple model of two ions in an spheroidal cavity in a conducting medium. The actual or Madelung potential experienced by the second solute ion is found to decay rapidly with distance and does not show the oscillations found in the Poisson potential around a single solute ion. We conclude that ionic liquids provide very effective electrostatic screening between solute molecules.

Towards understanding water: simulation of modified water models.

The unusual properties of liquid water have been attributed to factors including hydrogen bonds, the presence of a local tetrahedral network, or the high number density. Most of the properties of water can be reproduced in simulations using simple potential models with site-site pairwise interactions. Although in real water the factors listed above cannot be separated, one may construct liquids from modified water models ('not-waters') in which these factors are altered independently in a controlled way. With various collaborators we have studied the changes in liquid properties, anomalies and solvation which result from various modifications.

Simulations of imidazolium ionic liquids: when does the cation charge distribution matter?

We compare the properties of models of liquids and crystals constructed from a number of intermolecular potentials for dimethylimidazolium chloride [dmim][Cl]. The force fields differ in the charge distribution in the cation but all include short range interactions which determine the shape of the cation. In addition to 'realistic' models intended for simulation of [dmim][Cl] we take two extreme 'unrealistic' models in which the cation charge is localized on the ring atoms or at the ring centre in order to study the effects of the cation charge distribution. The effects of polarizability are investigated by using shell models for the chloride ion. We find that, while equilibrium properties such as energetics, crystal structure, liquid structure and charge screening depend on the charge distribution in the cation but are little affected by including polarizability, dynamical properties such as diffusion are strongly affected by polarizability.

Redox potentials and screening in ionic liquids: effects of sizes and shapes of solute ions.

Simulations of a model ionic liquid, [dmim][PF(6)] (dimethylimidazolium hexafluorophosphate), containing solute ions of different sizes and shapes have been used to investigate the changes in redox potentials of and screening around solute ions of different sizes and shapes. The effective solute size of spherical ions increases with the actual solute size although more slowly than expected. The effective solute size of tetrahedral or square planar ions varies little with actual ligand size. These results are clarified by reference to the charge density in the solvent around the ions, which is also used to calculate the potential within the solvent. Screening is essentially complete within 1 nm of the solute ion although charge density oscillations propagate further into the liquid. The results are compared to theoretical models and the implications for experiments are discussed.

Can marcus theory be applied to redox processes in ionic liquids? A comparative simulation study of dimethylimidazolium liquids and acetonitrile.

Simulations of a model system of charged spherical ions in the ionic liquids dimethylimidazolium chloride, [dmim][Cl], dimethylimidazolium hexafluorophosphate, [dmim][PF6], and the polar liquid acetonitrile, MeCN, are used to investigate the applicability of Marcus theory to electrochemical half-cell redox processes in these liquids. The free energy curves for solvent fluctuations are found to be approximately parabolic and the Marcus solvent reorganization free energies and activation free energies are determined for six possible redox processes in each solvent. The similarities between the different types of solvent are striking and are attributed to the essentially long-range nature of the relevant interactions and the effectiveness of the screening of the ion potential. Nevertheless, molecular effects are seen in the variation of solvent screening potential with distances up to 2 nm.

Polarization relaxation in an ionic liquid confined between electrified walls.

The response of a room temperature molten salt to an external electric field when it is confined to a nanoslit is studied by molecular dynamics simulations. The fluid is confined between two parallel and oppositely charged walls, emulating two electrified solid-liquid interfaces. Attention is focused on structural, electrostatic, and dynamical properties, which are compared with those of the nonpolarized fluid. It is found that the relaxation of the electrostatic potential, after switching the electric field off, occurs in two stages. A first, subpicosecond process accounts for 80% of the decay and is followed by a second subdiffusive process with a time constant of 8 ps. Diffusion is not involved in the relaxation, which is mostly driven by small anion translations. The relaxation of the polarization in the confined system is discussed in terms of the spectrum of charge density fluctuations in the bulk.

The surface structure of ionic liquids: comparing simulations with x-ray measurements.

The surface-normal electron density profile of an ionic liquid, [bmim][PF6], derived from x-ray reflectivity measurements, is compared with two independent molecular-dynamics simulations. It is shown that a meaningful comparison requires a detailed accounting for both thermal and nonthermal surface roughening effects. The former is due to thermally excited capillary waves, and the latter is due to the molecular zero-point motion and form. These quantities influence very significantly, but differently, the simulated and measured density profiles. Stripping off these effects from both types of profiles yields the intrinsic structure factor of the surface. The simulated intrinsic structure factors are found to deviate considerably from the measured one. The introduction of additional ad hoc surface roughness to the simulated profiles greatly reduces the deviation, however, no physical origin for this effect can be identified. The method employed in this study should prove useful for simulation-experiment comparisons of other liquid surfaces, provided they obey capillary-wave theory, as do almost all liquid surfaces studied to date by x-ray reflectivity.

Simulation of the surface structure of butylmethylimidazolium ionic liquids.

Molecular dynamics simulations of the liquid/vacuum surfaces of the room temperature ionic liquids [bmim][PF(6)], [bmim][BF(4)] and [bmim][Cl] have been carried out at various temperatures. The surfaces are structured with a top monolayer containing oriented cations and anions. The butyl side chains tend to face the vacuum and the methyl side chains the liquid. However, as the butyl chains are not densely packed, both anions and rings are visible from the vacuum phase. The effects of temperature and the anion on the degree of cation orientation is small, but the potential drop from the vacuum to the interior of the liquid is greater for liquids with smaller anions. We compare the simulation results with a range of experimental observations and suggest that neutron reflection from samples with protiated butyl groups would be a sensitive probe of the structure.

Solvent-induced symmetry breaking: varying solvent strength.

The triiodide ion is an example of a system where symmetry breaking may be induced by a solvent. The Landau free energy is expected to have a similar form to that for the mean field Ising model, but with solvent strength rather than temperature as the control parameter determining whether there is symmetry breaking. In order to examine the extent of anomalous behavior near the critical point we have studied the properties of the ion in a solvent based on a model for water with charges scaled by a factor lambda . As lambda is increased from zero the solvent strength increases and the system changes from one with no symmetry breaking to one with strong symmetry breaking. The Shannon entropy as a function of lambda shows only a weak maximum near the critical value of lambda= lambda(c) , while the susceptibility has no anomalous behavior. We examine a simple model and show that anomalies near the critical point would increase as the temperature decreases, but divergences associated with a second order phase transition would only be seen in the limit of zero temperature.

Simulation of interfaces between room temperature ionic liquids and other liquids.

The structure and properties of the interfaces between the room temperature ionic liquid dimethylimidazolium chloride ([dmim]Cl) and different Lennard-Jones fluids and between ionic liquid and water have been studied by molecular dynamics simulations, and compared to the ionic liquid-vapour interface. Two contrasting types of interface were investigated, thermodynamically stable interfaces between ionic liquid and vapour and between ionic liquid and Lennard-Jones fluids, and diffusing interfaces between miscible phases of different compositions involving water. The density profiles of different species through the interface are presented. The cations and water molecules near the former type of interface are aligned relative to the surface, but no orientational preference was found near or in the broad diffusing interface. The ionic liquid has a negative electrostatic potential relative to vapour or Lennard-Jones fluid, but is more positive than pure water. This contrast is explained in terms of the relative importance of orientation and concentration differences in the two types of interface.

Computational investigation of order, structure, and dynamics in modified water models.

Model liquids have been constructed to study the role of local structure in the anomalous properties of liquid water. The intermolecular potentials were modified by increasing the weight of the Lennard-Jones term relative to the electrostatic term in the SPC/E model for water. The resulting family of liquids varies from SPC/E water to a Lennard-Jones-like liquid. Properties were measured as a function of density and temperature. The local structure was described by two order parameters, one measuring the tetrahedral order and the other measuring the translational order. The translational order parameter was found to be large for both tetrahedral and Lennard-Jones liquids, but to go through a minimum as the potentials were modified, demonstrating that the two types of structure are incompatible. Just as in water several properties (e.g., the translational diffusion coefficient, entropy) exhibit anomalous density dependence as a result of the breakdown of local tetrahedrality, we observed nonmonotonic behavior of the translational diffusion constant and reorientational relaxation rate as the fluids were transformed from tetrahedral to Lennard-Jones-like. This is also an indication of the incompatibility between Lennard-Jones and water-like structure.