Rodent models of heart failure: an updated review

Heart failure (HF) is one of the major health and economic burdens worldwide, and its prevalence is continuously increasing. The study of HF requires reliable animal models to study the chronic changes and pharmacologic interventions in myocardial structure and function and to follow its progression toward HF. Indeed, during the past 40 years, basic and translational scientists have used small animal models to understand the pathophysiology of HF and find more efficient ways of preventing and managing patients suffering from congestive HF (CHF). Each species and each animal model has advantages and disadvantages, and the choice of one model over another should take them into account for a good experimental design. The aim of this review is to describe and highlight the advantages and drawbacks of some commonly used HF rodents models, including both non-genetically and genetically engineered models, with a specific subchapter concerning diastolic HF models

Modulation of Myocardial Stiffness by beta-Adrenergic Stimulation Its Role in Normal and Failing Heart

The acute effects of ß-adrenergic stimulation on myocardial stiffness were evaluated. New-Zealand white rabbits were treated with saline (control group) or doxorubicin to induce heart failure (HF) (DOXO-HF group). Effects of isoprenaline (10 -10-1 -5 M), a non-selective ß-adrenergic agonist, were tested in papillary muscles from both groups. In the control group, the effects of isoprenaline were also evaluated in the presence of a damaged endocardial endothelium, atenolol (ßi-adrenoceptor antagonist), ICI-118551 (ßz-adrenoceptor antagonist), KT-5720 (PKA inhibitor), L-NNA (NO-synthase inhibitor), or indomethacin (cyclooxygenase inhibitor). Passive length-tension relations were constructed before and after adding isoprenaline (10 -5 M). In the control group, isoprenaline increased resting muscle length up to 1.017±0.006 L/L max. Correction of resting muscle length to its initial value resulted in a 28.5±3.1% decrease of resting tension, indicating decreased muscle stiffness, as confirmed by the isoprenaline-induced right-downward shift of the passive lengthtension relation. These effects were modulated by ßr and ß 2adrenoceptors and PKA. In DOXO-HF group, the effect on myocardial stiffness was significantly decreased. We conclude that ß-adrenergic stimulation is a relevant mechanism of acute neurohumoral modulation of the diastolic function. Furthermore, this study clarifies the mechanisms by which myocardial stiffness is decreased. (c) 2011 Institute of Physiology v.v.i., Academy of Sciences of the Czech Republic, Prague, Czech Republic

Measurement of the absolute reflectance of polytetrafluoroethylene (PTFE) immersed in liquid xenon

The performance of a detector using liquid xenon (LXe) as a scintillator is strongly dependent on the collection efficiency for xenon scintillation light, which in turn is critically dependent on the reflectance of the surfaces that surround the active volume. To improve the light collection in such detectors the active volume is usually surrounded by polytetrafluoroethylene (PTFE) reflector panels, used due to its very high reflectance—even at the short wavelength of scintillation light of LXe (peaked at 178 nm). In this work, which contributed to the overall R&D effort towards the LUX-ZEPLIN (LZ) experiment, we present experimental results for the absolute reflectance measurements of three different PTFE samples (including the material used in the LUX detector) immersed in LXe for its scintillation light. The obtained results show that very high bi-hemispherical reflectance values (≥ 97%) can be achieved, enabling very low energy thresholds in liquid xenon scintillator-based detectors.Peer Reviewe

Intraventricular Pressure Gradients in Heart Failure

The aim of the present study was to characterize intraventricular pressure gradients (IVPGs) in an animal model of chronic heart failure. New Zealand rabbits were treated with doxorubicin (heart failure group, n=5) or saline (control group, n=5) and instrumented with pressure catheters placed in the apex and outflow-tract of left ventricle (LV) and with sonomicrometer crystals placed in the apex and base of the LV free wall. In heart failure animals, ventricular filling was delayed and slower when compared with control animals. Moreover, the physiological nonuniformity observed between apical and basal segments in normal hearts was abolished in failing hearts. Simultaneously, physiological IVPGs observed during normal ventricular filling were entirely lost in heart failure animals. During ventricular emptying physiological nonuniformity between apical and basal segments observed in control animals was also abolished in heart failure animals. In failing hearts minimal length occurred later and almost at same time both in apical and in basal myocardial segments. Simultaneously, the characteristic IVPG pattern observed in healthy hearts during systole, which promotes ventricular emptying, was not observed in failing hearts. The present study showed that diastolic IVPGs, a marker of normal ventricular filling, and systolic IVPGs, a marker of normal ventricular emptying, are abolished in heart failure

Evaluation of allelic forms of the erythrocyte binding antigen 175 (EBA-175) in Plasmodium falciparum field isolates from Brazilian endemic area

<p>Abstract</p> <p>Background</p> <p>The <it>Plasmodium falciparum </it>Erythrocyte Binding Antigen-175 (EBA-175) is an antigen considered to be one of the leading malaria vaccine candidates. EBA-175 mediates sialic acid-dependent binding to glycophorin A on the erythrocytes playing a crucial role during invasion of the <it>P. falciparum </it>in the host cell. Dimorphic allele segments, termed C-fragment and F-fragment, have been found in high endemicity malaria areas and associations between the dimorphism and severe malaria have been described. In this study, the genetic dimorphism of EBA-175 was evaluated in <it>P. falciparum </it>field isolates from Brazilian malaria endemic area.</p> <p>Methods</p> <p>The study was carried out in rural villages situated near Porto Velho, Rondonia State in the Brazilian Amazon in three time points between 1993 and 2008. The allelic dimorphism of the EBA-175 was analysed by Nested PCR.</p> <p>Results</p> <p>The classical allelic dimorphism of the EBA-175 was identified in the studied area. Overall, C-fragment was amplified in a higher frequency than F-fragment. The same was observed in the three time points where C-fragment was observed in a higher frequency than F-fragment. Single infections (one fragment amplified) were more frequent than mixed infection (two fragments amplified).</p> <p>Conclusions</p> <p>These findings confirm the dimorphism of EBA175, since only the two types of fragments were amplified, C-fragment and F-fragment. Also, the results show the remarkable predominance of CAMP allele in the studied area. The comparative analysis in three time points indicates that the allelic dimorphism of the EBA-175 is stable over time.</p

The Val158Met COMT polymorphism is a modifier of the age at onset in Parkinson's disease with a sexual dimorphism

The catechol-O-methyltranferase (COMT) is one of the main enzymes that metabolise dopamine in the brain. The Val158Met polymorphism in the COMT gene (rs4680) causes a trimodal distribution of high (Val/Val), intermediate (Val/Met) and low (Met/Met) enzyme activity. We tested whether the Val158Met polymorphism is a modifier of the age at onset (AAO) in Parkinson's disease (PD). The rs4680 was genotyped in a total of 16 609 subjects from five independent cohorts of European and North American origin (5886 patients with PD and 10 723 healthy controls). The multivariate analysis for comparing PD and control groups was based on a stepwise logistic regression, with gender, age and cohort origin included in the initial model. The multivariate analysis of the AAO was a mixed linear model, with COMT genotype and gender considered as fixed effects and cohort and cohort-gender interaction as random effects. COMT genotype was coded as a quantitative variable, assuming a codominant genetic effect. The distribution of the COMT polymorphism was not significantly different in patients and controls (p=0.22). The Val allele had a significant effect on the AAO with a younger AAO in patients with the Val/Val (57.1±13.9, p=0.03) than the Val/Met (57.4±13.9) and the Met/Met genotypes (58.3±13.5). The difference was greater in men (1.9 years between Val/Val and Met/Met, p=0.007) than in women (0.2 years, p=0.81). Thus, the Val158Met COMT polymorphism is not associated with PD in the Caucasian population but acts as a modifier of the AAO in PD with a sexual dimorphism: the Val allele is associated with a younger AAO in men with idiopathic PD

The thromboxane receptor antagonist NTP42 promotes beneficial adaptation and preserves cardiac function in experimental models of right heart overload

Background: Pulmonary arterial hypertension (PAH) is a progressive disease characterized by increased pulmonary artery pressure leading to right ventricular (RV) failure. While current PAH therapies improve patient outlook, they show limited benefit in attenuating RV dysfunction. Recent investigations demonstrated that the thromboxane (TX) A2 receptor (TP) antagonist NTP42 attenuates experimental PAH across key hemodynamic parameters in the lungs and heart. This study aimed to validate the efficacy of NTP42:KVA4, a novel oral formulation of NTP42 in clinical development, in preclinical models of PAH while also, critically, investigating its direct effects on RV dysfunction. Methods: The effects of NTP42:KVA4 were evaluated in the monocrotaline (MCT) and pulmonary artery banding (PAB) models of PAH and RV dysfunction, respectively, and when compared with leading standard-of-care (SOC) PAH drugs. In addition, the expression of the TP, the target for NTP42, was investigated in cardiac tissue from several other related disease models, and from subjects with PAH and dilated cardiomyopathy (DCM). Results: In the MCT-PAH model, NTP42:KVA4 alleviated disease-induced changes in cardiopulmonary hemodynamics, pulmonary vascular remodeling, inflammation, and fibrosis, to a similar or greater extent than the PAH SOCs tested. In the PAB model, NTP42:KVA4 improved RV geometries and contractility, normalized RV stiffness, and significantly increased RV ejection fraction. In both models, NTP42:KVA4 promoted beneficial RV adaptation, decreasing cellular hypertrophy, and increasing vascularization. Notably, elevated expression of the TP target was observed both in RV tissue from these and related disease models, and in clinical RV specimens of PAH and DCM. Conclusion: This study shows that, through antagonism of TP signaling, NTP42:KVA4 attenuates experimental PAH pathophysiology, not only alleviating pulmonary pathologies but also reducing RV remodeling, promoting beneficial hypertrophy, and improving cardiac function. The findings suggest a direct cardioprotective effect for NTP42:KVA4, and its potential to be a disease-modifying therapy in PAH and other cardiac conditions

An effective field theory analysis of the first LUX dark matter search

The Large Underground Xenon (LUX) dark matter search was a 250-kg active mass dual-phase time projection chamber that operated by detecting light and ionization signals from particles incident on a xenon target. In December 2015, LUX reported a minimum 90% upper C.L. of 6e-46 cm^2 on the spin-independent WIMP-nucleon elastic scattering cross section based on a 1.4e4 kg*day exposure in its first science run. Tension between experiments and the absence of a definitive positive detection suggest it would be prudent to search for WIMPs outside the standard spin-independent/spin-dependent paradigm. Recent theoretical work has identified a complete basis of 14 independent effective field theory (EFT) operators to describe WIMP-nucleon interactions. In addition to spin-independent and spin-dependent nuclear responses, these operators can produce novel responses such as angular-momentum-dependent and spin-orbit couplings. Here we report on a search for all 14 of these EFT couplings with data from LUX's first science run. Limits are placed on each coupling as a function of WIMP mass

Search for two neutrino double electron capture of ¹²⁴Xe and ¹²⁶Xe in the full exposure of the LUX detector

Two-neutrino double electron capture is a process allowed in the standard model of particle physics. This rare decay has been observed in 78Kr, 130Ba and more recently in 124Xe. In this publication we report on the search for this process in 124Xe and 126Xe using the full exposure of the large underground xenon (LUX) experiment, in a total of 27769.5 kg-days. No evidence of a signal was observed, allowing us to set 90% C.L. lower limits for the half-lives of these decays of 2.0 × 1021 years for 124Xe and 1.9 × 1021 years for 126Xe

Improved measurements of the β-decay response of liquid xenon with the LUX detector

We report results from an extensive set of measurements of the β-decay response in liquid xenon. These measurements are derived from high-statistics calibration data from injected sources of both 3H and 14C in the LUX detector. The mean light-to-charge ratio is reported for 13 electric field values ranging from 43to491~V/cm, and for energies ranging from 1.5to145~keV