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A four-year field experiment was carried out to study the effects of different N levels on yield, yield components, N uptake and seed quality of sunflower genotypes grown in semiarid Mediterranean conditions. Five genotypes (four commercial hybrids and one newly selected genotype) and three N fertilization levels (0, 50 and 100 kg N ha-1) were compared over four years (1996, 1997, 1998 and 1999). Sunflower plants were taken at flowering time and their dry weight, leaf area index and total N content were determined. At maturity stage, yield, yield components, oil content, protein content, N uptake and seed quality were determined. The obtained results indicated significant differences in yield performance (seed, oil and protein production) throughout the years (from 2.52 t ha-1 in 1996 to 3.81 in 1999), confirming the need to use recommended genotypes and adjust fertilizer rates to crops requirements, especially in the Mediterranean environment where weather conditions are unpredictable and inconsistent. In fact, the genotypes showed different behavior in all years regarding total N uptake, seed, oil and protein production, indicating that the sunflower crop is responsive to agronomic management. The highest level of N fertilizer resulted in the best sunflower performance although, due to variations in year and genotype, fertilizer N could be applied according to total annual N uptake. Finally, the N uptake and the diameter of head were the most important parameters that influenced sunflower yield performance. [ABSTRACT FROM AUTHOR]

A four-year field experiment was carried out to study the effects of different N levels on yield, yield components, N uptake and seed quality of sunflower genotypes grown in semiarid Mediterranean conditions. Five genotypes (four commercial hybrids and one newly selected genotype) and three N fertilization levels (0, 50 and 100 kg N ha-1) were compared over four years (1996, 1997, 1998 and 1999). Sunflower plants were taken at flowering time and their dry weight, leaf area index and total N content were determined. At maturity stage, yield, yield components, oil content, protein content, N uptake and seed quality were determined. The obtained results indicated significant differences in yield performance (seed, oil and protein production) throughout the years (from 2.52 t ha-1 in 1996 to 3.81 in 1999), confirming the need to use recommended genotypes and adjust fertilizer rates to crops requirements, especially in the Mediterranean environment where weather conditions are unpredictable and inconsistent. In fact, the genotypes showed different behavior in all years regarding total N uptake, seed, oil and protein production, indicating that the sunflower crop is responsive to agronomic management. The highest level of N fertilizer resulted in the best sunflower performance although, due to variations in year and genotype, fertilizer N could be applied according to total annual N uptake. Finally, the N uptake and the diameter of head were the most important parameters that influenced sunflower yield performance. [ABSTRACT FROM AUTHOR]

Research was carried out in 2002-2003 on the quantitative, carpological and qualitative characteristics of 52 almond cultivars (Prunus amygdalus Batsch) from the Apulia region of Italy, part of the extensive almond germplasm collection of the Agronomic Experimental Institute of Ban. For each cultivar, the following parameters were taken into account: kernel yield, shelling percentage, number of double kernels, weight of almond nut and kernel, total lipid content, and α-tocopherol content. The most productive cultivar was found to be 'Barlettana', with just over 2 kg of kernels per tree, followed in order of productivity by 'Cristomorto', 'Santoro', 'Catuccia', 'Filippo Ceo', 'Piangente', and 'Pidocchioso'.The most productive ecotypes showed both a notable kernel weight and a high percentage of double kernels, but there were exceptions (e.g., 'Santoro' and 'Pidocchiosa' showed a low percentage of double kernels). The almond cultivars studied here had high total lipid contents, ranging from 633 mg g-1 kernel fresh weight (FW) for 'Filippo Ceo', to 450 mg g-1 FW for 'Cosimo di Ban' and 'Gioa'. The α-tocopherol content was the parameter with the highest coefficient of variability and was the most important factor when classifying cultivars into groups with the greatest similarities. The highest α-tocopherol contents were found in 'Senz'arte', 'Pizzuta D'Avola' and 'Rachele', which also had the lowest productivity in the period under study. 'Santoro' showed the best combined results across all factors under consideration. Principal component analysis and discriminant analysis between the different parameters were performed. [ABSTRACT FROM AUTHOR]

Cardiac arrest (CA) is one of the leading causes of death worldwide. Due to hypoxic ischemic brain injury, CA survivors may experience variable degrees of neurological dysfunction. This study, for the first time, describes the progression of CA-induced neuropathology in the rat. CA rats displayed neurological and exploratory deficits. Brain MRI revealed cortical and striatal edema at 3 days (d), white matter (WM) damage in corpus callosum (CC), external capsule (EC), internal capsule (IC) at d7 and d14. At d3 a brain edema significantly correlated with neurological score. Parallel neuropathological studies showed neurodegeneration, reduced neuronal density in CA1 and hilus of hippocampus at d7 and d14, with cells dying at d3 in hilus. Microgliosis increased in cortex (Cx), caudate putamen (Cpu), CA1, CC, and EC up to d14. Astrogliosis increased earlier (d3 to d7) in Cx, Cpu, CC and EC compared to CA1 (d7 to d14). Plasma levels of neurofilament light (NfL) increased at d3 and remained elevated up to d14. NfL levels at d7 correlated with WM damage. The study shows the consequences up to 14d after CA in rats, introducing clinically relevant parameters such as advanced neuroimaging and blood biomarker useful to test therapeutic interventions in this model., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Cardiopulmonary resuscitation-associated lung edema (CRALE) is a phenomenon that has been recently reported in both experimental and out-of-hospital cardiac arrest patients. We aimed to explore the respiratory and cardiovascular pathophysiology of CRALE in an experimental model of cardiac arrest undergoing prolonged manual and mechanical chest compression (CC). Oxygen delivery achieved during mechanical or manual CC were also investigated as a secondary aim, to describe CRALE evolution under different hemodynamic supports generated during CPR., Methods: Ventricular fibrillation (VF) was induced and left untreated for 5 min prior to begin cardiopulmonary resuscitation (CPR), including CC, ventilation with oxygen, epinephrine administration and defibrillation. Continuous mechanical and manual CC was performed alternating one of the two strategies every 5 min for a total of 25 min. Unsynchronized mechanical ventilation was resumed simultaneously to CC. A lung computed tomography (CT) was performed at baseline and 1 h after return of spontaneous circulation (ROSC) in surviving animals. Partitioned respiratory mechanics, gas exchange, hemodynamics, and oxygen delivery were evaluated during the experimental study at different timepoints. Lung histopathology was performed., Results: After 25 min of CPR, a marked decrease of the respiratory system compliance with reduced oxygenation and CO 2 elimination were observed in all animals. The worsening of the respiratory system compliance was driven by a significant decrease in lung compliance. The presence of CRALE was confirmed by an increased lung weight and a reduced lung aeration at the lung CT, together with a high lung wet-to-dry ratio and reduced airspace at histology. The average change in esophageal pressure during the 25-min CPR highly correlated with the severity of CRALE, i.e., lung weight increase., Conclusions: In this porcine model of cardiac arrest followed by a 25-min interval of CPR with mechanical and manual CC, CRALE was consistently present and was characterized by lung inhomogeneity with alveolar tissue and hemorrhage replacing alveolar airspace. Despite mechanical CPR is associated with a more severe CRALE, the higher cardiac output generated by the mechanical compression ultimately accounted for a greater oxygen delivery. Whether specific ventilation strategies might prevent CRALE while preserving hemodynamics remains to be proved., (© 2024. The Author(s).)

Background: Argon (Ar) has been proposed as a potential therapeutic agent in multiple clinical conditions, specifically in organ protection. However, conflicting data on pre-clinical models, together with a great variability in Ar administration protocols and outcome assessments, have been reported. The aim of this study was to review evidence on treatment with Ar, with an extensive investigation on its neuroprotective effect, and to summarise all tested administration protocols., Methods: Using the PubMed database, all existing pre-clinical and clinical studies on the treatment with Ar were systematically reviewed (registration: https://doi.org/10.17605/OSF.IO/7983D). Study titles and abstracts were screened, extracting data from relevant studies post full-text review. Exclusion criteria included absence of full text and non-English language. Furthermore, meta-analysis was also performed to assess Ar potential as neuroprotectant agent in different clinical conditions: cardiac arrest, traumatic brain injury, ischemic stroke, perinatal hypoxic-ischemic encephalopathy, subarachnoid haemorrhage. Standardised mean differences for neurological, cognitive and locomotor, histological, and physiological measures were evaluated, through appropriate tests, clinical, and laboratory variables. In vivo studies were evaluated for risk of bias using the Systematic Review Center for Laboratory Animal Experimentation tool, while in vitro studies underwent assessment with a tool developed by the Office of Health Assessment and Translation., Findings: The systematic review detected 60 experimental studies (16 in vitro, 7 ex vivo, 31 in vivo, 6 with both in vitro and in vivo) investigating the role of Ar. Only one clinical study was found. Data from six in vitro and nineteen in vivo studies were included in the meta-analyses. In pre-clinical models, Ar administration resulted in improved neurological, cognitive and locomotor, and histological outcomes without any change in physiological parameters (i.e., absence of adverse events)., Interpretation: This systematic review and meta-analysis based on experimental studies supports the neuroprotective effect of Ar, thus providing a rationale for potential translation of Ar treatment in humans. Despite adherence to established guidelines and methodologies, limitations in data availability prevented further analyses to investigate potential sources of heterogeneity due to study design., Funding: This study was funded in part by Italian Ministry of Health-Current researchIRCCS and by Ministero della Salute Italiano, Ricerca Finalizzata, project no. RF 2019-12371416., Competing Interests: Declaration of interests G.G received funding from Fischer&Paykel, MSD, Pfizer, and received fees from Getinge, Draeger Medical, Cook, MundiPharma, Fischer&Paykel, Pfizer. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Aims: There is little information from experimental studies regarding the evolution of post-resuscitation cardiac arrest [post-return of spontaneous circulation (post-ROSC)] myocardial dysfunction during mid-term follow-up. For this purpose, we assessed left ventricular (LV) function and circulating cardiac biomarkers at different time points in a rat model of cardiac arrest (CA)., Methods and Results: Rats were divided into two groups: control and post-ROSC rats. Eight minutes of untreated ventricular fibrillation were followed by 8 min of cardiopulmonary resuscitation. Conventional and speckle-tracking echocardiographic (STE) parameters and cardiac circulating biomarkers concentrations were assessed, at 3, 4, 72, and 96 h post-ROSC. At 3 and 4 h post-ROSC, LV systolic function was severely impaired, and high-sensitivity cardiac troponin T and N-terminal pro-atrial natriuretic peptide (NT-proANP) plasma concentrations were significantly increased, compared with control rats ( P < 0.0001 for all). At 72 and 96 h post-ROSC, LV ejection fraction (LVEF) normalized. At 96 h, the following variables were significantly different from control rats: early trans-mitral peak velocity, 56.8 ± 3.1 vs. 87.8 ± 3.8 cm/s, P < 0.0001; late trans-mitral peak velocity, 50.6 ± 4.7 vs. 73.7 ± 4.2 cm/s, P < 0.0001; mean s' wave velocity, 4.6 ± 0.3 vs. 5.9 ± 0.3 cm/s, P < 0.0001, global longitudinal strain (GLS) -7.5 ± 0.5 and vs. -11 ± 1.2%, P < 0.01; GLS rate (GLSR) -0.9 ± 0.4 and -2.3 ± 0.2 1/s, P < 0.01; and NT-proANP concentration, 2.5 (0.2; 6.0) vs. 0.4 (0.01; 1.0) nmol/L, P < 0.01., Conclusion: s' velocity, GLS, and GLSR indicated that LV systolic function was still impaired 96 h post-ROSC. These findings agree with NT-proANP concentrations, which continue to be high. Normalization of LVEF supports the use of STE for its greater sensitivity for monitoring post-CA cardiac function. Further investigations are needed to provide evidence of the post-ROSC LV diastolic function pattern., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Duchenne muscular dystrophy (DMD) is the most common form of muscle degenerative hereditary disease. Muscular replacement by fibrosis and calcification are the principal causes of progressive and severe musculoskeletal, respiratory, and cardiac dysfunction. To date, the D2.B10- Dmd mdx /J (D2- mdx ) model is proposed as the closest to DMD, but the results are controversial. In this study, the cardiac structure and function was characterized in D2- mdx mice from 16-17 up to 24-25 weeks of age. Echocardiographic assessment in conscious mice, gross pathology, and histological and cardiac biomarker analyses were performed. At 16-17 weeks of age, D2- mdx mice presented mild left ventricular function impairment and increased pulmonary vascular resistance. Cardiac fibrosis was more extended in the right ventricle, principally on the epicardium. In 24-25-week-old D2- mdx mice, functional and structural alterations increased but with large individual variation. High-sensitivity cardiac Troponin T, but not N-terminal pro-atrial natriuretic peptide, plasma levels were increased. In conclusion, left ventricle remodeling was mild to moderate in both young and adult mice. We confirmed that right ventricle epicardial fibrosis is the most outstanding finding in D2- mdx mice. Further long-term studies are needed to evaluate whether this mouse model can also be considered a model of DMD cardiomyopathy.

Aims: Viral myocarditis (VM) is an inflammatory pathology of the myocardium triggered by a viral infection that may cause sudden death or heart failure (HF), especially in the younger population. Current treatments only stabilize and improve cardiac function without resolving the underlying inflammatory cause. The factors that induce VM to progress to HF are still uncertain, but neutrophils have been increasingly associated with the negative evolution of cardiac pathologies. The present study investigates the contribution of neutrophils to VM disease progression in different ways., Methods and Results: In a coxsackievirus B3- (CVB3) induced mouse model of VM, neutrophils and neutrophil extracellular traps (NETs) were prominent in the acute phase of VM as revealed by enzyme-linked immunosorbent assay analysis and immunostaining. Anti-Ly6G-mediated neutrophil blockade starting at model induction decreased cardiac necrosis and leucocyte infiltration, preventing monocyte and Ly6CHigh pro-inflammatory macrophage recruitment. Furthermore, genetic peptidylarginine deiminase 4-dependent NET blockade reduced cardiac damage and leucocyte recruitment, significantly decreasing cardiac monocyte and macrophage presence. Depleting neutrophils with anti-Ly6G antibodies at 7 days post-infection, after the acute phase, did not decrease cardiac inflammation., Conclusion: Collectively, these results indicate that the repression of neutrophils and the related NET response in the acute phase of VM improves the pathological phenotype by reducing cardiac inflammation., Competing Interests: Conflict of interest: S.H. receives personal fees for scientific advice to Astra-Zeneca, Cellprothera, CSL Behring, and Merck; unrestricted research grant from Pfizer. K.M. has received consulting fees for scientific advice to PEEL Therapeutics. All the remaining authors, P.C., L.F.G., S.V.B., V.S., D.D.G., N.G., and E.A.V.J., declare no competing interests., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Purpose: Available animal models of acute heart failure (AHF) and their limitations are discussed herein. A novel and preclinically relevant porcine model of decompensated AHF (ADHF) is then presented., Methods: Myocardial infarction (MI) was induced by occlusion of left anterior descending coronary artery in 17 male pigs (34 ± 4 kg). Two weeks later, ADHF was induced in the survived animals (n = 15) by occlusion of the circumflex coronary artery, associated with acute volume overload and increases in arterial blood pressure by vasoconstrictor infusion. After onset of ADHF, animals received 48-h iv infusion of either serelaxin (n = 9) or placebo (n = 6). The pathophysiology and progression of ADHF were described by combining evaluation of hemodynamics, echocardiography, bioimpedance, blood gasses, circulating biomarkers, and histology., Results: During ADHF, animals showed reduced left ventricle (LV) ejection fraction < 30%, increased thoracic fluid content > 35%, pulmonary edema, and high pulmonary capillary wedge pressure ~ 30 mmHg (p < 0.01 vs. baseline). Other ADHF-induced alterations in hemodynamics, i.e., increased central venous and pulmonary arterial pressures; respiratory gas exchanges, i.e., respiratory acidosis with low arterial PO 2 and high PCO 2 ; and LV dysfunction, i.e., increased LV end-diastolic/systolic volumes, were observed (p < 0.01 vs. baseline). Representative increases in circulating cardiac biomarkers, i.e., troponin T, natriuretic peptide, and bio-adrenomedullin, occurred (p < 0.01 vs. baseline). Finally, elevated renal and liver biomarkers were observed 48 h after onset of ADHF. Mortality was ~ 50%. Serelaxin showed beneficial effects on congestion, but none on mortality., Conclusion: This new model, resulting from a combination of chronic and acute MI, and volume and pressure overload, was able to reproduce all the typical clinical signs occurring during ADHF in a consistent and reproducible manner., (© 2020. The Author(s).)

One of the main causes of out-of-hospital cardiac arrest is acute myocardial infarction (AMI). After successful resuscitation from cardiac arrest, approximately 70% of patients die before hospital discharge due to post-resuscitation myocardial and cerebral dysfunction. In experimental models, myocardial dysfunction after cardiac arrest, characterized by an impairment in both left ventricular (LV) systolic and diastolic function, has been described as reversible but very little data are available in cardiac arrest models associated with AMI in pigs. Transthoracic echocardiography is the first-line diagnostic test for the assessment of myocardial dysfunction, structural changes and/or AMI extension. In this pig model of ischemic cardiac arrest, echocardiography was done at baseline and 2-4 and 96 hours after resuscitation. In the acute phase, the examinations are done in anesthetized, mechanically ventilated pigs (weight 39.8 ± 0.6 kg) and ECG is recorded continuously. Mono- and bi-dimensional, Doppler and tissue Doppler recordings are acquired. Aortic and left atrium diameter, end-systolic and end-diastolic left ventricular wall thicknesses, end-diastolic and end-systolic diameters and shortening fraction (SF) are measured. Apical 2-, 3-, 4-, and 5-chamber views are acquired, LV volumes and ejection fraction are calculated. Segmental wall motion analysis is done to detect the localization and estimate the extent of myocardial infarction. Pulsed Wave Doppler echocardiography is used to record trans-mitral flow velocities from a 4-apical chamber view and trans-aortic flow from a 5-chamber view to calculate LV cardiac output (CO) and stroke volume (SV). Tissue Doppler Imaging (TDI) of LV lateral and septal mitral anulus is recorded (TDI septal and lateral s', e', a' velocities). All the recordings and measurements are done according to the recommendations of the American and European Societies of Echocardiography Guidelines.

Background Brain injury and neurological deficit are consequences of cardiac arrest (CA), leading to high morbidity and mortality. Peripheral activation of the kynurenine pathway (KP), the main catabolic route of tryptophan metabolized at first into kynurenine, predicts poor neurological outcome in patients resuscitated after out-of-hospital CA. Here, we investigated KP activation in hippocampus and plasma of rats resuscitated from CA, evaluating the effect of KP modulation in preventing CA-induced neurological deficit. Methods and Results Early KP activation was first demonstrated in 28 rats subjected to electrically induced CA followed by cardiopulmonary resuscitation. Hippocampal levels of the neuroactive metabolites kynurenine, 3-hydroxy-anthranilic acid, and kynurenic acid were higher 2 hours after CA, as in plasma. Further, 36 rats were randomized to receive the inhibitor of the first step of KP, 1-methyl-DL-tryptophan, or vehicle, before CA. No differences were observed in hemodynamics and myocardial function. The CA-induced KP activation, sustained up to 96 hours in hippocampus (and plasma) of vehicle-treated rats, was counteracted by the inhibitor as indicated by lower hippocampal (and plasmatic) kynurenine/tryptophan ratio and kynurenine levels. 1-Methyl-DL-tryptophan reduced the CA-induced neurological deficits, with a significant correlation between the neurological score and the individual kynurenine levels, as well as the kynurenine/tryptophan ratio, in plasma and hippocampus. Conclusions These data demonstrate the CA-induced lasting activation of the first step of the KP in hippocampus, showing that this activation was involved in the evolving neurological deficit. The degree of peripheral activation of KP may predict neurological function after CA.

Primary vasopressor efficacy of epinephrine during cardiopulmonary resuscitation (CPR) is due to its α-adrenergic effects. However, epinephrine plays β1-adrenergic actions, which increasing myocardial oxygen consumption may lead to refractory ventricular fibrillation (VF) and poor outcome. Effects of a single dose of esmolol in addition to epinephrine during CPR were investigated in a porcine model of VF with an underlying acute myocardial infarction. VF was ischemically induced in 16 pigs and left untreated for 12 min. During CPR, animals were randomized to receive epinephrine (30 µg/kg) with either esmolol (0.5 mg/kg) or saline (control). Pigs were then observed up to 96 h. Coronary perfusion pressure increased during CPR in the esmolol group compared to control (47 ± 21 vs. 24 ± 10 mmHg at min 5, p < 0.05). In both groups, 7 animals were successfully resuscitated and 4 survived up to 96 h. No significant differences were observed between groups in the total number of defibrillations delivered prior to final resuscitation. Brain histology demonstrated reductions in cortical neuronal degeneration/necrosis (score 0.3 ± 0.5 vs. 1.3 ± 0.5, p < 0.05) and hippocampal microglial activation (6 ± 3 vs. 22 ± 4%, p < 0.01) in the esmolol group compared to control. Lower circulating levels of neuron specific enolase were measured in esmolol animals compared to controls (2[1-3] vs. 21[16-52] ng/mL, p < 0.01). In this preclinical model, β1-blockade during CPR did not facilitate VF termination but provided neuroprotection.

Rationale: Cardiopulmonary resuscitation is the cornerstone of cardiac arrest (CA) treatment. However, lung injuries associated with it have been reported. Objectives: To assess 1 ) the presence and characteristics of lung abnormalities induced by cardiopulmonary resuscitation and 2 ) the role of mechanical and manual chest compression (CC) in its development. Methods: This translational study included 1 ) a porcine model of CA and cardiopulmonary resuscitation ( n  = 12) and 2 ) a multicenter cohort of patients with out-of-hospital CA undergoing mechanical or manual CC ( n  = 52). Lung computed tomography performed after resuscitation was assessed qualitatively and quantitatively along with respiratory mechanics and gas exchanges. Measurements and Main Results: The lung weight in the mechanical CC group was higher compared with the manual CC group in the experimental (431 ± 127 vs. 273 ± 66, P  = 0.022) and clinical study (1,208 ± 630 vs. 837 ± 306, P  = 0.006). The mechanical CC group showed significantly lower oxygenation ( P  = 0.043) and respiratory system compliance ( P  < 0.001) compared with the manual CC group in the experimental study. The variation of right atrial pressure was significantly higher in the mechanical compared with the manual CC group (54 ± 11 vs. 31 ± 6 mm Hg, P  = 0.001) and significantly correlated with lung weight ( r  = 0.686, P  = 0.026) and respiratory system compliance ( r  = -0.634, P  = 0.027). Incidence of abnormal lung density was higher in patients treated with mechanical compared with manual CC (37% vs. 8%, P  = 0.018). Conclusions: This study demonstrated the presence of cardiopulmonary resuscitation-associated lung edema in animals and in patients with out-of-hospital CA, which is more pronounced after mechanical as opposed to manual CC and correlates with higher swings of right atrial pressure during CC.

Ischaemic heart disease is the world's leading cause of mortality. Survival rates from acute myocardial infarction (MI) have improved in recent years; however, this has led to an increase in the prevalence of heart failure (HF) due to chronic remodelling of the infarcted myocardium, for which treatment options remain poor. We have previously shown that inhibition of isoform 4 of the plasma membrane calcium ATPase (PMCA4) prevents chronic remodelling and HF development during pressure overload, through fibroblast mediated Wnt signalling modulation. Given that Wnt signalling also plays a prominent role during remodelling of the infarcted heart, this study investigated the effect of genetic and functional loss of PMCA4 on cardiac outcomes following MI. Neither genetic deletion nor pharmacological inhibition of PMCA4 affected chronic remodelling of the post-MI myocardium. This was the case when PMCA4 was deleted globally, or specifically from cardiomyocytes or fibroblasts. PMCA4-ablated hearts were however less prone to acute arrhythmic events, which may offer a slight survival benefit. Overall, this study demonstrates that PMCA4 inhibition does not affect chronic outcomes following MI.

Background Ventilation with the noble gas argon (Ar) has shown neuroprotective and cardioprotective properties in different in vitro and in vivo models. Hence, the neuroprotective effects of Ar were investigated in a severe, preclinically relevant porcine model of cardiac arrest. Methods and Results Cardiac arrest was ischemically induced in 36 pigs and left untreated for 12 minutes before starting cardiopulmonary resuscitation. Animals were randomized to 4-hour post-resuscitation ventilation with: 70% nitrogen-30% oxygen (control); 50% Ar-20% nitrogen-30% oxygen (Ar 50%); and 70% Ar-30% oxygen (Ar 70%). Hemodynamic parameters and myocardial function were monitored and serial blood samples taken. Pigs were observed up to 96 hours for survival and neurological recovery. Heart and brain were harvested for histopathology. Ten animals in each group were successfully resuscitated. Ninety-six-hour survival was 60%, 70%, and 90%, for the control, Ar 50%, and Ar 70% groups, respectively. In the Ar 50% and Ar 70% groups, 60% and 80%, respectively, achieved good neurological recovery, in contrast to only 30% in the control group ( P <0.0001). Histology showed less neuronal degeneration in the cortex ( P <0.05) but not in the hippocampus, and less reactive microglia activation in the hippocampus ( P =0.007), after Ar compared with control treatment. A lower increase in circulating biomarkers of brain injury, together with less kynurenine pathway activation ( P <0.05), were present in Ar-treated animals compared with controls. Ar 70% pigs also had complete left ventricular function recovery and smaller infarct and cardiac troponin release ( P <0.01). Conclusions Post-resuscitation ventilation with Ar significantly improves neurologic recovery and ameliorates brain injury after cardiac arrest with long no-flow duration. Benefits are greater after Ar 70% than Ar 50%.

Heart failure with preserved ejection fraction (HFpEF) is currently untreated. Therapeutics development demands effective diagnosis of diastolic dysfunction in animal models mimicking human pathology, which requires appropriate anaesthetics. Here, we investigated which anaesthetic, ketamine/xylazine or isoflurane, could be used to reveal diastolic dysfunction in HFpEF-diseased obese ZSF1 rats by echocardiography. First, diastolic dysfunction was confirmed by pressure-volume loops in obese compared to lean control ZSF1 rats. In echocardiography, ketamine/xylazine, unlike isoflurane, was able to demonstrate impaired relaxation in obese ZSF1 rats, as reflected by impaired early (E) and late (A) filling peak velocities, decreased E/A ratio, and a prolonged deceleration and isovolumic relaxation time. Interestingly, ketamine/xylazine induced a wider separation of both tissue and pulsed wave Doppler-derived echocardiographic waves required for diastolic dysfunction diagnosis, potentially by reducing the heart rate (HR), while isoflurane resulted in merged waves. To assess whether HR-lowering alone explained the differences between the anaesthetics, echocardiography measurements under isoflurane with and without the HR-lowering drug ivabradine were compared. However, diastolic dysfunction could not be diagnosed in ivabradine-treated obese ZSF1 rats. In summary, ketamine/xylazine compared to isoflurane is the anaesthetic of choice to detect diastolic dysfunction by echocardiography in rodent HFpEF, which was only partly mediated by HR-lowering.

The identification of new treatments for primary pulmonary arterial hypertension (PAH) is a critical unmet need since there is no a definitive cure for this disease yet. Due to the complexity of PAH, a wide set of methods are necessary to assess the response to a pharmacological intervention. Thus, a rigorous protocol is crucial when experimental studies are designed. In the present experimental protocol, a stepwise approach was followed in a monocrotaline-induced PAH model in the rat, moving from the dose finding study of treatment compounds to the recognition of the onset of disease manifestation, in order to identify when to start a curative treatment. A complete multidimensional evaluation of treatment effects represented the last step. The primary study endpoint was the change in right ventricular systolic pressure after 14 days of treatment; echocardiographic and biohumoral markers together with heart and pulmonary arterial morphometric parameters were considered as secondary efficacy and/or safety endpoints and for the evaluation of the biologic coherence in the different results., Competing Interests: Marco Milioli, Fabrizio Facchinetti, Silvia Cantoni, Marcello Trevisani are employees of Chiesi Farmaceutici S.p.A. The other authors have no conflicts of interest to declare., (© 2019 The Authors.)

Novel pharmacological approaches are needed to improve outcomes of patients with idiopathic pulmonary hypertension. Rho-associated protein kinase (ROCK) inhibitors have shown beneficial effects in preclinical models of pulmonary arterial hypertension (PAH), because of their role in the regulation of pulmonary artery vasoconstrictor tone and remodeling. We compared a ROCK inhibitor, Y-27632, for the first time with the dual endothelin receptor antagonist, macitentan, in a monocrotaline-induced rat pulmonary hypertension model. Different methods (echocardiography, hemodynamics, histology of right ventricle and pulmonary vessels, and circulating biomarkers) showed consistently that 100 mg/kg daily of Y-27632 and 10 mg/kg daily of macitentan slowed the progression of PAH both at the functional and structural levels. Treatments started on day 14 after monocrotaline injection and lasted 14 days. The findings of all experimental methods show that the selective ROCK inhibitor Y-27632 has more pronounced effects than macitentan, but a major limitation to its use is its marked peripheral vasodilating action., (Copyright © 2019 Elsevier B.V. All rights reserved.)