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We sought to investigate the impact of sex on myocardial perfusion changes following chronic total coronary occlusion (CTO) percutaneous coronary intervention (PCI) as measured by [15O]H 2 O positron-emission tomography (PET) perfusion imaging. CTO PCI has been associated with an increase in myocardial perfusion, yet females are less likely to undergo revascularization. As such, data on the impact of sex on myocardial perfusion following CTO PCI is scarce. A total of 212 patients were prospectively enrolled and underwent CTO PCI combined with [15O]H 2 O PET perfusion imaging prior to and 3 months after PCI. Hyperemic myocardial blood flow (hMBF, mL·min−1·g−1) and coronary flow reserve (CFR) allocated to the CTO territory were quantitatively assessed. This study comprised 34 (16 %) females and 178 (84 %) males. HMBF at baseline did not differ between sexes. Females showed a higher increase in hMBF than males (Δ1.34 ± 0.67 vs. Δ1.06 ± 0.74, p = 0.044), whereas post-PCI hMBF was comparable (2.59 ± 0.85 in females vs. 2.28 ± 0.84 in males, p = 0.052). Female sex was independently associated with a higher increase in hMBF after correction for clinical covariates. CFR increase after revascularization was similar in females and males (Δ1.47 ± 0.99 vs. Δ1.30 ± 1.14, p = 0.711). The present study demonstrates a greater recovery of stress perfusion in females compared to males as measured by serial [15O]H 2 O PET imaging. In addition, a comparable increase in CFR was found in females and males. These results emphasize the benefit of performing CTO PCI in both sexes. What is new? • CTO PCI has been associated with an increase in myocardial perfusion, yet females are less likely to undergo revascularization. • We found a greater recovery of stress perfusion in females compared to males after CTO PCI as measured by serial [15O]H 2 O PET imaging, whereas coronary flow reserve was comparable between sexes. • The present study adds to the limited body of evidence on the impact of sex on myocardial perfusion following CTO PCI. What are the clinical implications? • Our findings suggest that recovery of myocardial perfusion following CTO PCI is achievable in both female and male patients. • These results underscore the need to adhere to current guidelines for optimal CTO management in both sexes. • Future studies with standardized preprocedural imaging are warranted to increase our understanding of the impact of sex on changes in myocardial perfusion following CTO PCI. • CTO PCI is associated with an increase in myocardial perfusion, yet females are less likely to undergo revascularization. • We found a greater recovery of stress perfusion in females after CTO PCI as measured by serial [15O]H 2 O PET imaging. • Our findings suggest that recovery of myocardial perfusion following CTO PCI is achievable in both female and male patients. • These results underscore the need to adhere to current guidelines for optimal CTO management in both sexes. • Studies with preprocedural imaging are warranted to increase our understanding of the impact of sex on MBF after CTO PCI. [ABSTRACT FROM AUTHOR]

Purpose: We sought to assess the impact of coronary revascularization on myocardial perfusion and fractional flow reserve (FFR) in patients without a cardiac history, with prior myocardial infarction (MI) or non-MI percutaneous coronary intervention (PCI). Furthermore, we studied the impact of scar tissue. Methods: Symptomatic patients underwent [15O]H2O positron emission tomography (PET) and FFR before and after revascularization. Patients with prior CAD, defined as prior MI or PCI, underwent scar quantification by magnetic resonance imaging late gadolinium enhancement. Results: Among 137 patients (87% male, age 62.2 ± 9.5 years) 84 (61%) had a prior MI or PCI. The increase in FFR and hyperemic myocardial blood flow (hMBF) was less in patients with prior MI or non-MI PCI compared to those without a cardiac history (FFR: 0.23 ± 0.14 vs. 0.20 ± 0.12 vs. 0.31 ± 0.18, p = 0.02; hMBF: 0.54 ± 0.75 vs. 0.62 ± 0.97 vs. 0.91 ± 0.96 ml/min/g, p = 0.04). Post-revascularization FFR and hMBF were similar across patients without a cardiac history or with prior MI or non-MI PCI. An increase in FFR was strongly associated to hMBF increase in patients without a cardiac history or with prior MI/non-MI PCI (r = 0.60 and r = 0.60, p < 0.01 for both). Similar results were found for coronary flow reserve. In patients with prior MI scar was negatively correlated to hMBF increase and independently predictive of an attenuated CFR increase. Conclusions: Post revascularization FFR and perfusion were similar among patients without a cardiac history, with prior MI or non-MI PCI. In patients with prior MI scar burden was associated to an attenuated perfusion increase. [ABSTRACT FROM AUTHOR]

Effective municipal solid waste (MSW) management is a crucial component for sustainable cities, as inefficient waste disposal contributes to the release of about a billion tons of CO 2 -eq in greenhouse gases (GHG) annually. With escalating global waste generation, there is an untapped opportunity to integrate carbon dioxide removal (CDR) technologies into existing MSW management processes. This review explores current research on utilizing MSW for CDR, emphasizing its potential for both energy generation and carbon sequestration. The investigation covers three waste management practices: landfilling, waste-to-energy (WtE), and biochar production, revealing two paths for carbon sequestration. First, MSW serves as a feedstock in bioenergy with carbon capture and storage (BECCS), acting as a carbon-neutral resource that avoids fossil fuel and energy crop use, reducing GHG emissions and generating value through energy production. Second, direct storage of organic MSW and its derivatives, like biochar, in various carbon sinks allows for extended sequestration, offering a comprehensive approach to address the challenges of waste management and climate change mitigation. Moreover, this review advocates for an extended exploration into several subjects including in-depth analysis of waste, research on MSW-derived biochar recalcitrance across different carbon sinks, and understanding the symbiotic connections with GHG-emitting sectors like agriculture and energy. Finally, this review emphasizes the necessity of conducting life-cycle assessment studies to fully discern the benefits and assess the impacts of any future endeavors exploring the role of MSW in carbon sequestration. [Display omitted] • Municipal solid waste (MSW) is an untapped resource for carbon dioxide removal. • Three strategies to utilize MSW for CO 2 removal include landfilling, waste-to-energy, and biochar production. • Carbon sequestration is achieved through MSW-burial and energy recovery with CCS. • Auditing carbon emissions and LCA are necessary to illuminate the impacts of MSW. [ABSTRACT FROM AUTHOR]

In this study, we investigated whether increased renin angiotensin aldosterone system (RAAS) activation and endothelin-1 levels are related to coronary artery calcium (CAC) score, total plaque volume (TPV), high risk plaque, hyperemic myocardial blood flow (MBF) and coronary microvascular dysfunction (CMD). In a prospective, observational, cross-sectional cohort, renin as a marker for RAAS activation and endothelin-1 were measured in peripheral venous blood of 205 patients (64% men; age 58 ± 8.7 years) with suspected coronary artery disease (CAD) who underwent coronary computed tomography angiography (CCTA), [15O]H 2 O positron emission tomography (PET) perfusion imaging and invasive fractional flow reserve (FFR) measurements. Patients were categorized into three groups based on FFR (≤0.80) and hyperemic MBF <2.3 ml/min/g: [1] obstructive CAD (n = 92), [2] CMD (n = 26) or [3] no or non-obstructive CAD (n = 85). After correction for baseline characteristics, including RAAS inhibiting therapy, renin associated positively with CAC score and TPV, but not with hyperemic MBF (p < 0.01; p = 0.02 and p = 0.23). Patients with high risk plaque displayed higher levels of renin (mean logarithmic renin 1.25 ± 0.43 vs. 1.12 ± 0.35 pg/ml; p = 0.04), but not endothelin-1. Compared to no or non-obstructive CAD patients, renin was significantly elevated in obstructive CAD patients but not in CMD patients (mean logarithmic renin 1.06 ± 0.34 vs. 1.23 ± 0.36; p < 0.01 and 1.06 ± 0.34 vs. 1.16 ± 0.41 pg/ml; p = 0.65). Endothelin-1 did not differ between the three patient groups. Our report provides evidence that RAAS activity measured by renin concentration is elevated in patients with coronary atherosclerosis and high risk plaque but not in patients with CMD, whereas endothelin-1 is not related to either. [Display omitted] • The mechanism of the pleiotropic effect of renin angiotensin aldosterone system (RAAS) inhibition is not unraveled. • 205 patients underwent coronary computed tomography angiography (CCTA), [15O]H 2 O positron emission tomography (PET) perfusion and invasive fractional flow reserve (FFR). • RAAS activation is an independent risk factor for plaque volume and coronary calcium. • RAAS activation is associated with high risk plaque. • RAAS activation and endothelin-1 are not associated with microvascular dysfunction. [ABSTRACT FROM AUTHOR]

Objectives: Quantitative flow ratio (QFR) computes fractional flow reserve (FFR) based on invasive coronary angiography (ICA). Residual QFR estimates post-percutaneous coronary intervention (PCI) FFR. This study sought to assess the relationship of residual QFR with post-PCI FFR.Methods: Residual QFR analysis, using pre-PCI ICA, was attempted in 159 vessels with post-PCI FFR. QFR lesion location was matched with the PCI location to simulate the performed intervention and allow computation of residual QFR. A post-PCI FFR < 0.90 was used to define a suboptimal PCI result.Results: Residual QFR computation was successful in 128 (81%) vessels. Median residual QFR was higher than post-PCI FFR (0.96 Q1-Q3: 0.91-0.99 vs. 0.91 Q1-Q3: 0.86-0.96, p < 0.001). A significant correlation and agreement were observed between residual QFR and post-PCI FFR (R = 0.56 and intraclass correlation coefficient = 0.47, p < 0.001 for both). Following PCI, an FFR < 0.90 was observed in 54 (42%) vessels. Specificity, positive predictive value, sensitivity, and negative predictive value of residual QFR for assessment of the PCI result were 96% (95% confidence interval (CI): 87-99%), 89% (95% CI: 72-96%), 44% (95% CI: 31-59%), and 70% (95% CI: 65-75%), respectively. Residual QFR had an accuracy of 74% (95% CI: 66-82%) and an area under the receiver operating characteristic curve of 0.79 (95% CI: 0.71-0.86).Conclusions: A significant correlation and agreement between residual QFR and post-PCI FFR were observed. Residual QFR ≥ 0.90 did not necessarily commensurate with a satisfactory PCI (post-PCI FFR ≥ 0.90). In contrast, residual QFR exhibited a high specificity for prediction of a suboptimal PCI result. [ABSTRACT FROM AUTHOR]

We present a fast method for calculating the effects of ammonia emission reduction scenarios on reduced nitrogen components over the Netherlands. The method combines the EMEP4NL model, which is a full atmospheric chemical transport model (ACTM), with the SHERPA tool, which is an approximate representation of a full ACTM. The SHERPA tool uses a geographically weighted regression method to derive source-receptor relations, based on a limited number of "training" runs of the ACTM (here, EMEP4NL). The training runs consist of a base run of the year of interest plus uniform emission reduction runs for the primary pollutants of interest. Once the source-receptor relations are derived, scenario studies can be performed at a much lower computational cost with SHERPA (i.e. order 104–105 more efficient) as compared to a full run with the EMEP4NL model. Here, we study five specific ammonia emission reduction scenarios, in which a 30% emission reduction is enforced for specific regions in The Netherlands, Germany and Belgium. Our analysis shows that the EMEP4NL model and the SHERPA tool yield similar results in terms of the reduction of the yearly average concentration and deposition of reduced nitrogen components. Because of its computational efficiency and ability to adequately reproduce the results of the EMEP4NL model, the SHERPA tool is relevant for policy making. It can provide predictions of the effects of many different local emission reduction measures in a computationally efficient manner. • We present a method to perform fast ammonia emission reduction studies with a focus on reduced nitrogen components. • An atmospheric chemical transport model is used to train a simplified model. • We validate our results for small, arbitrarily-shaped areas in The Netherlands, Belgium and Germany. • Our method leads to a factor 104 reduction in computation time and adequate accuracy compared to the full model. • It enables policy makers to efficiently study many different local emission reduction scenarios in an efficient manner. [ABSTRACT FROM AUTHOR]

The article offers information on the programs and implementation for English Language learners, Topics discussed include information on the programs for school finance for educational development; discussions on the need to develop effective legislation to support English Language learners and Latinx youth at the local level; and the information on the personal values or preferences of community and student needs.

The insulin-like growth factors (IGFs), IGF binding proteins (IGFBPs), and IGFBP proteases regulate somatic growth and cellular proliferation both in vivo and in vitro. IGFs are potent mitogens whose actions are determined by the availability of free IGFs to interact with IGF receptors. IGFBPs comprise a family of six proteins that bind IGFs with high affinity and specificity and thereby regulate IGF-dependent actions. IGFBPs have recently emerged as IGF-independent regulators of cell growth. Cleavage of IGFBPs by specific proteases modulate levels of free IGFs and IGFBPs and thereby their actions. IGFBP-related proteins (IGFBP-rPs) bind IGFs with low affinity and also play important roles in cell growth and differentiation. The GH-IGF-IGFBP axis is complex and powerful. Future research on its physiology promises exciting insights into cell biology as well as therapies for diseases such as cancer and diabetes mellitus. [ABSTRACT FROM AUTHOR]

• Inadequate identification of families care needs leads to sub-optimal care. • A novel methodology GIZ for joint assessment of care needs was developed. • The current study evaluated the effects of GIZ within preventive child health care. • GIZ has positive effects on discussing parenting and environmental circumstances, • On the parent-professional agreement and parental satisfaction. It is common for parents to have concerns or questions regarding their child. However, parental concerns are not always recognised by the youth healthcare professional. At the same time, not all parents agree with concerns identified by the professional. Identifying and agreeing on concerns is an essential step in the assessment of care needs within child health care. This article describes the effects of an innovative 'GIZ' 2 GIZ = Gezamenlijk Inschatten Zorgbehoeften [in Dutch], translated as Joint Assessment of Care Needs. 2 methodology for joint assessment of care-needs developed to support the professional in engaging parents in assessing strengths, developmental concerns and care needs of the child and family. The current study compares parent-professional agreement on concerns and follow-up actions, and parents' satisfaction with the consultation with and without the GIZ. During this non-randomised controlled trial, 733 parents of children aged 0–12 and their professional completed a questionnaire after the consultation. In 526 assessments, the GIZ was used, and in 207 care as usual. Outcome measures were: concerns discussed, parent-professional agreement on strengths, concerns and follow-up actions and parents' satisfaction with the consultation. Multilevel analyses were used to answer the research questions. In the GIZ group, parental concerns (specifically regarding parenting and the child's environment) were discussed significantly more often. The use of the GIZ was associated with increased parent-professional agreement on concerns regarding the child's development and increased agreement on the given advice. Parents' satisfaction was significantly higher. Using the GIZ within preventive child health care has positive effects on discussing parenting and environmental circumstances, on the parent-professional agreement and parents' satisfaction. [ABSTRACT FROM AUTHOR]

In the present study, we tested the hypothesis that multiple risk factors, including diabetes mellitus (DM), dyslipidaemia and chronic kidney disease (CKD) result in a loss of nitric oxide (NO) signalling, thereby contributing to coronary microvascular dysfunction. Risk factors were induced in 12 female swine by intravenous streptozotocin injections (DM), a high fat diet (HFD) and renal artery embolization (CKD). Female healthy swine (n=13) on normal diet served as controls (Normal). After 5 months, swine were chronically instrumented and studied at rest and during exercise. DM+HFD+CKD swine demonstrated signifcant hyperglycaemia, dyslipidaemia and impaired kidney function compared to Normal swine. These risk factors were accompanied by coronary microvascular endothelial dysfunction both in vivo and in isolated small arteries, due to a reduced NO bioavailability, associated with perturbations in myocardial oxygen balance at rest and during exercise. NO synthase inhibition caused coronary microvascular constriction in exercising Normal swine, but had no efect in DM + HFD +CKD animals, while inhibition of phosphodiesterase 5 produced similar vasodilator responses in both groups, indicating that loss of NO bioavailability was principally responsible for the observed coronary microvascular dysfunction. This was associated with an increase in myocardial 8-isoprostane levels and a decrease in antioxidant capacity, while antioxidants restored the vasodilation to bradykinin in isolated coronary small arteries, suggesting that oxidative stress was principally responsible for the reduced NO bioavailability. In conclusion, fve months of combined exposure to DM+ HFD +CKD produces coronary endothelial dysfunction due to impaired NO bioavailability, resulting in impaired myocardial perfusion at rest and during exercise. [ABSTRACT FROM AUTHOR]

We present a microfluidic device to expose cancer cells to a dynamic, in vivo-like concentration profile of a drug, and quantify efficacy on-chip. About 30% of cancer patients receive drug therapy. In conventional cell culture experiments drug efficacy is tested under static concentrations, e.g. 1 μM for 48 hours, whereas in vivo, drug concentration follows a pharmacokinetic profile with an initial peak and a decline over time. With the rise of microfluidic cell culture models, including organs-on-chips, there are opportunities to more realistically mimic in vivo-like concentrations. Our microfluidic device contains a cell culture chamber and a drug-dosing channel separated by a transparent membrane, to allow for shear stress-free drug exposure and label-free growth quantification. Dynamic drug concentration profiles in the cell culture chamber were controlled by continuously flowing controlled concentrations of drug in the dosing channel. The control over drug concentrations in the cell culture chambers was validated with fluorescence experiments and numerical simulations. Exposure of HCT116 colorectal cancer cells to static concentrations of the clinically used drug oxaliplatin resulted in a sensible dose-effect curve. Dynamic, in vivo-like drug exposure also led to statistically significant lower growth compared to untreated control. Continuous exposure to the average concentration of the in vivo-like exposure seems more effective than exposure to the peak concentration (Cmax) only. We expect that our microfluidic system will improve efficacy prediction of in vitro models, including organs-on-chips, and may lead to future clinical optimization of drug administration schedules. [ABSTRACT FROM AUTHOR]

Comorbidities of ischemic heart disease, including diabetes mellitus (DM), hypercholesterolemia (HC) and chronic kidney disease (CKD), are associated with coronary microvascular dysfunction (CMD). Increasing evidence suggests that CMD may contribute to myocardial ‘Ischemia and No Obstructive Coronary Artery disease’ (INOCA). In the present study, we tested the hypothesis that CMD results in perturbations in myocardial perfusion and oxygen delivery using a novel swine model with multiple comorbidities. DM (streptozotocin), HC (high-fat diet) and CKD (renal embolization) were induced in 10 female swine (DM + HC + CKD), while 12 healthy female swine on a normal diet served as controls (Normal). After 5 months, at a time when coronary atherosclerosis was still negligible, myocardial perfusion, metabolism, and function were studied at rest and during treadmill exercise. DM + HC + CKD animals showed hyperglycemia, hypercholesterolemia, and impaired kidney function. During exercise, DM + HC + CKD swine demonstrated perturbations in myocardial blood flow and oxygen delivery, necessitating a higher myocardial oxygen extraction—achieved despite reduced capillary density—resulting in lower coronary venous oxygen levels. Moreover, myocardial efficiency was lower, requiring higher oxygen consumption for a given level of myocardial work. These perturbations in myocardial oxygen balance were associated with lower myocardial lactate consumption, stroke volume, and LVdP/dtmax, suggestive of myocardial ischemia and dysfunction. Further analyses showed a reduction in adenosine-recruitable coronary flow reserve, but this was exclusively the result of an increase in basal coronary blood flow, while maximal coronary flow per gram of myocardium was maintained; the latter was consistent with the unchanged arteriolar wall/lumen ratio, arteriolar density and peri-arteriolar collagen content. However, isolated small arteries displayed selective blunting of endothelium-dependent vasodilation in response to bradykinin in DM + HC + CKD swine, suggesting that changes in coronary microvascular function rather than in structure contributed to the perturbations in myocardial oxygen delivery. In conclusion, common comorbidities in swine result in CMD, in the absence of appreciable atherosclerosis, which is severe enough to produce perturbations in myocardial oxygen balance, particularly during exercise, resembling key features of INOCA. [ABSTRACT FROM AUTHOR]

Background: Migraine is a disabling and chronic neurovascular headache disorder. Trigeminal vascular activation and release of calcitonin gene-related peptide (CGRP) play a pivotal role in the pathogenesis of migraine. This knowledge has led to the development of CGRP(-receptor) therapies. Yet, a substantial proportion of patients do not respond to these treatments. Therefore, alternative targets for future therapies are warranted. The current narrative review provides a comprehensive overview of the pathophysiological role of these possible non-CGRP targets in migraine. Findings: We covered targets of the metabotropic receptors (pituitary adenylate cyclase-activating polypeptide (PACAP), vasoactive intestinal peptide (VIP), amylin, and adrenomedullin), intracellular targets (nitric oxide (NO), phosphodiesterase-3 (PDE3) and -5 (PDE5)), and ion channels (potassium, calcium, transient receptor potential (TRP), and acid-sensing ion channels (ASIC)). The majority of non-CGRP targets were able to induce migraine-like attacks, except for (i) calcium channels, as it is not yet possible to directly target channels to elucidate their precise involvement in migraine; (ii) TRP channels, activation of which can induce non-migraine headache; and (iii) ASICs, as their potential in inducing migraine attacks has not been investigated thus far. Drugs that target its receptors exist for PACAP, NO, and the potassium, TRP, and ASIC channels. No selective drugs exist for the other targets, however, some existing (migraine) treatments appear to indirectly antagonize responses to amylin, adrenomedullin, and calcium channels. Drugs against PACAP, NO, potassium channels, TRP channels, and only a PAC1 antibody have been tested for migraine treatment, albeit with ambiguous results. Conclusion: While current research on these non-CGRP drug targets has not yet led to the development of efficacious therapies, human provocation studies using these targets have provided valuable insight into underlying mechanisms of migraine headaches and auras. Further studies are needed on these alternative therapies in non-responders of CGRP(-receptor) targeted therapies with the ultimate aim to pave the way towards a headache-free future for all migraine patients. [ABSTRACT FROM AUTHOR]

Pulmonary hypertension is common in heart failure with preserved ejection fraction (HFpEF). Here, we tested the hypothesis that comorbidities [diabetes mellitus (DM, streptozotocin), hypercholesterolemia (HC, high-fat diet) and chronic kidney disease (CKD, renal microembolization)] directly impair pulmonary vasomotor control in a DM + HC + CKD swine model. 6 months after induction of DM + HC + CKD, pulmonary arterial pressure was similar in chronically instrumented female DM + HC + CKD (n = 19) and Healthy swine (n = 18). However, cardiac output was lower both at rest and during exercise, implying an elevated pulmonary vascular resistance (PVR) in DM + HC + CKD swine (153 ± 10 vs. 122 ± 9 mmHg∙L−1∙min∙kg). Phosphodiesterase 5 inhibition and endothelin receptor antagonism decreased PVR in DM + HC + CKD (− 12 ± 12 and − 22 ± 7 mmHg∙L−1∙min∙kg) but not in Healthy swine (− 1 ± 12 and 2 ± 14 mmHg∙L−1∙min∙kg), indicating increased vasoconstrictor influences of phosphodiesterase 5 and endothelin. Inhibition of nitric oxide synthase produced pulmonary vasoconstriction that was similar in Healthy and DM + HC + CKD swine, but unmasked a pulmonary vasodilator effect of endothelin receptor antagonism in Healthy (− 56 ± 26 mmHg∙L−1∙min∙kg), whereas it failed to significantly decrease PVR in DM + HC + CKD, indicating loss of nitric oxide mediated inhibition of endothelin in DM + HC + CKD. Scavenging of reactive oxygen species (ROS) had no effect on PVR in either Healthy or DM + HC + CKD swine. Cardiovascular magnetic resonance imaging, under anesthesia, showed no right ventricular changes. Finally, despite an increased contribution of endogenous nitric oxide to vasomotor tone regulation in the systemic vasculature, systemic vascular resistance at rest was higher in DM + HC + CKD compared to Healthy swine (824 ± 41 vs. 698 ± 35 mmHg∙L−1∙min∙kg). ROS scavenging induced systemic vasodilation in DM + HC + CKD, but not Healthy swine. In conclusion, common comorbidities directly alter pulmonary vascular control, by enhanced PDE5 and endothelin-mediated vasoconstrictor influences, well before overt left ventricular backward failure or pulmonary hypertension develop. [ABSTRACT FROM AUTHOR]

Purpose: To compare cardiac magnetic resonance imaging (CMR) with [15O]H2O positron emission tomography (PET) for quantification of absolute myocardial blood flow (MBF) and myocardial flow reserve (MFR) in patients with coronary artery disease (CAD). Methods: Fifty-nine patients with stable CAD underwent CMR and [15O]H2O PET. The CMR imaging protocol included late gadolinium enhancement to rule out presence of scar tissue and perfusion imaging using a dual sequence, single bolus technique. Absolute MBF was determined for the three main vascular territories at rest and during vasodilator stress. Results: CMR measurements of regional stress MBF and MFR showed only moderate correlation to those obtained using PET (r = 0.39; P < 0.001 for stress MBF and r = 0.36; P < 0.001 for MFR). Bland-Altman analysis revealed a significant bias of 0.2 ± 1.0 mL/min/g for stress MBF and − 0.5 ± 1.2 for MFR. CMR-derived stress MBF and MFR demonstrated area under the curves of respectively 0.72 (95% CI: 0.65 to 0.79) and 0.76 (95% CI: 0.69 to 0.83) and had optimal cutoff values of 2.35 mL/min/g and 2.25 for detecting abnormal myocardial perfusion, defined as [15O]H2O PET-derived stress MBF ≤ 2.3 mL/min/g and MFR ≤ 2.5. Using these cutoff values, CMR and PET were concordant in 137 (77%) vascular territories for stress MBF and 135 (80%) vascular territories for MFR. Conclusion: CMR measurements of stress MBF and MFR showed modest agreement to those obtained with [15O]H2O PET. Nevertheless, stress MBF and MFR were concordant between CMR and [15O]H2O PET in 77% and 80% of vascular territories, respectively. [ABSTRACT FROM AUTHOR]

Heart failure with a preserved ejection fraction (HFpEF) is associated with multiple comorbidities, such as old age, hypertension, type 2 diabetes and obesity and is more prevalent in females. Although the male obese ZSF1 rat has been proposed as a suitable model to study the development of diastolic dysfunction and early HFpEF, studies in female animals have not been performed yet. Therefore, we aimed to characterize the cardiac phenotype in female obese ZSF1 rats and their lean counterparts. Additionally, we aimed to investigate whether differences exist in disease progression in obese male and female ZSF1 rats. Therefore, male and female ZSF1 rats, lean as well as obese (N = 6-9/subgroup), were used. Every two weeks, from 12 to 26 weeks of age, systolic blood pressure and echocardiographic measurements were performed, and venous blood was sampled. Female obese ZSF1 rats, as compared to female lean ZSF1 rats, developed diastolic dysfunction with cardiac hypertrophy and fibrosis in the presence of severe dyslipidemia, increased plasma growth differentiation factor 15 and mild hypertension, and preservation of systolic function. Although obese female ZSF1 rats did not develop hyperglycemia, their diastolic dysfunction was as severe as in the obese males. Taken together, the results from the present study suggest that the female obese ZSF1 rat is a relevant animal model for HFpEF with multiple comorbidities, suitable for investigating novel therapeutic interventions. [ABSTRACT FROM AUTHOR]

Introduction: Multiple comorbidities, including diabetes mellitus (DM), hypercholesterolemia and chronic kidney disease (CKD) are associated with diastolic dysfunction. These risk factors also cause coronary microvascular dysfunction leading to impaired myocardial perfusion and ischemia with non-obstructive coronary artery disease (INOCA). Recently a link has been proposed between INOCA and HFpEF. We investigated the detrimental effects of DM, CKD and high fat diet (HFD) on myocardial function and perfusion. Hypothesis: Prolonged exposure to multiple comorbidities in swine leads to diastolic dysfunction, associated with impaired myocardial perfusion, altered oxygen balance and anaerobic metabolism. Methods: DM (streptozotocin 3x50mg/kg i.v.) and CKD (renal embolization) were induced in 7 female swine fed a high fat diet (DM+HFD+CKD), while 10 female healthy swine on normal diet served as controls (CON). After 6 months, myocardial perfusion and oxygen balance were studied at rest and during treadmill exercise. At sacrifice PV-loop measurements and histology were performed. Results: DM+HFD+CKD swine had hyperglycemia, renal dysfunction and hypercholesterolemia. DM+HFD+CKD had an increased EDPVR (fig A) with preserved ejection fraction, a lower cardiac index compared to CON at similar levels of exercise (fig B). Left ventricular myocardial capillary density was decreased (fig C) and collagen content was increased (fig D). Their myocardium requiring more oxygen for similar levels of cardiac work, suggesting cardiac inefficiency (fig E). Furthermore, they showed a trend towards a lower coronary blood flow (fig F), forcing the myocardium to increase its oxygen extraction (fig G) both at rest and during exercise. This was accompanied by a decrease in myocardial lactate consumption for the same lactate supply compared to CON (fig H), suggestive of anaerobic metabolism. Importantly, DM+HFD+CKD showed no coronary atherosclerosis. Conclusions: Multiple co-morbidities in swine result in severe perturbations in myocardial oxygen balance and anaerobic metabolism in the absence of significant atherosclerosis, indicating severe coronary microvascular dysfunction in co-occurrence with diastolic dysfunction. [ABSTRACT FROM AUTHOR]

Introduction: Multiple comorbidities, such as diabetes mellitus (DM), hypercholesterolemia and chronic kidney disease (CKD) cause inflammation and alterations in coronary microvascular NO bioavailability, leading to impaired myocardial perfusion. Hypothesis: Increased production of reactive oxygen species (ROS) due to DM, CKD and high fat diet (HFD) results in loss of coronary microvascular NO bioavailability in exercising swine. Methods: In 6 female swine, DM (streptozotocin 3x50mg/kg iv) and CKD (renal embolization) were induced, and HFD was given for 6 months (DM+HFD+CKD). 8 female healthy swine on normal pig chow served as controls (CON). Coronary flow regulation and the role of ROS-NO balance herein, was studied at rest and during treadmill exercise with/without eNOS inhibition (nitro-L-arginine), and ROS scavengers (MPG+Tempol). Results: DM+HFD+CKD had hyperglycemia (18.7±1.9 vs 7.5±0.6mmol/L), renal dysfunction (glomerular filtration rate: 123±12 vs 202±8 ml/min), hypercholesterolemia (7.3±0.7 vs 1.7±0.1mmol/l) and sustained inflammation (TNF 51.6±5.1 vs 24.6±5.5pg/ml, all P<0.05). Myocardial superoxide production was increased in DM+HFD+CKD animals and was associated with a lower NO myocardial production, (P<0.5). Myocardial oxygen delivery was impaired in DM+HFD+CKD swine at rest and during exercise, resulting in reduced coronary venous oxygen saturation (cvSaO2) compared to CON, (P<0.05). eNOS-inhibition resulted in coronary microvascular constriction in CON, reflected by reduced cvSaO2, but had no effect in DM+HFD+CKD (Fig. A, B, *P<0.05). Interestingly, scavenging of ROS resulted in decreased cvSaO2 in DM+HFD+CKD and had no effect in CON (Fig. C, D), suggesting that the increased oxidative stress resulted in increased production of the vasodilator hydrogen peroxide. Conclusions: In swine with multiple co-morbidities, altered NO bioavailability was associated with increased oxidative stress. This was partially compensated by increased hydrogen peroxide-mediated vasodilation. [ABSTRACT FROM AUTHOR]

Acute medial dissection of aorta can occur in the context of a sudden and unexpected death. For medico-legal reasons it is important to estimate as accurately the histological age of dissections. We evaluated the additional value of a systematic application of immunohistochemistry, compared with conventional histology only, in determining chronological steps of injury and repair. Thirty two paraffin embedded specimens of aortic dissection were retrospectively allocated to one of four defined stages: acute (I), subacute (II), early organizing (III) and scarring (IV) using Hematoxylin and Eosin and Elastica van Gieson stained sections. Subsequent immunohistochemically staining was performed with the following markers: (myeloperoxidase (neutrophils), citrullinated-Histone 3 (neutrophil extracellular traps), CD68 (macrophages), CD3 (T-cells), CD31 and CD34 (endothelial cells), and smooth muscle actin. Immune stained sections were scored semi-quantitatively. Histologically, five cases were identified as stage I, 16 as II, 7 as III and 4 as IV. Additional immunostaining for smooth muscle cells and endothelial cells altered the classification in 25% of cases (all in groups II and III). Immunostaining and semi-quantitative grading of involvement of neutrophils, macrophages and NETs also provided specific distribution patterns over the 4 age categories, including unexpected involvement of the peri adventitial fat tissue. In conclusion, it appears that semi-quantitative immunohistochemistry of resident vascular wall cells, inflammatory cells and NETS represents a useful adjunct in detailed histopathological grading of the chronological age of aortic dissections. [ABSTRACT FROM AUTHOR]

Deficits in sensorimotor gating measured by prepulse inhibition (PPI) of the startle have been known as characteristics of patients with schizophrenia and related neuropsychiatric disorders. PPI disruption is thought to rely on the activity of the mesocorticolimbic dopaminergic system and is inhibited by most antipsychotic drugs. These drugs however act also at the nigrostriatal dopaminergic pathway and exert adverse locomotor responses. Finding a way to inhibit the mesocorticolimbicwithout affecting the nigrostriatal-dopaminergic pathway may thus be beneficial to antipsychotic therapies. The melaninconcentrating hormone (MCH) system has been shown to modulate dopamine-related responses. Its receptor (MCH1R) is expressed at high levels in the mesocorticolimbic and not in the nigrostriatal dopaminergic pathways. Interestingly a genomic linkage study revealed significant associations between schizophrenia and markers located in the MCH1R gene locus. We hypothesize that the MCH system can selectively modulate the behavior associated with the mesocorticolimbic dopamine pathway. Using mice, we found that central administration of MCH potentiates apomorphine-induced PPI deficits. Using congenic rat lines that differ in their responses to PPI, we found that the rats that are susceptible to apomorphine (APO-SUS rats) and exhibit PPI deficits display higher MCH mRNA expression in the lateral hypothalamic region and that blocking the MCH system reverses their PPI deficits. On the other hand, in mice and rats, activation or inactivation of the MCH system does not affect stereotyped behaviors, dopamine-related responses that depend on the activity of the nigrostriatal pathway. Furthermore MCH does not affect dizocilpine-induced PPI deficit, a glutamate related response. Thus, our data present the MCH system as a regulator of sensorimotor gating, and provide a new rationale to understand the etiologies of schizophrenia and related psychiatric disorders. [ABSTRACT FROM AUTHOR]