Acrobatic training prevents learning impairments and astrocyte remodeling in the hippocampus of rats undergoing chronic cerebral hypoperfusion: sex-specific benefits.

Background: Chronic cerebral hypoperfusion (CCH) leads to memory and learning impairments associated with degeneration and gliosis in the hippocampus. Treatment with physical exercise carries different therapeutic benefits for each sex. We investigated the effects of acrobatic training on astrocyte remodeling in the CA1 and CA3 subfields of the hippocampus and spatial memory impairment in male and female rats at different stages of the two-vessel occlusion (2VO) model. Methods: Wistar rats were randomly allocated into four groups of males and females: 2VO acrobatic, 2VO sedentary, sham acrobatic, and sham sedentary. The acrobatic training was performed for 4 weeks prior to the 2VO procedure. Brain samples were collected for morphological and biochemical analysis at 3 and 7 days after 2VO. The dorsal hippocampi were removed and prepared for Western blot quantification of Akt, p-Akt, COX IV, cleaved caspase-3, PARP, and GFAP. GFAP immunofluorescence was performed on slices of the hippocampus to count astrocytes and apply the Sholl's circle technique. The Morris water maze was run after 45 days of 2VO. Results: Acutely, the trained female rats showed increased PARP expression, and the 2VO-trained rats of both sexes presented increased GFAP levels in Western blot. Training, mainly in males, induced an increase in the number of astrocytes in the CA1 subfield. The 2VO rats presented branched astrocytes, while acrobatic training prevented branching. However, the 2VO-induced spatial memory impairment was partially prevented by the acrobatic training. Conclusion: Acrobatic training restricted the astrocytic remodeling caused by 2VO in the CA1 and CA3 subfields of the hippocampus. The improvement in spatial memory was associated with more organized glial scarring in the trained rats and better cell viability observed in females.

Involvement of SIRT1 and SIRT3 in Effects of Hypoxic Hypobaric Preconditioning on Hippocampal Damage Induced by Chronic Cerebral Hypoperfusion in C57/6j and a7nAchRs(-/-) Mice / Participación de SIRT1 y SIRT3 en los Efectos del Precondicionamiento Hipobárico Hipóxico sobre el Daño del Hipocampo Inducido por Hipoperfusión Cerebral Crónica en Ratones C57/6j y a7nAchRs (-/-)

SUMMARY: Hypoxic preconditioning is known to induce neuroprotection, but its effects and pathways in chronic brain pathology still unknown. The aim was to establish an involvement of a7 subunit of nicotinic acetylcholine receptors (a7nAchRs), and sirtuins of 1 (SIRT1) and 3 (SIRT3) types in the effects of hypoxic hypobaric preconditioning on brain damage in mice with chronic cerebral hypoperfusion caused by the left common carotid artery occlusion. The male C57/6j (C57, wild type) and a7nAchRs(-/-) mice were divided to six experimental groups (10 mice per group): sham-operated C57, C57 with chronic cerebral hypoperfusion, C57 with hypoxic hypobaric preconditioning and chronic cerebral hypoperfusion, sham-operated a7nAchRs(-/-) mice, a7nAchRs(-/-) with chronic cerebral hypoperfusion, a7nAchRs(-/-) with hypoxic hypobaric preconditioning and chronic cerebral hypoperfusion. For preconditioning, mice were exposed to hypoxia by "lifting" in barochamber to simulated altitude of 5600 m a.s.l. for 1 h/day on 3 consecutive days before surgical manipulation. Expressions of SIRT1, SIRT3 in brain tissue, and histopathological changes of the hippocampi were examined. It was shown that 8-week chronic hypoperfusion of the brain, caused by unilateral occlusion of the common carotid artery, was accompanied by injury to the neurons of the hippocampi of both hemispheres, which was more pronounced on the side of the occlusion. This damage, as well as the mechanisms of neuroprotection induced by hypoxic preconditioning, were maintained for at least 8 weeks by mechanisms mediated through a7nAChRs. Deficite of a7nAChRs was accompanied with reduction of neuronal damage caused CCH in 8 weeks, as well as preconditioning effects, and lead to compensatory activation of regulatory and protective mechanisms mediated by SIRT1, in normal conditions and in CCH. In wild-type (C57) mice, protective mechanisms in CCH were realized to a greater extent by increased expression of SIRT3 in both hemispheres of the brain.

Se sabe que el precondicionamiento hipóxico induce neuroprotección, pero aún se desconocen sus efectos y vías en la patología cerebral crónica. El objetivo fue establecer la participación de la subunidad a7 de los receptores nicotínicos de acetilcolina (a7nAchR) y las sirtuinas de tipo 1 (SIRT1) y 3 (SIRT3) en los efectos del precondicionamiento hipóxico hipobárico sobre el daño cerebral en ratones con hipoperfusión cerebral crónica causada por la oclusión de la arteria carótida común izquierda. Los ratones macho C57/6j (C57, tipo salvaje) y a7nAchRs(-/-) se dividieron en seis grupos experimentales (10 ratones por grupo): C57 con operación simulada, C57 con hipoperfusión cerebral crónica, C57 con precondicionamiento hipobárico hipóxico y crónica. hipoperfusión cerebral, ratones a7nAchRs(-/-) operados de forma simulada, a7nAchRs(-/-) con hipoperfusión cerebral crónica, a7nAchRs(-/-) con precondicionamiento hipobárico hipóxico e hipoperfusión cerebral crónica. Para el preacondicionamiento, los ratones fueron expuestos a hipoxia "levantándolos" en una cámara de barro a una altitud simulada de 5600 m s.n.m. durante 1 h/día durante 3 días consecutivos antes de la manipulación quirúrgica. Se examinaron las expresiones de SIRT1, SIRT3 en tejido cerebral y los cambios histopatológicos de los hipocampos. Se demostró que la hipoperfusión cerebral crónica de 8 semanas, causada por la oclusión unilateral de la arteria carótida común, se acompañaba de lesión de las neuronas del hipocampo de ambos hemisferios y que era más pronunciada en el lado de la oclusión. Este daño, así como los mecanismos de neuroprotección inducidos por el precondicionamiento hipóxico, se mantuvieron durante al menos 8 semanas mediante mecanismos mediados por a7nAChR. El déficit de a7nAChR se acompañó de una reducción del daño neuronal causado por CCH en 8 semanas, así como de efectos de precondicionamiento, y condujo a una activación compensatoria de mecanismos reguladores y protectores mediados por SIRT1, en condiciones normales y en CCH. En ratones de tipo salvaje (C57), los mecanismos de protección en CCH se realizaron en mayor medida mediante una mayor expresión de SIRT3 en ambos hemisfe- rios del cerebro.

Central venous-to-arterial CO2 difference as a biomarker of outcome in children who underwent surgery for congenital heart disease.

BACKGROUND: In congenital heart surgery, low cardiac output syndrome (LCOS) is a major cause of morbidity in the immediate post-operative period. A decrease in cardiac output leads to an increase in tissue oxygen consumption. Several biomarkers such as venous oxygen saturation (SvO2), arteriovenous oxygen difference (DavO2), and lactate can assess tissue perfusion in the presence of LCOS. Recently, central venous to arterial CO2 difference (ΔCO2) has been proposed as a biomarker of tissue ischemia that could be used as a predictor of death in neonatal patients. This study aimed to analyze the relationship between ΔCO2 and immediate post-operative outcomes in pediatric patients undergoing congenital heart surgery and its correlation with DavO2, SvO2, and lactate. METHODS: We conducted a longitudinal study of patients aged 0-18 years who underwent congenital heart surgery with or without cardiopulmonary bypass at the Instituto Nacional de Pediatría, from March 2019 to March 2021. RESULTS: Eighty-two patients were included; the median age was 17 months. About 59% had a ΔCO2 ≥ 6 mmHg. Patients with ΔCO2 ≥ 6 mmHg had a vasoactive-inotropic score > 5 (p < 0.001), DavO2 > 5 mL/dL (p = 0.048), and lactate > 2 mmol/L (p = 0.027), as well as a longer hospital stay (p = 0.043). Patients with ΔCO2 > 6 mmHg and vasoactive-inotropic score ≥ 10 were 12.6 times more likely to die. CONCLUSION: ΔCO2 is a good marker of tissue hypoperfusion and outcome in the post-operative period of congenital heart surgery.

INTRODUCCIÓN: En la cirugía cardiaca de malformaciones congénitas, el síndrome de bajo gasto cardiaco (SBGC) es una de las principales causas de morbilidad en el postoperatorio inmediato. La caída del gasto cardiaco aumenta el consumo de oxígeno en los tejidos. Varios biomarcadores, como la saturación venosa de oxígeno (SvO2), la diferencia arteriovenosa de oxígeno (DavO2) y el lactato han sido utilizados como indicadores hipoperfusión tisular en presencia de SBGC. Recientemente, la diferencia arteriovenosa de CO2 (ΔCO2) se ha propuesto como otro biomarcador de isquemia tisular que podría utilizarse como predictor de muerte en pacientes en edad neonatal. El objetivo de este estudio fue analizar la relación entre la ΔCO2 y la evolución postoperatoria de pacientes pediátricos operados de cardiopatías congénitas y correlacionarlo con la DavO2, SvO2 y lactato. MÉTODOS: Se realizó un estudio longitudinal en pacientes de 0 a 18 años operados de corazón con empleo de bomba de circulación extracorpórea en el Instituto Nacional de Pediatría. RESULTADOS: Se incluyeron 82 pacientes; la mediana de edad fue de 17 meses. El 59% presentó un ΔCO2 > 6 mmHg. Los pacientes con un ΔCO2 > 6 mmHg mostraron un puntaje de inotrópicos > 5 (p < 0.001), DavO2 > 5 mL/dL (p = 0.048) y lactato > 2 mmol/L (p = 0.027), así como mayor estancia hospitalaria (p = 0.043). Los pacientes con ΔCO2 > 6 mmHg y un puntaje de inotrópicos ≥ 10 presentaron una probabilidad de muerte 12.6 veces mayor. CONCLUSIONES: El ΔCO2 en el periodo postoperatorio de una cirugía cardiaca congénita es un buen marcador de hipoperfusión tisular y de desenlace.

Neuroprotection from protein misfolding in cerebral hypoperfusion concurrent with metabolic syndrome. A translational perspective.

Based on clinical and experimental evidence, metabolic syndrome (MetS) and type 2 diabetes (T2D) are considered risk factors for chronic cerebral hypoperfusion (CCH) and neurodegeneration. Scientific evidence suggests that protein misfolding is a potential mechanism that explains how CCH can lead to either Alzheimer's disease (AD) or vascular cognitive impairment and dementia (VCID). Over the last decade, there has been a significant increase in the number of experimental studies regarding this issue. Using several animal paradigms and different markers of CCH, scientists have discussed the extent to which MetSor T2D causes a decrease in cerebral blood flow (CBF). In addition, different models of CCH have explored how long-term reductions in oxygen and energy supply can trigger AD or VCID via protein misfolding and aggregation. Research that combines two or three animal models could broaden knowledge of the links between these pathological conditions. Recent experimental studies suggest novel neuroprotective properties of protein-remodeling factors. In this review, we present a summarized updated revision of preclinical findings, discussing clinical implications and proposing new experimental approaches from a translational perspective. We are confident that research studies, both clinical and experimental, may find new diagnostic and therapeutic tools to prevent neurodegeneration associated with MetS, diabetes, and any other chronic non-communicable disease (NCD) associated with diet and lifestyle risk factors.

Central venous-to-arterial CO2 difference as a biomarker of outcome in children who underwent surgery for congenital heart disease / Diferencia arteriovenosa de CO2 como biomarcador de desenlace en niños operados de cardiopatías congénitas

Abstract Background: In congenital heart surgery, low cardiac output syndrome (LCOS) is a major cause of morbidity in the immediate post-operative period. A decrease in cardiac output leads to an increase in tissue oxygen consumption. Several biomarkers such as venous oxygen saturation (SvO2), arteriovenous oxygen difference (DavO2), and lactate can assess tissue perfusion in the presence of LCOS. Recently, central venous to arterial CO2 difference (ΔCO2) has been proposed as a biomarker of tissue ischemia that could be used as a predictor of death in neonatal patients. This study aimed to analyze the relationship between ΔCO2 and immediate post-operative outcomes in pediatric patients undergoing congenital heart surgery and its correlation with DavO2, SvO2, and lactate. Methods: We conducted a longitudinal study of patients aged 0-18 years who underwent congenital heart surgery with or without cardiopulmonary bypass at the Instituto Nacional de Pediatría, from March 2019 to March 2021. Results: Eighty-two patients were included; the median age was 17 months. About 59% had a ΔCO2 ≥ 6 mmHg. Patients with ΔCO2 ≥ 6 mmHg had a vasoactive-inotropic score > 5 (p < 0.001), DavO2 > 5 mL/dL (p = 0.048), and lactate > 2 mmol/L (p = 0.027), as well as a longer hospital stay (p = 0.043). Patients with ΔCO2 > 6 mmHg and vasoactive-inotropic score ≥ 10 were 12.6 times more likely to die. Conclusion: ΔCO2 is a good marker of tissue hypoperfusion and outcome in the post-operative period of congenital heart surgery.

Resumen Introducción: En la cirugía cardiaca de malformaciones congénitas, el síndrome de bajo gasto cardiaco (SBGC) es una de las principales causas de morbilidad en el postoperatorio inmediato. La caída del gasto cardiaco aumenta el consumo de oxígeno en los tejidos. Varios biomarcadores, como la saturación venosa de oxígeno (SvO2), la diferencia arteriovenosa de oxígeno (DavO2) y el lactato han sido utilizados como indicadores hipoperfusión tisular en presencia de SBGC. Recientemente, la diferencia arteriovenosa de CO2 (ΔCO2) se ha propuesto como otro biomarcador de isquemia tisular que podría utilizarse como predictor de muerte en pacientes en edad neonatal. El objetivo de este estudio fue analizar la relación entre la ΔCO2 y la evolución postoperatoria de pacientes pediátricos operados de cardiopatías congénitas y correlacionarlo con la DavO2, SvO2 y lactato. Métodos: Se realizó un estudio longitudinal en pacientes de 0 a 18 años operados de corazón con empleo de bomba de circulación extracorpórea en el Instituto Nacional de Pediatría. Resultados: Se incluyeron 82 pacientes; la mediana de edad fue de 17 meses. El 59% presentó un ΔCO2 > 6 mmHg. Los pacientes con un ΔCO2 > 6 mmHg mostraron un puntaje de inotrópicos > 5 (p < 0.001), DavO2 > 5 mL/dL (p = 0.048) y lactato > 2 mmol/L (p = 0.027), así como mayor estancia hospitalaria (p = 0.043). Los pacientes con ΔCO2 > 6 mmHg y un puntaje de inotrópicos ≥ 10 presentaron una probabilidad de muerte 12.6 veces mayor. Conclusiones: El ΔCO2 en el periodo postoperatorio de una cirugía cardiaca congénita es un buen marcador de hipoperfusión tisular y de desenlace.

Autonomic denervation, myocardial hypoperfusion and fibrosis may predict ventricular arrhythmia in the early stages of Chagas cardiomyopathy.

BACKGROUND: Sudden cardiac death (SCD) can be the first clinical event of Chagas heart disease (CHD). However, current guidelines contain no clear recommendation for early cardioverter-defibrillator implantation. Using imaging modalities, we evaluated associations among autonomic denervation, myocardial hypoperfusion, fibrosis and ventricular arrhythmia in CHD. METHODS AND RESULTS: Twenty-nine patients with CHD and preserved left ventricular function underwent 123I-metaiodobenzylguanidine (MIBG) scintigraphy, 99mTc-methoxyisobutylisonitrile (MIBI) myocardial perfusion and cardiac magnetic resonance imaging (MRI). They were divided into arrhythmic (≥ 6 ventricular premature complexes/h and/or non-sustained ventricular tachycardia on 24-hour Holter, n = 15) and non-arrhythmic (< 6 ventricular premature complexes/h and no ventricular tachycardia; n = 14) groups. The arrhythmic group had higher denervation scores from MIBG imaging (23.2 ± 18.7 vs 5.6 ± 4.9; P < .01), hypoperfusion scores from MIBI SPECT (4.7 ± 6.8 vs 0.29 ± 0.6: P = .02), innervation/perfusion mismatch scores (18.5 ± 17.5 vs 5.4 ± 4.8; P = .01) and fibrosis by late gadolinium enhancement on MRI (14.3% ± 13.5% vs 4.0% ± 2.9%; P = .04) than the non-arrhythmic group. CONCLUSION: These imaging parameters were associated with ventricular arrhythmia in early CHD and may enable risk stratification and the implementation of primary preventive strategies for SCD.

Association of ictal aphasia with hypoperfusion in language areas in temporal lobe epilepsy patients.

Ictal clinical phenomenology, including aphasia, is usually associated with increased regional cerebral perfusion. We present an unusual pattern of ictal cerebral perfusion in three patients with pharmacoresistant, lesional temporal lobe epilepsy and ictal/postictal aphasia studied with prolonged video-EEG, ictal, and interictal SPECT and MRI for pre-surgical evaluation. Subtraction of ictal-interictal SPECT images co-registered with MRI (SISCOM) showed ictal hyperperfusion in the temporal epileptogenic area in all patients. In addition, hypoperfusion of Broca's area in one case, Wernicke's area in other patient, and both areas in the remaining one were observed. Ictal aphasia in these patients may be explained by functional inhibition of a primary language area, driven by the epileptogenic network. This pattern can contribute to understand the pathophysiology of some ictal signs, with an impact on the evaluation of individual surgical risks.

Comparison of gastric reactance with commonly used perfusion markers in a swine hypovolemic shock model.

BACKGROUND: The gut has been hypothesized to be a protagonist tissue in multiple organ dysfunction syndrome (MODS) for the past three decades. Gastric reactance (XL) is a potential perfusion marker derived from gastric impedance spectroscopy (GIS), which is an emerging tool through which living tissue can be continuously measured to determine its pathophysiological evolution. This study aimed to compare the performance of XL [positive predictive values (PPV), negative predictive values (NPV), and area under the curve (AUC)] against commonly used perfusion markers before and during hypovolemic shock in swine subjects. METHODS: Prospective, controlled animal trial with two groups, control group (CG) N = 5 and shock (MAP ≤ 48 mmHg) group (SG) N = 16. Comparison time points were defined as T-2 (2 h before shock), T-1 (1 h before shock), T0 (shock), T1 (1 h after shock), and T2 (2 h after shock). Shock severity was assessed through blood gases, systemic and hemodynamic variables, and via histological examination for assessing inflammation-edema and detachment in the gastric mucosa. Macroscopic assessment of the gastric mucosa was defined in five levels (0-normal mucosa, 1-stippling or epithelial hemorrhage, 2-pale mucosa, 3-violet mucosa, and 4-marmoreal mucosa). Receiver Operating Characteristic (ROC) curves of perfusion markers and XL were calculated to identify optimal cutoff values and their individual ability to predict hypovolemic shock. RESULTS: Comparison among the CG and the SG showed statistically significant differences in XL measurements at T-1, T0, T1, and T2, while lactate showed statistically significant differences until T1 and T2. Statistically significant differences were detected in mucosa class (p < 0.001) and in inflammation-edema in the gastric body and the fundus (p = 0.021 and p = 0.043). The performance of the minimum XL value per subject  per event (XL_Min) was better (0.81 ≤ AUC ≤ 0.96, 0.93 ≤ PPV ≤ 1.00, 0.45 ≤ NPV ≤ 0.83) than maximum lactate value (Lac_Max) per subject per event (0.29 ≤ AUC ≤ 0.82, 0.82 ≤ PPV ≤ 0.91, 0.24 ≤ NPV ≤ 0.82). Cutoff values for XL_Min show progressive increases at each time point, while cutoff values for Lac_Max increase only at T2. CONCLUSIONS: XL proved to be an indirect and consistent marker of inadequate gastric mucosal perfusion, which shows significant and detectable changes before commonly used markers of global perfusion under the hypovolemic shock conditions outlined in this work.

Choroidal ischemia as one cardinal sign in giant cell arteritis.

PURPOSE: To describe chorioretinal signs in a case series of Giant Cell Arteritis (GCA). METHODS: This is a multicenter retrospective observational case series with GCA that presented with a headache and an abrupt, unilateral loss in vision. Workup included temporal artery biopsies, intravenous fluorescein angiography, optical coherence tomography (OCT), optical coherence tomography angiography (OCTA), blood levels of erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). RESULTS: There are a total of 8 GCA instances presented. Average age was 74.5. (Range 68-83 years). The patients reported that one eye's visual loss had suddenly started, along with a fresh headache and other systemic symptoms. Eight patients exhibited choroidal ischemia, five paracentral acute middle maculopathy (PAMM) lesions, five cotton wool spots, four anterior ischemic optic neuropathy, and one central retinal arterial occlusion at the time of presentation. The average ESR at presentation was 68 mm/hr (range 4-110), and 4/6 individuals had a significant increase. The mean CRP level was 6.2 mg/dL (range 2.0-15.4), and the level was always over the normal range. All patients' temporal artery biopsies were positive. CONCLUSION: Alongside PAMM lesions, cotton wool spots, anterior ischemic optic neuropathy, and central retinal artery occlusion, choroidal ischemia is a key angiographic indicator in the diagnosis of GCA. It may be crucial to recognize these typical ischemic chorioretinal signs while diagnosing GCA.

Early Cerebral Hypoperfusion in Patients with Orthostatic Intolerance Without Tachycardia During Head-Up Tilt Test is Independent of Vasovagal Response.

BACKGROUND: Cerebral hypoperfusion before syncope has been shown in patients with chronic orthostatic intolerance (OI) without tachycardia, but it is unknown if an initial decrease of cerebral blood flow velocity (CBFv) could be related to the vasovagal response (VVR) to head-up tilt test (HUTT). OBJECTIVE: The objective of the study was to compare cardiovascular, cerebrovascular, and autonomic variables during HUTT in OI patients with or without a VVR. METHODS: We included 74 subjects (58% female, mean age 33 ± 12 years) who underwent a 30-min HUTT and were divided into three groups: OI with VVR positive (VVR+), OI without VVR negative (VVR-), and asymptomatic healthy subjects with negative HUTT (control group). Cardiovascular, cerebrovascular, and autonomic variables were assessed beat-to-beat during HUTT with a Task Force monitor and a trans-cranial Doppler. Mean values were evaluated at baseline and throughout the first 10 min of tilting. RESULTS: Cardiovascular variables were similar in the three groups. Systolic, diastolic, and mean CBFv were similar in VVR+ and VVR-, but both groups had lower CBFv than the control group. Systolic and diastolic CBFv decreased from baseline since min 1 in VVR+ and VVR- and since min 5 in the control group. The mean CBFv had a significant decrease since min 1 compared to baseline in all groups. Spectral indices of heart rate and blood pressure variability showed a similar autonomic response to HUTT in all groups. CONCLUSION: Patients with chronic OI without tachycardia have early postural cerebral hypoperfusion, regardless of the VVR during HUTT.

Physical exercise promotes astrocyte coverage of microvessels in a model of chronic cerebral hypoperfusion.

BACKGROUND: Brain circulation disorders such as chronic cerebral hypoperfusion have been associated with a decline in cognitive function during the development of dementia. Astrocytes together with microglia participate in the immune response in the CNS and make them potential sentinels in the brain parenchyma. In addition, astrocytes coverage integrity has been related to brain homeostasis. Currently, physical exercise has been proposed as an effective intervention to promote brain function improvement. However, the neuroprotective effects of early physical exercise on the astrocyte communication with the microcirculation and the microglial activation in a chronic cerebral hypoperfusion model are still unclear. The aim of this study was to investigate the impact of early intervention with physical exercise on cognition, brain microcirculatory, and inflammatory parameters in an experimental model of chronic cerebral hypoperfusion induced by permanent bilateral occlusion of the common carotid arteries (2VO). METHODS: Wistar rats aged 12 weeks were randomly divided into four groups: Sham-sedentary group (Sham-Sed), Sham-exercised group (Sham-Ex), 2VO-sedentary group (2VO-Sed), and 2VO-exercised group (2VO-Ex). The early intervention with physical exercise started 3 days after 2VO or Sham surgery during 12 weeks. Then, the brain functional capillary density and endothelial-leukocyte interactions were evaluated by intravital microscopy; cognitive function was evaluated by open-field test; hippocampus postsynaptic density protein 95 and synaptophysin were evaluated by western blotting; astrocytic coverage of the capillaries, microglial activation, and structural capillary density were evaluated by immunohistochemistry. RESULTS: Early moderate physical exercise was able to normalize functional capillary density and reduce leukocyte rolling in the brain of animals with chronic cerebral hypoperfusion. These effects were accompanied by restore synaptic protein and the improvement of cognitive function. In addition, early moderate exercise improves astrocytes coverage in blood vessels of the cerebral cortex and hippocampus, decreases microglial activation in the hippocampus, and improves structural capillaries in the hippocampus. CONCLUSIONS: Microcirculatory and inflammatory changes in the brain appear to be involved in triggering a cognitive decline in animals with chronic cerebral ischemia. Therefore, early intervention with physical exercise may represent a preventive approach to neurodegeneration caused by chronic cerebral hypoperfusion.

Characteristics of resuscitation, and association between use of dynamic tests of fluid responsiveness and outcomes in septic patients: results of a multicenter prospective cohort study in Argentina.

BACKGROUND: Resuscitation of septic patients regarding goals, monitoring aspects and therapy is highly variable. Our aim was to characterize cardiovascular and fluid management of sepsis in Argentina, a low and middle-income country (LMIC). Furthermore, we sought to test whether the utilization of dynamic tests of fluid responsiveness, as a guide for fluid therapy after initial resuscitation in patients with persistent or recurrent hypoperfusion, was associated with decreased mortality. METHODS: Secondary analysis of a national, multicenter prospective cohort study (n = 787) fulfilling Sepsis-3 definitions. Epidemiological characteristics, hemodynamic management data, type of fluids and vasopressors administered, physiological variables denoting hypoperfusion, use of tests of fluid responsiveness, and outcomes, were registered. Independent predictors of mortality were identified with logistic regression analysis. RESULTS: Initially, 584 of 787 patients (74%) had mean arterial pressure (MAP) < 65 mm Hg and/or signs of hypoperfusion and received 30 mL/kg of fluids, mostly normal saline (53%) and Ringer lactate (35%). Vasopressors and/or inotropes were administered in 514 (65%) patients, mainly norepinephrine (100%) and dobutamine (9%); in 22%, vasopressors were administered before ending the fluid load. After this, 413 patients (53%) presented persisting or recurrent hypotension and/or hypoperfusion, which prompted administration of additional fluid, based on: lactate levels (66%), urine output (62%), heart rate (54%), central venous O2 saturation (39%), central venous-arterial PCO2 difference (38%), MAP (31%), dynamic tests of fluid responsiveness (30%), capillary-refill time (28%), mottling (26%), central venous pressure (24%), cardiac index (13%) and/or pulmonary wedge pressure (3%). Independent predictors of mortality were SOFA and Charlson scores, lactate, requirement of mechanical ventilation, and utilization of dynamic tests of fluid responsiveness. CONCLUSIONS: In this prospective observational study assessing the characteristics of resuscitation of septic patients in Argentina, a LMIC, the prevalent use of initial fluid bolus with normal saline and Ringer lactate and the use of norepinephrine as the most frequent vasopressor, reflect current worldwide practices. After initial resuscitation with 30 mL/kg of fluids and vasopressors, 413 patients developed persistent or recurrent hypoperfusion, which required further volume expansion. In this setting, the assessment of fluid responsiveness with dynamic tests to guide fluid resuscitation was independently associated with decreased mortality.

Relationship between microvascular changes, autonomic denervation, and myocardial fibrosis in Chagas cardiomyopathy: Evaluation by MRI and SPECT imaging.

BACKGROUND: The relationship between microvasculopathy, autonomic denervation, and myocardial fibrosis, in Chagas cardiomyopathy is incompletely understood. The aim of this study was to explore the relative extent and anatomic distribution of myocardial hypoperfusion, autonomic denervation, and myocardial scarring using Single-Photon Emission Computerized Tomography (SPECT) imaging and Magnetic Resonance Imaging (MRI). METHODS: Thirteen patients with Chagas disease all had Iodine-123-metaiodobenzylguanidine (MIBG) SPECT, 99mTc-Sestamibi (MIBI) rest-stress SPECT, and gadolinium late enhancement MRI imaging within a 2-month interval. The anatomic location and extent of denervation, of stress-induced hypoperfusion and fibrosis, were assessed through image co-registration and quantification of abnormal tissue areas as a percent of total myocardium. RESULTS: The results showed a strong general anatomic concordance between areas of hypoperfusion, denervation, and fibrosis, suggesting that the three abnormal features may be correlated. Myocardial denervation was anatomically and quantitatively closely associated areas of stress hypoperfusion. CONCLUSION: Combined myocardial analysis of the extent and location of autonomic denervation, hypoperfusion, and scarring may allow for better understanding of the pathophysiology of Chagas cardiomyopathy. Autonomic myocardial denervation may be a more sensitive marker of cardiac involvement in Chagas Disease than finding by other imaging modalities.

Effects of Patent Ductus Arteriosus on Organ Blood Flow in Infants Born Very Preterm: A Prospective Study with Serial Echocardiography.

OBJECTIVE: To characterize the effects of a patent ductus arteriosus (PDA) on different organ blood flows in infants born preterm. STUDY DESIGN: Infants born preterm at ≤30 weeks of gestational age had daily echocardiography and Doppler assessments of middle cerebral artery, celiac artery, superior mesenteric (SMA), and renal arteries (RA) during the first postnatal week. Abnormal organ blood flow was defined as either reverse or absent diastolic flow, abnormally low mean or systolic velocities, or abnormally high pulsatility or resistance index. RESULTS: Twenty-five infants born very preterm (gestational age 27.0 ± 2.1 weeks) were enrolled. PDA presence at time of measurement increased the risk of abnormal organ blood flows (39% vs 8%, P < .001). Ductal diameter and left atrium-to-aortic root (LA/Ao) ratio correlated positively with resistance index (celiac artery, SMA, RA), and negatively with mean velocity (ductal diameter: SMA, RA; LA/Ao ratio: RA). A PDA >2.0 mm, LA/Ao ratio >1.4, and their combination were associated with 8.0 (95% CI 1.6-39.4)-, 6.7 (1.3-34.7)-, and 38.2 (3.2-455.5)-fold increase in risk of abnormal organ blood flow index, respectively. Abnormal descending aorta flow was detected in only 2% of measurements. CONCLUSIONS: Ductal size >2.0 mm and LA/Ao >1.4, especially in combination, are associated with a greater risk of abnormal organ blood flows. We suggest that Doppler assessment of the renal and superior mesenteric arteries are more likely to detect systemic hypoperfusion than the descending aorta.

Experience of combined use of a Bakri uterine balloon and a non-pneumatic anti-shock garment in a university hospital in Colombia.

OBJECTIVE: To compare the outcomes of women with postpartum hemorrhage (PPH) refractory to initial management and in a state of hypoperfusion between management with a non-pneumatic anti-shock garment (NASG) and Bakri balloon and management with other surgical interventions. METHODS: A retrospective observational descriptive study of women with PPH and hemorrhagic shock who were treated at a high complexity obstetric unit in Columbia between 2011 and 2017. Clinical records were reviewed and women were divided in two groups by clinical management. Group 1 women were managed with surgical interventions; group 2 women were managed with NASG plus a Bakri balloon. RESULTS: Overall, 142 women were treated for PPH, with 69 in group 1 and 73 in group 2). There were differences between group 1 and group 2 in the degree of hypovolemic shock (shock index: 1.1 vs 0.9, P=0.02), indicators associated with hypoperfusion (lactic acid, 2.9 vs 1.9 mmol/L, P=0.001), and frequency of transfusion of blood components (68% vs 44%, P<0.05). CONCLUSIONS: The joint use of NASG and Bakri balloon in PPH management seemed to improve hypoperfusion-related markers such as lactic acid and shock index, and reduce the frequency of additional blood transfusion.

Blood lactate increases with the progression of mitral valve disease in dogs / Aumento de lactato sanguíneo com progressão de valvopatia mitral em cães

In dogs with congestive heart failure, the upregulated sympathetic tone causes vasoconstriction that impairs peripheral blood supply, therefore causing the accumulation of lactate. In this prospective cross-sectional study with a longitudinal component, blood lactate was quantified in 10 healthy and 34 myxomatous mitral valve disease (MMVD) dogs to investigate its potential use as a diagnostic and prognostic biomarker. While there were no differences in lactate concentration between control animals and stages B1 (3.31±0.62mmol/L) and B2 (3.32±0.46mmol/L) dogs, significant differences were found between healthy (2.50±0.69mmol/L) and both C (3.99±0.47mmol/L) and D (6.97±1.23mmol/L) animals. When a cut-off of 3.35mmol/L was used, lactate was able to distinguish dogs with normal and remodeled hearts with a sensitivity of 78.2% and specificity of 63.6%. Also, significant correlations existed between lactate and indicators of cardiac remodeling. Finally, animals with blood lactate <3.5mmol/L carried a better prognosis when compared with dogs in which lactate was >5.0mmol/L. Our results suggest that the progression of MMVD results in accumulation of lactate within the bloodstream, which is likely attributable to the impaired peripheral tissue perfusion. In MMVD dogs, blood lactate may be used as a surrogate for cardiac remodeling, and an increased concentration is associated with a worse prognosis regarding the time to evolve into congestive heart failure.(AU)

Em cães com insuficiência cardíaca congestiva, o tônus simpático hiperregulado causa vasoconstrição e interfere com o suprimento sanguíneo periférico, resultando no acúmulo de lactato. Neste estudo prospectivo transversal com um componente longitudinal, o lactato sanguíneo foi quantificado em 10 cães saudáveis e 34 cães com doença mixomatosa da valva mitral (DMVM) para investigar seu potencial como biomarcador diagnóstico e prognóstico. Embora não tenham sido identificadas diferenças na concentração de lactato entre animais controle e cães com DMVM nos estágios B1 (3,31±0,62mmol/L) e B2 (3,32±0,46mmol/L), diferenças significativas foram constatadas entre os cães saudáveis (2,50±0,69mmol/L) e cães com DMVM estágio C (3,99±0,47mmol/L) ou D (6,97±1,23mmol/L). Quando utilizado o valor de corte de 3,35mmol/L, o lactato foi capaz de diferenciar cães com corações normais daqueles com corações remodelados com sensibilidade de 78,2% e especificidade de 63,6%. Além disso, correlações significativas foram encontradas entre o lactato e os indicadores de remodelamento cardíaco. Por fim, os animais com lactato sanguíneo <3,5mmol/L tiveram prognóstico melhor comparativamente aos cães com concentrações >5,0mmol/L. Nossos resultados sugerem que a progressão da DMVM resulta no acúmulo de lactato na corrente sanguínea, fato que é provavelmente atribuído à perfusão periférica prejudicada. Em cães com DMVM, o lactato sanguíneo pode ser utilizado como indicador de remodelamento cardíaco, cuja concentração elevada está associada com pior prognóstico relativo ao tempo para evoluir para insuficiência cardíaca congestiva.(AU)

Blood lactate increases with the progression of mitral valve disease in dogs / Aumento de lactato sanguíneo com progressão de valvopatia mitral em cães

In dogs with congestive heart failure, the upregulated sympathetic tone causes vasoconstriction that impairs peripheral blood supply, therefore causing the accumulation of lactate. In this prospective cross-sectional study with a longitudinal component, blood lactate was quantified in 10 healthy and 34 myxomatous mitral valve disease (MMVD) dogs to investigate its potential use as a diagnostic and prognostic biomarker. While there were no differences in lactate concentration between control animals and stages B1 (3.31±0.62mmol/L) and B2 (3.32±0.46mmol/L) dogs, significant differences were found between healthy (2.50±0.69mmol/L) and both C (3.99±0.47mmol/L) and D (6.97±1.23mmol/L) animals. When a cut-off of 3.35mmol/L was used, lactate was able to distinguish dogs with normal and remodeled hearts with a sensitivity of 78.2% and specificity of 63.6%. Also, significant correlations existed between lactate and indicators of cardiac remodeling. Finally, animals with blood lactate <3.5mmol/L carried a better prognosis when compared with dogs in which lactate was >5.0mmol/L. Our results suggest that the progression of MMVD results in accumulation of lactate within the bloodstream, which is likely attributable to the impaired peripheral tissue perfusion. In MMVD dogs, blood lactate may be used as a surrogate for cardiac remodeling, and an increased concentration is associated with a worse prognosis regarding the time to evolve into congestive heart failure.(AU)

Em cães com insuficiência cardíaca congestiva, o tônus simpático hiperregulado causa vasoconstrição e interfere com o suprimento sanguíneo periférico, resultando no acúmulo de lactato. Neste estudo prospectivo transversal com um componente longitudinal, o lactato sanguíneo foi quantificado em 10 cães saudáveis e 34 cães com doença mixomatosa da valva mitral (DMVM) para investigar seu potencial como biomarcador diagnóstico e prognóstico. Embora não tenham sido identificadas diferenças na concentração de lactato entre animais controle e cães com DMVM nos estágios B1 (3,31±0,62mmol/L) e B2 (3,32±0,46mmol/L), diferenças significativas foram constatadas entre os cães saudáveis (2,50±0,69mmol/L) e cães com DMVM estágio C (3,99±0,47mmol/L) ou D (6,97±1,23mmol/L). Quando utilizado o valor de corte de 3,35mmol/L, o lactato foi capaz de diferenciar cães com corações normais daqueles com corações remodelados com sensibilidade de 78,2% e especificidade de 63,6%. Além disso, correlações significativas foram encontradas entre o lactato e os indicadores de remodelamento cardíaco. Por fim, os animais com lactato sanguíneo <3,5mmol/L tiveram prognóstico melhor comparativamente aos cães com concentrações >5,0mmol/L. Nossos resultados sugerem que a progressão da DMVM resulta no acúmulo de lactato na corrente sanguínea, fato que é provavelmente atribuído à perfusão periférica prejudicada. Em cães com DMVM, o lactato sanguíneo pode ser utilizado como indicador de remodelamento cardíaco, cuja concentração elevada está associada com pior prognóstico relativo ao tempo para evoluir para insuficiência cardíaca congestiva.(AU)

Neuroprotection Targeting Protein Misfolding on Chronic Cerebral Hypoperfusion in the Context of Metabolic Syndrome.

Metabolic syndrome (MetS) is a cluster of risk factors that lead to microvascular dysfunction and chronic cerebral hypoperfusion (CCH). Long-standing reduction in oxygen and energy supply leads to brain hypoxia and protein misfolding, thereby linking CCH to Alzheimer's disease. Protein misfolding results in neurodegeneration as revealed by studying different experimental models of CCH. Regulating proteostasis network through pathways like the unfolded protein response (UPR), the ubiquitin-proteasome system (UPS), chaperone-mediated autophagy (CMA), and macroautophagy emerges as a novel target for neuroprotection. Lipoxin A4 methyl ester, baclofen, URB597, N-stearoyl-L-tyrosine, and melatonin may pose potential neuroprotective agents for rebalancing the proteostasis network under CCH. Autophagy is one of the most studied pathways of proteostatic cell response against the decrease in blood supply to the brain though the role of the UPR-specific chaperones and the UPS system in CCH deserves further research. Pharmacotherapy targeting misfolded proteins at different stages in the proteostatic pathway might be promising in treating cognitive impairment following CCH.