Statins prevent cognitive impairment after sepsis by reverting neuroinflammation, and microcirculatory/endothelial dysfunction.

Acute brain dysfunction is a frequent condition in sepsis patients and is associated with increased mortality and long-term neurocognitive consequences. Impaired memory and executive function are common findings in sepsis survivors. Although neuroinflammation and blood-brain barrier dysfunction have been associated with acute brain dysfunction and its consequences, no specific treatments are available that prevent cognitive impairment after sepsis. Experimental sepsis was induced in Swiss Webster mice by intraperitoneal injection of cecal material (5mg/kg, 500µL). Control groups (n=5/group each experiment) received 500µL of saline. Support therapy recover (saline 0.9%, 1mL and imipenem 30mg/kg) were applied (6, 24 and 48h post injection, n=5-10/group, each experiment), together or not with additive orally treatment with statins (atorvastatin/simvastatin 20mg/kg b.w.). Survival rate was monitored at 6, 24 and 48h. In a setting of experiments, animals were euthanized at 6 and 24h after induction for biochemical, immunohistochemistry and intravital analysis. Statins did not prevented mortality in septic mice, however survivors presented lower clinical score. At another setting of experiments, after 15days, mice survivors from fecal supernatant peritoneal sepsis presented cognitive dysfunction for contextual hippocampal and aversive amygdala-dependent memories, which was prevented by atorvastatin/simvastatin treatment. Systemic and brain tissue levels of proinflammatory cytokines/chemokines and activation of microglial were lower in septic mice treated with statins. Brain lipid peroxidation and myeloperoxidase levels were also reduced by statins treatment. Intravital examination of the brain vessels of septic animals revealed decreased functional capillary density and increased rolling and adhesion of leukocytes, and blood flow impairment, which were reversed by treatment with statins. In addition, treatment with statins restored the cholinergic vasodilator response due to sepsis. Taken together, these data demonstrated that statins reverse microvascular dysfunction and reduce neuroinflammation during sepsis, preventing the development of long-term cognitive decline.

Microvascular Function and Endothelial Progenitor Cells in Patients with Severe Hypercholesterolemia and the Familial Hypercholesterolemia Phenotype.

OBJECTIVE: To evaluate endothelial progenitor cells (EPCs) and systemic microvascular function in patients with severe hypercholesterolemia, comparing patients with the definite familial hypercholesterolemia (FH) phenotype (DFH) or probable/possible FH phenotype (PFH). There is a large spectrum of atherosclerotic disease between these two clinical phenotypes of FH, and to acquire further knowledge of the pathophysiology of vascular disease in both is desirable. METHODS: Subjects with severe hypercholesterolemia, defined as low-density lipoprotein cholesterol (LDL-C) >190 mg/dL, were classified as DFH or PFH and underwent measurement of the number of EPCs by flow cytometry and evaluation of cutaneous microvascular reactivity using a laser speckle contrast-imaging system with iontophoresis of acethylcholine (ACh) or sodium nitroprusside. EPCs were defined as CD45- or CD45low, CD34+CD133+CD309+ cells. Categorical variables were compared using Fisher test and continuous variables with Student t test or Mann-Whitney test, and a value of p < 0.05 was considered statistically significant. RESULTS: Patients with DFH had higher LDL-C than those with PFH. There was no difference in the median number of EPCs between patients with DFH or PFH, but there was a significant reduction of endothelial-dependent, ACh-induced vasodilatation in the former. CONCLUSION: Patients with DFH have impaired microvascular endothelial-dependent vasodilatation compared to those with PFH, indicating more severe vascular disease in the former.

Statins decrease neuroinflammation and prevent cognitive impairment after cerebral malaria.

Cerebral malaria (CM) is the most severe manifestation of Plasmodium falciparum infection in children and non-immune adults. Previous work has documented a persistent cognitive impairment in children who survive an episode of CM that is mimicked in animal models of the disease. Potential therapeutic interventions for this complication have not been investigated, and are urgently needed. HMG-CoA reductase inhibitors (statins) are widely prescribed for cardiovascular diseases. In addition to their effects on the inhibition of cholesterol synthesis, statins have pleiotropic immunomodulatory activities. Here we tested if statins would prevent cognitive impairment in a murine model of cerebral malaria. Six days after infection with Plasmodium berghei ANKA (PbA) mice displayed clear signs of CM and were treated with chloroquine, or chloroquine and lovastatin. Intravital examination of pial vessels of infected animals demonstrated a decrease in functional capillary density and an increase in rolling and adhesion of leukocytes to inflamed endothelium that were reversed by treatment with lovastatin. In addition, oedema, ICAM-1, and CD11b mRNA levels were reduced in lovastatin-treated PbA-infected mice brains. Moreover, HMOX-1 mRNA levels are enhanced in lovastatin-treated healthy and infected brains. Oxidative stress and key inflammatory chemokines and cytokines were reduced to non-infected control levels in animals treated with lovastatin. Fifteen days post-infection cognitive dysfunction was detected by a battery of cognition tests in animals rescued from CM by chloroquine treatment. In contrast, it was absent in animals treated with lovastatin and chloroquine. The outcome was similar in experimental bacterial sepsis, suggesting that statins have neuroprotective effects in severe infectious syndromes in addition to CM. Statin treatment prevents neuroinflammation and blood brain barrier dysfunction in experimental CM and related conditions that are associated with cognitive sequelae, and may be a valuable adjuvant therapeutic agent for prevention of cognitive impairment in patients surviving an episode of CM.

High-intensity interval training or continuous training, combined or not with fasting, in obese or overweight women with cardiometabolic risk factors: study protocol for a randomised clinical trial.

INTRODUCTION: Physical inactivity and increased caloric intake play important roles in the pathophysiology of obesity. Increasing physical activity and modifying eating behaviours are first-line interventions, frequently hampered by lack of time to exercise and difficulties in coping with different diets. High-intensity interval training (HIIT) may be a time-efficient method compared with moderate-intensity continuous training (CT). Conversely, diets with a fasting component may be more effective than other complex and restrictive diets, as it essentially limits caloric intake to a specified period without major diet composition changes. Therefore, the combination of HIIT and fasting may provide incremental benefits in terms of effectiveness and time efficiency in obese and sedentary populations. The aim of this study is to determine the effect of HIIT versus CT, combined or not with fasting, on microcirculatory function, cardiometabolic parameters, anthropometric indices, cardiorespiratory fitness and quality of life in a population of sedentary overweight or obese women with cardiometabolic risk factors. METHODS AND ANALYSIS: Sedentary women aged 30-50 years, with a body mass index ≥25 kg/m2 and cardiometabolic risk factors, will be randomised to HIIT performed in the fasting state, HIIT performed in the fed state, CT in the fasting state or CT in the fed state. Cardiometabolic parameters, anthropometric indices, cardiorespiratory fitness, quality of life and microvascular function (cutaneous capillary density and microvascular reactivity evaluated by laser speckle contrast imaging) will be evaluated before initiation of the interventions and 16 weeks thereafter. ETHICS AND DISSEMINATION: The trial complies with the Declaration of Helsinki and has been approved by the local ethics committee (Instituto Nacional de Cardiologia, Rio de Janeiro, Brazil). All patients provide written informed consent before enrolment and randomisation. The study's results will be disseminated to the healthcare community by publications and presentations at scientific meetings. TRIAL REGISTRATION NUMBER: NCT03236285.