RESUMO
Despite significant therapeutic advancements, morbidity and mortality following myocardial infarction (MI) remain unacceptably high. This clinical challenge is primarily attributed to two significant factors: delayed reperfusion and the myocardial injury resulting from coronary reperfusion. Following reperfusion, there is a rapid intracellular pH shift, disruption of ionic balance, heightened oxidative stress, increased activity of proteolytic enzymes, initiation of inflammatory responses, and activation of several cell death pathways, encompassing apoptosis, necroptosis, and pyroptosis. The inflammatory cell death or pyroptosis encompasses the activation of the intracellular multiprotein complex known as the NLRP3 inflammasome. High-density lipoproteins (HDL) are endogenous particles whose components can either promote or mitigate the activation of the NLRP3 inflammasome. In this comprehensive review, we explore the role of inflammasome activation in the context of MI and provide a detailed analysis of how HDL can modulate this process.
Assuntos
Infarto do Miocárdio , Traumatismo por Reperfusão Miocárdica , Humanos , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Apoptose , PiroptoseRESUMO
Evolocumab and empagliflozin yield a modest rise in plasma high-density lipoprotein cholesterol (HDL-C) through unknown mechanisms. This study aims to assess the effect of evolocumab plus empagliflozin vs. empagliflozin alone on HDL subspecies isolated from individuals with type 2 diabetes mellitus (T2D). This post hoc prespecified analysis of the EXCEED-BHS3 trial compared the effects of a 16-week therapy with empagliflozin (E) alone or in combination with evolocumab (EE) on the lipid profile and cholesterol content in HDL subspecies in individuals with T2D divided equally into two groups of 55 patients. Both treatments modestly increased HDL-C. The cholesterol content in HDL subspecies 2a (7.3%), 3a (7.2%) and 3c (15%) increased from baseline in the E group, while the EE group presented an increase from baseline in 3a (9.3%), 3b (16%) and 3c (25%). The increase in HDL 3b and 3c was higher in the EE group when compared to the E group (p < 0.05). No significant interactive association was observed between changes in hematocrit and HDL-C levels after treatment. Over a 16-week period, empagliflozin with or without the addition of evolocumab led to a modest but significant increase in HDL-C. The rise in smaller-sized HDL particles was heterogeneous amongst the treatment combinations.
Assuntos
Compostos Benzidrílicos , Diabetes Mellitus Tipo 2 , Glucosídeos , Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , HDL-ColesterolRESUMO
PURPOSE: Coronavirus disease 19 (COVID-19) has, to date, been diagnosed in over 130 million persons worldwide and is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Several variants of concern have emerged including those in the United Kingdom, South Africa, and Brazil. SARS-CoV-2 can cause a dysregulated inflammatory response known as a cytokine storm, which can progress rapidly to acute respiratory distress syndrome (ARDS), multi-organ failure, and death. Suppressing these cytokine elevations may be key to improving outcomes. Remote ischemic conditioning (RIC) is a simple, non-invasive procedure whereby a blood pressure cuff is inflated and deflated on the upper arm for several cycles. "RIC in COVID-19" is a pilot, multi-center, randomized clinical trial, designed to ascertain whether RIC suppresses inflammatory cytokine production. METHODS: A minimum of 55 adult patients with diagnosed COVID-19, but not of critical status, will be enrolled from centers in the United Kingdom, Brazil, and South Africa. RIC will be administered daily for up to 15 days. The primary outcome is the level of inflammatory cytokines that are involved in the cytokine storm that can occur following SARS-CoV-2 infection. The secondary endpoint is the time between admission and until intensive care admission or death. The in vitro cytotoxicity of patient blood will also be assessed using primary human cardiac endothelial cells. CONCLUSIONS: The results of this pilot study will provide initial evidence on the ability of RIC to suppress the production of inflammatory cytokines in the setting of COVID-19. TRIAL REGISTRATION: NCT04699227, registered January 7th, 2021.
Assuntos
COVID-19 , Adulto , Cuidados Críticos , Síndrome da Liberação de Citocina/prevenção & controle , Citocinas , Células Endoteliais , Humanos , Projetos Piloto , SARS-CoV-2 , Resultado do TratamentoRESUMO
PURPOSE: Patients hospitalized with COVID-19 may develop a hyperinflammatory, dysregulated cytokine "storm" that rapidly progresses to acute respiratory distress syndrome, multiple organ dysfunction, and even death. Remote ischaemic conditioning (RIC) has elicited anti-inflammatory and cytoprotective benefits by reducing cytokines following sepsis in animal studies. Therefore, we investigated whether RIC would mitigate the inflammatory cytokine cascade induced by COVID-19. METHODS: We conducted a prospective, multicentre, randomized, sham-controlled, single-blind trial in Brazil and South Africa. Non-critically ill adult patients with COVID-19 pneumonia were randomly allocated (1:1) to receive either RIC (intermittent ischaemia/reperfusion applied through four 5-min cycles of inflation (20 mmHg above systolic blood pressure) and deflation of an automated blood-pressure cuff) or sham for approximately 15 days. Serum was collected following RIC/sham administration and analyzed for inflammatory cytokines using flow cytometry. The endpoint was the change in serum cytokine concentrations. Participants were followed for 30 days. RESULTS: Eighty randomized participants (40 RIC and 40 sham) completed the trial. Baseline characteristics according to trial intervention were overall balanced. Despite downward trajectories of all cytokines across hospitalization, we observed no substantial changes in cytokine concentrations after successive days of RIC. Time to clinical improvement was similar in both groups (HR 1.66; 95% CI, 0.938-2.948, p 0.08). Overall RIC did not demonstrate a significant impact on the composite outcome of all-cause death or clinical deterioration (HR 1.19; 95% CI, 0.616-2.295, p = 0.61). CONCLUSION: RIC did not reduce the hypercytokinaemia induced by COVID-19 or prevent clinical deterioration to critical care. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04699227.
RESUMO
BACKGROUND: The glucose-lowering independent effect of sodium glucose cotransporter-2 inhibitors (SGLT2i) on arterial wall function has not yet been clarified. This study aims to assess whether SGLT2i treatment can attenuate endothelial dysfunction related to type 2 diabetes mellitus (T2D) compared with glucose-lowering equivalent therapy. METHODS: In a prospective, open-label, single-center, randomized clinical trial, 98 patients with T2DM and carotid intima-media thickness above the 75th percentile were randomized 1:1 to 12 weeks of therapy with dapagliflozin or glibenclamide in addition to metformin in glucose-lowering equivalent regimens. The coprimary endpoints were 1-min flow-mediated dilation (FMD) at rest and 1-min FMD after 15 min of ischemia followed by 15 min of reperfusion time (I/R). RESULTS: Ninety-seven patients (61% males, 57 ± 7 years) completed the study. The median HbA1c decreased by - 0.8 (0.7)% and -0.7 (0.95)% following dapagliflozin and glibenclamide, respectively. The first coprimary endpoint, i.e., rest FMD changed by + 3.3(8.2)% and - 1.2(7.5)% for the dapagliflozin and glibenclamide arms, respectively (p = 0.0001). Differences between study arms in the second coprimary endpoint were not significant. Plasma nitrite 1 min after rest FMD was higher for dapagliflozin [308(220) nmol/L] than for glibenclamide (258[110] nmol/L; p = 0.028). The resistive indices at 1 min [0.90 (0.11) vs. 0.93 (0.07); p = 0.03] and 5 min [0.93 (0.07) vs. 0.95 (0.05); p = 0.02] were higher for the glibenclamide group than for the dapagliflozin group. Plasma biomarkers for inflammation and oxidative stress did not differ between the treatments. CONCLUSIONS: Dapagliflozin improved micro- and macrovascular endothelial function compared to glibenclamide, regardless of glycemic control in patients with T2DM and subclinical carotid atherosclerotic disease.