Croston TL, Thapa D, Holden AA, Tveter KJ, Lewis SE, Shepherd DL, Nichols CE, Long DM, Olfert IM, Jagannathan R, Hollander JM. Functional deficiencies of subsarcolemmal mitochondria in the type 2 diabetic human heart. Am J Physiol Heart Circ Physiol 307: H54 -H65, 2014. First published April 28, 2014 doi:10.1152/ajpheart.00845.2013.-The mitochondrion has been implicated in the development of diabetic cardiomyopathy. Examination of cardiac mitochondria is complicated by the existence of spatially distinct subpopulations including subsarcolemmal (SSM) and interfibrillar (IFM). Dysfunction to cardiac SSM has been reported in murine models of type 2 diabetes mellitus; however, subpopulationbased mitochondrial analyses have not been explored in type 2 diabetic human heart. The goal of this study was to determine the impact of type 2 diabetes mellitus on cardiac mitochondrial function in the human patient. Mitochondrial subpopulations from atrial appendages of patients with and without type 2 diabetes were examined. Complex I-and fatty acid-mediated mitochondrial respiration rates were decreased in diabetic SSM compared with nondiabetic (P Յ 0.05 for both), with no change in IFM. Electron transport chain (ETC) complexes I and IV activities were decreased in diabetic SSM compared with nondiabetic (P Յ 0.05 for both), with a concomitant decline in their levels (P Յ 0.05 for both). Regression analyses comparing comorbidities determined that diabetes mellitus was the primary factor accounting for mitochondrial dysfunction. Linear spline models examining correlative risk for mitochondrial dysfunction indicated that patients with diabetes display the same degree of state 3 and electron transport chain complex I dysfunction in SSM regardless of the extent of glycated hemoglobin (HbA1c) and hyperglycemia. Overall, the results suggest that independent of other pathologies, mitochondrial dysfunction is present in cardiac SSM of patients with type 2 diabetes and the degree of dysfunction is consistent regardless of the extent of elevated HbA1c or blood glucose levels. mitochondria; diabetes mellitus; diabetic cardiomyopathy DIABETES MELLITUS IS A CONDITION that is becoming epidemic in proportion, with an estimated 330 million to be affected worldwide by the year 2030 (12). Of the individuals diagnosed, type 2 diabetes mellitus accounts for ϳ90 -95% of cases (12), which has been attributed to poor diet and sedentary lifestyles (21). Type 2 diabetes mellitus is characterized by insulin resistance resulting from an imbalance in glucose homeostasis (21). The body does not properly use the insulin produced in response to increased blood glucose levels, and over time the pancreas eventually loses its ability to produce insulin (12).Cardiomyopathies are a leading cause of morbidity and mortality in individuals with diabetes mellitus (18). Mitochondrial dysfunction contributes to the development of cardiovascular complications resulting from type 2 diabetes mellitus (7, 9, 15). The cardiomyocyte possesses spatially distinct subpopulati...

Mitofilin, also known as heart muscle protein, is an inner mitochondrial membrane structural protein that plays a central role in maintaining cristae morphology and structure. It is a critical component of the mitochondrial contact site and cristae organizing system (MICOS) complex which is important for mitochondrial architecture and cristae morphology. Our laboratory has previously reported alterations in mitochondrial morphology and proteomic make-up during type 1 diabetes mellitus, with mitofilin being significantly down-regulated in interfibrillar mitochondria (IFM). The goal of this study was to investigate whether overexpression of mitofilin can limit mitochondrial disruption associated with the diabetic heart through restoration of mitochondrial morphology and function. A transgenic mouse line overexpressing mitofilin was generated and mice injected intraperitoneally with streptozotocin using a multi low-dose approach. Five weeks following diabetes mellitus onset, cardiac contractile function was assessed. Restoration of ejection fraction and fractional shortening was observed in mitofilin diabetic mice as compared to wild-type controls (P<0.05 for both). Decrements observed in electron transport chain (ETC) complexes I, III, IV and V activities, state 3 respiration, lipid peroxidation as well as mitochondria membrane potential in type 1 diabetic IFM were restored in mitofilin diabetic mice (P<0.05 for all). Qualitative analyses of electron micrographs revealed restoration of mitochondrial cristae structure in mitofilin diabetic mice as compared to wild-type controls. Furthermore measurement of mitochondrial internal complexity using flow cytometry displayed significant reduction in internal complexity in diabetic IFM which was restored in mitofilin diabetic IFM (P<0.05). Taken together these results suggest that transgenic overexpression of mitofilin preserves mitochondrial structure, leading to restoration of mitochondrial function and attenuation of cardiac contractile dysfunction in the diabetic heart.

Nodal status seems to be an important prognostic factor in patients with thymic carcinoma and thymic neuroendocrine tumors. Nodal sampling should be performed during resection of these thymic malignancies.

ImportancePlatelet activation is a potential therapeutic target in patients with COVID-19.ObjectiveTo evaluate the effect of P2Y12 inhibition among critically ill patients hospitalized for COVID-19.Design, Setting, and ParticipantsThis international, open-label, adaptive platform, 1:1 randomized clinical trial included critically ill (requiring intensive care–level support) patients hospitalized with COVID-19. Patients were enrolled between February 26, 2021, through June 22, 2022. Enrollment was discontinued on June 22, 2022, by the trial leadership in coordination with the study sponsor given a marked slowing of the enrollment rate of critically ill patients.InterventionParticipants were randomly assigned to receive a P2Y12 inhibitor or no P2Y12 inhibitor (usual care) for 14 days or until hospital discharge, whichever was sooner. Ticagrelor was the preferred P2Y12 inhibitor.Main Outcomes and MeasuresThe primary outcome was organ support–free days, evaluated on an ordinal scale that combined in-hospital death and, for participants who survived to hospital discharge, the number of days free of cardiovascular or respiratory organ support up to day 21 of the index hospitalization. The primary safety outcome was major bleeding, as defined by the International Society on Thrombosis and Hemostasis.ResultsAt the time of trial termination, 949 participants (median [IQR] age, 56 [46-65] years; 603 male [63.5%]) had been randomly assigned, 479 to the P2Y12 inhibitor group and 470 to usual care. In the P2Y12 inhibitor group, ticagrelor was used in 372 participants (78.8%) and clopidogrel in 100 participants (21.2%). The estimated adjusted odds ratio (AOR) for the effect of P2Y12 inhibitor on organ support–free days was 1.07 (95% credible interval, 0.85-1.33). The posterior probability of superiority (defined as an OR &amp;gt; 1.0) was 72.9%. Overall, 354 participants (74.5%) in the P2Y12 inhibitor group and 339 participants (72.4%) in the usual care group survived to hospital discharge (median AOR, 1.15; 95% credible interval, 0.84-1.55; posterior probability of superiority, 80.8%). Major bleeding occurred in 13 participants (2.7%) in the P2Y12 inhibitor group and 13 (2.8%) in the usual care group. The estimated mortality rate at 90 days for the P2Y12 inhibitor group was 25.5% and for the usual care group was 27.0% (adjusted hazard ratio, 0.96; 95% CI, 0.76-1.23; P = .77).Conclusions and RelevanceIn this randomized clinical trial of critically ill participants hospitalized for COVID-19, treatment with a P2Y12 inhibitor did not improve the number of days alive and free of cardiovascular or respiratory organ support. The use of the P2Y12 inhibitor did not increase major bleeding compared with usual care. These data do not support routine use of a P2Y12 inhibitor in critically ill patients hospitalized for COVID-19.Trial RegistrationClinicalTrials.gov Identifier: NCT04505774

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