Citrate is a key intermediate in energy metabolism and an inhibitor of phosphofructokinase of the glycolytic pathway. During myocardial ischaemia glycolysis is the main source of cardiac ATP. The aim of the present study was to determine if myocardial ischaemia and reperfusion alter cardiac tissue levels of citrate. Open-chest, anaesthetized pigs were subjected to 10 min of regional myocardial ischaemia by occlusion of the left anterior descending coronary artery, with and without reperfusion, and to 10 min of global ischaemia by circulatory arrest. Citrate, amino acids, glucose and NH3 were measured in biopsies. Ischaemia, whether regional or global, caused a 60-70% increase in tissue levels of citrate. During 1 min of reperfusion following regional ischaemia the level of citrate increased 460%, to approximately 600 nmol g-1 wet weight. The level of glutamate decreased by 20-33% (corresponding to 1300-2200 nmol g-1 wet weight), indicating net consumption of this amino acid during ischaemia. The level of aspartate decreased 50% indicating conversion of aspartate to oxaloacetate for the synthesis of citrate. Theoretically, the accumulation of myocardial citrate during brief ischaemia and early reperfusion is large enough to significantly inhibit phosphofructokinase activity and could therefore affect the ability of the myocardium to increase the glycolytic rate in response to ischaemia. This could, however, be partly compensated by the metabolism of myocardial glutamate.
Understanding the neural underpinnings of major depressive disorder (MDD) and its treatment could improve treatment outcomes. While numerous studies have been conducted, findings are variable and large sample replications scarce. We aimed to replicate and extend altered functional connectivity findings in the default mode, salience and cognitive control networks (DMN, SN, and CCN respectively) associated with MDD and pharmacotherapy outcomes in a large, multi-site sample. Resting-state fMRI data were collected from 129 patients and 99 controls through the Canadian Biomarker Integration Network in Depression (CAN-BIND) initiative. Symptoms were assessed with the Montgomery-Åsberg Depression Rating Scale (MADRS). Connectivity was measured as correlations between four seeds (anterior and posterior DMN, SN and CCN) and all other brain voxels across participants. Partial least squares, a multivariate statistical technique, was used to compare connectivity prior to treatment between patients and controls, and between patients reaching remission early (MADRS ≤ 10 within 8 weeks), late (MADRS ≤ 10 within 16 weeks) or not at all. We replicated previous findings of altered connectivity in the DMN, SN and CCN in patients. In addition, baseline connectivity of the anterior/posterior DMN and SN seeds differentiated patients with different treatment outcomes. Weaker connectivity within the anterior DMN and between the anterior DMN and the SN and CCN characterised early remission; stronger connectivity within the SN and weaker connectivity between the SN and the DMN and CCN was related to late remission, of which the weaker SN – anterior DMN connectivity might specifically be associated with remission to dual pharmacotherapy; and connectivity strength between the posterior DMN and cingulate areas distinguished all three groups, with early remitters showing the strongest connections and non-remitters the weakest. The stability of these baseline patient differences was established in the largest single-site subsample of the data. Our replication and extension of altered connectivity within and between the DMN, SN and CCN highlighted previously reported and new differences between patients with MDD and controls, and revealed features that might predict remission prior to pharmacotherapy.Trial registrationClinicalTrials.gov: NCT01655706.
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