Search

Background and Objective A novel cocktail containing four substrates of key drug transporters was previously optimized to eliminate mutual drug–drug interactions between the probes digoxin (P-glycoprotein substrate), furosemide (organic anion transporter 1/3), metformin (organic cation transporter 2, multidrug and toxin extrusion protein 1/2-K), and rosuvastatin (organic anion transporting polypeptide 1B1/3, breast cancer resistance protein). This clinical trial investigated the effects of four commonly employed drug transporter inhibitors on cocktail drug pharmacokinetics. Methods In a randomized open-label crossover trial in 45 healthy male subjects, treatment groups received the cocktail with or without single oral doses of rifampin, verapamil, cimetidine or probenecid. Concentrations of the probe drugs in serial plasma samples and urine fractions were measured by validated liquid chromatography-tandem mass spectrometry assays to assess systemic exposure. Results The results were generally in accordance with known in vitro and/or clinical drug–drug interaction data. Single-dose rifampin increased rosuvastatin area under the plasma concentration–time curve up to the last quantifiable concentration (AUC0–tz) by 248% and maximum plasma concentration (Cmax) by 1025%. Probenecid increased furosemide AUC0–tz by 172% and Cmax by 23%. Cimetidine reduced metformin renal clearance by 26%. The effect of single-dose verapamil on digoxin systemic exposure was less than expected from multiple-dose studies (AUC0–tz unaltered, Cmax + 22%). Conclusions Taking all the interaction results together, the transporter cocktail is considered to be validated as a sensitive and specific tool for evaluating transporter-mediated drug–drug interactions in drug development. Clinical Trial Registration EudraCT number 2017-001549-29. Electronic supplementary material The online version of this article (10.1007/s40262-020-00907-w) contains supplementary material, which is available to authorized users.

While restoration of coronary blood flow to the ischemic heart is the most effective strategy for reducing infarct size, reperfusion injury represents a significant limiting factor on clinical outcomes in myocardial infarction patients. Ischemic preconditioning (IPC) has been shown to inhibit reperfusion injury and represents an attractive model for studying cardioprotective signal transduction pathways. Long non-coding RNAs (lncRNAs) are a structurally and functionally heterogenous class of RNA transcripts with unknown roles in IPC-induced cardioprotection. Through microarray-based expression profiling of 31,423 lncRNAs in cardiac tissue from IPC mice, we identified the nuclear transcript Neat1 to be rapidly and robustly decreased in response to IPC. siRNA-mediated knock down of Neat1 reduced apoptosis and necrosis in murine cardiomyocytes (CM) and human iPS-derived CMs in response to prolonged hypoxia and hypoxia-reoxygenation, assessed with Annexin V/propidium iodide-staining, a Caspase 3/7 activity assay, LDH release, and western blot for cleaved Caspase 3. Mechanistically, Neat1 was shown to regulate processing of pro-apoptotic microRNA-22 (miR-22) in murine and human CM nuclei using a luciferase reporter assay. Hypoxia-induced downregulation of Neat1 was shown to result in accumulation of unprocessed pri-miRNA and decreased availability of biologically active miRNA, including miR-22. Addition of exogenous synthetic miR-22 reversed the protective effect of Neat1 knock down in human iPS-CM. In conclusion, we have identified the nuclear lncRNA Neat1 as part of a conserved oxygen-sensitive feedback mechanism by regulation of miRNA processing and a potential target in cardioprotection.

Objective To investigate the relationship between circulating plasma copeptin values and infarct size as well as myocardial function at baseline and 4 months after mechanical reperfusion for ST segment elevation myocardial infarction (STEMI). Design Prospective observational cohort study. Setting University Hospital of Innsbruck. Patients 54 patients with acute STEMI. Main outcome measures Correlation of plasma copeptin with infarct size as well as left ventricular ejection fraction (LVEF) and remodelling. Methods Participants underwent contrast enhanced cardiac MRI at baseline and 4 months thereafter. Blood samples were drawn 2 days after the onset of symptoms. Copeptin values were determined by an immunofluorescent assay. Results Copeptin concentrations (median 10.4 pmol/l, IQR 6.0–14.4) were associated with early and chronic infarct size (r=0.388, p=0.004 at baseline; r=0.385, p=0.011 at follow-up) and inversely related to LVEF at both times (r=−0.484, p Conclusions Increased copeptin values 2 days after STEMI are associated with larger acute and chronic infarct sizes. Moreover, elevated copeptin concentrations at baseline were associated with myocardial function and remodelling 4 months post-STEMI. These findings strengthen the role of copeptin as a biomarker of adverse outcome after STEMI.

Background Ischemic preconditioning ( IPC ) protects the heart from prolonged ischemic insult and reperfusion injury through a poorly understood mechanism. Post‐translational modifications of histone residues can confer rapid and drastic switches in gene expression in response to various stimuli, including ischemia. The aim of this study was to investigate the effect of histone methylation in the response to cardiac ischemic preconditioning. Methods and Results We used cardiac biopsies from mice subjected to IPC to quantify global levels of 3 of the most well‐studied histone methylation marks (H3K9me2, H3K27me3, and H3K4me3) with Western blot and found that H3K9me2 levels were significantly increased in the area at risk compared to remote myocardium. In order to assess which genes were affected by the increase in H3K9me2 levels, we performed Ch IP ‐Seq and transcriptome profiling using microarray. Two hundred thirty‐seven genes were both transcriptionally repressed and enriched in H3K9me2 in the area at risk of IPC mice. Of these, Mtor (Mechanistic target of rapamycin) was chosen for mechanistic studies. Knockdown of the major H3K9 methyltransferase G9a resulted in a significant decrease in H3K9me2 levels across Mtor , increased Mtor expression, as well as decreased autophagic activity in response to rapamycin and serum starvation. Conclusions IPC confers an increase of H3K9me2 levels throughout the Mtor gene—a master regulator of cellular metabolism and a key player in the cardioprotective effect of IPC —leading to transcriptional repression via the methyltransferase G9a. The results of this study indicate that G9a has an important role in regulating cardiac autophagy and the cardioprotective effect of IPC .

Background: Impulsivity is a core feature of borderline personality disorder (BPD). However, previous clinical and experimental studies investigating impulsivity in BPD rendered mixed results. In this study, impulsivity was assessed by self-report scales and behavioral inhibition tasks to compare different data levels. Sampling and Methods: Fifteen women with BPD and 15 matched healthy control subjects (HC) completed the Barratt Impulsiveness Scale, Eysenck’s Impulsivity Questionnaire and the UPPS (Urgency, Lack of Perseverance, Lack of Premeditation and Sensation Seeking) scale, and participated in a Stroop task, an antisaccade task and a stop signal task. Results: Patients with BPD scored significantly higher on self-report measures as compared to HC, but not in behavioral tests. In BPD patients, but not in HC, behavioral inhibition errors were correlated with more intense emotional state. Conclusion: We found a discrepancy between self-report and behavioral data. Further studies need to assess additional possible mechanisms underlying increased impulsivity, their relation to emotional instability, and their neurobiological underpinnings.

Aims Increased myocardial wall strain triggers the cardiac hypertrophic response by increasing cardiomyocyte size, reprogramming gene expression, and enhancing contractile protein synthesis. The LIM protein, migfilin, is a cytoskeleton-associated protein that was found to translocate in vitro into the nucleus in a Ca2+-dependent manner, where it co-activates the pivotal cardiac transcription factor Csx/Nkx2.5. However, the in vivo role of migfilin in cardiac function and stress response is unclear. Methods and results To define the role of migfilin in cardiac hypertrophy, we induced hypertension by transverse aortic constriction (TAC) and compared cardiac morphology and function of migfilin knockout (KO) with wild-type (WT) hearts. Heart size and myocardial contractility were comparable in untreated migfilin KO and WT hearts, but migfilin-null hearts presented a reduced extent of hypertrophic remodelling in response to chronic hypertensile stress. Migfilin KO mice maintained their cardiac function for a longer time period compared with WT mice, which presented extensive fibrosis and death due to heart failure. Migfilin translocated into the nucleus of TAC-treated cardiomyocytes, and migfilin KO hearts showed reduced Akt activation during the early response to pressure overload. Conclusions Our findings indicate an important role of migfilin in the regulation of cardiac hypertrophy upon experimental TAC.

Pulse wave velocity is a measure of aortic stiffness and an independent predictor of cardiovascular morbidity and mortality. Adiponectin is involved in atherosclerosis and inflammation. In the present study we aimed to explore the association between plasma adiponectin concentrations and pulse wave velocity in the acute phase after ST-segment elevation myocardial infarction (STEMI).Forty-six consecutive STEMI patients (mean age 57 ± 11 years) treated with primary percutaneous coronary intervention (PCI) were enrolled in this cross-sectional study. Plasma adiponectin was measured 2 days after index event by enzyme-linked immunosorbent assay. Aortic pulse wave velocity (PWV) was calculated by the transit-time method with the use of a velocity-encoded, phase-contrast cardiac magnetic resonance protocol.Median plasma adiponectin concentration was 2385 ng/ml (interquartile range 1735-5403). Males had lower plasma adiponectin values than females and current smokers had lower values than non-smokers (all p0.02). Adiponectin was significantly associated with PWV (r=0.505, p0.001), age (r=0.437, p=0.002), and total cholesterol (r=0.468, p=0.001). Multiple linear regression analysis revealed adiponectin as a predictor of PWV independently of age, sex, smoking status, total cholesterol, and N-terminal pro-B-type natriuretic peptide (p=0.027).Plasma adiponectin concentrations are strongly associated with aortic stiffness in patients after acute STEMI treated with primary PCI. Our data support a possible role for adiponectin as an independent risk marker for increased aortic stiffness in STEMI patients.

Affective dysregulation is a clinical hallmark of borderline personality disorder (BPD). This study used an instructed fear task combined with functional MRI (fMRI) and skin conductance response (SCR) to test hypotheses about mechanisms of disturbed fronto-limbic neural circuitry underlying dysfunctional emotional processing in BPD.Female BPD patients and matched control subjects were exposed to two visual stimuli during fMRI scanning and SCR recording. Subjects were instructed shortly before scanning that one stimulus (Threat) potentially represents an aversive event whereas another stimulus (Safe) represents safety. The aversive event (electrodermal stimulation) itself was only experienced before this instruction and never occurred during fMRI scanning.Both groups showed stronger SCR to Threat compared to Safe indicating differential fear response which habituated over time. BPD compared to control subjects did not show fMRI signal decrease of amygdala activity or relative ventromedial prefrontal cortex (vmPFC) activity increase over time. Moreover, BPD patients showed increased connectivity of the amygdala with vmPFC but decreased connectivity of subgenual ACC with dorsal ACC compared to control subjects.Prolonged amygdala response and a functional disconnection between ventral and dorsal mPFC regions may be part of the neural mechanisms underlying emotional dysregulation in BPD patients.

Background: In this study we compared the effect of different emotion regulation strategies on positive and negative emotions in patients with borderline personality disorder.Methods: Emotion regulation strategies were a distracting task, individual positive memory imagery, individual soothing imagery, and a neutral comparison condition. During two separate sessions, 17 participants watched either neutral or negative movie segments before using these strategies.Results: All three strategies influenced emotions into a favorable direction as compared to the neutral comparison condition. The positive memory image increased positive emotions significantly stronger than counting colors and distracting.Discussion: Different strategies seem to have similar effects in decreasing negative emotions. Positive emotions may be affected in particular by positive and soothing imagery techniques.