SummaryEnergy metabolism is a key aspect of cardiomyocyte biology. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are a promising tool for biomedical application, but they are immature and have not undergone metabolic maturation related to early postnatal development. To assess whether cultivation of hiPSC-CMs in 3D engineered heart tissue format leads to maturation of energy metabolism, we analyzed the mitochondrial and metabolic state of 3D hiPSC-CMs and compared it with 2D culture. 3D hiPSC-CMs showed increased mitochondrial mass, DNA content, and protein abundance (proteome). While hiPSC-CMs exhibited the principal ability to use glucose, lactate, and fatty acids as energy substrates irrespective of culture format, hiPSC-CMs in 3D performed more oxidation of glucose, lactate, and fatty acid and less anaerobic glycolysis. The increase in mitochondrial mass and DNA in 3D was diminished by pharmacological reduction of contractile force. In conclusion, contractile work contributes to metabolic maturation of hiPSC-CMs.

Long non-coding RNAs (lncRNAs) have potential as novel therapeutic targets in cardiovascular diseases, but detailed information about the intercellular lncRNA shuttling mechanisms in the heart is lacking. Here, we report an important novel crosstalk between cardiomyocytes and fibroblasts mediated by the transfer of lncRNA-enriched extracellular vesicles (EVs) in the context of cardiac ischemia. lncRNA profiling identified two hypoxia-sensitive lncRNAs: ENSMUST00000122745 was predominantly found in small EVs, whereas lncRNA Neat1 was enriched in large EVs in vitro and in vivo. Vesicles were taken up by fibroblasts, triggering expression of profibrotic genes. In addition, lncRNA Neat1 was transcriptionally regulated by P53 under basal conditions and by HIF2A during hypoxia. The function of Neat1 was further elucidated in vitro and in vivo. Silencing of Neat1 in vitro revealed that Neat1 was indispensable for fibroblast and cardiomyocyte survival and affected fibroblast functions (reduced migration capacity, stalled cell cycle, and decreased expression of fibrotic genes). Of translational importance, genetic loss of Neat1 in vivo resulted in an impaired heart function after myocardial infarction highlighting its translational relevance.

Background This study compares the analgesic indices Analgesia Nociception Index (heart rate variability), Surgical Pleth Index (photoplethysmography), and pupillary dilatation, to heart rate, mean arterial pressure, and bispectral index, with regard to diagnostic accuracy and prediction probability for nociceptive response. The primary endpoint was the correlation between Δ values and the remifentanil dose administered. Methods We anesthetized 38 patients with propofol and increasing doses of remifentanil and applied standardized tetanic and intracutaneous electrical painful stimulations on each analgesic level. Baseline and Δ values of the Analgesia Nociception Index, the Surgical Pleth Index, pupillary dilatation, heart rate, mean arterial pressure, and bispectral index and their relation to remifentanil doses were analyzed by receiver operating characteristic curves, prediction probability (PK), and mixed-model analysis. Results Under propofol sedation, sensitivity and specificity of the Analgesia Nociception Index (PK = 0.98), the Surgical Pleth Index (PK = 0.87), and pupillary dilatation (PK = 0.98) for detecting both painful stimulations were high compared to heart rate (PK = 0.74), mean arterial pressure (PK = 0.75), and bispectral index (PK = 0.55). Baseline values had limited prediction probability toward the nociceptive response (Analgesia Nociception Index: PK = 0.7; Surgical Pleth Index: PK = 0.63; pupillary dilatation: PK = 0.67; and bispectral index: PK = 0.67). The remifentanil dose had an effect (P < 0.001) on all parameters except for bispectral index (P = 0.216). Conclusions The Analgesia Nociception Index, the Surgical Pleth Index, and pupillary dilatation are superior in detecting painful stimulations compared to heart rate and mean arterial pressure but had limited predictive value. These effects are attenuated by increasing dosages of remifentanil. Our data confirm that bispectral index is not a marker of analgesia.

Baseline n=47 n=11 n=12 n=12 n=12 23.

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Background Hemodynamic instability is frequent and outcome-relevant in critical illness. The understanding of complex hemodynamic disturbances and their monitoring and management plays an important role in treatment of intensive care patients. An increasing number of treatment recommendations and guidelines in intensive care medicine emphasize hemodynamic goals, which go beyond the measurement of blood pressures. Yet, it is not known to which extent the infrastructural prerequisites for extended hemodynamic monitoring are given in intensive care units (ICUs) and how hemodynamic management is performed in clinical practice. Further, it is still unclear which factors trigger the use of extended hemodynamic monitoring.MethodsIn this multicenter, 1-day (November 7, 2013, and the preceding 24 h) cross-sectional study, we retrieved data on patient monitoring from ICUs in Germany, Austria, and Switzerland by means of a web-based case report form. One hundred and sixty-one intensive care units contributed detailed information on availability of hemodynamic monitoring. In addition, detailed information on hemodynamic monitoring of 1789 patients that were treated on due date was collected, and independent factors triggering the use of extended hemodynamic monitoring were identified by multivariate analysis.ResultsBesides basic monitoring with electrocardiography (ECG), pulse oximetry, and blood pressure monitoring, the majority of patients received invasive arterial (77.9 %) and central venous catheterization (55.2 %). All over, additional extended hemodynamic monitoring for assessment of cardiac output was only performed in 12.3 % of patients, while echocardiographic examination was used in only 1.9 %. The strongest independent predictors for the use of extended hemodynamic monitoring of any kind were mechanical ventilation, the need for catecholamine therapy, and treatment backed by protocols. In 71.6 % of patients in whom extended hemodynamic monitoring was added during the study period, this extension led to changes in treatment.ConclusionsExtended hemodynamic monitoring, which goes beyond the measurement of blood pressures, to date plays a minor role in the surveillance of critically ill patients in German, Austrian, and Swiss ICUs. This includes also consensus-based recommended diagnostic and monitoring applications, such as echocardiography and cardiac output monitoring. Mechanical ventilation, the use of catecholamines, and treatment backed by protocol could be identified as factors independently associated with higher use of extended hemodynamic monitoring.Electronic supplementary materialThe online version of this article (doi:10.1186/s13613-016-0148-2) contains supplementary material, which is available to authorized users.

Compared to isoflurane and s-ketamine, xenon limited progressive adverse cardiac remodeling and contractile dysfunction 28 days after perioperative myocardial infarction.

BackgroundPostoperative morbidity and mortality in patients undergoing surgery is high, especially in patients who are at risk of complications and undergoing major surgery. We hypothesize that perioperative, algorithm-driven, hemodynamic therapy based on individualized fluid status and cardiac output optimization is able to reduce mortality and postoperative moderate and severe complications as a major determinant of the patients’ postoperative quality of life, as well as health care costs.Methods/designThis is a multi-center, international, prospective, randomized trial in 380 patients undergoing major abdominal surgery including visceral, urological, and gynecological operations. Eligible patients will be randomly allocated to two treatment arms within the participating centers. Patients of the intervention group will be treated perioperatively following a specific hemodynamic therapy algorithm based on pulse-pressure variation (PPV) and individualized optimization of cardiac output assessed by pulse-contour analysis (ProAQT© device; Pulsion Medical Systems, Feldkirchen, Germany). Patients in the control group will be treated according to standard local care based on established basic hemodynamic treatment. The primary endpoint is a composite comprising the occurrence of moderate or severe postoperative complications or death within 28 days post surgery. Secondary endpoints are: (1) the number of moderate and severe postoperative complications in total, per patient and for each individual complication; (2) the occurrence of at least one of these complications on days 1, 3, 5, 7, and 28 in total and for every complication; (3) the days alive and free of mechanical ventilation, vasopressor therapy and renal replacement therapy, length of intensive care unit, and hospital stay at day 7 and day 28; and (4) mortality and quality of life, assessed by the EQ-5D-5L™ questionnaire, after 6 months.DiscussionThis is a large, international randomized controlled study evaluating the effect of perioperative, individualized, algorithm-driven ,hemodynamic optimization on postoperative morbidity and mortality.Trial registrationTrial registration: NCT03021525. Registered on 12 January 2017.Electronic supplementary materialThe online version of this article (10.1186/s13063-018-2620-9) contains supplementary material, which is available to authorized users.