Stroke–Heart Syndrome: Recent Advances and Challenges

After ischemic stroke, there is a significant burden of cardiovascular complications, both in the acute and chronic phase. Severe adverse cardiac events occur in 10% to 20% of patients within the first few days after stroke and comprise a continuum of cardiac changes ranging from acute myocardial injury and coronary syndromes to heart failure or arrhythmia. Recently, the term stroke– heart syndrome was introduced to provide an integrated conceptual framework that summarizes neurocardiogenic mechanisms that lead to these cardiac events after stroke. New findings from experimental and clinical studies have further refined our understanding of the clinical manifestations, pathophysiology, and potential long-term consequences of the stroke– heart syndrome. Local cerebral and systemic mediators, which mainly involve autonomic dysfunction and increased inflammation, may lead to altered cardiomyocyte metabolism, dysregulation of (tissue-resident) leukocyte pop-ulations, and (micro-) vascular changes. However, at the individual patient level, it remains challenging to differentiate between comorbid cardiovascular conditions and stroke-induced heart injury. Therefore, further research activities led by joint teams of basic and clinical researchers with backgrounds in both cardiology and neurology are needed to identify the most relevant therapeutic targets that can be tested in clinical trials

Massive pre-main-sequence stars in M17: 1st1^{\rm st} and 2nd2^{\rm nd} overtone CO bandhead emission and the thermal infrared

Recently much progress has been made in probing the embedded stages of massive star formation, pointing to formation scenarios akin to a scaled up version of low-mass star formation. However, the latest stages of massive star formation have rarely been observed. Using 1st and 2nd overtone CO bandhead emission and near- to mid-infrared photometry we aim to characterize the remnant formation disks around 5 unique pre-main-sequence (PMS) stars with masses $6-12~\rm M_{\odot}$, that have constrained stellar parameters thanks to their detectable photospheres. We seek to understand this emission and the disks it originates from in the context of the evolutionary stage of the studied sources. We use an analytic LTE disk model to fit the CO bandhead and the dust emission, found to originate in different disk regions. For the first time we modeled the 2nd overtone emission. Furthermore, we fit continuum normalized bandheads and show the importance of this in constraining the emission region. We also include $^{13}\rm CO$ in our models as an additional probe of the young nature of the studied objects. We find that the CO emission originates in a narrow region close to the star (<1 AU) and under very similar disk conditions (temperatures and densities) for the different objects. This is consistent with previous modeling of this emission in a diverse range of young stellar objects. We discuss these results in the context of the positions of these PMS stars in the Hertzsprung-Russel diagram and the CO emission's association with early age and high accretion rates in (massive) young stellar objects. We conclude that, considering their mass range and for the fact that their photospheres are detected, the M17 PMS stars are observed in a relatively early formation stage. They are therefore excellent candidates for longer wavelength studies to further constrain the end stages of massive star formation.Comment: 21 pages, 12 figure

Spectroscopic variability of massive pre-main-sequence stars in M17

It is a challenge to study the formation process of massive stars: their formation time is short, they are few, often deeply embedded, and at relatively large distances. Our strategy is to study the outcome of the star formation process and to look for signatures remnant of the formation. We have access to a unique sample of (massive) pre-main-sequence (PMS) stars in the giant HII region M17, showing a photosphere and circumstellar disk. The aim is to determine the variability properties of the hot gaseous disks to understand the physical origin of the emission lines and identify dominant physical processes in these disks. We have obtained multiple-epoch (4-5 epochs) VLT/X-shooter spectra of six young stars in M17 covering about a decade. Using stacked spectra we update the spectral classification and identify circumstellar features. With the temporal variance method (TVS) we determine the extent and amplitude of the spectral line variations. The double-peaked emission lines in the PMS stars with gaseous disks are used to determine peak-to-peak velocities, V/R-ratios and the radial velocity of the systems. We identify many disk features, under which a new detection of CO bandhead and CI emission. In three of the stars we detect spectral variability, mainly in lines originating in the circumstellar disk, in a velocity range up to 320 km/s. In two PMS stars the ratio between the blue and red peaks shows a correlation with the peak-to-peak velocity, possibly explained by a spiral-arm structure in the disk. The PMS stars with variability are at similar positions in the HRD but show significant differences in disk lines and variability. The extent and timescale of the variability differs for each star and per line (sets). We find indications for an accretion flow, slow disk winds and/or disk structures in the hot gaseous inner disk as the cause of the variability in these PMS stars.Comment: 27 pages, 24 figures, accepted for publication in Astronomy and Astrophysics, abstract abbreviate

Growth factor stimulation of cardiomyocytes induces changes in the transcriptional contents of secreted exosomes

Exosomes are nano-sized extracellular vesicles, released from various cells, which can stimulate or repress responses in targets cells. We recently reported that cultured cardiomyocytes are able to release exosomes and that they, in turn, are involved in facilitating events in target cells by alteration of gene expression. We investigated whether external stimuli of the cardiomyocyte might influence the transcriptional content of the released exosomes.Exosomes were isolated from media collected from cultured cardiomyocytes (HL-1) with or without growth factor treatment (TGF-&#x03B2;2 and PDGF-BB), with a series of differential centrifugations, including preparative ultracentrifugation and separation with a sucrose gradient. The exosomes were characterized with dynamic light scattering (DLS), electron microscopy (EM) and Western blot and analyzed with Illumina whole genome microarray gene expression.The exosomes were rounded in shape and had an average size of 50&#x2013;90 nm in diameter with no difference between treatment groups. Analysis of the mRNA content in repeated experiments conclusively revealed 505 transcripts in the control group, 562 in the TGF-&#x03B2;2-treated group and 300 in the PDGF-BB-treated group. Common transcripts (217) were found in all 3 groups.We show that the mode of stimulation of parental cells affects the characteristics of exosomes released. Hence, there is a difference in mRNA content between exosomes derived from cultured cardiomyocytes stimulated, or not stimulated, with growth factors. We also conclude that all exosomes contain a basic package consisting of ribosomal transcripts and mRNAs coding for proteins with functions within the energy supply system. To access the supplementary material to this article, please see Supplementary files under Article Tools online

Heart rate variability (HRV) and muscular system activity (EMG) in cases of crash threat during simulated driving of a passenger car

Objectives: The aim of the study was to verify whether simultaneous responses from the muscular and circulatory system occur in the driver's body under simulated conditions of a crash threat. Materials and Methods: The study was carried out in a passenger car driving simulator. The crash was included in the driving test scenario developed in an urban setting. In the group of 22 young male subjects, two physiological signals - ECG and EMG were continuously recorded. The length of the RR interval in the ECG signal was assessed. A HRV analysis was performed in the time and frequency domains for 1-minute record segments at rest (seated position), during undisturbed driving as well as during and several minutes after the crash. For the left and right side muscles: m. trapezius (TR) and m. flexor digitorum superficialis (FDS), the EMG signal amplitude was determined. The percentage of maximal voluntary contraction (MVC) was compared during driving and during the crash. Results: As for the ECG signal, it was found that in most of the drivers changes occurred in the parameter values reflecting HRV in the time domain. Significant changes were noted in the mean length of RR intervals (mRR). As for the EMG signal, the changes in the amplitude concerned the signal recorded from the FDS muscle. The changes in ECG and EMG were simultaneous in half of the cases. Conclusion: Such parameters as mRR (ECG signal) and FDS-L amplitude (EMG signal) were the responses to accident risk. Under simulated conditions, responses from the circulatory and musculoskeletal systems are not always simultaneous. The results indicate that a more complete driver's response to a crash in road traffic is obtained based on parallel recording of two physiological signals (ECG and EMG)

Inflammation leads through PGE/EP3 signaling to HDAC5/MEF2-dependent transcription in cardiac myocytes

The myocyte enhancer factor 2 (MEF2) regulates transcription in cardiac myocytes and adverse remodeling of adult hearts. Activators of G protein-coupled receptors (GPCRs) have been reported to activate MEF2, but a comprehensive analysis of GPCR activators that regulate MEF2 has to our knowledge not been performed. Here, we tested several GPCR agonists regarding their ability to activate a MEF2 reporter in neonatal rat ventricular myocytes. The inflammatory mediator prostaglandin E2 (PGE2) strongly activated MEF2. Using pharmacological and protein-based inhibitors, we demonstrated that PGE2 regulates MEF2 via the EP3 receptor, the betagamma subunit of Gi/o protein and two concomitantly activated downstream pathways. The first consists of Tiam1, Rac1, and its effector p21-activated kinase 2, the second of protein kinase D. Both pathways converge on and inactivate histone deacetylase 5 (HDAC5) and thereby de-repress MEF2. In vivo, endotoxemia in MEF2-reporter mice induced upregulation of PGE2 and MEF2 activation. Our findings provide an unexpected new link between inflammation and cardiac remodeling by de-repression of MEF2 through HDAC5 inactivation, which has potential implications for new strategies to treat inflammatory cardiomyopathies

A roadmap for therapeutic discovery in pulmonary hypertension associated with left heart failure. A scientific statement of the Heart Failure Association (HFA) of the ESC and the ESC Working Group on Pulmonary Circulation &amp; Right Ventricular Function

\ua9 2024 The Authors. European Journal of Heart Failure published by John Wiley &amp; Sons Ltd on behalf of European Society of Cardiology.Pulmonary hypertension (PH) associated with left heart failure (LHF) (PH-LHF) is one of the most common causes of PH. It directly contributes to symptoms and reduced functional capacity and negatively affects right heart function, ultimately leading to a poor prognosis. There are no specific treatments for PH-LHF, despite the high number of drugs tested so far. This scientific document addresses the main knowledge gaps in PH-LHF with emphasis on pathophysiology and clinical trials. Key identified issues include better understanding of the role of pulmonary venous versus arteriolar remodelling, multidimensional phenotyping to recognize patient subgroups positioned to respond to different therapies, and conduct of rigorous pre-clinical studies combining small and large animal models. Advancements in these areas are expected to better inform the design of clinical trials and extend treatment options beyond those effective in pulmonary arterial hypertension. Enrichment strategies, endpoint assessments, and thorough haemodynamic studies, both at rest and during exercise, are proposed to play primary roles to optimize early-stage development of candidate therapies for PH-LHF

Bringing Stellar Evolution & Feedback Together: Summary of proposals from the Lorentz Center Workshop, 2022

Stars strongly impact their environment, and shape structures on all scales throughout the universe, in a process known as ``feedback''. Due to the complexity of both stellar evolution and the physics of larger astrophysical structures, there remain many unanswered questions about how feedback operates, and what we can learn about stars by studying their imprint on the wider universe. In this white paper, we summarize discussions from the Lorentz Center meeting `Bringing Stellar Evolution and Feedback Together' in April 2022, and identify key areas where further dialogue can bring about radical changes in how we view the relationship between stars and the universe they live in.Comment: Accepted to the Publications of the Astronomical Society of the Pacifi

The emotional movie database (EMDB): a self-report and psychophysiological study

Film clips are an important tool for evoking emotional responses in the laboratory. When compared with other emotionally potent visual stimuli (e.g., pictures), film clips seem to be more effective in eliciting emotions for longer periods of time at both the subjective and physiological levels. The main objective of the present study was to develop a new database of affective film clips without auditory content, based on a dimensional approach to emotional stimuli (valence, arousal and dominance). The study had three different phases: (1) the pre-selection and editing of 52 film clips (2) the self-report rating of these film clips by a sample of 113 participants and (3) psychophysiological assessment [skin conductance level (SCL) and the heart rate (HR)] on 32 volunteers. Film clips from different categories were selected to elicit emotional states from different quadrants of affective space. The results also showed that sustained exposure to the affective film clips resulted in a pattern of a SCL increase and HR deceleration in high arousal conditions (i.e., horror and erotic conditions). The resulting emotional movie database can reliably be used in research requiring the presentation of non-auditory film clips with different ratings of valence, arousal and dominance.Portuguese Foundation for Science and Technology with individual grants (SFRH/BD/41484/2007 and SFRH/BD/64355/2009

Secreted Frizzled-related protein-1 is a negative regulator of androgen receptor activity in prostate cancer

Secreted Frizzled-related protein-1 (sFRP1) associates with Wnt proteins and its loss can lead to activation of Wnt/β-catenin signalling. It is frequently downregulated in cancer, including prostate cancer, but its function in prostate cancer is unclear because it can increase proliferation of prostate epithelial cells. We investigated the function of sFRP1 in androgen-dependent prostate cancer and found that sFRP1 inhibited androgen receptor (AR) transcriptional activity. In addition, sFRP1 inhibited the proliferation of androgen-dependent LNCaP cells but not of an androgen-independent subline LNCaP-r, suggesting a role in androgen-dependent growth. The inhibition of AR by sFRP1 was unaffected by co-expression of Wnt3a, stabilised β-catenin or β-catenin shRNA, suggesting it does not involve Wnt/β-catenin signalling. Wnt5a also inhibited AR and expression of Wnt5a and sFRP1 together did not further inhibit AR, suggesting that Wnt5a and sFRP1 activate the same signal(s) to inhibit AR. However, sFRP1 inhibition of AR was unaffected by inhibitors of kinases involved in Wnt/Ca2+ and Wnt/planar cell polarity non-canonical Wnt signalling. Interestingly, the cysteine-rich domain of sFRP1 interacted with Frizzled receptors expressed in prostate cancer cells, suggesting that sFRP1/Frizzled complexes activate a signal that leads to repression of AR. Taken together, these observations highlight the function of β-catenin-independent Wnt signalling in the control of AR activity and provide one explanation for sFRP1 downregulation in prostate cancer