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A response by authors to a letter to the editor about their article Identifying community based chronic heart failure patients in the last year of life: A comparison of the Gold Standards Framework Prognostic Indicator Guide and the Seattle Heart Failure Model" in the August 21, 2012 issue is presented.

Glucocorticoids are steroid hormones, essential in mammals to prepare for life after birth. Blood levels of glucocorticoids (cortisol in most mammals including humans; corticosterone in rats and mice) rise dramatically shortly before birth. This is mimicked clinically in the routine administration of synthetic glucocorticoids to pregnant women threatened by a preterm birth or to preterm infants to improve neonatal survival. Whilst effects on lung are well documented and essential for postnatal survival, those on heart are less well known. In this study, we review recent evidence for a crucial role of glucocorticoids in late gestational heart maturation. Either insufficient or excessive glucocorticoid exposure before birth may alter the normal glucocorticoid-regulated trajectory of heart maturation with potential life-long consequences. [ABSTRACT FROM AUTHOR]

Objective. To determine the reproducibility of laser Doppler flowmetry coupled with intra-dermal saline delivery. Methods. Delivery of saline was judged visually by two operators (n=100), using a graduated syringe (Becton-Dickinson), by expelling saline onto a weighing boat. Volume was assessed by weight. Skin blood flow following intra-dermal injection of saline was assessed in 18 healthy volunteers; 10 attended twice to assess between-day reproducibility, and 8 attended once to assess between-site reproducibility. Results are expressed as mean value±SEM and 95% confidence interval for mean differences. Results. There was no difference between operators in mean injection weight, both weights being 10.3±0.1 mg (mean difference 0.08, 95% confidence interval, CI -0.23 to 0.39 mg; n=100, P=0.9). Intra-dermal saline caused a nine-fold increase in blood flow (0.03±0.003 to 0.27±0.02 perfusion units, PU; n=18, P<0.001). This response had a rapid onset, with the maximal effect seen at 4 min and a duration of greater than 30 min. There was no difference in the magnitude of the response between the dominant and non-dominant arms, AUC was 2.9±0.4 and 2.9±0.4, respectively (mean difference -0.05, 95% CI -0.8 to 0.73 PU; n=18, P=0.93). However, there was a trend towards differences between study visits 1 and 2: AUC was 3.2±0.6 and 2.0±0.5, respectively (mean difference 1.2, 95% CI -0.03 to 2.43 PU; n=10, P=0.7). There was no difference in the magnitude of responses between different sites on the forearm (n=64, P=0.6). Conclusions. These studies demonstrate that the technique of laser Doppler flowmetry coupled with intra-dermal injection is a safe, well-tolerated technique with good reproducibility. A trend towards reduced between-day reproducibility emphasizes the importance of vehicle control sites when investigating the effects of vasoactive compounds. This technique provides a reliable method for the intra-dermal delivery of drugs, despite the direct effect of injection of saline on blood flow. [ABSTRACT FROM AUTHOR]

Background frailty measurement may identify patients at risk of decline after hospital discharge, but many measures require specialist review and/or additional testing. Objective to compare validated frailty tools with routine electronic health record (EHR) data at hospital discharge, for associations with readmission or death. Design observational cohort study. Setting hospital ward. Subjects consented cardiology inpatients ≥70 years old within 24 hours of discharge. Methods patients underwent Fried, Short Physical Performance Battery (SPPB), PRISMA-7 and Clinical Frailty Scale (CFS) assessments. An EHR risk score was derived from the proportion of 31 possible frailty markers present. Electronic follow-up was completed for a primary outcome of 90-day readmission or death. Secondary outcomes were mortality and days alive at home ('home time') at 12 months. Results in total, 186 patients were included (79 ± 6 years old, 64% males). The primary outcome occurred in 55 (30%) patients. Fried (hazard ratio [HR] 1.47 per standard deviation [SD] increase, 95% confidence interval [CI] 1.18–1.81, P  < 0.001), CFS (HR 1.24 per SD increase, 95% CI 1.01–1.51, P  = 0.04) and EHR risk scores (HR 1.35 per SD increase, 95% CI 1.02–1.78, P  = 0.04) were independently associated with the primary outcome after adjustment for age, sex and co-morbidity, but the SPPB and PRISMA-7 were not. The EHR risk score was independently associated with mortality and home time at 12 months. Conclusions frailty measurement at hospital discharge identifies patients at risk of poorer outcomes. An EHR-based risk score appeared equivalent to validated frailty tools and may be automated to screen patients at scale, but this requires further validation. [ABSTRACT FROM AUTHOR]

Increasing scientific interest in the zebrafish as a model organism across a range of biomedical and biological research areas raises the need for the development of in vivo imaging tools appropriate to this subject. Development of the embryonic and early stage forms of the subject can currently be assessed using optical based techniques due to the transparent nature of the species at these early stages. However this is not an option during the juvenile and adult stages when the subjects become opaque. Magnetic resonance imaging (MRI) techniques would allow for the longitudinal and non-invasive assessment of development and health in these later life stages. However, the small size of the zebrafish and its aquatic environment represent considerable challenges for the technique. We have developed a suitable flow cell system that incorporates a dedicated MRI imaging coil to solve these challenges. The system maintains and monitors a zebrafish during a scan and allows for it to be fully recovered. The imaging properties of this system compare well with those of other preclinical MRI coils used in rodent models. This enables the rapid acquisition of MRI data which are comparable in terms of quality and acquisition time. This would allow the many unique opportunities of the zebrafish as a model organism to be combined with the benefits of non-invasive MRI. [ABSTRACT FROM AUTHOR]

Background: mineralocorticoid receptor antagonists (MRAs) improve outcomes in several populations of patients with heart failure (HF), but there has been no systematic review of MRAs in older patients. Objectives: systematic review and meta-analysis of the efficacy and safety of MRA treatment in elderly HF patients. Data sources: trials were identified through a literature search until 24 January 2015. Study selection: randomised controlled trials (RCTs) of MRAs in patients with HF and/or left ventricular systolic dysfunction aged ≥65 years, with subgroup analysis of patients ≥65 years or with mean participant age ≥70 years. Data extraction and synthesis: efficacy outcomes were mortality, hospitalisation for cardiovascular causes, symptom status or functional capacity. Safety outcomes were hyperkalaemia and renal dysfunction. Data were analysed using relative risk ratios with 95% confidence intervals. Relative risk ratios were pooled where more than three estimates were available. Results: seven RCTs were included (total n = 8,638). Three RCTs in HF with reduced ejection fraction (HEFREF) reported overall benefit from MRA therapy with no significant treatment interaction for age; the effects of MRAs on mortality in patients ≥75 years displayed marked inter-study heterogeneity. In four RCTs of HF with preserved ejection fraction (HEFPEF), MRA treatment had no significant effect on any efficacy outcome. Conclusions: MRAs improve clinical outcomes in selected cohorts of older patients with HEFREF but not HEFPEF. In patients ≥75 years with HEFREF, the effect of MRA treatment on overall mortality is uncertain. Further study is required in subgroups of elderly patients with both HEFREF and HEFPEF. [ABSTRACT FROM AUTHOR]

Cardiac injury leads to the loss of cardiomyocytes, which are rapidly replaced by the proliferation of the surviving cells in zebrafish, but not in mammals. In both the regenerative zebrafish and non-regenerative mammals, cardiac injury induces a sustained macrophage response. Macrophages are required for cardiomyocyte proliferation during zebrafish cardiac regeneration, but the mechanisms whereby macrophages facilitate this crucial process are fundamentally unknown. Using heartbeat-synchronized live imaging, RNA sequencing, and macrophage-null genotypes in the larval zebrafish cardiac injury model, we characterize macrophage function and reveal that these cells activate the epicardium, inducing cardiomyocyte proliferation. Mechanistically, macrophages are specifically recruited to the epicardial-myocardial niche, triggering the expansion of the epicardium, which upregulates vegfaa expression to induce cardiomyocyte proliferation. Our data suggest that epicardial Vegfaa augments a developmental cardiac growth pathway via increased endocardial notch signaling. The identification of this macrophage-dependent mechanism of cardiac regeneration highlights immunomodulation as a potential strategy for enhancing mammalian cardiac repair. [Display omitted] • Heart regeneration in larval zebrafish is characterized in detail • Macrophage ablation blocks cardiomyocyte proliferation after cardiac injury • Macrophages synapse with epicardial cells and promote their proliferation • Epicardial Vegfaa drives cardiomyocyte proliferation during cardiac regeneration In this study, Bruton et al. test the requirement for macrophages for cardiac regeneration in larval zebrafish, finding macrophages to be necessary for cardiomyocyte proliferation via the activation of the epicardium. The identification of this macrophage-dependent mechanism of cardiac regeneration supports immunomodulation as a promising strategy for enhancing mammalian cardiac repair. [ABSTRACT FROM AUTHOR]

Aims Low androgen levels have been linked with an increased risk of cardiovascular disease in men. Previous studies have suggested that androgens directly inhibit atherosclerotic lesion formation although the underlying mechanisms for this remain unclear. This study addressed the hypothesis that endogenous androgens inhibit arterial remodelling by a direct action on the androgen receptor (AR) in the vascular wall. Methods and results We studied a series of novel mouse lines with cell-specific deletion of the AR in either the endothelium or in smooth muscle cells or both cell types. Findings were compared with a model of global androgen deficiency in wild-type mice (castrated). We characterized the cardiovascular phenotype, vascular pharmacology and histology, and assessed neointimal lesion formation following vascular injury to the femoral artery. Cell-specific AR deletion did not alter body weight, circulating testosterone levels or seminal vesicle weight, but caused limited alterations in arterial contractility and blood pressure. Neointimal lesion formation was unaltered by selective deletion of AR from the vascular endothelium, smooth muscle, or both cell types. Castration in wild-type mice increased neointimal lesion volume (Sham vs. Castration: 2.4 × 107 ± 4.5 × 106 vs. 3.9 × 107 ± 4.9 × 106 µm3, P = 0.04, n = 9–10). Conclusion Vascular cell-specific AR deletion had no effect on neointimal lesion formation, while low systemic androgen levels adversely affect neointimal lesion size. These findings suggest that the cardio-protective effects of androgens are mediated either by AR outside the vasculature or by AR-independent mechanisms. [ABSTRACT FROM AUTHOR]

Aims and objectives To understand the views of patients and professionals on the acceptability and perceived usefulness of telemonitoring in the management of chronic heart failure in the context of day-to-day care provision. Background There is an increasing interest in the potential for telemonitoring to support the home-based management of patients with chronic heart failure. However, little is known about the views of patients and professionals on the use of telemonitoring in this context. A chronic heart failure telemonitoring service was set-up by NHS Lothian, Scotland, to evaluate the intervention. Design A qualitative design was adopted to explore the views of patients and professionals participating in the service. Methods Semi-structured interviews were undertaken with 18 patients (61% male, mean age 75 years) and five professionals participating at different time points in this new service. Interviews were audio recorded, coded and thematically analysed using the Framework approach. Results Five main themes were identified: 'information, support and reassurance'; 'compliance and dependence'; 'changes and challenges'; 'determining the criteria for patient applicability to telemonitoring'; and 'continuity of care'. Conclusion Patients and professionals considered telemonitoring useful in the management of chronic heart failure, although with some caveats. Telemonitoring was popular with patients because they felt reassurance arising from what was perceived as continuous practitioner surveillance. Professionals expressed concern regarding perceived patient dependence on practitioner support. Increased workload was also a concern. Both groups acknowledged the need for improved technology and changes to service provision in order to better meet the intended objectives of the service. Relevance to clinical practice Although popular with patients, professionals emphasised the importance of case selection and adequate training and support, both for patients and themselves, in order to maximise the expected benefits of the service, particularly with regard to enabling self-management. [ABSTRACT FROM AUTHOR]

Background: While the adult zebrafish (Danio rerio) heart demonstrates a remarkable capacity for self-renewal following apical resection little is known about the response to injury in the embryonic heart. Methods: Injury to the beating zebrafish embryo heart was induced by laser using a transgenic zebrafish expressing cardiomyocyte specific green fluorescent protein. Changes in ejection fraction (EF), heart rate (HR), and caudal vein blood flow (CVBF) assessed by video capture techniques were assessed at 2, 24 and 48h post-laser. Change in total and mitotic ventricular cardiomyocyte number following laser injury was also assessed by counting respectively DAPI (VCt) and Phospho-histone H3 (VCm) positive nuclei in isolated hearts using confocal microscopy. Results: Laser injury to the ventricle resulted in bradycardia and mild bleeding into the pericardium. At 2h post-laser injury, there was a significant reduction in cardiac performance in lasered-hearts compared with controls (HR 117±11 vs 167±9bpm, p≤0.001; EF 14.1±1.8 vs 20.1±1.3%, p≤0.001; CVBF 103±15 vs 316±13μms−1, p≤0.001, respectively). Isolated hearts showed a significant reduction in VCt at 2h post-laser compared to controls (195±15 vs 238±15, p≤0.05). Histology showed necrosis and apoptosis (TUNEL assay) at the site of laser injury. At 24h post-laser cardiac performance and VCt had recovered fully to control levels. Pretreatment with the cell-cycle inhibitor, aphidicolin, significantly inhibited functional recovery of the ventricle accompanied by a significant inhibition of cardiomyocyte proliferation. Conclusions: Laser-targeted injury of the zebrafish embryonic heart is a novel and reproducible model of cardiac injury and repair suitable for pharmacological and molecular studies. [ABSTRACT FROM AUTHOR]

Turner syndrome ( TS), the result of a structurally abnormal or absent X chromosome, occurs in one in 2 000 live born females. The phenotype is highly variable, but short stature and gonadal dysgenesis are usually present. The main objective in adults with TS is health surveillance, but TS still causes a reduction in life expectancy of up to 13 years, with cardiovascular disease, congenital or acquired, as the major cause of an early death. While it has been established that all women with TS should undergo in-depth cardiovascular examination at diagnosis, advice on the cardiovascular management of women with TS is limited. Here, we provide a summary of our current practice within a multidisciplinary team, supported by our expertise in various aspects of cardiovascular risk management, and the evidence from research where it is available, with the aim of providing optimal support to our patients with TS. Background A dedicated Adult Turner Clinic was established in South East Scotland in 2002. This gynaecology-led clinic serves a population of roughly 1·2 million and, currently, reviews around 50 women with TS annually. Referrals for adult care come from paediatrics or general practice. Following a series of individual case discussions regarding the management of more complex cardiovascular problems, we have assembled a dedicated multidisciplinary group to determine a timely cardiovascular screening strategy, a basis for specialist referral, and appropriate hypertension management. This team now includes a paediatric endocrinologist, gynaecologist, cardiologist (with an interest in inherited disorders), vascular radiologist and hypertension specialist. Here, we review the literature on cardiovascular disease in women with TS and, make recommendations, based on relatively limited high-quality evidence, together with our experience, on the optimal timing of cardiovascular screening. [ABSTRACT FROM AUTHOR]

The article offers information on a study regarding the implications of lowering the diagnostic threshold of plasma troponin concentration to the 99th centile. According to the results, it increased the diagnosis of myocardial infarction by 47 percent and identified patients who were 4 to5 times more likely to die or have a recurrent myocardial infarct than those below this threshold.

Aims: Transthoracic echocardiography is recommended in all patients with acute coronary syndrome but is time-consuming and lacks an evidence base. We aimed to assess the feasibility, diagnostic accuracy and time-efficiency of hand-held echocardiography in patients with acute coronary syndrome and describe the impact of echocardiography on clinical management in this setting., Methods and Results: Patients with acute coronary syndrome underwent both hand-held and transthoracic echocardiography with agreement between key imaging parameters assessed using kappa statistics. The immediate clinical impact of hand-held echocardiography in this population was systematically evaluated.Overall, 262 patients (65±12 years, 71% male) participated. Agreement between hand-held and transthoracic echocardiography was good-to-excellent (kappa 0.60-1.00) with hand-held echocardiography having an overall negative predictive value of 95%. Hand-held echocardiography was performed rapidly (7.7±1.6 min) and completed a median of 5 [interquartile range 3-20] hours earlier than transthoracic echocardiography. Systematic hand-held echocardiography in all patients with acute coronary syndrome identified an important cardiac abnormality in 50% and the clinical management plan was changed by echocardiography in 42%. In 85% of cases, hand-held echocardiography was sufficient for patient decision-making and transthoracic echocardiography was no longer deemed necessary., Conclusions: In patients with acute coronary syndrome, hand-held echocardiography provides comparable results to transthoracic echocardiography, can be more rapidly applied and gives sufficient imaging information for decision-making in the vast majority of patients. Systematic echocardiography has clinical impact in half of patients, supporting the clinical utility of echocardiography in this population, and providing an evidence-base for current guidelines., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Patients with advanced heart failure have substantial supportive care needs. Specialist palliative care can be beneficial, but it is unclear who is most appropriate for referral and when patients should be referred., Objectives: We conducted a Delphi study of international experts to identify consensus referral criteria for specialist palliative care for patients with advanced heart failure., Methods: Clinicians from 5 continents with expertise in the integration of cardiology and palliative care were asked to rate 34 disease-based, 24 needs-based, and 9 time-based criteria over 3 rounds. Consensus was defined a priori as ≥70% agreement. A criterion was coded as major if the experts endorsed that meeting that criterion alone was adequate to justify a referral., Results: The response rate was 44 of 46 (96%), 41 of 46 (89%), and 43 of 46 (93%) in the first, second, and third rounds, respectively. Panelists reached consensus on 25 major criteria for specialist palliative care referral. The 25 major criteria were categorized under 6 topics, including "advanced/refractory heart failure, comorbidities, and complications" (eg, cardiac cachexia, cardiorenal syndrome) (n = 8), "advanced heart failure therapies" (eg, chronic inotropes, precardiac transplant) (n = 4), "hospital utilization" (eg, emergency room visits, hospitalization) (n = 2), "prognostic estimate" (n = 1), "symptom burden/distress" (eg, severe physical/emotional/spiritual distress) (n = 6), and "decision making/social support" (eg, goals-of-care discussions) (n = 4). The majority (68%) of major criteria had ≥90% agreement., Conclusions: International experts reached consensus on a large number of criteria for referral to specialist palliative care. With further validation, these criteria may be useful for standardizing palliative care access in the inpatient and/or outpatient settings., Competing Interests: Funding Support and Author Disclosures Dr Hui has received grants from the National Institutes of Health (NIH) National Cancer Institute (R01CA214960, R01CA225701, and R01CA231471). The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Acute aortic syndrome is associated with aortic medial degeneration. 18 F-sodium fluoride ( 18 F-NaF) positron emission tomography (PET) detects microscopic tissue calcification as a marker of disease activity., Objectives: In a proof-of-concept study, this investigation aimed to establish whether 18 F-NaF PET combined with computed tomography (CT) angiography could identify aortic medial disease activity in patients with acute aortic syndrome., Methods: Patients with aortic dissection or intramural hematomas and control subjects underwent 18 F-NaF PET/CT angiography of the aorta. Aortic 18 F-NaF uptake was measured at the most diseased segment, and the maximum value was corrected for background blood pool activity (maximum tissue-to-background ratio [TBR max ]). Radiotracer uptake was compared with change in aortic size and major adverse aortic events (aortic rupture, aorta-related death, or aortic repair) over 45 ± 13 months., Results: Aortic 18 F-NaF uptake co-localized with histologically defined regions of microcalcification and elastin disruption. Compared with control subjects, patients with acute aortic syndrome had increased 18 F-NaF uptake (TBR max : 1.36 ± 0.39 [n = 20] vs 2.02 ± 0.42 [n = 47] respectively; P < 0.001) with enhanced uptake at the site of intimal disruption (+27.5%; P < 0.001). 18 F-NaF uptake in the false lumen was associated with aortic growth (+7.1 mm/year; P = 0.011), and uptake in the outer aortic wall was associated with major adverse aortic events (HR: 8.5 [95% CI: 1.4-50.4]; P = 0.019)., Conclusions: In patients with acute aortic syndrome, 18 F-NaF uptake was enhanced at sites of disease activity and was associated with aortic growth and clinical events. 18 F-NaF PET/CT holds promise as a noninvasive marker of disease severity and future risk in patients with acute aortic syndrome. ( 18 F Sodium Fluoride PET/CT in Acute Aortic Syndrome [FAASt]; NCT03647566)., Competing Interests: Funding Support and Author Disclosure All funding support is from the United Kingdom. Mr Syed and Drs Fletcher, Dweck, Shah, and Tavares, Mr Kaczynki, and Dr Newby were supported by the British Heart Foundation (FS/18/31/33676, FS/19/15/34155, FS/11/014, FS/14/78/31020, CH/09/002, RG/16/10/32375, RE/18/5/34216). Dr Dweck has received the Sir Jules Thorn Award for Biomedical Research 2015 (15/JTA). Dr Newby has received a Wellcome Trust Senior Investigator Award (WT103782AIA). Dr van Beek has been supported by the Scottish Imaging Network—a Platform of Scientific Excellence (SINAPSE). Edinburgh Clinical Research Facility and Edinburgh Imaging Facility are supported by NHS Research Scotland. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022. Published by Elsevier Inc.)

Sustained neutrophilic inflammation is detrimental for cardiac repair and associated with adverse outcomes following myocardial infarction (MI). An attractive therapeutic strategy to treat MI is to reduce or remove infiltrating neutrophils to promote downstream reparative mechanisms. CDK9 inhibitor compounds enhance the resolution of neutrophilic inflammation; however, their effects on cardiac repair/regeneration are unknown. We have devised a cardiac injury model to investigate inflammatory and regenerative responses in larval zebrafish using heartbeat-synchronised light-sheet fluorescence microscopy. We used this model to test two clinically approved CDK9 inhibitors, AT7519 and flavopiridol, examining their effects on neutrophils, macrophages and cardiomyocyte regeneration. We found that AT7519 and flavopiridol resolve neutrophil infiltration by inducing reverse migration from the cardiac lesion. Although continuous exposure to AT7519 or flavopiridol caused adverse phenotypes, transient treatment accelerated neutrophil resolution while avoiding these effects. Transient treatment with AT7519, but not flavopiridol, augmented wound-associated macrophage polarisation, which enhanced macrophage-dependent cardiomyocyte number expansion and the rate of myocardial wound closure. Using cdk9-/- knockout mutants, we showed that AT7519 is a selective CDK9 inhibitor, revealing the potential of such treatments to promote cardiac repair/regeneration., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2021. Published by The Company of Biologists Ltd.)

Isolation of high quality cardiac endothelial cells is a prerequisite for successful bulk and single cell sequencing for RNA (scRNA-seq). We describe a protocol using both enzymatic and mechanical dissociation and fluorescence-activated cell sorting (FACS) to isolate endothelial cells from larval and adult zebrafish hearts and from healthy and ischemic adult mouse hearts. Endothelial cells with high viability and purity can be obtained using this method for downstream transcriptional analyses applications., (© 2022. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Nuclear receptors play a central role in both energy metabolism and cardiomyocyte death and survival in the heart. Recent evidence suggests they may also influence cardiomyocyte endowment. Although several members of the nuclear receptor family play key roles in heart maturation (including thyroid hormone receptors) and cardiac metabolism, here, the focus will be on the corticosteroid receptors, the glucocorticoid receptor (GR) and mineralocorticoid receptor (MR). The heart is an important target for the actions of corticosteroids, yet the homeostatic role of GR and MR in the healthy heart has been elusive. However, MR antagonists are important in the treatment of heart failure, a condition associated with mitochondrial dysfunction and energy failure in cardiomyocytes leading to mitochondria-initiated cardiomyocyte death (Ingwall and Weiss, Circ Res 95:135-145, 2014; Ingwall , Cardiovasc Res 81:412-419, 2009; Zhou and Tian , J Clin Invest 128:3716-3726, 2018). In contrast, animal studies suggest GR activation in cardiomyocytes has a cardioprotective role, including in heart failure., (© 2022. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Despite the importance of nitric oxide signaling in multiple biological processes, its role in tissue regeneration remains largely unexplored. Here, we provide evidence that inducible nitric oxide synthase (iNos) translocates to the nucleus during zebrafish tailfin regeneration and is associated with alterations in the nuclear S-nitrosylated proteome. iNos inhibitors or nitric oxide scavengers reduce protein S-nitrosylation and impair tailfin regeneration. Liquid chromatography/tandem mass spectrometry reveals an increase of up to 11-fold in the number of S-nitrosylated proteins during regeneration. Among these, Kdm1a, a well-known epigenetic modifier, is S-nitrosylated on Cys334. This alters Kdm1a binding to the CoRest complex, thus impairing its H3K4 demethylase activity, which is a response specific to the endothelial compartment. Rescue experiments show S-nitrosylation is essential for tailfin regeneration, and we identify downstream endothelial targets of Kdm1a S-nitrosylation. In this work, we define S-nitrosylation as an essential post-translational modification in tissue regeneration., (© 2021. The Author(s).)

Decades of research have confirmed the beneficial and advantageous use of zebrafish ( Danio rerio ) as a model of human disease in biomedical studies. Not only are 71% of human genes shared with the zebrafish many of these genes are linked to human diseases. Currently, numerous transgenic and mutant genetic zebrafish lines are now widely available for use in research. Furthermore, zebrafish are relatively inexpensive to maintain compared to rodents. However, a limiting factor to fully utilising adult zebrafish in research is not the fish but the technological imaging tools available. In order to increase the utilisation of adult zebrafish, which are not naturally transparent, requires new imaging approaches. Therefore, this feasibility study: (1) presents an innovative designed PET/CT adult zebrafish imaging platform, capable of maintaining normal aquatic physiology during scanning; (2) assesses the practical aspects of adult zebrafish imaging; and (3) set basic procedural guidelines for zebrafish imaging during a PET/CT acquisition. Methods: With computer aided design (CAD) software an imaging platform was developed for 3D printing. A 3D printed zebrafish model was created from a CT acquisition of a zebrafish using the CAD software. This model and subsequently euthanised zebrafish were imaged post-injection using different concentrations of the radiotracer [ 18 F]FDG with CT contrast. Results: PET/CT imaging was successful, revealing levels as low as 0.01 MBq could be detected in the fish. In the zebrafish imaging post-injection distribution of the radiotracer was observed away from the injection site as well as tissue uptake. Potential preliminary husbandry and welfare guidelines for the fish during and after PET/CT imaging were determined. Conclusion: Using PET/CT for adult zebrafish imaging as a viable non-invasive technological tool is feasible. Adult zebrafish PET/CT imaging has the potential to be a key imaging technique offering the possibilities of enhanced biomedical understanding and new translational data sets., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Tucker, Collins, Denvir and McDougald.)

A network of molecular factors drives the development, differentiation, and maintenance of endothelial cells. Friend leukemia integration 1 transcription factor (FLI1) is a bona fide marker of endothelial cells during early development. In zebrafish Tg( f li1:EGFP) y1 , we identified two endothelial cell populations, high- fli1 + and low- fli1 + , by the intensity of green fluorescent protein signal. By comparing RNA-sequencing analysis of non- fli1 expressing cells ( fli1 - ) with these two ( fli1 + ) cell populations, we identified several up-regulated genes, not previously recognized as important, during endothelial development. Compared with fli1 - and low- fli1 + cells, high- fli1 + cells showed up-regulated expression of the zinc finger transcription factor PRDI-BF1 and RIZ homology domain containing 16 ( prdm16 ). Prdm16 knockdown (KD) by morpholino in the zebrafish larva was associated with impaired angiogenesis and increased number of low- fli1 This work unveils a mechanism by which + expression is activated in endothelial cells by Lmo2 and highlights a possible therapeutic pathway by which to modulate endothelial cell growth and repair.fli1 + cells. In addition, PRDM16 KD in endothelial cells derived from human-induced pluripotent stem cells impaired their differentiation and migration in vitro. Moreover, zebrafish mutants (mut) with loss of function for the oncogene LIM domain only 2 ( lmo2 ) also showed reduced prdm16 gene expression combined with impaired angiogenesis. Prdm16 expression was reduced further in endothelial (CD31 + ) cells compared with CD31 - cells isolated from l mo2 -mutants ( l mo2- mut) embryos. Chromatin immunoprecipitation-PCR demonstrated that Lmo2 binds to the promoter and directly regulates the transcription of prdm16 This work unveils a mechanism by which prdm16 expression is activated in endothelial cells by Lmo2 and highlights a possible therapeutic pathway by which to modulate endothelial cell growth and repair., Competing Interests: The authors declare no competing interest.

Purpose: To explore the utility of phosphorus magnetic resonance spectroscopy ( 31 P MRS) in identifying anthracycline-induced cardiac toxicity in patients with breast cancer. Methods: Twenty patients with newly diagnosed breast cancer receiving anthracycline-based chemotherapy had cardiac magnetic resonance assessment of left ventricular ejection fraction (LVEF) and 31 P MRS to determine myocardial Phosphocreatine/Adenosine Triphosphate Ratio (PCr/ATP) at three time points: pre-, mid-, and end-chemotherapy. Plasma high sensitivity cardiac troponin-I (cTn-I) tests and electrocardiograms were also performed at these same time points. Results: Phosphocreatine/Adenosine Triphosphate did not change significantly between pre- and mid-chemo (2.16 ± 0.46 vs. 2.00 ± 0.56, p = 0.80) and pre- and end-chemo (2.16 ± 0.46 vs. 2.17 ± 0.86, p = 0.99). Mean LVEF reduced significantly by 5.1% between pre- and end-chemo (61.4 ± 4.4 vs. 56.3 ± 8.1 %, p = 0.02). Change in PCr/ATP ratios from pre- to end-chemo correlated inversely with changes in LVEF over the same period ( r = -0.65, p = 0.006). Plasma cTn-I increased progressively during chemotherapy from pre- to mid-chemo (1.35 ± 0.81 to 4.40 ± 2.64 ng/L; p = 0.01) and from mid- to end-chemo (4.40 ± 2.64 to 18.33 ± 13.23 ng/L; p = 0.001). Conclusions: In this small cohort pilot study, we did not observe a clear change in mean PCr/ATP values during chemotherapy despite evidence of increased plasma cardiac biomarkers and reduced LVEF. Future similar studies should be adequately powered to take account of patient drop-out and variable changes in PCr/ATP and could include T1 and T2 mapping., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Macnaught, Oikonomidou, Rodgers, Clarke, Cooper, McVicars, Hayward, Mirsadraee, Semple and Denvir.)

Objective: Emergency Department (ED) attendances with chest pain reduced during the COVID-19 lockdown. We performed a service evaluation project in NHS Lothian to explore how and why the COVID-19 pandemic and public health advice had affected chest pain presentations and help-seeking behaviour at an individual patient level using a qualitative interview approach., Methods: We carried out 28 semi-structured telephone interviews with a convenience sample of patients who presented with chest pain during lockdown and in patients with known coronary heart disease under the outpatient care of a cardiologist in April and May 2020. Interviews were audio recorded and voice files listened to while making detailed notes. Salient themes and issues were documented as verbatim extracts. Interviews were analysed thematically., Results: Patient interviews revealed three main themes. 1) pandemic help-seeking behaviour; describing how participants made the decision to seek professional healthcare assessment. 2) COVID-19 exposure concerns; describing how the subthemes of perceived vulnerability, wishing to protect others and adding pressure to the health service shaped their decision making for an episode of acute chest pain. 3) hospital experience; describing the difference between the imagined and actual experience in hospital., Conclusions: Qualitative interviews revealed how the pandemic shaped help-seeking practices, how patients interpreted their personal vulnerability to the virus, and described patient experience of attending hospital for assessment during this time. As patient numbers presenting to hospital appeared to mirror public health messaging, dynamic monitoring of this messaging should evaluate public response to healthcare campaigns to ensure the net impact on health, pandemic and non-pandemic related, is optimised., Competing Interests: The authors have declared that no competing interests exist.

Neutrophils and macrophages are crucial effectors and modulators of repair and regeneration following myocardial infarction, but they cannot be easily observed in vivo in mammalian models. Hence many studies have utilized larval zebrafish injury models to examine neutrophils and macrophages in their tissue of interest. However, to date the migratory patterns and ontogeny of these recruited cells is unknown. In this study, we address this need by comparing our larval zebrafish model of cardiac injury to the archetypal tail fin injury model. Our in vivo imaging allowed comprehensive mapping of neutrophil and macrophage migration from primary hematopoietic sites, to the wound. Early following injury there is an acute phase of neutrophil recruitment that is followed by sustained macrophage recruitment. Both cell types are initially recruited locally and subsequently from distal sites, primarily the caudal hematopoietic tissue (CHT). Once liberated from the CHT, some neutrophils and macrophages enter circulation, but most use abluminal vascular endothelium to crawl through the larva. In both injury models the innate immune response resolves by reverse migration, with very little apoptosis or efferocytosis of neutrophils. Furthermore, our in vivo imaging led to the finding of a novel wound responsive mpeg1 + neutrophil subset, highlighting previously unrecognized heterogeneity in neutrophils. Our study provides a detailed analysis of the modes of immune cell migration in larval zebrafish, paving the way for future studies examining tissue injury and inflammation., (Copyright © 2020 Kaveh, Bruton, Buckley, Oremek, Tucker, Mullins, Taylor, Rossi and Denvir.)

Background: Patients with heart failure have significant symptom burden, care needs, and often a progressive course to end-stage disease. Palliative care referrals may be helpful but it is currently unclear when patients should be referred and by whom. We conducted a systematic review of the literature to examine referral criteria for palliative care among patients with heart failure., Methods: We searched Ovid, MEDLINE, Ovid Embase, and PubMed databases for articles in the English language from the inception of databases to January 17, 2019 related to palliative care referral in patients with heart failure. Two investigators independently reviewed each citation for inclusion and then extracted the referral criteria. Referral criteria were then categorized thematically., Results: Of the 1199 citations in our initial search, 102 articles were included in the final sample. We identified 18 categories of referral criteria, including 7 needs-based criteria and 10 disease-based criteria. The most commonly discussed criterion was physical or emotional symptoms (n=51 [50%]), followed by cardiac stage (n=46 [45%]), hospital utilization (n=38 [37%]), prognosis (n=37 [36%]), and advanced cardiac therapies (n=36 [35%]). Under cardiac stage, 31 (30%) articles suggested New York Heart Association functional class ≥III and 12 (12%) recommended New York Heart Association class ≥IV as cutoffs for referral. Prognosis of ≤1 year was mentioned in 21 (21%) articles as a potential trigger; few other criteria had specific cutoffs., Conclusions: This systematic review highlighted the lack of consensus regarding referral criteria for the involvement of palliative care in patients with heart failure. Further research is needed to identify appropriate and timely triggers for palliative care referral.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Background: Risk prediction after myocardial infarction is often complex in older patients. The Global Registry of Acute Coronary Events (GRACE) model includes clinical parameters and age, but not frailty. We hypothesised that frailty would enhance the prognostic properties of GRACE., Methods: We performed a prospective observational cohort study in two independent cardiology units: the Royal Infirmary of Edinburgh, UK (primary cohort) and the South Yorkshire Cardiothoracic Centre, Sheffield, UK (external validation). The study sample included 198 patients ≥65 years old hospitalised with type 1 myocardial infarction (primary cohort) and 96 patients ≥65 years old undergoing cardiac catheterisation for myocardial infarction (external validation). Frailty was assessed using the Clinical Frailty Scale (CFS). The GRACE 2.0 estimated risk of 12-month mortality, Charlson comorbidity index and Karnofsky disability scale were also determined for each patient., Results: Forty (20%) patients were frail (CFS ≥5). These individuals had greater comorbidity, functional impairment and a higher risk of death at 12 months (49% vs. 9% in non-frail patients, p < 0.001). The hazard of 12-month all-cause mortality nearly doubled per point increase in CFS after adjustment for age, sex and comorbidity (Hazard Ratio [HR] 1.90, 95% CI 1.47-2.44, p < 0.001). The CFS had good discrimination for mortality by Receiver Operating Characteristic (ROC) curve analysis (Area Under the Curve [AUC] 0.81, 95% CI 0.72-0.89) and enhanced the GRACE estimate (AUC 0.86 vs. 0.80 without CFS, p = 0.04). At existing GRACE thresholds, the CFS resulted in a Net Reclassification Improvement (NRI) of 0.44 (95% CI 0.28-0.60, p < 0.001), largely through reductions in risk estimates amongst non-frail patients. Similar findings were observed in the external validation cohort (NRI 0.46, 95% CI 0.23-0.69, p < 0.001)., Conclusions: The GRACE score overestimated mortality risk after myocardial infarction in these cohorts of older patients. The CFS is a simple guided frailty tool that may enhance prediction in this setting. These findings merit evaluation in larger cohorts of unselected patients., Trial Registration: Clinicaltrials.gov; NCT02302014 (November 26th 2014, retrospectively registered).

Three-dimensional fluorescence time-lapse imaging of the beating heart is extremely challenging, due to the heart's constant motion and a need to avoid pharmacological or phototoxic damage. Although real-time triggered imaging can computationally "freeze" the heart for 3D imaging, no previous algorithm has been able to maintain phase-lock across developmental timescales. We report a new algorithm capable of maintaining day-long phase-lock, permitting routine acquisition of synchronised 3D + time video time-lapse datasets of the beating zebrafish heart. This approach has enabled us for the first time to directly observe detailed developmental and cellular processes in the beating heart, revealing the dynamics of the immune response to injury and witnessing intriguing proliferative events that challenge the established literature on cardiac trabeculation. Our approach opens up exciting new opportunities for direct time-lapse imaging studies over a 24-hour time course, to understand the cellular mechanisms underlying cardiac development, repair and regeneration.

Aims: Heart failure may occur following acute myocardial infarction, but with the use of high-sensitivity cardiac troponin assays we increasingly diagnose patients with minor myocardial injury. Whether troponin concentrations remain a useful predictor of heart failure in patients with acute coronary syndrome is uncertain., Methods and Results: We identified all consecutive patients (n = 4748) with suspected acute coronary syndrome (61 ± 16 years, 57% male) presenting to three secondary and tertiary care hospitals. Cox-regression models were used to evaluate the association between high-sensitivity cardiac troponin I concentration and subsequent heart failure hospitalization. C-statistics were estimated to evaluate the predictive value of troponin for heart failure hospitalization. Over 2071 years of follow-up there were 83 heart failure hospitalizations. Patients with troponin concentrations above the upper reference limit (URL) were more likely to be hospitalized with heart failure than patients below the URL (118/1000 vs. 17/1000 person years, adjusted hazard ratio: 7.0). Among patients with troponin concentrations

Objectives: Cardiovascular disease (CVD) and chronic obstructive pulmonary disease (COPD) often coexist. We assessed the effect of inhaled COPD treatments on CVD outcomes and safety in patients with COPD and at heightened CVD risk., Methods: The SUMMIT (Study to Understand Mortality and MorbidITy) was a multicentre, randomised, double-blind, placebo-controlled, event-driven trial in 16 485 patients with moderate COPD who had or were at high risk of CVD. Here, we assessed the prespecified secondary endpoint of time to first on-treatment composite CVD event (CVD death, myocardial infarction, stroke, unstable angina or transient ischaemic attack (TIA)) by Cox regression and by clinician-reported CVD adverse events across the four groups: once-daily inhaled placebo (n=4111), long-acting beta 2 -agonist (vilanterol (VI) 25 µg; n=4118), corticosteroid (fluticasone furoate (FF) 100 µg; n=4135) and combination therapy (FF/VI; n=4121)., Results: Participants were predominantly middle-aged (mean 65 (SD 8) years) men (75%) with overt CVD (66%). The composite CVD endpoint occurred in 688 patients (first event: sudden death (35%), acute coronary syndrome (37%) and stroke or TIA (23%), and was not reduced in any treatment group versus placebo: VI (HR 0.99, 95% CI 0.80 to 1.22), FF (HR 0.90, 95% CI 0.72 to 1.11) and their combination (HR 0.93, 95% CI 0.75 to 1.14). Outcomes were similar among all subgroups. Adverse events, including palpitations and arrhythmias, did not differ by treatment., Conclusions: In patients with COPD with moderate airflow limitation and heightened CVD risk, treatment with inhaled VI, FF or their combination has an excellent safety profile and does not impact CVD outcomes., Trial Registration Number: NCT01313676., Competing Interests: Competing interests: RDB, PMAC, BRC, FJM, JV and DEN are external members of the SUMMIT Steering Committee. JAA, CC and JY are employed by GSK and are members of the SUMMIT Steering Committee. MAD and SM are members of the SUMMIT Clinical Endpoint Committee, and SR is a member of the SUMMIT Independent Data Monitoring Committee., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

[This corrects the article DOI: 10.1371/journal.pone.0174166.].

Cardiomyocytes proliferate profusely during early development and for a brief period after birth in mammals. Within a month after birth, this proliferative capability is dramatically reduced in mammals unlike lower vertebrates where it persists into adult life. The zebrafish, for example, retains the ability to regenerate the apex of the heart following resection by a mechanism predominantly driven by cardiomyocyte proliferation. Differences in proliferative capacity of cardiomyocytes in adulthood between mammals and lower vertebrates are closely liked to ontogenetic or phylogenetic factors. Elucidation of these factors has the potential to provide enormous benefits if they lead to the development of therapeutic strategies that facilitate cardiomyocyte proliferation. In this review, we highlight the differences between Mammalian and Zebrafish cardiomyocytes, which could explain at least in part the different proliferative capacities in these two species. We discuss the advantages of the zebrafish as a model of cardiomyocyte proliferation, particularly at the embryonic stage. We also identify a number of key molecular pathways with potential to reveal key steps in switching cardiomyocytes from a quiescent to a proliferative phenotype.

Objective: High sensitivity plasma cardiac troponin-I (cTnI) is emerging as a strong predictor of cardiac events in a variety of settings. We have explored its utility in patients with myotonic dystrophy type 1 (DM1)., Methods: 117 patients with DM1 were recruited from routine outpatient clinics across three health boards. A single measurement of cTnI was made using the ARCHITECT STAT Troponin I assay. Demographic, ECG, echocardiographic and other clinical data were obtained from electronic medical records. Follow up was for a mean of 23 months., Results: Fifty five females and 62 males (mean age 47.7 years) were included. Complete data were available for ECG in 107, echocardiography in 53. Muscle Impairment Rating Scale score was recorded for all patients. A highly significant excess (p = 0.0007) of DM1 patients presented with cTnI levels greater than the 99th centile of the range usually observed in the general population (9 patients; 7.6%). Three patients with elevated troponin were found to have left ventricular systolic dysfunction (LVSD), compared with four of those with normal range cTnI (33.3% versus 3.7%; p = 0.001). Sixty two patients had a cTnI level < 5ng/L, of whom only one had documented evidence of LVSD. Elevated cTnI was not predictive of severe conduction abnormalities on ECG, or presence of a cardiac device, nor did cTnI level correlate with muscle strength expressed by Muscle Impairment Rating Scale score., Conclusions: Plasma cTnI is highly elevated in some ambulatory patients with DM1 and shows promise as a tool to aid cardiac risk stratification, possibly by detecting myocardial involvement. Further studies with larger patient numbers are warranted to assess its utility in this setting.

The efficacy of mineralocorticoid receptor (MR) antagonism in the treatment of certain patients with heart failure has highlighted the pivotal role of aldosterone and MR in heart disease. The glucocorticoid (GC) receptor (GR) is also expressed in heart, but the role of cardiac GR had received much less attention until recently. GR and MR are highly homologous in both structure and function, although not in cellular readout. Recent evidence in animal models has uncovered a tonic role for GC action via GR in cardiomyocytes in prevention of heart disease. Here, we review this evidence and the implications for a balance between GR and MR activation in the early life maturation of the heart and its subsequent health and disease., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Aims: The primary aim of this study is to provide data to inform the design of a randomized controlled clinical trial (RCT) of a palliative care (PC) intervention in heart failure (HF). We will identify an appropriate study population with a high prevalence of PC needs defined using quantifiable measures. We will also identify which components a specific and targeted PC intervention in HF should include and attempt to define the most relevant trial outcomes., Methods: An unselected, prospective, near-consecutive, cohort of patients admitted to hospital with acute decompensated HF will be enrolled over a 2-year period. All potential participants will be screened using B-type natriuretic peptide and echocardiography, and all those enrolled will be extensively characterized in terms of their HF status, comorbidity, and PC needs. Quantitative assessment of PC needs will include evaluation of general and disease-specific quality of life, mood, symptom burden, caregiver burden, and end of life care. Inpatient assessments will be performed and after discharge outpatient assessments will be carried out every 4 months for up to 2.5 years. Participants will be followed up for a minimum of 1 year for hospital admissions, and place and cause of death. Methods for identifying patients with HF with PC needs will be evaluated, and estimates of healthcare utilisation performed., Conclusion: By assessing the prevalence of these needs, describing how these needs change over time, and evaluating how best PC needs can be identified, we will provide the foundation for designing an RCT of a PC intervention in HF.

Introduction: Social isolation in patients with chronic heart failure (CHF) is an adverse prognostic factor. This paper reports the creation of a supportive patient/carer network (Heart Failure Support Service), led by a voluntary sector/National Health Service (NHS) partnership which involved volunteer befriending, regular patient and carer forum and a newsletter., The Project: Over 3 years, 37 volunteers were 'befrienders' to over 50 individuals with CHF. A thorough training and matching process ensured that the first befriending visit was a positive experience. 100% of patients found the visits from the volunteer worthwhile and said they would recommend the service to other patients. Prior to the first patient-carer forum, 200 questionnaires were sent out with a 56% response rate, 44% of respondents believed that a forum and a newsletter would be valued. Over a period of 3 years, 12 quarterly meetings were held with an average attendance of 30-40 per meeting. The newsletter (current circulation >800 per quarter) contributed to self-management and encouraged communication between professionals and patients-carers., Conclusions: The Heart Failure Support Service (volunteers, forum and newsletter) created a supportive patient-carer network and represents a successful voluntary sector/NHS partnership., ((c) 2009 Elsevier B.V. All rights reserved.)