Search

Background: Spontaneous coronary artery dissection (SCAD) is a cause of acute coronary syndrome that predominantly affects women. Its pathophysiology remains unclear but connective tissue disorders (CTD) and other vasculopathies have been observed in many SCAD patients. A genetic component for SCAD is increasingly appreciated, although few genes have been robustly implicated. We sought to clarify the genetic cause of SCAD using targeted and genome-wide methods in a cohort of sporadic cases to identify both common and rare disease-associated variants. Methods: A cohort of 91 unrelated sporadic SCAD cases was investigated for rare, deleterious variants in genes associated with either SCAD or CTD, while new candidate genes were sought using rare variant collapsing analysis and identification of novel loss-of-function variants in genes intolerant to such variation. Finally, 2 SCAD polygenic risk scores were applied to assess the contribution of common variants. Results: We identified 10 cases with at least one rare, likely disease-causing variant in CTD-associated genes, although only one had a CTD phenotype. No genes were significantly associated with SCAD from genome-wide collapsing analysis, however, enrichment for TGF (transforming growth factor)-β signaling pathway genes was found with analysis of 24 genes harboring novel loss-of-function variants. Both polygenic risk scores demonstrated that sporadic SCAD cases have a significantly elevated genetic SCAD risk compared with controls. Conclusions: SCAD shares some genetic overlap with CTD, even in the absence of any major CTD phenotype. Consistent with a complex genetic architecture, SCAD patients also have a higher burden of common variants than controls.

Spontaneous coronary artery dissection (SCAD) is an under-recognised cause of acute coronary syndrome (ACS) with a strong female predominance. There are currently limited prospective studies and no randomised controlled trials that inform on SCAD's best clinical care. Little is also known about predictors of acute SCAD deterioration or recurrence. We describe the study design of a multi-centre prospective and historical cohort study recruiting patients with SCAD across 15-20 sites in Australia/New Zealand (NZ). The primary aim is to describe the clinical presentation, management and outcomes along with predictors of acute deterioration and recurrence in a large Australian/NZ SCAD cohort, with international data pooling.Consented patients diagnosed with SCAD during a hospital admission for an ACS will be prospectively followed at 30 days then yearly, for up to 5 years. Each recruiting site will also retrospectively identify historical cases of SCAD from the proceeding 10 years, with a waiver of consent. For historical cases, data will be collected in a de-identified manner with date of last follow-up or death obtained from the medical records. All cases undergo core laboratory adjudication of coronary angiography and any accompanying imaging to confirm SCAD diagnosis. The primary endpoint will be occurrence of major adverse cardiovascular events; a composite of all-cause mortality, recurrent myocardial infarction (including SCAD recurrence), stroke/transient ischaemic attack, heart failure, cardiogenic shock, cardiac arrest/ventricular arrhythmia, heart transplantation and, repeat/unplanned revascularisation. Secondary endpoints will include each individual primary outcome as well as acute SCAD extension and quality of life/Seattle Angina Score in prospectively recruited participants. Endpoints will be assessed at the end of the hospital admission and at 30-days, 1 year, and median long-term follow-up.Multicentre ethics approval has been granted from the Western Sydney Local Health District Human Research Ethics Committee (2021/ETH00040).The analysed results will be published in peer-reviewed journals on completion of the historical data collection and then on completion of the prospective data collection.The ANZ-SCAD registry has been prospectively registered with the Australia and New Zealand Clinical Trials Registry (ACTRN12621000824864).

The nomenclature of the Adrenoceptors has been agreed by the NC-IUPHAR Subcommittee on Adrenoceptors [64, 194]. Adrenoceptors, α1 The three α1-adrenoceptor subtypes α1A, α1B and α1D are activated by the endogenous agonists (-)-adrenaline and (-)-noradrenaline. -(-)phenylephrine, methoxamine and cirazoline are agonists and prazosin and doxazosin antagonists considered selective for α1- relative to α2-adrenoceptors. [3H]prazosin and [125I]HEAT (BE2254) are relatively selective radioligands. S(+)-niguldipine also has high affinity for L-type Ca2+ channels. Fluorescent derivatives of prazosin (Bodipy FLprazosin- QAPB) are used to examine cellular localisation of α1-adrenoceptors. α1-Adrenoceptor agonists are used as nasal decongestants; antagonists to treat symptoms of benign prostatic hyperplasia (alfuzosin, doxazosin, terazosin, tamsulosin and silodosin, with the last two compounds being α1A-adrenoceptor selective and claiming to relax bladder neck tone with less hypotension); and to a lesser extent hypertension (doxazosin, terazosin). The α1- and β2-adrenoceptor antagonist carvedilol is used to treat congestive heart failure, although the contribution of α1-adrenoceptor blockade to the therapeutic effect is unclear. Several anti-depressants and anti-psychotic drugs are α1-adrenoceptor antagonists contributing to side effects such as orthostatic hypotension. Adrenoceptors, α2 The three α2-adrenoceptor subtypes α2A, α2B and α2C are activated by (-)-adrenaline and with lower potency by (-)-noradrenaline. brimonidine and talipexole are agonists and rauwolscine and yohimbine antagonists selective for α2- relative to α1-adrenoceptors. [3H]rauwolscine, [3H]brimonidine and [3H]RX821002 are relatively selective radioligands. There are species variations in the pharmacology of the α2A-adrenoceptor. Multiple mutations of α2-adrenoceptors have been described, some associated with alterations in function. Presynaptic α2-adrenoceptors regulate many functions in the nervous system. The α2-adrenoceptor agonists clonidine, guanabenz and brimonidine affect central baroreflex control (hypotension and bradycardia), induce hypnotic effects and analgesia, and modulate seizure activity and platelet aggregation. clonidine is an anti-hypertensive (relatively little used) and counteracts opioid withdrawal. dexmedetomidine (also xylazine) is increasingly used as a sedative and analgesic in human [33] and veterinary medicine and has sympatholytic and anxiolytic properties. The α2-adrenoceptor antagonist mirtazapine is used as an anti-depressant. The α2B subtype appears to be involved in neurotransmission in the spinal cord and α2C in regulating catecholamine release from adrenal chromaffin cells. Although subtype-selective antagonists have been developed, none are used clinically and they remain experimental tools. Adrenoceptors, β The three β-adrenoceptor subtypes β1, β2 and β3 are activated by the endogenous agonists (-)-adrenaline and (-)-noradrenaline. Isoprenaline is selective for β-adrenoceptors relative to α1- and α2-adrenoceptors, while propranolol (pKi 8.2-9.2) and cyanopindolol (pKi 10.0-11.0) are relatively selective antagonists for β1- and β2- relative to β3-adrenoceptors. (-)-noradrenaline, xamoterol and (-)-Ro 363 show selectivity for β1- relative to β2-adrenoceptors. Pharmacological differences exist between human and mouse β3-adrenoceptors, and the 'rodent selective' agonists BRL 37344 and CL316243 have low efficacy at the human β3-adrenoceptor whereas CGP 12177 (low potency) and L 755507 activate human β3-adrenoceptors [88]. β3-Adrenoceptors are resistant to blockade by propranolol, but can be blocked by high concentrations of bupranolol. SR59230A has reasonably high affinity at β3-adrenoceptors, but does not discriminate between the three β- subtypes [332] whereas L-748337 is more selective. [125I]-cyanopindolol, [125I]-hydroxy benzylpindolol and [3H]-alprenolol are high affinity radioligands that label β1- and β2- adrenoceptors and β3-adrenoceptors can be labelled with higher concentrations (nM) of [125I]-cyanopindolol together with β1- and β2-adrenoceptor antagonists. Fluorescent ligands such as BODIPY-TMR-CGP12177 can be used to track β-adrenoceptors at the cellular level [8]. Somewhat selective β1-adrenoceptor agonists (denopamine, dobutamine) are used short term to treat cardiogenic shock but, chronically, reduce survival. β1-Adrenoceptor-preferring antagonists are used to treat cardiac arrhythmias (atenolol, bisoprolol, esmolol) and cardiac failure (metoprolol, nebivolol) but also in combination with other treatments to treat hypertension (atenolol, betaxolol, bisoprolol, metoprolol and nebivolol) [528]. Cardiac failure is also treated with carvedilol that blocks β1- and β2-adrenoceptors, as well as α1-adrenoceptors. Short (salbutamol, terbutaline) and long (formoterol, salmeterol) acting β2-adrenoceptor-selective agonists are powerful bronchodilators used to treat respiratory disorders. Many first generation β-adrenoceptor antagonists (propranolol) block both β1- and β2-adrenoceptors and there are no β2-adrenoceptor-selective antagonists used therapeutically. The β3-adrenoceptor agonist mirabegron is used to control overactive bladder syndrome. There is evidence to suggest that β-adrenoceptor antagonists can reduce metastasis in certain types of cancer [197].

Pressure overload-induced cardiac hypertrophy is a maladaptive response with poor outcomes and limited treatment options. The transient receptor potential melastatin 4 (TRPM4) ion channel is key to activation of a Ca2+/calmodulin-dependent kinase II (CaMKII)-reliant hypertrophic signaling pathway after pressure overload, but TRPM4 is neither stretch-activated nor Ca2+-permeable. Here we show that Piezo1, which is both stretch-activated and Ca2+-permeable, is the mechanosensor that transduces increased myocardial forces into the chemical signal that initiates hypertrophic signaling via a close physical interaction with TRPM4. Cardiomyocyte-specific deletion of Piezo1 in adult mice prevented activation of CaMKII and inhibited the hypertrophic response: residual hypertrophy was associated with calcineurin activation in the absence of its usual inhibition by activated CaMKII. Piezo1 deletion prevented upregulation of the sodium–calcium exchanger and changes in other Ca2+ handling proteins after pressure overload. These findings establish Piezo1 as the cardiomyocyte mechanosensor that instigates the maladaptive hypertrophic response to pressure overload, and as a potential therapeutic target.

The 'fight or flight' response to physiological stress involves sympathetic nervous system activation, catecholamine release and adrenergic receptor stimulation. In the heart, this induces positive inotropy, previously attributed to the β1-adrenergic receptor subtype. However, the role of the α1A-adrenergic receptor, which has been suggested to be protective in cardiac pathology, has not been investigated in the setting of physiological stress. To explore this, we developed a tamoxifen-inducible, cardiomyocyte-specific α1A-adrenergic receptor knock-down mouse model, challenged mice to four weeks of endurance swim training and assessed cardiac outcomes. With 4-OH tamoxifen treatment, expression of the α1A-adrenergic receptor was knocked down by 80-89%, without any compensatory changes in the expression of other adrenergic receptors, or changes to baseline cardiac structure and function. Swim training caused eccentric hypertrophy, regardless of genotype, demonstrated by an increase in heart weight/tibia length ratio (30% and 22% in vehicle- and tamoxifen-treated animals, respectively) and an increase in left ventricular end diastolic volume (30% and 24% in vehicle- and tamoxifen-treated animals, respectively) without any change in the wall thickness/chamber radius ratio. Consistent with physiological hypertrophy, there was no increase in fetal gene program (Myh7, Nppa, Nppb or Acta1) expression. In response to exercise-induced volume overload, stroke volume (39% and 30% in vehicle- and tamoxifen-treated animals, respectively), cardiac output/tibia length ratio (41% in vehicle-treated animals) and stroke work (61% and 33% in vehicle- and tamoxifen-treated animals, respectively) increased, regardless of genotype. These findings demonstrate that cardiomyocyte α1A-adrenergic receptors are not necessary for cardiac adaptation to endurance exercise stress and their acute ablation is not deleterious.

OBJECTIVES: This study aimed to determine the safety and efficacy of combined low-dose everolimus and low-dose tacrolimus compared with standard-dose tacrolimus in attenuating left ventricular hypertrophy (LVH) after orthotopic heart transplantation (OHT). BACKGROUND: Calcineurin inhibitors (CNIs) such as tactrolimus are important in preventing cardiac allograft rejection and reducing mortality after OHT. However CNIs are causatively linked to the development of LVH, and are associated with nephrotoxicity and vasculopathy. CNI-sparing agents such as everolimus have been hypothesized to inhibit adverse effects of CNIs. METHODS: In this prospective, randomized, open-label study, OHT recipients were randomized at 12 weeks after OHT to a combination of low-dose everolimus and tacrolimus (the RADTAC group) or standard-dose tacrolimus (the TAC group), with both groups coadministered mycophenolate and prednisolone. The primary endpoint was LVH indexed as the change in left ventricular mass (DeltaLVM) by cardiovascular magnetic resonance (CMR) imaging from 12 to 52 weeks. Secondary endpoints included CMR-based myocardial performance, T1 fibrosis mapping, blood pressure, and renal function. Safety endpoints included episodes of allograft rejection and infection. RESULTS: Forty stable OHT recipients were randomized. Recipients in the RADTAC group had significantly lower tacrolimus levels compared with the TAC group (6.5 +/- 3.5 mug/l vs. 8.6 +/- 2.8 mug/l; p = 0.02). The mean everolimus level in the RADTAC group was 4.2 +/- 1.7 mug/l. A significant reduction in LVM was observed in the RADTAC group compared with an increase in LVM in the TAC group (DeltaLVM = -13.0 +/- 16.8 g vs. 2.1 +/- 8.4 g; p < 0.001). Significant differences were also noted in secondary endpoints measuring function and fibrosis (Delta circumferential strain = -2.9 +/- 2.8 vs. 2.1 +/- 2.3; p < 0.001; DeltaT1 mapping values = -32.7 +/- 51.3 ms vs. 26.3 +/- 90.4 ms; p = 0.003). No significant differences were observed in blood pressure (Delta mean arterial pressure = 4.2 +/- 18.8 mm Hg vs. 2.8 +/- 13.8 mm Hg; p = 0.77), renal function (Delta creatinine = 3.1 +/- 19.9 mumol/l vs. 9 +/- 21.8 mumol/l; p = 0.31), frequency of rejection episodes (p = 0.69), or frequency of infections (p = 0.67) between groups. CONCLUSIONS: The combination of low-dose everolimus and tacrolimus compared with standard-dose tacrolimus safely attenuates LVH in the first year after cardiac transplantation with an observed reduction in CMR-measured fibrosis and an improvement in myocardial strain.

Murine surgical models play an important role in preclinical research. Mechanistic insights into myocardial regeneration after cardiac injury may be gained from cardiothoracic surgery models in 0-14-day-old mice, the cardiomyocytes of which, unlike those of adults, retain proliferative capacity. Mouse pups up to 7 days old are effectively immobilized by hypothermia and do not require intubation for cardiothoracic surgery. Preadolescent (8-14-day-old) mouse pups, however, do require intubation, but this is challenging and there is little information regarding anesthesia to facilitate intubation. Here, we present dosage regimens of ketamine/xylazine/atropine in 10-day-old C57BL/6J mouse pups that allow endotracheal intubation, while minimizing animal mortality. Empirical titration of ketamine/xylazine/atropine dosage regimens to body weight indicated that the response to anesthesia of mouse pups of different weights was non-linear, whereby doses of 20/4/0.12 mg/kg, 30/4/0.12 mg/kg, and 50/6/0.18 mg/kg facilitated intubation of pups weighing between 3.15-4.49 g (n = 22), 4.50-5.49 g (n = 20), and 5.50-8.10 g (n = 20), respectively. Lower-body-weight pups required more intubation attempts than heavier pups (p0.001). Survival post-intubation correlated with body weight (59%, 70%, and 80% for low-, mid-, and high-weight groups, respectively, R

The joint WWRP–WCRP Subseasonal to Seasonal Prediction Project (e.g., Robertson et al. 2014) created a global repository of experimental or operational near-real-time S2S forecasts and reforecasts (hindcasts) from 11 international meteorological institutions, cohosted by ECMWF and CMA (Vitart et al. 2017). These data are publicly accessible by researchers and users (https://apps.ecmwf.int/datasets/data/s2s and http://s2s.cma.cn/index). With the exception of the fourth case study, which uses GloSea5 forecasts (MacLachlan et al. 2015), all case studies use selected S2S forecasts and reforecasts that are available from this repository, providing a consistent basis for S2S forecast skill assessment and evaluation of their utility. The subseasonal-to-seasonal (S2S) predictive time scale, encompassing lead times ranging from 2 weeks to a season, is at the frontier of forecasting science. Forecasts on this time scale provide opportunities for enhanced application-focused capabilities to complement existing weather and climate services and products. There is, however, a “knowledge–value” gap, where a lack of evidence and awareness of the potential socioeconomic benefits of S2S forecasts limits their wider uptake. To address this gap, here we present the first global community effort at summarizing relevant applications of S2S forecasts to guide further decision-making and support the continued development of S2S forecasts and related services. Focusing on 12 sectoral case studies spanning public health, agriculture, water resource management, renewable energy and utilities, and emergency management and response, we draw on recent advancements to explore their application and utility. These case studies mark a significant step forward in moving from potential to actual S2S forecasting applications. We show that by placing user needs at the forefront of S2S forecast development—demonstrating both skill and utility across sectors—this dialogue can be used to help promote and accelerate the awareness, value, and cogeneration of S2S forecasts. We also highlight that while S2S forecasts are increasingly gaining interest among users, incorporating probabilistic S2S forecasts into existing decision-making operations is not trivial. Nevertheless, S2S forecasting represents a significant opportunity to generate useful, usable, and actionable forecast applications for and with users that will increasingly unlock the potential of this forecasting time scale. DD gratefully acknowledges support from the Swiss National Science Foundation through project PP00P2_170523. For case study 1, ACP and WTKH were funded by the U.K. Climate Resilience Programme, supported by the UKRI Strategic Priorities Fund. RWL was funded by NERC Grant NE/P00678/1 and by the BER DOE Office of Science Federal Award DE-SC0020324. TS was funded by NERC Independent Research Fellowship (NE/P018637/1). CMG and DB were funded by the Helmholtz Young Investigator Group “SPREADOUT” Grant VH-NG-1243. Case study 2 was supported by the U.K. Global Challenges Research Fund NE/P021077/1 (GCRF African SWIFT) and the Tertiary Education Trust Fund (TETFUND) of Nigeria TETFund/DR&D/CE/NRF/STI/73/VOL.1. EO thanks Adrian Tomkins of ICTP, Italy, for his contribution. Case study 3 was undertaken as part of the Columbia World Project, ACToday, Columbia University (https://iri.columbia.edu/actoday/). Case study 4 was supported by the ForPAc (Towards Forecast-based Preparedness Action) project within the NERC/FCDO SHEAR Programme NE/P000428/1, NE/P000673/1, and NE/P000568/1. Case study 5 was undertaken as part of the International Research Applications Project, funded by the U.S. National Oceanic and Atmospheric Administration. EO thanks IRAP project colleagues at The University of Arizona, Indian Meteorological Department, Regional Integrated Multi-Hazard Early Warning System for Africa and Asia, and two of Bihar’s State Agricultural Universities for their contributions. For case study 6, CASC thanks Conselho Nacional de Desenvolvimento Científico e Tecnológico Process 305206/2019-2 and Fundação de Amparo à Pesquisa do Estado de São Paulo Process 2015/50687-8 (CLIMAX Project) for their support. For case study 7, DW’s contributions were carried out under contract with the National Aeronautics and Space Administration. Case study 8 was funded by the EU Horizon 2020 Research and Innovation Programme Grant 7767874 (S2S4E). We also acknowledge the Subseasonal-to-Seasonal Project’s Real-Time Pilot Initiative for providing access to real-time forecasts. For case study 9, TIC-LCPE Hydro-04 was funded by the University of Strathclyde’s Low Carbon Power and Energy program. JB was supported by EPSRC Innovation Fellowship EP/R023484/1. We thank Andrew Low and Richard Hearnden from SSE Renewables for their input. Case study 10 was supported by the Earth Systems and Climate Change Hub under the Australian Government’s National Environmental Science Program, and the Decadal Climate Forecasting Project (CSIRO). Case study 11 was funded by the Technologies for Sustainable Built Environments Centre, Reading University, in conjunction with the EPSRC Grant EP/G037787/1 and BT PLC. Case study 12 was funded through the framework service contract for operating the EFAS Computational Center Contract 198702 and the Copernicus Fire Danger Computations Contract 389730 295 in support of the Copernicus Emergency Management Service and Early Warning Systems between the Joint Research Centre and ECMWF. Peer Reviewed "Article signat per 60 autors/es: Christopher J. White, Daniela I. V. Domeisen, Nachiketa Acharya, Elijah A. Adefisan, Michael L. Anderson, Stella Aura, Ahmed A. Balogun, Douglas Bertram, Sonia Bluhm, David J. Brayshaw, Jethro Browell, Dominik Büeler, Andrew Charlton-Perez, Xandre Chourio, Isadora Christel, Caio A. S. Coelho, Michael J. DeFlorio, Luca Delle Monache, Francesca Di Giuseppe, Ana María García-Solórzano, Peter B. Gibson, Lisa Goddard, Carmen González Romero, Richard J. Graham, Robert M. Graham, Christian M. Grams, Alan Halford, W. T. Katty Huang, Kjeld Jensen, Mary Kilavi, Kamoru A. Lawal, Robert W. Lee, David MacLeod, Andrea Manrique-Suñén, Eduardo S. P. R. Martins, Carolyn J. Maxwell, William J. Merryfield, Ángel G. Muñoz, Eniola Olaniyan, George Otieno, John A. Oyedepo, Lluís Palma, Ilias G. Pechlivanidis, Diego Pons, F. Martin Ralph, Dirceu S. Reis Jr., Tomas A. Remenyi, James S. Risbey, Donald J. C. Robertson, Andrew W. Robertson, Stefan Smith, Albert Soret, Ting Sun, Martin C. Todd, Carly R. Tozer, Francisco C. Vasconcelos Jr., Ilaria Vigo, Duane E. Waliser, Fredrik Wetterhall, and Robert G. Wilson"

Background: Endomyocardial biopsy (EMB) is the gold standard method for surveillance of acute cardiac allograft rejection (ACAR) despite its invasive nature. Cardiovascular magnetic resonance (CMR)–based myocardial tissue characterization allows detection of myocarditis. The feasibility of CMR-based surveillance for ACAR-induced myocarditis in the first year after heart transplantation is currently undescribed. Methods: CMR-based multiparametric mapping was initially assessed in a prospective cross-sectional fashion to establish agreement between CMR- and EMB-based ACAR and to determine CMR cutoff values between rejection grades. A prospective randomized noninferiority pilot study was then undertaken in adult orthotopic heart transplant recipients who were randomized at 4 weeks after orthotopic heart transplantation to either CMR- or EMB-based rejection surveillance. Clinical end points were assessed at 52 weeks. Results: Four hundred one CMR studies and 354 EMB procedures were performed in 106 participants. Forty heart transplant recipients were randomized. CMR-based multiparametric assessment was highly reproducible and reliable at detecting ACAR (area under the curve, 0.92; sensitivity, 93%; specificity, 92%; negative predictive value, 99%) with greater specificity and negative predictive value than either T1 or T2 parametric CMR mapping alone. High-grade rejection occurred in similar numbers of patients in each randomized group (CMR, n=7; EMB, n=8; P =0.74). Despite similarities in immunosuppression requirements, kidney function, and mortality between groups, the rates of hospitalization (9 of 20 [45%] versus 18 of 20 [90%]; odds ratio, 0.091; P =0.006) and infection (7 of 20 [35%] versus 14 of 20 [70%]; odds ratio, 0.192; P =0,019) were lower in the CMR group. On 15 occasions (6%), patients who were randomized to the CMR arm underwent EMB for clarification or logistic reasons, representing a 94% reduction in the requirement for EMB-based surveillance. Conclusions: A noninvasive CMR-based surveillance strategy for ACAR in the first year after orthotopic heart transplantation is feasible compared with EMB-based surveillance. Registration: HREC/13/SVH/66 and HREC/17/SVH/80. Australian New Zealand Clinical Trials Registry: ACTRN12618000672257.

Spontaneous coronary artery dissection (SCAD) is an increasingly recognised cause of acute myocardial infarction, particularly in younger women without classic cardiac risk factors. While recent quantitative studies have noted high anxiety and depression in SCAD survivors, the full range and extent of psychosocial impacts of SCAD is unknown. The present study used a qualitative approach to investigate the psychosocial impacts of SCAD in Australian SCAD survivors. Focus group participants were recruited as part of a larger study of SCAD survivors currently being undertaken by the Victor Chang Cardiac Research Institute. Thirty SCAD survivors participated in one of seven online focus groups, conducted using a semi-structured format. Focus group duration was 1.5 hours. Each was digitally recorded and transcribed. Data were analyzed thematically according to recommended guidelines. One over-arching theme, five main themes and 26 sub-themes were identified. The over-arching theme related to lack of information, while the five main themes related to emotional impacts, issues with self-management, issues with family, impacts on work life, and the need for psychosocial support. The ‘emotional impacts’ theme comprised 11 sub-themes, namely shock and disbelief, confusion and uncertainty, unfairness, fear and anxiety, loss and grief, isolation and loneliness, guilt, invalidation and embarrassment, depression, vulnerability, and frustration. Findings are discussed in light of relevant psychological theories. This qualitative study extends previous quantitative investigations of SCAD survivors by providing an in-depth understanding of the complex, inter-related and highly distressing impacts of SCAD. The findings point to the urgent need for a coherent approach to information provision, the development and delivery of SCAD-specific cardiac rehabilitation programs, and the provision of psychosocial support programs for SCAD survivors.

Rationale: Doxorubicin is a widely used anticancer drug. However, its major side effect, cardiotoxicity, results from cardiomyocyte loss that causes left ventricle (LV) wall thinning, chronic LV dysfunction and heart failure. Cardiomyocyte number expansion by thyroid hormone (T3) during preadolescence is suppressed by the developmental induction of an ERK1/2-specific dual specificity phosphatase 5 (DUSP5). Here, we sought to determine if a brief course of combined DUSP5 suppression plus T3 therapy replaces cardiomyocytes lost due to preexisting doxorubicin injury and reverses heart failure. Methods: We used in vivo-jetPEI to deliver DUSP5 or scrambled siRNA to ~5-week-old C57BL6 mice followed by 5 daily injections of T3 (2 ng/µg body weight). Genetic lineage tracing using Myh6-MerCreMer::Rosa26fs-Confetti mice and direct cardiomyocyte number counting, along with cell cycle inhibition (danusertib), was used to test if this treatment leads to de novo cardiomyocyte generation and improves LV contractile function. Three doses of doxorubicin (20 µg/g) given at 2-weekly intervals, starting at 5-weeks of age in C57BL6 mice, caused severe heart failure, as evident by a decrease in LV ejection fraction. Mice with an ~40 percentage point decrease in LVEF post-doxorubicin injury were randomized to receive either DUSP5 siRNA plus T3, or scrambled siRNA plus vehicle for T3. Age-matched mice without doxorubicin injury served as controls. Results: In uninjured adult mice, transient therapy with DUSP5 siRNA and T3 increases cardiomyocyte numbers, which is required for the associated increase in LV contractile function, since both are blocked by danusertib. In mice with chronic doxorubicin injury, DUSP5 siRNA plus T3 therapy rebuilds LV muscle by increasing cardiomyocyte numbers, which reverses LV dysfunction and prevents progressive chamber dilatation. Conclusion: RNA therapies are showing great potential. Importantly, a GMP compliant in vivo-jetPEI system for delivery of siRNA is already in use in humans, as is T3. Given these considerations, our findings provide a potentially highly translatable strategy for addressing doxorubicin cardiomyopathy, a currently untreatable condition.

GPR37L1 is an orphan G protein-coupled receptor expressed exclusively in the brain and linked to seizures, neuroprotection and cardiovascular disease. Based upon the observation that fragments of the GPR37L1 N-terminus are found in human cerebrospinal fluid, we hypothesized that GPR37L1 was subject to post-translational modification. Heterologous expression of GPR37L1-eYFP in either HEK293 or U87 glioblastoma cells yielded two cell surface species of approximately equivalent abundance, the larger of which is N-glycosylated at Asn105. The smaller species is produced by matrix metalloprotease/ADAM-mediated proteolysis (shown by the use of pharmacological inhibitors) and has a molecular weight identical to that of a mutant lacking the entire N-terminus, Δ122 GPR37L1. Serial truncation of the N-terminus prevented GPR37L1 expression except when the entire N-terminus was removed, narrowing the predicted site of N-terminal proteolysis to residues 105-122. Using yeast expressing different G protein chimeras, we found that wild type GPR37L1, but not Δ122 GPR37L1, coupled constitutively to Gpa1/Gαs and Gpa1/Gα16 chimeras, in contrast to previous studies. We tested the peptides identified in cerebrospinal fluid as well as their putative newly-generated N-terminal ‘tethered’ counterparts in both wild type and Δ122 GPR37L1 Gpa1/Gαs strains but saw no effect, suggesting that GPR37L1 does not signal in a manner akin to the protease-activated receptor family. We also saw no evidence of receptor activation or regulation by the reported GPR37L1 ligand, prosaptide/TX14A. Finally, the proteolytically processed species predominated both in vivo and ex vivo in organotypic cerebellar slice preparations, suggesting that GPR37L1 is rapidly processed to a signaling-inactive form. Our data indicate that the function of GPR37L1 in vivo is tightly regulated by metalloprotease-dependent N-terminal cleavage.

Subseasonal-to-seasonal (S2S) forecasts are bridging the gap between weather forecasts and long-range predictions. Decisions in various sectors are made in this forecast timescale, therefore there is a strong demand for this new generation of predictions. While much of the focus in recent years has been on improving forecast skill, if S2S predictions are to be used effectively, it is important that along with scientific advances, we also learn how best to develop, communicate and apply these forecasts.In this presentation, we present recent progress in the applications of S2S forecasts. We summarise case studies from a recently-published applications community review paper in the Bulletin of the American Meteorological Society (BAMS), covering sectoral applications of S2S predictions from around the world, including public health, disaster preparedness, water management, telecommunications, energy and agriculture. Involving over 60 authors and drawing from the recent advances and experience of researchers and users working with S2S forecasts globally, we explore the value of applications-relevant S2S predictions through a series of sectoral cases where uptake is starting to occur.From across 12 case studies, we show that:The S2S forecasting timescale is a new concept for many users. While the additional value of S2S forecasts for decision-making is increasingly gaining interest among users, incorporating probabilistic ensemble S2S forecasts into existing operations is not trivial. Barriers to widespread adoption of S2S forecasts include lack of access to the forecasts and the co-production to tailor forecasts to user needs, as well as varying ‘in house’ expertise in how to interpret and effectively apply them. This can create a ‘knowledge-value’ gap in some instances. S2S forecasts do not produce a ‘go/no go’ answer of how a user should respond to a potential hazard; instead they provide additional, supplementary ‘situational awareness’ information that can be used to support decision-making on S2S timescales. While S2S forecasting is still a maturing discipline globally, this publication marks a significant step forward in moving from potential to actual S2S forecasting applications – a collective body of evidence demonstrating both skill and utility across sectors that places user needs and applications at the forefront of S2S forecast development.Our paper, ‘Advances in the application and utility of subseasonal-to-seasonal predictions’, is available from BAMS as an open access publication: https://doi.org/10.1175/BAMS-D-20-0224.1.

Primary cardiomyocytes are invaluable for understanding postnatal heart development. However, a universal method to obtain freshly purified cardiomyocytes without using different age-dependent isolation procedures and cell culture, is lacking. Here, we report the development of a standardised method that allows rapid isolation and purification of high-quality cardiomyocytes from individual neonatal through to adult C57BL/6J murine hearts. Langendorff retrograde perfusion, which is currently limited to adult hearts, was adapted for use in neonatal and infant hearts by developing an easier in situ aortic cannulation technique. Tissue digestion conditions were optimised to achieve efficient digestion of hearts of all ages in a comparable timeframe (14 min). This resulted in a high yield (1.56-2.2 × 10

Mitochondria-generated reactive oxygen species (mROS) are frequently associated with DNA damage and cell cycle arrest, but physiological increases in mROS serve to regulate specific cell functions. T3 is a major regulator of mROS, including hydrogen peroxide (H2O2). Here we show that exogenous thyroid hormone (T3) administration increases cardiomyocyte numbers in neonatal murine hearts. The mechanism involves signaling by mitochondria-generated H2O2 (mH2O2) acting via the redox sensor, peroxiredoxin-1, a thiol peroxidase with high reactivity towards H2O2 that activates c-Jun N-terminal kinase-2α2 (JNK2α2). JNK2α2, a relatively rare member of the JNK family of mitogen-activated protein kinases (MAPK), phosphorylates c-Jun, a component of the activator protein 1 (AP-1) early response transcription factor, resulting in enhanced insulin-like growth factor 1 (IGF-1) expression and activation of proliferative ERK1/2 signaling. This non-canonical mechanism of MAPK activation couples T3 actions on mitochondria to cell cycle activation. Although T3 is regarded as a maturation factor for cardiomyocytes, these studies identify a novel redox pathway that is permissive for T3-mediated cardiomyocyte proliferation—this because of the expression of a pro-proliferative JNK isoform that results in growth factor elaboration and ERK1/2 cell cycle activation.

Murine surgical models play an important role in preclinical research. Mechanistic insights into myocardial regeneration after cardiac injury may be gained from cardiothoracic surgery models in 0-14-day-old mice, the cardiomyocytes of which, unlike those of adults, retain proliferative capacity. Mouse pups up to 7 days old are effectively immobilized by hypothermia and do not require intubation for cardiothoracic surgery. Preadolescent (8-14-day-old) mouse pups, however, do require intubation, but this is challenging and there is little information regarding anesthesia to facilitate intubation. Empirical titration of ketamine/xylazine/atropine dosage regimens to body weight indicated the response to anesthesia of 10-day-old C57BL6/J mouse pups of different weights was non-linear, whereby doses of 20/4/0.12 mg/kg, 30/4/0.12 mg/kg and 50/6/0.18 mg/kg, facilitated intubation of pups weighing between 3.15-4.49 g (n=22), 4.50-5.49 g (n=20) and 5.50-8.10 g (n=20), respectively. Lower-body-weight pups required more intubation attempts than heavier pups (p2=0.995). For myocardial infarction surgery after intubation, a surgical plane of anesthesia was induced with 4.5% isoflurane in 100% oxygen and maintained with 2% isoflurane in 100% oxygen. Survival post-surgery was similar for the three weight groups at 92%, 86% and 88% (p=0.91). Together with refinements in animal handling practices for intubation and surgery, and to minimize cannibalization by the dam post-surgery, overall survival for the entire procedure (intubation plus surgery) was inversely correlated with body weight (55%, 60% and 70% for low-, mid- and high-weight groups, respectively, R2=0.978). Given the difficulty encountered with intubation of 10-day old pups and the associated high mortality, we recommend cardiothoracic surgery in 10-day-old pups be restricted to those weighing at least 5.5 g.

Rationale: Primary cardiomyocytes are invaluable for understanding postnatal heart development and elucidating disease mechanisms in genetic and pharmacological models, however, a method to obtain freshly purified cardiomyocytes at any postnatal age, without using different age-dependent isolation procedures and cell culture, is lacking. Objective: To develop a standardized method that allows rapid isolation and purification of cardiomyocytes in high yield and viability from individual neonatal, infant, and adult mice. Methods and Results: Hearts of C57BL/6J mice were cannulated using a novel in situ aortic cannulation procedure optimized to allow cannulation of even the very small vessel of neonates (postnatal day 0-2, P0-2). Hearts were then subjected to Langendorff retrograde perfusion and enzymatic digestion. Cardiomyocytes were isolated after subsequent tissue disaggregation and filtration, in high yield (1.56-2.2x106 cardiomyocytes/heart) and viability (~70-100%). The larger size of infant (P10 and P13) and adult (P70), but not neonatal, cardiomyocytes relative to non-myocytes, allowed enrichment by differential centrifugation. Cardiomyocytes from all ages were further purified by immunomagnetic bead-based depletion of non-myocytes. Together, these procedures resulted in the isolation of highly purified cardiomyocytes (~94%) within 1 hour, enabling experiments using individual replicates. For example, RNA-sequencing of cardiomyocytes purified from one P2 male and female heart per litter (n=4 litters) showed distinct clustering by litters and sex differences for nine differentially expressed genes (FDR

This study characterizes systolic blood pressure (SBP) in a Gpr37l1 knockout mouse line, which was previously reported to have ∼60 mmHg higher SBP compared with a transgenic line. We observed only a ∼27 mmHg SBP difference between the lines. However, when compared with C57BL/6J mice, knockout mice showed no difference in SBP. We also investigated GPR37L1 mRNA abundance in human hearts and observed no difference between healthy and failing heart samples.

Pressure overload-induced cardiac hypertrophy is a maladaptive response with poor outcomes and limited treatment options. The transient receptor potential melastatin 4 (TRPM4) ion channel is key to activation of a Ca2+-calmodulin kinase II (CaMKII)-dependent hypertrophic signalling pathway after pressure overload, but TRPM4 is neither stretch-activated nor Ca2+-permeable. Here we show that Piezo1, which is both stretch-activated and Ca2+-permeable, is the mechanosensor that transduces increased myocardial forces into the chemical signal that initiates hypertrophic signalling via TRPM4. Cardiomyocyte-specific deletion of Piezo1 in adult mice prevented activation of CaMKII and inhibited the hypertrophic response: residual hypertrophy was associated with calcineurin activation in the absence of its usual inhibition by activated CaMKII. Piezo1 deletion prevented upregulation of the sodium-calcium exchanger and downregulation of the T-type calcium channel after pressure overload. These findings establish Piezo1 as the cardiomyocyte mechanosensor that instigates the maladaptive hypertrophic response to pressure overload, opening an avenue to novel therapies.

The nomenclature of the Adrenoceptors has been agreed by the NC-IUPHAR Subcommittee on Adrenoceptors [60, 186]. Adrenoceptors, α1 The three α1-adrenoceptor subtypes α1A, α1B and α1D are activated by the endogenous agonists (-)-adrenaline and (-)-noradrenaline. -(-)phenylephrine, methoxamine and cirazoline are agonists and prazosin and doxazosin antagonists considered selective for α1- relative to α2-adrenoceptors. [3H]prazosin and [125I]HEAT (BE2254) are relatively selective radioligands. S(+)-niguldipine also has high affinity for L-type Ca2+ channels. Fluorescent derivatives of prazosin (Bodipy FLprazosin- QAPB) are used to examine cellular localisation of α1-adrenoceptors. α1-Adrenoceptor agonists are used as nasal decongestants; antagonists to treat symptoms of benign prostatic hyperplasia (alfuzosin, doxazosin, terazosin, tamsulosin and silodosin, with the last two compounds being α1A-adrenoceptor selective and claiming to relax bladder neck tone with less hypotension); and to a lesser extent hypertension (doxazosin, terazosin). The α1- and β2-adrenoceptor antagonist carvedilol is used to treat congestive heart failure, although the contribution of α1-adrenoceptor blockade to the therapeutic effect is unclear. Several anti-depressants and anti-psychotic drugs are α1-adrenoceptor antagonists contributing to side effects such as orthostatic hypotension. Adrenoceptors, α2 The three α2-adrenoceptor subtypes α2A, α2B and α2C are activated by (-)-adrenaline and with lower potency by (-)-noradrenaline. brimonidine and talipexole are agonists and rauwolscine and yohimbine antagonists selective for α2- relative to α1-adrenoceptors. [3H]rauwolscine, [3H]brimonidine and [3H]RX821002 are relatively selective radioligands. There are species variations in the pharmacology of the α2A-adrenoceptor. Multiple mutations of α2-adrenoceptors have been described, some associated with alterations in function. Presynaptic α2-adrenoceptors regulate many functions in the nervous system. The α2-adrenoceptor agonists clonidine, guanabenz and brimonidine affect central baroreflex control (hypotension and bradycardia), induce hypnotic effects and analgesia, and modulate seizure activity and platelet aggregation. clonidine is an anti-hypertensive (relatively little used) and counteracts opioid withdrawal. dexmedetomidine (also xylazine) is increasingly used as a sedative and analgesic in human [31] and veterinary medicine and has sympatholytic and anxiolytic properties. The α2-adrenoceptor antagonist mirtazapine is used as an anti-depressant. The α2B subtype appears to be involved in neurotransmission in the spinal cord and α2C in regulating catecholamine release from adrenal chromaffin cells. Although subtype-selective antagonists have been developed, none are used clinically and they remain experimental tools. Adrenoceptors, β The three β-adrenoceptor subtypes β1, β2 and β3 are activated by the endogenous agonists (-)-adrenaline and (-)-noradrenaline. Isoprenaline is selective for β-adrenoceptors relative to α1- and α2-adrenoceptors, while propranolol (pKi 8.2-9.2) and cyanopindolol (pKi 10.0-11.0) are relatively selective antagonists for β1- and β2- relative to β3-adrenoceptors. (-)-noradrenaline, xamoterol and (-)-Ro 363 show selectivity for β1- relative to β2-adrenoceptors. Pharmacological differences exist between human and mouse β3-adrenoceptors, and the 'rodent selective' agonists BRL 37344 and CL316243 have low efficacy at the human β3-adrenoceptor whereas CGP 12177 (low potency) and L 755507 activate human β3-adrenoceptors [88]. β3-Adrenoceptors are resistant to blockade by propranolol, but can be blocked by high concentrations of bupranolol. SR59230A has reasonably high affinity at β3-adrenoceptors, but does not discriminate between the three β- subtypes [320] whereas L-748337 is more selective. [125I]-cyanopindolol, [125I]-hydroxy benzylpindolol and [3H]-alprenolol are high affinity radioligands that label β1- and β2- adrenoceptors and β3-adrenoceptors can be labelled with higher concentrations (nM) of [125I]-cyanopindolol together with β1- and β2-adrenoceptor antagonists. Fluorescent ligands such as BODIPY-TMR-CGP12177 can be used to track β-adrenoceptors at the cellular level [8]. Somewhat selective β1-adrenoceptor agonists (denopamine, dobutamine) are used short term to treat cardiogenic shock but, chronically, reduce survival. β1-Adrenoceptor-preferring antagonists are used to treat cardiac arrhythmias (atenolol, bisoprolol, esmolol) and cardiac failure (metoprolol, nebivolol) but also in combination with other treatments to treat hypertension (atenolol, betaxolol, bisoprolol, metoprolol and nebivolol) [507]. Cardiac failure is also treated with carvedilol that blocks β1- and β2-adrenoceptors, as well as α1-adrenoceptors. Short (salbutamol, terbutaline) and long (formoterol, salmeterol) acting β2-adrenoceptor-selective agonists are powerful bronchodilators used to treat respiratory disorders. Many first generation β-adrenoceptor antagonists (propranolol) block both β1- and β2-adrenoceptors and there are no β2-adrenoceptor-selective antagonists used therapeutically. The β3-adrenoceptor agonist mirabegron is used to control overactive bladder syndrome. There is evidence to suggest that β-adrenoceptor antagonists can reduce metastasis in certain types of cancer [189].

Pathological left ventricular hypertrophy (LVH) occurs in response to pressure overload and remains the single most important clinical predictor of cardiac mortality. The molecular pathways in the induction of pressure overload LVH are potential targets for therapeutic intervention. Current treatments aim to remove the pressure overload stimulus for LVH, but do not completely reverse adverse cardiac remodelling. Although numerous molecular signalling steps in the induction of LVH have been identified, the initial step by which mechanical stretch associated with cardiac pressure overload is converted into a chemical signal that initiates hypertrophic signalling remains unresolved. In this study, we show that selective deletion of transient receptor potential melastatin 4 (TRPM4) channels in mouse cardiomyocytes results in an approximately 50% reduction in the LVH induced by transverse aortic constriction. Our results suggest that TRPM4 channel is an important component of the mechanosensory signalling pathway that induces LVH in response to pressure overload and represents a potential novel therapeutic target for the prevention of pathological LVH. ispartof: ELIFE vol:10 ispartof: location:England status: published

© Copyright 19 June 2019 American Meteorological Society (AMS). Permission to use figures, tables, and brief excerpts from this work in scientific and educational works is hereby granted provided that the source is acknowledged. Any use of material in this work that is determined to be “fair use” under Section 107 of the U.S. Copyright Act or that satisfies the conditions specified in Section 108 of the U.S. Copyright Act (17 USC §108) does not require the AMS’s permission. Republication, systematic reproduction, posting in electronic form, such as on a website or in a searchable database, or other uses of this material, except as exempted by the above statement, requires written permission or a license from the AMS. All AMS journals and monograph publications are registered with the Copyright Clearance Center (http://www.copyright.com). Questions about permission to use materials for which AMS holds the copyright can also be directed to permissions@ametsoc.org. Additional details are provided in the AMS Copyright Policy statement, available on the AMS website (http://www.ametsoc.org/CopyrightInformation). This study evaluates the performance of six atmospheric reanalyses (ERA-Interim, ERA5, JRA-55, CFSv2, MERRA-2, and ASRv2) over Arctic sea ice from winter to early summer. The reanalyses are evaluated using observations from the Norwegian Young Sea Ice campaign (N-ICE2015), a 5-month ice drift in pack ice north of Svalbard. N-ICE2015 observations include surface meteorology, vertical profiles from radiosondes, as well as radiative and turbulent heat fluxes. The reanalyses simulate surface analysis variables well throughout the campaign, but have difficulties with most forecast variables. Wintertime (January–March) correlation coefficients between the reanalyses and observations are above 0.90 for the surface pressure, 2-m temperature, total column water vapor, and downward longwave flux. However, all reanalyses have a positive wintertime 2-m temperature bias, ranging from 1° to 4°C, and negative (i.e., upward) net longwave bias of 3–19 W m−2. These biases are associated with poorly represented surface inversions and are largest during cold-stable periods. Notably, the recent ERA5 and ASRv2 datasets have some of the largest temperature and net longwave biases, respectively. During spring (April–May), reanalyses fail to simulate observed persistent cloud layers. Therefore they overestimate the net shortwave flux (5–79 W m−2) and underestimate the net longwave flux (8–38 W m−2). Promisingly, ERA5 provides the best estimates of downward radiative fluxes in spring and summer, suggesting improved forecasting of Arctic cloud cover. All reanalyses exhibit large negative (upward) residual heat flux biases during winter, and positive (downward) biases during summer. Turbulent heat fluxes over sea ice are simulated poorly in all seasons.