Impact of ovary-intact menopause in a mouse model of heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) afflicts over half of all patients with heart failure and is a debilitating and fatal syndrome affecting postmenopausal women more than any other demographic. This bias toward older females calls into question the significance of menopause in the development of HFpEF, but this question has not been probed in detail. In this study, we report the first investigation into the impact of ovary-intact menopause in the context of HFpEF. To replicate the human condition as faithfully as possible, vinylcyclohexene dioxide (VCD) was used to accelerate ovarian failure (AOF) in female mice while leaving the ovaries intact. HFpEF was established with a mouse model that involves two stressors typical in humans: a high-fat diet and hypertension induced from the nitric oxide synthase inhibitor NG-nitro-l-arginine methyl ester (l-NAME). In young female mice, AOF or HFpEF-associated stressors independently induced abnormal myocardial strain indicative of early subclinical systolic and diastolic cardiac dysfunction. HFpEF but not AOF was associated with elevations in systolic blood pressure. Increased myocyte size and reduced myocardial microvascular density were not observed in any group. Also, a broad panel of measurements that included echocardiography, invasive pressure measurements, histology, and serum hormones revealed no interaction between AOF and HFpEF. Interestingly, AOF did evoke a higher density of infiltrating cardiac immune cells in both healthy and HFpEF mice, suggestive of proinflammatory effects. In contrast to young mice, middle-aged "old" mice did not exhibit cardiac dysfunction from estrogen deprivation alone or from HFpEF-related stressors.NEW & NOTEWORTHY This is the first preclinical study to examine the impact of ovary-intact menopause [accelerated ovarian failure (AOF)] on HFpEF. Echocardiography of young female mice revealed early evidence of diastolic and systolic cardiac dysfunction apparent only on strain imaging in HFpEF only, AOF only, or the combination. Surprisingly, AOF did not exacerbate the HFpEF phenotype. Results in middle-aged "old" females also showed no interaction between HFpEF and AOF and, importantly, no cardiovascular impact from HFpEF or AOF.

GDF5 deficiency prevents cardiac rupture following acute myocardial infarction in mice.

BACKGROUND: We previously showed that growth differentiation factor 5 (GDF5) limits infarct expansion post-myocardial infarction (MI). We now examine the acute post-MI role of GDF5 in cardiac rupture. METHODS AND RESULTS: Following permanent ligation of the left anterior descending artery, GDF5 deficiency (i.e., GDF5 knockout mice) reduced the incidence of cardiac rupture (4/24 vs. 17/24; P < .05), and improved survival over 28-d compared to wild-type (WT) mice (79% vs. 25%; P < .0001). Moreover, at 3-d post-MI, GDF5-deficient mice manifest: (a) reduced heart weight/body weight ratio (P < .0001) without differences in infarct size or cardiomyocyte size; (b) increased infarct zone expression of Col1a1 (P < .05) and Col3a1 (P < .01), suggesting increased myocardial fibrosis; and (c) reduced aortic and left ventricular peak systolic pressures (P ≤ .05), suggesting reduced afterload. Despite dysregulated inflammatory markers and reduced circulating monocytes in GDF5-deficient mice at 3-d post-MI, reciprocal bone marrow transplantation (BMT) failed to implicate GDF5 in BM-derived cells, suggesting the involvement of tissue-resident GDF5 expression in cardiac rupture. CONCLUSIONS: Loss of GDF5 reduces cardiac rupture post-MI with increased myocardial fibrosis and lower afterload, albeit at the cost of chronic adverse remodeling.

Microbial energy metabolism fuels an intestinal macrophage niche in solitary isolated lymphoid tissues through purinergic signaling.

Maintaining macrophage (MΦ) heterogeneity is critical to ensure intestinal tissue homeostasis and host defense. The gut microbiota and host factors are thought to synergistically guide intestinal MΦ development, although the exact nature, regulation, and location of such collaboration remain unclear. Here, we report that microbial biochemical energy metabolism promotes colony-stimulating factor 2 (CSF2) production by group 3 innate lymphoid cells (ILC3s) within solitary isolated lymphoid tissues (SILTs) in a cell-extrinsic, NLRP3/P2X7R-dependent fashion in the steady state. Tissue-infiltrating monocytes accumulating around SILTs followed a spatially constrained, distinct developmental trajectory into SILT-associated MΦs (SAMs). CSF2 regulated the mitochondrial membrane potential and reactive oxygen species production of SAMs and contributed to the antimicrobial defense against enteric bacterial infections. Collectively, these findings identify SILTs and CSF2-producing ILC3s as a microanatomic niche for intestinal MΦ development and functional programming fueled by the integration of commensal microbial energy metabolism.

Draft-genome analysis provides insights into the virulence properties and genome plasticity of Vibrio fluvialis organisms isolated from shrimp farms and Turag river in Bangladesh.

Vibrio fluvialis is an opportunistic waterborne and seafood-borne enteric pathogen capable of causing severe diarrhea leading to death. This pathogen is endemic to Bangladesh, a country which is a major producer of cultured shrimp and wild-caught prawns. In this study, we carried out whole-genome sequencing of three V. fluvialis organisms isolated from shrimp farm and river sediment showing strong pathogenic characteristics in vivo and in vitro and compared their genomes against other V. fluvialis and related pathogenic species to glean insights into their potential as pathogens. Numerous virulence-associated genes including hemolysins, cytolysins, three separate Type IV pili, Types II and VI secretion systems, biofilm, and the V. cholerae pathogenesis regulating gene, toxR, were identified. Moreover, we found strain S-10 to have the propensity to acquire antibiotic resistance genes through horizontal gene transfer. These findings indicate that shrimp farms and rivers could be potential sources of V. fluvialis organisms which are an infection threat of public health concern.

Three tissue resident macrophage subsets coexist across organs with conserved origins and life cycles.

Resident macrophages orchestrate homeostatic, inflammatory, and reparative activities. It is appreciated that different tissues instruct specialized macrophage functions. However, individual tissues contain heterogeneous subpopulations, and how these subpopulations are related is unclear. We asked whether common transcriptional and functional elements could reveal an underlying framework across tissues. Using single-cell RNA sequencing and random forest modeling, we observed that four genes could predict three macrophage subsets that were present in murine heart, liver, lung, kidney, and brain. Parabiotic and genetic fate mapping studies revealed that these core markers predicted three unique life cycles across 17 tissues. TLF+ (expressing TIMD4 and/or LYVE1 and/or FOLR2) macrophages were maintained through self-renewal with minimal monocyte input; CCR2+ (TIMD4−LYVE1−FOLR2−) macrophages were almost entirely replaced by monocytes, and MHC-IIhi macrophages (TIMD4−LYVE1−FOLR2−CCR2−), while receiving modest monocyte contribution, were not continually replaced. Rather, monocyte-derived macrophages contributed to the resident macrophage population until they reached a defined upper limit after which they did not outcompete pre-existing resident macrophages. Developmentally, TLF+ macrophages were first to emerge in the yolk sac and early fetal organs. Fate mapping studies in the mouse and human single-cell RNA sequencing indicated that TLF+ macrophages originated from both yolk sac and fetal monocyte precursors. Furthermore, TLF+ macrophages were the most transcriptionally conserved subset across mouse tissues and between mice and humans, despite organ- and species-specific transcriptional differences. Here, we define the existence of three murine macrophage subpopulations based on common life cycle properties and core gene signatures and provide a common starting point to understand tissue macrophage heterogeneity.

Difficulties to enter the left ventricle during percutaneous transvenous mitral commissurotomy (PTMC)- our experiences of 80 cases with modified techniques.

BACKGROUND: Percutaneous transvenous mitral commissurotomy (PTMC) is the standard of treatment for symptomatic severe rheumatic mitral stenosis (MS). PTMC has the standard Inoue technique, but we have to modify the procedure in many technically challenging cases, especially to cross the mitral valve. METHODOLOGY: Two over-the-wire strategies to enter the LV were taken in 80 complex cases of PTMC. The first one was done by exchanging the J-shaped wire from the balloon, introducing the spring wire into it, and pushing it into LV. The second one-removal of balloon keeping the spring wire in LA and the Mullin's sheath was introduced, and the tip of the wire was pushed into LV, and the balloon was introduced over the wire. We also changed the left atrium (LA) graphy in the RAO view instead of the AP view to facilitating entry into LV. RESULTS: We succeeded in 76 (95 %) cases. Strategy one was applied to all but successful in only 25 cases (31 %), and strategy 2 was applied in the remaining. Strategy 1 required less procedural time and fluoroscopic time in comparison to strategy 2 (40 ± 10 vs 60 ± 16 min, 25 ± 7 vs 35 ± 8 min). After modification of taking the LA graphy in RAO view, our rate of facing the difficulties decreased from 21 % to 9 %. Critical MS (31 %) and the giant LA (30 %) were the topmost causes of difficulties. No major complications were recorded. CONCLUSION: Over-the-wire entry into LV is cost-effective, requiring no new equipment and is safe and can be used in complex cases.

Selective loss of resident macrophage-derived insulin-like growth factor-1 abolishes adaptive cardiac growth to stress.

Hypertension affects one-third of the world's population, leading to cardiac dysfunction that is modulated by resident and recruited immune cells. Cardiomyocyte growth and increased cardiac mass are essential to withstand hypertensive stress; however, whether immune cells are involved in this compensatory cardioprotective process is unclear. In normotensive animals, single-cell transcriptomics of fate-mapped self-renewing cardiac resident macrophages (RMs) revealed transcriptionally diverse cell states with a core repertoire of reparative gene programs, including high expression of insulin-like growth factor-1 (Igf1). Hypertension drove selective in situ proliferation and transcriptional activation of some cardiac RM states, directly correlating with increased cardiomyocyte growth. During hypertension, inducible ablation of RMs or selective deletion of RM-derived Igf1 prevented adaptive cardiomyocyte growth, and cardiac mass failed to increase, which led to cardiac dysfunction. Single-cell transcriptomics identified a conserved IGF1-expressing macrophage subpopulation in human cardiomyopathy. Here we defined the absolute requirement of RM-produced IGF-1 in cardiac adaptation to hypertension.

Genotype-phenotype correlation of ß-lactamase-producing uropathogenic Escherichia coli (UPEC) strains from Bangladesh.

Escherichia coli is a pathogen commonly encountered in clinical laboratories, and is capable of causing a variety of diseases, both within the intestinal tract (intestinal pathogenic strains) and outside (extraintestinal pathogenic E. coli, or ExPEC). It is associated with urinary tract infections (UTIs), one of the most common infectious diseases in the world. This report represents the first comparative analysis of the draft genome sequences of 11 uropathogenic E. coli (UPEC) strains isolated from two tertiary hospitals located in Dhaka and Sylhet, Bangladesh, and is focused on comparing their genomic characteristics to each other and to other available UPEC strains. Multilocus sequence typing (MLST) confirmed the strains belong to ST59, ST131, ST219, ST361, ST410, ST448 and ST4204, with one of the isolates classified as a previously undocumented ST. De novo identification of the antibiotic resistance genes blaNDM-5, blaNDM-7, blaCTX-M-15 and blaOXA-1 was determined, and phenotypic-genotypic analysis of virulence revealed significant heterogeneity within UPEC phylogroups.

Whole genome sequencing provides genomic insights into three Morganella morganii strains isolated from bovine rectal swabs in Dhaka, Bangladesh.

Morganella morganii, a gram negative, facultative anaerobic bacterium belonging to the Proteeae tribe of the Morganellaceae family, is an unusual opportunistic pathogen mainly responsible for nosocomial and urinary tract infections. While cattle have long been established as a source of a few zoonotic pathogens, no such data has been recorded for M. morganii despite its ubiquitous presence in nature and a number of animal hosts. In this study, draft genomes were produced of three M. morganii isolates from Bangladeshi cattle. The three isolates, named B2, B3 and B5, possessed an average genome size of 3.9 Mp, a GC% of ∼51% and pan and core genomes of 4637 and 3812 genes, respectively. All strains were bearers of the qnrD1 carrying plasmid Col3M and possessed roughly similar virulence profiles and prophage regions. The strains also carried genes that were unique when compared with other publicly available M. morganii genomes. Many of these genes belonged to metabolic pathways associated with adaptation to environmental stresses and were predicted in silico to be borne in genomic islands. The findings of this study expand on the current understanding of M. morganii''s genomic nature and its adaptation in cattle.

Anaesthesia care providers employed in humanitarian settings by Médecins Sans Frontières: a retrospective observational study of 173 084 surgical cases over 10 years.

OBJECTIVE: To describe the extent to which different categories of anaesthesia provider are used in humanitarian surgical projects and to explore the volume and nature of their surgical workload. DESIGN: Descriptive analysis using 10 years (2008-2017) of routine case-level data linked with routine programme-level data from surgical projects run exclusively by Médecins Sans Frontières-Operational Centre Brussels (MSF-OCB). SETTING: Projects were in contexts of natural disaster (ND, entire expatriate team deployed by MSF-OCB), active conflict (AC) and stable healthcare gaps (HG). In AC and HG settings, MSF-OCB support pre-existing local facilities. Hospital facilities ranged from basic health centres with surgical capabilities to tertiary referral centres. PARTICIPANTS: The full dataset included 178 814 surgical cases. These were categorised by most senior anaesthetic provider for the project, according to qualification: specialist physician anaesthesiologists, qualified nurse anaesthetists and uncertified anaesthesia providers. PRIMARY OUTCOME MEASURE: Volume and nature of surgical workload of different anaesthesia providers. RESULTS: Full routine data were available for 173 084 cases (96.8%): 2518 in ND, 42 225 in AC, 126 936 in HG. Anaesthesia was predominantly led by physician anaesthesiologists (100% in ND, 66% in AC and HG), then nurse anaesthetists (19% in AC and HG) or uncertified anaesthesia providers (15% in AC and HG). Across all settings and provider groups, patients were mostly healthy young adults (median age range 24-27 years), with predominantly females in HG contexts, and males in AC contexts. Overall intra-operative mortality was 0.2%. CONCLUSION: Our findings contribute to existing knowledge of the nature of anaesthetic provision in humanitarian settings, while demonstrating the value of high-quality, routine data collection at scale in this sector. Further evaluation of perioperative outcomes associated with different models of humanitarian anaesthetic provision is required.

Cardioprotective GLP-1 metabolite prevents ischemic cardiac injury by inhibiting mitochondrial trifunctional protein-α.

Mechanisms mediating the cardioprotective actions of glucagon-like peptide 1 (GLP-1) were unknown. Here, we show in both ex vivo and in vivo models of ischemic injury that treatment with GLP-1(28-36), a neutral endopeptidase-generated (NEP-generated) metabolite of GLP-1, was as cardioprotective as GLP-1 and was abolished by scrambling its amino acid sequence. GLP-1(28-36) enters human coronary artery endothelial cells (caECs) through macropinocytosis and acts directly on mouse and human coronary artery smooth muscle cells (caSMCs) and caECs, resulting in soluble adenylyl cyclase Adcy10-dependent (sAC-dependent) increases in cAMP, activation of protein kinase A, and cytoprotection from oxidative injury. GLP-1(28-36) modulates sAC by increasing intracellular ATP levels, with accompanying cAMP accumulation lost in sAC-/- cells. We identify mitochondrial trifunctional protein-α (MTPα) as a binding partner of GLP-1(28-36) and demonstrate that the ability of GLP-1(28-36) to shift substrate utilization from oxygen-consuming fatty acid metabolism toward oxygen-sparing glycolysis and glucose oxidation and to increase cAMP levels is dependent on MTPα. NEP inhibition with sacubitril blunted the ability of GLP-1 to increase cAMP levels in coronary vascular cells in vitro. GLP-1(28-36) is a small peptide that targets novel molecular (MTPα and sAC) and cellular (caSMC and caEC) mechanisms in myocardial ischemic injury.

Publisher Correction: Self-renewing resident cardiac macrophages limit adverse remodeling following myocardial infarction.

In the version of this article initially published, the equal contribution of the third author was omitted. The footnote links for that author should be "Sara Nejat1,11" and the correct statement is as follows: "11These authors contributed equally: Sarah A. Dick, Jillian A. Macklin, Sara Nejat." The error has been corrected in the HTML and PDF versions of the article.

B-Cell Deficiency Lowers Blood Pressure in Mice.

The proto-oncogene c-myb (and corresponding nuclear transcription factor, c-Myb) regulates the proliferation and differentiation of hematologic and vascular smooth muscle cells; however, the role of c-Myb in blood pressure regulation is unknown. Here, we show that mice homozygous for a hypomorphic c-myb allele ( c-myb h/h) conferring reduced c-Myb activity manifest reduced peripheral blood and kidney B220+ B-cells and have decreased systolic (104±2 versus 120±1 mm Hg; P<0.0001) and diastolic blood pressure (71±2 versus 83±1 mm Hg; P<0.0001) compared with WT (wild type) mice. Additionally, c-myb h/h mice had lower susceptibility to deoxycorticosterone acetate-salt experimental hypertension. Although cardiac (echocardiography) and resistance artery (perfusion myography) functions were normal, metabolic cage studies revealed that c-myb h/h mice had increased 24-hour urine output and sodium excretion versus WT. Reconstitution of WT mice with c-myb h/h bone marrow transplant and chimeric bone marrow transplant using mice lacking B-cells ( J H T; h/h>WT and h/h:J H T>WT, respectively) decreased blood pressure and increased 24-hour urine output compared with controls ( WT>WT; WT:J H T>WT). J H T mice also had decreased systolic (103±2 versus 115±1 mm Hg; P<0.0001) and diastolic blood pressure (71±2 versus 79±1; P<0.01) and increased 24-hour urine output versus WT. Real-time quantitative reverse transcription polymerase chain reaction of kidney medulla revealed reduced V2R (vasopressin receptor 2) expression in c-myb h/h and J H T mice. These data implicate B-cells in the regulation of V2R and its associated effects on salt and water handling and blood pressure homeostasis.

CFTR Therapeutics Normalize Cerebral Perfusion Deficits in Mouse Models of Heart Failure and Subarachnoid Hemorrhage.

Heart failure (HF) and subarachnoid hemorrhage (SAH) chronically reduce cerebral perfusion, which negatively affects clinical outcome. This work demonstrates a strong relationship between cerebral artery cystic fibrosis transmembrane conductance regulator (CFTR) expression and altered cerebrovascular reactivity in HF and SAH. In HF and SAH, CFTR corrector compounds (C18 or lumacaftor) normalize pathological alterations in cerebral artery CFTR expression, vascular reactivity, and cerebral perfusion, without affecting systemic hemodynamic parameters. This normalization correlates with reduced neuronal injury. Therefore, CFTR therapeutics have emerged as valuable clinical tools to manage cerebrovascular dysfunction, impaired cerebral perfusion, and neuronal injury.

Self-renewing resident cardiac macrophages limit adverse remodeling following myocardial infarction.

Macrophages promote both injury and repair after myocardial infarction, but discriminating functions within mixed populations remains challenging. Here we used fate mapping, parabiosis and single-cell transcriptomics to demonstrate that at steady state, TIMD4+LYVE1+MHC-IIloCCR2- resident cardiac macrophages self-renew with negligible blood monocyte input. Monocytes partially replaced resident TIMD4-LYVE1-MHC-IIhiCCR2- macrophages and fully replaced TIMD4-LYVE1-MHC-IIhiCCR2+ macrophages, revealing a hierarchy of monocyte contribution to functionally distinct macrophage subsets. Ischemic injury reduced TIMD4+ and TIMD4- resident macrophage abundance, whereas CCR2+ monocyte-derived macrophages adopted multiple cell fates within infarcted tissue, including those nearly indistinguishable from resident macrophages. Recruited macrophages did not express TIMD4, highlighting the ability of TIMD4 to track a subset of resident macrophages in the absence of fate mapping. Despite this similarity, inducible depletion of resident macrophages using a Cx3cr1-based system led to impaired cardiac function and promoted adverse remodeling primarily within the peri-infarct zone, revealing a nonredundant, cardioprotective role of resident cardiac macrophages.

Cardiac-specific inducible overexpression of human plasma membrane Ca2+ ATPase 4b is cardioprotective and improves survival in mice following ischemic injury.

Background: Heart failure (HF) is associated with reduced expression of plasma membrane Ca2+-ATPase 4 (PMCA4). Cardiac-specific overexpression of human PMCA4b in mice inhibited nNOS activity and reduced cardiac hypertrophy by inhibiting calcineurin. Here we examine temporally regulated cardiac-specific overexpression of hPMCA4b in mouse models of myocardial ischemia reperfusion injury (IRI) ex vivo, and HF following experimental myocardial infarction (MI) in vivoMethods and results: Doxycycline-regulated cardiomyocyte-specific overexpression and activity of hPMCA4b produced adaptive changes in expression levels of Ca2+-regulatory genes, and induced hypertrophy without significant differences in Ca2+ transients or diastolic Ca2+ concentrations. Total cardiac NOS and nNOS-specific activities were reduced in mice with cardiac overexpression of hPMCA4b while nNOS, eNOS and iNOS protein levels did not differ. hMPCA4b-overexpressing mice also exhibited elevated systolic blood pressure vs. controls, with increased contractility and lusitropy in vivo In isolated hearts undergoing IRI, hPMCA4b overexpression was cardioprotective. NO donor-treated hearts overexpressing hPMCA4b showed reduced LVDP and larger infarct size versus vehicle-treated hearts undergoing IRI, demonstrating that the cardioprotective benefits of hPMCA4b-repressed nNOS are lost by restoring NO availability. Finally, both pre-existing and post-MI induction of hPMCA4b overexpression reduced infarct expansion and improved survival from HF.Conclusions: Cardiac PMCA4b regulates nNOS activity, cardiac mass and contractility, such that PMCA4b overexpression preserves cardiac function following IRI, heightens cardiac performance and limits infarct progression, cardiac hypertrophy and HF, even when induced late post-MI. These data identify PMCA4b as a novel therapeutic target for IRI and HF.

Influence of ABO blood group on von Willebrand factor tests in healthy Saudi blood donors.

: Von Willebrand disease is a common bleeding disorder. The wide variation in von Willebrand factor (VWF) levels between and within normal individuals highlights the clinical challenge of defining its cutoff value. Although studies on the influence of ethnicity on ABO phenotypes and the levels of VWF have been carried out on different ethnicities, there is a lack of such data among Arab population. We aimed to evaluate the correlation of ABO phenotypes with all the parameters of the minimal test panel of VWF including VWF antigen, VWF activity using the ristocetin cofactor and the collagen binding activity assays, and factor VIII coagulant activity (VWF:Ag, VWF:RCo, VWF:CB and FVIII:C) tested in a normal Arab population, and to estimate ABO-specific normal reference range. Blood samples were collected from 87 healthy donors in Riyadh to determine levels of factor VIII and VWF panel between the various ABO phenotypes. The highest mean values of factor VIII : C (128 U/dl), VWF : Ag (125 U/dl), VWF : RCo (109 U/dl) and VWF : CB (91 U/dl) were observed with type AB and the lowest mean values of factor VIII : C (81 U/dl), VWF : Ag (85 U/dl), VWF : RCo (73 U/dl) and VWF : CB (70 U/dl) corresponded to type O. ABO phenotypes significantly influence plasma levels of VWF parameters in Arab nations as seen with other ethnicity. Hence, ABO-specific normal ranges of the minimal test panel of VWF and factor VIII : C are essential for the appropriate prediction of mild von Willebrand disease. Further study including a larger categorized sample size is required to generalize the test panel on the Arab population.

HDL protects against doxorubicin-induced cardiotoxicity in a scavenger receptor class B type 1-, PI3K-, and Akt-dependent manner.

Doxorubicin is a widely used chemotherapeutic with deleterious cardiotoxic side effects. HDL has been shown to protect cardiomyocytes in vitro against doxorubicin-induced apoptosis. Scavenger receptor class B type 1 (SR-B1), a high-affinity HDL receptor, mediates cytoprotective signaling by HDL through Akt. Here, we assessed whether increased HDL levels protect against doxorubicin-induced cardiotoxicity in vivo and in cardiomyocytes in culture and explored the intracellular signaling mechanisms involved, particularly the role of SR-B1. Transgenic mice with increased HDL levels through overexpression of human apolipoprotein A1 (apoA1Tg/Tg) and wild-type mice (apoA1+/+) with normal HDL levels were treated repeatedly with doxorubicin. After treatment, apoA1+/+ mice displayed cardiac dysfunction, as evidenced by reduced left ventricular end-systolic pressure and +dP/d t, and histological analysis revealed cardiomyocyte atrophy and increased cardiomyocyte apoptosis after doxorubicin treatment. In contrast, apoA1Tg/Tg mice were protected against doxorubicin-induced cardiac dysfunction and cardiomyocyte atrophy and apoptosis. When SR-B1 was knocked out, however, overexpression of apoA1 did not protect against doxorubicin-induced cardiotoxicity. Using primary neonatal mouse cardiomyocytes and human immortalized ventricular cardiomyocytes in combination with genetic knockout, inhibitors, or siRNA-mediated knockdown, we demonstrated that SR-B1 is required for HDL-mediated protection of cardiomyocytes against doxorubicin-induced apoptosis in vitro via a pathway involving phosphatidylinositol 3-kinase and Akt1/2. Our findings provide proof of concept that raising apoA1 to supraphysiological levels can dramatically protect against doxorubicin-induced cardiotoxicity via a pathway that is mediated by SR-B1 and involves Akt1/2 activation in cardiomyocytes. NEW & NOTEWORTHY We have identified an important role for the scavenger receptor class B type 1 in facilitating high-density lipoprotein-mediated protection of cardiomyocytes against stress-induced apoptosis and shown that increasing plasma high-density lipoprotein protects against the deleterious side effects of the chemotherapeutic and cardiotoxic drug doxorubicin.

A CD103+ Conventional Dendritic Cell Surveillance System Prevents Development of Overt Heart Failure during Subclinical Viral Myocarditis.

Innate and adaptive immune cells modulate heart failure pathogenesis during viral myocarditis, yet their identities and functions remain poorly defined. We utilized a combination of genetic fate mapping, parabiotic, transcriptional, and functional analyses and demonstrated that the heart contained two major conventional dendritic cell (cDC) subsets, CD103+ and CD11b+, which differentially relied on local proliferation and precursor recruitment to maintain their tissue residency. Following viral infection of the myocardium, cDCs accumulated in the heart coincident with monocyte infiltration and loss of resident reparative embryonic-derived cardiac macrophages. cDC depletion abrogated antigen-specific CD8+ T cell proliferative expansion, transforming subclinical cardiac injury to overt heart failure. These effects were mediated by CD103+ cDCs, which are dependent on the transcription factor BATF3 for their development. Collectively, our findings identified resident cardiac cDC subsets, defined their origins, and revealed an essential role for CD103+ cDCs in antigen-specific T cell responses during subclinical viral myocarditis.

Flexible shape-memory scaffold for minimally invasive delivery of functional tissues.

Despite great progress in engineering functional tissues for organ repair, including the heart, an invasive surgical approach is still required for their implantation. Here, we designed an elastic and microfabricated scaffold using a biodegradable polymer (poly(octamethylene maleate (anhydride) citrate)) for functional tissue delivery via injection. The scaffold's shape memory was due to the microfabricated lattice design. Scaffolds and cardiac patches (1 cm × 1 cm) were delivered through an orifice as small as 1 mm, recovering their initial shape following injection without affecting cardiomyocyte viability and function. In a subcutaneous syngeneic rat model, injection of cardiac patches was equivalent to open surgery when comparing vascularization, macrophage recruitment and cell survival. The patches significantly improved cardiac function following myocardial infarction in a rat, compared with the untreated controls. Successful minimally invasive delivery of human cell-derived patches to the epicardium, aorta and liver in a large-animal (porcine) model was achieved.