<div><h4>Aircraft noise exposure induces pro-inflammatory vascular conditioning and amplifies vascular dysfunction and impairment of cardiac function after myocardial infarction.</h4><i>Molitor M, Jimenez MTB, Hahad O, Witzler C, ... Münzel T, Wenzel P</i><br /><b>Aims</b><br />Traffic noise may play an important role in the development and deterioration of ischemic heart disease. Thus, we sought to determine the mechanisms of cardiovascular dysfunction and inflammation induced by aircraft noise in a mouse model of myocardial infarction (MI) and in humans with incident MI.<br /><b>Methods and results</b><br />C57BL/6J mice were exposed to noise alone (average sound pressure level 72 dB; peak level 85 dB) up to 4d, resulting in pro-inflammatory aortic gene expression in the myeloid cell adhesion/diapedesis pathways. Noise alone promoted adhesion and infiltration of inflammatory myeloid cells in vascular/cardiac tissue, paralleled by an increased percentage of leukocytes with a pro-inflammatory, reactive oxygen species (ROS)-producing phenotype and augmented expression of Nox-2/phospho-NFκB in peripheral blood. Ligation of the LAD resulted in worsening of cardiac function, pronounced cardiac infiltration of CD11b+ myeloid cells and Ly6Chigh monocytes and induction of interleukin (IL) 6, IL-1β, CCL-2 and Nox-2, being aggravated by noise exposure prior to MI. MI induced stronger endothelial dysfunction and more pronounced increases in vascular ROS in animals preconditioned with noise. Participants of the population-based Gutenberg Health Cohort Study (median follow-up:11.4y) with incident MI revealed elevated CRP at baseline and worse LVEF after MI in case of a history of noise exposure and subsequent annoyance development.<br /><b>Conclusion</b><br />Aircraft noise exposure before MI substantially amplifies subsequent cardiovascular inflammation and aggravates ischemic heart failure, facilitated by a pro-inflammatory vascular conditioning. Our translational results suggest, that measures to reduce environmental noise exposure will be helpful in improving clinical outcome of subjects with MI.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Cardiovasc Res: 26 Jan 2023; epub ahead of print</small></div>

<div><h4>Fibrin clot properties in cardiovascular disease: from basic mechanisms to clinical practice.</h4><i>Ząbczyk M, Ariëns RAS, Undas A</i><br /><AbstractText>Fibrinogen conversion into insoluble fibrin and formation of a stable clot is the final step of the coagulation cascade. Fibrin clot porosity and its susceptibility to plasmin-mediated lysis are the key fibrin measures, describing properties of clots prepared ex vivo from citrated plasma. Cardiovascular disease, referring to coronary heart disease, heart failure, stroke, and hypertension, has been shown to be associated with a formation of dense fibrin networks that are relatively resistant to lysis. Denser fibrin mesh characterized acute patients at the onset of myocardial infarction or ischemic stroke, while hypofibrinolysis has been identified as a persistent fibrin feature in patients following thrombotic events or in those with stable coronary artery disease. Traditional cardiovascular risk factors, such as smoking, diabetes mellitus, hyperlipidaemia, obesity, and hypertension have also been linked with unfavourably altered fibrin clot properties, while some lifestyle modifications and pharmacological treatment, in particular statins and anticoagulants, may improve fibrin structure and function. Prospective studies have suggested that prothrombotic fibrin clot phenotype can predict cardiovascular events in a short- and long-term follow-up. Mutations and splice variants of the fibrinogen molecule that have been proven to be associated with thrombophilia or increased cardiovascular risk, along with fibrinogen post-translational modifications, prothrombotic state, inflammation, platelet activation, and neutrophil extracellular traps formation contribute also to prothrombotic fibrin clot phenotype. Moreover, about 500 clot-bound proteins have been identified within plasma fibrin clots, including fibronectin, α2-antiplasmin, factor XIII, complement component C3, and histidine-rich glycoprotein. This review summarizes the current knowledge on the mechanisms underlying unfavourable fibrin clot properties and their implications in cardiovascular disease and its thromboembolic manifestations.</AbstractText><br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.<br /><br /><small>Cardiovasc Res: 20 Jan 2023; epub ahead of print</small></div>

<div><h4>Alternative polyadenylation regulation in cardiac development and cardiovascular disease.</h4><i>Cao J, Kuyumcu-Martinez MN</i><br /><AbstractText>Cleavage and polyadenylation of pre-mRNAs is a necessary step for gene expression and function. Majority of human genes exhibit multiple polyadenylation sites, which can be alternatively used to generate different mRNA isoforms from a single gene. Alternative polyadenylation (APA) of pre-mRNAs is important for proteome and transcriptome landscape. APA is tightly regulated during development and contributes to tissue-specific gene regulation. Mis-regulation of APA is linked to a wide range of pathological conditions. APA-mediated gene regulation in the heart is emerging as new area of research. Here, we will discuss the impact of APA on gene regulation during heart development and in cardiovascular diseases. First, we will briefly review how APA impacts gene regulation and discuss molecular mechanisms that control APA. Then, we will address APA regulation during heart development and its dysregulation in cardiovascular diseases. Finally, we will discuss pre-mRNA targeting strategies to correct aberrant APA patterns of essential genes for the treatment or prevention of cardiovascular diseases. The RNA field is blooming due to the advancements in RNA-based technologies. RNA-based vaccines and therapies are becoming the new line of effective and safe approaches for the treatment and prevention of human diseases. Overall, this review will be influential for understanding gene regulation at the RNA level via APA in the heart and will help design RNA-based tools for the treatment of cardiovascular diseases in the future.</AbstractText><br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.<br /><br /><small>Cardiovasc Res: 20 Jan 2023; epub ahead of print</small></div>

<div><h4>Bone marrow inflammatory memory in cardiometabolic disease and inflammatory comorbidities.</h4><i>Mitroulis I, Hajishengallis G, Chavakis T</i><br /><AbstractText>Cardiometabolic disorders are chief causes of morbidity and mortality, with chronic inflammation playing a crucial role in their pathogenesis. The release of differentiated myeloid cells with elevated pro-inflammatory potential, as a result of maladaptively trained myelopoiesis may be a crucial factor for the perpetuation of inflammation. Several cardiovascular risk factors, including sedentary lifestyle, unhealthy diet, hypercholesterolemia and hyperglycemia, may modulate bone marrow hematopoietic progenitors, causing sustained functional changes that favor chronic metabolic and vascular inflammation. In the present review, we summarize recent studies that support the function of long-term inflammatory memory in progenitors of the bone marrow for development and progression of cardiometabolic disease and related inflammatory comorbidities, including periodontitis and arthritis. We also discuss how maladaptive myelopoiesis associated with the presence of mutated hematopoietic clones, as present in clonal hematopoiesis, may accelerate atherosclerosis via increased inflammation.</AbstractText><br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Cardiovasc Res: 19 Jan 2023; epub ahead of print</small></div>

<div><h4>Association of COVID-19 with short- and long-term risk of cardiovascular disease and mortality: a prospective cohort in UK Biobank.</h4><i>Wan EYF, Mathur S, Zhang R, Yan VKC, ... Yiu KH, Wong ICK</i><br /><b>Aims</b><br />This study aims to evaluate the short- and long-term associations between COVID-19 and development of cardiovascular disease (CVD) outcomes and mortality in the general population.<br /><b>Methods and results</b><br />A prospective cohort of patients with COVID-19 infection between 16 March 2020 and 30 November 2020 was identified from UK Biobank, and followed for up to 18 months, until 31 August 2021. Based on age (within 5 years) and sex, each case was randomly matched with up to 10 participants without COVID-19 infection from two cohorts-a contemporary cohort between 16 March 2020 and 30 November 2020 and a historical cohort between 16 March 2018 and 30 November 2018. The characteristics between groups were further adjusted with propensity score-based marginal mean weighting through stratification. To determine the association of COVID-19 with CVD and mortality within 21 days of diagnosis (acute phase) and after this period (post-acute phase), Cox regression was employed. In the acute phase, patients with COVID-19 (n = 7584) were associated with a significantly higher short-term risk of CVD {hazard ratio (HR): 4.3 [95% confidence interval (CI): 2.6- 6.9]; HR: 5.0 (95% CI: 3.0-8.1)} and all-cause mortality [HR: 81.1 (95% CI: 58.5-112.4); HR: 67.5 (95% CI: 49.9-91.1)] than the contemporary (n = 75 790) and historical controls (n = 75 774), respectively. Regarding the post-acute phase, patients with COVID-19 (n = 7139) persisted with a significantly higher risk of CVD in the long-term [HR: 1.4 (95% CI: 1.2-1.8); HR: 1.3 (95% CI: 1.1- 1.6)] and all-cause mortality [HR: 5.0 (95% CI: 4.3-5.8); HR: 4.5 (95% CI: 3.9-5.2) compared to the contemporary (n = 71 296) and historical controls (n = 71 314), respectively.<br /><b>Conclusions</b><br />COVID-19 infection, including long-COVID, is associated with increased short- and long-term risks of CVD and mortality. Ongoing monitoring of signs and symptoms of developing these cardiovascular complications post diagnosis and up till at least a year post recovery may benefit infected patients, especially those with severe disease.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.<br /><br /><small>Cardiovasc Res: 19 Jan 2023; epub ahead of print</small></div>

<div><h4>Smooth muscle mineralocorticoid receptor as an epigenetic regulator of vascular ageing.</h4><i>Ibarrola J, Kim SK, Lu Q, DuPont JJ, ... Jaffe JD, Jaffe IZ</i><br /><b>Aims</b><br />Vascular stiffness increases with age and independently predicts cardiovascular disease risk. Epigenetic changes, including histone modifications, accumulate with age but the global pattern has not been elucidated nor are the regulators known. Smooth muscle cell-mineralocorticoid receptor (SMC-MR) contributes to vascular stiffness in ageing mice. Thus, we investigated the regulatory role of SMC-MR in vascular epigenetics and stiffness.<br /><b>Methods and results</b><br />Mass spectrometry-based proteomic profiling of all histone modifications completely distinguished 3 from 12-month-old mouse aortas. Histone-H3 lysine-27 (H3K27) methylation (me) significantly decreased in ageing vessels and this was attenuated in SMC-MR-KO littermates. Immunoblotting revealed less H3K27-specific methyltransferase EZH2 with age in MR-intact but not SMC-MR-KO vessels. These ageing changes were examined in primary human aortic (HA)SMC from adult vs. aged donors. MR, H3K27 acetylation (ac), and stiffness gene (connective tissue growth factor, integrin-α5) expression significantly increased, while H3K27me and EZH2 decreased, with age. MR inhibition reversed these ageing changes in HASMC and the decline in stiffness genes was prevented by EZH2 blockade. Atomic force microscopy revealed that MR antagonism decreased intrinsic stiffness and the probability of fibronectin adhesion of aged HASMC. Conversely, ageing induction in young HASMC with H2O2; increased MR, decreased EZH2, enriched H3K27ac and MR at stiffness gene promoters by chromatin immunoprecipitation, and increased stiffness gene expression. In 12-month-old mice, MR antagonism increased aortic EZH2 and H3K27 methylation, increased EZH2 recruitment and decreased H3K27ac at stiffness genes promoters, and prevented ageing-induced vascular stiffness and fibrosis. Finally, in human aortic tissue, age positively correlated with MR and stiffness gene expression and negatively correlated with H3K27me3 while MR and EZH2 are negatively correlated.<br /><b>Conclusion</b><br />These data support a novel vascular ageing model with rising MR in human SMC suppressing EZH2 expression thereby decreasing H3K27me, promoting MR recruitment and H3K27ac at stiffness gene promoters to induce vascular stiffness and suggests new targets for ameliorating ageing-associated vascular disease.<br /><br />Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2022. For permissions, please email: journals.permissions@oup.com.<br /><br /><small>Cardiovasc Res: 18 Jan 2023; 118:3386-3400</small></div>

<div><h4>Sex differences and disparities in cardiovascular outcomes of COVID-19.</h4><i>Bugiardini R, Nava S, Caramori G, Yoon J, ... Zdravkovic M, Manfrini O</i><br /><b>Background</b><br />Previous analyses on sex differences in case fatality rates at population-level data had limited adjustment for key patient clinical characteristics thought to be associated with COVID-19 outcomes. We aimed to estimate the risk of specific organ dysfunctions and mortality in women and men.<br /><b>Methods and results</b><br />This retrospective cross-sectional study included 17 hospitals within 5 European countries participating in the International Survey of Acute Coronavirus Syndromes (ISACS) COVID-19(NCT05188612). Participants were individuals hospitalized with positive SARS-CoV-2 from March 2020 to February 2022. Risk-adjusted ratios(RR) of in-hospital mortality, acute respiratory failure(ARF), acute heart failure(AHF), and acute kidney injury(AKI) were calculated for women versus men. Estimates were evaluated by inverse probability of weighting and logistic regression models. The overall care cohort included 4,499 patients with COVID-19 associated hospitalizations. Of these, 1,524(33.9%) were admitted to ICU, and 1,117(24.8%) died during hospitalization. Compared with men, women were less likely to be admitted to ICU (RR:0.80; 95%CI: 0.71-0.91). In general wards (GW) and ICU cohorts, the adjusted women-to-men RRs for in-hospital mortality were of 1.13(95%CI: 0.90-1.42) and 0.86(95%CI: 0.70-1.05; pinteraction=0.04). Development of AHF, AKI and ARF was associated with increased mortality risk (ORs: 2.27; 95%CI; 1.73-2.98,3.85; 95%CI:3.21-4.63 and 3.95; 95%CI:3.04-5.14, respectively). The adjusted RRs for AKI and ARF were comparable among women and men regardless of intensity of care. By contrast, female sex was associated with higher odds for AHF in GW, but not in ICU (RRs:1.25; 95%CI0.94-1.67 versus 0.83; 95%CI:0.59-1.16, pinteraction=0.04).<br /><b>Conclusions</b><br />Women in GW were at increased risk of AHF and in-hospital mortality for COVID-19 compared with men. For patients receiving ICU care, fatal complications including AHF and mortality appeared to be independent of sex. Equitable access to COVID-19 ICU care is needed to minimize the unfavourable outcome of women presenting with COVID-19 related complications.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.<br /><br /><small>Cardiovasc Res: 18 Jan 2023; epub ahead of print</small></div>

<div><h4>PTX3 from vascular endothelial cells contributes to trastuzumab-induced cardiac complications.</h4><i>Xu Z, Gao Z, Fu H, Zeng Y, ... He Q, Luo P</i><br /><b>Aims</b><br />Trastuzumab, the first humanized monoclonal antibody that targets human epidermal growth factor receptor 2 (ERBB2/HER2), is currently used as a first-line treatment for HER2 (+) tumours. However, trastuzumab increases the risk of cardiac complications without affecting myocardial structure, suggesting a distinct mechanism of cardiotoxicity.<br /><b>Methods and results</b><br />We used medium from trastuzumab-treated human umbilical vein endothelial cells (HUVECs) to treat CCC-HEH-2 cells, the human embryonic cardiac tissue-derived cell lines, and human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) to assess the crosstalk between vascular endothelial cells (VECs) and cardiomyocytes. Protein mass spectrometry analysis was used to identify the key factors from VECs that regulate the function of cardiomyocytes. We applied RNA-sequencing to clarify the mechanism, by which PTX3 causes cardiac dysfunction. We used an anti-human/rat HER2 (neu) monoclonal antibody to generate a rat model that was used to evaluate the effects of trastuzumab on cardiac structure and function and the rescue effects of lapatinib on trastuzumab-induced cardiac side effects. Medium from trastuzumab-treated HUVECs apparently impaired the contractility of CCC-HEH-2 cells and iPSC-CMs. PTX3 from VECs caused defective cardiomyocyte contractility and cardiac dysfunction in mice, phenocopying trastuzumab treatment. PTX3 affected calcium homeostasis in cardiomyocytes, which led to defective contractile properties. EGFR/STAT3 signalling in VECs contributed to the increased expression and release of PTX3. Notably, lapatinib, a dual inhibitor of EGFR/HER2, could rescue the cardiac complications caused by trastuzumab by blocking the release of PTX3.<br /><b>Conclusions</b><br />We identified a distinct mode of cardiotoxicity, wherein the activation of EGFR/STAT3 signalling by trastuzumab in VECs promotes PTX3 excretion, which contributes to the impaired contractility of cardiomyocytes by inhibiting cellular calcium signalling. We confirmed that lapatinib could be a feasible preventive agent against trastuzumab-induced cardiac complications and provided the rationale for the combined application of lapatinib and trastuzumab in cancer-therapy.<br /><b>Translational perspective</b><br />We identified PTX3 as a potential biomarker and target for the treatment of trastuzumab-induced cardiac complications and demonstrated that lapatinib can prevent cardiac dysfunction caused by trastuzumab by blocking EFGR/STAT3-mediated PTX3 release from VECs, which provided a mechanistic rationale for the combined application of lapatinib and trastuzumab in cancer.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Cardiovasc Res: 18 Jan 2023; epub ahead of print</small></div>

<div><h4>Circular RNAs at the intersection of cancer and heart disease: potential therapeutic targets in cardio-oncology.</h4><i>Neufeldt D, Cushman S, Bär C, Thum T</i><br /><AbstractText>Considerable progress has been made for managing cancer, however, with these advancements, comes the discovery of previously unknown adverse events. In particular, the prolonged lifespan of patients has uncovered severe cardiotoxic side effects of widely used anticancer therapies, which restrict their administration and thus compromise the success of the seemingly most suitable treatments in large cancer patient cohorts. Vice versa, cardiovascular diseases can also promote both the onset and progression of different cancers, highlighting that both conditions are deeply interlinked. Recognizing these close interactions, the novel interdisciplinary field of cardio-oncology has emerged to closely study these uniquely correlating diseases. In this regard, non-coding RNAs are gaining increasing attention since they constitute crucial regulators in many physiological but also pathological signaling pathways, including those of cancer and cardiac dysfunction. In this review, we focus on the new subtype of non-coding RNA, circular RNAs, in their distinct exchange within cardio-oncology and discuss their suitability as potent targets for the simultaneous treatment of cardiac dysfunction and cancer.</AbstractText><br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.<br /><br /><small>Cardiovasc Res: 18 Jan 2023; epub ahead of print</small></div>

<div><h4>Cardiac muscle patches containing four types of cardiac cells derived from human pluripotent stem cells improve recovery from cardiac injury in mice.</h4><i>Lou X, Tang Y, Ye L, Pretorius D, ... Thomson JA, Zhang J</i><br /><b>Aims</b><br />We have shown that human cardiac muscle patches (hCMPs) containing three different types of cardiac cells-cardiomyocytes (CMs), smooth-muscle cells (SMCs), and endothelial cells (ECs), all of which were differentiated from human pluripotent stem cells (hPSCs)-significantly improved cardiac function, infarct size, and hypertrophy in a pig model of myocardial infarction (MI). However, hPSC-CMs are phenotypically immature, which may lead to arrythymogenic concerns; thus, since hPSC-derived cardiac fibroblasts (hPSC-CFs) appear to enhance the maturity of hPSC-CMs, we compared hCMPs containing hPSC-CMs, -SMCs, -ECs, and -CFs (4TCC-hCMPs) with a second hCMP construct that lacked hPSC-CFs but was otherwise identical (3TCC-hCMPs).<br /><b>Methods</b><br />hCMPs were generated in a fibrin scaffold. MI was induced in SCID mice through permanent coronary artery (LAD) ligation, followed by treatment with cardiac muscle patches. Animal groups included: MI heart treated with 3TCC-hCMP; with 4TCC-hCMP; MI heart treated with no patch (MI group) and sham group. Cardiac function was evaluated via echocardiography, and cell engraftment rate while infarct size was evaluated histologically at four weeks after patch transplantation.<br /><b>Results</b><br />The results from experiments in cultured hCMPs demonstrate that the inclusion of CF in 4TCC-hCMPs had: 1) better organized sarcomeres; 2) abundant structural, metabolic, and ion- channel markers of CM maturation; and 3) greater conduction velocities (31 ± 3.23 cm/s, p<0.005) and action-potential durations (APD50 = 365 ms ± 2.649, P<0.0001; APD = 408 ms ± 2.757, P<0.0001) than those (velocity and AP duration time) in 3TCC-hCMPs. Furthermore, when 4TCC- hCMPs transplantation resulted in better cardiac function (EF = 49.18% ± 0.86, p<0.05), reduced infarct size (22.72% ± 0.98, p<0.05), and better engraftment (15.99% ± 1.56, p<0.05) as compared with 3TCC-hCMPs (EF = 41.55 ± 0.92%, infarct size = 39.23 ± 4.28%, and engraftment = 8.56 ± 1.79%, respectively).<br /><b>Conclusion</b><br />Collectively, these observations suggest that the inclusion of hPSC-CFs during hCMP manufacture promotes hPSC-CM maturation and increases the potency of implanted hCMPs for improving cardiac recovery in mice model of MI.<br /><b>Translational perspective</b><br />Heart transplantation surgery remains the only established treatment for end-stage heart disease, and the supply of donated hearts is far lower than the number of patients in need of treatment. Thus, the goal of cardiac tissue engineering is to replace the scarred region of an injured heart with functional cardiac muscle. The results presented in this report suggest that engineered human cardiac-muscle patches may be more effective for the treatment of heart disease when they are constructed with cardiomyocytes, smooth-muscle cells, endothelial cells, and cardiac fibroblasts than when the cardiac fibroblasts are omitted.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Cardiovasc Res: 17 Jan 2023; epub ahead of print</small></div>

<div><h4>STRA6 is essential for induction of vascular smooth muscle lineages in human embryonic cardiac outflow tract development.</h4><i>Zhou C, Häneke T, Rohner E, Sohlmér J, ... Adameyko I, Sahara M</i><br /><b>Aims</b><br />Retinoic acid (RA) signaling is essential for heart development, and dysregulation of the RA signaling can cause several types of cardiac outflow tract (OFT) defects, the most frequent congenital heart disease (CHD) in humans. Matthew-Wood syndrome is caused by inactivating mutations of a transmembrane protein gene STRA6 that transports vitamin A (retinol) from extracellular into intracellular spaces. This syndrome shows a broad spectrum of malformations including CHD, although murine Stra6-null neonates did not exhibit overt heart defects. Thus, the detailed mechanisms by which STRA6 mutations could lead to cardiac malformations in humans remain unclear. Here, we investigated the role of STRA6 in the context of human cardiogenesis and CHD.<br /><b>Methods and results</b><br />To gain molecular signatures in species-specific cardiac development, we first compared single-cell RNA sequencing (RNA-seq) datasets, uniquely obtained from human and murine embryonic hearts. We found that while STRA6 mRNA was much less frequently expressed in murine embryonic heart cells derived from the Mesp1+ lineage tracing mice (Mesp1Cre/+; Rosa26tdTomato), it was expressed predominantly in the OFT region-specific heart progenitors in human developing hearts. Next, we revealed that STRA6-knockout human embryonic stem cells (hESCs) could differentiate into cardiomyocytes similarly to wild-type hESCs, but could not differentiate properly into mesodermal nor neural crest cell-derived smooth muscle cells (SMCs) in vitro. This is supported by the population RNA-seq data showing downregulation of the SMC-related genes in the STRA6-knockout hESC-derived cells. Further, through machinery assays, we identified the previously unrecognized interaction between RA nuclear receptors RARα/RXRα and TBX1, an OFT-specific cardiogenic transcription factor, which would likely act downstream to STRA6-mediated RA signaling in human cardiogenesis.<br /><b>Conclusion</b><br />Our study highlights a critical role of human-specific STRA6 progenitors for proper induction of vascular SMCs that is essential for normal OFT formation. Thus, these results shed light on novel and human-specific CHD mechanisms, driven by STRA6 mutations.<br /><b>Translational perspectives</b><br />Dysregulation of the RA signaling can cause cardiac OFT defects, however, the detailed mechanisms by which STRA6 mutations lead to cardiac malformations have remained unclear. Our study highlights a critical role of human-specific STRA6 progenitors for proper induction of vascular SMCs that is essential for normal OFT formation. These results shed light on novel and human-specific CHD programs, driven by STRA6 mutations. Thus, our study paves the way for further studies of deciphering the origins and the disease mechanisms of a rare genetic disorder Matthew-Wood syndrome, which would help us develop diagnosis, prevention, and novel treatment for the disease.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Cardiovasc Res: 13 Jan 2023; epub ahead of print</small></div>

<div><h4>The longevity-associated BPIFB4 gene supports cardiac function and vascularization in aging cardiomyopathy.</h4><i>Cattaneo M, Beltrami AP, Thomas AC, Spinetti G, ... Puca AA, Madeddu P</i><br /><b>Aims</b><br />The aging heart naturally incurs a progressive decline in function and perfusion that available treatments cannot halt. However, some exceptional individuals maintain good health until the very late stage of their life due to favourable gene-environment interaction. We have previously shown that carriers of a longevity-associated variant (LAV) of the BPIFB4 gene enjoy prolonged health spans and lesser cardiovascular complications. Moreover, supplementation of LAV-BPIFB4 via an adeno-associated viral vector improves cardiovascular performance in limb ischemia, atherosclerosis, and diabetes models. Here, we asked if the LAV-BPIFB4 gene could address the unmet therapeutic need to delay the heart\'s spontaneous aging.<br /><b>Methods and results</b><br />Immunohistological studies showed a remarkable reduction in vessel coverage by pericytes in failing hearts explanted from elderly patients. This defect was attenuated in patients carrying the homozygous LAV-BPIFB4 genotype. Moreover, pericytes isolated from older hearts showed low levels of BPIFB4, depressed pro-angiogenic activity, and loss of ribosome biogenesis. LAV-BPIFB4 supplementation restored pericyte function and pericyte-endothelial cell interactions through a mechanism involving the nucleolar protein nucleolin. Conversely, BPIFB4 silencing in normal pericytes mimed the heart failure pericytes. Finally, gene therapy with LAV-BPIFB4 prevented cardiac deterioration in middle-aged mice and rescued cardiac function and myocardial perfusion in older mice by improving microvasculature density and pericyte coverage.<br /><b>Conclusions</b><br />We report the success of the LAV-BPIFB4 gene/protein in improving homeostatic processes in the heart\'s aging. These findings open to using LAV-BPIFB4 to reverse the decline of heart performance in older people.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Cardiovasc Res: 13 Jan 2023; epub ahead of print</small></div>

<div><h4>Empagliflozin inhibits excessive autophagy through the AMPK/GSK3β signaling pathway in diabetic cardiomyopathy.</h4><i>Madonna R, Moscato S, Cufaro MC, Pieragostino D, ... Zucchi R, De Caterina R</i><br /><b>Background:</b><br/>and aims</b><br />Sodium-glucose cotransporter 2 (SGLT2) inhibitors have beneficial effects on heart failure and cardiovascular mortality in diabetic and nondiabetic patients, with unclear mechanisms. Autophagy is a cardioprotective mechanism under acute stress conditions, but excessive autophagy accelerates myocardial cell death leading to autosis. We evaluated the protective role of empagliflozin (EMPA) against cardiac injury in murine diabetic cardiomyopathy.<br /><b>Methods and results</b><br />Male mice, rendered diabetics by one single intraperitoneal injection of streptozotocin and treated with EMPA (30 mg/kg/day) had fewer apoptotic cells (4.9 ± 2.1 vs 1 ± 0.5 TUNEL-positive cells %, p < 0.05), less senescence (10.1 ± 2 vs 7.9 ± 1.2 β-gal positivity/tissue area, p < 0.05), fibrosis (0.2 ± 0.05 vs 0.15 ± 0.06, p < 0.05 fibrotic area/tissue area), autophagy (7.9 ± 0.05 vs 2.3 ± 0.6 fluorescence intensity/total area, p < 0.01), and connexin (Cx)-43 lateralization compared with diabetic mice. Proteomic analysis showed a downregulation of the 5\' adenosine monophosphate-activated protein kinase (AMPK) pathway and upstream activation of sirtuins in the heart of diabetic mice treated with EMPA compared with diabetic mice. Because sirtuin activation leads to modulation of cardiomyogenic transcription factors, we analyzed the DNA binding activity to serum response elements (SRE) of serum response factor (SRF) by electromobility shift assay. Compared with diabetic mice (0.5 ± 0.01 densitometric units, DU), nondiabetic mice treated with EMPA (2.2 ± 0.01 DU, p < 0.01) and diabetic mice treated with EMPA (2.0 ± 0.1 DU, p < 0.01) significantly increased SRF binding activity to SRE, paralleled by increased cardiac actin expression (4.1 ± 0.1 vs 2.2 ± 0.01 target protein/β-actin ratio, p < 0.01). EMPA significantly reversed cardiac dysfunction on echocardiography in diabetic mice and inhibited excessive autophagy in high-glucose-treated cardiomyocytes by inhibiting the autophagy inducer GSK3β, leading to reactivation of cardiomyogenic transcription factors.<br /><b>Conclusions</b><br />Taken together, our results describe a novel paradigm in which EMPA inhibits hyperactivation of autophagy through the AMPK/GSK3β signaling pathway in the context of diabetes.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.<br /><br /><small>Cardiovasc Res: 11 Jan 2023; epub ahead of print</small></div>

<div><h4>The RNA-binding protein QKI governs a muscle-specific alternative splicing program that shapes the contractile function of cardiomyocytes.</h4><i>Montañés-Agudo P, Aufiero S, Schepers EN, van der Made I, ... Pinto YM, Creemers EE</i><br /><b>Aims</b><br />In the heart, splicing factors orchestrate the functional properties of cardiomyocytes by regulating the alternative splicing of multiple genes. Work in embryonic stem cells has shown that the splicing factor Quaking (QKI) regulates alternative splicing during cardiomyocyte differentiation. However, the relevance and function of QKI in adult cardiomyocytes remains unknown. In this study we aim to identify the in vivo function of QKI in the adult mouse heart.<br /><b>Methods and results</b><br />We generated mice with conditional deletion of QKI in cardiomyocytes by the Cre-Lox system. Mice with cardiomyocyte-specific deletion of QKI died during the fetal period (E14.5), without obvious anatomical abnormalities of the heart. Adult mice with tamoxifen-inducible QKI deletion rapidly developed heart failure associated with severe disruption of sarcomeres, already 7 days after knocking out QKI. RNA sequencing revealed that QKI regulates the alternative splicing of more than 1000 genes, including sarcomere and cytoskeletal components, calcium handling genes and (post)transcriptional regulators. Many of these splicing changes corresponded to the loss of muscle-specific isoforms in the heart. Forced overexpression of QKI in cultured neonatal rat ventricular myocytes directed these splicing events in the opposite direction, and enhanced contractility of cardiomyocytes.<br /><b>Conclusion</b><br />Altogether, our findings show that QKI is an important regulator of the muscle-specific alternative splicing program that builds the contractile apparatus of cardiomyocytes.<br /><b>Translational perspective</b><br />Alternative splicing generates protein isoforms to maintain mechanical, structural, and metabolic properties of cardiomyocytes. We are the first to show that QKI is one of the essential splicing factors in the adult heart. During heart failure, alternative splicing of numerous genes is altered, thereby affecting cardiac function. Recent observations that QKI expression is downregulated in hearts of heart failure patients indicates that loss of QKI-mediated processes contributes to decreased sarcomere organization in these patients. Modulation of QKI activity may serve as a future therapeutic strategy to adapt cardiac isoform expression and improve cardiac function in heart failure patients.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Cardiovasc Res: 11 Jan 2023; epub ahead of print</small></div>

<div><h4>Dietary essential amino acids for the treatment of heart failure with reduced ejection fraction.</h4><i>Ragni M, Greco CM, Felicetta A, Ren SV, ... Condorelli G, Nisoli E</i><br /><b>Aims</b><br />Heart failure with reduced ejection fraction (HFrEF) is a leading cause of mortality worldwide, requiring novel therapeutic and lifestyle interventions. Metabolic alterations and energy production deficit are hallmarks and thereby promising therapeutic targets for this complex clinical syndrome. We aim to study the molecular mechanisms and effects on cardiac function in rodents with HFrEF of a designer diet in which free essential amino acids - in specifically designed percentages - substituted for protein.<br /><b>Methods and results</b><br />Wild-type mice were subjected to transverse aortic constriction (TAC) to induce left ventricle (LV) pressure overload or sham surgery. Whole body glucose homeostasis was studied with glucose tolerance test, while myocardial dysfunction and fibrosis were measured with echocardiogram and histological analysis. Mitochondrial bioenergetics and morphology were investigated with oxygen consumption rate measurement and electron microscopy evaluation. Circulating and cardiac non-targeted metabolite profiles were analyzed by ultrahigh performance liquid chromatography-tandem mass spectroscopy, while RNA sequencing was used to identify signalling pathways mainly affected. The amino acid-substituted diet shows remarkable preventive and therapeutic effects. This dietary approach corrects the whole-body glucose metabolism and restores the unbalanced metabolic substrate usage - by improving mitochondrial fuel oxidation - in the failing heart. In particular, biochemical, molecular, and genetic approaches suggest that renormalization of branched-chain amino acid oxidation in cardiac tissue, which is suppressed in HFrEF, plays a relevant role. Beyond the changes of systemic metabolism, cell-autonomous processes may explain at least in part the diet\'s cardioprotective impact.<br /><b>Conclusion</b><br />Collectively, these results suggest that manipulation of dietary amino acids, and especially essential amino acids, is a potential adjuvant therapeutic strategy to treat systolic dysfunction and HFrEF in humans.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Cardiovasc Res: 10 Jan 2023; epub ahead of print</small></div>

<div><h4>Targeting RUNX1 as a novel treatment modality for pulmonary arterial hypertension.</h4><i>Jeong EM, Pereira M, So EY, Wu KQ, ... Klinger JR, Liang OD</i><br /><b>Aims</b><br />Pulmonary arterial hypertension (PAH) is a fatal disease without a cure. Previously, we found that transcription factor RUNX1-dependent haematopoietic transformation of endothelial progenitor cells may contribute to the pathogenesis of PAH. However, the therapeutic potential of RUNX1 inhibition to reverse established PAH remains unknown. In the current study, we aimed to determine whether RUNX1 inhibition was sufficient to reverse Sugen/hypoxia (SuHx)-induced pulmonary hypertension (PH) in rats. We also aimed to demonstrate possible mechanisms involved.<br /><b>Methods and results</b><br />We administered a small molecule specific RUNX1 inhibitor Ro5-3335 before, during, and after the development of SuHx-PH in rats to investigate its therapeutic potential. We quantified lung macrophage recruitment and activation in vivo and in vitro in the presence or absence of the RUNX1 inhibitor. We generated conditional VE-cadherin-CreERT2; ZsGreen mice for labelling adult endothelium and lineage tracing in the SuHx-PH model. We also generated conditional Cdh5-CreERT2; Runx1(flox/flox) mice to delete Runx1 gene in adult endothelium and LysM-Cre; Runx1(flox/flox) mice to delete Runx1 gene in cells of myeloid lineage, and then subjected these mice to SuHx-PH induction. RUNX1 inhibition in vivo effectively prevented the development, blocked the progression, and reversed established SuHx-induced PH in rats. RUNX1 inhibition significantly dampened lung macrophage recruitment and activation. Furthermore, lineage tracing with the inducible VE-cadherin-CreERT2; ZsGreen mice demonstrated that a RUNX1-dependent endothelial to haematopoietic transformation occurred during the development of SuHx-PH. Finally, tissue-specific deletion of Runx1 gene either in adult endothelium or in cells of myeloid lineage prevented the mice from developing SuHx-PH, suggesting that RUNX1 is required for the development of PH.<br /><b>Conclusion</b><br />By blocking RUNX1-dependent endothelial to haematopoietic transformation and pulmonary macrophage recruitment and activation, targeting RUNX1 may be as a novel treatment modality for pulmonary arterial hypertension.<br /><br />© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Cardiovasc Res: 29 Dec 2022; 118:3211-3224</small></div>

<div><h4>Interferon-stimulated gene 15 pathway is a novel mediator of endothelial dysfunction and aneurysms development in angiotensin II infused mice through increased oxidative stress.</h4><i>González-Amor M, García-Redondo AB, Jorge I, Zalba G, ... Salaices M, Briones AM</i><br /><b>Aims</b><br />Interferon-stimulated gene 15 (ISG15) encodes a ubiquitin-like protein that induces a reversible post-translational modification (ISGylation) and can also be secreted as a free form. ISG15 plays an essential role as host-defence response to microbial infection; however, its contribution to vascular damage associated with hypertension is unknown.<br /><b>Methods and results</b><br />Bioinformatics identified ISG15 as a mediator of hypertension-associated vascular damage. ISG15 expression positively correlated with systolic and diastolic blood pressure and carotid intima-media thickness in human peripheral blood mononuclear cells. Consistently, Isg15 expression was enhanced in aorta from hypertension models and in angiotensin II (AngII)-treated vascular cells and macrophages. Proteomics revealed differential expression of proteins implicated in cardiovascular function, extracellular matrix and remodelling, and vascular redox state in aorta from AngII-infused ISG15-/- mice. Moreover, ISG15-/- mice were protected against AngII-induced hypertension, vascular stiffness, elastin remodelling, endothelial dysfunction, and expression of inflammatory and oxidative stress markers. Conversely, mice with excessive ISGylation (USP18C61A) show enhanced AngII-induced hypertension, vascular fibrosis, inflammation and reactive oxygen species (ROS) generation along with elastin breaks, aortic dilation, and rupture. Accordingly, human and murine abdominal aortic aneurysms showed augmented ISG15 expression. Mechanistically, ISG15 induces vascular ROS production, while antioxidant treatment prevented ISG15-induced endothelial dysfunction and vascular remodelling.<br /><b>Conclusion</b><br />ISG15 is a novel mediator of vascular damage in hypertension through oxidative stress and inflammation.<br /><br />Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.<br /><br /><small>Cardiovasc Res: 29 Dec 2022; 118:3250-3268</small></div>

<div><h4>Wall shear stress-related plaque growth of lipid-rich plaques in human coronary arteries: an near-infrared spectroscopy and optical coherence tomography study.</h4><i>Hartman EMJ, De Nisco G, Kok AM, Tomaniak M, ... Daemen J, Wentzel JJ</i><br /><b>Aims</b><br />Low wall shear stress (WSS) is acknowledged to play a role in plaque development through its influence on local endothelial function. Also, lipid-rich plaques (LRPs) are associated with endothelial dysfunction. However, little is known about the interplay between WSS and the presence of lipids with respect to plaque progression. Therefore, we aimed to study the differences in WSS-related plaque progression between LRPs, non-LRPs, or plaque-free regions in human coronary arteries.<br /><b>Methods and results</b><br />In the present single-centre, prospective study, 40 patients who presented with an acute coronary syndrome successfully underwent near-infrared spectroscopy intravascular ultrasound (NIRS-IVUS) and optical coherence tomography (OCT) of at least one non-culprit vessel at baseline and completed a 1-year follow-up. WSS was computed applying computational fluid dynamics to a three-dimensional reconstruction of the coronary artery based on the fusion of the IVUS-segmented lumen with a CT-derived centreline, using invasive flow measurements as boundary conditions. For data analysis, each artery was divided into 1.5 mm/45° sectors. Plaque growth based on IVUS-derived percentage atheroma volume change was compared between LRPs, non-LRPs, and plaque-free wall segments, as assessed by both OCT and NIRS. Both NIRS- and OCT-detected lipid-rich sectors showed a significantly higher plaque progression than non-LRPs or plaque-free regions. Exposure to low WSS was associated with a higher plaque progression than exposure to mid or high WSS, even in the regions classified as a plaque-free wall. Furthermore, low WSS and the presence of lipids had a synergistic effect on plaque growth, resulting in the highest plaque progression in lipid-rich regions exposed to low shear stress.<br /><b>Conclusion</b><br />This study demonstrates that NIRS- and OCT-detected lipid-rich regions exposed to low WSS are subject to enhanced plaque growth over a 1-year follow-up. The presence of lipids and low WSS proves to have a synergistic effect on plaque growth.<br /><br />© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Cardiovasc Res: 28 Dec 2022; epub ahead of print</small></div>

<div><h4>Cholesterol accumulation in macrophages drives NETosis in atherosclerotic plaques via IL-1β secretion.</h4><i>Yalcinkaya M, Fotakis P, Liu W, Endo-Umeda K, ... Tall AR, Westerterp M</i><br /><b>Objective</b><br />Neutrophil extracellular trap formation (NETosis) increases atherosclerotic plaque vulnerability and athero-thrombosis. However, mechanisms promoting NETosis during atherogenesis are poorly understood. We have shown that cholesterol accumulation due to myeloid cell deficiency of the cholesterol transporters ATP Binding Cassette A1 and G1 (ABCA1/G1) promotes NLRP3 inflammasome activation in macrophages and neutrophils and induces prominent NETosis in atherosclerotic plaques. We investigated whether NETosis is a cell intrinsic effect in neutrophils or is mediated indirectly by cellular crosstalk from macrophages to neutrophils involving IL-1β.<br /><b>Methods and results</b><br />We generated mice with neutrophil or macrophage-specific Abca1/g1 deficiency (S100A8CreAbca1fl/flAbcg1fl/fl or CX3CR1CreAbca1fl/flAbcg1fl/fl mice, respectively), and transplanted their bone marrow into low-density lipoprotein receptor knockout mice. We then fed the mice a cholesterol-rich diet. Macrophage, but not neutrophil Abca1/g1 deficiency activated inflammasomes in macrophages and neutrophils, reflected by caspase-1 cleavage, and induced NETosis in plaques. NETosis was suppressed by administering an interleukin (IL)-1β neutralizing antibody. The extent of NETosis in plaques correlated strongly with the degree of neutrophil accumulation, irrespective of blood neutrophil counts, and neutrophil accumulation was decreased by IL-1β antagonism. In vitro, IL-1β or media transferred from Abca1/g1 deficient macrophages increased NETosis in both control and Abca1/Abcg1 deficient neutrophils. This cell-extrinsic effect of IL-1β on NETosis was blocked by an NLRP3 inhibitor.<br /><b>Conclusions</b><br />These studies establish a new link between inflammasome mediated IL-1β production in macrophages and NETosis in atherosclerotic plaques. Macrophage-derived IL-1β appears to increase NETosis both by increasing neutrophil recruitment to plaques and by promoting neutrophil NLRP3 inflammasome activation.<br /><br />© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Cardiovasc Res: 20 Dec 2022; epub ahead of print</small></div>

<div><h4>Low leukocyte mitochondrial DNA abundance drives atherosclerotic cardiovascular diseases: cohort and Mendelian randomization study.</h4><i>Luo J, Noordam R, Jukema JW, Willems van Dijk K, ... le Cessie S, van Heemst D</i><br /><b>Aim</b><br />Mitochondrial DNA dysfunction has been implicated in the pathogenesis of cardiovascular diseases. We aimed to investigate the associations of leukocyte mitochondrial DNA (mtDNA) abundance, as a proxy of mitochondrial copy numbers and function, and coronary artery disease (CAD) and heart failure (HF) in a cohort study and approximate the causal nature of these relationships using Mendelian randomization (MR) in genetic studies.<br /><b>Methods and results</b><br />Multivariable-adjusted Cox regression analyses were conducted in 273,619 unrelated participants of European ancestry from UK Biobank (UKB). For genetic studies, we first performed MR analyses with individual-level data from the UKB using a weighted genetic risk score (GRS); two-sample MR analyses were subsequently performed using summary-level data from the publicly available three consortia/biobank for CAD and two for HF. MR analyses were performed per database separately and results were subsequently meta-analyzed using fixed-effects models. During a median follow-up of 11.8 years, cox regression restricted cubic spline analyses showed associations between lower mtDNA abundance and higher risk of CAD and HF. Hazard ratios for participants in the lowest quintile of mtDNA abundance compared with those in the highest quintile were 1.08 (95% confidence interval: 1.03, 1.14) and 1.15 (1.05, 1.24) for CAD and HF. Genetically, no evidence was observed for a possible non-linear causal effect using individual-level weighted genetic risk scores calculated in the UKB on the study outcomes; the pooled odds ratios from two-sample MR of genetically predicted per one-SD decrease in mtDNA abundance were 1.09 (1.03, 1.16) for CAD and 0.99 (0.92, 1.08) for HF, respectively.<br /><b>Conclusion</b><br />Our findings support a possible causal role of lower leukocyte mtDNA abundance in higher CAD risk, but not in HF.<br /><br />© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.<br /><br /><small>Cardiovasc Res: 20 Dec 2022; epub ahead of print</small></div>

<div><h4>Mechanisms of current therapeutic strategies for heart failure: more questions than answers?</h4><i>Khan MS, Shahid I, Greene SJ, Mentz RJ, DeVore AD, Butler J</i><br /><AbstractText>Heart failure (HF) is a complex, multifactorial and heterogeneous syndrome with substantial mortality and morbidity. Over the last few decades, numerous attempts have been made to develop targeted therapies which may attenuate the known pathophysiological pathways responsible for causing progression of HF. However, therapies developed with this objective have sometimes failed to show benefit. The pathophysiological construct of HF with numerous etiologies suggests that interventions with broad mechanisms of action which simultaneously target more than one pathway maybe more effective in improving outcomes of patients with HF. Indeed, current therapeutics with clinical benefit in HF have targeted a wider range of intermediate phenotypes. Despite extensive scientific breakthroughs in HF research recently, questions persist regarding the ideal therapeutic targets which may help achieve maximum benefit. In this review, we evaluate the mechanism of action of current therapeutic strategies, the pathophysiological pathways they target and highlight remaining knowledge gaps regarding the mode of action of these interventions.</AbstractText><br /><br />© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.<br /><br /><small>Cardiovasc Res: 20 Dec 2022; epub ahead of print</small></div>

<div><h4>Interferon-γ drives macrophage reprogramming, cerebrovascular remodeling, and cognitive dysfunction in a zebrafish and a mouse model of ion imbalance and pressure overload.</h4><i>Apaydin DC, Zakarauskas-Seth BI, Carnevale L, Apaydin O, ... Filosa A, Sawamiphak S</i><br /><b>Aims</b><br />Dysregulated immune response contributes to inefficiency of treatment strategies to control hypertension and reduce the risk of end-organ damage. Uncovering the immune pathways driving the transition from the onset of hypertensive stimulus to the manifestation of multi-organ dysfunction are much-needed insights for immune targeted therapy.<br /><b>Methods and results</b><br />To aid visualization of cellular events orchestrating multi-organ pathogenesis, we modeled hypertensive cardiovascular remodeling in zebrafish. Zebrafish larvae exposed to ion-poor environment exhibited rapid angiotensinogen upregulation, followed by manifestation of arterial hypertension and cardiac remodeling that recapitulates key characteristics of incipient Heart Failure with preserved Ejection Fraction. In the brain, time-lapse imaging revealed the occurrence of cerebrovascular regression through endothelial retraction and migration in response to the ion-poor treatment. This phenomenon is associated with macrophage/microglia-endothelial contacts and endothelial junctional retraction. Cytokine and transcriptomic profiling identified systemic upregulation of interferon-γ and interleukin 1β, and revealed altered macrophage/microglia transcriptional program characterized by suppression of innate immunity and vasculo/neuroprotective gene expression. Both zebrafish and a murine model of pressure overload-induced brain damage demonstrated that the brain pathology and macrophage/microglia phenotypic alteration are dependent on interferon-γ signaling. In zebrafish, interferon-γ receptor 1 mutation prevents cerebrovascular remodeling and dysregulation of macrophage/microglia transcriptomic profile. Supplementation of bone morphogenetic protein 5, identified from the transcriptomic approach as a downregulated gene in ion-poor-treated macrophages/microglia that is rescued by interferon-γ blockage, mitigated cerebral microvessel loss. In mice subjected to transverse aortic constriction-induced pressure overload, typically developing cerebrovascular injury, neuroinflammation and cognitive dysfunction, interferon-γ neutralization protected them from blood-brain-barrier disruption, cerebrovascular rarefaction, and cognitive decline.<br /><b>Conclusions</b><br />These findings uncover cellular and molecular players of an immune pathway communicating hypertensive stimulus to structural and functional remodeling of the brain and identify anti-interferon-γ treatment as a promising intervention strategy capable of preventing pressure overload-induced damage of the cerebrovascular and nervous systems.<br /><b>Translational perspective</b><br />Hypertension is a major risk factor for damages of the vasculature, heart, and brain, and thereby a major healthcare burden. Inadequate cerebral blood supply due to altered cerebrovascular structure and vasoregulatory disruption upon hypertension render the brain highly susceptible to stroke and cognitive decline. We envision that the cellular and molecular mechanisms uncovered here linking immune dysregulation to cerebrovascular remodeling and functional impairment of the brain will inform future development of immunomodulatory therapeutic strategies for counteracting derangement of macrophage/microglia activation and their vasculo/neuroprotective function in response to systemic inflammation in hypertension.<br /><br />© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.<br /><br /><small>Cardiovasc Res: 20 Dec 2022; epub ahead of print</small></div>

<div><h4>A transposable element into the human long noncoding RNA CARMEN is a switch for cardiac precursor cell specification.</h4><i>Plaisance I, Chouvardas P, Sun Y, Nemir M, ... Palpant N, Pedrazzini T</i><br /><b>Aims</b><br />The major cardiac cell types composing the adult heart arise from common multipotent precursor cells. Cardiac lineage decisions are guided by extrinsic and cell-autonomous factors, including recently discovered long noncoding RNAs (lncRNAs). The human lncRNA CARMEN, which is known to dictate specification towards the cardiomyocyte (CM) and the smooth muscle cell (SMC) fates, generates a diversity of alternatively spliced isoforms.<br /><b>Methods and results</b><br />The CARMEN locus can be manipulated to direct human primary cardiac precursor cells (CPCs) into specific cardiovascular fates. Investigating CARMEN isoform usage in differentiating CPCs represents therefore a unique opportunity to uncover isoform-specific function in lncRNAs. Here, we identify one CARMEN isoform, CARMEN-201, to be crucial for SMC commitment. CARMEN-201 activity is encoded within an alternatively-spliced exon containing a MIRc short interspersed nuclear element. This element binds the transcriptional repressor REST (RE1 Silencing Transcription Factor), targets it to cardiogenic loci, including ISL1, IRX1, IRX5, and SFRP1, and thereby blocks the CM gene program. In turn, genes regulating SMC differentiation are induced.<br /><b>Conclusions</b><br />These data show how a critical physiological switch is wired by alternative splicing and functional transposable elements in a long noncoding RNA. They further demonstrated the crucial importance of the lncRNA isoform CARMEN-201 in SMC specification during heart development.<br /><br />© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Cardiovasc Res: 20 Dec 2022; epub ahead of print</small></div>

<div><h4>Aortic stenosis and the hemostatic system.</h4><i>Trimaille A, Hmadeh S, Matsushita K, Marchandot B, Kauffenstein G, Morel O</i><br /><AbstractText>Aortic stenosis (AS) affects more than 10% of the population over 80 years of age and constitutes a major risk factor for heart failure, thromboembolic stroke, and death. A better understanding of the disease, including its interaction with the hemostatic system, is a prerequisite to develop prophylactic treatments. AS pathogenesis is a dynamic process involving endothelial dysfunction, inflammation, fibrosis, and calcification. Several studies support the interplay between the components of the hemostatic system such as platelets, the coagulation system, von Willebrand factor, and extracellular microparticles at each pathophysiological stage of AS. Previous reports have evidenced persistent biological activity of the native valve after transcatheter aortic valve replacement (TAVR) and the subsequent development of microthrombosis that may impact the function of the newly implanted valve. Here, we review the current evidence on the interplay between AS and prothrombotic activity, and we emphasize the clinical consequences of these interactions after aortic valve replacement.</AbstractText><br /><br />© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.<br /><br /><small>Cardiovasc Res: 20 Dec 2022; epub ahead of print</small></div>

<div><h4>Partial endothelial-to-mesenchymal transition mediated by HIF-induced CD45 in neointima formation upon carotid artery ligation.</h4><i>Yamashiro Y, Ramirez K, Nagayama K, Hattori N, ... Kubota Y, Yanagisawa H</i><br /><b>Aims</b><br />Endothelial-to-mesenchymal transition (EndMT) is a fundamental process in vascular remodeling. However, the precise regulatory mechanism of vascular remodeling during neointima formation and source of neointima cells are not entirely understood.<br /><b>Methods and results</b><br />To investigate the origin of neointima cells and their relevance to vascular wall remodeling, we used an EC-specific lineage tracing system (VE-Cadherin (Cdh5)-BAC-CreERT2 mice) and carotid artery ligation model, and showed evidence that resident endothelial cells (ECs) transdifferentiate into neointima cells with expression of CD45. During the early stages of neointima formation, ECs transiently expressed CD45, a hematopoietic marker, accompanied by a host of EndMT markers, and CD31 and αSMA were prominently expressed in developing neointima. In vitro, CD45-positive EndMT was induced by stabilization of HIF1α with cobalt chloride or with a VHL inhibitor in human primary ECs, which mimicked the hypoxic condition of the ligated artery, and promoted the formation of an integrin α11-SHARPIN complex. Notably, a CD45 phosphatase inhibitor disrupted this complex, thereby destabilizing cell-cell junctions. Deletion of Hif1α in ECs suppressed expression of CD45 and EndMT markers, and ameliorated neointima formation.<br /><b>Conclusions</b><br />These results suggest that the HIF-induced CD45 expression is normally required for the retention of an EC fate and cell-cell junctions, CD45-positive EndMT (termed as \"partial EndMT\") contributes to neointima formation and vascular wall remodeling.<br /><b>Translational perspective</b><br />Our study identifies ECs as an origin of neointima, which is generated through partial EndMT and provides new evidence to the long-debated origin of neointimal cells after vascular injury. The ectopic CD45 expression in ECs is involved in the maintenance of endothelial cell-cell junction during EndMT process. Our data suggests a potential therapeutic strategy targeting the EndMT process to control neointima formation.<br /><br />© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.<br /><br /><small>Cardiovasc Res: 20 Dec 2022; epub ahead of print</small></div>

<div><h4>Lower levels of small HDL particles associated with increased infectious disease morbidity and mortality: a population-based cohort study of 30 195 individuals.</h4><i>Harsløf M, Pedersen KM, Afzal S, Smith GD, Nordestgaard BG</i><br /><b>Aim</b><br />Low levels of high-density lipoprotein (HDL) cholesterol have been associated with increased risk of infectious disease morbidity and mortality. Nuclear magnetic resonance (NMR) spectroscopy permits the measurement of HDL particle count and allows further subclassification according to particle size. We tested the hypothesis that low number of different HDL subfractions is associated with increased infectious disease morbidity and mortality.<br /><b>Methods and results</b><br />HDL particle counts were measured using NMR spectroscopy in 30 195 individuals aged 22-99 from the Copenhagen General Population Study. Using multiple-event Cox regression and cause-specific hazard models, we assessed risk of hospitalizations due to infection and infectious disease-related death, from 2003 through 2018. During follow-up, 9303 individuals had one or more infectious disease events, and 1558 experienced infectious disease-related death. In multifactorial adjusted analyses, low number of small and medium HDL particles was associated with increased risk of any infection and infectious disease-related death, whereas low number of large and extra-large HDL particles was not. A very high number of small and medium HDL particles was also associated with increased risk of any infection, but not with infectious disease-related death. For small and medium HDL particles and compared to individuals in the 91-95th percentile, hazard ratios in individuals in the lowest percentile were 2.31 (95% confidence interval: 1.75, 3.05) for any infection and 3.23 (2.08, 5.02) for infectious disease-related death. For the highest percentile, corresponding hazard ratios were 1.36 (1.07, 1.74) and 1.06 (0.57, 1.98), respectively. Individuals in the lowest percentile had increased risk of pneumonia (hazard ratio 1.86; 95%CI: 1.30, 2.65), sepsis (2.17; 1.37, 3.35), urinary tract infection (1.76; 1.17, 2.63), skin infection (1.87; 1.24, 2.81), gastroenteritis (1.78; 1.01, 3.16), and other infections (2.57; 1.28, 5.16).<br /><b>Conclusion</b><br />Low number of the small HDL particles was associated with increased infectious disease morbidity and mortality.<br /><br />© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.<br /><br /><small>Cardiovasc Res: 20 Dec 2022; epub ahead of print</small></div>

<div><h4>Endothelial PTP4A1 mitigates vascular inflammation via USF1/A20 axis-mediated NF-κB inactivation.</h4><i>Cho MJ, Lee DG, Lee JW, Hwang B, ... Park JG, Min JK</i><br /><b>Aims</b><br />The nuclear factor-κB (NF-κB) signalling pathway plays a critical role in the pathogenesis of multiple vascular diseases. However, in endothelial cells (ECs), the molecular mechanisms responsible for the negative regulation of the NF-κB pathway are poorly understood. In this study, we investigated a novel role for protein tyrosine phosphatase type IVA1 (PTP4A1) in NF-κB signalling in ECs.<br /><b>Methods and results</b><br />In human tissues, human umbilical artery ECs, and mouse models for loss of function and gain of function of PTP4A1, we conducted histological analysis, immunostaining, laser-captured microdissection assay, lentiviral infection, small interfering RNA transfection, quantitative real-time PCR and reverse transcription-PCR, as well as luciferase reporter gene and chromatin immunoprecipitation assays. Short hairpin RNA-mediated knockdown of PTP4A1 and overexpression of PTP4A1 in ECs indicated that PTP4A1 is critical for inhibiting the expression of cell adhesion molecules (CAMs). PTP4A1 increased the transcriptional activity of upstream stimulatory factor 1 (USF1) by dephosphorylating its S309 residue and subsequently inducing the transcription of tumour necrosis factor-alpha-induced protein 3 (TNFAIP3/A20) and the inhibition of NF-κB activity. Studies on Ptp4a1 knockout or transgenic mice demonstrated that PTP4A1 potently regulates the interleukin 1β-induced expression of CAMs in vivo. In addition, we verified that PTP4A1 deficiency in apolipoprotein E knockout mice exacerbated high-fat high-cholesterol diet-induced atherogenesis with upregulated expression of CAMs.<br /><b>Conclusion</b><br />Our data indicate that PTP4A1 is a novel negative regulator of vascular inflammation by inducing USF1/A20 axis-mediated NF-κB inactivation. Therefore, the expression and/or activation of PTP4A1 in ECs might be useful for the treatment of vascular inflammatory diseases.<br /><b>Translational perspective</b><br />The inhibitory effect of PTP4A1 in the dysfunction of vascular endothelial cells could apply to develop a drug for vascular inflammatory diseases including atherosclerosis. This study highlights an alternative as well as an effective therapeutic approach to increase A20 expression, which is an endogenous negative regulator of NF-κB signalling in vascular inflammatory disorders.<br /><br />© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.<br /><br /><small>Cardiovasc Res: 19 Dec 2022; epub ahead of print</small></div>

<div><h4>GLUT-1/PKM2 loop dysregulation in patients with non-ST-segment elevation myocardial infarction promotes metainflammation.</h4><i>Canonico F, Pedicino D, Severino A, Vinci R, ... Crea F, Liuzzo G</i><br /><b>Aim</b><br />The functional capacity of the immune cells is strongly dependent on their metabolic state and inflammatory responses are characterized by a greater use of glucose in immune cells. This study is aimed to establish the role of glucose metabolism and its players [glucose transporter-1 (GLUT-1) and pyruvate kinase isozyme M2 (PKM2)] in the dysregulation of adaptive immunity and inflammation observed in patients with non-ST-segment elevation myocardial infarction (NSTEMI).<br /><b>Methods and results</b><br />We enrolled 248 patients allocated to three groups: NSTEMI patients, chronic coronary syndromes (CCS) patients, healthy subjects (HS). NSTEMI patients showed higher expression of GLUT-1 and an enhanced glucose uptake in T cells as compared to CCS patients (p < 0.0001; p = 0.0101, respectively) and HS (p = 0.0071; p = 0.0122, respectively). PKM2 had a prevalent nuclear localization in T lymphocytes in NSTEMI (p = 0.0005 for nuclear versus cytoplasm localization), while in CCS and HS was equally distributed in both compartments. In addition, the nuclear fraction of PKM2 was significantly higher in NSTEMI compared to HS (p = 0.0023). In NSTEMI patients, treatment with Shikonin and Fasentin, which inhibits PKM2 enzyme activity and GLUT-1 mediated glucose internalization, respectively, led to a significant reduction in GLUT-1 expression along with the downregulation of pro-inflammatory cytokine expression.<br /><b>Conclusions</b><br />NSTEMI patients exhibit dysregulation of the GLUT-1/PKM2 metabolic loop characterized by nuclear translocation of PKM2, where it acts as a transcription regulator of pro-inflammatory genes. This detrimental loop might represent a new therapeutic target for personalized medicine.<br /><br />© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.<br /><br /><small>Cardiovasc Res: 13 Dec 2022; epub ahead of print</small></div>

<div><h4>Cardiac metabolism in HFpEF: from fuel to signalling.</h4><i>Capone F, Sotomayor-Flores C, Bode D, Wang R, ... Strocchi S, Schiattarella GG</i><br /><AbstractText>Heart failure (HF) is marked by distinctive changes in myocardial uptake and utilization of energy substrates. Among the different types of HF, HF with preserved ejection fraction (HFpEF) is a highly prevalent, complex, and heterogeneous condition for which metabolic derangements seem to dictate disease progression. Changes in intermediate metabolism in cardiometabolic HFpEF-among the most prevalent forms of HFpEF-have a large impact both on energy provision and on a number of signalling pathways in the heart. This dual, metabolic vs. signalling, role is played in particular by long-chain fatty acids (LCFAs) and short-chain carbon sources [namely, short-chain fatty acids (SCFAs) and ketone bodies (KBs)]. LCFAs are key fuels for the heart, but their excess can be harmful, as in the case of toxic accumulation of lipid by-products (i.e. lipotoxicity). SCFAs and KBs have been proposed as a potential major, alternative source of energy in HFpEF. At the same time, both LCFAs and short-chain carbon sources are substrate for protein post-translational modifications and other forms of direct and indirect signalling of pivotal importance in HFpEF pathogenesis. An in-depth molecular understanding of the biological functions of energy substrates and their signalling role will be instrumental in the development of novel therapeutic approaches to HFpEF. Here, we summarize the current evidence on changes in energy metabolism in HFpEF, discuss the signalling role of intermediate metabolites through, at least in part, their fate as substrates for post-translational modifications, and highlight clinical and translational challenges around metabolic therapy in HFpEF.</AbstractText><br /><br />© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.<br /><br /><small>Cardiovasc Res: 12 Dec 2022; epub ahead of print</small></div>

<div><h4>Interleukin-23 receptor expressing γδ T cells locally promote early atherosclerotic lesion formation and plaque necrosis in mice.</h4><i>Gil-Pulido J, Amézaga N, Jorgacevic I, Manthey HD, ... Cochain C, Zernecke A</i><br /><b>Aims</b><br />Atherosclerosis is a chronic inflammatory disease of the vessel wall controlled by local and systemic immune responses. The role of interleukin-23 receptor (IL-23R), expressed in adaptive immune cells (mainly T-helper 17 cells) and γδ T cells, in atherosclerosis is only incompletely understood. Here, we investigated the vascular cell types expressing IL-23R and addressed the function of IL-23R and γδ T cells in atherosclerosis.<br /><b>Methods and results</b><br />IL-23R+ cells were frequently found in the aortic root in contrast to the aorta in low-density lipoprotein receptor deficient IL-23R reporter mice (Ldlr-/-Il23rgfp/+), and mostly identified as γδ T cells that express IL-17 and GM-CSF. scRNA-seq confirmed γδ T cells as the main cell type expressing Il23r and Il17a in the aorta. Ldlr-/-Il23rgfp/gfp mice deficient in IL-23R showed a loss of IL-23R+ cells in the vasculature, and had reduced atherosclerotic lesion formation in the aortic root compared to Ldlr-/- controls after 6 weeks of high-fat diet feeding. In contrast, Ldlr-/-Tcrδ-/- mice lacking all γδ T cells displayed unaltered early atherosclerotic lesion formation compared to Ldlr-/- mice. In both HFD-fed Ldlr-/-Il23rgfp/gfp and Ldlr-/-Tcrδ-/- mice a reduction in the plaque necrotic core area was noted as well as an expansion of splenic regulatory T cells. In vitro, exposure of bone marrow-derived macrophages to both IL-17A and GM-CSF induced cell necrosis, and necroptotic RIP3K and MLKL expression, as well as inflammatory mediators.<br /><b>Conclusions</b><br />IL-23R+ γδ T cells are predominantly found in the aortic root rather than the aorta and promote early atherosclerotic lesion formation, plaque necrosis, and inflammation at this site. Targeting IL-23R may thus be explored as a therapeutic approach to mitigate atherosclerotic lesion development.<br /><br />Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.<br /><br /><small>Cardiovasc Res: 10 Dec 2022; 118:2932-2945</small></div>

<div><h4>Animal models and animal-free innovations for cardiovascular research: current status and routes to be explored. Consensus document of the ESC Working Group on Myocardial Function and the ESC Working Group on Cellular Biology of the Heart.</h4><i>van der Velden J, Asselbergs FW, Bakkers J, Batkai S, ... Zwaagman D, Thum T</i><br /><AbstractText>Cardiovascular diseases represent a major cause of morbidity and mortality, necessitating research to improve diagnostics, and to discover and test novel preventive and curative therapies, all of which warrant experimental models that recapitulate human disease. The translation of basic science results to clinical practice is a challenging task, in particular for complex conditions such as cardiovascular diseases, which often result from multiple risk factors and comorbidities. This difficulty might lead some individuals to question the value of animal research, citing the translational \'valley of death\', which largely reflects the fact that studies in rodents are difficult to translate to humans. This is also influenced by the fact that new, human-derived in vitro models can recapitulate aspects of disease processes. However, it would be a mistake to think that animal models do not represent a vital step in the translational pathway as they do provide important pathophysiological insights into disease mechanisms particularly on an organ and systemic level. While stem cell-derived human models have the potential to become key in testing toxicity and effectiveness of new drugs, we need to be realistic, and carefully validate all new human-like disease models. In this position paper, we highlight recent advances in trying to reduce the number of animals for cardiovascular research ranging from stem cell-derived models to in situ modelling of heart properties, bioinformatic models based on large datasets, and state-of-the-art animal models, which show clinically relevant characteristics observed in patients with a cardiovascular disease. We aim to provide a guide to help researchers in their experimental design to translate bench findings to clinical routine taking the replacement, reduction, and refinement (3R) as a guiding concept.</AbstractText><br /><br />Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2022. For permissions, please email: journals.permissions@oup.com.<br /><br /><small>Cardiovasc Res: 09 Dec 2022; 118:3016-3051</small></div>

<div><h4>Electrophysiological heterogeneity in large populations of rabbit ventricular cardiomyocytes.</h4><i>Lachaud Q, Aziz MHN, Burton FL, Macquaide N, ... Simitev RD, Smith GL</i><br /><b>Aims</b><br />Cardiac electrophysiological heterogeneity includes: (i) regional differences in action potential (AP) waveform, (ii) AP waveform differences in cells isolated from a single region, (iii) variability of the contribution of individual ion currents in cells with similar AP durations (APDs). The aim of this study is to assess intra-regional AP waveform differences, to quantify the contribution of specific ion channels to the APD via drug responses and to generate a population of mathematical models to investigate the mechanisms underlying heterogeneity in rabbit ventricular cells.<br /><b>Methods and results</b><br />APD in ∼50 isolated cells from subregions of the LV free wall of rabbit hearts were measured using a voltage-sensitive dye. When stimulated at 2 Hz, average APD90 value in cells from the basal epicardial region was 254 ± 25 ms (mean ± standard deviation) in 17 hearts with a mean interquartile range (IQR) of 53 ± 17 ms. Endo-epicardial and apical-basal APD90 differences accounted for ∼10% of the IQR value. Highly variable changes in APD occurred after IK(r) or ICa(L) block that included a sub-population of cells (HR) with an exaggerated (hyper) response to IK(r) inhibition. A set of 4471 AP models matching the experimental APD90 distribution was generated from a larger population of models created by random variation of the maximum conductances (Gmax) of 8 key ion channels/exchangers/pumps. This set reproduced the pattern of cell-specific responses to ICa(L) and IK(r) block, including the HR sub-population. The models exhibited a wide range of Gmax values with constrained relationships linking ICa(L) with IK(r), ICl, INCX, and INaK.<br /><b>Conclusion</b><br />Modelling the measured range of inter-cell APDs required a larger range of key Gmax values indicating that ventricular tissue has considerable inter-cell variation in channel/pump/exchanger activity. AP morphology is retained by relationships linking specific ionic conductances. These interrelationships are necessary for stable repolarization despite large inter-cell variation of individual conductances and this explains the variable sensitivity to ion channel block.<br /><br />© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Cardiovasc Res: 09 Dec 2022; 118:3112-3125</small></div>

<div><h4>The molecular makeup of peripheral and central baroreceptors: stretching a role for Transient Receptor Potential (TRP), Epithelial Sodium Channel (ENaC), Acid Sensing Ion Channel (ASIC), and Piezo channels.</h4><i>Yang H, Tenorio Lopes L, Barioni NO, Roeske J, ... Raj SR, Wilson RJA</i><br /><AbstractText>The autonomic nervous system maintains homeostasis of cardiovascular, respiratory, gastrointestinal, urinary, immune, and thermoregulatory function. Homeostasis involves a variety of feedback mechanisms involving peripheral afferents, many of which contain molecular receptors sensitive to mechanical deformation, termed mechanosensors. Here, we focus on the molecular identity of mechanosensors involved in the baroreflex control of the cardiovascular system. Located within the walls of the aortic arch and carotid sinuses, and/or astrocytes in the brain, these mechanosensors are essential for the rapid moment-to-moment feedback regulation of blood pressure (BP). Growing evidence suggests that these mechanosensors form a co-existing system of peripheral and central baroreflexes. Despite the importance of these molecules in cardiovascular disease and decades of research, their precise molecular identity remains elusive. The uncertainty surrounding the identity of these mechanosensors presents a major challenge in understanding basic baroreceptor function and has hindered the development of novel therapeutic targets for conditions with known arterial baroreflex impairments. Therefore, the purpose of this review is to (i) provide a brief overview of arterial and central baroreflex control of BP, (ii) review classes of ion channels currently proposed as the baroreflex mechanosensor, namely Transient Receptor Potential (TRP), Epithelial Sodium Channel (ENaC), Acid Sensing Ion Channel (ASIC), and Piezo, along with additional molecular candidates that serve mechanotransduction in other organ systems, and (iii) summarize the potential clinical implications of impaired baroreceptor function in the pathophysiology of cardiovascular disease.</AbstractText><br /><br />Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.<br /><br /><small>Cardiovasc Res: 09 Dec 2022; 118:3052-3070</small></div>

<div><h4>Loss of myeloid cell-specific SIRPα, but not CD47, attenuates inflammation and suppresses atherosclerosis.</h4><i>Singla B, Lin HP, Ahn W, Xu J, ... White J, Csányi G</i><br /><b>Aims</b><br />Inhibitors of the anti-phagocytic CD47-SIRPα immune checkpoint are currently in clinical development for a variety of haematological and solid tumours. Application of immune checkpoint inhibitors to the cardiovascular field is limited by the lack of preclinical studies using genetic models of CD47 and SIRPα inhibition. In this study, we comprehensively analysed the effects of global and cell-specific SIRPα and CD47 deletion on atherosclerosis development.<br /><b>Methods and results</b><br />Here, we show that both SIRPα and CD47 expression are increased in human atherosclerotic arteries and primarily co-localize to CD68+ areas in the plaque region. Hypercholesterolaemic mice homozygous for a Sirpa mutant lacking the signalling cytoplasmic region (Sirpamut/mut) and myeloid cell-specific Sirpa-knockout mice are protected from atherosclerosis. Further, global Cd47-/- mice are protected from atherosclerosis but myeloid cell-specific deletion of Cd47 increased atherosclerosis development. Using a combination of techniques, we show that loss of SIRPα signalling in macrophages stimulates efferocytosis, reduces cholesterol accumulation, promotes lipid efflux, and attenuates oxidized LDL-induced inflammation in vitro and induces M2 macrophage phenotype and inhibits necrotic core formation in the arterial wall in vivo. Conversely, loss of myeloid cell CD47 inhibited efferocytosis, impaired cholesterol efflux, augmented cellular inflammation, stimulated M1 polarization, and failed to decrease necrotic core area in atherosclerotic vessels. Finally, comprehensive blood cell analysis demonstrated lower haemoglobin and erythrocyte levels in Cd47-/- mice compared with wild-type and Sirpamut/mut mice.<br /><b>Conclusion</b><br />Taken together, these findings identify SIRPα as a potential target in atherosclerosis and suggest the importance of cell-specific CD47 inhibition as a future therapeutic strategy.<br /><br />Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.<br /><br /><small>Cardiovasc Res: 09 Dec 2022; 118:3097-3111</small></div>

<div><h4>Impacts of a high-fat diet on the metabolic profile and the phenotype of atrial myocardium in mice.</h4><i>Suffee N, Baptista E, Piquereau J, Ponnaiah M, ... Le Goff W, Hatem SN</i><br /><b>Aims</b><br />Obesity, diabetes, and metabolic syndromes are risk factors of atrial fibrillation (AF). We tested the hypothesis that metabolic disorders have a direct impact on the atria favouring the formation of the substrate of AF.<br /><b>Methods and results</b><br />Untargeted metabolomic and lipidomic analysis was used to investigate the consequences of a prolonged high-fat diet (HFD) on mouse atria. Atrial properties were characterized by measuring mitochondria respiration in saponin-permeabilized trabeculae, by recording action potential (AP) with glass microelectrodes in trabeculae and ionic currents in myocytes using the perforated configuration of patch clamp technique and by several immuno-histological and biochemical approaches. After 16 weeks of HFD, obesogenic mice showed a vulnerability to AF. The atrial myocardium acquired an adipogenic and inflammatory phenotypes. Metabolomic and lipidomic analysis revealed a profound transformation of atrial energy metabolism with a predominance of long-chain lipid accumulation and beta-oxidation activation in the obese mice. Mitochondria respiration showed an increased use of palmitoyl-CoA as energy substrate. APs were short duration and sensitive to the K-ATP-dependent channel inhibitor, whereas K-ATP current was enhanced in isolated atrial myocytes of obese mouse.<br /><b>Conclusion</b><br />HFD transforms energy metabolism, causes fat accumulation, and induces electrical remodelling of the atrial myocardium of mice that become vulnerable to AF.<br /><br />Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.<br /><br /><small>Cardiovasc Res: 09 Dec 2022; 118:3126-3139</small></div>

<div><h4>Contributions of obesity to kidney health and disease: insights from Mendelian randomization and the human kidney transcriptomics.</h4><i>Xu X, Eales JM, Jiang X, Sanderson E, ... Holmes MV, Tomaszewski M</i><br /><b>Aims</b><br />Obesity and kidney diseases are common complex disorders with an increasing clinical and economic impact on healthcare around the globe. Our objective was to examine if modifiable anthropometric obesity indices show putatively causal association with kidney health and disease and highlight biological mechanisms of potential relevance to the association between obesity and the kidney.<br /><b>Methods and results</b><br />We performed observational, one-sample, two-sample Mendelian randomization (MR) and multivariable MR studies in ∼300 000 participants of white-British ancestry from UK Biobank and participants of predominantly European ancestry from genome-wide association studies. The MR analyses revealed that increasing values of genetically predicted body mass index and waist circumference were causally associated with biochemical indices of renal function, kidney health index (a composite renal outcome derived from blood biochemistry, urine analysis, and International Classification of Disease-based kidney disease diagnoses), and both acute and chronic kidney diseases of different aetiologies including hypertensive renal disease and diabetic nephropathy. Approximately 13-16% and 21-26% of the potentially causal effect of obesity indices on kidney health were mediated by blood pressure and type 2 diabetes, respectively. A total of 61 pathways mapping primarily onto transcriptional/translational regulation, innate and adaptive immunity, and extracellular matrix and metabolism were associated with obesity measures in gene set enrichment analysis in up to 467 kidney transcriptomes.<br /><b>Conclusions</b><br />Our data show that a putatively causal association of obesity with renal health is largely independent of blood pressure and type 2 diabetes and uncover the signatures of obesity on the transcriptome of human kidney.<br /><br />© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Cardiovasc Res: 09 Dec 2022; 118:3151-3161</small></div>

<div><h4>Non-coding RNAs: key regulators of reprogramming, pluripotency, and cardiac cell specification with therapeutic perspective for heart regeneration.</h4><i>Hunkler HJ, Groß S, Thum T, Bär C</i><br /><AbstractText>Myocardial infarction causes a massive loss of cardiomyocytes (CMs), which can lead to heart failure accompanied by fibrosis, stiffening of the heart, and loss of function. Heart failure causes high mortality rates and is a huge socioeconomic burden, which, based on diets and lifestyle in the developed world, is expected to increase further in the next years. At present, the only curative treatment for heart failure is heart transplantation associated with a number of limitations such as donor organ availability and transplant rejection among others. Thus, the development of cellular reprogramming and defined differentiation protocols provide exciting new possibilities for cell therapy approaches and which opened up a new era in regenerative medicine. Consequently, tremendous research efforts were undertaken to gain a detailed molecular understanding of the reprogramming processes and the in vitro differentiation of pluripotent stem cells into functional CMs for transplantation into the patient\'s injured heart. In the last decade, non-coding RNAs, particularly microRNAs, long non-coding RNAs, and circular RNAs emerged as critical regulators of gene expression that were shown to fine-tune cellular processes both on the transcriptional and the post-transcriptional level. Unsurprisingly, also cellular reprogramming, pluripotency, and cardiac differentiation and maturation are regulated by non-coding RNAs. In here, we review the current knowledge on non-coding RNAs in these processes and highlight how their modulation may enhance the quality and quantity of stem cells and their derivatives for safe and efficient clinical application in patients with heart failure. In addition, we summarize the clinical cell therapy efforts undertaken thus far.</AbstractText><br /><br />© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Cardiovasc Res: 09 Dec 2022; 118:3071-3084</small></div>

<div><h4>Co-inhibition of immunoproteasome subunits LMP2 and LMP7 enables prevention of transplant arteriosclerosis.</h4><i>Li J, Hu S, Johnson HWB, Kirk CJ, ... Groettrup M, Basler M</i><br /><b>Aims</b><br />The loss of vascular wall cells in allotransplanted arteries is the initial event leading to transplant arteriosclerosis (TA) and ensuing loss of allograft function. Pharmacological agents able to prevent TA are currently lacking. We previously showed that selective inhibition of the immunoproteasome prevented the chronic rejection of renal allografts. However, the role and mechanisms of selective inhibition of a single immunoproteasome subunit suffices to prevent immune-mediated vascular allograft rejection and TA is not clear.<br /><b>Methods and results</b><br />The effect and potential mechanism of combined or individual inhibition of peptidolytically active immunoproteasome LMP7 (β5i) and LMP2 (β1i) subunits on immune rejection-mediated TA was investigated using the epoxyketone inhibitor ONX 0914, and the recently developed LMP7-selective inhibitor KZR-329 and LMP2-selective inhibitor KZR-504 in a rat aorta transplantation model. We find that co-inhibition of LMP7 and LMP2 in allogeneic recipients significantly suppressed T cell activation and function by expressing inhibitory surface markers and then activating inhibitory signals. Moreover, co-inhibition of LMP7 and LMP2 substantially reduced the number of IgG secreting cells and plasma cells and production of alloantibodies through activating the unfolded protein response and incapacitating the survival niche of plasma cells in the bone marrow. Consequentially, the accumulation of inflammatory cytokines, complement and antibodies is reduced and the apoptosis of vascular wall cells decreased in aortic allografts via LMP7 and LMP2 co-inhibition with ONX 0914 treatment or combined KZR-329 and KZR-504 treatment. However, neither individual inhibition of LMP7 by KZR-329 nor individual inhibition of LMP2 by KZR-504 showed suppression of immune rejection and TA.<br /><b>Conclusions</b><br />We define a critical role of LMP7 and LMP2 in TA and strongly propose co-inhibition of both immunoproteasome subunits as promising therapeutic approach to suppress TA and allograft rejection.<br /><b>Translational perspective</b><br />So far, effective pharmacological agents to treat transplant arteriosclerosis and ensuing chronic allograft rejection are lacking. Co-inhibition, but neither individual inhibition, of peptidolytically active immunoproteasome LMP7 and/nor LMP2 subunits using epoxyketone inhibitors significantly prevents transplant arteriosclerosis by suppressing T cell-mediated and humoral immune rejection. LMP7 and LMP2 are identified as targets for the prevention of chronic immune rejection after transplantation. Pharmaceuticals that co-inhibit immunoproteasome subunits are currently clinically tested as drugs against autoimmunity. These drugs hold great promise for suppressing transplant arteriosclerosis and allograft rejection, potentially improving prognosis of patients after solid organ transplantation.<br /><br />© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.<br /><br /><small>Cardiovasc Res: 04 Dec 2022; epub ahead of print</small></div>

<div><h4>CARDIAC XENOTRANSPLANTATION - FROM CONCEPT TO CLINIC.</h4><i>Reichart B, Cooper DKC, Längin M, Tönjes RR, Pierson RN, Wolf E</i><br /><AbstractText>For many patients with terminal/advanced cardiac failure, heart transplantation is the most effective, durable treatment option, and offers the best prospects for a high quality of life. The number of potentially life-saving donated human organs is far fewer than the population who could benefit from a new heart, resulting in increasing numbers of patients awaiting replacement of their failing heart, high waitlist mortality, and frequent reliance on interim mechanical support for many of those deemed among the best candidates but who are deteriorating as they wait. Currently, mechanical assist devices supporting left ventricular or biventricular heart function are the only alternative to heart transplant that is in clinical use. Unfortunately, the complication rate with mechanical assistance remains high despite advances in device design and patient selection and management, and the quality of life of the patients even with good outcomes is only moderately improved. Cardiac xenotransplantation from genetically multi-modified (GM) organ-source pigs is an emerging new option as demonstrated by consistent long-term success of heterotopic (non-life-supporting) abdominal and life-supporting orthotopic porcine heart transplantation in baboons, and by a recent \'compassionate use\' transplant of the heart from a GM pig with 10 modifications into a terminally ill patient who survived for two months. In this review, we discuss pig heart xenotransplantation as a concept, including pathobiological aspects related to immune rejection, coagulation dysregulation, and detrimental overgrowth of the heart, as well as GM strategies in pigs to prevent or minimize these problems. Relevant results of heterotopic and orthotopic heart transplantation experiments in the pig-to-baboon model, microbiological and virologic safety concepts, and efficacy requirements for initiating formal clinical trials are additional topics discussed. An adequate regulatory and ethical framework as well as stringent criteria for the selection of patients will be critical for the safe clinical development of cardiac xenotransplantation, which we expect will be clinically tested during the next few years.</AbstractText><br /><br />© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Cardiovasc Res: 03 Dec 2022; epub ahead of print</small></div>

<div><h4>The RAGE/DIAPH1 axis: mediator of obesity and proposed biomarker of human cardiometabolic disease.</h4><i>Arivazhagan L, Popp CJ, Ruiz HH, Wilson RA, ... Sevick MA, Schmidt AM</i><br /><AbstractText>Overweight and obesity are leading causes of cardiometabolic dysfunction. Despite extensive investigation, the mechanisms mediating the increase in these conditions are yet to be fully understood. Beyond endogenous formation of advanced glycation end products (AGEs) in overweight and obesity, exogenous sources of AGEs accrue through the heating, production and consumption of highly-processed foods. Evidence from cellular and mouse model systems indicates that the interaction of AGEs with their central cell surface receptor for AGE (RAGE) in adipocytes suppresses energy expenditure and that AGE/RAGE contributes to increased adipose inflammation and processes linked to insulin resistance. In human subjects, the circulating soluble forms of RAGE, which are mutable, may serve as biomarkers of obesity and weight loss. Antagonists of RAGE signaling, through blockade of the interaction of the RAGE cytoplasmic domain with the formin, Diaphanous-1 (DIAPH1), target aberrant RAGE activities in metabolic tissues. This review focuses on the potential roles for AGEs and other RAGE ligands and RAGE/DIAPH1 in the pathogenesis of overweight and obesity and their metabolic consequences.</AbstractText><br /><br />© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.<br /><br /><small>Cardiovasc Res: 30 Nov 2022; epub ahead of print</small></div>

<div><h4>New therapies for obesity.</h4><i>Papamargaritis D, le Roux CW, Holst JJ, Davies MJ</i><br /><AbstractText>Obesity is a chronic disease associated with serious complications and increased mortality. Weight loss through lifestyle changes results in modest weight loss long-term possibly due to compensatory biological adaptations (increased appetite and reduced energy expenditure) promoting weight gain. Bariatric surgery was until recently the only intervention that consistently resulted in ≥ 15% weight loss and maintenance. Our better understanding of the endocrine regulation of appetite has led to the development of new medications over the last decade for treatment of obesity with main target the reduction of appetite. The efficacy of semaglutide 2.4 mg/week - the latest glucagon like peptide-1 (GLP-1) receptor analogue - on weight loss for people with obesity suggests that we are entering a new era in obesity pharmacotherapy where ≥15% weight loss is feasible. Moreover, the weight loss achieved with the dual agonist tirzepatide (GLP-1/glucose-dependent insulinotropic polypeptide) for people with type 2 diabetes and most recently also obesity, indicate that combining the GLP-1 with other gut hormones may lead to additional weight loss compared to GLP-1 receptor analogues alone and in the future, multi-agonist molecules may offer the potential to bridge further the efficacy gap between bariatric surgery and the currently available pharmacotherapies. This article provides a review of the currently available interventions for weight loss and weight maintenance with a focus on pharmacological therapies for obesity approved over the last decade, as well as the emerging development of new obesity pharmacotherapies.</AbstractText><br /><br />© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Cardiovasc Res: 30 Nov 2022; epub ahead of print</small></div>

<div><h4>Phenomapping in heart failure with preserved ejection fraction - insights, limitations, and future directions.</h4><i>Peters AE, Tromp J, Shah SJ, Lam CSP, ... Kitzman DW, Mentz RJ</i><br /><AbstractText>Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous entity with complex pathophysiology and manifestations. Phenomapping is the process of applying statistical learning techniques to patient data to identify distinct subgroups based on patterns in the data. Phenomapping has emerged as a technique with potential to improve the understanding of different HFpEF phenotypes. Phenomapping efforts have been increasing in HFpEF over the past several years using a variety of data sources, clinical variables, and statistical techniques. This review summarises methodologies and key takeaways from these studies, including consistent discriminating factors and conserved HFpEF phenotypes. We argue that phenomapping results to date have had limited implications for clinical care and clinical trials, given that the phenotypes, as currently described, are not reliably identified in each study population and may have significant overlap. We review the inherent limitations of aggregating and utilising phenomapping results. Lastly, we discuss potential future directions, including using phenomapping to optimise the likelihood of clinical trial success or to drive discovery in mechanisms of the disease process of HFpEF.</AbstractText><br /><br />© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.<br /><br /><small>Cardiovasc Res: 30 Nov 2022; epub ahead of print</small></div>

<div><h4>E-cigarette exposure augments murine abdominal aortic aneurysm development: role of Chil1.</h4><i>Mulorz J, Spin JM, Mulorz P, Wagenhäuser M, ... Maegdefessel L, Tsao PS</i><br /><b>Aims</b><br />Abdominal aortic aneurysm (AAA) is a common cardiovascular disease with a strong correlation to smoking, although underlying mechanisms have been minimally explored. Electronic cigarettes (e-cigs) have gained recent broad popularity and can deliver nicotine at comparable levels to tobacco cigarettes, but effects on AAA development are unknown.<br /><b>Methods and results</b><br />We evaluated the impact of daily e-cig vaping with nicotine on AAA using two complementary murine models and found that exposure enhanced aneurysm development in both models and genders. E-cigs induced changes in key mediators of AAA development including cytokine chitinase-3-like protein 1 (CHI3L1/Chil1) and its targeting microRNA-24 (miR-24). We show that nicotine triggers inflammatory signaling and reactive oxygen species while modulating miR-24 and CHI3L1/Chil1 in vitro, and that Chil1 is crucial to e-cig-augmented aneurysm formation using a knockout model.<br /><b>Conclusions</b><br />In conclusion our work shows increased aneurysm formation along with augmented vascular inflammation in response to e-cig exposure with nicotine. Further we identify Chil1 as a key mediator in this context. Our data raise concerns regarding the potentially harmful long-term effects of e-cig nicotine vaping.<br /><b>Translational perspective</b><br />Smoking is one of the most hazardous modifiable risk factors, with clear links to abdominal aortic aneurysm. E-cig vaping has displayed explosive growth in popularity. Intended for smoking cessation, it has been taken up by millions with no such clinical need, delivering nicotine addiction to new generations. The presumption that vaping is safer than tobacco overlooks the potential cardiovascular risks of nicotine. This study shows for the first time that inhaled e-cig nicotine vapor augments experimental AAA and aortic inflammation, suggests a mechanistic role for the cytokine Chil1/CHI3L1 and its regulator microRNA-24, and raises red flags regarding longitudinal e-cig safety.<br /><br />Published by Oxford University Press on behalf of the European Society of Cardiology 2022.<br /><br /><small>Cardiovasc Res: 22 Nov 2022; epub ahead of print</small></div>

<div><h4>Disrupting circadian control of peripheral myogenic reactivity mitigates cardiac injury following myocardial infarction.</h4><i>Kroetsch JT, Lidington D, Alibhai FJ, Reitz CJ, ... Martino TA, Bolz SS</i><br /><b>Aims</b><br />Circadian rhythms orchestrate important functions in the cardiovascular system: the contribution of microvascular rhythms to cardiovascular disease progression/severity is unknown. This study hypothesized that (i) myogenic reactivity in skeletal muscle resistance arteries is rhythmic and (ii) that disrupting this rhythmicity would alter cardiac injury post-myocardial infarction (MI).<br /><b>Methods and results</b><br />Cremaster skeletal muscle resistance arteries were isolated and assessed using standard pressure myography. Circadian rhythmicity was globally disrupted with the ClockΔ19/Δ19 mutation or discretely through smooth muscle cell-specific Bmal1 deletion (Sm-Bmal1 KO). Cardiac structure and function were determined by echocardiographic, hemodynamic and histological assessments. Myogenic reactivity in cremaster muscle resistance arteries is rhythmic. This rhythm is putatively mediated by the circadian modulation of a mechanosensitive signalosome incorporating tumor necrosis factor and casein kinase 1. Following left anterior descending coronary artery ligation, myogenic responsiveness is locked at the circadian maximum, although circadian molecular clock gene expression cycles normally. Disrupting the molecular clock abolishes myogenic rhythmicity: myogenic tone is suspended at the circadian minimum and no longer augmented by MI. The reduced myogenic tone in ClockΔ19/Δ19 mice and Sm-Bmal1 KO mice associates with reduced total peripheral resistance (TPR), improved cardiac function and reduced infarct expansion post-MI.<br /><b>Conclusions</b><br />Augmented microvascular constriction aggravates cardiac injury post-MI. Following MI, skeletal muscle resistance artery myogenic reactivity increases specifically within the rest phase, when TPR would normally decline. Disrupting the circadian clock interrupts the MI-induced augmentation in myogenic reactivity: therapeutics targeting the molecular clock, therefore, may be useful for improving MI outcomes.<br /><b>Translational perspective</b><br />A portion of peripheral vascular tone and hence, total peripheral resistance, is under circadian control. Myocardial infarction preferentially augments vascular tone in the active phase, when the heart works hardest to provide adequate tissue perfusion. Disrupting the circadian clock reduces peripheral resistance and is associated with improved cardiac function and reduced infarct expansion post-myocardial infarction. The intersection between the circadian clock and myogenic signaling could be a potential therapeutic target to manage peripheral resistance and improve cardiac outcome following an infarction. This mechanism may be safer than current vasodilators, since the therapeutic maximum does not threaten essential hemodynamic control.<br /><br />© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Cardiovasc Res: 22 Nov 2022; epub ahead of print</small></div>

<div><h4>Pathophysiology and pharmacology of G protein-coupled receptors in the heart.</h4><i>Grogan A, Lucero EY, Jiang H, Rockman HA</i><br /><AbstractText>G protein-coupled receptors (GPCRs), comprising the largest superfamily of cell surface receptors, serve as fundamental modulators of cardiac health and disease owing to their key roles in the regulation of heart rate, contractile dynamics, and cardiac function. Accordingly, GPCRs are heavily pursued as drug targets for a wide variety of cardiovascular diseases ranging from heart failure, cardiomyopathy, and arrhythmia to hypertension and coronary artery disease. Recent advancements in understanding the signalling mechanisms, regulation, and pharmacological properties of GPCRs have provided valuable insights that will guide the development of novel therapeutics. Herein, we review the cellular signalling mechanisms, pathophysiological roles, and pharmacological developments of the major GPCRs in the heart, highlighting the β-adrenergic, muscarinic, and angiotensin receptors as exemplar subfamilies.</AbstractText><br /><br />© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.<br /><br /><small>Cardiovasc Res: 22 Nov 2022; epub ahead of print</small></div>

<div><h4>Marine omega-3 fatty acid supplementation and prevention of cardiovascular disease: update on the randomized trial evidence.</h4><i>Bassuk SS, Manson JE, VITAL Research Group</i><br /><AbstractText>To date, the VITamin D and OmegA-3 TriaL (VITAL) is the only large-scale randomized trial of marine omega-3 fatty acid (n-3 FA) supplementation for cardiovascular disease (CVD) prevention in a general population unselected for elevated cardiovascular risk. We review the findings of VITAL, as well as results from recent secondary prevention trials and updated meta-analyses of n-3 FA trials in the primary and secondary prevention of CVD. In VITAL, a nationwide sample of 25,871 U.S. adults aged 50 and older, including 5,106 African Americans, were randomized in a 2 × 2 factorial design to n-3 FAs (1 g/day; 1.2:1 ratio of eicosapentaenoic to docosahexaenoic acid) and vitamin D3 (2000IU/day) for a median of 5.3 years. Compared with an olive-oil placebo, the n-3 FA intervention did not significantly reduce the primary endpoint of major CVD events (composite of myocardial infarction [MI], stroke, and CVD mortality; hazard ratio [HR] = 0.92 [95% confidence interval 0.80-1.06]) but did significantly reduce total MI (HR = 0.72 [0.59-0.90]), percutaneous coronary intervention (HR = 0.78 [0.63-0.95]), fatal MI (HR = 0.50 [0.26-0.97]), and recurrent (but not first) hospitalization for heart failure (HR = 0.86 [0.74-0.998]). The intervention neither decreased nor increased risk of atrial fibrillation. African Americans derived the greatest treatment benefit for MI and for recurrent hospitalization for heart failure (p, interaction < 0.05 for both outcomes). Meta-analyses that include VITAL and high-risk or secondary prevention n-3 FA trials show coronary, but generally not stroke, risk reduction. More research is needed to determine which individuals may be most likely to derive net benefit. (VITAL clinicaltrials.gov identifier: NCT01169259).</AbstractText><br /><br />© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.<br /><br /><small>Cardiovasc Res: 15 Nov 2022; epub ahead of print</small></div>

<div><h4>High salt intake activates the hypothalamic-pituitary-adrenal axis, amplifies the stress response, and alters tissue glucocorticoid exposure in mice.</h4><i>Costello HM, Krilis G, Grenier C, Severs D, ... Dhaun N, Bailey MA</i><br /><b>Aims</b><br />High salt intake is common and contributes to poor cardiovascular health. Urinary sodium excretion correlates directly with glucocorticoid excretion in humans and experimental animals. We hypothesized that high salt intake activates the hypothalamic-pituitary-adrenal axis activation and leads to sustained glucocorticoid excess.<br /><b>Methods and results</b><br />In male C57BL/6 mice, high salt intake for 2-8 weeks caused an increase in diurnal peak levels of plasma corticosterone. After 2 weeks, high salt increased Crh and Pomc mRNA abundance in the hypothalamus and anterior pituitary, consistent with basal hypothalamic-pituitary-adrenal axis activation. Additionally, high salt intake amplified glucocorticoid response to restraint stress, indicative of enhanced axis sensitivity. The binding capacity of Corticosteroid-Binding Globulin was reduced and its encoding mRNA downregulated in the liver. In the hippocampus and anterior pituitary, Fkbp5 mRNA levels were increased, indicating increased glucocorticoid exposure. The mRNA expression of the glucocorticoid-regenerating enzyme, 11β-hydroxysteroid dehydrogenase Type 1, was increased in these brain areas and in the liver. Sustained high salt intake activated a water conservation response by the kidney, increasing plasma levels of the vasopressin surrogate, copeptin. Increased mRNA abundance of Tonebp and Avpr1b in the anterior pituitary suggested that vasopressin signalling contributes to hypothalamic-pituitary-adrenal axis activation by high salt diet.<br /><b>Conclusion</b><br />Chronic high salt intake amplifies basal and stress-induced glucocorticoid levels and resets glucocorticoid biology centrally, peripherally and within cells.<br /><br />© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Cardiovasc Res: 11 Nov 2022; epub ahead of print</small></div>

<div><h4>The role of immunoglobulin E and mast cells in hypertension.</h4><i>Ge W, Guo X, Song X, Pang J, ... Gao R, Wang J</i><br /><b>Aims</b><br />Hypertension is the major cause of cardiovascular diseases and global mortality. Immunoglobulin E (IgE), which plays crucial roles in allergic diseases, has been implicated in the pathogenesis of vascular and cardiac remodelling via its receptor (FcεR1). In this study, we aimed to reveal the role of IgE and FcεR1 in hypertension.<br /><b>Methods and results</b><br />Herein, we reported that IgE levels were significantly increased in hypertensive patients as well as in hypertensive mice induced by angiotensin II (Ang II). Ang II-induced vascular remodelling and hypertension were significantly alleviated in FcεR1 genetic knockout mice or in mice treated with anti-IgE monoclonal antibody. Similarly, treatment with omalizumab (a clinical IgE antagonist) also markedly inhibited Ang II-induced hypertension. Furthermore, the cellular contribution of IgE-FcεR1 in hypertension was evaluated in mice with FcεR1 conditional knockout in mast cell (MC), smooth muscle cell (SMC), or endothelial cell (EC). Our data revealed that IgE-mediated hypertension is largely dependent on FcεR1 in MCs but not SMCs and ECs. Finally, RNA-seq and signalling pathway analyses of mouse bone marrow-derived MCs suggested that interleukin 6 (IL-6) is one of critical mediators in IgE-mediated hypertension. IL-6 derived from IgE-stimulated MCs promoted reactive oxygen species production and decreased the levels of phosphorylated endothelial nitric oxide synthase in ECs, leading to endothelial dysfunction.<br /><b>Conclusion</b><br />Our findings reveal that IgE contributes to the pathogenesis of hypertension, at least partially through activating the IgE-FcεR1 signalling in MCs. Thus, IgE may represent a new therapeutic target for IgE-mediated hypertension.<br /><br />Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2022. For permissions, please email: journals.permissions@oup.com.<br /><br /><small>Cardiovasc Res: 10 Nov 2022; 118:2985-2999</small></div>

<div><h4>Statins for primary prevention among elderly men and women.</h4><i>Bergami M, Cenko E, Yoon J, Mendieta G, ... Badimon L, Bugiardini R</i><br /><b>Aims</b><br />We undertook a propensity match-weighted cohort study to investigate whether statin treatment recommendations for statins translate into improved cardiovascular (CV) outcomes in the current routine clinical care of the elderly.<br /><b>Methods and results</b><br />We included in our analysis (ISACS Archives -NCT04008173) a total of 5619 Caucasian patients with no known prior history of CV disease who presented to hospital with a first manifestation of CV disease with age of 65 years or older. The risk of ST-segment elevation myocardial infarction (STEMI) was much lower in statin users than in non-users in both patients aged 65-75 years [14.7% absolute risk reduction; relative risk (RR): 0.55, 95% CI 0.45-0.66] and those aged 76 years and older (13.3% absolute risk reduction; RR: 0.58, 95% CI 0.46-0.72). Estimates were similar in patients with and without history of hypercholesterolaemia (interaction test; P-values = 0.24 and 0.35). Proportional reductions in STEMI diminished with female sex in the old (P for interaction = 0.002), but not in the very old age (P for interaction = 0.26). We also observed a remarkable reduction in the risk of 30 day mortality from STEMI with statin therapy in both age groups (10.2% absolute risk reduction; RR: 0.39; 95% CI 0.23-0.68 for patients aged 76 or over and 3.8% absolute risk reduction; RR 0.37; 95% CI 0.17-0.82 for patients aged 65-75 years old; interaction test, P-value = 0.46).<br /><b>Conclusions</b><br />Preventive statin therapy in the elderly reduces the risk of STEMI with benefits in mortality from STEMI, irrespective of the presence of a history of hypercholesterolaemia. This effect persists after the age of 76 years. Benefits are less pronounced in women. Randomized clinical trials may contribute to more definitively determine the role of statin therapy in the elderly.<br /><br />Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.<br /><br /><small>Cardiovasc Res: 10 Nov 2022; 118:3000-3009</small></div>

<div><h4>Cholesteryl ester transfer protein inhibitors: from high-density lipoprotein cholesterol to low-density lipoprotein cholesterol lowering agents?</h4><i>Nurmohamed NS, Ditmarsch M, Kastelein JJP</i><br /><AbstractText>Cholesteryl ester transfer protein (CETP) is a liver-synthesized glycoprotein whose main functions are facilitating transfer of both cholesteryl esters from high-density lipoprotein (HDL) particles to apolipoprotein B (apoB)-containing particles as well as transfer of triglycerides from apoB-containing particles to HDL particles. Novel crystallographic data have shown that CETP exchanges lipids in the circulation by a dual molecular mechanism. Recently, it has been suggested that the atherosclerotic cardiovascular disease (ASCVD) benefit from CETP inhibition is the consequence of the achieved low-density lipoprotein cholesterol (LDL-C) and apoB reduction, rather than through the HDL cholesterol (HDL-C) increase. The use of CETP inhibitors is supported by genetic evidence from Mendelian randomization studies, showing that LDL-C lowering by CETP gene variants achieves equal ASCVD risk reduction as LDL-C lowering through gene proxies for statins, ezetimibe, and proprotein convertase subtilisin-kexin Type 9 inhibitors. Although first-generation CETP inhibitors (torcetrapib, dalcetrapib) were mainly raising HDL-C or had off-target effects, next generation CETP inhibitors (anacetrapib, evacetrapib) were also effective in reducing LDL-C and apoB and have been proven safe. Anacetrapib was the first CETP inhibitor to be proven effective in reducing ASCVD risk. In addition, CETP inhibitors have been shown to lower the risk of new-onset diabetes, improve glucose tolerance, and insulin sensitivity. The newest-generation CETP inhibitor obicetrapib, specifically designed to lower LDL-C and apoB, has achieved significant reductions of LDL-C up to 45%. Obicetrapib, about to enter phase III development, could become the first CETP inhibitor as add-on therapy for patients not reaching their guideline LDL-C targets.</AbstractText><br /><br />© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Cardiovasc Res: 10 Nov 2022; 118:2919-2931</small></div>

<div><h4>NOX1 mediates metabolic heart disease in mice and is upregulated in monocytes of humans with diastolic dysfunction.</h4><i>Xu L, Balzarolo M, Robinson EL, Lorenz V, ... Pfister O, Kuster GM</i><br /><b>Aims</b><br />Microvascular inflammation plays an important role in the pathogenesis of diastolic dysfunction (DD) and metabolic heart disease. NOX1 is expressed in vascular and immune cells and has been implicated in the vascular pathology of metabolic disease. However, its contribution to metabolic heart disease is less understood.<br /><b>Methods and results</b><br />NOX1-deficient mice (KO) and male wild-type (WT) littermates were fed a high-fat high-sucrose diet (HFHS) and injected streptozotocin (75 mg/kg i.p.) or control diet (CTD) and sodium citrate. Despite similar weight gain and increase in fasting blood glucose and insulin, only WT-HFHS but not KO-HFHS mice developed concentric cardiac hypertrophy and elevated left ventricular filling pressure. This was associated with increased endothelial adhesion molecule expression, accumulation of Mac-2-, IL-1β-, and NLRP3-positive cells and nitrosative stress in WT-HFHS but not KO-HFHS hearts. Nox1 mRNA was solidly expressed in CD45+ immune cells isolated from healthy mouse hearts but was negligible in cardiac CD31+ endothelial cells. However, in vitro, Nox1 expression increased in response to lipopolysaccharide (LPS) in endothelial cells and contributed to LPS-induced upregulation of Icam-1. Nox1 was also upregulated in mouse bone marrow-derived macrophages in response to LPS. In peripheral monocytes from age- and sex-matched symptomatic patients with and without DD, NOX1 was significantly higher in patients with DD compared to those without DD.<br /><b>Conclusions</b><br />NOX1 mediates endothelial activation and contributes to myocardial inflammation and remodelling in metabolic disease in mice. Given its high expression in monocytes of humans with DD, NOX1 may represent a potential target to mitigate heart disease associated with DD.<br /><br />© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Cardiovasc Res: 10 Nov 2022; 118:2973-2984</small></div>

<div><h4>Environmental risk factors and cardiovascular diseases: a comprehensive expert review.</h4><i>Münzel T, Hahad O, Sørensen M, Lelieveld J, ... Nieuwenhuijsen M, Daiber A</i><br /><AbstractText>Non-communicable diseases (NCDs) are fatal for more than 38 million people each year and are thus the main contributors to the global burden of disease accounting for 70% of mortality. The majority of these deaths are caused by cardiovascular disease (CVD). The risk of NCDs is strongly associated with exposure to environmental stressors such as pollutants in the air, noise exposure, artificial light at night, and climate change, including heat extremes, desert storms, and wildfires. In addition to the traditional risk factors for CVD such as diabetes, arterial hypertension, smoking, hypercholesterolaemia, and genetic predisposition, there is a growing body of evidence showing that physicochemical factors in the environment contribute significantly to the high NCD numbers. Furthermore, urbanization is associated with accumulation and intensification of these stressors. This comprehensive expert review will summarize the epidemiology and pathophysiology of environmental stressors with a focus on cardiovascular NCDs. We will also discuss solutions and mitigation measures to lower the impact of environmental risk factors with focus on CVD.</AbstractText><br /><br />© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Cardiovasc Res: 10 Nov 2022; 118:2880-2902</small></div>

<div><h4>Titin (TTN): from molecule to modifications, mechanics, and medical significance.</h4><i>Loescher CM, Hobbach AJ, Linke WA</i><br /><AbstractText>The giant sarcomere protein titin is a major determinant of cardiomyocyte stiffness and contributor to cardiac strain sensing. Titin-based forces are highly regulated in health and disease, which aids in the regulation of myocardial function, including cardiac filling and output. Due to the enormous size, complexity, and malleability of the titin molecule, titin properties are also vulnerable to dysregulation, as observed in various cardiac disorders. This review provides an overview of how cardiac titin properties can be changed at a molecular level, including the role isoform diversity and post-translational modifications (acetylation, oxidation, and phosphorylation) play in regulating myocardial stiffness and contractility. We then consider how this regulation becomes unbalanced in heart disease, with an emphasis on changes in titin stiffness and protein quality control. In this context, new insights into the key pathomechanisms of human cardiomyopathy due to a truncation in the titin gene (TTN) are discussed. Along the way, we touch on the potential for titin to be therapeutically targeted to treat acquired or inherited cardiac conditions, such as HFpEF or TTN-truncation cardiomyopathy.</AbstractText><br /><br />© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Cardiovasc Res: 10 Nov 2022; 118:2903-2918</small></div>