BMPR1A Promotes ID2-ZEB1 Interaction to Suppress Excessive Endothelial to Mesenchymal Transition.

Lee HW, Adachi T, Pak B, Park S, ... Jin SW, Chun HJ
Aims
Components of BMP signaling have been implicated in both pathogenesis of pulmonary arterial hypertension (PAH) and endothelial-mesenchymal transition (EndoMT). In particular, the importance of BMP Type 2 Receptor (BMPR2) in these processes have been extensively analyzed. However, the contribution of BMP Type1 Receptors (BMPR1s) to the onset of PAH and EndoMT remains poorly understood. BMPR1A, one of BMPR1s, was recently implicated in the pathogenesis of PAH, and was found to be downregulated in the lungs of PAH patients, neither the downstream mechanism nor its contribution to EndoMT has been described. Therefore, we aim to delineate the role of endothelial BMPR1A in modulating EndoMT and pathogenesis of PAH.
Methods and results
We find that BMPR1A knockdown in endothelial cells (ECs) induces hallmarks of EndoMT, and deletion of endothelial Bmpr1a in adult mice (Bmpr1aiECKO) leads to development of PAH-like symptoms due to excessive EndoMT. By lineage tracing, we show that endothelial-derived smooth muscle cells are increased in endothelial Bmpr1a deleted mice. Mechanistically, we identify ZEB1 as a primary target for BMPR1A in this setting; Upon BMPR1A activation, ID2 physically interacts and sequesters ZEB1 to attenuate transcription of Tgfbr2, which in turn lowers the responses of ECs toward TGF-β stimulation and prevents excessive EndoMT. In Bmpr1aiECKO mice, administering endothelial targeting lipid nanoparticles containing siRNA against Tgfbr2 effectively ameliorate PAH, reiterating the importance of BMPR1A-ID2/ZEB1-TGFBR2 axis in modulating progression of EndoMT and pathogenesis of PAH.
Conclusions
We demonstrate that BMPR1A is key to maintain endothelial identity and to prevent excessive EndoMT. We identify BMPR1A-induced interaction between ID2 and ZEB1 is the key regulatory step for onset of EndoMT and pathogenesis of PAH. Our findings indicate that BMPR1A-ID2/ZEB1-TGFBR2 signaling axis could serve as a potential novel therapeutic target for PAH and other EndoMT-related vascular disorders.

© 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.

Cardiovasc Res: 27 Sep 2022; epub ahead of print

Role of PDE10A in vascular smooth muscle cell hyperplasia and pathological vascular remodelling.

Luo L, Cai Y, Zhang Y, Hsu CG, ... Berk BC, Yan C
Aims
Intimal hyperplasia is a common feature of vascular remodelling disorders. Accumulation of synthetic smooth muscle cell (SMC)-like cells is the main underlying cause. Current therapeutic approaches including drug-eluting stents are not perfect due to the toxicity on endothelial cells and novel therapeutic strategies are needed. Our preliminary screening for dysregulated cyclic nucleotide phosphodiesterases (PDEs) in growing SMCs revealed the alteration of PDE10A expression. Herein, we investigated the function of PDE10A in SMC proliferation and intimal hyperplasia both in vitro and in vivo.
Methods and results
RT-qPCR, immunoblot, and in situ proximity ligation assay were performed to determine PDE10A expression in synthetic SMCs and injured vessels. We found that PDE10A mRNA and/or protein levels are up-regulated in cultured SMCs upon growth stimulation, as well as in intimal cells in injured mouse femoral arteries. To determine the cellular functions of PDE10A, we focused on its role in SMC proliferation. The anti-mitogenic effects of PDE10A on SMCs were evaluated via cell counting, BrdU incorporation, and flow cytometry. We found that PDE10A deficiency or inhibition arrested the SMC cell cycle at G1-phase with a reduction of cyclin D1. The anti-mitotic effect of PDE10A inhibition was dependent on cGMP-dependent protein kinase Iα (PKGIα), involving C-natriuretic peptide (CNP) and particulate guanylate cyclase natriuretic peptide receptor 2 (NPR2). In addition, the effects of genetic depletion and pharmacological inhibition of PDE10A on neointimal formation were examined in a mouse model of femoral artery wire injury. Both PDE10A knockout and inhibition decreased injury-induced intimal thickening in femoral arteries by at least 50%. Moreover, PDE10A inhibition decreased ex vivo remodelling of cultured human saphenous vein segments.
Conclusions
Our findings indicate that PDE10A contributes to SMC proliferation and intimal hyperplasia at least partially via antagonizing CNP/NPR2/cGMP/PKG1α signalling and suggest that PDE10A may be a novel drug target for treating vascular occlusive disease.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.

Cardiovasc Res: 20 Sep 2022; 118:2703-2717

Diseases of the Aorta and Kidney Disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference.

Sarafidis P, Martens S, Saratzis A, Kadian-Dodov D, ... Johansen K, for Conference Participants
Chronic kidney disease (CKD) is an independent risk factor for the development of abdominal aortic aneurysm (AAA), as well as for cardiovascular and renal events and all-cause mortality following surgery for AAA or thoracic aortic dissection. In addition, the incidence of acute kidney injury (AKI) after any aortic surgery is particularly high, and this AKI per se is independently associated with future cardiovascular events and mortality. On the other hand, both development of AKI after surgery and the long-term evolution of kidney function differ significantly depending on the type of AAA intervention (open surgery vs. the various subtypes of endovascular repair). Current knowledge regarding AAA in the general population may not be always applicable to CKD patients, as they have a high prevalence of co-morbid conditions and an elevated risk for periprocedural complications. This summary of a Kidney Disease: Improving Global Outcomes Controversies Conference group discussion reviews the epidemiology, pathophysiology, diagnosis, and treatment of Diseases of the Aorta in CKD and identifies knowledge gaps, areas of controversy, and priorities for future research.

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Cardiovasc Res: 20 Sep 2022; 118:2582-2595

Thymosin β4 and prothymosin α promote cardiac regeneration post-ischemic injury in mice.

Gladka MM, Johansen AKZ, van Kampen SJ, Peters MMC, ... Giacca M, van Rooij E
The adult mammalian heart is a post-mitotic organ. Even in response to necrotic injuries, where regeneration would be essential to reinstate cardiac structure and function, only a minor percentage of cardiomyocytes undergo cytokinesis. The gene program that promotes cell division within this population is not fully understood. Here, we demonstrate increased EdU incorporation in cardiomyocytes at 3 days post-myocardial infarction (MI) in mice. By applying multi-color lineage tracing, we show that this is paralleled by clonal expansion of cardiomyocytes in the borderzone of the infarcted tissue. Bioinformatic analysis of single-cell RNA sequencing (scRNA-seq) data from cardiomyocytes at 3 days post ischemic injury revealed a distinct transcriptional profile in cardiomyocytes expressing cell cycle markers. Combinatorial overexpression of the enriched genes within this population in neonatal rat cardiomyocytes (NRCM) and mice at postnatal day 12 (P12) unveiled key genes that promoted increased cardiomyocyte proliferation. Therapeutic delivery of these gene cocktails into the myocardial wall after ischemic injury demonstrated that a combination of thymosin beta 4 (TMSB4) and prothymosin alpha (PTMA) provide a permissive environment for cardiomyocyte proliferation and thereby attenuated cardiac dysfunction. This work indicates that in addition to activating cardiomyocyte proliferation, a supportive environment is key for regeneration to occur.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.

Cardiovasc Res: 20 Sep 2022; epub ahead of print

Circadian rhythms in ischaemic heart disease: key aspects for preclinical and translational research: position paper of the ESC working group on cellular biology of the heart.

Lecour S, Du Pré BC, Bøtker HE, Brundel BJJM, ... Young ME, Van Laake LW
Circadian rhythms are internal regulatory processes controlled by molecular clocks present in essentially every mammalian organ that temporally regulate major physiological functions. In the cardiovascular system, the circadian clock governs heart rate, blood pressure, cardiac metabolism, contractility, and coagulation. Recent experimental and clinical studies highlight the possible importance of circadian rhythms in the pathophysiology, outcome, or treatment success of cardiovascular disease, including ischaemic heart disease. Disturbances in circadian rhythms are associated with increased cardiovascular risk and worsen outcome. Therefore, it is important to consider circadian rhythms as a key research parameter to better understand cardiac physiology/pathology, and to improve the chances of translation and efficacy of cardiac therapies, including those for ischaemic heart disease. The aim of this Position Paper by the European Society of Cardiology Working Group Cellular Biology of the Heart is to highlight key aspects of circadian rhythms to consider for improvement of preclinical and translational studies related to ischaemic heart disease and cardioprotection. Applying these considerations to future studies may increase the potential for better translation of new treatments into successful clinical outcomes.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.

Cardiovasc Res: 20 Sep 2022; 118:2566-2581

PLX3397, a CSF1 receptor inhibitor, limits allotransplantation-induced vascular remodelling.

Almonte VM, Uriyanghai U, Egaña-Gorroño L, Parikh D, ... Riascos-Bernal DF, Sibinga NES
Aims
Graft vascular disease (GVD), a clinically important and highly complex vascular occlusive disease, arises from the interplay of multiple cellular and molecular pathways. While occlusive intimal lesions are composed predominantly of smooth-muscle-like cells (SMLCs), the origin of these cells and the stimuli leading to their accumulation in GVD are uncertain. Macrophages have recently been identified as both potential drivers of intimal hyperplasia and precursors that undergo transdifferentiation to become SMLCs in non-transplant settings. Colony-stimulating factor-1 (CSF1) is a well-known regulator of macrophage development and differentiation, and prior preclinical studies have shown that lack of CSF1 limits GVD. We sought to identify the origins of SMLCs and of cells expressing the CSF1 receptor (CSF1R) in GVD, and to test the hypothesis that pharmacologic inhibition of CSF1 signalling would curtail both macrophage and SMLC activities and decrease vascular occlusion.
Methods and results
We used genetically modified mice and a vascular transplant model with minor antigen mismatch to assess cell origins. We found that neointimal SMLCs derive from both donor and recipient, and that transdifferentiation of macrophages to SMLC phenotype is minimal in this model. Cells expressing CSF1R in grafts were identified as recipient-derived myeloid cells of Cx3cr1 lineage, and these cells rarely expressed smooth muscle marker proteins. Blockade of CSF1R activity using the tyrosine kinase inhibitor PLX3397 limited the expression of genes associated with innate immunity and decreased levels of circulating monocytes and intimal macrophages. Importantly, PLX3397 attenuated the development of GVD in arterial allografts.
Conclusion
These studies provide proof of concept for pharmacologic inhibition of the CSF1/CSF1R signalling pathway as a therapeutic strategy in GVD. Further preclinical testing of this pathway in GVD is warranted.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.

Cardiovasc Res: 20 Sep 2022; 118:2718-2731

Multi-species meta-analysis identifies transcriptional signatures associated with cardiac endothelial responses in the ischaemic heart.

Li Z, Solomonidis EG, Berkeley B, Tang MNH, ... Baker AH, Brittan M
Aim
Myocardial infarction remains the leading cause of heart failure. The adult human heart lacks the capacity to undergo endogenous regeneration. New blood vessel growth is integral to regenerative medicine necessitating a comprehensive understanding of the pathways that regulate vascular regeneration. We sought to define the transcriptomic dynamics of coronary endothelial cells following ischaemic injuries in the developing and adult mouse and human heart and to identify new mechanistic insights and targets for cardiovascular regeneration.
Methods and results
We carried out a comprehensive meta-analysis of integrated single cell RNA-sequencing data of coronary vascular endothelial cells from the developing and adult mouse and human heart spanning healthy and acute and chronic ischaemic cardiac disease. We identified species-conserved gene regulatory pathways aligned to endogenous neovascularisation. We annotated injury-associated temporal shifts of the endothelial transcriptome and validated four genes: VEGF-C, KLF4, EGR1 and ZFP36. Moreover, we showed that ZFP36 regulates human coronary endothelial cell proliferation and defined that VEGF-C administration in vivo enhances clonal expansion of the cardiac vasculature post-myocardial infarction. Finally, we constructed a coronary endothelial cell meta-atlas, CrescENDO, to empower future in-depth research to target pathways associated with coronary neovascularisation.
Conclusion
We present a high-resolution single cell meta-atlas of healthy and injured coronary endothelial cells in the mouse and human heart, revealing a suite of novel targets with great potential to promote vascular regeneration, and providing a rich resource for therapeutic development.
Translational perspective
Myocardial infarction is the leading cause of heart failure, a condition with high morbidity and mortality. Vascular regeneration is vital to tissue survival and functional restoration while a comprehensive understanding of the underpinning mechanisms is lacking. We show that the meta-analysis of single cell RNA-sequencing data excels at deciphering multi-faceted vascular responses conserved between mouse and human following ischaemic injury. We envision that these data will inform future strategies and accelerate therapeutic development for promoting vascular regeneration in the ischaemic heart.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.

Cardiovasc Res: 09 Sep 2022; epub ahead of print

The need for adjusting experimental models to meet clinical reality.

Lezoualc\'h F, Badimon L, Baker H, Bernard M, ... Watson C, Derumeaux GA
Diabetic cardiomyopathy (CM), occurring in the absence of hypertension, coronary artery disease and valvular or congenital heart disease, is now recognized as a distinct, multifactorial disease leading to ventricular hypertrophy and abnormal myocardial contractility that correlates with an array of complex molecular and cellular changes. Animal models provide the unique opportunity to investigate mechanistic aspects of diabetic CM, but important caveats exist when extrapolating findings obtained from preclinical models of diabetes to humans. Indeed, animal models do not recapitulate the complexity of environmental factors, most notably the duration of the exposure to insulin resistance that may play a crucial role in the development of diabetic CM. Moreover, most preclinical studies are performed in animals with uncontrolled or poorly controlled diabetes, whereas patients tend to undergo therapeutic intervention. Finally, whilst T2DM prevalence trajectory mainly increases at 40- < 75 years (with a currently alarming increase at younger ages, however), it is a legitimate concern how closely rodent models employing young animals recapitulate the disease developing in old people. The aim of this review is to identify the current limitations of rodent models, and to discuss how future mechanistic and preclinical studies should integrate key confounding factors to better mimic the diabetic CM phenotype.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Cardiovasc Res: 09 Sep 2022; epub ahead of print

Group 2 innate lymphoid cells protect mouse heart from myocardial infarction injury via interleukin 5, eosinophils, and dendritic cells.

Liu T, Meng Z, Liu J, Li J, ... Guo J, Shi GP
Aims
Group 2 innate lymphoid cells (ILC2) regulate adaptive and innate immunities. In mouse heart, production of myocardial infarction (MI) increased ILC2 accumulation, suggesting a role for ILC2 in cardiac dysfunction post-MI.
Methods and results
We produced MI in ILC2-deficeint Rorafl/flIl7rCre/+ mice and in Icosfl-DTR-fl/+Cd4Cre/+ mice that allowed diphtheria toxin-induced ILC2 depletion. Genetic or induced deficiency of ILC2 in mice exacerbated cardiac dysfunction post-MI injury along with increased myocardial accumulation of neutrophils, CD11b+Ly6Chi monocytes, and CD4+ T cells but deficiency of eosinophils (EOS) and dendritic cells (DC). Post-MI hearts from genetic and induced ILC2-deficient mice contained many more apoptotic cells than those of control mice, and Rorafl/flIl7rCre/+ mice showed thinner and larger infarcts and more collagen-I depositions than the Il7rCre/+ mice only at early time points post-MI. Mechanistic studies revealed elevated blood IL5 in Il7rCre/+ mice at 1, 7, and 28 days post-MI. Such increase was blunted in Rorafl/flIl7rCre/+ mice. Administration of recombinant IL5 reversed EOS losses in Rorafl/flIl7rCre/+ mice, but IL5 did not correct the DC loss in these mice. Adoptive transfer of ILC2, EOS, or DC from wild-type mice, but not ILC2 from Il5-/- mice improved post-MI cardiac functions in Rorafl/flIl7rCre/+ recipient mice. EOS are known to protect cardiomyocytes from apoptosis. Here we showed that DC acted like EOS in blocking cardiomyocyte apoptosis. Yet, ILC2 or IL5 alone did not directly affect cardiomyocyte apoptosis or TGF-β-induced cardiac fibroblast Smad signaling.
Conclusion
This study revealed an indirect cardiac reparative role of ILC2 in post-MI hearts via the IL5, EOS, and DC mechanism.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Cardiovasc Res: 05 Sep 2022; epub ahead of print

Blood pressure and risk of venous thromboembolism: a cohort analysis of 5.5 million UK adults and Mendelian randomization studies.

Nazarzadeh M, Bidel Z, Mohseni H, Canoy D, ... Rahimi K, INVENT Consortium
Aim
Evidence for the effect of elevated blood pressure on the risk of venous thromboembolism (VTE) has been conflicting. We sought to assess the association between systolic blood pressure and the risk of VTE.
Methods and results
Three complementary studies comprising an observational cohort analysis, a one-sample and two-sample Mendelian randomization were conducted using data from 5,588,280 patients registered in the Clinical Practice Research Datalink (CPRD) dataset and 432,173 UK Biobank participants with valid genetic data. Summary statistics of International Network on Venous Thrombosis (INVENT) genome-wide association meta-analysis was used for two-sample Mendelian randomization. The primary outcome was the first occurrence of VTE event, identified from hospital discharge reports, death registers, and/or primary care records. In the CPRD cohort, 104,017 (1.9%) patients had a first diagnosis of VTE during the 9.6-year follow-up. Each 20 mmHg increase in systolic blood pressure was associated with a 7% lower risk of VTE (hazard ratio 0.93, 95% CI [0.92 to 0.94]). Statistically significant interactions were found for sex and body mass index, but not for age and subtype of VTE (pulmonary embolism and deep venous thrombosis). Mendelian randomization studies provided strong evidence for the association between systolic blood pressure and VTE, both in the one-sample (odds ratio [OR]: 0.69 [95% CI 0.57 to 0.83] and two-sample analyses (OR 0.80, 95% CI [0.70 to 0.92]).
Conclusions
We found an increased risk of VTE with lower blood pressure and this association was independently confirmed in two Mendelian randomization analyses. The benefits of blood pressure reduction are likely to outweigh the harms in most patient groups, but in people with predisposing factors for VTE, further blood pressure reduction should be made cautiously.
Translational perspective
In a large-scale population cohort, with over 100,000 first episodes of VTE and a median follow-up of about 10 years, we found a 7% higher risk of VTE for each 20 mmHg lower systolic blood pressure. The association was comparable when we examined pulmonary embolism and deep venous thrombosis separately, and persisted after taking into account age and other factors, including anticoagulant treatment during follow-up. These results were confirmed using two independent Mendelian randomization studies. Although the beneficial effects of blood pressure-lowering are likely to outweigh any harms in most patient groups, clinicians should be aware of the potential risk of VTE from antihypertensive therapy, in particular in people who have predisposing factors for VTE.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Cardiovasc Res: 29 Aug 2022; epub ahead of print

Mechanisms shared between cancer, heart failure, and targeted anti-cancer therapies.

de Wit S, Glen C, de Boer RA, Lang NN
Heart failure (HF) and cancer are the leading causes of death worldwide and accumulating evidence demonstrates that HF and cancer affect one another in a bidirectional way. Patients with HF are at increased risk for developing cancer, and HF is associated with accelerated tumour growth. The presence of malignancy may induce systemic metabolic, inflammatory, and microbial alterations resulting in impaired cardiac function. In addition to pathophysiologic mechanisms that are shared between cancer and HF, overlaps also exist between pathways required for normal cardiac physiology and for tumour growth. Therefore, these overlaps may also explain the increased risk for cardiotoxicity and HF as a result of targeted anti-cancer therapies. This review provides an overview of mechanisms involved in the bidirectional connection between HF and cancer, specifically focusing upon current \'hot-topics\' in these shared mechanisms. It subsequently describes targeted anti-cancer therapies with cardiotoxic potential as a result of overlap between their anti-cancer targets and pathways required for normal cardiac function.

© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.

Cardiovasc Res: 25 Aug 2022; epub ahead of print

Natriuretic peptide pathways in heart failure - further therapeutic possibilities.

Jeson Sangaralingham S, Kuhn M, Cannone V, Chen HH, Burnett JC
The discovery of the heart as an endocrine organ resulted in a remarkable recognition of the natriuretic peptide system (NPS). Specifically, research has established the production of atrial (ANP) and B-type natriuretic peptides (BNP) from the heart, which exert pleiotropic cardiovascular, endocrine, renal, and metabolic actions via the particulate guanylyl cyclase A receptor (GC-A) and the second messenger, cGMP. C-type natriuretic peptide (CNP) is produced in the endothelium and kidney and mediates important protective auto/paracrine actions via GC-B and cGMP. These actions, in part, participate in the efficacy of sacubitril/valsartan in heart failure (HF) due to augmentation of the NPS. Here we will review important insights into the biology of the NPS, the role of precision medicine and focus on the phenotypes of human genetic variants of ANP and BNP in the general population and the relevance to HF. We will also provide an update of the existence of NP deficiency states, including in HF, which provide the rationale for further therapeutics for the NPS. Finally, we will review the field of peptide engineering and the development of novel designer NPs for the treatment of HF. Notably, the recent discovery of a first-in-class small molecule GC-A enhancer, which is orally deliverable, will be highlighted. These innovative designer NPs and small molecule possess enhanced and novel properties for the treatment of HF and cardiovascular diseases.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.

Cardiovasc Res: 25 Aug 2022; epub ahead of print

Inflammatory pathways in heart failure with preserved left ventricular ejection fraction: implications for future interventions.

Pugliese NR, Pellicori P, Filidei F, De Biase N, ... Taddei S, Cleland JG
Many patients with symptoms and signs of heart failure have a left ventricular ejection fraction ≥50%, termed heart failure with preserved ejection fraction (HFpEF). HFpEF is a heterogeneous syndrome mainly affecting older people who have many other cardiac and non-cardiac conditions that often cast doubt on the origin of symptoms, such as breathlessness, or signs, such as peripheral oedema, rendering them neither sensitive nor specific to the diagnosis of HFpEF. Currently, management of HFpEF is mainly directed at controlling symptoms and treating comorbid conditions such as hypertension, atrial fibrillation, anaemia and coronary artery disease. HFpEF is also characterised by a persistent increase in inflammatory biomarkers. Inflammation may be a key driver of the development and progression of HFpEF and many of its associated comorbidities. Detailed characterisation of specific inflammatory pathways may provide insights into the pathophysiology of HFpEF and guide its future management. There is growing interest in novel therapies specifically designed to target deregulated inflammation in many therapeutic areas, including cardiovascular disease. However, large-scale clinical trials investigating the effectiveness of anti-inflammatory treatments in HFpEF are still lacking. In this manuscript, we review the role of inflammation in HFpEF and the possible implications for future trials.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.

Cardiovasc Res: 25 Aug 2022; epub ahead of print

Emerging epigenetic therapies of cardiac fibrosis and remodeling in heart failure: from basic mechanisms to early clinical development.

McKinsey TA, Foo R, Anene-Nzelu CG, Travers JG, ... Weber N, Thum T
Cardiovascular diseases and specifically heart failure (HF) impact global health and impose a significant economic burden on society. Despite current advances in standard of care, the risks for death and readmission of HF patients remain unacceptably high and new therapeutic strategies to limit HF progression are highly sought. In disease settings, persistent mechanical or neurohormonal stress to the myocardium triggers maladaptive cardiac remodeling, which alters cardiac function and structure at both the molecular and cellular level. The progression and magnitude of maladaptive cardiac remodeling ultimately leads to the development of HF. Classical therapies for HF are largely protein-based and mostly are targeted to ameliorate the dysregulation of neuroendocrine pathways and halt averse remodeling. More recently, investigation of novel molecular targets and the application of cellular therapies, epigenetic modifications, and regulatory RNAs has uncovered promising new avenues to address HF. In this review we summarize the current knowledge on novel cellular and epigenetic therapies and focus on two non-coding RNA-based strategies that reached the phase of early clinical development to counteract cardiac remodeling and HF. The current status of the development of translating those novel therapies to clinical practice, limitations and future perspectives are additionally discussed.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Cardiovasc Res: 25 Aug 2022; epub ahead of print

Nicotine exacerbates endothelial dysfunction and drives atherosclerosis via extracellular vesicle-miRNA.

Wang C, Liu C, Shi J, Li H, ... Sun P, Tian J
Aims
Nicotine, a major component of tobacco, is an important factor contributing to atherosclerosis. However, the molecular mechanisms underlying the link between nicotine and atherosclerosis are unclear. As extracellular vesicles (EVs) are involved in intercellular communication in atherosclerosis, we investigated whether their influence on arterial pathophysiology under nicotine stimulation.
Methods
and results: EVs from the serum of smokers (smoker-EVs) were significantly increased and exacerbated endothelial inflammation as well as apoptosis according to functional studies. Meanwhile, inhibition of EVs blunted the nicotine-induced atherosclerosis progression, and injection of nicotine-induced EVs promoted atherosclerosis progression in ApoE-/- mice. Furthermore, quantitative reverse transcription-polymerase chain reaction analysis revealed a remarkable increase in miR-155 levels in smoker-EVs, which was correlated with carotid plaque formation in patients measured by ultrasound imaging. Moreover, CD14 levels were significantly increased in EVs from smokers (representing EVs derived from monocytes), indicating that monocytes are an important source of smoker-EVs. DNA methylation and the transcription factor HIF1α may contribute to increased miR-155 levels in monocytes, as assessed with bisulfite conversion sequencing and chromatin immunoprecipitation. Mechanistically, EVs encapsulated miR-155 induced endothelial cell dysfunction by directedly targeting BCL2, MCL1, TIMP3, BCL6 and activating NF-κB pathway, as verified in a series of molecular and biological experiments. Injecting EVs from nicotine-stimulated monocytes promoted plaque formation and triggered vascular endothelial injury in ApoE-/- mice, whereas inhibition of miR-155 weakened this effect.
Conclusion
Our findings revealed an EV-dependent mechanism of nicotine-aggravated atherosclerosis. Accordingly, we propose an EV-based intervention strategy for atherosclerosis management.
Translational perspective
Based on the findings of our study, strategies preventing or blocking the production of abnormal EVs, particularly monocyte EVs, after nicotine stimulation may protect against atherosclerosis. Moreover, detection of circulating EVs-carried miR-155 expression may reveal the progression of atherosclerosis. On the molecular level, blocking miR-155 biogenesis, which constituted a novel therapeutic approach, may protect against nicotine aggravating atherosclerosis.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Cardiovasc Res: 25 Aug 2022; epub ahead of print

Multimodality imaging and transciptomics to phenotype mitral valve dystrophy in a unique knock-in Filamin-A rat model.

Delwarde C, Toquet C, Aumond P, Kayvanjoo AH, ... Merot J, Capoulade R
Aims
Degenerative mitral valve dystrophy (MVD) leading to mitral valve prolapse is the most frequent form of MV disease, and there is currently no pharmacological treatment available. The limited understanding of the pathophysiological mechanisms leading to MVD limits our ability to identify therapeutic targets. This study aimed to reveal the main pathophysiological pathways involved in MVD via the multimodality imaging and transcriptomic analysis of the new and unique Knock-In (KI) rat model for the FlnA-P637Q mutation associated-MVD.
Methods and results
WT and KI rats were evaluated morphologically, functionally, and histologically between 3-week-old and 3-to-6-month-old based on Doppler echocardiography, 3D micro-computed tomography (microCT), and standard histology. RNA-sequencing and Assay for Transposase-Accessible Chromatin (ATAC-seq) were performed on 3-week-old WT and KI mitral valves and valvular cells, respectively, to highlight the main signaling pathways associated with MVD. Echocardiographic exploration confirmed MV elongation (2.0 ± 0.1  mm versus 1.8 ± 0.1, p = 0.001), as well as MV thickening and prolapse in KI animals compared to WT at 3 weeks. 3D MV volume quantified by microCT was significantly increased in KI animals (+58% versus WT, p = 0.02). Histological analyses revealed a myxomatous remodeling in KI MV characterized by proteoglycans accumulation. A persistent phenotype was observed in adult KI rats. Signaling pathways related to extracellular matrix homeostasis, response to molecular stress, epithelial cell migration, endothelial to mesenchymal transition, chemotaxis and immune cell migration, were identified based on RNA-seq analysis. ATAC-seq analysis points to the critical role of TGF-β and inflammation in the disease.
Conclusion
The KI FlnA-P637Q rat model mimics human myxomatous mitral valve dystrophy, offering a unique opportunity to decipher pathophysiological mechanisms related to this disease. Extracellular matrix organization, epithelial cell migration, response to mechanical stress, and a central contribution of immune cells are highlighted as the main signaling pathways leading to myxomatous mitral valve dystrophy. Our findings pave the road to decipher underlying molecular mechanisms and the specific role of distinct cell populations in this context.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Cardiovasc Res: 24 Aug 2022; epub ahead of print

Gut microbiota, dysbiosis and atrial fibrillation. Arrhythmogenic mechanisms and potential clinical implications.

Gawałko M, Agbaedeng TA, Saljic A, Müller DN, ... Dobrev D, Linz D
Recent preclinical and observational cohort studies have implicated imbalances in gut microbiota composition as a contributor to atrial fibrillation (AF). The gut microbiota is a complex and dynamic ecosystem containing trillions of microorganisms, which produces bioactive metabolites influencing host health and disease development. In addition to host-specific determinants, lifestyle-related factors such as diet and drugs are important determinants of the gut microbiota composition. In this review, we discuss the evidence suggesting a potential bidirectional association between AF and gut microbiota, identifying gut microbiota-derived metabolites as possible regulators of the AF substrate. We summarize the effect of gut microbiota on the development and progression of AF risk factors, including heart failure, hypertension, obesity, and coronary artery disease. We also discuss the potential anti-arrhythmic effects of pharmacological and diet-induced modifications of gut microbiota composition, which may modulate and prevent the progression to AF. Finally, we highlight important gaps in knowledge and areas requiring future investigation. Although data supporting a direct relationship between gut microbiota and AF are very limited at the present time, emerging preclinical and clinical research dealing with mechanistic interactions between gut microbiota and AF is important as it may lead to new insights into AF pathophysiology and the discovery of novel therapeutic targets for AF.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.

Cardiovasc Res: 24 Aug 2022; 118:2415-2427

Endothelial Poldip2 regulates sepsis-induced lung injury via Rho pathway activation.

Dolmatova EV, Forrester SJ, Wang K, Ou Z, ... Hernandes MS, Griendling KK
Aims
Sepsis-induced lung injury is associated with significant morbidity and mortality. Previously, we showed that heterozygous deletion of polymerase δ-interacting protein 2 (Poldip2) was protective against sepsis-induced lung injury. Since endothelial barrier disruption is thought to be the main mechanism of sepsis-induced lung injury, we sought to determine if the observed protection was specifically due to the effect of reduced endothelial Poldip2.
Methods and results
Endothelial-specific Poldip2 knock-out mice (EC-/-) and their wild-type littermates (EC+/+) were injected with saline or lipopolysaccharide (18 mg/kg) to model sepsis-induced lung injury. At 18 h post-injection mice, were euthanized and bronchoalveolar lavage (BAL) fluid and lung tissue were collected to assess leucocyte infiltration. Poldip2 EC-/- mice showed reduced lung leucocyte infiltration in BAL (0.21 ± 0.9×106 vs. 1.29 ± 1.8×106 cells/mL) and lung tissue (12.7 ± 1.8 vs. 23 ± 3.7% neutrophils of total number of cells) compared to Poldip2 EC+/+ mice. qPCR analysis of the lung tissue revealed a significantly dampened induction of inflammatory gene expression (TNFα 2.23 ± 0.39 vs. 4.15 ± 0.5-fold, IκBα 4.32 ± 1.53 vs. 8.97 ± 1.59-fold), neutrophil chemoattractant gene expression (CXCL1 68.8 ± 29.6 vs. 147 ± 25.7-fold, CXCL2 65 ± 25.6 vs. 215 ± 27.3-fold) and a marker of endothelial activation (VCAM1 1.25 ± 0.25 vs. 3.8 ± 0.38-fold) in Poldip2 EC-/- compared to Poldip2 EC+/+ lungs. An in vitro model using human pulmonary microvascular endothelial cells was used to assess the effect of Poldip2 knock-down on endothelial activation and permeability. TNFα-induced endothelial permeability and VE-cadherin disruption were significantly reduced with siRNA-mediated knock-down of Poldip2 (5 ± 0.5 vs. 17.5 ± 3-fold for permeability, 1.5 ± 0.4 vs. 10.9 ± 1.3-fold for proportion of disrupted VE-cadherin). Poldip2 knock-down altered expression of Rho-GTPase-related genes, which correlated with reduced RhoA activation by TNFα (0.94 ± 0.05 vs. 1.29 ± 0.01 of relative RhoA activity) accompanied by redistribution of active-RhoA staining to the centre of the cell.
Conclusion
Poldip2 is a potent regulator of endothelial dysfunction during sepsis-induced lung injury, and its endothelium-specific inhibition may provide clinical benefit.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.

Cardiovasc Res: 24 Aug 2022; 118:2506-2518

Single-cell RNA sequencing profiling of mouse endothelial cells in response to pulmonary arterial hypertension.

Rodor J, Chen SH, Scanlon JP, Monteiro JP, ... Brittan M, Baker AH
Aims
Endothelial cell (EC) dysfunction drives the initiation and pathogenesis of pulmonary arterial hypertension (PAH). We aimed to characterize EC dynamics in PAH at single-cell resolution.
Methods and results
We carried out single-cell RNA sequencing (scRNA-seq) of lung ECs isolated from an EC lineage-tracing mouse model in Control and SU5416/hypoxia-induced PAH conditions. EC populations corresponding to distinct lung vessel types, including two discrete capillary populations, were identified in both Control and PAH mice. Differential gene expression analysis revealed global PAH-induced EC changes that were confirmed by bulk RNA-seq. This included upregulation of the major histocompatibility complex class II pathway, supporting a role for ECs in the inflammatory response in PAH. We also identified a PAH response specific to the second capillary EC population including upregulation of genes involved in cell death, cell motility, and angiogenesis. Interestingly, four genes with genetic variants associated with PAH were dysregulated in mouse ECs in PAH. To compare relevance across PAH models and species, we performed a detailed analysis of EC heterogeneity and response to PAH in rats and humans through whole-lung PAH scRNA-seq datasets, revealing that 51% of up-regulated mouse genes were also up-regulated in rat or human PAH. We identified promising new candidates to target endothelial dysfunction including CD74, the knockdown of which regulates EC proliferation and barrier integrity in vitro. Finally, with an in silico cell ordering approach, we identified zonation-dependent changes across the arteriovenous axis in mouse PAH and showed upregulation of the Serine/threonine-protein kinase Sgk1 at the junction between the macro- and microvasculature.
Conclusion
This study uncovers PAH-induced EC transcriptomic changes at a high resolution, revealing novel targets for potential therapeutic candidate development.

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Cardiovasc Res: 24 Aug 2022; 118:2519-2534

Recommendations for nomenclature and definition of cell products intended for human cardiovascular use.

Taylor DA, Chacon-Alberty L, Sampaio LC, Hierro MGD, ... Bolli R, Cardiovascular Cell Therapy Research Network (CCTRN)
Exogenous cell-based therapy has emerged as a promising new strategy to facilitate repair of hearts damaged by acute or chronic injury. However, the field of cell-based therapy is handicapped by the lack of standardized definitions and terminology, making comparisons across studies challenging. Even the term \'stem cell therapy\' is misleading because only a small percentage of cells derived from adult bone marrow, peripheral blood, or adipose tissue meets the accepted haematopoietic or developmental definition of stem cells. Furthermore, cells (stem or otherwise) are dynamic biological products, meaning that their surface-marker expression, phenotypic and functional characteristics, and the products they secrete in response to their microenvironment can change. It is also important to point out that most surface markers are seldom specific for a cell type. In this article, we discuss the lack of consistency in the descriptive terminology used in cell-based therapies and offer guidelines aimed at standardizing nomenclature and definitions to improve communication among investigators and the general public.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.

Cardiovasc Res: 24 Aug 2022; 118:2428-2436

Pharmacological inhibition of adipose tissue adipose triglyceride lipase by Atglistatin prevents catecholamine-induced myocardial damage.

Thiele A, Luettges K, Ritter D, Beyhoff N, ... Kintscher U, Foryst-Ludwig A
Aims
Heart failure (HF) is characterized by an overactivation of β-adrenergic signalling that directly contributes to impairment of myocardial function. Moreover, β-adrenergic overactivation induces adipose tissue lipolysis, which may further worsen the development of HF. Recently, we demonstrated that adipose tissue-specific deletion of adipose triglyceride lipase (ATGL) prevents pressure-mediated HF in mice. In this study, we investigated the cardioprotective effects of a new pharmacological inhibitor of ATGL, Atglistatin, predominantly targeting ATGL in adipose tissue, on catecholamine-induced cardiac damage.
Methods and results
Male 129/Sv mice received repeated injections of isoproterenol (ISO, 25 mg/kg BW) to induce cardiac damage. Five days prior to ISO application, oral Atglistatin (2 mmol/kg diet) or control treatment was started. Two and twelve days after the last ISO injection cardiac function was analysed by echocardiography. The myocardial deformation was evaluated using speckle-tracking-technique. Twelve days after the last ISO injection, echocardiographic analysis revealed a markedly impaired global longitudinal strain, which was significantly improved by the application of Atglistatin. No changes in ejection fraction were observed. Further studies included histological-, WB-, and RT-qPCR-based analysis of cardiac tissue, followed by cell culture experiments and mass spectrometry-based lipidome analysis. ISO application induced subendocardial fibrosis and a profound pro-apoptotic cardiac response, as demonstrated using an apoptosis-specific gene expression-array. Atglistatin treatment led to a dramatic reduction of these pro-fibrotic and pro-apoptotic processes. We then identified a specific set of fatty acids (FAs) liberated from adipocytes under ISO stimulation (palmitic acid, palmitoleic acid, and oleic acid), which induced pro-apoptotic effects in cardiomyocytes. Atglistatin significantly blocked this adipocytic FA secretion.
Conclusion
This study demonstrates cardioprotective effects of Atglistatin in a mouse model of catecholamine-induced cardiac damage/dysfunction, involving anti-apoptotic and anti-fibrotic actions. Notably, beneficial cardioprotective effects of Atglistatin are likely mediated by non-cardiac actions, supporting the concept that pharmacological targeting of adipose tissue may provide an effective way to treat cardiac dysfunction.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.

Cardiovasc Res: 24 Aug 2022; 118:2488-2505

Lymphatic contractile function: a comprehensive review of drug effects and potential clinical application.

Russell PS, Hong J, Trevaskis NL, Windsor JA, Martin ND, Phillips ARJ
The lymphatic system and the cardiovascular (CV) system work together to maintain body fluid homeostasis. Despite that, the lymphatic system has been relatively neglected as a potential drug target and a source of adverse effects from CV drugs. Like the heart, the lymphatic vessels undergo phasic contractions to promote lymph flow against a pressure gradient. Dysfunction or failure of the lymphatic pump results in fluid imbalance and tissue oedema. While this can be due to drug effects, it is also a feature of breast cancer-associated lymphoedema, chronic venous insufficiency, congestive heart failure, and acute systemic inflammation. There are currently no specific drug treatments for lymphatic pump dysfunction in clinical use despite the wealth of data from pre-clinical studies. The aim of this study was to identify (i) drugs with direct effects on lymphatic tonic and phasic contractions with potential for clinical application, and (ii) drugs in current clinical use that have a positive or negative side effect on lymphatic function. We comprehensively reviewed all studies that tested the direct effect of a drug on the contractile function of lymphatic vessels. Of the 208 drugs identified from 193 studies, about a quarter had only stimulatory effects on lymphatic tone, contraction frequency, and/or contraction amplitude. Of Food and Drug Administration-approved drugs, there were 14 that increased lymphatic phasic contractile function. The most frequently used class of drugs with inhibitory effects on lymphatic pump function were the calcium channels blockers. This review highlights the opportunity for specific drug treatments of lymphatic dysfunction in various disease states and for avoiding adverse drug effects on lymphatic contractile function.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.

Cardiovasc Res: 24 Aug 2022; 118:2437-2457

Impairment of mitophagy and autophagy accompanies calcific aortic valve stenosis favouring cell death and the severity of disease.

Morciano G, Patergnani S, Pedriali G, Cimaglia P, ... Ferrari R, Pinton P
Aims
In the last 15 years, some observations tried to shed light on the dysregulation of the cellular self-digestion process in calcific aortic valve stenosis (CAVS), but the results obtained remain still controversial. This work is aimed to definitively establish the trend of autophagy in patients affected by CAVS, to analyse the putative involvement of other determinants, which impact on the mitochondrial quality control mechanisms and to explore possible avenues for pharmacological interventions in the treatment of CAVS.
Methods and results
This observational study, performed exclusively in ex vivo human samples (cells and serum), by using biochemical approaches and correlations with clinical data, describes new biological features of the calcified valve in terms of mitochondrial dysfunctions. In detail, we unveiled a significant deficiency in mitochondrial respiration and in ATP production coupled to increase production of lactates. In addition, mitochondrial population in the pathologic group is aged with significant alterations in biogenesis and mitophagy pathways. We are also reporting an updated view about autophagy accompanying the calcification process and advanced stages of the disease. We provided evidence for a rapamycin-based therapeutic strategy to revert the calcified phenotype to the wild type one.
Conclusion
Our data suggest that the CAVS phenotype is featured by defects in mitochondrial quality control mechanisms and that autophagy is not activated enough to counteract cell death and sustain cell functions. Thus, boosting autophagy and mitophagy from short- to long-term reverts quite all pathological phenotypes.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.

Cardiovasc Res: 24 Aug 2022; 118:2548-2559

The pulmonary vasculature in lethal COVID-19 and idiopathic pulmonary fibrosis at single cell resolution.

de Rooij LPMH, Becker LM, Teuwen LA, Boeckx B, ... Lambrechts D, Carmeliet P
Aims
SARS-CoV-2 infection causes COVID-19, which in severe cases evokes life-threatening acute respiratory distress syndrome (ARDS). Transcriptome signatures and the functional relevance of non-vascular cell types (e.g. immune and epithelial cells) in COVID-19 are becoming increasingly evident. However, despite its known contribution to vascular inflammation, recruitment/invasion of immune cells, vascular leakage and perturbed hemostasis in the lungs of severe COVID-19 patients, an in-depth interrogation of the endothelial cell (EC) compartment in lethal COVID-19 is lacking. Moreover, progressive fibrotic lung disease represents one of the complications of COVID-19 pneumonia and ARDS. Analogous features between idiopathic pulmonary fibrosis (IPF) and COVID-19 suggest partial similarities in their pathophysiology, yet, a head-to-head comparison of pulmonary cell transcriptomes between both conditions has not been implemented to date.
Methods and results
We performed single nucleus RNA-seq (snRNA-seq) on frozen lungs from 7 deceased COVID-19 patients, 6 IPF explant lungs and 12 controls. The vascular fraction, comprising 38,794 nuclei, could be subclustered into 14 distinct EC subtypes. Non-vascular cell types, comprising 137,746 nuclei, were subclustered and used for EC-interactome analyses. Pulmonary ECs of deceased COVID-19 patients showed an enrichment of genes involved in cellular stress, as well as signatures suggestive of dampened immunomodulation and impaired vessel wall integrity. In addition, increased abundance of a population of systemic capillary and venous ECs was identified in COVID-19 and IPF. COVID-19 systemic ECs closely resembled their IPF counterparts, and a set of 30 genes was found congruently enriched in systemic ECs across studies. Receptor-ligand interaction analysis of ECs with non-vascular cell types in the pulmonary micro-environment revealed numerous previously unknown interactions specifically enriched/depleted in COVID-19 and/or IPF.
Conclusions
This study uncovered novel insights into the abundance, expression patterns and interactomes of EC subtypes in COVID-19 and IPF, relevant for future investigations into the progression and treatment of both lethal conditions.
Translational perspective
While assessing clinical and molecular characteristics of severe and lethal COVID-19 cases, the vasculature\'s undeniable role in disease progression has been widely acknowledged. COVID-19 lung pathology moreover shares certain clinical features with late-stage IPF - yet an in-depth interrogation and direct comparison of the endothelium at single-cell level in both conditions is still lacking. By comparing the transcriptomes of ECs from lungs of deceased COVID-19 patients to those from IPF explant and control lungs, we gathered key insights the heterogeneous composition and potential roles of ECs in both lethal diseases, which may serve as a foundation for development of novel therapeutics.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.

Cardiovasc Res: 23 Aug 2022; epub ahead of print

SGLT-2 inhibition by empagliflozin has no effect on experimental arterial thrombosis in a murine model of low-grade inflammation.

Liberale L, Kraler S, Puspitasari YM, Bonetti NR, ... Lüscher TF, Camici GG
Aims
Low-grade inflammation couples dysmetabolic states to insulin resistance and atherosclerotic cardiovascular (CV) disease (ASCVD). Selective sodium-glucose co-transporter 2 (SGLT-2) inhibition by empagliflozin improves clinical outcomes in patients with ASCVD independently of its glucose lowering effects. Yet, its mechanism of action remains largely undetermined. Here, we aimed to test whether empagliflozin affects arterial thrombus formation in baseline (BSL) conditions or low-grade inflammatory states, a systemic milieu shared among patients with ASCVD.
Methods and results
Sixteen-week-old C57BL/6 mice were randomly assigned to acute administration of empagliflozin (25 mg/kg body weight) or vehicle, of which a subgroup was pre-treated biweekly over 4 weeks with super-low-dose lipopolysaccharide (LPS; 5 ng/kg body weight), before carotid thrombosis was induced by photochemical injury. The between-group difference in Doppler-flow probe detected time-to-occlusion remained within the predefined equivalence margin (Δ = |10.50|), irrespective of low-grade inflammation (95% confidence interval, -9.82 to 8.85 and -9.20 to 9.69), while glucose dropped by 1.64 and 4.84 mmoL/L, respectively. Ex vivo platelet aggregometry suggested similar activation status, corroborated by unchanged circulating platelet-factor 4 plasma levels. In concert, carotid PAI-1 expression and tissue factor (TF) activity remained unaltered upon SGLT-2 inhibition, and no difference in plasma d-dimer levels was detected, suggesting comparable coagulation cascade activation and fibrinolytic activity. In human aortic endothelial cells pre-treated with LPS, empagliflozin neither changed TF activity nor PAI-1 expression. Accordingly, among patients with established ASCVD or at high CV risk randomized to a daily dose of 10 mg empagliflozin signatures of thrombotic (i.e. TF) and fibrinolytic activity (i.e. PAI-1) remained unchanged, while plasma glucose declined significantly during 3 months of follow-up.
Conclusion
SGLT-2 inhibition by empagliflozin does not impact experimental arterial thrombus formation, neither under BSL conditions nor during sustained low-grade inflammation, and has no impact on proxies of thrombotic/fibrinolytic activity in patients with ASCVD. The beneficial pleiotropic effects of empagliflozin are likely independent of pathways mediating arterial thrombosis.

© 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.

Cardiovasc Res: 22 Aug 2022; epub ahead of print

Cellular mechanisms of oligoclonal vascular smooth muscle cell expansion in cardiovascular disease.

Worssam MD, Lambert J, Oc S, Taylor JC, ... Spivakov M, Jørgensen HF
Aims
Quiescent, differentiated adult vascular smooth muscle cells (VSMCs) can be induced to proliferate and switch phenotype. Such plasticity underlies blood vessel homeostasis and contributes to vascular disease development. Oligoclonal VSMC contribution is a hallmark of end-stage vascular disease. Here we aim to understand cellular mechanisms underpinning generation of this VSMC oligoclonality.
Methods and results
We investigate the dynamics of VSMC clone formation using confocal microscopy and single cell transcriptomics in VSMC-lineage-traced animal models. We find that activation of medial VSMC proliferation occurs at low frequency after vascular injury and that only a subset of expanding clones migrate, which together drives formation of oligoclonal neointimal lesions. VSMC contribution in small atherosclerotic lesions is typically from one or two clones, similar to observations in mature lesions. Low frequency (<0.1%) of clonal VSMC proliferation is also observed in vitro. Single-cell RNA-sequencing revealed progressive cell state changes across a contiguous VSMC population at onset of injury-induced proliferation. Proliferating VSMCs mapped selectively to one of two distinct trajectories and were associated with cells showing extensive phenotypic switching. A proliferation-associated transitory state shared pronounced similarities with atypical SCA1+ VSMCs from uninjured mouse arteries and VSMCs in healthy human aorta. We show functionally that clonal expansion of SCA1+ VSMCs from healthy arteries occurs at higher rate and frequency compared to SCA1- cells.
Conclusion
Our data suggest that activation of proliferation at low frequency is a general, cell-intrinsic feature of VSMCs. We show that rare VSMCs in healthy arteries display VSMC phenotypic switching akin to that observed in pathological vessel remodelling and that this is a conserved feature of mouse and human healthy arteries. The increased proliferation of modulated VSMCs from healthy arteries suggests that these cells respond more readily to disease-inducing cues and could drive oligoclonal VSMC expansion.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.

Cardiovasc Res: 22 Aug 2022; epub ahead of print

The microsomal prostaglandin E synthase-1/PGE2 axis induces recovery from ischemia via recruitment of regulatory T cells.

Amano H, Eshima K, Ito Y, Nakamura M, ... Narumiya S, Majima M
Aims
Microsomal prostaglandin E synthase-1 (mPGES-1)/prostaglandin E2 (PGE2) induces angiogenesis through the prostaglandin E2 receptor (EP1-4). Among immune cells, regulatory T cells (Tregs), which inhibit immune responses, have been implicated in angiogenesis, and PGE2 is known to modulate function and differentiation of Tregs. We hypothesized that mPGES-1/PGE2-EP signaling could contribute to recovery from ischemic conditions by promoting the accumulation of Tregs.
Methods and results
Wild-type (WT), mPGES-1-deficient (mPges-1-/-), and EP4 receptor-deficient (Ep4-/-) male mice 6-8 weeks old were used. Hindlimb ischemia was induced by femoral artery ligation. Recovery from ischemia was suppressed in mPges-1-/- mice and compared with WT mice. The number of accumulated forkhead box protein P3 (FoxP3)+ cells in ischemic muscle tissue was decreased in mPges-1-/- mice compared with that in WT mice. Expression levels of transforming growth factor-β (TGF-β) and stromal cell derived factor-1 (SDF-1) in ischemic tissue were also suppressed in mPges-1-/- mice. The number of accumulated FoxP3+ cells and blood flow recovery were suppressed when Tregs were depleted by injecting antibody against folate receptor 4 (FR4) in WT mice but not in mPges-1-/- mice. Recovery from ischemia was significantly suppressed in Ep4-/- mice compared with WT mice. Furthermore, mRNA levels of Foxp3 and Tgf-β were suppressed in Ep4-/- mice. Moreover, the numbers of accumulated FoxP3+ cells in ischemic tissue were diminished in Ep4-/- mice compared with Ep4+/+ mice.
Conclusions
These findings suggested that mPGES-1/PGE2 induced neovascularization from ischemia via EP4 by promoting accumulation of Tregs. Highly selective EP4 agonists could be useful for treatment of peripheral artery disease (PAD).
Translational perspective
Although surgical treatment for PAD in patients improved, some patients with advanced disease have no other option for treatments other than amputation. In the present study, we revealed that endogenous mPGES-1/PGE2-EP4 signaling induced recovery from ischemia by promoting Tregs accumulation at the ischemic site. In addition, we showed that selective EP4 agonist, or transplantation of Tregs, induced recovery from ischemic conditions. These results indicate that the use of selective EP4 agonist, or cell therapy of Tregs, may be a potential treatment option for severe critical limb ischemia patients.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Cardiovasc Res: 20 Aug 2022; epub ahead of print

Mitochondrial calcium and reactive oxygen species in cardiovascular disease.

Murphy E, Liu J
Cardiomyocytes are one of the most mitochondria-rich cell types in the body, with ∼30-40% of the cell volume being composed of mitochondria. Mitochondria are well established as the primary site of ATP generation in a beating cardiomyocyte, generating up to 90% of its ATP. Mitochondria have many functions in the cell which could contribute to the susceptibility and development of cardiovascular disease (CVD). Mitochondria are key players in cell metabolism, ATP production, reactive oxygen species (ROS) production and cell death. Mitochondrial calcium (Ca2+) plays a critical role in many of these pathways, and thus the dynamics of mitochondrial Ca2+ are important in regulating mitochondria processes. Alterations in these varied and in many cases interrelated functions play an important role in CVD. This review will focus on the interrelationship of mitochondrial energetics, Ca2+, and ROS and their roles in CVD. Recent insights into the regulation and dysregulation of these pathways has led to some novel therapeutic approaches.

Published by Oxford University Press on behalf of European Society of Cardiology 2022.

Cardiovasc Res: 20 Aug 2022; epub ahead of print

Dynamics of monocyte-derived macrophage diversity in experimental myocardial infarction.

Rizzo G, Gropper J, Piollet M, Vafadarnejad E, ... Saliba AE, Cochain C
Aims
Macrophages have a critical and dual role in post-ischaemic cardiac repair, as they can foster both tissue healing and damage. Multiple subsets of tissue resident and monocyte-derived macrophages coexist in the infarcted heart, but their precise identity, temporal dynamics, and the mechanisms regulating their acquisition of discrete states are not fully understood. To address this, we used multi-modal single-cell immune profiling, combined with targeted cell depletion and macrophage fate mapping, to precisely map monocyte/macrophage transitions after experimental myocardial infarction.
Methods and results
We performed single-cell transcriptomic and cell-surface marker profiling of circulating and cardiac immune cells in mice challenged with acute myocardial infarction, and integrated single-cell transcriptomes obtained before and at 1, 3, 5, 7, and 11 days after infarction. Using complementary strategies of CCR2+ monocyte depletion and fate mapping of tissue resident macrophages, we determined the origin of cardiac macrophage populations. The macrophage landscape of the infarcted heart was dominated by monocyte-derived cells comprising two pro-inflammatory populations defined as Isg15hi and MHCII+Il1b+, alongside non-inflammatory Trem2hi cells. Trem2hi macrophages were observed in the ischaemic area, but not in the remote viable myocardium, and comprised two subpopulations sequentially populating the heart defined as Trem2hiSpp1hi monocyte-to-macrophage intermediates, and fully differentiated Trem2hiGdf15hi macrophages. Cardiac Trem2hi macrophages showed similarities to \'lipid-associated macrophages\' found in mouse models of metabolic diseases and were observed in the human heart, indicating conserved features of this macrophage state across diseases and species. Ischaemic injury induced a shift of circulating Ly6Chi monocytes towards a Chil3hi state with granulocyte-like features, but the acquisition of the Trem2hi macrophage signature occurred in the ischaemic tissue. In vitro, macrophages acquired features of the Trem2hi signature following apoptotic-cell efferocytosis.
Conclusion
Our work provides a comprehensive map of monocyte/macrophage transitions in the ischaemic heart, constituting a valuable resource for further investigating how these cells may be harnessed and modulated to promote post-ischaemic heart repair.

© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.

Cardiovasc Res: 11 Aug 2022; epub ahead of print

Role of thermogenic adipose tissue in lipid metabolism and atherosclerotic cardiovascular disease: lessons from studies in mice and humans.

Ying Z, Tramper N, Zhou E, Boon MR, Rensen PCN, Kooijman S
Brown adipocytes within brown adipose tissue (BAT) and beige adipocytes within white adipose tissue dissipate nutritional energy as heat. Studies in mice have shown that activation of thermogenesis in brown and beige adipocytes enhances the lipolytic processing of triglyceride-rich lipoproteins (TRLs) in plasma to supply these adipocytes with fatty acids for oxidation. This process results in formation of TRL remnants that are removed from the circulation through binding of apolipoprotein E (ApoE) on their surface to the low-density lipoprotein receptor (LDLR) on hepatocytes, followed by internalization. Concomitantly, lipolytic processing of circulating TRLs leads to generation of excess surface phospholipids that are transferred to nascent high-density lipoproteins (HDL), increasing their capacity for reverse cholesterol transport. Activation of thermogenic adipocytes thus lowers circulating triglycerides and non-HDL-cholesterol, while it increases HDL-cholesterol. The combined effect is protection from atherosclerosis development, which becomes evident in humanized mouse models with an intact ApoE-LDLR clearance pathway only, and is additive to the effects of classical lipid-lowering drugs including statins and proprotein convertase subtilisin/kexin type 9 inhibitors. A large recent study revealed that the presence of metabolically active BAT in humans is associated with lower triglycerides, higher HDL-cholesterol and lower risk of cardiovascular diseases. This narrative review aims to provide leads for further exploration of thermogenic adipose tissue as a therapeutic target. To this end, we describe the latest knowledge on the role of BAT in lipoprotein metabolism and address, for example, the discovery of the β2-adrenergic receptor as the dominant adrenergic receptor in human thermogenic adipocytes.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.

Cardiovasc Res: 10 Aug 2022; epub ahead of print

The effect of probiotic and synbiotic supplementation on lipid parameters among patients with cardiometabolic risk factors: a systematic review and meta-analysis of clinical trials.

Ghorbani Z, Kazemi A, Bartolomaeus TUP, Martami F, ... Forslund SK, Mahdavi-Roshan M
Although the available evidence emphasizes the beneficial effects of probiotics in normalizing various cardiometabolic markers, there is still substantial uncertainty in this regard. Thus, we set out to determine the effect sizes of probiotics on blood lipid parameters more coherently. A systematic literature search of the Medline (PubMed) and Scopus databases was conducted from inception to February 12, 2021, applying both MeSH terms and free text terms to find the relevant randomized controlled trials (RCTs). The meta-analysis was conducted based on a random-effect model to calculate the mean effect sizes demonstrated as weighted mean differences (WMD) and the 95% confidence intervals (95%CI). To explore the heterogeneity, the Cochrane Chi-squared test, and analysis of Galbraith plots were performed. Meta-analysis of data from 40 RCTs (n = 2795) indicated a significant decrease in serum/plasma triglyceride (WMD (95%CI)    -12.26 (-17.11- -7.41) mg/dL; P-value <0.001; I2 (%)= 29.9; P heterogeneity = 0.034)), total cholesterol (with high heterogeneity) (WMD (95%CI)    -8.43 (-11.90- -4.95) mg/dL; P-value <0.001; I2 (%) =56.8; P heterogeneity < 0.001), LDL-C (WMD (95%CI)    -5.08 (-7.61, -2.56) mg/dL; P-value <0.001; I2 (%) =42.7; P heterogeneity =0.002), and HDL-C (with high heterogeneity) (WMD (95%CI)    1.14 (0.23, 2.05) mg/dL; P-value =0.014; I2 (%) = 59.8; P heterogeneity < 0.001) following receiving probiotic/synbiotic supplements. Collectively, the current preliminary evidence supports the effectiveness of probiotics/synbiotics in improving dyslipidemia and various lipid parameters more prominently among subjects with hyperlipidemia, diabetes, and metabolic syndrome. However, large and well conducted RCTs are required to provide further convincing support for these results.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Cardiovasc Res: 08 Aug 2022; epub ahead of print

Transthyretin cardiac amyloidosis.

Porcari A, Fontana M, Gillmore JD
Transthyretin cardiac amyloidosis (ATTR-CA) is an increasingly recognized cause of heart failure (HF) and mortality worldwide. Advances in non-invasive diagnosis, coupled with the development of effective treatments, have shifted ATTR-CA from a rare and untreatable disease to a relatively prevalent condition that clinicians should consider on a daily basis. Amyloid fibril formation results from age-related failure of homoeostatic mechanisms in wild-type ATTR (ATTRwt) amyloidosis (non-hereditary form) or destabilizing mutations in variant ATTR (ATTRv) amyloidosis (hereditary form). Longitudinal large-scale studies in the United States suggest an incidence of cardiac amyloidosis in the contemporary era of 17 per 100 000, which has increased from a previous estimate of 0.5 per 100 000, which was almost certainly due to misdiagnosis and underestimated. The presence and degree of cardiac involvement is the leading cause of mortality both in ATTRwt and ATTRv amyloidosis, and can be identified in up to 15% of patients hospitalized for HF with preserved ejection fraction. Associated features, such as carpal tunnel syndrome, can preceed by several years the development of symptomatic HF and may serve as early disease markers. Echocardiography and cardiac magnetic resonance raise suspicion of disease and might offer markers of treatment response at a myocardial level, such as extracellular volume quantification. Radionuclide scintigraphy with \'bone\' tracers coupled with biochemical tests may differentiate ATTR from light chain amyloidosis. Therapies able to slow or halt ATTR-CA progression and increase survival are now available. In this evolving scenario, early disease recognition is paramount to derive the greatest benefit from treatment.

© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.

Cardiovasc Res: 05 Aug 2022; epub ahead of print

Cardiovascular effects of incretins - focus on GLP-1 receptor agonists.

Madsbad S, Holst JJ
GLP-1 receptor agonists (GLP-1 RAs) have been used to treat patients with type 2 diabetes since 2005 and have become popular because of the efficacy and durability in relation to glycaemic control in combination with weight loss in most patients. Today in 2022, seven GLP-1 RAs, including oral semaglutide are available for treatment of type 2 diabetes. Since the efficacy in relation to reduction of HbA1c and body weight as well as tolerability and dosing frequency vary between agents, the GLP-1 RAs cannot be considered equal. The short acting lixisenatide showed no cardiovascular benefits, while once daily liraglutide and the weekly agonists, subcutaneous semaglutide, dulaglutide, and efpeglenatide, all lowered the incidence of cardiovascular events. Liraglutide, oral semaglutide and exenatide once weekly also reduced mortality. GLP-1 RAs reduce the progression of diabetic kidney disease. In the 2019 consensus report from EASD/ADA, GLP-1 RAs with demonstrated cardio-renal benefits (liraglutide, semaglutide and dulaglutide) are recommended after metformin to patients with established cardiovascular diseases or multiple cardiovascular risk factors. European Society of Cardiology (ESC) suggests starting with a SGLT-2 inhibitor or a GLP-1 RA in drug naïve patients with type 2 diabetes and atherosclerotic CVD or high CV Risk. However, the results from cardiovascular outcome trials (CVOT) are very heterogeneous suggesting that some GLP-1RA are more suitable to prevent CVD than others. The CVOTs provide a basis upon which individual treatment decisions for patients with T2D and CVD can be made.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Cardiovasc Res: 04 Aug 2022; epub ahead of print

Quantifying the impact of gut microbiota on inflammation and hypertensive organ damage.

Avery EG, Bartolomaeus H, Rauch A, Chen CY, ... Müller DN, Wilck N
Aims
Hypertension (HTN) can lead to heart and kidney damage. The gut microbiota has been linked to HTN, although it is difficult to estimate its significance due to the variety of other features known to influence HTN. In the present study, we used germ-free (GF) and colonized (COL) littermate mice to quantify the impact of microbial colonization on organ damage in HTN.
Methods and results
Four-week-old male GF C57BL/6J littermates were randomized to remain GF or receive microbial colonization. HTN was induced by subcutaneous infusion with angiotensin (Ang) II (1.44 mg/kg/d) and 1% NaCl in the drinking water; sham-treated mice served as control. Renal damage was exacerbated in GF mice, whereas cardiac damage was more comparable between COL and GF, suggesting that the kidney is more sensitive to microbial influence. Multivariate analysis revealed a larger effect of HTN in GF mice. Serum metabolomics demonstrated that the colonization status influences circulating metabolites relevant to HTN. Importantly, GF mice were deficient in anti-inflammatory fecal short-chain fatty acids (SCFA). Flow cytometry showed that the microbiome has an impact on the induction of anti-hypertensive myeloid-derived suppressor cells and pro-inflammatory Th17 cells in HTN. In vitro inducibility of Th17 cells was significantly higher for cells isolated from GF than conventionally raised mice.
Conclusions
Microbial colonization status of mice had potent effects on their phenotypic response to a hypertensive stimulus, and the kidney is a highly microbiota-susceptible target organ in HTN. The magnitude of the pathogenic response in GF mice underscores the role of the microbiome in mediating inflammation in HTN.
Translation perspective
To assess the potential of microbiota-targeted interventions to prevent organ damage in hypertension, an accurate quantification of microbial influence is necessary. We provide evidence that the development of hypertensive organ damage is dependent on colonization status and suggest that a healthy microbiota provides anti-hypertensive immune and metabolic signals to the host. In the absence of normal symbiotic host-microbiome interactions, hypertensive damage to the kidney in particular is exacerbated. We suggest that hypertensive patients experiencing perturbations to the microbiota, which are common in CVD, may be at a greater risk for target-organ damage than those with a healthy microbiome.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.

Cardiovasc Res: 29 Jul 2022; epub ahead of print

Fasting triglycerides are positively associated with cardiovascular mortality risk in people with diabetes.

Wang Y, Fang Y, Magliano DJ, Charchar FJ, ... Drummond GR, Golledge J
Aims
We investigated the association of fasting triglycerides with cardiovascular disease (CVD) mortality.
Methods and results
This cohort study included US adults from the National Health and Nutrition Examination Surveys from 1988 to 2014. CVD mortality outcomes were ascertained by linkage to the National Death Index records. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of triglycerides for CVD mortality. The cohort included 26,570 adult participants, among which 3,978 had diabetes. People with higher triglycerides had a higher prevalence of diabetes at baseline. The cohort was followed up for a mean of 12.0 years with 1,492 CVD deaths recorded. A 1-natural-log-unit higher triglyceride was associated with a 30% higher multivariate-adjusted risk of CVD mortality in participants with diabetes (HR, 1.30; 95% CI, 1.08-1.56) but not in those without diabetes (HR, 0.95; 95% CI, 0.83-1.07). In participants with diabetes, people with high triglycerides (200-499 mg/dL) had a 44% (HR, 1.44; 95% CI, 1.12-1.85) higher multivariate-adjusted risk of CVD mortality compared with those with normal triglycerides (<150 mg/dL). The findings remained significant when diabetes was defined by fasting glucose levels alone, or after further adjustment for the use of lipid-lowering medications, or after the exclusion of those who took lipid-lowering medications.
Conclusions
This study demonstrates that fasting triglycerides of ≥200 mg/dl are associated with an increased risk of CVD mortality in patients with diabetes but not in those without diabetes. Future clinical trials of new treatments to lower triglycerides should focus on patients with diabetes.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.

Cardiovasc Res: 29 Jul 2022; epub ahead of print

From novel discovery tools and biomarkers to precision medicine - basic cardiovascular science highlights of 2021/2022.

Evans PC, Davidson SM, Wojta J, Bäck M, ... Waltenberger J, Weber C
Here we review the highlights of cardiovascular basic science in published in 2021 and early 2022 on behalf of the European Society of Cardiology Council for Basic Cardiovascular Science. We begin with non-coding RNAs which have emerged as central regulators cardiovascular biology, and then discuss how technological developments in single-cell \'omics are providing new insights in cardiovascular development, inflammation and disease. We also review recent discoveries on the biology of extracellular vesicles in driving either protective or pathogenic responses. The Nobel Prize in Physiology or Medicine 2021 recognised the importance of the molecular basis of mechanosensing and here we review breakthroughs in cardiovascular sensing of mechanical force. We also summarise discoveries in the field of atherosclerosis including the role of clonal haematopoiesis of indeterminate potential, and new mechanisms of cross-talk between hyperglycemia, lipid mediators and inflammation. The past 12 months also witnessed major advances in the field of cardiac arrhythmia including new mechanisms of fibrillation. We also focus on inducible pluripotent stem cell (iPSC) technology which has demonstrated disease causality for several genetic polymorphisms in long QT syndrome and aortic valve disease, paving the way for personalized medicine approaches. Finally, the cardiovascular community has continued to better understand COVID-19 with significant advancement in our knowledge of cardiovascular tropism, molecular markers, the mechanism of vaccine-induced thrombotic complications and new anti-viral therapies that protect the cardiovascular system.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Cardiovasc Res: 28 Jul 2022; epub ahead of print

MMP-2 knockdown blunts age-dependent carotid stiffness by decreasing elastin degradation and augmenting eNOS activation.

Diaz-Canestro C, Puspitasari YM, Liberale L, Guzik TJ, ... Sudano I, Camici GG
Aims
Arterial stiffness is a hallmark of vascular ageing that precedes and strongly predicts the development of cardiovascular diseases. Age-dependent stiffening of large elastic arteries is primarily attributed to increased levels of matrix metalloproteinase-2 (MMP-2). However, the mechanistic link between age-dependent arterial stiffness and MMP-2 remains unclear. Thus, we aimed to investigate the efficacy of MMP-2 knockdown using small-interfering RNA (siRNA) on age-dependent arterial stiffness.
Methods and results
Pulse wave velocity (PWV) was assessed in right carotid artery of wild-type (WT) mice from different age groups. MMP-2 levels in the carotid artery and plasma of young (3 months) and old (20-25 months) WT mice were determined. Carotid PWV as well as vascular and circulating MMP-2 were elevated with increasing age in mice. Old WT mice (18- to 21-month old) were treated for 4 weeks with either MMP-2 or scrambled (Scr) siRNA via tail vein injection. Carotid PWV was assessed at baseline, 2 and 4 weeks after start of the treatment. MMP-2 knockdown reduced vascular MMP-2 levels and attenuated age-dependent carotid stiffness. siMMP-2-treated mice showed increased elastin-to-collagen ratio, lower plasma desmosine (DES), enhanced phosphorylation of endothelial nitric oxide synthase (eNOS), and higher levels of vascular cyclic guanosine monophosphate (cGMP). An age-dependent increase in direct protein-protein interaction between MMP-2 and eNOS was also observed. Lastly, DES, an elastin breakdown product, was measured in a patient cohort (n = 64, 23-86 years old), where carotid-femoral PWV was also assessed; here, plasma levels of DES directly correlated with age and arterial stiffness.
Conclusion
MMP-2 knockdown attenuates age-dependent carotid stiffness by blunting elastin degradation and augmenting eNOS bioavailability. Given the increasing clinical use of siRNA technology, MMP2 knockdown should be investigated further as a possible strategy to mitigate age-dependent arterial stiffness and related CV diseases.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.

Cardiovasc Res: 27 Jul 2022; 118:2385-2396

Risk factors profile of young and older patients with myocardial infarction.

Sagris M, Antonopoulos AS, Theofilis P, Oikonomou E, ... Kaski JC, Tousoulis D
Myocardial infarction (MI) among young adults (<45 years) represents a considerable proportion of the total heart attack incidents. The underlying pathophysiologic characteristics, atherosclerotic plaque features, and risk factors profile differ between young and older patients with MI. This review article discusses the main differences between the younger and elderly MI patients as well as the different pathogenic mechanisms underlying the development of MI in the younger. Young patients with MI often have eccentric atherosclerotic plaques with inflammatory features but fewer lesions, and are more likely to be smokers, obese, and have poor lifestyle, such as inactivity and alcohol intake. Compared to older MI patients, younger are more likely to be men, have familial-combined hyperlipidaemia and increased levels of lipoprotein-a. In addition, MI in younger patients may be related to use of cannabis, cocaine use, and androgenic anabolic steroids. Genomic differences especially in the pathways of coagulation and lipid metabolism have also been identified between young and older patients with MI. Better understanding of the risk factors and the anatomic and pathophysiologic processes in young adults can improve MI prevention and treatment strategies in this patient group. Awareness could help identify young subjects at increased risk and guide primary prevention strategies. Additional studies focusing on gene pathways related to lipid metabolism, inflammation, and coagulation are needed.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.

Cardiovasc Res: 27 Jul 2022; 118:2281-2292

Cardiovascular effects of non-insulin glucose-lowering agents: a comprehensive review of trial evidence and potential cardioprotective mechanisms.

Savarese G, Butler J, Lund LH, Bhatt DL, Anker SD
Type 2 diabetes mellitus (T2DM) is highly prevalent and associated with a two-fold increased mortality, mostly explained by cardiovascular diseases. Trial evidence on older glucose-lowering agents such as metformin and sulfonylureas is limited in terms of cardiovascular efficacy. Since 2008, after rosiglitazone was observed to increase the risk of myocardial infarction and heart failure (HF), cardiovascular outcome trials (CVOTs) have been required by regulators for licensing new glucose-lowering agents. In the following CVOTs, dipeptidyl peptidase 4 inhibitors (DPP4i) have been shown to be safe but not to improve mortality/morbidity, except for saxagliptin which increased the risk of HF. Several glucagon-like peptide-1 receptor agonists (GLP1-Ra) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) have been demonstrated to reduce the risk of cardiovascular mortality and morbidity. SGLT2i have shown a class effect for the reduction in risk of HF events in patients with T2DM, leading to trials testing their efficacy/safety in HF regardless of T2DM. In the DAPA-HF and the EMPEROR-Reduced trials dapagliflozin and empagliflozin, respectively, improved cardiovascular mortality/morbidity in patients with HF with reduced ejection fraction (HFrEF), with and without T2DM. Therefore, these drugs are now key part of HFrEF pharmacotherapy. In the SOLOIST-WHF, sotagliflozin reduced cardiovascular mortality/morbidity in patients with T2DM and a recent acute episode of HF regardless of ejection fraction (EF). In the EMPEROR-Preserved, empagliflozin reduced CV mortality/morbidity in patients with heart failure with mildly reduced (HFmrEF) and preserved (HFpEF) EF regardless of comorbid T2DM. The DELIVER is currently testing dapagliflozin in patients with HFmrEF and HFrEF. A strong renal protective role of SGLT2i has also emerged in trials enrolling patients with and without T2DM.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.

Cardiovasc Res: 27 Jul 2022; 118:2231-2252

Antihypertensive drugs and brain function: mechanisms underlying therapeutically beneficial and harmful neuropsychiatric effects.

Carnovale C, Perrotta C, Baldelli S, Cattaneo D, ... Clementi E, Pozzi M
A bidirectional relationship exists between hypertension and psychiatric disorders, including unipolar and bipolar depression, anxiety, post-traumatic stress disorder (PTSD), psychosis, schizophrenia, mania, and dementia/cognitive decline. Repurposing of antihypertensive drugs to treat mental disorders is thus being explored. A systematic knowledge of the mechanisms of action and clinical consequences of the use of antihypertensive agents on neuropsychiatric functions has not been achieved yet. In this article, we review the putative role of antihypertensive agents in psychiatric disorders, discuss the targets and mechanisms of action, and examine how and to what extent specific drug classes/molecules may trigger, worsen, or mitigate psychiatric symptoms. In addition, we review pharmacokinetics (brain penetration of drugs) and pharmacogenetics data that add important information to assess risks and benefits of antihypertensive drugs in neuropsychiatric settings. The scientific literature shows robust evidence of a positive effect of α1 blockers on PTSD symptoms, nightmares and sleep quality, α2 agonists on core symptoms, executive function and quality of life in Attention-Deficit/Hyperactivity Disorder, PTSD, Tourette\'s syndrome, and β blockers on anxiety, aggression, working memory, and social communication. Renin-angiotensin system modulators exert protective effects on cognition, depression, and anxiety, and the loop diuretic bumetanide reduced the core symptoms of autism in a subset of patients. There is no evidence of clear benefits of calcium channel blockers in mood disorders in the scientific literature. These findings are mainly from preclinical studies; clinical data are still insufficient or of anecdotal nature, and seldom systematic. The information herewith provided can support a better therapeutic approach to hypertension, tailored to patients with, or with high susceptibility to, psychiatric illness. It may prompt clinical studies exploring the potential benefit of antihypertensive drugs in selected patients with neuropsychiatric comorbidities that include outcomes of neuropsychiatric interest and specifically assess undesirable effects or interactions.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.

Cardiovasc Res: 27 Jul 2022; epub ahead of print

Molecular stratification of arrhythmogenic mechanisms in the Andersen Tawil Syndrome.

Manuel AIM, Gutiérrez LK, Pedrosa MLV, Uréndez FMC, ... Macías Á, Jalife J
Andersen Tawil Syndrome (ATS) is a rare inheritable disease associated with loss-of-function mutations in KCNJ2, the gene coding the strong inward rectifier potassium channel Kir2.1, which forms an essential membrane protein controlling cardiac excitability. ATS is usually marked by a triad of periodic paralysis, life-threatening cardiac arrhythmias and dysmorphic features, but its expression is variable and not all patients with a phenotype linked to ATS have a known genetic alteration. The mechanisms underlying this arrhythmogenic syndrome are poorly understood. Knowing such mechanisms would be essential to distinguish ATS from other channelopathies with overlapping phenotypes and to develop individualized therapies. For example, the recently suggested role of Kir2.1 as a countercurrent to sarcoplasmic calcium reuptake might explain the arrhythmogenic mechanisms of ATS and its overlap with catecholaminergic polymorphic ventricular tachycardia (CPVT). Here we summarize current knowledge on the mechanisms of arrhythmias leading to sudden cardiac death in ATS. We first provide an overview of the syndrome and its pathophysiology, from the patient´s bedside to the protein, and discuss the role of essential regulators and interactors that could play a role in cases of ATS. The review highlights novel ideas related to some post-translational channel interactions with partner proteins that might help define the molecular bases of the arrhythmia phenotype. We then propose a new all-embracing classification of the currently known ATS loss-of-function mutations according to their position in the Kir2.1 channel structure and their functional implications. We also discuss specific ATS pathogenic variants, their clinical manifestations and treatment stratification. The goal is to provide a deeper mechanistic understanding of the syndrome toward the development of novel targets and personalized treatment strategies.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.

Cardiovasc Res: 27 Jul 2022; epub ahead of print

Ischaemic tissue released microvesicles induce monocyte reprogramming and increase tissue repair by a tissue factor-dependent mechanism.

Arderiu G, Peña E, Badimon L
Aims
Despite increasing evidence that monocytes may acquire endothelial features, it remains unclear how monocytes participate in angiogenesis after ischaemic damage. We investigated whether ischaemic cells can release microvesicles (MVs) and promote neovascularization in a model of peripheral artery disease (PAD).
Methods and results
To model PAD, we used an in vivo experimental model of hind-limb ischaemia (HLI) in mice. MVs were isolated from the ischaemic muscle and from peripheral blood at different times after unilateral femoral artery ligation. MVs were phenotypically characterized to identify cell origin. HLI in mice induced the release of MVs with a much higher content of tissue factor (TF) than non-HLI control mice both in the MVs isolated from the affected limb muscle area and from blood. MVs were mainly released from endothelial cells (ECs) and induced Mo differentiation to endothelial cell-like (ECL) cells. Differentiation to ECL cells encompassed highly strict hierarchical transcription factor activation, initiated by ETS1 activation. MVs secreted by microvascular ECs over-expressing TF (upTF-EMVs), were injected in the ischaemic hind-limb in parallel with control EMVs (from random siRNA-treated cells) or EMVs released by silenced TF ECs. In animals treated with upTF-EMVs in the ischaemic zone, there was a highly significant increase in functional new vessels formation (seen by magnetic resonance angiography), a concomitant increase in the pool of circulating Ly6Clow Mo expressing vascular EC markers, and a significantly higher number of Mo/macrophages surrounding and integrating the newly formed collaterals.
Conclusion
Ischaemia-activated ECs release EMVs rich in TF that induce monocyte differentiation into ECL cells and the formation of new vessels in the ischaemic zone. TF by this mechanism of formation of new blood microvessels can contribute to ischaemic tissue repair.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.

Cardiovasc Res: 27 Jul 2022; 118:2354-2366

Vascular endothelial tissue factor contributes to trimethylamine N-oxide-enhanced arterial thrombosis.

Witkowski M, Witkowski M, Friebel J, Buffa JA, ... Rauch U, Hazen SL
Aims
Gut microbiota and their generated metabolites impact the host vascular phenotype. The metaorganismal metabolite trimethylamine N-oxide (TMAO) is both associated with adverse clinical thromboembolic events, and enhances platelet responsiveness in subjects. The impact of TMAO on vascular Tissue Factor (TF) in vivo is unknown. Here, we explore whether TMAO-enhanced thrombosis potential extends beyond TMAO effects on platelets, and is linked to TF. We also further explore the links between gut microbiota and vascular endothelial TF expression in vivo.
Methods and results
In initial exploratory clinical studies, we observed that among sequential stable subjects (n = 2989) on anti-platelet therapy undergoing elective diagnostic cardiovascular evaluation at a single-site referral centre, TMAO levels were associated with an increased incident (3 years) risk for major adverse cardiovascular events (MACE) (myocardial infarction, stroke, or death) [4th quartile (Q4) vs. Q1 adjusted hazard ratio (HR) 95% confidence interval (95% CI), 1.73 (1.25-2.38)]. Similar results were observed within subjects on aspirin mono-therapy during follow-up [adjusted HR (95% CI) 1.75 (1.25-2.44), n = 2793]. Leveraging access to a second higher risk cohort with previously reported TMAO data and monitoring of anti-platelet medication use, we also observed a strong association between TMAO and incident (1 year) MACE risk in the multi-site Swiss Acute Coronary Syndromes Cohort, focusing on the subset (n = 1469) on chronic dual anti-platelet therapy during follow-up [adjusted HR (95% CI) 1.70 (1.08-2.69)]. These collective clinical data suggest that the thrombosis-associated effects of TMAO may be mediated by cells/factors that are not inhibited by anti-platelet therapy. To test this, we first observed in human microvascular endothelial cells that TMAO dose-dependently induced expression of TF and vascular cell adhesion molecule (VCAM)1. In mouse studies, we observed that TMAO-enhanced aortic TF and VCAM1 mRNA and protein expression, which upon immunolocalization studies, was shown to co-localize with vascular endothelial cells. Finally, in arterial injury mouse models, TMAO-dependent enhancement of in vivo TF expression and thrombogenicity were abrogated by either a TF-inhibitory antibody or a mechanism-based microbial choline TMA-lyase inhibitor (fluoromethylcholine).
Conclusion
Endothelial TF contributes to TMAO-related arterial thrombosis potential, and can be specifically blocked by targeted non-lethal inhibition of gut microbial choline TMA-lyase.

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Cardiovasc Res: 27 Jul 2022; 118:2367-2384

Surface Lin28A expression consistent with cellular stress parallels indicators of senescence.

Broughton K, Esquer C, Echeagaray O, Firouzi F, ... Gude N, Sussman MA
Aims
Declining cellular functional capacity resulting from stress or aging is a primary contributor to impairment of myocardial performance. Molecular pathway regulation of biological processes in cardiac interstitial cells (CICs) is pivotal in stress and aging responses. Altered localization of the RNA binding protein Lin28A has been reported in response to environmental stress, but the role of Lin28A in response to stress in CICs has not been explored. Surface Lin28A redistribution is indicative of stress response in CIC associated with aging and senescence.
Methods and results
Localization of Lin28A was assessed by multiple experimental analyses and treatment conditions and correlated to oxidative stress, senescence, and ploidy in adult murine CICs. Surface Lin28A expression is present on 5% of fresh CICs and maintained through passage 2, increasing to 21% in hyperoxic conditions but lowered to 14% in physiologic normoxia. Surface Lin28A is coincident with elevated senescence marker p16 and beta-galactosidase (β-gal) expression in CICs expanded in hyperoxia, and also increases with polyploidization and binucleation of CICs regardless of oxygen culture. Transcriptional profiling of CICs using single cell RNASeq reveals upregulation of pathways associated with oxidative stress in CICs exhibiting surface Lin28A. Induction of surface Lin28A by oxidative stress is blunted by treatment of cells with the antioxidant Trolox in a dose-dependent manner, with 300uM Trolox exposure maintaining characteristics of freshly isolated CICs possessing low expression of surface Lin28A and β-gal with predominantly diploid content.
Conclusion
Surface Lin28A is a marker of environmental oxidative stress in CICs and antioxidant treatment antagonizes this phenotype. The biological significance of Lin28 surface expression and consequences for myocardial responses may provide important insights regarding mitigation of cardiac stress and aging.
Translational perspective
Cellular phenotypic changes occurring in response to oxidative stress provides critical insights into biological processes of pathological injury and aging. Surface Lin28A is novel surface marker of oxidative stress conditions that cause DNA damage and cellular senescence. Accumulation of surface Lin28A was inhibited by antioxidant treatment with lowered indices of cellular stress and senescence, revealing the potential of surface Lin28A as a diagnostic stress marker. Furthermore, therapeutic strategies targeted toward surface Lin28 expression set the stage for next generation senolytics to remove stressed or senescent cells and promote recovery from tissue injury or aging.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Cardiovasc Res: 26 Jul 2022; epub ahead of print

Obesity and heart failure with preserved ejection fraction: new insights and pathophysiologic targets.

Borlaug BA, Jensen MD, Kitzman DW, Lam CSP, Obokata M, Rider OJ
Obesity and heart failure (HF) with preserved ejection fraction (HFpEF) represent two intermingling epidemics driving perhaps the greatest unmet health problem in cardiovascular medicine in the 21st century. Many patients with HFpEF are either overweight or obese, and recent data have shown that increased body fat and its attendant metabolic sequelae have widespread, protean effects systemically and on the cardiovascular system leading to symptomatic HFpEF. The paucity of effective therapies in HFpEF underscores the importance of understanding the distinct pathophysiological mechanisms of obese HFpEF to develop novel therapies. In this review, we summarize the current understanding of the cardiovascular and non-cardiovascular features of the obese phenotype of HFpEF, how increased adiposity might pathophysiologically contribute to the phenotype, and how these processes might be targeted therapeutically.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Cardiovasc Res: 26 Jul 2022; epub ahead of print

A functional connectome signature of blood pressure in >30,000 participants from the UK Biobank.

Jiang R, Calhoun VD, Noble S, Sui J, ... Qi S, Scheinost D
Aims
Elevated blood pressure (BP) is a prevalent modifiable risk factor for cardiovascular diseases and contributes to cognitive decline in late life. Despite the fact that functional changes may precede irreversible structural damage and emerge in an ongoing manner, studies have been predominantly informed by brain structure and group-level inferences. Here, we aim to delineate neurobiological correlates of BP at an individual level using machine learning and functional connectivity.
Methods and results
Based on whole-brain functional connectivity from the UK Biobank, we built a machine learning model to identify neural representations for individuals\' past (∼8.9 years before scanning, N = 35,882), current (N = 31,367), and future (∼2.4 years follow-up, N = 3,138) BP levels within a repeated cross-validation framework. We examined the impact of multiple potential covariates, as well as assessed these models\' generalizability across various contexts.The predictive models achieved significant correlations between predicted and actual systolic/diastolic BP and pulse pressure while controlling for multiple confounders. Predictions for participants not on antihypertensive medication were more accurate than for currently medicated patients. Moreover, the models demonstrated robust generalizability across contexts in terms of ethnicities, imaging centers, medication status, participant visits, gender, age, and BMI. The identified connectivity patterns primarily involved the cerebellum, prefrontal, anterior insula, anterior cingulate cortex, supramarginal gyrus, and precuneus, which are key regions of the central autonomic network, and involved in cognition processing and susceptible to neurodegeneration in Alzheimer\'s disease. Results also showed more involvement of default mode and frontoparietal networks in predicting future BP levels and in medicated participants.
Conclusion
This study, based on the largest neuroimaging sample currently available and using machine learning, identifies brain signatures underlying BP, providing evidence for meaningful BP-associated neural representations in connectivity profiles.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Cardiovasc Res: 25 Jul 2022; epub ahead of print

Long COVID and the cardiovascular system - elucidating causes and cellular mechanisms in order to develop targeted diagnostic and therapeutic strategies: A joint Scientific Statement of the ESC Working Groups on Cellular Biology of the Heart and Myocardial & Pericardial Diseases.

Gyöngyösi M, Alcaide P, Asselbergs FW, Brundel BJJM, ... Van Linthout S, Davidson SM
Long COVID has become a world-wide, non-communicable epidemic, caused by long-lasting multi-organ symptoms that endure for weeks or months after SARS-CoV-2 infection has already subsided. This scientific document aims to provide insight into the possible causes and therapeutic options available for the cardiovascular manifestations of long COVID. In addition to chronic fatigue, which is a common symptom of long COVID, patients may present with chest pain, ECG abnormalities, postural orthostatic tachycardia, or newly developed supraventricular or ventricular arrhythmias. Imaging of the heart and vessels has provided evidence of chronic, post-infectious peri-myocarditis with consequent left or right ventricular failure, arterial wall inflammation or micro-thrombosis in certain patient populations. Better understanding of the underlying cellular and molecular mechanisms of long COVID will aid in the development of effective treatment strategies for its cardiovascular manifestations. A number of mechanisms have been proposed, including those involving direct effects on the myocardium, micro-thrombotic damage to vessels or endothelium, or persistent inflammation. Unfortunately, existing circulating biomarkers, coagulation and inflammatory markers, are not highly predictive for either the presence or outcome of long COVID when measured 3 months after SARS-CoV-2 infection. Further studies are needed to understand underlying mechanisms, identify specific biomarkers and guide future preventive strategies or treatments to address long COVID and its cardiovascular sequelae.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.

Cardiovasc Res: 25 Jul 2022; epub ahead of print

The size of apolipoprotein (a) is an independent determinant of the reduction in lipoprotein (a) induced by PCSK9 inhibitors.

Blanchard V, Chemello K, Hollstein T, Hong-Fong CC, ... Steinhagen-Thiessen E, Lambert G
Aims
Lipoprotein (a) [Lp(a)] is a lipoprotein species causatively associated with atherosclerosis. Unlike statins, PCSK9 inhibitors (PCSK9i) reduce Lp(a), but this reduction is highly variable. Levels of Lp(a) are chiefly governed by the size of its signature protein, apolipoprotein (a) [apo(a)]. Whether this parameter determines some of the reduction in Lp(a) induced by PCSK9i remains unknown. We aimed to investigate if the Lp(a) lowering efficacy of PCSK9i is modulated by the size of apo(a), which is genetically determined by the variable number of KIV domains present on that protein.
Methods and results
The levels of Lp(a) and the size of apo(a) were assessed in plasma samples from 268 patients before and after treatment with PCSK9i. Patients were recruited at the Outpatient Lipid Clinic of the Charité Hospital (Berlin) between 2015 and 2020. They were hypercholesterolaemic at very high cardiovascular disease risk with low-density lipoprotein (LDL)-cholesterol levels above therapeutic targets despite maximally tolerated lipid-lowering therapy. Patients received either Alirocumab (75 or 150 mg) or Evolocumab (140 mg) every 2 weeks. Apo(a), apoB100, and apoE concentrations as well as apoE major isoforms were determined by liquid chromatography high-resolution mass spectrometry. Apo(a) isoforms sizes were determined by western blot. PCSK9i sharply reduced LDL-cholesterol (-57%), apoB100 (-47%), and Lp(a) (-36%). There was a positive correlation between the size of apo(a) and the relative reduction in Lp(a) induced by PCSK9i (r = 0.363, P = 0.0001). The strength of this association remained unaltered after adjustment for baseline Lp(a) levels and all other potential confounding factors. In patients with two detectable apo(a) isoforms, there was also a positive correlation between the size of apo(a) and the reduction in Lp(a), separately for the smaller (r = 0.350, P = 0.0001) and larger (r = 0.324, P = 0.0003) isoforms. The relative contribution of the larger isoform to the total concentration of apo(a) was reduced from 29% to 15% (P < 0.0001).
Conclusions
The size of apo(a) is an independent determinant of the response to PCSK9i. Each additional kringle domain is associated with a 3% additional reduction in Lp(a). This explains in part the variable efficacy of PCSK9i and allows to identify patients who will benefit most from these therapies in terms of Lp(a) lowering.

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Cardiovasc Res: 20 Jul 2022; 118:2103-2111

Using multimarker screening to identify biomarkers associated with cardiovascular death in patients with atrial fibrillation.

Pol T, Hijazi Z, Lindbäck J, Oldgren J, ... Siegbahn A, Wallentin L
Aims
Atrial fibrillation (AF) is associated with higher mortality. Biomarkers may improve the understanding of key pathophysiologic processes in AF that lead to death. Using a new multiplex analytic technique, we explored the association between 268 biomarkers and cardiovascular (CV) death in anticoagulated patients with AF.
Methods and results
A case-cohort design with 1.8- to 1.9-year follow-up. The identification cohort included 517 cases and 4057 randomly selected patients from ARISTOTLE. The validation cohort included 277 cases and 1042 randomly selected controls from RE-LY. Plasma collected at randomization was analysed with conventional immunoassays and the OLINK proximity extension assay panels: CVDII, CVDIII, and Inflammation. Association between biomarkers and CV death was evaluated using Random Survival Forest, Boruta, and adjusted Cox-regression analyses. The biomarkers most strongly and consistently associated with CV death were as follows (hazard ratio for inter-quartile comparison [95% CI]): N-terminal pro-B-type natriuretic peptide [NT-proBNP; 1.63 (1.37-1.93)], cardiac troponin T [cTnT-hs; 1.60 (1.35-1.88)], interleukin-6 [IL-6; 1.29 (1.13-1.47)], growth differentiation factor-15 [GDF-15; 1.30 (1.10-1.53)], fibroblast growth factor 23 [FGF-23; 1.21 (1.10-1.33)], urokinase receptor [uPAR; 1.38 (1.16-1.64)], trefoil factor 3 [TFF3; 1.27 (1.10-1.46)], tumour necrosis factor receptor 1 [TNFR1; 1.21 (1.01-1.45)], TNF-related apoptosis-inducing ligand receptor 2 [TRAILR2; 1.18 (1.04-1.34)], and cathepsin L1 [CTSL1; 1.22 (1.07-1.39)].
Conclusion
In this comprehensive screening of 268 biomarkers in anticoagulated patients with AF, the underlying mechanisms most strongly associated with CV death were cardiorenal dysfunction (NT-proBNP, cTnT-hs, CTSL1, TFF3), oxidative stress (GDF-15), inflammation (IL-6, GDF-15), calcium balance, vascular and renal dysfunction (FGF-23), fibrinolysis (suPAR), and apoptosis (TNFR1, TRAILR2). These findings provide novel insights into pathophysiologic aspects associated with CV death in AF.
Clinicaltrials.gov identifier
NCT00412984 and NCT00262600.

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Cardiovasc Res: 20 Jul 2022; 118:2112-2123

MicroRNA-27b-3p down-regulates FGF1 and aggravates pathological cardiac remodelling.

Li G, Shao Y, Guo HC, Zhi Y, ... Lai YQ, Li Y
Aims
The heart undergoes pathological remodelling under increased stress and neuronal imbalance. MicroRNAs (miRNAs) are involved in post-transcriptional regulation of genes in cardiac physiology and pathology. However, the mechanisms underlying miRNA-mediated regulation of pathological cardiac remodelling remain to be studied. This study aimed to explore the function of endogenous microRNA-27b-3p (miR-27b-3p) in pathological cardiac remodelling.
Methods and results
miR-27b-3p expression was elevated in the heart of a transverse aortic constriction (TAC)-induced cardiac hypertrophy mouse model. miR-27b-knockout mice showed significantly attenuated cardiac hypertrophy, fibrosis, and inflammation induced by two independent pathological cardiac hypertrophy models, TAC and Angiotensin II (Ang II) perfusion. Transcriptome sequencing analysis revealed that miR-27b deletion significantly down-regulated TAC-induced cardiac hypertrophy, fibrosis, and inflammatory genes. We identified fibroblast growth factor 1 (FGF1) as a miR-27b-3p target gene in the heart which was up-regulated in miR-27b-null mice. We found that both recombinant FGF1 (rFGF1) and inhibition of miR-27b-3p enhanced mitochondrial oxidative phosphorylation (OXPHOS) and inhibited cardiomyocyte hypertrophy. Importantly, rFGF1 administration inhibited cardiac hypertrophy and fibrosis in TAC- or Ang II-induced models and enhanced OXPHOS by activating PGC1α/β.
Conclusions
Our study demonstrated that miR-27b-3p induces pathological cardiac remodelling and suggests that inhibition of endogenous miR-27b-3p or administration of FGF1 might have the potential to suppress cardiac remodelling in a clinical setting.

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Cardiovasc Res: 20 Jul 2022; 118:2139-2151

Cardiac natriuretic peptide deficiency sensitizes the heart to stress-induced ventricular arrhythmias via impaired CREB signalling.

Hall EJ, Pal S, Glennon MS, Shridhar P, ... Lal H, Becker JR
Aims
The cardiac natriuretic peptides [atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP)] are important regulators of cardiovascular physiology, with reduced natriuretic peptide (NP) activity linked to multiple human cardiovascular diseases. We hypothesized that deficiency of either ANP or BNP would lead to similar changes in left ventricular structure and function given their shared receptor affinities.
Methods and results
We directly compared murine models deficient of ANP or BNP in the same genetic backgrounds (C57BL6/J) and environments. We evaluated control, ANP-deficient (Nppa-/-) or BNP-deficient (Nppb-/-) mice under unstressed conditions and multiple forms of pathological myocardial stress. Survival, myocardial structure, function and electrophysiology, tissue histology, and biochemical analyses were evaluated in the groups. In vitro validation of our findings was performed using human-derived induced pluripotent stem cell cardiomyocytes (iPS-CMs). In the unstressed state, both ANP- and BNP-deficient mice displayed mild ventricular hypertrophy which did not increase up to 1 year of life. NP-deficient mice exposed to acute myocardial stress secondary to thoracic aortic constriction (TAC) had similar pathological myocardial remodelling but a significant increase in sudden death. We discovered that the NP-deficient mice are more susceptible to stress-induced ventricular arrhythmias using both in vivo and ex vivo models. Mechanistically, deficiency of either ANP or BNP led to reduced myocardial cGMP levels and reduced phosphorylation of the cAMP response element-binding protein (CREBS133) transcriptional regulator. Selective CREB inhibition sensitized wild-type hearts to stress-induced ventricular arrhythmias. ANP and BNP regulate cardiomyocyte CREBS133 phosphorylation through a cGMP-dependent protein kinase 1 (PKG1) and p38 mitogen-activated protein kinase (p38 MAPK) signalling cascade.
Conclusions
Our data show that ANP and BNP act in a non-redundant fashion to maintain myocardial cGMP levels to regulate cardiomyocyte p38 MAPK and CREB activity. Cardiac natriuretic peptide deficiency leads to a reduction in CREB signalling which sensitizes the heart to stress-induced ventricular arrhythmias.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.

Cardiovasc Res: 20 Jul 2022; 118:2124-2138

Non-coding RNAs in cardiac inflammation: key drivers in the pathophysiology of heart failure.

Sansonetti M, De Windt LJ
Heart failure is among the most progressive diseases and a leading cause of morbidity. Despite several advances in cardiovascular therapies, pharmacological treatments are limited to relieve symptoms without curing cardiac injury. Multiple observations point to the involvement of immune cells as key drivers in the pathophysiology of heart failure. In particular, there is a growing recognition that heart failure is related to a prolonged and insufficiently repressed inflammatory response leading to molecular, cellular, and functional cardiac alterations. Over the last decades, non-coding RNAs are recognized as prominent mediators of cardiac inflammation, affecting the function of several immune cells. In the current review, we explore the contribution of the diverse immune cells in the progression of heart failure, revealing mechanistic functions for non-coding RNAs in cardiac immune cells as a new and exciting field of investigation.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.

Cardiovasc Res: 20 Jul 2022; 118:2058-2073

Testosterone therapy and cardiovascular diseases.

Cittadini A, Isidori AM, Salzano A
Since it was first synthesized in 1935, testosterone (T) has been viewed as the mythical Fountain of Youth, promising rejuvenation, restoring sexual appetites, growing stronger muscles, and quicker thinking. T is endowed with direct effects on myocardial and vascular structure and function, as well as on risk factors for cardiovascular (CV) disease. Indeed, low serum T levels are a risk factor for diabetes, metabolic syndrome, inflammation, and dyslipidaemia. Moreover, many studies have shown that T deficiency per se is an independent risk factor of CV and all-cause mortality. On this background and due to direct-to-patient marketing by drug companies, we have witnessed to the widespread use of T replacement therapy without clear indications particularly in late-life onset hypogonadism. The current review will dwell upon current evidence and controversies surrounding the role of T in the pathophysiology of CV diseases, the link between circulating T levels and CV risk, and the use of replacing T as a possible adjuvant treatment in specific CV disorders. Specifically, recent findings suggest that heart failure and type 2 diabetes mellitus represent two potential targets of T therapy once that a state of hypogonadism is diagnosed. However, only if ongoing studies solve the CV safety issue the T orchid may eventually \'bloom\'.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.

Cardiovasc Res: 20 Jul 2022; 118:2039-2057

Nicotine promotes vascular calcification via intracellular Ca2+-mediated, Nox5-induced oxidative stress, and extracellular vesicle release in vascular smooth muscle cells.

Petsophonsakul P, Burgmaier M, Willems B, Heeneman S, ... Furmanik M, Schurgers L
Aims
Smokers are at increased risk of cardiovascular events. However, the exact mechanisms through which smoking influences cardiovascular disease resulting in accelerated atherosclerosis and vascular calcification are unknown. The aim of this study was to investigate effects of nicotine on initiation of vascular smooth muscle cell (VSMC) calcification and to elucidate underlying mechanisms.
Methods and results
We assessed vascular calcification of 62 carotid lesions of both smoking and non-smoking patients using ex vivo micro-computed tomography (µCT) scanning. Calcification was present more often in carotid plaques of smokers (n = 22 of 30, 73.3%) compared to non-smokers (n = 11 of 32, 34.3%; P < 0.001), confirming higher atherosclerotic burden. The difference was particularly profound for microcalcifications, which was 17-fold higher in smokers compared to non-smokers. In vitro, nicotine-induced human primary VSMC calcification, and increased osteogenic gene expression (Runx2, Osx, BSP, and OPN) and extracellular vesicle (EV) secretion. The pro-calcifying effects of nicotine were mediated by Ca2+-dependent Nox5. SiRNA knock-down of Nox5 inhibited nicotine-induced EV release and calcification. Moreover, pre-treatment of hVSMCs with vitamin K2 ameliorated nicotine-induced intracellular oxidative stress, EV secretion, and calcification. Using nicotinic acetylcholine receptor (nAChR) blockers α-bungarotoxin and hexamethonium bromide, we found that the effects of nicotine on intracellular Ca2+ and oxidative stress were mediated by α7 and α3 nAChR. Finally, we showed that Nox5 expression was higher in carotid arteries of smokers and correlated with calcification levels in these vessels.
Conclusion
In this study, we provide evidence that nicotine induces Nox5-mediated pro-calcific processes as novel mechanism of increased atherosclerotic calcification. We identified that activation of α7 and α3 nAChR by nicotine increases intracellular Ca2+ and initiates calcification of hVSMCs through increased Nox5 activity, leading to oxidative stress-mediated EV release. Identifying the role of Nox5-induced oxidative stress opens novel avenues for diagnosis and treatment of smoking-induced cardiovascular disease.

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Cardiovasc Res: 20 Jul 2022; 118:2196-2210

Interleukin-5-induced eosinophil population improves cardiac function after myocardial infarction.

Xu JY, Xiong YY, Tang RJ, Jiang WY, ... Li XD, Yang YJ
Aims
Interleukin (IL)-5 mediates the development of eosinophils (EOS) that are essential for tissue post-injury repair. It remains unknown whether IL-5 plays a role in heart repair after myocardial infarction (MI). This study aims to test whether IL-5-induced EOS population promotes the healing and repair process post-MI and to reveal the underlying mechanisms.
Methods and results
MI was induced by permanent ligation of the left anterior descending coronary artery in wild-type C57BL/6 mice. Western blot and real-time polymerase chain reaction revealed elevated expression of IL-5 in the heart at 5 days post-MI. Immunohistostaining indicated that IL-5 was secreted mainly from macrophages and CD127+ cells in the setting of experimental MI. External supply of recombinant mouse IL-5 (20 min, 1 day, and 2 days after MI surgery) reduced the infarct size and increased ejection fraction and angiogenesis in the border zone. A significant expansion of EOS was detected in both the peripheral blood and infarcted myocardium after IL-5 administration. Pharmacological depletion of EOS by TRFK5 pretreatment muted the beneficial effects of IL-5 in MI mice. Mechanistic studies demonstrated that IL-5 increased the accumulation of CD206+ macrophages in infarcted myocardium at 7 days post-MI. In vitro co-culture experiments showed that EOS shifted bone marrow-derived macrophage polarization towards the CD206+ phenotypes. This activity of EOS was abolished by IL-4 neutralizing antibody, but not IL-10 or IL-13 neutralization. Western blot analyses demonstrated that EOS promoted the macrophage downstream signal transducer and activator of transcription 6 (STAT6) phosphorylation.
Conclusion
IL-5 facilitates the recovery of cardiac dysfunction post-MI by promoting EOS accumulation and subsequent CD206+ macrophage polarization via the IL-4/STAT6 axis.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.

Cardiovasc Res: 20 Jul 2022; 118:2165-2178

Determining a minimum set of variables for machine learning cardiovascular event prediction: results from REFINE SPECT registry.

Rios R, Miller RJH, Hu LH, Otaki Y, ... Berman DS, Slomka P
Aims
Optimal risk stratification with machine learning (ML) from myocardial perfusion imaging (MPI) includes both clinical and imaging data. While most imaging variables can be derived automatically, clinical variables require manual collection, which is time-consuming and prone to error. We determined the fewest manually input and imaging variables required to maintain the prognostic accuracy for major adverse cardiac events (MACE) in patients undergoing a single-photon emission computed tomography (SPECT) MPI.
Methods and results
This study included 20 414 patients from the multicentre REFINE SPECT registry and 2984 from the University of Calgary for training and external testing of the ML models, respectively. ML models were trained using all variables (ML-All) and all image-derived variables (including age and sex, ML-Image). Next, ML models were sequentially trained by incrementally adding manually input and imaging variables to baseline ML models based on their importance ranking. The fewest variables were determined as the ML models (ML-Reduced, ML-Minimum, and ML-Image-Reduced) that achieved comparable prognostic performance to ML-All and ML-Image. Prognostic accuracy of the ML models was compared with visual diagnosis, stress total perfusion deficit (TPD), and traditional multivariable models using area under the receiver-operating characteristic curve (AUC). ML-Minimum (AUC 0.798) obtained comparable prognostic accuracy to ML-All (AUC 0.799, P = 0.19) by including 12 of 40 manually input variables and 11 of 58 imaging variables. ML-Reduced achieved comparable accuracy (AUC 0.796) with a reduced set of manually input variables and all imaging variables. In external validation, the ML models also obtained comparable or higher prognostic accuracy than traditional multivariable models.
Conclusion
Reduced ML models, including a minimum set of manually collected or imaging variables, achieved slightly lower accuracy compared to a full ML model but outperformed standard interpretation methods and risk models. ML models with fewer collected variables may be more practical for clinical implementation.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.

Cardiovasc Res: 20 Jul 2022; 118:2152-2164

Nitro-oleic acid reduces thoracic aortic aneurysm progression in a mouse model of Marfan syndrome.

Nettersheim FS, Lemties J, Braumann S, Geißen S, ... Mollenhauer M, Adam M
Aims
Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in the Fibrillin-1 gene. It is associated with formation of thoracic aortic aneurysms that can potentially be a life-threatening condition due to aortic rupture or dissection. Excessive non-canonical transforming growth factor beta signalling, mediated by activation of extracellular signal-regulated kinases 1/2 (ERK1/2), as well as inducible nitric oxide synthase (NOS2)-dependent nitric oxide production, have been identified to drive aortic pathology in MFS through induction of elastin fragmentation and smooth muscle cell apoptosis. Despite promising results in animal studies, specific pharmacological interventions approved for clinical use in patients with MFS-related aortic disease are rare. Nitro-oleic acid (NO2-OA) is an endogenously generated signalling modulator, which is available as an oral compound and has been shown to inhibit ERK1/2 activation and NOS2 expression in different disease models, thereby exerting promising therapeutic effects. In this study, we investigated whether NO2-OA decreases aortic dilation in MFS.
Methods and results
Eight-week-old MFS (Fbn1C1041G/+) mice were treated with NO2-OA or vehicle for 4 weeks via subcutaneously implanted osmotic minipumps. Echocardiography indicated progressive ascending aortic dilation and wall stiffening in MFS mice, which was significantly attenuated by NO2-OA treatment. This protective effect was mediated by inhibition of aortic ERK1/2, Smad2 as well as nuclear factor kappa B overactivation and consequent attenuation of elastin fragmentation by matrix metalloproteinase 2, apoptosis, and collagen deposition. Critically, the therapeutic efficacy of NO2-OA in MFS was further emphasized by demonstrating its capability to reduce lethal aortic complications in Fbn1C1041G/+ mice challenged with Angiotensin II.
Conclusion
NO2-OA distinctly attenuates progression of aortic dilation in MFS via modulation of well-established disease-mediating pathways, thereby meriting further investigation into its application as a therapeutic agent for the treatment of this condition.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.

Cardiovasc Res: 20 Jul 2022; 118:2211-2225

EDIL3 deficiency ameliorates adverse cardiac remodelling by neutrophil extracellular traps (NET)-mediated macrophage polarization.

Wei X, Zou S, Xie Z, Wang Z, ... Cui K, Li J
Aims
After myocardial infarction (MI), injured cardiomyocytes recruit neutrophils and monocytes/macrophages to myocardium, which in turn initiates inflammatory and reparative cascades, respectively. Either insufficient or excessive inflammation impairs cardiac healing. As an endogenous inhibitor of neutrophil adhesion, EDIL3 plays a crucial role in inflammatory regulation. However, the role of EDIL3 in MI remains obscure. We aimed to define the role of EDIL3 in cardiac remodelling after MI.
Methods and results
Serum EDIL3 levels in MI patients were negatively associated with MI biomarkers. Consistently, WT mice after MI showed low levels of cardiac EDIL3. Compared with WT mice, Edil3-/- mice showed improvement of post-MI adverse remodelling, as they exhibited lower mortality, better cardiac function, shorter scar length, and smaller LV cavity. Accordingly, infarcted hearts of Edil3-/- mice contained fewer cellular debris and lower amounts of fibrosis content, with decreased collagen I/III expression and the percentage of α-smooth muscle actin myofibroblasts. Mechanistically, EDIL3 deficiency did not affect the recruitment of monocytes or T cells, but enhanced neutrophil recruitment and following expansion of pro-inflammatory Mertk-MHC-IIlo-int (myeloid-epithelial-reproductive tyrosine kinase/major histocompatibility complex II) macrophages. The injection of neutrophil-specific C-X-C motif chemokine receptor 2 antagonist eliminated the differences in macrophage polarization and cardiac function between WT and Edil3-/- mice after MI. Neutrophil extracellular traps (NETs), which were more abundant in the hearts of Edil3-/- mice, contributed to Mertk-MHC-IIlo-int polarization via Toll-like receptor 9 pathway. The inhibition of NET formation by treatment of neutrophil elastase inhibitor or DNase I impaired macrophage polarization, increased cellular debris and aggravated cardiac adverse remodelling, thus removed the differences of cardiac function between WT and Edil3-/- mice. Totally, EDIL3 plays an important role in NET-primed macrophage polarization and cardiac remodelling during MI.
Conclusion
We not only reveal that EDIL3 deficiency ameliorates adverse cardiac healing via NET-mediated pro-inflammatory macrophage polarization but also discover a new crosstalk between neutrophil and macrophage after MI.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.

Cardiovasc Res: 20 Jul 2022; 118:2179-2195

Adiponectin and cardiometabolic trait and mortality: where do we go?

Jang AY, Scherer PE, Kim JY, Lim S, Koh KK
Adiponectin is an adipocyte-derived cytokine known for its cardioprotective effects in preclinical studies. Early epidemiologic studies replicated these findings and drew great interest. Subsequent large-scale prospective cohorts, however, showed that adiponectin levels seemed not to relate to incident coronary artery disease (CAD). Even more surprisingly, a paradoxical increase of all-cause and cardiovascular (CV) mortality with increased adiponectin levels was reported. The adiponectin-mortality paradox has been explained by some groups asserting that adiponectin secretion is promoted by elevated natriuretic peptides (NP). Other groups have proposed that adiponectin is elevated due to adiponectin resistance in subjects with metabolic syndrome or heart failure (HF). However, there is no unifying theory that can clearly explain this paradox. In patients with HF with reduced ejection fraction (HFrEF), stretched cardiomyocytes secrete NPs, which further promote release of adiponectin from adipose tissue, leading to adiponectin resistance. On the other hand, adiponectin biology may differ in patients with heart failure with preserved ejection fraction (HFpEF), which constitutes 50% of all of HF. Most HFpEF patients are obese, which exerts inflammation and myocardial stiffness, i.e. likely to prevent myocardial stretch and subsequent NP release. This segment of the patient population may display different adiponectin biology from its HFrEF counterpart. Dissecting the adiponectin-mortality relationship in terms of different HF subtypes may help to comprehensively understand this paradox. Mendelian randomization (MR) analyses claimed that adiponectin levels are not causally related to CAD or metabolic syndrome. Results from MR studies, however, should be interpreted with great caution because the underlying history of CAD or CHF was not taken into account in these analyses, an issue that may substantially confound the results. Here, we discuss many aspects of adiponectin; cardiometabolic traits, therapeutic interventions, and the ongoing debate about the adiponectin paradox, which were recently described in basic, epidemiologic, and clinical studies.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.

Cardiovasc Res: 20 Jul 2022; 118:2074-2084

Cyclic GMP modulating drugs in cardiovascular diseases: mechanism-based network pharmacology.

Petraina A, Nogales C, Krahn T, Mucke H, ... Hobbs AJ, Schmidt HHHW
Mechanism-based therapy centred on the molecular understanding of disease-causing pathways in a given patient is still the exception rather than the rule in medicine, even in cardiology. However, recent successful drug developments centred around the second messenger cyclic guanosine-3\'-5\'-monophosphate (cGMP), which is regulating a number of cardiovascular disease modulating pathways, are about to provide novel targets for such a personalized cardiovascular therapy. Whether cGMP breakdown is inhibited or cGMP synthesis is stimulated via guanylyl cyclases or their upstream regulators in different cardiovascular disease phenotypes, the outcomes seem to be so far uniformly protective. Thus, a network of cGMP-modulating drugs has evolved that act in a mechanism-based, possibly causal manner in a number of cardiac conditions. What remains a challenge is the detection of cGMPopathy endotypes amongst cardiovascular disease phenotypes. Here, we review the growing clinical relevance of cGMP and provide a glimpse into the future on how drugs interfering with this pathway may change how we treat and diagnose cardiovascular diseases altogether.

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Cardiovasc Res: 20 Jul 2022; 118:2085-2102

Nogo-A reduces ceramide de novo biosynthesis to protect from heart failure.

Sasset L, Manzo OL, Zhang Y, Marino A, ... Lu TT, Di Lorenzo A
Aims
Growing evidence correlate the accrual of the sphingolipid ceramide in plasma and cardiac tissue with heart failure (HF). Regulation of sphingolipid metabolism in the heart and the pathological impact of its derangement remain poorly understood. Recently, we discovered that Nogo-B, a membrane protein of endoplasmic reticulum, abundant in the vascular wall, down-regulates the sphingolipid de novo biosynthesis, via serine palmitoyltransferase (SPT), first and rate liming enzyme, to impact vascular functions and blood pressure. Nogo-A, a splice isoform of Nogo, is transiently expressed in cardiomyocyte (CM) following pressure overload. Cardiac Nogo is upregulated in dilated and ischemic cardiomyopathies in animals and humans. However, its biological function in the heart remains unknown.
Methods and results
We discovered that Nogo-A is a negative regulator of SPT activity and refrains ceramide de novo biosynthesis in CM exposed to hemodynamic stress, hence limiting ceramide accrual.At 7 days following transverse aortic constriction (TAC), SPT activity was significantly upregulated in CM lacking Nogo-A and correlated with ceramide accrual, particularly very long chain ceramides, which are the most abundant in CM, resulting in the suppression of \"beneficial\" autophagy. At 3 months post-TAC, mice lacking Nogo-A in CM showed worse pathological cardiac hypertrophy and dysfunction, with ca.50% mortality rate.
Conclusions
Mechanistically, Nogo-A refrains ceramides from accrual, therefore preserves the \"beneficial\" autophagy, mitochondrial function, and metabolic gene expression, limiting the progression to HF under sustained stress.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.

Cardiovasc Res: 11 Jul 2022; epub ahead of print

Evolution of drug-eluting coronary stents: a back-and-forth journey from the bench-to-bedside.

Nicolas J, Pivato CA, Chiarito M, Beerkens F, Cao D, Mehran R
Coronary stents have revolutionized the treatment of coronary artery disease. Compared with balloon angioplasty, bare-metal stents effectively prevented abrupt vessel closure but were limited by in-stent restenosis due to smooth muscle cell proliferation and neointimal hyperplasia. The first-generation drug-eluting stent (DES), with its antiproliferative drug coating, offered substantial advantages over bare-metal stents as it mitigated the risk of in-stent restenosis. Nonetheless, they had several design limitations that increased the risk of late stent thrombosis. Significant advances in stent design, including thinner struts, enhanced polymers\' formulation, and more potent antiproliferative agents, have led to the introduction of new-generation DES with a superior safety profile. Cardiologists have over 20 different DES types to choose from, each with its unique features and characteristics. This review highlights the evolution of stent design and summarizes the clinical data on the different stent types. We conclude by discussing the clinical implications of stent design in high-risk subsets of patients.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Cardiovasc Res: 05 Jul 2022; epub ahead of print

Soil and water pollution and human health: what should cardiologists worry about?

Münzel T, Hahad O, Daiber A, Landrigan PJ
Healthy soil is foundational to human health. Healthy soil is needed to grow crops, provides food, and sustains populations. It supports diverse ecosystems and critical ecological services such as pollination. It stores water and prevents floods. It captures carbon and slows global climate change. Soil pollution is a great and growing threat to human health. Soil may be polluted by heavy metals, organic chemicals such as pesticides, biological pathogens, and micro/nanoplastic particles. Pollution reduces soil\'s ability to yield food. It results in food crop contamination and disease. Soil pollutants wash into rivers causing water pollution. Deforestation causes soil erosion, liberates sequestered pollutants, and generates airborne dust. Pollution of air, water, and soil is responsible for at least 9 million deaths each year. More than 60% of pollution-related disease and death is due to cardiovascular disease. Recognizing the importance of pollution to human health, the European Commission and the EU Action Plan for 2050: A Healthy Planet for All, have determined that air, water, and soil pollution must be reduced to levels that cause no harm to human or ecosystem health. We are thus required to create a toxic-free environment, respect the concept of a safe operating space for humanity, and sustain the health of our planet for future generations. This review article summarizes current knowledge of the links between soil health and human health and discusses the more important soil pollutants and their health effects.

© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.

Cardiovasc Res: 30 Jun 2022; epub ahead of print