Vascular biology and medicine: amyloid-beta alterations in neurocardiovascular diseases and new targets to treat smooth muscle cell dysfunction

With thanks to Amelia Meier-Batschelet, Johanna Huggler, and Martin Meyer for help with compilation of this article. For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts. This Focus Issue on cardio-oncology, vascular biology and medicine, and brain health contains the State of the Art Review article ‘Non-bacterial thrombotic endocarditis: a clinical and pathophysiological reappraisal’ by Omair Ahmed from the Henry Ford Jackson Hospital in Jackson, MI, USA, and colleagues.1 While a lot is known about infective endocarditis,2–4 much less is known about non-bacterial thrombotic endocarditis (NBTE). The authors point out that NBTE, formerly recognized as marantic endocarditis, represents a rare cardiovascular pathology intricately linked with hypercoagulable. Characterized by the development of sterile vegetations comprised of fibrin and platelets on cardiac valves, NBTE poses a diagnostic challenge due to its resemblance to infective endocarditis. Therapeutic endeavours primarily revolve around addressing the underlying aetiology and instituting anticoagulant regimens to forestall embolic events, with surgical intervention seldom warranted. NBTE frequently co-exists with malignancies and autoimmune conditions, such as lupus and antiphospholipid antibody syndrome, and, more recently, has been associated with COVID-19. Its pathogenesis is underpinned by a complex interplay of endothelial dysfunction, hypercoagulability, hypoxia, and immune complex deposition. Clinical manifestations typically present as embolic phenomena, particularly cerebrovascular accidents, bearing substantial mortality rates. Diagnosis necessitates a high index of suspicion and meticulous exclusion of infective endocarditis, often facilitated by advanced cardiac imaging modalities. Anticoagulation, typically employing low molecular weight heparin or warfarin, constitutes the cornerstone of pharmacological intervention. Surgical recourse may be warranted in instances of recurrent embolic events. Given its multifaceted nature, the management of NBTE mandates a multidisciplinary approach. Future endeavours should prioritize further research to refine therapeutic strategies and enhance patient outcomes. There is growing interrest in cardiac amylodosis.5–9 In a State of the Art Review article entitled ‘Amyloid-beta metabolism in age-related neurocardiovascular diseases’ Evmorfia Aivalioti from the National and Kapodistrian University of Athens Medical School in Greece, and colleagues remind us that accumulation of harmful blood signals may induce organotypical endothelial dysfunction affecting blood–brain barrier function and vascular health in age-related diseases.10 Genetic-, age-, lifestyle-, or cardiovascular therapy-associated imbalance of amyloid-beta (Aβ) peptide metabolism in the brain and periphery may be the missing link between age-related neurocardiovascular diseases. Genetic polymorphisms of genes related to Aβ metabolism, lifestyle modifications, drugs used in clinical practice, and Aβ-specific treatments may modulate Aβ levels, affecting brain, vascular, and cardiac diseases. This narrative review elaborates on the effects of interventions on Aβ metabolism in the brain, cerebrospinal fluid, blood, and peripheral heart or vascular tissues. Implications for clinical applicability, gaps in knowledge, and future perspectives of Aβ as the link among age-related neurocardiovascular diseases are also discussed (Figure 1). Determinants of amyloid-beta metabolism in age-related neurocardiovascular diseases. Increased amyloid-beta blood levels, triggered by the presence of specific genetic traits or cardiometabolic risk factors, are associated with numerous circulatory diseases such as cerebral amyloid angiopathy, dementia, atherosclerosis progression, coronary artery disease, acute coronary syndrome, and heart failure. Cardiovascular therapies exert off-target effects beyond their known impact on cardiovascular diseases by decreasing (green) or increasing (red) amyloid-beta levels in specific body compartments (statins, brain; angiotensin receptor blockers, cerebrospinal fluid [increase] and brain [decrease]; haemodialysis, blood; angiotensin receptor neprilysin inhibitors, blood; angiotensin-converting enzyme inhibitors, blood). Amyloid-beta metabolism may be a novel therapeutic target to treat neurocardiovascular diseases.10 Baseline cardiovascular toxicity risk stratification is critical in cardio-oncology.11,12 In a Clinical Research article entitled ‘Anthracycline-induced cardiovascular toxicity: validation of the Heart Failure Association and International Cardio-Oncology Society risk score’, Borja Rivero-Santana from La Paz University Hospital in Madrin, Spain, and colleagues indicate that the Heart Failure Association (HFA) and International Cardio-Oncology Society (ICOS) score aims to assess this risk but lacks real-life validation.13 This study validates the HFA-ICOS score for anthracycline-induced cardiovascular toxicity. Anthracycline-treated patients in the CARDIOTOX registry (NCT02039622) were stratified by the HFA-ICOS score. The primary endpoint was symptomatic or moderate to severe asymptomatic cancer therapy-related cardiac dysfunction (CTRCD), with all-cause mortality and cardiovascular mortality as secondary endpoints. The analysis included ∼1000 patients (mean age 54 years; 82% women). According to the HFA-ICOS criteria, 54% of patients were classified as low risk, 31% as moderate risk, 14% as high risk, and 1% as very high risk. Median follow-up was 55 months. A total of 18% of patients died, and 67% developed CTRCD. Incidence rates of symptomatic or moderate to severe asymptomatic CTRCD and all-cause mortality significantly increased with HFA-ICOS score [hazard ratio (HR) 28.74, P < .001; and HR 7.43, P < .001] for very high-risk patients (Figure 2). The predictive model demonstrated good calibration and discrimination (area under the curve 0.78) for predicting symptomatic or severe/moderate asymptomatic CTRCD at 12 months. This study aimed to validate the Heart Failure Association and International Cardio-Oncology Society score for anthracycline-induced cardiovascular toxicity in a real-world cohort, the CARDIOTOX registry (NCT02039622). The Heart Failure Association and International Cardio-Oncology Society score effectively categorized patients based on their cardiovascular toxicity risk, demonstrating strong predictive capabilities for high-risk anthracycline-related cardiovascular toxicity and all-cause mortality.13 The authors conclude that the HFA-ICOS score demonstrates strong predictive ability for CTCRD and all-cause mortality. This manuscript is accompanied by an Editorial by Lloyd Butel-Simoes and Aaron Sverdlov from the John Hunter Hospital, and Doan T.M. Ngo University of Newcastle and Calvary Mater Newcastle, Newcastle, NSW, Australia.14 The authors note that enhancing national and international collaborations in cardio-oncology with a view to addressing multiple gaps in our knowledge is critical for this emerging field and, importantly, for our patients, who stand to benefit from more individualized approaches that can only be developed collaboratively. Vascular smooth muscle cell (VSMC) phenotype switching is a pathological hallmark in various cardiovascular diseases. In a Translational Research article entitled ‘NAT10 promotes vascular remodelling via mRNA ac4C acetylation’, Cheng Yu from the Fujian Medical University Union Hospital in Fuzhou, China, and colleagues point out that N4-acetylcytidine (ac4C) catalysed by N-acetyltransferase 10 (NAT10) is well conserved in the enzymatic modification of RNA.15 NAT10-mediated ac4C acetylation is involved in various physiological and pathological processes, including cardiac remodelling. However, the biological functions and underlying regulatory mechanisms of mRNA ac4C modifications in vascular diseases remain elusive. By combining in vitro and in vivo vascular injury models, NAT10 was identified as a crucial protein involved in the promotion of post-injury neointima formation, as well as VSMC phenotype switching. The potential mechanisms of NAT10 in the formation of the vascular neointima were clarified by RNA sequencing (RNA-seq), acetylated mRNA immunoprecipitation sequencing (acRIP-seq), and RNA-binding protein immunoprecipitation sequencing (RIP-seq). NAT10 and ac4C modifications were up-regulated in injured human and rodent arteries. Deletion of NAT10 in VSMCs effectively reduced post-injury neointima formation and VSMC phenotype switching. Further, RNA-seq, RIP-seq, and acRIP-seq revealed that NAT10, by its ac4C modification, directly interacted with integrin-β1 (ITGB1) and collagen type I alpha 2 chain (Col1a2) mRNAs. The regulation of NAT10 on the VSMC phenotype is of translational significance because the administration of Remodelin, a NAT10 inhibitor, effectively prevented neointima formation by suppressing VSMC proliferation, down-regulating ITGB1 expression, and deactivating its focal adhesion kinase (FAK) signalling. The authors conclude that this study reveals that NAT10 promotes vascular remodelling via mRNA ac4C acetylation, which may be a promising therapeutic target against vascular remodelling. The contribution is accompanied by an Editorial by Timothy Warwick, Leo Kurian, and Ralf P. Brandes from the Goethe University Frankfurt in Germany.16 The authors note that an important aspect of this study is the therapeutic targeting of NAT10 by the NAT10 inhibitor Remodelin. The compound is already being explored for its safety and efficacy in other diseases, making it a potential treatment for vascular disease. The study by Yu et al. advocates NAT10 as a novel and accessible structure to fight vascular disease. The role of VSMCs in atherosclerosis has evolved to indicate causal genetic links with the disease. In a Translational Research article entitled ‘Atheroma transcriptomics identifies ARNTL as a smooth muscle cell regulator and with clinical and genetic data improves risk stratification’, Sampath Narayanan from the Karolinska University Hospital and Karolinska Institutet in Stockholm, Sweden, and colleagues point out that single-cell RNA sequencing (scRNAseq) studies have identified multiple cell populations of mesenchymal origin within atherosclerotic lesions, including various SMC sub-phenotypes, but it is unknown how they relate to patient clinical parameters and genetics.17 Here, mesenchymal cell populations in atherosclerotic plaques were correlated with major coronary artery disease (CAD) genetic variants and functional analyses performed to identify SMC markers involved in the disease. Bioinformatic deconvolution was done on bulk microarrays from carotid plaques in the Biobank of Karolinska Endarterectomies (BiKE) using public plaque scRNAseq data and associated with patient clinical data and follow-up information. BiKE patients were clustered based on the deconvoluted cell fractions. Quantitative trait locus (QTL) analyses were performed to predict the effect of CAD-associated genetic variants on mesenchymal cell fractions (cfQTLs) and gene expression (eQTLs) in plaques. Lesions from symptomatic patients had higher fractions of Type 1 macrophages and pericytes, but lower fractions of classical and modulated SMCs compared with asymptomatic patients, particularly females. Presence of diabetes or statin treatment did not affect the cell fraction distribution. Clustering based on plaque cell fractions revealed three patient groups, with relative differences in their stability profiles and associations with stroke, even during long-term follow-up. Several single nucleotide polymorphisms (SNPs) associated with plaque mesenchymal cell fractions, upstream of the circadian rhythm Aryl Hydrocarbon Receptor Nuclear Translocator Like (ARNTL) gene, were identified. In vitro silencing of ARNTL in human carotid SMCs increased the expression of contractile markers and attenuated cell proliferation. The authors conclude that combining scRNAseq data with vertically integrated clinical, genetic, and transcriptomic data from a large biobank of human plaques can refine patient vulnerability and risk prediction stratification. The study reveals novel CAD-associated variants that may be functionally linked to SMCs in atherosclerotic plaques. Specifically, variants in the ARNTL gene may influence SMC ratios and function, and its role as a regulator of SMC proliferation should be further investigated. The manuscript is accompanied by an Editorial by Elisa Duregotti and Manuel Mayr from the Imperial College London in the UK.18 The authors highlight that the present study used bioinformatic deconvolution tools to infer relative cell fractions in carotid plaques. This approach can complement scRNAseq experiments, where VSMCs can be under-represented. However, deconvolution of bulk gene expression cannot achieve the same confidence as single-cell resolved quantitative gene expression data. A strength of this study is its prospective follow-up. Clustering based on plaque cell fractions revealed three distinct groups of patients, characterized by different stability profiles and stroke incidence. Analysis of CAD genetic variants associated with different cell fractions revealed several eQTLs upstream of the circadian rhythm gene ARNTL. ARNTL gene expression negatively correlated with contractile VSMC markers in plaques but was reduced in atherosclerotic lesions compared with normal arteries. Finally, a role for ARNTL in modulating VSMC phenotype and proliferation has been proposed based on in vitro silencing experiments on human VSMCs. Notably, ARNTL knockdown was not sufficient to significantly reduce BMAL1 protein levels in these experiments. Thus, the observed effects in VSMCs occurred without a significant reduction in the ARNTL protein product. While further studies will be required to confirm a causal relationship between ARNTL SNPs and atherosclerosis, investigations into the cell-specific effects of CAD-related variants are of great interest. The editors hope that this issue of the European Heart Journal will be of interest to its readers. Dr. Crea reports speaker fees from Abbott, Amgen, Astra Zeneca, BMS, Chiesi, Daiichi Sankyo, enarini outside the submitted work.