Ischaemic heart disease: antithrombotic treatment and new therapeutic targets

For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts. This issue contains the first two contributions from our annual series summarizing the most important publications in the past year in different areas of cardiovascular medicine. ‘The year in cardiovascular medicine 2022: the top 10 papers in dyslipidaemias’, is contributed by the EHJ Editors of the Dyslipidaemias team (Lale Tokgozoglu, Carl Orringer, and Alberico Catapano).1 The lipid-lowering landscape is rapidly evolving and several trials published this year provided new insights. The authors explore these and put them into perspective. In ‘The year in cardiovascular medicine 2022: the top 10 papers in interventional cardiology’, the EHJ Editors of the Interventional Cardiology team (Emanuele Barbato, Tommaso Gori, and Margaret McEntegart) note that congresses, in person or in hybrid format, including EuroPCR, ESC, and TCT, took place again, allowing the return of scientific exchange in the previously known formats now enriched by virtual remote hubs.2 Despite the pandemic affecting the recruitment rates and consequent delayed publication of several randomized clinical trials, the field has significantly advanced in several areas, as highlighted in the 10 papers selected for their Viewpoint. Antithrombotic therapy in older adults: challenges and selected consensus points. AC, anticoagulant; ACS, acute coronary syndrome; AF, atrial fibrillation; AP, antiplatelet; APT, antiplatelet therapy; ARC HBR, Academic Research Consortium High Bleeding Risk; ATT, antithrombotic therapy; BP, blood pressure; CCS, chronic coronary syndrome; DAPT, dual antiplatelet therapy; EMA, European Medicines Agency; Hb, haemoglobin; LAAC, left atrial appendage closure; MI, myocardial infarction; NOAC, non-vitamin K antagonist oral anticoagulant; NSTE, non-ST-elevation; NSAID, non-steroidal anti-inflammatory drugs; PAD, peripheral artery disease; PPI, proton pump inhibitor; TAT, triple antithrombotic therapy; TAVI, transcatheter aortic valve implantation; TNK, tenecteplase.7 The issue continues with a focus on ischaemic heart disease, highlighting thrombosis and antithrombotic treatment which play a key role in several cardiovascular (CV) diseases.3–6 In a Special Article entitled ‘Acute, periprocedural, and long-term antithrombotic therapy in older adults: 2022 update by the ESC Working Group on Thrombosis’, Felicita Andreotti from the Fondazione Policlinico Universitario Gemelli IRCCS in Rome, Italy, and colleagues note that the first international guidance on antithrombotic therapy in the elderly came from the European Society of Cardiology Working Group on Thrombosis in 2015.7 This same group has updated its previous report on antiplatelet and anticoagulant drugs for older patients with acute or chronic coronary syndromes, atrial fibrillation, or undergoing surgery or procedures typical of the elderly (transcatheter aortic valve implantation and left atrial appendage closure). The aim is to provide a succinct but comprehensive tool for readers to understand the bases of antithrombotic therapy in older patients, despite the complexities of comorbidities, co-medications, and uncertain ischaemic vs. bleedingrisk balance. Fourteen updated consensus statements integrate recent trial data and other evidence, with a focus on high bleeding risk. Guideline recommendations, when present, are highlighted, as are gaps in evidence. Key consensus points include efforts to improve medical adherence through deprescribing and polypill use; adoption of universal risk definitions for bleeding, myocardial infarction (MI), stroke, and cause-specific death; and multiple bleeding avoidance strategies, ranging from gastroprotection with aspirin use to selection of antithrombotic drug composition, dosing, and duration tailored to multiple variables (setting, history, overall risk, age, weight, renal function, co-medications, and procedures) that need special consideration when managing older adults (Figure 1). Anticoagulants are the cornerstone for prevention and treatment of thrombosis but are not completely effective, and concerns about the risk of bleeding continue to limit their uptake.8–12 In a State of the Art Review article entitled ‘Factor XI inhibitors: cardiovascular perspectives’, Raffaele De Caterina from Pisa University Hospital in Italy, and colleagues indicate that animal studies and experience from patients with genetic coagulation factor XI deficiency, which suggest that this factor is more important for thrombosis than for haemostasis, raise the potential for drugs that target factor XI to provide safer anticoagulation.13 Multiple factor XI inhibitors are currently under evaluation in clinical trials, including parenterally administered antisense oligonucleotides, monoclonal antibodies, and orally active small-molecule inhibitors. Promising results of Phase II trials in patients undergoing major orthopaedic surgery, and in those with end-stage kidney disease, atrial fibrillation, and acute coronary syndromes have led to large Phase III trials that are currently ongoing. The authors review premises for the use of these agents, results so far accrued, ongoing studies, and perspectives for future patient care. Levels of growth differentiation factor 15 (GDF-15), a cytokine secreted in response to cellular stress and inflammation, have been associated with multiple types of cardiovascular events. In a Clinical Research article entitled ‘Growth differentiation factor 15 and cardiovascular risk: individual patient meta-analysis’, Eri Toda Kato from Kyoto University Hospital in Japan, and colleagues note that its comparative prognostic performance across different presentations of atherosclerotic cardiovascular disease (ASCVD) remains unknown.14 An individual patient meta-analysis was performed using data pooled from eight trials including 53 486 patients. Baseline GDF-15 concentration was analysed as a continuous variable, and established cut-off points (<1200 ng/L, 1200–1800 ng/L, and >1800 ng/L) were used to evaluate its prognostic performance for CV death/hospitalization for heart failure (HHF), major adverse cardiovascular events (MACE), and their components using Cox models adjusted for clinical variables and established CV biomarkers. Analyses were further stratified on ASCVD status: acute coronary syndrome (ACS), stabilized after recent ACS, and stable ASCVD. Overall, higher GDF-15 concentrations were significantly and independently associated with an increased rate of CV death/HHF and MACE (P < 0.001 for each). However, while GDF-15 showed a robust and consistent independent association with CV death and HHF across all presentations of ASCVD, its prognostic association with future MI and stroke only remained significant in patients stabilized after recent ACS or with stable ASCVD [hazard ratio (HR) 1.24 and HR 1.16 for MI and stroke, respectively] but not in ACS. The authors conclude that GDF-15 consistently adds prognostic information for CV death and HHF across the spectrum of ASCVD. GDF-15 also adds prognostic information for MI and stroke beyond clinical risk factors and cardiac biomarkers, but not in the setting of ACS. This manuscript is accompanied by an Editorial by Christian Mueller and Tamar Muench-Gerber from the University Hospital Basel in Switzerland, and Rudolf de Boer from the Thoraxcenter in Rotterdam, the Netherlands.15 The authors conclude that we still have many clear clinical needs in CV disease. Future clinical studies should predominantly assess the possible clinical utility of novel cardiovascular biomarkers in clinical settings with a major unmet clinical need despite the use of the cardiac-specific biochemical signals high-sensitivity cardiac troponin (hs-cTn) and brain natriuretic protein/N-terminal probrain natriuretic protein. These include, for example, the early diagnosis of acute MI in patients remaining in the observe zone of the ESC 0/1h-hs-cTn algorithm, the non-invasive discrimination of type 1 vs. type 2 acute MI, the simple and inexpensive non-invasive detection of functionally relevant coronary artery disease (CAD) in stable outpatients, the detection of an ACS as a trigger of acute HF, the early identification of patients who have a cardiac origin of their syncope, and subclinical HF with ambiguous imaging results and natriuretic peptides in the grey zone. Future clinical studies should ideally assess the possible clinical utility of novel cardiovascular biomarkers in such clinical settings. Biomarkers filling these gaps will undoubtedly be used at a massive scale and will help us advance the care of our patients. Proposed mechanisms by which disturbed flow induces vinculin phosphorylation at serine 721 (VCLS721p) in vascular endothelium, leading to atherosclerosis. A combination of porcine models, large-scale phosphoproteomics, transgenic mice, and clinical specimens was used to demonstrate that disturbed flow induces endothelial VCLS721p via G-protein-coupled receptor kinase 2 (GRK2)S29p, resulting in an inactive form of VCL with a closed conformation. This disrupted the VE-cadherin junction/catenin complex to enhance endothelial permeability and atherosclerosis. Statin therapy was associated with reduced levels of sVCLS721p and sVCLS721p/sVCL in the serum of patients with coronary artery disease. Thus, endothelial VCLS721p and serum levels of sVCLS721p and sVCLS721p/sVCL are promising molecular targets for the clinical assessment and treatment of atherosclerosis. AJ, adherens junction.21 Endothelial dysfunction plays a key role in atherosclerosis.16–20 In a Translational Research article entitled ‘Vinculin phosphorylation impairs vascular endothelial junctions promoting atherosclerosis’, Yu-Tsung Shih from the National Health Research Institutes in Taiwan, and colleagues note that atherosclerosis preferentially develops in arterial branches and curvatures where vascular endothelium is exposed to disturbed flow.21 In this study, the effects of disturbed flow on the regulation of vascular endothelial phosphoproteins and their contribution to atherogenesis were elucidated. Porcine models, large-scale phosphoproteomics, transgenic mice, and clinical specimens were used to discover novel site-specific phosphorylation alterations induced by disturbed flow in endothelial cells (ECs). A large-scale phosphoproteomics analysis of native endothelium from disturbed (athero-susceptible) vs. pulsatile flow (athero-resistant) regions of porcine aortas led to the identification of the novel atherosclerosis-related phosphoprotein vinculin (VCL) with disturbed flow-induced phosphorylation at serine 721 (VCLS721p). The induction of VCLS721p was mediated by G-protein-coupled receptor kinase 2 (GRK2)S29p and resulted in an inactive form of VCL with a closed conformation, leading to disruption of the VE-cadherin/catenin complex to enhance endothelial permeability and atherogenesis. The generation of novel apolipoprotein E-deficient (ApoE−/−) mice overexpressing the S721-non-phosphorylatable VCL mutant in ECs confirmed the critical role of VCLS721p in promoting atherosclerosis. The administration of a GRK2 inhibitor to ApoE−/− mice suppressed plaque formation by inhibiting endothelial VCLS721p. Studies on clinical specimens from patients with CAD revealed that endothelial VCLS721p is a critical clinicopathological biomarker for atherosclerosis progression and that the serum VCLS721p level is a promising biomarker for CAD diagnosis (Figure 2). The authors conclude that the findings of this study indicate that endothelial VCLS721p is a valuable haemodynamic-based target for clinical assessment and treatment of vascular disorders resulting from atherosclerosis. The contribution is accompanied by an Editorial by Fabrizia Bonacina and Giuseppe Danilo Norata from the University of Milan in Italy.22 The authors indicate that the study by Shih et al. opens up a new direction in the field of endothelial function in the context of CV diseases by pointing toward the possibility of modulating vinculin phosphorylation to preserve VE-cadherin junctions and endothelial barrier integrity. How this can be achieved selectively remains an open question for pharmacologists. The editors hope that this issue of the European Heart Journal will be of interest to its readers. Dr. Crea reports speaker fees from Amgen, Astra Zeneca, Servier, BMS, other from GlyCardial Diagnostics, outside the submitted work. With thanks to Amelia Meier-Batschelet, Johanna Huggler, and Martin Meyer for help with compilation of this article.