Ischaemic heart disease: prevention, management, mechanisms, and new therapeutic targets

For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts. This Focus Issue on ischaemic heart disease, diabetes, and metabolic disorders contains the Clinical Research contribution entitled ‘Routine stress testing in diabetic patients after percutaneous coronary intervention: the POST-PCI trial’ by Hoyun Kim from the University of Ulsan College of Medicine in Seoul, South Korea, and colleagues.1 The management of patients with chronic coronary syndromes is complex.2–7 In particular, the optimal follow-up surveillance strategy after percutaneous coronary intervention (PCI) is debated. The POST-PCI (Pragmatic Trial Comparing Symptom-Oriented versus Routine Stress Testing in High-Risk Patients Undergoing Percutaneous Coronary Intervention) study was a randomized trial comparing a follow-up strategy of routine functional testing at 1 year vs. standard care alone after high-risk PCI. Randomization was stratified according to diabetes status. The primary outcome was a composite of death from any cause, myocardial infarction (MI), or hospitalization for unstable angina at 2 years. Among 1706 randomized patients, participants with diabetes (n = 660, 39%) had more frequent comorbidities and a higher prevalence of complex anatomical or procedural characteristics than those without diabetes. Patients with diabetes had a 52% greater risk of primary composite events [hazard ratio (HR) 1.52; P = .039]. The 2-year incidences of the primary composite outcome were similar between strategies of routine functional testing or standard care alone in diabetic patients (7.1% vs. 7.5%) and non-diabetic patients (4.6% vs. 5.1%) (Figure 1). The incidences of invasive coronary angiography and repeat revascularization after 1 year were higher in the routine functional testing group than in the standard care group irrespective of diabetes status. Study flow diagram of patients stratified by the presence of diabetes and Kaplan–Meier curves of the cumulative incidence of the primary composite outcome of death from any cause, myocardial infarction, or hospitalization for unstable angina according to diabetes status and randomization group. PCI, percutaneous coronary intervention; POST-PCI, Pragmatic Trial Comparing Symptom-Oriented versus Routine Stress Testing in High-Risk Patients Undergoing Percutaneous Coronary Intervention; MI, myocardial infarction; HR, hazard ratio; CI, confidence interval.1 The authors conclude that routine surveillance stress testing after complex PCI is not associated with a better outcome as compared with standard care alone regardless of the diabetes status. The contribution is accompanied by an Editorial by Roxy Senior and Rajdeep Khattar from the Royal Brompton Hospital and Imperial College in the UK.8 The authors note that the data from the POST-PCI trial and ISCHEMIA trial with the subgroup analyses in diabetic patients seem to indicate the futility of routinely performing surveillance stress tests in high-risk patients. Indeed, the very recent AHA/ACC guidelines in 2023 support this notion, ruling against follow-up routine ischaemia or coronary anatomy assessment after revascularization. Survivors of acute coronary syndromes face an elevated risk of recurrent atherosclerosis-related vascular events despite advanced medical treatments. The underlying causes remain unclear although inflammation is likely to play a key role.9–14 In a Translational Research article entitled ‘Myocardial infarction drives trained immunity of monocytes, accelerating atherosclerosis’, Zheng Dong from the Shanghai Institute of Cardiovascular Diseases in China, and colleagues investigate whether MI-induced trained immunity in monocytes could sustain proatherogenic traits and expedite atherosclerosis.15 Apolipoprotein-E deficient (ApoE−/−) mice and adoptive bone marrow transfer chimeric mice underwent MI or myocardial ischaemia–reperfusion (IR). A subsequent 12-week high-fat diet (HFD) regimen was implemented to elucidate the mechanism behind monocyte trained immunity. In addition, classical monocytes were analysed by flow cytometry in the blood of enrolled patients. In MI and IR mice, blood monocytes and bone marrow-derived macrophages exhibited elevated spleen tyrosine kinase (SYK), lysine methyltransferase 5A (KMT5A), and CCHC-type zinc finger nucleic acid-binding protein (CNBP) expression upon exposure to a HFD or oxidized LDL-cholesterol (oxLDL-C) stimulation. MI-induced trained immunity was transmissible by transplantation of bone marrow to accelerate atherosclerosis in naive recipients. KMT5A specifically enhanced monomethylation of Lys20 of histone H4 (H4K20me) to the gene body of SYK and synergistically transactivated SYK with CNBP. In vivo small interfering RNA (siRNA) inhibition of KMT5A or CNBP slowed post-MI atherosclerosis. Sympathetic denervation with 6-hydroxydopamine reduced atherosclerosis and inflammation after MI. Classical monocytes from ST-elevation MI (STEMI) patients with advanced coronary lesions expressed higher SYK and KMT5A levels. The authors conclude that these findings underscore the crucial role of monocyte trained immunity in accelerated atherosclerosis after MI, implying that SYK in blood classical monocytes may serve as a predictive factor for the progression of atherosclerosis in STEMI patients. This manuscript is accompanied by an Editorial by Niranjana Natarajan and Partha Dutta from the University of Pittsburgh School of Medicine in Pennsylvania, USA.16 The authors note that it is currently not known if anti-inflammatory therapies might future cardiovascular risk by reversing epigenetic rewiring of myeloid cells. Targeting epigenetic modifiers by delivering small molecule inhibitors in these cells by nanoparticles might allow personalized precision medicine in patients with cardiovascular disease and potentially prevent future cardiovascular events. Role of DKK1 in inducing the development of hypertension and organ injury in diabetes. Under normal conditions, LRP5/6 bind to and fine-tunes GPCRs to maintain normal GPCR signal transduction and organ homeostasis. Under diseased conditions such as type 2 diabetes, elevated circulating DKK1 induces membrane LRP5/6 endocytosis, which leads to deregulations of GPCRs. For example, deregulation of AT1R activation leads to hypertension, while deregulations of other LRP5/6-interacting GPCRs lead to organ injury, and these can be prevented by an anti-DKK1 neutralizing antibody or MDC that prevents DKK1-induced LRP5/6 endocytosis. AT1R, angiotensin II type 1 receptor; DKK1, Dickkopf-1; GPCR, G protein-coupled receptor; LRP5/6, LDL receptor-related proteins 5 and 6; LDLR, LDL receptor; MDC, monodansylcadaverine.17 Antihypertensive agents are one of the most frequently used drugs worldwide. Previous findings show that Wnt co-receptors LDL receptor-related proteins 5 and 6 (LRP5/6) can directly bind to several G protein-coupled receptors (GPCRs). In another Translational Research article entitled ‘Inhibition of a novel Dickkopf-1–LDL receptor-related proteins 5 and 6 axis prevents diabetic cardiomyopathy in mice’, En Ma from the Fujian University of Traditional Chinese Medicine in China, and colleagues note that because angiotensin II type 1 receptor (AT1R) is the most important GPCR in regulating hypertension (HTN), this study examines the possible mechanistic association between LRP5/6 and their binding protein Dickkopf-1 (DKK1) and activation of the AT1R, and further hypothesizes that the LRP5/6–GPCR interaction may affect hypertension and potentiate cardiac impairment in the setting of diabetes. 17 The roles of serum DKK1 and DKK1–LRP5/6 signalling in diabetic damage were investigated in humans and diabetic mice. Blood pressure up-regulation positively correlated with serum DKK1 elevations in humans. In diabetic mice LRP5/6 physically and functionally interacted with AT1R. The loss of membrane LRP5/6 caused by injection of a recombinant DKK1 protein or conditional LRP5/6 deletions resulted in AT1R activation and HTN, as well as β-arrestin1 activation and cardiac impairment, possibly because of multiple GPCR alterations. Importantly, unlike commonly used antihypertensive agents, administration of the anti-DKK1 neutralizing antibody effectively prevented diabetic cardiac impairment in mice. Ma and colleagues conclude that these findings establish a novel DKK1–LRP5/6–GPCR pathway in inducing diabetic damage and may resolve the long-standing conundrum as to why elevated blood DKK1 has deleterious effects in diabetic patients. Thus, monitoring and therapeutic targeting of blood DKK1 may be a promising strategy to attenuate diabetic injuries. The contribution is accompanied by an Editorial by Peter Toth from the Johns Hopkins University School of Medicine in Baltimore, MD, USA.18 Toth indicates that this study reveals that DKK-1 induces HTN and, in a murine model, drove adverse structural changes in the left ventricle that impaired left ventricular ejection fraction. DKK-1 also caused alterations in cardiac myocyte DNA, which could lead to irreversible changes in gene expression and added pathophysiology. DKK-1 induces numerous changes in endothelial cells, vascular smooth muscle cells, cardiac myocytes, and platelets, which increase the risk for CVD. These experiments suggest that treatment with an anti-DKK-1 monoclonal antibody may be a viable approach to treating DKK-1-mediated HTN in patients with diabetes mellitus. It is time to test the efficacy of such an approach in large-scale prospective randomized clinical trials and determine if DKK-1 inhibition reduces cardiovascular events and improves survival. If confirmed, this would establish DKK-1 as an important, novel CVD risk factor. RNA-based, antibody-based, and genome editing-based therapies are generating growing interest.19–22 In particular, inhibition of angiopoietin-like protein-3 (ANGPTL3) could reduce lipoprotein-lipid levels and atherosclerotic cardiovascular disease (ASCVD) risk. In a Translational Research article entitled ‘Genetic inhibition of angiopoietin-like protein-3, lipids, and cardiometabolic risk’, Émilie Gobeil from the Université Laval in Québec, Canada, and colleagues used Mendelian randomization (MR) to determine whether genetic variations influencing ANGPTL3 liver gene expression, blood levels, and protein structure could causally influence triglyceride and apolipoprotein B (apoB) levels as well as coronary artery disease (CAD), ischaemic stroke (IS), and other cardiometabolic diseases.23 RNA sequencing of 246 explanted liver samples and genome-wide genotyping was performed to identify single nucleotide polymorphisms (SNPs) associated with liver expression of ANGPTL3. Genome-wide summary statistics of plasma protein levels of ANGPTL3 from the deCODE study (n = 35 359) were used. A total of 647 carriers of protein-truncating variants (PTVs) of ANGPTL3 associated with lower plasma triglyceride levels were identified in the UK Biobank. Two-sample MR using SNPs that influence ANGPTL3 liver expression or ANGPTL3 plasma protein levels as exposure and cardiometabolic diseases as outcomes was performed (CAD, IS, heart failure, non-alcoholic fatty liver disease, acute pancreatitis, and type 2 diabetes). The impact of rare PTVs influencing plasma triglyceride levels on apoB levels and CAD was also investigated in the UK Biobank. In two-sample MR studies, common genetic variants influencing ANGPTL3 hepatic or blood expression levels of ANGPTL3 had a very strong effect on plasma triglyceride levels, a more modest effect on LDL-C, a weaker effect on apoB levels, and no effect on CAD or other cardiometabolic diseases. In the UK Biobank, the carriers of rare ANGPTL3 PTVs providing lifelong reductions in median plasma triglyceride levels had slightly lower apoB levels and similar CAD event rates compared with non-carriers. The authors conclude that PTVs influencing ANGPTL3 protein structure as well as common genetic variants influencing ANGPTL3 hepatic expression and/or blood protein levels exhibit a strong effect on circulating plasma triglyceride levels, a weak effect on circulating apoB levels, and no effect on ASCVD. Thus, near-complete inhibition of ANGPTL3 function in patients with very elevated apoB levels may be required to reduce ASCVD risk. The manuscript is accompanied by an Editorial by Robert A. Hegele from Western University in London, Ontario, Canada.24 Hegele concludes by wondering if these findings clarify or cloud our understanding of ANGPTL3. This target is obviously biologically complex without straightforward explanations for the diverse clinical trial findings. The benefit of targeting ANGPTL3 is clear in homozygous familial hypercholesterolaemia (HoFH) patients without hypertriglyceridaemia, but becomes cloudy when the clinical picture includes hypertriglyceridaemia. The impact of ANGPTL3 inhibition depends on the site of inhibition (i.e. liver vs. plasma), the mode by which inhibition is mediated [i.e. siRNA vs. allele-specific oligonucleotide (ASO) vs. monoclonal antibody vs. future genome editing] and also the genetic and metabolic context of the patient (i.e. HoFH vs. familial chylomicronaemia syndrome, vs. complex polygenic multifactorial chylomicronaemia syndrome vs. obese patient with combined hyperlipidaemia). Future work could help scatter the clouds, allowing us to see ANGPTL3 from both sides and to maximize the benefit of inhibiting this interesting and challenging target. In a Rapid Communications contribution entitled ‘Colchicine to prevent sympathetic denervation after acute myocardial infarction: the COLD-MI trial’, Fabien Huet from the Vannes Regional Hospital in Vannes, France and colleagues assessed the impact of colchicine on myocardial denervation following reperfused acute myocardial infarction (AMI) in a randomized trial. The loss of pre-synaptic adrenaline reuptake function was assessed by [123I]metaiodobenzylguanidine single-photon emission computed tomography imaging.25 The investigators assessed 46 patients randomized to colchicine or placebo. Myocardial denervation was lower in patients randomized to colchicine than in the control group. In particular, colchicine showed a significant protective effect on myocardial denervation in non-infarcted zones [adjusted odds ratio (OR) 0.43] and tended to have an effect on myocardial denervation in the infarcted zone (OR 0.54). The authors conclude that colchicine is gradually finding its place in the therapeutic arsenal for CAD, with new light now shed on the pathophysiological mechanisms involved in its beneficial effect. Small extracellular vesicles (sEVs) are non-replicating, membrane-derived nanoparticles secreted by cells into the extracellular space. They carry bioactive molecules that can modulate recipient cell functions. When derived from human cardiac progenitor cells (CPCs) or cardiosphere-derived cells, sEVs are hypoimmunogenic and cardioprotective, and exhibit proangiogenic capacity, making them attractive candidates for the treatment of AMI. In a Rapid Communications contribution entitled ‘Intracoronary delivery of extracellular vesicles from human cardiac progenitor cells reduces infarct size in porcine acute myocardial infarction’, Maximilian Emmert from the Deutsches Herzzentrum der Charite (DHZC) in Berlin, Germany, and colleagues26 established a CPC master cell bank from right atrial appendage tissue of a male patient (83 years old) undergoing aortic valve surgery. The sEVs were isolated from CPC-conditioned medium by tangential flow filtration. In a randomized study closed-chest, 90 min mid-left anterior descending artery balloon occlusion, IR AMI was induced in 11 pigs. Within 15 min of reperfusion, animals received either intracoronary sEVs or vehicle selectively instilled into the LAD. At the 3-month follow-up at cardiac magnetic resonance, LVEF was significantly higher while infarct was significantly lower in intracoronary sEV-treated pigs compared with controls. The authors conclude that pending validation by further studies, catheter-based intracoronary delivery of clinical-grade CPC sEVs may warrant phase I clinical evaluation in AMI patients. The issue is also complemented by two Discussion Forum contributions. In a commentary entitled ‘Fate of the unoperated ascending thoracic aortic aneurysm—patient selection and the importance of the denominator’, Matthew D. Solomon from the Kaiser Permanente Northern California in the USA, and D. Craig Miller and David H. Liang from Stanford University in Palo Alto, CA, USA comment on the recent publication ‘Fate of the unoperated ascending thoracic aortic aneurysm: three-decade experience from the Aortic Institute at Yale University’ by Jinlin Wu from Yale University School of Medicine in New Haven, CT, USA.27,28 Wu et al. respond in a separate comment.29 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, Menarini outside the submitted work. With thanks to Amelia Meier-Batschelet, Johanna Huggler, and Martin Meyer for help with compilation of this article.