Ischaemic heart disease: from the celebration of Heberden’s description of angina pectoris to novel therapeutic targets for angiogenesis and myocardial fibrosis

For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts. This Focus Issue on ischaemic heart disease contains a Viewpoint article entitled ‘Reprising Heberden’s description of angina pectoris after 250 years’.1 William Boden from the Boston University School of Medicine and Harvard Medical School in MA, USA, and colleagues remind us that in 1772, 4 years after his initial description of angina pectoris, William Heberden published his seminal account of this clinical disorder, which remarkably has stood the test of time despite profound developments in the diagnosis and management of ischaemic heart disease, particularly during the last half-century. Boden and colleagues note in their excellent overview that the paradigm that obstructive coronary artery disease (CAD) is synonymous with angina pectoris and myocardial ischaemia needs to be reconsidered because it is not universally applicable to the larger, more unselected universe of individuals presenting with stable angina in whom flow-limiting coronary stenoses are often not present.2–5 Perhaps this 250th anniversary of Heberden’s original description of angina may represent an opportunity to reprise this syndrome with a renewed recognition that the clinical manifestations of ischaemia are protean and that non-obstructive causes are common yet remain underappreciated. We must also recognize that knowledge of the precise mechanism of ischaemia due either to epicardial coronary stenoses or to non-obstructive causes may lead to more personalized antianginal treatment, which offers the hope of substantially improving symptoms and quality of life in a broader population of patients with ‘Heberden’s angina’ in the 21st century. In a Viewpoint article entitled ‘Primordial non-responsiveness: a neglected obstacle to cardioprotection’, Gerd Heusch from the University of Essen Medical School in Germany, and colleagues note that there is still a need for cardioprotection beyond that by rapid reperfusion, because 1-year mortality after reperfused acute myocardial infarction is still >10% and the incidence of post-infarct heart failure is still ∼20–30%.6 The authors’ contribution deals with immediate cardioprotection, as defined by reduced infarct size and coronary microvascular obstruction which are the major determinants of further clinical outcome. When clinical follow-up endpoints, such as mortality and development of post-infarct heart failure, are considered, the relevant pathophysiological processes which determine cardiac geometry and function also include inflammation, healing, and remodelling (adverse and reverse) with consequent fibrosis, cardiomyocyte hypertrophy, and angiogenesis, and the confounders are then even more complex. Nevertheless, in the authors’ view, primordial non-responsiveness to cardioprotection is a serious confounder that deserves recognition and attention in further pre-clinical and clinical studies. Primordial non-responsiveness to cardioprotection may be of particular importance when it comes to ‘personalized medicine’. Peri-operative myocardial infarction/injury (PMI) is a clinically relevant event.7–10 In a Clinical Research article entitled ‘Long-term outcomes of perioperative myocardial infarction/injury after non-cardiac surgery’, Christian Puelacher from the University of Basel in Switzerland, and colleagues note that a better understanding of the aetiologies and outcomes of PMI following non-cardiac surgery is urgently needed.11 Aetiologies of PMIs detected within an active surveillance and response programme were centrally adjudicated by two independent physicians based on all information obtained during clinically indicated PMI work-up including cardiac imaging among consecutive high-risk patients undergoing major non-cardiac surgery in a prospective multicentre study. PMI aetiologies were hierarchically classified into ‘extra-cardiac’ if caused by a primarily extra-cardiac disease such as severe sepsis or pulmonary embolism; and ‘cardiac’, further subtyped into type 1 myocardial infarction (T1MI), tachyarrhythmia, acute heart failure (AHF), or likely type 2 myocardial infarction (lT2MI). Major adverse cardiac events (MACEs) including acute MI (AMI), AHF (both only from day 3 to avoid inclusion bias), life-threatening arrhythmia, and cardiovascular death as well as all-cause death were assessed during 1-year follow-up. Among 7754 patients (age 45–98 years, 45% women), PMI occurred in 13.1% of patients. At least one MACE occurred in 8.8% of patients, and 10.5% of patients died within 1 year. Outcomes differed starkly according to aetiology: in patients with extra-cardiac PMI, T1MI, tachyarrhythmia, AHF, and lT2MI, 51, 41, 57, 64, and 25% had MACEs, and 38, 27, 40, 49, and 17% patients died within 1 year, respectively, compared with 7% and 9% in patients without PMI. These associations persisted in multivariable analysis (Figure 1). At 1 year, most PMI aetiologies have unacceptably high rates of major adverse cardiac events and all-cause death, highlighting the need for more comprehensive management strategies, taking different aetiologies, their incidence, and their associated outcomes into consideration. PMI was defined as an absolute increase in cTn from pre-operative to post-operative concentrations of at least the upper limit of normal of the used assay (for high sensitivity cTnT, this corresponds to an increase of at least +14 ng/L, e.g. from 10 ng/L pre-operatively to ≥24 ng/L post-operatively). cTn, cardiac troponin; PMI, peri-operative myocardial infarction/injury.11 Puelacher et al. conclude that at 1 year, most PMI aetiologies have unacceptably high rates of MACE and all-cause death, highlighting the urgent need for more intensive treatments. This manuscript is accompanied by an Editorial by Kristian Thygesen from the Aarhus University Hospital in Denmark and Allan S. Jaffe from the Mayo Clinic and Medical School in Rochester, MN, USA.12 Thygesen and Jaffe conclude that the authors have done the best they can with the available data. The data substantiate that those with clinical risk factors and a changing pattern of high-sensitivity cardiac troponin (hs-cTnT) should be taken seriously and evaluated extensively because of the high incidence of occurrence of subsequent events. The study does not, however, help with some other potentially high-risk groups such as those with chronic myocardial injury or those with less robust increases in hs-cTn. Clinicians must be aware of this critical caveat. However, if this study pushes others to carry out similar but more extensive evaluations, it will have made a major contribution. First studies are rarely definitive. Patients with suspected non-ST-segment elevation acute coronary syndrome (NSTE-ACS) are routinely transferred to the emergency department (ED).13–15 A clinical risk score with point-of-care (POC) troponin measurement might enable ambulance paramedics to identify low-risk patients in whom ED evaluation is unnecessary. In a Clinical Research article entitled ‘Rule-out of non-ST-segment elevation acute coronary syndrome by a single, pre-hospital troponin measurement: a randomized trial’, Cyril Camaro from the Radboud University Medical Centre in Nijmegen, the Netherlands, and colleagues assess safety and healthcare costs of a pre-hospital rule-out strategy using a POC troponin measurement in low-risk suspected NSTE-ACS patients.16 This investigator-initiated, randomized clinical trial was conducted in five ambulance regions in the Netherlands. Suspected NSTE-ACS patients with HEAR (History, ECG, Age, Risk factors) score ≤3 were randomized to pre-hospital rule-out with POC troponin measurement or direct transfer to the ED. The sample size calculation was based on the primary outcome of 30-day healthcare costs. Secondary outcome was safety, defined as 30-day MACE, consisting of ACS, unplanned revascularization, or all-cause death. A total of 863 participants were randomized. Healthcare costs were significantly lower in the pre-hospital strategy (P < 0.001). In the total population, MACE were comparable between groups (3.9% in pre-hospital strategy vs. 3.7% in ED strategy). In the ruled-out ACS population, MACE were very low (0.5% vs. 1.0%) (Figure 2). ACS, acute coronary syndrome; CI, confidence interval; ED, emergency department; MACE, major adverse cardiac events; NSTE-ACS, non-ST-elevation acute coronary syndrome; POC, point-of-care.16 The authors conclude that pre-hospital rule-out of ACS with a POC troponin measurement in low-risk patients significantly reduces healthcare costs, while the incidence of MACE is low in both strategies. The contribution is accompanied by an Editorial by Bruna Gigante from the Karolinska Institutet in Stockholm, Sweden.17 Gigante concludes that an effective, rational, and modern use of healthcare resources is highly advocated and needs to be investigated to improve modern clinical practice, as this clinical trial clearly shows. At the same time, a balance must be kept between the old and always actual ‘Observatio et ratio’ and the benefits of automatization of clinical decisions. Atherothrombotic events are influenced by systemic hypercoagulability and fibrinolytic activity.18 In a Clinical Research article entitled ‘Prognostic impact of hypercoagulability and impaired fibrinolysis in acute myocardial infarction’, Seung Hun Lee from the Chonnam National University Medical School in the Republic of Korea, and colleagues evaluated thrombogenicity indices and their prognostic implications according to disease acuity.19 From the consecutive patients undergoing percutaneous coronary intervention (PCI), 2705 with thrombogenicity indices were grouped according to disease acuity (AMI vs. non-AMI). Thrombogenicity indices were measured by thromboelastography (TEG). Blood samples for TEG were obtained immediately after insertion of the PCI sheath, and TEG tracing was performed within 4 h post-sampling. MACEs (a composite of cardiovascular death, non-fatal MI, and non-fatal stroke) were evaluated for up to 4 years. Compared with non-AMI patients, AMI patients had higher platelet–fibrin clot strength (P < 0.001) and lower fibrinolytic activity (P < 0.001). The presence of high platelet–fibrin clot strength and low fibrinolytic activity was synergistically associated with MACE occurrence. In the multivariable analysis, the combined phenotype was a major predictor of MACEs in the AMI group (P = 0.011), but not in the non-AMI group. The authors conclude that AMI occurrence is significantly associated with hypercoagulability and impaired fibrinolysis. Their combined phenotype increases the risk of a post-PCI atherothrombotic event only in AMI patients. These observations may support individualized therapy that targets thrombogenicity for better outcomes in patients with AMI. The manuscript is accompanied by an Editorial by Aaron Iding and colleagues from the Cardiovascular Research Institute Maastricht in the Netherlands.20 Iding et al. conclude that it is about time that we make smarter use of laboratory biomarkers for patient management. Cumulative evidence clearly shows that atherothrombosis, although a localized problem, is influenced by the systemic blood compartment. This systemic hypercoagulability, or thrombogenicity if one prefers, is a driver not only of atherosclerosis but also of thrombosis. They state that we should start phenotyping our patients more carefully using state-of-the-art methodology to guide the choice of antithrombotic management, minimizing the individual patient’s residual risks of thrombosis and bleeding. Will this require further studies? As always it will, but we need to be pragmatic too, as not all such efforts can be tested in randomized controlled trials (too large, too expensive) and we need to find ways to embed selected laboratory technology in the framework of management studies. Members of the chromogranin family play a role in angiogenesis. One such biologically active peptide, generated through the processing of chromogranin A, is vasostatin-2. In a Translational Research article entitled ‘Vasostatin-2 associates with coronary collateral vessel formation in diabetic patients and promotes angiogenesis via angiotensin-converting enzyme 2’, Xiao Lu Bao from the Shanghai Jiaotong University School of Medicine in Shanghai, the People’s Republic of China, and colleagues aimed at assessing the association of serum vasostatin-2 levels with coronary collateral vessels (CCVs) in diabetic patients with chronic total occlusions (CTOs) and the effects of vasostatin-2 on angiogenesis in diabetic mice with hindlimb or myocardial ischaemia.21 Among 452 diabetic CTO patients, the status of CCVs was categorized according to the Rentrop score. Serum levels of vasostatin-2 were significantly different and progressively higher across Rentrop score 0, 1, 2, and 3 groups (P < 0.001), with significantly lower levels in patients with poor CCVs (Rentrop score 0 and 1) than in those with good CCVs (Rentrop score 2 and 3) (P < 0.05). In the experimental part of the study, vasostatin-2 recombinant protein or phosphate-buffered saline were injected intraperitoneally in diabetic mouse models of hindlimb or myocardial ischaemia, followed by laser Doppler imaging and molecular biology examinations. The effects of vasostatin-2 were also ascertained in endothelial cells and macrophages, with mechanisms clarified using RNA sequencing (RNA-seq). Vasostatin-2 significantly promoted angiogenesis in diabetic mice with hindlimb or myocardial ischaemia. RNA-seq analyses verified an angiotensin-converting enzyme 2 (ACE2)-mediated vasostatin-2 induction of angiogenesis in ischaemic tissues. Bao et al. conclude that lower serum levels of vasostatin-2 are associated with poor CCVs in diabetic CTO patients compared with patients with good CCVs. Vasostatin-2 significantly promotes angiogenesis in diabetic mice with hindlimb or myocardial ischaemia. Such effects are mediated by ACE2. The contribution is accompanied by an Editorial by Ingrid Fleming from the Goethe University in Frankfurt am Main, Germany.22 Fleming notes that as impressive as the in vivo effects of vasostatin-2 are, there are a number of open questions; for example, which peptidase is responsible for the generation of vasostatin-2 from chromogranin A and how is it affected during atherogenesis and/or ischaemia? Is vasostatin-2 a substrate for ACE2? Moreover, what relationship exists between the different chromogranin A-derived proteins? This is a particularly relevant question given the positive association between pancreastatin and type 1 diabetes and the negative association between vasostatin-2 and type 2 diabetes. Moreover, it should also be noted that the effects described by Bao et al. for vasostatin-2 have also been reported for chromogranin A-derived catestatin. Indeed, the levels of the latter protein are also decreased in cardiovascular disease, and recombinant catestatin has been reported to prevent macrophage-driven atherosclerosis in ApoE−/− mice, via an as yet unidentified mechanism involving the activation of ACE2. Fibrosis is a key pathogenetic mechanism of several myocardial diseases.23–25 Epicardium and epicardium-derived cells are critical players in myocardial fibrosis. Mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) have been studied for cardiac repair to improve cardiac remodelling, but the actual mechanisms remain elusive. In a Translational Research article ‘Intrapericardial long non-coding RNA–Tcf21 antisense RNA inducing demethylation administration promotes cardiac repair’, Dashuai Zhu from the North Carolina State University and University of North Carolina at Chapel Hill in the USA, and colleagues investigate the mechanisms of EV therapy for improving cardiac remodelling and develop a promising treatment addressing myocardial fibrosis.26 EVs were intrapericardially injected for mice MI treatment. RNA-seq, in vitro gain- and loss-of-function experiments, and in vivo studies were performed to identify targets that can be used for myocardial fibrosis treatment. Afterward, a lipid nanoparticle-based long non-coding RNA (lncRNA) therapy was prepared for mouse and porcine models of myocardial infarction. Intrapericardial injection of EVs improved adverse myocardial remodelling in mouse models of myocardial infarction. Mechanistically, Tcf21 was identified as a potential target to improve cardiac remodelling. Loss of Tcf21 function in epicardium-derived cells caused increased myofibroblast differentiation, whereas forced Tcf21 overexpression suppressed transforming growth factor-β signalling and myofibroblast differentiation. LncRNA–Tcf21 antisense RNA inducing demethylation (TARID) that is enriched in EVs was identified to up-regulate Tcf21 expression. Formulated lncRNA–TARID-laden lipid nanoparticles (LNPs) up-regulated Tcf21 expression in epicardium-derived cells and improved cardiac function and histology in mouse and porcine models of myocardial infarction. The authors conclude that they have identified Tcf21 as a critical target for improving cardiac fibrosis. Up-regulating Tcf21 by using lncRNA–TARID-LNPs could be a promising way to treat myocardial fibrosis. Thus, this study establishes novel mechanisms underlying EV therapy for improving adverse remodelling and proposes a lncRNA therapy for cardiac fibrosis. The contribution is accompanied by an Editorial by Xuekun Wu, Joseph C. Wu, and Francesca Vacante from the Stanford University School of Medicine in Palo Alto, CA, USA.27 The authors note that Zhu and colleagues identified TCF21 as the underlying key regulator of MSC-EV treatment, helping to create a foundation for a novel potential non-coding lncRNA–TARID therapy to mitigate cardiac remodelling following MI. While more work is required to elucidate LNP-TARID therapy targets, this study has enhanced our understanding of the translational role of lncRNAs during cardiac fibrosis and provides a novel therapeutic angle for cardiac repair. 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.