Revisiting angina pectoris with and without obstructive coronary artery disease

For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts Angina pectoris is one of the most common symptoms in cardiology. Initially, this was exclusively associated with obstructive coronary artery disease. More recently, it was recognized that patients may present with signs of ischaemia, but non-obstructed coronary arteries, the so-called INOCA.1 Of note, even patients presenting as acute coronary syndromes may have myocardial infarction with non-obstructed coronary arteries or MINOCA2–4 (a condition distinct from Tako Tsubo syndrome that may present similarly).5 These conditions have been traditionally associated with microvascular disorders,6,7 although the exact causes are still elusive. Furthermore, the long-term prognosis of angina in patients without obstructive coronary artery disease is uncertain. The latter aspect is addressed in a meta-analysis entitled ‘Determinants of long-term clinical outcomes in patients with angina but without obstructive coronary artery disease: a systematic review and meta-analysis’ by Raffaele De Caterina and colleagues from the Ospedale SS. Annunziata in Chieti, Italy.8 The authors identified 54 studies, reporting outcomes in 35 039 such patients. After 5 years, the incidence of the primary outcome was 0.98/100 person-years, with considerable heterogeneity among studies. The primary outcome was associated with dyslipidaemia, diabetes, and hypertension. Ischaemia documented by non-invasive imaging techniques was associated with a higher incidence of events. Overall, these patients had frequent recurrent hospitalization. Thus, angina without obstructive coronary artery disease has a heterogeneous prognosis. A main determinant of major adverse events appears to be the presence of non-obstructive coronary plaques, while myocardial ischaemia may be related to microvascular dysfunction. Effective management of these patients needs to be evaluated in future trials. HIV-positive persons have increased cardiovascular event rates,9–11 but the prevalence of subclinical atherosclerosis compared with HIV-negative individuals is still uncertain. In their article ‘Subclinical coronary artery disease in Swiss HIV-positive and HIV-negative persons’, Philip E. Tarr and colleagues from the Swiss HIV Cohort Study assessed subclinical atherosclerosis utilizing coronary artery calcium scoring and coronary computed tomography (CT) angiography in 428 HIV-positive participants and 276 HIV-negative controls.12 HIV-positive participants were younger than HIV-negative participants but had similar 10-year Framingham risk scores as well as coronary artery calcium scores and the prevalence of non-calcified, mixed, or high-risk plaque. Surprisingly, HIV-positive participants had a lower prevalence of calcified plaque than HIV-negative subjects, lower coronary segment severity score, and lower segment involvement score. Advanced immunosuppression was associated with non-calcified or mixed plaque. Thus, in today’s medical environment, HIV-positive individuals have a similar degree of non-calcified, mixed plaque, and high-risk plaques, fewer calcified coronary plaques, and lower coronary atherosclerosis involvement and severity scores than HIV-negative subjects with similar Framingham risk scores. These surprising findings are put into context in an Editorial by Bruno R. Cotter from the University of California San Diego Health System in La Jolla, California, USA.13 With the increasing recognition of inflammation as a major component of atherosclerosis and coronary artery disease,14 the incidence of angina and infarction in inflammatory disease has generated a lot of interest.15–17 Indeed, rheumatoid arthritis is associated with a two-fold elevated risk of cardiovascular mortality. Of note, rheumatoid arthritis patients present with systemic inflammation including raised circulating myeloid cells, but no cardiovascular risk factors, particularly dyslipidaemia. In their article entitled ‘Defective cholesterol metabolism in haematopoietic stem cells promotes monocyte-driven atherosclerosis in rheumatoid arthritis’, Andrew James Murphy and colleagues from Baker IDI Heart and Diabetes Institute in Melbourne, Australia explored whether increased circulating myeloid cells are associated with impaired atherosclerotic lesion regression or altered progression in two mouse models of rheumatoid arthritis.18 Of note, monocytosis, neutrophilia, and thrombocytosis were prominent and due to enhanced proliferation of the haematopoietic stem and progenitor cells in the bone marrow and spleen. Expansion of haematopoietic stem cells and progenitor cells was associated with increased cholesterol content, due to down-regulation of the cholesterol efflux genes Apoe, Abca1, and Abcg1. Haematopoietic stem and progenitor cells expressed key myeloid-promoting growth factor receptors. Further, inflammation altered cellular cholesterol metabolism. Increased myeloid cells were associated with impaired lesion regression in rheumatoid mice, even though cholesterol levels were equivalent to those of non-arthritic mice. Also, their lesions exhibited a less stable phenotype. In a progression model, monocytosis, enhanced monocyte recruitment, and increased plaque macrophages was reversed by reconstituted HDL. Importantly, rheumatoid arthritis patients had expanded CD16+ monocyte subsets and down-regulation of ABCA1 and ABCG1. Thus, rheumatoid arthritis impairs atherosclerotic regression or even favours progression due to expansion of myeloid cells and disturbed cellular cholesterol handling. Whether cholesterol reduction in rheumatoid arthritis even within normal levels may limit vascular disease is discussed in an Editorial by Laurant Yvan-Charvet from INSERM U1065, Université Côte d’Azur in Nice, France.19 Scavenger receptor class B type 1 or SR-BI is a major receptor for HDL that promotes hepatic uptake of cholesterol. Although considered protective, HDL may become dysfunctional as patients develop coronary artery disease or infarction.20–22 Nevertheless, mutations in SR-BI may play a role, a hypothesis that is tested in the article ‘Rare SCARB1 mutations associate with high-density lipoprotein cholesterol but not with coronary artery disease’ by Hilma Holm and colleagues from deCODE Genetics Inc. in Reykjavik, Iceland.23 Indeed, a rare mutation in the gene encoding SR-BI, SCARB1, is associated with elevated HDL-cholesterol and increased risk of coronary artery disease, suggesting that increased HDL-cholesterol due to an SR-BI mutation might be a marker of risk. Using a large resource of whole-genome sequenced Icelanders, they identified 13 SCARB1 mutations and examined their association with HDL-cholesterol in 136 672 individuals. Three rare SCARB1 mutations, encoding p.G319V, p.V111M, and p.V32M, associated with elevated levels of HDL-cholesterol, but not with coronary artery disease. Furthermore, HDL-cholesterol-raising alleles of three common SCARB1 non-coding variants that associate with higher HDL-cholesterol do not confer increased risk of coronary artery disease (Figure 1). Thus, increased HDL-cholesterol due to genetically compromised SR-BI function is not a marker of coronary artery disease risk. The manuscript is further discussed in a thought-provoking Editorial by Ulf Landmesser from the Charité–Universitätsmedizin Berlin in Germany.24 Change from baseline in exercise tolerance time (s), ITT population. Least squares mean changes (± SE) are plotted for each post-baseline time point. Red, auto-CD34+, blue, placebo (A). Change from baseline in exercise tolerance time (s), As-treated population. Least squares mean changes (± SE are plotted for each post-baseline time point. Red, auto-CD34+, blue placebo (B) (from Helgadottir A, Sulem P, Thorgeirsson G, Gretarsdottir S, Thorleifsson G, Jensson BÖ, Arnadottir GA, Olafsson I, Eyjolfsson GI, Sigurdardottir O, Thorsteinsdottir U, Gudbjartsson DF, Holm H, Stefansson K. Rare SCARB1 mutations associate with high-density lipoprotein cholesterol but not with coronary artery disease. See pages 2172–2178). Besides percutaneous coronary interventions,25 bypass surgery is the most important revascularization procedure.26 In general, cardiac surgery is associated with a certain risk that should be evaluated as precisely as possibly by the responsible HeartTeam. In 2009, age, creatinine, and ejection fraction were combined into the ACEF score and recommended by the most recent guidelines for myocardial revascularization of the European Society of Cardiology and Association for Cardio-Thoracic Surgery.27 In their article entitled ‘The ACEF II risk score for cardiac surgery: updated but still parsimonious’, Marco Ranucci and colleagues from the IRCCS Policlinico S. Donato in Milano, Italy28 introduce the updated ACEF II score which includes emergency surgery and pre-operative anaemia in the score. The score was developed in 7011 patients operated on at a single institution and validated in 1687 patients operated on in a different institution. Discrimination of the ACEF II score was significantly better than the ACEF, and equal to the EuroSCORE II. Thus, the ACEF II allows the inclusion of emergency patients and of anaemia with more adequate prediction. The value of this new score is critically discussed in an Editorial by Sir Magdi Yacoub from Imperial College London in the UK.29 Risk refers to unintended clinical events during or after surgery or interventions. Proper definition of such events is particularly important in clinical trials aiming to reduce their occurrence with novel therapeutic strategies. This is addressed in the article entitled ‘Standardized endpoint definitions for coronary intervention trials: the Academic Research Consortium-2 consensus document’ by Hector Manuel Garcia-Garcia from the Medstar Washington Hospital Center in the USA.30 The Academic Research Consortium or ARC-2 revisited these definitions to make them more suitable for clinical trials including complex lesions and patient populations or novel devices. This ARC-2 document provides further standardization of endpoint definitions that will aid in the interpretation of trial outcomes and comparison among studies. In spite of all the medical, interventional and surgical options to treat angina, some patients suffer from treatment of refractory angina.31 Gene therapy,32 growth factors, apheresis,33 and stem cells34,35 have been tested in such individuals with different results. As autologous CD34+ cells may still represent an attractive option for the treatment of refractory angina, Timothy D. Henry and colleagues from the Minneapolis Heart Institute Foundation at Abbott Northwestern Hospital in Minnesota, in the USA present a meta-analysis entitled ‘Autologous CD34+ cell therapy improves exercise capacity, angina frequency and reduces mortality in no-option refractory angina: a patient-level pooled analysis of randomized double-blinded trials.’36 Three double-blinded randomized trials with 304 patients compared the effects of intramyocardial autologous CD34+ cells with placebo injections on total exercise time, angina frequency, and major adverse cardiac events or MACE. Autologous CD34+ cells improved total exercise time by 46.6 s at 3 months, 49.5 s at 6 months, and 44.7 s at 12 months (Figure 2). Also, the relative frequency of angina decreased over time. Importantly, autologous CD34+ cells decreased mortality from 12.1% to 2.5%, and tended to reduce MACE at 24 months. Thus, autologous CD34+ cells provide meaningful improvements in exercise time and angina frequency up to 12 months and reduce mortality. The implications of these findings are assessed in an Editorial by Thomas Thum from the Hannover Medical School in Germany.37 (A) Change from baseline in exercise tolerance time (seconds), intent-to-treat population. Least squares mean changes (±standard error) are plotted for each post-baseline time point. (B) Change from baseline in exercise tolerance time (seconds), as-treated population. Least squares mean changes (±standard error) are plotted for each post-baseline time point. Red colour indicates autologous CD34+ and blue colour indicates placebo. ITT, intent-to-treat; TET, total exercise time (from Henry TD, Losordo DW, Traverse JH, Schatz RA, Jolicoeur EM, Schaer GL, Clare R, Chiswell K, White CJ, Fortuin FD, Kereiakes DJ, Zeiher AM, Sherman W, Hunt AS, Povsic TJ. Autologous CD34+ cell therapy improves exercise capacity, angina frequency and reduces mortality in no-option refractory angina: a patient-level pooled analysis of randomized double-blinded trials. See pages 2208–2216). The editors hope that readers of this issue of the European Heart Journal will find it of interest.