Frontiers of acute coronary and aortic syndromes: outcomes, novel prognostic markers, and cardiogenic shock

Morbidity and mortality of acute coronary syndromes (ACS) have dramatically declined over the last decades thanks to impressive diagnostic and therapeutic developments.1,2 When the famous German philosopher Theodor W. Adorno died after a visit to a Swiss mountain top 50 years ago, the hospital in the town of Visp where he presented himself with severe angina had not much more to offer than an ECG, nitrates, possibly heparin, and tender loving care.3 In spite of all the progress, cardiogenic shock, be it due to infarction4 or to Tako Tsubo syndrome,5,6 remains an unresolved therapeutic challenge, as outlined in the review article ‘Management of cardiogenic shock complicating myocardial infarction: an update 2019’ by Holger Thiele and colleagues from the University of Leipzig in Germany. They remind us that cardiogenic shock remains the most common cause of death in patients admitted with ACS; unfortunately, during the last two decades, mortality has remained nearly unchanged in the range of 40–50%.7 Early revascularization, vasopressors and inotropes,8,9 fluids, mechanical circulatory support (Figure 1), and general intensive care measures are widely used. However, there is only limited evidence for any of these treatment strategies except for target artery only revascularization,10 and the relative ineffectiveness of intra-aortic balloon pumping.11 This review updates the state of the art in the management of cardiogenic shock complicating acute myocardial infarction. Improvement in discrimination for prediction of 90-day mortality risk with each model. CardShock risk score includes age >75 years, confusion at presentation, previous myocardial infarction or coronary artery bypass grafting, ACS aetiology, LVEF <40%, blood lactate, and eGFrckd-epi. CS4P score includes circulating protein abundance measured by parallel reaction monitoring of the liver-type fatty acid-binding protein, the Fructose-bisphosphate aldolase B, the beta-2-microglobulin, and the SerpinG1. CardShock + CS4P includes CardShock risk score plus the CS4P score. AUC values for CS4P, CS4P + CardShock, and CardShock are 0.83, 0.84, and 0.78, respectively, and are indicated in brackets in the receiver operating characteristic plot. TheMann—Whitney test was used for statistical assessment (from Rueda F, Borràs E, García-García C, Iborra-Egea O, Revuelta-López E, Harjola V-P, Cediel G, Lassus J, Tarvasmäki T, Mebazaa A, Sabidó E, Bayés-Genís A. Protein-based cardiogenic shock patient classifier. See pages 2684–2694). Precise risk stratification of cardiogenic shock is another unmet need.12,13 It could guide interventions to improve patient outcome, as discussed in the research article ‘Protein-based cardiogenic shock patient classifier’ by Antoni Bayes-Genis and colleagues from the Hospital Universitari Germans Trias i Pujol in Badalona, Spain.14 They developed a score of circulating proteins to predict short-term mortality among such patients. Out of 2654 proteins, 51 proteins were used in the CardShock cohort of 97 patients. Interestingly, a combination of four circulating proteins (Cardiogenic Shock 4 proteins or CS4P), discriminated patients with low and high 90-day mortality risk. CS4P comprises the abundances of liver fatty acid-binding protein, beta-2-microglobulin, fructose-bisphosphate aldolase B, and SerpinG1. Within the CardShock cohort used for internal validation, the C-statistic was 0.78 for the CardShock risk score, 0.83 for the CS4P model, and 0.84 for the combination of CardShock risk score with the CS4P model. The CardShock risk score with the CS4P model improved reclassification compared with the IABP-SHOCK II risk score combined with CS4P. Thus, a new protein-based cardiogenic shock patient classifier, the CS4P, improves prediction of short-term mortality risk stratification in combination with contemporary risk scores, which may guide clinicians in selecting patients for advanced therapies. These clinically important results are further discussed in an Editorial by Anthony H. Gershlick from Glenfield Hospital in Leicester, UK.15 The microbiome and its metabolites have also attracted increasing interest in cardiovascular medicine.16,17 In particular, trimethylamine N-oxide or TMAO, derived mainly from read meat,18 predicts both severity of coronary artery disease and outcomes in stable and acute coronary patients.19,20 Trimethyllysine or TML serves as a nutrient precursor of the gut microbiota-derived metabolite TMAO which predicts cardiovascular risks in stable subjects. In a FAST TRACK article entitled ‘Trimethyllysine, a trimethylamine N-oxide precursor, provides near- and long-term prognostic value in patients presenting with acute coronary syndromes’, Stanley L. Hazen and colleagues from the Cleveland Clinic in Ohio, USA evaluated plasma TML levels in patients presenting with ACS.21 In 530 patients from Cleveland with suspected ACS, elevated TML levels predicted increased risk of major adverse cardiac events or MACE beyond traditional risks factors and indices of renal function. TML levels also independently predicted long-term MACE and mortality even amongst those persistently negative for cardiac troponin T (TnT) at presentation. TML further provided additive prognostic value in combination with TMAO for MACE even among patients negative for TnT. The clinical prognostic value of elevated TML levels was replicated in a multicentre Swiss ACS cohort comprising 1683 patients. Thus, plasma TML levels, alone and additive to TMAO, predict both short- and long-term risks in ACS patients. These novel findings are put into context in a thought-provoking Editorial by Gabriele G. Schiattarella from the University of Texas Southwestern Medical Center at Dallas, USA.22 Neutrophils have both detrimental and beneficial effects on myocardial infarction,23,24 but little is known about the underlying pathways. S100A8/A9 is a pro-inflammatory alarmin abundantly expressed in neutrophils that is rapidly released in the myocardium and circulation after myocardial ischaemia. In a Basic Science article ‘Inhibition of pro-inflammatory myeloid cell responses by short-term S100A9 blockade improves cardiac function after myocardial infarction’ Goran Marinkovic and colleagues from Lunds University in Malmo, Sweden investigated its role in the innate immune response to myocardial infarction.25 In 524 ACS patients, they found that high S100A8/A9 plasma levels were associated with lower left ventricular ejection fraction (LVEF) at 1 year, and increased hospitalizations for heart failure (Figure 2). In wild-type mice with myocardial infarction, treatment with the S100A9 blocker ABR-238901 during the inflammatory phase of the immune response inhibited haematopoietic stem cell proliferation and myeloid cell exit from the bone marrow, reduced neutrophils and monocytes/macrophages in the myocardium, promoted an anti-inflammatory environment, and improved LVEF. Compared with untreated mice, ABR-238901 significantly improved LVEF and cardiac output by 3 weeks after infarction. Thus, short-term S100A9 blockade inhibits inflammation and improves cardiac function in murine models of myocardial infarction. As an excessive S100A8/A9 release is linked to incident heart failure in ACS patients, S100A9 blockade might represent a feasible strategy to improve clinical outcomes, a hypothesis that is further discussed in a balanced Editorial by Nikolaos Frangogiannis from the Albert Einstein College of Medicine in New York, USA.26 Short-term S100A9 blockade reduces myocardial inflammation and improves cardiac function after myocardial infarction. S100A9 plays a central role in the inflammatory phase of the myocardial infarction, by stimulating haematopoietic stem cell proliferation in the bone marrow, neutrophil and monocyte egression into the blood stream and recruitment into the ischaemic myocardium. Short-term blockade of S100A9 using the specific inhibitor ABR-238901 leads to reduced inflammatory response in the myocardium and significantly improves cardiac function inmurine models of myocardial ischaemia (from Marinković G, Grauen Larsen H, Yndigegn T, Szabo IA, Mares RG, de Camp L, Weiland M, Tomas L, Goncalves I, Nilsson J, Jovinge S, Schiopu A. Inhibition of pro-inflammatorymyeloid cell responses by short-termS100A9 blockade improves cardiac function aftermyocardial infarction. See pages 2713–2723). Acute aortic syndrome cases may, similarly to ACS, present with chest pain, dyspnoea and/or syncope, and sudden death, and therefore represent a diagnostic challenge.27–29 The underlying cause may be intramural haematoma as well as type A or B dissection. This aspect is further investigated in the article ‘Differential clinical features and long-term prognosis of acute aortic syndrome according to disease entity’ by Jae-Kwan Song and colleagues from the University of Ulsan in Seoul, South Korea.30 Of 1012 patients, 672 had aortic dissection and 340 had intramural haematoma. Compared with aortic dissection, those with intramural haematoma were older and more commonly of female gender and with distal aortic involvement. In-hospital mortality of acute aortic syndrome was 8.6% and in type A aortic dissection 15%, in type A intramural haematoma 8%, in type B aortic dissection 5%, and in type B intramural haematoma 1.5%. During 8.5 years, aortic dissection and type A haematoma were associated with a higher risk of aortic death. Thus, the clinical features, response to treatment, and outcomes of intramural haematoma are distinct from those of aortic dissection. Both early and late survival were better for intramural haematoma than for aortic dissection. In addition to the anatomical location of acute aortic syndrome, the disease entity is an independent factor associated with both acute and long-term mortality in patients with acute aortic syndrome. These results are put into context in an interesting Editorial by Janet T. Powell from Imperial College London, UK.31 The editors hope that readers of this issue of the European Heart Journal will find it of interest. With thanks to Amelia Meier-Batschelet for help with compilation of this article.