Basic mechanisms in cardiogenic shock: part 1—definition and pathophysiology Konstantin A. Krychtiuk 1,2 *, Christiaan Vrints 3,4 , Johann Wojta 1,5,6 , Kurt Huber 5,7,8 , and Walter S. Speidl 1,5 1 Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria; 2 Duke Clinical Research Institute, Durham, NC, USA; 3 Research Group Cardiovascular Diseases, Department GENCOR, University of Antwerp, Antwerp, Belgium; 4 Department of Cardiology, Antwerp University Hospital (UZA), Edegem, Belgium; 5 Ludwig Boltzmann Institute for Cardiovascular Research, Vienna, Austria; 6 Core Facilities, Medical University of Vienna, Vienna, Austria; 7 3rd Department of Internal Medicine, Cardiology and Intensive Care Unit, Wilhelminenhospital, Vienna, Austria; and 8 Medical School, Sigmund Freud University, Vienna, Austria Received 16 September 2021; revised 17 January 2022; editorial decision 7 February 2022; accepted 7 February 2022 Cardiogenic shock mortality rates remain high despite significant advances in cardiovascular medicine and the widespread uptake of mech- anical circulatory support systems. Except for early invasive angiography and percutaneous coronary intervention of the infarct-related artery, the most widely used therapeutic measures are based on low-quality evidence. The grim prognosis and lack of high-quality data warrant further action. Part 1 of this two-part educational review defines cardiogenic shock and discusses current treatment strategies. In addition, we summarize current knowledge on basic mechanisms in the pathophysiology of cardiogenic shock, focusing on inflammation and microvascular disturbances, which may ultimately be translated into diagnostic or therapeutic approaches to improve the outcome of our patients. ................................................................................................................................................................................................... Keywords Cardiogenic shock • Inflammation • Microvasculature • Biomarkers Introduction Despite significant improvements in interventional cardiology and systems of care ensuring timely reperfusion in acute myocardial in- farction (AMI) patients and the widespread uptake of mechanical cir- culatory support (MCS) systems, mortality rates in cardiogenic shock remain unacceptably high. 1,2 While the general use of primary percu- taneous coronary intervention (PCI) in AMI-related cardiogenic shock after the publication of the SHOCK 3 trial seems to have caused a decline in cardiogenic shock-related mortality, 4 survival rates have plateaued in the last decade, as suggested by randomized clinical trials (RCTs) and registry data. 5–8 Recently published data even suggest ris- ing mortality rates within the last decade, 9,10 possibly owed to the fact that patients are becoming ‘sicker’ and medically more compli- cated. 11–13 Others have shown a stable mortality rate despite more frequent use of invasive treatment. 14 During the last two decades, cardiovascular clinical mega-trials mainly focused on the pharmacologic treatment of AMI, heart failure, lipid disorders, and diabetes. Only 11 RCTs recruiting patient cohorts between 40 and 706 patients have assessed cardiogenic shock man- agement. 15,16 Execution of high-quality RCTs in cardiogenic shock is hindered by a heterogeneous patient population and a significant time pressure in recruitment and communication barriers. Except for early invasive angiography and PCI of the infarct-related artery and the lack of substantial outcome effects using an intra-aortic balloon pump (IABP), there is only scarce evidence for other widely used interventions such as the use of vasopressors and inotropic agents, fluid management, MCS, and general intensive care unit (ICU) meas- ures. 16–18 The paucity and low-quality evidence for cardiogenic shock treat- ment strategies and the persistently grim prognosis warrant further action. 19 Within this educational review, we aimed to summarize basic mechanisms in the pathophysiology of cardiogenic shock, which may ultimately be translated into diagnostic or therapeutic approaches to improve the outcome of our patients. Definition Current guidelines and consensus papers use slightly different defini- tions of cardiogenic shock. Central to the definition is a state of tissue and end-organ hypoperfusion caused by the heart’s inability, due to * Corresponding author. Tel: þ 43 1 40400 46140, Fax: þ 43 1 40400 42160, Email: konstantin.krychtiuk@meduniwien.ac.at Published on behalf of the European Society of Cardiology. All rights reserved. V C The Author(s) 2022. For permissions, please email: journals.permissions@oup.com. European Heart Journal: Acute Cardiovascular Care REVIEW https://doi.org/10.1093/ehjacc/zuac021 Downloaded from https://academic.oup.com/ehjacc/advance-article/doi/10.1093/ehjacc/zuac021/6537495 by USC - Universidade de Santiago de Compostela user on 20 March 2022 pump failure, to deliver enough oxygen to organs and peripheral tis- sues to meet metabolic demands in the presence of adequate intra- vascular volume. 16–18,20 A seminal publication from 1994 has defined cardiogenic shock as a combination of low systolic blood pressure (<90 mmHg) and evidence of low output (cardiac index <2.2 L/min and elevated arteriovenous oxygen difference >5.5 mL/dL) in patients with elevated filling pressures (pulmonary-capillary wedge pressure > 15 mmHg). 20 In clinical practice, haemodynamic monitoring may not be available at the bedside. Therefore, most patients are initially diag- nosed using a pragmatic approach consisting of hypotension, bio- chemical, and clinical signs of tissue hypoperfusion, including cool extremities, elevated lactate levels, oliguria, and an altered mental state persisting after fluid challenge. While most current cardiogenic shock definitions include hypotension, compensatory mechanisms including vasoconstriction may (initially) preserve blood pressure. As data from the SHOCK registry suggests, those patients may still ex- perience tissue hypoperfusion and have a high mortality risk. 21 Table 1 gives an overview of various cardiogenic shock definitions used in recent position papers and cardiogenic shock trials. Of note, the mentioned trials have included only patients with cardiogenic shock due to AMI. Classical definitions using reduced blood pressure, signs of conges- tion, and signs of peripheral hypoperfusion may cover a broad array of disease severity with strongly diverging outcomes and intervention needs. Therefore, in a harmonization effort, the Society for Cardiovascular Angiography and Interventions (SCAI) has published a cardiogenic shock classification consisting of five stages from A to E, which has recently been updated. 22,23 Stage A refers to patients ‘at- risk’ for cardiogenic shock, Stage B categorizes patients with ‘begin- ning’ cardiogenic shock, Stage C describes the ‘classic’ cardiogenic shock, Stage D catalogues patients as ‘deteriorating’, and Stage E as ‘extremis’. Stage B is characterized by a blood pressure drop or other signs of haemodynamic instability without signs of hypoperfusion. In contrast, Stage C patients show hypoperfusion requiring an interven- tion to augment cardiac output, either pharmacologically using ino- tropes or mechanically using MCS systems. Patients that have not regained stability and adequate perfusion despite an initial set of inter- ventions are in Stage D, and patients in the ‘extremis’ category E are highly unstable patients with imminent cardiovascular collapse. The classification has already been externally validated and provided ro- bust mortality prediction in cardiogenic shock patients. 24,25 In its re- cent update, a three-axis model of cardiogenic shock evaluation and prognostication was introduced, consisting of shock severity, pheno- type and aetiology as well as risk modifiers. Although it is evident that patients in Stage D or E require a dramatically different management strategy than patients in Stage A or B, they all fit under the cardio- genic shock definition. They might thus all be included without any discrimination in cardiogenic shock trials using inclusion criteria solely based on this definition. Therefore, the SCAI classification represents a strongly needed disease severity classification to make trial popula- tions comparable and guide new trial designs and inclusion criteria. Patients after cardiac arrest may present with clinical findings fulfill- ing standard cardiogenic shock criteria and represent a significant proportion (around 50%) of patients included in large cardiogenic shock RCTs. 5,6,26 When testing the effects of specific interventions on outcomes such as mortality, it is critical to note that most cardiac arrest patients die of anoxic brain injury. In addition, however brief, cardiac arrest at any point during hospitalization for cardiogenic shock represents a serious event worsening clinical trajectory. Therefore, the SCAI classification introduced a cardiac arrest risk modifier (A) to be added to the respective cardiogenic shock stage. 22 Cardiogenic shock may occur in previously diseased hearts in patients with chronic heart failure or suddenly in a previously healthy heart due to severe myocardial infarction with or without mechanical complication, acute myocarditis, and other entities. 27 Such patients are characterized by more severe shock presentations and worse outcomes suggesting differing pathophysiological features and pos- sibly tailored treatment strategies. 28 Pump failure due to AMI has traditionally been described as the dominant cause of cardiogenic shock, while more recent observations suggest a steady decline in the proportion of AMI patients, possibly due to improved ST-eleva- tion myocardial infarction networks. 29,30 Cardiogenic shock paradigm In 1999, the groundwork was laid for today’s cardiogenic shock model as a downward spiral with compensatory mechanisms becom- ing maladaptive, further worsening the situation, ultimately leading to the patient’s death. 31 This paradigm has been updated several times within the last decades. 16,32–34 Central to this concept is a severely depressed myocardial contractility causing a reduction in both sys- temic and coronary perfusion, the latter worsening and extending myocardial ischaemia and thereby reducing contractility in an endless spiral. The reduction in peripheral perfusion leads to compensatory systemic vasoconstriction and fluid retention. Cerebral vasoconstric- tion may present as mental confusion, while splanchnic vasoconstric- tion further worsens volume overload and may cause intestinal ischaemia and intestinal barrier disruption. Rising filling pressures due to the worsening pump failure further reduce coronary perfusion and increase pulmonary pressures leading to pulmonary oedema, fuelling hypoxaemia, and tissue hypoperfusion. Lessons learned from the seminal SHOCK trial expanded the paradigm and brought inflam- mation into the spotlight. 33 Myocardial infarction and peripheral hypoperfusion result in tissue damage which may cause a strong in- flammatory activation [systemic inflammatory response syndrome (SIRS)]. Increased expression of inducible nitric oxide synthase (iNOS) releases high amounts of nitric oxide (NO) with pro- inflammatory and vasodilatory effects as well as deleterious effects on myocardial contractility and peripheral vascular tone. 33 Once micro-circulatory disturbances, an inflammatory response and multi- organ failure have developed, even restoring macrocirculatory haemodynamic parameters by MCS or/and inotropes may not re- verse this downward spiral, ultimately leading to the patient’s death. Current treatment strategies Patients presenting with cardiogenic shock due to AMI should always undergo urgent PCI based on the results of the seminal SHOCK trial. 3 In multivessel disease, culprit vessel PCI is preferred to multi- vessel PCI at presentation, based on the results of the CULPRIT- SHOCK trial. 5 In non-acute coronary syndrome cardiogenic shock, 2 K.A. Krychtiuk et al Downloaded from https://academic.oup.com/ehjacc/advance-article/doi/10.1093/ehjacc/zuac021/6537495 by USC - Universidade de Santiago de Compostela user on 20 March 2022 the aetiology needs to be established and treated specifically. Unless overt signs of fluid overload are present, patients should receive a fluid challenge. If a vasopressor is needed, nor-adrenaline is the sub- stance of choice. 35,36 Several inotropes are available to increase car- diac contractility, including dobutamine, levosimendan, and phosphodiesterase inhibitors. 37–39 The choice of first-line inotrope or combinations of inotropes in cardiogenic shock is still a matter of debate and ongoing research efforts (LevoHeartShock; NCT04020263). 38,40,41 General ICU measures include ventilation strategies, glycaemic control, nutrition, and more. 17,42 The concept of a cardiogenic shock team has gained popularity within the last years and centres with dedicated cardiogenic shock teams use more advanced haemodynamic monitoring and MCS systems and seem to have better outcomes. 43 While few interventions are based on high- quality evidence from RCTs, there is broad expert alignment with current guidance, with few exceptions. 44 Whenever possible, .................................................................................................................................................................................................................... Table 1 Common cardiogenic shock definitions 2020 ACVC pos- ition statement 16 SHOCK trial 3 IABP-SHOCK II 6 / CULPRIT -SHOCK 5 ECLS-SHOCK 48 EURO-SHOCK 49 DanGer shock 47 All CS AMI-CS AMI-CS AMI-CS AMI-CS AMI-CS SBP < 90 mmHg for >30 min OR cate- cholamines needed to maintain SBP > 90 mmHg SBP < 90 mmHg for >30 min OR cate- cholamines needed to maintain SBP > 90 mmHg SBP < 90 mmHg for >30 min OR cate- cholamines needed to maintain SBP > 90 mmHg SBP < 90 mmHg for >30 min OR cate- cholamines needed to maintain SBP > 90 mmHg SBP < 90 mmHg for >30 min OR cate- cholamines needed to maintain SBP > 90 mmHg SBP < 100 mmHg for >30 min and/or need for vasoactive therapy AND AND AND AND AND AND Cardiogenic cause: • LVEF <40% • mechanical causes • RV failure • severe arrhythmia AND Elevated LV filling pressures: • pulmonary congestion • elevated PCWP • mitral E-wave decel- eration time < _130 ms CI < 2.2 L/min/m 2 and PCWP > 15 mmHg Clinical signs of pul- monary congestion Clinical signs of pul- monary congestion LVEF < 45% on echocardiography LVEDP >20 mmHg AND AND AND AND AND Tissue hypoperfusion with at least one criterion: Altered mental status; cold, clammy skin, and extremities; oli- guria with a urine out- put <30 mL/h; arterial lactate >2 mmol/L Impaired end-organ perfusion: Cool extremities or a urine output <30 mL/ h and a heart rate >60/min Impaired end-organ perfusion with at least one of the following: Altered mental status; cold, clammy skin, and extremities; oli- guria with a urine out- put <30 mL/h; serum lactate >2 mmol/L Signs of impaired end- organ perfusion with at least one of the following: Altered mental status; cold, clammy skin, and extremities; oli- guria with a urine out- put <30 mL/h Signs of impaired end- organ perfusion with at least one of the following: Altered mental status; cold and clammy skin and limbs; oliguria with a urine output <30 mL/h; lactate >2 mmol/L Signs of tissue hypo- perfusion with arter- ial blood lactate >2.5 mmol/L AND Arterial lactate >3 mmol/L ACVC, Association for Acute CardioVascular Care; AMI-CS, acute myocardial infarction complicated by cardiogenic shock; CI, cardiac index; CS, cardiogenic shock; PCWP, pulmonary capillary wedge pressure; SBP, systolic blood pressure. Basic mechanisms in cardiogenic shock: part 1 3 Downloaded from https://academic.oup.com/ehjacc/advance-article/doi/10.1093/ehjacc/zuac021/6537495 by USC - Universidade de Santiago de Compostela user on 20 March 2022 cardiogenic shock patients should be included in well-designed and appropriately sized clinical trials. 15 The use of MCS systems in cardiogenic shock has increased dra- matically within the last decade, despite scarce evidence for beneficial effects. 45,46 After the neutral results of IABP-SHOCK II, the most common systems currently being used include percutaneous ven- tricular assist devices and extracorporeal life support systems. 27 Several large randomized controlled trials are on the way to test veno-arterial extracorporeal membrane oxygenation (VA-ECMO) and the Impella V R system in cardiogenic shock patients. 47–49 Awaiting the results of these trials, current guidelines recommend considering the use of these MCS in selected patients with an IIa C recommenda- tion. 18 As outlined above, dedicated cardiogenic shock teams were shown to be related to better outcomes and may be of great import- ance translating findings from MCS trials to real-world practice and ensure proper patient selection and standardization of acute and post-implant care. Focus on microcirculation In the early phase of cardiogenic shock, a sudden reduction in cardiac output causes macro-haemodynamic alterations such as hypotension and reduced tissue perfusion. Compensatory mechanisms cause an increase in heart rate and contractility to preserve cardiac output, while peripheral vasoconstriction initially preserves perfusion pres- sure. Impaired forward flow due to pump failure of extensive parts of the myocardium leads to a rapid rise in left ventricular filling pressure. The resulting near collapse of coronary flow further compromises cardiac output and macro-haemodynamics which ultimately translate into a reduced microvascular flow fuelling multi-organ injury. 50,51 A strong inflammatory activation, driven by various inflammatory cas- cades such as cytokine release, complement formation, free radical generation, and cellular responses may be the result. 52 Such an over- active inflammatory system and heightened expression of iNOS releasing high amounts of NO contributes to a paradoxically low and catecholamine-unresponsive (micro-) vascular resistance often observed in clinical trials and practice 3 characterizing refractory car- diogenic shock. 33,53 The term microcirculation traditionally includes the smallest blood vessels, the arterioles, capillaries, and venules. The main functions of the microcirculation comprise oxygen and nutrient delivery to and carbon dioxide removal from tissues. In a substudy of the CULPRIT- SHOCK trial using videomicroscopy examining the sublingual capil- lary network, microcirculatory disturbances were strongly associated with adverse clinical outcomes, while no association was present for macrocirculatory haemodynamic parameters. 54 In addition, normo- tensive patients with impaired microvascular perfusion were at higher risk of adverse outcomes than those with unaltered microvascular parameters, thus confirming the loss of correlation between macro- and micro-haemodynamic systems in cardiogenic shock. These find- ings support earlier observations in septic shock patients that restor- ing macro-haemodynamic parameters using traditional approaches such as vasopressors may not constantly improve outcomes in se- verely compromised patients. 55 Microvascular disturbances may have detrimental effects on the kidneys (kidney failure), the liver (hypoxic hepatitis, impaired coagulation factor synthesis), lungs (recruitment of arterio-venous shunts resulting in aggravating hypoxia), the gastrointestinal tract (bacterial translocation), the brain (mental confusion), and the heart itself, further fuelling the downward spiral of cardiogenic shock end- ing in multi-organ failure and death ( Figure 1 ). 56 Which pathophysio- logical mechanisms may contribute to microvascular disturbances? While the reduction in cardiac output undoubtedly represents the initial driving factor, other factors contribute in later stages, evi- denced by the dissociation between macro- and microvascular haemodynamic parameters in later stages. These include endothelial activation, subsequent platelet and leucocyte adhesion and coagula- tion activation, causing microvascular occlusion. 57 In addition, micro- vascular vasoconstriction caused by overshooting endogenous catecholamine levels and vascular leakage with interstitial oedema formation may cause reduced oxygen exchange. 56 The glycocalyx is a thin mesh layer covering the luminal surface of endothelial cells con- sisting mainly of proteoglycans, glycosaminoglycans, and glycopro- teins. It ensures vascular integrity by inhibiting the adhesion of cellular and protein components of the inflammatory and coagulation sys- tem. 58 Of interest, circulating levels of syndecan-1, the most preva- lent proteoglycan in the endothelial glycocalyx, were predictive of short-term mortality in AMI-cardiogenic shock patients. 59 Serum lactate has evolved to be the gold standard for the indirect evaluation of the microcirculation. 60 While elevated lactate levels are a sensitive marker for tissue hypoxia, they are non-specific. 61 Direct visualization of the microcirculation using various technologies has been used in several larger RCTs as outlined above, and technology is advancing rapidly. 56 Although vasopressors such as nor-adrenaline are regularly administered to maintain systemic blood pressure and thus perfusion pressure, most studies could not demonstrate benefi- cial effects on microvascular flow observed in septic shock patients, with one small study as an exception. 55,62–64 Inotropic substances including inodilators with pleiotropic effects such as levosimendan as well as low-dose nitrates may, however, positively influence the microcirculation. 62,65–68 Currently, MCS systems are widely used in cardiogenic shock patients. A substudy of the IABP-SHOCK-II trial showed that micro- circulatory dysfunction is strongly associated with adverse outcomes but is not improved by IABP treatment. 56,69 In a study in 48 patients on VA-ECMO support, early microcirculatory dysfunction predicted 28-day mortality superior to other routinely measured parameters. 70 In addition, sublingual microcirculation was indicative of successful VA-ECMO weaning in a small ( n = 15) cohort with cardiogenic shock patients due to various pathologies. 71 Taken together, low-quality observational data suggests it may be reasonable to use microcircula- tion as an additional marker to guide therapy. The concept of bedside microcirculation assessment however remains highly experimental at this moment and there is a strong need for large RCTs recruiting homogeneous patient populations using well-defined microcircula- tion assessment strategies undertaken by experienced operators to test a potential tailored approach to improve microcirculatory derangements in cardiogenic shock patients. 72 The gut represents an organ system especially prone to a low per- fusion state and microcirculatory disturbances, which may affect in- testinal integrity. 73 Once this integrity is compromised, abnormal intestinal permeability may allow bacterial translocation into the 4 K.A. Krychtiuk et al Downloaded from https://academic.oup.com/ehjacc/advance-article/doi/10.1093/ehjacc/zuac021/6537495 by USC - Universidade de Santiago de Compostela user on 20 March 2022 circulation causing a septic state and contributing to the otherwise sterile inflammatory response. 74 One study looking into circulating levels of intestinal fatty acid-binding protein (iFABP) in patients with severe acute heart failure and cardiogenic shock, a protein particular for small bowel enterocytes, could show an association between iFABP admission levels and early mortality. Those results suggest det- rimental effects of early, inadequate gut perfusion. 75 Of note, pharmacologic interventions such as vasopressor therapy may fur- ther aggravate intestinal injury in critically ill patients. 76 The last two analyses were small, of observational nature and thus only hypoth- esis-generating. Inflammation Evidence for the involvement of inflammatory mechanisms in the pathophysiology of cardiogenic shock derives from biomarker studies demonstrating elevated circulating levels of inflammatory cytokines, such as interleukin-6 (IL-6). 77,78 Additional studies suggested IL-6 is an independent predictor of early mortality in patients with AMI-car- diogenic shock. 79 Initially, it was hypothesized that bacterial translocation might solely be responsible for this observation. 80 A strong correlation with organ failure, serum lactate, and use of vaso- pressors, however, suggest that sterile inflammatory processes are an important contributor to deterioration. 81 Tissue hypoxia seems to be causally involved in the induction of IL-6 and other cytokines within the vasculature and the infarcted and reperfused myocar- dium. 82–84 Clinical observations from the CardShock study con- firmed an association between hypoperfusion and circulating IL-6 levels in patients with cardiogenic shock. 85 Myocardial pressure over- load may represent another pathway of inflammatory activation as shown in an animal model. 86 Tissue damage and subsequent release and recognition of danger-associated molecular patterns (DAMPs) via pattern recognition receptors (PRRs) on leucocytes and subse- quent production of cytokines might pose yet another critical mech- anism of cytokine release (see below). 87,88 One elegant study assessed the time course of circulating white blood cells and a wide array of inflammatory biomarkers. 89 The authors could show an early rise in cytokines accompanied by neutrophilia, followed by a tissue repair response and a white cell depletion in most severe cases pre- disposing such patients to secondary infections. Figure 1 Cardiogenic shock paradigm. NOMI, non-occlusive mesenteric ischaemia; SSC-CIP, secondary sclerosing cholangitis in critically ill patients. Basic mechanisms in cardiogenic shock: part 1 5 Downloaded from https://academic.oup.com/ehjacc/advance-article/doi/10.1093/ehjacc/zuac021/6537495 by USC - Universidade de Santiago de Compostela user on 20 March 2022 Activated neutrophils and monocytes may secrete high amounts of myeloperoxidase (MPO), a peroxidase responsible for forming re- active oxygen intermediates during respiratory burst. Besides its intended bactericidal effects in bacterial infections, MPO and MPO- derived reactive oxygen species may damage myocardial tissue and affect vascular tone in sterile inflammation as observed in cardiogenic shock. 52 Importantly, elevated MPO levels in patients with acute heart failure were predictive of 1-year mortality, additive to NT- proBNP levels. 90 Moreover, the shock state causes a strong (over-) activation of the sympathetic system, associated with both the release of endogenous catecholamines and inflammatory cytokines. 91,92 Experimental research suggests that catecholamines can activate leu- cocytes and even potentiate leucocyte activation caused by bacterial molecules. 93 On the other hand, the sympathetic nervous system may exert an anti-inflammatory effect through tonic inhibition of pro- inflammatory cytokines and suppression of cellular immunity. 92 Such effects may promote the development of bacterial infection in patients with shock. Furthermore, overactivation of the sympathetic nervous system may paradoxically promote shock development by causing cardiovascular dysautonomia, a syndrome characterized by an impaired baroreflex function, inappropriate tachycardia with reduced heart rate variability, and adrenoceptor desensitization due to excessive endogenous catecholamine release. 94–97 Danger-associated molecular patterns Cardiogenic shock-induced multi-organ failure is not fundamentally different from that caused by sepsis. 98 Upon infection, the innate im- mune system is activated by detecting exogenous molecules derived from micro-organisms. It identifies molecular structures expressed by pathogens but not humans, so-called pathogen-associated mo- lecular patterns, as ‘non-self’ via PRRs such as toll-like receptors (TLRs) and triggers a robust inflammatory response subsequently. 99 Upon cell damage, as it occurs in severe cardiogenic shock in re- sponse to decreased perfusion, tissue hypoxia, and subsequent reperfusion, intracellular molecules are released into the circulation. They can be identified as ‘non-self’ by the same PRRs, causing a similar activation of the inflammatory cascade. 87 These inflammation trigger- ing molecules are reported as DAMPs. This firm inflammatory activa- tion in the absence of microbial pathogens affecting many cardiogenic shock patients has been called SIRS. 100,101 According to the endosymbiont theory, mitochondria originated from bacteria entering our cells billions of years ago, where they now live in symbiosis. 102 Mitochondria still exhibit several bacterial charac- teristics, such as circular DNA without histones. Thus, circulating mitochondrial particles may act as DAMPs due to their resemblance of bacteria. Indeed, mitochondrial DNA (mtDNA) is recognized by the same PRR that usually recognizes bacterial and viral DNA, namely TLR-9. 103,104 In an animal model, injected mitochondrial DAMPs were recognized via TLR-9 which triggered a strong SIRS-like reac- tion. In patients with severe acute heart failure and cardiogenic shock admitted to a medical ICU, the extent of mtDNA release was pre- dictive of early mortality. 105 Several additional features, including methylation, transportation in vesicles, and sheer concentration, may play a role in the immunogenicity of circulating mtDNA. Whether circulating mtDNA is a simple surrogate parameter of tissue damage and cell death or distinctively involved in the downward spiral of car- diogenic shock by fuelling the inflammatory response is currently un- known and warrants further research. Other candidate DAMPs potentially responsible for an overactive inflammatory activation in cardiogenic shock include the family of heat shock proteins, the high mobility group protein-1 (HMGB-1), S100 proteins, and other cell death products which act as TLR-2 or TLR-4 ligands. 98 Of interest, patients suffering from cardiogenic shock and other critical illnesses show up-regulation of TLR-2 expression on circulating immune cells. 88,106 Another important DAMP-receptor worth mentioning in the context of cardiogenic shock is the receptor for advanced glyca- tion end products (RAGE). 107 It is expressed on peripheral blood mononuclear cells and endothelial cells and acts as a receptor for advanced glycation end products but also several other ligands that were described as DAMPS, including S100 proteins, advanced glyca- tion end products, HMGB-1 and others. 108 Ligand binding causes strong cellular and inflammatory activation with detrimental systemic effects. A soluble form of RAGE (sRAGE) has been described in the circulation and it has been hypothesized that sRAGE might have beneficial effects by acting as a decoy and neutralizing ligand- mediated damage. A small observational study including 40 patients with cardiogenic shock due to AMI demonstrated that patients that died within 28 days had lower levels of circulating sRAGE and showed higher RAGE expression levels on monocytes as compared to survivors. 107 These findings imply that the RAGE pathway may offer potential diagnostic and therapeutic options if studied further. Cytokines as inflammatory drivers and biomarkers Within the last two decades, various cellular and protein mediators of the immune system have been studied and shown to be involved within cardiogenic shock at least on a biomarker level. 109–112 This includes the complement system as well as interferon- c , tumour ne- crosis factor- a (TNF- a ), macrophage inflammatory protein-1, mono- cyte chemoattractant protein-1, as well as IL-7, -8 and -10. 113,114 Those observations beg the question of whether those cytokines are pure bystanders and act as surrogates for an overactive immune sys- tem or whether they exert deleterious effects themselves. Interferons for instance have been described to induce myocarditis and cardiomyopathies. 115 The pro-inflammatory cytokine TNF- a , mainly produced by activated macrophages but also other cell types, together with IL-1 and IL-6, have been suggested to exhibit cardio- depressant and vasodilating features. 52,116,117 Other deleterious effects include the enhancement of oxidative stress and consequent mitochondrial DNA damage, the stimulation of apoptosis in cardio- myocytes and reduction of beta-receptor responsiveness as well as an increased endothelial activation and permeability promoting the recruitment of leucocytes to the myocardium. 52 The above described cytokine-mediated cardiodepressive and inappropriate vasodilatory effects are mainly dependent on NO-mediated effects and the use of NO synthase (NOS) inhibitors reversed those effects in experimental models. 118,119 6 K.A. Krychtiuk et al Downloaded from https://academic.oup.com/ehjacc/advance-article/doi/10.1093/ehjacc/zuac021/6537495 by USC - Universidade de Santiago de Compostela user on 20 March 2022 Inflammation and nitric oxide The exceedingly high mortality rate of patients with high vasopressor needs suggests an important role of paradoxical vasodilatation in re- fractory shock states. 120 Nitric oxide, which is synthesized by NOS upon stimulation by cytokines such as IL-6, exhibits potent vasodila- tory effects and therefore inhibitors of NOS may have a beneficial ef- fect in cardiogenic shock. 121 One proof-of-concept study and one small RCT tested this concept using L-NMMA, a non-selective NO- synthase inhibitor in cardiogenic shock patients. 122,123 They showed an improvement in haemodynamics accompanied by increased urine output without any adverse effects and a strongly reduced mortality rate of 27% in patients receiving L-NMMA compared to 67% in the control group. Subsequently, the phase II dose-ranging SHOCK-II trial randomized 79 patients to four doses of L-NMMA or placebo and demonstrated modest improvements in haemodynamics without any signs of harm. 124 The TRIUMPH trial, a multicentre, randomized, double-blind, placebo-controlled trial planned to randomize 658 AMI-cardiogenic shock patients to standard of care or 5-h infusion of L-NMMA on top of standard of care. 125 Inclusion criteria comprised AMI complicated by cardiogenic shock with infarct-related artery pa- tency, refractory cardiogenic shock of at least 24 h, evidence of ele- vated left ventricular filling pressures and a left ventricular ejection fraction of <40%. The trial was stopped prematurely after an interim analysis at 50% enrolment suggested futility. It is important to note that while early trials in sepsis and septic shock suggested a benefit of unselective NOS-inhibitors, the largest RCT to date in this arena was stopped early due to an increase in mortality in patients treated with tilarginine, which, together with the TRIUMPH results, questions the concept of NOS-inhibition. 120 Why did the TRIUMPH trial fail? One hypothesis suggests that the disad- vantages of unselective NOS inhibition may simply outweigh the advantages, which may especially be important in sick patient groups such as the one recruited in TRIUMPH, which received the study drug only after revascularization. Important disadvantages include ex- cessive vasoconstriction especially in the pulmonary bed, platelet ac- tivation, and a decrease in cardiac output. Conclusion Cardiogenic shock is a condition characterized by a severely depressed cardiac output that initiates a downward spiral with mal- adaptive compensatory mechanisms that will ultimately lead to multi- organ failure and death of the patient. Notably, an overactive immune system damaging the microvasculature in vital organs may play a cen- tral role in the pathophysiology of cardiogenic shock that contributes to the progressive deteriorating of the patient’s condition. Still, cur- rent therapies focus mainly on inotropic and vasopressor drugs, MCS, and general ICU measures as other therapeutic approaches could not have been translated to clinical practice yet. Biomarkers, both established ones such as lactate but also investigational novel ones, may be of help in early recognition of cardiogenic shock and changes in the patient’s status. In addition, biomarker research can potentially elucidate novel pathways of diagnosis, prognosis and ul- timately therapeutic intervention. Part 2 of this educational review will highlight the current status of biomarker research and summarize novel, translational therapeutic approaches. Funding This work was supported by the Association for the Promotion of Research on Arteriosclerosis, Thrombosis and Vascular Biology (ATVB) and the Ludwig Boltzmann Institute for Cardiovascular Research. Conflict of interest: none declared. References 1. Jeger RV, Radovanovic D, Hunziker PR, Pfisterer ME, Stauffer J-C, Erne P, Urban P; for the AMIS Plus Registry Investigators. Ten-year trends in the inci- dence and treatment of cardiogenic shock. Ann Intern Med 2008; 149 : 618–626. 2. Babaev A, Frederick PD, Pasta DJ, Every N, Sichrovsky T, Hochman JS; NRMI Investigators. Trends in management and outcomes of patients with acute myocardial infarction complicated by cardiogenic shock. JAMA 2005; 294 :448–454. 3. 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