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In most of the studies, staged procedures were performed during the initial hospital stay. At present, one-stage multivessel PCI during STEMI without cardiogenic shock should be considered in patients in the presence of multiple, critical stenoses or highly unstable lesions angiographic signs of possible thrombus or lesion disruption , and if there is persistent ischaemia after PCI on the supposed culprit lesion.
These findings need to be interpreted in light of a low Based on these findings, culprit lesion-only PCI is recommended as the default strategy in patients with AMI with cardiogenic shock. A more detailed discussion of the revascularization strategy in MI patients with cardiogenic shock is found in the Supplementary Data. As discussed in section Delaying stenting in primary PCI has been investigated as an option to reduce microvascular obstruction MVO and preserve microcirculatory function in two small trials with conflicting results.
Thrombus aspiration has been proposed as an adjunct during primary PCI to further improve epicardial and myocardial reperfusion by the prevention of distal embolization of thrombotic material and plaque debris. The benefits of early, routine PCI after thrombolysis were seen in the absence of an increased risk of adverse events stroke or major bleeding.
Based on data from the four most recent trials, all of which had a median delay between the start of thrombolysis and angiography of 2—6 h, a time frame of 2—24 h after successful lysis is recommended. Patients undergoing primary PCI benefit from full revascularization, but the optimal timing of treatment of the non-culprit lesion is not known. Future trials of improved thrombus aspiration technologies may address the role of this strategy in patients with high-risk features, such as large thrombus burden.
Primary percutaneous coronary intervention for myocardial reperfusion in ST-elevation myocardial infarction: indications and logistics. Primary percutaneous coronary intervention for myocardial reperfusion in ST-elevation myocardial infarction: procedural aspects strategy and technique. When compared with medical therapy alone, coronary revascularization is superior in improving survival in patients with HF of ischaemic origin and is recommended in clinical practice.
Considerations relating to the need for viability testing prior to revascularization are discussed in section 3. There are currently no dedicated randomized clinical trials comparing PCI vs. In addition, CABG vs.
PCI randomized trials have excluded patients with severe HF. In one prospective registry including patients with multivessel disease and severe HFrEF, propensity score-matched comparison revealed similar survival mean follow-up 2. CABG was associated with a higher risk of stroke. The conclusion of the study was that multivessel PCI can be a valuable option in HF patients if complete revascularization is possible. Event curves separated early during the first year and continued to separate out to 12 years.
PCI should be considered in older patients without diabetes in whom complete revascularization can be achieved, whereas CABG is preferred in younger patients with more extensive CAD or those with diabetes.
The aim of surgical ventricular reconstruction SVR is to restore physiological volume, and achieve an elliptical shape of the LV, by scar resection and LV wall reconstruction on a mannequin of predefined size.
The aim of ventricular aneurysmectomy is to remove fibrous scars in cases of severe dilatation, thrombus formation, or as a source of life-threatening ventricular arrhythmias.
Acute myocardial ischaemia in the setting of AMI is the antecedent event for the majority of patients with cardiogenic shock undergoing percutaneous revascularization.
Mechanical complications—such as papillary muscle rupture with severe mitral valve regurgitation, ventricular septal defect, or free wall rupture—are additional precipitating causes. All-cause mortality at 6 months was lower in the group assigned to revascularization than in the medically treated patients The revascularization strategy for patients with cardiogenic shock and multivessel disease is addressed in section 7.
The findings of this non-randomized comparison suggest that CABG should be considered in patients with cardiogenic shock who have suitable anatomy, particularly if successful PCI is not feasible. Short-term MCS may be considered in refractory cardiogenic shock depending on patient age, comorbidities, neurological function, and the prospects for long-term survival and quality of life. IABPs are low-cost devices that are easy to insert and remove. They moderately increase cardiac output and coronary and cerebral perfusion, while decreasing ventricular workload.
It decompresses the venous system; increases coronary, cerebral, and peripheral perfusion; and also provides supplementary blood oxygenation.
When performed percutaneously, it does not allow for LV decompression and leads to increasing LV afterload. In patients with cardiac arrest, evidence from observational trials supports better survival in patients treated with VA-ECMO compared with those without. The majority of clinical experience with currently available pLVADs is limited to two types of device: i a transaortic microaxial pump Impella that directly unloads the LV providing 2.
IABP, and demonstrated similar short-term mortality despite initial beneficial effects on arterial blood pressure and peripheral perfusion, measured by serum lactate levels.
The 30 day incidence of major adverse events was not different for patients with pLVAD vs. In summary, the evidence for pLVAD is insufficient to provide a recommendation on its clinical use in cardiogenic shock. A suggested algorithm for the management of patients with cardiogenic shock is shown in Figure 6.
There is limited evidence on the role of active MCS in patients with cardiogenic shock compared with standard therapy. Patients with diabetes mellitus have a higher prevalence of CAD, which often manifests earlier in life and confers a substantially worse prognosis than for patients without diabetes.
The anatomical pattern of CAD in patients with diabetes clearly influences their prognosis and response to revascularization. Angiographic studies have demonstrated that patients with diabetes are more likely to have LM disease and multivessel CAD, with more diffuse disease involving smaller vessels. In patients with diabetes, the indications for myocardial revascularization are the same as those in patients without diabetes see sections 5, 6, and 7. A meta-analysis of nine RCTs with ACS patients did not show an interaction between diabetic status and the benefit from invasive management and revascularization.
Consistent with the findings in the absence of diabetes, the adverse impact of incomplete revascularization in patients with diabetes was also demonstrated in the BARI-2D Bypass Angioplasty Revascularization Investigation 2 Diabetes trial.
Data from randomized trials on revascularization in patients with diabetes are summarized in Supplementary Table 5. The selection of the optimal myocardial revascularization strategy for patients with diabetes and multivessel CAD requires particular consideration. The recommendations are provided in section 5. The incidences of death PCI to prevent one event was The combined risk of death or non-fatal MI was In the subset of patients with diabetes and multivessel CAD who were enrolled in the SYNTAX trial, there were no differences in the composite safety endpoint of all-cause death, stroke, and MI at 5 year follow-up.
Further analyses according to treatment with either oral hypoglycaemic agents or insulin showed that the MACCE rate was significantly greater after PCI in both the oral hypoglycaemic agent group PCI CABG 7. When patients present with a comorbidity that increases surgical risk, the choice of revascularization method is best decided by multidisciplinary individualized risk assessment.
For the reasons discussed above, PCI in patients with diabetes is often more complex than PCI in the absence of diabetes. Nevertheless, irrespective of diabetic status, the same principles apply as discussed in section Placement of a new-generation DES is the default strategy. In the current context of the use of oral P2Y 12 -inhibitors, there is no indication that antithrombotic pharmacotherapy should differ between diabetics and patients without diabetes who are undergoing revascularization.
For detailed discussion refer to section There is a theoretical risk of lactic acidosis and deteriorating renal function in patients treated with metformin who are exposed to iodinated contrast media. However, clinical experience suggests that the actual risk of lactate acidosis is very small, and that checking renal function after angiography in patients on metformin and withholding the drug when renal function deteriorates appears to be an acceptable alternative.
Following successful revascularization, the rate of events during follow-up remains high in patients with diabetes, independent of the mode of revascularization. Future research should be focused on identifying new disease-modifying therapies to influence the progression of vascular disease in this high-risk cohort. After reviewing the subsequent literature, the current Task Force has not found any evidence to support a major update.
The risk of contrast-induced nephropathy CIN depends on patient-related factors, such as CKD, diabetes mellitus, congestive HF, haemodynamic instability, reduced plasma volume, female sex, advanced age, anaemia, and periprocedural bleeding, as well as on the type and volume of contrast administered.
Adequate hydration remains the mainstay of CIN prevention. Thus far, patients with CKD have been excluded from randomized trials on myocardial revascularization, hence current data are based on observational studies only. Moreover, additional randomized evidence on optimal strategies for CIN prevention is needed. Options are: infusion of normal saline adjusted to central venous pressure or furosemide with matched infusion of normal saline , for details see the Supplementary Data.
After reviewing the subsequent literature, the current Task Force endorses the recommendations of the Guidelines and has not found any evidence to support a major update. These recommendations are included below for ease of reference. Of note, the available evidence on invasive functional assessment of CAD with FFR or iwFR in patients with severe aortic stenosis AS is limited to a few small-scale observational studies.
The recommendations for patients undergoing CABG for the clinically leading problem of CAD, who also have coexisting severe aortic stenosis or regurgitation, remain unchanged from those of the Guidelines and support replacement of the aortic valve. Patients with concomitant severe primary mitral regurgitation MR should undergo mitral valve repair at the time of CABG in keeping with guidance for the surgical repair of primary MR.
The CTSN trial showed that addition of surgical mitral valve repair to CABG made no significant difference to survival, overall reduction of adverse events, or LV reverse remodelling at 2 years. For a more detailed discussion of this issue, please refer to the Supplementary Data.
In patients with concomitant valvular and coronary disease, the possibility of future transcatheter therapy for the aortic and mitral valves has made a significant impact on decision-making for patients with predominantly coronary disease with moderate valve lesions. However, there is currently little evidence on this topic.
The long-term outcomes of patients with concomitant surgical repair of ischaemic MR are also awaited. Ischaemic stroke after CABG is multifactorial: thrombo-embolism from the aorta, its branches, or the heart; atrial arrhythmias; inflammatory pro-thrombogenic milieu; lower levels of antiplatelet therapy perioperatively; and haemodynamic instability.
However, the most consistent predictor of perioperative stroke is previous stroke or TIA. There is no strong evidence that carotid artery stenosis is a significant cause of perioperative stroke except for bilateral severe carotid bifurcation stenosis.
It may be reasonable to restrict prophylactic carotid revascularization to patients at highest risk of post-operative stroke, i. The Guidelines on the diagnosis and treatment of peripheral arterial diseases in collaboration with the European Society of Vascular Surgery cover the screening for and management of carotid artery disease in patients scheduled for CABG, including screening, indications, and the timing and type of carotid revascularization.
Its management is discussed in section In addition, inter-arm blood pressure asymmetry should lead to the investigation of subclavian artery stenosis. Further details are provided in the peripheral arterial diseases Guidelines.
Recommendations on the management of carotid stenosis in patients undergoing coronary artery bypass grafting. Preoperative strategies to reduce the incidence of stroke in patients undergoing coronary artery bypass grafting.
Graft failure can be due to conduit defects, anastomotic technical errors, poor native vessel run-off, or competitive flow with the native vessel. When clinically relevant, acute graft failure may result in MI with consequently increased mortality and major cardiac events. The suspicion of early graft failure should arise in the presence of ECG signs of ischaemia, ventricular arrhythmias, biomarker changes, new wall motion abnormalities, or haemodynamic instability.
Perioperative angiography is recommended in cases of suspected severe myocardial ischaemia to detect its cause and aid decision-making on the most appropriate treatment.
In the case of early post-operative graft failure, emergency ad hoc PCI may limit the extent of infarction, if technically feasible. The target for PCI is the native vessel or the internal mammary artery IMA graft, while the acutely occluded saphenous vein graft SVG and any anastomotic site should be avoided, if possible, due to concerns regarding embolization or perforation. Redo surgery should be favoured if the anatomy is unsuitable for PCI, if several important grafts are occluded, or in the case of clear anastomotic errors.
In asymptomatic patients, repeat revascularization should be considered if the artery is of an appropriate size and supplies a large territory of myocardium. Further details on the diagnosis and management of perioperative MI are provided in a recent ESC position paper. Ischaemia after CABG may be due to the progression of disease in native vessels or de novo disease of bypass grafts.
In view of the higher risk of procedural mortality with redo CABG and the similar long-term outcome, PCI is the preferred revascularization strategy in patients with amenable anatomy. CABG should be considered for patients with extensively diseased or occluded bypass grafts and diffuse native vessel disease, especially in the absence of patent arterial grafts. Distal protection devices using filters have shown the most encouraging results.
However, although a single randomized trial supports the use of distal embolic protection during SVG PCI, observational studies including data from large-scale registries are conflicting. Based on data from a small number of randomized trials, implantation of DES in SVG lesions is associated with a lower risk of repeat revascularization than with BMS at 1 year follow-up.
However, at 5 year follow-up, the advantage of DES over BMS was lost due to a higher incidence of target lesion revascularization between years 1 and 5 in patients treated with DES. Recurrence of symptoms or ischaemia after PCI is the result of restenosis, incomplete initial revascularization, or disease progression. Restenosis associated with angina or ischaemia should be treated by repeat revascularization, and repeat PCI remains the strategy of choice for most of these patients.
In this setting, the results from DES are superior to those obtained with balloon angioplasty, BMS implantation, or brachytherapy. The use of intracoronary imaging provides unique insights into the underlying mechanisms of in-stent restenosis see section OCT is able to detect the presence of neoatherosclerosis in a significant number of these patients.
Underexpanded stents should be aggressively tackled with high-pressure dilatations using non-compliant balloons. The optimization of the final results remains crucial during reinterventions for in-stent restenosis and, in this regard, the use of intracoronary imaging may be particularly helpful.
Outcomes of patients with in-stent restenosis after DES are poorer than those in patients with BMS in-stent restenosis, independently of the therapeutic modality. Although stent thrombosis is very rare, particularly since the advent of new-generation DES, it may have devastating clinical consequences. Stent thrombosis usually presents as a large MI and patients should be treated according to the principles outlined in section 8.
Although repeat stenting in patients with stent thrombosis may be avoided when satisfactory results are obtained with balloon dilation, a new stent may be required to overcome edge-related dissections and adjacent lesions, or to optimize final results. There is no evidence that the post-interventional management of patients with stent thrombosis should differ from that of patients with thrombosis of a de novo lesion resulting in STEMI.
Electrical storm is a life-threatening syndrome related to incessant ventricular arrhythmias, which is most frequently observed in patients with ischaemic heart disease, advanced systolic HF, valve disease, corrected congenital heart disease, and genetic disorders such as Brugada syndrome, early repolarization, and long QT syndrome. Accordingly, the recommendation tables are taken from the Guidelines. For a detailed discussion, we refer to the previous Guidelines.
The combination and duration of anticoagulation and antiplatelet therapy should be assessed according to the clinical situation, as outlined in section 17 as well as in the ESC Guidelines on Atrial Fibrillation and the ESC Focused Update on Dual Antiplatelet Therapy. Post-operative AF affects one-third of patients undergoing cardiac surgery.
Post-operative AF is a common complication, in which prophylactic treatment has a moderate effect. Pre-operative anti-arrhythmic drug treatment may be initiated but will have to be weighed against side effects. Patients with post-operative AF have an increased stroke risk post-operatively as well as during follow-up, , and warfarin medication at discharge has been associated with a reduced long-term mortality.
Whether or not surgical left atrial appendage LAA obliteration reduces stroke risk has been studied in smaller trials and registry studies with conflicting results, — and is currently under investigation in a large randomized trial. Recommendations for the prevention of ventricular arrhythmias by revascularization. Recommendations for the prevention and treatment of atrial fibrillation in the setting of myocardial revascularization.
Likewise, the role of routine left atrial exclusion at surgery for the prevention of stroke is currently unclear. CABG remains the most common cardiac surgical procedure, and the techniques have been refined during 50 years of evolution. Certainly, in some patients with a stenosis in small vessels with little myocardium at risk, complete revascularization may not be necessary. FFR-guided surgical revascularization has been associated with improved graft patency, but more studies are needed to investigate whether it improves clinical outcomes.
In addition to patient-related factors, the outcome following CABG is related to the long-term patency of grafts and therefore is maximized with the use of arterial grafts, specifically the IMA. Whether or not the use of additional arterial grafts can translate into prolonged survival remains debatable. Interim analysis showed no difference at 5 years in the rate of death or the composite of death, MI, or stroke, and 10 year results are warranted to draw final conclusions.
The radial artery constitutes an alternative as the second arterial graft in patients in whom BIMA grafting is not feasible, patients with a high risk of sternal wound complications, or as a third arterial graft.
While the skeletonized technique of harvesting the IMA has a higher theoretical potential for injury, the potential benefits include a longer conduit, more versatility sequential anastomosis , higher blood flow, and fewer wound-healing problems. Endoscopic radial harvesting is possible, but robust evidence concerning its safety and efficacy is scarce. Saphenous vein harvesting can be accomplished using open and minimally invasive techniques, which include interrupted incisions and partial or full endoscopic procedures.
Endoscopic vein graft harvesting leads to a reduced rate of leg wound complications, — but the short- and long-term patency of endoscopically harvested vein grafts, compared with openly harvested grafts, has been challenged. A single cross-clamp technique may be preferred to multiple manipulations of the aorta, with the aim of reducing atheroembolic events, but a strict no-touch technique most effectively reduces embolization of atherosclerotic material.
Besides continuous ECG monitoring and transoesophageal echocardiography immediately after revascularization, intraoperative quality control may also include graft flow measurement to confirm or exclude a technical graft problem.
Two large, international randomized trials have shown no difference in 30 day or 1 year clinical outcomes between on- and off-pump surgery when performed by experienced surgeons. A summary of these technical aspects can be found in Figure 8. Technical aspects of CABG. Minimally invasive coronary surgery with LIMA, harvested either directly or under video-assisted vision, may represent an attractive alternative to a sternotomy. Hybrid revascularization can be performed consecutively in a hybrid operating room, or sequentially on separate occasions in the conventional surgical and PCI environments.
Perioperative reporting of outcomes after CABG procedures should be done on a risk-adjusted basis. The early risk period after CABG extends up to 3 months, is multifactorial, and depends on the interface between technical variability and patient comorbidity.
The role of FFR and iwFR in guiding surgical revascularization needs further investigation into whether it improves clinical outcomes. Likewise, there are insufficient data on the impact of intraoperative assessment of graft flow on outcomes. Multiple Arterial Grafts trial is recruiting to answer the question of whether the use of additional arterial conduits either BIMA or radial artery translates into superior clinical outcomes when compared with SIMA supplemented by SVG only.
Hybrid procedures, which combine minimally invasive arterial grafting with PCI, proved feasible and safe. However, multicentre studies are required to prove the efficacy and superiority of this approach in stable, multivessel coronary disease. Particularly in patients with poor vein grafts. The radial artery should not be used if previously catheterized, if the Allen test is positive or if calcific degeneration is present.
Patients with diabetes mellitus, chronic pulmonary obstructive disease, previous mediastinal radiation, and obesity, particularly when multiples of these are present. Plain balloon angioplasty has been superseded in the treatment of de novo coronary lesions after demonstration of the superiority of stenting in terms of the requirement for repeat revascularization.
Balloon angioplasty is no longer preferred to stenting with DES for patients who require urgent non-cardiac surgery as short-duration DAPT may be reasonable with both strategies. A major reduction in the risk of restenosis has been achieved with DES technology. Biodegradable polymer and polymer-free DES offer the potential to reduce late adverse events after PCI by eliminating inflammatory reactions to permanent polymer coatings.
A number of large-scale trials showed comparable efficacy and safety compared with permanent polymer stents. New-generation DES should therefore be considered as the default stent type for PCI regardless of clinical presentation, lesion subtype, concomitant therapies, or comorbidities. Completely bioresorbable scaffolds BRS , which degrade to predominantly inert end products after fulfilling their scaffold function in the lesion site of the coronary vessel, have been developed with the goal of reducing or eliminating stent-related adverse events at long-term follow-up.
Current scaffold platforms to have reached clinical testing are based on two different technologies: bioresorbable, polymer-based scaffolds resorption up to 3—4 years and resorbable, metallic magnesium scaffolds resorption up to 1 year. Findings of these trials as well as meta-analyses consistently indicate the inferior efficacy and safety of Absorb BVS compared with contemporary DES during long-term follow-up.
Specifically, the Absorb BVS is associated with a significantly increased risk of target lesion revascularization and device thrombosis, with numbers needed to harm of 40— Available evidence on the magnesium scaffold is limited to small observational studies. Initial results appear encouraging, but further evaluation is needed. The rationale for using DCBs is based on the concept that with highly lipophilic drugs, even short contact times between the balloon surface and the vessel wall are sufficient for effective drug delivery.
There are various types of DCB that are approved for use in Europe and their main characteristics are listed in Supplementary Table 8. Although specifically designed comparative randomized trials are lacking, a class effect for all DCBs cannot be assumed. In terms of the use of DCB angioplasty for de novo disease, a number of small randomized trials have been reported with somewhat conflicting results. Lesion preparation is critical for successful PCI. In addition to plain balloon angioplasty with standard or non-compliant balloons , cutting or scoring balloon angioplasty or rotational atherectomy may be required in selected lesions—particularly those with heavy calcification—in order to adequately dilate lesions prior to stent implantation.
However, studies investigating the systematic use of these adjunctive technologies, such as rotational atherectomy, have failed to show clear clinical benefit. Findings from one meta-analysis of randomized trials suggested better outcomes with IVUS guidance in terms of acute procedural results and reduced angiographic restenosis, repeat revascularization, and MACE, with no effect on death and MI.
In cases of stent failure, including restenosis and stent thrombosis, the use of IVUS should be considered in order to identify and correct underlying mechanical factors see section Two observational studies show that while OCT imaging changes operator behaviour, its impact on clinical outcomes is unclear. A number of observational studies have shown that OCT is feasible and safe in the assessment of stent failure due to thrombosis, and may yield information that may be clinically useful.
A number of RCTs have investigated the optimal intervention strategy in patients with bifurcation lesions and showed no benefit for the systematic two-stent approach vs. Recently, a multicentre trial conducted in China directly compared a double-kissing crush two-stent strategy with provisional stenting of the main branch in patients with distal LM bifurcation disease.
Double-kissing crush resulted in a lower risk of the primary endpoint target lesion failure at 1 year compared with provisional stenting. When a two-stent strategy is necessary, which two-stent technique should be preferred is debated. The three most widely used contemporary two-stent techniques are culotte, crush classic or double-kissing crush , and T and protrusion TAP.
In non-LM bifurcation lesions, there is no compelling evidence that one technique is superior to the others in terms of major clinical endpoints. Dedicated RCTs examining the outcomes of patients with chronic total occlusion CTO allocated to revascularization or conservative therapy are scarce.
Yet, MACE were comparable between the two groups. A systematic review of 25 observational studies showed that at median follow-up of 3 years, successful CTO-PCI was associated with improved clinical outcomes in comparison with failed revascularization, including overall survival, angina burden, and the requirement for bypass surgery.
In cases of regional wall motion abnormalities in the territory of the CTO, objective evidence of viability should be sought. In ostial coronary lesions, additional judgement and caution is essential before proceeding to PCI.
In particular, a catheter-induced coronary spasm must be rigorously excluded. FFR measurement may also be valuable in the assessment of ostial lesions of borderline significance, taking special care to avoid a wedge position of the guiding catheter and using i. When performing an intervention, due to interaction between the guide catheter and the proximal stent edge, the risk of longitudinal stent deformation must be considered and avoided with careful catheter manipulation.
The accurate positioning of the stent, precisely in the coronary ostium, may be technically challenging and some specialized techniques that may help to achieve optimal stent placement have been described. Major BARC 3 or 5 bleeding was significantly reduced in the radial group 1.
Treatment of restenotic and saphenous vein graft lesions are discussed in section Antithrombotic treatment is mandatory in CAD patients undergoing myocardial revascularization. CABG of revascularization. Both ischaemic and bleeding events significantly influence the outcome of CAD patients and their overall mortality risk during and after myocardial revascularization. The recommended drugs Figure 9 and doses Table 7 for anticoagulant and antiplatelet drugs used in conjunction with myocardial revascularization are summarized below.
Doses of antiplatelet and anticoagulant drugs used during and after myocardial revascularization. Antithrombotic treatment for myocardial revascularization and its pharmacological targets. For routine clopidogrel pre-treatment administration of the drug when the coronary anatomy is unknown , there is no compelling evidence for a significant clinical benefit in SCAD patients. While aspirin and clopidogrel are indicated for elective stenting procedures, prasugrel or ticagrelor may only be considered in selected patients for specific high-risk situations of elective stenting e.
In parallel with antiplatelet treatment, the use of anticoagulants is standard of care during elective PCI to inhibit thrombin generation and activity. Different agents, including unfractionated heparin UFH and bivalirudin, have been evaluated for their use in clinical practice. UFH treatment. An algorithm for the use of antithrombotic drugs in patients undergoing PCI is shown in Figure Algorithm for the use of antithrombotic drugs in patients undergoing percutaneous coronary intervention.
High bleeding risk is considered as an increased risk of spontaneous bleeding during DAPT e. Following elective stenting, DAPT consisting of clopidogrel in addition to aspirin is generally recommended for 6 months, irrespective of the stent type.
Recommendations for antithrombotic treatment in stable coronary artery disease patients undergoing percutaneous coronary intervention. These recommendations refer to stents that are supported by large-scale randomized trials with clinical endpoint evaluation leading to an unconditional CE mark. The evidence supporting this recommendation comes from two studies where the zotarolimus-eluting Endeavour stent was investigated in conjunction with a 3 month DAPT regimen.
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Bowlusd, M. Autoimmune hepatitis shows a female predominance and can present at any age and in any ethnicity. Genome-wide association studies The disease is thought to be a consequence of a break of immune tolerance leading to an autoimmune process Primary biliary cholangitis that induces liver injury. The self-attack is triggered by T-helper cell-mediated liver autoantigen recognition and Primary sclerosing cholangitis B-cell production of autoantibodies, and is sustained by impaired regulatory T cells number and function.
Hormones Microbiome Superimposed on a genetic predisposition, infections and environmental factors have been studied as triggering factors for the disease. Allelic variants in the HLA locus have been associated with susceptibility; associations with single nucleotide polymorphisms within non-HLA genes have also been assessed. Importantly, drugs and herbal agents may trigger classical autoimmune hepatitis, or may induce a liver disease with autoimmune features. Interactions between female hormones and genetic factors have been hypothesized to play a role in autoimmunity, although the exact role for these factors has not been fully established.
Herein we present a review of the etiology of autoimmune hepatitis including de novo autoimmune hepatitis post-liver transplantation as well as animal models for its study.
As reviewed by Czaja et al. The association of AIH with the tion. Among children, the annual incidence of AIH has been reported at presence of anti-nuclear antibodies ANAs led to coining the term 0. Prevalence rates for AIH range from 2. AIH shows a bimodal age per , persons in children in Canada to E-mail address: annarosa. All rights reserved. Floreani et al. The process of recruitment of Japan during , the incidence was 2. In South Korea the incidence and prevalence are lymphocytes with endothelial cell surface molecules .
Chemokines reported as 1. Antigenic uptake by resident immature dendritic cells DC of mental factors are likely to play an important role . Genes from the the liver promotes their maturation and migration to peripheral lymph human leucocyte antigen HLA have shown a strong association with nodes where they act as antigen-presenting cells APC [14,16].
In the AIH . T-cells [15,16]. The pathophysiology of autoimmune liver diseases is thought to be based on T-lymphocyte-mediated cell destruction, imbalance in the 2. Autoimmune mechanisms regulation of immune cells, and a defective immune response to foreign antigens caused by the loss of tolerance to immune stimulants [18—22]. Due to its location and function, the liver is continually exposed to As discussed by Arndtz et al.
Journal of Autoimmunity 95 — antigens. Antigen presentation may take place in the liver as well, 3. Genetic factors which is a peculiar feature of liver immunology . This event leads to the recruitment of Th1, Th2 and Th17 cells to the tissue [18,24,25]. Genome-wide association studies on the cytokines they release. Th2 cells produce IL-4, IL and IL- clear genetic component based on the observations made on twin pairs, 13 inducing maturation of B-cells into plasma cells responsible for the family studies and population-based studies [34,35].
Furthermore, extrahepatic autoimmune conditions are often limiting hepatic injury as they mediate the action of cytotoxic T-lym- observed in AIH patients .
As in other autoimmune liver diseases, AIH 3. Several autoantibodies have been postulated as contributing to the pathogenesis of AIH. Molecular mimicry has been implicated in the pathogenesis of many autoimmune diseases AD and is hypothesized as a possible mechanism behind AIH [6,28,29].
Natural history of autoimmune hepatitis. Although the exact etiology of AIH is still unknown, genetic and environmental factors are sup- thereby opening the possibility for environmental insults to induce posed to play a role in the pathogenesis of the disease.
Among the predisposing these sensitized autoreactive cells to generate an AD . HLA genes in the pathogenesis of the disease the most important HLA genes A study evaluating the role of molecular mimicry in a murine model have been noted, however others have been associated with AIH. The pre- of AIH, found that transfection with adenovirus delivering the major cipitating factors include several environmental exposures that are described as human autoantigen CYP2D6 into the mouse liver resulted in the de- either protective factors, as tobacco, alcohol and vitamin D, or as risk factors as velopment of AIH .
Molecular mimicry, rather than identity, was exposure to drugs, hormones, diet and pathogens as viruses, parasites and thought to induce a greater T-cell response . During chronic hepatitis B Th17 cells depending on the cytokine environment. Antibodies bind to liver cells and contribute lecular mimicry could be an important factor .
Multiple viruses to NK and complement-mediated cytotoxicity. IL secreted by NKT cells. Journal of Autoimmunity 95 — HLA region on the short arm of chromosome 6, particularly to allelic and nonalcoholic steatohepatitis NASH .
Type could be used to help in the diagnosis of various liver diseases . In Northern and Central America, an association with mechanisms of these conditions i. Autoimmune ecology Northern Europe there is a strong association with the ancestral 8. As men- ceptibility of AIH [46—48]. Some studies have also analyzed the pro- tioned, these conditions share common immunopathogenic mechan- tective role associated with some alleles.
De Boer et al. In fact, environ- AIH-1, similar to previous reports in Caucasian patients. In addition, ment, more than genetics, shapes immune system. Next, we discuss the main environmental factors asso- German cases and controls . A meta-analysis in the Latin American population including cases and controls found that in this region of the world the serological group DQ2 is associated with an increased risk of AIH, 4.
Viruses whereas DR5 and DQ3 are protective factors . Besides some geographical variations, it should be hypothesis of molecular mimicry between components of these viruses noted that GWAS have been performed in a few cohort studies [38,50]. Molecular mimicry The association between AIH-2 and HLA genes has been studied contributes to humoral and cellular manifestations of the disease, and only partially because of its low prevalence.
However, an association sustains and extends the autoreactive process . Non-HLA genes the disease . They con- chronic HCV infection . As reviewed mania . Additionally, alcohol- pattern to that of HCV infection, but at a lower frequency .
MMA adducts have been shown to contribute to the markers probably represent a true autoimmune group, including chil- onset of an autoimmune-like disease in murine models . Results from the univariate analysis showed that alcohol infection.
Two of the three subjects had a defect in suppressor-inducer T consumption lowered the risk of being diagnosed with AIH OR: 0. This results coincide with ob- episode of HAV infection .
Table 2 [68—75] shows four further servations in other ADs where low-to-moderate alcohol consumption is cases of AIH triggered by an acute episode of HAV infection.
Biopsies from patients were analyzed; 92 of them showed prior to the diagnosis of AIH . Results for tobacco use showed no interface hepatitis compatible with AIH. HCV Although a vegetarian diet was shown to be a risk factor for AIH, the infection has been associated epidemiologically With AIH and has been results could have been confounded by a lower alcohol intake in ve- considered a triggering factor as well .
In fact, and RA among others [59,83]. Pre-vitamin D infection before diagnosing and treating AIH . This molecule is transported to the liver by the vitamin D- 4. The bioactive form of VD . However, more studies are needed to make strong conclusions and to evaluate other Huppertz H Germany F 45 6 months possible bacteria that may be associated with AIH.
Journal of Autoimmunity 95 — regulation of the immune system as it induces downregulation of Th1 aerobes, Escherichia coli and Enterococcus, when compared to healthy and Th17 lymphocytes and upregulation of Th2 and Tregs, stimulates controls.
Compared to healthy controls, AIH patients also had higher the production of cathelicidin in monocytes, pulmonary, intestinal and serum levels of LPS suggesting bacterial translocation .
Additional in- Nguyen . The non-genetic role of VD in AIH is related to the mi- tegrative studies on the microbiome and epigenomics are probably re- togen-activated protein kinase MAPK pathway, which is upregulated quired to unveil the role of the microbiome on the pathogenesis of by the inhibition that VD exerts over cytokine production in monocytes autoimmunity .
Sex and hormones A case-control study of 68 patients and 34 age-and-sex matched controls evaluated the association of low VD levels with histological One hallmark of autoimmunity is the dominance of female gender features and poor response to therapy in patients with AIH .
The for most ADs . Higher serum levels of immunoglobulins after antigenic exposures, more frequent expression 4. Microbiome of autoantibodies and a more marked cell-mediated immunity after immunizations characterize the immune response of women [95,96]. The intestinal microbiome is a key factor for the promoting cell-mediated pathways [90,95,96].
Molecular mimicry is posed as a immune response by altering the cytokine secretion and the expression possible mechanism for the induction of autoimmunity in the re- of the estrogen receptor [95,96]. Prolactin stimulates both cellular and lationship of the microbiome and immunity [88,89].
Toll-like receptors humoral immune responses . Various transcription factors have TLR in the intestine are key to identifying molecular patterns of pa- been shown to regulate immune tolerance mechanisms, including the thogens, microbes and damaging stimulants. The consequence is that females show a lower expression the stimulus by pathogen-associated molecular patterns PAMPs or of transcription modulators than males in mice and humans . Variations in intestinal microbiomes have mones cannot solely explain the predominance of AIH in women as this been associated with the development of some ADs and, vice-versa, predominance is observed among children and elderly populations The certain autoimmune and non-autoimmune diseases have been asso- female predominance of AIH may be also explained by gender-related ciated with changes in gut microbiomes .
Other variations in the characteristics in antigenic presentation and T-cell activation . Disruption of in the hypotheses of the skewed X chromosome activation, X monosomy the gut barrier is a key event in the role of microbiomes on the devel- and microchimerism [90,95,98—]. The X inactivation process occurs opment of autoimmunity .
The frequency of creased mucosal permeability in the intestine or active transport of skewed X inactivation varies and increases with advancing age. This bacterial antigens across the intestinal barrier . Any of the men- inactivation process is a potential mechanism whereby X-linked self- tioned pathways can lead bacteria or bacterial products into the portal antigens may escape presentation in the thymus or in peripheral sites circulation in the liver where they generate an immune stimulus that involved in tolerance induction .
It . Journal of Autoimmunity 95 — Consequently, autoreactive T-cells are not exposed to self-antigens en- DILI with autoimmune features has been described for nitrofur- coded by one of the two X chromosomes, perpetuating the autoimmune antoin, minocycline, hydralazine, procainamide, methyldopa, statins, response .
The anti-TNF agents are thus suggested as agents both tion during pregnancy [90,95]. A cohort study in Holland  analyzed 88 cases of Microchimerism can persist for years and can compromise self-toler- DILI attributed to nitrofurantoin, minocycline, methyldopa or hy- ance, however, the exact role in AIH has not been fully established .
Acute liver failure attributed to drugs, one of the primary causes of The status of checkpoint inhibitors in use in cancer therapy today, liver failure, can show autoimmune manifestations similar to idiopathic which are reported as causing hepatitis with immune features, is not AIH [31,].
AIH, however, drugs cannot be completely ruled out as possible cau- sative agents of AIH even in the absence of a clear relationship with 5. Autoimmune hepatitis post-liver transplantation drug intake . Unrecognized previous exposure and sensitization to drugs could be responsible for the initiation or maintenance of liver Autoimmune hepatitis can recur or appear de novo after liver disease based on the hypothesis of genetic predisposition and molecular transplantation [16,].
In patients who were transplanted because triggering AIH may also be causative agents of DILI with autoimmune of AIH, recurrence may be asymptomatic and is usually characterized features and that old case-reports in the literature are described as AIH by similar features as the initial presentation of the disease with ele- without distinguishing the pathogenic mechanism .
Presentation of no previously diagnosed low grade AIH or predisposition to AIH in antigens or autoantigens by APCs, either from the donor or the re- whom a drug produces an autoimmune chronic process; c immune- cipient, stimulates the memory T-cells from the host’s immune system mediated-DILI, in patients who present with symptoms of an auto- leading to a self-directed immune response [,]. It is thought that immune hypersensitivity that remits after drug cessation; d mixed calcineurin inhibitors have an important role as they reduce the pro- autoimmune type DILI with positive autoantibodies .
Additionally the role of molecular mimicry between in- duction of drug metabolites that bind to proteins and act as antigenic fectious agents and the host supports the possibility that previous viral complexes stimulating the production of autoantibodies, principally infections could be a potential cause of de novo AIH [,].
They suggest that the main that de novo AIH occurs in the absence of these antibodies . As characteristics that favor the diagnosis of drug-induced AIH are genetic reviewed by Vukotic et al. Recurrence of AIH after [,]. Although DILI with autoimmune features is a syndrome characterized by AIH-2 is known to have a more aggressive course, AIH-1 has a higher biochemical and histological features of AIH following the ingestion of rate of recurrence after liver transplantation .
Recurrence is di- a drug or a herbal product . Improvement after drug withdrawal is often genic mechanisms of recurrence are not fully understood but cellular slow and recurrence is common if the drug is re-administered .
Ta- neoantigen and presented to T-cells with consequent immune activation crolimus therapy and severe initial disease have been suggested as process involving binding to T-cell receptors or the MHC which med- possible prognostic factors [,,,]. High levels of transa- iates the antigenic presentation . Journal of Autoimmunity 95 — appear to increase the risk for AIH recurrence . Transgenic mouse models 6.
Several strategies have been used to reproduce an immune- tablish a chronic hepatitis although it induced a short-lived hepatitis, mediated hepatitis in mice, which comprise concanavalin A ConA due to central host tolerance. Detailed descriptions of the evolution of treatment, immunization approaches and transgenic and knock-out such tempted models were recently reviewed [,]. In , the mice models.
Detailed reviews of the experimental AIH models de- group of Zierden et al. From the histological strategy to induce an acute and severe liver injury in mice [,]. Humanized mouse models responsible for ConA-induced liver damage [,]. The de- through cross-species immunization with human liver antigens. This velopment of tolerance mechanisms to ConA-mediated damage impairs strategy exploits the viral mechanism of molecular mimicry . Similarly, intravenous injection of NOD mice and self-tolerance is one of the strategies aimed at inducing an immune- with human FTDC-adenoviral vector induced chronic AIH-2 with hy- mediated hepatitis in mice .
Histologically, the livers had periportal and portal in- vels . Notably, circulating questionable. Several models aim to investigate the immune mechan- antinuclear antibodies were also detectable . Although both TGF- isms, or to assay new treatments. Immunization with liver homogenates immunotherapies . During the course of , immunization protocols through injec- 7. Conclusions tion of syngeneic liver homogenates were developed to induce the loss of hepatic tolerance in mice [—]. Journal of Autoimmunity 95 — the pathophysiology of this condition.
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Diabetic dyslipidemia: mechanisms leading to T2DM dyslipidemia and lipoprotein clearance in physiological an IR conditions. Basel Switz. Pleiotropic genetic effects contribute to the correlation between HDL cholesterol, triglycerides, and LDL particle size in hypertensive sibships. Insulin-bound insulin receptors or activated insulin receptors go through internalization at the plasma membrane, a phenomenon known as insulin receptor endocytosis [ 29 , ]. Figure 3. Zink WE et al.