Spontaneous Reperfusion in STEMI: its mechanisms and possible modulation

© 2024 The Author(s). This is an open access article under the Creative Commons Attribution-NonCommercial-NoDerivatives CC BY-NC-ND licence, https://creativecommons.org/licenses/by-nc-nd/4.0/Patients with transient ST-segment elevation myocardial infarction or spontaneous reperfusion, which occurs in approximately 20% of patients with ST-segment elevation myocardial infarction (STEMI), have smaller infarcts and more favourable clinical outcomes than patients without spontaneous reperfusion. Understanding the mechanisms underlying spontaneous reperfusion is therefore important, since this may identify possible novel therapeutic targets to improve outcomes in patients with STEMI. In this review, we discuss some of the possible determinants of spontaneous reperfusion including pro-thrombotic profile, endogenous fibrinolytic status, lipoprotein(a) (Lp(a)), inflammatory markers and neutrophil extracellular traps (NETs). Effective (rapid) endogenous fibrinolysis, as assessed in whole blood in vitro, using a point-of-care technique assessment of global thrombotic status, has been strongly linked to spontaneous reperfusion. Lp(a), which has a high degree of homology to plasminogen, may impair fibrinolysis through competitive inhibition of tissue plasminogen activator-mediated plasminogen activation as well as tissue plasminogen activator-mediated clot lysis and contributing to pathogenic clot properties by decreasing fibrin clot permeation. NETs appear to negatively modulate clot lysis by increasing thrombin fibre diameter and inhibiting plasmin-driven lysis of plasma clots. There are limited data that oral anticoagulation may modulate endogenous fibrinolysis but antiplatelet agents currently appear to have no impact. Phase III trials involving subcutaneous P2Y12 or glycoprotein IIb/IIIa inhibitors, oral factor XIa inhibitors, interleukin-6 inhibitors, and Apo(a) antisense oligonucleotides in patients with cardiovascular disease are ongoing. Future studies will be needed to determine the impact of these novel antithrombotic, anti-inflammatory and lipid lowering therapies on endogenous fibrinolysis and spontaneous reperfusion.Peer reviewe

Measuring thrombus stability at high shear, together with thrombus formation and endogenous fibrinolysis: first experience using the Global Thrombosis Test 3 (GTT-3)

© The Author(s) 2023. This is an open access article distributed under the Creative Commons Attribution License, to view a copy of the license, see: https://creativecommons.org/licenses/by-nc/4.0/Thrombus formation in a severely stenosed artery is initiated by high shear activation of platelets, with soluble platelet agonists, such as ADP and thromboxane, playing only a secondary role in the growth and stability of the thrombus. Conventional platelet function tests, however, assess only the soluble agonist-dependent pathway of platelet aggregation. As the thrombus evolves, its stability and ability to withstand dislodgement by arterial flow, will determine whether complete and persistent vessel occlusion will occur. The Global Thrombosis Test (GTT), an automated point-of-care technique, simulates the formation of thrombus in whole blood under high shear flow (shear rate >12,000 s-1) and measures the time for occlusive thrombus formation and spontaneous, endogenous thrombolysis/fibrinolysis. The latest GTT-3 model subjects the growing thrombus to upstream pressure, resembling that in a medium-sized artery, and provides additional assessment of thrombus stability and fibrinolysis rate. It can be used in three programs, including a new “hypershear” mode, whereby repetitive cycles of pressure are applied to the growing thrombus, increasing shear rate to ~22,000 s-1, such as that in patients on mechanical circulatory support. In addition to assessing the risk of arterial thrombosis, the GTT-3 could be used to assess the impact of antithrombotic medications on thrombus stability at high shear. While current anti platelet medications target the biochemical axis of platelet aggregation (soluble agonists) and also increase bleeding risk, novel shear-selective anti-platelet therapies may prevent thrombosis whilst preserving hemostasis. Future studies are needed to assess the usefulness of assessing thrombus stability on cardiovascular and pharmacological evaluation.Peer reviewe

Rationale and design of "Can Very Low Dose Rivaroxaban (VLDR) in addition to dual antiplatelet therapy improve thrombotic status in acute coronary syndrome (VaLiDate-R)" study : A randomised trial modulating endogenous fibrinolysis in patients with acute coronary syndrome

© The Author(s) 2019. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made.Impaired endogenous fibrinolysis is novel biomarker that can identify patients with ACS at increased cardiovascular risk. The addition of Very Low Dose Rivaroxaban (VLDR) to dual antiplatelet therapy has been shown to reduce cardiovascular events but at a cost of increased bleeding and is therefore not suitable for all-comers. Targeted additional pharmacotherapy with VLDR to improve endogenous fibrinolysis may improve outcomes in high-risk patients, whilst avoiding unnecessary bleeding in low-risk individuals. The VaLiDate-R study (ClinicalTrials.gov Identifier: NCT03775746, EudraCT: 2018-003299-11) is an investigator-initiated, randomised, open-label, single centre trial comparing the effect of 3 antithrombotic regimens on endogenous fibrinolysis in 150 patients with ACS. Subjects whose screening blood test shows impaired fibrinolytic status (lysis time > 2000s), will be randomised to one of 3 treatment arms in a 1:1:1 ratio: clopidogrel 75 mg daily (Group 1); clopidogrel 75 mg daily plus rivaroxaban 2.5 mg twice daily (Group 2); ticagrelor 90 mg twice daily (Group 3), in addition to aspirin 75 mg daily. Rivaroxaban will be given for 30 days. Fibrinolytic status will be assessed during admission and at 2, 4 and 8 weeks. The primary outcome measure is the change in fibrinolysis time from admission to 4 weeks follow-up, using the Global Thrombosis Test. If VLDR can improve endogenous fibrinolysis in ACS, future large-scale studies would be required to assess whether targeted use of VLDR in patients with ACS and impaired fibrinolysis can translate into improved clinical outcomes, with reduction in major adverse cardiovascular events in this high-risk cohort.Peer reviewedFinal Published versio

Myocardial infarction with non-obstructive coronary arteries in young women presenting with ST-segment elevation myocardial infarction: a case series

Introduction. Myocardial infarction with non-obstructive coronary arteries (MINOCA) is an increasingly recognised entity, with comparable mortality to myocardial infarction with obstructive coronary artery disease (CAD).Case presentation. We present the cases of two young females presenting to hospital with ST-segment elevation myocardial infarction without obstructive CAD. Common to both cases was the acute onset of chest pain with no prior cardiac history, minimal cardiac risk factors, and the use of hormone-based contraception. The first patient had an ostially occluded left anterior descending artery (LAD). Flow was restored with balloon inflation and the administration of tirofiban. However, no underlying obstructive CAD was identified, which was confirmed with repeat angiography and optical coherence tomography. The cause was later attributable to plaque erosion, after learning the results of a normal thrombophilia screening. The second patient had ST-segment resolution on arrival to the catheter lab, and on angiography, she had TIMI II flow down the LAD due to significant thrombus burden. Similarly, balloon inflation and tirofiban were administered to improve flow, and non-obstructive CAD was confirmed with repeat angiography and OCT 48 hours later. As with patient 1, this patient too had normal thrombophilia screening results. Both patients were discharged with dual-antiplatelet therapy and secondary prevention, and were advisedagainst hormone-based contraception.Discussion. Patients with MINOCA tend to be younger, with a higher female-to-male preponderance. Multiple causes have been identified, highlighting the importance of following a diagnostic algorithm. This will enable correct treatment, which may differ from that for patients with obstructive coronary disease, thus improving prognosis

Determinants of Endogenous Fibrinolysis in Whole Blood Under High Shear in Patients With Myocardial Infarction

This work was supported in part by a grant from Alpha MD, London, United Kingdom. Dr Mutch was supported by the British Heart Foundation PG/15/82/31721 and Friends of Anchor. Dr Gorog has received institutional research grants from Bayer, Medtronic, Alpha MD, and Boehringer Ingelheim; has received speaker’s fees from AstraZeneca and Boehringer Ingelheim; and is related through family to a company director in Thromboquest Ltd, but neither she, nor her spouse or children, have financial involvement or equity interest in and they have received no financial assistance, support, or grants from the aforementioned. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.Peer reviewedPublisher PD

Fibrinolysis in Platelet Thrombi

© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/)The extent and duration of occlusive thrombus formation following an arterial atherothrombotic plaque disruption may be determined by the effectiveness of endogenous fibrinolysis. The determinants of endogenous fibrinolysis are the source of much research, and it is now broadly accepted that clot composition, as well as the environment in which the thrombus was formed, play a significant role. Thrombi with a high platelet content demonstrate significant resistance to fibrinolysis, and this may be attributable to an augmented ability for thrombin generation and the release of fibrinolysis inhibitors, resulting in a fibrin-dense, stable thrombus. Additional platelet activators may augment thrombin generation further, and in the case of coronary stenosis, high shear has been shown to strengthen the attachment of the thrombus to the vessel wall. Neutrophil extra cellular traps contribute to the fibrinolysis resistance. Additionally, platelet-mediated clot retraction, release of Factor XIII and resultant crosslinking with fibrinolysis inhibitors imparts structural stability to the thrombus against dislodgment by flow. Further work is needed in this rapidly evolving field, and efforts to mimic the pathophysiological environment in vitro are essential to further elucidate the mechanism of fibrinolysis resistance and in providing models to assess the effects of pharmacotherapy.Peer reviewe

Effect of remote ischaemic conditioning on clinical outcomes in patients with acute myocardial infarction (CONDI-2/ERIC-PPCI): a single-blind randomised controlled trial.

BACKGROUND: Remote ischaemic conditioning with transient ischaemia and reperfusion applied to the arm has been shown to reduce myocardial infarct size in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). We investigated whether remote ischaemic conditioning could reduce the incidence of cardiac death and hospitalisation for heart failure at 12 months. METHODS: We did an international investigator-initiated, prospective, single-blind, randomised controlled trial (CONDI-2/ERIC-PPCI) at 33 centres across the UK, Denmark, Spain, and Serbia. Patients (age >18 years) with suspected STEMI and who were eligible for PPCI were randomly allocated (1:1, stratified by centre with a permuted block method) to receive standard treatment (including a sham simulated remote ischaemic conditioning intervention at UK sites only) or remote ischaemic conditioning treatment (intermittent ischaemia and reperfusion applied to the arm through four cycles of 5-min inflation and 5-min deflation of an automated cuff device) before PPCI. Investigators responsible for data collection and outcome assessment were masked to treatment allocation. The primary combined endpoint was cardiac death or hospitalisation for heart failure at 12 months in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT02342522) and is completed. FINDINGS: Between Nov 6, 2013, and March 31, 2018, 5401 patients were randomly allocated to either the control group (n=2701) or the remote ischaemic conditioning group (n=2700). After exclusion of patients upon hospital arrival or loss to follow-up, 2569 patients in the control group and 2546 in the intervention group were included in the intention-to-treat analysis. At 12 months post-PPCI, the Kaplan-Meier-estimated frequencies of cardiac death or hospitalisation for heart failure (the primary endpoint) were 220 (8·6%) patients in the control group and 239 (9·4%) in the remote ischaemic conditioning group (hazard ratio 1·10 [95% CI 0·91-1·32], p=0·32 for intervention versus control). No important unexpected adverse events or side effects of remote ischaemic conditioning were observed. INTERPRETATION: Remote ischaemic conditioning does not improve clinical outcomes (cardiac death or hospitalisation for heart failure) at 12 months in patients with STEMI undergoing PPCI. FUNDING: British Heart Foundation, University College London Hospitals/University College London Biomedical Research Centre, Danish Innovation Foundation, Novo Nordisk Foundation, TrygFonden

Angiotensin Converting Enzyme 2 may mediate disease severity in COVID-19

© 2020 Elsevier Ltd. All rights reserved. This manuscript is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International Licence http://creativecommons.org/licenses/by-nc-nd/4.0/.Identification of vulnerability to severe coronavirus disease 2019 (COVID-19) is extremely important and might allow optimised shielding and easing of lockdown. The disease is attributed to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which enters host cells through binding to angiotensin converting enzyme 2 (ACE2) on the cell surface. Clinical syndromes such as hypertension that display reduced ACE2 expression tend to correlate with a more severe disease course, whereas treatments which upregulate ACE2 such as the use of angiotensin converting enzyme inhibitors (ACE-i) appear to have a protective effect against COVID-19. Pre-clinical studies have shown that plasma soluble ACE2 could render SARS-CoV-2 inactive in a dose-dependent manner. The association of clinical syndromes or treatments that impact ACE2 expression and clinical severity of COVID-19 infection combined with the reduction in viral load with human recombinant serum ACE2 shown in pre-clinical studies indicate a key role for ACE2 in determining COVID-19 severity. In conclusion, we propose that measurement of ACE2 level may help identify individuals at risk of severe infection where targeted shielding can be used and could provide a novel therapeutic target. Identification of vulnerability to severe COVID-19 is extremely important, and might allow optimised shielding and easing of lockdown. We propose a pathological role for soluble angiotensin converting enzyme (sACE2) modulating COVID-19 disease severity, which could be used in screening and treatment. Hypertension, diabetes and obesity are risk factors for severe disease.1 SARS-CoV-2 enters the host cell through the spike (S) protein binding to ACE2,2 and since ACE-inhibitors (ACE-i) and angiotensin-II receptor blockers (ARB) upregulate cellular ACE2 expression, this could theoretically facilitate SARS-CoV-2 binding and severe disease manifestation, while renin-angiotensin-aldosterone inhibition appears protective.3 After SARS-CoV-2 binds to host cells, ACE2 expression and enzymatic activity are significantly reduced through enhanced shedding, with the extracellular component of ACE2 cleaved and resultant soluble protein released. The resultant increased sACE2 may act as a ‘dummy’ receptor, binding the S protein on circulating virus. Thus, higher numbers of ACE2 receptors expressed prior to first binding event may lead to higher sACE2 level and reduced circulating SARS-CoV-2 with ‘active’ S protein sites, reduced numbers of affected host cells, and less systemic impact. Therefore, conditions that upregulate ACE2 may confer protection, whereas reduced ACE2 expression may result in more severe disease. Clinical findings support such pathological role for reduced ACE2 levels in mediating disease severity. Patients with hypertension, exhibiting marked ACE up-regulation and ACE2 downregulation, are at higher risk of severe disease, whereas those taking ACE-i/ARB exhibit less disease severity and lower mortality.3 The ACE2 gene is linked to metabolic syndrome and obesity.4 ACE2 gene knockout leads to metabolic syndrome in mice. In patients with diabetic renal disease, ACE2 expression is reduced compared to patients with non-diabetic renal disease or controls. Lower ACE2 expression in obese patients and metabolic syndrome may explain worse outcomes with COVID-19.1 The ACE2 gene is located on the X-chromosome, and ACE2 activity and expression in rats was decreased by oophorectomy and restored by oestrogen. Thus, women would be expected to have higher ACE2 activity, which might explain better outcomes. Recent studies show that human recombinant sACE2 (hrsACE2) can bind and neutralise SARS-CoV-2 S protein,5 reducing SARS-CoV-2 entry into cells in a dose-dependent manner.2 The association of clinical syndromes and treatments that impact ACE2 expression and the reduction in viral load with hrsACE2, indicate a key role for ACE2 in COVID-19 severity. We propose that measurement of ACE2 level may help identify individuals at risk of severe infection and provide a novel therapeutic target.Peer reviewe

Thrombotic complications in 2,928 patients with COVID-19 treated in intensive care: a systematic review

© The Author(s) 2021. This article is licensed under a Creative Commons Attribution 4.0 International License, http://creativecommons.org/licenses/by/4.0/.A prothrombotic state is reported with severe COVID-19 infection, which can manifest in venous and arterial thrombotic events. Coagulopathy is reflective of more severe disease and anticoagulant thromboprophylaxis is recommended in hospitalized patients. However, the prevalence of thrombosis on the intensive care unit (ICU) remains unclear, including whether this is sufficiently addressed by conventional anticoagulant thromboprophylaxis. We aimed to identify the rate of thrombotic complications in ICU-treated patients with COVID-19, to inform recommendations for diagnosis and management. A systematic review was conducted to assess the incidence of thrombotic complications in ICU-treated patients with COVID-19. Observational studies and registries reporting thrombotic complications in ICU-treated patients were included. Information extracted included patient demographics, use of thromboprophylaxis or anticoagulation, method of identifying thrombotic complications, and reported patient outcomes. In 28 studies including 2928 patients, thrombotic complications occurred in 34% of ICU-managed patients, with deep venous thrombosis reported in 16.1% and pulmonary embolism in 12.6% of patients, despite anticoagulant thromboprophylaxis, and were associated with high mortality. Studies adopting systematic screening for venous thrombosis with Duplex ultrasound reported a significantly higher incidence of venous thrombosis compared to those relying on clinical suspicion (56.3% vs. 11.0%, p < 0.001). Despite thromboprophylaxis, there is a very high incidence of thrombotic complications in patients with COVID-19 on the ICU. Systematic screening identifies many thrombotic complications that would be missed by relying on clinical suspicion and should be employed, with consideration given to increased dose anticoagulant thromboprophylaxis, whilst awaiting results of prospective trials of anticoagulation in this cohort.Peer reviewe

MINOCA presenting with STEMI- a review of incidence, aetiology, assessment and treatment

© Radcliffe Cardiology 2020. This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly (https://creativecommons.org/licenses/by-nc/4.0/).Myocardial infarction with non-obstructive coronary artery (MINOCA) is a condition previously thought to be benign but has recently been shown to have comparable mortality to that of acute coronary syndrome with obstructive coronary disease. The heterogeneity of the underlying aetiology makes the assessment, investigation and treatment of patients with MINOCA challenging. The majority of patients with MINOCA presenting with ST-segment elevation myocardial infarction (STEMI) generally have an underlying coronary or myocardial cause, predominantly plaque disruption or myocarditis. In order to make the correct diagnosis, including the cause of the presentation, a meticulous and methodical approach is required, with targeted investigations. Stratification of patients to guide investigations that are more likely to provide the diagnosis will allow correct treatment to be initiated promptly. Herein, we review the contemporary incidence, aetiology, recommended assessment and treatment of patients with MINOCA presenting with STEMI.Peer reviewe