Myocardial Infarction Injury Research Articles

The Role of Long Noncoding RNAs in Cardiomyocyte Proliferation and Heart Regeneration After Myocardial Infarction: A Systematic Review.

Many studies support the idea that long noncoding RNAs (lncRNAs) are significantly involved in the process of cardiomyocyte (CM) regeneration following a myocardial infarction (MI). This study aimed to systematically review the emerging role of lncRNAs in cardiac regeneration by promoting CM proliferation after MI. Furthermore, the review summarized potential targets and the underlying mechanisms of lncRNAs to induce heart regeneration, suggesting utilizing lncRNAs as innovative therapeutic targets for mitigating MI injuries. We searched the PubMed, Scopus, and Web of Science databases for studies on lncRNAs that play a role in heart regeneration after MI. We used search terms that included MI, lncRNAs, CM, and proliferation. Relevant English articles published until June 11, 2023, were systematically reviewed based on inclusion and exclusion criteria. A total of 361 publications were initially identified, and after applying the inclusion and exclusion criteria, nine articles were included in this systematic review. These studies investigated the role of critical lncRNAs in cardiac regeneration after MI, including five upregulated and four downregulated lncRNAs. Acting as a competitive endogenous RNA is one of the main roles of lncRNAs in regulating genes involved in CM proliferation through binding to target microRNAs. The main molecular processes that greatly increase CM proliferation are those that turn on the Hippo/YAP1, PI3K/Akt, JAK2-STAT3, and E2F1-ECRAR-ERK1/2 signaling pathways. This systematic review highlights the significant role of lncRNAs in heart regeneration after MI and their impact on CM proliferation. The findings suggest that lncRNAs could serve as potential targets for therapeutic interventions aiming to enhance cardiac function.

Ticagrelor vs Clopidogrel for Complex Percutaneous Coronary Intervention in Chronic Coronary Syndrome

BackgroundWhether ticagrelor in chronic coronary syndrome patients undergoing complex percutaneous coronary intervention (PCI) can prevent cardiovascular events is unknown. ObjectivesThe authors sought to evaluate outcomes of complex PCI and the efficacy of ticagrelor vs clopidogrel in stable patients randomized in the ALPHEUS (Assessment of Loading with the P2Y12 inhibitor ticagrelor or clopidogrel to Halt ischemic Events in patients Undergoing elective coronary Stenting) trial. MethodsAll PCI procedures were blindly reviewed and classified as complex if they had at least 1 of the following criteria: stent length >60 mm, 2-stent bifurcation, left main, bypass graft, chronic total occlusion, use of atherectomy or guiding catheter extensions, multiwire technique, multiple stents. The primary endpoint was a composite of type 4a or b myocardial infarction (MI) and major myocardial injury during the 48 hours after PCI. We compared the event rates according to the presence or not of complex PCI criteria and evaluated the interaction with ticagrelor or clopidogrel. ResultsAmong the 1,866 patients randomized, 910 PCI (48.3%) were classified as complex PCI. The primary endpoint was more frequent in complex PCI (45.6% vs 26.6%; P < 0.001) driven by higher rates of type 4 MI and angiographic complications (12.2% vs 4.8 %; P < 0.001 and 19.3% vs 8.6%; P < 0.05, respectively). The composite of death, MI, and stroke at 48 hours (12.7% vs 5.1 %; P < 0.05) and at 30 days (13.4% vs 5.3%; P < 0.05) was more frequent in complex PCI. No interaction was found between PCI complexity and the randomized treatment for the primary endpoint (Pinteraction = 0.47) nor the secondary endpoints. ConclusionsIn chronic coronary syndrome, patients undergoing a complex PCI have higher rates of periprocedural and cardiovascular events that are not reduced by ticagrelor as compared with clopidogrel.

Abstract TP196: Ischemic Stroke With Large Vessel Occlusion and Systemic Acidosis: Associations With Functional Outcomes and Mortality

Introduction: Systemic acidosis is common in critical conditions, including severe myocardial infarction, renal and liver injuries, and traumatic brain injury. However, the potential connection between ischemic stroke involving large vessel occlusion (LVO) and acidosis has not been extensively explored. With this study we aimed to assess the prevalence of respiratory and metabolic acidosis in ischemic stroke with LVO and their potential links to functional outcomes and mortality. Methods: Retrospective single center cohort of patients with ischemic stroke and LVO status post endovascular thrombectomy. Univariate logistic regression was used to examine the relationship between acidosis on admission and (1) hospital mortality and (2) 90-day modified Rankin Scale (mRS) dichotomized as unfavorable (&gt;3) vs favorable (≤3). In addition, we investigated association with acidosis and symptomatic ICH. Metabolic acidosis was defined by the presence of one of the following: Serum bicarbonate &lt;22 mEq/L, lactic acid &gt;2 mmol/L or pH &lt;7.35. Respiratory acidosis was defined by pCO2 &gt;45 mmHg. Results: There was a total of 346 patients, average age was 68.5 (±15) years, 169 (49%) were females. 168 (49%) patients were acidotic on admission, 4 (1%) had respiratory acidosis, 7 (2%) had mixed acidosis and the remaining 157 (45%) had metabolic acidosis. There was no statistically significant association between systemic acidosis with either hospital mortality (p=0.31]) or 90-day favorable functional outcome (p=0.23]). There was no association between acidosis with symptomatic ICH (p=0.47). Conclusion: In our retrospective cohort study, we observed that approximately half of the patients with stroke and LVO had systemic acidosis. Unlike other critical neurological conditions like traumatic brain injury, we did not identify a substantial correlation between systemic acidosis and either mortality or the functional outcome at the 90-day mark. Given the high prevalence of acidosis in patients with LVO, larger multi-center studies are needed to further investigate its association with the outcomes and mortality.

Culprit Lesion Vessel Size and Risk of Reperfusion Injury in ST-Segment Elevation Myocardial Infarction: A Cardiac Magnetic Resonance Imaging Study.

Microvascular obstruction (MVO) and intramyocardial hemorrhage (IMH) are well-established imaging biomarkers of failed myocardial tissue reperfusion in patients with ST-segment elevation-myocardial infarction treated with percutaneous coronary intervention. MVO and IMH are associated with an increased risk of adverse outcome independent of infarct size, but whether the size of the culprit lesion vessel plays a role in the occurrence and severity of reperfusion injury is currently unknown. This study aimed to evaluate the association between culprit lesion vessel size and the occurrence and severity of reperfusion injury as determined by cardiac magnetic resonance imaging. Patients (n=516) with first-time ST-segment-elevation myocardial infarction underwent evaluation with cardiac magnetic resonance at 4 (3-5) days after infarction. MVO was assessed with late gadolinium enhancement imaging and IMH with T2* mapping. Vessel dimensions were determined using catheter-based reference. Median culprit lesion vessel size was 3.1 (2.7-3.6) mm. MVO and IMH were found in 299 (58%) and 182 (35%) patients. Culprit lesion vessel size was associated with body surface area, diabetes, total ischemic time, postinterventional thrombolysis in myocardial infarction flow, and infarct size. There was no association between vessel size and MVO or IMH in univariable and multivariable analysis (P>0.05). These findings were consistent across patient subgroups with left anterior descending artery and non-left anterior descending artery infarctions and those with thrombolysis in myocardial infarction 3 flow post-percutaneous coronary intervention. Comprehensive characterization of myocardial tissue reperfusion injury by cardiac magnetic resonance revealed no association between culprit lesion vessel size and the occurrence of MVO and IMH in patients treated with primary percutaneous coronary intervention for ST-segment-elevation myocardial infarction.

Perioperative myocardial injury and infarction after noncardiac surgery: a review of pathophysiology, diagnosis, and management.

Perioperative myocardial injury is a relatively common complication after noncardiac surgery associated with significant morbidity and mortality. It is frequently driven by physiologic factors such as hypotension, tachycardia, and anemia. Diagnosis of perioperative myocardial injury after noncardiac surgery is based on elevated cardiac troponin levels, greater than the 99th percentile of the assay's upper reference limit within 30 days of surgery. Perioperative myocardial injury is further classified into non-ischemic and ischemic based on the underlying pathophysiology. Ischemic injury, also called myocardial injury after non-cardiac surgery (MINS), is further classified into perioperative myocardial infarction or myocardial injury without infarction. Classifying perioperative myocardial injury further is particularly important for clinical management and prognosis. MINS-with or without infarction-is independently and strongly associated with short- and long-term mortality. Compared to nonoperative myocardial infarction, perioperative myocardial infarction carries an increased risk of adverse outcomes including all-cause mortality. Preventative measures include a thorough preoperative risk assessment, risk factor optimization, and avoidance of intraoperative mismatch of myocardial oxygen supply and demand. Surveillance of patients at higher risk of cardiovascular complications is warranted and can lead to early recognition, closer monitoring, and appropriate management. This review will provide a framework for understanding perioperative myocardial injury and highlight the contemporary literature addressing its diagnosis and management.

Novel Role for Cardiolipin as a Target of Therapy to Mitigate Myocardial Injury Caused by Venoarterial Extracorporeal Membrane Oxygenation.

Cardiolipin is a mitochondrial-specific phospholipid that maintains integrity of the electron transport chain (ETC) and plays a central role in myocardial ischemia/reperfusion injury. Tafazzin is an enzyme that is required for cardiolipin maturation. Venoarterial extracorporeal membrane oxygenation (VA-ECMO) use to provide hemodynamic support for acute myocardial infarction has grown exponentially, is associated with poor outcomes, and is under active clinical investigation, yet the mechanistic effect of VA-ECMO on myocardial damage in acute myocardial infarction remains poorly understood. We hypothesized that VA-ECMO acutely depletes myocardial cardiolipin and exacerbates myocardial injury in acute myocardial infarction. We examined cardiolipin and tafazzin levels in human subjects with heart failure and healthy swine exposed to VA-ECMO and used a swine model of closed-chest myocardial ischemia/reperfusion injury to evaluate the effect of VA-ECMO on cardiolipin expression, myocardial injury, and mitochondrial function. Cardiolipin and tafazzin levels are significantly reduced in the left ventricles of individuals requiring VA-ECMO compared with individuals without VA-ECMO before heart transplantation. Six hours of exposure to VA-ECMO also decreased left ventricular levels of cardiolipin and tafazzin in healthy swine compared with sham controls. To explore whether cardiolipin depletion by VA-ECMO increases infarct size, we performed left anterior descending artery occlusion for a total of 120 minutes followed by 180 minutes of reperfusion in adult swine in the presence and absence of MTP-131, an amphipathic molecule that interacts with cardiolipin to stabilize the inner mitochondrial membrane. Compared with reperfusion alone, VA-ECMO activation beginning after 90 minutes of left anterior descending artery occlusion increased infarct size (36±8% versus 48±7%; P<0.001). VA-ECMO also decreased cardiolipin and tafazzin levels, disrupted mitochondrial integrity, reduced electron transport chain function, and promoted oxidative stress. Compared with reperfusion alone or VA-ECMO before reperfusion, delivery of MTP-131 before VA-ECMO activation reduced infarct size (22±8%; P=0.03 versus reperfusion alone and P<0.001 versus VA-ECMO alone). MTP-131 restored cardiolipin and tafazzin levels, stabilized mitochondrial function, and reduced oxidative stress in the left ventricle. We identified a novel mechanism by which VA-ECMO promotes myocardial injury and further identify cardiolipin as an important target of therapy to reduce infarct size and to preserve mitochondrial function in the setting of VA-ECMO for acute myocardial infarction.

Effect of ischaemic postconditioning on markers of myocardial injury in ST-elevation myocardial infarction: a meta-analysis

ObjectivesThis study aimed to perform a meta-analysis of the short-term impact of ischaemic postconditioning (IPoC) on myocardial injury in ST elevation myocardial infarction (STEMI) using surrogate cardiac biomarkers.MethodsEligible studies were...

Carbonic Anhydrase 3 is required for cardiac repair post myocardial infarction via Smad7-Smad2/3 signaling pathway.

Appropriate fibrosis is required to prevent subsequent adverse remodeling and heart failure post myocardial infarction (MI), and cardiac fibroblasts (CFs) play a critical role during the process. Carbonic anhydrase 3 (CAR3) is an important mediator in multiple biological processes besides its CO2 hydration activity; however, the role and underlying mechanism of CAR3 on cardiac repair post MI injury remains unknown. Here, we found that CAR3 expression was up-regulated in cardiac tissue in infarct area at the reparative phase of MI, with a peak at 7 days post MI. The upregulation was detected mainly on fibroblast instead of cardiomyocyte, and primary cardiac fibroblasts treated with TGF-β1 recaptured our observation. While CAR3 deficiency leads to weakened collagen density, enlarged infarct size and aggravated cardiac dysfunction post-MI. In fibroblast, we observed that CAR3 deficiency restrains collagen synthesis, cell migration and gel contraction of cardiac fibroblasts, whereas overexpression of CAR3 in CFs improves wound healing and cardiac fibroblast activation. Mechanistically, CAR3 stabilizes Smad7 protein via modulating its acetylation, which dampens phosphorylation of Smad2 and Smad3, thus inhibiting fibroblast transformation. In contrast, inhibition of Smad7 acetylation with C646 blunts CAR3 deficiency induced suppression of fibroblast activation and impaired cardiac healing. Our data demonstrate a protective role of CAR3 in cardiac wound repair post MI via promoting fibroblasts activation through Smad7-TGF-β/Smad2/3 signaling pathway.

Exosomes Induce Crosstalk Between Multiple Types of Cells and Cardiac Fibroblasts: Therapeutic Potential for Remodeling After Myocardial Infarction.

Recanalization therapy can significantly improve the prognosis of patients with acute myocardial infarction (AMI). However, infarction or reperfusion-induced cardiomyocyte death, immune cell infiltration, fibroblast proliferation, and scarring formation lead to cardiac remodeling and gradually progress to heart failure or arrhythmia, resulting in a high mortality rate. Due to the inability of cardiomyocytes to regenerate, the healing of infarcted myocardium mainly relies on the formation of scars. Cardiac fibroblasts, as the main effector cells involved in repair and scar formation, play a crucial role in maintaining the structural integrity of the heart after MI. Recent studies have revealed that exosome-mediated intercellular communication plays a huge role in myocardial repair and signaling transduction after myocardial infarction (MI). Exosomes can regulate the biological behavior of fibroblasts by activating or inhibiting the intracellular signaling pathways through their contents, which are derived from cardiomyocytes, immune cells, endothelial cells, mesenchymal cells, and others. Understanding the interactions between fibroblasts and other cell types during cardiac remodeling will be the key to breakthrough therapies. This review examines the role of exosomes from different sources in the repair process after MI injury, especially the impacts on fibroblasts during myocardial remodeling, and explores the use of exosomes in the treatment of myocardial remodeling after MI.

Puerarin attenuates myocardial ischemic injury and endoplasmic reticulum stress by upregulating the Mzb1 signal pathway.

This study investigated the role of Mzb1 in puerarin protection against heart injury and dysfunction in acute myocardial infarction (AMI) mice. C57BL/6 mice were pretreated with and without puerarin at doses of 50mg/kg and 100mg/kg for 14days before establishing the AMI model. An AMI model was induced by ligating the left descending anterior coronary artery, and AC16 cardiomyocytes were treated with H2O2 in vitro. Echocardiography was performed to measure cardiac function. DHE staining, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase assay, and DCFH-DA oxidative fluorescence staining were used to determine reactive oxygen species (ROS) production in vivo and in vitro. Bioinformatics analysis was used to predict potential upstream transcription factors of Mzb1. Puerarin dose-dependently reduced myocardial infarction area and injury, accompanied by the improvement of cardiac function in AMI mice. AMI mice manifested an increase in myocardial oxidative stress, endoplasmic reticulum (ER) stress, apoptosis, and mitochondrial biogenesis dysfunction, which were inhibited by pretreatment with puerarin. Puerarin also prevented Mzb1 downregulation in the hearts of AMI mice or H2O2-treated AC16 cells. Consistent with the in vivo findings, puerarin inhibited H2O2-induced cardiomyocyte apoptosis, ER stress, and mitochondrial dysfunction, which were attenuated by siRNA Mzb1. Furthermore, the JASPAR website predicted that KLF4 may be a transcription factor for Mzb1. The expression of KLF4 was partially reversed by puerarin in the cardiomyocyte injury model, and KLF4 inhibitor (kenpaullone) inhibited Mzb1 expression and affected its function. These results suggest that puerarin can protect against cardiac injury by attenuating oxidative stress and endoplasmic reticulum stress through upregulating the KLF4/Mzb1 pathway and that puerarin may expand our armamentarium for the prevention and treatment of ischemic heart diseases.

Exploring the role and mechanism of hyperoside against cardiomyocyte injury in mice with myocardial infarction based on JAK2/STAT3 signaling pathway

BackgroundMyocardial infarction (MI) is one of the most deadly diseases in the world. Hyperoside (Hyp) has been shown to have a protective effect on cardiovascular function through various signaling pathways, but whether it can protect myocardial infarction by regulating JAK2/STAT3 signaling pathway is unknown. Aim of the studyTo investigate whether Hyp could protect the heart against myocardial infarction injury in mice by modulating JAK2/STAT3 signaling pathway and its potential mechanism. MethodsIn vivo experiments, the myocardial infarction model was established by ligating the left anterior descending coronary artery (LAD) of male C57BL/6 mice permanently. The mice were divided into seven groups: sham group, MI group, MI+Hyp (9 mg/kg), MI+Hyp (18 mg/kg) group, MI+Hyp (36 mg/kg) group, MI+Captopril group (15 mg/kg) group and MI+Hyp (36 mg/kg)+AG490 (7.5 mg/kg) group. Each group of animals were given different concentrations of hyperoside, positive control drug or inhibitor of JAK2/STAT3 singaling. After 14 days of administration, the electrocardiogram (ECG), echocardiography and serum myocardial injury markers were examined; Slices of mouse myocardial tissue were assessed for histopathological changes by HE, Masson and Sirius Red staining. TTC and TUNEL staining were used to evaluate the myocardial infarction area and cardiomyocytes apoptosis respectively. The expression of JAK2/STAT3 signaling pathway, apoptosis and autophagy-related proteins were detected by western blot. In vitro experiments, rat H9c2 cardiomyocytes were deprived of oxygen and glucose (OGD) to stimulate myocardial ischemia. The experiment was divided into seven groups: Control group, OGD group, OGD+Hyp (20 μM) group, OGD+Hyp (40 μM) group, OGD+Hyp (80 μM), OGD+Captopril (10 μM) group and OGD+Hyp (80 μM)+AG490 (100 μM) group. Myocardial cell damage and redox index were measured 12 h after OGD treatment. ROS content in cardiomyocytes was detected by immunofluorescence. Cardiomyocytes apoptosis was detected by flow cytometry. The expressions of JAK2/STAT3 signaling pathway-related proteins, apoptosis and autophagy related proteins were detected by western blot. ResultsIn vivo, hyperoside could ameolirate ECG abnormality, increase cardiac function, reduce myocardial infarction size and significantly reduce myocardial fibrosis level and oxidation level. The experimental results in vitro showed that Hyp could reduce the ROS content in cardiomyocytes, decrease the level of oxidative stress and counteract the apoptosis induced by OGD injury . Both in vivo and in vitro experiments showed that hyperoside could increase phosphorylated JAK2 and STAT3, indicating that hyperoside could play a cardioprotective role by activating JAK2/STAT3 signaling pathway. It was also shown that hyperoside could increase the autophagy level of cardiomyocytes in vivo and in vitro. However the cardiomyocyte-protective effect of Hyp was abolished in combination with JAK2/ STAT3 signaling pathway inhibitor AG490. These results indicated that the protective effect of Hyp on cardiomyocyte injury was at least partially achieved through the activation of the JAK2/STAT3 signaling pathway. ConclusionHyp can significantly improve cardiac function, ameliorate myocardial hypertrophy and myocardial remodeling in MI mice. The mechanism may be related to improving mitochondrial autophagy of cardiomyocytes to maintain the advantage of autophagy, and blocking apoptosis pathway through phagocytosis, thus suppressing apoptosis level of cardiomyocytes. These effects of Hyp are achieved, at least in part, by activating the JAK2/STAT3 signaling pathway.

A Perspective on Hormonal Contraception Usage in Central Nervous System Injury.

Naturally occurring life stages in women are associated with changes in the milieu of endogenous ovarian hormones. Women of childbearing age may be exposed to exogenous ovarian hormone(s) because of their use of varying combinations of estrogen and progesterone hormones-containing oral contraceptives (OC; also known as "the pill"). If women have central nervous system (CNS) injury such as spinal cord injury (SCI) and traumatic brain injury (TBI) during their childbearing age, they are likely to retain their reproductive capabilities and may use OC. Many deleterious side effects of long-term OC use have been reported, such as aberrant blood clotting and endothelial dysfunction that consequently increase the risk of myocardial infarction, venous thromboembolism, and ischemic brain injury. Although controversial, studies have suggested that OC use is associated with neuropsychiatric ramifications, including uncontrollable mood swings and poorer cognitive performance. Our understanding about how the combination of endogenous hormones and OC-conferred exogenous hormones affect outcomes after CNS injuries remains limited. Therefore, understanding the impact of OC use on CNS injury outcomes needs further investigation to reveal underlying mechanisms, promote reporting in clinical or epidemiological studies, and raise awareness of possible compounded consequences. The goal of the current review is to discuss the impacts of CNS injury on endogenous ovarian hormones and vice-versa, as well as the putative consequences of exogenous ovarian hormones (OC) on the CNS to identify potential gaps in our knowledge to consider for future laboratory, epidemiological, and clinical studies.

Impact of continuous and wireless monitoring of vital signs on clinical outcomes: a propensity-matched observational study of surgical ward patients

BackgroundContinuous and wireless vital sign monitoring is superior to intermittent monitoring in detecting vital sign abnormalities; however, the impact on clinical outcomes has not been established. MethodsWe performed a propensity-matched analysis of data describing patients admitted to general surgical wards between January 2018 and December 2019 at a single, tertiary medical centre in the USA. The primary outcome was a composite of in-hospital mortality or ICU transfer during hospitalisation. Secondary outcomes were the odds of individual components of the primary outcome, and heart failure, myocardial infarction, acute kidney injury, and rapid response team activations. Data are presented as odds ratios (ORs) with 95% confidence intervals (CIs) and n (%). ResultsWe initially screened a population of 34,636 patients (mean age 58.3 (Range 18–101) yr, 16,456 (47.5%) women. After propensity matching, intermittent monitoring (n=12 345) was associated with increased risk of a composite of mortality or ICU admission (OR 3.42, 95% CI 3.19–3.67; P<0.001), and heart failure (OR 1.48, 95% CI 1.21–1.81; P<0.001), myocardial infarction (OR 3.87, 95% CI 2.71–5.71; P<0.001), and acute kidney injury (OR 1.32, 95% CI 1.09–1.57; P<0.001) compared with continuous wireless monitoring (n=7955). The odds of rapid response team intervention were similar in both groups (OR 0.86, 95% CI 0.79–1.06; P=0.726). ConclusionsPatients who received continuous ward monitoring were less likely to die or be admitted to ICU than those who received intermittent monitoring. These findings should be confirmed in prospective randomised trials.

Endothelial cells adopt a pro-reparative immune responsive signature during cardiac injury.

Modulation of the heart's immune microenvironment is crucial for recovery after ischemic events such as myocardial infarction (MI). Endothelial cells (ECs) can have immune regulatory functions; however, interactions between ECs and the immune environment in the heart after MI remain poorly understood. We identified an EC-specific IFN responsive and immune regulatory gene signature in adult and pediatric heart failure (HF) tissues. Single-cell transcriptomic analysis of murine hearts subjected to MI uncovered an EC population (IFN-ECs) with immunologic gene signatures similar to those in human HF. IFN-ECs were enriched in regenerative-stage mouse hearts and expressed genes encoding immune responsive transcription factors (Irf7, Batf2, and Stat1). Single-cell chromatin accessibility studies revealed an enrichment of these TF motifs at IFN-EC signature genes. Expression of immune regulatory ligand genes by IFN-ECs suggests bidirectional signaling between IFN-ECs and macrophages in regenerative-stage hearts. Our data suggest that ECs may adopt immune regulatory signatures after cardiac injury to accompany the reparative response. The presence of these signatures in human HF and murine MI models suggests a potential role for EC-mediated immune regulation in responding to stress induced by acute injury in MI and chronic adverse remodeling in HF.

Cucurbitacin B protects against myocardial ischemia-reperfusion injury through activating JAK2/STAT3 signaling pathway.

Cucurbitacin B, a tetracyclic triterpenoid compound extracted from various plants, has been proven to exert a vital role in various diseases. However, the effect of cucurbitacin B on myocardial infarction (MI) and ischemia-reperfusion (I/R) injury is still relatively unclear. The main purpose of the present study was to investigate the effect of cucurbitacin B on cell apoptosis and oxidative damage after myocardial I/R injury in vitro and in vivo and elucidate the molecular mechanisms underlying its role. The 56-day-old adult mice and 1-day-old neonatal mice cardiomyocytes were used to construct I/R or oxygen-glucose deprivation/reoxygenation (OGD/R) injury models. The oxidative injury, western blot and TUNEL assay were performed to evaluate cardiomyocyte damage in the present study. In vitro， we confirmed that cucurbitacin B could attenuate LDH release, oxidative stress and cell apoptosis in cardiomyocytes exposed to OGD/R. Besides, we confirmed in an adult I/R mouse model that cucurbitacin B can improve cardiac repair and block cell apoptosis in the acute phase (24 h) post-myocardial I/R injury, as well as promote long-term cardiac function and fiber scar area after 28 days of I/R. Mechanically, we clarify that cucurbitacin B exerts cardiomyocyte protective effects through activating the JAK2/STAT3 signaling pathway. In conclusion, our study elucidates for the first time the protective role of cucurbitacin B in cardiac I/R injury, which provides a novel perspective for better prevention of I/R injury through the JAK2/STAT3 signaling pathway.

Incidence and prediction of periprocedural myocardial infarction in elective PCI: the ALPHEUS-MI sub-study

Abstract Background PCI-related myocardial infarction (MI) or injury are frequent events that have been shown to be associated with long-term ischemic outcomes and mortality. Determinants of these events with the validated definition of PCI-related myocardial infarction (MI) or injury are not well documented in contemporary elective PCI. Methods The ALPHEUS-MI study is a prespecified analysis of the ALPHEUS randomized trial conducted in 49 centers of two European countries which recruited 1910 patients with chronic coronary syndrome undergoing elective PCI. We analyzed the rate and predictors of periprocedural myocardial necrosis using the primary and secondary endpoint of the ALPHEUS trial (3rd and 4th universal definition of MI) and the ARC2/SCAI definitions. Multivariable model including patient’s demographic, angiographic and procedural characteristics were performed for each definition to determine predictors of periprocedural events. Findings : The primary endpoint of the ALPHEUS trial (type 4a MI or major myocardial injury) occurred in 35.85% of the patients (3rd universal definition of MI); the secondary endpoint of the ALPHEUS trial (type 4a MI and any myocardial injury) occurred in 77.21% of the patients (4th universal definition of MI); significant periprocedural myocardial injury occurred in 3.24% of the patients (ARC2/SCAI definition) and periprocedural MI (ARC2/SCAI definition) in 2.02% of the patients. The rate of events followed a stepwise increase according to the number of high-risk features with all definitions (figure). High risk features were characterized by patients’ characteristics, the complexity of the coronary lesion (anatomy and atheroma burden) and the complexity of the PCI procedure itself. The only common predictor of MI or myocardial injury present with the 4 definitions was the total length of stent implanted (&amp;gt;60mm) ; adjOR 3.23 (2.49-4.18) p&amp;lt;0,001 (type 4a MI/major injury 3rd UDMI ) , adjOR 3.82 (2.51-5.8) p&amp;lt;0,001 (type 4a MI/any injury 4th UDMI) , adjOR 2.2 (1.24-3.91) p=0,007 (myocardial injury ARC2/SCAI) and adjOR 6.0 (3.04-11.9) p&amp;lt;0,001 (MI ARC2/SCAI). Conclusion Whatever definition of type 4aMI and myocardial injury, the strongest predictor of myocardial necrosis seems to be the length of stent implanted which reflects both the severity of atheroma burden and the complexity of PCI.

Long-term follow-up of patients with myocardial infarction and myocardial injury

Abstract Introduction Patients with symptoms indicative of acute myocardial infarction (MI) frequently present to the emergency department (ED) and undergo a structured diagnostic assessment. Apart from MI, other diagnoses are frequently identified, including myocardial injury. In these patients estimation of long-term risk is crucial to guide preventive strategies. Purpose To assess and compare the long-term incidence of all-cause death and cardiovascular events in patients with MI, myocardial injury and other causes of acute chest pain. Methods We conducted a prospective, observational cohort study enrolling consecutive patients presenting with suspected MI to the ED of a tertiary hospital. The final diagnoses were adjudicated by two independent cardiologists according to the 4th Universal Definition of MI using high-sensitivity cardiac troponin T (hs-cTnT). Patients were followed to assess incidental all-cause death and a composite endpoint (cardiovascular death, MI, or myocardial revascularization). We used Kaplan-Meier plots for crude and Cox regression models (providing hazard ratios [95% confidence intervals]) for adjusted (sex, age, cardiovascular risk factors, heart failure, renal function) time-to-event analyses, respectively, using patients with other causes of chest pain as reference. Results Overall, we prospectively included 2,714 patients with a median age of 64 (25th, 75th: 51, 75) years, of whom 1,745 (64.3%) were male. In total, 143 (5.3%) had ST-elevation MI (STEMI), 128 (4.7%) Type 1 Non-ST-elevation MI (NSTEMI), 236 (8.7%) Type 2 NSTEMI, 86 (3.2%) acute myocardial injury, 677 (24.9%) chronic myocardial injury, and 1,444 (53.2%) other diagnoses of chest pain not involving hs-cTn elevation. The median follow-up time was 4.6 (4.5, 7.3) years. The highest rates of all-cause death were observed in patients with myocardial injury (81.6 [71.7, 92.3] events/1000 patient-years) and infarction (55.9 [46.3, 66.7]), compared to other diagnoses (12.2 (9.8, 15.1). Figure 1 provides the Kaplain-Meier estimates for the final diagnoses. In adjusted Cox regression analyses, all patients with MI or myocardial injury were at significantly higher risk for all-cause death, compared to patients with other causes of chest pain (Figure 2A). Additionally, the risk for the secondary composite endpoint (cardiovascular death, MI, revascularization) was significantly increased in those with acute or chronic myocardial injury, and patients with Type 1 NSTEMI or STEMI, but not Type 2 NSTEMI (Figure 2B). Conclusion Patients with acute myocardial infarction and acute or chronic myocardial injury are at high long-term risk for death and incident cardiovascular events. Importantly, those patients with acute myocardial injury showed the highest mortality rate. Further studies need to determine appropriate management strategies for patients with myocardial injury.Kaplan-Meier plot for final diagnosesForest plot of adjusted outcome analysis

Ticagrelor or Clopidogrel to reduce ischemic events after Percutaneous Coronary Intervention in chronic coronary syndrome in clopidogrel naive patient: the ALPHEUS Naive sub-study

Abstract Background The ALPHEUS trial showed a similar rate of type 4 myocardial infarction (MI) or major myocardial injury in elective PCI treated by clopidogrel or ticagrelor. Whether clopidogrel therapy at baseline might have affected these results is unknown. Purpose We evaluated the impact of ticagrelor versus clopidogrel loading dose in clopidogrel naïve patients as compared to patients already treated by clopidogrel in this pre-specified analysis. Methods We divided 1882 randomized patients with complete data on baseline clopidogrel into 2 groups according to presence of clopidogrel therapy &amp;gt; 7 days (long term clopidogrel = Clopi+) or its absence (clopidogrel naïve = Clopi-). The primary endpoint was the rate of PCI-related MI and myocardial injury as defined by the 3rd and 4th universal definition of MI evaluated within 48 h of PCI (or hospital discharge if earlier) and major and minor bleeding. Angiographic complications evaluated by the core laboratory (coronary slow flow, no flow, dissection, and thrombus) were also compared. Event rates were compared and the interaction of the allocated treatment in the randomized groups was evaluated. Results 1077 patients (57.2%) were Clopi- and 805 patients were Clopi+. Patients in the Clopi- group were less frequently male (78.0% vs 81.9%, p= 0.04) with less often dyslipidemia (57.8% vs 65.6%, p&amp;lt; 0.001) and peripheral artery disease (11.1% vs 14.4%, p= 0.03) and had less acute coronary syndrome in the last 12 months (3.4% vs 8.7% p= 0.002). The primary endpoint was less frequent in Clopi- as compared to tClopi+ (32.8% vs 40%, OR =0.73, CI [0.60-0.88], p=0.001). This difference was mainly driven by a lower rate of major myocardial injury 24.% vs 31.6% while the rate of type 4a MI and stent thrombosis were similar (8.4% vs 8.2%) and (0.4% vs 0.2%) respectively. Angiographic complication rate was similar in the Clopi- and the Clopi+ groups (14.6% vs 12.9%) OR=1.15 CI [0.88-1.5], p=0.31. Major bleedings were infrequent in the trial. (0.1% vs 0%), and minor bleeding did not differ significantly between Clopi- and Clopi+ patients (7.0% vs 4.8% OR=1.47, CI [0.99-2.19], p=0.06). At 30 days, no difference in any outcomes were reported between the two groups. Alike for the main trial results, in the Clopi- group, ticagrelor was not superior to clopidogrel in reducing periprocedural myocardial necrosis, p for interaction was 0.83. Conclusions Periprocedural MI and procedural angiographic complications were less frequent in clopidogrel naïve patients as compared to patients already on clopidogrel therapy, and not influenced by the potency of the P2Y12 inhibitor’s loading dose prior to PCI. These results globally suggest no benefit of a long term clopidogrel pretreatment in patients receiving a loading dose of P2Y12 in the 24 hours prior to PCI in chronic coronary syndrome undergoing elective PCI and support the use of clopidogrel as the standard of care.

Ticagrelor versus clopidogrel for complex percutaneous coronary intervention in chronic coronary syndrome: a post-hoc analysis of the ALPHEUS study

Abstract Background Whether ticagrelor utilization in chronic coronary syndrome patients undergoing complex percutaneous coronary intervention (PCI) could prevent type 4 myocardial infarction (MI) or myocardial injury as compared to clopidogrel is unknown. Purposes To evaluate the frequency and outcomes of complex PCI in stable coronary patients and the efficacy of ticagrelor versus clopidogrel in these patients randomized in the ALPHEUS trial. Methods All PCI procedures were blindly reviewed by two core laboratory readers and classified as complex if they had at least one of the following criteria: stent length ≥60 mm, two-stent bifurcation, use of atherectomy, left main, bypass graft, chronic total occlusion, use of guide catheter extensions, multiwire technique, multiple stents. The primary endpoint was a composite of type 4a or b MI and major myocardial injury, defined by the 3rd and 4th universal definition of MI, during the 48h after PCI. Angiographic complications and the composite of death, MI, stroke at 48 hours and at 30 days were also evaluated. We compared the event rates in the randomized groups according to the presence or not of complex PCI criteria and evaluated the interaction with the randomization to ticagrelor or clopidogrel. Results Among the 1866 patients randomized, 910 (48.3%) PCI were classified as complex PCI and 956 (51.7%) as not complex. Multiple criteria of complex PCI were found in 14.4% (2 criteria) and 9.1% (≥3 criteria) of the patients. The primary endpoint was more frequent in complex PCI than in the not-complex PCI (45.6% vs 26.6%; p&amp;lt;0.001) driven by higher rates of type 4MI and angiographic complications (12.2% vs 4.8 %; p&amp;lt;0.001 and 19.3% vs 8.6%; p&amp;lt;0.05, respectively). The composite of death, MI, stroke at 48 hours (12.7% vs 5.1 %; p&amp;lt;0.05) and at 30 days (13.4% vs 5.3%; p&amp;lt;0.05) were also more frequent in complex PCI. No interaction was found between the complexity of PCI and the randomized treatment for the primary endpoint (p for interaction = 0.35) nor the secondary endpoints. Conclusions Complex PCI patients have higher rates of periprocedural and cardiovascular events which are not reduced by ticagrelor as compared with clopidogrel.

The diagnostic accuracy of experienced physicians to clinically discriminate type 1 myocardial infarction from type 2 myocardial infarction or myocardial injury

Abstract Background The early differentiation of patients with type 1 myocardial infarction (T1MI) from type 2 myocardial infarction (T2MI) or myocardial injury is crucial and has immediate clinical implications. It remains uncertain how precise experienced cardiologists (&amp;gt;10years experience) can discern a T1MI from T2MI or myocardial injury by solely integrating clinical information. Methods From a prospective, multicenter cohort study 1636 patients referred for urgent angiography for suspected T1MI, cardiologists were asked to estimate the likelihood of an underlying T1MI prior and following invasive angiography. All cases were independently reviewed and adjudicated for their final diagnosis (T1MI or T2MI/ myocardial injury). Results Finally, 1354 and 282 were adjudicated with T1MI and T2MI/myocardial injury, whereas 173 (17.2%) patients presented with myocardial injury, see Figure below. There was a male predominance, especially among patients with T1MI (1016 (75%), p&amp;lt;0.001). The prevalence of NSTEMI presentation was significantly higher in patients with T2MI/ myocardial injury. The level of hs-TnT at baseline was significantly higher in T1M1 compared to T2MI/ myocardial injury patients (133 (38; 571) ng/L versus 42 (26;92) ng/L and 68 (31; 212) ng/L, respectively; p=0.001). Overall, the number of angiography and PCI-related complications was low, but higher among T1MI compared to T2MI/ myocardial injury patients (0.4% versus 1.8%/ 0.0%, p=0.047, respectively). In terms of in-hospital adverse outcomes, the number of clinically relevant bleedings and revascularization procedures was higher in T1M1 compared to T2MI/ myocardial injury patients (9 (0.6%) versus 2 (1.8%), and 34 (2.5%) versus 3 (2.7%)). After 1-year follow-up (in unadjusted analyzes), the risk for MACE was higher among T1M1 compared to T2MI/ myocardial injury patients (230 (17%) versus 28 (7.3%), p=0.008). This was mainly driven by a higher risk for repeat revascularization procedures and MIs. Of note, there was no significant difference in death. Overall, we found that including the angiographic information had a significant impact on the diagnostic accuracy (p&amp;lt;0.001) (Figure). Prior to the invasive angiogram, the diagnostic accuracy of the cardiologists´ clinical evaluation and submitted likelihood for T1M1 reached an AUC 0.87 (95% confidence interval (95%CI) 0.85–0.90), and after integrating the angiographic information, the AUC increased (0.96 (95%CI 0.94–0.98). Conclusions Patients diagnose with T1M1 compared to T2MI/myocardial injury relevantly differ in their presentation and demographics as well as clinical outcomes. In order to reliably identify patients with T2MI/ myocardial injury and accordingly guide their further management, physicians should aim for delineation of the coronary anatomy. In this context, using invasive angiography with contemporary practice seems safe.Accuracy of clinical judgment for T1M1CONSORT diagram - study cohort