Outcome Of Myocardial Infarction Research Articles

Vericiguat enhances the therapeutic efficacy of mesenchymal stem cells-derived exosomes in acute myocardial infarction through microRNA-1180-3p/ETS1 pathway.

Reversing cardiac fibrosis contributes to the restoration of cardiac function in acute myocardial infarction (MI). Exosomes-derived mesenchymal stem cells (MSCs) have been established as potential biomarkers of cardiovascular diseases. While vericiguat has demonstrated promising outcomes in MI via reverse hypertrophy and fibrosis, previous studies about vericiguat pretreatment with MSCs is limited. We aim at exploring whether exosomes derived from vericiguat pretreatment MSCs could augment cardioprotective function and the underlying mechanisms. In our study, exosomes isolated from MSCs (MSC-Exo) and pretreated with vericiguat (MSCVER-Exo) were administered to cardiac fibroblasts (CFs) in vitro and male infarcted Sprague-Dawley rat hearts in vivo. In vivo, MSCVER-Exo could significantly improve cardiac function and attenuate cardiac fibrosis and decrease the expression of α-smooth muscle actin (α-SMA), Ι and III collagen (Col Ι and Col III) compared to MSC-Exo treatment. In vitro, MSCVER-Exo could also restrain proliferation, migration, and the profibrotic genes expression in CFs. miR-1180-3p was enrich in MSCVER-Exo. Besides, miR-1180-3p could be delivered to CFs via Exo and alleviated TGF-β1-induced fibrosis through inhibiting ETS1 signaling. The elucidation of this mechanism suggested that exosomes derived from vericiguat pretreatment MSCs could improve cardioprotective effects through promoting CFs function. MiR-1180-3p targeting ETS1 played an important role in antifibrosis.

Long-term outcomes after percutaneous coronary intervention versus coronary artery bypass grafting in women, a meta-analysis

BackgroundDespite the advances in the last decades for treatment of ischemic heart disease, women continue to experience poorer prognosis than men and currently, there is a gap in knowledge regarding the optimal revascularization strategy in women.ObjectiveCompare the long-term outcomes of percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) for the treatment of stable ischemic heart disease in women.MethodsA systematic search was conducted including randomized clinical trials (RCTs) comparing PCI with drug-eluting stents with CABG. The primary outcome were the composite outcomes of death, stroke or myocardial infarction (MI) and death, stroke, MI or repeat revascularization. Secondary outcomes included the individual components of the primary outcomes. Pooled hazard ratios with 95% confidence intervals were calculated in a fixed- effects meta-analysis using the inverse of variance method. Risk of bias and sensitivity analyses were also conducted.ResultsSix multicenter, RCTs were included after eligibility assessment. Median follow-up was 6.25 years (IQR: 5- 2.5). A significant benefit for CABG over PCI was observed for the primary composite outcomes of death, stroke, MI (HR = 1.24; 95% CI 1.01–1.52; p = 0.037) and death, stroke, MI or repeat revascularization (HR = 1.60; 95% CI 1.25–2.03; p < 0.000).ConclusionIn the present study-level metanalysis, CABG is associated with a lower risk of major adverse cardiovascular events than PCI at long term follow-up in women.

Synergistic combinations of Angelica sinensis for myocardial infarction treatment: network pharmacology and quadratic optimization approach

Background and aimAngelica sinensis (Oliv.) Diels (Danggui, DG), exhibits potential in myocardial infarction (MI) treatment. However, research on its synergistic combinations for cardioprotective effects has been limited owing to inadequate approaches.Experimental procedureWe identified certain phenolic acids and phthalein compounds in DG. Network pharmacology analysis and experimental validation revealed the components that protected H9c2 cells and reduced lactate dehydrogenase levels. Subsequently, a combination of computational experimental strategies and a secondary phenotypic optimization platform was employed to identify effective component combinations with synergistic interactions. The Chou-Talalay and Zero Interaction Potency (ZIP) models were utilized to quantify the synergistic relationships. The optimal combination identified, Z-Ligustide and Chlorogenic acid (Z-LIG/CGA), was evaluated for its protective effects on cardiac function and cardiomyocytes apoptosis induced by inflammatory in a mouse model of induced by left anterior descending coronary artery ligation. Flow cytometry was further utilized to detect the polarization ratio of M1/M2 macrophages and the expression of inflammatory cytokines in serum was measured, assessing the inhibition of inflammatory responses and pro-inflammatory signaling factors by Z-LIG/CGA.Key resultsQuadratic surface analysis revealed that the Z-LIG/CGA combination displayed synergistic cardioprotective effects (combination index value &amp;lt;1; ZIP value &amp;gt;10). In vivo, Z-LIG/CGA significantly improved cardiac function and reduced the fibrotic area in mice post-MI, surpassing the results in groups treated with Z-LIG or CGA alone. Compared to the MI group, the Z-LIG/CGA group exhibited decreased ratios of the myocardial cell apoptosis-related proteins BAX/Bcl-2 and Cleaved Caspase-3/Caspase-3 in mice. Further research revealed that Z-LIG/CGA treatment significantly increased IL-1R2 levels, significantly decreased IL-17RA levels, and inhibited the activation of p-STAT1, thereby alleviating cell apoptosis after MI. Additionally, the Z-LIG/CGA combination significantly inhibited the ratio of M1/M2 macrophages and suppressed the expression levels of pro-inflammatory cytokines IL-1β, IL-6, IL-17, and TNF-α in the serum.Conclusion and implicationsWe successfully identified a synergistic drug combination, Z-LIG/CGA, which improves MI outcomes by inhibiting cardiomyocyte apoptosis and inflammatory damage through modulating macrophage polarization and regulating the IL-1R2/IL-17RA/STAT1 signaling pathway. This study provides a charming paradigm to explore effective drug combinations in traditional Chinese medicine and a promising treatment for MI.

Restrictive Versus Liberal Transfusion in Patients With Type 1 or Type 2 Myocardial Infarction: A Prespecified Analysis of the MINT Trial.

The MINT trial (Myocardial Ischemia and Transfusion) raised concern for harm from a restrictive versus liberal transfusion strategy in patients with acute myocardial infarction (MI) and anemia. Type 1 and type 2 MI are distinct pathophysiologic entities that may respond differently to blood transfusion. This analysis sought to determine whether the effects of transfusion varied among patients with a type 1 or a type 2 MI and anemia. The authors hypothesized that the liberal transfusion strategy would be of greater benefit in type 2 than in type 1 MI. The authors compared rates of death or MI at 30 days in patients with type 1 (n=1460) and type 2 (n=1955) MI and anemia who were randomly allocated to a restrictive (threshold, 7-8 g/dL) or a liberal (threshold, 10 g/dL) transfusion strategy. The primary outcome of death or MI was observed in 16% of type 1 MI and 15.4% of type 2 MI patients. The rate of death or MI was higher in patients with type 1 MI randomized to a restrictive (18.2%) versus liberal (13.8%) transfusion strategy (relative risk [RR], 1.32 [95% CI, 1.04-1.67]) with no difference observed between the restrictive (15.8%) and liberal (15.1%) transfusion strategies in patients with type 2 MI (RR, 1.05 [95% CI, 0.85-1.29]). The test for a differential effect of transfusion strategy by MI type was not statistically significant (Pinteraction = 0.16). The concern for harm with a restrictive transfusion strategy in patients with acute MI and anemia raised in the MINT primary outcome manuscript may be more apparent in patients with type 1 than type 2 MI. URL: https://www.clinicaltrials.gov; Unique identifier: NCT02981407.

Building Artificial Intelligence, Machine Learning, and Causal Models to Improve Cardiac Health

Abstract The prediction of myocardial infarction (MI) outcomes remains pivotal for advancing treatment strategies in cardiology. This study proposes to compare the variable selection efficacy and predictive power of LASSO logistic regression and XGBoost, incorporating a causal mediation approach to elaborate on the underlying mechanisms influencing MI risks. Leveraging the GUSTO-I dataset on MI patients, this research has employed LASSO logistic regression to facilitate variable selection, aiming to identify critical predictors with substantial impacts on MI outcomes. Alternatively, the XGBoost algorithm has been utilized to assess its approach to variable selection and prediction. Both methods have been evaluated based on their Area Under the Receiver Operating Characteristic Curve (AUC) to determine their predictive accuracy. Furthermore, causal mediation analysis has been integrated to explore the putative effects of key predictors, identified in previous studies. The analysis aimed to reveal which method offers superior predictive performance and how well each can be interpreted in a clinical context. This study can contribute valuable insights into the comparative advantages of using LASSO logistic regression versus XGBoost in the field of cardiovascular disease research. By integrating causal mediation analysis, we aim to extend beyond mere prediction to offer a deeper understanding of the causal relationships and mechanisms at play.

Effect of iron status on myocardial infarction: A two-sample mendelian randomization study

BackgroundIn observational studies, connections have been identified between iron status and myocardial infarction (MI). The significance of changes in iron status as either a risk factor or a result of MI remains unclear. MethodsWe obtained our instrumental variables from a meta-analysis of three GWASs in Iceland, the UK, and Denmark, which discovered 62 independent sequence variants across 56 loci linked to blood iron levels, ferritin, total iron binding capacity (TIBC), transferrin saturation (TSAT), and the Genetics of Iron Status (GIS) database for transferrin. To evaluate the connection between iron status markers and myocardial infarction (MI), we used three GWAS datasets focused on MI outcomes. The chosen datasets included one representing the European population (ebi-a-GCST011364: n case=14,825, n control=380,970; finn-b-I9_MI: n case=12,801, n control=187,840) and another with a mixed population (ieu-a-798: n case=43,676, n control=128,199). The primary method used in our study was inverse variance-weighting, while we also assessed heterogeneity and horizontal pleiotropy to enhance the robustness of our findings. ResultsThe main analysis with the inverse variance-weighted method showed no significant impact of iron marker levels on MI risk in the ebi-a-GCST011364 and finn-b-I9-MI cohorts. In contrast, the ieu-a-798 cohort indicated that higher ferritin levels had a protective effect against MI (OR = 0.87, 95% CI 0.78-0.98, P=0.03). Additionally, TSAT showed an association with decreased MI risk (OR = 0.91, 95% CI 0.84-0.98, P=0.01). No significant correlations were observed for other iron status traits examined in this study. Evaluations of horizontal pleiotropy and heterogeneity showed no abnormalities, further strengthening the reliability of our results. ConclusionsOur multi-cohort MR analysis suggests a potential protective effect of higher ferritin levels and TSAT against MI risk. These findings contribute to our understanding of the relationship between iron status markers and cardiovascular health, offering insights for future research and potential therapeutic interventions.

Polygenic Prediction of Recurrent Events After Early-Onset Myocardial Infarction.

Myocardial infarction (MI) is a complex disease caused by both lifestyle and genetic factors. This study aims to investigate the predictive value of genetic risk, in addition to traditional cardiovascular risk factors, for recurrent events following early-onset MI. The Italian Genetic Study of Early-Onset Myocardial Infarction is a cohort study enrolling patients with MI before 45 years. Monogenic variants causing familial hypercholesterolemia were identified, and a coronary artery disease polygenic score (PGS) was calculated. Ten-fold cross-validated Cox proportional hazards models were fitted sequentially including all clinical variables, the PGS, and monogenic variants on the composite outcome of cardiovascular death, recurrent MI, stroke, or revascularization. During a 19.9-year follow-up, 847 (50.7%) patients experienced recurrent events. Each 1-SD higher PGS was associated with a 21% higher hazard of recurrent events (hazard ratio, 1.21 [95% CI, 1.13-1.31]; P=4.04×10-6). Except for secondary prevention, PGS was the strongest determinant of recurrent event risk (C index, 0.56 [95% CI, 0.54-0.58]) compared with clinical risk factors. Overall, predictive performance of clinical risk factors (C index, 0.69 [95% CI, 0.67-0.71]) improved after adding the PGS (C index, 0.69 [95% CI, 0.68-0.71]; P=0.006). When dividing the population by PGS quintiles, the highest fifth had a 57% higher hazard of recurrent events than the lowest fifth (hazard ratio, 1.57 [95% CI, 1.26-1.96]; P=5.57×10-5). When compared with other clinical risk factors, PGS was the strongest predictor of event recurrence among patients with an early-onset MI. Though the discriminative power of recurrent event prediction in this cohort was modest, the addition of PGS significantly improved discrimination.

Associations Between Plasma Levels of NLRP3 Protein, Interleukin-1 Beta and Features of Acute ST-Elevation Myocardial Infarction.

Phenotyping inflammation in ST-elevation myocardial infarction (STEMI) is a challenge for modern cardiology. NLRP3 inflammasome is a proven predictor of adverse outcomes in cardiovascular disease, but its specificity in stratifying inflammatory activity in patients with myocardial infarction (MI) has not been demonstrated. The aim of this paper is to describe the levels of NLRP3 protein and IL-1β concentrations and their changes in dynamics and associations with clinical, laboratory and instrumental characteristics of patients with STEMI. A total of 45 patients with STEMI were enrolled. Concentrations of NLRP3 and IL-1β were evaluated in arterial and venous EDTA blood from the infarct-related coronary and peripheral arteries and veins on days 1, 3 and 7 after MI. The concentrations of markers were higher on the first day after MI with a maximum decrease on the third day. The levels of both markers in venous plasma correlated with those in arterial blood, allowing their routine determination in venous plasma on the first day after MI. IL-1β levels correlated directly with the wall motion index and inversely with left ventricular ejection fraction and stroke volume, which characterize the potential contribution to adverse myocardial remodeling. There were two multidirectional trends in changes in NLRP3 and IL-1β levels during hospitalization. Initially higher levels with a gradual decrease by day 7 were associated with a longer duration of myocardial ischemia and higher plasma troponin I levels. Further evaluation of the long-term outcomes of MI will allow identifying inflammatory factors that input to the development of secondary major adverse cardiac events and will provide a new step in the understanding of inflammatory phenotyping.

Abstract 4136930: Plasminogen Activator Urokinase Receptor (PLAUR) Levels are a Predictor of Adverse Cardiovascular Outcomes in the General Population, Independent of High-Sensitive CRP (hs-CRP)

Background: The gene Plasminogen Activator Urokinase Receptor (PLAUR) encodes the urokinase plasminogen activator surface receptor (uPAR), which upon cleavage releases Soluble Urokinase Plasminogen Activator Receptor (suPAR). SuPAR has emerged as a novel biomarker of inflammation and immunity and is associated with adverse cardiovascular events, particularly coronary artery disease (CAD), regardless of hs-CRP levels, a well-established inflammatory biomarker. However, whether the PLAUR gene predicts adverse cardiovascular events remains uncertain. Methods: We investigated the relationship between PLAUR levels, measured via Olink Immunoassay, in 40,790 individuals from the UK Biobank, and the occurrence of adverse cardiovascular events such as myocardial infarction (MI), as well as all-cause and cardiovascular mortality. Our analysis involved the use of Cox and Fine and Gray proportional hazards models, adjusting for age, sex, race, HDL, LDL, triglyceride levels, BMI, prevalence of hypertension (HTN), prevalence of type 2 diabetes (T2D), smoking history, and use of blood pressure and cholesterol medications. Main Outcomes: The primary outcome was a composite outcome of cardiovascular mortality and MI and the secondary outcome was all-cause mortality. Results: The mean (SD) age was 58 (8) years, 45% men and 94% white. During a median follow-up of 14 (interquartile range 12.3 – 15) years, 7.9% of the population had an MI, 2.7% suffered cardiovascular death, 9.5% all-cause mortality. After adjusting for aforementioned demographic and clinical factors, as well as medication usage, each standard deviation increase in PLAUR levels was associated with a heightened risk of incident non-fatal MI and cardiovascular (CV) death, with a hazard ratio (HR) of 2.31 (95% CI 2.00-2.45), and all-cause mortality, with an HR of 3.81 (95% CI 3.48-4.18). Even after further adjustment for hs-CRP levels, PLAUR levels remained predictive of non-fatal MI and CV death (HR 2.03, 95% CI 1.83-2.26) and all-cause mortality (HR 3.43, 95% CI 3.12-3.77). Furthermore, in a fully adjusted Cox regression model, a significant interaction between PLAUR levels and sex (p = 0.0003) was observed in predicting the primary outcome. The interaction was found to have a stronger predictive value in females compared to males. Conclusion: PLAUR levels are a strong predictor of adverse cardiovascular outcomes in the general population, independent of traditional risk factors and inflammation.

Comparison of multiple high sensitivity cardiac troponin assays for early low risk rule out of myocardial infarction: SCORECARD

Abstract Background/Introduction The use of a single low high-sensitivity cardiac troponin measurement to rule out myocardial infarction (MI) at presentation is advocated by international guidelines. Studies have not systematically compared high-sensitivity cardiac troponin (hs-cTn) I and T assays to determine which values should be used to rule out MI in patients with suspected acute coronary syndrome. Methods In a pooled analysis from three prospective observational cohort studies the lowest cTn concentration was determined that gave a negative predictive value (NPV) of ≥99.5% for MI or death at 30 days on presentation to the emergency department. EDTA or lithium heparin plasma or serum samples collected at presentation were measured using five hs-cTnI assays (Abbott ARCHITECT i2000, Beckman Coulter Access 2, Siemens Atellica IM, Ortho-Clinical Diagnostics VITROS 5600, LSI Medience PATHFAST) and one hs-cTnT assay (Roche Cobas e411). The diagnostic outcome of MI or death at 30 days was adjudicated according to the Fourth Universal Definition of MI. Optimal thresholds were determined to identify the highest proportion of patients that could be considered for discharge for a NPV of ≥99.5% for each assay. Results Among 941 patients, MI or death at 30 days occurred in 113 (12%). Optimized thresholds varied between assays ranging from &amp;lt;2 to &amp;lt;7 ng/L (Table) that identified between 22% and 60% of patients as low risk (0-1%) for MI or death at 30 days. Conclusions Our data identify differences in the effectiveness of thresholds between hs-cTnI and hs-cTnT assays for the same safety performance to rule out MI on presentation using a single measurement. In some cases, these thresholds differ from those used in clinical practice. Due to lack of assay standardization, optimal decision thresholds should be defined and validated for each high sensitivity cTn assay.

Implementation of prasugrel and prognostic outcomes after percutaneous coronary intervention for myocardial infarction: a nationwide observational study

Abstract Background Prasugrel has shown superior efficacy and similar safety compared to ticagrelor for patients with acute coronary syndrome treated with percutaneous coronary intervention (PCI) in a randomised setting. Since 2020, prasugrel has been recommended over ticagrelor in our country. It remains unknown if these recommendations have been implemented, and if the findings from the randomised trial can be expanded to an all-comer population. Purpose To assess the implementation of prasugrel and compare effectiveness and safety between prasugrel and ticagrelor in PCI-treated, all-comer patients with myocardial infarction (MI). Methods From January 1st, 2019, to December 31st, 2021 patients with MI treated with PCI were identified by use of nationwide health registries. We included patients who were alive and claimed a prescription of prasugrel or ticagrelor within 7 days from discharge. Incidence rates per 100 person-years (IRs) 6 months from discharge were calculated for a composite outcome of all-cause mortality, recurrent MI (&amp;gt;28 days after index MI), and stroke (MACE), all-cause mortality alone, ischaemic events (a composite of recurrent MI and stroke) and bleeding leading to hospitalisation. We illustrated a Kaplan Meier curve with log-rank test and a cumulative incidence curve with Gray’s test and performed Cox models to assess adjusted comparative differences of the outcomes between prasugrel and ticagrelor after adjusting for age, sex, relevant comorbidities, and calendar year. Results We identified 14,365 PCI-treated patients with MI, of whom 13,887 (96.7%) were alive 7 days from discharge. After excluding patients who did not collect a P2Y12 inhibitor (n=1097 [7.9%]) or collected clopidogrel within 7 days from discharge (n=2696 [21.1%]), the final study population counted 10,094 patients of whom 2045 (20.3%) patients collected prasugrel and 8049 (79.7%) ticagrelor. Figure 1 shows the temporal use of P2Y12 inhibitors. The mean age was 64.4 (±11.7) years and 23.9% were female. Patients with prasugrel were less often ≥75 years old (16.3% vs. 23.2%), female (22.1% vs. 24.3%), and had fewer comorbidities (hypertension, hypercholesterolemia, diabetes, stroke or transient ischaemic attack, bleeding, and prior PCI) than ticagrelor-treated patients. Figure 2 illustrates IRs of the outcomes and Kaplan Meier and cumulative incidence curves. Prasugrel treatment was associated with reduced risk of MACE (HR 0.67 [95% CI 0.47-0.95]) and ischaemic events (HR 0.68 [0.47-0.97]) compared with ticagrelor after adjustment, and there were no differences in all-cause mortality or bleeding (Figure 2). Conclusion Prasugrel use increased from 1% to 44% from 2019 to 2021, but most all-comer patients with MI were treated with ticagrelor after PCI. Prasugrel showed lower risk of MACE and ischaemic events without excess in bleeding 6 months post-discharge compared to ticagrelor, consistent with the findings of a previous randomised trial.Temporal use of potent P2Y12 inhibitorsSix-months outcomes of potent P2Y12i

Volume-outcome relationships for intra-aortic balloon pump in acute myocardial infarction

Abstract Background Acute myocardial infarction (MI) is one of the major scenarios of intra-aortic balloon pump (IABP) use, particularly when complicated by cardiogenic shock. The utilization of mechanical circulatory support devices including IABP varies widely per hospital, while whether a higher IABP volume at each hospital is translated into better outcomes in acute MI is unclear. Purpose To evaluate the relationship between the volume of IABP use and mortality at the hospital level in patients with acute MI undergoing percutaneous coronary intervention (PCI). Methods Using a Japanese nationwide administrative database, a total of 26,490 patients with acute MI undergoing primary PCI from 154 hospitals were included. The primary endpoint was the observed/predicted in-hospital mortality ratio. The predicted mortality per patient was calculated using baseline variables and was averaged for each hospital. The associations among PCI volume for acute MI, observed and predicted in-hospital mortality, and observed and predicted IABP use were assessed at the hospital level. Results Of the 26,490 patients, 2,959 (11.2%) were treated with IABP and 1,283 (4.8%) died during hospitalization. The annualized number of IABP use per hospital in acute MI was 4.5 [2.4-10.7]. In lower primary PCI volume centers, IABP was more likely to be underused than expected, and the observed/predicted in-hospital mortality ratio was higher than in higher volume centers (Figure). The observed/predicted mortality ratio seemed lowest in hospitals where the observed/predicted IABP use ratio was around one. Conclusions The present study showed that the lower annual number of IABP use was associated with an increased mortality risk at the hospital level, and suggested that standardized IABP use can be an institutional quality indicator in a setting of acute MI.

Troponin T as a risk marker for recurrent cardiovascular events in the post-discharge setting one month after acute coronary syndrome: a TRACER substudy

Abstract Background Troponin T (TnT) is a protein found in cardiac myocytes that is released during myocardial injury, such as myocardial infarction (MI). TnT levels rapidly rise during an MI, remain elevated for several days, and are a key criterion for diagnosing MI. Additionally, circulating TnT levels may offer prognostic information later, particularly during the rehabilitation phase after an acute coronary syndrome (ACS). Purpose To examine the relationship between circulating TnT at one month after hospitalisation for ACS and subsequent cardiovascular (CV) events. Methods The TRACER trial randomly assigned 12,944 patients diagnosed with non-ST-segment elevation ACS (NSTE-ACS) to receive either vorapaxar or placebo. Plasma samples were obtained after one month, and high-sensitivity (hs)-TnT was measured among 5,313 patients using the Elecsys electrochemiluminescence immunoassays. In this sub-study, the primary composite endpoint was the one-year risk of CV mortality, MI, or ischaemic stroke. Associations with outcomes were evaluated using Cox regression models, both unadjusted and adjusted for clinical baseline characteristics. Results The median concentration of hs-TnT was 11 ng/L one month after hospitalisation for ACS. Higher levels of hs-TnT at one month were associated with older age, coronary artery bypass surgery during the index ACS, male sex, a history of heart failure, renal disease, and diabetes mellitus. The composite outcome of CV mortality, MI, or ischaemic stroke occurred in 381 patients (incidence rate 5.4 per 100 person-years). Hs-TnT at one month after ACS was independently associated with the risk of the composite CV endpoint (relative hazard ratio with 95% confidence interval comparing the third vs. the first sample quartile: 2.40 [1.80 – 3.20]) (see Figure 2). Similarly, hs-TnT, when added to a model including established risk factors, increased the concordance index of the multivariable model from 0.711 to 0.740 (p&amp;lt;0.001). The results were consistent across the different components of the composite endpoint. Conclusions The level of hs-TnT provides useful information on the risk of future CV events in patients when measured one month after an ACS. This information might be useful for optimising secondary preventive treatment following an ACS.Figure.Hs-TnT and composite CV outcome

Older women with non-ST-elevation acute coronary syndrome undergoing invasive or conservative management: an individual patient data meta-analysis.

Women and older patients are underrepresented in randomized controlled trials (RCTs) investigating treatment strategies following acute coronary syndrome. This study aims to evaluate the benefit of invasive vs. conservative strategy of older women with non-ST-elevation acute coronary syndrome (NSTEACS). This analysis from an individual patient data meta-analysis included six RCTs comparing an invasive management with a conservative management in older NSTEACS patients. The primary endpoint was the composite of all-cause mortality or myocardial infarction (MI). Secondary endpoints included all-cause mortality, cardiovascular death, MI, urgent revascularization, and stroke. Follow-up time was censored at 1 year. In total, 717 women [median age 84.0 (interquartile range 81.0-87.0) years] were included. The primary endpoint occurred in 21.0% in the invasive strategy vs. 27.8% in the conservative strategy [hazard ratio (HR) 0.77, 95% confidence interval (CI) 0.52-1.13, P = 0.160 using random effect] at 1-year follow-up. The invasive management was associated with reduced risk of MI (HR 0.49, 95% CI 0.32-0.73, P < 0.001) and urgent revascularization (HR 0.44, 95% CI 0.20-0.98, P = 0.045). No significant differences were identified in the risk of all-cause mortality, cardiovascular death, and stroke. Among males, there was no significant association between the treatment strategy and primary or secondary endpoints. An invasive strategy compared with a conservative strategy did not reduce the composite outcome of all-cause mortality or MI in older NSTEACS women at 1-year follow-up. An invasive strategy reduced the individual risk of MI and urgent revascularization. Our results support the beneficial role of the invasive strategy in older NSTEACS women. This meta-analysis is registered with PROSPERO (CRD42023379819).

Effect of Four Hemoglobin Transfusion Threshold Strategies in Patients With Acute Myocardial Infarction and Anemia : A Target Trial Emulation Using MINT Trial Data.

The optimal hemoglobin threshold to guide red blood cell (RBC) transfusion for patients with acute myocardial infarction (MI) and anemia is uncertain. To estimate the efficacy of 4 individual hemoglobin thresholds (<10 g/dL [<100 g/L], <9 g/dL [<90 g/L], <8 g/dL [<80 g/L], and <7 g/dL [<70 g/L]) to guide transfusion in patients with acute MI and anemia. Prespecified secondary analysis of the MINT (Myocardial Ischemia and Transfusion) trial using target trial emulation methods. (ClinicalTrials.gov: NCT02981407). 144 clinical sites in 6 countries. 3492 MINT trial participants with acute MI and a hemoglobin level below 10 g/dL. Four transfusion strategies to maintain patients' hemoglobin concentrations at or above thresholds of 10, 9, 8, or 7 g/dL. Protocol exceptions were permitted for specified adverse clinical events. Data from the MINT trial were leveraged to emulate 4 transfusion strategies and estimate per protocol effects on the composite outcome of 30-day death or recurrent MI (death/MI) and 30-day death using inverse probability weighting. The 30-day risk for death/MI was 14.8% (95% CI, 11.8% to 18.4%) for a <10-g/dL strategy, 15.1% (CI, 11.7% to 18.2%) for a <9-g/dL strategy, 15.9% (CI, 12.4% to 19.0%) for a <8-g/dL strategy, and 18.3% (CI, 14.6% to 22.0%) for a <7-g/dL strategy. Absolute risk differences and risk ratios relative to the <10-g/dL strategy for 30-day death/MI increased as thresholds decreased, although 95% CIs were wide. Findings were similar and imprecise for 30-day death. Unmeasured confounding may have persisted despite adjustment. The 30-day risks for death/MI and death among patients with acute MI and anemia seem to increase progressively with lower hemoglobin concentration thresholds for transfusion. However, the imprecision around estimates from this target trial analysis precludes definitive conclusions about individual hemoglobin thresholds. National Heart, Lung, and Blood Institute.

Outcome of Saphenous Vein Graft Percutaneous Coronary Intervention Using Contemporary Drug-Eluting Stents: A SCAAR Report

BackgroundPercutaneous coronary intervention (PCI) of saphenous vein grafts (SVG) is associated with poor outcomes and is often regarded as inferior to native vessel PCI. We investigated clinical outcomes of SVG-PCI using contemporary drug-eluting stents (DES), in a complete, nationwide population. MethodsThe complete Swedish Coronary Angiography and Angioplasty Registry (SCAAR) was used to identify all patients in Sweden who underwent SVG-PCI with a contemporary DES between 2013 and 2020. Baseline characteristics, procedures, and outcomes were described. ResultsA total of 2198 SVG-PCI procedures with 3106 contemporary DES were included. Patients had a high incidence of comorbidities such as diabetes (40%), prior myocardial infarction (MI) (69%), and acute coronary syndrome (74%) at presentation. SVG-PCI procedures commonly involved multiple DES (41%). Native vessel PCI, in addition to SVG-PCI, was performed in only 13% of procedures. At 1 year, adverse clinical outcomes were frequent as exemplified by any death (9.2%), MI (9.1%), or revascularization (21.1%), whereas stent and lesion-related outcomes on a patient level were less common: stent thrombosis (1.2%), in-stent restenosis (4.3%) and target lesion revascularization (4.3%). Similarly, at 3 years, clinical outcomes were frequent: death (19.8%), MI (21.1%), revascularization (32.8%); and stent-related outcomes were less common: stent thrombosis (2.9%), restenosis (10.8), and target lesion revascularization (13.6%). ConclusionsIn this nationwide cohort of patients who underwent SVG-PCI with contemporary DES, patients were characterized by a high-risk profile and high rates of adverse clinical events. However, the incidence of stent and lesion-related events was low.

Inhibition of ubiquitin-specific protease 7 ameliorates ferroptosis-mediated myocardial infarction by contrasting oxidative stress: An in vitro and in vivo analysis

BackgroundOur prior research determined that USP7 exacerbates myocardial injury. Additionally, existing studies indicate a strong connection between USP7 and ferroptosis. However, the influence of USP7 on ferroptosis-mediated myocardial infarction (MI) remains unclear. Given these findings, we are particularly interested in USP7's regulatory role in ferroptosis-mediated MI and its underlying mechanisms. MethodsIn this study, we established MI models and lentivirus-transfected groups to inhibit USP7 expression both in vivo and in vitro. Cardiac function was detected with Echocardiography. TTC and HE staining were employed to assess myocardial alterations. The expression of ferroptosis markers (PTGS2, ACSL4, GPX4) were analyzed by RT-qPCR and Western blotting. Flow cytometry and ELISA were used for measuring Fe2+, lipid ROS, GSH, and GSSG levels. TEM and Prussian blue staining were used to observe mitochondrial alterations and iron deposition. RT-qPCR, Western blotting, and immunofluorescence were conducted to analyze Keap1, Nrf2, and nuclear Nrf2 expression in vitro and in vivo. ResultsIn the MI model group, USP7 expression significantly increased, worsening ferroptosis-mediated MI. Conversely, in the USP7-inhibited group, activation of the Keap1-Nrf2 signaling pathway improved ferroptosis-mediated MI outcomes. In vitro, the MI model exhibited a marked decline in cardiomyocyte viability and notable mitochondrial damage. However, these issues improved in the USP7-inhibited groups. In vivo, USP7 intensified MI and iron deposition within the MI model group, with decreased values of LVEF, LVFS, SV, LVAWd, and LVPWs, all of which showed improvement in the USP7-inhibited group, except for LVPWd and LVPWs, which showed no significant variation. Importantly, both the in vitro and in vivo experiments revealed analogous results: a reduction in Keap1 expression and an increase in both Nrf2 and nuclear Nrf2 post USP7 inhibition. Additionally, GPX4 expression decreased while PTGS2 and ACSL4 expressions increased. Notably, concentrations of Fe2+, lipid ROS, GSH, and GSSG significantly decreased. ConclusionIn vitro and in vivo studies have found that inhibition of USP7 attenuates iron deposition and suppresses oxidative stress, resulting in amelioration of ferroptosis-induced MI.

Impact of Immediate Versus Staged Complete Revascularization on Short-Term and Long-Term Clinical Outcomes in Patients With Acute Coronary Syndrome and Multivessel Disease: A Systematic Review and Meta-Analysis.

In patients with acute coronary syndrome (ACS) and multivessel disease (MVD), complete revascularization (CR) improves prognosis. This meta-analysis, summarizing recent RCTs, contrasts short-term and long-term clinical outcomes between immediate complete revascularization (ICR) and staged complete revascularization (SCR). We systematically searched the online database and eight RCTs were involved. The primary outcomes included long-term unplanned ischemia-driven revascularization, re-infarction, combined cardiovascular (CV) death or myocardial infarction (MI), all-cause death, CV death, stroke, and hospitalization for heart failure (HHF). The secondary outcomes were 1-month unplanned ischemia-driven revascularization, re-infarction, all-cause death, and CV death. Safety endpoints included stent thrombosis and major bleeding. Eight RCTs comprising 5198 patients were involved. ICR reduced long-term unplanned ischemia-driven revascularization (RR 0.64, 95% CI 0.51-0.81, p < 0.001), combined CV death or MI (HR 0.51, 95% CI 0.34-0.78, p = 0.002), and re-infarction (RR 0.66,95% CI 0.48 to 0.91, p = 0.012) compared with SCR. ICR also decreased 1-month unplanned ischemia-driven revascularization (RR 0.41, 95% CI: 0.21-0.77, p = 0.006) and re-infarction (RR 0.33, 95% CI:0.15-0.74, p = 0.007) but increased 1-month all-cause death (RR 2.22, 95% CI 1.06-4.65, p = 0.034). In ACS patients with MVD, we first found that ICR significantly lowered the risk of both short-term and long-term unplanned ischemia-driven revascularization and re-infarction, as well as the long-term composite outcome of CV death or MI compared with SCR. However, there may be an increase in 1-month all-cause death in the ICR group.

Abstract We065: Sex Differences in Autoimmune Signatures After Myocardial Infarction in Mice

Introduction: Myocardial infarction (MI) is caused by ischemic injury to the left ventricle (LV), leading to an inflammatory response, scar formation, and loss of LV function. The role of the autoimmune (AI) response during chronic MI, such as B cell activation and autoantibody production, is not well understood. As AI disease is much more prevalent in females, we hypothesized that female mice are more susceptible to MI-induced development of AI signatures. Methods: Permanent MI was induced by left coronary artery ligation in adult male and female C57BL/6J mice for 7, 28, or 56 days. LV function was tracked using echocardiography (VEVO 3100). Cytokines were measured by qPCR. LV IgG and IgM antibody deposition was measured by immunofluorescence. Plasma IgG and IgM were measured by ELISA, and plasma autoantibodies (AABs) (IgG and IgM subclasses) were measured with an autoantigen (AAN) array. Results: In both sexes, MI led to progressive LV hypertrophy, dilation, and wall thinning. MI increased spleen mass in D7, 28, and 56 females, but decreased spleen mass in D28 and 56 males. LV infarct cytokines (IL-1β, IL-6, IL-18, IFN-γ, TNF, CCL2, IL-10) were increased at D7, while IL-6 and IL-18 remained elevated at D28 and 56 to a higher degree in females. Several cytokines in the remote LV were increased in females relative to males, including TNF, IL-6, CCL2, and IL-18. Splenic cytokines were also differentially expressed between sexes, with IL-1β, IL-12a, IL-10, IFN-γ, IL-18, CCL2, and IL-4 increased in females at several time points. Infarct IgG and IgM deposition occurred in both sexes, but to a higher degree in females. Remote IgG and IgM deposition occurred at D56 in both sexes. For plasma AABs, we detected 34 AANs against which IgG AABs were significantly elevated (p&lt;0.05) at D56 in females vs 9 in males, and 30 IgM AABs vs 1 in males. Of note, anti-IL-6 IgM AABs were elevated in D56 females (9.8±0.8-fold), likely due to persistently elevated IL-6 in the female infarct and remote LV vs males. Total levels of plasma IgM were increased only in females at D56 (1.79±0.15-fold). Conclusions: MI promotes development of AI signatures which is exacerbated in females, including increased spleen mass, LV and splenic cytokines, LV infarct and remote IgG and IgM antibody deposition, increased plasma IgG and IgM AABs, and increased total levels of plasma IgM. Targeting the AI response may be a viable option for treating chronic MI outcomes, particularly in females.

Abstract We060: Hypoxia Inducible Factor-2α Enhances Neutrophil Survival and Promotes Cardiac Injury Following Myocardial Infarction via cIAP-1 Signaling

Rationale: Heart failure is a major cause of mortality following myocardial infarction (MI). Neutrophils (PMNs) are among the first immune cells to accumulate in the infarcted region. While some long-term beneficial functions of PMN in heart injury are now appreciated, en mase PMN accumulation in injured hearts is still associated with worsened resolution of inflammation and disease outcomes. MI causes extensive hypoxic injury to heart tissue, where hypoxia-inducible factors (HIFs) play critical roles in cellular functions. While HIF1α regulation of cell survival, migration and metabolism have been well-studied, the role of HIF-2α in these processes is not well-understood. Even less is known of HIF-2α contributions to PMN effector functions, especially in the context of MI. Objectives: The current study aimed to 1. Mechanistically explore how HIF-2α regulates survival of tissue infiltrating PMNs post-MI and 2. Determine how HIF-2α activity in PMNs impacts heart injury resolution post-MI, and whether specific HIF-2α deletion in PMNs can alleviate MI-induced tissue injury. Methods &amp; Results: Infarct size, cardiac functions monitored by echocardiography, and scar tissue formation after left anterior descending coronary ligation injury model were compared between littermate control and specific PMN HIF-2α depletion (Ly6G-cre +/- HIF-2α fl/fl ) mice. Myocardial infarction size, cardiac dysfunction, scare tissue deposit and survival of tissue infiltrating PMNs post-MI were substantially attenuated in mice with PMN HIF-2α deletion. A significantly reduced lifespan of HIF-2α knockout PMNs was further confirmed by fate-mapping EdU pulse chase experiments. Mechanistically, molecular studies revealed that HIF-2α transcriptionally regulates expression of the pro-survival factor cIAP1 in PMNs binding to an HRE located in the promoter region of BIRC2 , in a hypoxia-inducible manner. Ex-vivo pharmacological inhibition of cIAP1 expression in PMNs using Birinapant resulted in dramatic cell death, establishing the critical role of cIAP1 in PMN survival. Finally, our data demonstrate that the protective effect of HIF-2α deletion in PMNs on MI outcomes was due to elevated recruitment of reparative macrophages into infarcted hearts. Conclusion: HIF-2α, through cIAP1 regulation, promotes PMN survival and tissue retention post-MI, leading to worsen cardiac functions and scar formation.