Infarction Mortality Research Articles

Protective mechanisms of betablockers for coronary artery disease are by distal vasoconstriction and slower speed: a study by angiographic assessment and artificial intelligence program

Abstract Background Patients with coronary artery disease (CAD) were protected with betablockers (BB) for lower mortality and lower rate of new myocardial infarction. What are the protective mechanisms? In prior studies, our hypothesis was that damage to the intima of the coronary arteries was caused by cavitation or rupture of bubbles which was seen frequently in industrial pipes. The bubbles ruptured when they flew in areas of different pressures among the layers and segments of the coronary flows. How did BB change the dynamic of coronary flow? Methods After percutaneous coronary interventions (PCI) patients were started on BB. Later, when there was indication, the patient underwent another angiogram. The diameter of the distal LAD was measured and compared between the two angiograms. The distance reached the coronary flow after 0.6seconds was calculated in both angiograms and compared. In the reviewing protocol, the coronary angiograms were done with the contrast injected until the index coronary artery was completely opacified. As the injection of contrast stopped, the blood in white color moved in and displaced the contrast in black color. The morphologies, movements, directions, and interactions of the blood flow in white color above a black background were reviewed frame by frame by investigators analyzing flow dynamics. At the same time, the artificial intelligence (AI) program has 2 models (build on Python), The model 1 was built based on U-net and Densenet-121 for vessel segmentation. Model 2 was used for classification of stagnant flow or normal, the model 2 was trained based on the convolutional neural network with the dataset selected from model 1 results. Results In total, 50 patients were included with a total of 50 pairs of angiograms. In 80% patients, the diameter of the distal segment of the LAD was 20% smaller in BB compared with before BB (p≤0.05). In 75%, the speed of the coronary after BB was lower (p<0.05), A lower speed guaranteed laminar flow and less chance for cavitation. The above data was confirmed by the AI programs. Conclusion BB improved the coronary flow by decreasing the diameter of the arteries so decreased the turbulent flow and promoted laminar flow. BB also decreased the speed of the flow so decreased the chance for cavitation. Both decreased the possibility of ACS. Funding Acknowledgement Type of funding sources: None. Artery with centerlineMeasuring the diameter of the artery by

Contemporary in-hospital and long-term prognosis of patients with acute ST-elevation myocardial infarction and chronic kidney disease in Germany

Abstract Background Although acute myocardial infarction (AMI) incidence and mortality have decreased over the last decades, survival rates of AMI patients remain rather stable. About 25% of patients with ST-elevation myocardial infarction (STEMI) suffer from chronic kidney disease (CKD). Purpose We sought to determine short- and long-term mortality in STEMI patients with different stages of CKD. Methods We identified all patients who were hospitalised with a main diagnosis of STEMI between 2010 and 2017 from the dataset of the Federal Association of the Local Health Insurance Funds (Allgemeine Ortskasse), Germany. The patients were grouped according to their CKD stage at index hospitalisation. We analysed concomitant diseases, in-hospital treatment and complications. Overall survival was analysed using Kaplan Meier methods and predictors for overall survival were identified by Cox regression analysis. Results A total of 175,187 patients were identified with an index hospitalisation for STEMI, thereof 137,682 (78.6%) patients without CKD, 8,347 (4.8%) patients with CKD stage 2, 20,459 (11.7%) patients with CKD stage 3, and 4,960 (2.8%) patients with CKD stage 4. The CKD stages 1, 5 and 5d (dialysis dependent CKD) each comprised less than 1,500 patients (<1.0%). STEMI patients with CKD were older and had more often cardiovascular risk factors, e.g. diabetes (no CKD: 33.2% vs CKD stage 5: 66.1%, p<0.001). Overall, patients with CKD received percutaneous coronary interventions (no CKD: 84.4% vs CKD stage 4: 62.0%, p<0.001) less frequently, and suffered more often from complications like shock (no CKD: 12.5% vs. CKD stage 5: 27.7%, p<0.001) or requirement of invasive/non-invasive ventilation (no CKD: 17.3% vs. CKD stage 5: 42.7%, p<0.001) than patients without CKD. With increasing CKD stages, patients were more likely to die within 30 days after STEMI (30-day mortality no CKD: 13.7% vs. CKD stage 5d: 37.2%, p<0.001). Kaplan-Meier estimates showed dramatically decreasing survival with decreasing renal function (Figure 1). Multivariable time-dependent Cox regression analysis for overall survival showed that the CKD stages 4, 5 and 5d, as well as chronic limb threatening ischemia (CLTI) were associated with a higher risk for death (CKD stage 5d: hazard ratio (HR) 5.64; 95% CI 5.42–5.86; CKD stage 5: HR 2.55; 95% CI 2.37–2.73; CKD stage 4: 1.72; 95% CI 1.66–1.78; CLTI: 2.06; 95% CI 1.98–2.13; all p<0.001). Conclusion CKD is a frequent co-morbidity in patients with STEMI which is associated with a devastating prognosis especially for patients with advanced CKD stages. More research is needed to gain evidence on optimized treatment strategies for patients with STEMI and concomitant CKD in this highly vulnerable cohort. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): The project upon which this publication is based was funded by The Federal Joint Committee, Innovation Committee (G-BA, Innovationsfonds, number 01VSF18051). Figure 1. Unadjusted Kaplan-Meier survival curves

Single antiplatelet therapy versus dual antiplatelet therapy after transcatheter aortic valve replacement: a meta-analysis of randomized controlled trials

Abstract Background The performance of transcatheter aortic valve replacement (TAVR) has expanded considerably during the past decade. Technological advances and refinement in implantation techniques have resulted in improved procedural outcomes, whereas indications are progressively extending toward lower-risk patients. Ischemic/embolic complications and major bleeding remain important and strongly correlate to mortality. In this regard, the optimal antithrombotic regimen after successful transcatheter aortic valve replacement remains unclear. Purpose To compare the efficacy and safety of single antiplatelet therapy (SAPT) versus dual antiplatelet therapy (DAPT) for post Transcatheter Aortic Valve Replacement. Search strategy Key Terms: transcatheter aortic valve replacement, transcatheter aortic valve implantation, antiplatelet, single antiplatelet therapy, dual antiplatelet therapy. Selection criteria Four randomized, controlled clinical trials comparing single antiplatelet therapy versus dual antiplatelet therapy for post TAVR patients were included in this study. Method Extensive search of PubMed, Medline, Cochrane and Ovid was done for articles published until November 20, 2020. Studies were limited to RCTs comparing SAPT and DAPT among patients who underwent TAVR. Outcome measures include: stroke, myocardial infarction, all-cause mortality and major bleeding. Two reviewers independently reviewed the studies. Results were gathered from published articles, journals and clinical trials. Studies were critically appraised with regards to methods of minimizing bias. All four studies included received a quality scale for meta-analysis overall score of not less than B. Statistical analysis was done using Review manager V5.4. Main results Four RCTs with 1086 patients were included in this meta-analysis. Overall, the risk of stroke (OR 0.94 [0.54 −1.64]), myocardial infarction (OR 0.50 [0.18–1.40]), and overall mortality (OR 1.01 [0.65–1.57]) did not differ significantly between DAPT and SAPT. There was noted increased risk of bleeding noted with DAPT, thus favoring SAPT (OR 0.44 [0.30–0.65]). Author's conclusions Among patients who underwent TAVR, DAPT compared to SAPT had similar rates of stroke, myocardial infarction and death. Due to lower rates of bleeding, we recommend using single antiplatelet therapy after TAVR. Funding Acknowledgement Type of funding sources: None.

Association between off-hours admission with acute myocardial infarction and in-hospital mortality

Abstract Background The effect of time of admission on clinical outcomes in patients with acute myocardial infarction (AMI) is still a matter of debate. Purpose To investigate the association between off-hours admission and in-hospital mortality in patients with ST-elevation myocardial infarction (STEMI) and non-STEMI (NSTEMI). Methods We used a two-stage, random sampling method to create a nationally representative sample of patients with AMI in 167 Chinese hospitals in four years (2001, 2006, 2011, and 2015). Off-hours were defined as 20:00–07:59 and on-hours as 08:00–19:59. We used hierarchical logistic regression model to examine whether off-hour admissions were associated with in-hospital mortality and 7-day mortality. Inverse-probability weighting propensity score analysis was also conducted to assess the robustness of the results. Results We identified 25654 patients admitted with AMI (median age 67.0 years; 31.6% women), of whom 20133 (78.5%) were diagnosed as STEMI and 5521 (21.5%) as NSTEMI. There were 5368 (26.7%) admissions for STEMI, and 1356 (24.6%) for NSTEMI occurring during off-hours, respectively. After adjusting for case mix, year of admission, comorbidities, clinical presentation, and in-hospital treatments, a significant association was observed between off-hours admissions and in-hospital mortality among the patients with STEMI (adjusted OR 1.14; 95% CI 1.01 to 1.28). The magnitude of the association became greater in the secondary analysis with 7-day mortality as the outcome (adjusted OR 1.16; 95% CI 1.02 to 1.31). But among patients with NSTEMI, no significant association was observed for in-hospital and 7-day mortality. Propensity score analysis showed similar results to hierarchical logistic model for both outcomes in patients with STEMI and NSTEMI. Conclusion Off-hours admission with STEMI is associated with higher in-hospital mortality. Reducing the disparity of care of STEMI by the time of admission represents a potential opportunity for quality improvement in China. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): National Key Research and Development Program (2017YFC1310803, 2017YFC1310801) from the Ministry of Science and Technology of China

Impacts of Residual SNYTAX Score on The Clinical Outcomes following Percutaneous Coronary Intervention in Chronic Coronary Syndrome Patients

Background: The residual SYNTAX score (RSS) can be used to measure the residual stenosis severity and complexity. The prognostic role of RSS in CCS patients is still unknown. We purposed to investigate the impact of RSS on the clinical outcomes following PCI in CCS patients. Methods: A prospective cohort study was performed. Based on the residual SYNTAX score, patients were divided into three groups: RSS 0, RSS 0 to 9.5, and RSS >9.5. The primary outcome was patient-oriented composite endpoint (POCE), including repeat revascularization, myocardial infarction, and all-cause mortality. Results: After 1-year follow-up period, patients in RSS >9.5 group revealed the greater POCE (4.3% vs. 6.4% vs. 23.9%; p = 0.016) than others. The repeat revascularization rate also was greater in the RSS >9.5 group (0.0% vs. 6.4% vs. 19.6%; p = 0.012). However, the hospitalization due to angina rates in all groups was not significantly different (4.3% vs. 4.2% vs. 4.3%; p = 1.000). The multivariate analysis revealed that RSS >9.5 was the strong predictor for repeat revascularization during 1 year follow-up (Odds ratio [OR] = 9.605; 95% confidence interval [CI] = 1.207 - 76.458; p = 0.033). Conclusion: The greater RSS was associated with the higher 1-year POCE and repeat revascularization rate in CCS patients. The high RSS was also the strong predictor for 1-year repeat revascularization for CCS patients.

1134-P: Polygenic Risk Score of Type 2 Diabetes as a Predictive Factor for Macrovascular Complications: A Prospective Population-Based UK Biobank Study

Background: We aimed to investigate the associations between polygenic risk score (PRS) for T2DM and future risk of cardiovascular disease (CVD) in middle-aged UK Biobank participants of European ancestry. Methods: We used data from UK Biobank participants aged 40-69 years at baseline, registered from 22 assessment centers across the United Kingdom with standardized procedures. Genome-wide PRSs were constructed using >9 million genetic variants, and newly developed myocardial infarction (MI), ischemic stroke, and cardiovascular (CV) mortality were considered as outcomes. Cox proportional hazard models were used to analyze the relationship between PRSs and CV mortality with stratification by age, sex, and lifestyle behavior. Results: Of 362,405 participants having European ancestry, 8,787 (2.4%) experienced cardiovascular events and 2,414 (0.7%) died due to CVD during a median follow-up of 8.9 years. Risk of CV mortality and of myocardial infarction (MI) were both significantly associated with T2DM PRS (low vs. very high T2DM genetic risk groups, hazard ratio [HR] of CV mortality 1.73 [1.23-2.44] and HR of MI 1.55 [1.24-1.96], P <0.001). By contrast, the risk of ischemic stroke was not associated with T2DM PRS (low vs. very high T2DM genetic risk groups, hazard ratio [HR] of CV mortality 1.24 [0.87-1.79], P =0.232). Adherence to an unfavorable lifestyle in the very high genetic risk group was further associated with a substantially increased risk of CV mortality (HR 6.38 [3.46-11.77]) and with risk of MI (HR 3.28 [2.02-5.32]). There was no evidence of significant interaction between PRS and lifestyle behavior in predicting the risk of CVD. Conclusion: PRS for T2DM is an independent predictive factor for future CVD and associated mortality in the white, middle-aged population. PRS-based genetic risk assessment could be useful to identify individuals who need intensive behavioral or therapeutic interventions to reduce the risk of CVD. Disclosure S. Jung: None. D. Kim: None. M. Shivakumar: None. H. Won: None. J. Yun: None.

MO114NEPHROLITHIASIS AS CAUSE OF KIDNEY FAILURE AND MAJOR CARDIOVASCULAR OUTCOMES IN INCIDENT DIALYSIS PATIENTS

Abstract Background and Aims Symptomatic kidney stone formers experience excess rates of cardiovascular events and are at increased risk of chronic kidney disease and its progression. Little is known about the cardiovascular outcomes of persons with kidney failure in whom nephrolithiasis or urolithiasis was listed as their presumed cause of kidney failure. Method We used the United States Renal Data Service (USRDS), a national kidney failure registry, to identify all persons initiating dialysis between 1/1/1996 and 9/30/2015. Patients were required to have Medicare fee-for-service coverage on day 90 of dialysis, which served as index date. The presumed cause of kidney failure was abstracted from information reported on the Medical Evidence Report (form CMS-2728) and categorized as: nephro-/urolithiasis, diabetes, hypertension, glomerulonephritis, cystic kidney disease, other urologic cause, and other cause. Eligible patients were then followed for the occurrence of a major adverse cardiovascular event (MACE; nonfatal myocardial infarction, nonfatal stroke, or cardiovascular mortality) using claims-based algorithms and causes of death reported in the Death Notification (form CMS-2746). Multivariable Cox regression models were fit while controlling for incident year, sociodemographic characteristics, initial dialysis modality, reported comorbidities and disabilities, biometric data (body mass index [BMI], eGFR, serum albumin, hemoglobin). Multiple imputation was used for missing data. Both cause-specific and Fine-Gray sub-distribution hazard ratios (HR) with corresponding 95% confidence intervals (CI) were estimated. Results Of 2,000,072 persons with incident kidney failure, 1,048,006 (52.4%) were alive and satisfied all inclusion criteria on day 90 (71.9% of the excluded due had no Medicare coverage). Among those, 2207 (0.2%) had nephro-/urolithiasis as cause of kidney failure, while 47% had diabetes, 30.4% had hypertension, 8.1% had GN, and 1.6% had cystic kidney disease listed. Persons with nephro-/urolithiasis tended to be older, more likely to be female and non-Hispanic white, had lower rates of most comorbidities, higher serum albumin and hemoglobin concentrations and lower BMI and eGFR at dialysis initiation. The composite cardiovascular event rate (MI, stroke, cardiovascular death; 721 events) was 74.4/1000 person years for nephro-/urolithiasis. Compared with those whose cause was nephro-/urolithiasis, persons whose cause of kidney failure was listed as diabetes had fully adjusted 57% (95% CI, 46%-69%) higher hazards of MACE and those in whom it was attributed to hypertension the hazards were 33% (95% CI, 24%-44%) higher. While no difference in the hazards of MACE was observed compared with persons with glomerulonephritis (HR 0.97; 95% CI, 0.90-1.05), those with cystic kidney disease had a 14% (95% CI, 7%-20%) lower hazards of MACE than those with nephro-/urolithiasis. Qualitatively similar results were obtained when examining the individual components of MACE as well as when considering kidney transplant and non-cardiovascular death as competing risks. However, competing risk analysis substantially attenuated the magnitude of the associations with diabetes and hypertension as reported cause of kidney failure. Limitations include heterogeneity of the underlying pathology among patients with nephro-/urolithiasis as well as the possibility that some patients with nephro-/urolithiasis were not captured if a different cause of kidney disease was listed. Conclusion Patients with kidney failure presumably from nephro- or urolithiasis have distinct cardiovascular risk profiles, with lower major cardiovascular event rates compared with patients whose kidney failure was due to diabetes or hypertension, but slightly higher rates compared with those with cystic kidney disease.

Abstract 65: Targeted Drug Delivery via Acid-Triggered Release Antioxidant Nanoparticles Improves Efficacy of Na1 for Stroke Treatment

Introduction: Recently, NA1, a peptide designed to protect neurons against NMDA receptor-mediated excitotoxicity, demonstrated promise for acute stroke treatment. Enhanced efficiency of peptide delivery may result in improved efficacy. Hypothesis: The bioactive fragment of NA1 is nine amino acids of the carboxyl tail of GluN2B. Delivery of NR2B9c to cells in the brain is achieved through fusion with TAT, a peptide that binds to biological membranes without selectivity. We hypothesize that enhancing targeted delivery of NA1 to the ischemic brain improve the efficacy of NA1. Methods: We previously identified betulinic acid (BA) forming nanoparticles (NPs) as a novel formulation of stroke treatment delivery. After intravenous administration, BA NP penetrate the ischemic brain, reduce ischemia-induced infarction as an antioxidant agent, and allow for encapsulation and delivery of drugs. In this study, we engineered BA NPs for improved drug delivery preferentially to the ischemic brain through surface conjugation of AMD3100, and for acid-triggered drug release to selectively in the ischemic region, which is known to be acidic, through chemical modification. The resulting acid responsive, stroke- targeting antioxidant NPs, or ARSTA NPs, were evaluated for stroke treatment in the mouse transient middle cerebral artery occlusion (MCAO) model either alone or in combination with NA1, based on changes of infarct volumes, edema, mortality, and outcomes. Results: We found that ARSTA NPs enabled targeted delivery of NA1 preferentially to the ischemic brain and allowed for prompt drug release. We showed that intravenous delivery of 50 ug NA1 (or 1nM/g) encapsulated in 1 mg ARSTAs effectively reduced infarct volumes by 69.8%, edema by 60.3%, mortality (median survival >14 days). In contrast, delivery of ARSTA NPs alone (52.2%, 30.2%, 10) or NA1 (0.7%, 3.3%, 6 days) alone at a comparable dose exhibited significantly less efficacy. Consistently, treatment with NA1-loaded ARSTAs improved neurological outcomes in a degree significantly greater than that by either ARSTA NPs or NA1 alone. Conclusion: BA-NP encapsulating NA-1 may represent a novel platform for improved delivery to the ischemic brain. Improved delivery may result in improved efficacy.

Abstract P757: Social Isolation After Stroke Reduces Cell Proliferation and Alters Brain MiRNA Profiles in the Aged Female Mice

Background: Social isolation (SI) and loneliness are risk factors for stroke. Epidemiological studies have shown that women tend to have a higher risk of stroke at later age and elderly women are more likely to be isolated. The mechanisms underlying the detrimental effects of SI have not been well studied in older females. We hypothesized that SI in aged female mice would lead to impaired post-stroke recovery and could lead to differential regulation of microRNAs (miRNAs). Methods: In this study, aged C57BL/6N female mice were subjected to a 60-minute middle cerebral artery occlusion (MCAO) and were randomly assigned to either single housing (SI) or continued pair housing (PH) immediately after stroke for 15 days. Infarct size, mortality and recovery was assessed using open field, the adhesive-tape removal task and the Y-maze test. MiRNAs were comprehensively analyzed by miRNAome analysis on stroke brain, and changes in hippocampal cell proliferation was assessed from perfused brain sections. Results: Importantly, SI immediately after stroke led to significantly larger tissue loss and higher mortality in aged females, it also significantly delayed motor/sensory recovery in the adhesive removal test and impaired overall locomotor activity. In addition, these mice also demonstrated worse post-stroke cognitive function. In parallel, brains of these mice showed reduced miR-297a-3p expression and increased miR-18a-3p and miR-200c-3p expression with SI compared to PH cohort and reduced hippocampal cell proliferation. Conclusion: The results from this study suggest that SI after stroke can increase mortality and significantly impair post-stroke recovery in aged female mice. These worse outcomes are in parallel to the significant changes in several miRNAs and reduced hippocampal cell proliferation.

Effects of angiotensin II receptor blockers on serum levels of epoxyeicosatrienoic acids and dihydroxyeicosatrienoic acids in patients admitted to a cardiovascular center

PurposeSeveral clinical studies have demonstrated that angiotensin-converting enzyme inhibitors, but not angiotensin II receptor blockers (ARBs), reduce the risk of non-fatal myocardial infarction and cardiovascular mortality. We found that ARBs inhibited the activity of various cytochrome enzymes in arachidonic acid metabolism, resulting in decreased in vitro production of epoxyeicosatrienoic acids (EETs), which exhibit vasodilation and anti-inflammatory effects, and their subsequent metabolites, dihydroxyeicosatrienoic acids (DHETs). The present study examined the effects of ARBs on serum levels of EETs and DHETs in patients admitted to a cardiovascular center.MethodsA total of 223 patients were enrolled, of which 107 were exposed to ARBs in this study. ARB-free individuals were defined as the control group (n = 116). Serum levels of EETs and DHETs were measured by liquid chromatography–tandem mass spectrometry. Multiple linear regression analyses were carried out to identify covariates for total serum levels of EETs and DHETs.ResultsA significant negative association was observed between ARB use and serum EET and DHET levels (p = 0.034), whereas a significant positive association was observed between the estimated glomerular filtration rate (eGFR) and serum EET and DHET levels (p = 0.007). The median serum total EET and DHET level in the ARB group tended to become lower than that in the control group, although the difference was not significant.ConclusionARB use and eGFR were significantly associated with total serum levels of EETs and DHETs. Our results suggest that ARBs could affect the concentration of EETs in vivo.

Epidemiological trends in mortality, event rates and case fatality of acute myocardial infarction from 2004 to 2015: results from the KORA MI registry

Aim This study examines epidemiological trends of acute myocardial infarction (AMI) in Germany from 2004–2015 across different age groups, using data of the population-based KORA myocardial infarction registry. Methods Annual age-standardised, age-group- and sex-specific mortality and event rates (incident and recurrent) per 100,000 population as well as 28-day case fatality were calculated from all registered cases of AMI and coronary heart disease deaths in 25–74-year-olds from 2004–2015 and 75–84-year-olds from 2009–2015. Average annual percentage changes (AAPC) were calculated by joinpoint regression. Results Mortality rates declined considerably among the elderly (75–84 years), in men by –6.0% annually, due to declines of case fatality by –3.0% and incidence rate by 3.4% and in women by –10.0%, driven by declines in incidence (–9.1%) and recurrence rate (–4.9%). Significant mortality declines also occurred in males, 65–74 years of age (AAPC –3.8%). Among the age groups 25–54 years and 55–64 years, there was no substantial decline in mortality, event rates or case fatality except for a decline of incidence rate in 55–64-year-old men (AAPC –1.8%). Conclusion Inhomogeneous AMI trends across age-groups indicate progress in prevention and treatment for the population >64 years, while among <55-year-olds, we found no significant trend in AMI morbidity and mortality. KEY MESSAGES Age standardised AMI mortality continued to decline from 2009 to 2015 in the study region. Declines in AMI mortality were driven by declines in event rates (both incidence and recurrence rates) and case fatality. AMI trends were inconsistent across different age groups with the strongest declines in mortality and event rates among the elderly population (75–84 years of age).

Improving prediction of one-year mortality of acute myocardial infarction using machine learning techniques

Improving prediction of one-year mortality of acute myocardial infarction using machine learning techniques

91 Overlapping effects of MI-R-21 inhibition and oral anti-fibrotic and anti-inflammatory drugs: rationale for drug repurposing to relieve ischemia/reperfusion injury

Abstract Aims Reperfusion strategies have reduced the mortality of ST-segment elevation myocardial infarction (STEMI), but ischemia/reperfusion (I/R) injury still represents an important issue, and the prevalence of heart failure (HF) after STEMI is raising. Intracoronary infusion of miR-21 inhibitors after reperfusion has been reported to reduce cardiac fibrosis and hypertrophy and improve cardiac function in pigs. Possible drawbacks of miR-21 inhibitors are their high costs and the need for intracoronary administration. Oral drugs with anti-fibrotic or anti-inflammatory actions could have similar effects on protein expression than miR-21 inhibition. We examined the 2 drugs approved for idiopathic pulmonary fibrosis (nintedanib and pirfenidone) and colchicine, which is being evaluated for the prevention of adverse ventricular remodelling after STEMI (NCT03156816). Methods and results We identified the regulatory profile of miR-21 (588 target genes). Only 99 of these interactions were supported by robust experimental data (i.e., information from reporter gene assays), and were then considered for further examination. The biological significance of these 99 targets was evaluated through over-representation analysis, and 13 genes were identified as potentially related to cardiovascular diseases. We retrieved all known targets and main downstream interactions of nintedanib, pirfenidone and colchicine (source: www.drugbank.ca). We cross-validated these datasets by using neural network analyses to search for protein-protein interactions, focusing on those shared by miR-21 inhibition and each one of the 3 drugs. Nintedanib and miR-21 inhibition shared many targets, which could indicate overlapping mechanisms of action. The proto-oncogene SRC, which participates in gene transcription, immune response, apoptosis and migration, emerged as the leading signaling effector. By blocking SRC expression and many downstream effectors of SRC, as well as platelet derived growth factor, nintedanib could decreased miR-21 expression. The molecular effects of nintedanib include an inhibition of inflammation, fibrosis and angiogenesis, and then ultimately a relief from I/R injury, in a similar fashion than anti-miR-21. Contrary to nintedanib, no overlap between the effects of pirfenidone and miR-21 inhibition was found. Conversely, colchicine seems to determine an indirect blockade of the important pro-inflammatory signaling pathway AKT/NFKB, similarly to miR-21 inhibition. Colchicine has also been proposed to inhibit SRC, but few published data are available. Conclusion miR-21 inhibition is emerging as a potential treatment for I/R cardiac injury, but its applicability in clinical practice is burdened by several limitations. Drug repurposing could aid this situation by mimicking the molecular activity of miR-21 inhibition. Through a bioinformatic approach, we found that nintedanib could exert beneficial effects similar to those reported for miR-21 inhibition, with a lower degree of overlap between the effects of colchicine and anti-miR-21. If confirmed by experimental evidence, nintedanib or colchicine could enter the stage of clinical trials to assess their efficacy as cardioprotective therapies in human patients with STEMI.

Abstract 13154: Cardiovascular Risk in Users of Mirabegron Relative to Users of Antimuscarinic Treatments for Overactive Bladder: Findings From a Non-interventional, Real-world Data Safety Study

Introduction: During clinical trials, mirabegron, a β3-adrenoreceptor agonist, was associated with increased heart rate and systolic/diastolic blood pressure vs placebo in patients with overactive bladder (OAB). We studied the association between mirabegron and cardiovascular (CV) outcomes in an observational post-marketing safety study using real-world data. Methods: The study population was identified within five data sources: Danish and Swedish National Registers, Clinical Practice Research Datalink (UK), Optum (US), and Humana (US). Episodes of time when patients were new users of mirabegron or antimuscarinic medications (AMs) from 2012 to 2018 were sourced from prescription/dispensing information and matched on propensity scores. Major adverse CV events (MACE), acute myocardial infarction (AMI), stroke, and CV and all-cause mortality were identified from register linkage or validated through medical record review or physician questionnaires. Incidence rates of these outcomes during person-time of current use were estimated along with hazard ratios (HRs) from Cox models. Results: In total, 152,026 mirabegron episodes were matched to an equal number of AM episodes. The study population was 63.2% female and 72.6% were ≥65 years old. Baseline CV risk factors were similar between matched groups. There were no appreciable differences in the incidence rates of MACE, AMI, and stroke among current users of mirabegron relative to AMs (Table). The incidence rates of CV mortality (HR: 0.83, 95% confidence interval [CI]: 0.73, 0.95) and all-cause mortality (HR: 0.80, CI: 0.76, 0.84) were no higher with mirabegron vs AMs. Results restricted to episodes at high risk for CV events or stratified by age (&lt;65, ≥65 years) or prior OAB medication use were consistent with overall findings. Conclusions: This large, multinational study found no higher risk of MACE, AMI, stroke, or CV or all-cause mortality among current users of mirabegron relative to users of AMs.

Abstract 12682: Accuracy of Expert Electrocardiography versus ST-Segment Elevation Myocardial Infarction Criteria for Diagnosis of Acute Coronary Occlusion Myocardial Infarction

Introduction: In the current STEMI paradigm of Acute Myocardial Infarction (AMI), many NonSTEMI patients have unrecognized acute coronary occlusion. Such patients do not receive emergent reperfusion and are known to have higher mortality than NSTEMI patients without occlusion. Thus, we have proposed a new Occlusion MI vs. Non-Occlusion MI (OMI vs. NOMI) paradigm. We sought to compare the diagnostic accuracy for OMI of blinded expert ECG interpretation vs. STEMI criteria advocated in the fourth Universal Definition of MI. We hypothesized that blinded expert ECG interpretation would be more accurate than STEMI criteria for the diagnosis of OMI, and that STEMI(-) OMI patients would have similar characteristics to STEMI(+) OMI but greater delays to cardiac catheterization. Methods: Retrospective case-control study of patients with suspected acute coronary syndrome, collecting demographics, laboratory results, ECGs, angiographic data, and outcomes. The primary definition of OMI was defined as either 1) acute TIMI 0-2 flow culprit or 2) TIMI 3 flow culprit with peak troponin T &gt;1.0 ng/mL or troponin I &gt;10.0 ng/mL. Results: 808 patients were included, of whom 49% had AMI (33% OMI; 16% NOMI). Sensitivity, specificity, and accuracy of STEMI criteria vs Expert 1 for OMI among all 808 patients were 41% vs 86%, 94% vs 91%, and 77% vs 89%, and for Expert 2 among 250 patients were 36% vs 80%, 91% vs 92%, and 76% vs 89%. When experts outperformed STEMI criteria (55% of OMI), they diagnosed OMI a median of 1.5 hours earlier than STEMI criteria. Seven key ECG findings were identified by experts as important signs of OMI in STEMI(-) cases. STEMI(-) OMI patients had similar infarct size and mortality as STEMI(+) OMI patients, but greater delays to angiography. Conclusions: Blinded expert ECG interpretation was superior to STEMI criteria for the ECG diagnosis of Occlusion MI. STEMI(-) OMI patients had greater delays to catheterization but similar outcomes to STEMI(+) OMI patients. These data support the OMI vs. NOMI paradigm and suggest that STEMI(-) OMI patients could be identified rapidly and noninvasively for emergent reperfusion using expert ECG interpretation.

Abstract 15440: Bleeding Complications May Outweigh the Risk of Thrombosis in Patients With End-stage Liver Disease Taking Dual Antiplatelet Therapy After Percutaneous Coronary Intervention

Introduction: Randomized trials have demonstrated the safety and efficacy of one month of dual antiplatelet therapy (DAPT) after placement of drug-eluting stents in patients with high bleeding risk. Patients with end-stage liver disease (ESLD) are underrepresented in these trials. Patients who undergo percutaneous coronary intervention (PCI) in preparation for orthotopic liver transplantation (OLT) exhibit a high incidence of bleeding complications on DAPT. The rates of bleeding versus thrombotic complications in ESLD patients placed on DAPT following PCI are poorly described. Methods: We retrospectively collected data from 61 patients who were evaluated for OLT between 2016 and 2019 and underwent PCI prior to listing. Bleeding events were classified using the Bleeding Academic Research Consortium (BARC) definitions and included if the following criteria were met: events occurred in the setting of DAPT, were non-procedural in etiology, and occurred during the time following PCI and prior to OLT. Ischemic complications were evaluated by the incidence of myocardial infarction (MI), stent thrombosis, in-stent restenosis (&gt;50%) and all-cause mortality at 1 year follow-up. Results: A total of 55/61 patients (90%) were placed on DAPT following PCI. Among them, 21/55 patients (38%) bled while taking DAPT, including 15 patients (27%) with BARC types 3-5 first-time bleeding events and 10 patients (18%) requiring early discontinuation of therapy. The median time to first bleeding event was 8 days (range 1 to 477 days, 85 th percentile 17 days). Among ischemic complications, MI occurred in 11/55 patients (20%) however only one patient had a type 1 MI with the remaining being type 2 in etiology. There were no episodes of stent thrombosis and 2 episodes of in-stent restenosis during the 1 year follow-up. A total of 12/55 patients (22%) went on to receive OLT and 18/55 (33%) passed away by 1 year post-PCI. Conclusions: Patients with ESLD exhibit a high rate of clinically significant bleeding on DAPT when compared to overall thrombotic events. The majority of bleeds occurred within the first month after PCI. These findings illustrate the need for larger studies to assess the safety of single instead of dual antiplatelet therapy in patients with ESLD who receive PCI.

Abstract 13173: Unusual Fatigue and Failure to Utilize Emergency Medical Services Are Associated With Prolonged Prehospital Delay for Suspected Acute Coronary Syndrome

Introduction: Rapid reperfusion reduces infarct size and mortality for acute coronary syndrome (ACS) but efficacy is time dependent. Time to presentation in the Emergency Department (ED) remains excessive and patient-controlled prehospital delay may be a modifiable variable for intervention. The aim of the study was to determine if transportation factors and clinical presentation predicted prehospital delay for suspected ACS stratified by final diagnosis (ACS vs. no ACS). Hypothesis: Symptoms other than chest pain would contribute to longer prehospital delay that would vary by final diagnosis. Methods: Secondary analysis of data collected from a multi-center prospective study. A heterogeneous sample of ED patients with symptoms suggestive of ACS were enrolled at five sites in the US. Accelerated failure time (AFT) models were used to specify a direct relationship between delay time and variables to predict prehospital delay by final diagnosis. Results: The sample of 975 adults included 609 (62.5%) men and 366 (37.5%) women who were predominantly Caucasian (69.1%), had a mean age of 60.32 (±14.07) years, and had lower income levels (66.4% ≤$50,000 annually). Median delay time was 6.68 (1.91, 24.94) hours and only 26.2% had a prehospital delay of 2 hours or less. Patients with and without ACS presenting with unusual fatigue (TR=1.71, p=0.002; TR=1.54, p=0.003 , respectively) or self-transporting to the ED experienced significantly longer prehospital delay (TR 1.93, p&lt;0.001; TR 1.71, p&lt;0.001 , respectively). Predictors of shorter delay in patients with ACS were shoulder pain and lightheadedness (TR=0.65, p =0.013 and TR=0.67, p =0.022, respectively). Predictors of shorter delay for patients ruled-out for ACS were the presence of chest pain, sweating (TR=0.071, p =0.025 and TR=0.073, p =0.032, respectively). Conclusion: Patients self-transporting to the ED had prolonged prehospital delays. Encouraging the use of EMS is an important modifiable factor for patients with symptoms concerning for ACS. Calling 911 can be positively framed to at risk patients and the community as having advanced care come to them since EMS diagnostic capabilities include 12-lead ECG acquisition and possibly high sensitivity troponin assays.

Abstract 16276: Lipoprotein (a) Predicts Recurrent Worse Outcomes in Type 2 Diabetes Mellitus Patients With Prior Cardiovascular Events: A Prospective, Observational Cohort Study

Introduction: Merging studies have reported the association of lipoprotein(a) [Lp(a)] with poor outcomes of coronary artery disease (CAD) in patients with type 2 diabetes mellitus (T2DM). However, the prognostic importance of Lp(a) for recurrent cardiovascular events (CVEs) is currently undetermined in patients with T2DM and prior CVEs. Methods: From April 2011 to March 2017, we consecutively recruited 2,284 T2DM patients with prior CVEs. Patients were categorized into low, medium, and high groups by Lp(a) levels and followed up for hard, recurrent CVEs, including nonfatal acute myocardial infarction, stroke, and cardiovascular mortality. Caplan-Meier, Cox regression and C-statistic analyses were performed. Results: During 7,613 patient-years’ follow-up, 153 recurrent CVEs occurred. Lp(a) levels were significantly higher in patients with recurrent CVEs than counterparts (20.44 vs. 14.71 mg/dL, p=0.002). Kaplan-Meier analysis revealed that the event-free survival rate was dramatically lower in high and medium Lp(a) groups than that in low group irrespective of HBA1c status (&lt;7.0%; ≥7.0%, both p&lt;0.05). Furthermore, multivariate Cox regression models indicated that Lp(a) was independently associated with high risk of recurrent CVEs [HR(95% CI): 2.049(1.308-3.212)], such data remains in different HBA1c status (HR(95% CI): &lt;7.0%, 2.009(1.051-3.840); ≥7.0%, 2.162(1.148-4.073)). Moreover, the results of C-statistic were significantly improved by 0.029 when added Lp(a) to the Cox model. Conclusions: Our data, for the first time, confirmed that Lp(a) was an independent predictor for recurrent CVEs in T2DM patients with prior CVEs, suggesting that Lp(a) measurement may help to further risk stratification for T2DM patients after they suffered a first CVE.

Outcomes of 7560 chronic total occlusion patients undergoing percutaneous coronary intervention: results from a Dutch nationwide registry

Abstract Background The presence of a chronic total coronary occlusion (CTO) is associated with worse clinical outcomes. We aimed to identify CTO patients that are at risk of these outcomes in a nationwide registry. Methods The Netherlands Heart Registration (NHR) is a nationwide registry that registers outcomes of cardiac interventions. For the purpose of this analysis, the data of all patients undergoing PCI from inception of the NHR to December 2019 were selected, that included PCI with at least one CTO in one of the treated coronary arteries. We used multivariate logistic regression of baseline characteristics for the outcome measures target vessel revascularization (TVR) &amp;lt;1 year, 30-day myocardial infarction (MI) and 1-year mortality. The impact of the assessed risk factors on outcomes was described as odds ratio (OR) with corresponding 95% confidence intervals (CI). Results A total of 7560 patients underwent PCI with ≥1 CTO in one of the treated arteries between January 1, 2015 until December 31, 2018 (mean age 65±10 years, 77.4% male [n=5850]). Five percent of patients deceased within 1 year after PCI (n=375), TVR&amp;lt;1 year occurred in 11% (n=525/4804) and 30-day MI occurred in 0.5% (25/4985). In multivariate regression, the only predictor for TVR&amp;lt;1 year was the presence of diabetes mellitus (OR 1.29, 95% CI 1.06–1.56). Predictors for the outcome MI &amp;lt;30 days were female gender (OR 2.24, 95% CI 1.05–4.79), chronic kidney disease (OR 3.94, 95% CI 1.15–13.50) and cardiogenic shock at presentation (OR 7.94, 95% CI 2.28–27.7). Strong predictors for 1 year mortality were the presence of cardiogenic shock at presentation (OR 17.86, 95% CI 2.90–109.92) and the presence of chronic kidney disease (OR 4.56, 95% CI 2.04–10.16), other predictors were age (OR 1.04, 95% CI 1.01–1.07), female gender (OR 1.83, 95% CI 1.08–3.10), diabetes (OR 1.66, 95% CI 1.01–2.73) and left ventricular ejection fraction (LVEF; OR 0.95, 95% CI 0.93–0.97). Conclusion In this nationwide registry of 7560 CTO patients undergoing PCI, cardiogenic shock and chronic kidney disease were strong predictors for 1 year mortality and 30 day MI. Diabetes mellitus was the only predictor for the occurrence of TVR &amp;lt;1 year. Identification of patients at risk for poor clinical outcomes may help improve the outcomes of CTO patients in the future. Funding Acknowledgement Type of funding source: None

Systematic review and meta-analysis of placebo-controlled invasive interventions for the management of chronic stable angina

Abstract Background The benefits of invasive therapies for chronic stable angina are in large part supported by open label studies comparing invasive procedures to medical therapy alone. Placebo effects are frequently unaccounted for as control arms rarely receive placebo (sham) interventions. This review pools studies comparing invasive therapies for chronic stable angina to placebo interventions and aims to measure the true effects of different invasive interventions. Methods We performed a systematic review and meta-analysis of double blinded randomized placebo-controlled trials of invasive therapies for the management of chronic stable angina. The outcomes of interest were change in exercise tolerance time, change in Canadian cardiovascular society angina grade and rate of post-procedural complications including myocardial infarction and all-cause mortality. Results Six randomized placebo-controlled trials were included, with a total of 742 participants. Median follow-up ranged from 6 weeks to 16 months. Contrary to data reported in individual studies, pooled analysis favored invasive therapies over placebo procedures: exercise tolerance time was higher (standard mean difference (SMD) 35.2 seconds [4.4- 66.0]), angina scores were more likely to improve by ≥1 class (Odds Ratio (OR) 2.16 [1.05- 4.46]) and by ≥2 classes (OR 1.76 [1.13- 2.74]). There was no difference in post-procedural myocardial infarction (incidence rate ratio (IRR) 2.91 [0.61–13.93]) and all-cause mortality (IRR 0.39 [0.35–4.27]). Conclusions This meta-analysis of placebo-controlled trials for chronic stable angina found a beneficial effect from invasive therapies. This favorable effect has not been seen in individual studies. Our findings suggest that sample sizes should be adjusted upwards in placebo-controlled studies to detect true treatment effects independent of the placebo effect. Funding Acknowledgement Type of funding source: None