Preventive percutaneous coronary intervention versus optimal medical therapy alone for the treatment of vulnerable atherosclerotic coronary plaques (PREVENT): a multicentre, open-label, randomised controlled trial.

BACKGROUND: Acute coronary syndrome and sudden cardiac death are often caused by rupture and thrombosis of lipid-rich atherosclerotic coronary plaques (known as vulnerable plaques), many of which are non-flow-limiting. The safety and effectiveness of focal preventive therapy with percutaneous coronary intervention of vulnerable plaques in reducing adverse cardiac events are unknown. We aimed to assess whether preventive percutaneous coronary intervention of non-flow-limiting vulnerable plaques improves clinical outcomes compared with optimal medical therapy alone. METHODS: PREVENT was a multicentre, open-label, randomised controlled trial done at 15 research hospitals in four countries (South Korea, Japan, Taiwan, and New Zealand). Patients aged 18 years or older with non-flow-limiting (fractional flow reserve >0·80) vulnerable coronary plaques identified by intracoronary imaging were randomly assigned (1:1) to either percutaneous coronary intervention plus optimal medical therapy or optimal medical therapy alone, in block sizes of 4 or 6, stratified by diabetes status and the performance of percutaneous coronary intervention in a non-study target vessel. Follow-up continued annually in all enrolled patients until the last enrolled patient reached 2 years after randomisation. The primary outcome was a composite of death from cardiac causes, target-vessel myocardial infarction, ischaemia-driven target-vessel revascularisation, or hospitalisation for unstable or progressive angina, assessed in the intention-to-treat population at 2 years. Time-to-first-event estimates were calculated with the Kaplan-Meier method and were compared with the log-rank test. This report is the principal analysis from the trial and includes all long-term analysed data. The trial is registered at ClinicalTrials.gov, NCT02316886, and is complete. FINDINGS: Between Sept 23, 2015, and Sept 29, 2021, 5627 patients were screened for eligibility, 1606 of whom were enrolled and randomly assigned to percutaneous coronary intervention (n=803) or optimal medical therapy alone (n=803). 1177 (73%) patients were men and 429 (27%) were women. 2-year follow-up for the primary outcome assessment was completed in 1556 (97%) patients (percutaneous coronary intervention group n=780; optimal medical therapy group n=776). At 2 years, the primary outcome occurred in three (0·4%) patients in the percutaneous coronary intervention group and in 27 (3·4%) patients in the medical therapy group (absolute difference -3·0 percentage points [95% CI -4·4 to -1·8]; p=0·0003). The effect of preventive percutaneous coronary intervention was directionally consistent for each component of the primary composite outcome. Serious clinical or adverse events did not differ between the percutaneous coronary intervention group and the medical therapy group: at 2 years, four (0·5%) versus ten (1·3%) patients died (absolute difference -0·8 percentage points [95% CI -1·7 to 0·2]) and nine (1·1%) versus 13 (1·7%) patients had myocardial infarction (absolute difference -0·5 percentage points [-1·7 to 0·6]). INTERPRETATION: In patients with non-flow-limiting vulnerable coronary plaques, preventive percutaneous coronary intervention reduced major adverse cardiac events arising from high-risk vulnerable plaques, compared with optimal medical therapy alone. Given that PREVENT is the first large trial to show the potential effect of the focal treatment for vulnerable plaques, these findings support consideration to expand indications for percutaneous coronary intervention to include non-flow-limiting, high-risk vulnerable plaques. FUNDING: The CardioVascular Research Foundation, Abbott, Yuhan Corp, CAH-Cordis, Philips, and Infraredx, a Nipro company.

Prognostic Implications of N-Terminal Pro-B-Type Natriuretic Peptide in Patients With Non-ST-Elevation Myocardial Infarction.

BACKGROUND: Limited data exist regarding the prognostic implications of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in patients with non-ST-elevation myocardial infarction (NSTEMI) who undergo percutaneous coronary intervention (PCI).Methods and Results: Of 13,104 patients in the nationwide Korea Acute Myocardial Infarction Registry-National Institutes of Health, 3,083 patients with NSTEMI who underwent PCI were included in the present study. The primary endpoint was major adverse cardiovascular events (MACE) at 3 years, a composite of all-cause death, recurrent myocardial infarction, unplanned repeat revascularization, and admission for heart failure. NT-proBNP was measured at the time of initial presentation for the management of NSTEMI, and patients were divided into a low (<700 pg/mL; n=1,813) and high (≥700 pg/mL; n=1,270) NT-proBNP group. The high NT-proBNP group had a significantly higher risk of MACE, driven primarily by a higher risk of cardiac death or admission for heart failure. These results were consistent after confounder adjustment by propensity score matching and inverse probability weighting analysis. CONCLUSIONS: In patients with NSTEMI who underwent PCI, an initial elevated NT-proBNP concentration was associated with higher risk of MACE at 3 years, driven primarily by higher risks of cardiac death or admission for heart failure. These results suggest that the initial NT-proBNP concentration may have a clinically significant prognostic value in NSTEMI patients undergoing PCI.

Prognostic Implication of Platelet Reactivity According to Left Ventricular Systolic Dysfunction Status in Patients Treated With Drug-Eluting Stent Implantation: Analysis of the PTRG-DES Consortium.

BACKGROUND: Coronary artery disease patients undergoing percutaneous coronary intervention (PCI) often exhibit reduced left ventricular ejection fraction (LVEF). However, the impact of LV dysfunction status in conjunction with platelet reactivity on clinical outcomes has not been previously investigated. METHODS: From the multicenter PTRG-DES (Platelet function and genoType-Related long-term prognosis in DES-treated patients) consortium, the patients were classified as preserved-EF (PEF: LVEF ≥ 50%) and reduced-EF (REF: LVEF< 5 0%) group by echocardiography. Platelet reactivity was measured using VerifyNow P2Y12 assay and high platelet reactivity (HPR) was defined as PRU ≥ 252. The major adverse cardiac and cerebrovascular events (MACCEs) were a composite of death, myocardial infarction, stent thrombosis and stroke at 5 years after PCI. Major bleeding was defined as Bleeding Academic Research Consortium bleeding types 3-5. RESULTS: A total of 13,160 patients from PTRG-DES, 9,319 (79.6%) patients with the results of both PRU and LVEF were analyzed. The incidence of MACCE and major bleeding was higher in REF group as compared with PEF group (MACCEs: hazard ratio [HR] 2.17, P < 0.001, 95% confidence interval [CI] 1.85-2.55; major bleeding: HR 1.78, P < 0.001, 95% CI 1.39-2.78). The highest rate of MACCEs was found in patients with REF and HPR, and the difference between the groups was statistically significant (HR 3.14 in REF(+)/HPR(+) vs. PEF(+)/HPR(-) group, P < 0.01, 95% CI 2.51-3.91). The frequency of major bleeding was not associated with the HPR in either group. CONCLUSION: LV dysfunction was associated with an increased incidence of MACCEs and major bleeding in patients who underwent PCI. The HPR status further exhibited significant increase of MACCEs in patients with LV dysfunction in a large, real-world registry. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04734028.

Transradial Versus Transfemoral Access for Bifurcation Percutaneous Coronary Intervention Using Second-Generation Drug-Eluting Stent.

BACKGROUND: The benefits of transradial access (TRA) over transfemoral access (TFA) for bifurcation percutaneous coronary intervention (PCI) are uncertain because of the limited availability of device selection. This study aimed to compare the procedural differences and the in-hospital and long-term outcomes of TRA and TFA for bifurcation PCI using second-generation drug-eluting stents (DESs). METHODS: Based on data from the Coronary Bifurcation Stenting Registry III, a retrospective registry of 2,648 patients undergoing bifurcation PCI with second-generation DES from 21 centers in South Korea, patients were categorized into the TRA group (n = 1,507) or the TFA group (n = 1,141). After propensity score matching (PSM), procedural differences, in-hospital outcomes, and device-oriented composite outcomes (DOCOs; a composite of cardiac death, target vessel-related myocardial infarction, and target lesion revascularization) were compared between the two groups (772 matched patients each group). RESULTS: Despite well-balanced baseline clinical and lesion characteristics after PSM, the use of the two-stent strategy (14.2% vs. 23.7%, P = 0.001) and the incidence of in-hospital adverse outcomes, primarily driven by access site complications (2.2% vs. 4.4%, P = 0.015), were significantly lower in the TRA group than in the TFA group. At the 5-year follow-up, the incidence of DOCOs was similar between the groups (6.3% vs. 7.1%, P = 0.639). CONCLUSION: The findings suggested that TRA may be safer than TFA for bifurcation PCI using second-generation DESs. Despite differences in treatment strategy, TRA was associated with similar long-term clinical outcomes as those of TFA. Therefore, TRA might be the preferred access for bifurcation PCI using second-generation DES. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03068494.

Dual antiplatelet therapy de-escalation in acute coronary syndrome: an individual patient meta-analysis.

AIMS: Dual-antiplatelet therapy (DAPT) with aspirin and a potent P2Y12 inhibitor is the standard treatment for patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). De-escalation of the potent P2Y12 inhibtor is an appealing concept to balance the ischaemic and bleeding risks after PCI. An individual patient data meta-analysis was performed to compare de-escalation versus standard DAPT in patients with ACS. METHODS AND RESULTS: Electronic databases, including PubMed, Embase, and the Cochrane database, were searched to identify randomised clinical trials (RCTs) comparing the de-escalation strategy with the standard DAPT after PCI in patients with ACS. Individual patient-level data were collected from the relevant trials. The co-primary endpoints of interest were the ischaemic composite endpoint (a composite of cardiac death, myocardial infarction, and cerebrovascular events) and bleeding endpoint (any bleeding) at 1-year post-PCI. Four RCTs (the TROPICAL-ACS, POPular Genetics, HOST-REDUCE-POLYTECH-ACS, and TALOS-AMI trials) including 10 133 patients were analysed. The ischaemic endpoint was significantly lower in the patients assigned to the de-escalation strategy than in those assigned to the standard strategy (2.3% vs. 3.0%, hazard ratio [HR] 0.761, 95% confidence interval [CI] 0.597-0.972, log rank P = 0.029). Bleeding was also significantly lower in the de-escalation strategy group (6.5% vs. 9.1%, HR 0.701, 95% CI 0.606-0.811, log rank P < 0.001). No significant intergroup differences were observed in terms of all-cause death and major bleeding events. Subgroup analyses revealed that compared to guided de-escalation, unguided de-escalation had a significantly larger impact on bleeding endpoint reduction (P for interaction = 0.007); no intergroup differences were observed for the ischaemic endpoints. CONCLUSION: In this individual patient data meta-analysis, DAPT-based de-escalation was associated with both decreased ischaemic and bleeding endpoints. Reduction in bleeding endpoints was more prominent for the unguided than the guided de-escalation strategy. STUDY REGISTRATION NUMBER: This study was registered in the PROSPERO (ID: CRD42021245477).

Preventive PCI or medical therapy alone for vulnerable atherosclerotic coronary plaque: Rationale and design of the randomized, controlled PREVENT trial.

BACKGROUND: Acute coronary syndromes are commonly caused by the rupture of vulnerable plaque, which often appear angiographically not severe. Although pharmacologic management is considered standard therapy for stabilizing plaque vulnerability, the potential role of preventive local treatment for vulnerable plaque has not yet been determined. The PREVENT trial was designed to compare preventive percutaneous coronary intervention (PCI) plus optimal medical therapy (OMT) with OMT alone in patients with functionally nonsignificant high-risk vulnerable plaques. METHODS: The PREVENT trial is a multinational, multicenter, prospective, open-label, active-treatment-controlled randomized trial. Eligible patients have at least 1 angiographically significant stenosis (diameter stenosis >50% by visual estimation) without functional significance (fractional flow reserve [FFR] >0.80). Target lesions are assessed by intracoronary imaging and must meet at least 2 imaging criteria for vulnerable plaque; (1) minimal lumen area <4.0 mm2; (2) plaque burden >70%; (3) maximal lipid core burden index in a 4 mm segment >315 by near infrared spectroscopy; and (4) thin cap fibroatheroma as determined by virtual histology or optical coherence tomography. Enrolled patients are randomly assigned in a 1:1 ratio to either preventive PCI with either bioabsorbable vascular scaffolds or metallic everolimus-eluting stents plus OMT or OMT alone. The primary endpoint is target-vessel failure, defined as the composite of death from cardiac causes, target-vessel myocardial infarction, ischemic-driven target-vessel revascularization, or hospitalization for unstable or progressive angina, at 2 years after randomization. RESULTS: Enrollment of a total of 1,608 patients has been completed. Follow-up of the last enrolled patient will be completed in September 2023 and primary results are expected to be available in early 2024. CONCLUSIONS: The PREVENT trial is the first large-scale, randomized trial to evaluate the effect of preventive PCI on non-flow-limiting vulnerable plaques containing multiple high-risk features that is appropriately powered for clinical outcomes. PREVENT will provide compelling evidence as to whether preventive PCI of vulnerable plaques plus OMT improves patient outcomes compared with OMT alone. CLINICAL TRIAL REGISTRATION: URL: https://www. CLINICALTRIALS: gov. Unique identifier: NCT02316886. KEY POINTS: The PREVENT trial is the first, large-scale randomized clinical trial to evaluate the effect of preventive PCI on non-flow-limiting vulnerable plaque with high-risk features. It will provide compelling evidence to determine whether PCI of focal vulnerable plaques on top of OMT improves patient outcomes.

Implication of diabetic status on platelet reactivity and clinical outcomes after drug-eluting stent implantation: results from the PTRG-DES consortium.

BACKGROUND: Diabetes mellitus (DM) is associated with thrombogenicity, clinically manifested with atherothrombotic events after percutaneous cutaneous intervention (PCI). This study aimed to investigate association between DM status and platelet reactivity, and their prognostic implication in PCI-treated patients. METHODS: The Platelet function and genoType-Related long-term Prognosis-Platelet Function Test (PTRG-PFT) cohort was established to determine the linkage of platelet function test (PFT) with long-term prognosis during dual antiplatelet therapy including clopidogrel in patients treated with drug-eluting stent (DES). We assessed platelet reactivity using VerifyNow and 'high platelet reactivity (HPR)' was defined as ≥ 252 P2Y12 reaction unit (PRU). Major adverse cardiac and cerebrovascular event (MACCE) was a composite of all-cause death, myocardial infarction, stent thrombosis or stroke. RESULTS: Between July 2003 and Aug 2018, DES-treated patients with available PFT were enrolled (n = 11,714). Diabetic patients demonstrated significant higher levels of platelet reactivity (DM vs. non-DM: 225.7 ± 77.5 vs. 213.6 ± 79.1 PRU, P < 0.001) and greater prevalence of HPR compared to non-diabetic patients (38.1% vs. 32.0%, P < 0.001). PRU level and prevalence of HPR were significantly associated with insulin requirement and HbA1c level, as well as diabetic status. DM status and HPR phenotype had a similar prognostic implication, which showed the synergistic clinical impact on MACCE. Association between PRU level and MACCE occurrence seemed higher in diabetic vs. non-diabetic patients. In non-DM patients, HPR phenotype did not significantly increase the risk of MACCE (adjusted hazard ratio [HRadj]: 1.073; 95% confidence interval [CI]: 0.869-1.325; P = 0.511), whereas HPR was an independent determinant for MACCE occurrence among diabetic patients (HRadj: 1.507; 95% CI: 1.193-1.902; P < 0.001). CONCLUSION: The levels of on-clopidogrel platelet reactivity are determined by diabetic status and the severity of DM. In addition, HPR phenotype significantly increases the risk of MACCE only in diabetic patients. CLINICAL TRIAL REGISTRATION: URL: https://www. CLINICALTRIALS: gov . Unique identifier: NCT04734028.

Effect of Angiotensin Receptor Blocker Dose in Myocardial Infarction With Preserved Left Ventricular Systolic Function.

ABSTRACT: There have been few studies of angiotensin receptor blocker (ARB) dose in myocardial infarction (MI) with preserved left ventricular (LV) systolic function. We evaluated the association of ARB dose with clinical outcomes after MI with preserved LV systolic function. We used MI multicenter registry. Six months after discharge, the ARB dose was indexed to the target ARB doses used in randomized clinical trials and grouped as >0%-25% (n = 2333), >25% of the target dose (n = 1204), and no ARB (n = 1263). The primary outcome was the composite of cardiac death or MI. Univariate analysis showed that mortality of those with any ARB dose was lower than those without ARB therapy. After multivariable adjustment, patients receiving >25% of target dose had a similar risk of cardiac death or MI compared with those receiving ≤25% or no ARB [hazard ratio (HR) 1.05, 95% confidence interval (CI) 0.83-1.33; HR 0.94, 95% CI 0.82-1.08, respectively]. Propensity score analysis also demonstrated that patients with >25% dose had no difference in primary endpoint compared with those ≤25% dose or the no ARB group (HR 1.03, 95% CI 0.79-1.33; HR 0.86, 95% CI 0.64-1.14, respectively). The present study demonstrates that patients treated with >25% of target ARB dose do not have better clinical outcomes than those treated with ≤25% of target ARB dose or those with no ARB dose in MI patients with preserved LV systolic function.

Impact of the risk of malnutrition on bleeding, mortality, and ischemic events in patients with acute myocardial infarction.

BACKGROUND & AIMS: Data regarding the relationship between malnutrition and clinical outcomes of acute myocardial infarction (AMI) is limited. The study aims to evaluate the clinical impact of malnutrition in AMI patients after percutaneous coronary intervention (PCI). METHODS AND RESULTS: The COREA-AMI registries identified 10,161 AMI patients who underwent PCI from January 2004 to August 2014. Patients with geriatric nutritional risk index (GNRI) scores of <82, 82 to <92, 92 to <98, and ≥98 were categorized as having severe, moderate, mild malnutrition risk, and absence of risk, respectively. Associations of GNRI with Bleeding Academic Research Consortium (BARC) 3 or 5 bleeding, all-cause death, and major cardiovascular events (MACEs; a composite of cardiovascular death, myocardial infarction, or ischemic stroke) were evaluated. Over 50% of AMI patients were malnourished, with 25.0%, 22.7%, and 4.9% having mild, moderate, and severe malnutrition risks, respectively. Over a median 4.9-year follow-up, patients with malnutrition risk had higher risks of BARC 3 or 5 bleeding (adjusted hazard ratios [aHRs], 1.27, 1.55, and 2.02 for mild, moderate, and severe, respectively; p < 0.001), all-cause death (aHRs, 1.26, 1.46, and 1.85 for mild, moderate, and severe, respectively; p < 0.001), and MACEs (aHRs, 1.14, 1.32, and 1.67 for mild, moderate, and severe, respectively; p < 0.001) than patients without risk. CONCLUSION: Elevated malnutrition risk was common among AMI patients undergoing PCI and was strongly associated with a higher risk of major bleeding, all-cause death, and major ischemic events.

The Protective Role of TREM2 in the Heterogenous Population of Macrophages during Post-Myocardial Infarction Inflammation.

Advances in interventions after myocardial infarction (MI) have dramatically increased survival, but MI remains the leading cause of heart failure due to maladaptive ventricular remodeling following ischemic damage. Inflammation is crucial in both the initial response to ischemia and subsequent wound healing in the myocardium. To date, preclinical and clinical efforts have been made to elucidate the deleterious effects of immune cells contributing to ventricular remodeling and to identify therapeutic molecular targets. The conventional concept classifies macrophages or monocytes into dichotomous populations, while recent studies support their diverse subpopulations and spatiotemporal dynamicity. The single-cell and spatial transcriptomic landscapes of macrophages in infarcted hearts successfully revealed the heterogeneity of cell types and their subpopulations post-MI. Among them, subsets of Trem2hi macrophages were identified that were recruited to infarcted myocardial tissue in the subacute phase of MI. The upregulation of anti-inflammatory genes was observed in Trem2hi macrophages, and an in vivo injection of soluble Trem2 during the subacute phase of MI significantly improved myocardial function and the remodeling of infarcted mice hearts, suggesting the potential therapeutic role of Trem2 in LV remodeling. Further investigation of the reparative role of Trem2 in LV remodeling would provide novel therapeutic targets for MI.

Unguided de-escalation from ticagrelor to clopidogrel in stabilised patients with acute myocardial infarction undergoing percutaneous coronary intervention (TALOS-AMI): an investigator-initiated, open-label, multicentre, non-inferiority, randomised trial.

BACKGROUND: In patients with acute myocardial infarction receiving potent antiplatelet therapy, the bleeding risk remains high during the maintenance phase. We sought data on a uniform unguided de-escalation strategy of dual antiplatelet therapy (DAPT) from ticagrelor to clopidogrel after acute myocardial infarction. METHODS: In this open-label, assessor-masked, multicentre, non-inferiority, randomised trial (TALOS-AMI), patients at 32 institutes in South Korea with acute myocardial infarction receiving aspirin and ticagrelor without major ischaemic or bleeding events during the first month after index percutaneous coronary intervention (PCI) were randomly assigned in a 1:1 ratio to a de-escalation (clopidogrel plus aspirin) or active control (ticagrelor plus aspirin) group. Unguided de-escalation without a loading dose of clopidogrel was adopted when switching from ticagrelor to clopidogrel. The primary endpoint was a composite of cardiovascular death, myocardial infarction, stroke, or bleeding type 2, 3, or 5 according to Bleeding Academic Research Consortium (BARC) criteria from 1 to 12 months. A non-inferiority test was done to assess the safety and efficacy of de-escalation DAPT compared with standard treatment. The hazard ratio (HR) for de-escalation versus active control group in a stratified Cox proportional hazards model was assessed for non-inferiority by means of an HR margin of 1·34, which equates to an absolute difference of 3·0% in the intention-to-treat population and, if significant, a superiority test was done subsequently. To ensure statistical robustness, additional analyses were also done in the per-protocol population. This trial is registered at ClinicalTrials.gov, NCT02018055. FINDINGS: From Feb 26, 2014, to Dec 31, 2018, from 2901 patients screened, 2697 patients were randomly assigned: 1349 patients to de-escalation and 1348 to active control groups. At 12 months, the primary endpoints occurred in 59 (4·6%) in the de-escalation group and 104 (8·2%) patients in the active control group (pnon-inferiority<0·001; HR 0·55 [95% CI 0·40-0·76], psuperiority=0·0001). There was no significant difference in composite of cardiovascular death, myocardial infarction, or stroke between de-escalation (2·1%) and the active control group (3·1%; HR 0·69; 95% CI 0·42-1·14, p=0·15). Composite of BARC 2, 3, or 5 bleeding occurred less frequently in the de-escalation group (3·0% vs 5·6%, HR 0·52; 95% CI 0·35-0·77, p=0·0012). INTERPRETATION: In stabilised patients with acute myocardial infarction after index PCI, a uniform unguided de-escalation strategy significantly reduced the risk of net clinical events up to 12 months, mainly by reducing the bleeding events. FUNDING: ChongKunDang Pharm, Medtronic, Abbott, and Boston Scientific.

Long-Term Clinical Outcomes and Its Predictors Between the 1- and 2-Stent Strategy in Coronary Bifurcation Lesions　- A Baseline Clinical and Lesion Characteristic-Matched Analysis.

BACKGROUND: Differences in the impact of the 1- or 2-stent strategy in similar coronary bifurcation lesion conditions are not well understood. This study investigated the clinical outcomes and its predictors between 1 or 2 stents in propensity score-matched (PSM) complex bifurcation lesions.Methods and Results: We analyzed the data of patients with bifurcation lesions, obtained from a multicenter registry of 2,648 patients (median follow up, 53 months). The patients were treated by second generation drug-eluting stents (DESs). The primary outcome was target lesion failure (TLF), composite of cardiac death, target vessel myocardial infarction (TVMI), and ischemia-driven target lesion revascularization (TLR). PSM was performed to balance baseline clinical and angiographic discrepancies between 1 and 2 stents. After PSM (N=333 from each group), the 2-stent group had more TLRs (hazard ratio [HR] 3.14, 95% confidence interval [CI] 1.42-6.97, P=0.005) and fewer hard endpoints (composite of cardiac death and TVMI; HR 0.44, 95% CI 0.19-1.01, P=0.054), which resulted in a similar TLF rate (HR 1.40, 95% CI 0.83-2.37, P=0.209) compared to the 1-stent group. Compared with 1-stent, the 2-stent technique was more frequently associated with less TLF in the presence of main vessel (pinteraction=0.008) and side branch calcification (pinteraction=0.010). CONCLUSIONS: The 2-stent strategy should be considered to reduce hard clinical endpoints in complex bifurcation lesions, particularly those with calcifications.

Nanoparticle-Mediated Blocking of Excessive Inflammation for Prevention of Heart Failure Following Myocardial Infarction.

Severe cardiac damage following myocardial infarction (MI) causes excessive inflammation, which sustains tissue damage and often induces adverse cardiac remodeling toward cardiac function impairment and heart failure. Timely resolution of post-MI inflammation may prevent cardiac remodeling and development of heart failure. Cell therapy approaches for MI are time-consuming and costly, and have shown marginal efficacy in clinical trials. Here, nanoparticles targeting the immune system to attenuate excessive inflammation in infarcted myocardium are presented. Liposomal nanoparticles loaded with MI antigens and rapamycin (L-Ag/R) enable effective induction of tolerogenic dendritic cells presenting the antigens and subsequent induction of antigen-specific regulatory T cells (Tregs). Impressively, intradermal injection of L-Ag/R into acute MI mice attenuates inflammation in the myocardium by inducing Tregs and an inflammatory-to-reparative macrophage polarization, inhibits adverse cardiac remodeling, and improves cardiac function. Nanoparticle-mediated blocking of excessive inflammation in infarcted myocardium may be an effective intervention to prevent the development of post-MI heart failure.

J-curve relationship between long term glycemic control and mortality in diabetic patients with acute myocardial infarction undergoing percutaneous coronary intervention.

BACKGROUND: Intensive glycemic control is generally recommended for diabetic patients to reduce complications. However, the role of glycemic control in the mortality in diabetic patients with acute myocardial infarction (AMI) remained unclear. METHODS: We selected diabetic patients who measured HbA1c more than 3 times after AMI among 10,719 patients enrolled in the multicenter AMI registry. Patients (n = 1384) were categorized into five groups: according to mean HbA1c level: ≤ 6.5%, > 6.5 to ≤ 7.0%, > 7.0 to ≤ 7.5%, > 7.5 to ≤ 8.0% and > 8.0%. The primary endpoint was all-cause mortality. RESULTS: During a median follow-up of 6.2 years, the patients with a mean HbA1c of 6.5 to 7.0% had the lowest all-cause mortality. Compared to patients with mean HbA1c of 6.5 to 7.0%, the risk of all-cause mortality increased in subjects with mean HbA1c ≤ 6.5% (adjusted hazard ratio [HR] 2.00, 95% confidence interval [CI] 1.02-3.95) and in those with mean HbA1c > 8.0% (adjusted HR 3.35, 95% CI 1.78-6.29). In the subgroup analysis by age, the J-curve relationship between mean HbA1c and all-cause mortality was accentuated in elderly patients (age ≥ 65 years), while there was no difference in all-cause mortality across the HbA1c groups in younger patients (age < 65 years). CONCLUSIONS: The less strict glycemic control in diabetic patients with AMI would be optimal for preventing mortality, especially in elderly patients.

Comparison of 2-Stenting Strategies Depending on Sequence or Technique for Bifurcation Lesions in the Second-Generation Drug-Eluting Stent Era　- Analysis From the COBIS (Coronary Bifurcation Stenting) III Registry.

BACKGROUND: It has not been determined which specific 2-stenting strategy is the best for bifurcation lesions. Our aim was to investigate the clinical outcomes of various 2-stenting strategies in the era of 2nd-generation drug-eluting stents (2G-DES).Methods and Results:We analyzed 454 patients who finally underwent 2-stenting for a bifurcation lesion, from among 2,648 patients enrolled in the COBIS III registry. The primary outcome was target lesion failure (TLF). Patients were analyzed according to stenting sequence (provisional [main vessel stenting first] vs. systemic [side branch stenting first]) and stenting technique (crush vs. T vs. culotte vs. kissing/V stenting). Overall, 4.4 years' TLF after 2-stenting treatment for bifurcation lesion was excellent: TLF 11.2% and stent thrombosis 1.3%. There was no difference in TLF according to 2-stenting strategy (11.1% vs. 10.5%, P=0.990 for provisional and systemic sequence; 8.6% vs. 14.4% vs. 12.9% vs. 12.2%, P=0.326 for crush, T, culotte, kissing/V technique, respectively). Only left main (LM) disease and a shorter duration of dual antiplatelet therapy (DAPT) were associated with TLF. The distribution of DAPT duration differed between patients with and without TLF, and the time-point of intersection was 2.5 years. Also, the side branch was the most common site of restenosis. CONCLUSIONS: The stenting sequence or technique did not affect clinical outcomes, but LM disease and shorter DAPT were associated with TLF, in patients with bifurcation lesions undergoing 2-stenting with 2G-DES.

Clinical Implication of 'Obesity Paradox' in Elderly Patients With Acute Myocardial Infarction.

BACKGROUND: The clinical impact of body mass index (BMI), especially in the elderly with acute myocardial infarction (AMI), has not been sufficiently evaluated. The purpose of this study was to elucidate the clinical impact of BMI in very old patients (≥80 years) with AMI. METHODS: The study analysed 2,489 AMI patients aged ≥80 years from the Korea Acute Myocardial Infarction Registry and the Korea Working Group on Myocardial Infarction (KAMIR/KorMI) registries between November 2005 and March 2012. The study population was categorised into four groups based on their BMI: underweight (n=301), normal weight (n=1,150), overweight (n=890), and obese (n=148). The primary endpoint was major adverse cardiovascular event (MACE), a composite of cardiac death, myocardial infarction, target lesion revascularisation, and target vessel revascularisation. RESULTS: Baseline characteristics among the four groups were similar, except for hypertension (45.1 vs 58.4 vs 66.2 vs 69.9%, respectively; p<0.001) and diabetes (16.6 vs 23.6 vs 30.7 vs 35.1%, respectively; p<0.001). Coronary care unit length of stay was significantly different among the four groups during hospitalisation (5.3±5.9 vs 4.8±6.8 vs 4.2±4.0 vs 3.5±2.1 days; p=0.007). MACE (16.9 vs 14.9 vs 13.7 vs 8.8%; p=0.115) and cardiac death (10.3 vs 8.4 vs 7.9 vs 4.1%; p=0.043) less frequently occurred in the obese group than in other groups during the 1-year follow-up. A multivariate regression model showed obese status (BMI ≥27.5 kg/m2) as an independent predictor of reduced MACE (hazard ratio [HR], 0.20; 95% confidence interval [CI], 0.06-0.69; p=0.010) along with reduced left ventricular ejection fraction (≤40%) as a predictor of increased MACE (HR,1.87; 95% CI, 1.31-2.68; p=0.001). CONCLUSION: Body mass index in elderly patients with acute myocardial infarction was significantly associated with coronary care unit stay and clinical cardiovascular outcomes.

Predictors of Significant Coronary Artery Disease in Patients with Cerebral Artery Atherosclerosis.

OBJECTIVE: There are few existing data on the status of coronary artery disease (CAD) in patients with atherosclerosis of the cerebral artery detected by brain imaging studies. We aimed to analyze the predictors of asymptomatic angiographically significant CAD detected by simultaneous cerebral and coronary angiography. METHODS: This retrospective cohort study screened data obtained between August 2009 and April 2019; 11,047 patients underwent cerebral angiography for atherosclerotic change (>50% stenosis or aneurysm) seen in brain magnetic resonance angiography (MRA) or computed tomography angiography (CTA) at a single center by endovascular neurosurgeon's decision. Of these, 700 patients including 622 patients who underwent simultaneous coronary and cerebral angiography and 78 patients who underwent coronary angiography within a month were enrolled. We investigated the characteristics and predictors of angiographically significant CAD (>50% stenosis). Furthermore, we also analyzed the major adverse cardiovascular and cerebrovascular events (MACCE), including all-cause death, myocardial infarction, and stroke for 5 years. RESULTS: The frequency of significant CAD was 59% (413/700), the mean age was 68.9 ± 10.3 years, and 60.6% were male. During mean follow-up of 50 months, the MACCE rate of our whole cohort was significantly higher in the CAD group (21.5%) than in the non-CAD group (14.6%; hazard ratio 1.65, 95% CI 1.17-2.33, p value = 0.005). Considering that the embolic stroke is less associated with atherosclerotic change, our predictive model of significant CAD was made without embolic stroke (n = 599). In our multivariate model 2 including univariate <0.1, the independent predictors of significant CAD were male (OR 1.62, 95% CI 1.11-2.35, p = 0.012), diabetes mellitus (OR 1.81, 95% CI 1.22-2.68, p = 0.003), previous stroke (OR 1.63, 95% CI 1.02-2.60, p = 0.039), low ankle-brachial index (ABI; <0.9; OR 3.25, 95% CI 1.21-8.73, p = 0.019), left ventricular ejection fraction (EF) <50% on echocardiography (OR 2.82, 95% CI 1.25-6.35, p = 0.012), troponin I or T positive (OR 2.76, 95% CI 1.69-4.53, p < 0.001), and complex features on cerebral angiography (OR 2.73, 95% CI 1.78-4.19, p < 0.001). CONCLUSIONS: Accurate coronary evaluation by coronary angiography might be considered when patients with atherosclerotic cerebral artery detected on brain MRA or CTA planned cerebral angiography were male or have diabetes mellitus, previous stroke, low ABI (<0.9), left ventricular EF <50% on echocardiography, troponin I or T positivity, and complex features on cerebral angiography.

Beyond dichotomy: patterns and amplitudes of SSEPs and neurological outcomes after cardiac arrest.

BACKGROUND: We hypothesized that the absence of P25 and the N20-P25 amplitude in somatosensory evoked potentials (SSEPs) have higher sensitivity than the absence of N20 for poor neurological outcomes, and we evaluated the ability of SSEPs to predict long-term outcomes using pattern and amplitude analyses. METHODS: Using prospectively collected therapeutic hypothermia registry data, we evaluated whether cortical SSEPs contained a negative or positive short-latency wave (N20 or P25). The N20-P25 amplitude was defined as the largest difference in amplitude between the N20 and P25 peaks. A good or poor outcome was defined as a Glasgow-Pittsburgh Cerebral Performance Category (CPC) score of 1-2 or 3-5, respectively, 6 months after cardiac arrest. RESULTS: A total of 192 SSEP recordings were included. In all patients with a good outcome (n = 51), both N20 and P25 were present. Compared to the absence of N20, the absence of N20-P25 component improved the sensitivity for predicting a poor outcome from 30.5% (95% confidence interval [CI], 23.0-38.8%) to 71.6% (95% CI, 63.4-78.9%), while maintaining a specificity of 100% (93.0-100.0%). Using an amplitude < 0.64 µV, i.e., the lowest N20-P25 amplitude in the good outcome group, as the threshold, the sensitivity for predicting a poor neurological outcome was 74.5% (95% CI, 66.5-81.4%). Using the highest N20-P25 amplitude in the CPC 4 group (2.31 µV) as the threshold for predicting a good outcome, the sensitivity and specificity were 52.9% (95% CI, 38.5-67.1%) and 96.5% (95% CI, 91.9-98.8%), respectively. The predictive performance of the N20-P25 amplitude was good, with an area under the receiver operating characteristic curve (AUC) of 0.94 (95% CI, 0.90-0.97). The absence of N20 was statistically inferior regarding outcome prediction (p < 0.05), and amplitude analysis yielded significantly higher AUC values than did the pattern analysis (p < 0.05). CONCLUSIONS: The simple pattern analysis of whether the N20-P25 component was present had a sensitivity comparable to that of the N20-P25 amplitude for predicting a poor outcome. Amplitude analysis was also capable of predicting a good outcome.

Angiotensin Receptor Blockers as an Alternative to Angiotensin-Converting Enzyme Inhibitors in Patients with Acute Myocardial Infarction Undergoing Percutaneous Coronary Intervention.

BACKGROUND: Angiotensin-converting enzyme inhibitors (ACEIs) are the first choice for the treatment of acute myocardial infarction (AMI), and angiotensin receptor blockers (ARBs) should be considered in patients intolerant to ACEIs. Although previous studies support the use of ARBs as an alternative to ACEIs, these studies showed inconsistent results. The objective of this study was to demonstrate the clinical impact of ARBs as an alternative to ACEIs in patients with AMI undergoing percutaneous coronary intervention (PCI). METHODS: The CardiOvascular Risk and idEntificAtion of potential high-risk population in AMI (COREA-AMI) registry enrolled all consecutive patients with AMI undergoing PCI. The primary endpoint was the composite of cardiovascular death, myocardial infarction, stroke, or hospitalization due to heart failure. RESULTS: Of the 3,328 eligible patients, ARBs replaced ACEIs in 816 patients, while 824 patients continued to use ACEIs and 826 patients continued to use ARBs. The remaining 862 patients did not receive ACEIs/ARBs. After the adjustment with inverse probability weighting, the primary endpoints in the first groups were similar (7.5% vs. 8.0%, hazard ratio [HR], 0.89; 95% confidence interval [CI], 0.75-1.05; P = 0.164). Composite events were less frequent in the ACEI to ARB group than no ACEI/ARB group (7.5% vs. 11.8%, HR, 0.76; 95% CI, 0.64-0.90; P = 0.002). CONCLUSION: The alternative use of ARBs following initial treatment with ACEIs demonstrates comparable clinical outcomes to those with continued use of ACEIs and is associated with an improved rate of composite events compared to no ACEI/ARB use in patients with AMI undergoing PCI. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02385682.

Infarcted Myocardium-Primed Dendritic Cells Improve Remodeling and Cardiac Function After Myocardial Infarction by Modulating the Regulatory T Cell and Macrophage Polarization.

BACKGROUND: Inflammatory responses play a critical role in left ventricular remodeling after myocardial infarction (MI). Tolerogenic dendritic cells (tDCs) can modulate immune responses, inducing regulatory T cells in a number of inflammatory diseases. METHODS: We generated tDCs by treating bone marrow-derived dendritic cells with tumor necrosis factor-α and cardiac lysate from MI mice. We injected MI mice, induced by a ligation of the left anterior descending coronary artery in C57BL/6 mice, twice with tDCs within 24 hours and at 7 days after the ligation. RESULTS: In vivo cardiac magnetic resonance imaging and ex vivo histology confirmed the beneficial effect on postinfarct left ventricular remodeling in MI mice treated with tDCs. Subcutaneously administered infarct lysate-primed tDCs near the inguinal lymph node migrated to the regional lymph node and induced infarct tissue-specific regulatory T-cell populations in the inguinal and mediastinal lymph nodes, spleen, and infarcted myocardium, indicating that a local injection of tDCs induces a systemic activation of MI-specific regulatory T cells. These events elicited an inflammatory-to-reparative macrophage shift. The altered immune environment in the infarcted heart resulted in a better wound remodeling, preserved left ventricular systolic function after myocardial tissue damage, and improved survival. CONCLUSIONS: This study showed that tDC therapy in a preclinical model of MI was potentially translatable into an antiremodeling therapy for ischemic tissue repair.