QuestionDoes achieving guideline-recommended low-density lipoprotein cholesterol (LDL-C) levels help prevent neoatherosclerosis after drug-eluting stent implantation in patients with ST-segment elevation myocardial infarction (STEMI)?FindingsIn this secondary analysis of the CONNECT randomized clinical trial, neoatherosclerosis was less frequent in patients who achieved guideline-endorsed LDL-C levels and received high-intensity statin therapy. On-treatment LDL-C level emerged as an independent determinant of neoatherosclerosis.MeaningAchieving guideline-recommended LDL-C levels through intensive lipid-lowering therapy may help prevent neoatherosclerosis formation and prevent late stent failure in patients with STEMI. ImportanceNeoatherosclerosis represents a major cause of late stent failure and results in cardiac events after drug-eluting stent (DES) implantation. Achieving secondary preventive low-density lipoprotein cholesterol (LDL-C) target levels can reduce plaque progression in native coronary arteries; however, its association with neoatherosclerosis formation remains unclear.ObjectiveTo determine whether achieving guideline-endorsed LDL-C levels after DES implantation is associated with reduced risk of long-term neoatherosclerosis formation.Design, Setting, and ParticipantsThis is a post hoc analysis of the CONNECT randomized clinical trial conducted at 7 sites in Switzerland and Japan that had randomized 239 patients with ST-segment elevation myocardial infarction (STEMI) to percutaneous coronary intervention (PCI) with biodegradable- or durable-polymer everolimus-eluting stents between June 2017 and June 2020. The prevalence of neoatherosclerosis was assessed with optical coherence tomography (OCT) 3 years after primary PCI. Data analysis for this post hoc analysis was conducted from September 2024 to October 2025.InterventionPatients with STEMI received primary PCI with DES, and statin therapy was recommended according to country-specific guidelines.Main Outcomes and MeasuresThe prevalence of neoatherosclerosis 3 years after primary PCI was compared between patients with vs without achievement of guideline-endorsed target LDL-C levels. A multivariable predictor analysis was performed to determine whether on-treatment LDL-C levels were associated with occurrence of neoatherosclerosis.ResultsAmong 178 patients (mean [SD] age, 63.4 [10.9] years; 27 [15%] female) who underwent OCT at 3 years, 98 patients (55%) achieved the target LDL-C level and 80 patients (45%) did not. The mean (SD) on-treatment LDL-C levels for these groups were 48 (13) and 87 (37) mg/dL, respectively (to convert to millimoles per liter, multiply by 0.0259). The prevalence of neoatherosclerosis was lower in patients who achieved the target LDL-C level as compared with patients who did not (7 patients [7%] vs 15 patients [19%], respectively; odds ratio for those who did not achieve the LDL-C target level, 3.00; 95% CI, 1.19-8.24; P = .02). On-treatment LDL-C level (per 25-mg/dL increase) emerged as an independent determinant of neoatherosclerosis at 3 years in multivariable logistic regression analysis (odds ratio, 1.46; 95% CI, 1.09-2.01; P = .01).Conclusions and RelevanceOn-treatment LDL-C level emerged as an independent predictor of neoatherosclerosis 3 years after DES implantation for STEMI. Neoatherosclerosis was less frequent among patients who achieved the guideline-recommended on-treatment LDL-C level, underscoring the importance of LDL-C lowering in preventing neoatherosclerosis formation.Trial RegistrationClinicalTrials.gov Identifier: NCT03440801 This secondary analysis of the CONNECT randomized clinical trial evaluates whether achieving a guideline-endorsed low-density lipoprotein cholesterol level after drug-eluting stent implantation in patients with ST-segment elevation myocardial infarction (STEMI) is associated with reduced risk of long-term neoatherosclerosis formation.

Background:Established biomarkers are used for risk stratification after STEMI, but their relationship with cardiac magnetic resonance (CMR)-derived infarct characteristics at 30 days remains incompletely understood. Because 30-day CMR reflects an intermediate post-infarction stage between acute myocardial injury and the later chronic infarct state, we evaluated whether baseline high-sensitivity troponin T (hsTnT), N-terminal pro-B-type natriuretic peptide (NT-proBNP), cellular communication network factor 1 (CCN1), and proprotein convertase subtilisin/kexin type 9 (PCSK9) are associated with 30-day CMR parameters. Methods:In this pre-specified CLEVER-ACS substudy, associations between baseline biomarkers and 30-day CMR parameters were assessed using Spearman correlation. Receiver operating characteristic (ROC) analysis with area under the curve (AUC) was performed for associations after median dichotomization. Exploratory analyses assessed associations with relative CMR changes. Results:56 STEMI patients were analyzed. hsTnT and NT-proBNP showed the strongest association pattern across functional, structural, volumetric, and microvascular 30-day CMR parameters. CCN1 was associated only with left ventricular ejection fraction (LVEF), and PCSK9 showed no significant associations. hsTnT and NT-proBNP showed relevant discriminatory performance for parameters including LVEF (AUC 0.79, 95% CI 0.67-0.91, and 0.81 [0.69-0.93]), left ventricular scar (0.87 [0.77-0.96] and 0.76 [0.63-0.89]), scar mass (0.84 [0.74-0.95] and 0.79 [0.67-0.91]), and microvascular obstruction (0.72 [0.56-0.87] and 0.71 [0.55-0.86]), respectively. Exploratory analyses linked only hsTnT and NT-proBNP to changes in CMR parameters. Conclusions:Baseline hsTnT and NT-proBNP showed strong associations with 30-day CMR parameters after STEMI, whereas CCN1 and PCSK9 provided no discriminatory value in this intermediate post-infarction stage.

AIMS:Hybrid intravascular ultrasound-optical coherence tomography (IVUS-OCT) can enable more accurate plaque characterization than single-modality intravascular imaging, enhancing treatment planning and vulnerable plaque detection. However, image interpretation in IVUS-OCT is challenging and time-consuming. To overcome this limitation, we introduce a novel histology-trained deep learning (DL)-classifier for plaque component classification in IVUS-OCT images and compare its performance against single-modality DL and expert analysts. METHODS AND RESULTS:IVUS-OCT frames and matched histological sections from 10 cadaveric human hearts were included in this analysis. The histological data were used to define fibrotic, calcific, and necrotic core tissue regions of interest (ROIs) in IVUS-OCT and used to train three DL-classifiers for IVUS, OCT, or hybrid IVUS-OCT image analysis (992 frames) and test their performance (264 frames). The test set was additionally annotated by experts from three different core labs, and their estimations and those of the DL-classifiers were compared with histology.The IVUS-OCT DL-classifier had a superior performance to the IVUS-DL, OCT-DL, and the expert analysts in detecting plaque phenotypes (Kappa 0.60 vs. 0.19, 0.35, and 0.53, respectively) and accurately classified 68% of histologically defined fibroatheromas. The hybrid IVUS-OCT DL-classifier also had a better performance than single-modality DL-classifiers and the experts in assessing tissue types in ROIs annotated by histology (overall accuracy 86.7% compared with 73.2% for IVUS-DL, 66.6% for OCT-DL, and 70.6% for the experts). CONCLUSION:Plaque characterization using a histology-trained hybrid IVUS-OCT DL-classifier is feasible and enables more accurate detection of plaque components and phenotype classification than single-modality DL-classifiers and expert analysts.

BACKGROUND:PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibition is a potent cholesterol-lowering strategy. This study examined the effects of PCSK9 monoclonal antibodies (mAbs) and high-intensity statins beyond low-density lipoprotein cholesterol reduction, which are not fully defined, particularly in patients with acute myocardial infarction (MI). METHODS:Proteomic and lipidomic analyses were conducted on plasma from 265 patients with acute MI from the PACMAN-AMI (Effects of the PCSK9 Antibody Alirocumab on Coronary Atherosclerosis in Patients With Acute Myocardial Infarction) randomized, placebo-controlled PCSK9 mAb trial and 34 patients without MI with hyperlipidemia from the Vienna Lipid Clinic registry, also receiving PCSK9 mAbs. RESULTS:Discovery proteomics revealed changes in apolipoproteins and increased PCOLCE (procollagen C-endopeptidase enhancer 1) levels in both the PCSK9 mAb and placebo groups after MI. UK Biobank data confirmed PCOLCE and PCSK9 upregulation as associated with statin use. Hepatoma cell experiments demonstrated a dose-dependent PCOLCE induction on statin treatment. Compared with placebo (statins only), PCSK9 mAb therapy resulted in greater reductions in APOB (apolipoprotein B), APOE (apolipoprotein E), APOC2 (apolipoprotein C2), and APOC3 (apolipoprotein C3), as shown by targeted proteomics. Mediation analysis indicated that these changes were largely explained by low-density lipoprotein cholesterol lowering. Lipidomics identified more pronounced reductions in cholesteryl esters, ceramides, sphingomyelins, phosphatidylcholines, triglycerides, and diglycerides in PCSK9 mAb-treated patients with MI. Results were largely consistent in patients without MI. However, levels of LPA (apolipoprotein[a]), the characteristic protein component of lipoprotein(a), remained unchanged in PCSK9 mAb-treated patients with MI, since a rise of LPA was observed in the placebo group post-MI. CONCLUSIONS:Most apolipoprotein changes after PCSK9 mAb therapy following MI were mediated by low-density lipoprotein cholesterol lowering. Statin use is associated with increased circulating PCOLCE, with hepatoma cell experiments supporting a predominant hepatic origin. Combining PCSK9 mAbs with high-intensity statins mitigates post-MI increases in lipoprotein(a). REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT03067844.

Importance:Neoatherosclerosis represents a major cause of late stent failure and results in cardiac events after drug-eluting stent (DES) implantation. Achieving secondary preventive low-density lipoprotein cholesterol (LDL-C) target levels can reduce plaque progression in native coronary arteries; however, its association with neoatherosclerosis formation remains unclear. Objective:To determine whether achieving guideline-endorsed LDL-C levels after DES implantation is associated with reduced risk of long-term neoatherosclerosis formation. Design, Setting, and Participants:This is a post hoc analysis of the CONNECT randomized clinical trial conducted at 7 sites in Switzerland and Japan that had randomized 239 patients with ST-segment elevation myocardial infarction (STEMI) to percutaneous coronary intervention (PCI) with biodegradable- or durable-polymer everolimus-eluting stents between June 2017 and June 2020. The prevalence of neoatherosclerosis was assessed with optical coherence tomography (OCT) 3 years after primary PCI. Data analysis for this post hoc analysis was conducted from September 2024 to October 2025. Intervention:Patients with STEMI received primary PCI with DES, and statin therapy was recommended according to country-specific guidelines. Main Outcomes and Measures:The prevalence of neoatherosclerosis 3 years after primary PCI was compared between patients with vs without achievement of guideline-endorsed target LDL-C levels. A multivariable predictor analysis was performed to determine whether on-treatment LDL-C levels were associated with occurrence of neoatherosclerosis. Results:Among 178 patients (mean [SD] age, 63.4 [10.9] years; 27 [15%] female) who underwent OCT at 3 years, 98 patients (55%) achieved the target LDL-C level and 80 patients (45%) did not. The mean (SD) on-treatment LDL-C levels for these groups were 48 (13) and 87 (37) mg/dL, respectively (to convert to millimoles per liter, multiply by 0.0259). The prevalence of neoatherosclerosis was lower in patients who achieved the target LDL-C level as compared with patients who did not (7 patients [7%] vs 15 patients [19%], respectively; odds ratio for those who did not achieve the LDL-C target level, 3.00; 95% CI, 1.19-8.24; P = .02). On-treatment LDL-C level (per 25-mg/dL increase) emerged as an independent determinant of neoatherosclerosis at 3 years in multivariable logistic regression analysis (odds ratio, 1.46; 95% CI, 1.09-2.01; P = .01). Conclusions and Relevance:On-treatment LDL-C level emerged as an independent predictor of neoatherosclerosis 3 years after DES implantation for STEMI. Neoatherosclerosis was less frequent among patients who achieved the guideline-recommended on-treatment LDL-C level, underscoring the importance of LDL-C lowering in preventing neoatherosclerosis formation. Trial Registration:ClinicalTrials.gov Identifier: NCT03440801.

BACKGROUND AND AIMS:Atherosclerotic plaque rupture is largely acknowledged as the main mechanism of acute coronary syndrome. However, the prognostic significance of plaque rupture detected in nonculprit coronary sites remains largely unknown. METHODS:We investigated the long-term clinical outcomes of nonculprit plaque rupture detected by optical coherence tomography in the prospective CLIMA study. The primary composite endpoint was cardiac death or target-segment myocardial infarction (TS-MI) through 5-year follow-up. RESULTS:Among 1003 patients (age 64.8y; 24.6% women), nonculprit plaque rupture was observed in 7.3% of patients. Three-vessel disease, total plaque length, thin-cap fibroatheroma and large lipid arc were independently associated with nonculprit plaque rupture. The presence of nonculprit plaque rupture was associated with the primary endpoint at univariable (HR 2.09, 95%CI 1.07-4.08, p = 0.030) but not clinical (adjusted HR 1.70, 95%CI 0.83-3.48, p = 0.145) and morphological (adjusted HR 1.63, 95%CI 0.83-3.21, p = 0.156) multivariable analysis. The individual rates of cardiac death (HR 1.64, 95%CI 0.70-3.85, p = 0.252) and TS-MI (HR 2.87, 95%CI 0.97-8.47, p = 0.057) did not significantly differ between patients with vs without nonculprit plaque rupture. At the Kaplan-meier analysis, the presence of nonculprit plaque rupture was significantly associated with the primary endpoint only in presence of a thin-cap fibroatheroma (TCFA). The presence of nonculprit plaque rupture did not improve the predictive accuracy of any TCFA in multiple prediction models. CONCLUSIONS:Nonculprit plaque rupture was associated with cardiac events at univariable but not multivariable analysis. Identification of nonculprit PR did not improve the predictive value of established high-risk morphological features such as TCFA; however, future ad hoc studies are needed to further clarify its potential independent clinical relevance. CLINICAL TRIAL REGISTRATION:URL: https://www. CLINICALTRIALS:gov; Unique identifier: NCT02883088.

Background and Aims Plaque rupture can occur at non-obstructive lesions in non-infarct-related coronary arteries (non-IRAs) without inducing ischaemia. This study aimed to: (1) assess the frequency and lesion characteristics of plaque rupture in non-IRAs of acute myocardial infarction (AMI) patients, (2) evaluate morphological changes in rupture sites over 52 weeks, and (3) investigate the baseline morphology of new-onset ruptures.Methods This study analysed pooled data from the IBIS-4 and PACMAN-AMI trials. Patients presenting with AMI underwent multimodality intracoronary imaging of non-IRAs at baseline and after 52 weeks.Results Among 783 lesions from 336 patients evaluated at baseline, plaque rupture was observed in 41 lesions of 40 patients (12%). Biomarkers including lipid and inflammation markers were comparable between patients with and without rupture in non-IRAs. Lesions with rupture showed larger percent atheroma volume (53.3 +/- 6.4 vs. 49.5 +/- 5.8%, estimated difference 3.6[1.9 to 5.4]), larger external elastic membrane area (20.5 +/- 4.8 vs. 15.7 +/- 5.6 mm2, 4.1[2.5 to 5.7]), and smaller minimum fibrous cap thickness (69 +/- 49 vs. 116 +/- 84 mu m, -43[-75 to -11]) compared to those without. Among 41 rupture sites assessed serially, 21 (51%) healed by 52 weeks. At follow-up, 10 rupture sites were newly identified, and thin-cap fibroatheroma was the most frequent baseline morphology of those.Conclusions Plaque rupture in non-obstructive lesions of non-IRAs was present in 12% of AMI patients. Larger plaque volume, positive remodeling, and thinner fibrous cap were associated with rupture. More than half of untreated ruptures transitioned into stable morphologies. Thin-cap fibroatheroma was the most frequent underlying morphology of new-onset rupture.

BACKGROUND AND AIMS:Cardiogenic shock (CS) is the most dreadful complication of acute coronary syndromes (ACS). Endothelial dysfunction and vascular leakage are hallmarks of CS pathophysiology; however, biomarkers reflecting these early processes are lacking. The adrenomedullin (ADM) system-the inactive precursor glycine-extended ADM (ADM-Gly), the activating enzyme peptidylglycine α-amidating monooxygenase (PAM), and biologically active ADM (bio-ADM)-modulates vascular tone and permeability. This study investigated associations of ADM system components with CS and 1-year mortality risk after ACS. METHODS:ADM-Gly, PAM, and bio-ADM were assessed in 4098 (Switzerland; SPUM-ACS) and 824 (France; FAST-MI) ACS patients without CS on admission. The primary endpoint was in-hospital CS; the secondary endpoint was 1-year mortality. Biomarker-outcome associations were analysed using multivariable-adjusted regression models, and the incremental predictive value beyond established risk scores was quantified. RESULTS:Higher ADM-Gly and bio-ADM, but not PAM, were associated with systemic inflammation and haemodynamic compromise. ADM-Gly and bio-ADM independently predicted CS risk in Switzerland (adjusted odds ratio [aOR] per log2 increase, 1.44, 95% confidence interval [CI] 1.22-1.71, P < .001 and aOR 1.37, 95% CI 1.10-1.70, P = .004) and France (adjusted risk ratio [RR] per log2 increase, 1.82, 95% CI 1.34-2.48, P < .001 and aRR 1.55, 95% CI 1.15-2.10, P = .004), and were associated with 1-year mortality risk (adjusted hazard ratio [aHR] per log2 increase, 1.33, 95% CI 1.09-1.61, P = .005 and aHR 1.46, 95% CI 1.15-1.86, P = .002). Addition of ADM-Gly and bio-ADM to the ORBI risk score improved its discrimination (Δ area under the receiver operating characteristic curve 0.02), reclassification (net reclassification improvement 0.229), and model fit (Δ Akaike information criterion -26.9), with consistent results in external validation. CONCLUSIONS:ADM-Gly and bio-ADM, but not PAM, independently predict in-hospital CS and 1-year mortality risk in initially stable patients with ACS and improve early risk stratification.

BACKGROUND:The incorporation of side branches in vessel geometry influences wall shear stress (WSS) distribution. However, complete vessel reconstruction is time-consuming, and there is no evidence that its WSS estimations better predict atherosclerotic disease progression compared with the output of the conventional single-vessel reconstruction (SVR). METHODS:Patients who had baseline and 1-year follow-up intravascular ultrasound imaging (n=40 vessels), and patients with neoatherosclerotic lesions (n=13 vessels) on optical coherence tomography were included. All the studied vessels had at least one side branch with a diameter >1 mm; 3-dimensional complete vessel reconstruction and SVR were performed, and the time-averaged WSS and multidirectional WSS were computed. The performance of both methods in predicting disease progression in intravascular ultrasound and optical coherence tomography models was assessed. RESULTS:The incorporation of side branches in 3-dimensional geometry resulted in lower minimum predominant time-averaged WSS in the intravascular ultrasound (1.09 versus 1.58 Pa, P<0.001) and optical coherence tomography-based reconstructions (0.68 versus 1.33 Pa, P<0.001) and influenced the multidirectional WSS distribution. In native segments, complete vessel reconstruction-derived WSS metrics demonstrated superior predictive performance for disease progression-defined as lumen area reduction and plaque burden increase-compared with SVR, as evidenced by improved out-of-sample accuracy (leave-one-out information criterion: 429 versus 551), discrimination (C statistic: 0.725 versus 0.651), calibration (Brier score: 0.172 versus 0.226), and explained variance (27.8% versus 20.7%). Consistent findings were observed in stented segments, where complete vessel reconstruction-derived WSS metrics more accurately predicted neointimal proliferation than SVR-derived metrics. CONCLUSIONS:Incorporating side branches into vessel reconstruction influences WSS distribution and enables more accurate prediction of atherosclerotic disease progression in native and stented segments than SVR.

Intravascular ultrasound (IVUS) and optical coherence tomography (OCT) are complementary imaging modalities to assess atherosclerosis in vivo. Combining both modalities in a single imaging system has been shown to improve the characterization of vulnerable plaques that are likely to cause acute coronary events. However, fundamental differences in tissue sensitivities and acquisition protocols make the registration of sequences challenging. Anatomical landmarks used to align IVUS and OCT sequences can be masked or lack visual similarity between modalities which renders manual alignment time-consuming and prone to observer variability, limiting its clinical use. Existing methods impose strict frame-level correspondences leading to instability in low information regions, and rely on a two-step registration process that compounds alignment errors. We propose IntraCross, a novel graph matching framework that learns partial assignments between landmarks rather than enforcing rigid frame-by-frame matching, enabling flexible correspondences while rejecting unmatchable landmarks. This is the first method to perform both temporal and rotational registration simultaneously, aligning with clinical workflows. We extend existing partial matching techniques from 2D to 3D sequences and incorporate a temporal prior to regularize the matching process. Testing in 77 vessels from 22 patients showed a high agreement with expert analysts (Williams Index=1.1; p=0.62, 0.89, 0.07) and our approach outperforms existing methods reported in the literature for circumferential registration (p=0.01, 0.04).

BACKGROUND:Acute coronary syndrome during pregnancy is rare with limited evidence; management must be tailored to safeguard both mother and fetus. CASE SUMMARY:A 40-year-old woman with type 2 diabetes presented with acute coronary syndrome at 11+3 weeks' gestation. She underwent intracoronary imaging-guided percutaneous coronary intervention (PCI) (3.0- × 28-mm stent, mean external elastic lamina diameter: 3.07 mm, lesion length: 28 mm) under minimal radiation (estimated fetal dose: ≈0.00004 mGy). After optimal stent implantation, 6 weeks of dual antiplatelet therapy with aspirin and clopidogrel were followed by lifelong aspirin. Pregnancy was uncomplicated with healthy infant delivered at 39 weeks. Postpartum angiography confirmed good result, and statin was initiated. DISCUSSION:Intracoronary imaging-guided PCI enables precise diagnosis and tailored therapy with reduced radiation exposure. Drug regimens balance maternal benefit and fetal safety. TAKE-HOME MESSAGES:Intracoronary imaging-guided PCI allows precise and safe treatment in pregnant ACS patients. Drug therapy must be adapted to avoid fetal risk while ensuring maternal protection.

BACKGROUND:Anomalous aortic origin of a right coronary artery (R-AAOCA) can cause stress-induced ischemia owing to dynamic stenosis of the intramural course. While fractional flow reserve during dobutamine challenge (FFRDobutamine) is the reference standard for hemodynamic assessment, specific scenarios favoring instantaneous wave-free ratio (iFR) over FFR remain unclear. CASE SUMMARY:An 11-year-old male competitive basketball athlete with exertional angina and R-AAOCA underwent invasive angiography. Intravascular ultrasound showed a reduction in the intramural coronary lumen cross-sectional areafrom rest to dobutamine stress (from 4.6 to 3.1 mm2 in systole; from 7.6 to 3.7 mm2 in diastole), while FFRDobutamine was 0.85 and iFRDobutamine was 0.72. DISCUSSION:The patient's iFRDobutamine matched geometrical changes and clinical presentation, while his FFRDobutamine underestimated ischemia. TAKE-HOME MESSAGE:In the case of predominant diastolic, stress-induced intramural deformation of the R-AAOCA vessel, iFRDobutamine-targeting diastolic stress-pressure ratio-may be preferred over FFRDobutamine, as the latter may miss ischemia given its cardiac cycle-averaged hyperemic calculations.

Since its introduction in 2002, left atrial appendage closure (LAAC) has rapidly expanded as an alternative to anticoagulation in patients with atrial fibrillation at high risk of stroke. Harmonized processes for data collection, analysis, and reporting in LAAC trials are essential to enhance research quality and improve clinical practice. The Left Atrial Appendage Academic Research Consortium (LAARC) initiative is an independent collaboration of academic research organizations, cardiology and neurology experts, clinical trialists, and regulatory authorities from the USA, Europe, and Asia. The consortium engaged clinical experts, regulators-including the US Food and Drug Administration (FDA), European Notified Bodies, and Japan's Pharmaceuticals and Medical Devices Agency (PMDA)-and industry leaders to define standardized study elements and endpoints for LAAC trials. Key considerations included alignment with prior Academic Research Consortium initiatives, procedural and mechanistic insights, and clinical relevance. Consensus definitions were proposed for mortality, stroke, bleeding, and device performance, along with composite endpoints for safety and effectiveness. The proposed LAARC consensus definitions aim to standardize endpoint reporting, improve comparability across studies, and support regulatory and clinical trial applications for this evolving therapy through broad dissemination in the peer-reviewed literature.

BACKGROUND AND AIMS:Patients with acute coronary syndromes (ACS) are at high ischaemic risk to which cholesterol, inflammation, and yet-to-be-identified pathways jointly contribute. The junctional protein associated with coronary artery disease (JCAD) drives incident cardiovascular events by acting on coagulation and fibrinolysis. This study aimed to assess whether JCAD serves as a novel marker of or target to address residual risk. METHODS:In the discovery cohort (SPUM-ACS; n = 4787), ACS patients at residual lipid risk [RLR; on-statin LDL cholesterol (LDL-c) ≥70 mg/dL or ≥1.8 mmol/L], residual inflammatory risk [RIR; on-statin high-sensitivity C-reactive protein (hs-CRP) ≥2.0 mg/L], or both (RILR; on-statin LDL-c ≥70 mg/dL and hs-CRP ≥2.0 mg/L) were identified and compared with propensity-score matched controls. Contributions of hs-CRP, LDL-c and JCAD to recurrent major adverse cardiovascular events (MACE) were analysed. In an independent cohort (RISK-PPCI study; n = 496), effects of JCAD on endogenous coagulation and fibrinolysis were gauged, and JCAD-MACE associations were externally validated. RESULTS:At 1 year, patients at RLR, RIR, or RILR were at higher MACE risk as compared to controls [hazard ratio (HR), 1.55, 95% confidence interval (CI) 1.08-2.23; HR 1.80, 95% CI 1.24-2.61; and HR 1.75, 95% CI 1.12-2.75, respectively]. In those at RLR, MACE risk rose with increasing hs-CRP and JCAD, respectively, in uni- (HR per log2 increase, 1.17, 95% CI 1.06-1.30; HR 1.29, 95% CI 1.03-1.62) and multivariable-adjusted models [adjusted (a)HR 1.16, 95% CI 1.03-1.30; aHR 1.27, 95% CI 1.01-1.60]. In those at RIR, MACE risk increased 1.28-fold per log2 increase in JCAD (HR 1.28, 95% CI 1.03-1.59), which prevailed in multivariable-adjusted models (aHR 1.31, 95% CI 1.04-1.65). Similarly, in patients at RILR, MACE risk increased almost linearly with increasing JCAD (HR 1.45, 95% CI 1.09-1.92), independently of potential confounders (aHR 1.47, 95% CI 1.11-1.97). Plasma levels of JCAD correlated positively with proxies of impaired endogenous fibrinolysis, with the JCAD-MACE association being similarly observed in the external validation cohort. CONCLUSIONS:Acute coronary syndrome patients at RLR, RIR, or both are at high ischaemic risk. By modulating coagulation and endogenous fibrinolysis, JCAD represents a promising candidate to address the high residual risk that persists in ACS patients receiving guideline-recommended care. CLINICALTRIALS.GOV IDENTIFIERS:NCT01000701, NCT02562690.

BACKGROUND:Aortic root injury during transseptal puncture (TSP) is a rare but well-recognized complication. However, injury to the descending aorta has not previously been described in this context. CASE SUMMARY:A 57-year-old woman underwent left atrial appendage closure. During TSP using the VersaCross Connect radiofrequency-powered system and a 15-F steerable sheath, an unrecognized perforation of the descending aorta occurred. Despite repeated transthoracic echocardiograms showing no pericardial effusion and initial hemodynamic stability, she subsequently developed a mediastinal hematoma and bilateral pleural effusion. Management required an emergency percutaneous thoracic endovascular aortic repair, followed by surgical evacuation of the hematoma. DISCUSSION:Excessive tenting during radiofrequency-powered TSP, related to interatrial septum aneurysm, resulted in injury to the descending aorta with life-threatening consequences. TAKE-HOME MESSAGE:Radiofrequency-powered systems for TSP have enhanced tissue penetration capability and should therefore be used with caution, particularly in the presence of an interatrial septum aneurysm and atypical echocardiographic windows.

Background and Aims The gut microbiota is a modulator of cardiometabolic disease. Circulating imidazole propionate (ImP) is a microbiota-derived proatherogenic amino acid metabolite modulating the inflammatory response of myeloid cells, endothelial function, and glucose metabolism. This study examined the prognostic value of ImP in patients with coronary artery disease (CAD). Methods Circulating ImP levels were measured in independent prospective cohorts of patients with acute coronary syndrome (ACS; Swiss ACS cohort n = 4787, Swiss cardiac magnetic resonance imaging cohort n = 150, German ACS cohort n = 1428) and chronic coronary syndrome (CCS; German CCS cohort n = 701). Major adverse cardiovascular events (MACE), defined as the first occurrence of a composite of death, non-fatal myocardial infarction, or non-fatal stroke after admission, were the primary endpoint. Cox models, accounting for established risk factors including the gut-derived cardiovascular risk factor trimethylamine N-oxide, were used to evaluate the predictive value of ImP. Results Circulating ImP was associated with more advanced CAD and with cardiometabolic characteristics including diabetes and elevated high-sensitivity C-reactive protein. High ImP was an independent predictor of MACE [Swiss ACS cohort: hazard ratio (HR) per log2 increase 1.22, 95% confidence interval (CI) 1.10-1.35, P < .001; German ACS cohort: HR 2.34, 95% CI 1.46-3.76, P < .001; German CCS cohort: HR 1.32, 95% CI 1.13-1.53, P < .001)] and of mortality (Swiss ACS cohort: HR 1.34, 95% CI 1.17-1.54, P < .001; German ACS cohort: HR 2.38, 95% CI 1.48-3.82, P < .001; German CCS cohort: HR 1.50, 95% CI 1.14-1.98, P = .004) after adjustment for established risk factors. Imidazole propionate provided predictive value beyond trimethylamine N-oxide (Swiss ACS cohort: HR 1.30, 95% CI 1.05-1.61, P = .014; German CCS cohort: HR 1.31, 95% CI 1.12-1.53, P = .001). Conclusions Gut microbiota-derived ImP predicted MACE in patients with CAD independently of traditional risk factors and holds promise as a therapeutic target. Imidazole propionate may refine risk stratification for personalized secondary prevention strategies.