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Background: This study aims to evaluate the progression of morphological and functional alterations over time in patients with hypertrophic cardiomyopathy (HCM) using Cardiac Magnetic Resonance (CMR)., Methods: A retrospective analysis was conducted on patients with HCM who underwent serial CMR at 1.5 Tesla. Left ventricular (LV) mass was measured during diastole, including papillary muscles and trabeculae assessment. Appearance of Late Gadolinium Enhancement (LGE) was volumetrically quantified using a 5-standard-deviation (SD) threshold., Results: Thirty-two patients, with a mean age of 44 ± 16 years (range: 11-70 years), were evaluated after an average follow-up period of 5.2 ± 2.4 years (range: 0.8-9.1 years). Significant increases were observed in LV mass (from 194 ± 56 g to 217 ± 60 g; p = 0.0001), septal wall thickness (from 18 ± 4 mm to 19 ± 4 mm; p = 0.01), LGE mass (from 6 ± 17 g to 8 ± 18 g; p = 0.006), and left atrial volume (from 109 ± 41 ml to 129 ± 40 ml; p = 0.0001). Both left and right ventricular ejection fractions (LVEF and RVEF) significantly decreased over time (LVEF: from 70 ± 9 % to 66 ± 9 %; p = 0.04 and RVEF: from 70 ± 7 % to 67 ± 9 %; p = 0.02). Multivariate regression analysis revealed that HCM mass gain was independently associated with age (B = -0.43; p = 0.02) and LGE mass (B = -0.46; p = 0.02). The median LV mass gain rate in adults was 1.7 g per year/BSA (IQR, 0.6-2.7) compared to 6.0 g per year/BSA (IQR, 0.5-11.6) in adolescents (mean age: 16 years; range: 11-20 years). A positive correlation was found between LV mass and LGE mass (B = 0.55; p = 0.001), while an inverse relationship was observed between LV mass gain and LGE mass gain rates (-0.37; p = 0.03)., Conclusion: The range of morphological changes in HCM seems to reflect an age-related equilibrium between hypertrophy and fibrosis. The extent of changes in LV mass, fibrosis, and functional decline in HCM may help identify patients at risk, emphasizing the importance of ongoing follow-up studies., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Low endothelial shear stress (ESS) and associated adverse biomechanical features stimulate inflammation, contribute to atherogenesis, and predispose to coronary plaque disruption. The mechanistic links between adverse flow-related hemodynamics and inflammatory mediators implicated in plaque erosion, however, remain little explored. We investigated the relationship of high-risk ESS metrics to culprit lesion proinflammatory/proatherogenic cells and cytokines/chemokines implicated in coronary plaque erosion in patients with acute coronary syndromes. In eroded plaques, low ESS, high ESS gradient, and steepness of plaque topographical slope associated with increased numbers of local T cells and subsets (CD4 + , CD8 + , natural killer T cells) as well as inflammatory mediators (interleukin [IL]-6, macrophage inflammatory protein-1β, IL-1β, IL-2)., Competing Interests: Dr Libby has received funding support from the National Heart, Lung, and Blood Institute (1R01HL134892, 1R01HL163099-01, R01AG063839, R01HL151627, R01HL157073, R01HL166538), and the RRM Charitable Fund. Dr Libby is an unpaid consultant to, or involved in clinical trials for Amgen, Baim Institute, Beren Therapeutics, Esperion Therapeutics, Genentech, Kancera, Kowa Pharmaceuticals, Novo Nordisk, Novartis, and Sanofi-Regeneron. Dr Libby is a member of the scientific advisory board for Amgen, Caristo Diagnostics, CSL Behring, Eulicid Bioimaging, Kancera, Kowa Pharmaceuticals, Olatec Therapeutics, Novartis, PlaqueTec, Polygon Therapeutics, TenSixteen Bio, Soley Thereapeutics, and XBiotech, Inc. Dr Libby's laboratory has received research funding in the last 2 years from Novartis, Novo Nordisk and Genentech. Dr Libby is on the Board of Directors of XBiotech, Inc. Dr Libby has a financial interest in Xbiotech, a company developing therapeutic human antibodies, in TenSixteen Bio, a company targeting somatic mosaicism and clonal hematopoiesis of indeterminate potential (CHIP) to discover and develop novel therapeutics to treat age-related diseases, and in Soley Therapeutics, a biotechnology company that is combining artificial intelligence with molecular and cellular response detection for discovering and developing new drugs, currently focusing on cancer therapeutics. Dr Libby's interests were reviewed and are managed by Brigham and Women's Hospital and Mass General Brigham in accordance with their conflict-of-interest policies. Dr Landmesser has received institutional research grants from Amgen, Abbott, Bayer and Novartis. Dr Abdelwahed receives consultancy fees from Boston Scientific and Shockwave. Dr Stone's laboratory was funded by the National Heart, Lung, and Blood Institute (R01HL146144-01A1 and R01HL140498). Dr Ahmed was supported by grants from the Swedish Heart-Lung Foundation (20200165 and 20230167), the Swedish Research Council (202100456), the Swedish Society of Medicine (SLS-961835), Erik and Edith Fernströms Foundation (FS-2021:0004), Karolinska Institutet (FS2020:0007), the Sweden-America Foundation, and the Swedish Heart Foundation. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

(1) Background: Dyslipidemia represents a major risk factor for atherosclerosis-driven cardiovascular disease. Emerging evidence suggests a close relationship between cholesterol metabolism and gut microbiota. Recently, we demonstrated that the short-chain fatty acid (SCFA) propionate (PA) reduces serum cholesterol levels through an immunomodulatory mechanism. Here, we investigated the effects of oral PA supplementation on the human serum metabolome and analyzed changes in the serum metabolome in relation to the cholesterol-lowering properties of PA. (2) Methods: The serum metabolome of patients supplemented with either placebo or propionate orally for 8 weeks was assessed using a combination of flow injection analysis-tandem (FIA-MS/MS) as well as liquid chromatography (LC-MS/MS) and mass spectrometry using a targeted metabolomics kit (MxP ® Quant 500 kit: BIOCRATES Life Sciences AG, Innsbruck, Austria). A total of 431 metabolites were employed for further investigation in this study. (3) Results: We observed a significant increase in distinct bile acids (GCDCA: fold change = 1.41, DCA: fold change = 1.39, GUDCA: fold change = 1.51) following PA supplementation over the study period, with the secondary bile acid DCA displaying a significant negative correlation with the serum cholesterol levels. (4) Conclusions: Oral supplementation with PA modulates the serum metabolome with a particular impact on the circulatory bile acid profile. Since cholesterol and bile acid metabolism are interconnected, the elevation of the secondary bile acid DCA may contribute to the cholesterol-lowering effect of PA.

Purpose To examine the clinical feasibility of workstation-based CT fractional flow reserve (CT-FFR) for coronary artery disease (CAD) evaluation during preprocedural planning in patients undergoing transcatheter aortic valve replacement (TAVR). Materials and Methods In this retrospective single-center study, 434 patients scheduled for TAVR between 2018 and 2020 were screened for study inclusion; a relevant proportion of patients (35.0% [152 of 434]) was not suitable for evaluation due to insufficient imaging properties. A total of 112 patients (mean age, 82.1 years ± 6.7 [SD]; 58 [52%] men) were included in the study. Invasive angiography findings, coronary CT angiography results, and Agatston score were acquired and compared with on-site CT-FFR computation for evaluation of CAD and prediction of major adverse cardiovascular events (MACE) within a 24-month follow-up. Results Hemodynamic relevant CAD, as suggested by CT-FFR of 0.80 or less, was found in 41 of 70 (59%) patients with stenosis of 50% or more. MACE occurred in 23 of 112 (20.5%) patients, from which 14 of 23 had stenoses with CT-FFR of 0.80 or less (hazard ratio [HR], 3.33; 95% CI: 1.56, 7.10; P = .002). CT-FFR remained a significant predictor of MACE after inclusion in a multivariable model with relevant covariables (HR, 2.89; 95% CI: 1.22, 6.86; P = .02). An Agatston score of 1000 Agatston units or more (HR, 2.25; 95% CI: 0.98, 5.21; P = .06) and stenoses of 50% or more determined via invasive angiography (HR, 0.94; 95% CI: 0.41, 2.17; P = .88) were not significant predictors of MACE. Conclusion Compared with conventional CAD markers, CT-FFR better predicted adverse outcomes after TAVR. A relevant portion of the screened cohort, however, was not suitable for CT-based CAD evaluation. Keywords: CT, Transcatheter Aortic Valve Implantation/Replacement (TAVI/TAVR), Cardiac, Coronary Arteries, Outcomes Analysis © RSNA, 2024 See also the commentary by Weir-McCall and Pugliese in this issue.

Critical care cardiology (CCC) in the modern era is shaped by a multitude of innovative treatment options and an increasingly complex, ageing patient population. Generating high-quality evidence for novel interventions and devices in an intensive care setting is exceptionally challenging. As a result, formulating the best possible therapeutic approach continues to rely predominantly on expert opinion and local standard operating procedures. Fostering the full potential of CCC and the maturation of the next generation of decision-makers in this field calls for an updated training concept, that encompasses the extensive knowledge and skills required to care for critically ill cardiac patients while remaining adaptable to the trainee's individual career planning and existing educational programs. In the present manuscript, we suggest a standardized training phase in preparation of the first ICU rotation, propose a modular CCC core curriculum, and outline how training components could be conceptualized within three sub-specialization tracks for aspiring cardiac intensivists., Competing Interests: PL received speaker honoraria and consulting fees from Astra Zeneca, Bayer, Pfizer, Edwards Lifesciences, and research honoraria from Edwards Lifesciences outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Binzenhöfer, Gade, Roden, Saleh, Lanz, Sierra, Seifert, Scherer, Schrage, Haertel, Spieth, Mangner, Adler, Hoyer, Graf, Billig, Salem, Rangel, Speidl, Hagl, Hausleiter, Massberg, Preusch, Meder, Leistner, Luedike, Rassaf, Zimmer, Westermann, Zeymer, Schäfer, Thiele and Lüsebrink.)

Introduction: Risk stratification based on Euroscore II (ESII) is used in some centres to assist decisions to perform transcatheter aortic valve implant (TAVI) procedures. ESII is a generic, non-TAVI-specific metric, and its performance fades for mortality at follow-up longer than 30 days. We investigated if a TAVI-specific predictive model could achieve improved predictive preinterventional accuracy of 1-year mortality compared with ESII., Patients and Methods: In this prospective pilot study, 284 participants with severe symptomatic aortic valve stenosis who underwent TAVI were enrolled. Standard clinical metrics (American Society of Anesthesiology (ASA), New York Heart Association and ESII) and patient-reported outcome measures (EuroQol-5 Dimension-Visual Analogue Scale, Kansas City Cardiomyopathy Questionnaire and Clinical Frailty Scale (CFS)) were assessed 1 day before TAVI. Using these data, we tested predictive models (logistic regression and decision tree algorithm (DTA)) with 1-year mortality as the dependent variable., Results: Logistic regression yielded the best prediction, with ASA and CFS as the strongest predictors of 1-year mortality. Our logistic regression model score showed significantly better prediction accuracy than ESII (area under the curve=0.659 vs 0.800; p=0.002). By translating our results to a DTA, cut-off score values regarding 1-year mortality risk emerged for low, intermediate and high risk. Treatment costs and length of stay (LoS) significantly increased in high-risk patients., Conclusions and Significance: A novel TAVI-specific model predicts 1-year mortality, LoS and costs after TAVI using simple, established, transparent and inexpensive metrics before implantation. Based on this preliminary evidence, TAVI team members and patients can make informed decisions based on a few key metrics. Validation of this score in larger patient cohorts is needed., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Randomized evidence suggested improved outcomes in fractional flow reserve (FFR) guidance of coronary revascularization compared to medical therapy in well-defined patient cohorts. However, the impact of FFR-guided revascularization on long-term outcomes of unselected patients with chronic or acute coronary syndromes (ACS) is unknown., Aims: The FLORIDA (Fractional FLOw Reserve In cardiovascular DiseAses) study sought to investigate outcomes of FFR-guided vs. angiography-guided treatment strategies in a large, real-world cohort., Methods: This study included patients enrolled into the German InGef Research Database. Patients undergoing coronary angiography between January 2014 and December 2015 were included in the analysis. Eligible patients had at least one inpatient coronary angiogram for suspected coronary artery disease between January 2014 and December 2015. Patients were stratified into FFR arm if a coronary angiography with adjunctive FFR measurement was performed, otherwise into the angiography-only arm. Matching was applied to ensure a balanced distribution of baseline characteristics in the study cohort. Patients were followed for 3 years after index date and primary endpoint was all-cause mortality., Results: In the matched population, mortality at 3 years was 9.6% in the FFR-assessed group and 12.6% in the angiography-only group ( p  = 0.002), corresponding to a 24% relative risk reduction with use of FFR. This effect was most pronounced in patients in whom revascularization was deferred based on FFR (8.7% vs. 12.3%, p  = 0.04) and in high-risk subgroups including patients aged ≥75 years (14.9% vs. 20.1%, p  < 0.01) and those presenting with ACS (10.2% vs. 14.0%, p  = 0.04)., Conclusions: FFR-based revascularization strategy was associated with reduced mortality at 3 years. These findings further support the use of FFR in everyday clinical practice., Competing Interests: BS reports grants from Boston Scientific and grants from Edwards Lifesciences outside the submitted work. TR reports personal fees from Vulcano Philips and personal fees from Abbott Vascular outside the submitted work. ML reports grants, personal fees and other from Abbott Medical during the conduct of the study. TV reports grants from Abbott Vascular during the conduct of the study, personal fees from Abbott Vascular, personal fees from B. Braun, personal fees from In review Boston Scientific, personal fees from Edwards Lifescience, all outside the submitted work. MS, NW and EB are employees of Abbott Vascular. DL reports personal fees and non-financial support from Abbott Vascular, during the conduct of the study, personal fees from Boston Scientific, grants and personal fees from Abbott Vascular outside the submitted work. FB, AS-S, and AE have nothing to disclose. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (© 2024 Boeckling, Stähli, Rudolph, Lutz, Schatz, Vogelmann, Stueve, West, Boone, Erbay and Leistner.)

Aims: Coronary microevaginations (CMEs) represent an outward bulge of coronary plaques and have been introduced as a sign of adverse vascular remodelling following coronary device implantation. However, their role in atherosclerosis and plaque destabilization in the absence of coronary intervention is unknown. This study aimed to investigate CME as a novel feature of plaque vulnerability and to characterize its associated inflammatory cell-vessel-wall interactions., Methods and Results: A total of 557 patients from the translational OPTICO-ACS study programme underwent optical coherence tomography imaging of the culprit vessel and simultaneous immunophenotyping of the culprit lesion (CL). Two hundred and fifty-eight CLs had a ruptured fibrous cap (RFC) and one hundred had intact fibrous cap (IFC) acute coronary syndrome (ACS) as an underlying pathophysiology. CMEs were significantly more frequent in CL when compared with non-CL (25 vs. 4%, P < 0.001) and were more frequently observed in lesions with IFC-ACS when compared with RFC-ACS (55.0 vs. 12.7%, P < 0.001). CMEs were particularly prevalent in IFC-ACS-causing CLs independent of a coronary bifurcation (IFC-ICB) when compared with IFC-ACS with an association to a coronary bifurcation (IFC-ACB, 65.4 vs. 43.7%, P = 0.030). CME emerged as the strongest independent predictor of IFC-ICB (relative risk 3.36, 95% confidence interval 1.67-6.76, P = 0.001) by multivariable regression analysis. IFC-ICB demonstrated an enrichment of monocytes in both culprit blood analysis (culprit ratio: 1.1 ± 0.2 vs. 0.9 ± 0.2, P = 0.048) and aspirated culprit thrombi (326 ± 162 vs. 96 ± 87 cells/mm2, P = 0.017), while IFC-ACB confirmed the accumulation of CD4+ T cells, as recently described., Conclusion: This study provides novel evidence for a pathophysiological involvement of CME in the development of IFC-ACS and provides first evidence for a distinct pathophysiological pathway for IFC-ICB, driven by CME-derived flow disturbances and inflammatory activation involving the innate immune system., Trial Registration: Registration of the study at clinicalTrials.gov (NCT03129503)., Competing Interests: Conflict of interest: D.M.L. received lecture honoraria from Amgen, Abbott Vascular, AstraZeneca, and Novo Nordisk. M.J. received consulting fees from Biotronik, TriCares, Veryan, and Shockwave, and is in the Steering Committee of Biotronik and Edwards Lifesciences. T.D.T. received payment honoraria from Novartis, AstraZeneca, Berlin Chemie, Abbott, NeoVasc, and Amgen. U.L. reports lecture and advisory honorary from Abbott. All other authors report no conflicts of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Rationale and Objectives: To investigate the diagnostic value of radiomics features and dual-source dual-energy CT (DECT) based material decomposition in differentiating low-risk thymomas, high-risk thymomas, and thymic carcinomas., Materials and Methods: This retrospective study included 32 patients (16 males, mean age 66 ± 14 years) with pathologically confirmed thymic masses who underwent contrast-enhanced DECT between 10/2014 and 01/2023. Two experienced readers evaluated all patients regarding conventional radiomics features, as well as DECT-based features, including attenuation (HU), iodine density (mg/mL), and fat fraction (%). Data comparisons were performed using analysis of variance and chi-square statistic tests. Receiver operating characteristic curve analysis and Cox-regression tests were used to discriminate between low-risk/high-risk thymomas and thymic carcinomas., Results: Of the 32 thymic tumors, 12 (38%) were low-risk thymomas, 11 (34%) were high-risk thymomas, and 9 (28%) were thymic carcinomas. Values differed significantly between low-risk thymoma, high-risk thymoma, and thymic carcinoma regarding DECT-based features (p ≤ 0.023) and 30 radiomics features (p ≤ 0.037). The area under the curve to differentiate between low-risk/high-risk thymomas and thymic cancer was 0.998 (95% CI, 0.915-1.000; p < 0.001) for the combination of DECT imaging parameters and radiomics features, yielding a sensitivity of 100% and specificity of 96%. During a follow-up of 60 months (IQR, 35-60 months), the multiparametric approach including radiomics features, DECT parameters, and clinical parameters showed an excellent prognostic power to predict all-cause mortality (c-index = 0.978 [95% CI, 0.958-0.998], p = 0.003)., Conclusion: A multiparametric approach including conventional radiomics features and DECT-based features facilitates accurate, non-invasive discrimination between low-risk/high-risk thymomas and thymic carcinomas., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ibrahim Yel reports a relationship with Siemens that includes: speaking and lecture fees. Christian Booz reports a relationship with Siemens that includes: speaking and lecture fees., (Copyright © 2023 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

An 80-year-old post-coronary artery bypass graft (CABG) patient had an acute coronary syndrome with non-ST-segment elevation myocardial infarction (ACS-NSTE) with saphenous vein graft (SVG)-obtuse marginal stenosis. High-definition intravascular ultrasound revealed an underexpanded SVG stent with a hyperechoic structure. Optical coherence tomography confirmed surgical clip causing compression, resolved by post-dilation. This case underscores ACS-NSTE complexity post-CABG and the critical role of coronary imaging in optimizing interventions by addressing surgical clip-induced compression., Competing Interests: The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Introduction: The Berlin Long-term Observation of Vascular Events is a prospective cohort study that aims to improve prediction and disease-overarching mechanistic understanding of cardiovascular (CV) disease progression by comprehensively investigating a high-risk patient population with different organ manifestations., Methods and Analysis: A total of 8000 adult patients will be recruited who have either suffered an acute CV event (CVE) requiring hospitalisation or who have not experienced a recent acute CVE but are at high CV risk. An initial study examination is performed during the acute treatment phase of the index CVE or after inclusion into the chronic high risk arm. Deep phenotyping is then performed after ~90 days and includes assessments of the patient's medical history, health status and behaviour, cardiovascular, nutritional, metabolic, and anthropometric parameters, and patient-related outcome measures. Biospecimens are collected for analyses including 'OMICs' technologies (e.g., genomics, metabolomics, proteomics). Subcohorts undergo MRI of the brain, heart, lung and kidney, as well as more comprehensive metabolic, neurological and CV examinations. All participants are followed up for up to 10 years to assess clinical outcomes, primarily major adverse CVEs and patient-reported (value-based) outcomes. State-of-the-art clinical research methods, as well as emerging techniques from systems medicine and artificial intelligence, will be used to identify associations between patient characteristics, longitudinal changes and outcomes., Ethics and Dissemination: The study was approved by the Charité-Universitätsmedizin Berlin ethics committee (EA1/066/17). The results of the study will be disseminated through international peer-reviewed publications and congress presentations., Study Registration: First study phase: Approved WHO primary register: German Clinical Trials Register: https://drks.de/search/de/trial/DRKS00016852; WHO International Clinical Registry Platform: http://apps.who.int/trialsearch/Trial2.aspx?TrialID=DRKS00016852. Recruitment started on July 18, 2017.Second study phase: Approved WHO primary register: German Clinical Trials Register DRKS00023323, date of registration: November 4, 2020, URL: http://www.drks.de/ DRKS00023323. Recruitment started on January 1, 2021., Competing Interests: Competing interests: FE reports grants from German Research Foundation (DFG), grants from German Ministry of Education and Research, grants from the German Herta Foundation; during the conduct of the study; personal fees and non-financial support from Novartis, grants and personal fees from Boehringer Ingelheim, personal fees from CVRx, Pfizer, Medtronic, grants and personal fees from Servier, personal fees from MSD, personal fees from Merck & Co., grants from AstraZeneca, personal fees from Bayer, personal fees from Resmed, personal fees from Berlin Chemie, grants from Thermo Fischer, personal fees from Vifor Pharma, personal fees from PharmaCosmos outside the submitted work; ME reports grants from Bayer and fees paid to the Charité from Abbot, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Daiichi Sankyo, Amgen, Sanofi, Novartis, Pfizer, all outside the submitted work. ME received funding from DFG under Germany’s Excellence Strategy – EXC-2049 – 390688087, Collaborative Research Center ReTune TRR 295- 424778381, BMBF, DZNE, DZHK, EU, Corona Foundation, and Fondation Leducq. HG reports grants from the DFG, the Leducq Foundation, the Federal Ministry of Education and Research (BMBF) and the DZHK during the conduct of the study, outside of the submitted work. UL reports research funding from DZHK; Fondation Leducq; research grants from Novartis, Bayer and Amgen. KM declares that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported. DNM received funding for research from Bayer Healthcare, Deutsche Forschungsgemeinschaft and from BMBF. CHN received research grants from German Ministry of Research and Education, German Center for neurodegenerative Diseases (DZNE), DZHK, and speaker and/or consultation fees from Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer Pharma, Abbott, Novartis, Daichii-Sankyo and Alexion all outside the submitted work. BP reports personal fees and other from Bayer Healthcare, personal fees and other from MSD, personal fees and other from Novartis, personal fees from Astrazeneca, grants and personal fees from Servier, personal fees from Medscape, outside the submitted work. No other relationships or activities that could appear to have influenced the submitted work have exist beyond those listed. TP received grants from the BMBF, the Federal Ministry of Food and Agriculture (BMEL), the Federal Ministry for Economic Affairs and Energy (BMWi), the DFG, Deutsche Herzstiftung, German Academic Exchange Service (DAAD). KMSO reports having consultancy fees with BioPorto Diagnostics; having received license revenue related to the use of a neutrophil gelatinase-associated lipocalin assay via Columbia University; receiving research funding from FAST BioMedical, for being a principal investigator of the EMPAKT-CHF trial, and Quark Pharmaceuticals, for being the site principal investigator for QRK309 trial; and being an editorial board member for Kidney International and Kidney International Reports; each outside the submitted work. JSM reports grants from Bayer Healthcare, non-financial support from Siemens healthineers, non-financial support from Circle cardiovascular, non-financial support from Medis, outside the submitted work, and Bayer Healthcare, Advisor. Furthermore, funding for research from the EU, DZHK, Deutsche Herzstiftung. JS received funding for research from DFG and from BMBF. MW received funding for research from DFG, BMBF, Deutsche Gesellschaft für Pneumologie, European Respiratory Society, Marie Curie Foundation, Else Kröner Fresenius Foundation, Capnetz Foundation, International Max Planck Research School, Actelion, Bayer Health Care, Biotest, Boehringer Ingelheim, Noxxon, Pantherna, Quark Pharma, Vaxxilon, and for lectures and advisory from Actelion, Aptarion, Astra Zeneca, Bayer Health Care, Berlin Chemie, Biotest, Boehringer Ingelheim, Chiesi, Glaxo Smith Kline, Novartis, Noxxon, Pantherna, Teva und Vaxxilon. All remaining authors MA, L-HB, K-UE, UG, NH, JK-H, DL, DNM, SKP, SR, GR, KS, OS, BS, SS, RV, JEW do not report potential conflicts of interest., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Aims: In one-third of patients with acute coronary syndrome (ACS), thrombosis occurs despite an intact fibrous cap (IFC) (IFC-ACS, 'plaque erosion'). Recent studies emphasize neutrophils as the immediate inflammatory response in this pathology, but their exact molecular activation patterns are still poorly understood and may represent future therapeutic targets., Methods and Results: Thirty-two patients with IFC-ACS and matched patients with ACS with ruptured fibrous cap (RFC) (RFC-ACS) from the OPTICO-ACS study were included, and blood samples were collected from the local site of the culprit lesion and the systemic circulation. Neutrophil surface marker expression was quantified by flow cytometry. Neutrophil cytotoxicity towards endothelial cells was examined in an ex vivo co-culture assay. Secretion of active matrix metalloproteinase 9 (MMP9) by neutrophils was evaluated using zymography in supernatants and in plasma samples. Optical coherence tomography (OCT)-embedded thrombi were used for immunofluorescence analysis. Toll-like receptor 2 (TLR2) expression was higher on neutrophils from IFC-ACS than RFC-ACS patients. TLR2 stimulation increased the release of active MMP9 from local IFC-ACS-derived neutrophils, which also aggravated endothelial cell death independently of TLR2. Thrombi of IFC-ACS patients exhibited more hyaluronidase 2 with concomitant increase in local plasma levels of the TLR2 ligand: hyaluronic acid., Conclusion: The current study provides first in-human evidence for distinct TLR2-mediated neutrophil activation in IFC-ACS, presumably triggered by elevated soluble hyaluronic acid. Together with disturbed flow conditions, neutrophil-released MMP9 might be promoting endothelial cell loss-triggered thrombosis and therefore providing a potential future target for a phenotype-specific secondary therapeutic approach in IFC-ACS., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aims: Rupture of the fibrous cap (RFC) and erosion of an intact fibrous cap (IFC) are the two predominant mechanisms causing acute coronary syndromes (ACS). It is uncertain whether clinical outcomes are different following RFC-ACS vs. IFC-ACS and whether this is affected by a specific inflammatory response. The prospective, translational OPTIcal-COherence Tomography in Acute Coronary Syndrome study programme investigates the impact of the culprit lesion phenotype on inflammatory profiles and prognosis in ACS patients., Methods and Results: This analysis included 398 consecutive ACS patients, of which 62% had RFC-ACS and 25% had IFC-ACS. The primary endpoint was a composite of cardiac death, recurrent ACS, hospitalization for unstable angina, and target vessel revascularization at 2 years [major adverse cardiovascular events (MACE+)]. Inflammatory profiling was performed at baseline and after 90 days. Patients with IFC-ACS had lower rates of MACE+ than those with RFC-ACS (14.3% vs. 26.7%, P = 0.02). In 368-plex proteomic analyses, patients with IFC-ACS showed lower inflammatory proteome expression compared with those with RFC-ACS, including interleukin-6 and proteins associated with the response to interleukin-1β. Circulating plasma levels of interleukin-1β decreased from baseline to 3 months following IFC-ACS (P < 0.001) but remained stable following RFC-ACS (P = 0.25). Interleukin-6 levels decreased in patients with RFC-ACS free of MACE+ (P = 0.01) but persisted high in those with MACE+., Conclusion: This study demonstrates a distinct inflammatory response and a lower risk of MACE+ following IFC-ACS. These findings advance our understanding of inflammatory cascades associated with different mechanisms of plaque disruption and provide hypothesis generating data for personalized anti-inflammatory therapeutic allocation to ACS patients, a strategy that merits evaluation in future clinical trials., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Chronic total occlusions (CTO) in coronary angiographies present a significant challenge nowadays. Intravascular ultrasound (IVUS) is a valuable tool during CTO-PCI, aiding in planning and achieving procedural success. However, the impact of IVUS on clinical and procedural outcomes in CTO-PCI remains uncertain. This meta-analysis aimed to compare IVUS-guided and angiography-guided approaches in CTO-PCI. The study included five studies and 2320 patients with stable coronary artery disease (CAD) and CTO. The primary outcome of major adverse cardiac events (MACE) did not significantly differ between the groups ( p = 0.40). Stent thrombosis was the only secondary clinical outcome that showed a significant difference, favoring the IVUS-guided approach ( p = 0.01). Procedural outcomes revealed that IVUS-guided procedures had longer stents, larger diameters, and longer procedure and fluoroscopy times ( p = 0.007, p < 0.001, p = 0.03, p = 0.002, respectively). Stent number and contrast volume did not significantly differ between the approaches ( p = 0.88 and p = 0.33, respectively). In summary, routine IVUS use did not significantly improve clinical outcomes, except for reducing stent thrombosis. Decisions in CTO-PCI should be individualized based on patient characteristics and supported by a multi-parametric approach.

Acute coronary syndrome (ACS) remains a major cause of worldwide mortality. The syndrome occurs when blood flow to the heart muscle is decreased or blocked, causing muscle tissues to die or malfunction. There are three main types of ACS: Non-ST-elevation myocardial infarction, ST-elevation myocardial infarction, and unstable angina. The treatment depends on the type of ACS, and this is decided by a combination of clinical findings, such as electrocardiogram and plasma biomarkers. Circulating cell-free DNA (ccfDNA) is proposed as an additional marker for ACS since the damaged tissues can release DNA to the bloodstream. We used ccfDNA methylation profiles for differentiating between the ACS types and provided computational tools to repeat similar analysis for other diseases. We leveraged cell type specificity of DNA methylation to deconvolute the ccfDNA cell types of origin and to find methylation-based biomarkers that stratify patients. We identified hundreds of methylation markers associated with ACS types and validated them in an independent cohort. Many such markers were associated with genes involved in cardiovascular conditions and inflammation. ccfDNA methylation showed promise as a non-invasive diagnostic for acute coronary events. These methods are not limited to acute events, and may be used for chronic cardiovascular diseases as well., (© The Author(s) 2023. Published by Oxford University Press on behalf of NAR Genomics and Bioinformatics.)

Aims: Mosaic loss of Y chromosome (LOY) in blood cells is the most common acquired mutation, increases with age, and is related to cardiovascular disease. Loss of Y chromosome induces cardiac fibrosis in murine experiments mimicking the consequences of aortic valve stenosis, the prototypical age-related disease. Cardiac fibrosis is the major determinant of mortality even after transcatheter aortic valve replacement (TAVR). It was hypothesized that LOY affects long-term outcome in men undergoing TAVR., Methods and Results: Using digital PCR in DNA of peripheral blood cells, LOY (Y/X ratio) was assessed by targeting a 6 bp sequence difference between AMELX and AMELY genes using TaqMan. The genetic signature of monocytes lacking the Y chromosome was deciphered by scRNAseq. In 362 men with advanced aortic valve stenosis undergoing successful TAVR, LOY ranged from -4% to 83.4%, and was >10% in 48% of patients. Three-year mortality increased with LOY. Receiver operating characteristic (ROC) curve analysis revealed an optimal cut-off of LOY >17% to predict mortality. In multivariate analysis, LOY remained a significant (P < 0.001) independent predictor of death during follow-up. scRNAseq disclosed a pro-fibrotic gene signature with LOY monocytes displaying increased expression of transforming growth factor (TGF) β-associated signaling, while expression of TGFβ-inhibiting pathways was down-regulated., Conclusion: This is the first study to demonstrate that LOY in blood cells is associated with profoundly impaired long-term survival even after successful TAVR. Mechanistically, the pro-fibrotic gene signature sensitizing the patient-derived circulating LOY monocytes for the TGFβ signaling pathways supports a prominent role of cardiac fibrosis in contributing to the effects of LOY observed in men undergoing TAVR., Competing Interests: Conflict of interest A.M.Z. is scientific advisor for NovoNordisk, AstraZeneca, Boehringer Ingelheim, and Sanofi and reports lecture honoraria for NovoNordisk, AstraZeneca, Boehringer Ingelheim, Sanofi, Pfizer, Bayer Healthcare, Lilly, and Daichi., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Objectives: This study aims to assess the attenuation of pericoronary adipose tissue (PCAT) surrounding the proximal right coronary artery (RCA) in patients with aortic stenosis (AS) and undergoing transcatheter aortic valve replacement (TAVR). RCA PCAT attenuation is a novel computed tomography (CT)-based marker for evaluating coronary inflammation. Coronary artery disease (CAD) in TAVR patients is common and usually evaluated prior to intervention. The most sensible screening method and consequential treatment approach are unclear and remain a matter of ceaseless discussion. Thus, interest remains for safe and low-demand predictive markers to identify patients at risk for adverse outcomes postaortic valve replacement., Methods: This single-center retrospective study included patients receiving a standard planning CT scan prior to TAVR. Conventional CAD diagnostic tools, such as coronary artery calcium score and significant stenosis via invasive coronary angiography and coronary computed tomography angiography, were determined in addition to RCA PCAT attenuation using semiautomated software. These were assessed for their relationship with major adverse cardiovascular events (MACE) during a 24-month follow-up period., Results: From a total of 62 patients (mean age: 82 ± 6.7 years), 15 (24.2%) patients experienced an event within the observation period, 10 of which were attributed to cardiovascular death. The mean RCA PCAT attenuation was higher in patients enduring MACE than that in those without an endpoint (-69.8 ± 7.5 vs. -74.6 ± 6.2, P  = 0.02). Using a predefined cutoff of >-70.5 HU, 20 patients (32.3%) with high RCA PCAT attenuation were identified, nine (45%) of which met the endpoint within 2 years after TAVR. In a multivariate Cox regression model including conventional CAD diagnostic tools, RCA PCAT attenuation prevailed as the only marker with significant association with MACE ( P  = 0.02). After dichotomization of patients into high- and low-RCA PCAT attenuation groups, high attenuation was related to greater risk of MACE (hazard ration: 3.82, P  = 0.011)., Conclusion: RCA PCAT attenuation appears to have predictive value also in a setting of concomitant AS in patients receiving TAVR. RCA PCAT attenuation was more reliable than conventional CAD diagnostic tools in identifying patients at risk for MACE ., Competing Interests: DML reports personal fees from Boston Scientific. VOP and EN have received speaker fees from Bayer AG and Siemens Healthineers as well as educational grants from Bayer AG and NeoSoft. DD has received software royalties from Cedars-Sinai Medical Center and has a patent. CB received speaker fees from Siemens Healthineers. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Steyer, Mas-Peiro, Leistner, Puntmann, Nagel, Dey, Goeller, Koch, Booz, Vogl and Martin.)

Background Cerebral microbleeds (CMBs) are increasingly recognized as "covert" brain lesions indicating increased risk of future neurological events. However, data on CMBs in patients undergoing catheter-based structural heart interventions are scarce. Therefore, we assessed occurrence and predictors of new CMBs in patients undergoing catheter-based left atrial appendage closure and percutaneous mitral valve repair using the MitraClip System. Methods and Results We conducted an exploratory analysis using data derived from 2 prospective, observational studies. Eligible patients underwent cerebral magnetic resonance imaging (3 Tesla) examinations and cognitive tests (using the Montreal Cognitive Assessment) before and after catheter-based left atrial appendage closure and percutaneous mitral valve repair. Forty-seven patients (53% men; median age, 77 years) were included. New CMBs occurred in 17 of 47 patients (36%) following catheter-based structural heart interventions. Occurrences of new CMBs did not differ significantly between patients undergoing catheter-based left atrial appendage closure and percutaneous mitral valve repair (7/25 versus 10/22; P =0.348). In univariable analysis, longer procedure time was significantly associated with new CMBs. Adjustment for heparin attenuated this association (adjusted odds ratio [per 30 minutes]: 1.77 [95% CI, 0.92-3.83]; P =0.090). Conclusions New CMBs occur in approximately one-third of patients after catheter-based left atrial appendage closure and percutaneous mitral valve repair using the MitraClip System. Our data suggest that longer duration of the procedure may be a risk factor for new CMBs. Future studies in larger populations are needed to further investigate their clinical relevance. Clinical Trial Registration German Clinical Trials Register: DRKS00010300 (https://drks.de/search/en/trial/DRKS00010300); ClinicalTrials.gov : NCT03104556 (https://clinicaltrials.gov/ct2/show/NCT03104556?term=NCT03104556&draw=2&rank=1).

The evolutionary conserved NEAT1-MALAT1 gene cluster generates large noncoding transcripts remaining nuclear, while tRNA-like transcripts (mascRNA, menRNA) enzymatically generated from these precursors translocate to the cytosol. Whereas functions have been assigned to the nuclear transcripts, data on biological functions of the small cytosolic transcripts are sparse. We previously found NEAT1 -/- and MALAT1 -/- mice to display massive atherosclerosis and vascular inflammation. Here, employing selective targeted disruption of menRNA or mascRNA, we investigate the tRNA-like molecules as critical components of innate immunity. CRISPR-generated human ΔmascRNA and ΔmenRNA monocytes/macrophages display defective innate immune sensing, loss of cytokine control, imbalance of growth/angiogenic factor expression impacting upon angiogenesis, and altered cell-cell interaction systems. Antiviral response, foam cell formation/oxLDL uptake, and M1/M2 polarization are defective in ΔmascRNA/ΔmenRNA macrophages, defining first biological functions of menRNA and describing new functions of mascRNA. menRNA and mascRNA represent novel components of innate immunity arising from the noncoding genome. They appear as prototypes of a new class of noncoding RNAs distinct from others (miRNAs, siRNAs) by biosynthetic pathway and intracellular kinetics. Their NEAT1-MALAT1 region of origin appears as archetype of a functionally highly integrated RNA processing system.

Aims: Rupture of the fibrous cap (RFC) represents the main pathophysiological mechanism causing acute coronary syndromes (ACS). Destabilization due to plaque biomechanics is considered to be importantly involved, exact mechanisms triggering plaque ruptures are, however, unknown. This study aims at characterizing the relation between plaque components and rupture points at ACS-causing culprit lesions in a large cohort of ACS-patients assessed by high-resolution intracoronary imaging., Methods and Results: Within the prospective, multicentric OPTICO-ACS study program, the ACS-causing culprit plaques of 282 consecutive patients were investigated following a standardized optical coherence tomography (OCT) imaging protocol. Each pullback was assessed on a frame-by-frame basis for the presence of lipid components (LC), calcium components (CC), and coexistence of both LC and CC (LCC) by two independent OCT-core labs. Of the 282 ACS-patients, 204 patients (72.3%) presented with ACS caused by culprit lesions with rupture of the fibrous cap (RFC-ACS) and 27.7% patients had ACS caused by culprit lesions with intact fibrous cap (IFC-ACS). When comparing RFC-ACS to IFC-ACS, a preferential occurrence of all three plaque components (LC, CC, and LCC) in RFC-ACS became apparent (P < 0.001). Within ruptured culprit lesions, the zone straight at the rupture point [extended rupture zone (RZ)] was characterized by similar (24.7% vs. 24.0%; P = ns) calcium content when compared with the proximal and distal border of the culprit lesion [border zone (BZ)]. The RZ displayed a significantly higher amount of both, LC (100% vs. 69.8%; P < 0.001) and LCC (22.7% vs. 6.8%; P < 0.001), when compared with the BZ. The relative component increase towards the RZ was particularly evident for LCC (+233.8%), while LC showed only a modest increase (+43.3%)., Conclusions: Calcified- and lipid-containing components characterize ruptured fibrous cap ACS-causing culprit lesions. Their coexistence is accelerated directly at the ruptured point, suggesting a pathophysiological contribution in the development of RFC-ACS., Competing Interests: Conflict of interest: The authors have nothing to declare., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Aims: 18F-sodium fluoride ([18F]fluoride) and gadobutrol are promising probes for positron emission tomography (PET) and magnetic resonance imaging (MRI) characterizing coronary artery disease (CAD) activity. Unlike [18F]fluoride-PET/computed tomography (CT), the potential of PET/MR using [18F]fluoride and gadobutrol simultaneously, has so far not been evaluated. This study assessed feasibility and diagnostic potential of [18F]fluoride and gadobutrol enhanced dual-probe PET/MR in patients with CAD., Methods and Results: Twenty-one patients (age, 66.7 ± 6.7 years) with CAD scheduled for invasive coronary angiography (XCA) underwent simultaneous [18F]fluoride (mean activity/effective dose: 157.2 ± 29.7 MBq/3.77 ± 0.72 mSv) and gadobutrol enhanced PET/MR on an integrated PET/MRI (3 T) scanner. Optical coherence tomography (OCT) was used as reference. Target-to-background ratio (TBR, [18F]fluoride-PET) and contrast-to-noise ratio (CNR) values (MRI, gadobutrol) were calculated for each coronary segment. Previously suggested PET/CT-TBR thresholds for adverse coronary events were evaluated. High-risk plaques, i.e. calcified and non-calcified thin-cap fibroatheromas (TCFAs) were predominantly located in segments with a TBR >1.28 (P = 0.012). Plaques containing a lipid core on OCT, were more frequently detected in segments with a TBR >1.25 (P < 0.001). TBR values significantly correlated with maximum calcification thickness (P = 0.009), while fibrous cap thickness was significantly less in segments with a TBR >1.28 (P = 0.044). Above a TBR threshold of >1.28, CNR values significantly correlated with the presence of calcified TCFAs (P = 0.032)., Conclusion: Simultaneous [18F]fluoride and gadobutrol dual-probe PET/MRI is feasible in clinical practice and may facilitate the identification of high-risk patients. The combination of coronary MR-derived CNR values post gadobutrol and [18F]fluoride based TBR values may improve identification of high-risk plaque features., Competing Interests: Conflict of interest: none declared., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2022. For permissions, please email: journals.permissions@oup.com.)

Background: In most cases of transcatheter valve embolization and migration (TVEM), the embolized valve remains in the aorta after implantation of a second valve into the aortic root. There is little data on potential late complications such as valve thrombosis or aortic wall alterations by embolized valves., Aims: The aim of this study was to analyze the incidence of TVEM in a large cohort of patients undergoing transcatheter aortic valve implantation (TAVI) and to examine embolized valves by computed tomography (CT) late after TAVI., Methods: The patient database of our center was screened for cases of TVEM between July 2009 and July 2021. To identify risk factors, TVEM cases were compared to a cohort of 200 consecutive TAVI cases. Out of 35 surviving TVEM patients, ten patients underwent follow-up by echocardiography and CT., Results: 54 TVEM occurred in 3757 TAVI procedures, 46 cases were managed percutaneously. Horizontal aorta (odds ratio [OR] 7.51, 95% confidence interval [CI] 3.4-16.6, p < 0.001), implantation of a self-expanding valve (OR 4.63, 95% CI 2.2-9.7, p < 0.01) and a left ventricular ejection fraction < 40% (OR 2.94, 95% CI 1.1-7.3, p = 0.016) were identified as risk factors for TVEM. CT scans were performed on average 26.3 months after TAVI (range 2-84 months) and detected hypoattenuated leaflet thickening (HALT) in two patients as well as parts of the stent frame protruding into the aortic wall in three patients., Conclusion: TVEM represents a rare complication of TAVI. Follow up-CT detected no pathological findings requiring intervention., Competing Interests: HD, KS, ML, DL, UL, and MS were received financial research support and speakers’ fees from Abbott, Edwards LifeSciences and Medtronic. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Frumkin, Pietron, Kind, Brand, Knebel, Laule, Leistner, Landmesser, Krackhardt, Sherif, Sündermann, Grubitzsch, Lembcke, Niehues, Stangl and Dreger.)

Background: New ischaemic brain lesions on magnetic resonance imaging (MRI) are reported in up to 86% of patients after transcatheter edge-to-edge repair of the mitral valve (TEER-MV). Knowledge of the exact procedural step(s) that carry the highest risk for cerebral embolisation may help to further improve the procedure., Aims: The aim of this study was to identify the procedural step(s) that are associated with an increased risk of cerebral embolisation during TEER-MV with the MitraClip system. Furthermore, the risk of overt stroke and silent brain ischaemia after TEER-MV was assessed., Methods: In this prospective, pre-specified observational study, all patients underwent continuous transcranial Doppler examination during TEER-MV to detect microembolic signals (MES). MES were assigned to specific procedural steps: (1) transseptal puncture and placement of the guide, (2) advancing and adjustment of the clip in the left atrium, (3) device interaction with the MV, and (4) removal of the clip delivery system and the guide. Neurological examination using the National Institutes of Health Stroke Scale (NIHSS) and cerebral MRI were performed before and after TEER-MV., Results: Fifty-four patients were included. The number of MES differed significantly between the procedural steps with the highest numbers observed during device interaction with the MV. Mild neurological deterioration (NIHSS ≤3) occurred in 9/54 patients. New ischaemic lesions were detected in 21/24 patients who underwent MRI. Larger infarct volume was significantly associated with neurological deterioration., Conclusions: Cerebral embolisation is immanent to TEER-MV and predominantly occurs during device interaction with the MV. Improvements to the procedure may focus on this procedural step.

Antegrade wire crossing of a mid calcified left anterior descending (LAD) artery was achieved. However, the wire was seen deflecting in a different pathway than the angiographically anticipated course of the vessel. Therefore, the computed tomography images were reanalyzed and the wire was seen to be within the tented site of the left internal mammary artery to the LAD anastomosis and correctly positioned according to the vessel course.

Background Stent underexpansion has been known to be associated with worse outcomes. We sought to define optical coherence tomography assessed optimal stent expansion index (SEI), which associates with lower incidence of follow-up major adverse cardiac events (MACEs). Methods and Results A total of 315 patients (involving 370 lesions) who underwent optical coherence tomography-aided coronary stenting were retrospectively included. SEI was calculated separately for equal halves of each stented segment using minimum stent area/mean reference lumen area ([proximal reference area+distal reference area]/2). The smaller of the 2 was considered to be the SEI of that case. Follow-up MACE was defined as a composite of all-cause death, myocardial infarction, stent thrombosis, and target lesion revascularization. Average minimum stent area was 6.02 (interquartile range, 4.65-7.92) mm 2 , while SEI was 0.79 (interquartile range, 0.71-0.86). Forty-seven (12.7%) incidences of MACE were recorded for 370 included lesions during a median follow-up duration of 557 (interquartile range, 323-1103) days. Receiver operating characteristic curve analysis identified 0.85 as the best SEI cutoff (<0.85) to predict follow-up MACE (area under the curve, 0.60; sensitivity, 0.85; specificity, 0.34). MACE was observed in 40 of 260 (15.4%) lesions with SEI <0.85 and in 7 of 110 (6.4%) lesions with SEI ≥0.85 ( P =0.02). Least absolute shrinkage and selection operator regression identified SEI <0.85 (odds ratio, 3.55; 95% CI, 1.40-9.05; P <0.01) and coronary calcification (odds ratio, 2.47; 95% CI, 1.00-6.10; P =0.05) as independent predictors of follow-up MACE. Conclusions The present study identified SEI <0.85, associated with increased incidence of MACE, as the optimal cutoff in daily practice. Along with suboptimal SEI (<0.85), coronary calcification was also found to be a significant predictor of follow-up MACE.

Background Proctoring represents a cornerstone in the acquisition of state-of-the-art cardiovascular interventions. Yet, travel restrictions and containment measures during the COVID-19 pandemic limited on-site proctoring for training and expert support in interventional cardiology. Methods and Results We established a teleproctoring setup for training in a novel patent foramen ovale closure device system (NobleStitch EL, HeartStitch Inc, Fountain Valley, CA) at our institution using web-based real-time bidirectional audiovisual communication. A total of 6 patients with prior paradoxical embolic stroke and a right-to-left shunt of grade 2 or 3 were treated under remote proctorship after 3 cases were performed successfully under on-site proctorship. No major device/procedure-related adverse events occurred, and none of the patients had a residual right-to-left shunt of grade 1 or higher after the procedure. Additionally, we sought to provide an overview of current evidence available for teleproctoring in interventional cardiology. Literature review was performed identifying 6 previous reports on teleproctoring for cardiovascular interventions, most of which were related to the current COVID-19 pandemic. In all reports, teleproctoring was carried out in similar settings with comparable setups; no major adverse events were reported. Conclusions Teleproctoring may represent a feasible and safe tool for location-independent and cost-effective training in a novel patent foramen ovale closure device system. Future prospective trials comparing teleproctoring with traditional on-site proctoring are warranted.

Although great strides have been made in the pathophysiological understanding, diagnosis and management of cardiogenic shock (CS), morbidity and mortality in patients presenting with the condition remain high. Acute MI is the commonest cause of CS; consequently, most existing literature concerns MI-associated CS. However, there are many more phenotypes of patients with acute heart failure. Medical treatment and mechanical circulatory support are well-established therapeutic options, but evidence for many current treatment regimens is limited. The issue is further complicated by the fact that implementing adequately powered, randomized controlled trials are challenging for many reasons. In this review, the authors discuss the history, landmark trials, current topics of medical therapy and mechanical circulatory support regimens, and future perspectives of CS management., Competing Interests: Disclosure: SO has received research and study grants from Novartis; EP is proctor and consultant for and has received institutional grants from Abbott, Medtronic, and Abiomed; BO is a consultant for Teleflex and has received research funding from the British Heart Foundation and the National Institute for Health Science Research. All other authors have no conflict of interest to declare., (Copyright © The Author(s), 2022. Published by Radcliffe Group Ltd.)

Aims: Atherosclerotic cardiovascular disease (ACVD) is a major cause of mortality and morbidity worldwide, and increased low-density lipoproteins (LDLs) play a critical role in development and progression of atherosclerosis. Here, we examined for the first time gut immunomodulatory effects of the microbiota-derived metabolite propionic acid (PA) on intestinal cholesterol metabolism., Methods and Results: Using both human and animal model studies, we demonstrate that treatment with PA reduces blood total and LDL cholesterol levels. In apolipoprotein E-/- (Apoe-/-) mice fed a high-fat diet (HFD), PA reduced intestinal cholesterol absorption and aortic atherosclerotic lesion area. Further, PA increased regulatory T-cell numbers and interleukin (IL)-10 levels in the intestinal microenvironment, which in turn suppressed the expression of Niemann-Pick C1-like 1 (Npc1l1), a major intestinal cholesterol transporter. Blockade of IL-10 receptor signalling attenuated the PA-related reduction in total and LDL cholesterol and augmented atherosclerotic lesion severity in the HFD-fed Apoe-/- mice. To translate these preclinical findings to humans, we conducted a randomized, double-blinded, placebo-controlled human study (clinical trial no. NCT03590496). Oral supplementation with 500 mg of PA twice daily over the course of 8 weeks significantly reduced LDL [-15.9 mg/dL (-8.1%) vs. -1.6 mg/dL (-0.5%), P = 0.016], total [-19.6 mg/dL (-7.3%) vs. -5.3 mg/dL (-1.7%), P = 0.014] and non-high-density lipoprotein cholesterol levels [PA vs. placebo: -18.9 mg/dL (-9.1%) vs. -0.6 mg/dL (-0.5%), P = 0.002] in subjects with elevated baseline LDL cholesterol levels., Conclusion: Our findings reveal a novel immune-mediated pathway linking the gut microbiota-derived metabolite PA with intestinal Npc1l1 expression and cholesterol homeostasis. The results highlight the gut immune system as a potential therapeutic target to control dyslipidaemia that may introduce a new avenue for prevention of ACVDs., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Aims: In acute heart failure (AHF), changes of venous haemoglobin (Hb) concentrations, haematocrit (Hct), and estimated plasma volume (ePV) have been proposed as surrogates of decongestion. These estimates are based on the theoretical assumptions that changes of Hb concentrations and Hct are driven by the intravascular volume status and that the intravascular Hb pool remains stable. The objective of this study was to assess the relationship of changes of measured plasma volume (mPV) with changes of Hb, Hct, and ePV in AHF., Methods and Results: We studied 36 AHF patients, who received two sequential assessments of mPV, measured red cell volume (mRCV) and measured total blood volume (mTBV) (48 h apart), during the course of diuretic therapy using a novel visible fluorescent injectate (VFI) technique based on the indicator dilution principle. Changes of ePV were calculated based on the Kaplan-Hakim or Strauss formula. AHF patients receiving diuretics (median intravenous furosemide equivalent 160 mg/48 h) displayed a wide range of changes of mPV (-25.4% to +37.0%). Changes in mPV were not significantly correlated with changes of Hb concentration [Pearson's r (r) = -0.241, P = 0.157], Hct (r = -0.307, P = 0.069), ePV Kaplan-Hakim (r = 0.228, P = 0.182), or ePV Strauss (r = 0.237, P = 0.163). In contrast to theoretical assumptions, changes of mTBV were poorly correlated with changes of Hb concentrations and some patients displayed unanticipated variability of mRCV, suggesting an unstable intravascular red cell pool., Conclusions: Changes of Hb or Hct were not reflective of directly measured changes of intravascular volume status in AHF patients. Basing clinical assessment of decongestion on changes of Hb or Hct may misguide clinical decision-making on an individual patient level., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Control of pulmonary pressures monitored remotely reduced heart failure hospitalizations mainly by lowering filling pressures through the use of loop diuretics. Sacubitril/valsartan improves heart failure outcomes and increases the kidney sensitivity for diuretics. We explored whether sacubitril/valsartan is associated with less utilization of loop diuretics in patients guided with haemodynamic monitoring in the CardioMEMS European Monitoring Study for Heart Failure (MEMS-HF)., Methods and Results: The MEMS-HF population (n = 239) was separated by the use of sacubitril/valsartan (n = 68) or no use of it (n = 164). Utilization of diuretics and their doses was prespecified in the protocol and was monitored in both groups. Multivariable regression, ANCOVA, and a generalized linear model were used to fit baseline covariates with furosemide equivalents and changes for 12 months. MEMS-HF participants (n = 239) were grouped in sacubitril/valsartan users [n = 68, 64 ± 11 years, left ventricular ejection fraction (LVEF) 25 ± 9%, cardiac index (CI) 1.89 ± 0.4 L/min/m 2 ] vs. non-users (n = 164, 70 ± 10 years, LVEF 36 ± 16%, CI 2.11 ± 0.58 L/min/m 2 , P = 0.0002, P < 0.0001, and P = 0.0015, respectively). In contrast, mean pulmonary artery pressure (PAP) values were comparable between groups (29 ± 11 vs. 31 ± 11 mmHg, P = 0.127). Utilization of loop diuretics was lower in patients taking sacubitril/valsartan compared with those without (P = 0.01). Significant predictor of loop diuretic use was a history of renal failure (P = 0.005) but not age (P = 0.091). After subjects were stratified by sacubitril/valsartan or other diuretic use, PAP was nominally, but not significantly lower in sacubitril/valsartan-treated patients (baseline: P = 0.52; 6 months: P = 0.07; 12 months: P = 0.53), while there was no difference in outcome or PAP changes. This difference was observed despite lower CI (P = 0.0015). Comparable changes were not observed for other non-loop diuretics (P = 0.21)., Conclusions: In patients whose treatment was guided by remote PAP monitoring, concomitant use of sacubitril/valsartan was associated with reduced utilization of loop diuretics, which could potentially be relevant for outcomes., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Inflammation crucially drives atherosclerosis from disease initiation to the emergence of clinical complications. Targeting pivotal inflammatory pathways without compromising the host defense could compliment therapy with lipid-lowering agents, anti-hypertensive treatment, and lifestyle interventions to address the substantial residual cardiovascular risk that remains beyond classical risk factor control. Detailed understanding of the intricate immune mechanisms that propel plaque instability and disruption is indispensable for the development of novel therapeutic concepts. In this review, we provide an overview on the role of key immune cells in plaque inception and progression, and discuss recently identified maladaptive immune phenomena that contribute to plaque destabilization, including epigenetically programmed trained immunity in myeloid cells, pathogenic conversion of autoreactive regulatory T-cells and expansion of altered leukocytes due to clonal hematopoiesis. From a more global perspective, the article discusses how systemic crises such as acute mental stress or infection abruptly raise plaque vulnerability and summarizes recent advances in understanding the increased cardiovascular risk associated with COVID-19 disease. Stepping outside the box, we highlight the role of gut dysbiosis in atherosclerosis progression and plaque vulnerability. The emerging differential role of the immune system in plaque rupture and plaque erosion as well as the limitations of animal models in studying plaque disruption are reviewed., Competing Interests: DL reports conflict of interest by research and educational grants as well as speaker fees from Abbott Vascular. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Gerhardt, Haghikia, Stapmanns and Leistner.)

Background: Quantitative flow ratio (QFR) has been introduced as a novel angiography-based modality for fast hemodynamic assessment of coronary artery lesions and validated against fractional flow reserve. This study sought to define the prognostic role of pancoronary QFR assessment in patients with acute coronary syndrome (ACS) including postinterventional culprit and nonculprit vessels., Methods: In a total of 792 patients with ACS (48.6% ST-segment-elevation ACS and 51.4% non-ST-segment-elevation ACS), QFR analyses of postinterventional culprit (n=792 vessels) and nonculprit vessels (n=1231 vessels) were post hoc performed by investigators blinded to clinical outcomes. The follow-up comprised of major adverse cardiovascular events, including all-cause mortality, nonfatal myocardial infarction, and ischemia-driven coronary revascularization within 2 years after the index ACS event., Results: Major adverse cardiovascular events as composite end point occurred in 99 patients (12.5%). QFR with an optimal cutoff value of 0.89 for postinterventional culprit vessels and 0.85 for nonculprit vessels emerged as independent predictor of major adverse cardiovascular events after ACS (nonculprit arteries: adjusted odds ratio, 3.78 [95% CI, 2.21-6.45], P <0.001 and postpercutaneous coronary intervention culprit arteries: adjusted odds ratio, 3.60 [95% CI, 2.09-6.20], P <0.001)., Conclusions: The present study for the first time demonstrates the prognostic implications of a pancoronary angiography-based functional lesion assessment in patients with ACS. Hence, QFR offers a novel tool to advance risk stratification and guide therapeutic management after ACS.

Aims: We aimed to test whether the endogenous filtration markers serum creatinine or cystatin C and equation-based estimates of glomerular filtration rate (GFR) based on these markers appropriately reflect changes of measured GFR in patients with acute heart failure., Methods: In this prospective cohort study of 50 hospitalized acute heart failure patients undergoing decongestive therapy, we applied an intravenous visible fluorescent injectate (VFI), consisting of a low molecular weight component to measure GFR and a high molecular weight component to correct for measured plasma volume. Thirty-eight patients had two sequential GFR measurements 48 h apart. The co-primary endpoints of the study were safety of VFI and plasma stability of the high molecular weight component. A key secondary endpoint was to compare changes in measured GFR (mGFR) to changes of serum creatinine, cystatin C and estimated GFR., Results: VFI-based GFR measurements were safe and consistent with plasma stability of the high molecular weight component and glomerular filtration of the low molecular weight component. Filtration marker-based point estimates of GFR, when compared with mGFR, provided only moderate correlation (Pearson's r, range 0.80-0.88, depending on equation used), precision (r 2 , range 0.65-0.78) and accuracy (56%-74% of estimates scored within 30% of mGFR). Correlations of 48-h changes GFR estimates and changes of mGFR were significant (P < 0.05) but weak (Pearson's r, range 0.35-0.39). Observed decreases of eGFR by more than 15% had a low sensitivity (range 38%-46%, depending on equation used) in detecting true worsening mGFR, defined by a >15% decrease in mGFR., Conclusions: In patients hospitalized for acute heart failure, serum creatinine- and cystatin C-based predictions performed poorly in detecting actual changes of GFR. These data challenge current clinical strategies to evaluate dynamics of kidney function in acute heart failure., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: A regimen of dual (DAT) vs. triple (TAT) antithrombotic therapy reduces bleeding in patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI). However, recent evidence suggests that DAT may be associated with an increased ischemic risk. This raises the question whether DAT rather than TAT should be recommended to AF patients that undergo PCI for acute coronary syndrome (ACS), carrying a particularly high risk of both bleeding and ischemic events, studied only as subgroups of previous trials., Methods and Design: The APPROACH-ACS-AF-(DZHK-7) trial is a multicenter prospective, randomized, open-label, blinded endpoint (PROBE) trial which will include patients presenting with an ACS managed by PCI and requiring oral anticoagulation (OAC) due to AF. The trial will test, whether a DAT-regimen comprising clopidogrel plus the non-Vitamin-K-antagonist oral anticoagulant (NOAC) apixaban is superior to a TAT-regimen of vitamin-K-antagonist (VKA) plus dual anti-platelet therapy (APT) with respect to bleeding. A total of 400 patients will be randomized 1:1 to a control-arm with guideline-recommended TAT with VKA plus clopidogrel and acetylsalicylic-acid and a study arm receiving DAT comprising apixaban plus clopidogrel. Patients will be followed-up for 6 months. The primary endpoint of the study is the cumulative incidence of BARC type ≥2 bleeding, secondary endpoints include a composite clinical ischemic outcome and net clinical outcome., Conclusions: APPROACH-ACS-AF is the first trial dedicated to ACS patients, testing whether in terms of bleeding a DAT with NOAC is superior to a TAT regimen with VKA in high-risk ACS patients with AF., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: D.M.L reports grants from Deutsches Zentrum für Herz-Kreislaufforschung (DZHK), Bayer AG, AstraZeneca, Novartis, Abbott Vascular, Biotronik and Sahajanand Medical Technologies Pvt Ltd. (SMT) and personal fees from Bayer AG, Daiichi Sankyo, Amgen, B.Braun, Abbott Vascular, Boehringer Ingelheim, Boston, Sahajanand Medical Technologies Pvt Ltd. (SMT), Medtronik, Bayer AG, Vifor, Novartis and AstraZeneca; T.G. reports a research grant from Abbott Vascular and neovasc, lecture/consulting fees from Abbott Vascular, Neovasc, Boston Scientific, Daiichi-Sankyo, Bayer, Astra Zeneca, BMS, SMT, Eli Lilly, Pfizer, all outside the submitted work; I.A. reports personal fees from Daiichi Sankyo, Pfizer/BMS, Boston Scientific, GORE Medical; A.A.M. reports personal fees from AMGEN, AtraZeneca, BAYER, Berlin Chemie, Daiichi Sankyo outside the submitted work; M.B. received personal fees from Bayer, Boehringer-Ingelheim, Boston-Scientific, Daiichi-Sankyo, Medtronic, ZOLL CMS; F.E. reports grants from German Research Foundation (DFG), grants from German Ministry of Education and Research, during the conduct of the study; personal fees and non-financial support from Novartis, grants and personal fees from Boehringer Ingelheim, personal fees from CVRx, Pfizer, Medtronic, grants and personal fees from Servier, personal fees from MSD/Bayer, personal fees from Bayer, personal fees from Resmed, personal fees from Berlin Chemie, grants from Thermo Fischer, personal fees from Vifor Pharma, personal fees from PharmaCosmos, personal fees from Merck, outside the submitted work; N.S. received travel grants from BMS/Pfizer outside the submitted work; D.S. reports grants from Roche Diagnostics, grants from Daiichi Sankyo, personal fees from Bayer, personal fees from Astra Zeneca, personal fees from Daiichi Sankyo, personal fees from Eli Lilly, personal fees from MSD, personal fees from Pfizer, and personal fees from Sanofi, outside the submitted work; H.I. reports lecture fees from Bayer, Boehringer, Daichi Sankyo, Pfizer, Bristol-Myers-Squibb, outside the submitted work; T.R reports personal fees from Astra Zeneca, Bayer, Boehringer, Daichi Sankyo, Bristol-Myers-Squibb, Medtronic outside the submitted work; J.M. reports an institutional grant from Boston Scientific, lecture fees from Boston Scientific, Edwards LifeScience, Medtronic, Biotronik, Astra Zeneca, BMS and Terumo, Siemens outside the submitted work; J.H. reports speaker and advisory board activities for Abbott Vascular and Edwards Lifesciences and institutional research support from Abbott Vascular and Edwards Lifesciences outside the submitted work; S.M. received research grants from Roche (Tropical ACS trial) and Pfizer/BMS (APPROACH-ACS-AF trial). S.M. also reports grants from Deutsches Zentrum für Herz-Kreislaufforschung, during the conduct of the study; grants from Pfizer, from Roche, outside the submitted work; R.W. reports grants from Deutsches Zentrum für Herz-Kreislaufforschung, during the conduct of the study. R.W. reports grants from Boston Scientific (MULTASA trial). R.W. reports personal fees from Bayer, Boehringer, Daichi Sankyo, Pfizer, Bristol-Myers-Squibb, Boston Scientific, Biotronik outside the submitted work; L.R., C.S., M.M., A.K., H.B. and U.M. do not have any conflicts of interest., (© 2021 The Authors.)

Background: The COVID-19 pandemic triggered countermeasures like #StayAtHome initiatives, which have changed the whole world. Despite the success of such initiatives in limiting the spread of COVID-19 to #FlattenTheCurve, physicians are now confronted with the adverse effects of the current restrictive pandemic management strategies and social distancing measures., Objective: We aim to draw attention to the particular importance and magnitude of what may be the adverse effects of COVID-19-related policies., Methods: We herein report a case of an otherwise healthy 84-year-old woman with deep vein thrombosis (DVT) due to COVID-19-related directives. #StayAtHome policies and consequential social isolation have diminished our patient's social life and reduced her healthy movement behaviors. The patient spent long hours in a seated position while focusing on the intensive flow of media information regarding the pandemic., Results: Reduced mobility due to preventive social isolation during the COVID-19 pandemic was the only identified cause of the DVT., Conclusions: While evaluating the effect of the COVID-19 pandemic and governmentally implemented containment measures, including social isolation and mobility reduction, adverse events should be considered. Digital approaches might play a crucial role in supporting public health., (©Edna Blum, Youssef S Abdelwahed, Eileen Spiess, Ursula Mueller-Werdan, David M Leistner, Adrian Rosada. Originally published in the Interactive Journal of Medical Research (http://www.i-jmr.org/), 14.01.2021.)

Cardiologists need a better understanding of stroke and of cardiac implications in modern stroke management. Stroke is a leading disease in terms of mortality and disability in our society. Up to half of ischaemic strokes are directly related to cardiac and large artery diseases and cardiovascular risk factors are involved in most other strokes. Moreover, in an acute stroke direct central brain signals and a consecutive autonomic/vegetative imbalance may account for severe and life-threatening cardiovascular complications. The strong cerebro-cardiac link in acute stroke has recently been addressed as the stroke-heart syndrome that requires careful cardiovascular monitoring and immediate therapeutic measures. The regular involvement of cardiologic expertise in daily work on a stroke unit is therefore of high importance and a cornerstone of up-to-date comprehensive stroke care concepts. The main targets of the cardiologists' contribution to acute stroke care can be categorized in three main areas (i) diagnostics workup of stroke aetiology, (ii) treatment and prevention of complications, and (iii) secondary prevention and sub-acute workup of cardiovascular comorbidity. All three aspects are by themselves highly relevant to support optimal acute management and to improve the short-term and long-term outcomes of patients. In this article, an overview is provided on these main targets of cardiologists' contribution to acute stroke management., (Published on behalf of the European Society of Cardiology. © The Author(s) 2020.)

Aims: Acute coronary syndromes with intact fibrous cap (IFC-ACS), i.e. caused by coronary plaque erosion, account for approximately one-third of ACS. However, the underlying pathophysiological mechanisms as compared with ACS caused by plaque rupture (RFC-ACS) remain largely undefined. The prospective translational OPTICO-ACS study programme investigates for the first time the microenvironment of ACS-causing culprit lesions (CL) with intact fibrous cap by molecular high-resolution intracoronary imaging and simultaneous local immunological phenotyping., Methods and Results: The CL of 170 consecutive ACS patients were investigated by optical coherence tomography (OCT) and simultaneous immunophenotyping by flow cytometric analysis as well as by effector molecule concentration measurements across the culprit lesion gradient (ratio local/systemic levels). Within the study cohort, IFC caused 24.6% of ACS while RFC-ACS caused 75.4% as determined and validated by two independent OCT core laboratories. The IFC-CL were characterized by lower lipid content, less calcification, a thicker overlying fibrous cap, and largely localized near a coronary bifurcation as compared with RFC-CL. The microenvironment of IFC-ACS lesions demonstrated selective enrichment in both CD4+ and CD8+ T-lymphocytes (+8.1% and +11.2%, respectively, both P < 0.05) as compared with RFC-ACS lesions. T-cell-associated extracellular circulating microvesicles (MV) were more pronounced in IFC-ACS lesions and a significantly higher amount of CD8+ T-lymphocytes was detectable in thrombi aspirated from IFC-culprit sites. Furthermore, IFC-ACS lesions showed increased levels of the T-cell effector molecules granzyme A (+22.4%), perforin (+58.8%), and granulysin (+75.4%) as compared with RFC plaques (P < 0.005). Endothelial cells subjected to culture in disturbed laminar flow conditions, i.e. to simulate coronary flow near a bifurcation, demonstrated an enhanced adhesion of CD8+T cells. Finally, both CD8+T cells and their cytotoxic effector molecules caused endothelial cell death, a key potential pathophysiological mechanism in IFC-ACS., Conclusions: The OPTICO-ACS study emphasizes a novel mechanism in the pathogenesis of IFC-ACS, favouring participation of the adaptive immune system, particularly CD4+ and CD8+ T-cells and their effector molecules. The different immune signatures identified in this study advance the understanding of coronary plaque progression and may provide a basis for future development of personalized therapeutic approaches to ACS with IFC., Trial Registration: The study was registered at clinicalTrials.gov (NCT03129503)., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Background: Current guidelines recommend measurement of troponin in acute ischemic stroke (AIS) patients. In AIS patients, troponin elevation is associated with increased mortality and worse outcome. However, uncertainty remains regarding the underlying pathophysiology of troponin elevation after stroke, particularly regarding diagnostic and therapeutic consequences. Troponin elevation may be caused by coronary artery disease (CAD) and more precisely acute coronary syndrome (ACS). Both have a high prevalence in stroke patients and contribute to poor outcome. Therefore, better diagnostic algorithms are needed to identify those AIS patients likely to have ACS or other manifestations of CAD., Methods/design: The primary goal of the "PRediction of Acute coronary syndrome in acute Ischemic StrokE" (PRAISE) study is to develop a diagnostic algorithm for prediction of ACS in AIS patients. The primary hypothesis will test whether dynamic high-sensitivity troponin levels determined by repeat measurements (i.e., "rise or fall-pattern") indicate presence of ACS when compared to stable (chronic) troponin elevation. PRAISE is a prospective, multicenter, observational trial with central reading and predefined endpoints guided by a steering committee. Clinical symptoms, troponin levels as well as findings on electrocardiogram, echocardiogram, and coronary angiogram will be recorded and assessed by central academic core laboratories. Diagnosis of ACS will be made by an endpoint adjudication committee. Severe adverse events will be evaluated by a critical event committee. Safety will be judged by a data and safety monitoring board. Follow-up will be conducted at three and twelve months and will record new vascular events (i.e., stroke and myocardial infarction) as well as death, functional and cognitive status. According to sample size calculation, 251 patients have to be included., Discussion: PRAISE will prospectively determine the frequency of ACS and characterize cardiac and coronary pathologies in a large, multicenter cohort of AIS patients with troponin elevation. The findings will elucidate the origin of troponin elevation, shed light on its impact on necessary diagnostic procedures and provide data on the safety and diagnostic yield of coronary angiography early after stroke. Thereby, PRAISE will help to refine algorithms and develop guidelines for the cardiac workup in AIS., Trial Registration: NCT03609385 registered 1st August 2018.

Background: Polymerase chain reaction analyses of cardiac tissues have detected viral sequences in up to 67% of cases of myocarditis. However, viruses have not been implicated in giant cell myocarditis (GCM). Furthermore, efforts to detect viruses implicated in myocarditis have been unsuccessful in more accessible samples such as peripheral blood., Methods: We used Virome Capture Sequencing for Vertbrate Viruses (VirCapSeq-VERT), a method that simultaneously screens for all known vertebrate viruses, to investigate viruses in 33 patients with myocarditis. We investigated peripheral blood mononuclear cells (n=24), plasma (n=27), endomyocardial biopsies (n=2), and cardiac tissue samples from explanted hearts (n=13)., Results: Nine patients (27%) had GCM and 4 patients (13%) had fulminant myocarditis. We found the following viruses in the blood of patients with myocarditis: Epstein Barr virus (n=11, 41%), human pegivirus (n=1, 4%), human endogenous retrovirus K (n=27, 100%), and anellovirus (n=15, 56%). All tissue samples from fulminant myocarditis (n=2) and GCM (n=13) contained human endogenous retrovirus K., Conclusions: No nucleic acids from viruses previously implicated in myocarditis or other human illnesses were detected in relevant amounts in cardiac tissue samples from GCM or in blood samples from other types of myocarditis. These findings do not exclude a role for viral infection in GCM but do suggest that if viruses are implicated, the mechanism is likely to be indirect rather than due to cytotoxic infection of myocardium.

Purpose: The LipidCardio Study was established for in-depth analyses of cardiovascular risk factors, providing well-defined cardiovascular and metabolic phenotypes. In particular, the role of lipoproteins in the pathobiological process and treatment of cardiovascular disease (CVD) will be a main focus., Participants: 1005 individuals aged 21 years and older undergoing cardiac catheterisation during 17 months at a tertiary academic cardiology centre were enrolled (troponin-positive acute coronary syndrome was exclusion criterion). The baseline data not only contain detailed phenotyping, broad biochemical parameters, genetic data, but also standardised personal and family history, a screening test for cognitive impairment, pulse wave analysis and measurements of hand grip strength, among others. Blood samples were stored in a biobank for future analyses., Findings to Date: The mean age of the participants at enrolment was 70.9±11.1 years (70% male). Coronary angiography provided evidence of obstructive coronary artery disease (CAD) in 69.9% of participants. Those with evidence of CAD were significantly more likely to be male, inactive, diabetic and with a family history of CVD than participants without CAD.About 20% of patients had lipoprotein(a) (Lp(a)) concentrations above 106.9 nmol/L (fifth quintile). These patients had significantly increased odds of obstructive CAD compared with participants in quintiles 1-4 (crude OR 1.70, 95% CI 1.17 to 2.48, p=0.005). There was reasonable evidence that with increasing severity of CAD the odds of having elevated Lp(a) increased. We were able to replicate the established strong association between specified single nucleotide polymorphisms (SNPs) in the LPA gene (rs10455872, rs3798220 and rs186696265) and the APOE gene (rs7412), and the concentration of Lp(a), validating our phenotype database and biobank., Future Plans: Mortality information will be obtained in 2 year intervals. Follow-up phone interviews will be conducted at 3 and 6 years after enrolment. We seek to cooperate with other researchers, for example, by sharing data and biobank samples., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims: Fibroblast growth factor 23 (FGF-23) is known to be elevated in patients with congestive heart failure (CHF). As FGF-23 is expressed in the bone but can also be expressed in the myocardium, the origin of serum FGF-23 in CHF remains unclear. It is also unclear if FGF-23 expressed in the bone is associated with outcome in CHF. The aim of the present study was to investigate FGF-23 levels measured in bone marrow plasma (FGF-23-BM) and in peripheral blood (FGF-23-P) in CHF patients to gain further insights into the heart-bone axis of FGF-23 expression. We also investigated possible associations between FGF-23-BM as well as FGF-23-P and outcome in CHF patients., Methods and Results: We determined FGF-23-P and FGF-23-BM levels in 203 CHF patients (85% male, mean age 61.3 years) with a left ventricular ejection fraction (LVEF) ≤45% and compared them with those of 48 healthy controls (48% male, mean age 39.2 years). We investigated the association between FGF-23-BM and FGF-23-P with all-cause mortality in CHF patients, 32 events, median follow-up 1673 days, interquartile range [923, 1828]. FGF-23-P (median 60.3 vs. 22.0 RU/mL, P < 0.001) and FGF-23-BM (median 130.7 vs. 93.1 RU/mL, P < 0.001) levels were higher in CHF patients compared with healthy controls. FGF-23-BM levels were significantly higher than FGF-23-P levels in both CHF patients and in healthy controls (P < 0.001). FGF-23-P and FGF-23-BM correlated significantly with LVEF (r = -0.37 and r = -0.33, respectively), N terminal pro brain natriuretic peptide levels (r = 0.57 and r = 0.6, respectively), New York Heart Association status (r = 0.28 and r = 0.25, respectively), and estimated glomerular filtration rate (r = -0.43 and r = -0.41, respectively) (P for all <0.001) and were independently associated with all-cause mortality in CHF patients after adjustment for LVEF, estimated glomerular filtration rate, New York Heart Association status, and N terminal pro brain natriuretic peptide, hazard ratio 2.71 [confidence interval: 1.18-6.20], P = 0.018, and hazard ratio 2.80 [confidence interval: 1.19-6.57], P = 0.018, respectively., Conclusions: In CHF patients, FGF-23 is elevated in bone marrow plasma and is independently associated with heart failure severity and all-cause mortality. The failing heart seems to interact via FGF-23 within a heart-bone axis., (© 2019 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

Objective: We investigated the benefit of Impella, a modern percutaneous mechanical support (pMCS) device, versus former standard intra-aortic balloon pump (IABP) in acute myocardial infarction complicated by cardiogenic shock (AMICS)., Methods: This single-centre, retrospective study included patients with AMICS receiving pMCS with either Impella or IABP. Disease severity at baseline was assessed with the IABP-SHOCK II score. The primary outcome was all-cause mortality at 30 days. Secondary outcomes were parameters of shock severity at the early postimplantation phase. Adjusted Cox proportional hazards models identified independent predictors of the primary outcome., Results: Of 116 included patients, 62 (53%) received Impella and 54 (47%) IABP. Despite similar baseline mortality risk (IABP-SHOCK II high-risk score of 18 % vs 20 %; p = 0.76), Impella significantly reduced the inotropic score (p < 0.001), lactate levels (p < 0.001) and SAPS II (p = 0.02 ) and improved left ventricular ejection fraction (p = 0.01). All-cause mortality at 30 days was similar with Impella and IABP (52 % and 67 %, respectively; p = 0.13), but bleeding complications were more frequent in the Impella group (3 vs 4 units of transfused erythrocytes concentrates due to bleeding complications, p = 0.03). Previous cardiopulmonary resuscitation (HR 3.22, 95% CI 1.76 to 5.89; p < 0.01) and an estimated intermediate (HR 2.77, 95% CI 1.42 to 5.40; p < 0.01) and high (HR 4.32 95% CI 2.03 to 9.24; p = 0.01) IABP-SHOCK II score were independent predictors of all-cause mortality., Conclusions: In patients with AMICS, haemodynamic support with the Impella device had no significant effect on 30-day mortality as compared with IABP. In these patients, large randomised trials are warranted to ascertain the effect of Impella on the outcome., Competing Interests: CONFLICT OF INTEREST STATEMENT: Dr Carsten Skurk has perceived lecturer fees from Abiomed, outside the submitted work. Dr Landmesser reports grants from Edwards Lifesciences, grants and personal fees from Abbott, outside the submitted work. All other authors report no relationships relevant to the contents of this paper to disclose.

The aim of this study was to compare endothelial permeability, which is considered a hallmark of coronary artery disease, between patients with different HbA 1c levels using an albumin-binding magnetic resonance (MR) probe. This cross-sectional study included 26 patients with clinical indication for X-ray angiography who were classified into three groups according to HbA 1c level (<5.7% [<39 mmol/mol], 5.7-6.4% [39-47 mmol/mol], and ≥6.5% [48 mmol/mol]). Subjects underwent gadofosveset-enhanced coronary magnetic resonance and X-ray angiography including optical coherence within 24 h. Contrast-to-noise ratios (CNRs) were assessed to measure the probe uptake in the coronary wall by coronary segment, excluding those with culprit lesions in X-ray angiography. In the group of patients with HbA 1c levels between 5.7 and 6.4%, 0.30 increased normalized CNR values were measured, compared with patients with HbA 1c levels <5.7% (0.30 [95% CI 0.04, 0.57]). In patients with HbA 1c levels ≥6.5%, we found 0.57 higher normalized CNR values compared with patients with normal HbA 1c levels (0.57 [95% CI 0.28, 0.85]) and 0.26 higher CNR values for patients with HbA 1c level ≥6.5% compared with patients with HbA 1c levels between 5.7 and 6.4% (0.26 [95% CI -0.04, 0.57]). Additionally, late atherosclerotic lesions were more common in patients with high HbA 1c levels (HbA 1c ≥6.5%, n = 14 [74%]; HbA 1c 5.7-6.4%, n = 6 [60%]; and HbA 1c <5.7%, n = 10 [53%]). In conclusion, coronary MRI in combination with an albumin-binding MR probe suggests that both patients with intermediate and patients with high HbA 1c levels are associated with a higher extent of endothelial damage of the coronary arteries compared with patients with HbA 1c levels <5.7%., (© 2018 by the American Diabetes Association.)

Coronary heart disease is a common cause of death despite being preventable. To treat the underlying plaque deposits in the arterial walls, intravascular optical coherence tomography can be used by experts to detect and characterize the lesions. In clinical routine, hundreds of images are acquired for each patient, which require automatic plaque detection for fast and accurate decision support. So far, automatic approaches rely on classic machine learning methods and deep learning solutions have rarely been studied. Given the success of deep learning methods with other imaging modalities, a thorough understanding of deep learning-based plaque detection for future clinical decision support systems is required. We address this issue with a new data set consisting of in vivo patient images labeled by three trained experts. Using this data set, we employ the state-of-the-art deep learning models that directly learn plaque classification from the images. For improved performance, we study different transfer learning approaches. Furthermore, we investigate the use of Cartesian and polar image representations and employ data augmentation techniques tailored to each representation. We fuse both representations in a multi-path architecture for more effective feature exploitation. Last, we address the challenge of plaque differentiation in addition to detection. Overall, we find that our combined model performs best with an accuracy of 91.7%, a sensitivity of 90.9%, and a specificity of 92.4%. Our results indicate that building a deep learning-based clinical decision support system for plaque detection is feasible.

Objectives: This study sought to investigate the potential of the noninvasive albumin-binding probe gadofosveset-enhanced cardiac magnetic resonance (GE-CMR) for detection of coronary plaques that can cause acute coronary syndromes (ACS)., Background: ACS are frequently caused by rupture or erosion of coronary plaques that initially do not cause hemodynamically significant stenosis and are therefore not detected by invasive x-ray coronary angiography (XCA)., Methods: A total of 25 patients with ACS or symptoms of stable coronary artery disease underwent GE-CMR, clinically indicated XCA, and optical coherence tomography (OCT) within 24 h. GE-CMR was performed approximately 24 h following a 1-time application of gadofosveset-trisodium. Contrast-to-noise ratio (CNR) was quantified within coronary segments in comparison with blood signal., Results: A total of 207 coronary segments were analyzed on GE-CMR. Segments containing a culprit lesion in ACS patients (n = 11) showed significant higher signal enhancement (CNR) following gadofosveset-trisodium application than segments without culprit lesions (n = 196; 6.1 [3.9 to 16.5] vs. 2.1 [0.5 to 3.5]; p < 0.001). GE-CMR was able to correctly identify culprit coronary lesions in 9 of 11 segments (sensitivity 82%) and correctly excluded culprit coronary lesions in 162 of 195 segments (specificity 83%). Additionally, segmented areas of thin-cap fibroatheroma (n = 22) as seen on OCT demonstrated significantly higher CNR than segments without coronary plaque or segments containing early atherosclerotic lesions (n = 185; 9.2 [3.3 to 13.7] vs. 2.1 [0.5 to 3.4]; p = 0.001)., Conclusions: In this study, we demonstrated for the first time the noninvasive detection of culprit coronary lesions and thin-cap fibroatheroma of the coronary arteries in vivo by using GE-CMR. This method may represent a novel approach for noninvasive cardiovascular risk prediction., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)