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In eukaryotic ribosome biogenesis, the small subunit (SSU) Processome is a meta-stable intermediate in the assembly of the small (40S) subunit. In the SSU Processome, the ribosomal RNA domains are splayed open by the intervention of assembly factors as well as U3 snoRNA. A critical step during the transition from the SSU Processome to the nearly mature pre-40S particle is the removal of the U3 snoRNA to allow the formation of the central pseudoknot (CPK), a universally conserved structure which connects all domains of the subunit and contributes to its dynamic nature during translation. We previously identified the DEAH/RHA RNA helicase Dhr1 as the enzyme responsible for displacing the U3 snoRNA and the SSU Processome factor Utp14 as an activator of Dhr1. Here, we have utilized biochemical and yeast genetic methods to further characterize Dhr1. We show that the N-terminus as well as an internal loop within the RecA2 domain are autoinhibitory. We found that Utp14 can activate the ATPase activity of Dhr1 lacking the autoinhibitory N-terminal loop but not full-length Dhr1. We considered the possibility that Utp14 activates Dhr1 by relieving the autoinhibition of the loop within the RecA2 domain. However, our results are more consistent with Utp14 activating Dhr1 by binding to the surface of the RecA1 and RecA2 domains rather than displacing the inhibitory loop. This position of Utp14 is distinct from how G-patch proteins activate other DEXH/RHA helicases and is consistent with our previous conclusion that Utp14 is not a canonical G-patch protein., Competing Interests: Conflict of interest "The authors declare that they have no conflicts of interest with the contents of this article.", (Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.)

Compared to men, women have been reported to have increased morbidity and mortality after ST-elevation myocardial infarction (STEMI); but sex differences in cardiac function in the acute and subacute phases of STEMI are incompletely understood. The objective of this study was to prospectively compare changes in cardiac function over the acute and subacute phases after anterior STEMI with timely reperfusion in women versus men. The Stunning in Takotsubo versus Acute Myocardial Infarction (STAMI) study (NCT04448639) prospectively enrolled 105 men and 41 women with anterior STEMI. Echocardiography and blood sampling were performed within 4 hours of admission and at 1, 2, 3, 7, 14 and 30 days after admission. The primary outcome was akinesia recovery, defined as the difference in the percentage of akinesia observed at baseline versus follow-up. Secondary outcomes included wall motion score index (WMSI), left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS). Mixed effects linear regression or zero-inflated tobit models with random intercepts were used to model echocardiographic parameters over time. Baseline patient characteristics were similar in both groups. The difference between women and men in akinesia recovery at 30 days was 8.3% [95% credible interval 0.8%, 15.5%]. The covariate-adjusted posterior probability that akinesia recovery and WMSI improvement at 30 days are greater in women than men were 96.0% and 99.0% respectively. Similar but less pronounced trends towards greater improvement in women than men were observed for LVEF and GLS. In conclusion, cardiac dysfunction recovered to a greater extent in women than in men after anterior STEMI with timely reperfusion., Competing Interests: Declaration of competing interest None declared., (Copyright © 2025. Published by Elsevier Inc.)

Randomized clinical trials (RCT) are the gold standard for guiding treatment recommendations. Their results reflect the average treatment effect generated in samples from a selected patient population. Observational studies may serve as external validation of RCT findings, but are influenced by various biases. Conducting clinical trials in the cardiovascular field faces many challenges, including financial constraints, end-point selection including determining their value for doctors and patients, and assessment of long-term treatment effects. In addition, there is renewed debate about the optimal statistical approach for the evaluation of trial outcomes. These factors occur in parallel to efforts to develop novel clinical trial designs that address the above challenges. Pragmatic trials, for instance, may use data already collected during patient care. As alternative to fixed sample size, two-arm designs, adaptive trial designs have been introduced, that allow for pre-specified adaptations throughout a trial. Master protocols are used to govern platform, umbrella and basket trial designs all allowing to address more than one aspect at a time (e.g., the impact of multiple treatments on a single condition or a single treatment on multiple conditions). Cluster designs may allow the evaluation of new treatments into clinical routine. Here, we review strengths and limitations of conventional and novel trial designs. We provide a general description of current topics with a focus on treatment comparisons in the field of cardiovascular research., (© The Author(s) 2025. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Studies on sex differences in myocardial infarction (MI) typically focus on males versus females, the exploration of hormonal physiologic variations and their impact on the infarct size remains limited. The objective of this study was to examine whether infarct size after myocardial ischemia/reperfusion injury in female rats differs in different phases of the estrous cycle, and according to the levels of sex hormones; and to assess whether the effect of ischemic preconditioning on infarct size varies in different phases of the estrous cycle and between sexes. Female rats were divided into three groups based on the estrous cycle: proestrus, estrus, and diestrus. A fourth group consisted of ovariectomized female rats. Male rats were included as a fifth group, and orchiectomized males as a sixth group. Each group underwent ischemia/reperfusion injury, with or without prior ischemic preconditioning (IPC). Plasma sex hormone levels were measured with gas chromatography-tandem mass spectrometry. Females in the proestrus showed significantly smaller infarct size compared to all other groups. Multivariable analyses identified proestrus, IPC, and estradiol as independent predictors of smaller infarct size while male sex and gonadectomy as independent predictors of larger infarct size. There was a statistical interaction between IPC and both sex and hormonal status, with a greater protective effect of IPC on infarct size in males and gonadectomized rats. After ischemia-reperfusion, proestrus female rats developed the smallest while male and gonadectomized rats the largest infarct size. Conversely, IPC conferred greater cardioprotection in male and gonadectomized rats than females in proestrus., Competing Interests: Declarations. Conflict of interest: The authors have reported that they have no interests relevant to the contents of this paper to disclose. Ethical approval: All experiments were approved by the Gothenburg Animal Ethics Committee (Dnr 5.8.18–11014/2023) and performed after the ARRIVE guidelines and in accordance with the local legislation and institutional requirements., (© 2025. The Author(s).)

Background: The use of inotropic agents in treating cardiogenic shock (CS) remains controversial. This study investigates the effect of inotropes on 30-day mortality in CS patients using data from the SWEDEHEART registry (The Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies)., Methods and Results: Data were sourced from the national SWEDEHEART registry for all CS patients in Sweden from 2000 to 2022. The primary endpoint was 30-day all-cause mortality. We employed multilevel Cox proportional-hazards regression with instrumental variable and inverse probability weighting propensity score to adjust for confounders. The treatment-preference instrument was the quintile of preference for inotrope use at the treating hospital. A total of 16 214 patients (60.5% men, 39.5% women) were included; 23.5% had diabetes, 10.2% had a previous myocardial infarction (MI), and 13.8% had previous heart failure (HF). The median age was 70 years [interquartile range (IQR); 19], with 66.4% over 70. Acute coronary syndrome (ACS) caused CS in 82.9%. Inotropes were administered to 43.8% of patients, while 56.2% did not receive them. There were 7875 (48.1%) deaths. Patients treated with inotropes were, on average, 2 years younger and more likely to have ACS, while those not treated had more previous MI and were less likely to undergo percutaneous coronary intervention (PCI). The number of CS cases decreased by 12% per year (Ptrend < 0.001), and inotrope use increased by 5% per year (Ptrend < 0.001). Unadjusted mortality in CS rose by 2% per calendar year (Ptrend < 0.001). Inotropes were associated with higher mortality [adjusted hazard ratio (HR) 1.72; 95% CI 1.26-2.35; P = 0.001], with significant interactions between inotrope treatment, age, and diagnosis (Pinteraction < 0.001 and Pinteraction = 0.018)., Conclusion: In this observational study, inotropes were linked to higher mortality in CS patients, particularly those younger than 70. While CS cases decreased, inotrope use and mortality increased in Sweden., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background and Aims: The long-term outcomes of percutaneous coronary intervention (PCI) vs. coronary artery bypass grafting (CABG) in patients with non-ST-segment elevation myocardial infarction (NSTEMI) and multivessel disease remain debated., Methods: The Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies registry was used to analyse 57 097 revascularized patients with NSTEMI with multivessel disease in Sweden from January 2005 to June 2022. The primary endpoint was all-cause mortality, encompassing both in-hospital and long-term mortality; the secondary endpoints included myocardial infarction (MI), stroke, new revascularization, and heart failure. Multilevel logistic regression with follow-up time as a log-transformed offset variable and double-robust adjustment with the instrumental variable method were applied to control for known and unknown confounders., Results: Percutaneous coronary intervention was the primary therapy in 42 190 (73.9%) patients, while 14 907 (26.1%) received CABG. Percutaneous coronary intervention patients were generally older with more prior cardiovascular events, whereas CABG patients had higher incidences of diabetes, hypertension, left main and three-vessel disease, and reduced ejection fraction. Over a median follow-up of 7.1 years, PCI was associated with higher risks of death [adjusted odds ratio (aOR) 1.67; 95% confidence interval (CI) 1.54-1.81] and MI (aOR 1.51; 95% CI 1.41-1.62) but there was no significant difference in stroke. Repeat revascularization was three times more likely to PCI (aOR 3.01; 95% CI 2.57-3.51), while heart failure risk was 15% higher (aOR 1.15; 95% CI 1.07-1.25). Coronary artery bypass grafting provided longer survival within 15 years, especially in patients under 70 years of age, with left main disease or left ventricular dysfunction, though this benefit diminished over shorter time horizons., Conclusions: Coronary artery bypass grafting is associated with lower risks of mortality, MI, repeat revascularization, and heart failure in patients with NSTEMI, particularly in high-risk subgroups. However, its survival benefit lessens with shorter life expectancy., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Aortic stenosis (AS) is the leading cause of valvular heart disease-related morbidity and mortality, but there are no medical treatments to slow its progression. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have pleiotropic effects which could be disease modifying in AS., Objectives: Determine if SGLT2i usage is associated with slower progression of AS., Methods: A target trial emulation comparing the effect of the initiation of SGLT2i compared with no SGLT2i in patients with nonsevere AS was performed using retrospective electronic medical record data from the Yale New Haven Health System from January 2016 to September 2022. Patients with native aortic valve sclerosis or nonsevere AS with at least 12 months of echocardiographic follow-up were included. Patients were excluded if they had an estimated glomerular filtration rate <30 mL/min/1.73 m 2 or had initiated SGLT2i >1 year before the index echocardiogram. The prespecified primary outcome was progression to severe AS., Results: 458 patients prescribed SGLT2i and 11,240 patients never prescribed SGLT2i were included. Patients were on SGLT2i for a median of 0.9 years. Patients on SGLT2i were younger and had higher rates of diabetes and chronic kidney disease. Patients on SGLT2i were more likely to have ejection fraction ≤40%. There were no differences between groups in baseline AS severity (66% sclerosis, 23% mild stenosis, and 11% moderate in overall cohort). Patients ever prescribed SGLT2i were less likely to progress to severe AS (HR: 0.61; 95% CI: 0.39-0.94; P = 0.03) with a progressively lower risk among patients on SGLT2i for >3, 6, and 12 months (HR: 0.54, 0.48, and 0.27, respectively)., Conclusions: This retrospective, multicenter, observational study suggests that SGLT2i may slow the progression of nonsevere AS., Competing Interests: Funding Support and Author Disclosures Dr Shah has been paid speaking honoraria by Abiomed. Dr Nathan has received institutional funding from Abiomed and Biosense Webster; and speaker fees from Abiomed and Edwards Lifesciences. Dr Herrmann has received institutional research funding from Abbott, Boston Scientific, Edwards Lifesciences, and Medtronic; and consultant fees from Abbott, Edwards Lifesciences, and Medtronic. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2025 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Men develop larger infarct sizes than women after a myocardial infarction (MI), but the mechanism underlying this sex difference is unknown. Here, we demonstrated that blood neutrophil counts post-MI were higher in male than female mice. Castration-induced testosterone deficiency reduced blood neutrophil counts to the level in females and increased survival post-MI. These effects were mimicked by Osterix-directed ablation of the androgen receptor in bone marrow (BM). Mechanistically, androgens downregulated the leukocyte retention factor CXCL12 in BM stromal cells. Post-hoc analysis of clinical trial data showed that neutrophilia was greater in men than women after reperfusion of first-time ST-elevation MI, and tocilizumab, an interleukin-6 receptor inhibitor, reduced blood neutrophil counts and infarct size to a greater extent in men than women. Our work reveals a previously unknown mechanism connecting testosterone with neutrophilia and MI injury via BM and identifies the importance of considering sex when developing anti-inflammatory strategies to treat MI., Competing Interests: Competing interests: K.B. has received lecture fees from Amgen, AstraZeneca, Boehringer, Novartis, NovoNordisk, Pharmacosmos, Pfizer, and consultant fees from AstraZeneca, Boehringer, Pharmacosmos, and Pfizer. L.G. has received lecture fees from AstraZeneca, Boehringer Ingelheim, Novartis, and Amgen. The remaining authors declare no competing interests., (© 2025. The Author(s).)

Transient regional wall motion abnormalities (RWMA) after stress are a hallmark of experimental and clinical Takotsubo Syndrome (TS). The mechanisms driving RWMA remain incompletely understood. This study investigates these mechanisms in a small-animal model of TS, validating the model's complication profile, recovery dynamics, and recurrence, while assessing the predictive value of echocardiography. Male, 7-9-week-old rats underwent TS induction via isoprenaline infusion. The effects of body temperature and repeated catecholaminergic surges on RWMA were assessed using high-resolution speckle-tracking echocardiography. Complications were evaluated through ECG, autopsy, and blood gas analysis. The TS phenotype showed reduced longitudinal strain with RWMA characterized by apical end-systolic akinesia/dyskinesia, a contracting base, and a narrow transition zone, resulting in apical ballooning. RWMA originated from the apex and recovered in the opposite direction. Hyperthermia increased RWMA incidence, while hypothermia attenuated RWMA (p = 0.008). A repeated catecholamine surge exacerbated RWMA in the acute phase (p = 0.042) but not during recovery (p = 0.308), with reduced RWMA susceptibility after recovery (RR 0.45, 95%CI; 0.27-0.76). Systolic function at initial echocardiography predicted worse outcomes (odds ratio 0.73; 95%CI 0.57-0.85), and RWMA extent correlated with recovery time (Rho = 0.772). TS rats developed complications similar to patients, including heart failure, arrhythmias, and thrombus formation. This study validates the small-animal TS model by replicating patient findings, and emphasizing the importance of controlling body temperature and limiting adrenergic drug use in managing TS. RWMA analysis offers promise as a diagnostic and prognostic tool in TS, and the delayed adaptive response presents a potential pathway for therapeutic intervention., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Somatic stem cell pools comprise diverse, highly specialized subsets whose individual contribution is critical for the overall regenerative function. In the bone marrow, myeloid-biased hematopoietic stem cells (myHSCs) are indispensable for replenishment of myeloid cells and platelets during inflammatory response but, at the same time, become irreversibly damaged during inflammation and aging. Here we identify an extrinsic factor, Semaphorin 4A (Sema4A), which non-cell-autonomously confers myHSC resilience to inflammatory stress. We show that, in the absence of Sema4A, myHSC inflammatory hyper-responsiveness in young mice drives excessive myHSC expansion, myeloid bias and profound loss of regenerative function with age. Mechanistically, Sema4A is mainly produced by neutrophils, signals via a cell surface receptor, Plexin D1, and safeguards the myHSC epigenetic state. Our study shows that, by selectively protecting a distinct stem cell subset, an extrinsic factor preserves functional diversity of somatic stem cell pool throughout organismal lifespan., Competing Interests: Competing interests: L.S., S. Radtke and H.P.-K. are listed inventors on patent application 18/717,971 relating to this work. All other authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Purpose: We examined whether end-to-end deep-learning models could detect moderate (≥50%) or severe (≥70%) stenosis in the left anterior descending artery (LAD), right coronary artery (RCA) or left circumflex artery (LCX) in iodine contrast-enhanced ECG-gated coronary CT angiography (CCTA) scans., Methods: From a database of 6293 CCTA scans, we used pre-existing curved multiplanar reformations (CMR) images of the LAD, RCA and LCX arteries to create end-to-end deep-learning models for the detection of moderate or severe stenoses. We preprocessed the images by exploiting domain knowledge and employed a transfer learning approach using EfficientNet, ResNet, DenseNet and Inception-ResNet, with a class-weighted strategy optimised through cross-validation. Heatmaps were generated to indicate critical areas identified by the models, aiding clinicians in understanding the model's decision-making process., Results: Among the 900 CMR cases, 279 involved the LAD artery, 259 the RCA artery and 253 the LCX artery. EfficientNet models outperformed others, with EfficientNetB3 and EfficientNetB0 demonstrating the highest accuracy for LAD, EfficientNetB2 for RCA and EfficientNetB0 for LCX. The area under the curve for receiver operating characteristic (AUROC) reached 0.95 for moderate and 0.94 for severe stenosis in the LAD. For the RCA, the AUROC was 0.92 for both moderate and severe stenosis detection. The LCX achieved an AUROC of 0.88 for the detection of moderate stenoses, though the calibration curve exhibited significant overestimation. Calibration curves matched probabilities for the LAD but showed discrepancies for the RCA. Heatmap visualisations confirmed the models' precision in delineating stenotic lesions. Decision curve analysis and net reclassification index assessments reinforced the efficacy of EfficientNet models, confirming their superior diagnostic capabilities., Conclusion: Our end-to-end deep-learning model demonstrates, for the LAD artery, excellent discriminatory ability and calibration during internal validation, despite a small dataset used to train the network. The model reliably produces precise, highly interpretable images., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Aims: Men are more likely to suffer a myocardial infarction than women, but population-based studies on sex differences in imaging-detected atherosclerosis are lacking. The aims were to assess sex differences in the prevalence of imaging-detected coronary and carotid atherosclerosis, as well as multivariable adjusted associations between sex and atherosclerosis., Methods and Results: Participants aged 50-65, recruited from the general population to the Swedish Cardiopulmonary bioImage Study (SCAPIS), were included in this population-based cross-sectional study. Comprehensive diagnostics, including coronary computed tomography angiography and carotid ultrasound, were performed. The image findings were any coronary atherosclerosis, coronary stenosis ≥ 50%, segment involvement score (SIS) ≥ 4, coronary artery calcium score (CACS) > 100, and any ultrasound-detected carotid plaque. In 25 580 participants (50% women), men had more hypertension (20.3% vs. 17.0%), hyperlipidaemia (9.0% vs. 5.5%), and diabetes (8.5% vs. 4.7%). The prevalence was 56.2% vs. 29.5% for any coronary atherosclerosis (P < 0.01), 9.0% vs. 2.3% for coronary stenosis ≥ 50% (P < 0.01), 20.2% vs. 5.3% for SIS ≥ 4 (P < 0.01), 18.2% vs. 5.6% for CACS > 100 (P < 0.01), and 60.9% vs. 48.7% for carotid plaque (P < 0.01), in men vs. women, respectively. Multivariable adjustment only marginally changed these associations: odds ratios (ORs) (95% confidence interval): 2.75 (2.53-2.99) for coronary atherosclerosis, 2.88 (2.40-3.45) for coronary stenosis ≥ 50%, 3.99 (3.50-4.55) for SIS ≥ 4, 3.29 (2.88-3.75) for CACS > 100, and 1.57 (1.45-1.70) for carotid plaque., Conclusion: Men had higher prevalence of imaging-detected carotid and coronary atherosclerosis with prevalence in women aged 65 corresponding to men 11-13 years younger. The associations remained after extensive multivariable adjustment., Competing Interests: Conflict of interest: L.J. receives consulting fees from MEDICALgorithmics. S.S.L. has received speaker fees from Pfizer and Bayer. J.S. is a shareholder in Anagram kommunikation AB and Symptoms Europe AB, unrelated to the present study. The remaining authors have nothing to disclose., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Elevated troponin levels are a sensitive biomarker for cardiac injury. The quick and reliable prediction of troponin elevation for patients with chest pain from readily available ECGs may pose a valuable time-saving diagnostic tool during decision-making concerning this patient population., Methods and Results: The data used included 15 856 ECGs from patients presenting to the emergency rooms with chest pain or dyspnoea at two centres in Sweden from 2015 to June 2023. All patients had high-sensitivity troponin test results within 6 hours after 12-lead ECG. Both troponin I (TnI) and TnT were used, with biomarker-specific cut-offs and sex-specific cut-offs for TnI. On this dataset, a residual convolutional neural network (ResNet) was trained 10 times, each on a unique split of the data. The final model achieved an average area under the curve for the receiver operating characteristic curve of 0.7717 (95% CI±0.0052), calibration curve analysis revealed a mean slope of 1.243 (95% CI±0.075) and intercept of -0.073 (95% CI±0.034), indicating a good correlation between prediction and ground truth. Post-classification, tuned for F1 score, accuracy was 71.43% (95% CI±1.28), with an F1 score of 0.5642 (95% CI±0.0052) and a negative predictive value of 0.8660 (95% CI±0.0048), respectively. The ResNet displayed comparable or surpassing metrics to prior presented models., Conclusion: The model exhibited clinically meaningful performance, notably its high negative predictive accuracy. Therefore, clinical use of comparable neural networks in first-line, quick-response triage of patients with chest pain or dyspnoea appears as a valuable option in future medical practice., 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: Percutaneous coronary intervention (PCI) is frequently used for patients with chronic coronary syndrome (CCS). However, the role of PCI beyond symptom relief in CCS remains controversial. The objective of this study was to determine whether PCI is associated with better outcomes, compared with medical therapy (MT) alone., Methods: We conducted a retrospective cohort study. Using the Swedish Coronary Angiography and Angioplasty Registry, we included all patients with CCS undergoing coronary angiography in Sweden between 2010 and 2020. Two groups were formed based on treatment strategy: PCI+MT versus MT alone. One-to-one propensity score (PS) matching was used to address confounding. Outcome was assessed using matched win ratio analysis, a statistical method that ranks the components of the composite by clinical importance. The primary outcome was net adverse clinical event (NACE) within 5 years. In the win ratio analysis, the components of NACE were ranked as follows: (1) all-cause mortality, (2) myocardial infarction (MI), (3) bleeding and (4) urgent revascularisation. Secondary outcomes were the individual components of NACE, major adverse cardiovascular events (MACE) and cardiovascular mortality., Results: After PS matching, two groups of 7220 patients each were formed. The hierarchical outcome analysis of NACE and MACE showed that PCI was associated with improved outcome (matched win ratio: 1.28 (95% CI 1.20 to 1.36, p<0.001) and matched win ratio: 1.38 (95% CI 1.29 to 1.48, p<0.001), respectively). The use of PCI was associated with higher win ratio of MI (matched win ratio: 1.15, 95% CI 1.04 to 1.28, p=0.008), urgent revascularisation (matched win ratio: 1.85, 95% CI 1.69 to 2.03, p<0.001) and cardiovascular mortality (matched win ratio: 1.15, 95% CI 1.00 to 1.34, p=0.044). No difference in win ratio was observed for all-cause mortality or bleeding., Conclusions: In this study, which sought to evaluate the outcomes of patients with CCS using a hierarchical approach, patients selected for revascularisation with PCI experienced better outcome compared with MT alone., 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: ST-elevation myocardial infarction (STEMI) and Takotsubo syndrome (TS) are two distinct cardiac conditions that both result in sudden loss of cardiac dysfunction and that are difficult to distinguish clinically. This study compared plasma protein changes in 24 women with STEMI and 12 women with TS in the acute phase (days 0-3 post symptom onset) and the stabilization phase (days 7, 14, and 30) to examine the molecular differences between these conditions., Methods: Plasma proteins from STEMI and TS patients were extracted during the acute and stabilization phases and analyzed via quantitative proteomics. Differential expression and functional significance were assessed. Data are accessible on ProteomeXchange, ID PXD051367., Results: During the acute phase, STEMI patients showed higher levels of myocardial inflammation and tissue damage proteins compared to TS patients, along with reduced tissue repair and anti-inflammatory proteins. In the stabilization phase, STEMI patients exhibited ongoing inflammation and disrupted lipid metabolism. Notably, ADIPOQ was consistently downregulated in STEMI patients in both phases. When comparing the acute to the stabilization phase, STEMI patients showed increased inflammatory proteins and decreased structural proteins. Conversely, TS patients showed increased proteins involved in inflammation and the regulatory response to counter excessive inflammation. Consistent protein changes between the acute and stabilization phases in both conditions, such as SAA2, CRP, SAA1, LBP, FGL1, AGT, MAN1A1, APOA4, COMP, and PCOLCE, suggest shared underlying pathophysiological mechanisms., Conclusions: This study presents protein changes in women with STEMI or TS and identifies ADIPOQ, SAA2, CRP, SAA1, LBP, FGL1, AGT, MAN1A1, APOA4, COMP, and PCOLCE as candidates for further exploration in both therapeutic and diagnostic contexts.

Background: Lipid content in untreated nonobstructive coronary artery lesions is associated with adverse clinical outcomes, and residual in-stent or stent edge lipid may worsen outcomes after percutaneous coronary intervention (PCI)., Methods: Near-infrared spectroscopy-intravascular ultrasound was performed before and after PCI in patients with myocardial infarction. We evaluated the impact of lipid assessed by near-infrared spectroscopy (maximal lipid core burden index over 4 mm [maxLCBI 4mm ]) along with intravascular ultrasound information including residual plaque burden on in-stent or edge-related major adverse cardiac events (MACE) in de novo PCI-treated culprit coronary artery lesions. The primary end point was culprit lesion-related MACE (CL-MACE), defined as cardiac death, myocardial infarction, or unstable or progressive angina either requiring revascularization or with rapid lesion progression and classified as in-stent or stent edge-related., Results: During a median follow-up of 3.8 years, 25 CL-MACE (11 stent edge-related, 13 in-stent, and 1 in-lesion without a stent) occurred in 1041 PCI-treated lesions in 768 patients. Pre-PCI or post-PCI measures of lipid content were not related to in-stent CL-MACE. However, stent edge-related CL-MACE was increased if both the post-PCI stent edge maxLCBI 4mm was greater than the upper quartile (108.7) and the stent edge plaque burden was >50% (adjusted odds ratio, 4.11 [95% CI, 1.12-15.2]; P =0.03)., Conclusions: In PROSPECT II (Providing Regional Observations to Study Predictors of Events in the Coronary Tree), CL stent implantation leaving behind greater stent edge-related lipid and uncovered plaque burden was associated with an increased risk of stent edge-related CL-MACE during follow-up. In contrast, CL lipid content was not related to in-stent CL-MACE., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02171065., Competing Interests: Dr Maehara is a consultant to Boston Scientific, Philips, and SpectraWave; and speaker honoraria from Nipro. Dr Matsumura is a consultant to Boston Scientific and Terumo. Dr Maeng is supported by a grant from the Novo Nordisk Foundation (grant number NNF22OC0074083); has received lecture and advisory board fees from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, and Novo Nordisk; has received research grants from Philips, Bayer, and Novo Nordisk; has research contracts with Novo Nordisk, Janssen, and Philips; and is a minor shareholder in Verve Therapeutics, Eli Lilly, and Novo Nordisk. Dr Engstrøm has received advisory board fees from Novo Nordisk, Abbot Vascular, and Opsens; and speakers fee from Abbott Vascular. Dr Fröbert has received grants from Sanofi Pasteur. Dr Persson has received unrestricted grants from Abbott. Dr Jensen has received institutional unrestricted research grants from Biotronik, BioSensors, and OrbusNeich. Dr Held has received Advisory board fees from Novo Nordisk, AstraZeneca, Boehringer Ingelheim, Coala Life, and Pharmacosmos; research grants from Pfizer; and lecture fees from Bayer. Dr Mintz has received honoraria from Boston Scientific, Philips, Abbott, SpectraWave, and Gentuity. Dr Ali has received institutional grant support from Abbott, Abiomed, Acist Medical, Amgen, Boston Scientific, Cathworks, Canon, Conavi, Heartflow, Inari, Medtronic Inc, National Institutes of Health, Nipro, Opsens Medical, Medis, Philips, Shockwave, Siemens, Spectrawave, and Teleflex Inc; consultant honoraria from Abiomed, AstraZeneca, Boston Scientific, Cathworks, Opsens, Philips, and Shockwave; and equity in Elucid, Lifelink, Spectrawave, Shockwave, and VitalConnect. Dr Stone has received speaker honoraria from Medtronic, Pulnovo, Infraredx, Abiomed, Amgen, and Boehringer Ingelheim; has served as a consultant to Abbott, Daiichi Sankyo, Ablative Solutions, CorFlow, Cardiomech, Robocath, Miracor, Vectorious, Apollo Therapeutics, Elucid Bio, Cardiac Success, Valfix, TherOx, HeartFlow, Neovasc, Ancora, Occlutech, Impulse Dynamics, Adona Medical, Millennia Biopharma, Oxitope, HighLife, Elixir, Remote Cardiac Enablement, and Aria; and has equity/options from Cardiac Success, Ancora, Cagent, Applied Therapeutics, Biostar family of funds, SpectraWave, Orchestra Biomed, Aria, Valfix, and Xenter. Dr Stone’s employer, Mount Sinai Hospital, receives research grants from Shockwave, Abbott, Abiomed, Bioventrix, Cardiovascular Systems Inc, Phillips, Biosense-Webster, Vascular Dynamics, Pulnovo, and V-wave. Dr Erlinge has received speakers fees from Amgen, AstraZeneca, Bayer, and Chiesi; and advisory board fees from Bayer, Boehringer Ingelheim, and Sanofi. The other authors report no conflicts.

Introduction: Calcium metabolism dysregulation in the setting of primary hyperparathyroidism (PHPT) mediated chondrocalcinosis is implicated in joint pain, a key element in the decision regarding arthroplasty for osteoarthritis. The relationship between hypercalcemia and joint pain, before and after arthroplasty, is unknown. This study investigates the association between preoperative hypercalcemia and postoperative outcomes following total knee (TKA) and total hip arthroplasty (THA)., Methods: A retrospective chart review was conducted on patients who underwent initial elective THA or TKA. Patients with a preoperative serum calcium >10.2 mg/dL were matched (1:2-1:4) with nearest neighbor to patients with normal serum calcium. THA and TKA functional outcomes were measured at baseline and 1-y postoperatively using patient-reported Hip Disability and Osteoarthritis Outcome Scores and Knee Injury and Osteoarthritis Outcome Scores surveys. Postoperative complications, readmissions, length of stay, and functional outcome scores were compared., Results: Four hundred ninety-five patients (106 hypercalcemic cases, 389 matched controls) were included. Of these, 223 patients underwent THA (46 cases; 177 controls) and 272 patients underwent TKA (61 cases; 211 controls). There were no differences in Hip Disability and Osteoarthritis Outcome Scores and Knee Injury and Osteoarthritis Outcome Scores scores, postoperative complications, readmissions, or length of stay between cases and controls. Only 19/106 (18%) hypercalcemic patients had a parathyroid hormone (PTH); of these, 9 (47%) had possible PHPT (PTH > 40)., Conclusions: Patients with hypercalcemia undergoing arthroplasty have similar functional and postoperative outcomes as normocalcemic patients. As PTH was obtained in <20% of hypercalcemic cases and 50% had possible PHPT, we recommend that hypercalcemic patients undergo PHPT workup. Additional investigation is needed to determine the effect of PHPT on arthroplasty outcomes., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: The registry-based randomized VALIDATE-SWEDEHEART trial (NCT02311231) compared bivalirudin vs. heparin in patients undergoing percutaneous coronary intervention (PCI) for myocardial infarction (MI). It showed no difference in the composite primary endpoint of death, MI, or major bleeding at 180 days. Here, we report outcomes at two years., Methods: Analysis of primary and secondary endpoints at two years of follow-up was prespecified in the study protocol. We report the study results for the extended follow-up time here., Results: In total, 6006 patients were enrolled, 3005 with ST-segment elevation MI (STEMI) and 3001 with Non-STEMI (NSTEMI), representing 70 % of all eligible patients with these diagnoses during the study. The primary endpoint occurred in 14.0 % (421 of 3004) in the bivalirudin group compared with 14.3 % (429 of 3002) in the heparin group (hazard ratio [HR] 0.97; 95 % confidence interval [CI], 0.85-1.11; P = 0.70) at one year and in 16.7 % (503 of 3004) compared with 17.1 % (514 of 3002), (HR 0.97; 95 % CI, 0.96-1.10; P = 0.66) at two years. The results were consistent in patients with STEMI and NSTEMI and across major subgroups., Conclusions: Until the two-year follow-up, there were no differences in endpoints between patients with MI undergoing PCI and allocated to bivalirudin compared with those allocated to heparin., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT02311231., Competing Interests: Declaration of competing interest Elmir Omerovic reports grants from Astra Zeneca, personal fees from Astra Zeneca, MSD, Bayer, Janssen outside the submitted work. Stefan James reports grants from Astra Zeneca, grants from The Medicines Company, grants from Swedish Heart and Lung Foundation, and grants from Swedish Research Council during the conduct of the study; personal fees from Bayer and grants from Jansen outside the submitted work. Truls Råmunddal reports personal fees from Boston Scientific and personal fees from Abbot outside the submitted work. Ole Fröbert reports personal fees from GE Medical and from Astra Zeneca outside the submitted work. Pontus Lindroos reports personal fees from Astra Zeneca outside the submitted work. Anders Ulvenstam reports personal fees from Boston Scientific outside the submitted work. Matthias Götberg reports grants and personal fees from Volcano Corporation, personal fees from Boston Scientific, and personal fees from Medtronic Corporation outside the submitted work. Oskar Angerås Dr. reports personal fees from Astra Zeneca outside the submitted work. Olie Östlund reports grants from AstraZeneca, grants from The Medicines Company. Cleas Held reports grants and personal fees from AstraZeneca, grants from GlaxoSmithKline, grants from BristolMyers Squibb, and grants from Merck outside the submitted work. Sasha Koul reports personal fees from Pfizer, personal fees from BMS, and personal fees from Astra Zeneca outside the submitted work. David Erlinge reports personal fees from Astrazeneca and The Medicines Company outside the submitted work. All others co-authors have nothing to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Takotsubo syndrome (TTS) is an acute heart failure syndrome with symptoms similar to acute myocardial infarction. TTS is often triggered by acute emotional or physical stress and is a significant cause of morbidity and mortality. Predictors of mortality in patients with TS are not well understood, and there is a need to identify high-risk patients and tailor treatment accordingly. This study aimed to assess the importance of various clinical factors in predicting 30-day mortality in TTS patients using a machine learning algorithm., Methods: We analyzed data from the nationwide Swedish Coronary Angiography and Angioplasty Registry (SCAAR) for all patients with TTS in Sweden between 2015 and 2022. Gradient boosting was used to assess the relative importance of variables in predicting 30-day mortality in TTS patients., Results: Of 3,180 patients hospitalized with TTS, 76.0% were women. The median age was 71.0 years (interquartile range 62-77). The crude all-cause mortality rate was 3.2% at 30 days. Machine learning algorithms by gradient boosting identified treating hospitals as the most important predictor of 30-day mortality. This factor was followed in significance by the clinical indication for angiography, creatinine level, Killip class, and age. Other less important factors included weight, height, and certain medical conditions such as hyperlipidemia and smoking status., Conclusions: Using machine learning with gradient boosting, we analyzed all Swedish patients diagnosed with TTS over seven years and found that the treating hospital was the most significant predictor of 30-day mortality., (© 2024. The Author(s).)

Background: Dual antiplatelet therapy (DAPT) reduces ischemic events but increases bleeding risk, especially in patients with high bleeding risk (HBR). This study aimed to compare outcomes of abbreviated versus standard DAPT strategies in patients with HBR with acute coronary syndrome undergoing percutaneous coronary intervention., Methods and Results: Patients from the SWEDEHEART (Swedish Web-system for Enhancement and Development of Evidence-Based Bare in Heart Disease Evaluated According to Recommended Therapies) registry with at least 1 HBR criterion who underwent percutaneous coronary intervention for acute coronary syndrome were identified and included. Patients were divided into 2 groups based on their planned DAPT time at discharge: 12-month DAPT or an abbreviated DAPT strategy and matched according to their prescribed P2Y12 inhibitor at discharge. The primary outcome assessed was time to net adverse clinical events at 1 year, which encompassed cardiac death, myocardial infarction, ischemic stroke, or clinically significant bleeding. Time to major adverse cardiovascular events and the individual components of net adverse clinical events were considered secondary end points. A total of 4583 patients were included in each group. The most frequently met HBR criteria was age older than 75 years (65.6%) and Predicting Bleeding Complications in Patients Undergoing Stent Implantation and Subsequent Dual Antiplatelet Therapy score ≥25 (44.6%) in the standard DAPT group and oral anticoagulant therapy (79.6%) and age 75 years and older (55.2%) in the abbreviated DAPT group. There was no statistically significant difference in net adverse clinical events (12.9% versus 13.1%; hazard ratio [HR], 0.99 [95% CI, 0.88-1.11], P =0.83), major adverse cardiovascular events (8.6% versus 7.9%; HR, 1.08 [95% CI, 0.94-1.25]), or their components between groups. The results were consistent among all of the investigated subgroups., Conclusions: In patients with HBR undergoing percutaneous coronary intervention due to acute coronary syndrome, abbreviated DAPT was associated with comparable rates of net adverse clinical events and major adverse cardiovascular events to a DAPT duration of 12 months.

Aims: Adequate animal models are necessary to understand human conditions, such as takotsubo syndrome (TS) characterized by the heart's transient regional wall motion abnormalities. This study aims to develop a reproducible, low-mortality TS model that closely mimics the human condition and addresses the limitations of existing models., Methods and Results: We conducted six experiments using 309 Sprague Dawley rats, each approximately 300 g and aged 7-8 weeks. Initially, we replicated an established model using intraperitoneal isoprenaline injections. Subsequent experiments varied the doses and infusion durations of intravenous isoprenaline and assessed the effects of sex, strain, and breeder on the development of reversible akinetic segments. High-resolution echocardiography monitored the regional wall motion over 30 days to correlate with histological changes. Increasing the isoprenaline dose and the infusion time significantly enhanced akinesia ( P < 0.01), resulting in pronounced apical ballooning observed in three-dimensional imaging. Akinesia peaked at 6 h post-infusion, with recovery observed at 24 h; most rats recovered from akinetic segments within 48-72 h. Optimizing the mode of administration, dose, and duration achieved a TS-like phenotype in 90% of cases, with a 16.7% mortality rate. Histological examinations confirmed that myocardial injury occurred, independent of apical ballooning., Conclusion: This study presents a refined TS model that reliably replicates the syndrome's key features, including morphological and electrocardiographic changes, demonstrating its transient nature with high fidelity and reduced mortality. The model's reproducibility, evidenced by consistent results across trials, suggests its potential for broader application pending further validation., Competing Interests: Conflict of interest: none declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Takotsubo syndrome (TS) is a heart condition mimicking acute myocardial infarction. TS is characterized by a sudden weakening of the heart muscle, usually triggered by physical or emotional stress. In this study, we aimed to investigate the effect of pharmacological interventions on short- and long-term mortality in patients with TS., Methods and Results: We analysed data from the SWEDEHEART (the Swedish Web System for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies) registry, which included patients who underwent coronary angiography between 2009 and 2016. In total, we identified 1724 patients with TS among 228 263 individuals in the registry. The average age was 66 ± 14 years, and 77% were female. Nearly half of the TS patients (49.4%) presented with non-ST-elevation acute coronary syndrome, and a quarter (25.9%) presented with ST-elevation myocardial infarction. Most patients (79.1%) had non-obstructive coronary artery disease on angiography, while 11.7% had a single-vessel disease and 9.2% had a multivessel disease. All patients received at least one pharmacological intervention; most of them used beta-blockers (77.8% orally and 8.3% intravenously) or antiplatelet agents [aspirin (66.7%) and P2Y 12 inhibitors (43.6%)]. According to the Kaplan-Meier estimator, the probability of all-cause mortality was 2.5% after 30 days and 16.6% after 6 years. The median follow-up time was 877 days. Intravenous use of inotropes and diuretics was associated with increased 30 day mortality in TS [hazard ratio (HR) = 9.92 (P < 0.001) and HR = 3.22 (P = 0.001), respectively], while angiotensin-converting enzyme inhibitors and statins were associated with decreased long-term mortality [HR = 0.60 (P = 0.025) and HR = 0.62 (P = 0.040), respectively]. Unfractionated and low-molecular-weight heparins were associated with reduced 30 day mortality [HR = 0.63 (P = 0.01)]. Angiotensin receptor blockers, oral anticoagulants, P2Y 12 antagonists, aspirin, and beta-blockers did not statistically correlate with mortality., Conclusions: Our findings suggest that some medications commonly used to treat TS are associated with higher mortality, while others have lower mortality. These results could inform clinical decision-making and improve patient outcomes in TS. Further research is warranted to validate these findings and to identify optimal pharmacological interventions for patients with TS., (© 2024 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Introduction: Human immunodeficiency virus (HIV) / hepatitis B virus (HBV) causes higher rates of liver disease compared to infection with just one virus. Co-infection can accelerate the progression to liver fibrosis or hepatocellular carcinoma and disturb the treatment response. APOBEC3G is a host defense factor which interferes with HIV-1 and HBV. We aimed to determine the prevalence of hepatitis B surface antigen (HBsAg) among HIV-infected patients and seronegative controls, and screen the HIV/HBV population for APOBEC3G variants rs8177832, rs35228531 and rs2294367, previously associated with HIV-1 infection susceptibility in Morocco., Methodology: A case control study was conducted on 404 individuals (204 HIV-infected and 200 eligible blood donors) from April to November 2021. HBsAg was measured on the Roche Cobas e411 automatic analyzer (Roche Diagnostics, Basel, Switzerland) and APOBEC3G polymorphisms were identified using the TaqMan genotyping allelic discrimination method. Fisher Exact test, odds ratio (OR) with 95% confidence interval (CI), and haplotype frequencies were calculated., Results: Of the 204 HIV-1 seropositive patients and 200 controls, 4.9% (95%CI: 2.38-8.83) and 2.50% (95% CI: 0.82-5.74) were HBsAg-positive respectively. There was a significant association between increasing age (> 40 years) and HBV infection among controls (p = 0.04). The distribution of genotypes and alleles frequencies of APOBEC3G variants was heterogenous and five different haplotypes with frequencies ≥ 5% were obtained, of which ACC (rs8177832, rs35228531, rs2294367) was the most prevalent., Conclusions: HBV co-infection is common among HIV-1 infected individuals in Morocco. Efforts should be made to prevent, treat and control HBV transmission in this population., Competing Interests: No Conflict of Interest is declared, (Copyright (c) 2024 Imane Belbacha, Rajae Bensghir, Kamal Filali Marhoum, Majda Laboudi, Khadija Hajoutt, Elmir ElHarti, Khalid Sadki, Hicham Oumzil.)

Modelling human diseases serves as a crucial tool to unveil underlying mechanisms and pathophysiology. Takotsubo syndrome (TS), an acute form of heart failure resembling myocardial infarction, manifests with reversible regional wall motion abnormalities (RWMA) of the ventricles. Despite its mortality and clinical similarity to myocardial infarction, TS aetiology remains elusive, with stress and catecholamines playing central roles. This review delves into current animal models of TS, aiming to assess their ability to replicate key clinical traits and identifying limitations. An in-depth evaluation of published animal models reveals a variation in the definition of TS among studies. We notice a substantial prevalence of catecholamine-induced models, particularly in rodents. While these models shed light on TS, there remains potential for refinement. Translational success in TS research hinges on models that align with human TS features and exhibit the key features, including transient RWMA. Animal models should be comprehensively evaluated regarding the various systemic changes of the applied trigger(s) for a proper interpretation. This review acts as a guide for researchers, advocating for stringent TS model standards and enhancing translational validity., Competing Interests: The 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 Zulfaj, Nejat, Haamid, Elmahdy, Espinosa, Redfors and Omerovic.)

Background: Few studies have explored long-term trends and risk factors for peripheral arterial complications in type 2 diabetes compared to the general population. Our research focuses on identifying optimal risk factors, their significance, risk associated with multifactorial risk factor control, and trends for these complications in diabetic patients versus general controls., Methods: This study included persons with type 2 diabetes mellitus entered into the Swedish National Diabetes Register 2001-2019 and controls matched for age-, sex- and county of residence. Outcomes comprised of extracranial large artery disease, aortic aneurysm, aortic dissection, lower extremity arterial disease and diabetes foot disease. Standardized incidence rates and Cox regression were used for analyses., Findings: The study comprises 655,250 persons with type 2 diabetes mellitus; average age 64.2; 43.8% women. Among persons with type 2 diabetes mellitus, the incidence rates per 100,000 person years for each non-coronary peripheral arterial complication event changed between 2001 and 2019 as follows: extracranial large artery disease 170.0-84.9; aortic aneurysm 40.6-69.2; aortic dissection 9.3 to 5.6; lower extremity artery disease from 338.8 to 190.8; and diabetic foot disease from 309.8 to 226.8. Baseline hemoglobin A1c (HbA1c), systolic blood pressure (SBP), smoking status and lipid levels were independently associated with all outcomes in the type 2 diabetes mellitus cohort. Within the cohort with type 2 diabetes mellitus, the risk for extracranial large artery disease and lower extremity artery disease increased in a stepwise fashion for each risk factor not within target. Excess risk for non-coronary peripheral arterial complications in the entire cohort for persons with type 2 diabetes mellitus, compared to matched controls, were as follows: extracranial large artery disease adjusted hazard ratio (HR) 1.69 (95% confidence interval (CI), 1.65-1.73), aortic aneurysm HR 0.89 (95% CI, 0.87-0.92), aortic dissection HR 0.51 (95% CI, 0.46-0.57) and lower extremity artery disease HR 2.59 (95% CI, 2.55-2.64)., Interpretation: The incidence of non-coronary peripheral arterial complications has declined significantly among persons with type 2 diabetes mellitus, with the exception of aortic aneurysm. HbA1c, smoking and blood pressure demonstrated greatest relative contribution for outcomes and lower levels of cardiometabolic risk factors are associated with reduced relative risk of outcomes., Funding: Swedish Governmental and the County support of research and education of doctors, the Swedish Heart-Lung Foundation and Åke-Wibergs grant., Competing Interests: Dr. Bhatt discloses the following relationships - Advisory Board: Angiowave, Bayer, Boehringer Ingelheim, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Stasys; Board of Directors: American Heart Association New York City, Angiowave (stock options), Bristol Myers Squibb (stock), DRS.LINQ (stock options), High Enroll (stock); Consultant: Broadview Ventures, GlaxoSmithKline, Hims, SFJ, Youngene; Data Monitoring Committees: Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Boston Scientific (Chair, PEITHO trial), Cleveland Clinic, Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo; for the ABILITY-DM trial, funded by Concept Medical; for ALLAY-HF, funded by Alleviant Medical), Novartis, Population Health Research Institute; Rutgers University (for the NIH-funded MINT Trial); Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org” title = “http://ACC.org”>ACC.org; Chair, ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol-Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), CSL Behring (AHA lecture), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), K2P (Co-Chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Oakstone CME (Course Director, Comprehensive Review of Interventional Cardiology), Piper Sandler, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), WebMD (CME steering committees), Wiley (steering committee); Other: Clinical Cardiology (Deputy Editor); Patent: Sotagliflozin (named on a patent for sotagliflozin assigned to Brigham and Women’s Hospital who assigned to Lexicon; neither I nor Brigham and Women’s Hospital receive any income from this patent); Research Funding: Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Alnylam, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, Cleerly, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Otsuka, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, 89Bio; Royalties: Elsevier (Editor, Braunwald’s Heart Disease); Site Co-Investigator: Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St. Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, Vascular Solutions; Trustee: American College of Cardiology; Unfunded Research: FlowCo. JN reports no conflicts of interest. Dr. McGuire reports research support for Clinical Trials Leadership from Boehringer Ingelheim, Merck & Co, Pfizer, AstraZeneca, Novo Nordisk, Esperion, Lilly USA, Lexicon, CSL Behringm New Amsterdam; honoraria for consultancy from Lilly USA, Boehringer Ingelheim, Merck & Co, Novo Nordisk, Applied Therapeutics, Altimmune, CSL Behring, Bayer, GlaxoSmithKline, Intercept. Dr. Eliasson reports personal fees from Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck Sharp and Dohme, Mundipharma, NovoNordisk and Sanofi, all outside the submitted work. Dr. Borén reports personal fees from Novartis, Pfizer, Novo Nordisk, Amgen and Akcea. Dr. Sattar reports personal fees from Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck Sharp & Dohme, Novartis, Novo Nordisk, Pfizer, Sanofi, Roche Diagnostics, Abbot Laboratories, AbbVie, Hanmi Pharmaceuticals, Janssen, Menarini-Richerche. Dr. Gerstein reports personal fees and grants from Sanofi, Eli Lilly, Novo Nordisk, Merck, Abbott, Hanmi, Boehringer Ingelheim, Carbon Bran, Bioling, AstraZZeneca, Zuellig, DKSH, Jiangsu Hanson Pharma and Kowa Research Institute. Dr. Beckman has received grants from Bristol Myers Squibb and consulting fees from JanOne. The remaining authors have nothing to disclose., (© 2024 The Author(s).)

Background and Aims: Ischemic preconditioning (IPC), i.e., brief periods of ischemia, protect the heart from subsequent prolonged ischemic injury, and reduces infarction size. Myocardial stunning refers to transient loss of contractility in the heart after myocardial ischemia that recovers without permanent damage. The relationship between IPC and myocardial stunning remains incompletely understood. This study aimed primarily to examine the effects of IPC on the relationship between ischemia duration, stunning, and infarct size in an ischemia-reperfusion injury model. Secondarily, this study aimed to examine to which extent the phosphoproteomic changes induced by IPC relate to myocardial contractile function., Methods and Results: Rats were subjected to different durations of left anterior descending artery (LAD) occlusion, with or without preceding IPC. Echocardiograms were acquired to assess cardiac contraction in the affected myocardial segment. Infarction size was evaluated using triphenyl tetrazolium chloride staining. Phosphoproteomic analysis was performed in heart tissue from preconditioned and non-preconditioned animals. In contrast to rats without IPC, reversible akinesia was observed in a majority of the rats that were subjected to IPC and subsequently exposed to ischemia of 13.5 or 15 min of ischemia. Phosphoproteomic analysis revealed significant differential regulation of 786 phosphopeptides between IPC and non-IPC groups, with significant associations with the sarcomere, Z-disc, and actin binding., Conclusion: IPC induces changes in phosphosites of proteins involved in myocardial contraction; and both accentuates post-ischemic myocardial stunning and reduces infarct size., Competing Interests: The 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 Elmahdy, Shekka Espinosa, Kakaei, Pylova, Jha, Zulfaj, Krasnikova, Al-Awar, Sheybani, Sevastianova, Berger, Nejat, Molander, Andersson, Omerovic, Hussain and Redfors.)

Background: Observational studies on long-term trends, risk factor association and importance are scarce for type 1 diabetes mellitus and peripheral arterial outcomes. We set out to investigate trends in non-coronary complications and their relationships with cardiovascular risk factors in persons with type 1 diabetes mellitus compared to matched controls., Methods: 34,263 persons with type 1 diabetes mellitus from the Swedish National Diabetes Register and 164,063 matched controls were included. Incidence rates of extracranial large artery disease, aortic aneurysm, aortic dissection, lower extremity artery disease, and diabetic foot syndrome were analyzed using standardized incidence rates and Cox regression., Findings: Between 2001 and 2019, type 1 diabetes mellitus incidence rates per 100,000 person-years were as follows: extracranial large artery disease 296.5-84.3, aortic aneurysm 0-9.2, aortic dissection remained at 0, lower extremity artery disease 456.6-311.1, and diabetic foot disease 814.7-77.6. Persons with type 1 diabetes mellitus with cardiometabolic risk factors at target range did not exhibit excess risk of extracranial large artery disease [HR 0.83 (95% CI, 0.20-3.36)] or lower extremity artery disease [HR 0.94 (95% CI, 0.30-2.93)], compared to controls. Persons with type 1 diabetes with all risk factors at baseline, had substantially elevated risk for diabetic foot disease [HR 29.44 (95% CI, 3.83-226.04)], compared to persons with type 1 diabetes with no risk factors. Persons with type 1 diabetes mellitus continued to display a lower risk for aortic aneurysm, even with three cardiovascular risk factors at baseline [HR 0.31 (95% CI, 0.15-0.67)]. Relative importance analyses demonstrated that education, glycated hemoglobin (HbA1c), duration of diabetes and lipids explained 54% of extracranial large artery disease, while HbA1c, smoking and systolic blood pressure explained 50% of lower extremity artery disease and HbA1c alone contributed to 41% of diabetic foot disease. Income, duration of diabetes and body mass index explained 66% of the contribution to aortic aneurysm., Interpretation: Peripheral arterial complications decreased in persons with type 1 diabetes mellitus, except for aortic aneurysm which remained low. Besides glycemic control, traditional cardiovascular risk factors were associated with incident outcomes. Risk of these outcomes increased with additional risk factors present. Persons with type 1 diabetes mellitus exhibited a lower risk of aortic aneurysm compared to controls, despite presence of cardiovascular risk factors., Funding: Swedish Governmental and the county support of research and education of doctors, the Swedish Heart and Lung Foundation, Sweden and Åke-Wibergs grant., Competing Interests: Dr. Bhatt discloses the following relationships - Advisory Board: Angiowave, Bayer, Boehringer Ingelheim, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Stasys; Board of Directors: American Heart Association New York City, Angiowave (stock options), Bristol Myers Squibb (stock), DRS. LINQ (stock options), High Enroll (stock); Consultant: Broadview Ventures, GlaxoSmithKline, Hims, SFJ, Youngene; Data Monitoring Committees: Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Boston Scientific (Chair, PEITHO trial), Cleveland Clinic, Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo; for the ABILITY-DM trial, funded by Concept Medical; for ALLAY-HF, funded by Alleviant Medical), Novartis, Population Health Research Institute; Rutgers University (for the NIH-funded MINT Trial); Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Chair, ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol-Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), CSL Behring (AHA lecture), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), K2P (Co-Chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Oakstone CME (Course Director, Comprehensive Review of Interventional Cardiology), Piper Sandler, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), WebMD (CME steering committees), Wiley (steering committee); Other: Clinical Cardiology (Deputy Editor); Patent: Sotagliflozin (named on a patent for sotagliflozin assigned to Brigham and Women's Hospital who assigned to Lexicon; neither I nor Brigham and Women's Hospital receive any income from this patent); Research Funding: Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Alnylam, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, Cleerly, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Otsuka, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, 89Bio; Royalties: Elsevier (Editor, Braunwald's Heart Disease); Site Co-Investigator: Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St. Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, Vascular Solutions; Trustee: American College of Cardiology; Unfunded Research: FlowCo. JN reports no conflicts of interest. Dr. McGuire reports research support for Clinical Trials Leadership from Boehringer Ingelheim, Merck & Co, Pfizer, AstraZeneca, Novo Nordisk, Esperion, Lilly USA, Lexicon, CSL Behringm New Amsterdam; honoraria for consultancy from Lilly USA, Boehringer Ingelheim, Merck & Co, Novo Nordisk, Applied Therapeutics, Altimmune, CSL Behring, Bayer, GlaxoSmithKline, Intercept. BE reports personal fees from Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck Sharp and Dohme, Mundipharma, NovoNordisk and Sanofi, all outside the submitted work. The remaining authors have nothing to disclose., (© 2024 The Author(s).)

Objectives: This study aims to assess the seroprevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) IgG antibodies against the spike (S) and nucleocapsid (NP) proteins, as well as neutralizing antibodies against the receptor-binding domain (RBD). Additionally, it aims to detect viral RNA of SARS-CoV-2 in pre-pandemic archival pediatric specimens collected before the announcement of the COVID-19 pandemic spread on March 20 th , 2020, in Morocco. The objective is to investigate the existence of pre-pandemic immunity to SARS-CoV-2., Methods: We conducted a cross-sectional study, to analyze IgG antibody levels in a cohort of 106 pre-pandemic pediatric participants. Using an indirect enzyme-linked immunosorbent assay (ELISA), we measured the IgG levels against the S and NP proteins of SARS-CoV-2. Additionally, we staged a competitive ELISA assay to evaluate the neutralizing capability of these antibodies. We used reverse transcription polymerase chain reaction (rRT-PCR) to detect viral NP and ORF1ab genes of SARS-CoV-2 in oropharyngeal swabs. Moreover, we conducted on the same specimens a multiplexed RT-PCR to detect RNA of the most common 27 pathogens involved in lower respiratory tract infections., Results: Among the 106 serum samples, 13% ( n n = =14) tested positive for SARS-CoV-2 IgG antibodies using ELISA. Temporal analysis indicated varying IgG positivity levels across 2019. Neutralizing antibodies were found in 21% of the 28 samples analyzed, including two with high inhibition rates (93%). The SARS-CoV-2 RNA was detected using rRT-PCR in 14 samples. None of the samples tested positive for the other 27 pathogens associated with lower respiratory tract infections, using multiplexed RT-PCR., Conclusion: Our study addresses the possibility, that COVID-19 infections occurred in Morocco before the recognized outbreak. On the other hand, some of the cases might reflect cross-reactivity with other coronaviruses or be influenced by previous viral exposures or vaccinations. Understanding these factors is crucial to comprehending pediatric immune responses to newly emerging infectious diseases., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Neurocognitive dysfunction is common in heart failure (HF), with 30% to 80% of patients experiencing some degree of deficits in one or more cognitive domains, including memory, attention, learning ability, executive function, and psychomotor speed. Although the mechanism is not fully understood, reduced cardiac output, comorbidities, chronic cerebral hypoperfusion, and cardioembolic brain injury leading to cerebral hypoxia and brain damage seem to trigger the neurocognitive dysfunction in HF. Cognitive impairment is independently associated with worse outcomes including mortality, rehospitalization, and reduced quality of life. Patients with poorer cognitive function are at an increased risk of severe disease as they tend to have greater difficulty complying with treatment requirements. Coronary revascularization in patients with ischemic HF has the potential to improve cardiovascular outcomes but risks worsening neurocognitive dysfunction even further. Revascularization by coronary artery bypass grafting carries inherent risks for delirium, cognitive impairment, neurologic injury, and stroke, which are known to exacerbate the risk of neurocognitive dysfunction. Alternatively, percutaneous coronary intervention, as a less-invasive approach, has the potential to minimize the risk of cognitive impairment but has not yet been evaluated as an alternative to coronary artery bypass grafting in patients with ischemic HF. Therefore, it is paramount to raise awareness of the neurocognitive consequences in ischemic HF and devise strategies for recognition and prevention as an important target of patient management and personalized decision making that contributes to patient outcomes., Competing Interests: Yousif Ahmad is a consultant for Shockwave Medical and Cardiovascular Systems Inc and is on the Medical Advisory Board for Boston Scientific. Other authors reported no financial interests., (Crown Copyright © 2023 Published by Elsevier Inc. on behalf of the Society for Cardiovascular Angiography and Interventions Foundation.)

Aims: The role of coronary calcification on clinical outcomes among different revascularization strategies in patients presenting with acute coronary syndromes (ACSs) has been rarely investigated. The aim of this investigation is to evaluate the role of coronary calcification, detected by coronary angiography, in the whole spectrum of patients presenting with acute ACS., Methods and Results: The present study was a post hoc analysis of the MATRIX programme. The primary endpoint was major adverse cardiovascular events (MACE), defined as the composite of all-cause mortality, myocardial infarction (MI), or stroke up to 365 days. Among the 8404 patients randomized in the MATRIX trial, data about coronary calcification were available in 7446 (88.6%) and therefore were included in this post hoc analysis. Overall, 875 patients (11.7%) presented with severe coronary calcification, while 6571 patients (88.3%) did not present severe coronary calcification on coronary angiography. Fewer patients with severe coronary calcification underwent percutaneous coronary intervention whereas coronary artery bypass grafting or medical therapy-only was more frequent compared with patients without severe calcification. At 1-year follow-up, MACE occurred in 237 (27.1%) patients with severe calcified coronary lesions and 985 (15%) patients without severe coronary calcified lesions [hazard ratio (HR) 1.91; 95% confidence interval (CI) 1.66-2.20, P < 0.001]. All-cause mortality was 8.6% in patients presenting with and 3.7% in those without severe coronary calcification (HR 2.38, 1.84-3.09, P < 0.001). Patients with severe coronary calcification incurred higher rate of MI (20.1% vs. 11.5%, HR 1.81; 95% CI 1.53-2.1, P < 0.001) and similar rate of stroke (0.8% vs. 0.6%, HR 1.35; 95% CI 0.61-3.02, P = 0.46)., Conclusion: Patients with ACS and severe coronary calcification, as compared to those without, are associated with worse clinical outcomes irrespective of the management strategy., Competing Interests: Conflict of interest: J.S.S. has received minor speaking honoraria from Terumo, Cordis, Biotronik, and Medtronic. H.M.G.-G. reports the following institutional grant support: Biotronik, Boston Scientific, Medtronic, Abbott, Neovasc, Shockwave, Phillips, and Corflow. G.A. reports minor speaking honoraria from Chiesi, Daiichi Sankyo, Boeringer Ingelheim, Bayer, Pfizer, and Biosensors. D.H. has participated on data safety monitoring board or advisory board of switch. S.L. has received consulting fees from AstraZeneca, Bayer, BMS/Pfizer, Chiesi, Daiichi-Sankyo, Icon, and Novonordisk. M.S. has received consulting fees from Abbott Vascular and iVascular. A.v.H. reports unrestricted grants from Medtronic, Abbott Vascular, and Boehringer Ingelheim and consulting fees from Celecor Therapeutics. P.V. reports consulting fees from Daiichi Sankyo, CSL Behring, Pfizer/Bristol Meyers Squibb alliance, Bayer AG, and Novartis; minor speaking honoraria from Daicchi Sankyo and Pfizer/Bristol Meyers Squibb alliance. M.V. reports consulting fees from Abbott, Alvimedica, Bayer Healthcare, Biotronik, Boston Scientific Corporation, Chiesi Farmaceutici, CoreFlow, Daiichi Sankyo, Idorsia, Medtronic, Novartis Pharma, PHASEBIO, Terumo, University of Basel, Vesalio, and Vifor Pharma. The rest of authors have no disclosures to declare., (© 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.)

Aim: The aim of this study was to present a comprehensive overview of out-of-hospital cardiac arrests (OHCA) in young adults., Methods: The data set analyzed included all cases of OHCA from 1990 to 2020 in the age-range 16-49 years in the Swedish Registry of Cardiopulmonary Resuscitation (SRCR). OHCA between 2010 and 2020 were analyzed in more detail. Clinical characteristics, survival, neurological outcomes, and long-time trends in survival were studied. Logistic regression was used to study 30-days survival, neurological outcomes and Utstein determinants of survival., Results: Trends were assessed in 11,180 cases. The annual increase in 30-days survival during 1990-2020 was 5.9% with no decline in neurological function among survivors. Odds ratio (OR) for heart disease as the cause was 0.55 (95% CI 0.44 to 0.67) in 2017-2020 compared to 1990-1993. Corresponding ORs for overdoses and suicide attempts were 1.61 (95% CI 1.23-2.13) and 2.06 (95% CI 1.48-2.94), respectively. Exercise related OHCA was noted in roughly 5%. OR for bystander CPR in 2017-2020 vs 1990-1993 was 3.11 (95% CI 2.57 to 3.78); in 2020 88 % received bystander CPR. EMS response time increased from 6 to 10 minutes., Conclusion: Survival has increased 6% annually, resulting in a three-fold increase over 30 years, with stable neurological outcome. EMS response time increased with 66% but the majority now receive bystander CPR. Cardiac arrest due to overdoses and suicide attempts are increasing., 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., (© 2023 The Author(s).)

Aims: Ticagrelor is associated with a lower risk of ischemic events than clopidogrel. However, it is uncertain whether the benefits of more intensive anti-ischemic therapy outweigh the risks of major bleeding in patients who have a high bleeding risk (HBR). Therefore, this study compared ticagrelor and clopidogrel in myocardial infarction (MI) patients with HBR., Methods and Results: This study included all patients enrolled in the SWEDEHEART registry who were discharged with dual antiplatelet therapy using ticagrelor or clopidogrel following MI between 2010 and 2017. High bleeding risk was defined as a PRECISE-DAPT score ≥25. Information on ischemic events, major bleeding, and mortality was obtained from national registries, with 365 days of follow-up. Additional outcomes include major adverse cardiovascular events (MACE), a composite of MI, stroke and all-cause mortality, and net adverse clinical events (NACE), a composite of MACE and bleeding. This study included 25 042 HBR patients, of whom 11 848 were treated with ticagrelor. Ticagrelor was associated with a lower risk of MI, stroke, and MACE, but a higher risk of bleeding compared to clopidogrel. There were no significant differences in mortality and NACE. Additionally, when examining the relationship between antiplatelet therapy and bleeding risk in 69 040 MI patients, we found no statistically significant interactions between the PRECISE-DAPT score and treatment effect., Conclusions: We observed no difference in NACE when comparing ticagrelor and clopidogrel in HBR patients. Moreover, we found no statistically significant interactions between bleeding risk and the comparative effectiveness of clopidogrel and ticagrelor in a larger population of MI patients., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: An observational nationwide all-comers prospective register study to analyse outcomes after coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI) in unprotected left main coronary artery (LMCA) disease., Methods and Results: All patients undergoing coronary angiography in Sweden are registered in the Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies registry. Between 01/01/2005 and 12/31/2015, 11 137 patients with LMCA disease underwent CABG (n = 9364) or PCI (n = 1773). Patients with previous CABG, ST-elevation myocardial infarction (MI) or cardiac shock were excluded. Death, MI, stroke, and new revascularization during follow-up until 12/31/2015 were identified using national registries. Cox regression with inverse probability weighting (IPW) and an instrumental variable (IV), administrative region, were used. Patients undergoing PCI were older, had higher prevalence of comorbidity but lower prevalence of three-vessel disease. PCI patients had higher mortality than CABG patients after adjustments for known cofounders with IPW analysis (hazard ratio [HR] 2.0 [95% confidence interval (CI) 1.5-2.7]) and known/unknown confounders with IV analysis (HR 1.5 [95% CI 1.1-2.0]). PCI was associated with higher incidence of major adverse cardiovascular and cerebrovascular events (MACCE; death, MI, stroke, or new revascularization) than CABG, with IV analysis (HR 2.8 [95% CI 1.8-4.5]). There was a quantitative interaction for diabetic status regarding mortality (P = 0.014) translating into 3.6 years (95% CI 3.3-4.0) longer median survival time favouring CABG in patients with diabetes., Conclusion: In this non-randomized study, CABG in patients with LMCA disease was associated with lower mortality and fewer MACCE compared to PCI after multivariable adjustment for known and unknown confounders., Competing Interests: Conflict of interest J.P. has received unrestricted grants from Abbott Inc., unrelated to the present work. J.Y. has no conflicts of interest. O.A. has received research grant and lecture fees from Abbott Inc. D.V. has no conflicts of interest. A.J. has received fees for consultancy or lectures from AstraZeneca, Werfen, Portola, Baxter and LFB Biotechnologies, all unrelated to the present work. I.S. has no conflicts of interest. R.L. has no conflicts of interest. D.E. has no conflicts of interest. T.I. has no conflicts of interest. E.O. has no conflicts of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Survival in left-sided valvular heart disease (VHD; aortic stenosis [AS], aortic regurgitation [AR], mitral stenosis [MS], mitral regurgitation [MR]) in out-of-hospital cardiac arrest (OHCA) is unknown. We studied all cases of OHCA in the Swedish Registry for Cardiopulmonary Resuscitation. All degrees of VHD, diagnosed prior to OHCA, were included. Association between VHD and survival was studied using logistic regression, gradient boosting and Cox regression. We studied time to cardiac arrest, comorbidities, survival, and cerebral performance category (CPC) score. We included 55,615 patients; 1948 with AS (3,5%), 384 AR (0,7%), 17 MS (0,03%), and 704 with MR (1,3%). Patients with MS were not described due to low case number. Time from VHD diagnosis to cardiac arrest was 3.7 years in AS, 4.5 years in AR and 4.1 years in MR. ROSC occurred in 28% with AS, 33% with AR, 36% with MR and 35% without VHD. Survival at 30 days was 5.2%, 10.4%, 9.2%, 11.4% in AS, AR, MR and without VHD, respectively. There were no survivors in people with AS presenting with asystole or PEA. CPC scores did not differ in those with VHD compared with no VHD. Odds ratio (OR) for MR and AR showed no difference in survival, while AS displayed OR 0.58 (95% CI 0.46-0.72), vs no VHD. AS is associated with halved survival in OHCA, while AR and MR do not affect survival. Survivors with AS have neurological outcomes comparable to patients without VHD., (© 2023. Springer Nature Limited.)

Introduction: Left ventricular (LV) dysfunction is estimated to occur in 10%-25% of the general intensive care unit (ICU) population and is frequently seen as regional wall motion abnormalities (RWMAs). Although RWMA is mostly attributed to myocardial ischemia or infarction, some studies have suggested that nonischemic RWMA might also be prevalent. We sought to establish that RWMA can be seen in critically ill patients with normal coronary arteries and to explore reasons for RWMA in this population., Methods: In this retrospective study, data from the hospital angiography register and the ICU register were collated between 2012 and 2019. Patients were identified who underwent angiography in conjunction with their ICU stay and had RWMA on echocardiography. Patients were divided into either those with non-obstructed or those with obstructed coronary arteries. Cardiac magnetic resonance imaging (cMRI) examinations were reviewed if they had been performed on patients with non-obstructed coronaries., Results: We identified 53 patients with RWMA and non-obstructed coronary arteries and 204 patients with RWMA and obstructed coronary arteries. Patients with non-obstructed coronary arteries were more often female, younger, and had fewer cardiovascular risk factors. They less commonly had ST elevation, but more frequently had T-wave inversion or serious arrhythmias. Troponin levels were higher in patients with obstructed coronary arteries, but NT-proBNP was similar between the groups. There were no differences in risk-adjusted 90-day mortality between patients with non-obstructed versus obstructed coronary arteries (OR 1.21, [95% CI 0.56-2.64], p = .628). In those with non-obstructed coronary arteries, follow-up echocardiography was available for 38 patients, of whom 30 showed normalization of cardiac function. Of the 14 patients with non-obstructed coronary arteries on whom cMRI was performed, 7 had a tentative diagnosis of Takotsubo syndrome or myocardial stunning; 4 had a myocardial infarction (preexisting in 3 cases); 1 patient had acute myocarditis; 1 patient had post-myocarditis; and 1 patient was diagnosed with dilated cardiomyopathy., Conclusion: RWMA can be seen to occur in critically ill patients in the absence of coronary artery obstruction. Several conditions can cause regional hypokinesia, and cMRI is useful to evaluate the underlying etiology., (© 2023 The Authors. Acta Anaesthesiologica Scandinavica published by John Wiley & Sons Ltd on behalf of Acta Anaesthesiologica Scandinavica Foundation.)

Background: The goal of this work was to investigate trends (2001-2019) for cardiovascular events and cardiometabolic risk factor levels in individuals with type 2 diabetes (T2D) and matched control subjects., Methods: This study included 679 072 individuals with T2D from the Swedish National Diabetes Register and 2 643  800 matched control subjects. Incident outcomes comprised coronary artery disease, acute myocardial infarction, cerebrovascular disease, and heart failure (HF). Trends in time to first event for each outcome were analyzed with Cox regression and standardized incidence rates. In the group with T2D, Cox regression was also used to assess risk factor levels beyond target and outcomes, as well as the relative importance of each risk factor to each model., Results: Among individuals with T2D, incidence rates per 10 000 person-years in 2001 and 2019 were as follows: acute myocardial infarction, 73.9 (95% CI, 65.4-86.8) and 41.0 (95% CI, 39.5-42.6); coronary artery disease, 205.1 (95% CI, 186.8-227.5) and 80.2 (95% CI, 78.2-82.3); cerebrovascular disease, 83.9 (95% CI, 73.6-98.5) and 46.2 (95% CI, 44.9-47.6); and HF, 98.3 (95% CI, 89.4-112.0) and 75.9 (95% CI, 74.4-77.5). The incidence for HF plateaued around 2013, a trend that then persisted. In individuals with T2D, glycated hemoglobin, systolic blood pressure, estimated glomerular filtration rate, and lipids were independently associated with outcomes. Body mass index alone potentially explained >30% of HF risk in T2D. For those with T2D with no risk factor beyond target, there was no excess cardiovascular risk compared with control subjects except for HF, with increased hazard with T2D even when no risk factor was above target (hazard ratio, 1.50 [95% CI, 1.35-1.67]). Risk for coronary artery disease and cerebrovascular disease increased in a stepwise fashion for each risk factor not within target. Glycated hemoglobin was most prognostically important for incident atherosclerotic events, as was body mass index for incident of HF., Conclusions: Risk and rates for atherosclerotic complications and HF are generally decreasing among individuals with T2D, although HF incidence has notably plateaued in recent years. Modifiable risk factors within target levels were associated with lower risks for outcomes. This was particularly notable for systolic blood pressure and glycated hemoglobin for atherosclerotic outcomes and body mass index for heart failure., Competing Interests: Disclosures Dr Bhatt discloses the following relationships: advisory boards for Angiowave, Bayer, Boehringer Ingelheim, Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences, and Stasys; boards of directors for Angiowave (stock options), Boston VA Research Institute, Bristol Myers Squibb (stock), DRS.LINQ (stock options), High Enroll (stock), Society of Cardiovascular Patient Care, and TobeSoft; chair/inaugural chair of the American Heart Association Quality Oversight Committee; consultant for Broadview Ventures and Hims; data monitoring committees for Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Boston Scientific (chair, PEITHO trial), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Contego Medical (chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo; for the ABILITY-DM trial, funded by Concept Medical), Novartis, Population Health Research Institute, and Rutgers University (for the National Institutes of Health–funded MINT Trial); honoraria from the American College of Cardiology (senior associate editor, Clinical Trials and News, ACC.org; chair of the ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol-Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI Clinical Trial Steering Committee funded by Boehringer Ingelheim; AEGIS-II executive committee, funded by CSL Behring), Belvoir Publications (editor in chief of Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (editor in chief of the Journal of Invasive Cardiology), Journal of the American College of Cardiology (guest editor; associate editor), K2P (co-chair for interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Oakstone CME (course director of Comprehensive Review of Interventional Cardiology), Piper Sandler, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and US national coleader, funded by Bayer), Slack Publications (chief medical editor of Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (secretary/treasurer), WebMD (CME steering committees), Wiley (steering committee); other: clinical cardiology (deputy editor), NCDR-ACTION Registry steering committee (chair), and VA CART Research and Publications Committee (chair); named on a patent for sotagliflozin assigned to Brigham and Women’s Hospital (assigned to Lexicon; neither Dr Bhatt nor Brigham and Women’s Hospital receives any income from this patent); research funding from Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, Cleerly, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, and 89Bio; royalties from Elsevier (editor of Braunwald’s Heart Disease); site co- investigator for Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St. Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, and Vascular Solutions; trustee of the American College of Cardiology; and unfunded research from FlowCo and Takeda. Dr McGuire reports receiving executive committee fees and consulting fees from Boehringer Ingelheim, Sanofi US, and AstraZeneca; data monitoring committee fees from CSL Behring; executive committee fees, consulting fees, and advisory board fees from Lilly USA and Novo Nordisk; executive committee fees from Lexicon and Eisai; steering committee fees from Esperion; consulting fees from Metavant, Applied Therapeutics, Bayer, and Afimmune; and advisory board fees from Pfizer, Merck Sharp, and Dohme. Dr Sattar has consulted for Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Hanmi, MSD, Novartis, Novo Nordisk, Pfizer, and Sanofi, and received grant support from AstraZeneca, Boehringer Ingelheim, Novartis, and Roche Diagnostics outside the submitted work. The other authors report no conflicts.

Background: Deferral of coronary revascularization is safe whether guided by instantaneous wave-free ratio (iFR) or by fractional flow reserve (FFR). We aimed to assess long-term outcomes in patients deferred from revascularization based on iFR or FFR in a large real-world population., Methods: From 2013 through 2017, 201,933 coronary angiographies were registered in the Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies (SWEDEHEART). We included all patients (n = 11,324) with at least 1 coronary lesion deferred from PCI during an index procedure using iFR (>0.89; n = 1998) or FFR (>0.80; n = 9326). The primary outcome was major adverse cardiac events (MACE) defined as the composite of all-cause death, nonfatal myocardial infarction, or unplanned revascularization. A multivariable-adjusted Cox proportional hazards model was used, with analysis for interaction of prespecified subgroups., Results: Patients presented with stable angina pectoris (iFR 46.9% vs FFR 48.6%), unstable angina or non-ST-elevation myocardial infarction (iFR 37.7% vs FFR 33.1%), ST-elevation myocardial infarction (iFR 1.9% vs FFR 1.6%), and other indications (iFR 12.5% vs FFR 15.7%). The median follow-up was 2 years for both iFR and FFR groups. At the conclusion of the study, the cumulative MACE risks were 26.7 for the iFR group and 25.9% for FFR group. In the adjusted analysis, no difference was found between the 2 groups (adjusted hazard ratio: iFR vs FFR, 0.947; 95% CI, 0.84-1.08; P = 39). Consistent with the overall findings, the prespecified subgroups showed no interaction with the FFR/iFR results., Conclusions: Deferral of revascularization showed similar long-term safety whether based on iFR or on FFR., (© 2023 Published by Elsevier Inc. on behalf of Society for Cardiovascular Angiography and Interventions Foundation.)

Aims: Cardiac troponin T (cTnT) and troponin I (cTnI) are expressed as an obligate 1:1 complex in the myocardium. However, blood levels of cTnI often rise much higher than that of cTnT in myocardial infarction (MI), whereas cTnT is often higher in patients with stable conditions such as atrial fibrillation. Here we examine high-sensitive (hs) cTnI and hs-cTnT after different durations of experimental cardiac ischaemia., Methods and Results: hs-cTnI, hs-cTnT, and the hs-cTnT/hs-cTnI ratio were measured in plasma samples from rats before and at 30 and 120 min after 5, 10, 15, and 30 min of myocardial ischaemia. The animals were killed after 120 min of reperfusion, and the infarct volume and volume at risk were measured. hs-cTnI, hs-cTnT, and the hs-cTnT/hs-cTnI ratio were also measured in plasma samples collected from patients with ST-elevation myocardial infarction (STEMI). hs-cTnT and hs-cTnI increased over 10-fold in all rats subjected to ischaemia. The increase of hs-cTnI and hs-cTnT after 30 min was similar, resulting in a hs-cTnI/hs-cTnT ratio around 1. The hs-cTnI/hs-cTnT ratio was also around 1 in blood samples collected at 120 min in rats subjected to 5 or 10 min of ischaemia where no localized necrosis was observed. In contrast, the hs-cTnI/hs-cTnT ratio at 2 h was 3.6-5.5 after longer ischaemia that induced cardiac necrosis. The large hs-cTnI/hs-cTnT ratio was confirmed in patients with anterior STEMI., Conclusion: Both hs-cTnI and hs-cTnT increased similarly after brief periods of ischaemia that did not cause overt necrosis, whereas the hs-cTnI/hs-cTnT ratio tended to increase following longer ischaemia that induced substantial necrosis. A low hs-cTnI/hs-cTnT ratio around 1 may signify non-necrotic cTn release., Competing Interests: Conflict of interest: None declared., (© 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.)

Background: The pleiotropic action of ticagrelor, with effects in addition to platelet inhibition, has been shown to improve endothelial function in patients with coronary artery disease. These positive effects are possibly adenosine mediated. This study investigated the association of ticagrelor therapy and coronary artery flow reserve in survivors of myocardial infarction (MI)., Methods: This was an exploratory, cross-sectional, open substudy of PROFLOW. High-risk individuals with a history of MI were identified. Coronary flow reserve (CFR) was measured non-invasively in the left anterior descending artery using transthoracic Doppler echocardiography. Coronary flow velocity was measured at rest and at maximal flow after induction of hyperaemia by intravenous infusion of adenosine at 140 μg/kg/min. Patients receiving ticagrelor (n=75) were compared with those not receiving ticagrelor (n=506), using simple and multiple linear regression models. Most patients in both groups were treated with aspirin (97% in the ticagrelor and 94% in the non-ticagrelor group). Adjustment for traditional risk factors was conducted., Results: The mean age at study inclusion was 68.5±6.8 years, and most patients were male (81.8%). The simple linear regression analysis showed ticagrelor treatment to be significantly associated with increased CFR: ticagrelor 2.95±0.76 (mean±SD), non-ticagrelor 2.70±0.77, (coefficient 0.25; 95% CI 0.063-0.438; p=0.009). This association was significant in two of the three multiple linear regression models with increasing numbers of variables: Model 1 (0.28; 0.06-0.50; p=0.014), Model 2 (0.26; 0.03-0.48; p=0.025), and borderline significant in Model 3 (0.21; -0.01 to 0.43; p=0.058)., Conclusions: Ticagrelor treatment was associated with increased CFR in this high-risk population. Increased CFR may be a clinically important therapeutic effect of ticagrelor in addition to platelet inhibition., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Aims: The aim was to describe the prevalence, characteristics, and outcome of patients with acute myocardial infarction (MI) developing left ventricular (LV) systolic dysfunction or pulmonary congestion by applying different criteria to define the population., Methods and Results: In patients with MI included in the Swedish web-system for enhancement and development of evidence-based care in heart disease (SWEDEHEART) registry, four different sets of criteria were applied, creating four not mutually exclusive subsets of patients: patients with MI and ejection fraction (EF) < 50% and/or pulmonary congestion (subset 1); EF < 40% and/or pulmonary congestion (subset 2); EF < 40% and/or pulmonary congestion and at least one high-risk feature (subset 3, PARADISE-MI like); and EF < 50% and no diabetes mellitus (subset 4, DAPA-MI like). Subsets 1, 2, 3, and 4 constituted 31.6%, 15.0%, 12.8%, and 22.8% of all patients with MI (n = 87 177), respectively. The age and prevalence of different co-morbidities varied between subsets. For median age, 70 to 77, for diabetes mellitus, 22 to 33%; for chronic kidney disease, 22 to 38%, for prior MI, 17 to 21%, for atrial fibrillation, 7 to 14%, and for ST-elevations, 38 to 50%. The cumulative incidence of death or heart failure hospitalization at 3 years was 17.4% (95% CI: 17.1-17.7%) in all MIs; 26.9% (26.3-27.4%) in subset 1; 37.6% (36.7-38.5%) in subset 2; 41.8% (40.7-42.8%) in subset 3; and 22.6% (22.0-23.2%) in subset 4., Conclusions: Depending on the definition, LV systolic dysfunction or pulmonary congestion is present in 13-32% of all patients with MI and is associated with a two to three times higher risk of subsequent death or HF admission. There is a need to optimize management and improve outcomes for this high-risk population., (© 2023 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Takotsubo syndrome (TS) is a life-threatening acute heart failure syndrome without any evidence-based treatment options. No treatment for TS has been examined in a randomized trial., Study Design and Objectives: BROKEN-SWEDEHEART is a multicenter, randomized, open-label, registry-based 2 × 2 factorial clinical trial in patients with TS designed to test whether treatment with adenosine and dipyridamole accelerates cardiac recovery and improves clinical outcomes compared to standard care (study 1); and apixaban reduces the risk of thromboembolic events compared to no treatment with antithrombotic drugs (study 2). The trial will enroll 1,000 patients. Study 1 (adenosine hypothesis) will evaluate 2 coprimary end points: (1) wall motion score index at 48 to 96 hours (evaluated in the first 200 patients); and (2) the composite of death, cardiac arrest, need for mechanical assist device or heart failure hospitalization within 30 days or left ventricular ejection fraction <50% at 48 to 96 hours (evaluated in 1,000 patients). The primary end point in study 2 (apixaban hypothesis) is the composite of death or thromboembolic events within 30 days or the presence of intraventricular thrombus on echocardiography at 48 to 96 hours., Conclusions: BROKEN-SWEDEHEART will be the first prospective randomized multicenter trial in patients with TS. It is designed as 2 parallel studies to evaluate whether adenosine accelerates cardiac recovery and improves cardiac function in the acute phase and the efficacy of anticoagulation therapy for preventing thromboembolic complications in TS. If either of its component studies is successful, the trial will provide the first evidence-based treatment recommendation in TS., Clinical Trials Identifier: The trial has been approved by the Swedish Medicinal Product Agency and the Swedish Ethical Board and is registered at ClinicalTrials.gov (NCT04666454)., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)