Topic: Journal Club Selection

Abstract
<div><h4>Long-Term Outcomes of Resynchronization-Defibrillation for Heart Failure.</h4><i>Sapp JL, Sivakumaran S, Redpath CJ, Khan H, ... Tang ASL, RAFT Long-Term Study Team</i><br /><b>Background</b><br />The Resynchronization-Defibrillation for Ambulatory Heart Failure Trial (RAFT) showed a greater benefit with respect to mortality at 5 years among patients who received cardiac-resynchronization therapy (CRT) than among those who received implantable cardioverter-defibrillators (ICDs). However, the effect of CRT on long-term survival is not known.<br /><b>Methods</b><br />We randomly assigned patients with New York Heart Association (NYHA) class II or III heart failure, a left ventricular ejection fraction of 30% or less, and an intrinsic QRS duration of 120 msec or more (or a paced QRS duration of 200 msec or more) to receive either an ICD alone or a CRT defibrillator (CRT-D). We assessed long-term outcomes among patients at the eight highest-enrolling participating sites. The primary outcome was death from any cause; the secondary outcome was a composite of death from any cause, heart transplantation, or implantation of a ventricular assist device.<br /><b>Results</b><br />The trial enrolled 1798 patients, of whom 1050 were included in the long-term survival trial; the median duration of follow-up for the 1050 patients was 7.7 years (interquartile range, 3.9 to 12.8), and the median duration of follow-up for those who survived was 13.9 years (interquartile range, 12.8 to 15.7). Death occurred in 405 of 530 patients (76.4%) assigned to the ICD group and in 370 of 520 patients (71.2%) assigned to the CRT-D group. The time until death appeared to be longer for those assigned to receive a CRT-D than for those assigned to receive an ICD (acceleration factor, 0.80; 95% confidence interval, 0.69 to 0.92; P = 0.002). A secondary-outcome event occurred in 412 patients (77.7%) in the ICD group and in 392 (75.4%) in the CRT-D group.<br /><b>Conclusions</b><br />Among patients with a reduced ejection fraction, a widened QRS complex, and NYHA class II or III heart failure, the survival benefit associated with receipt of a CRT-D as compared with ICD appeared to be sustained during a median of nearly 14 years of follow-up. (RAFT ClinicalTrials.gov number, NCT00251251.).<br /><br />Copyright © 2024 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 18 Jan 2024; 390:212-220</small></div>
Sapp JL, Sivakumaran S, Redpath CJ, Khan H, ... Tang ASL, RAFT Long-Term Study Team
N Engl J Med: 18 Jan 2024; 390:212-220 | PMID: 38231622
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<div><h4>Merging machine learning and patient preference: a novel tool for risk prediction of percutaneous coronary interventions.</h4><i>Hamilton DE, Albright J, Seth M, Painter I, ... Sukul D, Gurm HS</i><br /><b>Background:</b><br/>and aims</b><br />Predicting personalized risk for adverse events following percutaneous coronary intervention (PCI) remains critical in weighing treatment options, employing risk mitigation strategies, and enhancing shared decision-making. This study aimed to employ machine learning models using pre-procedural variables to accurately predict common post-PCI complications.<br /><b>Methods</b><br />A group of 66 adults underwent a semiquantitative survey assessing a preferred list of outcomes and model display. The machine learning cohort included 107 793 patients undergoing PCI procedures performed at 48 hospitals in Michigan between 1 April 2018 and 31 December 2021 in the Blue Cross Blue Shield of Michigan Cardiovascular Consortium (BMC2) registry separated into training and validation cohorts. External validation was conducted in the Cardiac Care Outcomes Assessment Program database of 56 583 procedures in 33 hospitals in Washington.<br /><b>Results</b><br />Overall rate of in-hospital mortality was 1.85% (n = 1999), acute kidney injury 2.51% (n = 2519), new-onset dialysis 0.44% (n = 462), stroke 0.41% (n = 447), major bleeding 0.89% (n = 942), and transfusion 2.41% (n = 2592). The model demonstrated robust discrimination and calibration for mortality {area under the receiver-operating characteristic curve [AUC]: 0.930 [95% confidence interval (CI) 0.920-0.940]}, acute kidney injury [AUC: 0.893 (95% CI 0.883-0.903)], dialysis [AUC: 0.951 (95% CI 0.939-0.964)], stroke [AUC: 0.751 (95%CI 0.714-0.787)], transfusion [AUC: 0.917 (95% CI 0.907-0.925)], and major bleeding [AUC: 0.887 (95% CI 0.870-0.905)]. Similar discrimination was noted in the external validation population. Survey subjects preferred a comprehensive list of individually reported post-procedure outcomes.<br /><b>Conclusions</b><br />Using common pre-procedural risk factors, the BMC2 machine learning models accurately predict post-PCI outcomes. Utilizing patient feedback, the BMC2 models employ a patient-centred tool to clearly display risks to patients and providers (https://shiny.bmc2.org/pci-prediction/). Enhanced risk prediction prior to PCI could help inform treatment selection and shared decision-making discussions.<br /><br />© The Author(s) 2024. 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.<br /><br /><small>Eur Heart J: 17 Jan 2024; epub ahead of print</small></div>
Hamilton DE, Albright J, Seth M, Painter I, ... Sukul D, Gurm HS
Eur Heart J: 17 Jan 2024; epub ahead of print | PMID: 38233027
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<div><h4>Aspirin-free antiplatelet strategies after percutaneous coronary interventions.</h4><i>Capranzano P, Moliterno D, Capodanno D</i><br /><AbstractText>Dual antiplatelet therapy (DAPT) with aspirin and a platelet P2Y12 receptor inhibitor is the standard antithrombotic treatment after percutaneous coronary interventions (PCI). Several trials have challenged guideline-recommended DAPT after PCI by testing the relative clinical effect of an aspirin-free antiplatelet approach-consisting of P2Y12 inhibitor monotherapy after a short course (mostly 1-3 months) of DAPT-among patients undergoing PCI without a concomitant indication for oral anticoagulation (OAC). Overall, these studies have shown P2Y12 inhibitor monotherapy after short DAPT to be associated with a significant reduction in the risk of bleeding without an increase in thrombotic or ischaemic events compared with continued DAPT. Moreover, the effects of the P2Y12 inhibitor monotherapy without prior DAPT or following a very short course of DAPT after PCI are being investigated in emerging studies, of which one has recently reported unfavourable efficacy results associated with the aspirin-free approach compared with conventional DAPT. Finally, P2Y12 inhibitor alone has been compared with aspirin alone as chronic therapy after DAPT discontinuation, thus challenging the historical role of aspirin as a standard of care for secondary prevention following PCI. A thorough understanding of study designs, populations, treatments, results, and limitations of trials testing P2Y12 inhibitor monotherapy vs. DAPT or vs. aspirin is required to consider adopting this treatment in clinical practice. This review addresses the use of aspirin-free antiplatelet strategies among patients undergoing PCI without a concomitant indication for OAC, providing an overview of clinical evidence, guideline indications, practical implications, ongoing issues, and future perspectives.</AbstractText><br /><br />© The Author(s) 2024. 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.<br /><br /><small>Eur Heart J: 18 Jan 2024; epub ahead of print</small></div>
Capranzano P, Moliterno D, Capodanno D
Eur Heart J: 18 Jan 2024; epub ahead of print | PMID: 38240716
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<div><h4>Risk of Death in Patients With Coronary Artery Disease Taking Nitrates and Phosphodiesterase-5 Inhibitors.</h4><i>Trolle Lagerros Y, Grotta A, Freyland S, Grannas D, Andersson DP</i><br /><b>Background</b><br />Phosphodiesterase-5 inhibitor (PDE5i) treatment for erectile dysfunction is associated with lower mortality compared with no treatment for erectile dysfunction after myocardial infarction (MI). There are conflicting results regarding the impact of PDE5i treatment on mortality in conjunction with nitrate medication.<br /><b>Objectives</b><br />The purpose of this study was to investigate the association between PDE5i treatment and cardiovascular outcomes in men with stable coronary artery disease treated with nitrate medication.<br /><b>Methods</b><br />Using the Swedish Patient Register and the Prescribed Drug Register we included men with previous MI or revascularization in 2006-2013 who had 2 dispensed nitrate prescriptions within 6 months. Exposure was defined as at least 2 filled prescriptions of any PDE5i. We performed multivariable Cox proportional hazard regression to estimate HRs with 95% CIs for all-cause, cardiovascular, and noncardiovascular mortality, MI, heart failure, cardiac revascularization, and major cardiovascular events (MACE).<br /><b>Results</b><br />In total, 55,777 men were treated with nitrates and 5,710 men with nitrates and a PDE5i. The combined use of PDE5i treatment with nitrates was associated with higher mortality (HR: 1.39; 95% CI: 1.28-1.51), cardiovascular mortality (HR: 1.34; 95% CI: 1.11-1.62), noncardiovascular mortality (HR: 1.40; 95% CI: 1.27-1.54), MI (HR: 1.72; 95% CI: 1.55-1.90), heart failure (HR: 1.67; 95% CI: 1.48-1.90), cardiac revascularization (HR: 1.95; 95% CI: 1.78-2.13), and MACE (HR: 1.70; 95% CI: 1.58-1.83).<br /><b>Conclusions</b><br />The use of a PDE5i in combination with nitrate medication in men with stable coronary artery disease may pose an increased hazard for cardiovascular morbidity and mortality. Careful patient-centered consideration before prescribing PDE5is to patients with cardiovascular disease using nitrate medication is warranted.<br /><br />Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.<br /><br /><small>J Am Coll Cardiol: 23 Jan 2024; 83:417-426</small></div>
Trolle Lagerros Y, Grotta A, Freyland S, Grannas D, Andersson DP
J Am Coll Cardiol: 23 Jan 2024; 83:417-426 | PMID: 38233015
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<div><h4>Clonal haematopoiesis of indeterminate potential and atrial fibrillation: an east Asian cohort study.</h4><i>Ahn HJ, An HY, Ryu G, Lim J, ... Koh Y, Choi EK</i><br /><b>Background:</b><br/>and aims</b><br />Both clonal haematopoiesis of indeterminate potential (CHIP) and atrial fibrillation (AF) are age-related conditions. This study investigated the potential role of CHIP in the development and progression of AF.<br /><b>Methods</b><br />Deep-targeted sequencing of 24 CHIP mutations (a mean depth of coverage = 1000×) was performed in 1004 patients with AF and 3341 non-AF healthy subjects. Variant allele fraction ≥ 2.0% indicated the presence of CHIP mutations. The association between CHIP and AF was evaluated by the comparison of (i) the prevalence of CHIP mutations between AF and non-AF subjects and (ii) clinical characteristics discriminated by CHIP mutations within AF patients. Furthermore, the risk of clinical outcomes-the composite of heart failure, ischaemic stroke, or death-according to the presence of CHIP mutations in AF was investigated from the UK Biobank cohort.<br /><b>Results</b><br />The mean age was 67.6 ± 6.9 vs. 58.5 ± 6.5 years in AF (paroxysmal, 39.0%; persistent, 61.0%) and non-AF cohorts, respectively. CHIP mutations with a variant allele fraction of ≥2.0% were found in 237 (23.6%) AF patients (DNMT3A, 13.5%; TET2, 6.6%; and ASXL1, 1.5%) and were more prevalent than non-AF subjects [356 (10.7%); P < .001] across the age. After multivariable adjustment (age, sex, smoking, body mass index, diabetes, and hypertension), CHIP mutations were 1.4-fold higher in AF [adjusted odds ratio (OR) 1.38; 95% confidence interval 1.10-1.74, P < .01]. The ORs of CHIP mutations were the highest in the long-standing persistent AF (adjusted OR 1.50; 95% confidence interval 1.14-1.99, P = .004) followed by persistent (adjusted OR 1.44) and paroxysmal (adjusted OR 1.33) AF. In gene-specific analyses, TET2 somatic mutation presented the highest association with AF (adjusted OR 1.65; 95% confidence interval 1.05-2.60, P = .030). AF patients with CHIP mutations were older and had a higher prevalence of diabetes, a longer AF duration, a higher E/E\', and a more severely enlarged left atrium than those without CHIP mutations (all P < .05). In UK Biobank analysis of 21 286 AF subjects (1297 with CHIP and 19 989 without CHIP), the CHIP mutation in AF is associated with a 1.32-fold higher risk of a composite clinical event (heart failure, ischaemic stroke, or death).<br /><b>Conclusions</b><br />CHIP mutations, primarily DNMT3A or TET2, are more prevalent in patients with AF than non-AF subjects whilst their presence is associated with a more progressive nature of AF and unfavourable clinical outcomes.<br /><br />© The Author(s) 2024. 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.<br /><br /><small>Eur Heart J: 17 Jan 2024; epub ahead of print</small></div>
Ahn HJ, An HY, Ryu G, Lim J, ... Koh Y, Choi EK
Eur Heart J: 17 Jan 2024; epub ahead of print | PMID: 38231881
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<div><h4>Changes in frailty and incident cardiovascular disease in three prospective cohorts.</h4><i>He D, Wang Z, Li J, Yu K, ... Zhou D, Zhu Y</i><br /><b>Background:</b><br/>and aims</b><br />Previous studies found that frailty was an important risk factor for cardiovascular disease (CVD). However, previous studies only focused on baseline frailty status, not taking into consideration the changes in frailty status during follow-up. The aim of this study was to investigate the associations of changes in frailty status with incident CVD.<br /><b>Methods</b><br />This study used data of three prospective cohorts: China Health and Retirement Longitudinal Study (CHARLS), English Longitudinal Study of Ageing (ELSA), and Health and Retirement Study (HRS). Frailty status was evaluated by the Rockwood frailty index and classified as robust, pre-frail, or frail. Changes in frailty status were assessed by frailty status at baseline and the second survey which was two years after the baseline. Cardiovascular disease was ascertained by self-reported physician-diagnosed heart disease (including angina, heart attack, congestive heart failure, and other heart problems) or stroke. Cox proportional hazard models were used to calculate the hazard ratio (HR) and 95% confidence interval (95% CI) after adjusting for potential confounders.<br /><b>Results</b><br />A total of 7116 participants from CHARLS (female: 48.6%, mean age: 57.4 years), 5303 from ELSA (female: 57.7%, mean age: 63.7 years), and 7266 from HRS (female: 64.9%, mean age: 65.1 years) were included according to inclusion and exclusion criteria. The median follow-up periods were 5.0 years in the CHARLS, 10.7 years in the ELSA, and 9.5 years in the HRS. Compared with stable robust participants, robust participants who progressed to pre-frail or frail status had increased risks of incident CVD (CHARLS, HR = 1.84, 95% CI: 1.54-2.21; ELSA, HR = 1.53, 95% CI: 1.25-1.86; HRS, HR = 1.59, 95% CI: 1.31-1.92). In contrast, frail participants who recovered to robust or pre-frail status presented decreased risks of incident CVD (CHARLS, HR = 0.62, 95% CI: 0.47-0.81; ELSA, HR = 0.49, 95% CI: 0.34-0.69; HRS, HR = 0.70, 95% CI: 0.55-0.89) when compared with stable frail participants. These decreased risks of incident CVD were also observed in pre-frail participants who recovered to robust status (CHARLS, HR = 0.66, 95% CI: 0.52-0.83; ELSA, HR = 0.65, 95% CI: 0.49-0.85; HRS, HR = 0.71, 95% CI: 0.56-0.91) when compared with stable pre-frail participants.<br /><b>Conclusions</b><br />Different changes in frailty status are associated with different risks of incident CVD. Progression of frailty status increases incident CVD risks, while recovery of frailty status decreases incident CVD risks.<br /><br />© The Author(s) 2024. 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.<br /><br /><small>Eur Heart J: 18 Jan 2024; epub ahead of print</small></div>
He D, Wang Z, Li J, Yu K, ... Zhou D, Zhu Y
Eur Heart J: 18 Jan 2024; epub ahead of print | PMID: 38241094
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<div><h4>Artificial intelligence-derived risk score for mortality in secondary mitral regurgitation treated by transcatheter edge-to-edge repair: the EuroSMR risk score.</h4><i>Hausleiter J, Lachmann M, Stolz L, Bedogni F, ... Rudolph V, EuroSMR Investigators </i><br /><b>Background:</b><br/>and aims</b><br />Risk stratification for mitral valve transcatheter edge-to-edge repair (M-TEER) is paramount in the decision-making process to appropriately select patients with severe secondary mitral regurgitation (SMR). This study sought to develop and validate an artificial intelligence-derived risk score (EuroSMR score) to predict 1-year outcomes (survival or survival + clinical improvement) in patients with SMR undergoing M-TEER.<br /><b>Methods</b><br />An artificial intelligence-derived risk score was developed from the EuroSMR cohort (4172 and 428 patients treated with M-TEER in the derivation and validation cohorts, respectively). The EuroSMR score was validated and compared with established risk models.<br /><b>Results</b><br />The EuroSMR risk score, which is based on 18 clinical, echocardiographic, laboratory, and medication parameters, allowed for an improved discrimination of surviving and non-surviving patients (hazard ratio 4.3, 95% confidence interval 3.7-5.0; P < .001), and outperformed established risk scores in the validation cohort. Prediction for 1-year mortality (area under the curve: 0.789, 95% confidence interval 0.737-0.842) ranged from <5% to >70%, including the identification of an extreme-risk population (2.6% of the entire cohort), which had a very high probability for not surviving beyond 1 year (hazard ratio 6.5, 95% confidence interval 3.0-14; P < .001). The top 5% of patients with the highest EuroSMR risk scores showed event rates of 72.7% for mortality and 83.2% for mortality or lack of clinical improvement at 1-year follow-up.<br /><b>Conclusions</b><br />The EuroSMR risk score may allow for improved prognostication in heart failure patients with severe SMR, who are considered for a M-TEER procedure. The score is expected to facilitate the shared decision-making process with heart team members and patients.<br /><br />© The Author(s) 2024. 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.<br /><br /><small>Eur Heart J: 19 Jan 2024; epub ahead of print</small></div>
Hausleiter J, Lachmann M, Stolz L, Bedogni F, ... Rudolph V, EuroSMR Investigators
Eur Heart J: 19 Jan 2024; epub ahead of print | PMID: 38243773
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<div><h4>Bi-atrial arrhythmogenic substrate in patients with hypertrophic obstructive cardiomyopathy.</h4><i>Ramdat Misier NL, Amesz JH, Taverne YJHJ, Nguyen H, ... Brundel BJJM, de Groot NMS</i><br /><b>Background</b><br />Atrial fibrillation (AF) in patients with hypertrophic obstructive cardiomyopathy (HOCM) may be caused by a primary atrial myopathy. Whether HOCM-related atrial myopathy affects mainly electrophysiological properties of the left atrium (LA) or also the right atrium (RA) has never been investigated.<br /><b>Objective</b><br />To characterize atrial conduction and explore differences in the prevalence of conduction disorders, potential fractionation, and low voltage areas (LVA) between the RA and LA during sinus rhythm (SR) as indicators of potential arrhythmogenic areas.<br /><b>Methods</b><br />Intra-operative epicardial mapping of both atria during SR was performed in 15 HOCM patients (age: 50±12 years). Conduction delay and block (CD, CB), unipolar potential characteristics (voltages, fractionation) and LVA were quantified.<br /><b>Results</b><br />Conduction disorders and LVA were found scattered throughout both atria in all patients, and did not differ between the RA and LA (CD: 2.9 [1.9-3.6]% versus 2.6 [2.1-6.4]%, p=0.541; CB: 1.7 [0.9-3.1]% versus 1.5 [0.5-2.8]%, p=0.600; LVA: 4.7 [1.6-7.7]% versus 2.9 [2.1-7.1]%, p=0.793). Compared to the RA, unipolar voltages of single- and fractionated potentials (SP, FP) were higher in the LA (SP: P75 7.3mV versus 10.9mV, FP: P75 2.0mV versus 3.7mV). FP contained low voltage components in only 18% of all LA sites compared to 36% of all RA sites.<br /><b>Conclusion</b><br />In patients with HOCM, conduction disorders, LVA and FP are equally present in both atria, supporting the hypothesis of a primary atrial myopathy. Conceptually, the presence of a bi-atrial substrate and high voltage FP may contribute to failure of ablative therapy of atrial tachyarrhythmias in this population.<br /><br />Copyright © 2024. Published by Elsevier Inc.<br /><br /><small>Heart Rhythm: 19 Jan 2024; epub ahead of print</small></div>
Ramdat Misier NL, Amesz JH, Taverne YJHJ, Nguyen H, ... Brundel BJJM, de Groot NMS
Heart Rhythm: 19 Jan 2024; epub ahead of print | PMID: 38246568
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<div><h4>\"But for the Blind Spot\": Accuracy and Diagnostic Performance of Smart Watch Cardiac Features in Pediatric Patients.</h4><i>Nash D, Shah MJ, Shehab O, Jones AL, ... Vetter V, Janson C</i><br /><b>Background</b><br />The Apple Watch™ (AW) offers heart rate (HR) tracking by photoplethysmography (PPG) and single-lead ECG recordings. The accuracy of AW-HR and diagnostic performance of AW-ECGs among children during both sinus rhythm and arrhythmias have not been explored.<br /><b>Objective</b><br />The primary objective was to assess accuracy of AW-HR measurements compared to gold-standard modalities in children during sinus rhythm and arrhythmias. Secondary objectives included identification of non-sinus rhythms using AW-ECGs.<br /><b>Methods</b><br />Subjects ≤18 years wore an AW during 1) telemetry admission, 2) electrophysiology study (EPS), or 3) exercise stress test (EST). AW-HRs were compared to gold-standard modality values. Recorded AW-ECGs were reviewed by three blinded pediatric electrophysiologists.<br /><b>Results</b><br />80 subjects (median-age 13 years, IQR 1.0-16.0, 50% females) wore AW (telemetry [41%, n=33], EPS [34%, n=27], or EST [25%, n=20]). 1,090 AW-HR measurements were compared to time-synchronized gold-standard modality HR values. Intraclass correlation coefficient (ICC) was high 0.99 (0.98-0.99) for AW-HR during sinus rhythm, when compared to gold-standard modalities. ICC was poor comparing AW-HR to gold-standard modality HR in tachyarrhythmias (ICC 0.24-0.27) due to systematic undercounting of AW-HR values. 126 AW-ECGs were reviewed. Identification of non-sinus rhythm by AW-ECG showed a sensitivity of 89-96% and a specificity of 78-87%.<br /><b>Conclusions</b><br />We found high levels of agreement for AW-HR values with gold-standard modalities during sinus rhythm, and poor agreement during tachyarrhythmias, likely due to hemodynamic effects of tachyarrhythmias on PPG-based measurements. AW-ECGs had good sensitivity and moderate specificity in identification of non-sinus rhythm in children.<br /><br />Copyright © 2024. Published by Elsevier Inc.<br /><br /><small>Heart Rhythm: 19 Jan 2024; epub ahead of print</small></div>
Nash D, Shah MJ, Shehab O, Jones AL, ... Vetter V, Janson C
Heart Rhythm: 19 Jan 2024; epub ahead of print | PMID: 38246569
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<div><h4>Atrial electro-functional predictors of incident atrial fibrillation in cardiac amyloidosis.</h4><i>Sinigiani G, De Michieli L, Porcari A, Zocchi C, ... Cappelli F, Cipriani A</i><br /><b>Background</b><br />Atrial fibrillation (AF) is common in patients with cardiac amyloidosis (CA) and is a significant risk factor for heart failure hospitalization and thromboembolic events.<br /><b>Objective</b><br />to investigate the atrial electro-functional predictors of incident AF in CA.<br /><b>Methods</b><br />A multicenter, observational study performed in 4 CA referral centers including sinus rhythm patients with light-chain (AL) and transthyretin (ATTR) CA undergoing electrocardiogram (ECG) and cardiac magnetic resonance (CMR). The primary endpoint was new-onset AF occurrence.<br /><b>Results</b><br />Overall, 96 patients (AL-CA: n=40; ATTR-CA n=56) were enrolled. During an 18-month median follow-up (Q1-Q3:7-29), 30 patients (29%) had incident AF. Compared with those without, patients with AF were older (79 vs 73 years, p=0.001) and more frequently with ATTR (73% vs 27%, p<0.001), ECG inter-atrial block (IAB), either partial (47% vs 21%, p=0.011) or advanced (17% vs 3%,p=0.017), and lower left atrium ejection fraction (LAEF) (29% vs 41%, p=0.004). Age (HR=1.059; 95%CI 1.002-1.118,p=0.042), any type of IAB (HR=2.211; 95%CI 1.03-4.75, p=0.041) and LAEF (HR=0.967; 95%CI 0.936-0.998, p=0.044) emerged as independent predictors of incident AF. Patients exhibiting any type of IAB, LAEF<40%, and aged>78 years showed a cumulative incidence for AF of 40% at 12 months. This risk was significantly higher than that carried by one (8.5%) or none (7.6%) of these three risk factors.<br /><b>Conclusions</b><br />In patients with CA, older age, IAB on 12-lead ECG and reduced LAEF on CMR are significant and independent predictors of incident AF. A closer screening for AF is advisable in CA patients carrying these features.<br /><br />Copyright © 2024. Published by Elsevier Inc.<br /><br /><small>Heart Rhythm: 01 Feb 2024; epub ahead of print</small></div>
Sinigiani G, De Michieli L, Porcari A, Zocchi C, ... Cappelli F, Cipriani A
Heart Rhythm: 01 Feb 2024; epub ahead of print | PMID: 38309449
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<div><h4>Long-term outcomes of cardioneuroablation with and without extra-cardiac vagal stimulation confirmation in severe cardioinhibitory neurocardiogenic syncope.</h4><i>Pachon-M JC, Pachon-M EI, Pachon CTC, Santillana-P TG, ... Osorio TG, Peixoto LA</i><br /><b>Background</b><br />Cardioneuroablation (CNA) is a novel therapeutic approach for functional bradyarrhythmias, specifically neurocardiogenic syncope or atrial fibrillation, achieved through endocardial radiofrequency catheter ablation of vagal innervation, obviating the need for pacemaker implantation. Originating in the nineties, the first series of CNA procedures was published in 2005. Extra-cardiac vagal stimulation (ECVS) is employed as a direct method for stepwise denervation control during CNA.<br /><b>Objective</b><br />This study aimed to compare the long-term follow-up outcomes of patients with severe cardioinhibitory syncope undergoing CNA with and without denervation confirmation via ECVS.<br /><b>Method</b><br />A cohort of 48 patients, predominantly female (56.3%), suffering from recurrent syncope (5.1 ± 2.5 episodes annually) that remained unresponsive to clinical and pharmacological interventions, underwent CNA, divided into two groups: ECVS and NoECVS, consisting of 34 and 14 cases, respectively. ECVS procedures were conducted with and without atrial pacing.<br /><b>Results</b><br />Demographic characteristics, left atrial size, and ejection fraction displayed no statistically significant differences between the groups. Follow-up duration was comparable, with 29.1 ± 15 months for the ECVS group and 31.9 ± 20 months for the NoECVS group (p = .24). Notably, syncope recurrence was significantly lower in the ECVS group (two cases vs. four cases, Log Rank p = .04). Moreover, the Hazard ratio revealed a fivefold higher risk of syncope recurrence in the NoECVS group.<br /><b>Conclusion</b><br />This study demonstrates that concluding CNA with denervation confirmation via ECVS yields a higher success rate and a substantially reduced risk of syncope recurrence compared to procedures without ECVS confirmation.<br /><br />© 2024 Wiley Periodicals LLC.<br /><br /><small>J Cardiovasc Electrophysiol: 19 Jan 2024; epub ahead of print</small></div>
Pachon-M JC, Pachon-M EI, Pachon CTC, Santillana-P TG, ... Osorio TG, Peixoto LA
J Cardiovasc Electrophysiol: 19 Jan 2024; epub ahead of print | PMID: 38240356
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<div><h4>Ablation of epicardial ventricular focus through coronary sinus using pulsed-field ablation. A case report.</h4><i>Mestrovic IP, Breskovic T, Markovic M, Kurtic E, Mestrovic T, Anic A</i><br /><b>Introduction</b><br />With the entry of pulsed-field ablation (PFA) into electrophysiology, new possibilities for ablation of different substrates such as epicardial foci of premature ventricular contractions (PVCs) from coronary venous system (CVS) have been opened.<br /><b>Methods</b><br />This article focuses on a case of a 27-year-old patient with frequent monomorphic PVCs of epicardial origin, treated by radiofrequency ablation, followed by PFA.<br /><b>Results</b><br />After unsuccessful focus ablation through CVS with RFA, successful ablations from the same region with PFA were achieved.<br /><b>Conclusion</b><br />This is the first described case of successful ablation of epicardial PVCs using PFA, which we hope will help in defining indications for this novel technology and enhance quality of treatment for patients with different arrhythmias.<br /><br />© 2024 Wiley Periodicals LLC.<br /><br /><small>J Cardiovasc Electrophysiol: 31 Jan 2024; epub ahead of print</small></div>
Mestrovic IP, Breskovic T, Markovic M, Kurtic E, Mestrovic T, Anic A
J Cardiovasc Electrophysiol: 31 Jan 2024; epub ahead of print | PMID: 38297424
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<div><h4>Risk Prediction in Male Adolescents With Congenital Long QT Syndrome: Implications for Sex-Specific Risk Stratification in Potassium Channel-Mediated Long QT Syndrome.</h4><i>Bjelic M, Goldenberg I, Younis A, Chen AY, ... Ackerman MJ, Goldenberg I</i><br /><b>Background</b><br />Sex-specific risk management may improve outcomes in congenital long QT syndrome (LQTS). We recently developed a prediction score for cardiac events (CEs) and life-threatening events (LTEs) in postadolescent women with LQTS. In the present study, we aimed to develop personalized risk estimates for the burden of CEs and LTEs in male adolescents with potassium channel-mediated LQTS.<br /><b>Methods and results</b><br />The prognostic model was derived from the LQTS Registry headquartered in Rochester, NY, comprising 611 LQT1 or LQT2 male adolescents from age 10 through 20 years, using the following variables: genotype/mutation location, QTc-specific thresholds, history of syncope, and β-blocker therapy. Anderson-Gill modeling was performed for the end point of CE burden (total number of syncope, aborted cardiac arrest, and appropriate defibrillator shocks). The applicability of the CE prediction model was tested for the end point of the first LTE (excluding syncope and adding sudden cardiac death) using Cox modeling. A total of 270 CEs occurred during follow-up. The genotype-phenotype risk prediction model identified low-, intermediate-, and high-risk groups, comprising 74%, 14%, and 12% of the study population, respectively. Compared with the low-risk group, high-risk male subjects experienced a pronounced 5.2-fold increased risk of recurrent CEs (<i>P</i><0.001), whereas intermediate-risk patients had a 2.1-fold (<i>P</i>=0.004) increased risk . At age 20 years, the low-, intermediate-, and high-risk adolescent male patients had on average 0.3, 0.6, and 1.4 CEs per person, respectively. Corresponding 10-year adjusted probabilities for a first LTE were 2%, 6%, and 8%.<br /><b>Conclusions</b><br />Personalized genotype-phenotype risk estimates can be used to guide sex-specific management in male adolescents with potassium channel-mediated LQTS.<br /><br /><br /><br /><small>J Am Heart Assoc: 19 Jan 2024:e028902; epub ahead of print</small></div>
Bjelic M, Goldenberg I, Younis A, Chen AY, ... Ackerman MJ, Goldenberg I
J Am Heart Assoc: 19 Jan 2024:e028902; epub ahead of print | PMID: 38240206
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<div><h4>Atrial Fibrillation Detection and Ischemic Stroke Recurrence in Cryptogenic Stroke: A Retrospective, Multicenter, Observational Study.</h4><i>Todo K, Okazaki S, Doijiri R, Yamazaki H, ... Mochizuki H, CRYPTON‐ICM Registry Investigators</i><br /><b>Background</b><br />Atrial fibrillation (AF) is known to be a strong risk factor for stroke. However, the risk of stroke recurrence in patients with cryptogenic stroke with AF detected after stroke by an insertable cardiac monitor (ICM) is not well known. We sought to evaluate the risk of ischemic stroke recurrence in patients with cryptogenic stroke with and without ICM-detected AF.<br /><b>Methods and results</b><br />We retrospectively reviewed patients with cryptogenic stroke who underwent ICM implantation at 8 stroke centers in Japan. Cox regression models were developed using landmark analysis and time-dependent analysis. We set the target sample size at 300 patients based on our estimate of the annualized incidence of ischemic stroke recurrence to be 3% in patients without AF detection and 9% in patients with AF detection. Of the 370 patients, 121 were found to have AF, and 110 received anticoagulation therapy after AF detection. The incidence of ischemic stroke recurrence was 4.0% in 249 patients without AF detection and 5.8% in 121 patients with AF detection (<i>P</i>=0.45). In a landmark analysis, the risk of ischemic stroke recurrence was not higher in patients with AF detected ≤90 days than in those without (hazard ratio, 1.47 [95% CI, 0.41-5.28]). In a time-dependent analysis, the risk of ischemic stroke recurrence did not increase after AF detection (hazard ratio, 1.77 [95% CI, 0.70-4.47]).<br /><b>Conclusions</b><br />The risk of ischemic stroke recurrence in patients with cryptogenic stroke with ICM-detected AF, 90% of whom were subsequently anticoagulated, was not higher than in those without ICM-detected AF.<br /><br /><br /><br /><small>J Am Heart Assoc: 19 Jan 2024:e031508; epub ahead of print</small></div>
Todo K, Okazaki S, Doijiri R, Yamazaki H, ... Mochizuki H, CRYPTON‐ICM Registry Investigators
J Am Heart Assoc: 19 Jan 2024:e031508; epub ahead of print | PMID: 38240210
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<div><h4>Impact on wine sales of removing the largest serving size by the glass: An A-B-A reversal trial in 21 pubs, bars, and restaurants in England.</h4><i>Mantzari E, Ventsel M, Pechey E, Lee I, ... Hollands GJ, Marteau TM</i><br /><b>Background</b><br />Interventions that alter aspects of the physical environments in which unhealthy behaviours occur have the potential to change behaviour at scale, i.e., across populations, and thereby decrease the risk of several diseases. One set of such interventions involves reducing serving sizes, which could reduce alcohol consumption. The effect of modifying the available range of serving sizes of wine in a real-world setting is unknown. We aimed to assess the impact on the volume of wine sold of removing the largest serving size by the glass from the options available in licensed premises.<br /><b>Methods and findings</b><br />The study was conducted between September 2021 and May 2022 in 21 licensed premises in England that sold wine by the glass in serving sizes greater than 125 ml (i.e., 175 ml or 250 ml) and used an electronic point of sale till system. It used an A-B-A reversal design, set over 3 four-weekly periods. \"A\" represented the nonintervention periods during which standard serving sizes were served and \"B\" the intervention period when the largest serving size for a glass of wine was removed from the existing range in each establishment: 250 ml (18 premises) or 175 ml (3 premises). The primary outcome was the daily volume of wine sold, extracted from sales data. Twenty-one premises completed the study, 20 of which did so per protocol and were included in the primary analysis. After adjusting for prespecified covariates, the intervention resulted in -420·8 millilitres (ml) (95% confidence intervals (CIs) -681·4 to -160·2 p = 0·002) or -7·6% (95% CI -12·3%, -2·9%) less wine being sold per day. There was no evidence that sales of beer and cider or total daily revenues changed but the study was not powered to detect differences in these outcomes. The main study limitation is that we were unable to assess the sales of other alcoholic drinks apart from wine, beer, and cider, estimated to comprise approximately 30% of alcoholic drinks sold in participating premises.<br /><b>Conclusions</b><br />Removing the largest serving size of wine by the glass from those available reduced the volume of wine sold. This promising intervention for decreasing alcohol consumption across populations merits consideration as part of alcohol licensing regulations.<br /><b>Trial registration</b><br />ISRCTN https://doi.org/10.1186/ISRCTN33169631; OSF https://osf.io/xkgdb.<br /><br />Copyright: © 2024 Mantzari et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br /><br /><small>PLoS Med: 01 Jan 2024; 21:e1004313</small></div>
Mantzari E, Ventsel M, Pechey E, Lee I, ... Hollands GJ, Marteau TM
PLoS Med: 01 Jan 2024; 21:e1004313 | PMID: 38236840
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<div><h4>Optimal thrombin injection method for the treatment of femoral artery pseudoaneurysm.</h4><i>Kim KW, Lee C, Im G, Kang HJ, ... Choi YH, Kim HH</i><br /><b>Background</b><br />Iatrogenic femoral artery pseudoaneurysm (IFP) incidence is increasing as diagnostic and therapeutic angiography has increased, and so, the less invasive percutaneous thrombin injection (PTI) treatment is most widely used. Moreover, studies that minimize PTI complications and highlight therapeutic effects are lacking.<br /><b>Objectives</b><br />This study performed in vitro thrombosis modeling of pseudoaneurysms and analyzed thrombosis within and thromboembolism outside the sac during thrombin injection.<br /><b>Methods and materials</b><br />We evaluated PTI in aspects of thrombin injection location (at the junction of the IFP sac and neck, the center, and the dome, located farthest from the neck of the sac), thrombin injection time (5 seconds and 8 seconds), and blood flow rate (ranging from 210 ml/min to 300 ml/min). Porcine blood was used as the working fluid in this study.<br /><b>Results</b><br />Thrombin injection at the junction of the IFP sac and the pseudoaneurysm neck led to less thrombosis within the sac but substantial thrombi consistently outside the sac; whereas thrombin injected at the sac center, led mostly to complete thrombosis within the sac, preventing further blood flow into the sac and reducing likelihood of thrombi outside the sac. A longer thrombin injection time enhanced the therapeutic effect and decreased the possibility of thromboembolism. Thromboembolism occurred more frequently at flow rates exceeding 240 ml/min.<br /><b>Conclusion</b><br />The thrombin injection site in a pseudoaneurysm significantly influenced thrombogenesis within and thromboembolism outside the sac. Thus, slow and deliberate injection of thrombin into the center of the sac could potentially reduce complications and enhance treatment efficacy.<br /><br />Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.<br /><br /><small>J Thromb Haemost: 24 Jan 2024; epub ahead of print</small></div>
Kim KW, Lee C, Im G, Kang HJ, ... Choi YH, Kim HH
J Thromb Haemost: 24 Jan 2024; epub ahead of print | PMID: 38278416
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<div><h4>Outcomes of Valve-In-Valve Transcatheter Aortic Valve Replacement.</h4><i>Ahmad D, Yousef S, Kliner D, Brown JA, ... Thoma FW, Sultan I</i><br /><AbstractText>Structural valve degeneration (SVD) is increasingly seen given the higher rates of bioprosthetic heart valve (BHV) usage for surgical and transcatheter aortic valve replacement (TAVR). Valve-in-valve TAVR (VIV-TAVR) is an attractive alternate for patients who are otherwise at high risk for reoperative surgery. We compared patients undergoing VIV-TAVR and native-valve TAVR through a retrospective analysis of our institutional TVT database from 2013 to 2022. Patients undergoing either a native-valve TAVR or VIV-TAVR were included. VIV-TAVR was defined as TAVR in previous SAVR patients. Kaplan-Meier survival analysis was used to obtain survival estimates. A Cox proportional hazards regression model was used for the multivariable analysis of mortality. A total of 3532 patients underwent TAVR of which 198 (5.6%) underwent VIV-TAVR. Patients in the VIV-TAVR cohort were younger than native-valve TAVR patients (79.5 vs. 84 years, p<0.001) with comparable number of women and a higher STS risk score (6.28 vs 4.46, p<0.001). The VIV-TAVR cohort had a higher incidence of major vascular complications (2.5% vs. 0.8%, p=0.008) but less permanent pacemaker (PPM) placement (2.5% vs. 8.1%, p=0.004). The incidence of stroke was comparable between the groups (VIV-TAVR: 2.5% vs. Native-TAVR: 2.4%, p=0.911). The 30-day readmission rates (VIV-TAVR: 7.1% vs. Native-TAVR: 9%, p=0.348) as well as the in-hospital (VIV-TAVR: 2% vs. Native-TAVR: 1.4%, p=0.46) and overall (VIV-TAVR: 26.3% vs. Native-TAVR: 30.8%, p=0.18) mortality at a follow-up of 1.8 years (0.83-3.5) were comparable between the groups. Survival estimates were comparable between the groups (Log rank p=0.27). On multivariable cox regression analysis, VIV-TAVR was associated with decreased hazards of death (Hazard ratio (HR): 0.68 (0.5-0.9), p=0.02). In conclusion, ViV-TAVR is a feasible and safe strategy for high-risk patients with bioprosthetic valve failure. There may be potentially higher short-term morbidity with VIV-TAVR with no overt impact on survival.</AbstractText><br /><br />Copyright © 2024. Published by Elsevier Inc.<br /><br /><small>Am J Cardiol: 15 Jan 2024; epub ahead of print</small></div>
Ahmad D, Yousef S, Kliner D, Brown JA, ... Thoma FW, Sultan I
Am J Cardiol: 15 Jan 2024; epub ahead of print | PMID: 38232811
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<div><h4>Left Atrial Appendage Closure in Patients With Left Atrial Appendage Thrombus Guided by Intracardiac Echocardiography.</h4><i>Wang B, Chu H, Wang Z, Fu G, ... Feng M, Du X</i><br /><b>Background</b><br />Data regarding left atrial appendage closure (LAAC) in patients with left atrial appendage (LAA) thrombus are limited. Recently published cases have mostly been guided by transesophageal echocardiography (TEE). Intracardiac echocardiography (ICE) is now widely used during LAAC procedures.<br /><b>Objective</b><br />This is the first study to report the feasibility of LAAC in patients with LAA thrombus guided by ICE.<br /><b>Methods</b><br />Patients with persistent LAA thrombus despite anticoagulation or contraindications to anticoagulation who underwent a modified ICE-guided LAAC procedure between June 2021 and April 2023 were included. Periprocedural events and clinical outcomes during follow-up were recorded.<br /><b>Results</b><br />A total of 12 patients (aged 65 ± 7 years; 92% male) were included: 10 with persistent LAA thrombus and 2 with contraindications to anticoagulation. Most of the thrombus was at the apex (n = 6), followed by the body (n = 3) and the ostium (n = 3). LAmbre device was used and successfully implanted into all patients with the guidance of ICE. No thrombotic material was retrieved from patients with the protection of cerebral protection device (n = 11). No patient experienced severe periprocedural complications. All patients completed TEE follow-up, and no device-related thrombus or peridevice leakage > 3 mm was detected. None of the patients experienced stroke/TIA, systemic embolism, or major bleeding events during a median follow-up of 147 (80-306) days.<br /><b>Conclusion</b><br />LAAC using the LAmbre device guided by ICE may be feasible in patients with LAA thrombus when performed by experienced operators.<br /><br />Copyright © 2024. Published by Elsevier Inc.<br /><br /><small>Heart Rhythm: 23 Jan 2024; epub ahead of print</small></div>
Wang B, Chu H, Wang Z, Fu G, ... Feng M, Du X
Heart Rhythm: 23 Jan 2024; epub ahead of print | PMID: 38272283
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<div><h4>Clinical Impact of In-Stent Calcification in Coronary Arteries: Optical Coherence Tomography Study.</h4><i>Jinnouchi H, Sakakura K, Taniguchi Y, Yamamoto K, ... Seguchi M, Fujita H</i><br /><AbstractText>In-stent restenosis with neoatherosclerosis has been known as the predictor of target lesion revascularization (TLR) after percutaneous coronary intervention (PCI). However, impact of in-stent calcification (ISC) alone on clinical outcomes remains unknown since neoatherosclerosis by optical coherence tomography (OCT) includes both in-stent lipid and calcification. We aimed to assess an effect of ISC on clinical outcomes and clinical differences among different types of ISC. We included 126 lesions that underwent OCT-guided PCI and divided those into the ISC group (n=38) and the non-ISC group (n=88) according to the presence of ISC. The cumulative incidence of clinically-driven TLR (CD-TLR) was compared between the ISC and non-ISC groups. Impact of in-stent calcified nodule and nodular calcification on CD-TLR was evaluated in the Cox hazard model. The incidence of CD-TLR was significantly higher in the ISC group than in the non-ISC group (p=0.004). In the multivariate Cox hazard model, ISC was significantly associated with CD-TLR [hazard ratio (HR): 3.58; 95% confidence interval (CI): 1.33-9.65; p=0.01]. In-stent calcified nodule/nodular calcification and in-stent nodular calcification alone were also the factors significantly associated with CD-TLR (HR: 3.34; 95%CI: 1.15-9.65; p=0.03 and HR: 5.21; 95%CI: 1.82-14.91; p=0.002, respectively). ISC without in-stent calcified nodule/nodular calcification, which was defined as in-stent smooth calcification, was not associated with CD-TLR. In conclusion, ISC was associated with the higher rate of CD-TLR. Types of calcifications that led to the high rate of CD-TLR were in-stent calcified nodule/nodular calcification and in-stent nodular calcification alone but not in-stent smooth calcification. In-stent calcified nodule and nodular calcification should be paid more attention.</AbstractText><br /><br />Copyright © 2024. Published by Elsevier Inc.<br /><br /><small>Am J Cardiol: 15 Jan 2024; epub ahead of print</small></div>
Jinnouchi H, Sakakura K, Taniguchi Y, Yamamoto K, ... Seguchi M, Fujita H
Am J Cardiol: 15 Jan 2024; epub ahead of print | PMID: 38232806
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<div><h4>Effects of reduced sedentary time on resting, exercise and post-exercise blood pressure in inactive adults with metabolic syndrome - a six-month exploratory RCT.</h4><i>Norha J, Sjöros T, Garthwaite T, Laine S, ... Kalliokoski KK, Heinonen IHA</i><br /><AbstractText>Evidence on the long-term effects of reducing sedentary behaviour (SB) on blood pressure (BP) is scarce. Therefore, we performed a sub-analysis of the BP effects of a six-month intervention that aimed at reducing SB by 1 h/day and replacing it with non-exercise activities. Sixty-four physically inactive and sedentary adults with metabolic syndrome (58% female, 58 [SD 7] years, BP 143/88 [16/9] mmHg, SB 10 [1] h/day) were randomised into intervention (INT, n = 33) and control (CON, n = 31) groups. Resting BP and BP at each stage during and after a graded maximal bicycle ergometer test were measured before and after the intervention. SB, standing, moderate-to-vigorous physical activity (MVPA), and light physical activity (LPA) were measured in six-second intervals at baseline and during the whole six-month intervention using hip-worn accelerometers. The analyses were adjusted for BP medication status. The intervention resulted in a 40 min/day reduction in SB and concomitant 20 min/day increase in MVPA. Resting systolic BP was lower in the CON group before and after the intervention. No group x time interactions were observed in resting BP or BP during exercise at submaximal or maximal intensities, or during recovery. The changes in LPA and MVPA were inversely correlated with the changes in BP during light-to-moderate intensity exercise. An intervention that resulted in a 40 min/day reduction in SB for six months was not sufficient at influencing BP at rest, during or after exercise in adults with metabolic syndrome. However, successfully increasing LPA or MVPA might lower BP during light-to-moderate-intensity activities.</AbstractText><br /><br />© 2024. The Author(s).<br /><br /><small>J Hum Hypertens: 24 Jan 2024; epub ahead of print</small></div>
Norha J, Sjöros T, Garthwaite T, Laine S, ... Kalliokoski KK, Heinonen IHA
J Hum Hypertens: 24 Jan 2024; epub ahead of print | PMID: 38267651
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<div><h4>Implications of Mitral Annular Calcification on Outcomes Following Mitral Transcatheter Edge-to-Edge Repair.</h4><i>Shechter A, Lee M, Kaewkes D, Patel V, ... Makkar RR, Siegel RJ</i><br /><b>Background</b><br />Limited data exist regarding the impact of mitral annular calcification (MAC) on outcomes of transcatheter edge-to-edge repair for mitral regurgitation (MR).<br /><b>Methods</b><br />We retrospectively analyzed 968 individuals (median age, 79 [interquartile range, 70-86] years; 60.0% males; 51.8% with functional MR) who underwent an isolated, first-time intervention. Stratified by MAC extent per baseline transthoracic echocardiogram, the cohort was assessed for residual MR, functional status, all-cause mortality, heart failure hospitalizations, and mitral reinterventions post-procedure.<br /><b>Results</b><br />Patients with above-mild MAC (n=101; 10.4%) were older and more likely to be female, exhibited a greater burden of comorbidities, and presented more often with severe, primary MR. Procedural aspects and technical success rate were unaffected by MAC magnitude, as was the significant improvement from baseline in MR severity and functional status along the first postprocedural year. However, the persistence of above-moderate MR or functional classes III and IV at 1 year and the cumulative incidence of reinterventions at 2 years were overall more pronounced within the above-mild MAC group (significant MR or functional impairment, 44.7% versus 29.9%, <i>P</i>=0.060; reinterventions, 11.9% versus 6.2%, <i>P</i>=0.033; log-rank <i>P</i>=0.035). No link was demonstrated between MAC degree and the cumulative incidence or risk of mortality and mortality or heart failure hospitalizations. Differences in outcomes frequencies were mostly confined to the primary MR subgroup, in which patients with above-mild MAC also experienced earlier, more frequent 2-year heart failure hospitalizations (20.8% versus 9.6%; <i>P</i>=0.016; log-rank <i>P</i>=0.020).<br /><b>Conclusions</b><br />Mitral transcatheter edge-to-edge repair in patients with and without above-mild MAC is equally feasible and safe; however, its postprocedural course is less favorable among those with primary MR.<br /><br /><br /><br /><small>Circ Cardiovasc Interv: 18 Jan 2024:e013424; epub ahead of print</small></div>
Shechter A, Lee M, Kaewkes D, Patel V, ... Makkar RR, Siegel RJ
Circ Cardiovasc Interv: 18 Jan 2024:e013424; epub ahead of print | PMID: 38235546
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<div><h4>Use of coronarycomputed tomography for cardiovascular risk assessment in immune-mediated inflammatory diseases.</h4><i>Peverelli M, Maughan RT, Gopalan D, Dweck MR, ... Rudd JHF, Tarkin JM</i><br /><AbstractText>Immune-mediated inflammatory diseases (IMIDs) are recognised risk factors for accelerated atherosclerotic cardiovascular disease (CVD), particularly in younger individuals and women who lack traditional CVD risk factors. Reflective of the critical role that inflammation plays in the formation, progression and rupture of atherosclerotic plaques, research into immune mechanisms of CVD has led to the identification of a range of therapeutic targets that are the subject of ongoing clinical trials. Several key inflammatory pathways implicated in the pathogenesis of atherosclerosis are targeted in people with IMIDs. However, cardiovascular risk continues to be systematically underestimated by conventional risk assessment tools in the IMID population, resulting in considerable excess CVD burden and mortality. Hence, there is a pressing need to improve methods for CVD risk-stratification among patients with IMIDs, to better guide the use of statins and other prognostic interventions. CT coronary angiography (CTCA) is the current first-line investigation for diagnosing and assessing the severity of coronary atherosclerosis in many individuals with suspected angina. Whether CTCA is also useful in the general population for reclassifying asymptomatic individuals and improving long-term prognosis remains unknown. However, in the context of IMIDs, it is conceivable that the information provided by CTCA, including state-of-the-art assessments of coronary plaque, could be an important clinical adjunct in this high-risk patient population. This narrative review discusses the current literature about the use of coronary CT for CVD risk-stratification in three of the most common IMIDs including rheumatoid arthritis, psoriasis and systemic lupus erythematosus.</AbstractText><br /><br />© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.<br /><br /><small>Heart: 18 Jan 2024; epub ahead of print</small></div>
Peverelli M, Maughan RT, Gopalan D, Dweck MR, ... Rudd JHF, Tarkin JM
Heart: 18 Jan 2024; epub ahead of print | PMID: 38238078
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<div><h4>Epidemiology, Pathophysiology, and Imaging of Atherosclerotic Intracranial Disease.</h4><i>Chen LH, Spagnolo-Allende A, Yang D, Qiao Y, Gutierrez J</i><br /><AbstractText>Intracranial atherosclerotic disease (ICAD) is one of the most common causes of stroke worldwide. Among people with stroke, those of East Asia descent and non-White populations in the United States have a higher burden of ICAD-related stroke compared with Whites of European descent. Disparities in the prevalence of asymptomatic ICAD are less marked than with symptomatic ICAD. In addition to stroke, ICAD increases the risk of dementia and cognitive decline, magnifying ICAD societal burden. The risk of stroke recurrence among patients with ICAD-related stroke is the highest among those with confirmed stroke and stenosis ≥70%. In fact, the 1-year recurrent stroke rate of >20% among those with stenosis >70% is one of the highest rates among common causes of stroke. The mechanisms by which ICAD causes stroke include plaque rupture with in situ thrombosis and occlusion or artery-to-artery embolization, hemodynamic injury, and branch occlusive disease. The risk of stroke recurrence varies by the presumed underlying mechanism of stroke, but whether techniques such as quantitative magnetic resonance angiography, computed tomographic angiography, magnetic resonance perfusion, or transcranial Doppler can help with risk stratification beyond the degree of stenosis is less clear. The diagnosis of ICAD is heavily reliant on lumen-based studies, such as computed tomographic angiography, magnetic resonance angiography, or digital subtraction angiography, but newer technologies, such as high-resolution vessel wall magnetic resonance imaging, can help distinguish ICAD from stenosing arteriopathies.</AbstractText><br /><br /><br /><br /><small>Stroke: 01 Feb 2024; 55:311-323</small></div>
Chen LH, Spagnolo-Allende A, Yang D, Qiao Y, Gutierrez J
Stroke: 01 Feb 2024; 55:311-323 | PMID: 38252756
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<div><h4>Connectivity-guided intermittent theta burst versus repetitive transcranial magnetic stimulation for treatment-resistant depression: a randomized controlled trial.</h4><i>Morriss R, Briley PM, Webster L, Abdelghani M, ... Walters Y, Auer DP</i><br /><AbstractText>Disruption in reciprocal connectivity between the right anterior insula and the left dorsolateral prefrontal cortex is associated with depression and may be a target for neuromodulation. In a five-center, parallel, double-blind, randomized controlled trial we personalized resting-state functional magnetic resonance imaging neuronavigated connectivity-guided intermittent theta burst stimulation (cgiTBS) at a site based on effective connectivity from the right anterior insula to the left dorsolateral prefrontal cortex. We tested its efficacy in reducing the primary outcome depression symptoms measured by the GRID Hamilton Depression Rating Scale 17-item over 8, 16 and 26 weeks, compared with structural magnetic resonance imaging (MRI) neuronavigated repetitive transcranial magnetic stimulation (rTMS) delivered at the standard stimulation site (F3) in patients with \'treatment-resistant depression\'. Participants were randomly assigned to 20 sessions over 4-6 weeks of either cgiTBS (n = 128) or rTMS (n = 127) with resting-state functional MRI at baseline and 16 weeks. Persistent decreases in depressive symptoms were seen over 26 weeks, with no differences between arms on the primary outcome GRID Hamilton Depression Rating Scale 17-item score (intention-to-treat adjusted mean, -0.31, 95% confidence interval (CI) -1.87, 1.24, P = 0.689). Two serious adverse events were possibly related to TMS (mania and psychosis). MRI-neuronavigated cgiTBS and rTMS were equally effective in patients with treatment-resistant depression over 26 weeks (trial registration no. ISRCTN19674644).</AbstractText><br /><br />© 2024. The Author(s).<br /><br /><small>Nat Med: 16 Jan 2024; epub ahead of print</small></div>
Morriss R, Briley PM, Webster L, Abdelghani M, ... Walters Y, Auer DP
Nat Med: 16 Jan 2024; epub ahead of print | PMID: 38228914
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<div><h4>The mutual neutralization of hydronium and hydroxide.</h4><i>Bogot A, Poline M, Ji M, Dochain A, ... Thomas RD, Strasser D</i><br /><AbstractText>Mutual neutralization of hydronium (H<sub>3</sub>O<sup>+</sup>) and hydroxide (OH<sup>-</sup>) ions is a very fundamental chemical reaction. Yet, there is only limited experimental evidence about the underlying reaction mechanisms. Here, we report three-dimensional imaging of coincident neutral products of mutual-neutralization reactions at low collision energies of cold and isolated ions in the cryogenic double electrostatic ion-beam storage ring (DESIREE). We identified predominant H<sub>2</sub>O + OH + H and 2OH + H<sub>2</sub> product channels and attributed them to an electron-transfer mechanism, whereas a minor contribution of H<sub>2</sub>O + H<sub>2</sub>O with high internal excitation was attributed to proton transfer. The reported mechanism-resolved internal product excitation, as well as collision-energy and initial ion-temperature dependence, provide a benchmark for modeling charge-transfer mechanisms.</AbstractText><br /><br /><br /><br /><small>Science: 19 Jan 2024; 383:285-289</small></div>
Bogot A, Poline M, Ji M, Dochain A, ... Thomas RD, Strasser D
Science: 19 Jan 2024; 383:285-289 | PMID: 38236956
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<div><h4>Prediction of preeclampsia from retinal fundus images via deep learning in singleton pregnancies: a prospective cohort study.</h4><i>Zhou T, Gu S, Shao F, Li P, ... Gao P, Hua X</i><br /><b>Introduction</b><br />Early prediction of preeclampsia (PE) is of universal importance in controlling the disease process. Our study aimed to assess the feasibility of using retinal fundus images to predict PE via deep learning in singleton pregnancies.<br /><b>Methods</b><br />This prospective cohort study was conducted at Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine. Eligible participants included singleton pregnancies who presented for prenatal visits before 14 weeks of gestation from September 1, 2020, to February 1, 2022. Retinal fundus images were obtained using a nonmydriatic digital retinal camera during their initial prenatal visit upon admission before 20 weeks of gestation. In addition, we generated fundus scores, which indicated the predictive value of hypertension, using a hypertension detection model. To evaluate the predictive value of the retinal fundus image-based deep learning algorithm for preeclampsia, we conducted stratified analyses and measured the area under the curve (AUC), sensitivity, and specificity. We then conducted sensitivity analyses for validation.<br /><b>Results</b><br />Our study analyzed a total of 1138 women with risk factors for preeclampsia, 92 pregnancies developed into hypertension disorders of pregnancy (HDP), including 26 cases of gestational hypertension and 66 cases of preeclampsia. The adjusted odds ratio (aOR) of the fundus scores was 2.582 (95% CI, 1.883-3.616; P < 0.001). Otherwise, in the categories of prepregnancy BMI less than 28.0 and at least 28.0, the aORs were 3.073 (95%CI, 2.265-4.244; P < 0.001) and 5.866 (95% CI, 3.292-11.531; P < 0.001). In the categories of maternal age less than 35.0 and at least 35.0, the aORs were 2.845 (95% CI, 1.854-4.463; P < 0.001) and 2.884 (95% CI, 1.794-4.942; P < 0.001). The AUC of the fundus score combined with risk factors was 0.883 (sensitivity, 0.722; specificity, 0.934; 95% CI, 0.834-0.932) for predicting preeclampsia.<br /><b>Conclusion</b><br />Our study demonstrates that the use of deep learning algorithm-based retinal fundus images offers promising predictive value for the early detection of preeclampsia.<br /><br />Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.<br /><br /><small>J Hypertens: 16 Jan 2024; epub ahead of print</small></div>
Zhou T, Gu S, Shao F, Li P, ... Gao P, Hua X
J Hypertens: 16 Jan 2024; epub ahead of print | PMID: 38230614
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Abstract
<div><h4>Toward the eradication of medical diagnostic errors.</h4><i>Topol EJ</i><br /><AbstractText>The medical community does not broadcast the problem, but there are many studies that have reinforced a serious issue with diagnostic errors. A recent study concluded: \"We estimate that nearly 800,000 Americans die or are permanently disabled by diagnostic errors each year.\" Diagnostic errors are inaccurate assessments of a patient\'s root cause of illness, such as missing a heart attack or infection or assigning the wrong diagnosis of pneumonia when the correct one is pulmonary embolism. Despite ever-increasing use of medical imaging and laboratory tests intended to promote diagnostic accuracy, there is nothing to suggest improvement since the report by the National Academies of Sciences, Engineering and Medicine in 2015, which provided a conservative estimate that 5% of adults experience a diagnostic error each year, and that most people will experience at least one in their lifetime.</AbstractText><br /><br /><br /><br /><small>Science: 26 Jan 2024; 383:eadn9602</small></div>
Topol EJ
Science: 26 Jan 2024; 383:eadn9602 | PMID: 38271508
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<div><h4>Spatial Lipidomics of Coronary Atherosclerotic Plaque Development in a Familial Hypercholesterolemia Swine Model.</h4><i>Slijkhuis N, Razzi F, Korteland SA, Heijs B, ... van Beusekom HMM, van Soest G</i><br /><AbstractText>Coronary atherosclerosis is caused by plaque build-up, with lipids playing a pivotal role in its progression. However, lipid composition and distribution within coronary atherosclerosis remain unknown. This study aims to characterize lipids and investigate differences in lipid composition across disease stages to aid in the understanding of disease progression. Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) was used to visualize lipid distributions in coronary artery sections (n=17) from hypercholesterolemic swine. We performed histology on consecutive sections to classify the artery segments and to investigate colocalization between lipids and histological regions of interest in advanced plaque, including necrotic core and inflammatory cells. Segments were classified as healthy (n=6), mild (n=6), and advanced disease (n=5) artery segments. Multivariate data analysis was employed to find differences in lipid composition between the segment types, and the lipids\' spatial distribution was investigated using non-negative matrix factorization (NMF). Through this process, MALDI-MSI detected 473 lipid-related features. NMF clustering described three components in positive ionization mode: triacylglycerides (TAG), phosphatidylcholines (PC), and cholesterol species. In negative ionization mode, two components were identified: one driven by phosphatidylinositol(PI)(38:4), and one driven by ceramide-phosphoethanolamine(36:1). Multivariate data analysis showed the association between advanced disease and specific lipid signatures like PC(O-40:5) and cholesterylester(CE)(18:2). Ether-linked phospholipids and LysoPC species were found to colocalize with necrotic core, and mostly CE, ceramide, and PI species colocalized with inflammatory cells. This study, therefore, uncovers distinct lipid signatures correlated with plaque development and their colocalization with necrotic core and inflammatory cells, enhancing our understanding of coronary atherosclerosis progression.</AbstractText><br /><br />Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.<br /><br /><small>J Lipid Res: 19 Jan 2024:100504; epub ahead of print</small></div>
Slijkhuis N, Razzi F, Korteland SA, Heijs B, ... van Beusekom HMM, van Soest G
J Lipid Res: 19 Jan 2024:100504; epub ahead of print | PMID: 38246237
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<div><h4>Trial of Selective Early Treatment of Patent Ductus Arteriosus with Ibuprofen.</h4><i>Gupta S, Subhedar NV, Bell JL, Field D, ... Juszczak E, Baby-OSCAR Collaborative Group</i><br /><b>Background</b><br />The cyclooxygenase inhibitor ibuprofen may be used to treat patent ductus arteriosus (PDA) in preterm infants. Whether selective early treatment of large PDAs with ibuprofen would improve short-term outcomes is not known.<br /><b>Methods</b><br />We conducted a multicenter, randomized, double-blind, placebo-controlled trial evaluating early treatment (≤72 hours after birth) with ibuprofen for a large PDA (diameter of ≥1.5 mm with pulsatile flow) in extremely preterm infants (born between 23 weeks 0 days\' and 28 weeks 6 days\' gestation). The primary outcome was a composite of death or moderate or severe bronchopulmonary dysplasia evaluated at 36 weeks of postmenstrual age.<br /><b>Results</b><br />A total of 326 infants were assigned to receive ibuprofen and 327 to receive placebo; 324 and 322, respectively, had data available for outcome analyses. A primary-outcome event occurred in 220 of 318 infants (69.2%) in the ibuprofen group and 202 of 318 infants (63.5%) in the placebo group (adjusted risk ratio, 1.09; 95% confidence interval [CI], 0.98 to 1.20; P = 0.10). A total of 44 of 323 infants (13.6%) in the ibuprofen group and 33 of 321 infants (10.3%) in the placebo group died (adjusted risk ratio, 1.32; 95% CI, 0.92 to 1.90). Among the infants who survived to 36 weeks of postmenstrual age, moderate or severe bronchopulmonary dysplasia occurred in 176 of 274 (64.2%) in the ibuprofen group and 169 of 285 (59.3%) in the placebo group (adjusted risk ratio, 1.09; 95% CI, 0.96 to 1.23). Two unforeseeable serious adverse events occurred that were possibly related to ibuprofen.<br /><b>Conclusions</b><br />The risk of death or moderate or severe bronchopulmonary dysplasia at 36 weeks of postmenstrual age was not significantly lower among infants who received early treatment with ibuprofen than among those who received placebo. (Funded by the National Institute for Health Research Health Technology Assessment Programme; Baby-OSCAR ISRCTN Registry number, ISRCTN84264977.).<br /><br />Copyright © 2024 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 25 Jan 2024; 390:314-325</small></div>
Gupta S, Subhedar NV, Bell JL, Field D, ... Juszczak E, Baby-OSCAR Collaborative Group
N Engl J Med: 25 Jan 2024; 390:314-325 | PMID: 38265644
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<div><h4>Affinity-optimizing enhancer variants disrupt development.</h4><i>Lim F, Solvason JJ, Ryan GE, Le SH, ... Jandu SK, Farley EK</i><br /><AbstractText>Enhancers control the location and timing of gene expression and contain the majority of variants associated with disease<sup>1-3</sup>. The ZRS is arguably the most well-studied vertebrate enhancer and mediates the expression of Shh in the developing limb<sup>4</sup>. Thirty-one human single-nucleotide variants (SNVs) within the ZRS are associated with polydactyly<sup>4-6</sup>. However, how this enhancer encodes tissue-specific activity, and the mechanisms by which SNVs alter the number of digits, are poorly understood. Here we show that the ETS sites within the ZRS are low affinity, and identify a functional ETS site, ETS-A, with extremely low affinity. Two human SNVs and a synthetic variant optimize the binding affinity of ETS-A subtly from 15% to around 25% relative to the strongest ETS binding sequence, and cause polydactyly with the same penetrance and severity. A greater increase in affinity results in phenotypes that are more penetrant and more severe. Affinity-optimizing SNVs in other ETS sites in the ZRS, as well as in ETS, interferon regulatory factor (IRF), HOX and activator protein 1 (AP-1) sites within a wide variety of enhancers, cause gain-of-function gene expression. The prevalence of binding sites with suboptimal affinity in enhancers creates a vulnerability in genomes whereby SNVs that optimize affinity, even slightly, can be pathogenic. Searching for affinity-optimizing SNVs in genomes could provide a mechanistic approach to identify causal variants that underlie enhanceropathies.</AbstractText><br /><br />© 2024. The Author(s).<br /><br /><small>Nature: 17 Jan 2024; epub ahead of print</small></div>
Lim F, Solvason JJ, Ryan GE, Le SH, ... Jandu SK, Farley EK
Nature: 17 Jan 2024; epub ahead of print | PMID: 38233525
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<div><h4>AAV1-hOTOF gene therapy for autosomal recessive deafness 9: a single-arm trial.</h4><i>Lv J, Wang H, Cheng X, Chen Y, ... Li H, Shu Y</i><br /><b>Background</b><br />Autosomal recessive deafness 9, caused by mutations of the OTOF gene, is characterised by congenital or prelingual, severe-to-complete, bilateral hearing loss. However, no pharmacological treatment is currently available for congenital deafness. In this Article, we report the safety and efficacy of gene therapy with an adeno-associated virus (AAV) serotype 1 carrying a human OTOF transgene (AAV1-hOTOF) as a treatment for children with autosomal recessive deafness 9.<br /><b>Methods</b><br />This single-arm, single-centre trial enrolled children (aged 1-18 years) with severe-to-complete hearing loss and confirmed mutations in both alleles of OTOF, and without bilateral cochlear implants. A single injection of AAV1-hOTOF was administered into the cochlea through the round window. The primary endpoint was dose-limiting toxicity at 6 weeks after injection. Auditory function and speech were assessed by appropriate auditory perception evaluation tools. All analyses were done according to the intention-to-treat principle. This trial is registered with Chinese Clinical Trial Registry, ChiCTR2200063181, and is ongoing.<br /><b>Findings</b><br />Between Oct 19, 2022, and June 9, 2023, we screened 425 participants for eligibility and enrolled six children for AAV1-hOTOF gene therapy (one received a dose of 9 × 10<sup>11</sup> vector genomes [vg] and five received 1·5 × 10<sup>12</sup> vg). All participants completed follow-up visits up to week 26. No dose-limiting toxicity or serious adverse events occurred. In total, 48 adverse events were observed; 46 (96%) were grade 1-2 and two (4%) were grade 3 (decreased neutrophil count in one participant). Five children had hearing recovery, shown by a 40-57 dB reduction in the average auditory brainstem response (ABR) thresholds at 0·5-4·0 kHz. In the participant who received the 9 × 10<sup>11</sup> vg dose, the average ABR threshold was improved from greater than 95 dB at baseline to 68 dB at 4 weeks, 53 dB at 13 weeks, and 45 dB at 26 weeks. In those who received 1·5 × 10<sup>12</sup> AAV1-hOTOF, the average ABR thresholds changed from greater than 95 dB at baseline to 48 dB, 38 dB, 40 dB, and 55 dB in four children with hearing recovery at 26 weeks. Speech perception was improved in participants who had hearing recovery.<br /><b>Interpretation</b><br />AAV1-hOTOF gene therapy is safe and efficacious as a novel treatment for children with autosomal recessive deafness 9.<br /><b>Funding</b><br />National Natural Science Foundation of China, National Key R&D Program of China, Science and Technology Commission of Shanghai Municipality, and Shanghai Refreshgene Therapeutics.<br /><br />Copyright © 2024 Elsevier Ltd. All rights reserved.<br /><br /><small>Lancet: 24 Jan 2024; epub ahead of print</small></div>
Lv J, Wang H, Cheng X, Chen Y, ... Li H, Shu Y
Lancet: 24 Jan 2024; epub ahead of print | PMID: 38280389
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<div><h4>Management of pregnancy and delivery in congenital fibrinogen disorders: Communication from the ISTH SSC Subcommittee on Factor XIII and Fibrinogen.</h4><i>Casini A, Kadir RA, Abdelwahab M, Manco-Johnson MJ, ... Santoro C, Acharya S</i><br /><AbstractText>Congenital fibrinogen disorders (CFDs) are a heterogeneous group of rare congenital quantitative and / or qualitative fibrinogen deficiency. The spectrum of molecular anomalies is broad, leading to several subtypes of fibrinogen disorders (i.e., afibrinogenemia, hypofibrinogenemia, dysfibrinogenemia, hypodysfibrinogenemia). Pregnancy in women with CFDs is a high-risk clinical situation, with an increased tendency to miscarriages, bleeding, and thrombosis. Even though it is well established that management of such pregnancies requires a multidisciplinary approach involving specialists (hematologists and maternal / fetal medicine experts with expertise in the management of inherited bleeding disorders), specific guidelines are lacking. In this ISTH SSC communication, we aim to propose an expert consensus opinion with literature evidence where available on the strategy for management of pregnancy, delivery, and puerperium in CFDs.</AbstractText><br /><br />Copyright © 2024. Published by Elsevier Inc.<br /><br /><small>J Thromb Haemost: 22 Jan 2024; epub ahead of print</small></div>
Casini A, Kadir RA, Abdelwahab M, Manco-Johnson MJ, ... Santoro C, Acharya S
J Thromb Haemost: 22 Jan 2024; epub ahead of print | PMID: 38266678
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<div><h4>Clinical prediction tool to identify children at risk of pulmonary embolism.</h4><i>Tiratrakoonseree T, Charoenpichitnun S, Natesirinilkul R, Songthawee N, ... Vaewpanich J, Sirachainan N</i><br /><b>Introduction</b><br />The diagnosis of pediatric pulmonary embolism (PE) is often delayed due to non-specific symptoms, and clinical prediction tools designed for adults are unsuitable for children. This study aimed to create a PE predictive model and to evaluate the reported tools in the Thai pediatric population.<br /><b>Materials and methods</b><br />A multi-center retrospective study from 4 university hospitals included children ≤18 years of age undergoing computed tomography pulmonary angiogram from 2000 to 2020 with the suspicion of PE. Patients\' clinical presentations and risk factors of venous thromboembolism (VTE) were compared between the PE-positive and PE-negative groups. Significant risk factors from univariate and multivariate logistic regression were included to create a clinical prediction tool. The performance of the model was demonstrated by sensitivity, specificity, area under the curve (AUC), Hosmer Lemeshow test, ratio of observed and expected outcomes and bootstrapping.<br /><b>Results</b><br />Of the 104 patients included, 43 (41.3 %) were grouped as PE-positive and 61 (58.7 %) as PE-negative. Five parameters, including congenital heart disease/pulmonary surgery, known thrombophilia, previous VTE, nephrotic syndrome and chest pain showed significant differences between the two groups. Score ≥ 2 yielded a 74.4 % sensitivity and a 75.4 % specificity with an AUC of the model of 0.809. The model performance and validation results were within satisfactory ranges.<br /><b>Conclusion</b><br />The study created a clinical prediction tool indicating the likelihood of PE among Thai children. A score ≥2 was suggestive of PE.<br /><br />Copyright © 2024 Faculty of Medicine Ramathibodi Hospital, Mahidol University. Published by Elsevier Ltd.. All rights reserved.<br /><br /><small>Thromb Res: 12 Jan 2024; 234:151-157</small></div>
Tiratrakoonseree T, Charoenpichitnun S, Natesirinilkul R, Songthawee N, ... Vaewpanich J, Sirachainan N
Thromb Res: 12 Jan 2024; 234:151-157 | PMID: 38241765
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<div><h4>Pregnancy-An Ideal Period to Identify Women at Risk for Chronic Hypertension.</h4><i>Charakida M, Wright A, Magee LA, Syngelaki A, ... Wright D, Nicolaides KH</i><br /><b>Background</b><br />Cardiovascular disease is the leading cause of mortality in women. Pregnancy is an ideal period to implement cardiovascular prevention strategies as women seek medical help. We aimed to develop a predictive model to identify women at increased risk for chronic hypertension (CH) based on information collected in the index pregnancy.<br /><b>Methods</b><br />Cohort of 26 511 women seen in 2 consecutive pregnancies. Included were women without CH, with information on maternal characteristics and blood pressure at 11 to 13 weeks\' gestation, and the development of preeclampsia or gestational hypertension (GH) in the index pregnancy. Logistic regression models were fitted for the prediction of the development of future CH by the 20th week of the subsequent pregnancy. The performance of screening and risk calibration of the model were assessed.<br /><b>Results</b><br />In this study 1560 (5.9%) women developed preeclampsia or GH (index pregnancy), and 215 (0.8%) developed future CH, with a median of 3.0 years later. Predictors of development of future CH were maternal age, weight, and blood pressure; Black and South Asian ethnicity; family history of preeclampsia; parity; and development of preeclampsia or GH. Preeclampsia or GH detected 52.1% (45.2%-58.9%) of future CH. At a screen-positive rate of 10%, a model including maternal characteristics, early pregnancy blood pressure, and development of preeclampsia or GH detected 73.5% (67.1-79.3) of future CH.<br /><b>Conclusions</b><br />Early pregnancy maternal characteristics, blood pressure, and development of preeclampsia or GH identify three-fourths of women at risk for future CH. Our results offer an important preventative strategy for identifying women at increased risk of future CH, which is applicable worldwide.<br /><br /><br /><br /><small>Hypertension: 01 Feb 2024; 81:311-318</small></div>
Charakida M, Wright A, Magee LA, Syngelaki A, ... Wright D, Nicolaides KH
Hypertension: 01 Feb 2024; 81:311-318 | PMID: 38232144
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<div><h4>Depleting inositol pyrophosphate 5-InsP7 protected the heart against ischemia-reperfusion injury by elevating plasma adiponectin.</h4><i>Fu L, Du J, Furkert D, Shipton ML, ... Zhu Y, Fu C</i><br /><b>Aims</b><br />Adiponectin is an adipocyte-derived circulating protein that exerts cardiovascular and metabolic protection. Due to the futile degradation of endogenous adiponectin and the challenges of exogenous administration, regulatory mechanisms of adiponectin biosynthesis are of significant pharmacological interest.<br /><b>Methods and results</b><br />Here, we report that 5-diphosphoinositol 1,2,3,4,6-pentakisphosphate (5-InsP7) generated by inositol hexakisphosphate kinase 1 (IP6K1) governed circulating adiponectin levels via thiol-mediated protein quality control in the secretory pathway. IP6K1 bound to adiponectin and DsbA-L and generated 5-InsP7 to stabilize adiponectin/ERp44 and DsbA-L/Ero1-Lα interactions, driving adiponectin intracellular degradation. Depleting 5-InsP7 by either IP6K1 deletion or pharmacological inhibition blocked intracellular adiponectin degradation. Whole-body and adipocyte-specific deletion of IP6K1 boosted plasma adiponectin levels, especially its high molecular weight forms, and activated AMPK-mediated protection against myocardial ischemia-reperfusion injury. Pharmacological inhibition of 5-InsP7 biosynthesis in WT but not adiponectin knockout mice attenuated myocardial ischemia-reperfusion injury.<br /><b>Conclusions</b><br />Our findings revealed that 5-InsP7 is a physiological regulator of adiponectin biosynthesis that is amenable to pharmacological intervention for cardioprotection.<br /><br />© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Cardiovasc Res: 22 Jan 2024; epub ahead of print</small></div>
Fu L, Du J, Furkert D, Shipton ML, ... Zhu Y, Fu C
Cardiovasc Res: 22 Jan 2024; epub ahead of print | PMID: 38252884
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<div><h4>Histone demethylase KDM5 regulates cardiomyocyte maturation by promoting fatty acid oxidation, oxidative phosphorylation, and myofibrillar organization.</h4><i>Deogharia M, Venegas-Zamora L, Agrawal A, Shi M, ... Marian AJ, Gurha P</i><br /><b>Aims</b><br />Human pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) provide a platform to identify and characterize factors that regulate the maturation of CMs. The transition from an immature fetal to adult CM state entails coordinated regulation of the expression of genes involved in myofibril formation and OXPHOS among others. Lysine demethylase 5 (KDM5) specifically demethylate H3K4me1/2/3 and have emerged as potential regulators of expression of genes involved in cardiac development and mitochondrial function.The purpose of this study is to determine the role of KDM5 in iPSC-CM maturation.<br /><b>Methods and results</b><br />KDM5A, B, and C proteins were mainly expressed in the early post-natal stages and their expressions were progressively downregulated in the postnatal cardiomyocytes and were absent in adult hearts and CMs. In contrast, KDM5 proteins were persistently expressed in the iPSC-CMs up to 60 days after the induction of myogenic differentiation, consistent with the immaturity of these cells. Inhibition of KDM5 by KDM5-C70 -a pan-KDM5 inhibitor, induced differential expression of 2,372 genes, including upregulation of genes involved in fatty acid oxidation (FAO), OXPHOS, and myogenesis in the iPSC-CMs. Likewise, genome-wide profiling of H3K4me3 binding sites by the CUT&RUN (Cleavage Under Targets & Release Using Nuclease) assay showed enriched of the H3K4me3 peaks at the promoter regions of genes encoding FAO, OXPHOS, and sarcomere proteins. Consistent with the chromatin and gene expression data, KDM5 inhibition increased expression of multiple sarcomere proteins and enhanced myofibrillar organization. Furthermore, inhibition of KDM5 increased H3K4me3 deposits at the promoter region of the ESRRA gene and increased its RNA and protein levels. Knockdown of ESRRA in KDM5-C70-treated iPSC-CM suppressed expression of a subset of the KDM5 targets. In conjunction with changes in the gene expression, KDM5 inhibition increased oxygen consumption rate and contractility in iPSC-CMs.<br /><b>Conclusions</b><br />KDM5 inhibition enhances maturation of iPSC-CMs by epigenetically upregulating the expressions of OXPHOS, FAO, and sarcomere genes and enhancing myofibril organization and mitochondrial function.<br /><br />© The Author(s) 2024. 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.<br /><br /><small>Cardiovasc Res: 17 Jan 2024; epub ahead of print</small></div>
Deogharia M, Venegas-Zamora L, Agrawal A, Shi M, ... Marian AJ, Gurha P
Cardiovasc Res: 17 Jan 2024; epub ahead of print | PMID: 38230606
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<div><h4>Blood pressure response and symptoms during active standing test among hospitalized and outpatients with heart failure: results from the GRAVITY-HF prospective observational cohort study.</h4><i>Soloveva A, Fedorova D, Fudim M, Vinogradova N, ... Zvartau N, Villevalde S</i><br /><b>Background</b><br />We conducted a multicenter prospective observational study to describe the incidence of orthostatic hypotension (OH) and orthostatic hypertension (OHtn) and its association with symptoms at standing and outcomes in heart failure (HF) patients.<br /><b>Methods and results</b><br />321 active standing tests were performed in 87 inpatients during admission and 316 tests were done in 208 outpatients during follow-up. Blood pressure (BP) was measured by an automatic device 4 times in supine position and at 1, 3 and 5 min standing. Patients were queried about symptoms of orthostatic intolerance. The incidence of OH and OHtn was similar in both groups at baseline (classical OH 11-22%, OHtn 3-8% depending on definition and timing). Reproducibility of BP changes with standing was low. Up to 50% of cases with an abnormal response were asymptomatic. Symptoms were variable and mainly occurred during first minute of standing and had a U-shaped association with BP changes. OH in HF outpatients was associated with a higher risk of death or HF readmission.<br /><b>Conclusions</b><br />Patients with HF have variable hemodynamic responses and symptoms during repeated active standing tests. OH might identify HF outpatients at risk of long-term negative outcomes.<br /><br />Copyright © 2024. Published by Elsevier Inc.<br /><br /><small>J Card Fail: 17 Jan 2024; epub ahead of print</small></div>
Soloveva A, Fedorova D, Fudim M, Vinogradova N, ... Zvartau N, Villevalde S
J Card Fail: 17 Jan 2024; epub ahead of print | PMID: 38242427
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<div><h4>Early changes in estimated glomerular filtration rate post-initiation of empagliflozin in EMPEROR-Preserved.</h4><i>Rastogi T, Ferreira JP, Butler J, Kraus BJ, ... Anker SD, Zannad F</i><br /><b>Aims</b><br />Renal function (estimated glomerular filtration rate [eGFR]) changes early after the introduction of empagliflozin have not been described in heart failure with preserved ejection fraction (HFpEF). The aim of this study was to describe early eGFR changes, assess its determinants and its clinical impact on cardiovascular and renal outcomes in patients with HFpEF enrolled in EMPEROR-Preserved.<br /><b>Methods and results</b><br />Estimated glomerular filtration rate changes (absolute and relative) from randomization to week 4 were calculated and landmark analyses performed. Initial eGFR change was available in 5836 patients (97.5% of the population). Empagliflozin induced a mean eGFR change of -3.2 ml/min/1.73 m<sup>2</sup> versus placebo from baseline to week 4. After week 4, in the empagliflozin group, the risk of the primary outcome (composite of heart failure hospitalization or cardiovascular death), cardiovascular, all-cause mortality and sustained ≥50% eGFR decrease or end-stage renal disease (ESRD) did not differ by eGFR change levels. In contrast, in the placebo group, patients included in the tertile with most profound eGFR decrease (i.e. ≥5.1% from baseline) had a higher risk of the primary outcome (hazard ratio [HR] 1.46, 95% confidence interval [CI] 1.17-1.82), cardiovascular mortality (HR 1.38, 95% CI 1.01-1.89) and sustained ≥50% eGFR decrease or ESRD (HR 2.20, 95% CI 1.20-4.04) versus tertile with eGFR increase.<br /><b>Conclusion</b><br />An initial relatively small eGFR decrease may be expected after empagliflozin initiation. Such small eGFR decrease was not associated with adverse cardiovascular outcomes with empagliflozin. In contrast, eGFR decrease was associated with poor cardiovascular outcomes with placebo.<br /><br />© 2024 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.<br /><br /><small>Eur J Heart Fail: 21 Jan 2024; epub ahead of print</small></div>
Rastogi T, Ferreira JP, Butler J, Kraus BJ, ... Anker SD, Zannad F
Eur J Heart Fail: 21 Jan 2024; epub ahead of print | PMID: 38247160
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<div><h4>Associations of Sarcopenia and Body Composition Measures With Mortality After Transcatheter Aortic Valve Replacement.</h4><i>Stein EJ, Neill C, Nair S, Terry JG, ... Huang S, Lindman BR</i><br /><b>Background</b><br />Frailty associates with worse outcomes after transcatheter aortic valve replacement (TAVR). Sarcopenia underlies frailty, but the association between a comprehensive assessment of sarcopenia-muscle mass, strength, and performance-and outcomes after TAVR has not been examined.<br /><b>Methods</b><br />From a multicenter prospective registry of patients with symptomatic severe aortic stenosis undergoing TAVR, 445 who had a preprocedure computed tomography and clinical assessment of frailty were included. Cross-sectional muscle (psoas and paraspinal) areas were measured on computed tomography and indexed to height. Gait speed and handgrip strength were obtained, and patients were dichotomized into fast versus slow; strong versus weak; and normal versus low muscle mass. As measures of body composition, cross-sectional fat (subcutaneous and visceral) was measured and indexed to height.<br /><b>Results</b><br />The frequency of patients who were slow, weak, and had low muscle mass was 56%, 59%, and 42%, respectively. Among the 3 components of sarcopenia, only slower gait speed (muscle performance) was independently associated with increased post-TAVR mortality (adjusted hazard ratio, 1.12 per 0.1 m/s decrease [95% CI, 1.04-1.21]; <i>P</i>=0.004; adjusted hazard ratio, 1.38 per 1 SD decrease [95% CI, 1.11-1.72]; <i>P</i>=0.004). Meeting multiple sarcopenia criteria was not associated with higher mortality risk than fewer. Lower indexed visceral fat area (adjusted hazard ratio, 1.48 per 1 SD decrease [95% CI, 1.15-1.89]; <i>P</i>=0.002) was associated with mortality but indexed subcutaneous fat was not. Death occurred in 169 (38%) patients.<br /><b>Conclusions</b><br />Among patients with symptomatic severe aortic stenosis and comprehensive sarcopenia and body composition phenotyping, gait speed was the only sarcopenia measure associated with post-TAVR mortality. Lower visceral fat was also associated with increased risk pointing to an obesity paradox also observed in other patient populations. These findings reinforce the clinical utility of gait speed as a measure of risk and a potential target for adjunctive interventions alongside TAVR to optimize clinical outcomes.<br /><br /><br /><br /><small>Circ Cardiovasc Interv: 18 Jan 2024:e013298; epub ahead of print</small></div>
Stein EJ, Neill C, Nair S, Terry JG, ... Huang S, Lindman BR
Circ Cardiovasc Interv: 18 Jan 2024:e013298; epub ahead of print | PMID: 38235547
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Abstract
<div><h4>DQB1 Antigen Matching Improves Rejection-Free Survival in Pediatric Heart Transplant Recipients.</h4><i>Wright LK, Gajarski RJ, Hayes E, Parekh H, Yester JW, Nandi D</i><br /><b>Introduction</b><br />Presence of donor-specific antibodies (DSAs), particularly to class II antigens, remains a major challenge in pediatric heart transplantation. Donor-recipient human leukocyte antigen (HLA) matching is a potential strategy to mitigate poor outcomes associated with DSAs. We evaluated the hypothesis that antigen mismatching at the DQB1 locus is associated with worse rejection-free survival.<br /><b>Methods</b><br />Data was collected from Scientific Registry of Transplant Recipients for all pediatric heart transplant recipients 2010-2021. Only transplants with complete HLA typing at the DQB1 locus for recipient and donor were included. Primary outcome was rejection-free graft survival through 5 years.<br /><b>Results</b><br />Of 5,115 children, 4,135 had complete DQB1 typing and were included. Of those, 503 (12%) had 0 DQB1 donor-recipient mismatches, 2,203 (53%) had 1, and 1,429 (35%) had 2. Rejection-free survival through 5 years trended higher for children with 0 DQB1 mismatches (68%), compared to those with 1 (62%) or 2 (63%) mismatches (pairwise p=0.08 for both). In multivariable analysis, 0 DQB1 mismatches remained significantly associated with improved rejection-free graft survival compared to 2 mismatches, while 1 DQB1 mismatch was not. Subgroup analysis showed the strongest effect in non-Hispanic Black children and those undergoing retransplant.<br /><b>Conclusion</b><br />Matching at the DQB1 locus is associated with improved rejection-free survival after pediatric heart transplant, particularly in Black children, and those undergoing retransplant. Assessing high-resolution donor typing at the time of allocation may further corroborate and refine this association. DQB1 matching may improve long-term outcomes in children stabilized either with optimal pharmacotherapy or supported with durable devices able to await ideal donors.<br /><br />Copyright © 2024. Published by Elsevier Inc.<br /><br /><small>J Heart Lung Transplant: 15 Jan 2024; epub ahead of print</small></div>
Wright LK, Gajarski RJ, Hayes E, Parekh H, Yester JW, Nandi D
J Heart Lung Transplant: 15 Jan 2024; epub ahead of print | PMID: 38232791
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Abstract
<div><h4>CRISPR-Cas9 In Vivo Gene Editing of for Hereditary Angioedema.</h4><i>Longhurst HJ, Lindsay K, Petersen RS, Fijen LM, ... Lebwohl D, Cohn DM</i><br /><b>Background</b><br />Hereditary angioedema is a rare genetic disease that leads to severe and unpredictable swelling attacks. NTLA-2002 is an in vivo gene-editing therapy based on clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9. NTLA-2002 targets the gene encoding kallikrein B1 (<i>KLKB1</i>), with the goal of lifelong control of angioedema attacks after a single dose.<br /><b>Methods</b><br />In this phase 1 dose-escalation portion of a combined phase 1-2 trial of NTLA-2002 in adults with hereditary angioedema, we administered NTLA-2002 at a single dose of 25 mg, 50 mg, or 75 mg. The primary end points were the safety and side-effect profile of NTLA-2002 therapy. Secondary and exploratory end points included pharmacokinetics, pharmacodynamics, and clinical efficacy determined on the basis of investigator-confirmed angioedema attacks.<br /><b>Results</b><br />Three patients received 25 mg of NTLA-2002, four received 50 mg, and three received 75 mg. At all dose levels, the most common adverse events were infusion-related reactions and fatigue. No dose-limiting toxic effects, serious adverse events, grade 3 or higher adverse events, or clinically important laboratory findings were observed after the administration of NTLA-2002. Dose-dependent reductions in the total plasma kallikrein protein level were observed between baseline and the latest assessment, with a mean percentage change of -67% in the 25-mg group, -84% in the 50-mg group, and -95% in the 75-mg group. The mean percentage change in the number of angioedema attacks per month between baseline and weeks 1 through 16 (primary observation period) was -91% in the 25-mg group, -97% in the 50-mg group, and -80% in the 75-mg group. Among all the patients, the mean percentage change in the number of angioedema attacks per month from baseline through the latest assessment was -95%.<br /><b>Conclusions</b><br />In this small study, a single dose of NTLA-2002 led to robust, dose-dependent, and durable reductions in total plasma kallikrein levels, and no severe adverse events were observed. In exploratory analyses, reductions in the number of angioedema attacks per month were observed at all dose levels. (Funded by Intellia Therapeutics; ClinicalTrials.gov number, NCT05120830.).<br /><br />Copyright © 2024 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 01 Feb 2024; 390:432-441</small></div>
Longhurst HJ, Lindsay K, Petersen RS, Fijen LM, ... Lebwohl D, Cohn DM
N Engl J Med: 01 Feb 2024; 390:432-441 | PMID: 38294975
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Abstract
<div><h4>Alternative splicing of latrophilin-3 controls synapse formation.</h4><i>Wang S, DeLeon C, Sun W, Quake SR, Roth BL, Südhof TC</i><br /><AbstractText>The assembly and specification of synapses in the brain is incompletely understood<sup>1-3</sup>. Latrophilin-3 (encoded by Adgrl3, also known as Lphn3)-a postsynaptic adhesion G-protein-coupled receptor-mediates synapse formation in the hippocampus<sup>4</sup> but the mechanisms involved remain unclear. Here we show in mice that LPHN3 organizes synapses through a convergent dual-pathway mechanism: activation of Gα<sub>s</sub> signalling and recruitment of phase-separated postsynaptic protein scaffolds. We found that cell-type-specific alternative splicing of Lphn3 controls the LPHN3 G-protein-coupling mode, resulting in LPHN3 variants that predominantly signal through Gα<sub>s</sub> or Gα<sub>12/13</sub>. CRISPR-mediated manipulation of Lphn3 alternative splicing that shifts LPHN3 from a Gα<sub>s</sub>- to a Gα<sub>12/13</sub>-coupled mode impaired synaptic connectivity as severely as the overall deletion of Lphn3, suggesting that Gα<sub>s</sub> signalling by LPHN3 splice variants mediates synapse formation. Notably, Gα<sub>s</sub>-coupled, but not Gα<sub>12/13</sub>-coupled, splice variants of LPHN3 also recruit phase-transitioned postsynaptic protein scaffold condensates, such that these condensates are clustered by binding of presynaptic teneurin and FLRT ligands to LPHN3. Moreover, neuronal activity promotes alternative splicing of the synaptogenic Gα<sub>s</sub>-coupled variant of LPHN3. Together, these data suggest that activity-dependent alternative splicing of a key synaptic adhesion molecule controls synapse formation by parallel activation of two convergent pathways: Gα<sub>s</sub> signalling and clustered phase separation of postsynaptic protein scaffolds.</AbstractText><br /><br />© 2024. The Author(s).<br /><br /><small>Nature: 17 Jan 2024; epub ahead of print</small></div>
Wang S, DeLeon C, Sun W, Quake SR, Roth BL, Südhof TC
Nature: 17 Jan 2024; epub ahead of print | PMID: 38233523
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Abstract
<div><h4>Observation of interband Berry phase in laser-driven crystals.</h4><i>Uzan-Narovlansky AJ, Faeyrman L, Brown GG, Shames S, ... Ivanov M, Dudovich N</i><br /><AbstractText>Ever since its discovery<sup>1</sup>, the notion of the Berry phase has permeated all branches of physics and plays an important part in a variety of quantum phenomena<sup>2</sup>. However, so far all its realizations have been based on a continuous evolution of the quantum state, following a cyclic path. Here we introduce and demonstrate a conceptually new manifestation of the Berry phase in light-driven crystals, in which the electronic wavefunction accumulates a geometric phase during a discrete evolution between different bands, while preserving the coherence of the process. We experimentally reveal this phase by using a strong laser field to engineer an internal interferometer, induced during less than one cycle of the driving field, which maps the phase onto the emission of higher-order harmonics. Our work provides an opportunity for the study of geometric phases, leading to a variety of observations in light-driven topological phenomena and attosecond solid-state physics.</AbstractText><br /><br />© 2024. The Author(s).<br /><br /><small>Nature: 17 Jan 2024; epub ahead of print</small></div>
Uzan-Narovlansky AJ, Faeyrman L, Brown GG, Shames S, ... Ivanov M, Dudovich N
Nature: 17 Jan 2024; epub ahead of print | PMID: 38233521
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Abstract
<div><h4>Autoreactive T cells target peripheral nerves in Guillain-Barré syndrome.</h4><i>Súkeníková L, Mallone A, Schreiner B, Ripellino P, ... Sallusto F, Latorre D</i><br /><AbstractText>Guillain-Barré syndrome (GBS) is a rare heterogenous disorder of the peripheral nervous system, which is usually triggered by a preceding infection, and causes a potentially life-threatening progressive muscle weakness<sup>1</sup>. Although GBS is considered an autoimmune disease, the mechanisms that underlie its distinct clinical subtypes remain largely unknown. Here, by combining in vitro T cell screening, single-cell RNA sequencing and T cell receptor (TCR) sequencing, we identify autoreactive memory CD4<sup>+</sup> cells, that show a cytotoxic T helper 1 (T<sub>H</sub>1)-like phenotype, and rare CD8<sup>+</sup> T cells that target myelin antigens of the peripheral nerves in patients with the demyelinating disease variant. We characterized more than 1,000 autoreactive single T cell clones, which revealed a polyclonal TCR repertoire, short CDR3β lengths, preferential HLA-DR restrictions and recognition of immunodominant epitopes. We found that autoreactive TCRβ clonotypes were expanded in the blood of the same patient at distinct disease stages and, notably, that they were shared in the blood and the cerebrospinal fluid across different patients with GBS, but not in control individuals. Finally, we identified myelin-reactive T cells in the nerve biopsy from one patient, which indicates that these cells contribute directly to disease pathophysiology. Collectively, our data provide clear evidence of autoreactive T cell immunity in a subset of patients with GBS, and open new perspectives in the field of inflammatory peripheral neuropathies, with potential impact for biomedical applications.</AbstractText><br /><br />© 2024. The Author(s).<br /><br /><small>Nature: 17 Jan 2024; epub ahead of print</small></div>
Súkeníková L, Mallone A, Schreiner B, Ripellino P, ... Sallusto F, Latorre D
Nature: 17 Jan 2024; epub ahead of print | PMID: 38233524
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Abstract
<div><h4>Top-down control of flight by a non-canonical cortico-amygdala pathway.</h4><i>Borkar CD, Stelly CE, Fu X, Dorofeikova M, ... Tasker JG, Fadok JP</i><br /><AbstractText>Survival requires the selection of appropriate behaviour in response to threats, and dysregulated defensive reactions are associated with psychiatric illnesses such as post-traumatic stress and panic disorder<sup>1</sup>. Threat-induced behaviours, including freezing and flight, are controlled by neuronal circuits in the central amygdala (CeA)<sup>2</sup>; however, the source of neuronal excitation of the CeA that contributes to high-intensity defensive responses is unknown. Here we used a combination of neuroanatomical mapping, in vivo calcium imaging, functional manipulations and electrophysiology to characterize a previously unknown projection from the dorsal peduncular (DP) prefrontal cortex to the CeA. DP-to-CeA neurons are glutamatergic and specifically target the medial CeA, the main amygdalar output nucleus mediating conditioned responses to threat. Using a behavioural paradigm that elicits both conditioned freezing and flight, we found that CeA-projecting DP neurons are activated by high-intensity threats in a context-dependent manner. Functional manipulations revealed that the DP-to-CeA pathway is necessary and sufficient for both avoidance behaviour and flight. Furthermore, we found that DP neurons synapse onto neurons within the medial CeA that project to midbrain flight centres. These results elucidate a non-canonical top-down pathway regulating defensive responses.</AbstractText><br /><br />© 2024. The Author(s), under exclusive licence to Springer Nature Limited.<br /><br /><small>Nature: 17 Jan 2024; epub ahead of print</small></div>
Borkar CD, Stelly CE, Fu X, Dorofeikova M, ... Tasker JG, Fadok JP
Nature: 17 Jan 2024; epub ahead of print | PMID: 38233522
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Abstract
<div><h4>The Born in Guangzhou Cohort Study enables generational genetic discoveries.</h4><i>Huang S, Liu S, Huang M, He JR, ... Xia H, Qiu X</i><br /><AbstractText>Genomic research that targets large-scale, prospective birth cohorts constitutes an essential strategy for understanding the influence of genetics and environment on human health<sup>1</sup>. Nonetheless, such studies remain scarce, particularly in Asia. Here we present the phase I genome study of the Born in Guangzhou Cohort Study<sup>2</sup> (BIGCS), which encompasses the sequencing and analysis of 4,053 Chinese individuals, primarily composed of trios or mother-infant duos residing in South China. Our analysis reveals novel genetic variants, a high-quality reference panel, and fine-scale local genetic structure within BIGCS. Notably, we identify previously unreported East Asian-specific genetic associations with maternal total bile acid, gestational weight gain and infant cord blood traits. Additionally, we observe prevalent age-specific genetic effects on lipid levels in mothers and infants. In an exploratory intergenerational Mendelian randomization analysis, we estimate the maternal putatively causal and fetal genetic effects of seven adult phenotypes on seven fetal growth-related measurements. These findings illuminate the genetic links between maternal and early-life traits in an East Asian population and lay the groundwork for future research into the intricate interplay of genetics, intrauterine exposures and early-life experiences in shaping long-term health.</AbstractText><br /><br />© 2024. The Author(s), under exclusive licence to Springer Nature Limited.<br /><br /><small>Nature: 31 Jan 2024; epub ahead of print</small></div>
Huang S, Liu S, Huang M, He JR, ... Xia H, Qiu X
Nature: 31 Jan 2024; epub ahead of print | PMID: 38297123
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Abstract
<div><h4>Tuning commensurability in twisted van der Waals bilayers.</h4><i>Li Y, Zhang F, Ha VA, Lin YC, ... Giustino F, Shih CK</i><br /><AbstractText>Moiré superlattices based on van der Waals bilayers<sup>1-4</sup> created at small twist angles lead to a long wavelength pattern with approximate translational symmetry. At large twist angles (θ<sub>t</sub>), moiré patterns are, in general, incommensurate except for a few discrete angles. Here we show that large-angle twisted bilayers offer distinctly different platforms. More specifically, by using twisted tungsten diselenide bilayers, we create the incommensurate dodecagon quasicrystals at θ<sub>t</sub> = 30° and the commensurate moiré crystals at θ<sub>t</sub> = 21.8° and 38.2°. Valley-resolved scanning tunnelling spectroscopy shows disparate behaviours between moiré crystals (with translational symmetry) and quasicrystals (with broken translational symmetry). In particular, the K valley shows rich electronic structures exemplified by the formation of mini-gaps near the valence band maximum. These discoveries demonstrate that bilayers with large twist angles offer a design platform to explore moiré physics beyond those formed with small twist angles.</AbstractText><br /><br />© 2024. The Author(s), under exclusive licence to Springer Nature Limited.<br /><br /><small>Nature: 01 Jan 2024; 625:494-499</small></div>
Li Y, Zhang F, Ha VA, Lin YC, ... Giustino F, Shih CK
Nature: 01 Jan 2024; 625:494-499 | PMID: 38233619
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Abstract
<div><h4>Prospective prenatal cell-free DNA screening for genetic conditions of heterogenous etiologies.</h4><i>Zhang J, Wu Y, Chen S, Luo Q, ... Xu C, Huang H</i><br /><AbstractText>Prenatal cell-free DNA (cfDNA) screening uses extracellular fetal DNA circulating in the peripheral blood of pregnant women to detect prevalent fetal chromosomal anomalies. However, numerous severe conditions with underlying single-gene defects are not included in current prenatal cfDNA screening. In this prospective, multicenter and observational study, pregnant women at elevated risk for fetal genetic conditions were enrolled for a cfDNA screening test based on coordinative allele-aware target enrichment sequencing. This test encompasses the following three of the most frequent pathogenic genetic variations: aneuploidies, microdeletions and monogenic variants. The cfDNA screening results were compared to invasive prenatal or postnatal diagnostic test results for 1,090 qualified participants. The comprehensive cfDNA screening detected a genetic alteration in 135 pregnancies with 98.5% sensitivity and 99.3% specificity relative to standard diagnostics. Of 876 fetuses with suspected structural anomalies on ultrasound examination, comprehensive cfDNA screening identified 55 (56.1%) aneuploidies, 6 (6.1%) microdeletions and 37 (37.8%) single-gene pathogenic variants. The inclusion of targeted monogenic conditions alongside chromosomal aberrations led to a 60.7% increase (from 61 to 98) in the detection rate. Overall, these data provide preliminary evidence that a comprehensive cfDNA screening test can accurately identify fetal pathogenic variants at both the chromosome and single-gene levels in high-risk pregnancies through a noninvasive approach, which has the potential to improve prenatal evaluation of fetal risks for severe genetic conditions arising from heterogenous molecular etiologies. ClinicalTrials.gov registration: ChiCTR2100045739 .</AbstractText><br /><br />© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.<br /><br /><small>Nat Med: 22 Jan 2024; epub ahead of print</small></div>
Zhang J, Wu Y, Chen S, Luo Q, ... Xu C, Huang H
Nat Med: 22 Jan 2024; epub ahead of print | PMID: 38253798
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Abstract
<div><h4>Familial Hypercholesterolemia Variant and Cardiovascular Risk in Individuals With Elevated Cholesterol.</h4><i>Zhang Y, Dron JS, Bellows BK, Khera AV, ... de Ferranti SD, Moran AE</i><br /><b>Importance</b><br />Familial hypercholesterolemia (FH) is a genetic disorder that often results in severely high low-density lipoprotein cholesterol (LDL-C) and high risk of premature coronary heart disease (CHD). However, the impact of FH variants on CHD risk among individuals with moderately elevated LDL-C is not well quantified.<br /><b>Objective</b><br />To assess CHD risk associated with FH variants among individuals with moderately (130-189 mg/dL) and severely (≥190 mg/dL) elevated LDL-C and to quantify excess CHD deaths attributable to FH variants in US adults.<br /><b>Design, setting, and participants</b><br />A total of 21 426 individuals without preexisting CHD from 6 US cohort studies (Atherosclerosis Risk in Communities study, Coronary Artery Risk Development in Young Adults study, Cardiovascular Health Study, Framingham Heart Study Offspring cohort, Jackson Heart Study, and Multi-Ethnic Study of Atherosclerosis) were included, 63 of whom had an FH variant. Data were collected from 1971 to 2018, and the median (IQR) follow-up was 18 (13-28) years. Data were analyzed from March to May 2023.<br /><b>Exposures</b><br />LDL-C, cumulative past LDL-C, FH variant status.<br /><b>Main outcomes and measures</b><br />Cox proportional hazards models estimated associations between FH variants and incident CHD. The Cardiovascular Disease Policy Model projected excess CHD deaths associated with FH variants in US adults.<br /><b>Results</b><br />Of the 21 426 individuals without preexisting CHD (mean [SD] age 52.1 [15.5] years; 12 041 [56.2%] female), an FH variant was found in 22 individuals with moderately elevated LDL-C (0.3%) and in 33 individuals with severely elevated LDL-C (2.5%). The adjusted hazard ratios for incident CHD comparing those with and without FH variants were 2.9 (95% CI, 1.4-6.0) and 2.6 (95% CI, 1.4-4.9) among individuals with moderately and severely elevated LDL-C, respectively. The association between FH variants and CHD was slightly attenuated when further adjusting for baseline LDL-C level, whereas the association was no longer statistically significant after adjusting for cumulative past LDL-C exposure. Among US adults 20 years and older with no history of CHD and LDL-C 130 mg/dL or higher, more than 417 000 carry an FH variant and were projected to experience more than 12 000 excess CHD deaths in those with moderately elevated LDL-C and 15 000 in those with severely elevated LDL-C compared with individuals without an FH variant.<br /><br /><b>Conclusions:</b><br/>and relevance</b><br />In this pooled cohort study, the presence of FH variants was associated with a 2-fold higher CHD risk, even when LDL-C was only moderately elevated. The increased CHD risk appeared to be largely explained by the higher cumulative LDL-C exposure in individuals with an FH variant compared to those without. Further research is needed to assess the value of adding genetic testing to traditional phenotypic FH screening.<br /><br /><br /><br /><small>JAMA Cardiol: 31 Jan 2024; epub ahead of print</small></div>
Zhang Y, Dron JS, Bellows BK, Khera AV, ... de Ferranti SD, Moran AE
JAMA Cardiol: 31 Jan 2024; epub ahead of print | PMID: 38294787
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This program is still in alpha version.