Topic: Journal Club Selection

Abstract
<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>Legacy benefits of blood pressure treatment on cardiovascular events are primarily mediated by improved blood pressure variability: the ASCOT trial.</h4><i>Gupta A, Whiteley WN, Godec T, Rostamian S, ... Sever PS, ASCOT-10 Investigators </i><br /><b>Background:</b><br/>and aims</b><br />Visit-to-visit systolic blood pressure variability (BPV) is an important predictor of cardiovascular (CV) outcomes. The long-term effect of a period of blood pressure (BP) control, but with differential BPV, is uncertain. Morbidity and mortality follow-up of UK participants in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure-Lowering Arm has been extended for up to 21 years to determine the CV impact of mean systolic blood pressure (SBP) control and BPV during the trial, and amongst those allocated to amlodipine- and atenolol-based treatment.<br /><b>Methods</b><br />Eight thousand five hundred and eighty hypertensive participants (4305 assigned to amlodipine ± perindopril-based and 4275 to atenolol ± diuretic-based treatment during the in-trial period (median 5.5 years) were followed for up to 21 years (median 17.4 years), using linked hospital and mortality records. A subgroup of participants (n = 2156) was followed up 6 years after the trial closure with a self-administered questionnaire and a clinic visit. In-trial mean SBP and standard deviation of visit-to-visit SBP as a measure of BPV, were measured using >100 000 BP measurements. Cox proportional hazard models were used to estimate the risk [hazard ratios (HRs)], associated with (i) mean with SBP and BPV during the in-trial period, for the CV endpoints occurring after the end of the trial and (ii) randomly assigned treatment to events following randomization, for the first occurrence of pre-specified CV outcomes.<br /><b>Results</b><br />Using BP data from the in-trial period, in the post-trial period, although mean SBP was a predictor of CV outcomes {HR per 10 mmHg, 1.14 [95% confidence interval (CI) 1.10-1.17], P < .001}, systolic BPV independent of mean SBP was a strong predictor of CV events [HR per 5 mmHg 1.22 (95% CI 1.18-1.26), P < .001] and predicted events even in participants with well-controlled BP. During 21-year follow-up, those on amlodipine-based compared with atenolol-based in-trial treatment had significantly reduced risk of stroke [HR 0.82 (95% CI 0.72-0.93), P = .003], total CV events [HR 0.93 (95% CI 0.88-0.98), P = .008], total coronary events [HR 0.92 (95% CI 0.86-0.99), P = .024], and atrial fibrillation [HR 0.91 (95% CI 0.83-0.99), P = .030], with weaker evidence of a difference in CV mortality [HR 0.91 (95% CI 0.82-1.01), P = .073]. There was no significant difference in the incidence of non-fatal myocardial infarction and fatal coronary heart disease, heart failure, and all-cause mortality.<br /><b>Conclusions</b><br />Systolic BPV is a strong predictor of CV outcome, even in those with controlled SBP. The long-term benefits of amlodipine-based treatment compared with atenolol-based treatment in reducing CV events appear to be primarily mediated by an effect on systolic BPV during the trial period.<br /><br />© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Eur Heart J: 31 Jan 2024; epub ahead of print</small></div>
Gupta A, Whiteley WN, Godec T, Rostamian S, ... Sever PS, ASCOT-10 Investigators
Eur Heart J: 31 Jan 2024; epub ahead of print | PMID: 38291599
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<div><h4>Clinical Presentation, Classification, and Outcomes of Cardiogenic Shock in Children.</h4><i>Puri K, Jentzer JC, Spinner JA, Hope KD, ... Cabrera AG, Price JF</i><br /><b>Background</b><br />Despite growing cardiogenic shock (CS) research in adults, the epidemiology, clinical features, and outcomes of children with CS are lacking.<br /><b>Objectives</b><br />This study sought to describe the epidemiology, clinical presentation, hospital course, risk factors, and outcomes of CS among children hospitalized for acute decompensated heart failure (ADHF).<br /><b>Methods</b><br />We examined consecutive ADHF hospitalizations (<21 years of age) from a large single-center retrospective cohort. Patients with CS at presentation were analyzed and risk factors for CS and for the primary outcome of in-hospital mortality were identified. A modified Society for Cardiovascular Angiography and Interventions shock classification was created and patients were staged accordingly.<br /><b>Results</b><br />A total of 803 hospitalizations for ADHF were identified in 591 unique patients (median age 7.6 years). CS occurred in 207 (26%) hospitalizations. ADHF hospitalizations with CS were characterized by worse systolic function (P = 0.040), higher B-type natriuretic peptide concentration (P = 0.032), and more frequent early severe renal (P = 0.023) and liver (P < 0.001) injury than those without CS. Children presenting in CS received mechanical ventilation (87% vs 26%) and mechanical circulatory support (45% vs 16%) more frequently (both P < 0.001). Analyzing only the most recent ADHF hospitalization, children with CS were at increased risk of in-hospital mortality compared with children without CS (28% vs 11%; OR: 1.91; 95% CI: 1.05-3.45; P = 0.033). Each higher CS stage was associated with greater inpatient mortality (OR: 2.40-8.90; all P < 0.001).<br /><b>Conclusions</b><br />CS occurs in 26% of pediatric hospitalizations for ADHF and is independently associated with hospital mortality. A modified Society for Cardiovascular Angiography and Interventions classification for CS severity showed robust association with increasing mortality.<br /><br />Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>J Am Coll Cardiol: 06 Feb 2024; 83:595-608</small></div>
Puri K, Jentzer JC, Spinner JA, Hope KD, ... Cabrera AG, Price JF
J Am Coll Cardiol: 06 Feb 2024; 83:595-608 | PMID: 38296404
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<div><h4>The American Heart Association Emergency Cardiovascular Care 2030 Impact Goals and Call to Action to Improve Cardiac Arrest Outcomes: A Scientific Statement From the American Heart Association.</h4><i>Merchant RM, Becker LB, Brooks SC, Chan PS, ... Sasson C, American Heart Association</i><br /><AbstractText>Every 10 years, the American Heart Association (AHA) Emergency Cardiovascular Care Committee establishes goals to improve survival from cardiac arrest. These goals align with broader AHA Impact Goals and support the AHA\'s advocacy efforts and strategic investments in research, education, clinical care, and quality improvement programs. This scientific statement focuses on 2030 AHA emergency cardiovascular care priorities, with a specific focus on bystander cardiopulmonary resuscitation, early defibrillation, and neurologically intact survival. This scientific statement also includes aspirational goals, such as establishing cardiac arrest as a reportable disease and mandating reporting of standardized outcomes from different sources; advancing recognition of and knowledge about cardiac arrest; improving dispatch system response, availability, and access to resuscitation training in multiple settings and at multiple time points; improving availability, access, and affordability of defibrillators; providing a focus on early defibrillation, in-hospital programs, and establishing champions for debriefing and review of cardiac arrest events; and expanding measures to track outcomes beyond survival. The ability to track and report data from these broader aspirational targets will potentially require expansion of existing data sets, development of new data sets, and enhanced integration of technology to collect process and outcome data, as well as partnerships of the AHA with national, state, and local organizations. The COVID-19 (coronavirus disease 2019) pandemic, disparities in COVID-19 outcomes for historically excluded racial and ethnic groups, and the longstanding disparities in cardiac arrest treatment and outcomes for Black and Hispanic or Latino populations also contributed to an explicit focus and target on equity for the AHA Emergency Cardiovascular Care 2030 Impact Goals.</AbstractText><br /><br /><br /><br /><small>Circulation: 22 Jan 2024; epub ahead of print</small></div>
Merchant RM, Becker LB, Brooks SC, Chan PS, ... Sasson C, American Heart Association
Circulation: 22 Jan 2024; epub ahead of print | PMID: 38250800
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<div><h4>2024 Heart Disease and Stroke Statistics: A Report of US and Global Data From the American Heart Association.</h4><i>Martin SS, Aday AW, Almarzooq ZI, Anderson CAM, ... Palaniappan LP, American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee</i><br /><b>Background</b><br />The American Heart Association (AHA), in conjunction with the National Institutes of Health, annually reports the most up-to-date statistics related to heart disease, stroke, and cardiovascular risk factors, including core health behaviors (smoking, physical activity, nutrition, sleep, and obesity) and health factors (cholesterol, blood pressure, glucose control, and metabolic syndrome) that contribute to cardiovascular health. The AHA Heart Disease and Stroke Statistical Update presents the latest data on a range of major clinical heart and circulatory disease conditions (including stroke, brain health, complications of pregnancy, kidney disease, congenital heart disease, rhythm disorders, sudden cardiac arrest, subclinical atherosclerosis, coronary heart disease, cardiomyopathy, heart failure, valvular disease, venous thromboembolism, and peripheral artery disease) and the associated outcomes (including quality of care, procedures, and economic costs).<br /><b>Methods</b><br />The AHA, through its Epidemiology and Prevention Statistics Committee, continuously monitors and evaluates sources of data on heart disease and stroke in the United States and globally to provide the most current information available in the annual Statistical Update with review of published literature through the year before writing. The 2024 AHA Statistical Update is the product of a full year\'s worth of effort in 2023 by dedicated volunteer clinicians and scientists, committed government professionals, and AHA staff members. The AHA strives to further understand and help heal health problems inflicted by structural racism, a public health crisis that can significantly damage physical and mental health and perpetuate disparities in access to health care, education, income, housing, and several other factors vital to healthy lives. This year\'s edition includes additional global data, as well as data on the monitoring and benefits of cardiovascular health in the population, with an enhanced focus on health equity across several key domains.<br /><b>Results</b><br />Each of the chapters in the Statistical Update focuses on a different topic related to heart disease and stroke statistics.<br /><b>Conclusions</b><br />The Statistical Update represents a critical resource for the lay public, policymakers, media professionals, clinicians, health care administrators, researchers, health advocates, and others seeking the best available data on these factors and conditions.<br /><br /><br /><br /><small>Circulation: 24 Jan 2024; epub ahead of print</small></div>
Martin SS, Aday AW, Almarzooq ZI, Anderson CAM, ... Palaniappan LP, American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee
Circulation: 24 Jan 2024; epub ahead of print | PMID: 38264914
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<div><h4>Remnant cholesterol as a new lipid-lowering target to reduce cardiovascular events.</h4><i>Raggi P, Becciu ML, Navarese E</i><br /><b>Purpose of review</b><br />Remnant cholesterol has become increasingly recognized as a direct contributor to the development of atherosclerosis and as an additional marker of cardiovascular risk. This review aims to summarize the pathophysiological mechanisms, and the current evidence base from epidemiological investigations and genetic studies that support a causal link between remnant cholesterol and atherosclerotic cardiovascular disease. Current and novel therapeutic approaches to target remnant cholesterol are discussed.<br /><b>Recent findings</b><br />A recent Mendelian randomization study of over 12 000 000 single-nucleotide polymorphisms associated with high levels of remnant cholesterol, demonstrated a genetic association between remnant cholesterol and adverse cardiovascular events among 958 434 participants.<br /><b>Summary</b><br />In this light, the emerging role of remnant cholesterol as an independent lipid risk marker warrants a reevaluation of lipid management guidelines and underscores the potential for novel therapeutic targets in cardiovascular disease prevention.<br /><br />Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.<br /><br /><small>Curr Opin Lipidol: 24 Jan 2024; epub ahead of print</small></div>
Raggi P, Becciu ML, Navarese E
Curr Opin Lipidol: 24 Jan 2024; epub ahead of print | PMID: 38276967
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<div><h4>C-reactive protein, pharmacological treatments and diet: how to target your inflammatory burden.</h4><i>Bay B, Arnold N, Waldeyer C</i><br /><b>Purpose of review</b><br />This article focuses on pharmacological agents as well as dietary changes aimed at the reduction of the inflammatory burden measured by circulating C-reactive protein concentrations.<br /><b>Recent findings</b><br />Over the last years, repurposed as well as new anti-inflammatory agents have been investigated in outcome trials in the cardiovascular field. Currently, a specific inhibition of the inflammatory cascade via the interleukin-6 ligand antibody ziltivekimab is being explored in large-scale outcome trials, after the efficacy of this agent with regard to the reduction of inflammatory biomarkers was proven recently. Next to the investigated pharmacological agents, specific dietary patterns possess the ability to improve the inflammatory burden. This enables patients themselves to unlock a potential health benefit ahead of the initiation of a specific medication targeting the inflammatory pathway.<br /><b>Summary</b><br />Both pharmacological agents as well as diet provide the opportunity to improve the inflammatory profile and thereby lower C-reactive protein concentrations. Whilst advances in the field of specific anti-inflammatory treatments have been made over the last years, their broad implementation is currently limited. Therefore, optimization of diet (and other lifestyle factors) could provide a cost effective and side-effect free intervention to target low-grade vascular inflammation.<br /><br />Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.<br /><br /><small>Curr Opin Lipidol: 26 Jan 2024; epub ahead of print</small></div>
Bay B, Arnold N, Waldeyer C
Curr Opin Lipidol: 26 Jan 2024; epub ahead of print | PMID: 38277208
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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>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>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>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>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>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>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>Myocardial perfusion in cardiac amyloidosis.</h4><i>Chacko L, Kotecha T, Ioannou A, Patel N, ... Gillmore J, Fontana M</i><br /><b>Aims</b><br />Cardiac involvement is the main driver of clinical outcomes in systemic amyloidosis and preliminary studies support the hypothesis that myocardial ischaemia contributes to cellular damage. The aims of this study were to assess the presence and mechanisms of myocardial ischaemia using cardiovascular magnetic resonance (CMR) with multiparametric mapping and histopathological assessment.<br /><b>Methods and results</b><br />Ninety-three patients with cardiac amyloidosis (CA) (light-chain amyloidosis n = 42, transthyretin amyloidosis n = 51) and 97 without CA (three-vessel coronary disease [3VD] n = 47, unobstructed coronary arteries n = 26, healthy volunteers [HV] n = 24) underwent quantitative stress perfusion CMR with myocardial blood flow (MBF) mapping. Twenty-four myocardial biopsies and three explanted hearts with CA were analysed histopathologically. Stress MBF was severely reduced in patients with CA with lower values than patients with 3VD, unobstructed coronary arteries and HV (CA: 1.04 ± 0.51 ml/min/g, 3VD: 1.35 ± 0.50 ml/min/g, unobstructed coronary arteries: 2.92 ± 0.52 ml/min/g, HV: 2.91 ± 0.73 ml/min/g; CA vs. 3VD p = 0.011, CA vs. unobstructed coronary arteries p < 0.001, CA vs. HV p < 0.001). Myocardial perfusion abnormalities correlated with amyloid burden, systolic and diastolic function, structural parameters and blood biomarkers (p < 0.05). Biopsies demonstrated abnormal vascular endothelial growth factor staining in cardiomyocytes and endothelial cells, which may be related to hypoxia conditions. Amyloid infiltration in intramural arteries was associated with severe lumen reduction and severe reduction in capillary density.<br /><b>Conclusion</b><br />Cardiac amyloidosis is associated with severe inducible myocardial ischaemia demonstrable by histology and CMR stress perfusion mapping. Histological evaluation indicates a complex pathophysiology, where in addition to systolic and diastolic dysfunction, amyloid infiltration of the epicardial arteries and disruption and rarefaction of the capillaries play a role in contributing to myocardial ischaemia.<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>
Chacko L, Kotecha T, Ioannou A, Patel N, ... Gillmore J, Fontana M
Eur J Heart Fail: 21 Jan 2024; epub ahead of print | PMID: 38247182
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<div><h4>Comprehensive assessment of immune context and immunotherapy response via noninvasive imaging in gastric cancer.</h4><i>Sun Z, Zhang T, Ahmad MU, Zhou Z, ... Li G, Jiang Y</i><br /><b>Background</b><br />The tumor immune microenvironment can provide prognostic and therapeutic information. We aimed to develop noninvasive imaging biomarkers from computed tomography (CT) for comprehensive evaluation of immune context, and investigate their associations with prognosis and immunotherapy response in gastric cancer (GC).<br /><b>Methods</b><br />This study involved 2,600 GC patients of nine independent cohorts. We developed and validated two CT imaging biomarkers [lymphoid radiomics score (LRS) and myeloid radiomics score (MRS)] for evaluating the immunohistochemistry (IHC)-derived lymphoid and myeloid immune context respectively, and then integrated them into a combined imaging biomarker [LRS/MRS: low(-) or high(+)] with four radiomics immune subtypes: 1(-/-), 2(+/-), 3(-/+), and 4(+/+). We further evaluated the imaging biomarkers\' predictive values on prognosis and immunotherapy response.<br /><b>Results</b><br />The developed imaging biomarkers (LRS and MRS) had a high accuracy in predicting lymphoid (AUC range: 0.765-0.773) and myeloid (AUC range: 0.736-0.750) immune context. Furthermore, same as IHC-derived immune context, two imaging biomarkers (HR range: 0.240-0.761 for LRS; 1.301-4.012 for MRS) and the combined biomarker were independent predictors for disease-free and overall survival in the training and all validation cohorts (all P<0.05). In addition, patient with high LRS or low MRS may benefit more from immunotherapy (P<0.001). Furthermore, a highly heterogeneous outcome on objective response rate was observed in four imaging subtypes: 1(-/-) with 27.3%, 2(+/-) with 53.3%, 3(-/+) with 10.2%, and 4(+/+) with 30.0% (P<0.0001).<br /><b>Conclusion</b><br />The noninvasive imaging biomarkers could accurately evaluate the immune context, and provide information regarding prognosis and immunotherapy for GC.<br /><b>Funding</b><br />None.<br /><br /><br /><br /><small>J Clin Invest: 25 Jan 2024; epub ahead of print</small></div>
Sun Z, Zhang T, Ahmad MU, Zhou Z, ... Li G, Jiang Y
J Clin Invest: 25 Jan 2024; epub ahead of print | PMID: 38271117
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<div><h4>Reducing Clustering of Readouts in Non-Cartesian CINE MRI.</h4><i>Goolaub DS, Macgowan CK</i><br /><b>Background</b><br />The use of non-Cartesian MRI trajectories at golden angle increments has the advantage of allowing retrospective motion correction and image-based gating using intermediate real-time reconstructions. However, when the acquired data is cardiac binned for CINE imaging, trajectories are found to cluster together at certain heart rates and leave large unsampled gaps in k-space, leading to image artifacts. In this work, we (1) demonstrate an approach to reduce clustering by inserting additional angular rotations periodically within the trajectory, and (2) optimize for these additional angles using particle swarm optimization while still allowing for important intermediate reconstructions.<br /><b>Methods</b><br />Three acquisition models were simulated under constant and variable heart rates: traditional golden angle (M<sub>trd</sub>), random additional angles (M<sub>rnd</sub>), and optimized additional angles (M<sub>opt</sub>). To analyze clustering, the standard deviation of the trajectory angular differences (STAD) was computed. The resulting distributions of STAD were compared through their interquartile ranges and the Kolmogorov-Smirnov test (significance level: p = 0.05). Agreement between a reference image reconstructed with uniform sampling and images obtained from M<sub>trd</sub>, M<sub>rnd</sub>, and M<sub>opt</sub> was analyzed by computing the structural similarity index measure (SSIM) and its interquartile range. M<sub>trd</sub> and M<sub>opt</sub> were then compared in 3 healthy adults at 3 levels of heart rate variability (high, low and none).<br /><b>Results</b><br />The STAD distributions from M<sub>trd</sub> were significantly different (p < 0.05) from those with the M<sub>opt</sub> and M<sub>rnd</sub>. The STAD (interquartile range x 10<sup>-2</sup>rad) showed that clustering was reduced with M<sub>opt</sub> (0.5) and M<sub>rnd</sub> (0.5) when compared to M<sub>trd</sub> (1.9) at constant heart rates. Similarly for variable heart rates, M<sub>opt</sub> (0.5) and M<sub>rnd</sub> (0.5) outperformed M<sub>trd</sub> (0.9). Risk for clustering was reduced with the proposed approach. The SSIM (interquartile range), relative to a ground truth reconstruction, showed that the best image quality was produced by M<sub>opt</sub> (0.011), followed by M<sub>rnd</sub> (0.014), and M<sub>trd</sub> (0.030), which produced the worst image quality. In-vivo studies showed that at reduced heart variability M<sub>opt</sub> outperformed M<sub>trd</sub> with reduced risk for clustering. In high heartrate variability, both models performed well.<br /><b>Conclusion</b><br />This approach reduces occurrences of clustering in k-space and improves resulting image quality without affecting acquisition time.<br /><br />Copyright © 2024. Published by Elsevier Inc.<br /><br /><small>J Cardiovasc Magn Reson: 28 Jan 2024:101003; epub ahead of print</small></div>
Goolaub DS, Macgowan CK
J Cardiovasc Magn Reson: 28 Jan 2024:101003; epub ahead of print | PMID: 38290615
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<div><h4>Combined Free-running 4D anatomical and flow MRI with native contrast using Synchronization of Neighboring Acquisitions by Physiological Signals (SyNAPS).</h4><i>Falcão MBL, Mackowiak ALC, Rossi GMC, Prša M, ... Stuber M, Roy CW</i><br /><b>Background</b><br />4D flow MRI often relies on the injection of gadolinium- or iron-oxide-based contrast agents to improve vessel delineation. In this work, a novel technique is developed to acquire and reconstruct 4D flow data with excellent dynamic visualization of blood vessels but without the need for contrast injection. Synchronization of Neighboring Acquisitions by Physiological Signals (SyNAPS) uses Pilot Tone (PT) navigation to retrospectively synchronize the reconstruction of two free-running 3D radial acquisitions, to create co-registered anatomy and flow images.<br /><b>Methods</b><br />Thirteen volunteers and two Marfan Syndrome patients were scanned without contrast agent using one free-running fast interrupted steady-state (FISS) sequence and one free-running phase-contrast MRI (PC-MRI) sequence. PT signals spanning the two sequences were recorded for retrospective respiratory motion correction and cardiac binning. The magnitude and phase images reconstructed, respectively, from FISS and PC-MRI, were synchronized to create SyNAPS 4D flow datasets. Conventional 2D flow data were acquired for reference in ascending (AAo) and descending aorta (DAo). The blood-to-myocardium contrast ratio, dynamic vessel area, net volume, and peak flow were used to compare SyNAPS 4D flow with Native 4D flow (without FISS information) and 2D flow. A score of 0-4 was given to each dataset by two blinded experts regarding the feasibility of performing vessel delineation.<br /><b>Results</b><br />Blood-to-myocardium contrast ratio for SyNAPS 4D flow magnitude images (1.5±0.3) was significantly higher than for Native 4D flow (0.7±0.1, p<0.01), and was comparable to 2D flow (2.3±0.9, p=0.02). Image quality scores of SyNAPS 4D flow from the experts (MP: 1.9±0.3, ET: 2.5±0.5) were overall significantly higher than the scores from Native 4D flow (MP: 1.6±0.6, p=0.03, ET: 0.8±0.4, p<0.01) but still significantly lower than the scores from the reference 2D flow datasets (MP: 2.8±0.4, p<0.01, ET: 3.5±0.7, p<0.01). The Pearson correlation coefficient between the dynamic vessel area measured on SyNAPS 4D flow and that from 2D flow was 0.69±0.24 for the AAo and 0.83±0.10 for the DAo, whereas the Pearson correlation between Native 4D flow and 2D flow measurements was 0.12±0.48 for the AAo and 0.08±0.39 for the DAo. Linear correlations between SyNAPS 4D flow and 2D flow measurements of net volume (r<sup>2</sup>=0.83) and peak flow (r<sup>2</sup>=0.87) were larger than the correlations between Native 4D flow and 2D flow measurements of net volume (r<sup>2</sup>=0.79) and peak flow (r<sup>2</sup>=0.76).<br /><b>Discussion and conclusion</b><br />The feasibility and utility of SyNAPS was demonstrated for joint whole-heart anatomical and flow MRI without requiring ECG gating, respiratory navigators, or contrast agents. Using SyNAPS a high-contrast anatomical imaging sequence can be used to improve 4D flow measurements that often suffer from poor delineation of vessel boundaries in the absence of contrast agents.<br /><br />Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.<br /><br /><small>J Cardiovasc Magn Reson: 01 Feb 2024:101006; epub ahead of print</small></div>
Falcão MBL, Mackowiak ALC, Rossi GMC, Prša M, ... Stuber M, Roy CW
J Cardiovasc Magn Reson: 01 Feb 2024:101006; epub ahead of print | PMID: 38309581
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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>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>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>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>The role of mitochondrial DNA copy number in cardiometabolic disease: a bidirectional two-sample mendelian randomization study.</h4><i>Qin P, Qin T, Liang L, Li X, ... Zhang M, Hu D</i><br /><b>Background</b><br />This study used a bidirectional 2-sample Mendelian randomization study to investigate the potential causal links between mtDNA copy number and cardiometabolic disease (obesity, hypertension, hyperlipidaemia, type 2 diabetes [T2DM], coronary artery disease [CAD], stroke, ischemic stroke, and heart failure).<br /><b>Methods</b><br />Genetic associations with mtDNA copy number were obtained from a genome-wide association study (GWAS) summary statistics from the UK biobank (n = 395,718) and cardio-metabolic disease were from largest available GWAS summary statistics. Inverse variance weighting (IVW) was conducted, with weighted median, MR-Egger, and MR-PRESSO as sensitivity analyses. We repeated this in the opposite direction using instruments for cardio-metabolic disease.<br /><b>Results</b><br />Genetically predicted mtDNA copy number was not associated with risk of obesity (P = 0.148), hypertension (P = 0.515), dyslipidemia (P = 0.684), T2DM (P = 0.631), CAD (P = 0.199), stroke (P = 0.314), ischemic stroke (P = 0.633), and heart failure (P = 0.708). Regarding the reverse directions, we only found that genetically predicted dyslipidemia was associated with decreased levels of mtDNA copy number in the IVW analysis (β= - 0.060, 95% CI - 0.044 to - 0.076; P = 2.416e-14) and there was suggestive of evidence for a potential causal association between CAD and mtDNA copy number (β= - 0.021, 95% CI - 0.003 to - 0.039; P = 0.025). Sensitivity and replication analyses showed the stable findings.<br /><b>Conclusions</b><br />Findings of this Mendelian randomization study did not support a causal effect of mtDNA copy number in the development of cardiometabolic disease, but found dyslipidemia and CAD can lead to reduced mtDNA copy number. These findings have implications for mtDNA copy number as a biomarker of dyslipidemia and CAD in clinical practice.<br /><br />© 2024. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 28 Jan 2024; 23:45</small></div>
Qin P, Qin T, Liang L, Li X, ... Zhang M, Hu D
Cardiovasc Diabetol: 28 Jan 2024; 23:45 | PMID: 38282013
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<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>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>Motion of VAPB molecules reveals ER-mitochondria contact site subdomains.</h4><i>Obara CJ, Nixon-Abell J, Moore AS, Riccio F, ... Blackstone C, Lippincott-Schwartz J</i><br /><AbstractText>To coordinate cellular physiology, eukaryotic cells rely on the rapid exchange of molecules at specialized organelle-organelle contact sites<sup>1,2</sup>. Endoplasmic reticulum-mitochondrial contact sites (ERMCSs) are particularly vital communication hubs, playing key roles in the exchange of signalling molecules, lipids and metabolites<sup>3,4</sup>. ERMCSs are maintained by interactions between complementary tethering molecules on the surface of each organelle<sup>5,6</sup>. However, due to the extreme sensitivity of these membrane interfaces to experimental perturbation<sup>7,8</sup>, a clear understanding of their nanoscale organization and regulation is still lacking. Here we combine three-dimensional electron microscopy with high-speed molecular tracking of a model organelle tether, Vesicle-associated membrane protein (VAMP)-associated protein B (VAPB), to map the structure and diffusion landscape of ERMCSs. We uncovered dynamic subdomains within VAPB contact sites that correlate with ER membrane curvature and undergo rapid remodelling. We show that VAPB molecules enter and leave ERMCSs within seconds, despite the contact site itself remaining stable over much longer time scales. This metastability allows ERMCSs to remodel with changes in the physiological environment to accommodate metabolic needs of the cell. An amyotrophic lateral sclerosis-associated mutation in VAPB perturbs these subdomains, likely impairing their remodelling capacity and resulting in impaired interorganelle communication. These results establish high-speed single-molecule imaging as a new tool for mapping the structure of contact site interfaces and reveal that the diffusion landscape of VAPB at contact sites is a crucial component of ERMCS homeostasis.</AbstractText><br /><br />© 2024. The Author(s).<br /><br /><small>Nature: 24 Jan 2024; epub ahead of print</small></div>
Obara CJ, Nixon-Abell J, Moore AS, Riccio F, ... Blackstone C, Lippincott-Schwartz J
Nature: 24 Jan 2024; epub ahead of print | PMID: 38267577
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Abstract
<div><h4>Deciphering cell states and genealogies of human hematopoiesis.</h4><i>Weng C, Yu F, Yang D, Poeschla M, ... Weissman JS, Sankaran VG</i><br /><AbstractText>The human blood system is maintained through the differentiation and massive amplification of a limited number of long-lived hematopoietic stem cells (HSCs)<sup>1</sup>. Perturbations to this process underlie diverse diseases, but the clonal contributions to human hematopoiesis and how this changes with age remain incompletely understood. While recent insights have emerged from barcoding studies in model systems<sup>4,5,16,17</sup>, simultaneous detection of cell states and phylogenies from natural barcodes in humans has been challenging. Here, we introduce an improved single-cell lineage tracing system based on deep detection of naturally-occurring mitochondrial DNA (mtDNA) mutations with simultaneous readout of transcriptional states and chromatin accessibility. We use this system to define the clonal architecture of HSCs and map the physiological state and output of clones. We uncover functional heterogeneity in HSC clones, which is stable over months and manifests as differences in total HSC output as well as biases toward the production of different mature cell types. We also find that the diversity of HSC clones decreases dramatically with age leading to an oligoclonal structure with multiple distinct clonal expansions. Our study thus provides the first clonally-resolved and cell-state aware atlas of human hematopoiesis at single-cell resolution revealing an unappreciated functional diversity of human HSC clones and more broadly paves the way for refined studies of clonal dynamics across a range of tissues in human health and disease.</AbstractText><br /><br />© 2024. The Author(s), under exclusive licence to Springer Nature Limited.<br /><br /><small>Nature: 22 Jan 2024; epub ahead of print</small></div>
Weng C, Yu F, Yang D, Poeschla M, ... Weissman JS, Sankaran VG
Nature: 22 Jan 2024; epub ahead of print | PMID: 38253266
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Abstract
<div><h4>The HIV capsid mimics karyopherin engagement of FG-nucleoporins.</h4><i>Dickson CF, Hertel S, Tuckwell AJ, Li N, ... Böcking T, Jacques DA</i><br /><AbstractText>HIV can infect non-dividing cells because the viral capsid can overcome the selective barrier of the nuclear pore complex and deliver the genome directly into the nucleus<sup>1,2</sup>. Remarkably, the intact HIV capsid is more than 1,000 times larger than the size limit prescribed by the diffusion barrier of the nuclear pore<sup>3</sup>. This barrier in the central channel of the nuclear pore is composed of intrinsically disordered nucleoporin domains enriched in phenylalanine-glycine (FG) dipeptides. Through multivalent FG interactions, cellular karyopherins and their bound cargoes solubilize in this phase to drive nucleocytoplasmic transport<sup>4</sup>. By performing an in vitro dissection of the nuclear pore complex, we show that a pocket on the surface of the HIV capsid similarly interacts with FG motifs from multiple nucleoporins and that this interaction licences capsids to penetrate FG-nucleoporin condensates. This karyopherin mimicry model addresses a key conceptual challenge for the role of the HIV capsid in nuclear entry and offers an explanation as to how an exogenous entity much larger than any known cellular cargo may be able to non-destructively breach the nuclear envelope.</AbstractText><br /><br />© 2024. The Author(s).<br /><br /><small>Nature: 24 Jan 2024; epub ahead of print</small></div>
Dickson CF, Hertel S, Tuckwell AJ, Li N, ... Böcking T, Jacques DA
Nature: 24 Jan 2024; epub ahead of print | PMID: 38267582
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Abstract
<div><h4>HIV-1 capsids enter the FG phase of nuclear pores like a transport receptor.</h4><i>Fu L, Weiskopf EN, Akkermans O, Swanson NA, ... Schwartz TU, Görlich D</i><br /><AbstractText>HIV-1 infection requires nuclear entry of the viral genome. Previous evidence suggests that this entry proceeds through nuclear pore complexes (NPCs), with the 120 × 60 nm capsid squeezing through an approximately 60-nm-wide central channel<sup>1</sup> and crossing the permeability barrier of the NPC. This barrier can be described as an FG phase<sup>2</sup> that is assembled from cohesively interacting phenylalanine-glycine (FG) repeats<sup>3</sup> and is selectively permeable to cargo captured by nuclear transport receptors (NTRs). Here we show that HIV-1 capsid assemblies can target NPCs efficiently in an NTR-independent manner and bind directly to several types of FG repeats, including barrier-forming cohesive repeats. Like NTRs, the capsid readily partitions into an in vitro assembled cohesive FG phase that can serve as an NPC mimic and excludes much smaller inert probes such as mCherry. Indeed, entry of the capsid protein into such an FG phase is greatly enhanced by capsid assembly, which also allows the encapsulated clients to enter. Thus, our data indicate that the HIV-1 capsid behaves like an NTR, with its interior serving as a cargo container. Because capsid-coating with trans-acting NTRs would increase the diameter by 10 nm or more, we suggest that such a \'self-translocating\' capsid undermines the size restrictions imposed by the NPC scaffold, thereby bypassing an otherwise effective barrier to viral infection.</AbstractText><br /><br />© 2024. The Author(s).<br /><br /><small>Nature: 24 Jan 2024; epub ahead of print</small></div>
Fu L, Weiskopf EN, Akkermans O, Swanson NA, ... Schwartz TU, Görlich D
Nature: 24 Jan 2024; epub ahead of print | PMID: 38267583
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Abstract
<div><h4>A dedicated hypothalamic oxytocin circuit controls aversive social learning.</h4><i>Osakada T, Yan R, Jiang Y, Wei D, ... Mar AC, Lin D</i><br /><AbstractText>To survive in a complex social group, one needs to know who to approach and, more importantly, who to avoid. In mice, a single defeat causes the losing mouse to stay away from the winner for weeks<sup>1</sup>. Here through a series of functional manipulation and recording experiments, we identify oxytocin neurons in the retrochiasmatic supraoptic nucleus (SOR<sup>OXT</sup>) and oxytocin-receptor-expressing cells in the anterior subdivision of the ventromedial hypothalamus, ventrolateral part (aVMHvl<sup>OXTR</sup>) as a key circuit motif for defeat-induced social avoidance. Before defeat, aVMHvl<sup>OXTR</sup> cells minimally respond to aggressor cues. During defeat, aVMHvl<sup>OXTR</sup> cells are highly activated and, with the help of an exclusive oxytocin supply from the SOR, potentiate their responses to aggressor cues. After defeat, strong aggressor-induced aVMHvl<sup>OXTR</sup> cell activation drives the animal to avoid the aggressor and minimizes future defeat. Our study uncovers a neural process that supports rapid social learning caused by defeat and highlights the importance of the brain oxytocin system in social plasticity.</AbstractText><br /><br />© 2024. The Author(s), under exclusive licence to Springer Nature Limited.<br /><br /><small>Nature: 24 Jan 2024; epub ahead of print</small></div>
Osakada T, Yan R, Jiang Y, Wei D, ... Mar AC, Lin D
Nature: 24 Jan 2024; epub ahead of print | PMID: 38267576
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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.