Topic: Journal Club Selection

Abstract
<div><h4>Effect of Gamification, Financial Incentives, or Both to Increase Physical Activity Among Patients at High Risk of Cardiovascular Events: The BE ACTIVE Randomized Controlled Trial.</h4><i>Fanaroff AC, Patel MS, Chokshi N, Coratti S, ... Small DS, Volpp KGM</i><br /><b>Background</b><br />Physical activity is associated with a lower risk of major adverse cardiovascular events, but few individuals achieve guideline-recommended levels of physical activity. Strategies informed by behavioral economics increase physical activity, but their longer-term effectiveness is uncertain. We sought to determine the effect of behaviorally designed gamification, loss-framed financial incentives, or their combination on physical activity compared with attention control over 12-month intervention and 6-month postintervention follow-up periods.<br /><b>Methods</b><br />Between May 2019 and January 2024, participants with clinical atherosclerotic cardiovascular disease or a 10-year risk of myocardial infarction, stroke, or cardiovascular death of ≥7.5% by the Pooled Cohort equation were enrolled in a pragmatic randomized clinical trial. Participants received a wearable device to track daily steps, established a baseline, selected a step goal increase, and were randomly assigned to control (n=151), behaviorally designed gamification (n=304), loss-framed financial incentives (n=302), or gamification+financial incentives (n=305). The primary outcome of the trial was the change in mean daily steps from baseline through the 12-month intervention period.<br /><b>Results</b><br />A total of 1062 patients (mean±SD age, 67±8; 61% female; 31% non-White) were enrolled. Compared with control subjects, participants had significantly greater increases in mean daily steps from baseline during the 12-month intervention in the gamification arm (adjusted difference, 538.0 [95% CI, 186.2-889.9]; <i>P</i>=0.0027), financial incentives arm (adjusted difference, 491.8 [95% CI, 139.6-844.1]; <i>P</i>=0.0062), and gamification+financial incentives arm (adjusted difference, 868.0 [95% CI, 516.3-1219.7]; <i>P</i><0.0001). During the 6-month follow-up, physical activity remained significantly greater in the gamification+financial incentives arm than in the control arm (adjusted difference, 576.2 [95% CI, 198.5-954]; <i>P</i>=0.0028), but it was not significantly greater in the gamification (adjusted difference, 459.8 [95% CI, 82.0-837.6]; <i>P</i>=0.0171) or financial incentives (adjusted difference, 327.9 [95% CI, -50.2 to 706]; <i>P</i>=0.09) arms after adjustment for multiple comparisons.<br /><b>Conclusions</b><br />Behaviorally designed gamification, loss-framed financial incentives, and the combination of both increased physical activity compared with control over a 12-month intervention period, with the largest effect in gamification+financial incentives. These interventions could be a useful component of strategies to reduce cardiovascular risk in high-risk patients.<br /><b>Registration</b><br />URL: https://clinicaltrials.gov; Unique Identifier: NCT03911141.<br /><br /><br /><br /><small>Circulation: 21 May 2024; 149:1639-1649</small></div>
Fanaroff AC, Patel MS, Chokshi N, Coratti S, ... Small DS, Volpp KGM
Circulation: 21 May 2024; 149:1639-1649 | PMID: 38583084
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<div><h4>Novel Role for Cardiolipin as a Target of Therapy to Mitigate Myocardial Injury Caused by Venoarterial Extracorporeal Membrane Oxygenation.</h4><i>Swain L, Bhave S, Qiao X, Reyelt L, ... Chin MT, Kapur NK</i><br /><b>Background</b><br />Cardiolipin is a mitochondrial-specific phospholipid that maintains integrity of the electron transport chain (ETC) and plays a central role in myocardial ischemia/reperfusion injury. Tafazzin is an enzyme that is required for cardiolipin maturation. Venoarterial extracorporeal membrane oxygenation (VA-ECMO) use to provide hemodynamic support for acute myocardial infarction has grown exponentially, is associated with poor outcomes, and is under active clinical investigation, yet the mechanistic effect of VA-ECMO on myocardial damage in acute myocardial infarction remains poorly understood. We hypothesized that VA-ECMO acutely depletes myocardial cardiolipin and exacerbates myocardial injury in acute myocardial infarction.<br /><b>Methods</b><br />We examined cardiolipin and tafazzin levels in human subjects with heart failure and healthy swine exposed to VA-ECMO and used a swine model of closed-chest myocardial ischemia/reperfusion injury to evaluate the effect of VA-ECMO on cardiolipin expression, myocardial injury, and mitochondrial function.<br /><b>Results</b><br />Cardiolipin and tafazzin levels are significantly reduced in the left ventricles of individuals requiring VA-ECMO compared with individuals without VA-ECMO before heart transplantation. Six hours of exposure to VA-ECMO also decreased left ventricular levels of cardiolipin and tafazzin in healthy swine compared with sham controls. To explore whether cardiolipin depletion by VA-ECMO increases infarct size, we performed left anterior descending artery occlusion for a total of 120 minutes followed by 180 minutes of reperfusion in adult swine in the presence and absence of MTP-131, an amphipathic molecule that interacts with cardiolipin to stabilize the inner mitochondrial membrane. Compared with reperfusion alone, VA-ECMO activation beginning after 90 minutes of left anterior descending artery occlusion increased infarct size (36±8% versus 48±7%; <i>P</i><0.001). VA-ECMO also decreased cardiolipin and tafazzin levels, disrupted mitochondrial integrity, reduced electron transport chain function, and promoted oxidative stress. Compared with reperfusion alone or VA-ECMO before reperfusion, delivery of MTP-131 before VA-ECMO activation reduced infarct size (22±8%; <i>P</i>=0.03 versus reperfusion alone and <i>P</i><0.001 versus VA-ECMO alone). MTP-131 restored cardiolipin and tafazzin levels, stabilized mitochondrial function, and reduced oxidative stress in the left ventricle.<br /><b>Conclusions</b><br />We identified a novel mechanism by which VA-ECMO promotes myocardial injury and further identify cardiolipin as an important target of therapy to reduce infarct size and to preserve mitochondrial function in the setting of VA-ECMO for acute myocardial infarction.<br /><br /><br /><br /><small>Circulation: 23 Apr 2024; 149:1341-1353</small></div>
Swain L, Bhave S, Qiao X, Reyelt L, ... Chin MT, Kapur NK
Circulation: 23 Apr 2024; 149:1341-1353 | PMID: 38235580
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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 EP</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: 01 Jun 2024; 35:110-116</small></div>
Raggi P, Becciu ML, Navarese EP
Curr Opin Lipidol: 01 Jun 2024; 35:110-116 | 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: 01 Jun 2024; 35:141-148</small></div>
Bay B, Arnold N, Waldeyer C
Curr Opin Lipidol: 01 Jun 2024; 35:141-148 | PMID: 38277208
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<div><h4>Reducing the risk of atherosclerotic cardiovascular disease in people with hemophilia: the importance of primary prevention.</h4><i>Dix C, Dolan G, Hunt BJ</i><br /><AbstractText>Revolutionary advances in the treatment of hemophilia has led to a significant improvement in life expectancy. Associated with this has been an increase in age-related diseases especially atherosclerotic cardiovascular disease (CVD). While people with hemophilia (PWH) develop atherosclerosis at rates similar to those of the general population, rates of atherothrombosis and mortality related to CVD have been much lower, due to their hypocoagulable state. Changing treatment paradigms, aimed at reducing the risk of bleeding by improving hemostasis to levels approaching normality, has meant that the protection they are thought to have had may be lost. CVD risk factors are just as common in PWH as in the general population, but appear to be undertreated. In particular, primary prevention of CVD is vital in all individuals, but particularly in PWH as treatment of established CVD can be difficult. Active identification and management of CVD risk factors, such as obesity, physical inactivity, hypertension, and hypercholesterolemia, is required. In particular, statins have been shown to significantly reduce cardiovascular and all-cause mortality with few adverse events and no increased risk of bleeding in the general population, and their use needs urgent assessment in PWH. Further longitudinal research into preventing CVD in PWH, including accurate CVD risk assessment, is required to optimize prevention and management.</AbstractText><br /><br />Copyright © 2024 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.<br /><br /><small>J Thromb Haemost: 01 May 2024; 22:1304-1312</small></div>
Dix C, Dolan G, Hunt BJ
J Thromb Haemost: 01 May 2024; 22:1304-1312 | PMID: 38309435
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<div><h4>PCSK9-directed therapies: an update.</h4><i>Katzmann JL, Laufs U</i><br /><b>Purpose of review</b><br />Two large cardiovascular outcomes trials of monoclonal antibodies against proprotein convertase subtilisin/kexin type 9 (PCSK9) demonstrated that therapeutic inhibition of extracellular PCSK9 markedly reduces LDL cholesterol concentration and cardiovascular risk. Several novel strategies to inhibit PCSK9 function are in development. Different mechanisms of action may determine specific properties with potential relevance for patient care.<br /><b>Recent findings</b><br />For the monoclonal antibodies evolocumab und alirocumab as first-generation PCSK9 inhibitors, follow-up data of up to 8 years of exposure complement the information on efficacy and safety available from outcome trials. For the small-interfering RNA inclisiran as second-generation PCSK9 inhibitor, several phase III trials have been published and a cardiovascular outcome trial has completed recruitment and is ongoing. Third-generation PCSK9 inhibitors encompass, among others, orally available drugs such as MK-0616 and the fusion protein lerodalcibep. Additional strategies to inhibit PCSK9 include vaccination and gene editing.<br /><b>Summary</b><br />Long-term inhibition of PCSK9 with monoclonal antibodies is safe and conveys sustained cardiovascular benefit. Novel strategies to inhibit PCSK9 function such as orally available drugs, RNA targeting, and one-time treatment with gene editing may further enhance the therapeutic armamentarium and enable novel preventive strategies.<br /><br />Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.<br /><br /><small>Curr Opin Lipidol: 01 Jun 2024; 35:117-125</small></div>
Katzmann JL, Laufs U
Curr Opin Lipidol: 01 Jun 2024; 35:117-125 | PMID: 38277255
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<div><h4>Minimally invasive epicardial surgical left atrial appendage exclusion for atrial fibrillation patients at high risk for stroke and for bleeding.</h4><i>Rose DZ, DiGiorgi P, Ramlawi B, Pulungan Z, Teigland C, Calkins H</i><br /><b>Background</b><br />Atrial fibrillation (AF) patients at high risk for stroke and for bleeding may be unsuitable for either oral anticoagulation or endocardial left atrial appendage (LAA) occlusion. However, minimally invasive, epicardial left atrial appendage exclusion (LAAE) may be an option.<br /><b>Objective</b><br />The purpose of this study was to evaluate outcomes of LAAE in high-risk AF patients not receiving oral anticoagulation.<br /><b>Methods</b><br />A retrospective analysis of Medicare claims data was conducted to evaluate thromboembolic events in AF patients who underwent LAAE compared to a 1:4 propensity score-matched group of patients who did not receive LAAE (control). Neither group was receiving any oral anticoagulation at baseline or follow-up. Fine-Gray models estimated hazard ratios and evaluated between-group differences. Bootstrapping was applied to generate 95% confidence intervals (CIs).<br /><b>Results</b><br />The LAAE group (n = 243) was 61% male (mean age 75 years). AF was nonparoxysmal in 70% (mean CHA<sub>2</sub>DS<sub>2</sub>-VASc score 5.4; mean HAS-BLED score 4.2). The matched control group (n = 972) had statistically similar characteristics. One-year adjusted estimates of thromboembolic events were 7.3% (95% CI 4.3%-11.1%) in the LAAE group and 12.1% (95% CI 9.5%-14.8%) in the control group. Absolute risk reduction was 4.8% (95% CI 0.6%-8.9%; P = .028). Adjusted hazard ratio for thromboembolic events for LAAE vs non-LAAE was 0.672 (95% CI 0.394-1.146).<br /><b>Conclusion</b><br />In AF patients not taking oral anticoagulation who are at high risk for stroke and for bleeding, minimally invasive, thoracoscopic, epicardial LAAE was associated with a lower rate of thromboembolic events.<br /><br />Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.<br /><br /><small>Heart Rhythm: 01 Jun 2024; 21:771-779</small></div>
Rose DZ, DiGiorgi P, Ramlawi B, Pulungan Z, Teigland C, Calkins H
Heart Rhythm: 01 Jun 2024; 21:771-779 | PMID: 38296011
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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 electrocardiographic (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 purposes of this study were to assess the accuracy of AW-HR measurements compared to gold standard modalities in children during sinus rhythm and arrhythmias and to identify non-sinus rhythms using AW-ECGs.<br /><b>Methods</b><br />Subjects ≤18 years wore an AW during (1) telemetry admission, (2) electrophysiological study (EPS), or (3) exercise stress test (EST). AW-HRs were compared to gold standard modality values. Recorded AW-ECGs were reviewed by 3 blinded pediatric electrophysiologists.<br /><b>Results</b><br />Eighty subjects (median age 13 years; interquartile range 1.0-16.0 years; 50% female) wore AW (telemetry 41% [n = 33]; EPS 34% [n = 27]; EST 25% [n = 20]). A total of 1090 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 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. A total of 126 AW-ECGs were reviewed. Identification of non-sinus rhythm by AW-ECG showed sensitivity of 89%-96% and 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 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.<br /><br /><small>Heart Rhythm: 01 May 2024; 21:581-589</small></div>
Nash D, Shah MJ, Shehab O, Jones AL, ... Vetter V, Janson C
Heart Rhythm: 01 May 2024; 21:581-589 | PMID: 38246569
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<div><h4>Atrial electrofunctional 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 />This study was designed to investigate the atrial electrofunctional predictors of incident AF in CA.<br /><b>Methods</b><br />A multicenter, observational study was conducted in 4 CA referral centers including sinus rhythm patients with light-chain (AL) and transthyretin (ATTR) CA undergoing electrocardiography and cardiac magnetic resonance imaging. The primary end point 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 months), 30 patients (29%) had incident AF. Compared with those without AF, patients with AF were older (79 vs 73 years; P = .001). They more frequently had ATTR (87% vs 45%; P < .001); electrocardiographic interatrial block (IAB), either partial (47% vs 21%; P = .011) or advanced (17% vs 3%; P = .017); and lower left atrial ejection fraction (LAEF; 29% vs 41%; P = .004). Age (hazard ratio [HR], 1.059; 95% CI, 1.002-1.118; P = .042), any type of IAB (HR, 2.211; 95% CI, 1.03-4.75; P = .041), and LAEF (HR, 0.967; 95% CI, 0.936-0.998; P = .044) emerged as independent predictors of incident AF. Patients exhibiting any type of IAB, LAEF <40%, and age >78 years showed a cumulative incidence for AF of 40% at 12 months. This risk was significantly higher than that carried by 1 (8.5%) or none (7.6%) of these 3 risk factors.<br /><b>Conclusion</b><br />In patients with CA, older age, IAB on 12-lead electrocardiography, and reduced LAEF on cardiac magnetic resonance imaging 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 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.<br /><br /><small>Heart Rhythm: 01 Jun 2024; 21:725-732</small></div>
Sinigiani G, De Michieli L, Porcari A, Zocchi C, ... Cappelli F, Cipriani A
Heart Rhythm: 01 Jun 2024; 21:725-732 | PMID: 38309449
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<div><h4>Biatrial 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 />The purpose of this study was to characterize atrial conduction and explore differences in the prevalence of conduction disorders, potential fractionation, and low-voltage areas (LVAs) between the RA and LA during sinus rhythm (SR) as indicators of potential arrhythmogenic areas.<br /><b>Methods</b><br />Intraoperative epicardial mapping of both atria during SR was performed in 15 HOCM patients (age 50 ± 12 years). Conduction delay (CD) and conductin block (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%] vs 2.6% [2.1%-6.4%], P = .541; CB: 1.7% [0.9%-3.1%] vs 1.5% [0.5%-2.8%], P = .600; LVA: 4.7% [1.6%-7.7%] vs 2.9% [2.1%-7.1%], P = .793). Compared to the RA, unipolar voltages of single potentials (SPs) and fractionated potentials (FPs) were higher in the LA (SP: P75 7.3 mV vs 10.9 mV; FP: P75 2.0 mV vs 3.7 mV). 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 biatrial substrate and high-voltage FP may contribute to failure of ablative therapy of atrial tachyarrhythmias in this population.<br /><br />Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.<br /><br /><small>Heart Rhythm: 01 Jun 2024; 21:819-827</small></div>
Ramdat Misier NL, Amesz JH, Taverne YJHJ, Nguyen H, ... Brundel BJJM, de Groot NMS
Heart Rhythm: 01 Jun 2024; 21:819-827 | PMID: 38246568
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<div><h4>Surgical Debulking of Large Ventricular Fibromas in Children.</h4><i>Gikandi A, Chiu P, Secor J, Nathan M, ... Beroukhim R, Del Nido P</i><br /><b>Objective</b><br />This study aims to provide an update on the clinical presentation, diagnostic work-up, operative strategies, and mid-term outcomes in children undergoing ventricular fibroma resection.<br /><b>Methods</b><br />Single-center, retrospective cohort study of patients undergoing ventricular fibroma resection between 2000 and 2023.<br /><b>Results</b><br />Among 52 patients, median age at surgery was 2.0 years (IQR 0.8-4.6) and median tumor volume index was 69 milliliters/m<sup>2</sup> (IQR 49-169). Tumor distorted the atrioventricular (AV) valve/subvalvar apparatus in 30 (58%) patients and abutted major epicardial coronary arteries in 41 (79%) patients. Surgery was indicated for arrythmia (n=45, 86%), symptoms (n=14, 27%), and/or hemodynamic compromise (n=11, 21%). Tumor was debulked in 34 (65%) patients, including the last 21 patients. Concomitant AV valvuloplasty was performed in 18 patients and ventricular cavity closure in 15 (29%) patients. During a median follow-up of 2.4 years (IQR 0.8-6.2), there was no mortality, cardiac arrests, heart transplants, or single ventricle palliation. The 15-year risk of reoperation and clinical ventricular tachycardia/fibrillation was 6.7% (95% CI 0-14.3%) and 2.4% (95% CI 0-7.2%), respectively. On latest imaging, pre- and post-debulking LV ejection fraction did not significantly differ (P=.069), while no patients had signs of outflow tract obstruction, inflow tract obstruction, or > moderate AV valve regurgitation.<br /><b>Conclusions</b><br />Large ventricular fibromas can be resected safely with appropriate surgical planning and an emphasis on debulking. Most children maintain left ventricular function and remain free of recurrent ventricular arrhythmias at follow-up. Extended follow-up is warranted to understand whether patients remain at risk for scar-based ventricular arrhythmias in the future.<br /><br />Copyright © 2024. Published by Elsevier Inc.<br /><br /><small>J Thorac Cardiovasc Surg: 25 May 2024; epub ahead of print</small></div>
Gikandi A, Chiu P, Secor J, Nathan M, ... Beroukhim R, Del Nido P
J Thorac Cardiovasc Surg: 25 May 2024; epub ahead of print | PMID: 38802044
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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 with increase in diagnostic and therapeutic angiography, and so, the less invasive percutaneous thrombin injection (PTI) is the most widely used treatment. 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</b><br />We evaluated PTI in terms 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 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 mostly led 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 of >240 mL/min.<br /><b>Conclusion</b><br />The thrombin injection site in a pseudoaneurysm significantly influences 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: 01 May 2024; 22:1389-1398</small></div>
Kim KW, Lee C, Im G, Kang HJ, ... Choi YH, Kim HH
J Thromb Haemost: 01 May 2024; 22:1389-1398 | 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. 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 (mean age 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). A LAmbre device was used and successfully implanted in 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 transesophageal echocardiography follow-up, and no device-related thrombus or peridevice leak > 3 mm was detected. None of the patients experienced stroke/transient ischemic attack, systemic embolism, or major bleeding events during a median follow-up of 147 days (interquartile range 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 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.<br /><br /><small>Heart Rhythm: 01 Jun 2024; 21:812-818</small></div>
Wang B, Chu H, Wang Z, Fu G, ... Feng M, Du X
Heart Rhythm: 01 Jun 2024; 21:812-818 | PMID: 38272283
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<div><h4>Mesoscopic mapping of hemodynamic responses and neuronal activity during pharmacologically induced interictal spikes in awake and anesthetized mice.</h4><i>Li J, Yang F, Zhan F, Estin J, ... Ma H, Schwartz TH</i><br /><AbstractText>Imaging hemodynamic responses to interictal spikes holds promise for presurgical epilepsy evaluations. Understanding the hemodynamic response function is crucial for accurate interpretation. Prior interictal neurovascular coupling data primarily come from anesthetized animals, impacting reliability. We simultaneously monitored calcium fluctuations in excitatory neurons, hemodynamics, and local field potentials (LFP) during bicuculline-induced interictal events in both isoflurane-anesthetized and awake mice. Isoflurane significantly affected LFP amplitude but had little impact on the amplitude and area of the calcium signal. Anesthesia also dramatically blunted the amplitude and latency of the hemodynamic response, although not its area of spread. Cerebral blood volume change provided the best spatial estimation of excitatory neuronal activity in both states. Targeted silencing of the thalamus in awake mice failed to recapitulate the impact of anesthesia on hemodynamic responses suggesting that isoflurane\'s interruption of the thalamocortical loop did not contribute either to the dissociation between the LFP and the calcium signal nor to the alterations in interictal neurovascular coupling. The blood volume increase associated with interictal spikes represents a promising mapping signal in both the awake and anesthetized states.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 01 Jun 2024; 44:911-924</small></div>
Li J, Yang F, Zhan F, Estin J, ... Ma H, Schwartz TH
J Cereb Blood Flow Metab: 01 Jun 2024; 44:911-924 | PMID: 38230631
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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, Abdul Kadir R, 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 deficiencies. The spectrum of molecular anomalies is broad, leading to several subtypes of fibrinogen disorders (ie, afibrinogenemia, hypofibrinogenemia, dysfibrinogenemia, and hypodysfibrinogenemia). Pregnancy in women with CFDs is a high-risk clinical situation, with an increased tendency for 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 International Society on Thrombosis and Haemostasis (ISTH) Scientific and Standardization Committee 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 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.<br /><br /><small>J Thromb Haemost: 01 May 2024; 22:1516-1521</small></div>
Casini A, Abdul Kadir R, Abdelwahab M, Manco-Johnson MJ, ... Santoro C, Acharya S
J Thromb Haemost: 01 May 2024; 22:1516-1521 | PMID: 38266678
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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 foetal to an adult CM state entails coordinated regulation of the expression of genes involved in myofibril formation and oxidative phosphorylation (OXPHOS) among others. Lysine demethylase 5 (KDM5) specifically demethylates H3K4me1/2/3 and has 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 post-natal CMs 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 2372 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 cleavage under targets and 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 the 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 gene expression, KDM5 inhibition increased oxygen consumption rate and contractility in iPSC-CMs.<br /><b>Conclusion</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: 07 May 2024; 120:630-643</small></div>
Deogharia M, Venegas-Zamora L, Agrawal A, Shi M, ... Marian AJ, Gurha P
Cardiovasc Res: 07 May 2024; 120:630-643 | PMID: 38230606
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<div><h4>Risk Factors and Outcomes Associated With Heart Failure With Preserved and Reduced Ejection Fraction in People With Chronic Kidney Disease.</h4><i>Bansal N, Zelnick LR, Scherzer R, Estrella M, Shlipak MG</i><br /><b>Background</b><br />Heart failure (HF) is associated with poor outcomes in people with chronic kidney disease, yet it is unknown whether outcomes differ by HF subtype. This study aimed to examine associations of incident HF with preserved ejection fraction (HFpEF) versus HF with reduced ejection fraction (HFrEF) with progression to end-stage kidney disease (ESKD) and mortality.<br /><b>Methods</b><br />We studied individuals with chronic kidney disease in the CRIC study (Chronic Renal Insufficiency Cohort) who were free of HF at cohort entry. Incident HF hospitalizations were adjudicated and classified into HFpEF (ejection fraction, ≥50%) or HFrEF (ejection fraction, <50%) based on echocardiograms performed during the hospitalization or at a research study visit. ESKD was defined as need for chronic dialysis or kidney transplant. Cox proportional hazards were used to evaluate the association of time-updated HF subtype with risk of ESKD and mortality, adjusting for demographics, comorbidities, and medication use.<br /><b>Results</b><br />Among the 3557 study participants without HF at cohort entry, mean age was 57 years and mean estimated glomerular filtration rate was 45 mL/min per 1.73 m<sup>2</sup>. A total of 682 participants had incident HF. Incidence rates for HFpEF and HFrEF were 0.9 (95% CI, 0.8-1.0) and 0.7 (95% CI, 0.6-0.8) per 100 person-years, respectively (<i>P</i><sub>difference</sub>=0.005). Associations of incident HF with progression to ESKD were not statistically different for HFpEF (hazard ratio, 2.06 [95% CI, 1.66-2.56]) and HFrEF (hazard ratio, 1.80 [95% CI, 1.36-2.38]; <i>P</i>=0.42). The associations with mortality were stronger for HFrEF (hazard ratio, 2.73 [95% CI, 2.24-3.33]) compared with HFpEF (hazard ratio, 1.99 [95% CI, 1.65-2.40]; <i>P</i>=0.0002).<br /><b>Conclusions</b><br />In a chronic kidney disease population, the rates of HFpEF hospitalizations were greater than that of HFrEF. Risk of ESKD was high but not statically different across HF subtypes. There was a stronger association of HFrEF with mortality. Prevention and treatment of both HFpEF and HFrEF should be central priorities to improve outcomes in chronic kidney disease.<br /><br /><br /><br /><small>Circ Heart Fail: 14 May 2024:e011173; epub ahead of print</small></div>
Bansal N, Zelnick LR, Scherzer R, Estrella M, Shlipak MG
Circ Heart Fail: 14 May 2024:e011173; epub ahead of print | PMID: 38742428
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<div><h4>A polygenic risk score added to a QRISK®2 cardiovascular disease risk calculator demonstrated robust clinical acceptance and clinical utility in the primary care setting.</h4><i>Fuat A, Adlen E, Monane M, Coll R, ... Harrison S, Donnelly P</i><br /><b>Aims</b><br />The aim of the study was to assess the real-world feasibility, acceptability, and impact of an integrated risk tool for cardiovascular disease (CVD IRT, combining the standard QRISK®2 risk algorithm with a polygenic risk score), implemented within routine primary practice in the UK National Health Service.<br /><b>Methods and results</b><br />The Healthcare Evaluation of Absolute Risk Testing Study (NCT05294419) evaluated participants undergoing primary care health checks. Both QRISK2 and CVD IRT scores were returned to the healthcare providers (HCPs), who then communicated the results to participants. The primary outcome of the study was feasibility of CVD IRT implementation. Secondary outcomes included changes in CVD risk (QRISK2 vs. CVD IRT) and impact of the CVD IRT on clinical decision-making. A total of 832 eligible participants (median age 55 years, 62% females, 97.5% White ethnicity) were enrolled across 12 UK primary care practices. Cardiovascular disease IRT scores were obtained on 100% of the blood samples. Healthcare providers stated that the CVD IRT could be incorporated into routine primary care in a straightforward manner in 90.7% of reports. Participants stated they were \'likely\' or \'very likely\' to recommend the use of this test to their family or friends in 86.9% of reports. Participants stated that the test was personally useful (98.8%) and that the results were easy to understand (94.6%). When CVD IRT exceeded QRISK2, HCPs planned changes in management for 108/388 (27.8%) of participants and 47% (62/132) of participants with absolute risk score changes of >2%.<br /><b>Conclusion</b><br />Amongst HCPs and participants who agreed to the trial of genetic data for refinement of clinical risk prediction in primary care, we observed that CVD IRT implementation was feasible and well accepted. The CVD IRT results were associated with planned changes in prevention strategies.<br /><br />© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Eur J Prev Cardiol: 18 Apr 2024; 31:716-722</small></div>
Fuat A, Adlen E, Monane M, Coll R, ... Harrison S, Donnelly P
Eur J Prev Cardiol: 18 Apr 2024; 31:716-722 | PMID: 38243727
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<div><h4>Hypertension Trends and Disparities Over 12 Years in a Large Health System: Leveraging the Electronic Health Records.</h4><i>Brush JE, Lu Y, Liu Y, Asher JR, ... Burrows JS, Krumholz HM</i><br /><b>Background</b><br />The digital transformation of medical data enables health systems to leverage real-world data from electronic health records to gain actionable insights for improving hypertension care.<br /><b>Methods and results</b><br />We performed a serial cross-sectional analysis of outpatients of a large regional health system from 2010 to 2021. Hypertension was defined by systolic blood pressure ≥140 mm Hg, diastolic blood pressure ≥90 mm Hg, or recorded treatment with antihypertension medications. We evaluated 4 methods of using blood pressure measurements in the electronic health record to define hypertension. The primary outcomes were age-adjusted prevalence rates and age-adjusted control rates. Hypertension prevalence varied depending on the definition used, ranging from 36.5% to 50.9% initially and increasing over time by ≈5%, regardless of the definition used. Control rates ranged from 61.2% to 71.3% initially, increased during 2018 to 2019, and decreased during 2020 to 2021. The proportion of patients with a hypertension diagnosis ranged from 45.5% to 60.2% initially and improved during the study period. Non-Hispanic Black patients represented 25% of our regional population and consistently had higher prevalence rates, higher mean systolic and diastolic blood pressure, and lower control rates compared with other racial and ethnic groups.<br /><b>Conclusions</b><br />In a large regional health system, we leveraged the electronic health record to provide real-world insights. The findings largely reflected national trends but showed distinctive regional demographics and findings, with prevalence increasing, one-quarter of the patients not controlled, and marked disparities. This approach could be emulated by regional health systems seeking to improve hypertension care.<br /><br /><br /><br /><small>J Am Heart Assoc: 30 Apr 2024:e033253; epub ahead of print</small></div>
Brush JE, Lu Y, Liu Y, Asher JR, ... Burrows JS, Krumholz HM
J Am Heart Assoc: 30 Apr 2024:e033253; epub ahead of print | PMID: 38686864
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<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>Background</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 were 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>Conclusions</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 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>J Heart Lung Transplant: 01 May 2024; 43:816-825</small></div>
Wright LK, Gajarski RJ, Hayes E, Parekh H, Yester JW, Nandi D
J Heart Lung Transplant: 01 May 2024; 43:816-825 | PMID: 38232791
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<div><h4>Incidence, Outcomes, and Opportunity for Left Ventricular Assist Device Weaning for Myocardial Recovery.</h4><i>Itagaki S, Moss N, Toyoda N, Mancini D, ... Adams DH, Anyanwu AC</i><br /><b>Background</b><br />Myocardial recovery occurs in patients with advanced heart failure on left ventricular assist device (LVAD) support, but there is the premise that it is rare with uncertain results.<br /><b>Objectives</b><br />The goal of this study was to investigate the incidence and consequence of LVAD explant after myocardial recovery.<br /><b>Methods</b><br />Using the United Network for Organ Sharing registry, LVAD implants in the United States between 2005 and 2020 were tracked until death, transplantation, or explant for myocardial recovery. The cohort undergoing explant was followed up for heart failure relapse (defined as relisting followed by delisting due to death, being too ill, or transplantation; or second durable LVAD implant).<br /><b>Results</b><br />Of 15,728 LVAD implants, 126 patients underwent explant for recovery, which only occurred in 55 (38%) of 145 implanting centers. The crude cumulative incidence was 0.7% at 2 years, whereas the incidence reached 4.7% among designated centers in the selected young nonischemic cohort. Of 126 explanted patients, 76 (60%) were subsequently delisted for sustained recovery. Heart failure relapsing had a relatively higher hazard in the early phase, with a 30-day incidence of 6% (7 of 126) but tapered following with the freedom rate of 72.5% at 4 years.<br /><b>Conclusions</b><br />In the United States, LVAD explant for myocardial recovery was underutilized, leading to a very low incidence at the national level despite a realistic rate being achieved in designated centers for selected patients. With follow-up extending up to 4 years after explant, more than one-half were successfully removed and stayed off the waitlist, and approximately 70% were free from heart failure relapse events.<br /><br />Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 May 2024; 12:893-901</small></div>
Itagaki S, Moss N, Toyoda N, Mancini D, ... Adams DH, Anyanwu AC
JACC Heart Fail: 01 May 2024; 12:893-901 | PMID: 38276935
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<div><h4>Density-based lipoprotein depletion improves extracellular vesicle isolation and functional analysis.</h4><i>Merij LB, da Silva LR, Palhinha L, Gomes MT, ... de Oliveira Trugilho MR, Hottz ED</i><br /><b>Background</b><br />Blood plasma is the main source of extracellular vesicles (EVs) in clinical studies aiming to identify biomarkers and to investigate pathophysiological processes, especially regarding EV roles in inflammation and thrombosis. However, EV isolation from plasma has faced the fundamental issue of lipoprotein contamination, representing an important bias since lipoproteins are highly abundant and modulate cell signaling, metabolism, and thromboinflammation.<br /><b>Objectives</b><br />Here, we aimed to isolate plasma EVs after depleting lipoproteins, thereby improving sample purity and EV thromboinflammatory analysis.<br /><b>Methods</b><br />Density-based gradient ultracentrifugation (G-UC) was used for lipoprotein depletion before EV isolation from plasma through size-exclusion chromatography (SEC) or serial centrifugation (SC). Recovered EVs were analyzed by size, concentration, cellular source, ultrastructure, and bottom-up proteomics.<br /><b>Results</b><br />G-UC efficiently separated lipoproteins from the plasma, allowing subsequent EV isolation through SEC or SC. Combined analysis from EV proteomics, cholesterol quantification, and apoB-100 detection confirmed the significant reduction in lipoproteins from isolated EVs. Proteomic analysis identified similar gene ontology and cellular components in EVs, regardless of lipoprotein depletion, which was consistent with similar EV cellular sources, size, and ultrastructure by flow cytometry and transmission electron microscopy. Importantly, lipoprotein depletion increased the detection of less abundant proteins in EV proteome and enhanced thromboinflammatory responses of platelets and monocytes stimulated in vitro with EV isolates.<br /><b>Conclusion</b><br />Combination of G-UC+SEC significantly reduced EV lipoprotein contamination without interfering in EV cellular source, gene ontology, and ultrastructure, allowing the recovery of highly pure EVs with potential implications for functional assays and proteomic and lipidomic analyses.<br /><br />Copyright © 2024 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.<br /><br /><small>J Thromb Haemost: 01 May 2024; 22:1372-1388</small></div>
Merij LB, da Silva LR, Palhinha L, Gomes MT, ... de Oliveira Trugilho MR, Hottz ED
J Thromb Haemost: 01 May 2024; 22:1372-1388 | PMID: 38278418
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<div><h4>A new look at an old body: molecular determinants of Weibel-Palade body composition and von Willebrand factor exocytosis.</h4><i>Hordijk S, Carter T, Bierings R</i><br /><AbstractText>Endothelial cells, forming a monolayer along blood vessels, intricately regulate vascular hemostasis, inflammatory responses, and angiogenesis. A key determinant of these functions is the controlled secretion of Weibel-Palade bodies (WPBs), which are specialized endothelial storage organelles housing a presynthesized pool of the hemostatic protein von Willebrand factor and various other hemostatic, inflammatory, angiogenic, and vasoactive mediators. This review delves into recent mechanistic insights into WPB biology, including the biogenesis that results in their unique morphology, the acquisition of intraluminal vesicles and other cargo, and the contribution of proton pumps to organelle acidification. Additionally, in light of a number of proteomic approaches to unravel the regulatory networks that control WPB formation and secretion, we provide a comprehensive overview of the WPB exocytotic machinery, including their molecular and cellular mechanisms.</AbstractText><br /><br />Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.<br /><br /><small>J Thromb Haemost: 01 May 2024; 22:1290-1303</small></div>
Hordijk S, Carter T, Bierings R
J Thromb Haemost: 01 May 2024; 22:1290-1303 | PMID: 38307391
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<div><h4>Long-term simulated microgravity fosters carotid aging-like changes via Piezo1.</h4><i>Zhang J, Wang X, Fu Z, Xing C, ... Li J, Gao F</i><br /><b>Aims</b><br />Elucidating the impacts of long-term spaceflight on cardiovascular health is urgently needed in face of the rapid development of human space exploration. Recent reports including the NASA Twins Study on vascular deconditioning and aging of astronauts in spaceflight are controversial. The aims of this study were to elucidate whether long-term microgravity promotes vascular aging and the underlying mechanisms.<br /><b>Methods and results</b><br />Hindlimb unloading (HU) by tail suspension was used to simulate microgravity in rats and mice. The dynamic changes of carotid stiffness in rats during 8 weeks of HU were determined. Simulated microgravity led to carotid artery aging-like changes as evidenced by increased stiffness, thickness, fibrosis, and elevated senescence biomarkers in the HU rats. Specific deletion of the mechanotransducer Piezo1 in vascular smooth muscles significantly blunted these aging-like changes in mice. Mechanistically, mechanical stretch-induced activation of Piezo1 elevated microRNA-582-5p in vascular smooth muscle cells, with resultant enhanced synthetic cell phenotype and increased collagen deposition via PTEN/PI3K/Akt signalling. Importantly, inhibition of miRNA-582-5p alleviated carotid fibrosis and stiffness not only in HU rats but also in aged rats.<br /><b>Conclusions</b><br />Long-term simulated microgravity induces carotid aging-like changes via the mechanotransducer Piezo1-initiated and miRNA-mediated mechanism.<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: 30 Apr 2024; 120:548-559</small></div>
Zhang J, Wang X, Fu Z, Xing C, ... Li J, Gao F
Cardiovasc Res: 30 Apr 2024; 120:548-559 | PMID: 38271270
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<div><h4>Histone content, and thus DNA content, is associated with differential in vitro lysis of acute ischemic stroke clots.</h4><i>Akkipeddi SMK, Rahmani R, Ellens NR, Kohli GS, ... Morrell CN, Bender MT</i><br /><b>Background</b><br />Fibrin, von Willebrand factor, and extracellular DNA from neutrophil extracellular traps all contribute to acute ischemic stroke thrombus integrity.<br /><b>Objectives</b><br />In this study, we explored how the proteomic composition of retrieved thromboemboli relates to susceptibility to lysis with distinct thrombolytics.<br /><b>Methods</b><br />Twenty-six retrieved stroke thromboemboli were portioned into 4 segments, with each subjected to 1 hour of in vitro lysis at 37 °C in 1 of 4 solutions: tissue plasminogen activator (tPA), tPA + von Willebrand factor-cleaving ADAMTS-13, tPA + DNA-cleaving deoxyribonuclease (DNase) I, and all 3 enzymes. Lysis, characterized by the percent change in prelysis and postlysis weight, was compared across the solutions and related to the corresponding abundance of proteins identified on mass spectrometry for each of the thromboemboli used in lysis.<br /><b>Results</b><br />Solutions containing DNase resulted in approximately 3-fold greater thrombolysis than that with the standard-of-care tPA solution (post hoc Tukey, P < .01 for all). DNA content was directly related to lysis in solutions containing DNase (Spearman\'s ρ > 0.39 and P < .05 for all significant histones) and inversely related to lysis in solutions without DNase (Spearman\'s ρ < -0.40 and P < .05 for all significant histones). Functional analysis suggests distinct pathways associated with susceptibility to thrombolysis with tPA (platelet-mediated) or DNase (innate immune system-mediated).<br /><b>Conclusion</b><br />This study demonstrates synergy of DNase and tPA in thrombolysis of stroke emboli and points to DNase as a potential adjunct to our currently limited selection of thrombolytics in treating acute ischemic stroke.<br /><br />Copyright © 2024 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.<br /><br /><small>J Thromb Haemost: 01 May 2024; 22:1410-1420</small></div>
Akkipeddi SMK, Rahmani R, Ellens NR, Kohli GS, ... Morrell CN, Bender MT
J Thromb Haemost: 01 May 2024; 22:1410-1420 | PMID: 38296159
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<div><h4>Prothrombin conversion and thrombin decay in patients with cirrhosis-role of prothrombin and antithrombin deficiencies.</h4><i>Sinegre T, Abergel A, Lecompte T, Lebreton A</i><br /><b>Background</b><br />Thrombin generation (TG) in the presence of thrombomodulin (TG-TM) in the plasma of patients with cirrhosis (PWC) is tilted toward a hypercoagulable phenotype. Low protein C and elevated factor VIII levels play a role, but other determinants, such as the prothrombin/antithrombin pair, must also be studied.<br /><b>Objectives</b><br />The objectives were (i) to quantitatively assess the subprocesses (prothrombin conversion and thrombin decay) and (ii) to understand the underlying mechanism by studying TG dynamics after prothrombin and antithrombin plasma level correction in PWC.<br /><b>Methods</b><br />We studied TG-TM in plasma samples of 36 healthy controls (HCs) and 41 PWC with prothrombin and antithrombin levels of <70% and after their correction. We initiated coagulation with an intermediate picomolar concentration of tissue factor. We determined the overall thrombin potential, prothrombin conversion, and thrombin decay.<br /><b>Results</b><br />TG-TM was increased in PWC compared with HC due to impaired thrombin inhibition. Indeed, thrombin decay capacity (min<sup>-1</sup>) decreased from 0.37 (0.35-0.40) in HC to 0.33 (0.30-0.37) in the Child-Turcotte-Pugh A (CTP-A; P = .09), 0.27 (0.26-0.30) in the CTP-B (P < .001), and 0.20 (0.19-0.20) in the CTP-C (P < .001) group. Concomitant correction of prothrombin and antithrombin increased endogenous thrombin potential with prothrombin conversion surpassing thrombin decay. By contrast, when we corrected only antithrombin, TG-TM was normalized and even consistent with a hypocoagulable phenotype in the CTP-C group.<br /><b>Conclusion</b><br />Our results highlight that in PWC, hypercoagulability (evidenced in the presence of TM) is due to impaired thrombin decay, whereas low prothrombin levels do not translate into decreased prothrombin conversion, likely due to altered TM-activated protein C negative feedback.<br /><br />Copyright © 2024 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.<br /><br /><small>J Thromb Haemost: 01 May 2024; 22:1347-1357</small></div>
Sinegre T, Abergel A, Lecompte T, Lebreton A
J Thromb Haemost: 01 May 2024; 22:1347-1357 | PMID: 38309434
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<div><h4>NCAM mimetic peptide P2 synergizes with bone marrow mesenchymal stem cells in promoting functional recovery after stroke.</h4><i>Lan XY, Liang XS, Cao MX, Qin HM, ... Boltze J, Li S</i><br /><AbstractText>The neural cell adhesion molecule (NCAM) promotes neural development and regeneration. Whether NCAM mimetic peptides could synergize with bone marrow mesenchymal stem cells (BMSCs) in stroke treatment deserves investigation. We found that the NCAM mimetic peptide P2 promoted BMSC proliferation, migration, and neurotrophic factor expression, protected neurons from oxygen-glucose deprivation through ERK and PI3K/AKT activation and anti-apoptotic mechanisms <i>in vitro</i>. Following middle cerebral artery occlusion (MCAO) in rats, P2 alone or in combination with BMSCs inhibited neuronal apoptosis and induced the phosphorylation of ERK and AKT. P2 combined with BMSCs enhanced neurotrophic factor expression and BMSC proliferation in the ischemic boundary zone. Moreover, combined P2 and BMSC therapy induced translocation of nuclear factor erythroid 2-related factor, upregulated heme oxygenase-1 expression, reduced infarct volume, and increased functional recovery as compared to monotreatments. Treatment with LY294002 (PI3K inhibitor) and PD98059 (ERK inhibitor) decreased the neuroprotective effects of combined P2 and BMSC therapy in MCAO rats. Collectively, P2 is neuroprotective while P2 and BMSCs work synergistically to improve functional outcomes after ischemic stroke, which may be attributed to mechanisms involving enhanced BMSC proliferation and neurotrophic factor release, anti-apoptosis, and PI3K/AKT and ERK pathways activation.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 01 Jul 2024; 44:1128-1144</small></div>
Lan XY, Liang XS, Cao MX, Qin HM, ... Boltze J, Li S
J Cereb Blood Flow Metab: 01 Jul 2024; 44:1128-1144 | PMID: 38230663
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Abstract
<div><h4>Vitamin D deficiency promotes intracranial aneurysm rupture.</h4><i>Kimura T, Rahmani R, Miyamoto T, Kamio Y, ... Lawton MT, Hashimoto T</i><br /><AbstractText>Intracranial aneurysm rupture causes severe disability and high mortality. Epidemiological studies show a strong association between decreased vitamin D levels and an increase in aneurysm rupture. However, the causality and mechanism remain largely unknown. In this study, we tested whether vitamin D deficiency promotes aneurysm rupture and examined the underlying mechanism for the protective role of vitamin D against the development of aneurysm rupture utilizing a mouse model of intracranial aneurysm. Mice consuming a vitamin D-deficient diet had a higher rupture rate than mice with a regular diet. Vitamin D deficiency increased proinflammatory cytokines in the cerebral arteries. Concurrently, vitamin D receptor knockout mice had a higher rupture rate than the corresponding wild-type littermates. The vitamin D receptors on endothelial and vascular smooth muscle cells, but not on hematopoietic cells, mediated the effect of aneurysm rupture. Our results establish that vitamin D protects against the development of aneurysmal rupture through the vitamin D receptors on vascular endothelial and smooth muscle cells. Vitamin D supplementation may be a viable pharmacologic therapy for preventing aneurysm rupture.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 01 Jul 2024; 44:1174-1183</small></div>
Kimura T, Rahmani R, Miyamoto T, Kamio Y, ... Lawton MT, Hashimoto T
J Cereb Blood Flow Metab: 01 Jul 2024; 44:1174-1183 | PMID: 38241458
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