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Abstract

Four versus six cycles of CHOP chemotherapy in combination with six applications of rituximab in patients with aggressive B-cell lymphoma with favourable prognosis (FLYER): a randomised, phase 3, non-inferiority trial.

Poeschel V, Held G, Ziepert M, Witzens-Harig M, ... ,
Background
Six cycles of R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) are the standard treatment for aggressive B-cell non-Hodgkin lymphoma. In the FLYER trial, we assessed whether four cycles of CHOP plus six applications of rituximab are non-inferior to six cycles of R-CHOP in a population of patients with B-cell non-Hodgkin lymphoma with favourable prognosis.
Methods
This two-arm, open-label, international, multicentre, prospective, randomised phase 3 non-inferiority trial was done at 138 clinical sites in Denmark, Israel, Italy, Norway, and Germany. We enrolled patients aged 18-60 years, with stage I-II disease, normal serum lactate dehydrogenase concentration, ECOG performance status 0-1, and without bulky disease (maximal tumour diameter <7·5 cm). Randomisation was computer-based and done centrally in a 1:1 ratio using the Pocock minimisation algorithm after stratification for centres, stage (I vs II), and extralymphatic sites (no vs yes). Patients were assigned to receive either six cycles of R-CHOP or four cycles of R-CHOP plus two doses of rituximab. CHOP comprised cyclophosphamide (750 mg/m), doxorubicin (50 mg/m), and vincristine (1·4 mg/m, with a maximum total dose of 2 mg), all administered intravenously on day 1, plus oral prednisone or prednisolone at the discretion of the investigator (100 mg) administered on days 1-5. Rituximab was given at a dose of 375 mg/m of body surface area. Cycles were repeated every 21 days. No radiotherapy was planned except for testicular lymphoma treatment. The primary endpoint was progression-free survival after 3 years. The primary analysis was done in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of assigned treatment. A non-inferiority margin of -5·5% was chosen. The trial, which is completed, was prospectively registered at ClinicalTrials.gov, NCT00278421.
Findings
Between Dec 2, 2005, and Oct 7, 2016, 592 patients were enrolled, of whom 295 patients were randomly assigned to receive six cycles of R-CHOP and 297 were assigned to receive four cycles of R-CHOP plus two doses of rituximab. Four patients in the four-cycles group withdrew informed consent before the start of treatment, so 588 patients were included in the intention-to-treat analysis. After a median follow-up of 66 months (IQR 42-100), 3-year progression-free survival of patients who had four cycles of R-CHOP plus two doses of rituximab was 96% (95% CI 94-99), which was 3% better (lower limit of the one-sided 95% CI for the difference was 0%) than six cycles of R-CHOP, demonstrating the non-inferiority of the four-cycles regimen. 294 haematological and 1036 non-haematological adverse events were documented in the four-cycles group compared with 426 haematological and 1280 non-haematological adverse events in the six-cycles group. Two patients, both in the six-cycles group, died during study therapy.
Interpretation
In young patients with aggressive B-cell non-Hodgkin lymphoma and favourable prognosis, four cycles of R-CHOP is non-inferior to six cycles of R-CHOP, with relevant reduction of toxic effects. Thus, chemotherapy can be reduced without compromising outcomes in this population.
Funding
Deutsche Krebshilfe.

Copyright © 2019 Elsevier Ltd. All rights reserved.

Lancet: 20 Dec 2020; 394:2271-2281
Poeschel V, Held G, Ziepert M, Witzens-Harig M, ... ,
Lancet: 20 Dec 2020; 394:2271-2281 | PMID: 31868632
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Abstract

Penetrance of Hypertrophic Cardiomyopathy in Sarcomere Protein Mutation Carriers.

Lorenzini M, Norrish G, Field E, Ochoa JP, ... Kaski JP, Elliott PM
Background
Predictive genetic screening of relatives of patients with hypertrophic cardiomyopathy (HCM) caused by sarcomere protein (SP) gene mutations is current standard of care, but there are few data on long-term outcomes in mutation carriers without HCM.
Objectives
The aim of this study was to determine the incidence of new HCM diagnosis in SP mutation carriers.
Methods
This was a retrospective analysis of adult and pediatric SP mutation carriers identified during family screening who did not fulfill diagnostic criteria for HCM at first evaluation.
Results
The authors evaluated 285 individuals from 156 families (median age 14.2 years [interquartile range: 6.8 to 31.6 years], 141 [49.5%] male individuals); 145 (50.9%) underwent cardiac magnetic resonance (CMR). Frequency of causal genes was as follows: MYBPC3 n = 123 (43.2%), MYH7 n = 69 (24.2%), TNNI3 n = 39 (13.7%), TNNT2 n = 34 (11.9%), TPM1 n = 9 (3.2%), MYL2 n = 6 (2.1%), ACTC1 n = 1 (0.4%), multiple mutations n = 4 (1.4%). Median follow-up was 8.0 years (interquartile range: 4.0 to 13.3 years) and 86 (30.2%) patients developed HCM; 16 of 50 (32.0%) fulfilled diagnostic criteria on CMR but not echocardiography. Estimated HCM penetrance at 15 years of follow-up was 46% (95% confidence interval [CI]: 38% to 54%). In a multivariable model adjusted for age and stratified for CMR, independent predictors of HCM development were male sex (hazard ratio [HR]: 2.91; 95% CI: 1.82 to 4.65) and abnormal electrocardiogram (ECG) (HR: 4.02; 95% CI: 2.51 to 6.44); TNNI3 variants had the lowest risk (HR: 0.19; 95% CI: 0.07 to 0.55, compared to MYBPC3).
Conclusions
Following a first negative screening, approximately 50% of SP mutation carriers develop HCM over 15 years of follow-up. Male sex and an abnormal ECG are associated with a higher risk of developing HCM. Regular CMR should be considered in long-term screening.

Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 03 Aug 2020; 76:550-559
Lorenzini M, Norrish G, Field E, Ochoa JP, ... Kaski JP, Elliott PM
J Am Coll Cardiol: 03 Aug 2020; 76:550-559 | PMID: 32731933
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Abstract

Transcatheter Valve-in-Valve Aortic Valve Replacement as an Alternative to Surgical Re-Replacement.

Deharo P, Bisson A, Herbert J, Lacour T, ... Cuisset T, Fauchier L
Background
Valve-in-valve (VIV) transcatheter aortic valve replacement (TAVR) and redo surgical aortic valve replacement (SAVR) represent the 2 treatments for aortic bioprosthesis failure. Clinical comparison of both therapies remains limited by the number of patients analyzed.
Objectives
The purpose of this study was to analyze the outcomes of VIV TAVR versus redo SAVR at a nationwide level in France.
Methods
Based on the French administrative hospital-discharge database, the study collected information for patients treated for aortic bioprosthesis failure with isolated VIV TAVR or redo SAVR between 2010 and 2019. Propensity score matching was used for the analysis of outcomes.
Results
A total of 4,327 patients were found in the database. After matching on baseline characteristics, 717 patients were analyzed in each arm. At 30 days, VIV TAVR was associated with lower rates of the composite of all-cause mortality, all-cause stroke, myocardial infarction, and major or life-threatening bleeding (odds ratio: 0.62; 95% confidence interval: 0.44 to 0.88; p = 0.03). During follow-up (median 516 days), the combined endpoint of cardiovascular death, all-cause stroke, myocardial infarction, or rehospitalization for heart failure was not different between the 2 groups (odds ratio: 1.18; 95% confidence interval: 0.99 to 1.41; p = 0.26). Rehospitalization for heart failure and pacemaker implantation were more frequently reported in the VIV TAVR group. A time-dependent interaction between all-cause and cardiovascular mortality following VIV TAVR was reported (p-interaction <0.05).
Conclusions
VIV TAVR was observed to be associated with better short-term outcomes than redo SAVR. Major cardiovascular outcomes were not different between the 2 treatments during long-term follow-up.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 03 Aug 2020; 76:489-499
Deharo P, Bisson A, Herbert J, Lacour T, ... Cuisset T, Fauchier L
J Am Coll Cardiol: 03 Aug 2020; 76:489-499 | PMID: 32731926
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Abstract

Effect of Sacubitril/Valsartan on Biomarkers of Extracellular Matrix Regulation in Patients With HFpEF.

Cunningham JW, Claggett BL, O\'Meara E, Prescott MF, ... Solomon SD, Zile MR
Background
Myocardial fibrosis may contribute to the pathophysiology of heart failure with preserved ejection fraction. Given the biochemical targets of sacubitril/valsartan, this study hypothesized that circulating biomarkers reflecting the mechanisms that determine extracellular matrix homeostasis are altered by sacubitril/valsartan compared with valsartan alone.
Objectives
This study investigated the effects of sacubitril/valsartan on biomarkers of extracellular matrix homeostasis and the association between biomarkers and the primary endpoint (total heart failure hospitalizations and cardiovascular death).
Methods
N-terminal propeptide of collagen I and III, tissue inhibitor of matrix metalloproteinase 1, carboxyl-terminal telopeptide of collagen type I, and soluble ST2 were measured at baseline (n = 1,135) and 16 (n = 1,113) and 48 weeks (n = 1,016) after randomization. The effects of sacubitril/valsartan on these biomarkers were compared with those of valsartan alone. Baseline biomarker values and changes from baseline to 16 weeks were related to primary endpoint.
Results
At baseline, all 5 biomarkers were higher than published referent control values. Sixteen weeks after randomization, sacubitril/valsartan decreased tissue inhibitor of matrix metalloproteinase 1 by 8% (95% confidence interval [CI]: 6% to 10%; p < 0.001), soluble ST2 by 4% (95% CI: 1% to 7%; p = 0.002), and N-terminal propeptide of collagen III by 3% (95% CI: 0% to 6%; p = 0.04) and increased carboxyl-terminal telopeptide of collagen type I by 4% (95% CI: 1% to 8%; p = 0.02) compared with valsartan alone, consistently in men and women and patients with left ventricular ejection fraction above or below the median of 57%. Higher levels of tissue inhibitor of matrix metalloproteinase 1 and soluble ST2 at baseline and increases in these markers at 16 weeks were associated with higher primary endpoint event rates.
Conclusions
Biomarkers reflecting extracellular matrix homeostasis are elevated in heart failure with preserved ejection fraction, favorably altered by sacubitril/valsartan, and have important prognostic value. (Prospective Comparison of ARNI With ARB Global Outcomes in HF With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711).

Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 03 Aug 2020; 76:503-514
Cunningham JW, Claggett BL, O'Meara E, Prescott MF, ... Solomon SD, Zile MR
J Am Coll Cardiol: 03 Aug 2020; 76:503-514 | PMID: 32731928
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Abstract

Randomized Trials Versus Common Sense and Clinical Observation: JACC Review Topic of the Week.

Fanaroff AC, Califf RM, Harrington RA, Granger CB, ... Alexander JH, Lopes RD

Concerns about the external validity of traditional randomized clinical trials (RCTs), together with the widespread availability of real-world data and advanced data analytic tools, have led to claims that common sense and clinical observation, rather than RCTs, should be the preferred method to generate evidence to support clinical decision-making. However, over the past 4 decades, results from well-done RCTs have repeatedly contradicted practices supported by common sense and clinical observation. Common sense and clinical observation fail for several reasons: incomplete understanding of pathophysiology, biases and unmeasured confounding in observational research, and failure to understand risks and benefits of treatments within complex systems. Concerns about traditional RCT models are legitimate, but randomization remains a critical tool to understand the causal relationship between treatments and outcomes. Instead, development and promulgation of tools to apply randomization to real-world data are needed to build the best evidence base in cardiovascular medicine.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 03 Aug 2020; 76:580-589
Fanaroff AC, Califf RM, Harrington RA, Granger CB, ... Alexander JH, Lopes RD
J Am Coll Cardiol: 03 Aug 2020; 76:580-589 | PMID: 32731936
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Abstract

Cardiovascular and Bleeding Risks Associated With Nonsteroidal Anti-Inflammatory Drugs After Myocardial Infarction.

Kang DO, An H, Park GU, Yum Y, ... Seo HS, Choi CU
Background
Limited data are available regarding the risk for adverse clinical events with concomitant nonsteroidal anti-inflammatory drug (NSAID) treatment after myocardial infarction (MI).
Objectives
The aim of this study was to investigate the risk for cardiovascular and bleeding events according to groups of antithrombotic medications and subtypes of NSAIDs in patients with MI.
Methods
This was a nationwide cohort study to enroll a study population from the Health Insurance Review and Assessment Service database in Korea between 2009 and 2013. Patients were divided into groups on the basis of the prescribed antithrombotic medications. The primary and secondary outcomes were thromboembolic cardiovascular and clinically relevant bleeding events. The risk for adverse clinical events was assessed by ongoing NSAID treatment and subtypes of NSAIDs.
Results
In total, 108,232 patients (mean age 64.2 ± 12.8 years, 72.1% men, mean follow-up duration 2.3 ± 1.8 years) with first diagnosed MI were enrolled. Concomitant NSAID treatment significantly increased the risk for cardiovascular events (hazard ratio [HR]: 6.96; 95% confidence interval [CI]: 6.24 to 6.77; p < 0.001) and bleeding events (HR: 4.08; 95% CI: 3.51 to 4.73; p < 0.001) compared with no NSAID treatment. Among NSAID subtypes, the risk for cardiovascular and bleeding events was lowest with the use of celecoxib (HR: 4.65; 95% CI: 3.17 to 6.82; p < 0.001, and 3.44; 95% CI: 2.20 to 5.39; p < 0.001, respectively) and meloxicam (HR: 3.03; 95% CI: 1.68 to 5.47; p < 0.001, and 2.80; 95% CI: 1.40 to 5.60; p < 0.001, respectively).
Conclusions
Concomitant NSAID treatment significantly increased the risk for cardiovascular and bleeding events after MI. Although NSAID treatment should be avoided after MI, celecoxib and meloxicam could be considered as alternative options in cases in which NSAID use is unavoidable.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 03 Aug 2020; 76:518-529
Kang DO, An H, Park GU, Yum Y, ... Seo HS, Choi CU
J Am Coll Cardiol: 03 Aug 2020; 76:518-529 | PMID: 32731930
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Abstract

Targeting RNA With Antisense Oligonucleotides and Small Interfering RNA: JACC State-of-the-Art Review.

Katzmann JL, Packard CJ, Chapman MJ, Katzmann I, Laufs U

There is an unmet clinical need to reduce residual cardiovascular risk attributable to apolipoprotein B-containing lipoproteins, particularly low-density lipoprotein and remnant particles. Pharmacological targeting of messenger RNA represents an emerging, innovative approach. Two major classes of agents have been developed-antisense oligonucleotides and small interfering RNA. Early problems with their use have been overcome by conjugation with N-acetylgalactosamine, an adduct that targets their delivery to the primary site of action in the liver. Using these agents to inhibit the translation of key regulatory proteins such as PCSK9, apolipoprotein CIII, apolipoprotein(a), and angiopoietin-like 3 has been shown to be effective in attenuating dyslipidemic states. Cardiovascular outcome trials with N-acetylgalactosamine-conjugated RNA-targeting drugs are ongoing. The advantages of these agents include long dosing intervals of up to 6 months and the potential to regulate the abundance of any disease-related protein. Long-term safety has yet to be demonstrated in large-scale clinical trials.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 03 Aug 2020; 76:563-579
Katzmann JL, Packard CJ, Chapman MJ, Katzmann I, Laufs U
J Am Coll Cardiol: 03 Aug 2020; 76:563-579 | PMID: 32731935
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Abstract

Intracoronary ALLogeneic heart STem cells to Achieve myocardial Regeneration (ALLSTAR): a randomized, placebo-controlled, double-blinded trial.

Makkar RR, Kereiakes DJ, Aguirre F, Kowalchuk G, ... Marbán E, Henry TD
Aims
Cardiosphere-derived cells (CDCs) are cardiac progenitor cells that exhibit disease-modifying bioactivity in various models of cardiomyopathy and in previous clinical studies of acute myocardial infarction (MI), dilated cardiomyopathy, and Duchenne muscular dystrophy. The aim of the study was to assess the safety and efficacy of intracoronary administration of allogeneic CDCs in the multicentre, randomized, double-blinded, placebo-controlled, intracoronary ALLogeneic heart STem cells to Achieve myocardial Regeneration (ALLSTAR) trial.
Methods and results
We enrolled patients 4 weeks to 12 months after MI, with left ventricular ejection fraction (LVEF) ≤45% and LV scar size ≥15% of LV mass by magnetic resonance imaging (MRI). A pre-specified interim analysis was performed when 6-month MRI data were available. The trial was subsequently stopped due to the low probability of detecting a significant treatment effect of CDCs based on the primary endpoint. Patients were randomly allocated in a 2:1 ratio to receive CDCs or placebo in the infarct-related artery by stop-flow technique. The primary safety endpoint was the occurrence, during 1-month post-intracoronary infusion, of acute myocarditis attributable to allogeneic CDCs, ventricular tachycardia- or ventricular fibrillation-related death, sudden unexpected death, or a major adverse cardiac event (death or hospitalization for heart failure or non-fatal MI or need for left ventricular assist device or heart transplant). The primary efficacy endpoint was the relative percentage change in infarct size at 12 months post-infusion as assessed by contrast-enhanced cardiac MRI. We randomly allocated 142 eligible patients of whom 134 were treated (90 to the CDC group and 44 to the placebo group). The mean baseline LVEF was 40% and the mean scar size was 22% of LV mass. No primary safety endpoint events occurred. There was no difference in the percentage change from baseline in scar size (P = 0.51) between CDCs and placebo groups at 6 months. Compared with placebo, there were significant reductions in LV end-diastolic volume (P = 0.02), LV end-systolic volume (P = 0.02), and N-terminal pro b-type natriuretic peptide (NT-proBNP) (P = 0.02) at 6 months in CDC-treated patients.
Conclusion
Intracoronary infusion of allogeneic CDCs in patients with post-MI LV dysfunction was safe but did not reduce scar size relative to placebo at 6 months. Nevertheless, the reductions in LV volumes and NT-proBNP reveal disease-modifying bioactivity of CDCs.
Trial registration
Clinicaltrials.gov identifier: NCT01458405.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: [email protected]

Eur Heart J: 03 Aug 2020; epub ahead of print
Makkar RR, Kereiakes DJ, Aguirre F, Kowalchuk G, ... Marbán E, Henry TD
Eur Heart J: 03 Aug 2020; epub ahead of print | PMID: 32749459
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Abstract

Role of Cardiac Lymphatics in Myocardial Edema and Fibrosis: JACC Review Topic of the Week.

Brakenhielm E, González A, Díez J

The cardiac lymphatic network plays a key role in regulation of myocardial extracellular volume and immune cell homeostasis. In different pathological conditions cardiac lymphatics undergo significant remodeling, with insufficient lymphatic function and/or lymphangiogenesis leading to fluid accumulation and development of edema. Additionally, by modulating the reuptake of tissue-infiltrating immune cells, lymphatics regulate immune responses. Available evidence suggests that both edema and inadequate immune response resolution may contribute to extracellular matrix remodeling and interstitial myocardial fibrosis. Interestingly, stimulation of lymphangiogenesis has been shown to improve cardiac function and reduce the progression of myocardial fibrosis during heart failure development after myocardial infarction. This review goes through the available clinical and experimental data supporting a role for cardiac lymphatics in cardiac disease, focusing on the current evidence linking poor cardiac lymphatic transport to the fibrogenic process and discussing potential avenues for novel biomarkers and therapeutic targets to limit cardiac fibrosis and dysfunction.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 10 Aug 2020; 76:735-744
Brakenhielm E, González A, Díez J
J Am Coll Cardiol: 10 Aug 2020; 76:735-744 | PMID: 32762908
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Abstract

Heart Failure With Recovered Left Ventricular Ejection Fraction: JACC Scientific Expert Panel.

Wilcox JE, Fang JC, Margulies KB, Mann DL

Reverse left ventricular (LV) remodeling and recovery of LV function are associated with improved clinical outcomes in patients with heart failure with reduced ejection fraction. A growing body of evidence suggests that even among patients who experience a complete normalization of LV ejection fraction, a significant proportion will develop recurrent LV dysfunction accompanied by recurrent heart failure events. This has led to intense interest in understanding how to manage patients with heart failure with recovered ejection fraction (HFrecEF). Because of the lack of a standard definition for HFrecEF, and the paucity of clinical data with respect to the natural history of HFrecEF patients, there are no current guidelines on how these patients should be followed up and managed. Accordingly, this JACC Scientific Expert Panel reviews the biology of reverse LV remodeling and the clinical course of patients with HFrecEF, as well as provides guidelines for defining, diagnosing, and managing patients with HFrecEF.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 10 Aug 2020; 76:719-734
Wilcox JE, Fang JC, Margulies KB, Mann DL
J Am Coll Cardiol: 10 Aug 2020; 76:719-734 | PMID: 32762907
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Abstract

Transvalvular Ventricular Unloading Before Reperfusion in Acute Myocardial Infarction.

Swain L, Reyelt L, Bhave S, Qiao X, ... O\'Neill W, Kapur NK
Background
Myocardial damage due to acute ST-segment elevation myocardial infarction (STEMI) remains a significant global health problem. New approaches to limit myocardial infarct size and reduce progression to heart failure after STEMI are needed. Mechanically reducing left ventricular (LV) workload (LV unloading) before coronary reperfusion is emerging as a potential approach to reduce infarct size.
Objectives
Given the central importance of mitochondria in reperfusion injury, we hypothesized that compared with immediate reperfusion (IR), LV unloading before reperfusion improves myocardial energy substrate use and preserves mitochondrial structure and function.
Methods
To explore the effect of LV unloading duration on infarct size, we analyzed data from the STEMI-Door to Unload (STEMI-DTU) trial and then tested the effect of LV unloading on ischemia and reperfusion injury, cardiac metabolism, and mitochondrial function in swine models of acute myocardial infarction.
Results
The duration of LV unloading before reperfusion was inversely associated with infarct size in patients with large anterior STEMI. In preclinical models, LV unloading reduced the expression of hypoxia-sensitive proteins and myocardial damage due to ischemia alone. LV unloading with a transvalvular pump (TV-P) but not with venoarterial extracorporeal membrane oxygenation (ECMO) reduced infarct size. Using unbiased and blinded metabolic profiling, TV-P improved myocardial energy substrate use and preserved mitochondrial structure including cardiolipin content after reperfusion compared with IR or ECMO. Functional testing in mitochondria isolated from the infarct zone showed an intact mitochondrial structure including cardiolipin content, preserved activity of the electron transport chain including mitochondrial complex I, and reduced oxidative stress with TV-P-supported reperfusion but not with IR or ECMO.
Conclusions
These novel findings identify that transvalvular unloading limits ischemic injury before reperfusion, improves myocardial energy substrate use, and preserves mitochondrial structure and function after reperfusion.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 10 Aug 2020; 76:684-699
Swain L, Reyelt L, Bhave S, Qiao X, ... O'Neill W, Kapur NK
J Am Coll Cardiol: 10 Aug 2020; 76:684-699 | PMID: 32762903
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Abstract

Performance of Guideline Recommendations for Prevention of Myocardial Infarction in Young Adults.

Zeitouni M, Nanna MG, Sun JL, Chiswell K, Peterson ED, Navar AM
Background
The 2018 cholesterol guidelines of the American Heart Association and the American College of Cardiology (AHA/ACC) changed 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitor (statin) eligibility criteria for primary prevention to include multiple risk enhancers and novel intensive lipid-lowering therapies for secondary prevention.
Objectives
This study sought to determine how guideline changes affected identification for preventive therapy in young adults with premature myocardial infarction (MI).
Methods
The study identified adults presenting with first MI at Duke University Medical Center in Durham, North Carolina. Statin therapy eligibility was determined using the 2013 ACC/AHA and 2018 AHA/ACC guidelines criteria. The study also determined potential eligibility for intensive lipid-lowering therapies (very high risk) under the 2018 AHA/ACC guidelines, by assessing the composite of all-cause death, recurrent MI, or stroke rates in adults considered \"very high risk\" versus not.
Results
Among 6,639 patients with MI, 41% were <55 years of age (\"younger\"), 35% were 55 to 65 years of age (\"middle-aged\"), and 24% were 66 to 75 years of age (\"older\"). Younger adults were more frequently smokers (52% vs. 38% vs. 22%, respectively) and obese (42% vs. 34% vs. 31%, respectively), with metabolic syndrome (21% vs. 19% vs. 17%, respectively) and higher low-density lipoprotein cholesterol (117 vs. 107 vs. 103 mg/dl, respectively) (p trend <0.01 for all). Pre-MI, fewer younger adults met guideline indications for 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitor (statin) therapy than middle-aged and older adults. The 2018 guideline identified fewer younger adults eligible for statin therapy at the time of their MI than the 2013 guideline (46.4% vs. 56.7%; p < 0.01). Younger patients less frequently met very high-risk criteria for intensive secondary prevention lipid-lowering therapy (28.3% vs. 40.0% vs. 81.4%, respectively; p < 0.01). Over a median 8 years of follow-up, very high-risk criteria were associated with increased risk of major adverse cardiovascular events in individuals <55 years of age (hazard ratio: 2.09; 95% confidence interval: 1.82 to 2.41; p < 0.001), as was the case in older age groups (p interaction = 0.54).
Conclusions
Most younger patients with premature MI are not identified as statin candidates before their event on the basis of the 2018 guidelines, and most patients with premature MI are not recommended for intensive post-MI lipid management.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 10 Aug 2020; 76:653-664
Zeitouni M, Nanna MG, Sun JL, Chiswell K, Peterson ED, Navar AM
J Am Coll Cardiol: 10 Aug 2020; 76:653-664 | PMID: 32762899
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Abstract

Presentation and Outcome of Arrhythmic Mitral Valve Prolapse.

Essayagh B, Sabbag A, Antoine C, Benfari G, ... Michelena H, Enriquez-Sarano M
Background
Mitral valve prolapse (MVP) is often considered benign but recent suggestion of an arrhythmic MVP (AMVP) form remains incompletely defined and uncertain.
Objectives
This study determined ventricular arrhythmia prevalence, severity, phenotypical context, and independent impact on outcome in patients with MVP.
Methods
A cohort of 595 (age 65 ± 16 years; 278 women) consecutive patients with MVP and comprehensive clinical, arrhythmia (24-h Holter monitoring) and Doppler-echocardiographic characterization, was identified. Long-term outcomes were analyzed.
Results
Ventricular arrhythmia was frequent (43% with at least ventricular ectopy ≥5%), most often moderate (ventricular tachycardia [VT]; 120 to 179 beats/min) in 27%, and rarely severe (VT ≥180 beats/min) in 9%. Presence of ventricular arrhythmia was associated with male sex, bileaflet prolapse, marked leaflet redundancy, mitral annulus disjunction (MAD), a larger left atrium and left ventricular end-systolic diameter, and T-wave inversion/ST-segment depression (all p ≤ 0.001). Severe ventricular arrhythmia was independently associated with presence of MAD, leaflet redundancy, and T-wave inversion/ST-segment depression (all p < 0.0001) but not with mitral regurgitation severity or ejection fraction. Overall mortality after arrhythmia diagnosis (8 years; 13 ± 2%) was strongly associated with arrhythmia severity (8 years; 10 ± 2% for no/trivial, 15 ± 3% for mild and/or moderate, and 24 ± 7% for severe arrhythmia; p = 0.02). Excess mortality was substantial for severe arrhythmia (univariate hazard ratio [HR]: 2.70; 95% confidence interval [CI]: 1.27 to 5.77; p = 0.01 vs. no/trivial arrhythmia), even after it was comprehensively adjusted, including for MVP characteristics (adjusted HR: 2.94; 95% CI: 1.36 to 6.36; p = 0.006) and by time-dependent analysis (adjusted HR: 3.25; 95% CI: 1.56 to 6.78; p = 0.002). Severe arrhythmia was also associated with higher rates of mortality, defibrillator implantation, VT ablation (adjusted HR: 4.68; 95% CI: 2.45 to 8.92; p < 0.0001), particularly under medical management (adjusted HR: 5.80; 95% CI: 2.75 to 12.23; p < 0.0001), and weakly post-mitral surgery (adjusted HR: 3.69; 95% CI: 0.93 to 14.74; p = 0.06).
Conclusions
In this large cohort of patients with MVP, ventricular arrhythmia by Holter monitoring was frequent but rarely severe. AMVP was independently associated with phenotype dominated by MAD, marked leaflet redundancy, and repolarization abnormalities. Long-term severe arrhythmia was independently associated with notable excess mortality and reduced event-free survival, particularly under medical management. Therefore, AMVP is a clinical entity strongly associated with outcome and warrants careful risk assessment and well-designed clinical trials.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 10 Aug 2020; 76:637-649
Essayagh B, Sabbag A, Antoine C, Benfari G, ... Michelena H, Enriquez-Sarano M
J Am Coll Cardiol: 10 Aug 2020; 76:637-649 | PMID: 32762897
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Abstract

Focused Transesophageal Echocardiography During Cardiac Arrest Resuscitation: JACC Review Topic of the Week.

Teran F, Prats MI, Nelson BP, Kessler R, ... Arntfield RT, Bahner D

Focused transthoracic echocardiography (TTE) during cardiac arrest resuscitation can enable the characterization of myocardial activity, identify potentially treatable pathologies, assist with rhythm interpretation, and provide prognostic information. However, an important limitation of TTE is the difficulty obtaining interpretable images due to external and patient-related limiting factors. Over the last decade, focused transesophageal echocardiography (TEE) has been proposed as a tool that is ideally suited to image patients in extremis-those in cardiac arrest and periarrest states. In addition to the same diagnostic and prognostic role provided by TTE images, TEE provides unique advantages including the potential to optimize the quality of chest compressions, shorten cardiopulmonary resuscitation interruptions, guide resuscitative procedures, and provides a continuous image of myocardial activity. This review discusses the rationale, supporting evidence, opportunities, and challenges, and proposes a research agenda for the use of focused TEE in cardiac arrest with the goal to improve resuscitation outcomes.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 10 Aug 2020; 76:745-754
Teran F, Prats MI, Nelson BP, Kessler R, ... Arntfield RT, Bahner D
J Am Coll Cardiol: 10 Aug 2020; 76:745-754 | PMID: 32762909
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Abstract

Validation of a Genome-Wide Polygenic Score for Coronary Artery Disease in South Asians.

Wang M, Menon R, Mishra S, Patel AP, ... Gupta R, Khera AV
Background
Genome-wide polygenic scores (GPS) integrate information from many common DNA variants into a single number. Because rates of coronary artery disease (CAD) are substantially higher among South Asians, a GPS to identify high-risk individuals may be particularly useful in this population.
Objectives
This analysis used summary statistics from a prior genome-wide association study to derive a new GPS for South Asians.
Methods
This GPS was validated in 7,244 South Asian UK Biobank participants and tested in 491 individuals from a case-control study in Bangladesh. Next, a static ancestry and GPS reference distribution was built using whole-genome sequencing from 1,522 Indian individuals, and a framework was tested for projecting individuals onto this static ancestry and GPS reference distribution using 1,800 CAD cases and 1,163 control subjects newly recruited in India.
Results
The GPS, containing 6,630,150 common DNA variants, had an odds ratio (OR) per SD of 1.58 in South Asian UK Biobank participants and 1.60 in the Bangladeshi study (p < 0.001 for each). Next, individuals of the Indian case-control study were projected onto static reference distributions, observing an OR/SD of 1.66 (p < 0.001). Compared with the middle quintile, risk for CAD was most pronounced for those in the top 5% of the GPS distribution-ORs of 4.16, 2.46, and 3.22 in the South Asian UK Biobank, Bangladeshi, and Indian studies, respectively (p < 0.05 for each).
Conclusions
The new GPS has been developed and tested using 3 distinct South Asian studies, and provides a generalizable framework for ancestry-specific GPS assessment.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 10 Aug 2020; 76:703-714
Wang M, Menon R, Mishra S, Patel AP, ... Gupta R, Khera AV
J Am Coll Cardiol: 10 Aug 2020; 76:703-714 | PMID: 32762905
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Abstract

Loop Diuretic Prescription and 30-Day Outcomes in Older Patients With Heart Failure.

Faselis C, Arundel C, Patel S, Lam PH, ... Fonarow GC, Ahmed A
Background
Heart failure (HF) is a major source of morbidity and mortality. Fluid retention and shortness of breath are its cardinal manifestations for which loop diuretics are used. Although their usefulness is well accepted, less is known about their role in improving clinical outcomes.
Objectives
The purpose of this study was to determine the relationship between loop diuretics and clinical outcomes in patients with HF.
Methods
Of the 25,345 older patients hospitalized for HF in the Medicare-linked OPTIMIZE-HF (Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure) registry, 9,866 (39%) received no pre-admission diuretics. The study excluded 1,083 patients receiving dialysis and 847 discharged on thiazide diuretics. Of the remaining 7,936 patients, 5,568 (70%) were prescribed loop diuretics at discharge. Using propensity scores for receipt of loop diuretics estimated for each of the 7,936 patients, a matched cohort of 2,191 pairs of patients was assembled balanced on 74 baseline characteristics. Hazard ratios (HRs) and 95% confidence intervals (CIs) for outcomes were estimated in the matched cohort.
Results
Matched patients (n = 4,382) had a mean age of 78 years, 54% were women, and 11% were African American. The 30-day all-cause mortality occurred in 4.9% (107 of 2,191) and 6.6% (144 of 2,191) of patients in the loop diuretic and no loop diuretic groups, respectively (HR when the use of loop diuretics was compared with nonuse: 0.73; 95% CI: 0.57 to 0.94; p = 0.016). Patients in the loop diuretic group had a significantly lower risk of 30-day HF readmission (HR: 0.79; 95% CI: 0.63 to 0.99; p = 0.037) but not of 30-day all-cause readmission (HR: 0.89; 95% CI: 0.79 to 1.01; p = 0.081). None of the associations was statistically significant during 60 days of follow-up.
Conclusions
Hospitalized older patients not taking diuretics prior to hospitalization for HF decompensation who received a discharge prescription for loop diuretics had significantly better 30-day clinical outcomes than those not discharged on loop diuretics. These findings provide new information about short-term clinical benefits associated with loop diuretic use in HF.

Published by Elsevier Inc.

J Am Coll Cardiol: 10 Aug 2020; 76:669-679
Faselis C, Arundel C, Patel S, Lam PH, ... Fonarow GC, Ahmed A
J Am Coll Cardiol: 10 Aug 2020; 76:669-679 | PMID: 32762901
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Abstract

Medical Marijuana, Recreational Cannabis, and Cardiovascular Health: A Scientific Statement From the American Heart Association.

Page RL, Allen LA, Kloner RA, Carriker CR, ... Saucedo JF,

Cannabis, or marijuana, has potential therapeutic and medicinal properties related to multiple compounds, particularly Δ-9-tetrahydrocannabinol and cannabidiol. Over the past 25 years, attitudes toward cannabis have evolved rapidly, with expanding legalization of medical and recreational use at the state level in the United States and recreational use nationally in Canada and Uruguay. As a result, the consumption of cannabis products is increasing considerably, particularly among youth. Our understanding of the safety and efficacy of cannabis has been limited by decades of worldwide illegality and continues to be limited in the United States by the ongoing classification of cannabis as a Schedule 1 controlled substance. These shifts in cannabis use require clinicians to understand conflicting laws, health implications, and therapeutic possibilities. Cannabis may have therapeutic benefits, but few are cardiovascular in nature. Conversely, many of the concerning health implications of cannabis include cardiovascular diseases, although they may be mediated by mechanisms of delivery. This statement critically reviews the use of medicinal and recreational cannabis from a clinical but also a policy and public health perspective by evaluating its safety and efficacy profile, particularly in relationship to cardiovascular health.



Circulation: 04 Aug 2020:CIR0000000000000883; epub ahead of print
Page RL, Allen LA, Kloner RA, Carriker CR, ... Saucedo JF,
Circulation: 04 Aug 2020:CIR0000000000000883; epub ahead of print | PMID: 32752884
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Abstract

SARS-CoV-2 mRNA vaccine design enabled by prototype pathogen preparedness.

Corbett KS, Edwards DK, Leist SR, Abiona OM, ... Carfi A, Graham BS

A vaccine for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is needed to control the global coronavirus infectious disease (COVID-19) public health crisis. Atomic-level structures directed the application of prefusion-stabilizing mutations that improved the expression and immunogenicity of betacoronavirus spike proteins. Using this established immunogen design, the release of SARS-CoV-2 sequences triggered immediate rapid manufacturing of an mRNA vaccine expressing the prefusion-stabilized SARS-CoV-2 spike trimer (mRNA-1273). Here we show that mRNA-1273 induces both potent neutralizing antibody responses to wild-type (D614) and D614G mutant SARS-CoV-2 and CD8 T cell responses, and protects against SARS-CoV-2 infection in the lungs and noses of mice without evidence of immunopathology. mRNA-1273 is currently in Phase 3 efficacy evaluation.



Nature: 04 Aug 2020; epub ahead of print
Corbett KS, Edwards DK, Leist SR, Abiona OM, ... Carfi A, Graham BS
Nature: 04 Aug 2020; epub ahead of print | PMID: 32756549
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Abstract

Dichotomous engagement of HDAC3 activity governs inflammatory responses.

Nguyen HCB, Adlanmerini M, Hauck AK, Lazar MA

The histone deacetylases (HDACs) are a superfamily of chromatin-modifying enzymes that silence transcription through the modification of histones. Among them, HDAC3 is unique in that interaction with nuclear receptor corepressors 1 and 2 (NCoR1/2) is required to engage its catalytic activity. However, global loss of HDAC3 also results in the repression of transcription, the mechanism of which is currently unclear. Here we report that, during the activation of macrophages by lipopolysaccharides, HDAC3 is recruited to activating transcription factor 2 (ATF2)-bound sites without NCoR1/2 and activates the expression of inflammatory genes through a non-canonical mechanism. By contrast, the deacetylase activity of HDAC3 is selectively engaged at ATF3-bound sites that suppress Toll-like receptor signalling. Loss of HDAC3 in macrophages safeguards mice from lethal exposure to lipopolysaccharides, but this protection is not conferred upon genetic or pharmacological abolition of the catalytic activity of HDAC3. Our findings show that HDAC3 is a dichotomous transcriptional activator and repressor, with a non-canonical deacetylase-independent function that is vital for the innate immune system.



Nature: 04 Aug 2020; epub ahead of print
Nguyen HCB, Adlanmerini M, Hauck AK, Lazar MA
Nature: 04 Aug 2020; epub ahead of print | PMID: 32760002
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Abstract

Rescue of oxytocin response and social behaviour in a mouse model of autism.

Hörnberg H, Pérez-Garci E, Schreiner D, Hatstatt-Burklé L, ... Pecho-Vrieseling E, Scheiffele P

A fundamental challenge in developing treatments for autism spectrum disorders is the heterogeneity of the condition. More than one hundred genetic mutations confer high risk for autism, with each individual mutation accounting for only a small fraction of cases. Subsets of risk genes can be grouped into functionally related pathways, most prominently those involving synaptic proteins, translational regulation, and chromatin modifications. To attempt to minimize this genetic complexity, recent therapeutic strategies have focused on the neuropeptides oxytocin and vasopressin, which regulate aspects of social behaviour in mammals. However, it is unclear whether genetic risk factors predispose individuals to autism as a result of modifications to oxytocinergic signalling. Here we report that an autism-associated mutation in the synaptic adhesion molecule Nlgn3 results in impaired oxytocin signalling in dopaminergic neurons and in altered behavioural responses to social novelty tests in mice. Notably, loss of Nlgn3 is accompanied by a disruption of translation homeostasis in the ventral tegmental area. Treatment of Nlgn3-knockout mice with a new, highly specific, brain-penetrant inhibitor of MAP kinase-interacting kinases resets the translation of mRNA and restores oxytocin signalling and social novelty responses. Thus, this work identifies a convergence between the genetic autism risk factor Nlgn3, regulation of translation, and oxytocinergic signalling. Focusing on such common core plasticity elements might provide a pragmatic approach to overcoming the heterogeneity of autism. Ultimately, this would enable mechanism-based stratification of patient populations to increase the success of therapeutic interventions.



Nature: 04 Aug 2020; epub ahead of print
Hörnberg H, Pérez-Garci E, Schreiner D, Hatstatt-Burklé L, ... Pecho-Vrieseling E, Scheiffele P
Nature: 04 Aug 2020; epub ahead of print | PMID: 32760004
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Abstract

Position-specific oxidation of miR-1 encodes cardiac hypertrophy.

Seok H, Lee H, Lee S, Ahn SH, ... Jang ES, Chi SW

In pathophysiology, reactive oxygen species oxidize biomolecules that contribute to disease phenotypes. One such modification, 8-oxoguanine (oG), is abundant in RNA but its epitranscriptional role has not been investigated for microRNAs (miRNAs). Here we specifically sequence oxidized miRNAs in a rat model of the redox-associated condition cardiac hypertrophy. We find that position-specific oG modifications are generated in seed regions (positions 2-8) of selective miRNAs, and function to regulate other mRNAs through oG•A base pairing. oG is induced predominantly at position 7 of miR-1 (7oG-miR-1) by treatment with an adrenergic agonist. Introducing 7oG-miR-1 or 7U-miR-1 (in which G at position 7 is substituted with U) alone is sufficient to cause cardiac hypertrophy in mice, and the mRNA targets of oG-miR-1 function in affected phenotypes; the specific inhibition of 7oG-miR-1 in mouse cardiomyocytes was found to attenuate cardiac hypertrophy. oG-miR-1 is also implicated in patients with cardiomyopathy. Our findings show that the position-specific oxidation of miRNAs could serve as an epitranscriptional mechanism to coordinate pathophysiological redox-mediated gene expression.



Nature: 04 Aug 2020; epub ahead of print
Seok H, Lee H, Lee S, Ahn SH, ... Jang ES, Chi SW
Nature: 04 Aug 2020; epub ahead of print | PMID: 32760005
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Abstract

Mucosal or systemic microbiota exposures shape the B cell repertoire.

Li H, Limenitakis JP, Greiff V, Yilmaz B, ... Ganal-Vonarburg SC, Macpherson AJ

Colonization by the microbiota causes a marked stimulation of B cells and induction of immunoglobulin, but mammals colonized with many taxa have highly complex and individualized immunoglobulin repertoires. Here we use a simplified model of defined transient exposures to different microbial taxa in germ-free mice to deconstruct how the microbiota shapes the B cell pool and its functional responsiveness. We followed the development of the immunoglobulin repertoire in B cell populations, as well as single cells by deep sequencing. Microbial exposures at the intestinal mucosa generated oligoclonal responses that differed from those of germ-free mice, and from the diverse repertoire that was generated after intravenous systemic exposure to microbiota. The IgA repertoire-predominantly to cell-surface antigens-did not expand after dose escalation, whereas increased systemic exposure broadened the IgG repertoire to both microbial cytoplasmic and cell-surface antigens. These microbial exposures induced characteristic immunoglobulin heavy-chain repertoires in B cells, mainly at memory and plasma cell stages. Whereas sequential systemic exposure to different microbial taxa diversified the IgG repertoire and facilitated alternative specific responses, sequential mucosal exposure produced limited overlapping repertoires and the attrition of initial IgA binding specificities. This shows a contrast between a flexible response to systemic exposure with the need to avoid fatal sepsis, and a restricted response to mucosal exposure that reflects the generic nature of host-microbial mutualism in the mucosa.



Nature: 04 Aug 2020; epub ahead of print
Li H, Limenitakis JP, Greiff V, Yilmaz B, ... Ganal-Vonarburg SC, Macpherson AJ
Nature: 04 Aug 2020; epub ahead of print | PMID: 32760003
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Abstract

New Guinea has the world\'s richest island flora.

Cámara-Leret R, Frodin DG, Adema F, Anderson C, ... Zhang LB, van Welzen PC

New Guinea is the world\'s largest tropical island and has fascinated naturalists for centuries. Home to some of the best-preserved ecosystems on the planet and to intact ecological gradients-from mangroves to tropical alpine grasslands-that are unmatched in the Asia-Pacific region, it is a globally recognized centre of biological and cultural diversity. So far, however, there has been no attempt to critically catalogue the entire vascular plant diversity of New Guinea. Here we present the first, to our knowledge, expert-verified checklist of the vascular plants of mainland New Guinea and surrounding islands. Our publicly available checklist includes 13,634 species (68% endemic), 1,742 genera and 264 families-suggesting that New Guinea is the most floristically diverse island in the world. Expert knowledge is essential for building checklists in the digital era: reliance on online taxonomic resources alone would have inflated species counts by 22%. Species discovery shows no sign of levelling off, and we discuss steps to accelerate botanical research in the \'Last Unknown\'.



Nature: 04 Aug 2020; epub ahead of print
Cámara-Leret R, Frodin DG, Adema F, Anderson C, ... Zhang LB, van Welzen PC
Nature: 04 Aug 2020; epub ahead of print | PMID: 32760001
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Abstract

The tuatara genome reveals ancient features of amniote evolution.

Gemmell NJ, Rutherford K, Prost S, Tollis M, ... Stone C,

The tuatara (Sphenodon punctatus)-the only living member of the reptilian order Rhynchocephalia (Sphenodontia), once widespread across Gondwana-is an iconic species that is endemic to New Zealand. A key link to the now-extinct stem reptiles (from which dinosaurs, modern reptiles, birds and mammals evolved), the tuatara provides key insights into the ancestral amniotes. Here we analyse the genome of the tuatara, which-at approximately 5 Gb-is among the largest of the vertebrate genomes yet assembled. Our analyses of this genome, along with comparisons with other vertebrate genomes, reinforce the uniqueness of the tuatara. Phylogenetic analyses indicate that the tuatara lineage diverged from that of snakes and lizards around 250 million years ago. This lineage also shows moderate rates of molecular evolution, with instances of punctuated evolution. Our genome sequence analysis identifies expansions of proteins, non-protein-coding RNA families and repeat elements, the latter of which show an amalgam of reptilian and mammalian features. The sequencing of the tuatara genome provides a valuable resource for deep comparative analyses of tetrapods, as well as for tuatara biology and conservation. Our study also provides important insights into both the technical challenges and the cultural obligations that are associated with genome sequencing.



Nature: 04 Aug 2020; epub ahead of print
Gemmell NJ, Rutherford K, Prost S, Tollis M, ... Stone C,
Nature: 04 Aug 2020; epub ahead of print | PMID: 32760000
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Abstract

Zoonotic host diversity increases in human-dominated ecosystems.

Gibb R, Redding DW, Chin KQ, Donnelly CA, ... Newbold T, Jones KE

Land use change-for example, the conversion of natural habitats to agricultural or urban ecosystems-is widely recognized to influence the risk and emergence of zoonotic disease in humans. However, whether such changes in risk are underpinned by predictable ecological changes remains unclear. It has been suggested that habitat disturbance might cause predictable changes in the local diversity and taxonomic composition of potential reservoir hosts, owing to systematic, trait-mediated differences in species resilience to human pressures. Here we analyse 6,801 ecological assemblages and 376 host species worldwide, controlling for research effort, and show that land use has global and systematic effects on local zoonotic host communities. Known wildlife hosts of human-shared pathogens and parasites overall comprise a greater proportion of local species richness (18-72% higher) and total abundance (21-144% higher) in sites under substantial human use (secondary, agricultural and urban ecosystems) compared with nearby undisturbed habitats. The magnitude of this effect varies taxonomically and is strongest for rodent, bat and passerine bird zoonotic host species, which may be one factor that underpins the global importance of these taxa as zoonotic reservoirs. We further show that mammal species that harbour more pathogens overall (either human-shared or non-human-shared) are more likely to occur in human-managed ecosystems, suggesting that these trends may be mediated by ecological or life-history traits that influence both host status and tolerance to human disturbance. Our results suggest that global changes in the mode and the intensity of land use are creating expanding hazardous interfaces between people, livestock and wildlife reservoirs of zoonotic disease.



Nature: 04 Aug 2020; epub ahead of print
Gibb R, Redding DW, Chin KQ, Donnelly CA, ... Newbold T, Jones KE
Nature: 04 Aug 2020; epub ahead of print | PMID: 32759999
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Abstract

Fontan-Associated Liver Disease: Screening, Management, and Transplant Considerations.

Emamaullee J, Zaidi AN, Schiano T, Kahn J, ... Bucuvalas J, Fischer R

Surgical innovation and multidisciplinary management have allowed children born with univentricular physiology congenital heart disease to survive into adulthood. An estimated global population of 70 000 patients have undergone the Fontan procedure and are alive today, most of whom are <25 years of age. Several unexpected consequences of the Fontan circulation include Fontan-associated liver disease. Surveillance biopsies have demonstrated that virtually 100% of these patients develop clinically silent fibrosis by adolescence. As they mature, there are increasing reports of combined heart-liver transplantation resulting from advanced liver disease, including bridging fibrosis, cirrhosis, and hepatocellular carcinoma, in this population. In the absence of a transplantation option, these young patients face a poor quality of life and overall survival. Acknowledging that there are no consensus guidelines for diagnosing and monitoring Fontan-associated liver disease or when to consider heart transplantation versus combined heart-liver transplantation in these patients, a multidisciplinary working group reviewed the literature surrounding Fontan-associated liver disease, with a specific focus on considerations for transplantation.



Circulation: 10 Aug 2020; 142:591-604
Emamaullee J, Zaidi AN, Schiano T, Kahn J, ... Bucuvalas J, Fischer R
Circulation: 10 Aug 2020; 142:591-604 | PMID: 32776846
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Abstract

Venous Thromboembolism Research Priorities: A Scientific Statement From the American Heart Association and the International Society on Thrombosis and Haemostasis.

Cushman M, Barnes GD, Creager MA, Diaz JA, ... Wolberg AS,

Venous thromboembolism is a major cause of morbidity and mortality. The impact of the US Surgeon General\'sin 2008 has been lower than expected given the public health impact of this disease. This scientific statement highlights future research priorities in venous thromboembolism, developed by experts and a crowdsourcing survey across 16 scientific organizations. At the fundamental research level (T0), researchers need to identify pathobiological causative mechanisms for the 50% of patients with unprovoked venous thromboembolism and to better understand mechanisms that differentiate hemostasis from thrombosis. At the human level (T1), new methods for diagnosing, treating, and preventing venous thromboembolism will allow tailoring of diagnostic and therapeutic approaches to individuals. At the patient level (T2), research efforts are required to understand how foundational evidence impacts care of patients (eg, biomarkers). New treatments, such as catheter-based therapies, require further testing to identify which patients are most likely to experience benefit. At the practice level (T3), translating evidence into practice remains challenging. Areas of overuse and underuse will require evidence-based tools to improve care delivery. At the community and population level (T4), public awareness campaigns need thorough impact assessment. Large population-based cohort studies can elucidate the biological and environmental underpinnings of venous thromboembolism and its complications. To achieve these goals, funding agencies and training programs must support a new generation of scientists and clinicians who work in multidisciplinary teams to solve the pressing public health problem of venous thromboembolism.



Circulation: 10 Aug 2020; 142:e85-e94
Cushman M, Barnes GD, Creager MA, Diaz JA, ... Wolberg AS,
Circulation: 10 Aug 2020; 142:e85-e94 | PMID: 32776842
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Abstract

Mortality in adults with multidrug-resistant tuberculosis and HIV by antiretroviral therapy and tuberculosis drug use: an individual patient data meta-analysis.

Bisson GP, Bastos M, Campbell JR, Bang D, ... Walsh J, Marks SM
Background
HIV-infection is associated with increased mortality during multidrug-resistant tuberculosis treatment, but the extent to which the use of antiretroviral therapy (ART) and anti-tuberculosis medications modify this risk are unclear. Our objective was to evaluate how use of these treatments altered mortality risk in HIV-positive adults with multidrug-resistant tuberculosis.
Methods
We did an individual patient data meta-analysis of adults 18 years or older with confirmed or presumed multidrug-resistant tuberculosis initiating tuberculosis treatment between 1993 and 2016. Data included ART use and anti-tuberculosis medications grouped according to WHO effectiveness categories. The primary analysis compared HIV-positive with HIV-negative patients in terms of death during multidrug-resistant tuberculosis treatment, excluding those lost to follow up, and was stratified by ART use. Analyses used logistic regression after exact matching on country World Bank income classification and drug resistance and propensity-score matching on age, sex, geographic site, year of multidrug-resistant tuberculosis treatment initiation, previous tuberculosis treatment, directly observed therapy, and acid-fast-bacilli smear-positivity to obtain adjusted odds ratios (aORs) and 95% CIs. Secondary analyses were conducted among those with HIV-infection.
Findings
We included 11 920 multidrug-resistant tuberculosis patients. 2997 (25%) were HIV-positive and on ART, 886 (7%) were HIV-positive and not on ART, and 1749 (15%) had extensively drug-resistant tuberculosis. By use of HIV-negative patients as reference, the aOR of death was 2·4 (95% CI 2·0-2·9) for all patients with HIV-infection, 1·8 (1·5-2·2) for HIV-positive patients on ART, and 4·2 (3·0-5·9) for HIV-positive patients with no or unknown ART. Among patients with HIV, use of at least one WHO Group A drug and specific use of moxifloxacin, levofloxacin, bedaquiline, or linezolid were associated with significantly decreased odds of death.
Interpretation
Use of ART and more effective anti-tuberculosis drugs is associated with lower odds of death among HIV-positive patients with multidrug-resistant tuberculosis. Access to these therapies should be urgently pursued.
Funding
American Thoracic Society, Canadian Institutes of Health Research, US Centers for Disease Control and Prevention, European Respiratory Society, Infectious Diseases Society of America.

Copyright © 2020 Elsevier Ltd. All rights reserved.

Lancet: 07 Aug 2020; 396:402-411
Bisson GP, Bastos M, Campbell JR, Bang D, ... Walsh J, Marks SM
Lancet: 07 Aug 2020; 396:402-411 | PMID: 32771107
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Abstract

Surgery versus cast immobilisation for adults with a bicortical fracture of the scaphoid waist (SWIFFT): a pragmatic, multicentre, open-label, randomised superiority trial.

Dias JJ, Brealey SD, Fairhurst C, Amirfeyz R, ... Torgerson D, Warwick D
Background
Scaphoid fractures account for 90% of carpal fractures and occur predominantly in young men. The use of immediate surgical fixation to manage this type of fracture has increased, despite insufficient evidence of improved outcomes over non-surgical management. The SWIFFT trial compared the clinical effectiveness of surgical fixation with cast immobilisation and early fixation of fractures that fail to unite in adults with scaphoid waist fractures displaced by 2 mm or less.
Methods
This pragmatic, parallel-group, multicentre, open-label, two-arm, randomised superiority trial included adults (aged 16 years or older) who presented to orthopaedic departments of 31 hospitals in England and Wales with a clear bicortical fracture of the scaphoid waist on radiographs. An independent remote randomisation service used a computer-generated allocation sequence with randomly varying block sizes to randomly assign participants (1:1) to receive either early surgical fixation (surgery group) or below-elbow cast immobilisation followed by immediate fixation if non-union of the fracture was confirmed (cast immobilisation group). Randomisation was stratified by whether or not there was displacement of either a step or a gap of 1-2 mm inclusive on any radiographic view. The primary outcome was the total patient-rated wrist evaluation (PRWE) score at 52 weeks after randomisation, and it was analysed on an available case intention-to-treat basis. This trial is registered with the ISRCTN registry, ISRCTN67901257, and is no longer recruiting, but long-term follow-up is ongoing.
Findings
Between July 23, 2013, and July 26, 2016, 439 (42%) of 1047 assessed patients (mean age 33 years; 363 [83%] men) were randomly assigned to the surgery group (n=219) or to the cast immobilisation group (n=220). Of these, 408 (93%) participants were included in the primary analysis (203 participants in the surgery group and 205 participants in the cast immobilisation group). 16 participants in the surgery group and 15 participants in the cast immobilisation group were excluded because of either withdrawal, no response, or no follow-up data at 6, 12, 26, or 52 weeks. There was no significant difference in mean PRWE scores at 52 weeks between the surgery group (adjusted mean 11·9 [95% CI 9·2-14·5]) and the cast immobilisation group (14·0 [11·3 to 16·6]; adjusted mean difference -2·1 [95% CI -5·8 to 1·6], p=0·27). More participants in the surgery group (31 [14%] of 219 participants) had a potentially serious complication from surgery than in the cast immobilisation group (three [1%] of 220 participants), but fewer participants in the surgery group (five [2%]) had cast-related complications than in the cast immobilisation group (40 [18%]). The number of participants who had a medical complication was similar between the two groups (four [2%] in the surgery group and five [2%] in the cast immobilisation group).
Interpretation
Adult patients with scaphoid waist fractures displaced by 2 mm or less should have initial cast immobilisation, and any suspected non-unions should be confirmed and immediately fixed with surgery. This treatment strategy will help to avoid the risks of surgery and mostly limit the use of surgery to fixing fractures that fail to unite.
Funding
National Institute for Health Research Health Technology Assessment Programme.

Copyright © 2020 Elsevier Ltd. All rights reserved.

Lancet: 07 Aug 2020; 396:390-401
Dias JJ, Brealey SD, Fairhurst C, Amirfeyz R, ... Torgerson D, Warwick D
Lancet: 07 Aug 2020; 396:390-401 | PMID: 32771106
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Abstract

Effects of Interleukin-1β Inhibition on Incident Hip and Knee Replacement: Exploratory Analyses From a Randomized, Double-Blind, Placebo-Controlled Trial.

Schieker M, Conaghan PG, Mindeholm L, Praestgaard J, ... Roubenoff R, Ridker PM
Background
Osteoarthritis is a common inflammatory disorder with no disease-modifying therapies. Whether inhibition of interleukin-1β (IL-1β) can reduce the consequences of large joint osteoarthritis is unclear.
Objective
To determine whether IL-1β inhibition with canakinumab reduces incident total hip or knee replacement (THR/TKR).
Design
Exploratory analysis of a randomized trial. (ClinicalTrials.gov: NCT01327846).
Setting
1091 clinical sites in 39 countries.
Participants
10 061 CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study) participants.
Intervention
Random allocation to placebo or canakinumab (50, 150, or 300 mg) subcutaneously once every 3 months.
Measurements
The primary and secondary outcomes were time to first incident THR/TKR and time to first occurrence of an osteoarthritis-related adverse event (AE). Data were obtained through blinded ascertainment of trial clinical and safety databases.
Results
Median follow-up was 3.7 years. For the individual canakinumab dose groups, compared with placebo, hazard ratios (HRs) for incident THR/TKR during follow-up were 0.60 (95% CI, 0.38 to 0.95) for the 50-mg group, 0.53 (CI, 0.33 to 0.84) for the 150-mg group, and 0.60 (CI, 0.38 to 0.93) for the 300-mg group. Thus, in the pooled canakinumab groups, compared with the placebo group, incidence rates for THR/TKR were 0.31 and 0.54 events per 100 person-years (HR, 0.58 [CI, 0.42 to 0.80];  = 0.001), respectively. The HR for the secondary end point of osteoarthritis-related AEs was 0.73 (CI, 0.61 to 0.87). Similar findings were observed in analyses restricted to participants with a history of osteoarthritis.
Limitation
Because the parent trial was not designed to examine the efficacy of IL-1β inhibitors in osteoarthritis, information on structural joint outcomes was not collected.
Conclusion
Findings from this exploratory analysis of a randomized controlled trial support further investigation of IL-1β inhibition for treatment of large joint osteoarthritis.
Primary funding source
Novartis Pharmaceuticals.



Ann Intern Med: 03 Aug 2020; epub ahead of print
Schieker M, Conaghan PG, Mindeholm L, Praestgaard J, ... Roubenoff R, Ridker PM
Ann Intern Med: 03 Aug 2020; epub ahead of print | PMID: 32744862
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Abstract

Chronic Obstructive Pulmonary Disease.

Labaki WW, Rosenberg SR

Chronic obstructive pulmonary disease (COPD) is characterized by persistent respiratory symptoms and progressive airflow obstruction. Tobacco smoking is the leading cause but not the only one. A postbronchodilator FEV-FVC ratio less than 0.70 is required for a diagnosis of COPD. Inhaler therapy is the backbone of treatment and should be complemented by a multifaceted management strategy that includes counseling and pharmacotherapy for smoking cessation, pulmonary rehabilitation, treatment of comorbidities, administration of influenza and pneumococcal immunizations, and prescription of long-term oxygen therapy in hypoxemic patients.



Ann Intern Med: 03 Aug 2020; 173:ITC17-ITC32
Labaki WW, Rosenberg SR
Ann Intern Med: 03 Aug 2020; 173:ITC17-ITC32 | PMID: 32745458
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Abstract

Management Options for an Older Adult With Advanced Chronic Kidney Disease and Dementia: Grand Rounds Discussion From Beth Israel Deaconess Medical Center.

Burns RB, Waikar SS, Wachterman MW, Kanjee Z

About 15% of adults in the United States-37 million persons-have chronic kidney disease (CKD). Chronic kidney disease is divided into 5 groups, ranging from stage 1 to stage 5 CKD, whereas end-stage kidney disease (ESKD) is defined as permanent kidney failure. The treatment options for ESKD are kidney replacement therapy (KRT) and conservative management. The options for KRT include hemodialysis (either in-center or at home), peritoneal dialysis, and kidney transplant. Conservative management, a multidisciplinary model of care for patients with stage 5 CKD who want to avoid dialysis, is guided by patient values, preferences, and goals, with a focus on quality of life and symptom management. In 2015, the Kidney Disease Outcomes Quality Initiative recommended that patients with an estimated glomerular filtration rate below 30 mL/min/1.73 m be educated about options for both KRT and conservative management. In 2018, the National Institute for Health and Care Excellence recommended that assessment for KRT or conservative management start at least 1 year before the need for therapy. It also recommended that in choosing a management approach, predicted quality of life, predicted life expectancy, patient preferences, and other patient factors be considered, because little difference in outcomes has been found among options. Here, 2 experts-a nephrologist and a general internist-palliative care physician-reflect on the care of a patient with advanced CKD and mild to moderate dementia. They discuss the management options for patients with advanced CKD, the pros and cons of each method, and how to help a patient choose among the options.



Ann Intern Med: 03 Aug 2020; 173:217-225
Burns RB, Waikar SS, Wachterman MW, Kanjee Z
Ann Intern Med: 03 Aug 2020; 173:217-225 | PMID: 32745449
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Abstract

Endogenous Activation of Glucagon-Like Peptide-1 Receptor Contributes to Blood Pressure Control: Role of Proximal Tubule Na/H Exchanger Isoform 3, Renal Angiotensin II, and Insulin Sensitivity.

Martins FL, Bailey MA, Girardi ACC

The pharmacological administration of GLP-1R (glucagon-like peptide-1 receptor) agonists reduces blood pressure (BP) in type 2 diabetes mellitus and nondiabetic patients. This study tested the hypothesis that endogenous GLP-1R signaling influences the regulation of BP. To this end, SHRs (spontaneously hypertensive rats) and Wistar rats were treated with the GLP-1R antagonist Ex9 (exendin-9) or vehicle for 4 weeks. Rats receiving the GLP-1R agonist Ex4 (exenatide) were used as an additional control. We found that blockade of baseline GLP-1R signaling by Ex9 increased systolic BP in both SHR and Wistar rats, compared with vehicle-treated animals, while Ex4 only reduced systolic BP in SHR. Higher systolic BP induced by Ex9 was accompanied by reduced lithium clearance and lower levels of NHE3 (Na/H exchanger isoform 3) phosphorylation at the serine 552, indicative of increased proximal tubule sodium reabsorption. Additionally, urinary AGT (angiotensinogen) and renal cortical concentration of Ang II (angiotensin II) were enhanced by Ex9. Conversely, Ex4 decreased both urinary AGT and cortical Ang II but exclusively in SHRs. Moreover, both SHR and Wistar rats treated with Ex9 displayed hyperinsulinemia as compared with vehicle-treated rats, whereas Ex4 reduced fasting insulin concentration in SHR. Collectively, these results suggest that endogenous GLP-1R signaling exerts a physiologically relevant effect on BP control, which may be attributable, in part, to its tonic actions on the proximal tubule NHE3-mediated sodium reabsorption, intrarenal renin-angiotensin system, and insulin sensitivity. The possible role of impaired GLP-1R signaling in the pathogenesis of hypertension warrants further investigation.



Hypertension: 02 Aug 2020:HYPERTENSIONAHA12014868; epub ahead of print
Martins FL, Bailey MA, Girardi ACC
Hypertension: 02 Aug 2020:HYPERTENSIONAHA12014868; epub ahead of print | PMID: 32755467
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Abstract

Effects of Oral Sodium Nitrite on Blood Pressure, Insulin Sensitivity, and Intima-Media Arterial Thickening in Adults With Hypertension and Metabolic Syndrome.

Hughan KS, Levine A, Helbling N, Anthony S, ... Goodpaster BH, Gladwin MT

The nitrate-nitrite-NO pathway regulates NO synthase-independent vasodilation and NO signaling. Ingestion of inorganic nitrite has vasodilatory and blood pressure-lowering effects. Preclinical studies in rodent models suggest there may be a benefit of nitrite in lowering serum triglyceride levels and improving the metabolic syndrome. In a phase 2 study, we evaluated the safety and efficacy of chronic oral nitrite therapy in patients with hypertension and the metabolic syndrome. Twenty adult subjects with stage 1 or 2 hypertension and the metabolic syndrome were enrolled in an open-label safety and efficacy study. The primary efficacy end point was blood pressure reduction; secondary end points included insulin-dependent glucose disposal and endothelial function measured by flow-mediated dilation of the brachial artery and intima-media diameter of the carotid artery. Chronic oral nitrite therapy (40 mg/3× daily) was well tolerated. Oral nitrite significantly lowered systolic, diastolic, and mean arterial pressures, but tolerance was observed after 10 to 12 weeks of therapy. There was significant improvement in the intima-media thickness of the carotid artery and trends toward improvements in flow-mediated dilation of the brachial artery and insulin sensitivity. Chronic oral nitrite therapy is safe in patients with hypertension and the metabolic syndrome. Despite an apparent lack of enzymatic tolerance to nitrite, we observed tolerance after 10 weeks of chronic therapy, which requires additional mechanistic studies and possible therapeutic dose titration in clinical trials. Nitrite may be a safe therapy to concominantly improve multiple features of the metabolic syndrome including hypertension, insulin resistance, and endothelial dysfunction. Registration- URL: https://www.clinicaltrials.gov; Unique identifier: NCT01681810.



Hypertension: 02 Aug 2020:HYPERTENSIONAHA12014930; epub ahead of print
Hughan KS, Levine A, Helbling N, Anthony S, ... Goodpaster BH, Gladwin MT
Hypertension: 02 Aug 2020:HYPERTENSIONAHA12014930; epub ahead of print | PMID: 32755471
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Abstract

Brain Testosterone-CYP1B1 (Cytochrome P450 1B1) Generated Metabolite 6β-Hydroxytestosterone Promotes Neurogenic Hypertension and Inflammation.

Singh P, Dutta SR, Song CY, Oh S, Gonzalez FJ, Malik KU

Previously, we showed that peripheral administration of 6β-hydroxytestosterone, a CYP1B1 (cytochrome P450 1B1)-generated metabolite of testosterone, promotes angiotensin II-induced hypertension in male mice. However, the site of action and the underlying mechanism by which 6β-hydroxytestosterone contributes to angiotensin II-induced hypertension is not known. Angiotensin II increases blood pressure by its central action, and CYP1B1 is expressed in the brain. This study was conducted to determine whether testosterone-CYP1B1 generated metabolite 6β-hydroxytestosterone locally in the brain promotes the effect of systemic angiotensin II to produce hypertension in male mice. Central CYP1B1 knockdown in wild-type () mice by intracerebroventricular-adenovirus-GFP (green fluorescence protein)-CYP1B1-short hairpin (sh)RNA attenuated, whereas reconstitution of CYP1B1 by adenovirus-GFP-CYP1B1-DNA in the paraventricular nucleus but not in subfornical organ inmice restored angiotensin II-induced increase in systolic blood pressure measured by tail-cuff. Intracerebroventricular-testosterone in orchidectomized (Orchi)- but not in Orchi-, and intracerebroventricular-6β-hydroxytestosterone in the Orchi- mice restored the angiotensin II-induced: (1) increase in mean arterial pressure measured by radiotelemetry, and autonomic imbalance; (2) reactive oxygen species production in the subfornical organ and paraventricular nucleus; (3) activation of microglia and astrocyte, and neuroinflammation in the paraventricular nucleus. The effect of intracerebroventricular-6β-hydroxytestosterone to restore the angiotensin II-induced increase in mean arterial pressure and autonomic imbalance in Orchi- mice was inhibited by intracerebroventricular-small interfering (si)RNA-androgen receptor (AR) and GPRC6A (G protein-coupled receptor C6A). These data suggest that testosterone-CYP1B1-generated metabolite 6β-hydroxytestosterone, most likely in the paraventricular nucleus via AR and GPRC6A, contributes to angiotensin II-induced hypertension and neuroinflammation in male mice.



Hypertension: 02 Aug 2020:HYPERTENSIONAHA12015567; epub ahead of print
Singh P, Dutta SR, Song CY, Oh S, Gonzalez FJ, Malik KU
Hypertension: 02 Aug 2020:HYPERTENSIONAHA12015567; epub ahead of print | PMID: 32755412
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Abstract

Preconception Blood Pressure and Its Change Into Early Pregnancy: Early Risk Factors for Preeclampsia and Gestational Hypertension.

Nobles CJ, Mendola P, Mumford SL, Silver RM, ... Perkins NJ, Schisterman EF

Preeclampsia and gestational hypertension are common complications of pregnancy associated with significant maternal and infant morbidity. Despite extensive research evaluating risk factors during pregnancy, most women who develop a hypertensive disorder of pregnancy are not considered high-risk and strategies for prevention remain elusive. We evaluated preconception blood pressure and its change into early pregnancy as novel risk markers for development of a hypertensive disorder of pregnancy. The EAGeR (Effects of Aspirin in Gestation and Reproduction) trial (2007-2011) randomized 1228 healthy women with a history of pregnancy loss to preconception-initiated low-dose aspirin versus placebo and followed participants for up to 6 menstrual cycles attempting pregnancy and throughout pregnancy if they became pregnant. Blood pressure was measured during preconception and throughout early gestation. The primary outcomes, preterm preeclampsia, term preeclampsia, and gestational hypertension, were abstracted from medical records. Among 586 women with a pregnancy >20 weeks\' gestation, preconception blood pressure levels were higher for preterm preeclampsia (87.3±6.7 mm Hg mean arterial pressure), term preeclampsia (88.3±9.8 mm Hg), and gestational hypertension (87.9±9.1 mm Hg) as compared with no hypertensive disorder of pregnancy (83.9±8.6 mm Hg). Change in blood pressure from preconception into very early pregnancy was associated with development of preeclampsia (relative risk, 1.13 [95% CI, 1.02-1.25] per 2 mm Hg increase in mean arterial pressure at 4 weeks\' gestation), particularly preterm preeclampsia (relative risk, 1.21 [95% CI, 1.01-1.45]). Randomization to aspirin did not alter blood pressure trajectory or risk of hypertension in pregnancy. Preconception blood pressure and longitudinal changes during early pregnancy are underexplored but crucial windows in the detection and prevention of hypertensive disorders of pregnancy. Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00467363.



Hypertension: 02 Aug 2020:HYPERTENSIONAHA12014875; epub ahead of print
Nobles CJ, Mendola P, Mumford SL, Silver RM, ... Perkins NJ, Schisterman EF
Hypertension: 02 Aug 2020:HYPERTENSIONAHA12014875; epub ahead of print | PMID: 32755413
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Abstract

Pregnancy Protects Hyperandrogenemic Female Rats From Postmenopausal Hypertension.

Shawky NM, Patil CN, Dalmasso C, Maranon RO, ... Drummond H, Reckelhoff JF

Polycystic ovary syndrome, the most common endocrine disorder in women of reproductive age, is characterized by hyperandrogenemia, obesity, insulin resistance, and elevated blood pressure. However, few studies have focused on the consequences of pregnancy on postmenopausal cardiovascular disease and hypertension in polycystic ovary syndrome women. In hyperandrogenemic female (HAF) rats, the hypothesis was tested that previous pregnancy protects against age-related hypertension. Rats were implanted with dihydrotestosterone (7.5 mg/90 days, beginning at 4 weeks and continued throughout life) or placebo pellets (controls), became pregnant at 10 to 15 weeks, and pups were weaned at postnatal day 21. Dams and virgins were then aged to 10 months (still estrous cycling) or 16 months (postcycling). Although numbers of offspring per litter were similar for HAF and control dams, birth weights were lower in HAF offspring. At 10 months of age, there were no differences in blood pressure, proteinuria, nitrate/nitrite excretion, or body composition in previously pregnant HAF versus virgin HAF. However, by 16 months of age, despite no differences in dihydrotestosterone, fat mass/or lean mass/body weight, previously pregnant HAF had significantly lower blood pressure and proteinuria, higher nitrate/nitrite excretion, with increased intrarenal mRNA expression of endothelin B receptor and eNOS (endothelial nitric oxide synthase), and decreased ACE (angiotensin-converting enzyme), AT1aR (angiotensin 1a receptor), and endothelin A receptor than virgin HAF. Thus, pregnancy protects HAF rats against age-related hypertension, and the mechanism(s) may be due to differential regulation of the nitric oxide, endothelin, and renin-angiotensin systems. These data suggest that polycystic ovary syndrome women who have experienced uncomplicated pregnancy may be protected from postmenopausal hypertension.



Hypertension: 02 Aug 2020:HYPERTENSIONAHA12015504; epub ahead of print
Shawky NM, Patil CN, Dalmasso C, Maranon RO, ... Drummond H, Reckelhoff JF
Hypertension: 02 Aug 2020:HYPERTENSIONAHA12015504; epub ahead of print | PMID: 32755410
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Abstract

Management of Hypertension in the Digital Era: Small Wearable Monitoring Devices for Remote Blood Pressure Monitoring.

Kario K

Out-of-office blood pressure measurement is an essential part of diagnosing and managing hypertension. In the era of advanced digital health information technology, the approach to achieving this is shifting from traditional methods (ambulatory and home blood pressure monitoring) to wearable devices and technology. Wearable blood pressure monitors allow frequent blood pressure measurements (ideally continuous beat-by-beat monitoring of blood pressure) with minimal stress on the patient. It is expected that wearable devices will dramatically change the quality of detection and management of hypertension by increasing the number of measurements in different situations, allowing accurate detection of phenotypes that have a negative impact on cardiovascular prognosis, such as masked hypertension and abnormal blood pressure variability. Frequent blood pressure measurements and the addition of new features such as monitoring of environmental conditions allows interpretation of blood pressure data in the context of daily stressors and different situations. This new digital approach to hypertension contributes to anticipation medicine, which refers to strategies designed to identify increasing risk and predict the onset of cardiovascular events based on a series of data collected over time, allowing proactive interventions to reduce risk. To achieve this, further research and validation is required to develop wearable blood pressure monitoring devices that provide the same accuracy as current approaches and can effectively contribute to personalized medicine.



Hypertension: 02 Aug 2020:HYPERTENSIONAHA12014742; epub ahead of print
Kario K
Hypertension: 02 Aug 2020:HYPERTENSIONAHA12014742; epub ahead of print | PMID: 32755418
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Abstract

Obesity, Sex, Race, and Early Onset Hypertension: Implications for a Refined Investigation Strategy.

Thompson P, Logan I, Tomson C, Sheerin N, Ellam T

Investigation for secondary causes is recommended in early onset hypertension. However, obesity is associated with higher blood pressure (BP), so investigation for alternative secondary causes may not be necessary in all obese patients. We sought to define a rational approach to investigation across strata of age, body mass index (BMI) sex and race, based on BP distributions in the US National Health and Nutrition Examination Surveys 2005 to 2016. The majority (71% [95% CI, 59%-79%] and 64% [95% CI, 57%-69%] by European and US definitions respectively) of early onset hypertension cases were attributable to BP distribution shifts accompanying obesity and male sex. Male versus female sex, BMI>40 versus 18.2


Hypertension: 02 Aug 2020:HYPERTENSIONAHA12015557; epub ahead of print
Thompson P, Logan I, Tomson C, Sheerin N, Ellam T
Hypertension: 02 Aug 2020:HYPERTENSIONAHA12015557; epub ahead of print | PMID: 32755414
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Abstract

Office and Out-of-Office Blood Pressure Changes Over a Quarter of Century: Findings From the PAMELA Study.

Cuspidi C, Facchetti R, Dell\'Oro R, Quarti-Trevano F, ... Mancia G, Grassi G

Findings regarding long-terms variations in blood pressure (BP) taken in different setting (ie, office, home, and ambulatory BP) in the community are scanty. We sought to assess this issue in members of the general population enrolled in the PAMELA (Pressioni Monitorate E Loro Associazioni) study. The study included 562 participants who attended the second and third survey of the PAMELA study performed after 10 and 25 years from the initial evaluation. Data collection included medical history, anthropometric parameters, office, home, ambulatory BP, and standard blood examinations. Office, home, and 24-hour systolic BP over the 25-year interval between the first and third survey increased in a parallel way (ie, 12%, 10%, and 15.5%). The increments in office, home, and 24-hour diastolic BP were lower than the systolic BP ones (ie, 3.3%, 5.6%, and 6.1%). Thus, the combined changes in systolic BP and diastolic BP from the first to the third data collection resulted in a marked increase in pulse pressure (ie, 29%, 19%, and 30%). The prevalence of hypertension assessed at office visits and out-of-office either by self-BP measurements at home and ambulatory blood pressure monitoring increased ≈3 to 4× (3.1 office, 3.3 home, 3.9 ABPM, respectively). This trend was associated with adiposity indexes and worsening of the glucose profile. This community-based longitudinal study suggests that the progressive and marked increase in hypertension with age, consistently documented with different BP measurement methods, represents an epochal challenge for the prevention of cardiovascular diseases, due to the rapid growth the elderly population worldwide.



Hypertension: 02 Aug 2020:HYPERTENSIONAHA12015434; epub ahead of print
Cuspidi C, Facchetti R, Dell'Oro R, Quarti-Trevano F, ... Mancia G, Grassi G
Hypertension: 02 Aug 2020:HYPERTENSIONAHA12015434; epub ahead of print | PMID: 32755470
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Abstract

Interplay Between Statins, Cav1 (Caveolin-1), and Aldosterone.

Haas AV, Baudrand R, Easly RM, Murray GR, ... Williams GH, Adler GK

Statin use is associated with lower aldosterone levels. We hypothesized that caveolin-1 may be important for the uptake of statins into the adrenal gland and would affect statin\'s aldosterone-lowering effects. The aim of this study was to test whether the caveolin-1 risk allele (rs926198) would affect aldosterone levels associated with statin use. The Hypertensive Pathotype database includes healthy and hypertensive individuals who have undergone assessment of adrenal hormones. Individuals were studied off antihypertensive medications but were maintained on statins if prescribed by their personal physician. Adrenal hormones were measured at baseline and after 1 hour of angiotensin II stimulation on both high- and low-sodium diets. A mixed-model repeated-measures analysis was employed with a priori selected covariates of age, sex, body mass index, and protocol (low versus high sodium, baseline versus angiotensin II stimulated aldosterone). A total of 250 individuals were included in the study; 31 individuals were taking statins (12.4%) and 219 were not. Among statin users, carrying a caveolin-1 risk allele resulted in a 25% (95% CI, 1-43.2) lower aldosterone level (=0.04). However, among nonstatin users, carrying a caveolin-1 risk allele resulted in no significant effect on aldosterone levels (=0.38). Additionally, the interaction between caveolin-1 risk allele and statin use on aldosterone levels was significant (=0.03). These findings suggest caveolin-1 risk allele carrying individuals are likely to receive the most benefit from statin\'s aldosterone-lowering properties; however, due to the observational nature of this study, these findings need further investigation.



Hypertension: 02 Aug 2020:HYPERTENSIONAHA12014777; epub ahead of print
Haas AV, Baudrand R, Easly RM, Murray GR, ... Williams GH, Adler GK
Hypertension: 02 Aug 2020:HYPERTENSIONAHA12014777; epub ahead of print | PMID: 32755411
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Abstract

Risk of Cardiovascular Disease and Chronic Kidney Disease According to 2017 Blood Pressure Categories in Diabetes Mellitus.

Kim YT, Chung HJ, Park BR, Kim YY, ... Lee MY, Lee JY

The association between blood pressure (BP) defined by the 2017 American College of Cardiology/American Heart Association Hypertension Clinical Practice Guidelines with cardiovascular disease (CVD) and chronic kidney disease in patients with diabetes mellitus remains unclear. This study used the National Health Insurance Database of Korea that has health information of 8 922 940 persons who were screened from 2009 to 2014. We determined the BP status of 490 352 diabetes mellitus: level 1 (systolic <120 mm Hg and diastolic <80 mm Hg), level 2 (systolic 120-129 mm Hg and diastolic <80 mm Hg), level 3 (systolic 130-139 mm Hg or diastolic 80-89 mm Hg), and level 4 (systolic ≥140 mm Hg or diastolic ≥90 mm Hg). Over a mean follow-up of 5 years, 6508 CVD events (1.3%), 14 318 cases of chronic kidney disease development (2.9%), 9094 cerebrovascular events (2.0%), and 1150 CVD mortalities (0.2%) occurred. Compared with people with BP levels 1, the adjusted hazard ratios for CVD in people with BP levels 2, 3, and 4 were 1.07 (95% CI, 0.98-1.16), 1.12 (95% CI, 1.04-1.20), and 1.17 (95% CI, 1.08-1.26), respectively. There were also increased risks of chronic kidney disease (1.18 [95% CI, 1.12-1.24] and 1.22 [95% CI, 1.15-1.29]), cerebrovascular disease (1.21 [95% CI, 1.14-1.29] and 1.52 [95% CI, 1.42-1.63]), and CVD mortality (1.31 [95% CI, 1.09-1.56] and 1.91 [95% CI, 1.58-2.32]) among subjects with BP levels 3 and 4 compared with those with BP level 1. These findings provide evidence supporting the 2017 American College of Cardiology/American Heart Association Hypertension Clinical Practice Guidelines for BP targets in diabetes mellitus patients.



Hypertension: 02 Aug 2020:HYPERTENSIONAHA12015320; epub ahead of print
Kim YT, Chung HJ, Park BR, Kim YY, ... Lee MY, Lee JY
Hypertension: 02 Aug 2020:HYPERTENSIONAHA12015320; epub ahead of print | PMID: 32755407
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Abstract

Unraveling the Links Underlying Arterial Stiffness, Bone Demineralization, and Muscle Loss.

Tap L, Kirkham FA, Mattace-Raso F, Joly L, Rajkumar C, Benetos A

The effects of elevated arterial stiffness on cardiovascular outcomes are widely studied, whereas the relation to noncardiovascular outcomes relevant to older persons, such as the effect on bones and muscles, is less well established. Arterial stiffness, bone demineralization, and muscle loss are all age-related processes with common risk factors, however, whether these are just parallel age-related alterations or whether these processes share common pathways is not yet understood. In this review, we outline previous literature using different assessments of arterial stiffness in various populations across the world to produce a comprehensive overview. Although there are many studies showing an association between arterial stiffness and loss of bone and muscle, the majority are cross-sectional and there is limited longitudinal evidence to justify causal conclusions. We also give an in-depth review of hypotheses and possible mechanisms which may underlie these associations including hormone dysregulation, impaired glucose metabolism, and inflammation. This narrative review highlights the associations between vessels, bones, and muscles with aging, offering insights into possible shared pathways.



Hypertension: 02 Aug 2020:HYPERTENSIONAHA12015184; epub ahead of print
Tap L, Kirkham FA, Mattace-Raso F, Joly L, Rajkumar C, Benetos A
Hypertension: 02 Aug 2020:HYPERTENSIONAHA12015184; epub ahead of print | PMID: 32755468
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Abstract

Renal Perfusion Pressure Determines Infiltration of Leukocytes in the Kidney of Rats With Angiotensin II-Induced Hypertension.

Shimada S, Abais-Battad JM, Alsheikh AJ, Yang C, ... Mattson DL, Cowley AW

The present study examined the extent to which leukocyte infiltration into the kidneys in Ang II (angiotensin II)-induced hypertension is determined by elevation of renal perfusion pressure (RPP). Male Sprague-Dawley rats were instrumented with carotid and femoral arterial catheters for continuous monitoring of blood pressure and a femoral venous catheter for infusion. An inflatable aortic occluder cuff placed between the renal arteries with computer-driven servo-controller maintained RPP to the left kidney at control levels during 7 days of intravenous Ang II (50 ng/kg per minute) or vehicle (saline) infusion. Rats were fed a 0.4% NaCl diet throughout the study. Ang II-infused rats exhibited nearly a 50 mm Hg increase of RPP (carotid catheter) to the right kidney while RPP to the left kidney (femoral catheter) was controlled at baseline pressure throughout the study. As determined at the end of the studies by flow cytometry, right kidneys exhibited significantly greater numbers of T cells, B cells, and monocytes/macrophages compared with the servo-controlled left kidneys and compared with vehicle treated rats. No difference was found between Ang II servo-controlled left kidneys and vehicle treated kidneys. Immunostaining found that the density of glomeruli, cortical, and outer medullary capillaries were significantly reduced in the right kidney of Ang II-infused rats compared with servo-controlled left kidney. We conclude that in this model of hypertension the elevation of RPP, not Ang II nor dietary salt, leads to leukocyte infiltration in the kidney and to capillary rarefaction.



Hypertension: 02 Aug 2020:HYPERTENSIONAHA12015295; epub ahead of print
Shimada S, Abais-Battad JM, Alsheikh AJ, Yang C, ... Mattson DL, Cowley AW
Hypertension: 02 Aug 2020:HYPERTENSIONAHA12015295; epub ahead of print | PMID: 32755400
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Abstract

C-allele of rs4769613 Near Represents a High-Confidence Placental Risk Factor for Preeclampsia.

Kikas T, Inno R, Ratnik K, Rull K, Laan M

The variant rs4769613 T/C within the enhancer element nearan acknowledged gene in preeclampsia, was previously identified as a risk factor for preeclampsia in the genome-wide association study (GWAS) targeting placental genotypes. We aimed to test the robustness of this association in 2 Estonian cohorts. Both placental sample sets HAPPY PREGNANCY (Development of novel non-invasive biomarkers for fertility and healthy pregnancy; preeclampsia, n=44 versus nonpreeclampsia, n=1724) and REPROMETA (REPROgrammed fetal and/or maternal METAbolism; 52/277) exhibited suggestive association between rs4769613[C] variant and preeclampsia (logistic regression adjusted for gestational age and fetal sex, nominal <0.05). Meta-analysis across 2 samples (96/2001) replicated the genome-wide association study outcome (Bonferroni corrected =4×10; odds ratio, 1.75 [95% CI, 1.23-2.49]). No association was detected with gestational diabetes mellitus, preterm birth, and newborn parameters. Also, neither maternal nor paternal rs4769613 genotypes predisposed to preeclampsia. The exact role of placental rs4769613 genotype in the preeclampsia pathogenesis is to be clarified as no effect was detected on maternal baseline serum sFlt-1 (soluble fms-related receptor tyrosine kinase 1) levels. However, when placentalgene expression and maternal serum sFlt-1 measurements were stratified by placental rs4769613 genotypes, significantly higher transcript and biomarker levels were detected in preeclampsia versus nonpreeclampsia cases in the CC- and CT- (Studenttest, ≤0.02), but not in the TT-genotype subgroup. We suggest that rs4769613 represents a conditional expression Quantitative Trait Locus, whereby only the enhancer with the C-allele reacts to promote theexpression in unfavorable placental conditions. The study highlighted that the placentalrs4769613 C-allele is a preeclampsia-specific risk factor. It may contribute to early identification of high-risk women, for example, when genotyped in the cffDNA available in maternal blood plasma.



Hypertension: 02 Aug 2020:HYPERTENSIONAHA12015346; epub ahead of print
Kikas T, Inno R, Ratnik K, Rull K, Laan M
Hypertension: 02 Aug 2020:HYPERTENSIONAHA12015346; epub ahead of print | PMID: 32755415
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Abstract

Phenotypical, Clinical, and Molecular Aspects of Adults and Children With Homozygous Familial Hypercholesterolemia in Iberoamerica.

Alves AC, Alonso R, Diaz-Diaz JL, Medeiros AM, ... Bourbon M, Santos RD
Objective
Characterize homozygous familial hypercholesterolemia (HoFH) individuals from Iberoamerica. Approach and Results: In a cross-sectional retrospective evaluation 134 individuals with a HoFH phenotype, 71 adults (age 39.3±15.8 years, 38.0% males), and 63 children (age 8.8±4.0 years, 50.8% males) were studied. Genetic characterization was available in 129 (96%). The majority (91%) were true homozygotes (true HoFH, n=79, 43.0% children, 46.8% males) or compound heterozygotes (compound heterozygous familial hypercholesterolemia, n=39, 51.3% children, 46.2% males) with putative pathogenic variants in the . True HoFH due tovariants had higher total (=0.015) and LDL (low-density lipoprotein)-cholesterol (=0.008) compared with compound heterozygous familial hypercholesterolemia. Children with true HoFH (n=34) tended to be diagnosed earlier (=0.051) and had a greater frequency of xanthomas (=0.016) than those with compound heterozygous familial hypercholesterolemia (n=20). Previous major cardiovascular events were present in 25 (48%) of 52 children (missing information in 2 cases), and in 43 (67%) of 64 adults withvariants. Children who are true HoFH had higher frequency of major cardiovascular events (=0.02), coronary heart (=0.013), and aortic/supra-aortic valve diseases (=0.022) than compound heterozygous familial hypercholesterolemia. In adults, no differences were observed in major cardiovascular events according to type ofvariant. From 118 subjects withvariants, 76 (64%) had 2 likely pathogenic or pathogenic variants. In 89 subjects with 2variants, those with at least one null allele were younger (=0.003) and had a greater frequency of major cardiovascular events (=0.038) occurring at an earlier age (=0.001).
Conclusions
There was a high frequency of cardiovascular disease even in children. Phenotype and cardiovascular complications were heterogeneous and associated with the type of molecular defect.



Arterioscler Thromb Vasc Biol: 05 Aug 2020:ATVBAHA120313722; epub ahead of print
Alves AC, Alonso R, Diaz-Diaz JL, Medeiros AM, ... Bourbon M, Santos RD
Arterioscler Thromb Vasc Biol: 05 Aug 2020:ATVBAHA120313722; epub ahead of print | PMID: 32757650
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Abstract

Poly(ADP-Ribose) Polymerase Activity and Coronary Artery Disease in Type 2 Diabetes Mellitus: An Observational and Bidirectional Mendelian Randomization Study.

Cui NH, Yang JM, Liu X, Wang XB
Objective
Experimental evidence suggests a close link between PARP (poly[ADP-ribose] polymerase) activation and diabetic endothelial dysfunction. Here, we tested whether PARP activity in circulating leukocytes was associated with coronary artery disease (CAD) among patients with type 2 diabetes mellitus (T2DM). Approach and Results: We performed observational and bidirectional Mendelian randomization studies of 3149 Chinese individuals with T2DM who underwent coronary angiography, with leukocyte PARP activity, 16 tag single-nucleotide polymorphisms inand , and 17 CAD risk single-nucleotide polymorphisms analyzed. Of 3149 participants, 1180 who further received percutaneous coronary intervention were prospectively followed for 1 year to track major adverse cardiovascular and cerebrovascular events. Overall, greater PARP activity was cross-sectionally associated with an odds ratio of 1.23 for obstructive CAD, and prospectively with a hazard ratio of 1.34 for 1-year major adverse cardiovascular and cerebrovascular events after percutaneous coronary intervention (both <0.001). Using a genetic score of 5 screened single-nucleotide polymorphisms inandas the instrumental variable, genetically predicted elevation in PARP activity showed a causal association with obstructive CAD (odds ratio=1.35, <0.001). In contrast, the genetic risk of CAD had no significant effect on PARP activity. Ex vivo and in vitro cultures of human monocytes showed that rs747657, as the lead single-nucleotide polymorphism strongly associated with PARP activity, caused the differential binding of transcription factor GATA2 to an intronic regulatory region in , thus modulatingexpression and PARP activity.
Conclusions
Greater PARP activity may have causal roles in the development of obstructive CAD among patients with diabetes mellitus.



Arterioscler Thromb Vasc Biol: 05 Aug 2020:ATVBAHA120314712; epub ahead of print
Cui NH, Yang JM, Liu X, Wang XB
Arterioscler Thromb Vasc Biol: 05 Aug 2020:ATVBAHA120314712; epub ahead of print | PMID: 32757651
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Abstract

Apolipoprotein CIII Deficiency Protects Against Atherosclerosis in Knockout Rabbits.

Yan H, Niimi M, Matsuhisa F, Zhou H, ... Chen YE, Fan J
Objective
Apo (apolipoprotein) CIII mediates the metabolism of triglyceride (TG)-rich lipoproteins. High levels of plasma apoCIII are positively correlated with the plasma TG levels and increase the cardiovascular risk. However, whether apoCIII is directly involved in the development of atherosclerosis has not been fully elucidated. Approach and Results: To examine the possible roles of apoCIII in lipoprotein metabolism and atherosclerosis, we generated apoCIII KO (knockout) rabbits using ZFN (zinc finger nuclease) technique. On a normal standard diet, apoCIII KO rabbits exhibited significantly lower plasma levels of TG than those of WT (wild type) rabbits while total cholesterol and HDL (high-density lipoprotein) cholesterol levels were unchanged. Analysis of lipoproteins isolated by sequential ultracentrifugation revealed that reduced plasma TG levels in KO rabbits were accompanied by prominent reduction of VLDLs (very-low-density lipoproteins) and IDLs (intermediate-density lipoproteins). In addition, KO rabbits showed faster TG clearance rate after intravenous fat load than WT rabbits. On a cholesterol-rich diet, KO rabbits exhibited constantly and significantly lower levels of plasma total cholesterol and TG than WT rabbits, which was caused by a remarkable reduction of β-VLDLs-the major atherogenic lipoproteins. β-VLDLs of KO rabbits showed higher uptake by cultured hepatocytes and were cleared faster from the circulation than β-VLDLs isolated from WT rabbits. Both aortic and coronary atherosclerosis was significantly reduced in KO rabbits compared with WT rabbits.
Conclusions
These results indicate that apoCIII deficiency facilitates TG-rich lipoprotein catabolism, and therapeutic inhibition of apoCIII expression may become a novel means not only for the treatment of hyperlipidemia but also for atherosclerosis.



Arterioscler Thromb Vasc Biol: 05 Aug 2020:ATVBAHA120314368; epub ahead of print
Yan H, Niimi M, Matsuhisa F, Zhou H, ... Chen YE, Fan J
Arterioscler Thromb Vasc Biol: 05 Aug 2020:ATVBAHA120314368; epub ahead of print | PMID: 32757647
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Abstract

Plasma Biomarkers and Identification of Resilient Metabolic Disruptions in Patients With Venous Thromboembolism Using a Metabolic Systems Approach.

Fraser K, Roy NC, Goumidi L, Verdu A, ... Morange PE, Martin JC
Objective
Deep vein thrombosis and pulmonary embolism referred as venous thromboembolism (VTE) are a common cause of morbidity and mortality. Plasma from healthy controls or individuals who have experienced a VTE were analyzed using metabolomics to characterize biomarkers and metabolic systems of patients with VTE. Approach and Results: Polar metabolite and lipidomic profiles from plasma collected 3 months after an incident VTE were obtained using liquid chromatography mass spectrometry. Fasting-state plasma samples from 42 patients with VTE and 42 healthy controls were measured. Plasma metabolomic profiling identified 512 metabolites forming 62 biological clusters. Multivariate analysis revealed a panel of 21 metabolites altogether capable of predicting VTE status with an area under the curve of 0.92 (=0.00174, selectivity=0.857, sensitivity=0.971). Multiblock systems analysis revealed 25 of the 62 functional biological groups as significantly affected in the VTE group (<0.05 to control). Complementary correlation network analysis of the dysregulated functions highlighting a subset of the lipidome composed mainly of n-3 long-chain polyunsaturated fatty acids within the predominant triglycerides as a potential regulator of the post-VTE event biological response, possibly controlling oxidative and inflammatory defence systems, and metabolic disorder associated dysregulations. Of interest was microbiota metabolites including trimethylamine N-oxide that remained associated to post incident VTE patients, highlighting a possible involvement of gut microbiota on VTE risk and relapse.
Conclusions
These findings show promise for the elucidation of underlying mechanisms and the design of a diagnostic test to assess the likely efficacy of clinical care in patients with VTE.



Arterioscler Thromb Vasc Biol: 05 Aug 2020:ATVBAHA120314480; epub ahead of print
Fraser K, Roy NC, Goumidi L, Verdu A, ... Morange PE, Martin JC
Arterioscler Thromb Vasc Biol: 05 Aug 2020:ATVBAHA120314480; epub ahead of print | PMID: 32757649
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Abstract

Role of Extracellular Vesicles in Pulmonary Arterial Hypertension: Modulation of Pulmonary Endothelial Function and Angiogenesis.

Khandagale A, Åberg M, Wikström G, Lind SB, ... Siegbahn A, Christersson C
Objective
Extracellular vesicles (EVs) have the potential to act as intercellular communicators. The aims were to characterize circulating EVs in patients with pulmonary arterial hypertension (PAH) and to explore whether these EVs contribute to endothelial activation and angiogenesis. Approach and Results: Patients with PAH (n=70) and healthy controls (HC; n=20) were included in this cross-sectional study. EVs were characterized and human pulmonary endothelial cells (hPAECs) were incubated with purified EVs. Endothelial cell activity and proangiogenic markers were analyzed. Tube formation analysis was performed for hPAECs, and the involvement of PSGL-1 (P-selectin glycoprotein ligand 1) was evaluated. The numbers of CD62P, CD144, and CD235a EVs were higher in blood from PAH compared with HC. Thirteen proteins were differently expressed in PAH and HC EVs, where complement fragment C1q was the most significantly elevated protein (=0.0009) in PAH EVs. Upon EVs-internalization in hPAECs, more PAH compared with HC EVs evaded lysosomes (<0.01). As oppose to HC, PAH EVs stimulated hPAEC activation and induced transcription and translation of VEGF-A (vascular endothelial growth factor A; <0.05) and FGF (fibroblast growth factor; <0.005) which were released in the cell supernatant. These proangiogenic proteins were higher in patient with PAH plasma compered with HC. PAH EVs induced a complex network of angiotubes in vitro, which was abolished by inhibitory PSGL-1antibody. Anti-PSGL-1 also inhibited EV-induced endothelial cell activation and PAH EV dependent increase of VEGF-A.
Conclusions
Patients with PAH have higher levels of EVs harboring increased amounts of angiogenic proteins, which induce activation of hPAECs and in vitro angiogenesis. These effects were partly because of platelet-derived EVs evasion of lysosomes upon internalization within hPAEC and through possible involvement of P-selectin-PSGL-1 pathway.



Arterioscler Thromb Vasc Biol: 05 Aug 2020:ATVBAHA120314152; epub ahead of print
Khandagale A, Åberg M, Wikström G, Lind SB, ... Siegbahn A, Christersson C
Arterioscler Thromb Vasc Biol: 05 Aug 2020:ATVBAHA120314152; epub ahead of print | PMID: 32757648
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Abstract

Endothelial Dysfunction and Thrombosis in Patients With COVID-19.

Nagashima S, Mendes MC, Camargo Martins AP, Borges NH, ... Machado-Souza C, de Noronha L
Objective
Alveolar-capillary endothelial cells can be activated by severe acute respiratory syndrome coronavirus 2 infection leading to cytokine release. This could trigger endothelial dysfunction, pyroptosis, and thrombosis, which are the vascular changes, commonly referred to as coronavirus disease 2019 (COVID-19) endotheliopathy. Thus, this study aimed to identify tissue biomarkers associated with endothelial activation/dysfunction and the pyroptosis pathway in the lung samples of patients with COVID-19 and to compare them to pandemic influenza A virus H1N1 subtype 2009 and control cases. Approach and Results: Postmortem lung samples (COVID-19 group =6 cases; H1N1 group =10 cases, and control group =11 cases) were analyzed using immunohistochemistry and the following monoclonal primary antibodies: anti-IL (interleukin)-6, anti-TNF (tumor necrosis factor)-α, anti-ICAM-1 (intercellular adhesion molecule 1), and anticaspase-1. From the result, IL-6, TNF-α, ICAM-1, and caspase-1 showed higher tissue expression in the COVID-19 group than in the H1N1 and control groups.
Conclusions
Our results demonstrated endothelial dysfunction and suggested the participation of the pyroptosis pathway in the pulmonary samples. These conditions might lead to systemic thrombotic events that could impair the clinical staff\'s efforts to avoid fatal outcomes. One of the health professionals\' goals should be to identify the high risk of thrombosis patients early to block endotheliopathy and its consequences.



Arterioscler Thromb Vasc Biol: 06 Aug 2020:ATVBAHA120314860; epub ahead of print
Nagashima S, Mendes MC, Camargo Martins AP, Borges NH, ... Machado-Souza C, de Noronha L
Arterioscler Thromb Vasc Biol: 06 Aug 2020:ATVBAHA120314860; epub ahead of print | PMID: 32762443
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Abstract

Long Noncoding RNA Rps4l Mediates the Proliferation of Hypoxic Pulmonary Artery Smooth Muscle Cells.

Liu Y, Zhang H, Li Y, Yan L, ... Li G, Zhu D

Pulmonary hypertension (PH) is a rare and fatal disorder involving the vascular remodeling of pulmonary arteries mediated by the enhanced proliferation of pulmonary artery smooth muscle cells (PASMCs). Long noncoding RNAs are a subclass of regulatory molecules with diverse cellular functions, but their role in PH remains largely unexplored. We aimed to identify and determine the functions of long noncoding RNAs involved in hypoxia-induced PH and PASMC proliferation. RNA sequencing in a hypoxic mouse model identified hypoxia-regulated long noncoding RNAs, including Rps4l. Rps4l expression was significantly reduced in PH-model mice and hypoxic PASMCs. The subcellular localization of Rps4l was detected by RNA fluorescence in situ hybridization and quantification of nuclear/cytoplasmic RNA. Rps4l overexpression rescued pulmonary arterial hypertension features, as demonstrated by right ventricle hypertrophy, right ventricular systolic pressure, hemodynamics, cardiac function, and vascular remodeling. At the cellular level, Rps4l overexpression weakened cell viability and proliferation and suppressed cell cycle progression. Potential Rps4l-binding proteins were identified via RNA pull-down followed by mass spectrometry, RNA immunoprecipitation, and microscale thermophoresis. These results indicated that Rps4l is associated with and affects the stabilization of ILF3 (interleukin enhancer-binding factor 3). Rps41 further regulates the levels of HIF-1α and consequently leads to hypoxia-induced PASMC proliferation and migration. Our results showed that in hypoxic PASMCs, Rps4l expression decreases due to regulation by hypoxia. This decrease affects the proliferation, migration, and cell cycle progression of PASMCs through ILF3/HIF-1α. These results provide a theoretical basis for further investigations into the pathological mechanism of hypoxic PH and may provide insight for the development of novel treatments.



Hypertension: 09 Aug 2020:HYPERTENSIONAHA12014644; epub ahead of print
Liu Y, Zhang H, Li Y, Yan L, ... Li G, Zhu D
Hypertension: 09 Aug 2020:HYPERTENSIONAHA12014644; epub ahead of print | PMID: 32772647
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Abstract

Progress of Gene Therapy in Cardiovascular Disease.

Shimamura M, Nakagami H, Sanada F, Morishita R

Gene therapy has been extensively studied in peripheral and cardiac ischemia, heart and vein graft failure, and dyslipidemia, but most clinical trials failed to show their efficacies despite good outcomes in preclinical studies. So far, 2 gene therapies for dyslipidemia and one for critical limb ischemia in peripheral artery disease have been approved. In critical limb ischemia, gene therapy using proangiogenic factors has emerged as a novel therapeutic modality for promoting angiogenesis. Initial researches mainly focused on vascular endothelial growth factor, fibroblast growth factor, or hepatocyte growth factor. After the favorable results of basic research, several phase I and II clinical trials of these proangiogenic factors have shown promising results. However, only a phase III clinical trial of the intramuscular injection of hepatocyte growth factor plasmid DNA has shown successful outcomes, and it was recently approved in Japan for treating patients with critical limb ischemia who have ulcers and for whom no alternative therapeutic options are available. DNA vaccine is another promising modality of gene therapy. An antitumor vaccine suppressing angiogenesis through the inhibition of proangiogenic factors and an antihypertensive vaccine inhibiting the renin-angiotensin system are representative DNA vaccines. The advantage of DNA vaccine is its long-term effectiveness with a few vaccinations; however, the benefits and risks, such as adverse T-cell reaction against self-antigen or long-term side effects, of DNA vaccines should be carefully evaluated. In this review, we discuss the recent advances in proangiogenic gene therapy for critical limb ischemia and DNA vaccine for hypertension.



Hypertension: 09 Aug 2020:HYPERTENSIONAHA12014478; epub ahead of print
Shimamura M, Nakagami H, Sanada F, Morishita R
Hypertension: 09 Aug 2020:HYPERTENSIONAHA12014478; epub ahead of print | PMID: 32772646
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Abstract

Predictive Value of Pulmonary Arterial Compliance in Systemic Lupus Erythematosus Patients With Pulmonary Arterial Hypertension.

Guo X, Lai J, Wang H, Tian Z, ... Liu Y, Zeng X

Pulmonary arterial hypertension is a serious complication of systemic lupus erythematosus. It is characterized by increased right ventricular afterload which mainly comprises pulmonary arterial compliance (PAC) and pulmonary vascular resistance. The role of PAC in predicting the outcome of systemic lupus erythematosus-associated pulmonary arterial hypertension has not been investigated yet. Between February 2012 to December 2016, 120 consecutive patients diagnosed with systemic lupus erythematosus-associated pulmonary arterial hypertension based on right heart catheterization were enrolled, prospectively. Baseline clinical characteristics and hemodynamic assessment were analyzed. Baseline right ventricular afterload was stratified according to the PAC and pulmonary vascular resistance. The end point was a composite of all-cause mortality and clinical worsening. Among them, end points occurred in 49 (41%) patients after 15 months (interquartile range, 8.5-24.0). Patients with a PAC <1.39 mL/mm Hg had a 3.09-fold higher risk (95% CI, 1.54-6.20, =0.001) of the end point events than the patients with a PAC ≥1.39 mL/mm Hg. Multivariable Cox regression analysis showed that stratified right ventricular afterload was the only independent predictor for the end point (hazard ratio, 2.009 [95% CI, 1.390-2.904], <0.001). A 3-group prediction risk was created. The patients with the highest right ventricular afterload (PAC <1.39 mL/mm Hg and pulmonary vascular resistance ≥10.3Wood Unit) had the highest risk (χ, 6.10; <0.014) of experiencing the end point. Our results suggest that PAC is a good predictor of mortality and clinical worsening in systemic lupus erythematosus-associated pulmonary arterial hypertension. PAC, in addition to pulmonary vascular resistance, may be an attractive tool for screening high-risk populations in these patients.



Hypertension: 09 Aug 2020:HYPERTENSIONAHA12015682; epub ahead of print
Guo X, Lai J, Wang H, Tian Z, ... Liu Y, Zeng X
Hypertension: 09 Aug 2020:HYPERTENSIONAHA12015682; epub ahead of print | PMID: 32772648
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Abstract

Heart Failure With Reduced Ejection Fraction: A Review.

Murphy SP, Ibrahim NE, Januzzi JL
Importance
Worldwide, the burden of heart failure has increased to an estimated 23 million people, and approximately 50% of cases are HF with reduced ejection fraction (HFrEF).
Observations
Heart failure is a clinical syndrome characterized by dyspnea or exertional limitation due to impairment of ventricular filling or ejection of blood or both. HFrEF occurs when the left ventricular ejection fraction (LVEF) is 40% or less and is accompanied by progressive left ventricular dilatation and adverse cardiac remodeling. Assessment for heart failure begins with obtaining a medical history and physical examination. Also central to diagnosis are elevated natriuretic peptides above age- and context-specific thresholds and identification of left ventricular systolic dysfunction with LVEF of 40% or less as measured by echocardiography. Treatment strategies include the use of diuretics to relieve symptoms and application of an expanding armamentarium of disease-modifying drug and device therapies. Unless there are specific contraindications, patients with HFrEF should be treated with a β-blocker and one of an angiotensin receptor-neprilysin inhibitor, angiotensin-converting enzyme inhibitor, or angiotensin receptor blocker as foundational therapy, with addition of a mineralocorticoid receptor antagonist in patients with persistent symptoms. Ivabradine and hydralazine/isosorbide dinitrate also have a role in the care of certain patients with HFrEF. More recently, sodium-glucose cotransporter 2 (SGLT2) inhibitors have further improved disease outcomes, significantly reducing cardiovascular and all-cause mortality irrespective of diabetes status, and vericiguat, a soluble guanylate cyclase stimulator, reduces heart failure hospitalization in high-risk patients with HFrEF. Device therapies may be beneficial in specific subpopulations, such as cardiac resynchronization therapy in patients with interventricular dyssynchrony, transcatheter mitral valve repair in patients with severe secondary mitral regurgitation, and implantable cardiac defibrillators in patients with more severe left ventricular dysfunction particularly of ischemic etiology.
Conclusions and relevance
HFrEF is a major public health concern with substantial morbidity and mortality. The management of HFrEF has seen significant scientific breakthrough in recent decades, and the ability to alter the natural history of the disease has never been better. Recent developments include SGLT2 inhibitors, vericiguat, and transcatheter mitral valve repair, all of which incrementally improve prognosis beyond foundational neurohormonal therapies. Disease morbidity and mortality remain high, with a 5-year survival rate of 25% after hospitalization for HFrEF.



JAMA: 03 Aug 2020; 324:488-504
Murphy SP, Ibrahim NE, Januzzi JL
JAMA: 03 Aug 2020; 324:488-504 | PMID: 32749493
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Abstract

Association of Diagnosis Coding With Differences in Risk-Adjusted Short-term Mortality Between Critical Access and Non-Critical Access Hospitals.

Kosar CM, Loomer L, Thomas KS, White EM, Panagiotou OA, Rahman M
Importance
Critical access hospitals (CAHs) provide care to rural communities. Increasing mortality rates have been reported for CAHs relative to non-CAHs. Because Medicare reimburses CAHs at cost, CAHs may report fewer diagnoses than non-CAHs, which may affect risk-adjusted comparisons of outcomes.
Objective
To assess serial differences in risk-adjusted mortality rates between CAHs and non-CAHs after accounting for differences in diagnosis coding.
Design, setting, and participants
Serial cross-sectional study of rural Medicare Fee-for-Service beneficiaries admitted to US CAHs and non-CAHs for pneumonia, heart failure, chronic obstructive pulmonary disease, arrhythmia, urinary tract infection, septicemia, and stroke from 2007 to 2017. The final date of follow-up was December 31, 2017.
Exposure
Admission to a CAH vs non-CAH.
Main outcomes and measures
Discharge diagnosis count including trends from 2010 to 2011 when Medicare expanded the allowable number of billing codes for hospitalizations, and combined in-hospital and 30-day postdischarge mortality adjusted for demographics, primary diagnosis, preexisting conditions, and with vs without further adjustment for Hierarchical Condition Category (HCC) score to understand the contribution of in-hospital secondary diagnoses.
Results
There were 4 094 720 hospitalizations (17% CAH) for 2 850 194 unique Medicare beneficiaries (mean [SD] age, 76.3 [11.7] years; 55.5% women). Patients in CAHs were older (median age, 80.1 vs 76.8 years) and more likely to be female (58% vs 55%). In 2010, the adjusted mean discharge diagnosis count was 7.52 for CAHs vs 8.53 for non-CAHs (difference, -0.99 [95% CI, -1.08 to -0.90]; P < .001). In 2011, the CAH vs non-CAH difference in diagnoses coded increased (P < .001 for interaction between CAH and year) to 9.27 vs 12.23 (difference, -2.96 [95% CI, -3.19 to -2.73]; P < .001). Adjusted mortality rates from the model with HCC were 13.52% for CAHs vs 11.44% for non-CAHs (percentage point difference, 2.08 [95% CI, 1.74 to 2.42]; P < .001) in 2007 and increased to 15.97% vs 12.46% (difference, 3.52 [95% CI, 3.09 to 3.94]; P < .001) in 2017 (P < .001 for interaction). Adjusted mortality rates from the model without HCC were not significantly different between CAHs and non-CAHs in all years except 2007 (12.19% vs 11.74%; difference, 0.45 [95% CI, 0.12 to 0.79]; P = .008) and 2010 (12.71% vs 12.28%; difference, 0.42 [95% CI, 0.07 to 0.77]; P = .02).
Conclusions and relevance
For rural Medicare beneficiaries hospitalized from 2007 to 2017, CAHs submitted significantly fewer hospital diagnosis codes than non-CAHs, and short-term mortality rates adjusted for preexisting conditions but not in-hospital comorbidity measures were not significantly different by hospital type in most years. The findings suggest that short-term mortality outcomes at CAHs may not differ from those of non-CAHs after accounting for different coding practices for in-hospital comorbidities.



JAMA: 03 Aug 2020; 324:481-487
Kosar CM, Loomer L, Thomas KS, White EM, Panagiotou OA, Rahman M
JAMA: 03 Aug 2020; 324:481-487 | PMID: 32749490
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Abstract

Real-world evidence on the use of benzodiazepine receptor agonists and the risk of venous thromboembolism.

Chen TY, Winkelman JW, Mao WC, Tzeng NS, ... Tsai HJ, Wu CS
Background
Venous thromboembolism (VTE) is a life-threatening disease, and some studies reported that benzodiazepine receptor agonist (BZRA) use could increase the risk of VTE, but this association lacks population-based evidence.
Objectives
To investigate the association between BZRA use and the risk of VTE.
Patients/methods
A nested case-control study analyzing Taiwan\'s claims database was conducted of patients with at least one new BZRA prescription on record from January 1, 2002, to December 31, 2012. We included new users who did not have any BZRA prescriptions in the preceding 2 years and identified cases with VTE and disease risk score matched control subjects. We used a logistic regression model to investigate the association between BZRA exposure and the risk of VTE. The exposure duration, dose, and classes of BZRAs were comprehensively evaluated.
Results
We identified 2,800 VTE cases and 2,800 matched controls. Current BZRA prescription (≤ 90 days) was associated with VTE occurrence (adjusted Odds Ratios [aOR]:1.83; 95% CI: 1.62-2.06). The point estimates of benzodiazepine hypnotics (aOR: 2.00; 95% CI: 1.45-2.76) had a marginally higher risk of VTE than non-benzodiazepine hypnotics (aOR: 1.39; 95% CI: 1.07-1.81). The VTE risk was increased with combination BZRA use, number of BZRA used, and a higher dose of BZRA. On examination of individual BZRA, the risk of VTE was higher with flunitrazepam use (aOR: 2.99; 95% CI: 1.43-6.28) than other BZRAs.
Conclusions
This study presents that current BZRA use may increase the risk of VTE. Also, benzodiazepine hypnotics, especially flunitrazepam, have a higher risk of VTE.

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J Thromb Haemost: 01 Aug 2020; epub ahead of print
Chen TY, Winkelman JW, Mao WC, Tzeng NS, ... Tsai HJ, Wu CS
J Thromb Haemost: 01 Aug 2020; epub ahead of print | PMID: 32741123
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Abstract

Effect of Long-term Vitamin D3 Supplementation vs Placebo on Risk of Depression or Clinically Relevant Depressive Symptoms and on Change in Mood Scores: A Randomized Clinical Trial.

Okereke OI, Reynolds CF, Mischoulon D, Chang G, ... Buring JE, Manson JE
Importance
Low levels of 25-hydroxyvitamin D have been associated with higher risk for depression later in life, but there have been few long-term, high-dose large-scale trials.
Objective
To test the effects of vitamin D3 supplementation on late-life depression risk and mood scores.
Design, setting, and participants
There were 18 353 men and women aged 50 years or older in the VITAL-DEP (Vitamin D and Omega-3 Trial-Depression Endpoint Prevention) ancillary study to VITAL, a randomized clinical trial of cardiovascular disease and cancer prevention among 25 871 adults in the US. There were 16 657 at risk for incident depression (ie, no depression history) and 1696 at risk for recurrent depression (ie, depression history but no treatment for depression within the past 2 years). Randomization occurred from November 2011 through March 2014; randomized treatment ended on December 31, 2017, and this was the final date of follow-up.
Intervention
Randomized assignment in a 2 × 2 factorial design to vitamin D3 (2000 IU/d of cholecalciferol) and fish oil or placebo; 9181 were randomized to vitamin D3 and 9172 were randomized to matching placebo.
Main outcomes and measures
The primary outcomes were the risk of depression or clinically relevant depressive symptoms (total of incident and recurrent cases) and the mean difference in mood scores (8-item Patient Health Questionnaire depression scale [PHQ-8]; score range, 0 points [least symptoms] to 24 points [most symptoms]; the minimal clinically important difference for change in scores was 0.5 points).
Results
Among the 18 353 randomized participants (mean age, 67.5 [SD, 7.1] years; 49.2% women), the median treatment duration was 5.3 years and 90.5% completed the trial (93.5% among those alive at the end of the trial). Risk of depression or clinically relevant depressive symptoms was not significantly different between the vitamin D3 group (609 depression or clinically relevant depressive symptom events; 12.9/1000 person-years) and the placebo group (625 depression or clinically relevant depressive symptom events; 13.3/1000 person-years) (hazard ratio, 0.97 [95% CI, 0.87 to 1.09]; P = .62); there were no significant differences between groups in depression incidence or recurrence. No significant differences were observed between treatment groups for change in mood scores over time; mean change in PHQ-8 score was not significantly different from zero (mean difference for change in mood scores, 0.01 points [95% CI, -0.04 to 0.05 points]).
Conclusions and relevance
Among adults aged 50 years or older without clinically relevant depressive symptoms at baseline, treatment with vitamin D3 compared with placebo did not result in a statistically significant difference in the incidence and recurrence of depression or clinically relevant depressive symptoms or for change in mood scores over a median follow-up of 5.3 years. These findings do not support the use of vitamin D3 in adults to prevent depression.
Trial registration
ClinicalTrials.gov Identifiers: NCT01169259 and NCT01696435.



JAMA: 03 Aug 2020; 324:471-480
Okereke OI, Reynolds CF, Mischoulon D, Chang G, ... Buring JE, Manson JE
JAMA: 03 Aug 2020; 324:471-480 | PMID: 32749491
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Abstract

Non-invasive recanalization of deep venous thrombosis by high frequency ultrasound in a swine model with follow-up.

Goudot G, Khider L, Del Giudice C, Mirault T, ... Messas E, Pernot M
Aims
Pulsed Cavitational Ultrasound Therapy (thombotripsy) allows the accurate fractionation of a distant thrombus. We aimed at evaluating the efficacy and safety of non-invasive thrombotripsy using a robotic assisted and high frequency ultrasound approach to recanalize proximal deep venous thrombosis (DVT) in a swine model.
Methods
Occlusive thrombosis was obtained with a dual jugular and femoral endoveinous approach. The therapeutic device was composed of a 2.25 MHz focused transducer centred by a linear ultrasound probe, and a robotic arm. The feasibility, security, and efficacy (venous channel patency) assessment after thrombotripsy was performed on 13 pigs with acute occluded DVT. To assess the mid-term efficacy of this technique, 8 pigs were followed up for 14 days after thrombotripsy and compared with 8 control pigs. The primary efficacy endpoint was the venous patency. Safety was assessed by the search for local vessel wall injury and pulmonary embolism.
Results
We succeeded in treating all pigs except 2 with no accessible femoral vein. After median treatment duration of 23 min of cavitation, all treated DVT were fully recanalized acutely. At 14 days, in the treated group, 6 of the 8 pigs had a persistent patent vein and 2 pigs had a venous reocclusion. In the control group all pigs had a persistent venous occlusion. At sacrifice, no local vein nor arterial wall damage were observed as well as no evidence of pulmonary embolism in all pigs.
Conclusion
High frequency thrombotripsy seems to be effective and safe for non-invasive venous recanalization of DVT.

This article is protected by copyright. All rights reserved.

J Thromb Haemost: 01 Aug 2020; epub ahead of print
Goudot G, Khider L, Del Giudice C, Mirault T, ... Messas E, Pernot M
J Thromb Haemost: 01 Aug 2020; epub ahead of print | PMID: 32741128
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Abstract

B-type natriuretic peptide and cardiac remodelling after myocardial infarction: a randomised trial.

Hubers SA, Schirger JA, Sangaralingham SJ, Chen Y, ... Hodge D, Chen HH
Objective
B-type natriuretic peptide (BNP) has favourable effects on left ventricular remodelling, including antifibrotic and antiapoptotic properties. We tested the hypothesis that infusion of BNP after an acute myocardial infarction would reduce left ventricular systolic and diastolic volumes and improve left ventricular ejection fraction compared with placebo.
Methods
A total of 58 patients who underwent successful revascularisation for an acute ST elevation anterior myocardial infarction were randomised to receive 72-hour infusion of BNP at 0.006 µg/kg/min or placebo. Left ventricular end diastolic and systolic volumes and left ventricular ejection fraction were measured at baseline and at 30 days by multigated acquisition scan. Left ventricular infarction size was measured by cardiac MRI.
Results
BNP infusion led to significantly higher BNP levels and plasma cyclic guanosine monophosphate at 72 hours. No significant difference in change of left ventricular volumes or ejection fraction from baseline to 30 days was observed between groups. Although left ventricular infarction size measured by cardiac MRI was not significantly different between BNP infusion versus placebo (p=0.39), there was a trend towards reduced infarction size in patients with a baseline ejection fraction of <40% (p=0.14).
Conclusions
Infusion of BNP in patients with an anterior myocardial infarction did not affect parameters of left ventricular remodelling. Patients treated with BNP who had a baseline left ventricular ejection fraction of <40% had a trend towards reduced left ventricular infarction size compared with placebo. These results do not support the use of intravenous BNP in patients after recent myocardial infarction.
Trial registration number
NCT00573144.

© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 02 Aug 2020; epub ahead of print
Hubers SA, Schirger JA, Sangaralingham SJ, Chen Y, ... Hodge D, Chen HH
Heart: 02 Aug 2020; epub ahead of print | PMID: 32747497
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Abstract

The \'wait for symptoms\' strategy in asymptomatic severe aortic stenosis.

San Román JA, Vilacosta I, Antunes MJ, Iung B, Lopez J, Schäfers HJ

Calcific aortic stenosis is a prevalent and worrisome healthcare problem. The therapeutic approach in asymptomatic aortic stenosis is not well established. We argue that the natural history of this disease is based on old incomplete studies with many limitations. Likewise, studies suggesting that replacement, either surgical or percutaneous, improves prognosis in asymptomatic patients with severe aortic stenosis have important drawbacks and do not support this strategy as the treatment of choice. Despite the lack of evidence, some groups recommend early valve replacement in patients with severe asymptomatic aortic stenosis. There are five ongoing randomised trials which will shed light on this topic. Our conclusion is that unless a randomised study changes the evidence, valve replacement cannot be recommended in asymptomatic patients with severe aortic stenosis.

© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 02 Aug 2020; epub ahead of print
San Román JA, Vilacosta I, Antunes MJ, Iung B, Lopez J, Schäfers HJ
Heart: 02 Aug 2020; epub ahead of print | PMID: 32747494
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Abstract

In Memory of Professor Sadaaki Iwanaga, 1933-2020.

Kini RM, Kawabata SI, Miyata T

On Sunday June 21, 2020, our beloved teacher and mentor Professor Sadaaki Iwanaga passed away in Fukuoka, Japan, at the age of 87. He was a pioneer who made immense contributions to our understanding of blood coagulation factors and hemolymph clotting system of the horseshoe crab. He was born in Tokyo, Japan on January 5, 1933. During his high school education, he was an avid baseball player full of energy and enthusiasm. Professor Iwanaga lists losing the final of a regional qualifying round as one of the most serious blunders of his life.

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J Thromb Haemost: 01 Aug 2020; epub ahead of print
Kini RM, Kawabata SI, Miyata T
J Thromb Haemost: 01 Aug 2020; epub ahead of print | PMID: 32741061
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Abstract

Endothelial dysfunction in COVID-19: a position paper of the ESC Working Group for Atherosclerosis and Vascular Biology, and the ESC Council of Basic Cardiovascular Science.

Evans PC, Ed Rainger G, Mason JC, Guzik TJ, ... Bochaton-Piallat ML, Bäck M

The COVID-19 pandemic is an unprecedented healthcare emergency causing mortality and illness across the world. Although primarily affecting the lungs, the SARS-CoV-2 virus also affects the cardiovascular system. In addition to cardiac effects, e.g. myocarditis, arrhythmias, and myocardial damage, the vasculature is affected in COVID-19, both directly by the SARS-CoV-2 virus, and indirectly as a result of a systemic inflammatory cytokine storm. This includes the role of the vascular endothelium in the recruitment of inflammatory leucocytes where they contribute to tissue damage and cytokine release, which are key drivers of acute respiratory distress syndrome (ARDS), in disseminated intravascular coagulation, and cardiovascular complications in COVID-19. There is also evidence linking endothelial cells (ECs) to SARS-CoV-2 infection including: (i) the expression and function of its receptor angiotensin-converting enzyme 2 (ACE2) in the vasculature; (ii) the prevalence of a Kawasaki disease-like syndrome (vasculitis) in COVID-19; and (iii) evidence of EC infection with SARS-CoV-2 in patients with fatal COVID-19. Here, the Working Group on Atherosclerosis and Vascular Biology together with the Council of Basic Cardiovascular Science of the European Society of Cardiology provide a Position Statement on the importance of the endothelium in the underlying pathophysiology behind the clinical presentation in COVID-19 and identify key questions for future research to address. We propose that endothelial biomarkers and tests of function (e.g. flow-mediated dilatation) should be evaluated for their usefulness in the risk stratification of COVID-19 patients. A better understanding of the effects of SARS-CoV-2 on endothelial biology in both the micro- and macrovasculature is required, and endothelial function testing should be considered in the follow-up of convalescent COVID-19 patients for early detection of long-term cardiovascular complications.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions please email: [email protected]

Cardiovasc Res: 03 Aug 2020; epub ahead of print
Evans PC, Ed Rainger G, Mason JC, Guzik TJ, ... Bochaton-Piallat ML, Bäck M
Cardiovasc Res: 03 Aug 2020; epub ahead of print | PMID: 32750108
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Abstract

Role of R-spondin 2 in arterial lymphangiogenesis and atherosclerosis.

Singla B, Lin HP, Chen A, Ahn W, ... Stansfield BK, Csányi G
Background
Impaired lymphatic drainage of the arterial wall results in intimal lipid accumulation and atherosclerosis. However, the mechanisms regulating lymphangiogenesis in atherosclerotic arteries are not well understood. Our studies identified elevated levels of matrix protein R-Spondin 2 (RSPO2) in atherosclerotic arteries. In this study, we investigated the role of RSPO2 in lymphangiogenesis, arterial cholesterol efflux into lesion-draining lymph nodes and development of atherosclerosis.
Methods and results
The effect of RSPO2 on lymphangiogenesis was investigated using human lymphatic endothelial cells in vitro and implanted Matrigel plugs in vivo. Cellular and molecular approaches, pharmacological agents, and siRNA silencing of RSPO2 receptor LGR4 were used to investigate RSPO2-mediated signaling in lymphatic endothelial cells. In vivo LDL tracking and perivascular blockade of RSPO2-LGR4 signaling using LGR4-ECD pluronic gel in hypercholesterolemic mice were utilized to investigate the role of RSPO2 in arterial reverse cholesterol transport and atherosclerosis. Immunoblotting and imaging experiments demonstrated increased RSPO2 expression in human and mouse atherosclerotic arteries compared to non-atherosclerotic controls. RSPO2 treatment inhibited lymphangiogenesis both in vitro and in vivo. LGR4 silencing and inhibition of RSPO2-LGR4 signaling abrogated RSPO2-induced inhibition of lymphangiogenesis. Mechanistically, we found that RSPO2 inhibits PI3K-AKT-eNOS signaling via LGR4 and inhibits activation of the canonical Wnt-β-catenin pathway. ApoE-/- mice treated with LGR4-ECD developed significantly less atherosclerosis compared with control treatment. Finally, increased arterial lymphatic vessel density and improved lymphatic drainage of fluorescently-labeled LDL to deep cervical lymph nodes were observed in LGR4-ECD-treated mice.
Conclusions
These findings demonstrate that RSPO2 inhibits lymphangiogenesis via LGR4 and downstream impairment of AKT-eNOS-NO signaling. These results may also inform new therapeutic strategies to promote lymphangiogenesis and improve cholesterol efflux from atherosclerotic arteries.
Translational perspective
Atherosclerotic cardiovascular disease is the leading cause of death worldwide. Thus, attenuation of atherosclerotic lesion formation and prevention of its cardiovascular complications is an urgent medical need. The findings of the present study that inhibition of LGR4-mediated signaling increases arterial lymphangiogenesis, improves lymphatic drainage from the vessel wall and attenuates atherosclerosis, provide a framework from which novel therapeutic strategies to augment lymphatic vessel density and reduce atherosclerotic lesion formation can be developed and used for the treatment of patients with atherosclerosis. This pathway may also have important implications in other pathological conditions associated with lymphatic dysfunction, such as lymphedema, obesity, hypertension, and impaired wound healing.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions please email: [email protected]

Cardiovasc Res: 03 Aug 2020; epub ahead of print
Singla B, Lin HP, Chen A, Ahn W, ... Stansfield BK, Csányi G
Cardiovasc Res: 03 Aug 2020; epub ahead of print | PMID: 32750106
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Abstract

Obituary for Dr. Clive Kearon.

Weitz JI, Bates SM

The thrombosis community has lost one of its giants. Clive Kearon died at his home in Dundas, Ontario on June 3, 2020 surrounded by his family. Clive was born in Dublin, Ireland, studied medicine at Trinity College and graduated in 1980. He came to McMaster University in 1985 to further his training and never left. After a residency in respiratory medicine, Clive completed his PhD in exercise physiology. Turning his attention to thrombosis, he became a world-renowned expert in venous thromboembolism.

This article is protected by copyright. All rights reserved.

J Thromb Haemost: 03 Aug 2020; epub ahead of print
Weitz JI, Bates SM
J Thromb Haemost: 03 Aug 2020; epub ahead of print | PMID: 32749030
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Abstract

Periostin: A Potential Therapeutic Target For Pulmonary Arterial Hypertension?

Bian JS, Nie X, Shen C, Tan J, ... Ye S, Chen J

Periostin (POSTN) is an extracellular matrix protein involved in tissue remodeling in response to injury and a contributing factor in tumorigenesis, suggesting that POSTN plays a role in the pathogenesis of pulmonary hypertension (PH).We aimed to gain insight into the mechanistic contribution of POSTN in experimental mouse models of PH and correlate these findings with PH in humans.We utilized genetic epistasis approaches in human pulmonary artery endothelial cells (hPAECs), human pulmonary artery smooth muscle cells (PASMCs) and experimental mouse models of PH (Sugen 5416/hypoxia or chronic hypoxia) to discern the role of POSTN and its relationship to hypoxia inducible factor (HIF)-1 signaling. We found that POSTN expression was correlated with the extent of PH in mouse models and in humans. Decreasing POSTN improved hemodynamic and cardiac responses in PH mice, blunted the release of growth factors and HIF-1α and reversed the downregulated BMPR2 expression in hPAECs from PH patients, whereas increasing POSTIN had the opposite effects and induced a hyper-proliferative and pro-migratory phenotype in both hPAECs and hPASMCs. Overexpression of POSTN induced activation of HIFs and increased the production of ET-1 and VEGF in hPAECs. SiRNA-mediated knockdown of HIF-1α abolished the proangiogenic effect of POSTN. Blockade of TrkB attenuated the effect of POSTN on HIF-1α expression, while inhibition of HIF-1α reduced the expression of POSTN and TrkB. These results suggest that hPAECs produce POSTN via a HIF-1α-dependent mechanism.Our study reveals that POSTN expression is increased in human and animal models of PH and fosters PH development via a positive feedback loop between HIF-1α and POSTN during hypoxia. We propose that manipulating POSTIN expression may be an efficacious therapeutic target in the treatment of PH. Our results also suggest that POSTN may serve as a biomarker to estimate the severity of PH.



Circ Res: 04 Aug 2020; epub ahead of print
Bian JS, Nie X, Shen C, Tan J, ... Ye S, Chen J
Circ Res: 04 Aug 2020; epub ahead of print | PMID: 32752980
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Abstract

Impaired Retinal Microvascular Function Predicts Long-Term Adverse Events in Patients with Cardiovascular Disease.

Theuerle JD, Al-Fiadh AH, Amirul Islam FM, Patel SK, ... Wong TY, Farouque O
Aims
Endothelial dysfunction is a precursor to the development of symptomatic atherosclerosis. Retinal microvascular reactivity to flicker light stimulation is a marker of endothelial function and can be quantified in vivo. We sought to determine whether retinal microvascular endothelial dysfunction predicts long-term major adverse cardiovascular events (MACE).
Methods and results
In a single center prospective observational study, patients with coronary artery disease (CAD) or cardiovascular risk factors underwent dynamic retinal vessel assessment in response to flicker light stimulation and were followed up for MACE. Retinal microvascular endothelial dysfunction was quantified by measuring maximum flicker light-induced retinal arteriolar (FI-RAD) and venular dilatation (FI-RVD). In total, 252 patients underwent dynamic retinal vessel assessment and 242 (96%) had long-term follow-up. Of the 242 patients, 88 (36%) developed MACE over a median period of 8.6 years (IQR 6.0-9.1). After adjustment for traditional risk factors, patients within the lowest quintile of FI-RAD had the highest risk of MACE (OR 5.21; 95% CI 1.78, 15.28). Patients with lower FI-RAD were also more likely to die (OR 2.09; 95% CI 1.00, 4.40, per standard deviation decrease in FI-RAD). In Kaplan-Meier analysis, patients with FI-RAD responses below the cohort median of 1.4% exhibited reduced MACE-free survival (55.5 vs. 71.5%; log-rank p = 0.004). FI-RVD was not predictive of MACE.
Conclusions
Retinal arteriolar endothelial dysfunction is an independent predictor of MACE in patients with CAD or cardiovascular risk factors. Dynamic retinal vessel analysis may provide added benefit to traditional risk factors in stratifying patients at risk for cardiovascular events.
Translational perspective
Subclinical endothelial dysfunction precedes cardiovascular diseases and can be assessed non-invasively using the retinal microvascular network. Retinal arteriolar endothelial dysfunction is an independent predictor of MACE and all-cause mortality in patients with established coronary artery disease or cardiovascular risk factors. Validation studies and investigation into the lifestyle and pharmacological modifiability of endothelial dysfunction could enhance risk prediction and guide intensification of therapy.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions please email: [email protected]

Cardiovasc Res: 03 Aug 2020; epub ahead of print
Theuerle JD, Al-Fiadh AH, Amirul Islam FM, Patel SK, ... Wong TY, Farouque O
Cardiovasc Res: 03 Aug 2020; epub ahead of print | PMID: 32750111
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Abstract

MiR-18a inhibits BMP4 and HIF-1α Normalizing Brain Arteriovenous Malformations.

Marín-Ramos NI, Thein TZ, Ghaghada KB, Chen TC, Giannotta SL, Hofman F

Brain arteriovenous malformations (AVMs) are abnormal tangles of vessels where arteries and veins directly connect without intervening capillary nets, increasing the risk of intracerebral hemorrhage and stroke. Current treatments are highly invasive and often not feasible. Thus, effective non-invasive treatments are needed. We previously showed that AVM brain endothelial cells (AVM-BEC) secreted higher vascular endothelial growth factor (VEGF) and lower thrombospondin-1 (TSP-1) levels than control BEC; and that miR-18a normalized AVM-BEC function and phenotype, although its mechanism remained unclear.To elucidate the mechanism of action and potential clinical application of miR-18a as an effective non-invasive treatment to selectively restore the phenotype and functionality of AVM vasculature.The molecular pathways affected by miR-18a in patient-derived BECs and AVM-BECs were determined by western-blot, RT-qPCR, ELISA, co-IP, immunostaining, knockdown and overexpression studies, flow cytometry, and luciferase reporter assays. MiR-18a was shown to increase TSP-1 and decrease VEGF by reducing plasminogen activator inhibitor (PAI-1/SERPINE1) levels. Furthermore, miR-18a decreased the expression of bone morphogenetic protein 4 (BMP4) and hypoxia inducible factor 1α (HIF-1α), blocking the BMP4/activin-like kinase 2 (ALK2)/ALK1/ALK5 and Notch signaling pathways. As determined by Boyden chamber assays, miR-18a also reduced the abnormal AVM-BEC invasiveness, which correlated with a decrease in MMP2, MMP9 and ADAM10 levels. In vivo pharmacokinetic studies showed that miR-18a reaches the brain following intravenous (IV) and intranasal (IN) administration. IN co-delivery of miR-18a and NEO100, a good manufacturing practices (GMP)-quality form of perillyl alcohol (POH), improved the pharmacokinetic profile of miR-18a in the brain without affecting its pharmacologic properties. Ultra-high-resolution computed tomography angiography and immunostaining studies in an Mgp-/- AVM mouse model showed that miR-18a decreased abnormal cerebral vasculature, and restored the functionality of the bone marrow, lungs, spleen and liver.MiR-18a may have significant clinical value in preventing, reducing and potentially reversing AVM.



Circ Res: 04 Aug 2020; epub ahead of print
Marín-Ramos NI, Thein TZ, Ghaghada KB, Chen TC, Giannotta SL, Hofman F
Circ Res: 04 Aug 2020; epub ahead of print | PMID: 32755283
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Abstract

Cerebral Microbleeds and Leukoencephalopathy in Critically Ill Patients With COVID-19.

Agarwal S, Jain R, Dogra S, Krieger P, ... Melmed K, Galetta S
Background and purpose
We conducted this study to investigate the prevalence and distribution of cerebral microbleeds and leukoencephalopathy in hospitalized patients with coronavirus disease 2019 (COVID-19) and correlate with clinical, laboratory, and functional outcomes.
Methods
We performed a retrospective chart review of 4131 COVID-19 positive adult patients who were admitted to 3 tertiary care hospitals of an academic medical center at the epicenter of the COVID-19 pandemic in New York City from March 1, 2020, to May 10, 2020, to identify patients who had magnetic resonance imaging (MRI) of the brain. We evaluated the MRIs in detail, and identified a subset of patients with leukoencephalopathy and/or cerebral microbleeds. We compared clinical, laboratory, and functional outcomes for these patients to patients who had a brain MRI that did not show these findings.
Results
Of 115 patients who had an MRI of the brain performed, 35 (30.4%) patients had leukoencephalopathy and/or cerebral microbleeds. Patients with leukoencephalopathy and/or cerebral microbleeds had neuroimaging performed later during the hospitalization course (27 versus10.6 days; <0.001), were clinically sicker at the time of brain MRI (median GCS 6 versus14; <0.001), and had higher peak D-dimer levels (8018±6677 versus3183±3482; <0.001), lower nadir platelet count (116.9±62.2 versus158.3±76.2; =0.03), higher peak international normalized ratio (2.2 versus1.57; <0.001) values when compared withpatients who had a brain MRI that did not show these findings. They required longer ventilator support (34.6 versus9.1 days; <0.001) and were more likely to have moderate and severe acute respiratory distress syndrome score (88.6% versus23.8%, <0.001). These patients had longer hospitalizations (42.1 versus20.9 days; <0.001), overall worse functional status on discharge (mRS 5 versus4; =0.001), and higher mortality (20% versus9%; =0.144).
Conclusions
The presence of leukoencephalopathy and/or cerebral microbleeds is associated with a critical illness, increased mortality, and worse functional outcome in patients with COVID-19.



Stroke: 04 Aug 2020:STROKEAHA120030940; epub ahead of print
Agarwal S, Jain R, Dogra S, Krieger P, ... Melmed K, Galetta S
Stroke: 04 Aug 2020:STROKEAHA120030940; epub ahead of print | PMID: 32755456
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Abstract

Blacks Are Less Likely to Present With Strokes During the COVID-19 Pandemic: Observations From the Buckle of the Stroke Belt.

Cummings C, Almallouhi E, Al Kasab S, Spiotta AM, Holmstedt CA
Background and purpose
The impact of the coronavirus disease 2019 (COVID-19) pandemic on stroke systems has not been systematically evaluated. Our study aims to investigate trends in telestroke consults during the pandemic.
Methods
We did retrospective chart review of consecutive patients seen through a telestroke network in South Carolina from March 2019 to April 2020. We dichotomized patients to preCOVID-19 pandemic (March 2019 to February 2020) and during COVID-19 pandemic (March to April 2020).
Results
A total of 5852 patients were evaluated during the study period, 613 (10.5%) were seen during the pandemic. The median number of weekly consults dropped from 112 to 77 during the pandemic, =0.002. There was no difference in baseline features; however, Black patients were less likely to present with strokes during the pandemic (13.9% versus 29%, 0.002).
Conclusions
The COVID-19 pandemic has led to a significant drop in telestroke volume. The impact seems to disproportionately affect Black patients.



Stroke: 04 Aug 2020:STROKEAHA120031121; epub ahead of print
Cummings C, Almallouhi E, Al Kasab S, Spiotta AM, Holmstedt CA
Stroke: 04 Aug 2020:STROKEAHA120031121; epub ahead of print | PMID: 32755454
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Abstract

Determination of Brain Death/Death by Neurologic Criteria: The World Brain Death Project.

Greer DM, Shemie SD, Lewis A, Torrance S, ... Zirpe K, Sung G
Importance
There are inconsistencies in concept, criteria, practice, and documentation of brain death/death by neurologic criteria (BD/DNC) both internationally and within countries.
Objective
To formulate a consensus statement of recommendations on determination of BD/DNC based on review of the literature and expert opinion of a large multidisciplinary, international panel.
Process
Relevant international professional societies were recruited to develop recommendations regarding determination of BD/DNC. Literature searches of the Cochrane, Embase, and MEDLINE databases included January 1, 1992, through April 2020 identified pertinent articles for review. Because of the lack of high-quality data from randomized clinical trials or large observational studies, recommendations were formulated based on consensus of contributors and medical societies that represented relevant disciplines, including critical care, neurology, and neurosurgery.
Evidence synthesis
Based on review of the literature and consensus from a large multidisciplinary, international panel, minimum clinical criteria needed to determine BD/DNC in various circumstances were developed.
Recommendations
Prior to evaluating a patient for BD/DNC, the patient should have an established neurologic diagnosis that can lead to the complete and irreversible loss of all brain function, and conditions that may confound the clinical examination and diseases that may mimic BD/DNC should be excluded. Determination of BD/DNC can be done with a clinical examination that demonstrates coma, brainstem areflexia, and apnea. This is seen when (1) there is no evidence of arousal or awareness to maximal external stimulation, including noxious visual, auditory, and tactile stimulation; (2) pupils are fixed in a midsize or dilated position and are nonreactive to light; (3) corneal, oculocephalic, and oculovestibular reflexes are absent; (4) there is no facial movement to noxious stimulation; (5) the gag reflex is absent to bilateral posterior pharyngeal stimulation; (6) the cough reflex is absent to deep tracheal suctioning; (7) there is no brain-mediated motor response to noxious stimulation of the limbs; and (8) spontaneous respirations are not observed when apnea test targets reach pH <7.30 and Paco2 ≥60 mm Hg. If the clinical examination cannot be completed, ancillary testing may be considered with blood flow studies or electrophysiologic testing. Special consideration is needed for children, for persons receiving extracorporeal membrane oxygenation, and for those receiving therapeutic hypothermia, as well as for factors such as religious, societal, and cultural perspectives; legal requirements; and resource availability.
Conclusions and relevance
This report provides recommendations for the minimum clinical standards for determination of brain death/death by neurologic criteria in adults and children with clear guidance for various clinical circumstances. The recommendations have widespread international society endorsement and can serve to guide professional societies and countries in the revision or development of protocols and procedures for determination of brain death/death by neurologic criteria, leading to greater consistency within and between countries.



JAMA: 02 Aug 2020; epub ahead of print
Greer DM, Shemie SD, Lewis A, Torrance S, ... Zirpe K, Sung G
JAMA: 02 Aug 2020; epub ahead of print | PMID: 32761206
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Abstract

Treatment of acquired thrombotic thrombocytopenic purpura without plasma exchange in selected patients under caplacizumab.

Völker LA, Brinkkoetter PT, Knöbl P, Krstic M, ... Buxhofer-Ausch V, Miesbach W
Background
Acquired thrombotic thrombocytopenic purpura (aTTP) is a rare, life-threatening autoimmune thrombotic microangiopathy. Current standard of care is therapeutic plasma exchange, immunosuppression, and caplacizumab, an anti-von Willebrand Factor Nanobody, which is effective in treating aTTP episodes.
Patients/methods
Here we report on 7 episodes of aTTP treated without plasma exchange in 6 female patients in Germany and Austria. Two episodes were initial presentations of aTTP, in 5 instances patients experienced a relapse. In 4 episodes, moderate to severe organ dysfunction was observed, 3 cases presented with a mild course. All patients received caplacizumab immediately once aTTP was suspected or diagnosed, and plasma exchange was omitted based on shared decision making between patient and the treating physicians.
Results
We observed a rapid and robust increase of platelet counts already after the first dose of caplacizumab, leading to a doubling of platelet counts within 17 hours (median), platelet counts normalized (>150 G/L) after median 84 h. Lactate dehydrogenase (LDH), as a surrogate parameter of organ damage, improved in parallel to the platelet counts, indicating resolving microangiopathy.
Conclusions
In conclusion, in selected cases of acute bouts of aTTP, it seems feasible to delay or omit plasma exchange if platelet counts increase and organ function is stable after start of caplacizumab therapy.

This article is protected by copyright. All rights reserved.

J Thromb Haemost: 04 Aug 2020; epub ahead of print
Völker LA, Brinkkoetter PT, Knöbl P, Krstic M, ... Buxhofer-Ausch V, Miesbach W
J Thromb Haemost: 04 Aug 2020; epub ahead of print | PMID: 32757435
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Abstract

Anticoagulation Type and Early Recurrence in Cardioembolic Stroke: The IAC Study.

Yaghi S, Mistry E, Liberman AL, Giles J, ... Khan M, Henninger N
Background and purpose
In patients with acute ischemic stroke and atrial fibrillation, treatment with low molecular weight heparin increases early hemorrhagic risk without reducing early recurrence, and there is limited data comparing warfarin to direct oral anticoagulant (DOAC) therapy. We aim to compare the effects of the treatments above on the risk of 90-day recurrent ischemic events and delayed symptomatic intracranial hemorrhage.
Methods
We included consecutive patients with acute ischemic stroke and atrial fibrillation from the IAC (Initiation of Anticoagulation after Cardioembolic) stroke study pooling data from stroke registries of 8 comprehensive stroke centers across the United States. We compared recurrent ischemic events and delayed symptomatic intracranial hemorrhage between each of the following groups in separate Cox-regression analyses: (1) DOAC versus warfarin and (2) bridging with heparin/low molecular weight heparin versus no bridging, adjusting for pertinent confounders to test these associations.
Results
We identified 1289 patients who met the bridging versus no bridging analysis inclusion criteria and 1251 patients who met the DOAC versus warfarin analysis inclusion criteria. In adjusted Cox-regression models, bridging (versus no bridging) treatment was associated with a high risk of delayed symptomatic intracranial hemorrhage (hazard ratio, 2.74 [95% CI, 1.01-7.42]) but a similar rate of recurrent ischemic events (hazard ratio, 1.23 [95% CI, 0.63-2.40]). Furthermore, DOAC (versus warfarin) treatment was associated with a lower risk of recurrent ischemic events (hazard ratio, 0.51 [95% CI, 0.29-0.87]) but not delayed symptomatic intracranial hemorrhage (hazard ratio, 0.57 [95% CI, 0.22-1.48]).
Conclusions
Our study suggests that patients with ischemic stroke and atrial fibrillation would benefit from the initiation of a DOAC without bridging therapy. Due to our study limitations, these findings should be interpreted with caution pending confirmation from large prospective studies.



Stroke: 05 Aug 2020:STROKEAHA120028867; epub ahead of print
Yaghi S, Mistry E, Liberman AL, Giles J, ... Khan M, Henninger N
Stroke: 05 Aug 2020:STROKEAHA120028867; epub ahead of print | PMID: 32757753
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Abstract

Is the COVID-19 thrombotic catastrophe complement-connected?

Conway EM, Pryzdial ELG

In December 2019, the world was introduced to a new betacoronavirus, referred to as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) for its propensity to cause rapidly progressive lung damage, resulting in high death rates. As fast as the virus spread, it became evident that COVID-19 is a multi-system disease, that may involve multiple organs, and has a high risk of thrombosis, associated with striking elevations in pro-inflammatory cytokines, D-dimer and fibrinogen, but without disseminated intravascular coagulation. Postmortem studies have confirmed the high incidence of venous thromboembolism (VTE), but also notably revealed diffuse microvascular thrombi with endothelial swelling, consistent with a thrombotic microangiopathy (TMA), and inter-alveolar endothelial deposits of complement activation fragments. The clinicopathologic presentation of COVID-19 thus parallels that of other thrombotic diseases, such as atypical hemolytic uremic syndrome (aHUS), that are caused by dysregulation of the complement system. This raises the specter that many of the thrombotic complications arising from SARS-CoV-2 infections may be triggered and/or exacerbated by excess complement activation. This is of major potential clinical relevance, as currently available anti-complement therapies that are highly effective in protecting against thrombosis in aHUS, could be efficacious in COVID-19. In this review, we provide mounting evidence for complement participating in the pathophysiology underlying the thrombotic diathesis associated with pathogenic coronaviruses, including SARS-CoV-2. Based on current knowledge of complement, coagulation and the virus, we suggest lines of study to identify novel therapeutic targets and the rationale for clinical trials with currently available anti-complement agents for COVID-19.

This article is protected by copyright. All rights reserved.

J Thromb Haemost: 05 Aug 2020; epub ahead of print
Conway EM, Pryzdial ELG
J Thromb Haemost: 05 Aug 2020; epub ahead of print | PMID: 32762081
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Abstract

Treatment Restrictions and the Risk of Death in Patients With Ischemic Stroke or Intracerebral Hemorrhage.

Reinink H, Konya B, Geurts M, Kappelle LJ, van der Worp HB
Background and purpose
Do-not-resuscitate (DNR) orders in the first 24 hours after intracerebral hemorrhage have been associated with an increased risk of early death. This relationship is less certain for ischemic stroke. We assessed the relation between treatment restrictions and mortality in patients with ischemic stroke and in patients with intracerebral hemorrhage. We focused on the timing of treatment restrictions after admission and the type of treatment restriction (DNR order versus more restrictive care).
Methods
We retrospectively assessed demographic and clinical data, timing and type of treatment restrictions, and vital status at 3 months for 622 consecutive stroke patients primarily admitted to a Dutch university hospital. We used a Cox regression model, with adjustment for age, sex, comorbidities, and stroke type and severity.
Results
Treatment restrictions were installed in 226 (36%) patients, more frequently after intracerebral hemorrhage (51%) than after ischemic stroke (32%). In 187 patients (83%), these were installed in the first 24 hours. Treatment restrictions installed within the first 24 hours after hospital admission and those installed later were independently associated with death at 90 days (adjusted hazard ratios, 5.41 [95% CI, 3.17-9.22] and 5.36 [95% CI, 2.20-13.05], respectively). Statistically significant associations were also found in patients with ischemic stroke and in patients with just an early DNR order. In those who died, the median time between a DNR order and death was 520 hours (interquartile range, 53-737).
Conclusions
The strong relation between treatment restrictions (including DNR orders) and death and the long median time between a DNR order and death suggest that this relation may, in part, be causal, possibly due to an overall lack of aggressive care.



Stroke: 05 Aug 2020:STROKEAHA120029788; epub ahead of print
Reinink H, Konya B, Geurts M, Kappelle LJ, van der Worp HB
Stroke: 05 Aug 2020:STROKEAHA120029788; epub ahead of print | PMID: 32757755
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Abstract

In vitro hypercoagulability and ongoing in vivo activation of coagulation and fibrinolysis in COVID-19 patients on anticoagulation.

Blasi A, von Meijenfeldt FA, Adelmeijer J, Calvo A, ... Carlos Reverter J, Lisman T
Background
COVID-19 is associated with a substantial risk of venous thrombotic events, even in the presence of adequate thromboprophylactic therapy.
Objectives
We aimed to better characterize the hypercoagulable state of COVID-19 patients in patients receiving anticoagulant therapy.
Methods
We took plasma samples of 23 patients with COVID-19 who were on prophylactic or intensified anticoagulant therapy. Twenty healthy volunteers were included to establish reference ranges.
Results
COVID-19 patients had a mildly prolonged prothrombin time, high VWF levels and low ADAMTS13 activity. Most rotational thromboelastometry parameters were normal, with a hypercoagulable maximum clot firmness in part of the patients. Despite detectable anti-Xa activity in the majority of patients, ex vivo thrombin generation was normal, and in vivo thrombin generation elevated as evidenced by elevated levels of thrombin-antithrombin complexes and D-dimers. Plasma levels of activated factor VII were lower in patients, and levels of the platelet activation marker soluble CD40 ligand were similar in patients and controls. Plasmin-antiplasmin complex levels were also increased in patients despite an in vitro hypofibrinolytic profile.
Conclusions
COVID-19 patients are characterized by normal in vitro thrombin generation and enhanced clot formation and decreased fibrinolytic potential despite the presence of heparin in the sample. Anticoagulated COVID-19 patients have persistent in vivo activation of coagulation and fibrinolysis, but no evidence of excessive platelet activation. Ongoing activation of coagulation despite normal to intensified anticoagulant therapy indicates studies on alternative antithrombotic strategies are urgently required.

This article is protected by copyright. All rights reserved.

J Thromb Haemost: 05 Aug 2020; epub ahead of print
Blasi A, von Meijenfeldt FA, Adelmeijer J, Calvo A, ... Carlos Reverter J, Lisman T
J Thromb Haemost: 05 Aug 2020; epub ahead of print | PMID: 32762118
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Abstract

Prevalence and Outcomes of Medium Vessel Occlusions With Discrepant Infarct Patterns.

Ospel JM, Cimflova P, Marko M, Mayank A, ... Menon BK, Goyal M
Background and purpose
The prognosis of medium vessel occlusions (MeVOs), that is, M2/3 middle cerebral artery, A2/3 anterior cerebral artery, and P2/3 posterior cerebral artery occlusions, is generally better compared with large vessel occlusions, since brain ischemia is less extensive. However, in some MeVO patients, infarcts are seen outside the territory of the occluded vessel (MeVO with discrepant infarcts). This study aims to determine the prevalence and clinical impact of discrepant infarct patterns in acute ischemic stroke due to MeVO.
Methods
We pooled data of MeVO patients from INTERRSeCT (Identifying New Approaches to Optimize Thrombus Characterization for Predicting Early Recanalization and Reperfusion With IV Alteplase and Other Treatments Using Serial CT Angiography) and PRove-IT (Precise and Rapid Assessment of Collaterals Using Multi-Phase CTA in the Triage of Patients With Acute Ischemic Stroke for IA Therapy)-2 prospective cohort studies of patients with acute ischemic stroke. The combination of occlusion location on baseline computed tomography angiography and infarct location on follow-up computed tomography/magnetic resonance imaging was used to identify MeVOs with discrepant infarct patterns. Two definitions for discrepant infarcts were applied; one was more restrictive and purely based on infarct patterns of the basal ganglia, whereas the second one took cortical infarct patterns into account. Clinical outcomes of patients with versus without discrepant infarcts were summarized using descriptive statistics. Logistic regression was performed to obtain adjusted effect size estimates for the association of discrepant infarcts and good outcome, defined as a modified Rankin Scale score of 0 to 2, and excellent outcome (modified Rankin Scale score 0-1).
Results
Two hundred sixty-two patients with MeVO were included in the analysis. The prevalence of discrepant infarcts was 39.7% (definition 1) and 21.0% (definition 2). Patients with discrepant infarcts were less likely to achieve good outcome (definition 1: adjusted odds ratio, 0.48 [95% CI, 0.25-0.91]; definition 2: adjusted odds ratio, 0.47 [95% CI, 0.22-0.99]). When definition 1 was applied, patients with discrepant infarcts were also less likely to achieve excellent outcome (definition 1: adjusted odds ratio, 0.55 [95% CI, 0.31-0.99]; definition 2: adjusted odds ratio, 0.62 [95% CI, 0.31-1.25]).
Conclusions
MeVO patients with discrepant infarcts are common, and they are associated with more severe deficits and poor outcomes.



Stroke: 05 Aug 2020:STROKEAHA120030041; epub ahead of print
Ospel JM, Cimflova P, Marko M, Mayank A, ... Menon BK, Goyal M
Stroke: 05 Aug 2020:STROKEAHA120030041; epub ahead of print | PMID: 32757752
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Abstract

Plaque Distribution Correlates With Morphology of Lenticulostriate Arteries in Single Subcortical Infarctions.

Jiang S, Yan Y, Yang T, Zhu Q, ... Sun J, Wu B
Background and purpose
We aimed to use novel whole-brain vessel-wall magnetic resonance imaging (WB-VWI) to investigate the association between plaque distribution of middle cerebral artery (MCA) and morphological changes of the lenticulostriate arteries (LSAs) in single subcortical infarctions.
Methods
Forty single subcortical infarction patients with no relevant MCA disease on magnetic resonance angiography were prospectively enrolled. Plaque location in the MCA was dichotomized as proximal (located adjacent to the LSA origin) or distal (located distal to the LSA origin) on whole-brain vessel-wall magnetic resonance imaging. The MCAs with proximal plaques were divided into the symptomatic and asymptomatic side, and asymptomatic side MCAs without proximal plaques were the control group. The morphological characteristics of the LSAs and features of proximal plaques were analyzed.
Results
A total of 71 MCAs in 40 patients were analyzed (31 on the symptomatic side, 22 on the asymptomatic side, and 18 in the control group). Superior-wall plaques of MCAs were observed more frequently on the symptomatic side than the asymptomatic side (45.2% versus9.1%, =0.005). The wall area index, plaque burden, and remodeling index did not differ significantly between the symptomatic and asymptomatic side. The number of LSA branches was smaller (=0.011) in the symptomatic side (5.48±1.88) compared with the control group (6.83±1.92). The symptomatic side exhibited shorter average length of the LSAs (23.23±3.44 versus25.75±3.76 mm, =0.025) and shorter average distance of the LSAs (16.47±3.11 versus21.53±4.76 mm, <0.001) compared with the asymptomatic side.
Conclusions
Superiorly distributed MCA plaques at the LSA origin are closely associated with morphological changes of the LSA in symptomatic MCAs, suggesting that the distribution, rather than the inherent features of plaques, determines the occurrence of single subcortical infarctions. Our findings provide insight into the etiologic mechanism of branch atheromatous disease in single subcortical infarctions.



Stroke: 05 Aug 2020:STROKEAHA120030215; epub ahead of print
Jiang S, Yan Y, Yang T, Zhu Q, ... Sun J, Wu B
Stroke: 05 Aug 2020:STROKEAHA120030215; epub ahead of print | PMID: 32757756
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Abstract

Neuropathologic and Cognitive Correlates of Enlarged Perivascular Spaces in a Community-Based Cohort of Older Adults.

Javierre-Petit C, Schneider JA, Kapasi A, Makkinejad N, ... Bennett DA, Arfanakis K
Background and purpose
Enlarged perivascular spaces (EPVS) have been associated with aging, increased stroke risk, decreased cognitive function, and vascular dementia. However, the relationship of EPVS with age-related neuropathologies is not well understood. Therefore, the purpose of this study was to assess the neuropathologic correlates of EPVS in a large community-based cohort of older adults. The cognitive correlates of EPVS over and beyond those of other pathologies were also assessed.
Methods
This study included 654 older deceased and autopsied participants of 3 longitudinal community-based studies of aging that had available data on cognition, ex vivo brain magnetic resonance imaging, and detailed neuropathologic examination. EPVS seen on ex vivo magnetic resonance imaging were histologically validated. Experienced observers rated EPVS burden in ex vivo magnetic resonance imaging using a semiquantitative 4-level scale. Elastic-net regularized ordinal logistic regression was used to investigate associations of EPVS burden with age-related neuropathologies. Mixed-effects models of cognition controlling for neuropathologies, demographics, and clinical factors, were used to determine whether EPVS burden has additional contributions to cognitive decline.
Results
EPVS burden in the whole group was associated with gross infarcts (odds ratio=1.67, =0.0017) and diabetes mellitus (odds ratio=1.73, =0.004). When considering only nondemented participants (with mild or no cognitive impairment), EPVS burden was associated with gross infarcts (odds ratio=1.74, =0.016) and microscopic infarcts (odds ratio=1.79, =0.013). EPVS burden was associated with faster decline in visuospatial abilities (estimate=-0.009, =0.028), in the whole group, as well as lower levels of semantic memory (estimate=-0.13, =0.048) and visuospatial abilities (estimate=-0.11, =0.016) at the time of death.
Conclusions
EPVS and infarcts may share similar neurobiological pathways regardless of dementia status. EPVS burden is linked to diabetes mellitus independently of neuropathologies, extending recent findings in animal studies implicating diabetes mellitus in impairment of the glymphatic system. Finally, EPVS burden may reflect additional brain tissue injury that may contribute to cognitive decline, not captured with traditional neuropathologic measures.



Stroke: 05 Aug 2020:STROKEAHA120029388; epub ahead of print
Javierre-Petit C, Schneider JA, Kapasi A, Makkinejad N, ... Bennett DA, Arfanakis K
Stroke: 05 Aug 2020:STROKEAHA120029388; epub ahead of print | PMID: 32757750
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Abstract

Cerebrovascular Complications of COVID-19.

Katz JM, Libman RB, Wang JJ, Sanelli P, ... Najjar S, Azhar S
Background and purpose
Coronavirus disease 2019 (COVID-19) evolved quickly into a global pandemic with myriad systemic complications, including stroke. We report the largest case series to date of cerebrovascular complications of COVID-19 and compare with stroke patients without infection.
Methods
Retrospective case series of COVID-19 patients with imaging-confirmed stroke, treated at 11 hospitals in New York, between March 14 and April 26, 2020. Demographic, clinical, laboratory, imaging, and outcome data were collected, and cases were compared with date-matched controls without COVID-19 from 1 year prior.
Results
Eighty-six COVID-19-positive stroke cases were identified (mean age, 67.4 years; 44.2% women). Ischemic stroke (83.7%) and nonfocal neurological presentations (67.4%) predominated, commonly involving multivascular distributions (45.8%) with associated hemorrhage (20.8%). Compared with controls (n=499), COVID-19 was associated with in-hospital stroke onset (47.7% versus 5.0%; <0.001), mortality (29.1% versus 9.0%; <0.001), and Black/multiracial race (58.1% versus 36.9%; =0.001). COVID-19 was the strongest independent risk factor for in-hospital stroke (odds ratio, 20.9 [95% CI, 10.4-42.2]; <0.001), whereas COVID-19, older age, and intracranial hemorrhage independently predicted mortality.
Conclusions
COVID-19 is an independent risk factor for stroke in hospitalized patients and mortality, and stroke presentations are frequently atypical.



Stroke: 05 Aug 2020:STROKEAHA120031265; epub ahead of print
Katz JM, Libman RB, Wang JJ, Sanelli P, ... Najjar S, Azhar S
Stroke: 05 Aug 2020:STROKEAHA120031265; epub ahead of print | PMID: 32757751
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Abstract

Definition of major bleeding: Prognostic classification.

Franco L, Becattini C, Beyer-Westendorf J, Vanni S, ... Conti A, Agnelli G
Background
In patients on anticoagulant treatment, the major bleeding (MB) definition released by the International Society of Thrombosis and Haemostasis (ISTH) is widely accepted. However, this definition identifies MBs with highly variable short-term risk of death.
Objectives
The study aims were to derive and validate a classification of ISTH-defined MBs for the risk of short-term death.
Methods
Consecutive patients admitted for ISTH-defined MB occurring while on treatment with oral anticoagulants were included in the study and divided into a derivation and a validation cohort. Death within 30 days was the primary study outcome.
Results
Among 1077 patients with MB, 64/517 and 63/560 patients in the derivation and validation cohort died, respectively. In the derivation cohort, Glasgow Coma Scale (GCS)<14 and shock were predictors of death; critical site bleeding and hemoglobin decrease ≥2 g/dL, or transfusion ≥2 units were not. GCS<14 (HR 8.67, 95% CI 3.93-19.13) was predictor of death in intracranial hemorrhage (ICH) and shock at admission (HR 4.84, 95% CI 2.01-11.70) and pericardial bleeding (HR 11.37, 95% CI 1.33-97.31) in non-ICH MBs. The predictive value of GCS<14 in ICH and shock and pericardial bleeding in non-ICH MBs was confirmed in the validation cohort. None of the patients with isolated ocular or articular bleeding died. A prognostic classification of ISTH-defined MBs for the risk of short-term death is proposed as \'serious\', \'severe\' and \'life-threatening\' (ICH with GCS<14 or non-ICH with shock) MBs.
Conclusion
According to our study, ISTH-defined MBs can be stratified for the risk of death within 30 days.

This article is protected by copyright. All rights reserved.

J Thromb Haemost: 06 Aug 2020; epub ahead of print
Franco L, Becattini C, Beyer-Westendorf J, Vanni S, ... Conti A, Agnelli G
J Thromb Haemost: 06 Aug 2020; epub ahead of print | PMID: 32767653
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Abstract

Risk of Distal Embolization From tPA (Tissue-Type Plasminogen Activator) Administration Prior to Endovascular Stroke Treatment.

Flint AC, Avins AL, Eaton A, Uong S, ... Zrelak PA, Nguyen-Huynh MN
Background and purpose
In large artery occlusion stroke, both intravenous (IV) tPA (tissue-type plasminogen activator) and endovascular stroke treatment (EST) are standard-of-care. It is unknown how often tPA causes distal embolization, in which a procedurally accessible large artery occlusion is converted to a more distal and potentially inaccessible occlusion.
Methods
We analyzed data from a decentralized stroke telemedicine program in an integrated healthcare delivery system covering 21 hospitals, with 2 high-volume EST centers. We captured all cases sent for EST and examined the relationship between IV tPA administration and the rate of distal embolization, the rate of target recanalization (modified Treatment in Cerebral Infarction scale 2b/3), clinical improvement before EST, and short-term and long-term clinical outcomes.
Results
Distal embolization before EST was quite common (63/314 [20.1%]) and occurred more often after IV tPA before EST (57/229 [24.9%]) than among those not receiving IV tPA (6/85 [7.1%]; <0.001). Distal embolization was associated with an inability to attempt EST: after distal embolization, 26/63 (41.3%) could not have attempted EST because of the new clot location, while in cases without distal embolization, only 8/249 (3.2%) were unable to have attempted EST (<0.001). Among patients who received IV tPA, 13/242 (5.4%) had sufficient symptom improvement that a catheter angiogram was not performed; 6/342 (2.5%) had improvement to within 2 points of their baseline NIHSS. At catheter angiogram, 2/229 (0.9%) of patients who had received tPA had complete recanalization without distal embolization. Both IV tPA and EST recanalization were associated with improved long-term outcome.
Conclusions
IV tPA administration before EST for large artery occlusion is associated with distal embolization, which in turn may reduce the chance that EST can be attempted and recanalization achieved. At the same time, some IV tPA-treated patients show symptomatic improvement and complete recanalization. Because IV tPA is associated with both distal embolization and improved long-term clinical outcome, there is a need for prospective clinical trials testing the net benefit or harm of IV tPA before EST.



Stroke: 05 Aug 2020:STROKEAHA120029025; epub ahead of print
Flint AC, Avins AL, Eaton A, Uong S, ... Zrelak PA, Nguyen-Huynh MN
Stroke: 05 Aug 2020:STROKEAHA120029025; epub ahead of print | PMID: 32757749
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Abstract

ASK1 Regulates Immune-Mediated Thrombocytopenia, Thrombosis, and Systemic Shock.

Patel P, Shaik NF, Zhou Y, Golla K, McKenzie SE, Naik UP
Background
Immune complexes (ICs) bind to and activate platelets via FcγRIIA causing patients to experience thrombocytopenia, as well as an increased risk of forming occlusive thrombi. While platelets have been shown to mediate IC-induced pathologies, the mechanisms involved have yet to be fully elucidated. We identified that Apoptosis Signal-Regulating Kinase 1 (ASK1) is present in both human and mouse platelets and potentiates many platelet functions.
Objectives
Here we set out to study ASK1\'s role in regulating IC-mediated platelet functions in vitro and IC-induced pathologies using an in vivo mouse model.
Methods
Using human platelets treated with an ASK1-specific inhibitor and platelets from FCGR2A / Ask1 transgenic mice, we examined various platelet functions induced by model ICs in vitro and in vivo.
Results
We found that ASK1 was activated in human platelets following cross-linking of FcγRIIA using either anti-hCD9 or IV.3+GAM. While genetic deletion or inhibition of ASK1 significantly attenuated anti-CD9-induced platelet aggregation, activation of the canonical FcγRIIA signaling targets Syk and PLCγ2 was unaffected. We further found that anti-mCD9- induced cPla phosphorylation and TxA generation is delayed in Ask1 null transgenic mouse platelets leading to diminished δ-granule secretion. In vivo, absence of Ask1 protected FCGR2A transgenic mice from thrombocytopenia, thrombosis, and systemic shock following injection of anti-mCD9. In whole blood microfluidics, platelet adhesion and thrombus formation on fibrinogen was enhanced by Ask1.
Conclusions
These findings suggest that ASK1 inhibition may be a potential target for the treatment of IC-induced shock and other immune-mediated thrombotic disorders.

This article is protected by copyright. All rights reserved.

J Thromb Haemost: 06 Aug 2020; epub ahead of print
Patel P, Shaik NF, Zhou Y, Golla K, McKenzie SE, Naik UP
J Thromb Haemost: 06 Aug 2020; epub ahead of print | PMID: 32767736
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Abstract

Circulating endothelial progenitors are increased in Covid-19 patients and correlate with SARS-CoV-2 RNA in severe cases.

Mancuso P, Gidaro A, Gregato G, Raveane A, ... Cogliati C, Bertolini F
Background
During the course of Covid-19, the disease caused by the new Coronavirus SARS-CoV-2, thrombotic phenomena and/or diffuse vascular damage are frequent, and viral elements have been observed within endothelial cells.
Objectives
CD146+ circulating endothelial cells (CD146+ CECs) and their progenitors (CEPs) are increased in cardiovascular, thrombotic, infectious and cancer diseases. The present study was designed to investigate their kinetics in Covid-19 patients.
Method
We used a validated flow cytometry procedure to enumerate viable and apoptotic CD146+ CECs and CEPs in Covid-19 patients during the course of the disease and in patients who recovered.
Result
Viable CEPs/mL were significantly increased in Covid-19 patients compared to healthy controls. This increase was observed in patients with mild symptoms and not further augmented in patients with severe symptoms. In patients who recovered, CEPs decreased, but were in a range still significantly higher than normal controls. Regarding mature CD146+ CECs, in Covid-19 patients their absolute number was similar to those observed in healthy controls, but the viable/apoptotic CD146+ CEC ratio was significantly different. Both mild and severe Covid-19 patients had significantly less apoptotic CD146+ CECs compared to healthy controls. Patients who recovered had significantly less CD146+ CECs/mL when compared to controls as well as to mild and severe Covid-19 patients. A positive correlation was found between the copies of SARS-CoV-2 RNA in the cellular fraction and apoptotic CEPs/mL in severe Covid-19 patients.
Conclusions
CD146+ CECs and CEPs might be investigated as candidate biomarkers of endothelial damage in Covid-19 patients.

This article is protected by copyright. All rights reserved.

J Thromb Haemost: 05 Aug 2020; epub ahead of print
Mancuso P, Gidaro A, Gregato G, Raveane A, ... Cogliati C, Bertolini F
J Thromb Haemost: 05 Aug 2020; epub ahead of print | PMID: 32762140
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Impact:
Abstract

Acute Stroke Presentation, Care, and Outcomes in Community Hospitals in Northern California During the COVID-19 Pandemic.

Nguyen-Huynh MN, Tang XN, Vinson DR, Flint AC, ... Sidney S, Klingman JG
Background and purpose
Shelter-in-place (SIP) orders implemented to mitigate severe acute respiratory syndrome coronavirus 2 spread may inadvertently discourage patient care-seeking behavior for critical conditions like acute ischemic stroke. We aimed to compare temporal trends in volume of acute stroke alerts, patient characteristics, telestroke care, and short-term outcomes pre- and post-SIP orders.
Methods
We conducted a cohort study in 21 stroke centers of an integrated healthcare system serving 4.4+ million members across Northern California. We included adult patients who presented with suspected acute stroke and were evaluated by telestroke between January 1, 2019, and May 9, 2020. SIP orders announced the week of March 15, 2020, created pre (January 1, 2019, to March 14, 2020) and post (March 15, 2020, to May 9, 2020) cohort for comparison. Main outcomes were stroke alert volumes and inpatient mortality for stroke.
Results
Stroke alert weekly volume post-SIP (mean, 98 [95% CI, 92-104]) decreased significantly compared with pre-SIP (mean, 132 [95% CI, 130-136]; <0.001). Stroke discharges also dropped, in concordance with acute stroke alerts decrease. In total, 9120 patients were included: 8337 in pre- and 783 in post-SIP cohorts. There were no differences in patient demographics. Compared with pre-SIP, post-SIP patients had higher National Institutes of Health Stroke Scale scores (=0.003), lower comorbidity score (<0.001), and arrived more often by ambulance (<0.001). Post-SIP, more patients had large vessel occlusions (=0.03), and there were fewer stroke mimics (=0.001). Discharge outcomes were similar for post-SIP and pre-SIP cohorts.
Conclusions
In this cohort study, regional stroke alert and ischemic stroke discharge volumes decreased significantly in the early COVID-19 pandemic. Compared with pre-SIP, the post-SIP population showed no significant demographic differences but had lower comorbidity scores, more severe strokes, and more large vessel occlusions. The inpatient mortality was similar in both cohorts. Further studies are needed to understand the causes and implications of care avoidance to patients and healthcare systems.



Stroke: 06 Aug 2020:STROKEAHA120031099; epub ahead of print
Nguyen-Huynh MN, Tang XN, Vinson DR, Flint AC, ... Sidney S, Klingman JG
Stroke: 06 Aug 2020:STROKEAHA120031099; epub ahead of print | PMID: 32762619
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Impact:
Abstract

Lower socioeconomic status predicts higher mortality and morbidity in patients with heart failure.

Schrage B, Lund LH, Benson L, Stolfo D, ... Ferreira JP, Savarese G
Objective
It is not fully understood whether and how socioeconomic status (SES) has a prognostic impact in patients with heart failure (HF). We assessed SES and its association with patient characteristics and outcomes in a contemporary and well-characterised HF cohort.
Methods
Socioeconomic risk factors (SERF) were defined in the Swedish HF Registry based on income (low vs high according to the annual median value), education level (no degree/compulsory school vs university/secondary school) and living arrangement (living alone vs cohabitating).
Results
Of 44 631 patients, 21% had no, 33% one, 30% two and 16% three SERF. Patient characteristics strongly and independently associated with lower SES were female sex and no specialist referral. Additional independent associations were older age, more severe HF, heavier comorbidity burden, use of diuretics and less use of HF devices. Lower SES was associated with higher risk of HF hospitalisation/mortality, and overall cardiovascular and non-cardiovascular events. These associations persisted after extensive adjustment for patient characteristics, treatments and care. The magnitude of the association increased linearly with the increasing number of coexistent SERF: HR (95% CI) 1.09 (1.05 to 1.13) for one, 1.16 (1.12 to 1.20) for two and 1.22 (1.18 to 1.28) for three SERF (p<0.01).
Conclusions
In a contemporary and well-characterised HF cohort and after comprehensive adjustment for confounders, lower SES was linked with multiple factors such as less use of HF devices and age, but most strongly with female sex and lack of specialist referral; and associated with greater risk of morbidity/mortality.

© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 06 Aug 2020; epub ahead of print
Schrage B, Lund LH, Benson L, Stolfo D, ... Ferreira JP, Savarese G
Heart: 06 Aug 2020; epub ahead of print | PMID: 32769169
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Abstract

Mechanism of succinate efflux upon reperfusion of the ischemic heart.

Prag HA, Gruszczyk AV, Huang MM, Beach TE, ... Murphy MP, Aksentijević D
Aims
Succinate accumulates several-fold in the ischemic heart and is then rapidly oxidised upon reperfusion, contributing to reactive oxygen species (ROS) production by mitochondria. In addition, a significant amount of the accumulated succinate is released from the heart into the circulation at reperfusion, potentially activating the G-protein coupled succinate receptor (SUCNR1). However, the factors that determine the proportion of succinate oxidation or release, and the mechanism of this release, are not known.
Methods and results
To address these questions, we assessed the fate of accumulated succinate upon reperfusion of anoxic cardiomyocytes, and of the ischemic heart both ex vivo and in vivo. The release of accumulated succinate was selective and was enhanced by acidification of the intracellular milieu. Furthermore, pharmacological inhibition, or haploinsufficiency of the monocarboxylate transporter 1 (MCT1) significantly decreased succinate efflux from the reperfused heart.
Conclusion
Succinate release upon reperfusion of the ischemic heart is mediated by MCT1 and is facilitated by the acidification of the myocardium during ischemia. These findings will allow the signalling interaction between succinate released from reperfused ischemic myocardium and SUCNR1 to be explored.
Translational perspectives
In this study we demonstrate that succinate efflux upon reperfusion of the ischemic myocardium is mediated by the monocarboxylate transporter 1 (MCT1) and is enhanced by the ischemic acidification of the heart. These findings are an important advance in understanding how succinate is released upon reperfusion of ischemic organs. While this pathway is therapeutically tractable, greater understanding of the effects of succinate release is required before exploring this possibility.

© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.

Cardiovasc Res: 06 Aug 2020; epub ahead of print
Prag HA, Gruszczyk AV, Huang MM, Beach TE, ... Murphy MP, Aksentijević D
Cardiovasc Res: 06 Aug 2020; epub ahead of print | PMID: 32766828
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Impact:
Abstract

Measurement of carotid plaque burden.

Spence JD
Purpose of review
To describe the uses of measurement of carotid plaque burden, as total plaque area (TPA), total plaque volume (TPV), and vessel wall volume (VWV), which includes plaque burden and wall volume.
Recent findings
Measurement of plaque burden is useful for risk stratification, research into the genetics and biology of atherosclerosis, for measuring effects of new therapies for atherosclerosis, and for treatment of high-risk patients with severe atherosclerosis.
Summary
Measurement of plaque burden is far superior to measurement of carotid intima-media thickness (IMT) in many ways, and should replace it. Vessel wall volume can be measured in persons with no plaque as an alternative to IMT.



Curr Opin Lipidol: 05 Aug 2020; epub ahead of print
Spence JD
Curr Opin Lipidol: 05 Aug 2020; epub ahead of print | PMID: 32773468
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Abstract

Atherosclerosis: cell biology and lipoproteins.

Getz GS, Reardon CA
Purpose of review
Lipoproteins have significant role in both the promotion and prevention of atherosclerosis. This brief review will focus on recent reports on relationship between HDL and HDL subclasses and their composition and function, the role of apoC-III in metabolism of triglyceride-rich lipoproteins, the impact of Lipoprotein (a) (Lp(a)) on endothelial cells, and the mechanism of uptake of aggregated LDL by macrophages.
Recent findings
The complexity of the protein and lipid content of murine and human HDL and their relationship to its cholesterol efflux capacity have been examined. HDL has also been shown to have both antiatherogenic and proatherogenic properties. The relationship between apoC-III and LPL activity, apoprotein E mediated clearance of triglyceride-rich lipoproteins and the potential importance of apoC-III in the increased risk of cardiovascular disease in type 1 diabetics has been investigated. Oxidized phospholipid in Lp(a) promotes endothelial cells inflammatory and glycolytic responses. TLR4 participates in the uptake of aggregated LDL to contribute to foam cell formation.
Summary
These studies contribute to our mechanistic understanding of how lipoproteins contribute to atherogenesis and identify potential therapeutic targets.



Curr Opin Lipidol: 05 Aug 2020; epub ahead of print
Getz GS, Reardon CA
Curr Opin Lipidol: 05 Aug 2020; epub ahead of print | PMID: 32773467
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Impact:
Abstract

Fibroblasts in atherosclerosis: heterogeneous and plastic participants.

Tillie RJHA, van Kuijk K, Sluimer JC
Purpose of review
Fibroblasts are very heterogeneous and plastic cells in the vasculature. A growing interest in fibroblasts in healthy and atherosclerotic vasculature is observed, next to macrophages, endothelial cells, and smooth muscle cells (SMCs). In this review, we discuss fibroblast presence, heterogeneity, origin, and plasticity in health and atherosclerosis based on latest literature.
Recent findings
With help of single cell sequencing (SCS) techniques, we have gained more insight into presence and functions of fibroblasts in atherosclerosis. Next to SMCs, fibroblasts are extracellular matrix-producing cells abundant in the vasculature and involved in atherogenesis. Fibroblasts encompass a heterogeneous population and SCS data reveal several fibroblast clusters in healthy and atherosclerotic tissue with varying gene expression and function. Moreover, recent findings indicate interesting similarities between adventitial stem and/or progenitor cells and fibroblasts. Also, communication with inflammatory cells opens up a new therapeutic avenue.
Summary
Because of their highly plastic and heterogeneous nature, modulating fibroblast cell function and communication in the atherosclerotic vessel might be useful in battling atherosclerosis from within the plaque.



Curr Opin Lipidol: 05 Aug 2020; epub ahead of print
Tillie RJHA, van Kuijk K, Sluimer JC
Curr Opin Lipidol: 05 Aug 2020; epub ahead of print | PMID: 32773464
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Impact:
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