Topic: Basic Research

Abstract

Drug-Coated Balloon Angioplasty Versus Drug-Eluting Stent Implantation in Patients With Coronary Stent Restenosis.

Giacoppo D, Alfonso F, Xu B, Claessen BEPM, ... Kastrati A, Byrne RA
Background
In patients with coronary in-stent restenosis (ISR) requiring reintervention, it is unclear if the choice of treatment should depend on whether the restenotic stent was a bare-metal stent (BMS) or a drug-eluting stent (DES).
Objectives
This study aimed to assess the comparative efficacy and safety of the 2 most frequently used treatments - angioplasty with drug-coated balloon (DCB) and repeat stenting DES - in patients with BMS-and DES-ISR.
Methods
The DAEDALUS (Difference in Antirestenotic Effectiveness of Drug-Eluting Stent and Drug-Coated Balloon Angioplasty for the Occurrence of Coronary In-Stent Restenosis) study was a pooled analysis of individual patient data from all 10 existing randomized clinical trials comparing DCB angioplasty with repeat DES implantation for the treatment of coronary ISR. In this pre-specified analysis, patients were stratified according to BMS- versus DES-ISR and treatment assigned. The primary efficacy endpoint was target lesion revascularization (TLR) at 3 years. The primary safety endpoint was a composite of all-cause death, myocardial infarction, or target lesion thrombosis at 3 years. Primary analysis was performed by mixed-effects Cox models accounting for the trial of origin. Secondary analyses included nonparsimonious multivariable adjustment accounting also for multiple lesions per patient and 2-stage analyses.
Results
A total of 710 patients with BMS-ISR (722 lesions) and 1,248 with DES-ISR (1,377 lesions) were included. In patients with BMS-ISR, no significant difference between treatments was observed in terms of primary efficacy (9.2% vs. 10.2%; hazard ratio [HR]: 0.83; 95% confidence interval [CI]: 0.51 to 1.37) and safety endpoints (8.7% vs. 7.5%; HR: 1.13; 95% CI: 0.65 to 1.96); results of secondary analyses were consistent. In patients with DES-ISR, the risk of the primary efficacy endpoint was higher with DCB angioplasty than with repeat DES implantation (20.3% vs. 13.4%; HR: 1.58; 95% CI: 1.16 to 2.13), whereas the risk of the primary safety endpoint was numerically lower (9.5% vs. 13.3%; HR: 0.69; 95% CI: 0.47 to 1.00); results of secondary analyses were consistent. Regardless of the treatment used, the risk of TLR was lower in BMS- versus DES-ISR (9.7% vs. 17.0%; HR: 0.56; 95% CI: 0.42 to 0.74), whereas safety was not significantly different between ISR types.
Conclusions
At 3-year follow-up, DCB angioplasty and repeat stenting with DES are similarly effective and safe in the treatment of BMS-ISR, whereas DCB angioplasty is significantly less effective than repeat DES implantation in the treatment DES-ISR, and associated with a nonsignificant reduction in the primary composite safety endpoint. Overall, DES-ISR is associated with higher rates of treatment failure and similar safety compared with BMS-ISR.

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

J Am Coll Cardiol: 01 Jul 2020; 75:2664-2678
Giacoppo D, Alfonso F, Xu B, Claessen BEPM, ... Kastrati A, Byrne RA
J Am Coll Cardiol: 01 Jul 2020; 75:2664-2678 | PMID: 32466881
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Abstract

Associations Between Cardiovascular Risk, Structural Brain Changes, and Cognitive Decline.

Song R, Xu H, Dintica CS, Pan KY, ... Bennett DA, Xu W
Background
The impact of cardiovascular risk burden on cognitive trajectories and brain structure changes remains unclear.
Objectives
This study aimed to examine whether cardiovascular risk burden assessed by the Framingham General Cardiovascular Risk Score (FGCRS) is associated with cognitive decline and structural brain differences.
Methods
Within the Rush Memory and Aging Project, 1,588 dementia-free participants (mean age: 79.5 years) were followed for up to 21 years. FGCRS was assessed at baseline and categorized into tertiles (lowest, middle, and highest). Episodic memory, semantic memory, working memory, visuospatial ability, and perceptual speed were assessed annually with a battery of 19 tests, from which composite scores were derived. A subsample (n = 378) of participants underwent magnetic resonance imaging. Structural total and regional brain volumes were estimated. Data were analyzed using linear mixed-effects models and linear regression models.
Results
In all participants, FGCRS ranged from 4 to 28 (mean score: 15.6 ± 3.7). Compared with the lowest tertile of FGCRS, the highest tertile was associated with faster decline in global cognition (β = -0.019; 95% confidence interval [CI]: -0.035 to -0.003), episodic memory (β = -0.023; 95% CI: -0.041 to -0.004), working memory (β = -0.021; 95% CI: -0.035 to -0.007), and perceptual speed (β = -0.027; 95% CI: -0.042 to -0.011) over the follow-up. In magnetic resonance imaging data analyses, higher FGCRS was related to smaller volumes of the hippocampus (β = -0.021; 95% CI: -0.042 to -0.000), gray matter (β = -1.569; 95% CI: -2.757 to -0.382), and total brain (β = -1.588; 95% CI: -2.832 to -0.344), and greater volume of white matter hyperintensities (β = 0.035; 95% CI: 0.001 to 0.069).
Conclusions
Higher cardiovascular risk burden may predict decline in episodic memory, working memory, and perceptual speed and is associated with neurodegeneration and vascular lesions in the brain.

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

J Am Coll Cardiol: 25 May 2020; 75:2525-2534
Song R, Xu H, Dintica CS, Pan KY, ... Bennett DA, Xu W
J Am Coll Cardiol: 25 May 2020; 75:2525-2534 | PMID: 32439001
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Abstract

Longevity genes, cardiac ageing, and the pathogenesis of cardiomyopathy: implications for understanding the effects of current and future treatments for heart failure.

Packer M

The two primary molecular regulators of lifespan are sirtuin-1 (SIRT1) and mammalian target of rapamycin complex 1 (mTORC1). Each plays a central role in two highly interconnected pathways that modulate the balance between cellular growth and survival. The activation of SIRT1 [along with peroxisome proliferator-activated receptor-gamma coactivator (PGC-1α) and adenosine monophosphate-activated protein kinase (AMPK)] and the suppression of mTORC1 (along with its upstream regulator, Akt) act to prolong organismal longevity and retard cardiac ageing. Both activation of SIRT1/PGC-1α and inhibition of mTORC1 shifts the balance of cellular priorities so as to promote cardiomyocyte survival over growth, leading to cardioprotective effects in experimental models. These benefits may be related to direct actions to modulate oxidative stress, organellar function, proinflammatory pathways, and maladaptive hypertrophy. In addition, a primary shared benefit of both SIRT1/PGC-1α/AMPK activation and Akt/mTORC1 inhibition is the enhancement of autophagy, a lysosome-dependent degradative pathway, which clears the cytosol of dysfunctional organelles and misfolded proteins that drive the ageing process by increasing oxidative and endoplasmic reticulum stress. Autophagy underlies the ability of SIRT1/PGC-1α/AMPK activation and Akt/mTORC1 suppression to extend lifespan, mitigate cardiac ageing, alleviate cellular stress, and ameliorate the development and progression of cardiomyopathy; silencing of autophagy genes abolishes these benefits. Loss of SIRT1/PGC-1α/AMPK function or hyperactivation of Akt/mTORC1 is a consistent feature of experimental cardiomyopathy, and reversal of these abnormalities mitigates the development of heart failure. Interestingly, most treatments that have been shown to be clinically effective in the treatment of chronic heart failure with a reduced ejection fraction have been reported experimentally to exert favourable effects to activate SIRT1/PGC-1α/AMPK and/or suppress Akt/mTORC1, and thereby, to promote autophagic flux. Therefore, the impairment of autophagy resulting from derangements in longevity gene signalling is likely to represent a seminal event in the evolution and progression of cardiomyopathy.

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

Eur Heart J: 26 May 2020; epub ahead of print
Packer M
Eur Heart J: 26 May 2020; epub ahead of print | PMID: 32460327
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Abstract

Prevention of aortic dissection and aneurysm via an ALDH2-mediated switch in vascular smooth muscle cell phenotype.

Yang K, Ren J, Li X, Wang Z, ... Chen Y, Xu F
Aims
Aortic aneurysm/dissection (AAD) is a life-threatening disorder lacking effective pharmacotherapeutic remedies. Aldehyde dehydrogenase 2 (ALDH2) polymorphism is tied with various risk factors for AAD including hypertension, atherosclerosis, and hypercholesterolaemia although direct correlation between the two remains elusive.
Methods and results
Two independent case-control studies were conducted involving 307 AAD patients and 399 healthy controls in two geographically distinct areas in China. Our data revealed that subjects carrying mutant ALDH2 gene possessed a ∼50% reduced risk of AAD compared with wild-type (WT) alleles. Using 3-aminopropionitrile fumarate (BAPN)- and angiotensin II (Ang II)-induced AAD animal models, inhibition of ALDH2 was found to retard development of AAD. Mechanistically, ALDH2 inhibition ablated pathological vascular smooth muscle cell (VSMC) phenotypical switch through interaction with myocardin, a determinant of VSMC contractile phenotype. Using microarray and bioinformatics analyses, ALDH2 deficiency was found to down-regulate miR-31-5p, which further altered myocardin mRNA level. Gain-of-function and loss-of-function studies verified that miR-31-5p significantly repressed myocardin level and aggravated pathological VSMC phenotypical switch and AAD, an effect that was blunted by ALDH2 inhibition. We next noted that ALDH2 deficiency increased Max expression and decreased miR-31-5p level. Moreover, ALDH2 mutation or inhibition down-regulated levels of miR-31-5p while promoting myocardin downstream contractile genes in the face of Ang II in primary human VSMCs.
Conclusions
ALDH2 deficiency is associated with a lower risk of AAD in patients and mice, possibly via suppressing VSMC phenotypical switch in a miR-31-5p-myocardin-dependent manner. These findings favour a role for ALDH2 and miR-31-5p as novel targets for AAD therapy.

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: 17 May 2020; epub ahead of print
Yang K, Ren J, Li X, Wang Z, ... Chen Y, Xu F
Eur Heart J: 17 May 2020; epub ahead of print | PMID: 32428930
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Abstract

The thrombotic risk of spaceflight: has a serious problem been overlooked for more than half of a century?

Limper U, Tank J, Ahnert T, Maegele M, ... Hein M, Jordan J

The first ever venous thrombotic condition associated with spaceflight, an internal jugular vein thrombus requiring anticoagulation, has recently been reported. Systematic investigation of space travel-associated thrombotic risk has not been conducted. Cellular, animal, and human studies performed in ground-based models and in actual weightlessness revealed influences of weightlessness and gravity on the blood coagulation system. However, human study populations were small and limited to highly selected participants. Evidence in individuals with medical conditions and older persons is lacking. Evidence for thrombotic risk in spaceflight is unsatisfactory. This issue deserves further study in heterogeneous, high risk populations to find prevention strategies and to enable safe governmental and touristic human spaceflight.

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: 17 May 2020; epub ahead of print
Limper U, Tank J, Ahnert T, Maegele M, ... Hein M, Jordan J
Eur Heart J: 17 May 2020; epub ahead of print | PMID: 32428936
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Abstract

FDA Initiative for Drug Facts Label for Over-the-Counter Naloxone.

Cohen BR, Mahoney KM, Baro E, Squire C, ... Izem R, Woodcock J
Background
The opioid crisis highlights the need to increase access to naloxone, possibly through regulatory approval for over-the-counter sales. To address industry-perceived barriers to such access, the Food and Drug Administration (FDA) developed a model drug facts label for such sales to assess whether consumers understood the key statements for safe and effective use.
Methods
In this label-comprehension study, we conducted individual structured interviews with 710 adults and adolescents, including 430 adults who use opioids and their family and friends. Eight primary end points were developed to assess user comprehension of each of the key steps in the label. Each of these end points included a prespecified target threshold ranging from 80 to 90% that was evaluated through a comparison of the lower boundary of the 95% exact confidence interval.
Results
The results for performance on six primary end points met or exceeded thresholds, including the steps \"Check for a suspected overdose\" (threshold, 85%; point estimate [PE], 95.8%; 95% confidence interval [CI], 94.0 to 97.1) and \"Give the first dose\" (threshold, 85%; PE, 98.2%; 95% CI, 96.9 to 99.0). The lower boundaries for four other primary end points ranged from 88.8 to 94.0%. One exception was comprehension of \"Call 911 immediately,\" but this instruction closely approximated the target of 90% (PE, 90.3%; 95% CI, 87.9 to 92.4). Another exception was comprehension of the composite step of \"Check, give, and call 911 immediately\" (threshold, 85%; PE, 81.1%; 95% CI, 78.0 to 83.9).
Conclusions
Consumers met thresholds for sufficient understanding of six of eight components of the instructions in the drug facts label for naloxone use and came close on two others. Overall, the FDA found that the model label was adequate for use in the development of a naloxone product intended for over-the-counter sales.

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 27 May 2020; 382:2129-2136
Cohen BR, Mahoney KM, Baro E, Squire C, ... Izem R, Woodcock J
N Engl J Med: 27 May 2020; 382:2129-2136 | PMID: 32459923
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Abstract

WWP1 Gain-of-Function Inactivation of PTEN in Cancer Predisposition.

Lee YR, Yehia L, Kishikawa T, Ni Y, ... Eng C, Pandolfi PP
Background
Patients withhamartoma tumor syndrome (PHTS) have germline mutations in the tumor-suppressor gene encoding phosphatase and tensin homologue (). Such mutations have been associated with a hereditary predisposition to multiple types of cancer, including the Cowden syndrome. However, a majority of patients who have PHTS-related phenotypes have tested negative formutations. In a previous study, we found that the E3 ubiquitin ligase WWP1 negatively regulates the function of PTEN.
Methods
In a prospective cohort study conducted from 2005 through 2015, we enrolled 431 patients with wild-typewho met at least the relaxed diagnostic criteria of the International Cowden Consortium. Patients were scanned forgermline variants. We used the Cancer Genome Atlas (TCGA) data set as representative of apparently sporadic cancers and the Exome Aggregation Consortium data set excluding TCGA (non-TCGA ExAC) and the noncancer Genome Aggregation Database (gnomAD) as representative of population controls without a reported cancer diagnosis. We established both in vitro and murine in vivo models to functionally characterize representativevariants.
Results
The existence of germlinevariants was first established in a family with wild-typewho had oligopolyposis and early-onset colon cancers. A validation series indicated thatgermline variants occurred in 5 of 126 unrelated patients (4%) with oligopolyposis as a predominant phenotype. Germlinevariants, particularly theK740N and N745S alleles, were enriched in patients who did not have PHTS but had prevalent sporadic cancers, including related cancer types in TCGA (odds ratio, 1.5; 95% confidence interval, 1.1 to 2.1; P = 0.01). The prioritizedvariants resulted in gain-of-function effects, which led to aberrant enzymatic activation with consequent PTEN inactivation, thereby triggering hyperactive growth-promoting PI3K signaling in cellular and murine models.
Conclusions
In this study involving patients with disorders resulting in a predisposition to the development of multiple malignant neoplasms withoutgermline mutations, we confirmed the function ofas a cancer-susceptibility gene through direct aberrant regulation of the PTEN-PI3K signaling axis. (Funded by the National Institutes of Health and others.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 27 May 2020; 382:2103-2116
Lee YR, Yehia L, Kishikawa T, Ni Y, ... Eng C, Pandolfi PP
N Engl J Med: 27 May 2020; 382:2103-2116 | PMID: 32459922
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Abstract

Remdesivir for 5 or 10 Days in Patients with Severe Covid-19.

Goldman JD, Lye DCB, Hui DS, Marks KM, ... Subramanian A,
Background
Remdesivir is an RNA polymerase inhibitor with potent antiviral activity in vitro and efficacy in animal models of coronavirus disease 2019 (Covid-19).
Methods
We conducted a randomized, open-label, phase 3 trial involving hospitalized patients with confirmed SARS-CoV-2 infection, oxygen saturation of 94% or less while they were breathing ambient air, and radiologic evidence of pneumonia. Patients were randomly assigned in a 1:1 ratio to receive intravenous remdesivir for either 5 days or 10 days. All patients received 200 mg of remdesivir on day 1 and 100 mg once daily on subsequent days. The primary end point was clinical status on day 14, assessed on a 7-point ordinal scale.
Results
In total, 397 patients underwent randomization and began treatment (200 patients for 5 days and 197 for 10 days). The median duration of treatment was 5 days (interquartile range, 5 to 5) in the 5-day group and 9 days (interquartile range, 5 to 10) in the 10-day group. At baseline, patients randomly assigned to the 10-day group had significantly worse clinical status than those assigned to the 5-day group (P = 0.02). By day 14, a clinical improvement of 2 points or more on the ordinal scale occurred in 64% of patients in the 5-day group and in 54% in the 10-day group. After adjustment for baseline clinical status, patients in the 10-day group had a distribution in clinical status at day 14 that was similar to that among patients in the 5-day group (P = 0.14). The most common adverse events were nausea (9% of patients), worsening respiratory failure (8%), elevated alanine aminotransferase level (7%), and constipation (7%).
Conclusions
In patients with severe Covid-19 not requiring mechanical ventilation, our trial did not show a significant difference between a 5-day course and a 10-day course of remdesivir. With no placebo control, however, the magnitude of benefit cannot be determined. (Funded by Gilead Sciences; GS-US-540-5773 ClinicalTrials.gov number, NCT04292899.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 26 May 2020; epub ahead of print
Goldman JD, Lye DCB, Hui DS, Marks KM, ... Subramanian A,
N Engl J Med: 26 May 2020; epub ahead of print | PMID: 32459919
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Abstract

Survival of Patients With Angina Pectoris Undergoing Percutaneous Coronary Intervention With Intracoronary Pressure Wire Guidance.

Völz S, Dworeck C, Redfors B, Pétursson P, ... Erlinge D, Omerovic E
Background
Intracoronary pressure wire measurement of fractional flow reserve (FFR) provides decision-making guidance during percutaneous coronary intervention (PCI). However, limited data exist on the effect of FFR on long-term clinical outcomes in patients with stable angina pectoris.
Objectives
The purpose of this study was to determine the association between the usage of FFR and all-cause mortality in patients with stable angina undergoing PCI.
Methods
Data was used from the SCAAR (Swedish Coronary Angiography and Angioplasty Registry) on all patients undergoing PCI (with or without FFR guidance) for stable angina pectoris in Sweden between January 2005 and March 2016. The primary endpoint was all-cause mortality, and the secondary endpoints were stent thrombosis (ST) or restenosis and peri-procedural complications. The primary model was multilevel Cox proportional hazards regression adjusted with Kernel-based propensity score matching.
Results
In total, 23,860 patients underwent PCI for stable angina pectoris; of these, FFR guidance was used in 3,367. After a median follow-up of 4.7 years (range 0 to 11.2 years), the FFR group had lower adjusted risk estimates for all-cause mortality (hazard ratio: 0.81; 95% confidence interval [CI]: 0.73 to 0.89; p < 0.001), and ST and restenosis (hazard ratio: 0.74; 95% CI: 0.57 to 0.96; p = 0.022). The number of peri-procedural complications did not differ between the groups (adjusted odds ratio: 0.96; 95% CI: 0.77 to 1.19; p = 0.697).
Conclusions
In this observational study, the use of FFR was associated with a lower risk of long-term mortality, ST, and restenosis in patients undergoing PCI for stable angina pectoris. This study supports the current European and American guidelines for the use of FFR during PCI and shows that intracoronary pressure wire guidance confers prognostic benefit in patients with stable angina pectoris.

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

J Am Coll Cardiol: 08 Jun 2020; 75:2785-2799
Völz S, Dworeck C, Redfors B, Pétursson P, ... Erlinge D, Omerovic E
J Am Coll Cardiol: 08 Jun 2020; 75:2785-2799 | PMID: 32498806
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Abstract

Association of Age of Onset of Hypertension With Cardiovascular Diseases and Mortality.

Wang C, Yuan Y, Zheng M, Pan A, ... Wu S, Xue H
Background
The relations of hypertension onset age with cardiovascular diseases (CVD) and all-cause mortality remain inconclusive.
Objectives
This study sought to examine the associations of hypertension onset age with CVD and all-cause mortality.
Methods
This prospective study included 71,245 participants free of hypertension and CVD in the first survey (July 2006 to October 2007) of the Kailuan study, a prospective cohort study in Tangshan, China. All participants were followed biennially until December 31, 2017. A total of 20,221 new-onset hypertension cases were identified during follow-up. We randomly selected 1 control participant for each new-onset hypertensive participant, matching for age (±1 year) and sex, and included 19,887 case-control pairs. We used weighted Cox regression models to calculate the average hazard ratios of incident CVD and all-cause mortality across the age groups.
Results
During an average follow-up of 6.5 years, we identified 1,672 incident CVD cases and 2,008 deaths. After multivariate adjustment, with the increase in hypertension onset age, the hazards of outcomes were gradually attenuated. The average hazard ratio (95% confidence interval) of CVD and all-cause mortality were 2.26 (1.19 to 4.30) and 2.59 (1.32 to 5.07) for the hypertension onset age <45 years old group, 1.62 (1.24 to 2.12) and 2.12 (1.55 to 2.90) for the 45- to 54-year age group, 1.42 (1.12 to 1.79) and 1.30 (1.03 to 1.62) for the 55- to 64-year age group, and 1.33 (1.04 to 1.69) and 1.29 (1.11 to 1.51) for the ≥65-year age group, respectively (p for interaction = 0.38 for CVD and <0.01 for death).
Conclusions
Hypertension was associated with a higher risk for CVD and all-cause mortality, and the associations were stronger with a younger age of onset.

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

J Am Coll Cardiol: 15 Jun 2020; 75:2921-2930
Wang C, Yuan Y, Zheng M, Pan A, ... Wu S, Xue H
J Am Coll Cardiol: 15 Jun 2020; 75:2921-2930 | PMID: 32527401
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Abstract

A Validated Model for Sudden Cardiac Death Risk Prediction in Pediatric Hypertrophic Cardiomyopathy.

Miron A, Lafreniere-Roula M, Fan CS, Armstrong KR, ... Ho CY, Mital S

Hypertrophic cardiomyopathy (HCM) is the leading cause of sudden cardiac death (SCD) in children and young adults. Our objective was to develop and validate a SCD risk prediction model in pediatric HCM to guide SCD prevention strategies.In an international multi-center observational cohort study, phenotype-positive patients with isolated HCM <18 years at diagnosis were eligible. The primary outcome variable was the time from diagnosis to a composite of SCD events at 5-year follow-up: SCD, resuscitated sudden cardiac arrest (SCA), and aborted SCD, i.e. appropriate shock following primary prevention ICD. Competing risk models with cause-specific hazard regression were used to identify and quantify clinical and genetic factors associated with SCD. The cause-specific regression model was implemented using boosting, and tuned with ten repeated four-fold cross-validations. The final model was fitted using all data with the tuned hyperparameter value that maximizes the c-statistic, and its performance was characterized using c-statistic for competing risk models. The final model was validated in an independent external cohort (SHaRe, n=285).Overall, 572 patients met eligibility criteria with 2855 patient-years of follow-up. The 5-year cumulative proportion of SCD events was 9.1% (14 SCD, 25 resuscitated SCA, 14 aborted SCD). Risk predictors included age at diagnosis, documented non-sustained ventricular tachycardia, unexplained syncope, septal diameter z-score, LV posterior wall diameter z-score, LA diameter z-score, peak LV outflow tract (LVOT) gradient, and presence of a pathogenic variant. Unlike adults, LVOT gradient had an inverse association, and family history of SCD had no association with SCD. Clinical and clinical/genetic models were developed to predict 5-year freedom from SCD. Both models adequately discriminated patients with and without SCD events with a c-statistic of 0.75 and 0.76 respectively and demonstrated good agreement between predicted and observed events in the primary and validation cohorts (validation c-statistic 0.71 and 0.72 respectively). Our study provides a validated SCD risk prediction model with over 70% prediction accuracy and incorporates risk factors that are unique to pediatric HCM. An individualized risk prediction model has the potential to improve the application of clinical practice guidelines and shared decision-making for ICD insertion. URL: https://clinicaltrials.gov Unique Identifier: NCT04036799.



Circulation: 17 May 2020; epub ahead of print
Miron A, Lafreniere-Roula M, Fan CS, Armstrong KR, ... Ho CY, Mital S
Circulation: 17 May 2020; epub ahead of print | PMID: 32418493
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Abstract

Declines in Hospitalizations for Acute Cardiovascular Conditions During the COVID-19 Pandemic: A Multicenter Tertiary Care Experience.

Bhatt AS, Moscone A, McElrath EE, Varshney AS, ... Solomon SD, Vaduganathan M
Background
While patients with cardiovascular disease face excess risks of severe illness with coronavirus disease-2019 (COVID-19), there may be indirect consequences of the pandemic on this high-risk patient segment.
Objectives
To examine longitudinal trends in hospitalizations for acute cardiovascular conditions across a tertiary care healthcare system.
Methods
We tracked acute cardiovascular hospitalizations between January 1, 2019 and March 31, 2020. We estimated daily hospitalization rates using negative binomial models. Temporal trends in hospitalization rates were compared across the first 3 months of 2020, with the first 3 months of 2019 as a reference.
Results
From January 1, 2019 to March 31, 2020, 6,083 patients experienced 7,187 hospitalizations for primary acute cardiovascular reasons. There was 43.4% (27.4% to 56.0%) fewer estimated daily hospitalizations in March 2020 as compared with March 2019 (P<0.001). The daily rate of hospitalizations did not change throughout 2019 (-0.01% per day [-0.04% to +0.02%], P=0.50), January 2020 (-0.5% per day [-1.6% to +0.5%], P=0.31), or February 2020 (+0.7% per day [-0.6% to +2.0%], P=0.27). There was significant daily decline in hospitalizations in March 2020 (-5.9% per day [-7.6% to -4.3%], P<0.001). Length of stay was shorter (4.8 [2.4,8.3] days vs. 6.0 [3.1,9.6] days; P=0.003) and in-hospital mortality was not significantly different (6.2% vs. 4.4%; P=0.30) in March 2020 compared with March 2019.
Conclusions
During the first phase of the COVID-19 pandemic, there was a marked decline in acute cardiovascular hospitalizations and patients who were admitted had shorter lengths of stay. These data substantiate concerns that acute care of cardiovascular conditions may be delayed, deferred, or abbreviated during the COVID-19 pandemic.

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

J Am Coll Cardiol: 20 May 2020; epub ahead of print
Bhatt AS, Moscone A, McElrath EE, Varshney AS, ... Solomon SD, Vaduganathan M
J Am Coll Cardiol: 20 May 2020; epub ahead of print | PMID: 32470516
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Abstract

The Environment-Sensing Aryl-Hydrocarbon Receptor Inhibits the Chondrogenic Fate of Modulated Smooth Muscle Cells in Atherosclerotic Lesions.

Kim JB, Zhao Q, Nguyen T, Pjanic M, ... Kundu R, Quertermous T

Smooth muscle cells (SMC) play a critical role in atherosclerosis. The Aryl hydrocarbon receptor (AHR) is an environment-sensing transcription factor that contributes to vascular development, and has been implicated in coronary artery disease (CAD) risk. We hypothesized that AHR can affect atherosclerosis by regulating phenotypic modulation of SMC.We combined RNA-Seq, ChIP-Seq, ATAC-Seq and in-vitro assays in human coronary artery SMC (HCASMC), with single-cell RNA-Seq (scRNA-Seq), histology, and RNAscope in an SMC-specific lineage-tracingknockout mouse model of atherosclerosis to better understand the role ofin vascular disease.Genomic studies coupled with functional assays in cultured HCASMC revealed thatmodulates HCASMC phenotype and suppresses ossification in these cells. Lineage tracing and activity tracing studies in the mouse aortic sinus showed that thepathway is active in modulated SMC in the atherosclerotic lesion cap. Furthermore, scRNA-Seq studies of the SMC-specific Ahr knockout mice showed a significant increase in the proportion of modulated SMC expressing chondrocyte markers such asand , which localized to the lesion neointima. These cells, which we term \"chondromyocytes\" (CMC), were also identified in the neointima of human coronary arteries. In histological analyses, these changes manifested as larger lesion size, increased lineage-traced SMC participation in the lesion, decreased lineage-traced SMC in the lesion cap, and increased alkaline phosphatase activity in lesions in theknockout compared to wild-type mice. We propose thatis likely protective based on these data and inference from human genetic analyses.Overall, we conclude thatpromotes maintenance of lesion cap integrity and diminishes the disease related SMC-to-CMC transition in atherosclerotic tissues.



Circulation: 21 May 2020; epub ahead of print
Kim JB, Zhao Q, Nguyen T, Pjanic M, ... Kundu R, Quertermous T
Circulation: 21 May 2020; epub ahead of print | PMID: 32441123
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Abstract

Single-Cell RNA Sequencing to Dissect the Immunological Network of Autoimmune Myocarditis.

Hua X, Hu G, Hu Q, Chang Y, ... Li M, Song J

Myocarditis can develop into dilated cardiomyopathy (DCM), which may require heart transplantation (HTx). The immunological network of myocarditis phases remains unknown. This study aimed to investigate the immunological network during the transition from myocarditis to cardiomyopathy and to identify the genes contributing to the inflammatory response to myocarditis.Mice were treated with myosin heavy-chain-α peptides to generate an experimental autoimmune myocarditis (EAM) model. We performed single-cell RNA sequencing (scRNA-seq) analysis ofcells extracted from mouse hearts during different EAM phases, including normal control, acute inflammatory, subacute inflammatory and myopathy phases. Human heart tissues were collected from the surgically removed hearts of patients who had undergone HTx.We identified 26 cell subtypes among 34,665 cells. Macrophages constituted the main immune cell population at all disease phases (greater than 60%), and an inflammation-associated macrophage cluster was identified in which the expression of -regulated genes was upregulated. The neutrophil population was increased after the induction of EAM, and neutrophils then releasedto participate in the EAM process. T cells were observed at the highest percentage at the subacute inflammatory phase. Th17 cells, in which the expression of -regulated genes was upregulated, constituted the main T cell population detected at the acute inflammatory phase, while Treg cells were the main T cell population detected at the subacute inflammatory phase, and γδ T cells releasingwere the main T cell population observed at the myopathy phase. Moreover, theexpression level correlated with the extent of inflammation. Additionally, PX-478 could alleviate the inflammatory responses of the different EAM phases. Finally,was expressed at higher levels in acute autoimmune myocarditis patients than in DCM patients and healthy controls.We herein present a comprehensive single-cell landscape of the cardiac immune cells in different EAM phases. In addition, we elucidated the contribution ofto the inflammatory response through the regulation of immune cell activity, particularly of macrophage cluster 2 and Th17 cells. Moreover, ainhibitor alleviated inflammatory cell infiltration of the EAM model and may serve as a potential therapeutic target in the clinic.



Circulation: 19 May 2020; epub ahead of print
Hua X, Hu G, Hu Q, Chang Y, ... Li M, Song J
Circulation: 19 May 2020; epub ahead of print | PMID: 32431172
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Abstract

Implications of Altered Ketone Metabolism and Therapeutic Ketosis in Heart Failure.

Selvaraj S, Kelly DP, Margulies KB

Despite existing therapy, patients with heart failure (HF) experience substantial morbidity and mortality, highlighting the urgent need to identify novel pathophysiological mechanisms and therapies, as well. Traditional models for pharmacological intervention have targeted neurohormonal axes and hemodynamic disturbances in HF. However, several studies have now highlighted the potential for ketone metabolic modulation as a promising treatment paradigm. During the pathophysiological progression of HF, the failing heart reduces fatty acid and glucose oxidation, with associated increases in ketone metabolism. Recent studies indicate that enhanced myocardial ketone use is adaptive in HF, and limited data demonstrate beneficial effects of exogenous ketone therapy in studies of animal models and humans with HF. This review will summarize current evidence supporting a salutary role for ketones in HF including (1) normal myocardial ketone use, (2) alterations in ketone metabolism in the failing heart, (3) effects of therapeutic ketosis in animals and humans with HF, and (4) the potential significance of ketosis associated with sodium-glucose cotransporter 2 inhibitors. Although a number of important questions remain regarding the use of therapeutic ketosis and mechanism of action in HF, current evidence suggests potential benefit, in particular, in HF with reduced ejection fraction, with theoretical rationale for its use in HF with preserved ejection fraction. Although it is early in its study and development, therapeutic ketosis across the spectrum of HF holds significant promise.



Circulation: 01 Jun 2020; 141:1800-1812
Selvaraj S, Kelly DP, Margulies KB
Circulation: 01 Jun 2020; 141:1800-1812 | PMID: 32479196
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Abstract

Extracellular Vesicle-Mediated Delivery of CircSCMH1 Promotes Functional Recovery in Rodent and Nonhuman Primate Ischemic Stroke Models.

Yang L, Han B, Zhang Z, Wang S, ... Wang J, Yao H

Stroke is a leading cause of adult disability that can severely compromise patients\' quality of life, yet no effective medication currently exists to accelerate rehabilitation. A variety of circular RNA (circRNAs) molecules are known to function in ischemic brain injury. Lentivirus-based expression systems have been widely used in basic studies of circRNAs, but safety issues with such delivery systems have limited exploration of potential therapeutic roles for circRNAs.Circular RNA SCMH1 (circSCMH1) was screened from the plasma of acute ischemic stroke (AIS) patients using circRNA microarrays. Engineered RVG-circSCMH1-extracellular vesicles (RVG-circSCMH1-EVs) were generated to selectively deliver circSCMH1 to the brain. Nissl staining was used to examine infarct size. Behavioral tasks were performed to evaluate motor functions in both rodent and nonhuman primate ischemic stroke models. Golgi staining and immunostaining were used to examine neuroplasticity and glial activation. Proteomic assays and RNA-seq data combined with transcriptional profiling were used to identify downstream targets of circSCMH1.CircSCMH1 levels were significantly decreased in plasma of AIS patients, offering significant power in predicting stroke outcomes. The decreased levels of circSCMH1 were further confirmed in the plasma and peri-infarct cortex of photothrombotic (PT) stroke mice. Beyond demonstrating proof-of-concept for an RNA drug delivery technology, we observed that circSCMH1 treatment improved functional recovery post stroke in both mice and monkeys, and discovered that circSCMH1 enhanced the neuronal plasticity and also inhibited glial activation and peripheral immune cell infiltration. Mechanistically, circSCMH1 binds to the transcription factor MeCP2, thereby releasing repression of MeCP2 target gene transcription.RVG-circSCMH1-EVs afford protection by promoting functional recovery in the rodent and the nonhuman primate ischemic stroke models. Our study presents a potentially widely applicable nucleotide drug delivery technology and demonstrates the basic mechanism of how circRNAs can be therapeutically exploited to improve post-stroke outcomes.



Circulation: 21 May 2020; epub ahead of print
Yang L, Han B, Zhang Z, Wang S, ... Wang J, Yao H
Circulation: 21 May 2020; epub ahead of print | PMID: 32441115
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Abstract

Duration of Pre-Operative Antibiotic Treatment and Culture Results in Patients With Infective Endocarditis.

Gisler V, Dürr S, Irincheeva I, Limacher A, ... Englberger L, Sendi P
Background
Bacterial growth in cultures of resected heart valves of patients with infective endocarditis (IE) is influenced by pre-operative antibiotic treatment (preop-AT).
Objectives
This study sought to evaluate the time dependency of valve culture results (positive valve culture [PVC] vs. negative valve culture) on preop-AT.
Methods
A total of 352 IE episodes in 344 adult patients of our tertiary referral hospital were retrospectively investigated (2005 to 2016). The primary endpoint was PVC results. The study used a logistic additive model adjusted for bacterial species, the McCabe-Jackson classification, and the existence of foreign valve material as covariables.
Results
The 231 included IE cases (187 [81%] men, median age 62 years, 153 [66%] native valves) comprised 58 (25%) PVC results and 173 (75%) negative valve culture results. A multivariable analysis adjusted for bacterial species, McCabe-Jackson classification, and valve type resulted in odds ratios for PVC of 6.35 (95% confidence interval [CI]: 1.94 to 20.78; p = 0.002) and 3.93 (95% CI: 1.57 to 9.84; p = 0.003) for Enterococcus spp. and Staphylococcus spp., respectively. Model-based odds ratios for PVC risk reduction in 2-day intervals of preop-AT ranged from 0.64 (95% CI: 0.61 to 0.68) at day 7 to 0.74 (95% CI: 0.70 to 0.78) at day 13 and 0.98 (95% CI: 0.93 to 1.02) at day 21.
Conclusions
In IE cases treated with valve surgery, Staphylococcus aureus and Enterococcus spp. were associated with valve culture growth. After 7 days of antibiotic treatment, the additional effect of preop-AT on valve culture results per 2-day interval was minor. Antibiotic treatment beyond 21 days had no influence on culture results.

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

J Am Coll Cardiol: 06 Jul 2020; 76:31-40
Gisler V, Dürr S, Irincheeva I, Limacher A, ... Englberger L, Sendi P
J Am Coll Cardiol: 06 Jul 2020; 76:31-40 | PMID: 32616160
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Abstract

Early Cardiac Remodeling Promotes Tumor Growth and Metastasis.

Avraham S, Abu-Sharki S, Shofti R, Haas T, ... Shaked Y, Aronheim A

Recent evidence suggests that cancer and cardiovascular diseases are associated. Chemotherapy drugs are known to result in cardiotoxicity, and studies have shown that heart failure (HF) and stress correlate with poor cancer prognosis. Yet, whether cardiac remodeling in the absence of HF is sufficient to promote cancer is unknown.To investigate the effect of early cardiac remodeling on tumor growth and metastasis colonization, we used transverse aortic constriction (TAC), a model for pressure overload-induced cardiac hypertrophy, and followed it by cancer cell implantation.TAC-operated mice developed larger primary tumors with higher proliferation rate and displayed more metastatic lesions compared with controls. Serum derived from TAC-operated mice potentiated cancer cell proliferation , suggesting the existence of secreted tumor-promoting factors. Using RNA-seq data, we identified elevated mRNA levels ofin the hearts of TAC-operated mice. Periostin levels were also found high in the serum following TAC. Interestingly, depletion of Periostin from the serum abrogated the proliferation of cancer cells, conversely, the addition of Periostin enhanced cancer cell proliferation . Collectively, this is the first study to show that early cardiac remodeling nurtures tumor growth and metastasis, and therefore promotes cancer progression.Our study highlights the importance of early diagnosis and treatment of cardiac remodeling as it may attenuate cancer progression and improve cancer outcome.



Circulation: 31 May 2020; epub ahead of print
Avraham S, Abu-Sharki S, Shofti R, Haas T, ... Shaked Y, Aronheim A
Circulation: 31 May 2020; epub ahead of print | PMID: 32475164
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Abstract

Loss of Protease-Activated Receptor 4 Prevents Inflammation Resolution and Predisposes the Heart to Cardiac Rupture after Myocardial Infarction.

Kolpakov MA, Guo X, Rafiq K, Vlasenko L, ... Houser SR, Sabri A

Cardiac rupture is a major lethal complication of acute myocardial infarction (MI). Despite significant advances in reperfusion strategies, mortality from cardiac rupture remains high. Studies suggest that cardiac rupture can be accelerated by thrombolytic therapy, but the relevance of this risk factor remains controversial.We analyzed protease activated receptor (Par)4 expression in mouse hearts with MI and investigated the effects of Par4 deletion on cardiac remodeling and function post-MI by echocardiography, quantitative immunohistochemistry and flow cytometry.Par4 mRNA and protein levels were increased in mouse hearts after MI and in isolated cardiomyocytes in response to hypertrophic and inflammatory stimuli. Par4-deficient mice showed less myocyte apoptosis, reduced infarct size and improved functional recovery after acute MI relative to wild-type (WT). Conversely, Par4 mice showed impaired cardiac function, greater rates of myocardial rupture and increased mortality after chronic MI relative to WT. Pathological evaluation of hearts from Par4 mice demonstrated a greater infarct expansion, increased cardiac hemorrhage and delayed neutrophil accumulation, which resulted in impaired post-MI healing compared to WT. Par4 deficiency also attenuated neutrophil apoptosisand after MIand impaired inflammation resolution in infarcted myocardium. Transfer of Par4 neutrophils, but not of Par4 platelets, in WT recipient mice delayed inflammation resolution, increased cardiac hemorrhage and enhanced cardiac dysfunction. In parallel, adoptive transfer of WT neutrophils into Par4 mice restored inflammation resolution, reduced cardiac rupture incidence and improved cardiac function post-MI.These findings reveal essential roles of Par4 in neutrophil apoptosis and inflammation resolution during myocardial healing and point to Par4 inhibition as potential therapy that should be limited to the acute phases of ischemic insult and to be avoided for chronic treatment post-MI.



Circulation: 02 Jun 2020; epub ahead of print
Kolpakov MA, Guo X, Rafiq K, Vlasenko L, ... Houser SR, Sabri A
Circulation: 02 Jun 2020; epub ahead of print | PMID: 32489148
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Abstract

A randomized controlled trial of dapagliflozin on left ventricular hypertrophy in people with type two diabetes: the DAPA-LVH trial.

Brown AJM, Gandy S, McCrimmon R, Houston JG, Struthers AD, Lang CC
Aim
We tested the hypothesis that dapagliflozin may regress left ventricular hypertrophy (LVH) in people with type 2 diabetes (T2D).
Methods and results
We randomly assigned 66 people (mean age 67 ± 7 years, 38 males) with T2D, LVH, and controlled blood pressure (BP) to receive dapagliflozin 10 mg once daily or placebo for 12 months. Primary endpoint was change in absolute left ventricular mass (LVM), assessed by cardiac magnetic resonance imaging. In the intention-to-treat analysis, dapagliflozin significantly reduced LVM compared with placebo with an absolute mean change of -2.82g [95% confidence interval (CI): -5.13 to -0.51, P = 0.018]. Additional sensitivity analysis adjusting for baseline LVM, baseline BP, weight, and systolic BP change showed the LVM change to remain statistically significant (mean change -2.92g; 95% CI: -5.45 to -0.38, P = 0.025). Dapagliflozin significantly reduced pre-specified secondary endpoints including ambulatory 24-h systolic BP (P = 0.012), nocturnal systolic BP (P = 0.017), body weight (P < 0.001), visceral adipose tissue (VAT) (P < 0.001), subcutaneous adipose tissue (SCAT) (P = 0.001), insulin resistance, Homeostatic Model Assessment of Insulin Resistance (P = 0.017), and high-sensitivity C-reactive protein (hsCRP) (P = 0.049).
Conclusion
Dapagliflozin treatment significantly reduced LVM in people with T2D and LVH. This reduction in LVM was accompanied by reductions in systolic BP, body weight, visceral and SCAT, insulin resistance, and hsCRP. The regression of LVM suggests dapagliflozin can initiate reverse remodelling and changes in left ventricular structure that may partly contribute to the cardio-protective effects of dapagliflozin.
Clinicaltrials.gov identifier
NCT02956811.

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

Eur Heart J: 23 Jun 2020; epub ahead of print
Brown AJM, Gandy S, McCrimmon R, Houston JG, Struthers AD, Lang CC
Eur Heart J: 23 Jun 2020; epub ahead of print | PMID: 32578850
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Abstract

Impact of Left Atrial Appendage Exclusion on Short Term Outcomes In Isolated Coronary Artery Bypass Graft Surgery.

Mahmood E, Matyal R, Mahmood F, Xu X, ... Karani S, Khabbaz KR

The objective of this study was to evaluate the impact of LAA exclusion on short term outcomes in patients with atrial fibrillation undergoing isolated coronary artery bypass graft (CABG) surgery.We queried the 2010-2014 National Readmissions Database (NRD) for patients who underwent coronary artery bypass graft repair with and without left atrial appendage ligation using ICD-9 procedure codes (ICD-9: 36.1xx). Only patients with a history of atrial fibrillation were included in our analysis. The primary outcome of our study was 30-day readmissions following discharge. Secondary outcomes were in hospital mortality and stroke. To assess the postoperative outcomes, we utilized multivariate logistic regression models to adjust for clinical and demographic covariates.In total we analyzed 253,287 CABG patients, 7.0% of whom received LAA closure. LAA exclusion was associated with a greater risk of postoperative respiratory failure (8.2% vs. 6.2%, p <.0001), acute kidney injury (21.8% vs. 18.5%, p <.0001), but did not significantly change the rate of blood transfusions or occurrence of cardiac tamponade. LAA exclusion was associated with a non-significant reduction in stroke (7.9% vs. 8.6%, p = .12), no difference in in-hospital mortality (2.2% vs. 2.2% p = .99), and a greater risk of 30-day readmission (16.0% vs. 9.6%, p < .0001) After covariate adjustment, LAA ligation remained a significant predictor of 30-day readmission (OR: 1.640, 95% CI: 1.603 - 1.677, p <.0001).LAA exclusion during isolated CABG in patients with AF is associated with a higher rate of 30-day readmission. Post-operative measures to mitigate the loss of the hormonal and hemodynamic effects of the LAA may increase the therapeutic benefit of this procedure.



Circulation: 02 Jun 2020; epub ahead of print
Mahmood E, Matyal R, Mahmood F, Xu X, ... Karani S, Khabbaz KR
Circulation: 02 Jun 2020; epub ahead of print | PMID: 32489114
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Abstract

Targeting muscle-enriched long non-coding RNA H19 reverses pathological cardiac hypertrophy.

Viereck J, Bührke A, Foinquinos A, Chatterjee S, ... Bär C, Thum T
Aims
Pathological cardiac remodelling and subsequent heart failure represents an unmet clinical need. Long non-coding RNAs (lncRNAs) are emerging as crucial molecular orchestrators of disease processes, including that of heart diseases. Here, we report on the powerful therapeutic potential of the conserved lncRNA H19 in the treatment of pathological cardiac hypertrophy.
Method and results
Pressure overload-induced left ventricular cardiac remodelling revealed an up-regulation of H19 in the early phase but strong sustained repression upon reaching the decompensated phase of heart failure. The translational potential of H19 is highlighted by its repression in a large animal (pig) model of left ventricular hypertrophy, in diseased human heart samples, in human stem cell-derived cardiomyocytes and in human engineered heart tissue in response to afterload enhancement. Pressure overload-induced cardiac hypertrophy in H19 knock-out mice was aggravated compared to wild-type mice. In contrast, vector-based, cardiomyocyte-directed gene therapy using murine and human H19 strongly attenuated heart failure even when cardiac hypertrophy was already established. Mechanistically, using microarray, gene set enrichment analyses and Chromatin ImmunoPrecipitation DNA-Sequencing, we identified a link between H19 and pro-hypertrophic nuclear factor of activated T cells (NFAT) signalling. H19 physically interacts with the polycomb repressive complex 2 to suppress H3K27 tri-methylation of the anti-hypertrophic Tescalcin locus which in turn leads to reduced NFAT expression and activity.
Conclusion
H19 is highly conserved and down-regulated in failing hearts from mice, pigs and humans. H19 gene therapy prevents and reverses experimental pressure-overload-induced heart failure. H19 acts as an anti-hypertrophic lncRNA and represents a promising therapeutic target to combat pathological cardiac remodelling.

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

Eur Heart J: 12 Jul 2020; epub ahead of print
Viereck J, Bührke A, Foinquinos A, Chatterjee S, ... Bär C, Thum T
Eur Heart J: 12 Jul 2020; epub ahead of print | PMID: 32657324
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Abstract

Agrin Promotes Coordinated Therapeutic Processes Leading to Improved Cardiac Repair in Pigs.

Baehr A, Umansky KB, Bassat E, Jurisch V, ... Kupatt C, Tzahor E

Ischemic heart diseases are classified among the leading cause of death and reduced life quality worldwide. Although revascularization strategies significantly reduce mortality after acute myocardial infarction (MI), a significant number of MI patients develop chronic heart failure over time. We previously reported that a fragment of the extra cellular matrix (ECM) protein Agrin promotes cardiac regeneration following MI in adult mice.To test the therapeutic potential of Agrin in a preclinical porcine model we performed ischemia reperfusion (I/R) injuries using balloon occlusion for 60 minutes followed by either 3, 7 or 28 days reperfusion period.We first demonstrate that local (antegrade) delivery of recombinant human Agrin (rhAgrin) to the infarcted pig heart can target the affected regions in an efficient and clinically-relevant manner. Single dose of recombinant human Agrin improved heart function, infarct size, fibrosis and adverse remodeling parameters 28 days post MI. Short-term MI experiments along with complementary murine studies revealed myocardial protection, improved angiogenesis, inflammatory suppression and cell cycle re-entry, as Agrin\'s mechanisms of action.We show that a single dose of Agrin is capable of reducing ischemia reperfusion injury and improving heart function, demonstrating that Agrin could serve as a therapy for patients with acute MI and potentially heart failure.



Circulation: 07 Jun 2020; epub ahead of print
Baehr A, Umansky KB, Bassat E, Jurisch V, ... Kupatt C, Tzahor E
Circulation: 07 Jun 2020; epub ahead of print | PMID: 32508131
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Abstract

RNA Identification of PRIME Cells Predicting Rheumatoid Arthritis Flares.

Orange DE, Yao V, Sawicka K, Fak J, ... Troyanskaya OG, Darnell RB
Background
Rheumatoid arthritis, like many inflammatory diseases, is characterized by episodes of quiescence and exacerbation (flares). The molecular events leading to flares are unknown.
Methods
We established a clinical and technical protocol for repeated home collection of blood in patients with rheumatoid arthritis to allow for longitudinal RNA sequencing (RNA-seq). Specimens were obtained from 364 time points during eight flares over a period of 4 years in our index patient, as well as from 235 time points during flares in three additional patients. We identified transcripts that were differentially expressed before flares and compared these with data from synovial single-cell RNA-seq. Flow cytometry and sorted-blood-cell RNA-seq in additional patients were used to validate the findings.
Results
Consistent changes were observed in blood transcriptional profiles 1 to 2 weeks before a rheumatoid arthritis flare. B-cell activation was followed by expansion of circulating CD45-CD31-PDPN+ preinflammatory mesenchymal, or PRIME, cells in the blood from patients with rheumatoid arthritis; these cells shared features of inflammatory synovial fibroblasts. Levels of circulating PRIME cells decreased during flares in all 4 patients, and flow cytometry and sorted-cell RNA-seq confirmed the presence of PRIME cells in 19 additional patients with rheumatoid arthritis.
Conclusions
Longitudinal genomic analysis of rheumatoid arthritis flares revealed PRIME cells in the blood during the period before a flare and suggested a model in which these cells become activated by B cells in the weeks before a flare and subsequently migrate out of the blood into the synovium. (Funded by the National Institutes of Health and others.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 15 Jul 2020; 383:218-228
Orange DE, Yao V, Sawicka K, Fak J, ... Troyanskaya OG, Darnell RB
N Engl J Med: 15 Jul 2020; 383:218-228 | PMID: 32668112
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Abstract

Omega-3 Polyunsaturated Fatty Acids Decrease Aortic Valve Disease through the Resolvin E1 and ChemR23 Axis.

Artiach G, Carracedo M, Plunde O, Wheelock CE, ... Arnardottir H, Bäck M

Aortic valve stenosis (AVS), which is the most common valvular heart disease, causes a progressive narrowing of the aortic valve as a consequence of thickening and calcification of the aortic valve leaflets. The beneficial effects of omega-3 polyunsaturated fatty acids (n-3 PUFA) in cardiovascular prevention have been recently demonstrated in a large randomized controlled trial. In addition, n-3 PUFA serve as the substrate for the synthesis of specialized pro-resolving mediators (SPMs), which are known by their potent beneficial anti-inflammatory, pro-resolving and tissue-modifying properties in cardiovascular disease. However, the effects of n-3 PUFA and SPMs on AVS have not yet been determined. The aim of this study was to identify the role of n-3 PUFA-derived SPMs in relation to the development of AVS.Lipidomic and transcriptomic analyses were performed in human tricuspid aortic valves. Apoe mice and wire injury in C57BL/6J mice were used as models for mechanistic studies.We found that n-3 PUFA incorporation into human stenotic aortic valves was higher in non-calcified regions compared with calcified regions. LC-MS-MS based lipid mediator lipidomics identified that the n-3 PUFA-derived SPM resolvin E1 (RvE1) was dysregulated in calcified regions and acted as a calcification inhibitor. Apoe mice expressing theFat-1 transgene (Fat-1xApoe), which enables the endogenous synthesis of n-3 PUFA, increased valvular n-3 PUFA content, exhibited reduced valve calcification, lower aortic valve leaflet area, increased M2 macrophage polarization and improved echocardiographic parameters. Finally, abrogation of the RvE1 receptor ChemR23 enhanced disease progression, and the beneficial effects of Fat-1 were abolished in the absence of ChemR23.n-3 PUFA-derived RvE1 and its receptor ChemR23 emerge as a key axis in the inhibition of AVS progression, and may represent a novel potential therapeutic opportunity to be evaluated in patients with AVS.



Circulation: 07 Jun 2020; epub ahead of print
Artiach G, Carracedo M, Plunde O, Wheelock CE, ... Arnardottir H, Bäck M
Circulation: 07 Jun 2020; epub ahead of print | PMID: 32506925
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Abstract

PI3Kβ-Regulated Pericyte Maturation Governs Vascular Remodeling.

Figueiredo AM, Villacampa P, Diéguez-Hurtado R, Lozano JJ, ... Carracedo A, Graupera M

Pericytes regulate vessel stabilization and function and their loss is associated with diseases such as diabetic retinopathy or cancer. Despite their physiological importance, pericyte function and molecular regulation during angiogenesis remain poorly understood.To decipher the transcriptomic programs of pericytes during angiogenesis, we crossed theinto the RiboTag mice. Pericyte morphological changes were assessed in mural cell-specific R26-mTmG reporter mice, in which low doses of tamoxifen allowed labeling of single cell pericytes at high resolution. To study the role of phosphoinositide 3-kinase (PI3K) signaling in pericyte biology during angiogenesis, we used genetic mouse models which allow selective inactivation of PI3Kα and PI3Kβ isoforms and their negative regulator PTEN (phosphate and tensin homologue deleted on chromosome ten, PTEN) in mural cells.At the onset of angiogenesis, pericytes exhibit molecular traits of cell proliferation and activated PI3K signaling, whereas during vascular remodeling pericytes upregulate genes involved in mature pericyte cell function, together with a remarkable decrease in PI3K signaling. Immature pericytes showed stellate shape and high proliferation, and mature pericytes were quiescent and elongated. Unexpectedly, we demonstrate that the PI3Kβ, but not PI3Kα, regulates pericyte proliferation and maturation during vessel formation. Genetic PI3Kβ inactivation in pericytes triggered early pericyte maturation. Conversely, unleashing PI3K signaling by means of PTEN deletion delayed pericyte maturation. Pericyte maturation was necessary to undergo vessel remodeling during angiogenesis.Our results identify new molecular and morphological traits associated to pericyte maturation and uncover PI3Kβ activity as a checkpoint to ensure appropriate vessel formation. In turn, our results may open new therapeutic opportunities to regulate angiogenesis in pathological processes through the manipulation of pericyte PI3Kβ activity.



Circulation: 28 May 2020; epub ahead of print
Figueiredo AM, Villacampa P, Diéguez-Hurtado R, Lozano JJ, ... Carracedo A, Graupera M
Circulation: 28 May 2020; epub ahead of print | PMID: 32466671
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Abstract

Epidemiology, clinical course, and outcomes of critically ill adults with COVID-19 in New York City: a prospective cohort study.

Cummings MJ, Baldwin MR, Abrams D, Jacobson SD, ... Brodie D, O\'Donnell MR
Background
Over 40 000 patients with COVID-19 have been hospitalised in New York City (NY, USA) as of April 28, 2020. Data on the epidemiology, clinical course, and outcomes of critically ill patients with COVID-19 in this setting are needed.
Methods
This prospective observational cohort study took place at two NewYork-Presbyterian hospitals affiliated with Columbia University Irving Medical Center in northern Manhattan. We prospectively identified adult patients (aged ≥18 years) admitted to both hospitals from March 2 to April 1, 2020, who were diagnosed with laboratory-confirmed COVID-19 and were critically ill with acute hypoxaemic respiratory failure, and collected clinical, biomarker, and treatment data. The primary outcome was the rate of in-hospital death. Secondary outcomes included frequency and duration of invasive mechanical ventilation, frequency of vasopressor use and renal replacement therapy, and time to in-hospital clinical deterioration following admission. The relation between clinical risk factors, biomarkers, and in-hospital mortality was modelled using Cox proportional hazards regression. Follow-up time was right-censored on April 28, 2020 so that each patient had at least 28 days of observation.
Findings
Between March 2 and April 1, 2020, 1150 adults were admitted to both hospitals with laboratory-confirmed COVID-19, of which 257 (22%) were critically ill. The median age of patients was 62 years (IQR 51-72), 171 (67%) were men. 212 (82%) patients had at least one chronic illness, the most common of which were hypertension (162 [63%]) and diabetes (92 [36%]). 119 (46%) patients had obesity. As of April 28, 2020, 101 (39%) patients had died and 94 (37%) remained hospitalised. 203 (79%) patients received invasive mechanical ventilation for a median of 18 days (IQR 9-28), 170 (66%) of 257 patients received vasopressors and 79 (31%) received renal replacement therapy. The median time to in-hospital deterioration was 3 days (IQR 1-6). In the multivariable Cox model, older age (adjusted hazard ratio [aHR] 1·31 [1·09-1·57] per 10-year increase), chronic cardiac disease (aHR 1·76 [1·08-2·86]), chronic pulmonary disease (aHR 2·94 [1·48-5·84]), higher concentrations of interleukin-6 (aHR 1·11 [95%CI 1·02-1·20] per decile increase), and higher concentrations of D-dimer (aHR 1·10 [1·01-1·19] per decile increase) were independently associated with in-hospital mortality.
Interpretation
Critical illness among patients hospitalised with COVID-19 in New York City is common and associated with a high frequency of invasive mechanical ventilation, extrapulmonary organ dysfunction, and substantial in-hospital mortality.
Funding
National Institute of Allergy and Infectious Diseases and the National Center for Advancing Translational Sciences, National Institutes of Health, and the Columbia University Irving Institute for Clinical and Translational Research.

Copyright © 2020 Elsevier Ltd. All rights reserved.

Lancet: 18 May 2020; epub ahead of print
Cummings MJ, Baldwin MR, Abrams D, Jacobson SD, ... Brodie D, O'Donnell MR
Lancet: 18 May 2020; epub ahead of print | PMID: 32442528
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Abstract

Phosphodiesterase 3A and Arterial Hypertension.

Ercu M, Markó L, Schächterle C, Tsvetkov D, ... Luft FC, Klussmann E

High blood pressure is the primary risk factor for cardiovascular death worldwide. Autosomal-dominant hypertension with brachydactyly (HTNB) clinically resembles salt-resistant essential hypertension and causes death by stroke before age 50 years. Recently, we implicated the gene encoding phosphodiesterase 3A (); however,modeling of the genetic defect and thus showing an involvement of mutant PDE3A is lacking.We used genetic mapping, sequencing, transgenic technology, CRISPR-Cas9 gene editing, immunoblotting, and fluorescence resonance energy transfer (FRET). We identified new patients, performed extensive animal phenotyping, and explored new signaling pathways.We describe a novel mutation within a 15 bp region of thegene and define this segment as mutational hotspot in HTNB. The mutations cause an increase in enzyme activity. A CRISPR/Cas9-generated rat model, with a 9 bp deletion within the hotspot analogous to a human deletion, recapitulates HTNB. In mice, mutant transgenic PDE3A overexpression in smooth muscle cells confirmed that mutant PDE3A causes hypertension. The mutant PDE3A enzymes display consistent changes in their phosphorylation and an increased interaction with the 14-3-3θ adaptor protein. This aberrant signaling is associated with an increase in vascular smooth muscle cell proliferation and changes in vessel morphology and function.The mutatedgene drives mechanisms that increase peripheral vascular resistance causing hypertension. We present two new animal models that will serve to elucidate the underlying mechanisms further. Our findings could facilitate the search for new antihypertensive treatments.



Circulation: 10 Jun 2020; epub ahead of print
Ercu M, Markó L, Schächterle C, Tsvetkov D, ... Luft FC, Klussmann E
Circulation: 10 Jun 2020; epub ahead of print | PMID: 32524868
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Abstract

Mapping and characterization of structural variation in 17,795 human genomes.

Abel HJ, Larson DE, Regier AA, Chiang C, ... Stitziel NO, Hall IM

A key goal of whole-genome sequencing (WGS) for human genetics studies is to interrogate all forms of variation, including single nucleotide variants (SNV), small insertion/deletion (indel) variants and structural variants (SV). However, tools and resources for the study of SV have lagged behind those for smaller variants. Here, we used a scalable pipeline to map and characterize SV in 17,795 deeply sequenced human genomes. We publicly release site-frequency data to create the largest WGS-based SV resource to date. On average, individuals carry 2.9 rare SVs that alter coding regions, affecting the dosage or structure of 4.2 genes and accounting for 4.0-11.2% of rare high-impact coding alleles. Based on a computational model, we estimate that SVs account for 17.2% of rare alleles genome-wide with predicted deleterious effects equivalent to loss-of-function coding alleles; approximately 90% of such SVs are non-coding deletions (mean 19.1 per genome). We report 158,991 ultra-rare SVs and show that around 2% of individuals carry ultra-rare megabase-scale SVs, nearly half of which are balanced or complex rearrangements. Finally, we infer the dosage sensitivity of genes and non-coding elements, revealing trends related to element class and conservation. This work will help guide SV analysis and interpretation in the era of WGS.



Nature: 26 May 2020; epub ahead of print
Abel HJ, Larson DE, Regier AA, Chiang C, ... Stitziel NO, Hall IM
Nature: 26 May 2020; epub ahead of print | PMID: 32460305
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Abstract

Impact of Transcatheter Aortic Valve Durability on Life Expectancy in Low Risk Patients with Severe Aortic Stenosis.

Tam DY, Wijeysundera HC, Naimark D, Gaudino M, ... Cohen DJ, Fremes SE

Recent clinical trial results showed that transcatheter aortic valve replacement (TAVR) is non-inferior and may be superior to surgical aortic valve replacement (SAVR) for mortality, stroke, and rehospitalization. However, the impact of transcatheter valve durability remains uncertain.Discrete event simulation (DES) was used to model hypothetical scenarios of TAVR versus SAVR durability where TAVR failure times were varied to determine the impact of TAVR valve durability on life-expectancy in a cohort of low risk patients similar to those in recent trials. DES modeling was used to estimate the tradeoff between a less invasive procedure with unknown valve durability (TAVR) and that of a more invasive procedure with known durability (SAVR). Standardized differences were calculated and a difference>0.10 was considered clinically significant. In the base case analysis, patients with structural valve deterioration requiring reoperation were assumed to undergo a valve-in-valve TAVR procedure. A sensitivity analysis was conducted to determine the impact of TAVR valve durability on life expectancy in younger age groups (40, 50, and 60 years).Our cohort consisted of low surgical risk aortic stenosis patients with mean age 73.4±5.9 years. In the base case scenario, standardized difference in life expectancy was <0.10 between TAVR and SAVR until transcatheter valve prosthesis failure time was 70% shorter than surgical prostheses. At a transcatheter valve failure time <30% compared to surgical valves, SAVR was the preferred option. In younger patients, life expectancy was reduced when TAVR durability was 30%, 40%, and 50% shorter than surgical valves in 40, 50, and 60-year-old patients respectively.Based on our simulation models, the durability of TAVR valves must be 70% shorter than that of surgical valves to result in reduced life expectancy in patients with similar demographics to recent trials. However, in younger patients, this threshold for TAVR valve durability was substantially higher. These findings suggest that durability concerns should not influence the initial treatment decision regarding TAVR versus SAVR in older low risk patients based on current evidence supporting TAVR valve durability. However, in younger low risk patients, valve durability must be weighed against other patient factors such as life expectancy.



Circulation: 03 Jun 2020; epub ahead of print
Tam DY, Wijeysundera HC, Naimark D, Gaudino M, ... Cohen DJ, Fremes SE
Circulation: 03 Jun 2020; epub ahead of print | PMID: 32493077
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Abstract

Hepatic NADH reductive stress underlies common variation in metabolic traits.

Goodman RP, Markhard AL, Shah H, Sharma R, ... Kim JK, Mootha VK

The cellular NADH/NAD ratio is fundamental to biochemistry, but the extent to which it reflects versus drives metabolic physiology in vivo is poorly understood. Here we report the in vivo application of Lactobacillus brevis (Lb)NOX, a bacterial water-forming NADH oxidase, to assess the metabolic consequences of directly lowering the hepatic cytosolic NADH/NAD ratio in mice. By combining this genetic tool with metabolomics, we identify circulating α-hydroxybutyrate levels as a robust marker of an elevated hepatic cytosolic NADH/NAD ratio, also known as reductive stress. In humans, elevations in circulating α-hydroxybutyrate levels have previously been associated with impaired glucose tolerance, insulin resistance and mitochondrial disease, and are associated with a common genetic variant in GCKR, which has previously been associated with many seemingly disparate metabolic traits. Using LbNOX, we demonstrate that NADH reductive stress mediates the effects of GCKR variation on many metabolic traits, including circulating triglyceride levels, glucose tolerance and FGF21 levels. Our work identifies an elevated hepatic NADH/NAD ratio as a latent metabolic parameter that is shaped by human genetic variation and contributes causally to key metabolic traits and diseases. Moreover, it underscores the utility of genetic tools such as LbNOX to empower studies of \'causal metabolism\'.



Nature: 26 May 2020; epub ahead of print
Goodman RP, Markhard AL, Shah H, Sharma R, ... Kim JK, Mootha VK
Nature: 26 May 2020; epub ahead of print | PMID: 32461692
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Abstract

Ensuring meiotic DNA break formation in the mouse pseudoautosomal region.

Acquaviva L, Boekhout M, Karasu ME, Brick K, ... Jasin M, Keeney S

Sex chromosomes in males of most eutherian mammals share only a small homologous segment, the pseudoautosomal region (PAR), in which the formation of double-strand breaks (DSBs), pairing and crossing over must occur for correct meiotic segregation. How cells ensure that recombination occurs in the PAR is unknown. Here we present a dynamic ultrastructure of the PAR and identify controlling cis- and trans-acting factors that make the PAR the hottest segment for DSB formation in the male mouse genome. Before break formation, multiple DSB-promoting factors hyperaccumulate in the PAR, its chromosome axes elongate and the sister chromatids separate. These processes are linked to heterochromatic mo-2 minisatellite arrays, and require MEI4 and ANKRD31 proteins but not the axis components REC8 or HORMAD1. We propose that the repetitive DNA sequence of the PAR confers unique chromatin and higher-order structures that are crucial for recombination. Chromosome synapsis triggers collapse of the elongated PAR structure and, notably, oocytes can be reprogrammed to exhibit spermatocyte-like levels of DSBs in the PAR simply by delaying or preventing synapsis. Thus, the sexually dimorphic behaviour of the PAR is in part a result of kinetic differences between the sexes in a race between the maturation of the PAR structure, formation of DSBs and completion of pairing and synapsis. Our findings establish a mechanistic paradigm for the recombination of sex chromosomes during meiosis.



Nature: 26 May 2020; epub ahead of print
Acquaviva L, Boekhout M, Karasu ME, Brick K, ... Jasin M, Keeney S
Nature: 26 May 2020; epub ahead of print | PMID: 32461690
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Abstract

Cardiovascular Event Risks Associated With Masked Nocturnal Hypertension Defined by Home Blood Pressure Monitoring in the J-HOP Nocturnal Blood Pressure Study.

Fujiwara T, Hoshide S, Kanegae H, Kario K

There is no information regarding the potential association between cardiovascular disease (CVD) event risks and masked nocturnal hypertension defined by home blood pressure (BP) monitoring. We sought to examine this association in a general practice population. For this purpose, we used data from the J-HOP (Japan Morning Surge-Home Blood Pressure) Nocturnal BP Study, which recruited 2745 high-cardiovascular-risk participants (mean [SD] age, 63.6 [10.4] years; 48.7% men; 82.7% on antihypertensive medications). Nocturnal home BPs (HBPs) were measured at 2:00, 3:00, and 4:00 AM using a validated, automated HBP device for 14 consecutive days. The average (SD) of nocturnal HBP measures was 17.1 (13.5). The percentages of participants with controlled BP (nocturnal HBP <120/70 mm Hg and average morning and evening BP <135/85 mm Hg), daytime hypertension (nocturnal HBP <120/70 mm Hg and average morning and evening BP ≥135/85 mm Hg), masked nocturnal hypertension (nocturnal HBP ≥120/70 mm Hg and average morning and evening BP <135/85 mm Hg), and sustained hypertension (nocturnal HBP ≥120/70 mm Hg and average morning and evening BP ≥135/85 mm Hg) were 31.7%, 7.9%, 26.7%, and 33.7%, respectively. During a median 7.6-year follow-up (19 519 person-years), 162 CVD events occurred. The cumulative incidence of CVD events was higher in those with masked nocturnal hypertension and sustained hypertension than in the controlled BP group. Results from Cox models suggested that masked nocturnal hypertension (adjusted hazard ratio, 1.57 [95% CI, 1.00-2.46]) and sustained hypertension (adjusted hazard ratio, 1.97 [95% CI, 1.26-3.06]) were associated with increased risk of CVD events. Participants with masked nocturnal hypertension defined by HBP monitoring are at high risk of future CVD events.



Hypertension: 29 Jun 2020; 76:259-266
Fujiwara T, Hoshide S, Kanegae H, Kario K
Hypertension: 29 Jun 2020; 76:259-266 | PMID: 32520613
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Abstract

Comparison of Atrial Remodeling Caused by Sustained Atrial Flutter Versus Atrial Fibrillation.

Guichard JB, Naud P, Xiong F, Qi X, ... Da Costa A, Nattel S
Background
Atrial flutter (AFL) and atrial fibrillation (AF) are associated with AF-promoting atrial remodeling, but no experimental studies have addressed remodeling with sustained AFL.
Objectives
This study aimed to define the atrial remodeling caused by sustained atrial flutter (AFL) and/or atrial fibrillation (AF).
Methods
Intercaval radiofrequency lesions created a substrate for sustained isthmus-dependent AFL, confirmed by endocavity mapping. Four groups (6 dogs per group) were followed for 3 weeks: sustained AFL; sustained AF (600 beats/min atrial tachypacing); AF superimposed on an AFL substrate (AF+AFLs); sinus rhythm (SR) with an AFL substrate (SR+AFLs; control group). All dogs had atrioventricular-node ablation and ventricular pacemakers at 80 beats/min to control ventricular rate.
Results
Monitoring confirmed spontaneous AFL maintenance >99% of the time in dogs with AFL. At terminal open-chest study, left-atrial (LA) effective refractory period was reduced similarly with AFL, AF+AFLs and AF, while AF vulnerability to extrastimuli increased in parallel. Induced AF duration increased significantly in AF+AFLs and AF, but not AFL. Dogs with AF+AFLs had shorter cycle lengths and substantial irregularity versus dogs with AFL. LA volume increased in AF+AFLs and AF, but not dogs with AFL, versus SR+AFLs. Optical mapping showed significant conduction slowing in AF+AFLs and AF but not AFL, paralleling atrial fibrosis and collagen-gene upregulation. Left-ventricular function did not change in any group. Transcriptomic analysis revealed substantial dysregulation of inflammatory and extracellular matrix-signaling pathways with AF and AF+ALs but not AFL.
Conclusions
Sustained AFL causes atrial repolarization changes like those in AF but, unlike AF or AF+AFLs, does not induce structural remodeling. These results provide novel insights into AFL-induced remodeling and suggest that early intervention may be important to prevent irreversible fibrosis when AF intervenes in a patient with AFL.

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

J Am Coll Cardiol: 27 Jul 2020; 76:374-388
Guichard JB, Naud P, Xiong F, Qi X, ... Da Costa A, Nattel S
J Am Coll Cardiol: 27 Jul 2020; 76:374-388 | PMID: 32703507
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Abstract

Independent risk factors for simvastatin-related myopathy and relevance to different types of muscle symptom.

Hopewell JC, Offer A, Haynes R, Bowman L, ... Armitage J, Parish S
Aims
Statins are widely used to prevent cardiovascular events, but little is known about the impact of different risk factors for statin-related myopathy or their relevance to reports of other types of muscle symptom.
Methods and results
An observational analysis was undertaken of 171 clinically adjudicated cases of myopathy (defined as unexplained muscle pain or weakness with creatine kinase >10× upper limit of normal) and, separately, of 15 208 cases of other muscle symptoms among 58 390 individuals with vascular disease treated with simvastatin for a mean of 3.4 years. Cox proportional hazards models were used to identify independent predictors of myopathy. The rate of myopathy was low: 9 per 10 000 person-years of simvastatin therapy. Independent risk factors for myopathy included: simvastatin dose, ethnicity, sex, age, body mass index, medically treated diabetes, concomitant use of niacin-laropiprant, verapamil, beta-blockers, diltiazem and diuretics. In combination, these risk factors predicted more than a 30-fold risk difference between the top and bottom thirds of a myopathy risk score (hazard ratio : 34.35, 95% CI: 12.73-92.69, P across thirds = 9·1 × 10-48). However, despite the strong association with myopathy, this score was not associated with the other reported muscle symptoms (P across thirds = 0.93). Likewise, although SLCO1B1 genotype was associated with myopathy, it was not associated with other muscle symptoms.
Conclusions
The absolute risk of simvastatin-related myopathy is low, but individuals at higher risk can be identified to help guide patient management. The lack of association of the myopathy risk score with other muscle symptoms reinforces randomized placebo-controlled evidence that statins do not cause the vast majority of reported muscle symptoms.

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

Eur Heart J: 22 Jul 2020; epub ahead of print
Hopewell JC, Offer A, Haynes R, Bowman L, ... Armitage J, Parish S
Eur Heart J: 22 Jul 2020; epub ahead of print | PMID: 32702748
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Abstract

Trimethylamine-N-Oxide Promotes Age-Related Vascular Oxidative Stress and Endothelial Dysfunction in Mice and Healthy Humans.

Brunt VE, Gioscia-Ryan RA, Casso AG, VanDongen NS, ... Davy KP, Seals DR

Age-related vascular endothelial dysfunction is a major antecedent to cardiovascular diseases. We investigated whether increased circulating levels of the gut microbiome-generated metabolite trimethylamine-N-oxide induces endothelial dysfunction with aging. In healthy humans, plasma trimethylamine-N-oxide was higher in middle-aged/older (64±7 years) versus young (22±2 years) adults (6.5±0.7 versus 1.6±0.2 µmol/L) and inversely related to brachial artery flow-mediated dilation (=0.29, <0.00001). In young mice, 6 months of dietary supplementation with trimethylamine-N-oxide induced an aging-like impairment in carotid artery endothelium-dependent dilation to acetylcholine versus control feeding (peak dilation: 79±3% versus 95±3%, <0.01). This impairment was accompanied by increased vascular nitrotyrosine, a marker of oxidative stress, and reversed by the superoxide dismutase mimetic 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl. Trimethylamine-N-oxide supplementation also reduced activation of endothelial nitric oxide synthase and impaired nitric oxide-mediated dilation, as assessed with the nitric oxide synthase inhibitor L-NAME (N-nitro-L-arginine methyl ester). Acute incubation of carotid arteries with trimethylamine-N-oxide recapitulated these events. Next, treatment with 3,3-dimethyl-1-butanol for 8 to 10 weeks to suppress trimethylamine-N-oxide selectively improved endothelium-dependent dilation in old mice to young levels (peak: 90±2%) by normalizing vascular superoxide production, restoring nitric oxide-mediated dilation, and ameliorating superoxide-related suppression of endothelium-dependent dilation. Lastly, among healthy middle-aged/older adults, higher plasma trimethylamine-N-oxide was associated with greater nitrotyrosine abundance in biopsied endothelial cells, and infusion of the antioxidant ascorbic acid restored flow-mediated dilation to young levels, indicating tonic oxidative stress-related suppression of endothelial function with higher circulating trimethylamine-N-oxide. Using multiple experimental approaches in mice and humans, we demonstrate a clear role of trimethylamine-N-oxide in promoting age-related endothelial dysfunction via oxidative stress, which may have implications for prevention of cardiovascular diseases.



Hypertension: 29 Jun 2020; 76:101-112
Brunt VE, Gioscia-Ryan RA, Casso AG, VanDongen NS, ... Davy KP, Seals DR
Hypertension: 29 Jun 2020; 76:101-112 | PMID: 32520619
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Abstract

Hair-bearing human skin generated entirely from pluripotent stem cells.

Lee J, Rabbani CC, Gao H, Steinhart MR, ... Shipchandler TZ, Koehler KR

The skin is a multilayered organ, equipped with appendages (that is, follicles and glands), that is critical for regulating body temperature and the retention of bodily fluids, guarding against external stresses and mediating the sensation of touch and pain. Reconstructing appendage-bearing skin in cultures and in bioengineered grafts is a biomedical challenge that has yet to be met. Here we report an organoid culture system that generates complex skin from human pluripotent stem cells. We use stepwise modulation of the transforming growth factor β (TGFβ) and fibroblast growth factor (FGF) signalling pathways to co-induce cranial epithelial cells and neural crest cells within a spherical cell aggregate. During an incubation period of 4-5 months, we observe the emergence of a cyst-like skin organoid composed of stratified epidermis, fat-rich dermis and pigmented hair follicles that are equipped with sebaceous glands. A network of sensory neurons and Schwann cells form nerve-like bundles that target Merkel cells in organoid hair follicles, mimicking the neural circuitry associated with human touch. Single-cell RNA sequencing and direct comparison to fetal specimens suggest that the skin organoids are equivalent to the facial skin of human fetuses in the second trimester of development. Moreover, we show that skin organoids form planar hair-bearing skin when grafted onto nude mice. Together, our results demonstrate that nearly complete skin can self-assemble in vitro and be used to reconstitute skin in vivo. We anticipate that our skin organoids will provide a foundation for future studies of human skin development, disease modelling and reconstructive surgery.



Nature: 02 Jun 2020; epub ahead of print
Lee J, Rabbani CC, Gao H, Steinhart MR, ... Shipchandler TZ, Koehler KR
Nature: 02 Jun 2020; epub ahead of print | PMID: 32494013
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Abstract

Revealing enigmatic mucus structures in the deep sea using DeepPIV.

Katija K, Troni G, Daniels J, Lance K, ... Sherman AD, Robison BH

Many animals build complex structures to aid in their survival, but very few are built exclusively from materials that animals create . In the midwaters of the ocean, mucoid structures are readily secreted by numerous animals, and serve many vital functions. However, little is known about these mucoid structures owing to the challenges of observing them in the deep sea. Among these mucoid forms, the \'houses\' of larvaceans are marvels of nature, and in the ocean twilight zone giant larvaceans secrete and build mucus filtering structures that can reach diameters of more than 1 m. Here we describe in situ laser-imaging technology that reconstructs three-dimensional models of mucus forms. The models provide high-resolution views of giant larvacean houses and elucidate the role that house structure has in food capture and predator avoidance. Now that tools exist to study mucus structures found throughout the ocean, we can shed light on some of nature\'s most complex forms.



Nature: 02 Jun 2020; epub ahead of print
Katija K, Troni G, Daniels J, Lance K, ... Sherman AD, Robison BH
Nature: 02 Jun 2020; epub ahead of print | PMID: 32494011
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Abstract

Calcineurin Aβ-Specific Anchoring Confers Isoform-Specific Compartmentation and Function in Pathological Cardiac Myocyte Hypertrophy.

Li X, Li J, Martinez EC, Froese A, ... Nikolaev VO, Kapiloff MS

The Ca/calmodulin-dependent phosphatase calcineurin is a key regulator of cardiac myocyte hypertrophy in disease. An unexplained paradox is how the Aβ isoform of calcineurin (CaNAβ) is required for induction of pathological myocyte hypertrophy, despite calcineurin Aα expression in the same cells. In addition, it is unclear how the pleiotropic second messenger Ca drives excitation-contraction coupling, while not stimulating hypertrophy via calcineurin in the normal heart. Elucidation of the mechanisms conferring this selectively in calcineurin signaling should reveal new strategies for targeting the phosphatase in disease.Primary adult rat ventricular myocytes were studied for morphology and intracellular signaling. New Forster Resonance Energy Transfer (FRET) reporters were used to assay Ca and calcineurin activity in living cells. Conditional gene deletion and adeno-associated virus (AAV)-mediated gene delivery in the mouse were used to study calcineurin signaling following transverse aortic constriction .Cdc42-interacting protein (CIP4/TRIP10) was identified as a new polyproline domain-dependent scaffold for CaNAβ2 by yeast-2-hybrid screen. Cardiac myocyte-specific CIP4 gene deletion in mice attenuated pressure overload-induced pathological cardiac remodeling and heart failure. Accordingly, blockade of CaNAβ polyproline-dependent anchoring using a competing peptide inhibited concentric hypertrophy in cultured myocytes, while disruption of anchoringusing an AAV gene therapy vector inhibited cardiac hypertrophy and improved systolic function after pressure overload. Live cell FRET biosensor imaging of cultured myocytes revealed that Ca levels and calcineurin activity associated with the CIP4 compartment were increased by neurohormonal stimulation, but minimally by pacing. Conversely, Ca levels and calcineurin activity detected by non-localized FRET sensors were induced by pacing and minimally by neurohormonal stimulation, providing functional evidence for differential intracellular compartmentation of Ca and calcineurin signal transduction.These results support a structural model for Ca and CaNAβ compartmentation in cells based upon an isoform-specific mechanism for calcineurin protein-protein interaction and localization. This mechanism provides an explanation for the specific role of CaNAβ in hypertrophy and its selective activation under conditions of pathologic stress. Disruption of CaNAβ polyproline-dependent anchoring constitutes a rational strategy for therapeutic targeting of CaNAβ-specific signaling responsible for pathological cardiac remodeling in cardiovascular disease deserving of further pre-clinical investigation.



Circulation: 01 Jul 2020; epub ahead of print
Li X, Li J, Martinez EC, Froese A, ... Nikolaev VO, Kapiloff MS
Circulation: 01 Jul 2020; epub ahead of print | PMID: 32611257
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Abstract

Identification, Heritability, and Relation With Gene Expression of Novel DNA Methylation Loci for Blood Pressure.

Huang Y, Ollikainen M, Muniandy M, Zhang T, ... Kaprio J, Wang X

We conducted an epigenome-wide association study meta-analysis on blood pressure (BP) in 4820 individuals of European and African ancestry aged 14 to 69. Genome-wide DNA methylation data from peripheral leukocytes were obtained using the Infinium Human Methylation 450k BeadChip. The epigenome-wide association study meta-analysis identified 39 BP-related CpG sites with <1×10. In silico replication in the CHARGE consortium of 17 010 individuals validated 16 of these CpG sites. Out of the 16 CpG sites, 13 showed novel association with BP. Conversely, out of the 126 CpG sites identified as being associated (<1×10) with BP in the CHARGE consortium, 21 were replicated in the current study. Methylation levels of all the 34 CpG sites that were cross-validated by the current study and the CHARGE consortium were heritable and 6 showed association with gene expression. Furthermore, 9 CpG sites also showed association with BP with <0.05 and consistent direction of the effect in the meta-analysis of the Finnish Twin Cohort (199 twin pairs and 4 singletons; 61% monozygous) and the Netherlands Twin Register (266 twin pairs and 62 singletons; 84% monozygous). Bivariate quantitative genetic modeling of the twin data showed that a majority of the phenotypic correlations between methylation levels of these CpG sites and BP could be explained by shared unique environmental rather than genetic factors, with 100% of the correlations of systolic BP with cg19693031 () and cg00716257 () determined by environmental effects acting on both systolic BP and methylation levels.



Hypertension: 29 Jun 2020; 76:195-205
Huang Y, Ollikainen M, Muniandy M, Zhang T, ... Kaprio J, Wang X
Hypertension: 29 Jun 2020; 76:195-205 | PMID: 32520614
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Abstract

The liver-brain-gut neural arc maintains the T cell niche in the gut.

Teratani T, Mikami Y, Nakamoto N, Suzuki T, ... Iwasaki Y, Kanai T

The gut-brain axis, a reciprocal interaction between the central nervous system (CNS) and peripheral intestinal functions, is conceptually feasible from recent clinical and experimental evidence showing mutual interactions between the CNS and gut microbiota that are closely associated with the bidirectional effects of inflammatory bowel diseases (IBDs) and CNS disorders. Despite recent advances in our understanding of neuroimmune interactions, it remains unclear how the gut and brain communicate to maintain gut immune homeostasis, including induction and maintenance of peripheral regulatory T cells (pT cells) and what environmental cues prompt the host to protect host from development of IBDs. Here, we report a novel liver-brain-gut neural arc that ensures proper differentiation and maintenance of pT cells in the gut. The hepatic vagal sensory afferents were responsible for indirectly sensing the gut microenvironment and relaying the sensory inputs to the nucleus tractus solitarius of the brainstem, and ultimately to the vagal parasympathetic nerves and enteric neurons. Surgical and chemical perturbation of the vagal sensory afferents at the hepatic afferent level significantly impaired colonic pT cells, which was attributed to impairment of aldehyde dehydrogenase (ALDH) expression and retinoic acid (RA) synthesis by intestinal antigen-presenting cells (APCs). Muscarinic Ach receptor (mAChR) activation directly induced ALDH gene expression both in human and mouse colonic APCs, whereas genetic ablation of mAChRs abolished APC excitement in vitro. Disruption of left vagal sensory afferents from the liver to the brainstem in colitis models reduced the colonic pT pool, resulting in increased susceptibility to colitis. These results demonstrate that the novel vago-vagal liver-brain-gut reflex arc tunes the number of pT cells and maintains the gut homeostasis. Intervening in this autonomic feedback feed-forward system could help develop new therapeutic strategies to treat or prevent immunological disorders of the gut.



Nature: 10 Jun 2020; epub ahead of print
Teratani T, Mikami Y, Nakamoto N, Suzuki T, ... Iwasaki Y, Kanai T
Nature: 10 Jun 2020; epub ahead of print | PMID: 32526765
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Abstract

Gp130 Controls Cardiomyocyte Proliferation and Heart Regeneration.

Li Y, Feng J, Song S, Li H, ... Hu S, Nie Y

A key cause of cardiovascular diseases\' high mortality is the cardiomyocyte inability to renew after cardiac injury. As a promising strategy to supplement functional myocytes for cardiac repair, there is a pressing need to understand the cellular and molecular mechanisms of heart regeneration.Seven genetic mouse lines were used: global Oncostatin M (OSM) knockout, monocyte-/macrophage-specific OSM deletion, cardiomyocyte-specific lines, including OSMR deletion, gp130 deletion, gp130 activation, and Yap ablation with gp130 activation mice. A series of molecular signaling experiments, including RNA-Seq, immunostaining, co-immunoprecipitation, and Imaging Flow Cytometry, were conducted. Two models of cardiac injury, apical resection and myocardial infarction operation, were performed in neonatal, juvenile, and adult mice. Heart regeneration and cardiac function were evaluated by Masson\'s staining and echocardiography, respectively. Gene recombinant AAV9 was constructed and infected myocardial infarcted mice as a gene therapy.OSM was identified by RNA-Seq as a key upstream regulator of cardiomyocyte proliferation during neonatal heart regeneration in mice. Cardiomyocyte proliferation and heart regeneration was suspended in neonatal mice after cardiac injury when OSM was conditionally knockout in macrophages. The cardiomyocyte-specific deficiency of the OSM receptor heterodimers, OSMR and gp130, individually in cardiomyocytes reduced myocyte proliferation and neonatal heart regeneration. Conditional activation of gp130 in cardiomyocytes promoted cardiomyocyte proliferation and heart regeneration in juvenile and adult mice. Employing RNA-Seq and functional screening, we found that Src mediated gp130-triggered cardiomyocyte proliferation by activating Yap with Y357 phosphorylation independently of Hippo pathway. Cardiomyocyte-specific deletion of Yap inmice blocked the effect of gp130 activation-induced heart regeneration in juvenile mice. Gene therapy with AAV9 encoding constitutively activated gp130 promoted cardiomyocyte proliferation and heart regeneration in adult mice after myocardial infarction.Macrophage recruitment is essential for heart regenerationsecretion of OSM which promotes cardiomyocyte proliferation. As the co-receptor of OSM, gp130 activation is sufficient to promote cardiomyocyte proliferation by activating Yap via Src during heart regeneration. Gp130 is a potential therapeutic target to improve heart regeneration after cardiac injury.



Circulation: 29 Jun 2020; epub ahead of print
Li Y, Feng J, Song S, Li H, ... Hu S, Nie Y
Circulation: 29 Jun 2020; epub ahead of print | PMID: 32600062
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Impact:
Abstract

Mouse models of neutropenia reveal progenitor-stage-specific defects.

Muench DE, Olsson A, Ferchen K, Pham G, ... Salomonis N, Grimes HL

Advances in genetics and sequencing have identified a plethora of disease-associated and disease-causing genetic alterations. To determine causality between genetics and disease, accurate models for molecular dissection are required; however, the rapid expansion of transcriptional populations identified through single-cell analyses presents a major challenge for accurate comparisons between mutant and wild-type cells. Here we generate mouse models of human severe congenital neutropenia (SCN) using patient-derived mutations in the GFI1 transcription factor. To determine the effects of SCN mutations, we generated single-cell references for granulopoietic genomic states with linked epitopes, aligned mutant cells to their wild-type equivalents and identified differentially expressed genes and epigenetic loci. We find that GFI1-target genes are altered sequentially, as cells go through successive states of differentiation. These insights facilitated the genetic rescue of granulocytic specification but not post-commitment defects in innate immune effector function, and underscore the importance of evaluating the effects of mutations and therapy within each relevant cell state.



Nature: 30 May 2020; 582:109-114
Muench DE, Olsson A, Ferchen K, Pham G, ... Salomonis N, Grimes HL
Nature: 30 May 2020; 582:109-114 | PMID: 32494068
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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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Impact:
Abstract

Estimating the effects of non-pharmaceutical interventions on COVID-19 in Europe.

Flaxman S, Mishra S, Gandy A, Unwin HJT, ... Okell LC, Bhatt S

Following the emergence of a novel coronavirus (SARS-CoV-2) and its spread outside of China, Europe has experienced large epidemics. In response, many European countries have implemented unprecedented non-pharmaceutical interventions such as closure of schools and national lockdowns. We study the impact of major interventions across 11 European countries for the period from the start of COVID-19 until the 4 of May 2020 when lockdowns started to be lifted. Our model calculates backwards from observed deaths to estimate transmission that occurred several weeks prior, allowing for the time lag between infection and death. We use partial pooling of information between countries with both individual and shared effects on the reproduction number. Pooling allows more information to be used, helps overcome data idiosyncrasies, and enables more timely estimates. Our model relies on fixed estimates of some epidemiological parameters such as the infection fatality rate, does not include importation or subnational variation and assumes that changes in the reproduction number are an immediate response to interventions rather than gradual changes in behavior. Amidst the ongoing pandemic, we rely on death data that is incomplete, with systematic biases in reporting, and subject to future consolidation. We estimate that, for all the countries we consider, current interventions have been sufficient to drive the reproduction number [Formula: see text] below 1 (probability [Formula: see text]< 1.0 is 99.9%) and achieve epidemic control. We estimate that, across all 11 countries, between 12 and 15 million individuals have been infected with SARS-CoV-2 up to 4 May, representing between 3.2% and 4.0% of the population. Our results show that major non-pharmaceutical interventions and lockdown in particular have had a large effect on reducing transmission. Continued intervention should be considered to keep transmission of SARS-CoV-2 under control.



Nature: 07 Jun 2020; epub ahead of print
Flaxman S, Mishra S, Gandy A, Unwin HJT, ... Okell LC, Bhatt S
Nature: 07 Jun 2020; epub ahead of print | PMID: 32512579
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Abstract

IGF1R is an entry receptor for respiratory syncytial virus.

Griffiths CD, Bilawchuk LM, McDonough JE, Jamieson KC, ... Moraes TJ, Marchant DJ

Pneumonia resulting from infection is one of the leading causes of death worldwide. Pulmonary infection by the respiratory syncytial virus (RSV) is a large burden on human health, for which there are few therapeutic options. RSV targets ciliated epithelial cells in the airways, but how viruses such as RSV interact with receptors on these cells is not understood. Nucleolin is an entry coreceptor for RSV and also mediates the cellular entry of influenza, the parainfluenza virus, some enteroviruses and the bacterium that causes tularaemia. Here we show a mechanism of RSV entry into cells in which outside-in signalling, involving binding of the prefusion RSV-F glycoprotein with the insulin-like growth factor-1 receptor, triggers the activation of protein kinase C zeta (PKCζ). This cellular signalling cascade recruits nucleolin from the nuclei of cells to the plasma membrane, where it also binds to RSV-F on virions. We find that inhibiting PKCζ activation prevents the trafficking of nucleolin to RSV particles on airway organoid cultures, and reduces viral replication and pathology in RSV-infected mice. These findings reveal a mechanism of virus entry in which receptor engagement and signal transduction bring the coreceptor to viral particles at the cell surface, and could form the basis of new therapeutics to treat RSV infection.



Nature: 02 Jun 2020; epub ahead of print
Griffiths CD, Bilawchuk LM, McDonough JE, Jamieson KC, ... Moraes TJ, Marchant DJ
Nature: 02 Jun 2020; epub ahead of print | PMID: 32494007
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Abstract

Insights into variation in meiosis from 31,228 human sperm genomes.

Bell AD, Mello CJ, Nemesh J, Brumbaugh SA, Wysoker A, McCarroll SA

Meiosis, although essential for reproduction, is also variable and error-prone: rates of chromosome crossover vary among gametes, between the sexes, and among humans of the same sex, and chromosome missegregation leads to abnormal chromosome numbers (aneuploidy). To study diverse meiotic outcomes and how they covary across chromosomes, gametes and humans, we developed Sperm-seq, a way of simultaneously analysing the genomes of thousands of individual sperm. Here we analyse the genomes of 31,228 human gametes from 20 sperm donors, identifying 813,122 crossovers and 787 aneuploid chromosomes. Sperm donors had aneuploidy rates ranging from 0.01 to 0.05 aneuploidies per gamete; crossovers partially protected chromosomes from nondisjunction at the meiosis I cell division. Some chromosomes and donors underwent more-frequent nondisjunction during meiosis I, and others showed more meiosis II segregation failures. Sperm genomes also manifested many genomic anomalies that could not be explained by simple nondisjunction. Diverse recombination phenotypes-from crossover rates to crossover location and separation, a measure of crossover interference-covaried strongly across individuals and cells. Our results can be incorporated with earlier observations into a unified model in which a core mechanism, the variable physical compaction of meiotic chromosomes, generates interindividual and cell-to-cell variation in diverse meiotic phenotypes.



Nature: 02 Jun 2020; epub ahead of print
Bell AD, Mello CJ, Nemesh J, Brumbaugh SA, Wysoker A, McCarroll SA
Nature: 02 Jun 2020; epub ahead of print | PMID: 32494014
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Abstract

Potential circadian effects on translational failure for neuroprotection.

Esposito E, Li W, T Mandeville E, Park JH, ... Ji X, Lo EH

Neuroprotectant strategies that have worked in rodent models of stroke have failed to provide protection in clinical trials. Here we show that the opposite circadian cycles in nocturnal rodents versus diurnal humans may contribute to this failure in translation. We tested three independent neuroprotective approaches-normobaric hyperoxia, the free radical scavenger α-phenyl-butyl-tert-nitrone (αPBN), and the N-methyl-D-aspartic acid (NMDA) antagonist MK801-in mouse and rat models of focal cerebral ischaemia. All three treatments reduced infarction in day-time (inactive phase) rodent models of stroke, but not in night-time (active phase) rodent models of stroke, which match the phase (active, day-time) during which most strokes occur in clinical trials. Laser-speckle imaging showed that the penumbra of cerebral ischaemia was narrower in the active-phase mouse model than in the inactive-phase model. The smaller penumbra was associated with a lower density of terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL)-positive dying cells and reduced infarct growth from 12 to 72 h. When we induced circadian-like cycles in primary mouse neurons, deprivation of oxygen and glucose triggered a smaller release of glutamate and reactive oxygen species, as well as lower activation of apoptotic and necroptotic mediators, in \'active-phase\' than in \'inactive-phase\' rodent neurons. αPBN and MK801 reduced neuronal death only in \'inactive-phase\' neurons. These findings suggest that the influence of circadian rhythm on neuroprotection must be considered for translational studies in stroke and central nervous system diseases.



Nature: 02 Jun 2020; epub ahead of print
Esposito E, Li W, T Mandeville E, Park JH, ... Ji X, Lo EH
Nature: 02 Jun 2020; epub ahead of print | PMID: 32494010
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Abstract

Monumental architecture at Aguada Fénix and the rise of Maya civilization.

Inomata T, Triadan D, Vázquez López VA, Fernandez-Diaz JC, ... Aoyama K, Nasu H

Archaeologists have traditionally thought that the development of Maya civilization was gradual, assuming that small villages began to emerge during the Middle Preclassic period (1000-350 BC; dates are calibrated throughout) along with the use of ceramics and the adoption of sedentism. Recent finds of early ceremonial complexes are beginning to challenge this model. Here we describe an airborne lidar survey and excavations of the previously unknown site of Aguada Fénix (Tabasco, Mexico) with an artificial plateau, which measures 1,400 m in length and 10 to 15 m in height and has 9 causeways radiating out from it. We dated this construction to between 1000 and 800 BC using a Bayesian analysis of radiocarbon dates. To our knowledge, this is the oldest monumental construction ever found in the Maya area and the largest in the entire pre-Hispanic history of the region. Although the site exhibits some similarities to the earlier Olmec centre of San Lorenzo, the community of Aguada Fénix probably did not have marked social inequality comparable to that of San Lorenzo. Aguada Fénix and other ceremonial complexes of the same period suggest the importance of communal work in the initial development of Maya civilization.



Nature: 02 Jun 2020; epub ahead of print
Inomata T, Triadan D, Vázquez López VA, Fernandez-Diaz JC, ... Aoyama K, Nasu H
Nature: 02 Jun 2020; epub ahead of print | PMID: 32494009
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Abstract

Structure of a D2 dopamine receptor-G-protein complex in a lipid membrane.

Yin J, Chen KM, Clark MJ, Hijazi M, ... Barth P, Rosenbaum DM

The D2 dopamine receptor (DRD2) is a therapeutic target for Parkinson\'s disease and antipsychotic drugs. DRD2 is activated by the endogenous neurotransmitter dopamine and synthetic agonist drugs such as bromocriptine, leading to stimulation of G and inhibition of adenylyl cyclase. Here we used cryo-electron microscopy to elucidate the structure of an agonist-bound activated DRD2-G complex reconstituted into a phospholipid membrane. The extracellular ligand-binding site of DRD2 is remodelled in response to agonist binding, with conformational changes in extracellular loop 2, transmembrane domain 5 (TM5), TM6 and TM7, propagating to opening of the intracellular G-binding site. The DRD2-G structure represents, to our knowledge, the first experimental model of a G-protein-coupled receptor-G-protein complex embedded in a phospholipid bilayer, which serves as a benchmark to validate the interactions seen in previous detergent-bound structures. The structure also reveals interactions that are unique to the membrane-embedded complex, including helix 8 burial in the inner leaflet, ordered lysine and arginine side chains in the membrane interfacial regions, and lipid anchoring of the G protein in the membrane. Our model of the activated DRD2 will help to inform the design of subtype-selective DRD2 ligands for multiple human central nervous system disorders.



Nature: 10 Jun 2020; epub ahead of print
Yin J, Chen KM, Clark MJ, Hijazi M, ... Barth P, Rosenbaum DM
Nature: 10 Jun 2020; epub ahead of print | PMID: 32528175
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Abstract

A practical risk score for early prediction of neurological outcome after out-of-hospital cardiac arrest: MIRACLE2.

Pareek N, Kordis P, Beckley-Hoelscher N, Pimenta D, ... Noc M, MacCarthy P
Aims
The purpose of this study was to develop a practical risk score to predict poor neurological outcome after out-of-hospital cardiac arrest (OOHCA) for use on arrival to a Heart Attack Centre.
Methods and results
From May 2012 to December 2017, 1055 patients had OOHCA in our region, of whom 373 patients were included in the King\'s Out of Hospital Cardiac Arrest Registry (KOCAR). We performed prediction modelling with multivariable logistic regression to identify predictors of the primary outcome to derive a risk score. This was externally validated in two independent cohorts comprising 473 patients. The primary endpoint was poor neurological outcome at 6-month follow-up (Cerebral Performance Category 3-5). Seven independent predictors of outcome were identified: missed (unwitnessed) arrest, initial non-shockable rhythm, non-reactivity of pupils, age (60-80 years-1 point; >80 years-3 points), changing intra-arrest rhythms, low pH <7.20, and epinephrine administration (2 points). The MIRACLE2 score had an area under the curve (AUC) of 0.90 in the development and 0.84/0.91 in the validation cohorts. Three risk groups were defined-low risk (MIRACLE2 ≤2-5.6% risk of poor outcome); intermediate risk (MIRACLE2 of 3-4-55.4% of poor outcome); and high risk (MIRACLE2 ≥5-92.3% risk of poor outcome). The MIRACLE2 score had superior discrimination than the OHCA [median AUC 0.83 (0.818-0.840); P < 0.001] and Cardiac Arrest Hospital Prognosis models [median AUC 0.87 (0.860-0.870; P = 0.001] and equivalent performance with the Target Temperature Management score [median AUC 0.88 (0.876-0.887); P = 0.092].
Conclusions
The MIRACLE2 is a practical risk score for early accurate prediction of poor neurological outcome after OOHCA, which has been developed for simplicity of use on admission.

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: 29 Jul 2020; epub ahead of print
Pareek N, Kordis P, Beckley-Hoelscher N, Pimenta D, ... Noc M, MacCarthy P
Eur Heart J: 29 Jul 2020; epub ahead of print | PMID: 32731260
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Abstract

Neurons that regulate mouse torpor.

Hrvatin S, Sun S, Wilcox OF, Yao H, ... Griffith EC, Greenberg ME

The advent of endothermy, which is achieved through the continuous homeostatic regulation of body temperature and metabolism, is a defining feature of mammalian and avian evolution. However, when challenged by food deprivation or harsh environmental conditions, many mammalian species initiate adaptive energy-conserving survival strategies-including torpor and hibernation-during which their body temperature decreases far below its homeostatic set-point. How homeothermic mammals initiate and regulate these hypothermic states remains largely unknown. Here we show that entry into mouse torpor, a fasting-induced state with a greatly decreased metabolic rate and a body temperature as low as 20 °C, is regulated by neurons in the medial and lateral preoptic area of the hypothalamus. We show that restimulation of neurons that were activated during a previous bout of torpor is sufficient to initiate the key features of torpor, even in mice that are not calorically restricted. Among these neurons we identify a population of glutamatergic Adcyap1-positive cells, the activity of which accurately determines when mice naturally initiate and exit torpor, and the inhibition of which disrupts the natural process of torpor entry, maintenance and arousal. Taken together, our results reveal a specific neuronal population in the mouse hypothalamus that serves as a core regulator of torpor. This work forms a basis for the future exploration of mechanisms and circuitry that regulate extreme hypothermic and hypometabolic states, and enables genetic access to monitor, initiate, manipulate and study these ancient adaptations of homeotherm biology.



Nature: 10 Jun 2020; epub ahead of print
Hrvatin S, Sun S, Wilcox OF, Yao H, ... Griffith EC, Greenberg ME
Nature: 10 Jun 2020; epub ahead of print | PMID: 32528180
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Abstract

Glucocorticoid-induced tumour necrosis factor receptor family-related protein (GITR) drives atherosclerosis in mice and is associated with an unstable plaque phenotype and cerebrovascular events in humans.

Shami A, Atzler D, Bosmans LA, Winkels H, ... Gonçalves I, Lutgens E
Aims
GITR-a co-stimulatory immune checkpoint protein-is known for both its activating and regulating effects on T-cells. As atherosclerosis bears features of chronic inflammation and autoimmunity, we investigated the relevance of GITR in cardiovascular disease (CVD).
Methods and results
GITR expression was elevated in carotid endarterectomy specimens obtained from patients with cerebrovascular events (n = 100) compared to asymptomatic patients (n = 93) and correlated with parameters of plaque vulnerability, including plaque macrophage, lipid and glycophorin A content, and levels of interleukin (IL)-6, IL-12, and C-C-chemokine ligand 2. Soluble GITR levels were elevated in plasma from subjects with CVD compared to healthy controls. Plaque area in 28-week-old Gitr-/-Apoe-/- mice was reduced, and plaques had a favourable phenotype with less macrophages, a smaller necrotic core and a thicker fibrous cap. GITR deficiency did not affect the lymphoid population. RNA sequencing of Gitr-/-Apoe-/- and Apoe-/- monocytes and macrophages revealed altered pathways of cell migration, activation, and mitochondrial function. Indeed, Gitr-/-Apoe-/- monocytes displayed decreased integrin levels, reduced recruitment to endothelium, and produced less reactive oxygen species. Likewise, GITR-deficient macrophages produced less cytokines and had a reduced migratory capacity.
Conclusion
Our data reveal a novel role for the immune checkpoint GITR in driving myeloid cell recruitment and activation in atherosclerosis, thereby inducing plaque growth and vulnerability. In humans, elevated GITR expression in carotid plaques is associated with a vulnerable plaque phenotype and adverse cerebrovascular events. GITR has the potential to become a novel therapeutic target in atherosclerosis as it reduces myeloid cell recruitment to the arterial wall and impedes atherosclerosis progression.

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

Eur Heart J: 29 Jul 2020; epub ahead of print
Shami A, Atzler D, Bosmans LA, Winkels H, ... Gonçalves I, Lutgens E
Eur Heart J: 29 Jul 2020; epub ahead of print | PMID: 32728688
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Abstract

DNA of neutrophil extracellular traps promotes cancer metastasis via CCDC25.

Yang L, Liu Q, Zhang X, Liu X, ... Su S, Song E

Neutrophil extracellular traps (NETs), which consist of chromatin DNA filaments coated with granule proteins, are released by neutrophils to trap microorganisms. Recent studies have suggested that the DNA component of NETs (NET-DNA) is associated with cancer metastasis in mouse models. However, the functional role and clinical importance of NET-DNA in metastasis in patients with cancer remain unclear. Here we show that NETs are abundant in the liver metastases of patients with breast and colon cancers, and that serum NETs can predict the occurrence of liver metastases in patients with early-stage breast cancer. NET-DNA acts as a chemotactic factor to attract cancer cells, rather than merely acting as a \'trap\' for them; in several mouse models, NETs in the liver or lungs were found to attract cancer cells to form distant metastases. We identify the transmembrane protein CCDC25 as a NET-DNA receptor on cancer cells that senses extracellular DNA and subsequently activates the ILK-β-parvin pathway to enhance cell motility. NET-mediated metastasis is abrogated in CCDC25-knockout cells. Clinically, we show that the expression of CCDC25 on primary cancer cells is closely associated with a poor prognosis for patients. Overall, we describe a transmembrane DNA receptor that mediates NET-dependent metastasis, and suggest that targeting CCDC25 could be an appealing therapeutic strategy for the prevention of cancer metastasis.



Nature: 10 Jun 2020; epub ahead of print
Yang L, Liu Q, Zhang X, Liu X, ... Su S, Song E
Nature: 10 Jun 2020; epub ahead of print | PMID: 32528174
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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

An in vitro model of early anteroposterior organization during human development.

Moris N, Anlas K, van den Brink SC, Alemany A, ... van Oudenaarden A, Martinez Arias A

The body plan of the mammalian embryo is shaped through the process of gastrulation, an early developmental event that transforms an isotropic group of cells into an ensemble of tissues that is ordered with reference to three orthogonal axes. Although model organisms have provided much insight into this process, we know very little about gastrulation in humans, owing to the difficulty of obtaining embryos at such early stages of development and the ethical and technical restrictions that limit the feasibility of observing gastrulation ex vivo. Here we show that human embryonic stem cells can be used to generate gastruloids-three-dimensional multicellular aggregates that differentiate to form derivatives of the three germ layers organized spatiotemporally, without additional extra-embryonic tissues. Human gastruloids undergo elongation along an anteroposterior axis, and we use spatial transcriptomics to show that they exhibit patterned gene expression. This includes a signature of somitogenesis that suggests that 72-h human gastruloids show some features of Carnegie-stage-9 embryos. Our study represents an experimentally tractable model system to reveal and examine human-specific regulatory processes that occur during axial organization in early development.



Nature: 10 Jun 2020; epub ahead of print
Moris N, Anlas K, van den Brink SC, Alemany A, ... van Oudenaarden A, Martinez Arias A
Nature: 10 Jun 2020; epub ahead of print | PMID: 32528178
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Abstract

Physical distancing, face masks, and eye protection to prevent person-to-person transmission of SARS-CoV-2 and COVID-19: a systematic review and meta-analysis.

Chu DK, Akl EA, Duda S, Solo K, ... Schünemann HJ,
Background
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19 and is spread person-to-person through close contact. We aimed to investigate the effects of physical distance, face masks, and eye protection on virus transmission in health-care and non-health-care (eg, community) settings.
Methods
We did a systematic review and meta-analysis to investigate the optimum distance for avoiding person-to-person virus transmission and to assess the use of face masks and eye protection to prevent transmission of viruses. We obtained data for SARS-CoV-2 and the betacoronaviruses that cause severe acute respiratory syndrome, and Middle East respiratory syndrome from 21 standard WHO-specific and COVID-19-specific sources. We searched these data sources from database inception to May 3, 2020, with no restriction by language, for comparative studies and for contextual factors of acceptability, feasibility, resource use, and equity. We screened records, extracted data, and assessed risk of bias in duplicate. We did frequentist and Bayesian meta-analyses and random-effects meta-regressions. We rated the certainty of evidence according to Cochrane methods and the GRADE approach. This study is registered with PROSPERO, CRD42020177047.
Findings
Our search identified 172 observational studies across 16 countries and six continents, with no randomised controlled trials and 44 relevant comparative studies in health-care and non-health-care settings (n=25 697 patients). Transmission of viruses was lower with physical distancing of 1 m or more, compared with a distance of less than 1 m (n=10 736, pooled adjusted odds ratio [aOR] 0·18, 95% CI 0·09 to 0·38; risk difference [RD] -10·2%, 95% CI -11·5 to -7·5; moderate certainty); protection was increased as distance was lengthened (change in relative risk [RR] 2·02 per m; p=0·041; moderate certainty). Face mask use could result in a large reduction in risk of infection (n=2647; aOR 0·15, 95% CI 0·07 to 0·34, RD -14·3%, -15·9 to -10·7; low certainty), with stronger associations with N95 or similar respirators compared with disposable surgical masks or similar (eg, reusable 12-16-layer cotton masks; p=0·090; posterior probability >95%, low certainty). Eye protection also was associated with less infection (n=3713; aOR 0·22, 95% CI 0·12 to 0·39, RD -10·6%, 95% CI -12·5 to -7·7; low certainty). Unadjusted studies and subgroup and sensitivity analyses showed similar findings.
Interpretation
The findings of this systematic review and meta-analysis support physical distancing of 1 m or more and provide quantitative estimates for models and contact tracing to inform policy. Optimum use of face masks, respirators, and eye protection in public and health-care settings should be informed by these findings and contextual factors. Robust randomised trials are needed to better inform the evidence for these interventions, but this systematic appraisal of currently best available evidence might inform interim guidance.
Funding
World Health Organization.

© 2020 World Health Organization. Published by Elsevier Ltd. This is an Open Access article published under the CC BY 3.0 IGO license which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. In any use of this article, there should be no suggestion that WHO endorses any specific organisation, products or services. The use of the WHO logo is not permitted. This notice should be preserved along with the article\'s original URL.

Lancet: 31 May 2020; epub ahead of print
Chu DK, Akl EA, Duda S, Solo K, ... Schünemann HJ,
Lancet: 31 May 2020; epub ahead of print | PMID: 32497510
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Abstract

Molecular architecture of the human 17S U2 snRNP.

Zhang Z, Will CL, Bertram K, Dybkov O, ... Lührmann R, Stark H

The U2 small nuclear ribonucleoprotein (snRNP) has an essential role in the selection of the precursor mRNA branch-site adenosine, the nucleophile for the first step of splicing. Stable addition of U2 during early spliceosome formation requires the DEAD-box ATPase PRP5. Yeast U2 small nuclear RNA (snRNA) nucleotides that form base pairs with the branch site are initially sequestered in a branchpoint-interacting stem-loop (BSL), but whether the human U2 snRNA folds in a similar manner is unknown. The U2 SF3B1 protein, a common mutational target in haematopoietic cancers, contains a HEAT domain (SF3B1) with an open conformation in isolated SF3b, but a closed conformation in spliceosomes, which is required for stable interaction between U2 and the branch site. Here we report a 3D cryo-electron microscopy structure of the human 17S U2 snRNP at a core resolution of 4.1 Å and combine it with protein crosslinking data to determine the molecular architecture of this snRNP. Our structure reveals that SF3B1 interacts with PRP5 and TAT-SF1, and maintains its open conformation in U2 snRNP, and that U2 snRNA forms a BSL that is sandwiched between PRP5, TAT-SF1 and SF3B1. Thus, substantial remodelling of the BSL and displacement of BSL-interacting proteins must occur to allow formation of the U2-branch-site helix. Our studies provide a structural explanation of why TAT-SF1 must be displaced before the stable addition of U2 to the spliceosome, and identify RNP rearrangements facilitated by PRP5 that are required for stable interaction between U2 and the branch site.



Nature: 02 Jun 2020; epub ahead of print
Zhang Z, Will CL, Bertram K, Dybkov O, ... Lührmann R, Stark H
Nature: 02 Jun 2020; epub ahead of print | PMID: 32494006
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Abstract

Association of Factor V Leiden with Subsequent Atherothrombotic Events: A GENIUS-CHD Study of Individual Participant Data.

Mahmoodi BK, Tragante V, Kleber ME, Holmes MV, ... Asselbergs FW, Patel R

Studies examining the role of factor V Leiden among patients at higher risk of atherothrombotic events, such as those with established coronary heart disease (CHD) are lacking. Given that coagulation is involved in the thrombus formation stage upon atherosclerotic plaque rupture, we hypothesized that factor V Leiden may be a stronger risk factor for atherothrombotic events in patients with established CHD.We performed an individual-level meta-analysis including 25 prospective studies (18 cohorts, 3 case-cohorts, 4 randomized trials) from the GENIUS-CHD consortium involving patients with established CHD at baseline. Participating studies genotyped factor V Leiden status and shared risk estimates for the outcomes of interest using a centrally developed statistical code with harmonized definitions across studies. Cox-regression models were used to obtain age and sex adjusted estimates. The obtained estimates were pooled using fixed-effect meta-analysis. The primary outcome was composite of myocardial infarction and CHD death. Secondary outcomes included any stroke, ischemic stroke, coronary revascularization, cardiovascular mortality and all-cause mortality.The studies included 69,681 individuals of whom 3,190 (4.6%) were either heterozygous or homozygous (n=47) carriers of factor V Leiden. Median follow-up per study ranged from 1.0 to 10.6 years. A total of 20 studies with 61,147 participants and 6,849 events contributed to analyses of the primary outcome. Factor V Leiden was not associated with the combined outcome of myocardial infarction and CHD death (hazard ratio, 1.03; 95% CI, 0.92 - 1.16;= 28%; P-heterogeneity = 0.12). Subgroup analysis according to baseline characteristics or strata of traditional cardiovascular risk factors did not show relevant differences. Similarly, risk estimates for the secondary outcomes including stroke, coronary revascularization, cardiovascular mortality and all-cause mortality were close to identity.Factor V Leiden was not associated with increased risk of subsequent atherothrombotic events and mortality in high-risk participants with established and treated CHD. Routine assessment of factor V Leiden status is unlikely to improve atherothrombotic events risk stratification in this population.



Circulation: 12 Jul 2020; epub ahead of print
Mahmoodi BK, Tragante V, Kleber ME, Holmes MV, ... Asselbergs FW, Patel R
Circulation: 12 Jul 2020; epub ahead of print | PMID: 32654539
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Abstract

Senolytic CAR T cells reverse senescence-associated pathologies.

Amor C, Feucht J, Leibold J, Ho YJ, ... Sadelain M, Lowe SW

Cellular senescence is characterized by stable cell-cycle arrest and a secretory program that modulates the tissue microenvironment. Physiologically, senescence serves as a tumour-suppressive mechanism that prevents the expansion of premalignant cells and has a beneficial role in wound-healing responses. Pathologically, the aberrant accumulation of senescent cells generates an inflammatory milieu that leads to chronic tissue damage and contributes to diseases such as liver and lung fibrosis, atherosclerosis, diabetes and osteoarthritis. Accordingly, eliminating senescent cells from damaged tissues in mice ameliorates the symptoms of these pathologies and even promotes longevity. Here we test the therapeutic concept that chimeric antigen receptor (CAR) T cells that target senescent cells can be effective senolytic agents. We identify the urokinase-type plasminogen activator receptor (uPAR) as a cell-surface protein that is broadly induced during senescence and show that uPAR-specific CAR T cells efficiently ablate senescent cells in vitro and in vivo. CAR T cells that target uPAR extend the survival of mice with lung adenocarcinoma that are treated with a senescence-inducing combination of drugs, and restore tissue homeostasis in mice in which liver fibrosis is induced chemically or by diet. These results establish the therapeutic potential of senolytic CAR T cells for senescence-associated diseases.



Nature: 16 Jun 2020; epub ahead of print
Amor C, Feucht J, Leibold J, Ho YJ, ... Sadelain M, Lowe SW
Nature: 16 Jun 2020; epub ahead of print | PMID: 32555459
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Abstract

Safety and immunogenicity of a mosquito saliva peptide-based vaccine: a randomised, placebo-controlled, double-blind, phase 1 trial.

Manning JE, Oliveira F, Coutinho-Abreu IV, Herbert S, ... Valenzuela JG, Memoli MJ
Background
In animal models, immunity to mosquito salivary proteins protects animals against mosquito-borne disease. These findings provide a rationale to vaccinate against mosquito saliva instead of the pathogen itself. To our knowledge, no vector salivary protein-based vaccine has been tested for safety and immunogenicity in humans. We aimed to assess the safety and immunogenicity of Anopheles gambiae saliva vaccine (AGS-v), a peptide-based vaccine derived from four A gambiae salivary proteins, in humans.
Methods
In this randomised, placebo-controlled, double-blind, phase 1 trial, participants were enrolled at the National Institutes of Health Clinical Center in Bethesda, MD, USA. Participants were eligible if they were healthy adults, aged 18-50 years with no history of severe allergic reactions to mosquito bites. Participants were randomly assigned (1:1:1), using block randomisation and a computer-generated randomisation sequence, to treatment with either 200 nmol of AGS-v vaccine alone, 200 nmol of AGS-v with adjuvant (Montanide ISA 51), or sterile water as placebo. Participants and clinicians were masked to treatment assignment. Participants were given a subcutaneous injection of their allocated treatment at day 0 and day 21, followed by exposure to feeding by an uninfected Aedes aegypti mosquito at day 42 to assess subsequent risk to mosquito bites in a controlled setting. The primary endpoints were safety and immunogenicity at day 42 after the first immunisation. Participants who were given at least one dose of assigned treatment were assessed for the primary endpoints and analysis was by intention to treat. The trial was registered with ClinicalTrials.gov, NCT03055000, and is closed for accrual.
Findings
Between Feb 15 and Sept 10, 2017, we enrolled and randomly assigned 49 healthy adult participants to the adjuvanted vaccine (n=17), vaccine alone (n=16), or placebo group (n=16). Five participants did not complete the two-injection regimen with mosquito feeding at day 42, but were included in the safety analyses. No systemic safety concerns were identified; however, one participant in the adjuvanted vaccine group developed a grade 3 erythematous rash at the injection site. Pain, swelling, erythema, and itching were the most commonly reported local symptoms and were significantly increased in the adjuvanted vaccine group compared with both other treatment groups (nine [53%] of 17 participants in the adjuvanted vaccine group, two [13%] of 16 in the vaccine only group, and one [6%] of 16 in the placebo group; p=0·004). By day 42, participants who were given the adjuvanted vaccine had a significant increase in vaccine-specific total IgG antibodies compared with at baseline than did participants who were give vaccine only (absolute difference of log-fold change of 0·64 [95% CI 0·39 to 0·89]; p=0·0002) and who were given placebo (0·62 [0·34 to 0·91]; p=0·0001). We saw a significant increase in IFN-γ production by peripheral blood mononuclear cells at day 42 in the adjuvanted vaccine group compared with in the placebo group (absolute difference of log ratio of vaccine peptide-stimulated vs negative control 0·17 [95% CI 0·061 to 0·27]; p=0·009) but we saw no difference between the IFN-γ production in the vaccine only group compared with the placebo group (0·022 [-0·072 to 0·116]; p=0·63).
Interpretation
AGS-v was well tolerated, and, when adjuvanted, immunogenic. These findings suggest that vector-targeted vaccine administration in humans is safe and could be a viable option for the increasing burden of vector-borne disease.
Funding
Office of the Director and the Division of Intramural Research at the National Institute of Allergy and Infectious Diseases, and National Institutes of Health.

Copyright © 2020 Elsevier Ltd. All rights reserved.

Lancet: 10 Jun 2020; epub ahead of print
Manning JE, Oliveira F, Coutinho-Abreu IV, Herbert S, ... Valenzuela JG, Memoli MJ
Lancet: 10 Jun 2020; epub ahead of print | PMID: 32534628
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Abstract

Mapping geographical inequalities in childhood diarrhoeal morbidity and mortality in low-income and middle-income countries, 2000-17: analysis for the Global Burden of Disease Study 2017.


Background
Across low-income and middle-income countries (LMICs), one in ten deaths in children younger than 5 years is attributable to diarrhoea. The substantial between-country variation in both diarrhoea incidence and mortality is attributable to interventions that protect children, prevent infection, and treat disease. Identifying subnational regions with the highest burden and mapping associated risk factors can aid in reducing preventable childhood diarrhoea.
Methods
We used Bayesian model-based geostatistics and a geolocated dataset comprising 15 072 746 children younger than 5 years from 466 surveys in 94 LMICs, in combination with findings of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017, to estimate posterior distributions of diarrhoea prevalence, incidence, and mortality from 2000 to 2017. From these data, we estimated the burden of diarrhoea at varying subnational levels (termed units) by spatially aggregating draws, and we investigated the drivers of subnational patterns by creating aggregated risk factor estimates.
Findings
The greatest declines in diarrhoeal mortality were seen in south and southeast Asia and South America, where 54·0% (95% uncertainty interval [UI] 38·1-65·8), 17·4% (7·7-28·4), and 59·5% (34·2-86·9) of units, respectively, recorded decreases in deaths from diarrhoea greater than 10%. Although children in much of Africa remain at high risk of death due to diarrhoea, regions with the most deaths were outside Africa, with the highest mortality units located in Pakistan. Indonesia showed the greatest within-country geographical inequality; some regions had mortality rates nearly four times the average country rate. Reductions in mortality were correlated to improvements in water, sanitation, and hygiene (WASH) or reductions in child growth failure (CGF). Similarly, most high-risk areas had poor WASH, high CGF, or low oral rehydration therapy coverage.
Interpretation
By co-analysing geospatial trends in diarrhoeal burden and its key risk factors, we could assess candidate drivers of subnational death reduction. Further, by doing a counterfactual analysis of the remaining disease burden using key risk factors, we identified potential intervention strategies for vulnerable populations. In view of the demands for limited resources in LMICs, accurately quantifying the burden of diarrhoea and its drivers is important for precision public health.
Funding
Bill & Melinda Gates Foundation.

Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Lancet: 05 Jun 2020; 395:1779-1801
Lancet: 05 Jun 2020; 395:1779-1801 | PMID: 32513411
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Abstract

Genomic Binding Patterns of Forkhead Box Protein O1 Reveal its Unique Role in Cardiac Hypertrophy.

Pfleger J, Coleman RC, Ibetti J, Roy R, ... Drosatos K, Koch WJ

Cardiac hypertrophic growth is mediated by robust changes in gene expression, as well as changes that underlie the increase in cardiomyocyte size. The former is regulated by RNA polymerase (pol) IIrecruitment or loss, while the latter involves incremental increases in the transcriptional elongation activity of pol II that is preassembled at the transcription start site (TSS). The differential regulation of these distinct processes by transcription factors remains unknown. Forkhead box protein (Fox)O1 is an insulin-sensitive transcription factor, which is also regulated by hypertrophic stimuli in the heart, however, the scope of its gene regulation remains unexplored.To address this, we performed FoxO1 chromatin immunoprecipitation-deep sequencing (ChIP-Seq) in mouse hearts following 7-day isoproterenol injections (Iso- 3 mg/kg/day), transverse aortic constriction (TAC), or vehicle injection/sham surgery.Our data demonstrate increases in FoxO1 chromatin binding during cardiac hypertrophic growth, which positively correlate with extent of hypertrophy. To assess the role of FoxO1 on pol II dynamics and gene expression, the FoxO1 ChIP-Seq results were aligned with those of pol II ChIP-Seq across the chromosomal coordinates of sham- or TAC-operated mouse hearts. This uncovered that FoxO1 binds to the promoters of 60% of cardiac-expressed genes at baseline and 91% post-TAC. Interestingly, FoxO1 binding is increased in genes regulated by pol IIrecruitment, loss, or pause-release. , endothelin (Et-)1- and, , pressure overload, -induced cardiomyocyte hypertrophic growth is prevented with FoxO1 knockdown or deletion, which was accompanied by reductions in inducible genes, including , ,andand , .Together, our data suggest that FoxO1 may mediate cardiac hypertrophic growth via regulation of pol IIrecruitment and pause-release, as the latter represents the majority (59%) of FoxO1-bound, pol II regulated genes following pressure overload. These findings demonstrate the breadth of transcriptional regulation by FoxO1 during cardiac hypertrophy, information that is essential for its therapeutic targeting.



Circulation: 08 Jul 2020; epub ahead of print
Pfleger J, Coleman RC, Ibetti J, Roy R, ... Drosatos K, Koch WJ
Circulation: 08 Jul 2020; epub ahead of print | PMID: 32640834
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Abstract

Seroprevalence of anti-SARS-CoV-2 IgG antibodies in Geneva, Switzerland (SEROCoV-POP): a population-based study.

Stringhini S, Wisniak A, Piumatti G, Azman AS, ... Kaiser L, Guessous I
Background
Assessing the burden of COVID-19 on the basis of medically attended case numbers is suboptimal given its reliance on testing strategy, changing case definitions, and disease presentation. Population-based serosurveys measuring anti-severe acute respiratory syndrome coronavirus 2 (anti-SARS-CoV-2) antibodies provide one method for estimating infection rates and monitoring the progression of the epidemic. Here, we estimate weekly seroprevalence of anti-SARS-CoV-2 antibodies in the population of Geneva, Switzerland, during the epidemic.
Methods
The SEROCoV-POP study is a population-based study of former participants of the Bus Santé study and their household members. We planned a series of 12 consecutive weekly serosurveys among randomly selected participants from a previous population-representative survey, and their household members aged 5 years and older. We tested each participant for anti-SARS-CoV-2-IgG antibodies using a commercially available ELISA. We estimated seroprevalence using a Bayesian logistic regression model taking into account test performance and adjusting for the age and sex of Geneva\'s population. Here we present results from the first 5 weeks of the study.
Findings
Between April 6 and May 9, 2020, we enrolled 2766 participants from 1339 households, with a demographic distribution similar to that of the canton of Geneva. In the first week, we estimated a seroprevalence of 4·8% (95% CI 2·4-8·0, n=341). The estimate increased to 8·5% (5·9-11·4, n=469) in the second week, to 10·9% (7·9-14·4, n=577) in the third week, 6·6% (4·3-9·4, n=604) in the fourth week, and 10·8% (8·2-13·9, n=775) in the fifth week. Individuals aged 5-9 years (relative risk [RR] 0·32 [95% CI 0·11-0·63]) and those older than 65 years (RR 0·50 [0·28-0·78]) had a significantly lower risk of being seropositive than those aged 20-49 years. After accounting for the time to seroconversion, we estimated that for every reported confirmed case, there were 11·6 infections in the community.
Interpretation
These results suggest that most of the population of Geneva remained uninfected during this wave of the pandemic, despite the high prevalence of COVID-19 in the region (5000 reported clinical cases over <2·5 months in the population of half a million people). Assuming that the presence of IgG antibodies is associated with immunity, these results highlight that the epidemic is far from coming to an end by means of fewer susceptible people in the population. Further, a significantly lower seroprevalence was observed for children aged 5-9 years and adults older than 65 years, compared with those aged 10-64 years. These results will inform countries considering the easing of restrictions aimed at curbing transmission.
Funding
Swiss Federal Office of Public Health, Swiss School of Public Health (Corona Immunitas research program), Fondation de Bienfaisance du Groupe Pictet, Fondation Ancrage, Fondation Privée des Hôpitaux Universitaires de Genève, and Center for Emerging Viral Diseases.

Copyright © 2020 Elsevier Ltd. All rights reserved.

Lancet: 10 Jun 2020; epub ahead of print
Stringhini S, Wisniak A, Piumatti G, Azman AS, ... Kaiser L, Guessous I
Lancet: 10 Jun 2020; epub ahead of print | PMID: 32534626
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Abstract

Clinical benefit of remdesivir in rhesus macaques infected with SARS-CoV-2.

Williamson BN, Feldmann F, Schwarz B, Meade-White K, ... Munster VJ, de Wit E

Effective therapeutics to treat COVID-19 are urgently needed. While many investigational, approved, and repurposed drugs have been suggested, preclinical data from animal models can guide the search for effective treatments by ruling out treatments without in vivo efficacy. Remdesivir (GS-5734) is a nucleotide analog prodrug with broad antiviral activity, that is currently investigated in COVID-19 clinical trials and recently received Emergency Use Authorization from the US Food and Drug Administration. In animal models, remdesivir treatment was effective against MERS-CoV and SARS-CoV infection. In vitro, remdesivir inhibited replication of SARS-CoV-2. Here, we investigated the efficacy of remdesivir treatment in a rhesus macaque model of SARS-CoV-2 infection. In contrast to vehicle-treated animals, animals treated with remdesivir did not show signs of respiratory disease and had reduced pulmonary infiltrates on radiographs and reduced virus titers in bronchoalveolar lavages 12hrs after the first treatment administration. Virus shedding from the upper respiratory tract was not reduced by remdesivir treatment. At necropsy, lung viral loads of remdesivir-treated animals were lower and there was a reduction in damage to the lungs. Thus, therapeutic remdesivir treatment initiated early during infection had a clinical benefit in SARS-CoV-2-infected rhesus macaques. Although the rhesus macaque model does not represent the severe disease observed in a proportion of COVID-19 patients, our data support early remdesivir treatment initiation in COVID-19 patients to prevent progression to pneumonia.



Nature: 08 Jun 2020; epub ahead of print
Williamson BN, Feldmann F, Schwarz B, Meade-White K, ... Munster VJ, de Wit E
Nature: 08 Jun 2020; epub ahead of print | PMID: 32516797
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Abstract

Lineage dynamics of the endosymbiotic cell type in the soft coral Xenia.

Hu M, Zheng X, Fan CM, Zheng Y

Many corals harbour symbiotic dinoflagellate algae. The algae live inside coral cells in a specialized membrane compartment known as the symbiosome, which shares the photosynthetically fixed carbon with coral host cells while host cells provide inorganic carbon to the algae for photosynthesis. This endosymbiosis-which is critical for the maintenance of coral reef ecosystems-is increasingly threatened by environmental stressors that lead to coral bleaching (that is, the disruption of endosymbiosis), which in turn leads to coral death and the degradation of marine ecosystems. The molecular pathways that orchestrate the recognition, uptake and maintenance of algae in coral cells remain poorly understood. Here we report the chromosome-level genome assembly of a Xenia species of fast-growing soft coral, and use this species as a model to investigate coral-alga endosymbiosis. Single-cell RNA sequencing identified 16 cell clusters, including gastrodermal cells and cnidocytes, in Xenia sp. We identified the endosymbiotic cell type, which expresses a distinct set of genes that are implicated in the recognition, phagocytosis and/or endocytosis, and maintenance of algae, as well as in the immune modulation of host coral cells. By coupling Xenia sp. regeneration and single-cell RNA sequencing, we observed a dynamic lineage progression of the endosymbiotic cells. The conserved genes associated with endosymbiosis that are reported here may help to reveal common principles by which different corals take up or lose their endosymbionts.



Nature: 16 Jun 2020; epub ahead of print
Hu M, Zheng X, Fan CM, Zheng Y
Nature: 16 Jun 2020; epub ahead of print | PMID: 32555454
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Abstract

LEM2 phase separation promotes ESCRT-mediated nuclear envelope reformation.

von Appen A, LaJoie D, Johnson IE, Trnka MJ, ... Ullman KS, Frost A

During cell division, remodelling of the nuclear envelope enables chromosome segregation by the mitotic spindle. The reformation of sealed nuclei requires ESCRTs (endosomal sorting complexes required for transport) and LEM2, a transmembrane ESCRT adaptor. Here we show how the ability of LEM2 to condense on microtubules governs the activation of ESCRTs and coordinated spindle disassembly. The LEM motif of LEM2 binds BAF, conferring on LEM2 an affinity for chromatin, while an adjacent low-complexity domain (LCD) promotes LEM2 phase separation. A proline-arginine-rich sequence within the LCD binds to microtubules and targets condensation of LEM2 to spindle microtubules that traverse the nascent nuclear envelope. Furthermore, the winged-helix domain of LEM2 activates the ESCRT-II/ESCRT-III hybrid protein CHMP7 to form co-oligomeric rings. Disruption of these events in human cells prevented the recruitment of downstream ESCRTs, compromised spindle disassembly, and led to defects in nuclear integrity and DNA damage. We propose that during nuclear reassembly LEM2 condenses into a liquid-like phase and coassembles with CHMP7 to form a macromolecular O-ring seal at the confluence between membranes, chromatin and the spindle. The properties of LEM2 described here, and the homologous architectures of related inner nuclear membrane proteins, suggest that phase separation may contribute to other critical envelope functions, including interphase repair and chromatin organization.



Nature: 30 May 2020; 582:115-118
von Appen A, LaJoie D, Johnson IE, Trnka MJ, ... Ullman KS, Frost A
Nature: 30 May 2020; 582:115-118 | PMID: 32494070
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Abstract

Cardiac Ischemic Preconditioning Promotes MG53 Secretion Through HO-Activated PKC-δ Signaling.

Shan D, Guo S, Wu HK, Lv F, ... Zhang Y, Xiao RP

Ischemic heart disease is the leading cause of morbidity and mortality worldwide. Ischemic preconditioning (IPC) is the most powerful intrinsic protection against cardiac ischemia/reperfusion injury. Previous studies have shown that a multifunctional TRIM family protein, Mitsugumin 53 (MG53 or TRIM72), not only plays an essential role in IPC-mediated cardioprotection against ischemia/reperfusion injury, but also ameliorates mechanical damage. In addition to its intracellular actions, as a myokine/cardiokine, MG53 can be secreted from the heart and skeletal muscle in response to metabolic stress. However, it is unknown whether IPC-mediated cardioprotection is causally related to MG53 secretion and, if so, what is the underlying mechanism.Using proteomic analysis in conjunction with genetic and pharmacological approaches, we examined MG53 secretion in response to IPC and explored the underlying mechanism using rodents in , isolated perfused hearts, and cultured neonatal rat ventricular cardiomyocytes (NRVMs). Moreover, using recombinant MG53 proteins, we investigated the potential biological function of secreted MG53 in the context of IPC and ischemia/reperfusion injury.We found that IPC triggered robust MG53 secretion in rodents , perfused hearts, and cultured cardiac myocytes without causing cell membrane leakage. Mechanistically, IPC promoted MG53 secretion through HO-evoked activation of PKC-δ. Specifically, IPC-induced myocardial MG53 secretion was mediated by HO-triggered phosphorylation of PKC-δ at Y311, which is necessary and sufficient to facilitate MG53 secretion. Functionally, systemic delivery of recombinant MG53 proteins to mimic elevated circulating MG53 not only restored IPC function in MG53-deficient mice, but also protected rodent hearts from ischemia/reperfusion injury even in the absence of IPC. Moreover, oxidative stress by HO augmented MG53 secretion, and MG53 knockdown exacerbated HO-induced cell injury in human embryonic stem cell-derived cardiomyocytes, despite relatively low basal expression of MG53 in human heart.We conclude that IPC and oxidative stress can trigger MG53 secretion from the heart via an HO-PKC-δ-dependent mechanism, and that extracellular MG53 can participate in IPC protection against cardiac ischemia/reperfusion injury.



Circulation: 16 Jul 2020; epub ahead of print
Shan D, Guo S, Wu HK, Lv F, ... Zhang Y, Xiao RP
Circulation: 16 Jul 2020; epub ahead of print | PMID: 32677469
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Abstract

The Stem Cell Pluripotency Genes Klf4 and Oct4 Regulate Complex SMC Phenotypic Changes Critical in Late-Stage Atherosclerotic Lesion Pathogenesis.

Alencar GF, Owsiany KM, K S, Sukhavasi K, ... Bekiranov S, Owens GK

Rupture or erosion of advanced atherosclerotic lesions with a resultant myocardial infarction or stroke are the leading worldwide cause of death. However, we have a very limited understanding of the identity, origin, and function of many cells that make up late stage atherosclerotic lesions, as well as the mechanisms by which they control plaque stability.We conducted a comprehensive single-cell RNA-seq of advanced human carotid endarterectomy samples and compared these with scRNA-seq from murine micro-dissected advanced atherosclerotic lesions with smooth muscle cell (SMC) and endothelial lineage tracing to survey all plaque cell types and rigorously determine their origin. We further used ChIP-seq, bulk RNA-seq and an innovative dual lineage tracing mouse to understand the mechanism by which SMC phenotypic transitions affects lesion pathogenesis.We provide evidence SMC-specific Klf4- versus Oct4-knockout showed virtually opposite genomic signatures and their putative target genes play an important role regulating SMC phenotypic changes. scRNA-seq revealed remarkable similarity of transcriptomic clusters between mouse and human lesions and extensive plasticity of SMC- and EC-derived cells including seven distinct clusters, most negative for traditional markers. In particular, SMC contributed to a Myh11, Lgals3 population with a chondrocyte-like gene signature that was markedly reduced with SMC- knockout. We observed that SMC that activate Lgals3 comprise up to 2/3 of all SMC in lesions. However, initial activation of Lgals3 in these cells does not represent conversion to a terminally differentiated state, but rather represents transition of these cells to a unique stem cell marker gene, ECM-remodeling, \"pioneer\" cell phenotype that are the first to invest within lesions and subsequently give rise to at least 3 other SMC phenotypes within advanced lesions including Klf4-dependent osteogenic phenotypes likely to contribute to plaque calcification and plaque destabilization.Taken together, these results provide evidence that SMC-derived cells within advanced mouse and human atherosclerotic lesions exhibit far greater phenotypic plasticity than generally believed, with Klf4 regulating transition to multiple phenotypes including Lgals3 osteogenic cells likely to be detrimental for late stage atherosclerosis plaque pathogenesis.



Circulation: 16 Jul 2020; epub ahead of print
Alencar GF, Owsiany KM, K S, Sukhavasi K, ... Bekiranov S, Owens GK
Circulation: 16 Jul 2020; epub ahead of print | PMID: 32674599
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Abstract

Heart Regeneration by Endogenous Stem Cells and Cardiomyocyte Proliferation: Controversy, Fallacy, and Progress.

He L, Nguyen NB, Ardehali R, Zhou B

Ischemic heart disease is the leading cause of death worldwide. Myocardial infarction results in an irreversible loss of cardiomyocytes with subsequent adverse remodeling and heart failure. Identifying new sources for cardiomyocytes and promoting their formation represents a goal of cardiac biology and regenerative medicine. Within the past decade, many types of putative cardiac stem cells (CSCs) have been reported to regenerate the injured myocardium by differentiating into new cardiomyocytes. Some of these CSCs have been translated from bench to bed with reported therapeutic effectiveness. However, recent basic research studies on stem cell tracing have begun to question their fundamental biology and mechanisms of action, raising serious concerns over the myogenic potential of CSCs. We review the history of different types of CSCs within the past decade and provide an update of recent cell tracing studies that have challenged the origin and existence of CSCs. In addition to the potential role of CSCs in heart regeneration, proliferation of preexisting cardiomyocytes has recently gained more attention. This review will also evaluate the methodologic and technical aspects of past and current studies on CSCs and cardiomyocyte proliferation, with emphasis on technical strengths, advantages, and potential limitations of research approaches. While our understanding of cardiomyocyte generation and regeneration continues to evolve, it is important to address the shortcomings and inaccuracies in this field. This is best achieved by embracing technological advancements and improved methods to label single cardiomyocytes/progenitors and accurately investigate their developmental potential and fate/lineage commitment.



Circulation: 20 Jul 2020; 142:275-291
He L, Nguyen NB, Ardehali R, Zhou B
Circulation: 20 Jul 2020; 142:275-291 | PMID: 32687441
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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

Increasing Fatty Acid Oxidation Prevents High Fat Diet Induced Cardiomyopathy through Regulating Parkin Mediated Mitophagy.

Shao D, Kolwicz SC, Wang P, Roe ND, ... Regnier M, Tian R

Increased fatty acid oxidation (FAO) has long been considered a culprit in the development of obesity/diabetes induced cardiomyopathy. However, enhancing cardiac FAO by removing the inhibitory mechanism of long-chain fatty acids transport into mitochondria via deletion of acetyl-CoA carboxylase 2 (ACC2) does not cause cardiomyopathy in non-obese mice, suggesting that high FAO is distinct from cardiac lipotoxicity. We hypothesize that cardiac pathology associated obesity is attributable to the imbalance of fatty acid supply and oxidation. Thus, we here seek to determine whether further increasing FAO by inducing ACC2 deletion prevents obesity induced cardiomyopathy, and if so, to elucidate the underlying mechanisms.We induced high FAO in adult mouse hearts by cardiac-specific deletion of ACC2 using a tamoxifen inducible model (ACC2 iKO). Control (Con) and ACC2 iKO mice were subjected to high fat diet (HFD) feeding for 24 weeks to induce obesity. Cardiac function, mitochondria function and mitophagy activity were examined.Despite both Con and ACC2 iKO mice exhibiting similar obese phenotype, increasing FAO oxidation by deletion of ACC2 prevented HFD induced cardiac dysfunction, pathological remodeling as well as mitochondria dysfunction. Similarly, increasing FAO by knock down of ACC2 prevented palmitate induced mitochondria dysfunction and cardiomyocyte death in vitro. Furthermore, HFD suppressed mitophagy activity and caused damaged mitochondria to accumulate in the heart, which was partially attenuated in ACC2 iKO heart. Mechanistically, ACC2 iKO prevented HFD induced downregulation of parkin. During stimulation for mitophagy, mitochondria localized parkin was severely reduced in Con HFD-fed mouse heart, which was partially restored in ACC2 iKO HFD-fed mice.These data show that increasing cardiac FAO alone does not cause cardiac dysfunction but protect against cardiomyopathy in chronically obese mice. The beneficial effect of enhancing cardiac FAO in HFD induced obesity is mediated, in part, by maintenance of mitochondria function through regulating parkin mediated mitophagy. Our findings also suggest that targeting the parkin dependent mitophagy pathway could be an effective strategy against the development of obesity induced cardiomyopathy.



Circulation: 28 Jun 2020; epub ahead of print
Shao D, Kolwicz SC, Wang P, Roe ND, ... Regnier M, Tian R
Circulation: 28 Jun 2020; epub ahead of print | PMID: 32597196
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Abstract

An International Multi-Center Evaluation of Inheritance Patterns, Arrhythmic Risks, and Underlying Mechanisms of - Catecholaminergic Polymorphic Ventricular Tachycardia.

Ng K, Titus EW, Lieve KV, Roston TM, ... Deo RC, Roberts JD

Genetic variants in calsequestrin-2 () cause an autosomal recessive form of catecholaminergic polymorphic ventricular tachycardia (CPVT), though isolated reports have identified arrhythmic phenotypes among heterozygotes. Improved insight into the inheritance patterns, arrhythmic risks, and molecular mechanisms of -CPVT was sought through an international multi-center collaboration.Genotype-phenotype segregation in -CPVT families was assessed, and the impact of genotype on arrhythmic risk was evaluated using Cox regression models. Putative dominantmissense variants and the established recessive CASQ2-p.R33Q variant were evaluated using oligomerization assays and their locations mapped to a recent CASQ2 filament structure.A total of 112 individuals, including 36 CPVT probands (24 homozygotes/compound heterozygotes and 12 heterozygotes) and 76 family members possessing at least one presumed pathogenicvariant, were identified. Amonghomozygotes and compound heterozygotes, clinical penetrance was 97.1% and 26 of 34 (76.5%) individuals had experienced a potentially fatal arrhythmic event with a median age of onset of 7 years (95% CI: 6-11). Fifty-one of 66heterozygous family members had undergone clinical evaluation and 17/51 (33.3%) met diagnostic criteria for CPVT. Relative toheterozygotes,homozygote/compound heterozygote genotype status in probands was associated with a 3.2-fold (95% confidence intervals [CI]: 1.3-8.0, p=0.013) increased hazard of a composite of cardiac syncope, aborted cardiac arrest, and sudden cardiac death, but a 38.8-fold (95% CI: 5.6-269.1, p<0.001) increased hazard in genotype positive family members.turbidity assays revealed that p.R33Q and all 6 candidate dominantmissense variants evaluated exhibited filamentation defects, but only p.R33Q convincingly failed to dimerize. Structural analysis revealed that 3 of these 6 putative dominant negative missense variants localized to an electronegative pocket considered critical for back-to-back binding of dimers.This international multi-center study of -CPVT redefines its heritability and confirms that pathogenic heterozygousvariants may manifest with a CPVT phenotype, indicating a need to clinically screen these individuals. A dominant mode of inheritance appears intrinsic to certain missense variants owing to their location and function within the CASQ2 filament structure.



Circulation: 21 Jul 2020; epub ahead of print
Ng K, Titus EW, Lieve KV, Roston TM, ... Deo RC, Roberts JD
Circulation: 21 Jul 2020; epub ahead of print | PMID: 32693635
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Abstract

Reconstruction of the full transmission dynamics of COVID-19 in Wuhan.

Hao X, Cheng S, Wu D, Wu T, Lin X, Wang C

As countries in the world review interventions for containing the COVID-19 pandemic, important lessons can be drawn by studying the full transmission dynamics of SARS-CoV-2 in Wuhan, China, where vigorous non-pharmaceutical interventions have suppressed the local COVID-19 outbreak. Here, we use a modelling approach to reconstruct the full-spectrum dynamics of COVID-19 between January 1, 2020 and March 8, 2020 across five periods marked by events and interventions based on 32,583 laboratory-confirmed cases. Accounting for presymptomatic infectiousness, time-varying ascertainment rates, transmission rates and population movements, we identify two key features of the outbreak: high covertness and high transmissibility. We estimate 87% (lower bound 53%) of the infections before March 8 were unascertained, potentially including asymptomatic and mild-symptomatic cases; and a basic reproduction number R of 3.54 (95% credible interval [CrI]: 3.40-3.67) in the early outbreak, much higher than for SARS and MERS. We observe that multi-pronged interventions had considerable positive effects on controlling the outbreak, decreasing the reproduction number to 0.28 (0.23-0.33) and by projection reducing the total infections in Wuhan by 96.0% as of March 8. We furthermore explore the probability of resurgence following lifting of all interventions after 14 days of no ascertained infections, estimating it at 0.32 and 0.06 based on models with 87% and 53% unascertained infections, respectively, highlighting the risk posed by unascertained cases in changing intervention strategies. These results provide important implications for continuing surveillance and interventions to eventually contain COVID-19 outbreaks.



Nature: 15 Jul 2020; epub ahead of print
Hao X, Cheng S, Wu D, Wu T, Lin X, Wang C
Nature: 15 Jul 2020; epub ahead of print | PMID: 32674112
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Abstract

Gut Pathology and Its Rescue by ACE2 (Angiotensin-Converting Enzyme 2) in Hypoxia-Induced Pulmonary Hypertension.

Sharma RK, Oliveira AC, Yang T, Karas MM, ... Richards EM, Raizada MK

Therapeutic advances for pulmonary hypertension (PH) have been incremental because of the focus on the pulmonary vasculature in PH pathology. Here, we evaluate the concept that PH is, rather, a systemic disorder involving interplay among multiorgan systems, including brain, gut, and lungs. Therefore, the objective of this study was to evaluate the hypothesis that PH is associated with a dysfunctional brain-gut-lung axis and that global overexpression of ACE2 (angiotensin-converting enzyme 2) rebalances this axis and protects against PH. ACE2 knockin and wild-type (WT; C57BL/6) mice were subjected to chronic hypoxia (10% FIO2) or room air for 4 weeks. Cardiopulmonary hemodynamics, histology, immunohistochemistry, and fecal 16S rRNA microbial gene analyses were evaluated. Hypoxia significantly increased right ventricular systolic pressure, sympathetic activity as well as the number and activation of microglia in the paraventricular nucleus of the hypothalamus in WT mice. This was associated with a significant increase in muscularis layer thickening and decreases in both villi length and goblet cells and altered gut microbiota. Global overexpression of ACE2 prevented changes in hypoxia-induced pulmonary and gut pathophysiology and established distinct microbial communities from WT hypoxia mice. Furthermore, WT mice subjected to fecal matter transfer from ACE2 knockin mice were resistant to hypoxia-induced PH compared with their controls receiving WT fecal matter transfer. These observations demonstrate that ACE2 ameliorates these hypoxia-induced pathologies and attenuates PH. The data implicate dysfunctional brain-gut-lung communication in PH and provide novel avenues for therapeutic interventions.



Hypertension: 17 May 2020:HYPERTENSIONAHA12014931; epub ahead of print
Sharma RK, Oliveira AC, Yang T, Karas MM, ... Richards EM, Raizada MK
Hypertension: 17 May 2020:HYPERTENSIONAHA12014931; epub ahead of print | PMID: 32418496
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Abstract

TDAG51 (T-Cell Death Associated Gene 51) Is a Key Modulator of Vascular Calcification and Osteogenic Transdifferentiation of Arterial Smooth Muscle Cells.

Platko K, Lebeau PF, Gyulay G, Lhoták Š, ... Krepinsky JC, Austin RC
Objective
Cardiovascular disease is the primary cause of mortality in patients with chronic kidney disease. Vascular calcification (VC) in the medial layer of the vessel wall is a unique and prominent feature in patients with advanced chronic kidney disease and is now recognized as an important predictor and independent risk factor for cardiovascular and all-cause mortality in these patients. VC in chronic kidney disease is triggered by the transformation of vascular smooth muscle cells (VSMCs) into osteoblasts as a consequence of elevated circulating inorganic phosphate (P) levels, due to poor kidney function. The objective of our study was to investigate the role of TDAG51 (T-cell death-associated gene 51) in the development of medial VC.
Methods and results
Using primary mouse and human VSMCs, we found that TDAG51 is induced in VSMCs by P and is expressed in the medial layer of calcified human vessels. Furthermore, the transcriptional activity of Runx2 (Runt-related transcription factor 2), a well-established driver of P-mediated VC, is reduced in TDAG51 VSMCs. To explain these observations, we identified that TDAG51 VSMCs express reduced levels of the type III sodium-dependent Pit-1 (P transporter), a solute transporter responsible for cellular P uptake. Significantly, in response to hyperphosphatemia induced by vitamin D, medial VC was attenuated in TDAG51 mice.
Conclusions
Our studies highlight TDAG51 as an important mediator of P-induced VC in VSMCs through the downregulation of Pit-1. As such, TDAG51 may represent a therapeutic target for the prevention of VC and cardiovascular disease in patients with chronic kidney disease.



Arterioscler Thromb Vasc Biol: 20 May 2020:ATVBAHA119313779; epub ahead of print
Platko K, Lebeau PF, Gyulay G, Lhoták Š, ... Krepinsky JC, Austin RC
Arterioscler Thromb Vasc Biol: 20 May 2020:ATVBAHA119313779; epub ahead of print | PMID: 32434409
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Abstract

Fasting-mimicking diet and hormone therapy induce breast cancer regression.

Caffa I, Spagnolo V, Vernieri C, Valdemarin F, ... Longo VD, Nencioni A

Approximately 75% of all breast cancers express the oestrogen and/or progesterone receptors. Endocrine therapy is usually effective in these hormone-receptor-positive tumours, but primary and acquired resistance limits its long-term benefit. Here we show that in mouse models of hormone-receptor-positive breast cancer, periodic fasting or a fasting-mimicking diet enhances the activity of the endocrine therapeutics tamoxifen and fulvestrant by lowering circulating IGF1, insulin and leptin and by inhibiting AKT-mTOR signalling via upregulation of EGR1 and PTEN. When fulvestrant is combined with palbociclib (a cyclin-dependent kinase 4/6 inhibitor), adding periodic cycles of a fasting-mimicking diet promotes long-lasting tumour regression and reverts acquired resistance to drug treatment. Moreover, both fasting and a fasting-mimicking diet prevent tamoxifen-induced endometrial hyperplasia. In patients with hormone-receptor-positive breast cancer receiving oestrogen therapy, cycles of a fasting-mimicking diet cause metabolic changes analogous to those observed in mice, including reduced levels of insulin, leptin and IGF1, with the last two remaining low for extended periods. In mice, these long-lasting effects are associated with long-term anti-cancer activity. These results support further clinical studies of a fasting-mimicking diet as an adjuvant to oestrogen therapy in hormone-receptor-positive breast cancer.



Nature: 14 Jul 2020; epub ahead of print
Caffa I, Spagnolo V, Vernieri C, Valdemarin F, ... Longo VD, Nencioni A
Nature: 14 Jul 2020; epub ahead of print | PMID: 32669709
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Abstract

Chemokine Receptor CXCR-2 Initiates Atrial Fibrillation by Triggering Monocyte Mobilization in Mice.

Zhang YL, Cao HJ, Han X, Teng F, ... Guo SB, Li HH

Atrial fibrillation (AF) is frequently associated with increased inflammatory response characterized by infiltration of monocytes/macrophages. The chemokine receptor CXCR-2 is a critical regulator of monocyte mobilization in hypertension and cardiac remodeling, but it is not known whether CXCR-2 is involved in the development of hypertensive AF. AF was induced by infusion of Ang II (angiotensin II; 2000 ng/kg per minute) for 3 weeks in male C57BL/6 wild-type mice, CXCR-2 knockout mice, bone marrow-reconstituted chimeric mice, and mice treated with the CXCR-2 inhibitor SB225002. Microarray analysis revealed that 4 chemokine ligands of CXCR-2 were significantly upregulated in the atria during 3 weeks of Ang II infusion. CXCR-2 expression and the number of CXCR2 immune cells markedly increased in Ang II-infused atria in a time-dependent manner. Moreover, Ang II-infused wild-type mice had increased blood pressure, AF inducibility, atrial diameter, fibrosis, infiltration of macrophages, and superoxide production compared with saline-treated wild-type mice, whereas these effects were significantly attenuated in CXCR-2 knockout mice and wild-type mice transplanted with CXCR-2-deficient bone marrow cells or treated with SB225002. Moreover, circulating blood CXCL-1 levels and CXCR2 monocyte counts were higher and associated with AF in human patients (n=31) compared with sinus rhythm controls (n=31). In summary, this study identified a novel role for CXCR-2 in driving monocyte infiltration of the atria, which accelerates atrial remodeling and AF after hypertension. Blocking CXCR-2 activation may serve as a new therapeutic strategy for AF.



Hypertension: 30 Jul 2020; 76:381-392
Zhang YL, Cao HJ, Han X, Teng F, ... Guo SB, Li HH
Hypertension: 30 Jul 2020; 76:381-392 | PMID: 32639881
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Abstract

SPOCD1 is an essential executor of piRNA-directed de novo DNA methylation.

Zoch A, Auchynnikava T, Berrens RV, Kabayama Y, ... Allshire RC, O\'Carroll D

In mammals, the acquisition of the germline from the soma provides the germline with an essential challenge, the necessity to erase and reset genomic methylation. In the male germline, RNA-directed DNA methylation silences young active transposable elements (TEs). The PIWI protein MIWI2 (PIWIL4) and its associated PIWI-interacting RNAs (piRNAs) instruct TE DNA methylation. piRNAs are proposed to tether MIWI2 to nascent TE transcripts; however, the mechanism by which MIWI2 directs de novo TE methylation is poorly understood but central to the immortality of the germline. Here we define the interactome of MIWI2 in foetal gonocytes that are undergoing de novo genome methylation and identify a novel MIWI2-associated factor, SPOCD1, that is essential for young TE methylation and silencing. The loss of Spocd1 in mice results in male-specific infertility but impacts neither piRNA biogenesis nor localization of MIWI2 to the nucleus. SPOCD1 is a nuclear protein and its expression is restricted to the period of de novo genome methylation. We found SPOCD1 co-purified in vivo with DNMT3L and DNMT3A, components of the de novo methylation machinery as well as constituents of the NURD and BAF chromatin remodelling complexes. We propose a model whereby tethering of MIWI2 to a nascent TE transcript recruits repressive chromatin remodelling activities and the de novo methylation apparatus through SPOCD1. In summary, we have identified a novel and essential executor of mammalian piRNA-directed DNA methylation.



Nature: 15 Jul 2020; epub ahead of print
Zoch A, Auchynnikava T, Berrens RV, Kabayama Y, ... Allshire RC, O'Carroll D
Nature: 15 Jul 2020; epub ahead of print | PMID: 32674113
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Abstract

Potently neutralizing and protective human antibodies against SARS-CoV-2.

Zost SJ, Gilchuk P, Case JB, Binshtein E, ... Carnahan RH, Crowe JE

The COVID-19 pandemic is a major threat to global health for which there are limited medical countermeasures. Moreover, we currently lack a thorough understanding of mechanisms of humoral immunity. From a larger panel of human monoclonal antibodies (mAbs) targeting the spike (S) glycoprotein, we identified several that exhibited potent neutralizing activity and fully blocked the receptor-binding domain of S (S) from interacting with human ACE2 (hACE2). Competition-binding, structural, and functional studies allowed clustering of the mAbs into classes recognizing distinct epitopes on the S as well as distinct conformational states of the S trimer. Potent neutralizing mAbs recognizing non-overlapping sites, COV2-2196 and COV2-2130, bound simultaneously to S and synergistically neutralized authentic SARS-CoV-2 virus. In two mouse models of SARS-CoV-2 infection, passive transfer of either COV2-2196 or COV2-2130 alone or a combination of both mAbs protected mice from weight loss and reduced viral burden and inflammation in the lung. In addition, passive transfer of each of two of the most potently ACE2 blocking mAbs (COV2-2196 or COV2-2381) as monotherapy protected rhesus macaques from SARS-CoV-2 infection. These results identify protective epitopes on S and provide a structure-based framework for rational vaccine design and the selection of robust immunotherapeutics.



Nature: 14 Jul 2020; epub ahead of print
Zost SJ, Gilchuk P, Case JB, Binshtein E, ... Carnahan RH, Crowe JE
Nature: 14 Jul 2020; epub ahead of print | PMID: 32668443
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Abstract

Envelope protein ubiquitination drives entry and pathogenesis of Zika virus.

Giraldo MI, Xia H, Aguilera-Aguirre L, Hage A, ... Shi PY, Rajsbaum R

Zika virus (ZIKV) belongs to the family Flaviviridae, and is related to other viruses that cause human diseases. Unlike other flaviviruses, ZIKV infection can cause congenital neurological disorders and replicates efficiently in reproductive tissues. Here we show that the envelope protein (E) of ZIKV is polyubiquitinated by the E3 ubiquitin ligase TRIM7 through Lys63 (K63)-linked polyubiquitination. Accordingly, ZIKV replicates less efficiently in the brain and reproductive tissues of Trim7 mice. Ubiquitinated E is present on infectious virions of ZIKV when they are released from specific cell types, and enhances virus attachment and entry into cells. Specifically, K63-linked polyubiquitin chains directly interact with the TIM1 (also known as HAVCR1) receptor of host cells, which enhances virus entry in cells as well as in brain tissue in vivo. Recombinant ZIKV mutants that lack ubiquitination are attenuated in human cells and in wild-type mice, but not in live mosquitoes. Monoclonal antibodies against K63-linked polyubiquitin specifically neutralize ZIKV and reduce viraemia in mice. Our results demonstrate that the ubiquitination of ZIKV E is an important determinant of virus entry, tropism and pathogenesis.



Nature: 07 Jul 2020; epub ahead of print
Giraldo MI, Xia H, Aguilera-Aguirre L, Hage A, ... Shi PY, Rajsbaum R
Nature: 07 Jul 2020; epub ahead of print | PMID: 32641828
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Abstract

Early warning scores for detecting deterioration in adult hospital patients: systematic review and critical appraisal of methodology.

Gerry S, Bonnici T, Birks J, Kirtley S, ... Watkinson PJ, Collins GS
Objective
To provide an overview and critical appraisal of early warning scores for adult hospital patients.
Design
Systematic review.
Data sources
Medline, CINAHL, PsycInfo, and Embase until June 2019.
Eligibility criteria for study selection
Studies describing the development or external validation of an early warning score for adult hospital inpatients.
Results
13 171 references were screened and 95 articles were included in the review. 11 studies were development only, 23 were development and external validation, and 61 were external validation only. Most early warning scores were developed for use in the United States (n=13/34, 38%) and the United Kingdom (n=10/34, 29%). Death was the most frequent prediction outcome for development studies (n=10/23, 44%) and validation studies (n=66/84, 79%), with different time horizons (the most frequent was 24 hours). The most common predictors were respiratory rate (n=30/34, 88%), heart rate (n=28/34, 83%), oxygen saturation, temperature, and systolic blood pressure (all n=24/34, 71%). Age (n=13/34, 38%) and sex (n=3/34, 9%) were less frequently included. Key details of the analysis populations were often not reported in development studies (n=12/29, 41%) or validation studies (n=33/84, 39%). Small sample sizes and insufficient numbers of event patients were common in model development and external validation studies. Missing data were often discarded, with just one study using multiple imputation. Only nine of the early warning scores that were developed were presented in sufficient detail to allow individualised risk prediction. Internal validation was carried out in 19 studies, but recommended approaches such as bootstrapping or cross validation were rarely used (n=4/19, 22%). Model performance was frequently assessed using discrimination (development n=18/22, 82%; validation n=69/84, 82%), while calibration was seldom assessed (validation n=13/84, 15%). All included studies were rated at high risk of bias.
Conclusions
Early warning scores are widely used prediction models that are often mandated in daily clinical practice to identify early clinical deterioration in hospital patients. However, many early warning scores in clinical use were found to have methodological weaknesses. Early warning scores might not perform as well as expected and therefore they could have a detrimental effect on patient care. Future work should focus on following recommended approaches for developing and evaluating early warning scores, and investigating the impact and safety of using these scores in clinical practice.
Systematic review registration
PROSPERO CRD42017053324.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. No commercial re-use. See rights and permissions. Published by BMJ.

BMJ: 19 May 2020; 369:m1501
Gerry S, Bonnici T, Birks J, Kirtley S, ... Watkinson PJ, Collins GS
BMJ: 19 May 2020; 369:m1501 | PMID: 32434791
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Abstract

Attenuation of Oxidative Injury with Targeted Expression of NOX2 shRNA Prevents Onset and Maintenance of Electrical Remodeling in the Canine Atrium: A Novel Gene Therapy Approach to Atrial Fibrillation.

Yoo S, Pfenniger A, Hoffman J, Zhang W, ... Aistrup GL, Arora R

Atrial fibrillation (AF) is the most common heart rhythm disorder in adults and a major cause of stroke. Unfortunately, current treatments of AF are suboptimal as they are not targeted to the molecular mechanisms underlying AF. Using a highly novel gene therapy approach in a canine, rapid atrial pacing model of AF, we demonstrate that NADPH oxidase 2 (NOX2) generated oxidative injury, by causing upregulation of a constitutively active form of acetylcholine-dependent K current () - called- is an important mechanism underlying not only the genesis but also the perpetuation of electrical remodeling in the , fibrillating atrium.To understand the mechanism by which oxidative injury promotes the genesis and/or maintenance of AF, we performed targeted injection of NOX2 shRNA (followed by electroporation to facilitate gene delivery) in atria of normal dogs followed by rapid atrial pacing. We used in-vivo high density electrical mapping, isolation of atrial myocytes, whole-cell patch clamping, in-vitro tachypacing of atrial myocytes, lucigenin chemiluminescence assay, immunoblotting, real-time PCR, immunohistochemistry and Masson\'s trichrome staining.First, we demonstrate that generation of oxidative injury in atrial myocytes is a frequency-dependent process, with rapid pacing in canine atrial myocytes inducing oxidative injury through induction of NOX2 and generation of mitochondrial reactive oxygen species. We show that oxidative injury likely contributes to electrical remodeling in AF by upregulatingby a mechanism involving frequency-dependent activation of protein kinase C epsilon (PKC). The time to onset of non-sustained AF increased by more than 5-fold in NOX2 shRNA treated dogs. Furthermore, animals treated with NOX2 shRNA did not develop sustained AF for up to 12 weeks. The electrophysiological mechanism underlying AF prevention was prolongation of atrial effective refractory periods, at least in part due to attenuation of . Attenuated membrane translocation of PKC appeared to be a likely molecular mechanism underlying this beneficial electrophysiological remodeling.NOX2 oxidative injury: a) underlies onset as well as maintenance of electrical remodeling in AF, and b) can be successfully prevented with a novel, gene-based approach. Future optimization of this approach may lead to a novel, mechanism-guided therapy for AF.



Circulation: 19 Jul 2020; epub ahead of print
Yoo S, Pfenniger A, Hoffman J, Zhang W, ... Aistrup GL, Arora R
Circulation: 19 Jul 2020; epub ahead of print | PMID: 32686471
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Abstract

Thiazide Use and Decreased Risk of Heart Failure in Nondiabetic Patients Receiving Intensive Blood Pressure Treatment.

Tsujimoto T, Kajio H

The SPRINT (Systolic Blood Pressure Intervention Trial) study reported that intensive blood pressure (BP) treatment with a systolic BP target of <120 mm Hg decreased the risks of cardiovascular events. However, it remains unknown whether specific medications can further improve cardiovascular outcome in patients receiving intensive BP treatment. This study examined whether thiazide use improves cardiovascular outcome in patients receiving intensive BP treatment. We used data of nondiabetic patients receiving intensive BP treatment in the SPRINT study. The primary outcome was a composite end point of myocardial infarction, acute coronary syndrome, stroke, heart failure, or cardiovascular death. We analyzed hazard ratios for outcomes with 95% CIs in patients taking thiazides compared with those not taking thiazides using Cox proportional hazard models. This study included 2847 patients and the mean follow-up period was 3.3 years. The risk of primary outcome events was significantly lower in patients taking thiazides than in those not taking thiazides in both entire and propensity score-matched cohorts. Particularly, heart failure risk was significantly lower in those taking thiazides. These associations were also observed in various subgroups. In addition, thiazide use was associated with decreased risk of all-cause mortality. Hypokalemia occurred more frequently in patients taking thiazides than in those not taking thiazides. Thiazide use decreased risk of cardiovascular events, particularly heart failure, in nondiabetic high-risk patients receiving intensive BP treatment.



Hypertension: 30 Jul 2020; 76:432-441
Tsujimoto T, Kajio H
Hypertension: 30 Jul 2020; 76:432-441 | PMID: 32639892
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Abstract

A universal trade-off between growth and lag in fluctuating environments.

Basan M, Honda T, Christodoulou D, Hörl M, ... Hwa T, Sauer U

The rate of cell growth is crucial for bacterial fitness and drives the allocation of bacterial resources, affecting, for example, the expression levels of proteins dedicated to metabolism and biosynthesis. It is unclear, however, what ultimately determines growth rates in different environmental conditions. Moreover, increasing evidence suggests that other objectives are also important, such as the rate of physiological adaptation to changing environments. A common challenge for cells is that these objectives cannot be independently optimized, and maximizing one often reduces another. Many such trade-offs have indeed been hypothesized on the basis of qualitative correlative studies. Here we report a trade-off between steady-state growth rate and physiological adaptability in Escherichia coli, observed when a growing culture is abruptly shifted from a preferred carbon source such as glucose to fermentation products such as acetate. These metabolic transitions, common for enteric bacteria, are often accompanied by multi-hour lags before growth resumes. Metabolomic analysis reveals that long lags result from the depletion of key metabolites that follows the sudden reversal in the central carbon flux owing to the imposed nutrient shifts. A model of sequential flux limitation not only explains the observed trade-off between growth and adaptability, but also allows quantitative predictions regarding the universal occurrence of such tradeoffs, based on the opposing enzyme requirements of glycolysis versus gluconeogenesis. We validate these predictions experimentally for many different nutrient shifts in E. coli, as well as for other respiro-fermentative microorganisms, including Bacillus subtilis and Saccharomyces cerevisiae.



Nature: 14 Jul 2020; epub ahead of print
Basan M, Honda T, Christodoulou D, Hörl M, ... Hwa T, Sauer U
Nature: 14 Jul 2020; epub ahead of print | PMID: 32669712
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Abstract

Loss of SPEG Inhibitory Phosphorylation of RyR2 Promotes Atrial Fibrillation.

Campbell HM, Quick AP, Abu-Taha I, Chiang DY, ... Dobrev D, Wehrens XHT

Enhanced diastolic calcium (Ca) release via ryanodine receptor type-2 (RyR2) has been implicated in atrial fibrillation (AF) promotion. Diastolic sarcoplasmic reticulum (SR) Ca leak is caused by increased RyR2 phosphorylation by protein kinase A (PKA) or Ca/calmodulin-dependent kinase-II (CaMKII) phosphorylation, or less dephosphorylation by protein phosphatases. However, considerable controversy remains regarding the molecular mechanisms underlying altered RyR2 function in AF. We thus sought to determine the role of \'striated muscle preferentially expressed protein kinase\' (SPEG), a novel regulator of RyR2 phosphorylation, in AF pathogenesis.Western blotting was performed with right atrial biopsies from paroxysmal (p)AF patients. SPEG atrial knock-out (aKO) mice were generated using adeno-associated virus 9 (AAV9). In mice, AF inducibility was determined using intracardiac programmed electrical stimulation (PES), and diastolic Ca leak in atrial cardiomyocytes was assessed using confocal Ca imaging. Phospho-proteomics studies and western blotting were used to measure RyR2 phosphorylation. In order to test the effects of RyR2-S2367 phosphorylation, knock-in mice with an inactivated S2367 phosphorylation site (S2367A) and a constitutively activated S2367 residue (S2367D) were generated using CRISPR-Cas9.Western blotting revealed decreased SPEG protein levels in atrial biopsies from pAF patients in comparison to patients in sinus rhythm. SPEG aKO mice exhibited increased susceptibility to pacing-induced AF by PES and enhanced Ca spark frequency in atrial cardiomyocytes with Ca imaging, establishing a causal role for decreased SPEG in AF pathogenesis. Phospho-proteomics in hearts from SPEG cardiomyocyte knock-out mice identified RyR2-S2367 as a novel kinase substrate of SPEG. Additionally, western blotting demonstrated that RyR2-S2367 phosphorylation was also decreased in pAF patients. RyR2-S2367A mice exhibited an increased susceptibility to pacing-induced AF as well as aberrant atrial SR Ca leak. In contrast, RyR2-S2367D mice were resistant to pacing-induced AF.Unlike other kinases (PKA, CaMKII) that increase RyR2 activity, SPEG phosphorylation reduces RyR2-mediated SR Ca-release. Reduced SPEG levels and RyR2-S2367 phosphorylation typified patients with pAF. Studies in S2367 knock-in mouse models showed a causal relationship between reduced S2367 phosphorylation and AF susceptibility. Thus, modulating SPEG activity and phosphorylation levels of the novel S2367 site on RyR2 may represent a novel target for AF treatment.



Circulation: 19 Jul 2020; epub ahead of print
Campbell HM, Quick AP, Abu-Taha I, Chiang DY, ... Dobrev D, Wehrens XHT
Circulation: 19 Jul 2020; epub ahead of print | PMID: 32683896
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Abstract

Suppression of proteolipid protein rescues Pelizaeus-Merzbacher disease.

Elitt MS, Barbar L, Shick HE, Powers BE, ... Rigo F, Tesar PJ

Mutations in proteolipid protein 1 (PLP1) result in failure of myelination and neurological dysfunction in the X-linked leukodystrophy Pelizaeus-Merzbacher disease (PMD). Most PLP1 mutations, including point mutations and supernumerary copy variants, lead to severe and fatal disease. PLP1-null patients and mice, however, can display comparatively mild phenotypes, suggesting that PLP1-suppression might provide a general therapeutic strategy for PMD. Here we show effective in vivo Plp1-suppression in the severe jimpy (Plp1) point mutation mouse model of PMD. CRISPR-Cas9 mediated germline suppression of Plp1 in jimpy mice increased myelination and restored nerve conduction velocity, motor function, and lifespan to wild-type levels, validating PLP1-suppression as a therapeutic approach. To evaluate the translational potential of this strategy we identified antisense oligonucleotides (ASOs) that stably decrease Plp1 mRNA and protein throughout the neuraxis, in vivo. Administration of a single dose of Plp1-targeting ASOs to postnatal jimpy mice fully restored oligodendrocyte numbers, increased myelination, improved motor performance, normalized respiratory function, and extended lifespan through an 8-month endpoint. These results support the development of PLP1-suppression as a treatment for PMD. More broadly, we demonstrate that oligonucleotide therapeutics can be delivered to oligodendrocytes in vivo to modulate neurological function and lifespan, establishing a new pharmaceutical modality for myelin disorders.



Nature: 30 Jun 2020; epub ahead of print
Elitt MS, Barbar L, Shick HE, Powers BE, ... Rigo F, Tesar PJ
Nature: 30 Jun 2020; epub ahead of print | PMID: 32610343
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Abstract

N-methyladenine in DNA antagonizes SATB1 in early development.

Li Z, Zhao S, Nelakanti RV, Lin K, ... Li H, Xiao AZ

The recent discovery of N-methyladenine (N-mA) in mammalian genomes suggests that it may serve as an epigenetic regulatory mechanism. However, the biological role of N-mA and the molecular pathways that exert its function remain unclear. Here we show that N-mA has a key role in changing the epigenetic landscape during cell fate transitions in early development. We found that N-mA is upregulated during the development of mouse trophoblast stem cells, specifically at regions of stress-induced DNA double helix destabilization (SIDD). Regions of SIDD are conducive to topological stress-induced unpairing of the double helix and have critical roles in organizing large-scale chromatin structures. We show that the presence of N-mA reduces the in vitro interactions by more than 500-fold between SIDD and SATB1, a crucial chromatin organizer that interacts with SIDD regions. Deposition of N-mA also antagonizes SATB1 function in vivo by preventing its binding to chromatin. Concordantly, N-mA functions at the boundaries between euchromatin and heterochromatin to restrict the spread of euchromatin. Repression of SIDD-SATB1 interactions mediated by N-mA is essential for gene regulation during trophoblast development in cell culture models and in vivo. Overall, our findings demonstrate an unexpected molecular mechanism for N-mA function via SATB1, and reveal connections between DNA modification, DNA secondary structures and large chromatin domains in early embryonic development.



Nature: 14 Jul 2020; epub ahead of print
Li Z, Zhao S, Nelakanti RV, Lin K, ... Li H, Xiao AZ
Nature: 14 Jul 2020; epub ahead of print | PMID: 32669713
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Abstract

IL-18BP is a secreted immune checkpoint and barrier to IL-18 immunotherapy.

Zhou T, Damsky W, Weizman OE, McGeary MK, ... Bosenberg MW, Ring AM

Cytokines were the first modern immunotherapies to produce durable responses in patients with advanced cancer, but they have only modest efficacy and limited tolerability. In an effort to identify alternative cytokine pathways for immunotherapy, we found that components of the interleukin-18 (IL-18) pathway are upregulated on tumour-infiltrating lymphocytes, suggesting that IL-18 therapy could enhance anti-tumour immunity. However, recombinant IL-18 previously did not demonstrate efficacy in clinical trials. Here we show that IL-18BP, a high-affinity IL-18 decoy receptor, is frequently upregulated in diverse human and mouse tumours and limits the anti-tumour activity of IL-18 in mice. Using directed evolution, we engineered a \'decoy-resistant\' IL-18 (DR-18) that maintains signalling potential but is impervious to inhibition by IL-18BP. Unlike wild-type IL-18, DR-18 exerted potent anti-tumour effects in mouse tumour models by promoting the development of poly-functional effector CD8 T cells, decreasing the prevalence of exhausted CD8 T cells that express the transcriptional regulator of exhaustion TOX, and expanding the pool of stem-like TCF1 precursor CD8 T cells. DR-18 also enhanced the activity and maturation of natural killer cells to effectively treat anti-PD-1 resistant tumours that have lost surface expression of major histocompatibility complex class I molecules. These results highlight the potential of the IL-18 pathway for immunotherapeutic intervention and implicate IL-18BP as a major therapeutic barrier.



Nature: 23 Jun 2020; epub ahead of print
Zhou T, Damsky W, Weizman OE, McGeary MK, ... Bosenberg MW, Ring AM
Nature: 23 Jun 2020; epub ahead of print | PMID: 32581358
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Abstract

Opportunities of Antidiabetic Drugs in Cardiovascular Medicine: A Meta-Analysis and Perspectives for Trial Design.

Yan C, Thijs L, Cao Y, Trenson S, ... Staessen JA, Feng YM

To identify potential application of GLP1-RAs (glucagon-like peptide-1 receptor agonists) and SGLT2-Is (sodium-dependent glucose cotrasnsporter-2 inhibitors) in cardiovascular medicine, we performed PubMed search until March 31, 2020 and selected placebo-controlled randomized trials (RCTs) in patients with type 2 diabetes mellitus. Twenty-four hour ambulatory and office blood pressure (BP), major adverse cardiovascular events (MACE), progression of chronic kidney disease (CKD), and changes in glycated hemoglobin and body weight were aggregated across RCTs using random-effect models. In 2238 patients (7 RCTs), SGLT2-Is lowered 24-hour systolic/diastolic BP by 4.4/1.9 mm Hg (95% CI, 3.4-5.5/1.2-2.6 mm Hg), whereas 2 GLP1-RAs RCTs produced contradictory BP results. Over 1.3 to 5.4 years of follow-up of 56 004 patients (7 RCTs), aggregate hazard ratios associated with GLP1-RA treatment were 0.88 (0.84-0.93) for MACE, 0.84 (0.74-0.89) for CKD, and ranged from 0.84 to 0.90 for individual MACE end points (≤0.01). Across 5 SGLT2-Is RCTs, including 43 467 patients with 1.5 to 4.2 years follow-up, hazard ratios were 0.87 (0.82-0.93) for MACE, 0.68 (0.62-0.75) for HF, 0.82 (0.72-0.93) for cardiovascular death, 0.87 (0.79-0.96) for myocardial infarction, and 0.61 (0.56-0.67) for worsening CKD. The risk of HF and CKD, but not MACE, decreased with more BP lowering. Stricter glycemic control was associated with higher HF risk, but unrelated to MACE or CKD. The aggregate effect sizes on systolic BP, body weight, and glycated hemoglobin were -1.61 mm Hg, -2.40 kg, and -0.69% for GLP1-RAs, and -2.53 mm Hg, -1.15 kg and -0.24%, for SGLT2-Is (<0.001). In conclusion, GLP1-RAs and SGLT2-Is reduced cardiovascular risk with differential benefit profiles.



Hypertension: 30 Jul 2020; 76:420-431
Yan C, Thijs L, Cao Y, Trenson S, ... Staessen JA, Feng YM
Hypertension: 30 Jul 2020; 76:420-431 | PMID: 32639887
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