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Abstract

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

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

Copyright © 2019 Elsevier Ltd. All rights reserved.

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

Concomitant Mitral Regurgitation in Patients With Chronic Aortic Regurgitation.

Yang LT, Enriquez-Sarano M, Scott CG, Padang R, ... Pellikka PA, Michelena HI
Background
Etiology, mechanisms, and survival of mitral regurgitation (MR) plus hemodynamically-significant chronic aortic regurgitation (AR) are mostly unknown.
Objectives
The purpose of this study was to investigate the prevalence, mechanisms, etiologies, and survival impact of coexistent ≥ moderate MR in AR patients.
Methods
Consecutive patients with ≥ moderate-severe AR were retrospectively identified between 2004 and 2019.
Results
Of 1,239 eligible patients (61 ± 18 years, 80% men), 1,072 (86%) had pure AR, and 167 (14%) had AR + MR (9% functional mitral regurgitation [FMR] [84% nonischemic] and 5% organic mitral regurgitation [OMR] [62% degenerative]). At baseline transthoracic echocardiogram, pure AR versus AR + OMR versus AR + FMR exhibited differences in age (59 ± 18, 62 ± 16, and 73 ± 14 years, respectively), female sex (18%, 27%, and 39%, respectively), symptoms (36%, 41%, and 64%, respectively), atrial fibrillation (5%, 17%, and 36%, respectively), left ventricular (LV) ejection fraction (59%, 58%, and 46%, respectively), LV end-systolic dimension and volume index, ≥ moderate tricuspid regurgitation (TR) (7%, 35%, and 53%, respectively), and right ventricular systolic pressure (32 ± 11, 45 ± 15, and 50 ± 14 mm Hg, respectively), all p < 0.0001. After a median follow-up of 5.2 years (interquartile range: 2.2 to 10.0 years) and adjusting for demographics, New York Heart Association functional class, aortic valve surgery, LV ejection fraction, LV end-systolic dimension and volume index, presence of FMR was independently associated with all-cause mortality (p ≤ 0.004). Compared with pure AR, AR + MR + TR exhibited the highest adjusted risk of death (2.4-fold; p < 0.0001). When compared with expected population survival, excess mortality risks of pure AR, AR + OMR, and AR + FMR were 1.25-fold, 1.76-fold, and 2.34-fold, respectively (all p ≤ 0.02).
Conclusions
In hemodynamically significant AR, coexistent MR is not uncommon (approximately 14%) and mostly comprises FMR and less commonly OMR. As compared with pure AR, AR + MR + TR exhibit the largest mortality risk. Both AR + OMR and AR + FMR carry a survival penalty compared with the general population, but AR + FMR is associated with the largest excess mortality and represents an advanced stage within the AR clinical spectrum.

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

J Am Coll Cardiol: 20 Jul 2020; 76:233-246
Yang LT, Enriquez-Sarano M, Scott CG, Padang R, ... Pellikka PA, Michelena HI
J Am Coll Cardiol: 20 Jul 2020; 76:233-246 | PMID: 32674787
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Abstract

Hydroxychloroquine to Prevent Recurrent Congenital Heart Block in Fetuses of Anti-SSA/Ro-Positive Mothers.

Izmirly P, Kim M, Friedman DM, Costedoat-Chalumeau N, ... Saxena A, Buyon JP
Background
Experimental and clinical evidence support the role of macrophage Toll-like receptor signaling in maternal anti-SSA/Ro-mediated congenital heart block (CHB).
Objectives
Hydroxychloroquine (HCQ), an orally administered Toll-like receptor antagonist widely used in lupus including during pregnancy, was evaluated for efficacy in reducing the historical 18% recurrence rate of CHB.
Methods
This multicenter, open-label, single-arm, 2-stage clinical trial was designed using Simon\'s optimal approach. Anti-SSA/Ro-positive mothers with a previous pregnancy complicated by CHB were recruited (n = 19 Stage 1; n = 35 Stage 2). Patients received 400 mg daily of HCQ prior to completion of gestational week 10, which was maintained through pregnancy. The primary outcome was 2° or 3° CHB any time during pregnancy, and secondary outcomes included isolated endocardial fibroelastosis, 1° CHB at birth and skin rash.
Results
By intention-to-treat (ITT) analysis, 4 of 54 evaluable pregnancies resulted in a primary outcome (7.4%; 90% confidence interval: 3.4% to 15.9%). Because 9 mothers took potentially confounding medications (fluorinated glucocorticoids and/or intravenous immunoglobulin) after enrollment but prior to a primary outcome, to evaluate HCQ alone, 9 additional mothers were recruited and followed the identical protocol. In the per-protocol analysis restricted to pregnancies exposed to HCQ alone, 4 of 54 (7.4%) fetuses developed a primary outcome as in the ITT. Secondary outcomes included mild endocardial fibroelastosis (n = 1) and cutaneous neonatal lupus (n = 4).
Conclusions
These prospective data support that HCQ significantly reduces the recurrence of CHB below the historical rate by >50%, suggesting that this drug should be prescribed for secondary prevention of fetal cardiac disease in anti-SSA/Ro-exposed pregnancies. (Preventive Approach to Congenital Heart Block With Hydroxychloroquine [PATCH]; NCT01379573).

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

J Am Coll Cardiol: 20 Jul 2020; 76:292-302
Izmirly P, Kim M, Friedman DM, Costedoat-Chalumeau N, ... Saxena A, Buyon JP
J Am Coll Cardiol: 20 Jul 2020; 76:292-302 | PMID: 32674792
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Abstract

Atherosclerotic Risk and Statin Use Among Patients With Peripheral Artery Disease.

Colantonio LD, Hubbard D, Monda KL, Mues KE, ... Muntner P, Farkouh ME
Background
Peripheral artery disease (PAD) is associated with increased risk for atherosclerotic cardiovascular disease (ASCVD) events.
Objectives
The goal of this study was to compare the risk for ASCVD events and the use of statins among patients with PAD versus those with coronary heart disease (CHD) or cerebrovascular disease.
Methods
The authors conducted a retrospective cohort study of adults age ≥19 years with commercial or Medicare health insurance who had a history of PAD, CHD, or cerebrovascular disease on December 31, 2014. Patients were followed for ASCVD events comprising CHD, cerebrovascular disease, and PAD events until December 31, 2017.
Results
Among 943,232 patients included in the analysis, the age-standardized ASCVD event rate per 1,000 person-years for those with a history of 1, 2, and 3 conditions including PAD, CHD, and cerebrovascular disease was 40.8 (95% confidence interval [CI]: 40.3 to 41.3), 68.9 (95% CI: 67.9 to 70.0), and 119.5 (95% CI: 117.0 to 122.0), respectively. The ASCVD event rate among patients with PAD only, CHD only, and cerebrovascular disease only was 34.7 (95% CI: 33.2 to 36.2), 42.2 (95% CI: 41.5 to 42.8), and 38.9 (95% CI: 37.6 to 40.1), respectively. Among patients with PAD and CHD, with PAD and cerebrovascular disease, and with CHD and cerebrovascular disease, the ASCVD event rate was 72.8 (95% CI: 71.0 to 74.7), 63.9 (95% CI: 60.6 to 67.4), and 67.9 (95% CI: 66.4 to 69.3), respectively. Statin use was lower in patients with PAD only (33.9%) versus those with cerebrovascular disease only (43.0%) or CHD only (51.7%).
Conclusions
Despite having high risk for ASCVD events, patients with PAD were less likely to be taking a statin versus those with CHD or cerebrovascular disease. ASCVD risk-reduction interventions including statin therapy in patients with PAD are warranted.

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

J Am Coll Cardiol: 20 Jul 2020; 76:251-264
Colantonio LD, Hubbard D, Monda KL, Mues KE, ... Muntner P, Farkouh ME
J Am Coll Cardiol: 20 Jul 2020; 76:251-264 | PMID: 32674789
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Abstract

The Hybrid Coronary Approach for Optimal Revascularization: JACC Review Topic of the Week.

Moreno PR, Stone GW, Gonzalez-Lengua CA, Puskas JD

Coronary revascularization is accomplished either by percutaneous coronary intervention (PCI), with low risk of immediate complications, or coronary artery bypass graft (CABG), with improved long-term, event-free survival attributable to use of the left internal mammary artery graft. Hybrid coronary revascularization (HCR) combines both. The left internal mammary artery graft is done by sternal-sparing approaches or by robotic-assisted, endoscopic surgery. HCR reduces bleeding, ventilator time, and length of stay compared with traditional CABG. Compared with PCI, HCR offers the durability and survival advantages of the left internal mammary artery. The large-scale National Heart, Lung, and Blood Institute-sponsored, randomized Hybrid Trial (Hybrid Coronary Revascularization Trial) was initiated to examine whether HCR is superior to multivessel PCI. However, enrollment was suboptimal, triggering premature study discontinuation. HCR integrates the positive features of both PCI and CABG, albeit requiring 2 procedures rather than 1. Adequately powered randomized trials are required to evaluate the outcomes and cost-effectiveness of HCR compared with CABG and multivessel PCI alone.

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

J Am Coll Cardiol: 20 Jul 2020; 76:321-333
Moreno PR, Stone GW, Gonzalez-Lengua CA, Puskas JD
J Am Coll Cardiol: 20 Jul 2020; 76:321-333 | PMID: 32674795
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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

Long-Term Kidney Function After the Fontan Operation: JACC Review Topic of the Week.

Zafar F, Lubert AM, Katz DA, Hill GD, ... Goldstein SL, Alsaied T

The Fontan procedure has improved survival and quality of life for patients with single ventricle physiology. Along with extended life expectancy comes a growing population that is experiencing long-term multiorgan adverse effects. Whereas cardiorenal interactions have been extensively studied in patients with a structurally normal heart, these are less well understood in patients with a single ventricle. Several studies have investigated the prevalence of reduced glomerular filtration rate and albuminuria in the Fontan population; however, the long-term implication of renal dysfunction is not well established in this population. This paper provides a concise review of the published reports on the pathophysiology and spectrum of Fontan-associated renal disease. It also identifies gaps in currently available evidence that can guide ongoing and future research.

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

J Am Coll Cardiol: 20 Jul 2020; 76:334-341
Zafar F, Lubert AM, Katz DA, Hill GD, ... Goldstein SL, Alsaied T
J Am Coll Cardiol: 20 Jul 2020; 76:334-341 | PMID: 32674796
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Abstract

Ticagrelor and Aspirin or Aspirin Alone in Acute Ischemic Stroke or TIA.

Johnston SC, Amarenco P, Denison H, Evans SR, ... Wang Y,
Background
Trials have evaluated the use of clopidogrel and aspirin to prevent stroke after an ischemic stroke or transient ischemic attack (TIA). In a previous trial, ticagrelor was not better than aspirin in preventing vascular events or death after stroke or TIA. The effect of the combination of ticagrelor and aspirin on prevention of stroke has not been well studied.
Methods
We conducted a randomized, placebo-controlled, double-blind trial involving patients who had had a mild-to-moderate acute noncardioembolic ischemic stroke, with a National Institutes of Health Stroke Scale (NIHSS) score of 5 or less (range, 0 to 42, with higher scores indicating more severe stroke), or TIA and who were not undergoing thrombolysis or thrombectomy. The patients were assigned within 24 hours after symptom onset, in a 1:1 ratio, to receive a 30-day regimen of either ticagrelor (180-mg loading dose followed by 90 mg twice daily) plus aspirin (300 to 325 mg on the first day followed by 75 to 100 mg daily) or matching placebo plus aspirin. The primary outcome was a composite of stroke or death within 30 days. Secondary outcomes were first subsequent ischemic stroke and the incidence of disability within 30 days. The primary safety outcome was severe bleeding.
Results
A total of 11,016 patients underwent randomization (5523 in the ticagrelor-aspirin group and 5493 in the aspirin group). A primary-outcome event occurred in 303 patients (5.5%) in the ticagrelor-aspirin group and in 362 patients (6.6%) in the aspirin group (hazard ratio, 0.83; 95% confidence interval [CI], 0.71 to 0.96; P = 0.02). Ischemic stroke occurred in 276 patients (5.0%) in the ticagrelor-aspirin group and in 345 patients (6.3%) in the aspirin group (hazard ratio, 0.79; 95% CI, 0.68 to 0.93; P = 0.004). The incidence of disability did not differ significantly between the two groups. Severe bleeding occurred in 28 patients (0.5%) in the ticagrelor-aspirin group and in 7 patients (0.1%) in the aspirin group (P = 0.001).
Conclusions
Among patients with a mild-to-moderate acute noncardioembolic ischemic stroke (NIHSS score ≤5) or TIA who were not undergoing intravenous or endovascular thrombolysis, the risk of the composite of stroke or death within 30 days was lower with ticagrelor-aspirin than with aspirin alone, but the incidence of disability did not differ significantly between the two groups. Severe bleeding was more frequent with ticagrelor. (Funded by AstraZeneca; THALES ClinicalTrial.gov number, NCT03354429.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 15 Jul 2020; 383:207-217
Johnston SC, Amarenco P, Denison H, Evans SR, ... Wang Y,
N Engl J Med: 15 Jul 2020; 383:207-217 | PMID: 32668111
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Abstract

Dexamethasone in Hospitalized Patients with Covid-19 - Preliminary Report.

, Horby P, Lim WS, Emberson JR, ... Haynes R, Landray MJ
Background
Coronavirus disease 2019 (Covid-19) is associated with diffuse lung damage. Glucocorticoids may modulate inflammation-mediated lung injury and thereby reduce progression to respiratory failure and death.
Methods
In this controlled, open-label trial comparing a range of possible treatments in patients who were hospitalized with Covid-19, we randomly assigned patients to receive oral or intravenous dexamethasone (at a dose of 6 mg once daily) for up to 10 days or to receive usual care alone. The primary outcome was 28-day mortality. Here, we report the preliminary results of this comparison.
Results
A total of 2104 patients were assigned to receive dexamethasone and 4321 to receive usual care. Overall, 482 patients (22.9%) in the dexamethasone group and 1110 patients (25.7%) in the usual care group died within 28 days after randomization (age-adjusted rate ratio, 0.83; 95% confidence interval [CI], 0.75 to 0.93; P<0.001). The proportional and absolute between-group differences in mortality varied considerably according to the level of respiratory support that the patients were receiving at the time of randomization. In the dexamethasone group, the incidence of death was lower than that in the usual care group among patients receiving invasive mechanical ventilation (29.3% vs. 41.4%; rate ratio, 0.64; 95% CI, 0.51 to 0.81) and among those receiving oxygen without invasive mechanical ventilation (23.3% vs. 26.2%; rate ratio, 0.82; 95% CI, 0.72 to 0.94) but not among those who were receiving no respiratory support at randomization (17.8% vs. 14.0%; rate ratio, 1.19; 95% CI, 0.91 to 1.55).
Conclusions
In patients hospitalized with Covid-19, the use of dexamethasone resulted in lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen alone at randomization but not among those receiving no respiratory support. (Funded by the Medical Research Council and National Institute for Health Research and others; RECOVERY ClinicalTrials.gov number, NCT04381936; ISRCTN number, 50189673.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 16 Jul 2020; epub ahead of print
, Horby P, Lim WS, Emberson JR, ... Haynes R, Landray MJ
N Engl J Med: 16 Jul 2020; epub ahead of print | PMID: 32678530
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Abstract

Timing of Initiation of Renal-Replacement Therapy in Acute Kidney Injury.

, , Bagshaw SM, Wald R, ... Young P, Zarbock A
Background
Acute kidney injury is common in critically ill patients, many of whom receive renal-replacement therapy. However, the most effective timing for the initiation of such therapy remains uncertain.
Methods
We conducted a multinational, randomized, controlled trial involving critically ill patients with severe acute kidney injury. Patients were randomly assigned to receive an accelerated strategy of renal-replacement therapy (in which therapy was initiated within 12 hours after the patient had met eligibility criteria) or a standard strategy (in which renal-replacement therapy was discouraged unless conventional indications developed or acute kidney injury persisted for >72 hours). The primary outcome was death from any cause at 90 days.
Results
Of the 3019 patients who had undergone randomization, 2927 (97.0%) were included in the modified intention-to-treat analysis (1465 in the accelerated-strategy group and 1462 in the standard-strategy group). Of these patients, renal-replacement therapy was performed in 1418 (96.8%) in the accelerated-strategy group and in 903 (61.8%) in the standard-strategy group. At 90 days, death had occurred in 643 patients (43.9%) in the accelerated-strategy group and in 639 (43.7%) in the standard-strategy group (relative risk, 1.00; 95% confidence interval [CI], 0.93 to 1.09; P = 0.92). Among survivors at 90 days, continued dependence on renal-replacement therapy was confirmed in 85 of 814 patients (10.4%) in the accelerated-strategy group and in 49 of 815 patients (6.0%) in the standard-strategy group (relative risk, 1.74; 95% CI, 1.24 to 2.43). Adverse events occurred in 346 of 1503 patients (23.0%) in the accelerated-strategy group and in 245 of 1489 patients (16.5%) in the standard-strategy group (P<0.001).
Conclusions
Among critically ill patients with acute kidney injury, an accelerated renal-replacement strategy was not associated with a lower risk of death at 90 days than a standard strategy. (Funded by the Canadian Institutes of Health Research and others; STARRT-AKI ClinicalTrials.gov number, NCT02568722.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 15 Jul 2020; 383:240-251
, , Bagshaw SM, Wald R, ... Young P, Zarbock A
N Engl J Med: 15 Jul 2020; 383:240-251 | PMID: 32668114
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Abstract

Precision Health Analytics With Predictive Analytics and Implementation Research: JACC State-of-the-Art Review.

Pearson TA, Califf RM, Roper R, Engelgau MM, ... Goff DC, Mensah GA

Emerging data science techniques of predictive analytics expand the quality and quantity of complex data relevant to human health and provide opportunities for understanding and control of conditions such as heart, lung, blood, and sleep disorders. To realize these opportunities, the information sources, the data science tools that use the information, and the application of resulting analytics to health and health care issues will require implementation research methods to define benefits, harms, reach, and sustainability; and to understand related resource utilization implications to inform policymakers. This JACC State-of-the-Art Review is based on a workshop convened by the National Heart, Lung, and Blood Institute to explore predictive analytics in the context of implementation science. It highlights precision medicine and precision public health as complementary and compelling applications of predictive analytics, and addresses future research and training endeavors that might further foster the application of predictive analytics in clinical medicine and public health.

Copyright © 2020 American College of Cardiology Foundation. All rights reserved.

J Am Coll Cardiol: 20 Jul 2020; 76:306-320
Pearson TA, Califf RM, Roper R, Engelgau MM, ... Goff DC, Mensah GA
J Am Coll Cardiol: 20 Jul 2020; 76:306-320 | PMID: 32674794
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Abstract

Management of non-culprit coronary plaques in patients with acute coronary syndrome.

Montone RA, Niccoli G, Crea F, Jang IK

Approximately 50% of patients with ST-segment elevation myocardial infarction (STEMI) have multivessel coronary artery disease, a condition associated with an increased incidence of recurrent ischaemic events and higher mortality. Based on recent evidences, a strategy of staged percutaneous coronary intervention (PCI) of obstructive non-culprit lesions should be considered the gold standard for the management of these patients. However, several issues remain still unresolved. Indeed, what is the optimal timing of staged PCI is not completely defined. Moreover, assessment of intermediate non-culprit lesions represent still a clinical conundrum, as pressure-wire indexes do not seem able to correctly identify those patients in whom deferral is safe. Intracoronary imaging may help to identify untreated non-culprit lesions containing vulnerable plaques that may portend a higher risk of future cardiovascular events. However, there are hitherto no studies demonstrating that preventive PCI of vulnerable plaques or more intensive pharmacological treatment is associated with an improved clinical outcome. In this review, we discuss the recent evolving concepts about management of non-culprit plaques in STEMI patients, proposing a diagnostic and therapeutic algorithm to guide physicians in clinical practice. We also underscore the several knowledge gaps to address in future studies.

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: 16 Jul 2020; epub ahead of print
Montone RA, Niccoli G, Crea F, Jang IK
Eur Heart J: 16 Jul 2020; epub ahead of print | PMID: 32676644
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Abstract

Trial of Roflumilast Cream for Chronic Plaque Psoriasis.

Lebwohl MG, Papp KA, Stein Gold L, Gooderham MJ, ... Welgus H,
Background
Systemic oral phosphodiesterase type 4 (PDE-4) inhibitors have been effective in the treatment of psoriasis. Roflumilast cream contains a PDE-4 inhibitor that is being investigated for the topical treatment of psoriasis.
Methods
In this phase 2b, double-blind trial, we randomly assigned adults with plaque psoriasis in a 1:1:1 ratio to use roflumilast 0.3% cream, roflumilast 0.15% cream, or vehicle (placebo) cream once daily for 12 weeks. The primary efficacy outcome was the investigator\'s global assessment (IGA) of a status of clear or almost clear at week 6 (assessed on a 5-point scale of plaque thickening, scaling, and erythema; a score of 0 indicates clear, 1 almost clear, and 4 severe). Secondary outcomes included an IGA score indicating clear or almost clear plus a 2-grade improvement in the IGA score for the intertriginous area and the change in the Psoriasis Area and Severity Index (PASI) score (range, 0 to 72, with higher scores indicating worse disease). Safety was also assessed.
Results
Among 331 patients who underwent randomization, 109 were assigned to roflumilast 0.3% cream, 113 to roflumilast 0.15% cream, and 109 to vehicle cream. An IGA score indicating clear or almost clear at week 6 was observed in 28% of the patients in the roflumilast 0.3% group, in 23% in the roflumilast 0.15% group, and in 8% in the vehicle group (P<0.001 and P = 0.004 vs. vehicle for roflumilast 0.3% and 0.15%, respectively). Among the approximately 15% of patients overall who had baseline intertriginous psoriasis of at least mild severity, an IGA score at week 6 indicating clear or almost clear plus a 2-grade improvement in the intertriginous-area IGA score occurred in 73% of the patients in the roflumilast 0.3% group, 44% of those in the roflumilast 0.15% group, and 29% of those in the vehicle group. The mean baseline PASI scores were 7.7 in the roflumilast 0.3% group, 8.0 in the roflumilast 0.15% group, and 7.6 in the vehicle group; the mean change from baseline at week 6 was -50.0%, -49.0%, and -17.8%, respectively. Application-site reactions occurred with similar frequency in the roflumilast groups and the vehicle group.
Conclusions
Roflumilast cream administered once daily to affected areas of psoriasis was superior to vehicle cream in leading to a state of clear or almost clear at 6 weeks. Longer and larger trials are needed to determine the durability and safety of roflumilast in psoriasis. (Funded by Arcutis Biotherapeutics; ARQ-151 201 ClinicalTrials.gov number, NCT03638258.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 15 Jul 2020; 383:229-239
Lebwohl MG, Papp KA, Stein Gold L, Gooderham MJ, ... Welgus H,
N Engl J Med: 15 Jul 2020; 383:229-239 | PMID: 32668113
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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

Long-Term Outcomes of Implantable Cardioverter-Defibrillator Therapy in the SCD-HeFT.

Poole JE, Olshansky B, Mark DB, Anderson J, ... Bardy GH,
Background
The SCD-HeFT (Sudden Cardiac Death in Heart Failure Trial) randomized 2,521 patients with moderate heart failure (HF) to amiodarone, placebo drug, or implantable cardioverter-defibrillator (ICD) therapy. Original trial follow-up ended October 31, 2003. Over a median 45.5-month follow-up, amiodarone, compared with placebo, did not affect survival, whereas randomization to an ICD significantly decreased all-cause mortality by 23%.
Objectives
This study sought to describe the extended treatment group survival of the SCD-HeFT cohort.
Methods
Mortality outcomes for the 1,855 patients alive at the end of the SCD-HeFT trial were collected between 2010 and 2011. These data were combined with the 666 deaths from the original study to compare long-term outcomes overall and for key pre-specified subgroups.
Results
Median (25th to 75th percentiles) follow-up was 11.0 (10.0 to 12.2) years. On the basis of intention-to-treat analysis, the ICD group had overall survival benefit versus placebo drug (hazard ratio [HR]: 0.87; 95% confidence interval [CI]: 0.76 to 0.98; p = 0.028). When treatment benefit was examined as a function of time from randomization, attenuation of the ICD benefit was observed after 6 years (p value for the interaction = 0.0015). Subgroup analysis revealed long-term ICD benefit varied according to HF etiology and New York Heart Association (NYHA) functional class: ischemic HF HR: 0.81; 95% CI: 0.69 to 0.95; p = 0.009; nonischemic HF HR: 0.97; 95% CI: 0.79 to 1.20; p = 0.802; NYHA functional class II HR: 0.76; 95% CI: 0.65 to 0.90; p = 0.001; NYHA functional class III HR: 1.06; 95% CI: 0.86 to 1.31; p = 0.575.
Conclusions
Follow-up of SCD-HeFT patients to 11 years demonstrated heterogenous treatment-related patterns of long-term survival with ICD benefit most evident at 11 years for ischemic HF patients and for those with NYHA functional class II symptoms at trial enrollment. (SCD-HeFT 10 Year Follow-up [SCD-HeFT10 Yr]; NCT01058837).

Copyright © 2020 American College of Cardiology Foundation. All rights reserved.

J Am Coll Cardiol: 27 Jul 2020; 76:405-415
Poole JE, Olshansky B, Mark DB, Anderson J, ... Bardy GH,
J Am Coll Cardiol: 27 Jul 2020; 76:405-415 | PMID: 32703511
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Abstract

Cardiac Pacing Training in Africa: Endorsed by the Africa Heart Rhythm Association (AFHRA): JACC International.

Rwebembera J, Jeilan M, Ajijola OA, Talle M, ... Chin A, Bonny A

The field of pacing in Africa has evolved in an uncoordinated way across the continent with significant variation in local expertise, cost, and utilization. There are many countries where pacemaker services do not meet one-hundredth of the national demand. Regional, national, and institutional standards for pacemaker qualification and credentials are lacking. This paper reviews the current needs for bradycardia pacing and evaluates what standards should be set to develop pacemaker services in a resource-constrained continent, including the challenges and opportunities of capacity building and training as well as standards for training programs (training prerequisites, case volumes, program content, and evaluation).

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

J Am Coll Cardiol: 27 Jul 2020; 76:465-472
Rwebembera J, Jeilan M, Ajijola OA, Talle M, ... Chin A, Bonny A
J Am Coll Cardiol: 27 Jul 2020; 76:465-472 | PMID: 32703517
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Abstract

Pathophysiology and Acute Management of Tachyarrhythmias in Pheochromocytoma: JACC Review Topic of the Week.

Nazari MA, Rosenblum JS, Haigney MC, Rosing DR, Pacak K

Pheochromocytomas, arising from chromaffin cells, produce catecholamines, epinephrine and norepinephrine. The tumor biochemical phenotype is defined by which of these exerts the greatest influence on the cardiovascular system when released into circulation in high amounts. Action on the heart and vasculature can cause potentially lethal arrhythmias, often in the setting of comorbid blood pressure derangements. In a review of electrocardiograms obtained on pheochromocytoma patients (n = 650) treated at our institution over the last decade, severe and refractory sinus tachycardia, atrial fibrillation, and ventricular tachycardia were found to be the most common or life-threatening catecholamine-induced tachyarrhythmias. These arrhythmias, arising from catecholamine excess rather than from a primary electrophysiologic substrate, require special considerations for treatment and complication avoidance. Understanding the synthesis and release of catecholamines, the adrenoceptors catecholamines bind to, and the cardiac and vascular response to epinephrine and norepinephrine underlies optimal management in catecholamine-induced tachyarrhythmias.

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

J Am Coll Cardiol: 27 Jul 2020; 76:451-464
Nazari MA, Rosenblum JS, Haigney MC, Rosing DR, Pacak K
J Am Coll Cardiol: 27 Jul 2020; 76:451-464 | PMID: 32703516
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Abstract

Genetic variability in the absorption of dietary sterols affects the risk of coronary artery disease.

Helgadottir A, Thorleifsson G, Alexandersson KF, Tragante V, ... Gudbjartsson DF, Stefansson K
Aims
To explore whether variability in dietary cholesterol and phytosterol absorption impacts the risk of coronary artery disease (CAD) using as instruments sequence variants in the ABCG5/8 genes, key regulators of intestinal absorption of dietary sterols.
Methods and results
We examined the effects of ABCG5/8 variants on non-high-density lipoprotein (non-HDL) cholesterol (N up to 610 532) and phytosterol levels (N = 3039) and the risk of CAD in Iceland, Denmark, and the UK Biobank (105 490 cases and 844 025 controls). We used genetic scores for non-HDL cholesterol to determine whether ABCG5/8 variants confer greater risk of CAD than predicted by their effect on non-HDL cholesterol. We identified nine rare ABCG5/8 coding variants with substantial impact on non-HDL cholesterol. Carriers have elevated phytosterol levels and are at increased risk of CAD. Consistent with impact on ABCG5/8 transporter function in hepatocytes, eight rare ABCG5/8 variants associate with gallstones. A genetic score of ABCG5/8 variants predicting 1 mmol/L increase in non-HDL cholesterol associates with two-fold increase in CAD risk [odds ratio (OR) = 2.01, 95% confidence interval (CI) 1.75-2.31, P = 9.8 × 10-23] compared with a 54% increase in CAD risk (OR = 1.54, 95% CI 1.49-1.59, P = 1.1 × 10-154) associated with a score of other non-HDL cholesterol variants predicting the same increase in non-HDL cholesterol (P for difference in effects = 2.4 × 10-4).
Conclusions
Genetic variation in cholesterol absorption affects levels of circulating non-HDL cholesterol and risk of CAD. Our results indicate that both dietary cholesterol and phytosterols contribute directly to atherogenesis.

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

Eur Heart J: 20 Jul 2020; 41:2618-2628
Helgadottir A, Thorleifsson G, Alexandersson KF, Tragante V, ... Gudbjartsson DF, Stefansson K
Eur Heart J: 20 Jul 2020; 41:2618-2628 | PMID: 32702746
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Abstract

Relationship of Ventricular Morphology and Atrioventricular Valve Function to Long-Term Outcomes Following Fontan Procedures.

Moon J, Shen L, Likosky DS, Sood V, ... Bove EL, Si MS
Background
The influence of ventricular morphology on Fontan outcomes is controversial.
Objectives
This study hypothesized that dysfunction of the single right ventricle (RV) and right atrioventricular valve regurgitation (AVVR) increases over time and adversely impacts late outcomes following a Fontan operation. A single-center retrospective study was performed.
Methods
From 1985 through 2018, 1,162 patients underwent the Fontan procedure at our center and were included in this study. Transplant and takedown free survival, ventricular, and atrioventricular valve dysfunction after Fontan were analyzed. Death or heart transplantation information was obtained from the National Death Index and the Scientific Registry of Transplant Recipients.
Results
The follow-up rate was 99%. Morphologic RV was present in 58% of patients. Transplant and takedown free survival were 91%, 75%, and 71% at 10 years, 20 years, and 25 years, respectively. Morphologic RV was an independent risk factor for transplant, takedown free survival (hazard ratio: 2.4; p = 0.008). The AVVR, which preceded ventricular dysfunction in most cases, was associated with the development of ventricular dysfunction after Fontan (odds ratio: 4.3; 95% confidence interval: 2.7 to 6.7; p < 0.001). Furthermore, AVVR and ventricular dysfunction progressed over time after Fontan, especially in the RV (AVVR: p < 0.0001, ventricular dysfunction: p < 0.0001).
Conclusions
Morphologic RV is negatively associated with the long-term survival following the Fontan, possibly due to a tendency toward progressive AVVR and deterioration of the single ventricle function. Additional volume overload caused by AVVR may be one of the main factors accelerating the dysfunction of the single RV, implying that early valve intervention may be warranted.

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

J Am Coll Cardiol: 27 Jul 2020; 76:419-431
Moon J, Shen L, Likosky DS, Sood V, ... Bove EL, Si MS
J Am Coll Cardiol: 27 Jul 2020; 76:419-431 | PMID: 32703513
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Abstract

Phase-III Clinical Trial of Fluorine-18 Flurpiridaz Positron Emission Tomography for Evaluation of Coronary Artery Disease.

Maddahi J, Lazewatsky J, Udelson JE, Berman DS, ... Knuuti J, Orlandi C
Background
Fluorine-18 flurpiridaz is a novel positron emission tomography (PET) myocardial perfusion imaging tracer.
Objectives
This study sought to assess the diagnostic efficacy of flurpiridaz PET versus technetium-99m-labeled single photon emission computed tomography SPECT for the detection and evaluation of coronary artery disease (CAD), defined as ≥50% stenosis by quantitative invasive coronary angiography (ICA). Flurpiridaz safety was also evaluated.
Methods
In this phase III prospective multicenter clinical study, 795 patients with known or suspected CAD from 72 clinical sites in the United States, Canada, and Finland were enrolled. A total of 755 patients were evaluable, and the mean age was 62.3 ± 9.5 years, 31% were women, 55% had body mass index ≥30 kg/m, and 71% had pharmacological stress. Patients underwent 1-day rest-stress (pharmacological or exercise) flurpiridaz PET and 1- or 2-day rest-stress Tc-99m-labeled SPECT and ICA. Images were read by 3 experts blinded to clinical and ICA data.
Results
Sensitivity of flurpiridaz PET (for detection of ≥50% stenosis by ICA) was 71.9% (95% confidence interval [CI]: 67.0% to 76.3%), significantly (p < 0.001) higher than SPECT (53.7% [95% CI: 48.5% to 58.8%]), while specificity did not meet the prespecified noninferiority criterion (76.2% [95% CI: 71.8% to 80.1%] vs. 86.6% [95% CI: 83.2% to 89.8%]; p = NS). Receiver-operating characteristic curve analysis demonstrated superior discrimination of CAD by flurpiridaz PET versus SPECT in the overall population, in women, obese patients, and patients undergoing pharmacological stress testing (p < 0.001 for all). Flurpiridaz PET was superior to SPECT for defect size (p < 0.001), image quality (p < 0.001), diagnostic certainty (p < 0.001), and radiation exposure (6.1 ± 0.4 mSv vs. 13.4 ± 3.2 mSv; p < 0.001). Flurpiridaz PET was safe and well tolerated.
Conclusions
Flurpiridaz PET myocardial perfusion imaging shows promise as a new tracer for CAD detection and assessment of women, obese patients, and patients undergoing pharmacological stress testing. A second phase III Food and Drug Administration trial is ongoing. (A Phase 3 Multi-center Study to Assess PET Imaging of Flurpiridaz F 18 Injection in Patients with CAD; NCT01347710).

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

J Am Coll Cardiol: 27 Jul 2020; 76:391-401
Maddahi J, Lazewatsky J, Udelson JE, Berman DS, ... Knuuti J, Orlandi C
J Am Coll Cardiol: 27 Jul 2020; 76:391-401 | PMID: 32703509
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Impact:
Abstract

Improving the Design of Future PCI Trials for Stable Coronary Artery Disease: JACC State-of-the-Art Review.

Marquis-Gravel G, Moliterno DJ, Francis DP, Jüni P, ... Zannad F, Goodman SG

The role of percutaneous coronary interventions in addition to medical therapy for patients with stable coronary artery disease continues to be debated in routine clinical practice, despite more than 2 decades of randomized controlled trials. The residual uncertainty arises from particular challenges facing revascularization trials. Which endpoint do doctors care about, and which do patients care about? Which participants should be enrolled? What background medical therapy should we use? When is placebo control relevant? In this paper, we discuss how these questions can be approached and examine the merits and disadvantages of possible options. Engaging multiple stakeholders, including patients, researchers, regulators, and funders, to ensure the design elements are methodologically valid and clinically meaningful should be an aspirational goal in the development of future trials.

Copyright © 2020 American College of Cardiology Foundation. All rights reserved.

J Am Coll Cardiol: 27 Jul 2020; 76:435-450
Marquis-Gravel G, Moliterno DJ, Francis DP, Jüni P, ... Zannad F, Goodman SG
J Am Coll Cardiol: 27 Jul 2020; 76:435-450 | PMID: 32703515
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Abstract

Atherosclerotic Cardiovascular Disease Risk Stratification Based on Measurements of Troponin and Coronary Artery Calcium.

Sandoval Y, Bielinski SJ, Daniels LB, Blaha MJ, ... Decker PA, Jaffe AS
Background
Low values of high-sensitivity cardiac troponin (hs-cTn) and coronary artery calcium (CAC) scores of zero are associated with a low risk for atherosclerotic cardiovascular disease (ASCVD).
Objectives
The purpose of this study was to evaluate baseline hs-cTnT and CAC in relation to ASCVD.
Methods
Baseline hs-cTnT (limit of detection [LoD] 3 ng/l) and CAC measurements were analyzed across participants age 45 to 84 years without clinical cardiovascular disease from the prospective MESA (Multi-Ethnic Study of Atherosclerosis) in relationship to incident ASCVD.
Results
Among 6,749 participants, 1,002 ASCVD events occurred during a median follow-up of 15 years. Participants with detectable CAC (20.1 vs. 5.0 events per 1,000 person-years; adjusted hazard ratio [HR]: 2.35; 95% confidence interval [CI]: 2.0 to 2.76; p < 0.001) and detectable hs-cTnT (15.4 vs. 5.2 per 1,000 person-years; adjusted HR: 1.47; 95% CI: 1.21 to 1.77; p < 0.001) had higher rates of ASCVD than those with undetectable results. Individuals with undetectable hs-cTnT (32%) had similar risk for ASCVD as did those with a CAC of zero (50%) (5.2 vs. 5.0 per 1,000 person-years). Together, hs-cTnT and CAC (discordance 38%) resulted in the following ASCVD event rates: hs-cTnT < LoD/CAC = 0: 2.8 per 1,000 person-years (reference), hs-cTnT ≥ LoD/CAC = 0: 6.8 per 1,000 person-years (HR: 1.59; 95% CI: 1.17 to 2.16; p = 0.003), hs-cTnT < LoD/CAC > 0: 11.1 per 1,000 person-years (HR: 2.74; 95% CI: 1.96 to 3.83; p < 0.00001), and hs-cTnT ≥ LoD/CAC > 0: 22.6 per 1,000 person-years (HR: 3.50; 95% CI: 2.60 to 4.70; p < 0.00001).
Conclusions
An undetectable hs-cTnT identifies patients with a similar, low risk for ASCVD as those with a CAC score of zero. The increased risk among those with discordant results supports their conjoined use for risk prediction.

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

J Am Coll Cardiol: 27 Jul 2020; 76:357-370
Sandoval Y, Bielinski SJ, Daniels LB, Blaha MJ, ... Decker PA, Jaffe AS
J Am Coll Cardiol: 27 Jul 2020; 76:357-370 | PMID: 32703505
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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

Single-Dose Nirsevimab for Prevention of RSV in Preterm Infants.

Griffin MP, Yuan Y, Takas T, Domachowske JB, ... DeVincenzo JP,
Background
Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infection in infants, and a need exists for prevention of RSV in healthy infants. Nirsevimab is a monoclonal antibody with an extended half-life that is being developed to protect infants for an entire RSV season with a single intramuscular dose.
Methods
In this trial conducted in both northern and southern hemispheres, we evaluated nirsevimab for the prevention of RSV-associated lower respiratory tract infection in healthy infants who had been born preterm (29 weeks 0 days to 34 weeks 6 days of gestation). We randomly assigned the infants in a 2:1 ratio to receive nirsevimab, at a dose of 50 mg in a single intramuscular injection, or placebo at the start of an RSV season. The primary end point was medically attended RSV-associated lower respiratory tract infection through 150 days after administration of the dose. The secondary efficacy end point was hospitalization for RSV-associated lower respiratory tract infection through 150 days after administration of the dose.
Results
From November 2016 through November 2017, a total of 1453 infants were randomly assigned to receive nirsevimab (969 infants) or placebo (484 infants) at the start of the RSV season. The incidence of medically attended RSV-associated lower respiratory tract infection was 70.1% lower (95% confidence interval [CI], 52.3 to 81.2) with nirsevimab prophylaxis than with placebo (2.6% [25 infants] vs. 9.5% [46 infants]; P<0.001) and the incidence of hospitalization for RSV-associated lower respiratory tract infection was 78.4% lower (95% CI, 51.9 to 90.3) with nirsevimab than with placebo (0.8% [8 infants] vs. 4.1% [20 infants]; P<0.001). These differences were consistent throughout the 150-day period after the dose was administered and across geographic locations and RSV subtypes. Adverse events were similar in the two trial groups, with no notable hypersensitivity reactions.
Conclusions
A single injection of nirsevimab resulted in fewer medically attended RSV-associated lower respiratory tract infections and hospitalizations than placebo throughout the RSV season in healthy preterm infants. (Funded by AstraZeneca and Sanofi Pasteur; ClinicalTrials.gov number, NCT02878330.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 29 Jul 2020; 383:415-425
Griffin MP, Yuan Y, Takas T, Domachowske JB, ... DeVincenzo JP,
N Engl J Med: 29 Jul 2020; 383:415-425 | PMID: 32726528
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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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Impact:
Abstract

Pregnancy-associated arterial dissections: a nationwide cohort study.

Beyer SE, Dicks AB, Shainker SA, Feinberg L, ... Secemsky EA, Carroll BJ
Aims
Pregnancy is a known risk factor for arterial dissection, which can result in significant morbidity and mortality in the peripartum period. However, little is known about the risk factors, timing, distribution, and outcomes of arterial dissections associated with pregnancy.
Methods and results
We included all women ≥12 years of age with hospitalizations associated with pregnancy and/or delivery in the Nationwide Readmissions Database between 2010 and 2015. The primary outcome was any dissection during pregnancy, delivery, or the postpartum period (42-days post-delivery). Secondary outcomes included timing of dissection, location of dissection, and in-hospital mortality. Among 18 151  897 pregnant patients, 993 (0.005%) patients were diagnosed with a pregnancy-related dissection. Risk factors included older age (32.8 vs. 28.0 years), multiple gestation (3.6% vs. 1.9%), gestational diabetes (14.3% vs. 0.2%), gestational hypertension (6.0% vs. 0.6%), and pre-eclampsia/eclampsia (2.7% vs. 0.4%), in addition to traditional cardiovascular risk factors. Of the 993 patients with dissection, 150 (15.1%) dissections occurred in the antepartum period, 232 (23.4%) were diagnosed during the admission for delivery, and 611 (61.5%) were diagnosed in the postpartum period. The most common locations for dissections were coronary (38.2%), vertebral (22.9%), aortic (19.8%), and carotid (19.5%). In-hospital mortality was 3.7% among pregnant patients with a dissection vs. <0.001% in patients without a dissection. Deaths were isolated to patients with an aortic (8.6%), coronary (4.2%), or supra-aortic (<2.5%) dissection.
Conclusion
Arterial dissections occurred in 5.5/100 000 hospitalized pregnant or postpartum women, most frequently in the postpartum period, and were associated with high mortality risk. The coronary arteries were most commonly involved. Pregnancy-related dissections were associated with traditional risk factors, as well as pregnancy-specific conditions.

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
Beyer SE, Dicks AB, Shainker SA, Feinberg L, ... Secemsky EA, Carroll BJ
Eur Heart J: 29 Jul 2020; epub ahead of print | PMID: 32728725
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Impact:
Abstract

Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19.

Cavalcanti AB, Zampieri FG, Rosa RG, Azevedo LCP, ... Berwanger O,
Background
Hydroxychloroquine and azithromycin have been used to treat patients with coronavirus disease 2019 (Covid-19). However, evidence on the safety and efficacy of these therapies is limited.
Methods
We conducted a multicenter, randomized, open-label, three-group, controlled trial involving hospitalized patients with suspected or confirmed Covid-19 who were receiving either no supplemental oxygen or a maximum of 4 liters per minute of supplemental oxygen. Patients were randomly assigned in a 1:1:1 ratio to receive standard care, standard care plus hydroxychloroquine at a dose of 400 mg twice daily, or standard care plus hydroxychloroquine at a dose of 400 mg twice daily plus azithromycin at a dose of 500 mg once daily for 7 days. The primary outcome was clinical status at 15 days as assessed with the use of a seven-level ordinal scale (with levels ranging from one to seven and higher scores indicating a worse condition) in the modified intention-to-treat population (patients with a confirmed diagnosis of Covid-19). Safety was also assessed.
Results
A total of 667 patients underwent randomization; 504 patients had confirmed Covid-19 and were included in the modified intention-to-treat analysis. As compared with standard care, the proportional odds of having a higher score on the seven-point ordinal scale at 15 days was not affected by either hydroxychloroquine alone (odds ratio, 1.21; 95% confidence interval [CI], 0.69 to 2.11; P = 1.00) or hydroxychloroquine plus azithromycin (odds ratio, 0.99; 95% CI, 0.57 to 1.73; P = 1.00). Prolongation of the corrected QT interval and elevation of liver-enzyme levels were more frequent in patients receiving hydroxychloroquine, alone or with azithromycin, than in those who were not receiving either agent.
Conclusions
Among patients hospitalized with mild-to-moderate Covid-19, the use of hydroxychloroquine, alone or with azithromycin, did not improve clinical status at 15 days as compared with standard care. (Funded by the Coalition Covid-19 Brazil and EMS Pharma; ClinicalTrials.gov number, NCT04322123.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 22 Jul 2020; epub ahead of print
Cavalcanti AB, Zampieri FG, Rosa RG, Azevedo LCP, ... Berwanger O,
N Engl J Med: 22 Jul 2020; epub ahead of print | PMID: 32706953
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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

Phase 1 Trial of a Therapeutic Anti-Yellow Fever Virus Human Antibody.

Low JG, Ng JHJ, Ong EZ, Kalimuddin S, ... Sasisekharan R, Ooi EE
Background
Insufficient vaccine doses and the lack of therapeutic agents for yellow fever put global health at risk, should this virus emerge from sub-Saharan Africa and South America.
Methods
In phase 1a of this clinical trial, we assessed the safety, side-effect profile, and pharmacokinetics of TY014, a fully human IgG1 anti-yellow fever virus monoclonal antibody. In a double-blind, phase 1b clinical trial, we assessed the efficacy of TY014, as compared with placebo, in abrogating viremia related to the administration of live yellow fever vaccine (YF17D-204; Stamaril). The primary safety outcomes were adverse events reported 1 hour after the infusion and throughout the trial. The primary efficacy outcome was the dose of TY014 at which 100% of the participants tested negative for viremia within 48 hours after infusion.
Results
A total of 27 healthy participants were enrolled in phase 1a, and 10 participants in phase 1b. During phase 1a, TY014 dose escalation to a maximum of 20 mg per kilogram of body weight occurred in 22 participants. During phases 1a and 1b, adverse events within 1 hour after infusion occurred in 1 of 27 participants who received TY014 and in none of the 10 participants who received placebo. At least one adverse event occurred during the trial in 22 participants who received TY014 and in 8 who received placebo. The mean half-life of TY014 was approximately 12.8 days. At 48 hours after the infusion, none of the 5 participants who received the starting dose of TY014 of 2 mg per kilogram had detectable YF17D-204 viremia; these participants remained aviremic throughout the trial. Viremia was observed at 48 hours after the infusion in 2 of 5 participants who received placebo and at 72 hours in 2 more placebo recipients. Symptoms associated with yellow fever vaccine were less frequent in the TY014 group than in the placebo group.
Conclusions
This phase 1 trial of TY014 did not identify worrisome safety signals and suggested potential clinical benefit, which requires further assessment in a phase 2 trial. (Funded by Tysana; ClinicalTrials.gov number, NCT03776786.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 29 Jul 2020; 383:452-459
Low JG, Ng JHJ, Ong EZ, Kalimuddin S, ... Sasisekharan R, Ooi EE
N Engl J Med: 29 Jul 2020; 383:452-459 | PMID: 32726531
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Abstract

Uterine-Artery Embolization or Myomectomy for Uterine Fibroids.

Manyonda I, Belli AM, Lumsden MA, Moss J, ... McPherson K,
Background
Uterine fibroids, the most common type of tumor among women of reproductive age, are associated with heavy menstrual bleeding, abdominal discomfort, subfertility, and a reduced quality of life. For women who wish to preserve their uterus and who have not had a response to medical treatment, myomectomy and uterine-artery embolization are therapeutic options.
Methods
We conducted a multicenter, randomized, open-label trial to evaluate myomectomy, as compared with uterine-artery embolization, in women who had symptomatic uterine fibroids and did not want to undergo hysterectomy. Procedural options included open abdominal, laparoscopic, or hysteroscopic myomectomy. The primary outcome was fibroid-related quality of life, as assessed by the score on the health-related quality-of-life domain of the Uterine Fibroid Symptom and Quality of Life (UFS-QOL) questionnaire (scores range from 0 to 100, with higher scores indicating a better quality of life) at 2 years; adjustment was made for the baseline score.
Results
A total of 254 women, recruited at 29 hospitals in the United Kingdom, were randomly assigned: 127 to the myomectomy group (of whom 105 underwent myomectomy) and 127 to the uterine-artery embolization group (of whom 98 underwent embolization). Data on the primary outcome were available for 206 women (81%). In the intention-to-treat analysis, the mean (±SD) score on the health-related quality-of-life domain of the UFS-QOL questionnaire at 2 years was 84.6±21.5 in the myomectomy group and 80.0±22.0 in the uterine-artery embolization group (mean adjusted difference with complete case analysis, 8.0 points; 95% confidence interval [CI], 1.8 to 14.1; P = 0.01; mean adjusted difference with missing responses imputed, 6.5 points; 95% CI, 1.1 to 11.9). Perioperative and postoperative complications from all initial procedures, irrespective of adherence to the assigned procedure, occurred in 29% of the women in the myomectomy group and in 24% of the women in the uterine-artery embolization group.
Conclusions
Among women with symptomatic uterine fibroids, those who underwent myomectomy had a better fibroid-related quality of life at 2 years than those who underwent uterine-artery embolization. (Funded by the National Institute for Health Research Health Technology Assessment program; FEMME Current Controlled Trials number, ISRCTN70772394.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 29 Jul 2020; 383:440-451
Manyonda I, Belli AM, Lumsden MA, Moss J, ... McPherson K,
N Engl J Med: 29 Jul 2020; 383:440-451 | PMID: 32726530
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Abstract

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

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

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

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

Respiratory Syncytial Virus Vaccination during Pregnancy and Effects in Infants.

Madhi SA, Polack FP, Piedra PA, Munoz FM, ... Fries LF,
Background
Respiratory syncytial virus (RSV) is the dominant cause of severe lower respiratory tract infection in infants, with the most severe cases concentrated among younger infants.
Methods
Healthy pregnant women, at 28 weeks 0 days through 36 weeks 0 days of gestation, with an expected delivery date near the start of the RSV season, were randomly assigned in an overall ratio of approximately 2:1 to receive a single intramuscular dose of RSV fusion (F) protein nanoparticle vaccine or placebo. Infants were followed for 180 days to assess outcomes related to lower respiratory tract infection and for 364 days to assess safety. The primary end point was RSV-associated, medically significant lower respiratory tract infection up to 90 days of life, and the primary analysis of vaccine efficacy against the primary end point was performed in the per-protocol population of infants (prespecified criterion for success, lower bound of the 97.52% confidence interval [CI] of ≥30%).
Results
A total of 4636 women underwent randomization, and there were 4579 live births. During the first 90 days of life, the percentage of infants with RSV-associated, medically significant lower respiratory tract infection was 1.5% in the vaccine group and 2.4% in the placebo group (vaccine efficacy, 39.4%; 97.52% CI, -1.0 to 63.7; 95% CI, 5.3 to 61.2). The corresponding percentages for RSV-associated lower respiratory tract infection with severe hypoxemia were 0.5% and 1.0% (vaccine efficacy, 48.3%; 95% CI, -8.2 to 75.3), and the percentages for hospitalization for RSV-associated lower respiratory tract infection were 2.1% and 3.7% (vaccine efficacy, 44.4%; 95% CI, 19.6 to 61.5). Local injection-site reactions among the women were more common with vaccine than with placebo (40.7% vs. 9.9%), but the percentages of participants who had other adverse events were similar in the two groups.
Conclusions
RSV F protein nanoparticle vaccination in pregnant women did not meet the prespecified success criterion for efficacy against RSV-associated, medically significant lower respiratory tract infection in infants up to 90 days of life. The suggestion of a possible benefit with respect to other end-point events involving RSV-associated respiratory disease in infants warrants further study. (Funded by Novavax and the Bill and Melinda Gates Foundation; ClinicalTrials.gov NCT02624947.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 29 Jul 2020; 383:426-439
Madhi SA, Polack FP, Piedra PA, Munoz FM, ... Fries LF,
N Engl J Med: 29 Jul 2020; 383:426-439 | PMID: 32726529
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Abstract

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

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

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

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

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

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

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

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

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

Multimodality Imaging in Evaluation of Cardiovascular complications in Patients with COVID-19.

Rudski L, Januzzi JL, Rigolin VH, Bohula EA, ... Villines TC, Di Carli MF

Standard evaluation and management of the patient with suspected or proven cardiovascular complications of COVID-19, the disease caused by severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2), is challenging. Routine history, physical examination, laboratory testing, electrocardiography and plain x-ray imaging may often suffice for such patients but given overlap between COVID-19 and typical cardiovascular diagnoses such as heart failure and acute myocardial infarction, need frequently arises for advanced imaging techniques to assist in differential diagnosis and management. This document provides guidance in several common scenarios among patients with confirmed or suspected COVID-19 infection and possible cardiovascular involvement, including chest discomfort with electrocardiographic changes, acute hemodynamic instability, newly-recognized left ventricular dysfunction, as well as imaging during the sub-acute/chronic phase of COVID-19. For each, we consider the role of biomarker testing to guide imaging decision-making, provide differential diagnostic considerations, and offer general suggestions regarding application of various advanced imaging techniques. CONDENSED ABSTRACT: Standard evaluation and management of the patient with suspected or proven cardiovascular complications due to COVID-19 infection often requires advanced imaging techniques to assist in differential diagnosis and management. This document provides guidance in several common scenarios among patients with COVID-19 infection and for each provides advice regarding the role of biomarker testing to guide imaging decision-making, provides differential diagnostic considerations, and offers general suggestions regarding application of various advanced imaging techniques.

Copyright © 2020. Published by Elsevier Inc.

J Am Coll Cardiol: 19 Jul 2020; epub ahead of print
Rudski L, Januzzi JL, Rigolin VH, Bohula EA, ... Villines TC, Di Carli MF
J Am Coll Cardiol: 19 Jul 2020; epub ahead of print | PMID: 32710927
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Abstract

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

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

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

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

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

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

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

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

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

Dapagliflozin and Diuretic Use in Patients with Heart Failure and Reduced Ejection Fraction in DAPA-HF.

Jackson AM, Dewan P, Anand IS, Bělohlávek J, ... Jhund PS, McMurray JJV

In the DAPA-HF trial, the SGLT2 inhibitor dapagliflozin reduced the risk of worsening heart failure and death in patients with heart failure and reduced ejection fraction. We examined efficacy and tolerability of dapagliflozin in relation to background diuretic treatment and change in diuretic therapy following randomization to dapagliflozin or placebo.We examined the effects of study treatment in the following subgroups: no diuretic, diuretic dose equivalent to furosemide <40mg daily, 40mg daily and >40mg daily at baseline. We examined the primary composite endpoint of cardiovascular (CV) death or a worsening HF event, its components, all-cause death and symptoms.Of 4616 analyzable patients, 736 (15.9%) were on no diuretic, 1311 (28.4%) were on <40mg, 1365 (29.6%) on 40 mg and 1204 (26.1%) of patients were taking >40 mg. Compared with placebo, dapagliflozin reduced the risk of the primary endpoint across each of these subgroups: hazard ratio [HR]: 0.57 (95% CI 0.36-0.92), 0.83 (0.63-1.10), 0.77 (0.60-0.99) and 0.78 (0.63-0.97), respectively (P-interaction 0.61). The HR in patients taking any diuretic was 0.78 (0.68-0.90). Improvement in symptoms and treatment toleration was consistent across the diuretic subgroups. Diuretic dose did not change in most patients during follow-up and mean diuretic dose did not differ between the dapagliflozin and placebo group after randomization.The efficacy and safety of dapagliflozin was consistent across the diuretic subgroups examined in DAPA-HF.DAPA-HF: ClinicalTrials.gov Identifier NCT03036124.



Circulation: 15 Jul 2020; epub ahead of print
Jackson AM, Dewan P, Anand IS, Bělohlávek J, ... Jhund PS, McMurray JJV
Circulation: 15 Jul 2020; epub ahead of print | PMID: 32673497
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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

Dexmedetomidine for reduction of atrial fibrillation and delirium after cardiac surgery (DECADE): a randomised placebo-controlled trial.

Turan A, Duncan A, Leung S, Karimi N, ... Sessler DI,
Background
Atrial fibrillation and delirium are common consequences of cardiac surgery. Dexmedetomidine has unique properties as sedative agent and might reduce the risk of each complication. This study coprimarily aimed to establish whether dexmedetomidine reduces the incidence of new-onset atrial fibrillation and the incidence of delirium.
Methods
A randomised, placebo-controlled trial was done at six academic hospitals in the USA. Patients who had had cardiac surgery with cardiopulmonary bypass were enrolled. Patients were randomly assigned 1:1, stratified by site, to dexmedetomidine or normal saline placebo. Randomisation was computer generated with random permuted block size 2 and 4, and allocation was concealed by a web-based system. Patients, caregivers, and evaluators were all masked to treatment. The study drug was prepared by the pharmacy or an otherwise uninvolved research associate so that investigators and clinicians were fully masked to allocation. Participants were given either dexmedetomidine infusion or saline placebo started before the surgical incision at a rate of 0·1 μg/kg per h then increased to 0·2 μg/kg per h at the end of bypass, and postoperatively increased to 0·4 μg/kg per h, which was maintained until 24 h. The coprimary outcomes were atrial fibrillation and delirium occurring between intensive care unit admission and the earlier of postoperative day 5 or hospital discharge. All analyses were intention-to-treat. The trial is registered with ClinicalTrials.gov, NCT02004613 and is closed.
Findings
798 patients of 3357 screened were enrolled from April 17, 2013, to Dec 6, 2018. The trial was stopped per protocol after the last designated interim analysis. Among 798 patients randomly assigned, 794 were analysed, with 400 assigned to dexmedetomidine and 398 assigned to placebo. The incidence of atrial fibrillation was 121 (30%) in 397 patients given dexmedetomidine and 134 (34%) in 395 patients given placebo, a difference that was not significant: relative risk 0·90 (97·8% CI 0·72, 1·15; p=0·34). The incidence of delirium was non-significantly increased from 12% in patients given placebo to 17% in those given dexmedetomidine: 1·48 (97·8% CI 0·99-2·23). Safety outcomes were clinically important bradycardia (requiring treatment) and hypotension, myocardial infarction, stroke, surgical site infection, pulmonary embolism, deep venous thrombosis, and death. 21 (5%) of 394 patients given dexmedetomidine and 8 (2%) of 396 patients given placebo, had a serious adverse event as determined by clinicians. 1 (<1%) of 391 patients given dexmedetomidine and 1 (<1%) of 387 patients given placebo died.
Interpretation
Dexmedetomidine infusion, initiated at anaesthetic induction and continued for 24 h, did not decrease postoperative atrial arrhythmias or delirium in patients recovering from cardiac surgery. Dexmedetomidine should not be infused to reduce atrial fibrillation or delirium in patients having cardiac surgery.
Funding
Hospira Pharmaceuticals.

Copyright © 2020 Elsevier Ltd. All rights reserved.

Lancet: 17 Jul 2020; 396:177-185
Turan A, Duncan A, Leung S, Karimi N, ... Sessler DI,
Lancet: 17 Jul 2020; 396:177-185 | PMID: 32682483
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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

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

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

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

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

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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Abstract

Identification of The Long Non-Coding RNA H19 as a New Biomarker and Therapeutic Target in Right Ventricular Failure in Pulmonary Arterial Hypertension.

Omura J, Habbout K, Shimauchi T, Wu WH, ... Boucherat O, Bonnet S

Right ventricular (RV) function is the major determinant for both functional capacity and survival in patients with pulmonary arterial hypertension (PAH). Despite the recognized clinical importance of preserving RV function, the subcellular mechanisms that govern the transition from a compensated to a decompensated state remain poorly understood and as a consequence there are no clinically established treatments for RV failure and a paucity of clinically useful biomarkers. Accumulating evidence indicates that long non-coding RNAs (lncRNAs) are powerful regulators of cardiac development and disease. Nonetheless, their implication in adverse RV remodeling in PAH is unknown.Expression of the lncRNA H19 was assessed by quantitative PCR in plasma and RV from patients categorized as control RV, compensated RV (cRV) or decompensated RV (dRV) based on clinical history and cardiac index. The impact of H19 suppression using GapmeR was explored in two rat models mimicking RV failure, namely the monocrotaline (MCT) and pulmonary artery banding (PAB). Echocardiographic, hemodynamic, histological and biochemical analyses were conducted.gain- and loss-of-function experiments were performed in rat cardiomyocytes.We demonstrated that H19 is up-regulated in dRV from PAH patients and correlates with RV hypertrophy and fibrosis. Similar findings were observed in MCT and PAB rats. We found that silencing H19 limits pathological RV hypertrophy, fibrosis and capillary rarefaction, thus preserving RV function in MCT and PAB rats without affecting pulmonary vascular remodeling. This cardioprotective effect was accompanied by E2F transcription factor 1-mediated up-regulation of enhancer of zeste homolog 2. , knockdown of H19 suppressed cardiomyocyte hypertrophy induced by phenylephrine, while its overexpression has the opposite effect. Finally, we demonstrated that circulating H19 levels in plasma discriminate PAH patients from controls, correlate with RV function and predict long-term survival in two independent idiopathic PAH cohorts. Moreover, H19 levels delineate subgroups of patients with differentiated prognosis when combined with the NT-proBNP levels or the risk score proposed by both REVEAL and the 2015 European pulmonary hypertension guidelines.Our findings identify H19 as a new therapeutic target to impede the development of maladaptive RV remodeling and a promising biomarker of PAH severity and prognosis.



Circulation: 22 Jul 2020; epub ahead of print
Omura J, Habbout K, Shimauchi T, Wu WH, ... Boucherat O, Bonnet S
Circulation: 22 Jul 2020; epub ahead of print | PMID: 32698630
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Abstract

Cardiorespiratory Fitness in Youth: An Important Marker of Health: A Scientific Statement From the American Heart Association.

Raghuveer G, Hartz J, Lubans DR, Takken T, ... Edwards NM,

Cardiorespiratory fitness (CRF) refers to the capacity of the circulatory and respiratory systems to supply oxygen to skeletal muscle mitochondria for energy production needed during physical activity. CRF is an important marker of physical and mental health and academic achievement in youth. However, only 40% of US youth are currently believed to have healthy CRF. In this statement, we review the physiological principles that determine CRF, the tools that are available to assess CRF, the modifiable and nonmodifiable factors influencing CRF, the association of CRF with markers of health in otherwise healthy youth, and the temporal trends in CRF both in the United States and internationally. Development of a cost-effective CRF measurement process that could readily be incorporated into office visits and in field settings to screen all youth periodically could help identify those at increased risk.



Circulation: 19 Jul 2020:CIR0000000000000866; epub ahead of print
Raghuveer G, Hartz J, Lubans DR, Takken T, ... Edwards NM,
Circulation: 19 Jul 2020:CIR0000000000000866; epub ahead of print | PMID: 32686505
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Abstract

The Expected 30-year Benefits of Early Versus Delayed Primary Prevention of Cardiovascular Disease by Lipid Lowering.

Pencina M, Pencina K, Lloyd-Jones D, Catapano AL, Thanassoulis G, Sniderman AD

Current lipid-lowering recommendations for prevention of atherosclerotic cardiovascular disease rely principally on estimated 10-year risk. We sought to determine the optimal time for initiation of lipid-lowering in younger adults as a function of expected 30-year benefit.Data from 3148 NHANES (2009-2016) participants age 30-59 years, not eligible for lipid-lowering treatment recommendation under the most recent US guidelines, were analysed. We estimated the absolute and relative impact of lipid-lowering as a function of age, age of initiation and non-HDL cholesterol on the expected rates of atherosclerotic cardiovascular disease over the succeeding 30 years. We modeled expected risk reductions based on shorterterm effects observed in statin trials (model A) and longer-term benefits based on Mendelian randomization studies (model B).For both models, potential reductions in predicted 30-year atherosclerotic cardiovascular disease risk were greater in older age and higher non-HDL cholesterol. Immediate initiation of lipid lowering (i.e. treatment for full 30 years) in 40-49-year-olds with non-HDLcholesterol ≥160 mg/dL would be expected to reduce their average predicted 30-year risk of 17.1% to 11.6% (model A; absolute risk reduction, ARR 5.5%) or 6.5% (model B; ARR 10.6%). Delaying lipid lowering by 10 years (treatment for 20 years) would result in residual 30-year risk of 12.7% (A; ARR 4.4) or 9.9% (B; ARR 7.2%) and delaying by 20 years (treatment for 10 years) would lead to expected mean residual risk of 14.6 (A; ARR 2.6%) or 13.9% (B; ARR 3.2%). The slope of the achieved absolute risk reduction as a function of delay in treatment was also higher in older age and higher non-HDL cholesterol.Substantial reduction in expected atherosclerotic cardiovascular disease risk in the next 30 years is achievable by intensive lipid-lowering in individuals in their 40s and 50s, with non-HDL cholesterol ≥160 mg/dL. For many, the question of \"when\" to start lipid-lowering might be more relevant than \"if\".



Circulation: 22 Jul 2020; epub ahead of print
Pencina M, Pencina K, Lloyd-Jones D, Catapano AL, Thanassoulis G, Sniderman AD
Circulation: 22 Jul 2020; epub ahead of print | PMID: 32700572
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Abstract

Cardiovascular End Points and Mortality Are Not Closer Associated With Central Than Peripheral Pulsatile Blood Pressure Components.

Huang QF, Aparicio LS, Thijs L, Wei FF, ... Staessen JA,

Pulsatile blood pressure (BP) confers cardiovascular risk. Whether associations of cardiovascular end points are tighter for central systolic BP (cSBP) than peripheral systolic BP (pSBP) or central pulse pressure (cPP) than peripheral pulse pressure (pPP) is uncertain. Among 5608 participants (54.1% women; mean age, 54.2 years) enrolled in nine studies, median follow-up was 4.1 years. cSBP and cPP, estimated tonometrically from the radial waveform, averaged 123.7 and 42.5 mm Hg, and pSBP and pPP 134.1 and 53.9 mm Hg. The primary composite cardiovascular end point occurred in 255 participants (4.5%). Across fourths of the cPP distribution, rates increased exponentially (4.1, 5.0, 7.3, and 22.0 per 1000 person-years) with comparable estimates for cSBP, pSBP, and pPP. The multivariable-adjusted hazard ratios, expressing the risk per 1-SD increment in BP, were 1.50 (95% CI, 1.33-1.70) for cSBP, 1.36 (95% CI, 1.19-1.54) for cPP, 1.49 (95% CI, 1.33-1.67) for pSBP, and 1.34 (95% CI, 1.19-1.51) for pPP (<0.001). Further adjustment of cSBP and cPP, respectively, for pSBP and pPP, and vice versa, removed the significance of all hazard ratios. Adding cSBP, cPP, pSBP, pPP to a base model including covariables increased the model fit (<0.001) with generalizedincrements ranging from 0.37% to 0.74% but adding a second BP to a model including already one did not. Analyses of the secondary end points, including total mortality (204 deaths), coronary end points (109) and strokes (89), and various sensitivity analyses produced consistent results. In conclusion, associations of the primary and secondary end points with SBP and pulse pressure were not stronger if BP was measured centrally compared with peripherally.



Hypertension: 30 Jul 2020; 76:350-358
Huang QF, Aparicio LS, Thijs L, Wei FF, ... Staessen JA,
Hypertension: 30 Jul 2020; 76:350-358 | PMID: 32639894
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Impact:
Abstract

Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma (CANDOR): results from a randomised, multicentre, open-label, phase 3 study.

Dimopoulos M, Quach H, Mateos MV, Landgren O, ... Zahlten-Kumeli A, Usmani SZ
Background
Lenalidomide and bortezomib frontline exposure has raised a growing need for novel treatments for patients with relapsed or refractory multiple myeloma. Carfilzomib in combination with daratumumab has shown substantial efficacy with tolerable safety in relapsed or refractory multiple myeloma in a phase 1 study. In this study, we aimed to compare the efficacy and safety of carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma.
Methods
In this randomised, multicentre, open-label, phase 3 study, 466 patients recruited from 102 sites across North America, Europe, Australia, and Asia with relapsed or refractory multiple myeloma were randomly assigned 2:1 to carfilzomib, dexamethasone, and daratumumab (KdD) or carfilzomib and dexamethasone (Kd). All patients received twice per week carfilzomib at 56 mg/m (20 mg/m; days 1 and 2 during cycle 1). Daratumumab (8 mg/kg) was administered intravenously on days 1 and 2 of cycle 1 and at 16 mg/kg weekly for the remaining doses of the first two cycles, then every 2 weeks for four cycles (cycles 3-6), and every 4 weeks thereafter. Patients received 40 mg dexamethasone weekly (20 mg for patients ≥75 years old starting on the second week). The primary endpoint was progression-free survival assessed by intention to treat. Adverse events were assessed in the safety population. This trial (NCT03158688) is registered with ClinicalTrials.gov, and is active but not recruiting.
Findings
Between June 13, 2017, and June 25, 2018, 466 patients of 569 assessed for eligibility were enrolled. After median follow-up of approximately 17 months, median progression-free survival was not reached in the KdD group versus 15·8 months in the Kd group (hazard ratio 0·63; 95% CI 0·46-0·85; p=0·0027). Median treatment duration was longer in the KdD versus the Kd group (70·1 vs 40·3 weeks). Grade 3 or higher adverse events were reported in 253 (82%) patients in the KdD group and 113 (74%) patients in the Kd group. The frequency of adverse events leading to treatment discontinuation was similar in both groups (KdD, 69 [22%]; Kd, 38 [25%]).
Interpretation
KdD significantly prolonged progression-free survival versus Kd in patients with relapsed or refractory multiple myeloma and was associated with a favourable benefit-risk profile.
Funding
Amgen.

Copyright © 2020 Elsevier Ltd. All rights reserved.

Lancet: 17 Jul 2020; 396:186-197
Dimopoulos M, Quach H, Mateos MV, Landgren O, ... Zahlten-Kumeli A, Usmani SZ
Lancet: 17 Jul 2020; 396:186-197 | PMID: 32682484
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Impact:
Abstract

Markers of Myocardial Stress, Myocardial Injury, and Subclinical Inflammation and the Risk of Sudden Death.

Everett BM, Moorthy MV, Tikkanen JT, Cook NR, Albert CM

The majority of sudden cardiac deaths (SCD) occur in low risk populations often as the first manifestation of cardiovascular disease (CVD). Biomarkers are screening tools that may identify subclinical CVD and those at elevated risk for SCD. We sought to determine whether the total to high-density lipoprotein cholesterol ratio (TC:HDL), cardiac troponin I (hsTnI), B-type natriuretic peptide (NT-proBNP), or C-reactive protein (hsCRP) individually or in combination could identify individuals at higher SCD risk in large, free-living populations with and without CVD.We performed a nested case-control study within 6 prospective cohort studies utilizing 565 SCD cases matched to 1090 controls (1:2) by age, sex, ethnicity, smoking status, and presence of CVD.The median study follow-up time until SCD was 11.3 years. When examined as quartiles or continuous variables in conditional logistic regression models, each of the biomarkers was significantly and independently associated with SCD risk after mutually controlling for cardiac risk factors and other biomarkers. The mutually adjusted odds ratios (95% CI) for the top compared to the bottom quartile were 1.90 (1.30-2.76) for TC:HDL, 2.59 (1.76-3.83) for hsTnI, 1.65 (1.12 -2.44) for NT-proBNP, and 1.65 (1. 13 -2.41) for hsCRP. A biomarker score that awarded one point when the concentration of any of those four biomarkers was in the top quartile (score range, 0-4) was strongly associated with SCD, with an adjusted OR (95% CI) of 1.56 (1.37-1.77) per 1 unit increase in the score.Widely available measures of lipids, subclinical myocardial injury, myocardial strain, and vascular inflammation show significant independent associations with SCD risk in apparently low risk populations. In combination these measures may have utility to identify individuals at risk for SCD.



Circulation: 22 Jul 2020; epub ahead of print
Everett BM, Moorthy MV, Tikkanen JT, Cook NR, Albert CM
Circulation: 22 Jul 2020; epub ahead of print | PMID: 32700639
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Impact:
Abstract

Histopathology and ultrastructural findings of fatal COVID-19 infections in Washington State: a case series.

Bradley BT, Maioli H, Johnston R, Chaudhry I, ... Yarid N, Marshall DA
Background
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of an ongoing pandemic, with increasing deaths worldwide. To date, documentation of the histopathological features in fatal cases of the disease caused by SARS-CoV-2 (COVID-19) has been scarce due to sparse autopsy performance and incomplete organ sampling. We aimed to provide a clinicopathological report of severe COVID-19 cases by documenting histopathological changes and evidence of SARS-CoV-2 tissue tropism.
Methods
In this case series, patients with a positive antemortem or post-mortem SARS-CoV-2 result were considered eligible for enrolment. Post-mortem examinations were done on 14 people who died with COVID-19 at the King County Medical Examiner\'s Office (Seattle, WA, USA) and Snohomish County Medical Examiner\'s Office (Everett, WA, USA) in negative-pressure isolation suites during February and March, 2020. Clinical and laboratory data were reviewed. Tissue examination was done by light microscopy, immunohistochemistry, electron microscopy, and quantitative RT-PCR.
Findings
The median age of our cohort was 73·5 years (range 42-84; IQR 67·5-77·25). All patients had clinically significant comorbidities, the most common being hypertension, chronic kidney disease, obstructive sleep apnoea, and metabolic disease including diabetes and obesity. The major pulmonary finding was diffuse alveolar damage in the acute or organising phases, with five patients showing focal pulmonary microthrombi. Coronavirus-like particles were detected in the respiratory system, kidney, and gastrointestinal tract. Lymphocytic myocarditis was observed in one patient with viral RNA detected in the tissue.
Interpretation
The primary pathology observed in our cohort was diffuse alveolar damage, with virus located in the pneumocytes and tracheal epithelium. Microthrombi, where observed, were scarce and endotheliitis was not identified. Although other non-pulmonary organs showed susceptibility to infection, their contribution to the pathogenesis of SARS-CoV-2 infection requires further examination.
Funding
None.

Copyright © 2020 Elsevier Ltd. All rights reserved.

Lancet: 15 Jul 2020; epub ahead of print
Bradley BT, Maioli H, Johnston R, Chaudhry I, ... Yarid N, Marshall DA
Lancet: 15 Jul 2020; epub ahead of print | PMID: 32682491
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Impact:
Abstract

Temporary circulatory support for cardiogenic shock.

Combes A, Price S, Slutsky AS, Brodie D

Cardiogenic shock can occur due to acute ischaemic or non-ischaemic cardiac events, or from progression of long-standing underlying heart disease. When addressing the cause of underlying disease, the management of cardiogenic shock consists of vasopressors and inotropes; however, these agents can increase myocardial oxygen consumption, impair tissue perfusion, and are frequently ineffective. An alternative approach is to temporarily augment cardiac output using mechanical devices. The use of these devices-known as temporary circulatory support systems-has increased substantially in recent years, despite being expensive, resource intensive, associated with major complications, and lacking high-quality evidence to support their use. This Review summarises the physiological basis underlying the use of temporary circulatory support for cardiogenic shock, reviews the evidence informing indications and contraindications, addresses ethical considerations, and highlights the need for further research.

Copyright © 2020 Elsevier Ltd. All rights reserved.

Lancet: 17 Jul 2020; 396:199-212
Combes A, Price S, Slutsky AS, Brodie D
Lancet: 17 Jul 2020; 396:199-212 | PMID: 32682486
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Impact:
Abstract

Pregnancy-Related Complications in Patients With Fibromuscular Dysplasia: A Report From the European/International Fibromuscular Dysplasia Registry.

Pappaccogli M, Prejbisz A, Ciurică S, Bruno RM, ... Persu A,

Current literature suggests a higher risk of pregnancy-related complications in patients with renal fibromuscular dysplasia (FMD). The aim of our study was to assess the nature and prevalence of pregnancy-related complications in patients subsequently diagnosed with FMD. A call for participation was sent to centers contributing to the European/International FMD Registry. Patients with at least 1 pregnancy were included. Data on pregnancy were collected through medical files and FMD characteristics through the European/International FMD Registry. Data from 534 pregnancies were obtained in 237 patients. Despite the fact that, in 96% of cases, FMD was not diagnosed before pregnancy, 40% of women (n=93) experienced pregnancy-related complications, mostly gestational hypertension (25%) and preterm birth (20%), while preeclampsia was reported in only 7.5%. Only 1 patient experienced arterial dissection and another patient an aneurysm rupture. When compared with patients without pregnancy-related complications, patients with complicated pregnancies were younger at FMD diagnosis (43 versus 51 years old; <0.001) and had a lower prevalence of cerebrovascular FMD (30% versus 52%; =0.003) but underwent more often renal revascularization (63% versus 40%, <0.001). In conclusion, the prevalence of pregnancy-related complications such as gestational hypertension and preterm birth was high in patients with FMD, probably related to the severity of renal FMD. However, the prevalence of preeclampsia and arterial complications was low/moderate. These findings emphasize the need to screen hypertensive women for FMD to ensure revascularization before pregnancy if indicated and appropriate follow-up during pregnancy, without discouraging patients with FMD from considering pregnancy.



Hypertension: 30 Jul 2020; 76:545-553
Pappaccogli M, Prejbisz A, Ciurică S, Bruno RM, ... Persu A,
Hypertension: 30 Jul 2020; 76:545-553 | PMID: 32639884
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Impact:
Abstract

Urgent endoscopic retrograde cholangiopancreatography with sphincterotomy versus conservative treatment in predicted severe acute gallstone pancreatitis (APEC): a multicentre randomised controlled trial.

Schepers NJ, Hallensleben NDL, Besselink MG, Anten MGF, ... Bruno MJ,
Background
It remains unclear whether urgent endoscopic retrograde cholangiopancreatography (ERCP) with biliary sphincterotomy improves the outcome of patients with gallstone pancreatitis without concomitant cholangitis. We did a randomised trial to compare urgent ERCP with sphincterotomy versus conservative treatment in patients with predicted severe acute gallstone pancreatitis.
Methods
In this multicentre, parallel-group, assessor-masked, randomised controlled superiority trial, patients with predicted severe (Acute Physiology and Chronic Health Evaluation II score ≥8, Imrie score ≥3, or C-reactive protein concentration >150 mg/L) gallstone pancreatitis without cholangitis were assessed for eligibility in 26 hospitals in the Netherlands. Patients were randomly assigned (1:1) by a web-based randomisation module with randomly varying block sizes to urgent ERCP with sphincterotomy (within 24 h after hospital presentation) or conservative treatment. The primary endpoint was a composite of mortality or major complications (new-onset persistent organ failure, cholangitis, bacteraemia, pneumonia, pancreatic necrosis, or pancreatic insufficiency) within 6 months of randomisation. Analysis was by intention to treat. This trial is registered with the ISRCTN registry, ISRCTN97372133.
Findings
Between Feb 28, 2013, and March 1, 2017, 232 patients were randomly assigned to urgent ERCP with sphincterotomy (n=118) or conservative treatment (n=114). One patient from each group was excluded from the final analysis because of cholangitis (urgent ERCP group) and chronic pancreatitis (conservative treatment group) at admission. The primary endpoint occurred in 45 (38%) of 117 patients in the urgent ERCP group and in 50 (44%) of 113 patients in the conservative treatment group (risk ratio [RR] 0·87, 95% CI 0·64-1·18; p=0·37). No relevant differences in the individual components of the primary endpoint were recorded between groups, apart from the occurrence of cholangitis (two [2%] of 117 in the urgent ERCP group vs 11 [10%] of 113 in the conservative treatment group; RR 0·18, 95% CI 0·04-0·78; p=0·010). Adverse events were reported in 87 (74%) of 118 patients in the urgent ERCP group versus 91 (80%) of 114 patients in the conservative treatment group.
Interpretation
In patients with predicted severe gallstone pancreatitis but without cholangitis, urgent ERCP with sphincterotomy did not reduce the composite endpoint of major complications or mortality, compared with conservative treatment. Our findings support a conservative strategy in patients with predicted severe acute gallstone pancreatitis with an ERCP indicated only in patients with cholangitis or persistent cholestasis.
Funding
The Netherlands Organization for Health Research and Development, Fonds NutsOhra, and the Dutch Patient Organization for Pancreatic Diseases.

Copyright © 2020 Elsevier Ltd. All rights reserved.

Lancet: 17 Jul 2020; 396:167-176
Schepers NJ, Hallensleben NDL, Besselink MG, Anten MGF, ... Bruno MJ,
Lancet: 17 Jul 2020; 396:167-176 | PMID: 32682482
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Impact:
Abstract

Association of Markers of Microvascular Dysfunction With Prevalent and Incident Depressive Symptoms: The Maastricht Study.

Geraets AFJ, van Agtmaal MJM, Stehouwer CDA, Sörensen BM, ... Schram MT, Houben AJHM

The etiology of late-life depression (LLD) is still poorly understood. Microvascular dysfunction (MVD) has been suggested to play a role in the etiology of LLD, but direct evidence of this association is scarce. The aim of this study was to investigate whether direct and indirect markers of early microvascular dysfunction are associated with prevalent and incident LLD in the population-based Maastricht Study cohort. We measured microvascular dysfunction at baseline by use of flicker light-induced retinal vessel dilation response (Dynamic Vessel Analyzer), heat-induced skin hyperemic response (laser- Doppler flowmetry), and plasma markers of endothelial dysfunction (endothelial dysfunction; sICAM-1 [soluble intercellular adhesion molecule-1], sVCAM-1 [soluble vascular adhesion molecule-1], sE-selectin [soluble E-selectin], and vWF [Von Willebrand Factor]). Depressive symptoms were assessed with the 9-item Patient Health Questionnaire (PHQ-9) at baseline and annually over 4 years of follow-up (n=3029; mean age 59.6±8.2 years, 49.5% were women, n=132 and n=251 with prevalent and incident depressive symptoms [PHQ-9≥10]). We used logistic, negative binominal and Cox regression analyses, and adjusted for demographic, cardiovascular, and lifestyle factors. Retinal venular dilatation and plasma markers of endothelial dysfunction were associated with the more prevalent depressive symptoms after full adjustment (PHQ-9 score, RR, 1.05 [1.00-1.11] and RR 1.06 [1.01-1.11], respectively). Retinal venular dilatation was also associated with prevalent depressive symptoms (PHQ-9≥10; odds ratio, 1.42 [1.09-1.84]), after full adjustment. Retinal arteriolar dilatation and plasma markers of endothelial dysfunction were associated with incident depressive symptoms (PHQ-9≥10; HR, 1.23 [1.04-1.46] and HR, 1.19 [1.05-1.35]), after full adjustment. These findings support the concept that microvascular dysfunction in the retina, and plasma markers of endothelial dysfunction is involved in the etiology of LLD and might help in finding additional targets for the prevention and treatment of LLD.



Hypertension: 30 Jul 2020; 76:342-349
Geraets AFJ, van Agtmaal MJM, Stehouwer CDA, Sörensen BM, ... Schram MT, Houben AJHM
Hypertension: 30 Jul 2020; 76:342-349 | PMID: 32639880
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Impact:
Abstract

Hydroxychloroquine use against SARS-CoV-2 infection in non-human primates.

Maisonnasse P, Guedj J, Contreras V, Behillil S, ... de Lamballerie X, Le Grand R

COVID-19 has rapidly become a pandemic for which no antiviral drug or vaccine is yet available. Several clinical studies are ongoing to evaluate the efficacy of repurposed drugs that have demonstrated antiviral efficacy in vitro. Among these candidates, hydroxychloroquine (HCQ) has been given to thousands of individuals worldwide but definitive evidence for HCQ efficacy in treatment of COVID-19 is still missing. We evaluated the antiviral activity of HCQ both in vitro and in SARS-CoV-2-infected macaques. HCQ showed antiviral activity in African green monkey kidney cells (VeroE6) but not in a model of reconstituted human airway epithelium. In macaques, we tested different treatment strategies in comparison to placebo, before and after peak viral load, alone or in combination with azithromycin (AZTH). Neither HCQ nor HCQ+AZTH showed a significant effect on the viral load levels in any of the tested compartments. When the drug was used as a pre-exposure prophylaxis (PrEP), HCQ did not confer protection against acquisition of infection. Our findings do not support the use of HCQ, either alone or in combination with AZTH, as an antiviral treatment for COVID-19 in humans.



Nature: 21 Jul 2020; epub ahead of print
Maisonnasse P, Guedj J, Contreras V, Behillil S, ... de Lamballerie X, Le Grand R
Nature: 21 Jul 2020; epub ahead of print | PMID: 32698191
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Impact:
Abstract

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

Brakenhielm E, González A, Díez J

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

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

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

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

Wilcox JE, Fang JC, Margulies KB, Mann DL

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

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

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

Transvalvular Ventricular Unloading Before Reperfusion in Acute Myocardial Infarction.

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

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

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

Structure of the human sodium leak channel NALCN.

Kschonsak M, Chua HC, Noland CL, Weidling C, ... Pless SA, Payandeh J

Persistently depolarizing sodium (Na) leak currents that enhance electrical excitability have been described for decades. The entity responsible for the major background Na conductance in neurons had remained a mystery until characterization of NALCN (Na leak channel, non-selective). NALCN-mediated currents regulate neuronal excitability linked to respiration, locomotion and circadian rhythm. NALCN activity is under tight regulation and NALCN mutations cause severe neurological disorders and early death. NALCN is an orphan channel in humans, and fundamental aspects of channel assembly, gating, ion selectivity and pharmacology remain obscure. Here, we investigate this essential leak channel and determined the NALCN structure in complex with FAM155A (Family with sequence similarity 155, member A). FAM155A forms an extracellular dome that shields the ion selectivity filter from neurotoxin attack. The pharmacology of NALCN is further delineated by a walled-off central cavity with occluded lateral pore fenestrations. Clues to the modulation of NALCN activity are revealed by unusual voltage-sensor domains with asymmetric linkages to the pore. We discover a tightly closed pore gate where the vast majority of missense patient mutations cause gain-of-function phenotypes that cluster around the S6-gate and distinctive π-bulges. Our study provides a framework to demystify the physiology of NALCN and a foundation to discover treatments for NALCN channelopathies and other electrical disorders.



Nature: 21 Jul 2020; epub ahead of print
Kschonsak M, Chua HC, Noland CL, Weidling C, ... Pless SA, Payandeh J
Nature: 21 Jul 2020; epub ahead of print | PMID: 32698188
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Impact:
Abstract

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

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

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

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

Presentation and Outcome of Arrhythmic Mitral Valve Prolapse.

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

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

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

Potent neutralizing antibodies directed to multiple epitopes on SARS-CoV-2 spike.

Liu L, Wang P, Nair MS, Yu J, ... Shapiro L, Ho DD

The SARS-CoV-2 pandemic rages on with devasting consequences on human lives and the global economy. The discovery and development of virus-neutralizing monoclonal antibodies could be one approach to treat or prevent infection by this novel coronavirus. Here we report the isolation of 61 SARS-CoV-2-neutralizing monoclonal antibodies from 5 infected patients hospitalized with severe disease. Among these are 19 antibodies that potently neutralized the authentic SARS-CoV-2 in vitro, 9 of which exhibited exquisite potency, with 50% virus-inhibitory concentrations of 0.7 to 9 ng/mL. Epitope mapping showed this collection of 19 antibodies to be about equally divided between those directed to the receptor-binding domain (RBD) and those to the N-terminal domain (NTD), indicating that both of these regions at the top of the viral spike are immunogenic. In addition, two other powerful neutralizing antibodies recognized quaternary epitopes that overlap with the domains at the top of the spike. Cryo-electron microscopy reconstructions of one antibody targeting RBD, a second targeting NTD, and a third bridging two separate RBDs revealed recognition of the closed, \"all RBD-down\" conformation of the spike. Several of these monoclonal antibodies are promising candidates for clinical development as potential therapeutic and/or prophylactic agents against SARS-CoV-2.



Nature: 21 Jul 2020; epub ahead of print
Liu L, Wang P, Nair MS, Yu J, ... Shapiro L, Ho DD
Nature: 21 Jul 2020; epub ahead of print | PMID: 32698192
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Impact:
Abstract

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

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

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

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

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

Structural basis of GPBAR activation and bile acid recognition.

Yang F, Mao C, Guo L, Lin J, ... Yu X, Zhang Y

The G protein-coupled bile acid receptor (GPBAR) conveys the cross-membrane signaling of a vast variety of bile acids and is a signaling hub in the liver-bile-acid-microbiota-metabolism axis. Here, we report the cryo-EM structures of GPBAR-Gs complexes stabilized by either the high-affinity P395 or the semisynthesized bile acid derivative INT-777 at 3-Å resolution. These structures revealed a large oval-shaped pocket containing several polar groups positioned to accommodate the amphipathic cholic core of bile acids, a fingerprint of key residues to recognize diverse bile acids in the orthosteric site, a putative second bile acid binding site with allosteric properties and structural features contributing to bias properties. Moreover, GPBAR undertakes an atypical mode of activation and G-protein coupling featuring a different set of key residues connecting the ligand binding pocket to the Gs coupling site, and a specific interaction motif localized in intracellular loop 3. Overall, our study not only reveals unique structural features of GPBAR involved in bile acid recognition and allosteric effects, but also suggests the presence of distinct connecting mechanisms between the ligand binding pocket and the G protein binding site in the GPCR superfamily.



Nature: 21 Jul 2020; epub ahead of print
Yang F, Mao C, Guo L, Lin J, ... Yu X, Zhang Y
Nature: 21 Jul 2020; epub ahead of print | PMID: 32698187
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Impact:
Abstract

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

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

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

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

Chloroquine does not inhibit infection of human lung cells with SARS-CoV-2.

Hoffmann M, Mösbauer K, Hofmann-Winkler H, Kaul A, ... Drosten C, Pöhlmann S

The COVID-19 pandemic, which is caused by the novel coronavirus SARS-CoV-2, has been associated with more than 470,000 fatal cases worldwide. In order to develop antiviral interventions quickly, drugs used for treatment of unrelated diseases are currently being repurposed to combat COVID-19. Chloroquine is a anti-malaria drug that is frequently employed for COVID-19 treatment since it inhibits SARS-CoV-2 spread in the kidney-derived cell line Vero. Here, we show that engineered expression of TMPRSS2, a cellular protease that activates SARS-CoV-2 for entry into lung cells, renders SARS-CoV-2 infection of Vero cells insensitive to chloroquine. Moreover, we report that chloroquine does not block SARS-CoV-2 infection of the TMPRSS2-positive lung cell line Calu-3. These results indicate that chloroquine targets a pathway for viral activation that is not operative in lung cells and is unlikely to protect against SARS-CoV-2 spread in and between patients.



Nature: 21 Jul 2020; epub ahead of print
Hoffmann M, Mösbauer K, Hofmann-Winkler H, Kaul A, ... Drosten C, Pöhlmann S
Nature: 21 Jul 2020; epub ahead of print | PMID: 32698190
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Impact:
Abstract

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

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

Published by Elsevier Inc.

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

MeCP2 links heterochromatin condensates and neurodevelopmental disease.

Li CH, Coffey EL, Dall\'Agnese A, Hannett NM, ... Jaenisch R, Young RA

MeCP2 (methyl CpG binding protein 2) is a key component of constitutive heterochromatin, which plays important roles in chromosome maintenance and transcriptional silencing. Mutations in MeCP2 cause Rett syndrome (RTT), a postnatal progressive neurodevelopmental disorder associated with severe mental disability and autism-like symptoms that manifests in girls during early childhood. Heterochromatin, long considered a dense and relatively static structure, is now understood to exhibit properties consistent with a liquid-like condensate. Here we report that MeCP2 is a dynamic component of heterochromatin condensates in cells, is stimulated by DNA to form liquid-like condensates, contains multiple domains that contribute to condensate formation, manifests physicochemical properties that selectively concentrate heterochromatin cofactors compared to components of transcriptionally active condensates, and when altered by RTT-causing mutations is disrupted in its ability to form condensates. We propose that MeCP2 enhances heterochromatin/euchromatin separation through its condensate partitioning properties and that condensate disruption may be a common consequence of mutations found in patients with RTT.



Nature: 21 Jul 2020; epub ahead of print
Li CH, Coffey EL, Dall'Agnese A, Hannett NM, ... Jaenisch R, Young RA
Nature: 21 Jul 2020; epub ahead of print | PMID: 32698189
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Impact:
Abstract

Pathogenic Autoimmunity in Atherosclerosis Evolves from Initially Protective ApoB-Reactive CD4 T-Regulatory Cells.

Wolf D, Gerhardt T, Winkels H, Anto Michel N, ... Sette A, Ley K

Throughout the inflammatory response that accompanies atherosclerosis, autoreactive CD4 T-helper cells accumulate in the atherosclerotic plaque. Apolipoprotein B-100 (ApoB), the core protein of low-density lipoprotein (LDL), is an autoantigen that drives the generation of pathogenic T-helper type 1 (T1) cells with pro-inflammatory cytokine secretion. Clinical data suggest the existence of ApoB-specific CD4 T cells with an atheroprotective, regulatory T cell (T) phenotype in healthy individuals. Yet, the function of ApoB-reactive T and their relationship with pathogenic T1 cells remain unknown.To interrogate the function of autoreactive CD4+ T cells in atherosclerosis, we used a novel tetramer of MHC-II to track T cells reactive to the mouse self-peptide ApoB (ApoB) on a single cell level.We found that ApoB T cells build an oligoclonal population in lymph nodes of healthy mice that exhibit a T-like transcriptome, although only 21% of all ApoB T cells expressed the T-transcription factor FoxP3 protein as detected by flow cytometry. In single-cell RNAsequencing (scRNAseq), ApoB T cells formed several clusters with mixed T-signatures that suggested overlapping multilineage phenotypes with pro- and anti-inflammatory transcripts of T helper cells type -1, -2, -17, and of follicular-helper T cells. ApoB T cells were increased in mice and humans with atherosclerosis and progressively converted into pathogenic T1-/T17- like cells with pro-inflammatory properties and only a residual T transcriptome. Consistently, plaque T cells that expanded during progression of atherosclerosis showed a mixed T1-/T17 phenotype in scRNAseq. In addition, we observed a loss of FoxP3 in a fraction of ApoB T in lineage tracing of hyperlipidemicmice. In adoptive transfer experiments, converting ApoB T failed to protect from atherosclerosis.Our results demonstrate an unexpected mixed phenotype of ApoB-reactive autoimmune T cells in atherosclerosis and suggest an initially protective autoimmune response against ApoB with a progressive derangement in clinical disease. These findings identify ApoB auto-reactive T as a novel cellular target in atherosclerosis.



Circulation: 23 Jul 2020; epub ahead of print
Wolf D, Gerhardt T, Winkels H, Anto Michel N, ... Sette A, Ley K
Circulation: 23 Jul 2020; epub ahead of print | PMID: 32703007
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Impact:
Abstract

Glypicans shield the Wnt lipid moiety to enable signalling at a distance.

McGough IJ, Vecchia L, Bishop B, Malinauskas T, ... Jones EY, Vincent JP

A relatively small number of proteins have been suggested to act as morphogens-signalling molecules that spread within tissues to organize tissue repair and the specification of cell fate during development. Among them are Wnt proteins, which carry a palmitoleate moiety that is essential for signalling activity. How a hydrophobic lipoprotein can spread in the aqueous extracellular space is unknown. Several mechanisms, such as those involving lipoprotein particles, exosomes or a specific chaperone, have been proposed to overcome this so-called Wnt solubility problem. Here we provide evidence against these models and show that the Wnt lipid is shielded by the core domain of a subclass of glypicans defined by the Dally-like protein (Dlp). Structural analysis shows that, in the presence of palmitoleoylated peptides, these glypicans change conformation to create a hydrophobic space. Thus, glypicans of the Dlp family protect the lipid of Wnt proteins from the aqueous environment and serve as a reservoir from which Wnt proteins can be handed over to signalling receptors.



Nature: 21 Jul 2020; epub ahead of print
McGough IJ, Vecchia L, Bishop B, Malinauskas T, ... Jones EY, Vincent JP
Nature: 21 Jul 2020; epub ahead of print | PMID: 32699409
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Impact:
Abstract

Coherent many-body exciton in van der Waals antiferromagnet NiPS.

Kang S, Kim K, Kim BH, Kim J, ... Cheong H, Park JG

An exciton is the bosonic quasiparticle of electron-hole pairs bound by the Coulomb interaction. Bose-Einstein condensation of this exciton state has long been the subject of speculation in various model systems, and examples have been found more recently in optical lattices and two-dimensional materials. Unlike these conventional excitons formed from extended Bloch states, excitonic bound states from intrinsically many-body localized states are rare. Here we show that a spin-orbit-entangled exciton state appears below the Néel temperature of 150 kelvin in NiPS, an antiferromagnetic van der Waals material. It arises intrinsically from the archetypal many-body states of the Zhang-Rice singlet, and reaches a coherent state assisted by the antiferromagnetic order. Using configuration-interaction theory, we determine the origin of the coherent excitonic excitation to be a transition from a Zhang-Rice triplet to a Zhang-Rice singlet. We combine three spectroscopic tools-resonant inelastic X-ray scattering, photoluminescence and optical absorption-to characterize the exciton and to demonstrate an extremely narrow excitonic linewidth below 50 kelvin. The discovery of the spin-orbit-entangled exciton in antiferromagnetic NiPS introduces van der Waals magnets as a platform to study coherent many-body excitons.



Nature: 19 Jul 2020; epub ahead of print
Kang S, Kim K, Kim BH, Kim J, ... Cheong H, Park JG
Nature: 19 Jul 2020; epub ahead of print | PMID: 32690938
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Impact:
Abstract

Histone H3.3 phosphorylation amplifies stimulation-induced transcription.

Armache A, Yang S, Martínez de Paz A, Robbins LE, ... Li H, Josefowicz SZ

Complex organisms can rapidly induce select genes in response to diverse environmental cues. This regulation occurs in the context of large genomes condensed by histone proteins into chromatin. The sensing of pathogens by macrophages engages conserved signalling pathways and transcription factors to coordinate the induction of inflammatory genes. Enriched integration of histone H3.3, the ancestral histone H3 variant, is a general feature of dynamically regulated chromatin and transcription. However, how chromatin is regulated at induced genes, and what features of H3.3 might enable rapid and high-level transcription, are unknown. The amino terminus of H3.3 contains a unique serine residue (Ser31) that is absent in \'canonical\' H3.1 and H3.2. Here we show that this residue, H3.3S31, is phosphorylated (H3.3S31ph) in a stimulation-dependent manner along rapidly induced genes in mouse macrophages. This selective mark of stimulation-responsive genes directly engages the histone methyltransferase SETD2, a component of the active transcription machinery, and \'ejects\' the elongation corepressor ZMYND11. We propose that features of H3.3 at stimulation-induced genes, including H3.3S31ph, provide preferential access to the transcription apparatus. Our results indicate dedicated mechanisms that enable rapid transcription involving the histone variant H3.3, its phosphorylation, and both the recruitment and the ejection of chromatin regulators.



Nature: 21 Jul 2020; epub ahead of print
Armache A, Yang S, Martínez de Paz A, Robbins LE, ... Li H, Josefowicz SZ
Nature: 21 Jul 2020; epub ahead of print | PMID: 32699416
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Impact:
Abstract

Two dynamically distinct circuits drive inhibition in the sensory thalamus.

Martinez-Garcia RI, Voelcker B, Zaltsman JB, Patrick SL, ... Connors BW, Cruikshank SJ

Most sensory information destined for the neocortex is relayed through the thalamus, where considerable transformation occurs. One means of transformation involves interactions between excitatory thalamocortical neurons that carry data to the cortex and inhibitory neurons of the thalamic reticular nucleus (TRN) that regulate the flow of those data. Although the importance of the TRN has long been recognised, understanding of its cell types, their organization and their functional properties has lagged behind that of the thalamocortical systems they control. Here we address this by investigating the somatosensory and visual circuits of the TRN in mice. In the somatosensory TRN we observed two groups of genetically defined neurons that are topographically segregated and physiologically distinct, and that connect reciprocally with independent thalamocortical nuclei through dynamically divergent synapses. Calbindin-expressing cells-located in the central core-connect with the ventral posterior nucleus, the primary somatosensory thalamocortical relay. By contrast, somatostatin-expressing cells-which reside along the surrounding edges of the TRN-synapse with the posterior medial thalamic nucleus, a higher-order structure that carries both top-down and bottom-up information. The two TRN cell groups process their inputs in pathway-specific ways. Synapses from the ventral posterior nucleus to central TRN cells transmit rapid excitatory currents that depress deeply during repetitive activity, driving phasic spike output. Synapses from the posterior medial thalamic nucleus to edge TRN cells evoke slower, less depressing excitatory currents that drive more persistent spiking. Differences in the intrinsic physiology of TRN cell types, including state-dependent bursting, contribute to these output dynamics. The processing specializations of these two somatosensory TRN subcircuits therefore appear to be tuned to the signals they carry-a primary central subcircuit tuned to discrete sensory events, and a higher-order edge subcircuit tuned to temporally distributed signals integrated from multiple sources. The structure and function of visual TRN subcircuits closely resemble those of the somatosensory TRN. These results provide insights into how subnetworks of TRN neurons may differentially process distinct classes of thalamic information.



Nature: 21 Jul 2020; epub ahead of print
Martinez-Garcia RI, Voelcker B, Zaltsman JB, Patrick SL, ... Connors BW, Cruikshank SJ
Nature: 21 Jul 2020; epub ahead of print | PMID: 32699410
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Impact:
Abstract

The timing and effect of the earliest human arrivals in North America.

Becerra-Valdivia L, Higham T

The peopling of the Americas marks a major expansion of humans across the planet. However, questions regarding the timing and mechanisms of this dispersal remain, and the previously accepted model (termed \'Clovis-first\')-suggesting that the first inhabitants of the Americas were linked with the Clovis tradition, a complex marked by distinctive fluted lithic points-has been effectively refuted. Here we analyse chronometric data from 42 North American and Beringian archaeological sites using a Bayesian age modelling approach, and use the resulting chronological framework to elucidate spatiotemporal patterns of human dispersal. We then integrate these patterns with the available genetic and climatic evidence. The data obtained show that humans were probably present before, during and immediately after the Last Glacial Maximum (about 26.5-19 thousand years ago) but that more widespread occupation began during a period of abrupt warming, Greenland Interstadial 1 (about 14.7-12.9 thousand years before AD 2000). We also identify the near-synchronous commencement of Beringian, Clovis and Western Stemmed cultural traditions, and an overlap of each with the last dates for the appearance of 18 now-extinct faunal genera. Our analysis suggests that the widespread expansion of humans through North America was a key factor in the extinction of large terrestrial mammals.



Nature: 21 Jul 2020; epub ahead of print
Becerra-Valdivia L, Higham T
Nature: 21 Jul 2020; epub ahead of print | PMID: 32699413
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Impact:
Abstract

Distinct subnetworks of the thalamic reticular nucleus.

Li Y, Lopez-Huerta VG, Adiconis X, Levandowski K, ... Fu Z, Feng G

The thalamic reticular nucleus (TRN), the major source of thalamic inhibition, regulates thalamocortical interactions that are critical for sensory processing, attention and cognition. TRN dysfunction has been linked to sensory abnormality, attention deficit and sleep disturbance across multiple neurodevelopmental disorders. However, little is known about the organizational principles that underlie its divergent functions. Here we performed an integrative study linking single-cell molecular and electrophysiological features of the mouse TRN to connectivity and systems-level function. We found that cellular heterogeneity in the TRN is characterized by a transcriptomic gradient of two negatively correlated gene-expression profiles, each containing hundreds of genes. Neurons in the extremes of this transcriptomic gradient express mutually exclusive markers, exhibit core or shell-like anatomical structure and have distinct electrophysiological properties. The two TRN subpopulations make differential connections with the functionally distinct first-order and higher-order thalamic nuclei to form molecularly defined TRN-thalamus subnetworks. Selective perturbation of the two subnetworks in vivo revealed their differential role in regulating sleep. In sum, our study provides a comprehensive atlas of TRN neurons at single-cell resolution and links molecularly defined subnetworks to the functional organization of thalamocortical circuits.



Nature: 21 Jul 2020; epub ahead of print
Li Y, Lopez-Huerta VG, Adiconis X, Levandowski K, ... Fu Z, Feng G
Nature: 21 Jul 2020; epub ahead of print | PMID: 32699411
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Impact:
Abstract

A leptin-BDNF pathway regulating sympathetic innervation of adipose tissue.

Wang P, Loh KH, Wu M, Morgan DA, ... Cohen P, Friedman J

Mutations in the leptin gene (ob) result in a metabolic disorder that includes severe obesity, and defects in thermogenesis and lipolysis, both of which are adipose tissue functions regulated by the sympathetic nervous system. However, the basis of these sympathetic-associated abnormalities remains unclear. Furthermore, chronic leptin administration reverses these abnormalities in adipose tissue, but the underlying mechanism remains to be discovered. Here we report that ob/ob mice, as well as leptin-resistant diet-induced obese mice, show significant reductions of sympathetic innervation of subcutaneous white and brown adipose tissue. Chronic leptin treatment of ob/ob mice restores adipose tissue sympathetic innervation, which in turn is necessary to correct the associated functional defects. The effects of leptin on innervation are mediated via agouti-related peptide and pro-opiomelanocortin neurons in the hypothalamic arcuate nucleus. Deletion of the gene encoding the leptin receptor in either population leads to reduced innervation in fat. These agouti-related peptide and pro-opiomelanocortin neurons act via brain-derived neurotropic factor-expressing neurons in the paraventricular nucleus of the hypothalamus (BDNF). Deletion of BDNF blunts the effects of leptin on innervation. These data show that leptin signalling regulates the plasticity of sympathetic architecture of adipose tissue via a top-down neural pathway that is crucial for energy homeostasis.



Nature: 21 Jul 2020; epub ahead of print
Wang P, Loh KH, Wu M, Morgan DA, ... Cohen P, Friedman J
Nature: 21 Jul 2020; epub ahead of print | PMID: 32699414
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Impact:
Abstract

Global status and conservation potential of reef sharks.

MacNeil MA, Chapman DD, Heupel M, Simpfendorfer CA, ... Zarza-Gonzâlez E, Cinner JE

Decades of overexploitation have devastated shark populations, leaving considerable doubt as to their ecological status. Yet much of what is known about sharks has been inferred from catch records in industrial fisheries, whereas far less information is available about sharks that live in coastal habitats. Here we address this knowledge gap using data from more than 15,000 standardized baited remote underwater video stations that were deployed on 371 reefs in 58 nations to estimate the conservation status of reef sharks globally. Our results reveal the profound impact that fishing has had on reef shark populations: we observed no sharks on almost 20% of the surveyed reefs. Reef sharks were almost completely absent from reefs in several nations, and shark depletion was strongly related to socio-economic conditions such as the size and proximity of the nearest market, poor governance and the density of the human population. However, opportunities for the conservation of reef sharks remain: shark sanctuaries, closed areas, catch limits and an absence of gillnets and longlines were associated with a substantially higher relative abundance of reef sharks. These results reveal several policy pathways for the restoration and management of reef shark populations, from direct top-down management of fishing to indirect improvement of governance conditions. Reef shark populations will only have a high chance of recovery by engaging key socio-economic aspects of tropical fisheries.



Nature: 21 Jul 2020; epub ahead of print
MacNeil MA, Chapman DD, Heupel M, Simpfendorfer CA, ... Zarza-Gonzâlez E, Cinner JE
Nature: 21 Jul 2020; epub ahead of print | PMID: 32699418
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Impact:
Abstract

Discovery and engineering of colchicine alkaloid biosynthesis.

Nett RS, Lau W, Sattely ES

Few complete pathways have been established for the biosynthesis of medicinal compounds from plants. Accordingly, many plant-derived therapeutics are isolated directly from medicinal plants or plant cell culture. A lead example is colchicine, a US Food and Drug Administration (FDA)-approved treatment for inflammatory disorders that is sourced from Colchicum and Gloriosa species. Here we use a combination of transcriptomics, metabolic logic and pathway reconstitution to elucidate a near-complete biosynthetic pathway to colchicine without prior knowledge of biosynthetic genes, a sequenced genome or genetic tools in the native host. We uncovered eight genes from Gloriosa superba for the biosynthesis of N-formyldemecolcine, a colchicine precursor that contains the characteristic tropolone ring and pharmacophore of colchicine. Notably, we identified a non-canonical cytochrome P450 that catalyses the remarkable ring expansion reaction that is required to produce the distinct carbon scaffold of colchicine. We further used the newly identified genes to engineer a biosynthetic pathway (comprising 16 enzymes in total) to N-formyldemecolcine in Nicotiana benthamiana starting from the amino acids phenylalanine and tyrosine. This study establishes a metabolic route to tropolone-containing colchicine alkaloids and provides insights into the unique chemistry that plants use to generate complex, bioactive metabolites from simple amino acids.



Nature: 21 Jul 2020; epub ahead of print
Nett RS, Lau W, Sattely ES
Nature: 21 Jul 2020; epub ahead of print | PMID: 32699417
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Impact:
Abstract

Immunogenicity and safety of a recombinant adenovirus type-5-vectored COVID-19 vaccine in healthy adults aged 18 years or older: a randomised, double-blind, placebo-controlled, phase 2 trial.

Zhu FC, Guan XH, Li YH, Huang JY, ... Wang XH, Chen W
Background
This is the first randomised controlled trial for assessment of the immunogenicity and safety of a candidate non-replicating adenovirus type-5 (Ad5)-vectored COVID-19 vaccine, aiming to determine an appropriate dose of the candidate vaccine for an efficacy study.
Methods
This randomised, double-blind, placebo-controlled, phase 2 trial of the Ad5-vectored COVID-19 vaccine was done in a single centre in Wuhan, China. Healthy adults aged 18 years or older, who were HIV-negative and previous severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection-free, were eligible to participate and were randomly assigned to receive the vaccine at a dose of 1 × 10 viral particles per mL or 5 × 10 viral particles per mL, or placebo. Investigators allocated participants at a ratio of 2:1:1 to receive a single injection intramuscularly in the arm. The randomisation list (block size 4) was generated by an independent statistician. Participants, investigators, and staff undertaking laboratory analyses were masked to group allocation. The primary endpoints for immunogenicity were the geometric mean titres (GMTs) of specific ELISA antibody responses to the receptor binding domain (RBD) and neutralising antibody responses at day 28. The primary endpoint for safety evaluation was the incidence of adverse reactions within 14 days. All recruited participants who received at least one dose were included in the primary and safety analyses. This study is registered with ClinicalTrials.gov, NCT04341389.
Findings
603 volunteers were recruited and screened for eligibility between April 11 and 16, 2020. 508 eligible participants (50% male; mean age 39·7 years, SD 12·5) consented to participate in the trial and were randomly assigned to receive the vaccine (1 × 10 viral particles n=253; 5 × 10 viral particles n=129) or placebo (n=126). In the 1 × 10 and 5 × 10 viral particles dose groups, the RBD-specific ELISA antibodies peaked at 656·5 (95% CI 575·2-749·2) and 571·0 (467·6-697·3), with seroconversion rates at 96% (95% CI 93-98) and 97% (92-99), respectively, at day 28. Both doses of the vaccine induced significant neutralising antibody responses to live SARS-CoV-2, with GMTs of 19·5 (95% CI 16·8-22·7) and 18·3 (14·4-23·3) in participants receiving 1 × 10 and 5 × 10 viral particles, respectively. Specific interferon γ enzyme-linked immunospot assay responses post vaccination were observed in 227 (90%, 95% CI 85-93) of 253 and 113 (88%, 81-92) of 129 participants in the 1 × 10 and 5 × 10 viral particles dose groups, respectively. Solicited adverse reactions were reported by 183 (72%) of 253 and 96 (74%) of 129 participants in the 1 × 10 and 5 × 10 viral particles dose groups, respectively. Severe adverse reactions were reported by 24 (9%) participants in the 1 × 10 viral particles dose group and one (1%) participant in the 5 × 10 viral particles dose group. No serious adverse reactions were documented.
Interpretation
The Ad5-vectored COVID-19 vaccine at 5 × 10 viral particles is safe, and induced significant immune responses in the majority of recipients after a single immunisation.
Funding
National Key R&D Programme of China, National Science and Technology Major Project, and CanSino Biologics.

Copyright © 2020 Elsevier Ltd. All rights reserved.

Lancet: 19 Jul 2020; epub ahead of print
Zhu FC, Guan XH, Li YH, Huang JY, ... Wang XH, Chen W
Lancet: 19 Jul 2020; epub ahead of print | PMID: 32702299
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Abstract

Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial.

Folegatti PM, Ewer KJ, Aley PK, Angus B, ... Pollard AJ,
Background
The pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) might be curtailed by vaccination. We assessed the safety, reactogenicity, and immunogenicity of a viral vectored coronavirus vaccine that expresses the spike protein of SARS-CoV-2.
Methods
We did a phase 1/2, single-blind, randomised controlled trial in five trial sites in the UK of a chimpanzee adenovirus-vectored vaccine (ChAdOx1 nCoV-19) expressing the SARS-CoV-2 spike protein compared with a meningococcal conjugate vaccine (MenACWY) as control. Healthy adults aged 18-55 years with no history of laboratory confirmed SARS-CoV-2 infection or of COVID-19-like symptoms were randomly assigned (1:1) to receive ChAdOx1 nCoV-19 at a dose of 5 × 10 viral particles or MenACWY as a single intramuscular injection. A protocol amendment in two of the five sites allowed prophylactic paracetamol to be administered before vaccination. Ten participants assigned to a non-randomised, unblinded ChAdOx1 nCoV-19 prime-boost group received a two-dose schedule, with the booster vaccine administered 28 days after the first dose. Humoral responses at baseline and following vaccination were assessed using a standardised total IgG ELISA against trimeric SARS-CoV-2 spike protein, a muliplexed immunoassay, three live SARS-CoV-2 neutralisation assays (a 50% plaque reduction neutralisation assay [PRNT]; a microneutralisation assay [MNA, MNA, and MNA]; and Marburg VN), and a pseudovirus neutralisation assay. Cellular responses were assessed using an ex-vivo interferon-γ enzyme-linked immunospot assay. The co-primary outcomes are to assess efficacy, as measured by cases of symptomatic virologically confirmed COVID-19, and safety, as measured by the occurrence of serious adverse events. Analyses were done by group allocation in participants who received the vaccine. Safety was assessed over 28 days after vaccination. Here, we report the preliminary findings on safety, reactogenicity, and cellular and humoral immune responses. The study is ongoing, and was registered at ISRCTN, 15281137, and ClinicalTrials.gov, NCT04324606.
Findings
Between April 23 and May 21, 2020, 1077 participants were enrolled and assigned to receive either ChAdOx1 nCoV-19 (n=543) or MenACWY (n=534), ten of whom were enrolled in the non-randomised ChAdOx1 nCoV-19 prime-boost group. Local and systemic reactions were more common in the ChAdOx1 nCoV-19 group and many were reduced by use of prophylactic paracetamol, including pain, feeling feverish, chills, muscle ache, headache, and malaise (all p<0·05). There were no serious adverse events related to ChAdOx1 nCoV-19. In the ChAdOx1 nCoV-19 group, spike-specific T-cell responses peaked on day 14 (median 856 spot-forming cells per million peripheral blood mononuclear cells, IQR 493-1802; n=43). Anti-spike IgG responses rose by day 28 (median 157 ELISA units [EU], 96-317; n=127), and were boosted following a second dose (639 EU, 360-792; n=10). Neutralising antibody responses against SARS-CoV-2 were detected in 32 (91%) of 35 participants after a single dose when measured in MNA and in 35 (100%) participants when measured in PRNT. After a booster dose, all participants had neutralising activity (nine of nine in MNA at day 42 and ten of ten in Marburg VN on day 56). Neutralising antibody responses correlated strongly with antibody levels measured by ELISA (R=0·67 by Marburg VN; p<0·001).
Interpretation
ChAdOx1 nCoV-19 showed an acceptable safety profile, and homologous boosting increased antibody responses. These results, together with the induction of both humoral and cellular immune responses, support large-scale evaluation of this candidate vaccine in an ongoing phase 3 programme.
Funding
UK Research and Innovation, Coalition for Epidemic Preparedness Innovations, National Institute for Health Research (NIHR), NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland\'s NIHR Clinical Research Network, and the German Center for Infection Research (DZIF), Partner site Gießen-Marburg-Langen.

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

Lancet: 19 Jul 2020; epub ahead of print
Folegatti PM, Ewer KJ, Aley PK, Angus B, ... Pollard AJ,
Lancet: 19 Jul 2020; epub ahead of print | PMID: 32702298
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Abstract

Signalling input from divergent pathways subverts B cell transformation.

Chan LN, Murakami MA, Robinson ME, Caeser R, ... Weinstock DM, Müschen M

Malignant transformation of cells typically involves several genetic lesions, whose combined activity gives rise to cancer. Here we analyse 1,148 patient-derived B-cell leukaemia (B-ALL) samples, and find that individual mutations do not promote leukaemogenesis unless they converge on one single oncogenic pathway that is characteristic of the differentiation stage of transformed B cells. Mutations that are not aligned with this central oncogenic driver activate divergent pathways and subvert transformation. Oncogenic lesions in B-ALL frequently mimic signalling through cytokine receptors at the pro-B-cell stage (via activation of the signal-transduction protein STAT5) or pre-B-cell receptors in more mature cells (via activation of the protein kinase ERK). STAT5- and ERK-activating lesions are found frequently, but occur together in only around 3% of cases (P = 2.2 × 10). Single-cell mutation and phospho-protein analyses reveal the segregation of oncogenic STAT5 and ERK activation to competing clones. STAT5 and ERK engage opposing biochemical and transcriptional programs that are orchestrated by the transcription factors MYC and BCL6, respectively. Genetic reactivation of the divergent (suppressed) pathway comes at the expense of the principal oncogenic driver and reverses transformation. Conversely, deletion of divergent pathway components accelerates leukaemogenesis. Thus, persistence of divergent signalling pathways represents a powerful barrier to transformation, while convergence on one principal driver defines a central event in leukaemia initiation. Pharmacological reactivation of suppressed divergent circuits synergizes strongly with inhibition of the principal oncogenic driver. Hence, reactivation of divergent pathways can be leveraged as a previously unrecognized strategy to enhance treatment responses.



Nature: 21 Jul 2020; epub ahead of print
Chan LN, Murakami MA, Robinson ME, Caeser R, ... Weinstock DM, Müschen M
Nature: 21 Jul 2020; epub ahead of print | PMID: 32699415
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This program is still in alpha version.