Topic: Journal Club Selection

Abstract

Multisystem Inflammatory Syndrome in Children in New York State.

Dufort EM, Koumans EH, Chow EJ, Rosenthal EM, ... Zucker H,
Background
A multisystem inflammatory syndrome in children (MIS-C) is associated with coronavirus disease 2019. The New York State Department of Health (NYSDOH) established active, statewide surveillance to describe hospitalized patients with the syndrome.
Methods
Hospitals in New York State reported cases of Kawasaki\'s disease, toxic shock syndrome, myocarditis, and potential MIS-C in hospitalized patients younger than 21 years of age and sent medical records to the NYSDOH. We carried out descriptive analyses that summarized the clinical presentation, complications, and outcomes of patients who met the NYSDOH case definition for MIS-C between March 1 and May 10, 2020.
Results
As of May 10, 2020, a total of 191 potential cases were reported to the NYSDOH. Of 95 patients with confirmed MIS-C (laboratory-confirmed acute or recent severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] infection) and 4 with suspected MIS-C (met clinical and epidemiologic criteria), 53 (54%) were male; 31 of 78 (40%) were black, and 31 of 85 (36%) were Hispanic. A total of 31 patients (31%) were 0 to 5 years of age, 42 (42%) were 6 to 12 years of age, and 26 (26%) were 13 to 20 years of age. All presented with subjective fever or chills; 97% had tachycardia, 80% had gastrointestinal symptoms, 60% had rash, 56% had conjunctival injection, and 27% had mucosal changes. Elevated levels of C-reactive protein, d-dimer, and troponin were found in 100%, 91%, and 71% of the patients, respectively; 62% received vasopressor support, 53% had evidence of myocarditis, 80% were admitted to an intensive care unit, and 2 died. The median length of hospital stay was 6 days.
Conclusions
The emergence of multisystem inflammatory syndrome in children in New York State coincided with widespread SARS-CoV-2 transmission; this hyperinflammatory syndrome with dermatologic, mucocutaneous, and gastrointestinal manifestations was associated with cardiac dysfunction.

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 28 Jun 2020; epub ahead of print
Dufort EM, Koumans EH, Chow EJ, Rosenthal EM, ... Zucker H,
N Engl J Med: 28 Jun 2020; epub ahead of print | PMID: 32598830
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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

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

Suppression with Adeno-Associated Virus and MicroRNA in Familial ALS.

Mueller C, Berry JD, McKenna-Yasek DM, Gernoux G, ... Cudkowicz ME, Brown RH

Two patients with familial amyotrophic lateral sclerosis (ALS) and mutations in the gene encoding superoxide dismutase 1 () were treated with a single intrathecal infusion of adeno-associated virus encoding a microRNA targeting SOD1. In Patient 1, SOD1 levels in spinal cord tissue as analyzed on autopsy were lower than corresponding levels in untreated patients with SOD1-mediated ALS and in healthy controls. Levels of SOD1 in cerebrospinal fluid were transiently and only slightly lower in Patient 1 but were not affected in Patient 2. In Patient 1, meningoradiculitis developed after the infusion; Patient 2 was pretreated with immunosuppressive drugs and did not have this complication. Patient 1 had transient improvement in the strength of his right leg, a measure that had been relatively stable throughout his disease course, but there was no change in his vital capacity. Patient 2 had stable scores on a composite measure of ALS function and a stable vital capacity during a 12-month period. This study showed that intrathecal microRNA can be used as a potential treatment for SOD1-mediated ALS.

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 08 Jul 2020; 383:151-158
Mueller C, Berry JD, McKenna-Yasek DM, Gernoux G, ... Cudkowicz ME, Brown RH
N Engl J Med: 08 Jul 2020; 383:151-158 | PMID: 32640133
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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

Envelope protein ubiquitination drives entry and pathogenesis of Zika virus.

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

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



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

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

Cryoablation or Drug Therapy for Initial Treatment of Atrial Fibrillation.

Andrade JG, Wells GA, Deyell MW, Bennett M, ... Verma A, EARLY-AF Investigators
Background
Guidelines recommend a trial of one or more antiarrhythmic drugs before catheter ablation is considered in patients with atrial fibrillation. However, first-line ablation may be more effective in maintaining sinus rhythm.
Methods
We randomly assigned 303 patients with symptomatic, paroxysmal, untreated atrial fibrillation to undergo catheter ablation with a cryothermy balloon or to receive antiarrhythmic drug therapy for initial rhythm control. All the patients received an implantable cardiac monitoring device to detect atrial tachyarrhythmia. The follow-up period was 12 months. The primary end point was the first documented recurrence of any atrial tachyarrhythmia (atrial fibrillation, atrial flutter, or atrial tachycardia) between 91 and 365 days after catheter ablation or the initiation of an antiarrhythmic drug. The secondary end points included freedom from symptomatic arrhythmia, the atrial fibrillation burden, and quality of life.
Results
At 1 year, a recurrence of atrial tachyarrhythmia had occurred in 66 of 154 patients (42.9%) assigned to undergo ablation and in 101 of 149 patients (67.8%) assigned to receive antiarrhythmic drugs (hazard ratio, 0.48; 95% confidence interval [CI], 0.35 to 0.66; P<0.001). Symptomatic atrial tachyarrhythmia had recurred in 11.0% of the patients who underwent ablation and in 26.2% of those who received antiarrhythmic drugs (hazard ratio, 0.39; 95% CI, 0.22 to 0.68). The median percentage of time in atrial fibrillation was 0% (interquartile range, 0 to 0.08) with ablation and 0.13% (interquartile range, 0 to 1.60) with antiarrhythmic drugs. Serious adverse events occurred in 5 patients (3.2%) who underwent ablation and in 6 patients (4.0%) who received antiarrhythmic drugs.
Conclusions
Among patients receiving initial treatment for symptomatic, paroxysmal atrial fibrillation, there was a significantly lower rate of atrial fibrillation recurrence with catheter cryoballoon ablation than with antiarrhythmic drug therapy, as assessed by continuous cardiac rhythm monitoring. (Funded by the Cardiac Arrhythmia Network of Canada and others; EARLY-AF ClinicalTrials.gov number, NCT02825979.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 27 Jan 2021; 384:305-315
Andrade JG, Wells GA, Deyell MW, Bennett M, ... Verma A, EARLY-AF Investigators
N Engl J Med: 27 Jan 2021; 384:305-315 | PMID: 33197159
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Abstract

N-methyladenine in DNA antagonizes SATB1 in early development.

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

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



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

Multivessel PCI Guided by FFR or Angiography for Myocardial Infarction.

Puymirat E, Cayla G, Simon T, Steg PG, ... Danchin N, FLOWER-MI Study Investigators
Background
In patients with ST-elevation myocardial infarction (STEMI) who have multivessel disease, percutaneous coronary intervention (PCI) for nonculprit lesions (complete revascularization) is superior to treatment of the culprit lesion alone. However, whether complete revascularization that is guided by fractional flow reserve (FFR) is superior to an angiography-guided procedure is unclear.
Methods
In this multicenter trial, we randomly assigned patients with STEMI and multivessel disease who had undergone successful PCI of the infarct-related artery to receive complete revascularization guided by either FFR or angiography. The primary outcome was a composite of death from any cause, nonfatal myocardial infarction, or unplanned hospitalization leading to urgent revascularization at 1 year.
Results
The mean (±SD) number of stents that were placed per patient for nonculprit lesions was 1.01±0.99 in the FFR-guided group and 1.50±0.86 in the angiography-guided group. During follow-up, a primary outcome event occurred in 32 of 586 patients (5.5%) in the FFR-guided group and in 24 of 577 patients (4.2%) in the angiography-guided group (hazard ratio, 1.32; 95% confidence interval, 0.78 to 2.23; P = 0.31). Death occurred in 9 patients (1.5%) in the FFR-guided group and in 10 (1.7%) in the angiography-guided group; nonfatal myocardial infarction in 18 (3.1%) and 10 (1.7%), respectively; and unplanned hospitalization leading to urgent revascularization in 15 (2.6%) and 11 (1.9%), respectively.
Conclusions
In patients with STEMI undergoing complete revascularization, an FFR-guided strategy did not have a significant benefit over an angiography-guided strategy with respect to the risk of death, myocardial infarction, or urgent revascularization at 1 year. However, given the wide confidence intervals for the estimate of effect, the findings do not allow for a conclusive interpretation. (Funded by the French Ministry of Health and Abbott; FLOWER-MI ClinicalTrials.gov number, NCT02943954.).

Copyright © 2021 Massachusetts Medical Society.

N Engl J Med: 15 May 2021; epub ahead of print
Puymirat E, Cayla G, Simon T, Steg PG, ... Danchin N, FLOWER-MI Study Investigators
N Engl J Med: 15 May 2021; epub ahead of print | PMID: 33999545
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Abstract

Patterns of myocardial injury in recovered troponin-positive COVID-19 patients assessed by cardiovascular magnetic resonance.

Kotecha T, Knight DS, Razvi Y, Kumar K, ... Cole GD, Fontana M
Background
Troponin elevation is common in hospitalized COVID-19 patients, but underlying aetiologies are ill-defined. We used multi-parametric cardiovascular magnetic resonance (CMR) to assess myocardial injury in recovered COVID-19 patients.
Methods and results
One hundred and forty-eight patients (64 ± 12 years, 70% male) with severe COVID-19 infection [all requiring hospital admission, 48 (32%) requiring ventilatory support] and troponin elevation discharged from six hospitals underwent convalescent CMR (including adenosine stress perfusion if indicated) at median 68 days. Left ventricular (LV) function was normal in 89% (ejection fraction 67% ± 11%). Late gadolinium enhancement and/or ischaemia was found in 54% (80/148). This comprised myocarditis-like scar in 26% (39/148), infarction and/or ischaemia in 22% (32/148) and dual pathology in 6% (9/148). Myocarditis-like injury was limited to three or less myocardial segments in 88% (35/40) of cases with no associated LV dysfunction; of these, 30% had active myocarditis. Myocardial infarction was found in 19% (28/148) and inducible ischaemia in 26% (20/76) of those undergoing stress perfusion (including 7 with both infarction and ischaemia). Of patients with ischaemic injury pattern, 66% (27/41) had no past history of coronary disease. There was no evidence of diffuse fibrosis or oedema in the remote myocardium (T1: COVID-19 patients 1033 ± 41 ms vs. matched controls 1028 ± 35 ms; T2: COVID-19 46 ± 3 ms vs. matched controls 47 ± 3 ms).
Conclusions
During convalescence after severe COVID-19 infection with troponin elevation, myocarditis-like injury can be encountered, with limited extent and minimal functional consequence. In a proportion of patients, there is evidence of possible ongoing localized inflammation. A quarter of patients had ischaemic heart disease, of which two-thirds had no previous history. Whether these observed findings represent pre-existing clinically silent disease or de novo COVID-19-related changes remain undetermined. Diffuse oedema or fibrosis was not detected.

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J: 13 May 2021; 42:1866-1878
Kotecha T, Knight DS, Razvi Y, Kumar K, ... Cole GD, Fontana M
Eur Heart J: 13 May 2021; 42:1866-1878 | PMID: 33596594
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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

Effect of Evolocumab on Complex Coronary Disease Requiring Revascularization.

Oyama K, Furtado RHM, Fagundes A, Zelniker TA, ... Sabatine MS, Bergmark BA
Objectives
This study sought to evaluate the ability of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor evolocumab to reduce the risk of complex coronary atherosclerosis requiring revascularization.
Background
PCSK9 inhibitors induce plaque regression and reduce the risk of coronary revascularization overall.
Methods
FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) was a randomized trial of the PCSK9 inhibitor evolocumab versus placebo in 27,564 patients with stable atherosclerotic cardiovascular disease on statin therapy followed for a median of 2.2 years. Clinical documentation of revascularization events was blindly reviewed to assess coronary anatomy and procedural characteristics. Complex revascularization was the composite of complex percutaneous coronary intervention (PCI) (as per previous analyses, ≥1 of: multivessel PCI, ≥3 stents, ≥3 lesions treated, bifurcation PCI, or total stent length >60 mm) or coronary artery bypass grafting surgery (CABG).
Results
In this study, 1,724 patients underwent coronary revascularization, including 1,482 who underwent PCI, 296 who underwent CABG, and 54 who underwent both. Complex revascularization was performed in 632 (37%) patients. Evolocumab reduced the risk of any coronary revascularization by 22% (hazard ratio [HR]: 0.78; 95% CI: 0.71 to 0.86; p < 0.001), simple PCI by 22% (HR: 0.78; 95% CI: 0.70 to 0.88; p < 0.001), complex PCI by 33% (HR: 0.67; 95% CI: 0.54 to 0.84; p < 0.001), CABG by 24% (HR: 0.76; 95% CI: 0.60 to 0.96; p = 0.019), and complex revascularization by 29% (HR: 0.71; 95% CI: 0.61 to 0.84; p < 0.001). The magnitude of the risk reduction with evolocumab in complex revascularization tended to increase over time (20%, 36%, and 41% risk reductions in the first, second, and beyond second years).
Conclusions
Adding evolocumab to statin therapy significantly reduced the risk of developing complex coronary disease requiring revascularization, including complex PCI and CABG individually. (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER); NCT01764633.).

Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 25 Jan 2021; 77:259-267
Oyama K, Furtado RHM, Fagundes A, Zelniker TA, ... Sabatine MS, Bergmark BA
J Am Coll Cardiol: 25 Jan 2021; 77:259-267 | PMID: 33197560
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Impact:
Abstract

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

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



Circulation: 27 Jul 2020; 142:354-364
Tam DY, Wijeysundera HC, Naimark D, Gaudino M, ... Cohen DJ, Fremes SE
Circulation: 27 Jul 2020; 142:354-364 | PMID: 32493077
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Impact:
Abstract

Usefulness of Neuromuscular Co-morbidity, Left Bundle Branch Block, and Atrial Fibrillation to Predict the Long-Term Prognosis of Left Ventricular Hypertrabeculation/Noncompaction.

Stöllberger C, Hasun M, Winkler-Dworak M, Finsterer J

The prognosis of patients with left ventricular hypertrabeculation/noncompaction (LVHT) is assessed controversially. LVHT is associated with other cardiac abnormalities and with neuromuscular disorders (NMD). Aim of the study was to assess cardiac and neurological findings as predictors of mortality rate in adult LVHT-patients. Included were patients with LVHT diagnosed between 1995 and 2019 in 1 echocardiographic laboratory. Patients underwent a baseline cardiologic examination and were invited for a neurological investigation. In January 2020, their survival status was assessed. End points were death or heart transplantation. LVHT was diagnosed by echocardiography in 310 patients (93 female, aged 53 ± 18 years) with a prevalence of 0.4%/year. A neurologic investigation was performed in 205 patients (67%). A specific NMD was found in 33 (16%), NMD of unknown etiology in 123 (60%) and the neurological investigation was normal in 49 (24%) patients. During follow-up of 84 ± 71 months, 59 patients received electronic devices, 105 patients died, and 6 underwent heart transplantation. The mortality was 4.7%/year, the rate of heart transplantation/death 5%/year. By multivariate analysis, the following parameters were identified to elevate the risk of mortality/heart transplantation: increased age (p = 0.005), inpatient (p = 0.001), presence of a specific NMD (p = 0.0312) or NMD of unknown etiology (p = 0.0365), atrial fibrillation (p = 0.0000), ventricular premature complexes (p = 0.0053), exertional dyspnea (p = 0.0023), left bundle branch block (p = 0.0201), and LVHT of the posterior wall (p = 0.0158). In conclusion, LVHT patients should be systematically investigated neurologically since neurological co-morbidity has a prognostic impact.

Copyright © 2020 Elsevier Inc. All rights reserved.

Am J Cardiol: 31 Jul 2020; 128:168-173
Stöllberger C, Hasun M, Winkler-Dworak M, Finsterer J
Am J Cardiol: 31 Jul 2020; 128:168-173 | PMID: 32650915
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Abstract

Patterns of oral anticoagulation use with cardioversion in clinical practice.

Geurink K, Holmes D, Ezekowitz MD, Pieper K, ... Peterson ED, Pokorney SD
Background
Cardioversion is common among patients with atrial fibrillation (AF). We hypothesised that novel oral anticoagulants (NOAC) used in clinical practice resulted in similar rates of stroke compared with vitamin K antagonists (VKA) for cardioversion.
Methods
Using the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation II, patients with AF who had a cardioversion, follow-up data and an AF diagnosis within 6 months of enrolment were identified retrospectively. Clinical outcomes were compared for patients receiving a NOAC or VKA for 1 year following cardioversion.
Results
Among 13 004 patients with AF, 2260 (17%) underwent cardioversion. 1613 met the inclusion criteria for this analysis. At the time of cardioversion, 283 (17.5%) were receiving a VKA and 1330 (82.5%) a NOAC. A transoesophageal echocardiogram (TOE) was performed in 403 (25%) cardioversions. The incidence of stroke/transient ischaemic attack (TIA) at 30 days was the same for patients having (3.04 per 100 patient-years) or not having (3.04 per 100 patient-years) a TOE (p=0.99). There were no differences in the incidence of death (HR 1.19, 95% CI 0.62 to 2.28, p=0.61), cardiovascular hospitalisation (HR 1.02, 95% CI 0.76 to 1.35, p=0.91), stroke/TIA (HR 1.18, 95% CI 0.30 to 4.74, p=0.81) or bleeding-related hospitalisation (HR 1.29, 95% CI 0.66 to 2.52, p=0.45) at 1 year for patients treated with either a NOAC or VKA.
Conclusions
Cardioversion was a low-risk procedure for patients treated with NOAC, and there were statistically similar rates of stroke/TIA 30 days after cardioversion as for patients treated with VKA. There were no statically significant differences in death, stroke/TIA or major bleeding at 1 year among patients treated with NOAC compared with VKA after cardioversion.

© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 30 Mar 2021; 107:642-649
Geurink K, Holmes D, Ezekowitz MD, Pieper K, ... Peterson ED, Pokorney SD
Heart: 30 Mar 2021; 107:642-649 | PMID: 32591363
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Abstract

Left ventricular myocardial deformation as measure of hemodynamic burden in congenital valvular aortic stenosis.

Reddy SC, Zhang J, Jani V, Wolfe SB, ... Kutty S, Pignatelli RH
Background
Changes in 2D echocardiography (2DE) speckle tracking imaging (STI) derived left ventricular (LV) strain (S) and strain rate (SR) precedes diminution of LV ejection fraction (LVEF) in adult valvular aortic stenosis (AS). We prospectively examined whether 2DE-STI derived multidirectional LV S and SR correlate with AS severity in children using LV mass index (MI) as the principal outcome variable.
Methods
52 children (10.4 ± 7.3 years) with isolated congenital AS were included; 13 mild (2.5 m/s < V < 3.0 m/s), 25 moderate (3.0 m/s < V < 4.0 m/s), and 14 severe (V > 4.0 m/s). 2DE including Doppler and STI longitudinal strain (LS), strain rate (LSR), circumferential strain (CS), and strain rate (CSR) were measured. Univariate and multivariable linear regressions identified correlations between LVMI and strain indices.
Results
Three clinical and 2DE variables, and four strain indices were independently associated with LVMI. LVMI correlated positively with systolic blood pressure and aortic regurgitation, and negatively with LVEF. LVMI correlated positively with LSR (four-chamber) and CSR (basal), and negatively with segmental CS in the inferior (basal) and anteroseptal (distal) segments. LVMI showed significant inverse association with GLS (P = .05), GLSR (P < .001), CS (P < .005), CSR (P < .0001), RSR (P < .001), independent of AS severity.
Conclusions
Independent of clinical and 2DE findings including contemporaneous Doppler estimates of AS gradient, both longitudinal and circumferential strain indices correlate with LVMI as a measure of cumulative hemodynamic burden. This association implies subclinical LV dysfunction.

Copyright © 2020. Published by Elsevier B.V.

Int J Cardiol: 13 Jul 2020; epub ahead of print
Reddy SC, Zhang J, Jani V, Wolfe SB, ... Kutty S, Pignatelli RH
Int J Cardiol: 13 Jul 2020; epub ahead of print | PMID: 32679139
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Abstract

The ACTN3 577XX Null Genotype Is Associated with Low Left Ventricular Dilation-Free Survival Rate in Patients with Duchenne Muscular Dystrophy.

Nagai M, Awano H, Yamamoto T, Bo R, Matsuo M, Iijima K
Background
Duchenne muscular dystrophy (DMD) is a fatal progressive muscle-wasting disease caused by mutations in the DMD gene. Dilated cardiomyopathy is the leading cause of death in DMD; therefore, further understanding of this complication is essential to reduce morbidity and mortality.
Methods
A common null variant (R577X) in the ACTN3 gene, which encodes α-actinin-3, has been studied in association with muscle function in healthy individuals; however it has not yet been examined in relationship to the cardiac phenotype in DMD. In this study, we determined the ACTN3 genotype in 163 patients with DMD and examined the correlation between ACTN3 genotypes and echocardiographic findings in 77 of the 163 patients.
Results
The genotypes 577RR(RR), 577RX(RX) and 577XX(XX) were identified in 13 (17%), 44 (57%) and 20 (26%) of 77 patients, respectively. We estimated cardiac involvement-free survival rate analyses using Kaplan-Meier curves. Remarkably, the left ventricular dilation (> 55 mm)-free survival rate was significantly lower in patients with the XX null genotype (P < 0.01). The XX null genotype showed a higher risk for LV dilation (hazard ratio 9.04).
Conclusions
This study revealed that the ACTN3 XX null genotype was associated with a lower left ventricular dilation-free survival rate in patients with DMD. These results suggest that the ACTN3 genotype should be determined at the time of diagnosis of DMD to improve patients\' cardiac outcomes.

Copyright © 2020 Elsevier Inc. All rights reserved.

J Card Fail: 29 Sep 2020; 26:841-848
Nagai M, Awano H, Yamamoto T, Bo R, Matsuo M, Iijima K
J Card Fail: 29 Sep 2020; 26:841-848 | PMID: 32791185
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This program is still in alpha version.