Topic: Journal Club Selection

Abstract

Dexmedetomidine or Propofol for Sedation in Mechanically Ventilated Adults with Sepsis.

Hughes CG, Mailloux PT, Devlin JW, Swan JT, ... Pandharipande PP, MENDS2 Study Investigators
Background
Guidelines currently recommend targeting light sedation with dexmedetomidine or propofol for adults receiving mechanical ventilation. Differences exist between these sedatives in arousability, immunity, and inflammation. Whether they affect outcomes differentially in mechanically ventilated adults with sepsis undergoing light sedation is unknown.
Methods
In a multicenter, double-blind trial, we randomly assigned mechanically ventilated adults with sepsis to receive dexmedetomidine (0.2 to 1.5 μg per kilogram of body weight per hour) or propofol (5 to 50 μg per kilogram per minute), with doses adjusted by bedside nurses to achieve target sedation goals set by clinicians according to the Richmond Agitation-Sedation Scale (RASS, on which scores range from -5 [unresponsive] to +4 [combative]). The primary end point was days alive without delirium or coma during the 14-day intervention period. Secondary end points were ventilator-free days at 28 days, death at 90 days, and age-adjusted total score on the Telephone Interview for Cognitive Status questionnaire (TICS-T; scores range from 0 to 100, with a mean of 50±10 and lower scores indicating worse cognition) at 6 months.
Results
Of 432 patients who underwent randomization, 422 were assigned to receive a trial drug and were included in the analyses - 214 patients received dexmedetomidine at a median dose of 0.27 μg per kilogram per hour, and 208 received propofol at a median dose of 10.21 μg per kilogram per minute. The median duration of receipt of the trial drugs was 3.0 days (interquartile range, 2.0 to 6.0), and the median RASS score was -2.0 (interquartile range, -3.0 to -1.0). We found no difference between dexmedetomidine and propofol in the number of days alive without delirium or coma (adjusted median, 10.7 vs. 10.8 days; odds ratio, 0.96; 95% confidence interval [CI], 0.74 to 1.26), ventilator-free days (adjusted median, 23.7 vs. 24.0 days; odds ratio, 0.98; 95% CI, 0.63 to 1.51), death at 90 days (38% vs. 39%; hazard ratio, 1.06; 95% CI, 0.74 to 1.52), or TICS-T score at 6 months (adjusted median score, 40.9 vs. 41.4; odds ratio, 0.94; 95% CI, 0.66 to 1.33). Safety end points were similar in the two groups.
Conclusions
Among mechanically ventilated adults with sepsis who were being treated with recommended light-sedation approaches, outcomes in patients who received dexmedetomidine did not differ from outcomes in those who received propofol. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01739933.).

Copyright © 2021 Massachusetts Medical Society.

N Engl J Med: 14 Apr 2021; 384:1424-1436
Hughes CG, Mailloux PT, Devlin JW, Swan JT, ... Pandharipande PP, MENDS2 Study Investigators
N Engl J Med: 14 Apr 2021; 384:1424-1436 | PMID: 33528922
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Impact:
Abstract

Pathologic Antibodies to Platelet Factor 4 after ChAdOx1 nCoV-19 Vaccination.

Scully M, Singh D, Lown R, Poles A, ... Thomas W, Lester W
Background
The mainstay of control of the coronavirus disease 2019 (Covid-19) pandemic is vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Within a year, several vaccines have been developed and millions of doses delivered. Reporting of adverse events is a critical postmarketing activity.
Methods
We report findings in 23 patients who presented with thrombosis and thrombocytopenia 6 to 24 days after receiving the first dose of the ChAdOx1 nCoV-19 vaccine (AstraZeneca). On the basis of their clinical and laboratory features, we identify a novel underlying mechanism and address the therapeutic implications.
Results
In the absence of previous prothrombotic medical conditions, 22 patients presented with acute thrombocytopenia and thrombosis, primarily cerebral venous thrombosis, and 1 patient presented with isolated thrombocytopenia and a hemorrhagic phenotype. All the patients had low or normal fibrinogen levels and elevated d-dimer levels at presentation. No evidence of thrombophilia or causative precipitants was identified. Testing for antibodies to platelet factor 4 (PF4) was positive in 21 patients, negative in 1 patient, and equivocal in 1 patient. On the basis of the pathophysiological features observed in these patients, we recommend that treatment with platelet transfusions be avoided because of the risk of progression in thrombotic symptoms and that the administration of a nonheparin anticoagulant agent and intravenous immune globulin be considered for the first occurrence of these symptoms.
Conclusions
Vaccination against SARS-CoV-2 remains critical for control of the Covid-19 pandemic. A pathogenic PF4-dependent syndrome, unrelated to the use of heparin therapy, can occur after the administration of the ChAdOx1 nCoV-19 vaccine. Rapid identification of this rare syndrome is important because of the therapeutic implications.

Copyright © 2021 Massachusetts Medical Society.

N Engl J Med: 15 Apr 2021; epub ahead of print
Scully M, Singh D, Lown R, Poles A, ... Thomas W, Lester W
N Engl J Med: 15 Apr 2021; epub ahead of print | PMID: 33861525
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Impact:
Abstract

Bimekizumab versus Secukinumab in Plaque Psoriasis.

Reich K, Warren RB, Lebwohl M, Gooderham M, ... Peterson L, Blauvelt A
Background
Bimekizumab is a monoclonal IgG1 antibody that selectively inhibits both interleukin-17A and interleukin-17F. The efficacy and safety of bimekizumab as compared with secukinumab, which selectively inhibits interleukin-17A alone, in patients with moderate-to-severe plaque psoriasis have not been extensively examined.
Methods
In this phase 3b trial, we randomly assigned patients with moderate-to-severe plaque psoriasis, in a 1:1 ratio, to receive bimekizumab at a dose of 320 mg every 4 weeks or secukinumab at a dose of 300 mg weekly to week 4, followed by every 4 weeks to week 48. At week 16, patients receiving bimekizumab underwent rerandomization, in a 1:2 ratio, to receive maintenance dosing every 4 weeks or every 8 weeks to week 48. The primary end point was 100% reduction from baseline in the Psoriasis Area and Severity Index (PASI) score at week 16. The primary analysis was first tested for the noninferiority of bimekizumab to secukinumab at a margin of -10 percentage points and then tested for superiority.
Results
A total of 1005 patients were screened and 743 were enrolled; 373 patients were assigned to receive bimekizumab and 370 to receive secukinumab. At week 16, a total of 230 patients (61.7%) in the bimekizumab group and 181 (48.9%) in the secukinumab group had a 100% reduction from baseline in the PASI score (PASI 100) (adjusted risk difference, 12.7 percentage points; 95% confidence interval [CI], 5.8 to 19.6); bimekizumab was shown to be noninferior and superior to secukinumab (P<0.001 for noninferiority and superiority). At week 48, a total of 250 patients (67.0%) treated with bimekizumab had a PASI 100 response, as compared with 171 patients (46.2%) treated with secukinumab (adjusted risk difference, 20.9 percentage points; 95% CI, 14.1 to 27.7; P<0.001). At the week 4 time point, 265 patients (71.0%) in the bimekizumab group had 75% or greater reduction from baseline in the PASI score, as compared with 175 patients (47.3%) in the secukinumab group (adjusted risk difference, 23.7; 95% CI, 17.0 to 30.4; P<0.001). Oral candidiasis occurred more often with bimekizumab (72 patients, 19.3%) than with secukinumab (11 patients, 3.0%).
Conclusions
In patients with moderate-to-severe psoriasis, treatment with bimekizumab resulted in greater skin clearance than treatment with secukinumab over 16 and 48 weeks but was associated with oral candidiasis (predominantly mild or moderate as recorded by the investigator). Longer and larger trials are required to determine the comparative effect and risks of interleukin-17 inhibitors in psoriasis. (Funded by UCB Pharma; BE RADIANT ClinicalTrials.gov number, NCT03536884.).

Copyright © 2021 Massachusetts Medical Society.

N Engl J Med: 22 Apr 2021; epub ahead of print
Reich K, Warren RB, Lebwohl M, Gooderham M, ... Peterson L, Blauvelt A
N Engl J Med: 22 Apr 2021; epub ahead of print | PMID: 33891380
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Impact:
Abstract

Vaccine Breakthrough Infections with SARS-CoV-2 Variants.

Hacisuleyman E, Hale C, Saito Y, Blachere NE, ... Bieniasz PD, Darnell RB
Emerging variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are of clinical concern. In a cohort of 417 persons who had received the second dose of BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna) vaccine at least 2 weeks previously, we identified 2 women with vaccine breakthrough infection. Despite evidence of vaccine efficacy in both women, symptoms of coronavirus disease 2019 developed, and they tested positive for SARS-CoV-2 by polymerase-chain-reaction testing. Viral sequencing revealed variants of likely clinical importance, including E484K in 1 woman and three mutations (T95I, del142-144, and D614G) in both. These observations indicate a potential risk of illness after successful vaccination and subsequent infection with variant virus, and they provide support for continued efforts to prevent and diagnose infection and to characterize variants in vaccinated persons. (Funded by the National Institutes of Health and others.).

Copyright © 2021 Massachusetts Medical Society.

N Engl J Med: 20 Apr 2021; epub ahead of print
Hacisuleyman E, Hale C, Saito Y, Blachere NE, ... Bieniasz PD, Darnell RB
N Engl J Med: 20 Apr 2021; epub ahead of print | PMID: 33882219
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Impact:
Abstract

Clonal Hematopoiesis and Risk of Progression of Heart Failure With Reduced Left Ventricular Ejection Fraction.

Pascual-Figal DA, Bayes-Genis A, Díez-Díez M, Hernández-Vicente Á, ... Sánchez-Cabo F, Fuster JJ
Background
Clonal hematopoiesis driven by somatic mutations in hematopoietic cells, frequently called clonal hematopoiesis of indeterminate potential (CHIP), has been associated with adverse cardiovascular outcomes in population-based studies and in patients with ischemic heart failure (HF) and reduced left ventricular ejection fraction (LVEF). Yet, the impact of CHIP on HF progression, including nonischemic etiology, is unknown.
Objectives
The purpose of this study was to assess the clinical impact of clonal hematopoiesis on HF progression irrespective of its etiology.
Methods
The study cohort comprised 62 patients with HF and LVEF <45% (age 74 ± 7 years, 74% men, 52% nonischemic, and LVEF 30 ± 8%). Deep sequencing was used to detect CHIP mutations with a variant allelic fraction >2% in 54 genes. Patients were followed for at least 3.5 years for various adverse events including death, HF-related death, and HF hospitalization.
Results
CHIP mutations were detected in 24 (38.7%) patients, without significant differences in all-cause mortality (p = 0.151). After adjusting for risk factors, patients with mutations in either DNA methyltransferase 3 alpha (DNMT3A) or Tet methylcytosine dioxygenase 2 (TET2) exhibited accelerated HF progression in terms of death (hazard ratio [HR]: 2.79; 95% confidence interval [CI]: 1.31 to 5.92; p = 0.008), death or HF hospitalization (HR: 3.84; 95% CI: 1.84 to 8.04; p < 0.001) and HF-related death or HF hospitalization (HR: 4.41; 95% CI: 2.15 to 9.03; p < 0.001). In single gene-specific analyses, somatic mutations in DNMT3A or TET2 retained prognostic significance with regard to HF-related death or HF hospitalization (HR: 4.50; 95% CI: 2.07 to 9.74; p < 0.001, for DNMT3A mutations; HR: 3.18; 95% CI: 1.52 to 6.66; p = 0.002, for TET2 mutations). This association remained significant irrespective of ischemic/nonischemic etiology.
Conclusions
Somatic mutations that drive clonal hematopoiesis are common among HF patients with reduced LVEF and are associated with accelerated HF progression regardless of etiology.

Copyright © 2021. Published by Elsevier Inc.

J Am Coll Cardiol: 12 Apr 2021; 77:1747-1759
Pascual-Figal DA, Bayes-Genis A, Díez-Díez M, Hernández-Vicente Á, ... Sánchez-Cabo F, Fuster JJ
J Am Coll Cardiol: 12 Apr 2021; 77:1747-1759 | PMID: 33832602
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Abstract

Myocardial Angiotensin Metabolism in End-Stage Heart Failure.

Pavo N, Prausmüller S, Spinka G, Goliasch G, ... Zuckermann A, Hülsmann M
Background
The myocardium exhibits an adaptive tissue-specific renin-angiotensin system (RAS), and local dysbalance may circumvent the desired effects of pharmacologic RAS inhibition, a mainstay of heart failure with reduced ejection fraction (HFrEF) therapy.
Objectives
This study sought to investigate human myocardial tissue RAS regulation of the failing heart in the light of current therapy.
Methods
Fifty-two end-stage HFrEF patients undergoing heart transplantation (no RAS inhibitor: n = 9; angiotensin-converting enzyme [ACE] inhibitor: n = 28; angiotensin receptor blocker [ARB]: n = 8; angiotensin receptor neprilysin-inhibitor [ARNi]: n = 7) were enrolled. Myocardial angiotensin metabolites and enzymatic activities involved in the metabolism of the key angiotensin peptides angiotensin 1-8 (AngII) and Ang1-7 were determined in left ventricular samples by mass spectrometry. Circulating angiotensin concentrations were assessed for a subgroup of patients.
Results
AngII and Ang2-8 (AngIII) were the dominant peptides in the failing heart, while other metabolites, especially Ang1-7, were below the detection limit. Patients receiving an ARB component (i.e., ARB or ARNi) had significantly higher levels of cardiac AngII and AngIII (AngII: 242 [interquartile range (IQR): 145.7 to 409.9] fmol/g vs 63.0 [IQR: 19.9 to 124.1] fmol/g; p < 0.001; and AngIII: 87.4 [IQR: 46.5 to 165.3] fmol/g vs 23.0 [IQR: <5.0 to 59.3] fmol/g; p = 0.002). Myocardial AngII concentrations were strongly related to circulating AngII levels. Myocardial RAS enzyme regulation was independent from the class of RAS inhibitor used, particularly, a comparable myocardial neprilysin activity was observed for patients with or without ARNi. Tissue chymase, but not ACE, is the main enzyme for cardiac AngII generation, whereas AngII is metabolized to Ang1-7 by prolyl carboxypeptidase but not to ACE2. There was no trace of cardiac ACE2 activity.
Conclusions
The failing heart contains considerable levels of classical RAS metabolites, whereas AngIII might be an unrecognized mediator of detrimental effects on cardiovascular structure. The results underline the importance of pharmacologic interventions reducing circulating AngII actions, yet offer room for cardiac tissue-specific RAS drugs aiming to limit myocardial AngII/AngIII peptide accumulation and actions.

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

J Am Coll Cardiol: 12 Apr 2021; 77:1731-1743
Pavo N, Prausmüller S, Spinka G, Goliasch G, ... Zuckermann A, Hülsmann M
J Am Coll Cardiol: 12 Apr 2021; 77:1731-1743 | PMID: 33832600
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Impact:
Abstract

Transcatheter Versus Surgical Aortic Valve Replacement in Patients With Rheumatic Aortic Stenosis.

Mentias A, Saad M, Desai MY, Krishnaswamy A, ... Kapadia S, Sarrazin MV
Background
Patients with rheumatic aortic stenosis (AS) were excluded from transcatheter aortic valve replacement (TAVR) trials.
Objectives
The authors sought to examine outcomes with TAVR versus surgical aortic valve replacement (SAVR) in patients with rheumatic AS, and versus TAVR in nonrheumatic AS.
Methods
The authors identified Medicare beneficiaries who underwent TAVR or SAVR from October 2015 to December 2017, and then identified patients with rheumatic AS using prior validated International Classification of Diseases, Version 10 codes. Overlap propensity score weighting analysis was used to adjust for measured confounders. The primary study outcome was all-cause mortality. Multiple secondary outcomes were also examined.
Results
The final study cohort included 1,159 patients with rheumatic AS who underwent aortic valve replacement (SAVR, n = 554; TAVR, n = 605), and 88,554 patients with nonrheumatic AS who underwent TAVR. Patients in the SAVR group were younger and with lower prevalence of most comorbidities and frailty scores. After median follow-up of 19 months (interquartile range: 13 to 26 months), there was no difference in all-cause mortality with TAVR versus SAVR (11.2 vs. 7.0 per 100 person-year; adjusted hazard ratio: 1.53; 95% confidence interval: 0.84 to 2.79; p = 0.2). Compared with TAVR in nonrheumatic AS, TAVR for rheumatic AS was associated with similar mortality (15.2 vs. 17.7 deaths per 100 person-years (adjusted hazard ratio: 0.87; 95% confidence interval: 0.68 to 1.09; p = 0.2) after median follow-up of 17 months (interquartile range: 11 to 24 months). None of the rheumatic TAVR patients, <11 SAVR patients, and 242 nonrheumatic TAVR patients underwent repeat aortic valve replacement (124 redo-TAVR and 118 SAVR) at follow-up.
Conclusions
Compared with SAVR, TAVR could represent a viable and possibly durable option for patients with rheumatic AS.

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

J Am Coll Cardiol: 12 Apr 2021; 77:1703-1713
Mentias A, Saad M, Desai MY, Krishnaswamy A, ... Kapadia S, Sarrazin MV
J Am Coll Cardiol: 12 Apr 2021; 77:1703-1713 | PMID: 33832596
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Impact:
Abstract

Randomized Trial of Interleukin-6 Receptor Inhibition in Patients With Acute ST-Segment Elevation Myocardial Infarction.

Broch K, Anstensrud AK, Woxholt S, Sharma K, ... Aukrust P, Gullestad L
Background
Prompt myocardial revascularization with percutaneous coronary intervention (PCI) reduces infarct size and improves outcomes in patients with ST-segment elevation myocardial infarction (STEMI). However, as much as 50% of the loss of viable myocardium may be attributed to the reperfusion injury and the associated inflammatory response.
Objectives
This study sought to evaluate the effect of the interleukin-6 receptor inhibitor tocilizumab on myocardial salvage in acute STEMI.
Methods
The ASSAIL-MI trial was a randomized, double-blind, placebo-controlled trial conducted at 3 high-volume PCI centers in Norway. Patients admitted with STEMI within 6 h of symptom onset were eligible. Consenting patients were randomized in a 1:1 fashion to promptly receive a single infusion of 280 mg tocilizumab or placebo. The primary endpoint was the myocardial salvage index as measured by magnetic resonance imaging after 3 to 7 days.
Results
We randomized 101 patients to tocilizumab and 98 patients to placebo. The myocardial salvage index was larger in the tocilizumab group than in the placebo group (adjusted between-group difference 5.6 [95% confidence interval: 0.2 to 11.3] percentage points, p = 0.04). Microvascular obstruction was less extensive in the tocilizumab arm, but there was no significant difference in the final infarct size between the tocilizumab arm and the placebo arm (7.2% vs. 9.1% of myocardial volume, p = 0.08). Adverse events were evenly distributed across the treatment groups.
Conclusions
Tocilizumab increased myocardial salvage in patients with acute STEMI. (ASSessing the effect of Anti-IL-6 treatment in Myocardial Infarction [ASSAIL-MI]; NCT03004703).

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

J Am Coll Cardiol: 19 Apr 2021; 77:1845-1855
Broch K, Anstensrud AK, Woxholt S, Sharma K, ... Aukrust P, Gullestad L
J Am Coll Cardiol: 19 Apr 2021; 77:1845-1855 | PMID: 33858620
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Impact:
Abstract

Incidence and Outcomes of Pneumonia in Patients With Heart Failure.

Shen L, Jhund PS, Anand IS, Bhatt AS, ... Solomon SD, McMurray JJV
Background
The incidence of pneumonia and subsequent outcomes has not been compared in patients with heart failure and reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF).
Objectives
This study aimed to examine the rate and impact of pneumonia in the PARADIGM-HF (Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor With Angiotensin Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) and PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in Heart Failure with Preserved Ejection Fraction) trials.
Methods
The authors analyzed the incidence of investigator-reported pneumonia and the rates of HF hospitalization, cardiovascular death, and all-cause death before and after the occurrence of pneumonia, and estimated risk after the first occurrence of pneumonia in unadjusted and adjusted analyses (the latter including N-terminal pro-B-type natriuretic peptide).
Results
In PARADIGM-HF, 528 patients (6.3%) developed pneumonia after randomization, giving an incidence rate of 29 (95% CI: 27 to 32) per 1,000 patient-years. In PARAGON-HF, 510 patients (10.6%) developed pneumonia, giving an incidence rate of 39 (95% CI: 36 to 42) per 1,000 patient-years. The subsequent risk of all trial outcomes was elevated after the occurrence of pneumonia. In PARADIGM-HF, the adjusted hazard ratio (HR) for the risk of death from any cause was 4.34 (95% CI: 3.73 to 5.05). The corresponding adjusted HR in PARAGON-HF was 3.76 (95% CI: 3.09 to 4.58).
Conclusions
The incidence of pneumonia was high in patients with HF, especially HFpEF, at around 3 times the expected rate. A first episode of pneumonia was associated with 4-fold higher mortality. (Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor With Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure [PARADIGM-HF], NCT01035255; Prospective Comparison of ARNI [Angiotensin Receptor-Neprilysin Inhibitor] With ARB [Angiotensin Receptor Blocker] Global Outcomes in Heart Failure With Preserved Ejection Fraction [PARAGON-HF], NCT01920711).

Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 26 Apr 2021; 77:1961-1973
Shen L, Jhund PS, Anand IS, Bhatt AS, ... Solomon SD, McMurray JJV
J Am Coll Cardiol: 26 Apr 2021; 77:1961-1973 | PMID: 33888245
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Impact:
Abstract

Myocarditis-associated necrotizing coronary vasculitis: incidence, cause, and outcome.

Frustaci A, Alfarano M, Verardo R, Agrati C, ... Letizia C, Chimenti C
Aims 
Necrotizing coronary vasculitis (NCV) is a rare entity usually associated to myocarditis which incidence, cause, and response to therapy is unreported.
Methods and results 
Among 1916 patients with biopsy-proven myocarditis, 30 had NCV. Endomyocardial samples were retrospectively investigated with immunohistochemistry for toll-like receptor 4 (TLR4) and real-time polymerase chain reaction (PCR) for viral genomes. Serum samples were processed for anti-heart autoantibodies (Abs), IL-1β, IL-6, IL-8, tumour necrosis factor (TNF)-α. Identification of an immunologic pathway (including virus-negativity, TLR4-, and Ab-positivity) was followed by immunosuppression. Myocarditis-NCV cohort was followed for 6 months with 2D-echo and/or cardiac magnetic resonance and compared with 60 Myocarditis patients and 30 controls. Increase in left ventricular ejection fraction ≥10% was classified as response to therapy. Control endomyocardial biopsy followed the end of treatment. Twenty-six Myocarditis-NCV patients presented with heart failure; four with electrical instability. Cause of Myocarditis-NCV included infectious agents (10%) and immune-mediated causes (chest trauma 3%; drug hypersensitivity 7%; hypereosinophilic syndrome 3%; primary autoimmune diseases 33%, idiopathic 44%). Abs were positive in immune-mediated Myocarditis-NCV and virus-negative Myocarditis; Myocarditis-NCV patients with Ab+ presented autoreactivity in vessel walls. Toll-like receptor 4 was overexpressed in immune-mediated forms and poorly detectable in viral. Interleukin-1β was significantly higher in Myocarditis-NCV than Myocarditis, the former presenting 24% in-hospital mortality compared with 1.5% of Myocarditis cohort. Immunosuppression induced improvement of cardiac function in 88% of Myocarditis-NCV and 86% of virus-negative Myocarditis patients.
Conclusion 
Necrotizing coronary vasculitis is histologically detectable in 1.5% of Myocarditis. Necrotizing coronary vasculitis includes viral and immune-mediated causes. Intra-hospital mortality is 24%. The immunologic pathway is associated with beneficial response to immunosuppression.

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

Eur Heart J: 20 Apr 2021; 42:1609-1617
Frustaci A, Alfarano M, Verardo R, Agrati C, ... Letizia C, Chimenti C
Eur Heart J: 20 Apr 2021; 42:1609-1617 | PMID: 33355356
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Impact:
Abstract

MicroRNA-21-Dependent Macrophage-to-Fibroblast Signaling Determines the Cardiac Response to Pressure Overload.

Ramanujam D, Schön AP, Beck C, Vaccarello P, ... Schulz C, Engelhardt S
Background
Cardiac macrophages (cMPs) are increasingly recognized as important regulators of myocardial homeostasis and disease, yet the role of noncoding RNA in these cells is largely unknown. Small RNA sequencing of the entire miRNomes of the major cardiac cell fractions revealed microRNA-21 (miR-21) as the single highest expressed microRNA in cMPs, both in health and disease (25% and 43% of all microRNA reads, respectively). MiR-21 has been previously reported as a key microRNA driving tissue fibrosis. Here, we aimed to determine the function of macrophage miR-21 on myocardial homeostasis and disease-associated remodeling.
Methods
Macrophage-specific ablation of miR-21 in mice driven by Cx3cr1-Cre was used to determine the function of miR-21 in this cell type. As a disease model, mice were subjected to pressure overload for 6 and 28 days. Cardiac function was assessed in vivo by echocardiography, followed by histological analyses and single-cell sequencing. Cocultures of macrophages and cardiac fibroblasts were used to study macrophage-to-fibroblast signaling.
Results
Mice with macrophage-specific genetic deletion of miR-21 were protected from interstitial fibrosis and cardiac dysfunction when subjected to pressure overload of the left ventricle. Single-cell sequencing of pressure-overloaded hearts from these mice revealed that miR-21 in macrophages is essential for their polarization toward a M1-like phenotype. Systematic quantification of intercellular communication mediated by ligand-receptor interactions across all cell types revealed that miR-21 primarily determined macrophage-fibroblast communication, promoting the transition from quiescent fibroblasts to myofibroblasts. Polarization of isolated macrophages in vitro toward a proinflammatory (M1-like) phenotype activated myofibroblast transdifferentiation of cardiac fibroblasts in a paracrine manner and was dependent on miR-21 in cMPs.
Conclusions
Our data indicate a critical role of cMPs in pressure overload-induced cardiac fibrosis and dysfunction and reveal macrophage miR-21 as a key molecule for the profibrotic role of cMPs.



Circulation: 12 Apr 2021; 143:1513-1525
Ramanujam D, Schön AP, Beck C, Vaccarello P, ... Schulz C, Engelhardt S
Circulation: 12 Apr 2021; 143:1513-1525 | PMID: 33550817
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Impact:
Abstract

SARS-CoV-2 Cardiac Involvement in Young Competitive Athletes.

Moulson N, Petek BJ, Drezner JA, Harmon KG, ... Baggish AL, ORCCA Investigators
Background: Cardiac involvement among hospitalized patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is common and associated with adverse outcomes. The objective of this study was to determine the prevalence and clinical implications of SARS-CoV-2 cardiac involvement in young competitive athletes.
Methods:
In this prospective multicenter observational cohort study with data from 42 colleges/universities, we assessed the prevalence, clinical characteristics, and outcomes of SARS-CoV-2 cardiac involvement among collegiate athletes in the United States. Data were collected from September 1, 2020 to December 31, 2020. The primary outcome was the prevalence of definite, probable, or possible SARS-CoV-2 cardiac involvement based on imaging definitions adapted from the Updated Lake Louise Criteria. Secondary outcomes included the diagnostic yield of cardiac testing, predictors for cardiac involvement, and adverse cardiovascular events or hospitalizations.
Results:
Among 19,378 athletes tested for SARS-CoV-2 infection, 3018 (mean age 20 years [SD,1 year]; 32% female) tested positive and underwent cardiac evaluation. A total of 2820 athletes underwent at least one element of cardiac \'triad\' testing [12-lead electrocardiography (ECG), troponin, and/or transthoracic echocardiography(TTE)] followed by cardiac magnetic resonance (CMR) if clinically indicated. In contrast, primary screening CMR was performed in 198 athletes. Abnormal findings suggestive of SARS-CoV-2 cardiac involvement were detected by ECG (21/2999,0.7%), cardiac troponin (24/2719,0.9%), and TTE (24/2556,0.9%). Definite, probable, or possible SARS-COV-2 cardiac involvement was identified in 21/3018 (0.7%) athletes, including 15/2820 (0.5%) who underwent clinically indicated CMR (n=119) and 6/198 (3.0%) who underwent primary screening CMR. Accordingly, the diagnostic yield of CMR for SARS-COV-2 cardiac involvement was 4.2 times higher for a clinically indicated CMR (15/119,12.6%) versus a primary screening CMR (6/198,3.0%). After adjustment for race and sex, predictors of SARS-CoV-2 cardiac involvement included cardiopulmonary symptoms (OR:3.1,95% CI:1.2,7.7) or at least one abnormal triad test (OR:37.4,95% CI:13.3,105.3). Five (0.2%) athletes required hospitalization for non-cardiac complications of SARS-CoV-2. During clinical surveillance (median follow-up 113 days [IQR=90,146]), there was one (0.03%) adverse cardiac event likely unrelated to SARS-CoV-2 infection. Conclusions: SARS-CoV-2 infection among young competitive athletes is associated with a low prevalence of cardiac involvement and a low risk of clinical events in short term follow-up.




Circulation: 16 Apr 2021; epub ahead of print
Moulson N, Petek BJ, Drezner JA, Harmon KG, ... Baggish AL, ORCCA Investigators
Circulation: 16 Apr 2021; epub ahead of print | PMID: 33866822
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Impact:
Abstract

Excessive -GlcNAcylation Causes Heart Failure and Sudden Death.

Umapathi P, Mesubi OO, Banerjee PS, Abrol N, ... Zachara NE, Anderson ME
Background
Heart failure is a leading cause of death worldwide and is associated with the rising prevalence of obesity, hypertension, and diabetes. O-GlcNAcylation (the attachment of O-linked β-N-acetylglucosamine [O-GlcNAc] moieties to cytoplasmic, nuclear, and mitochondrial proteins) is a posttranslational modification of intracellular proteins and serves as a metabolic rheostat for cellular stress. Total levels of O-GlcNAcylation are determined by nutrient and metabolic flux, in addition to the net activity of 2 enzymes: O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). Failing myocardium is marked by increased O-GlcNAcylation, but whether excessive O-GlcNAcylation contributes to cardiomyopathy and heart failure is unknown.
Methods
We developed 2 new transgenic mouse models with myocardial overexpression of OGT and OGA to control O-GlcNAcylation independent of pathologic stress.
Results
We found that OGT transgenic hearts showed increased O-GlcNAcylation and developed severe dilated cardiomyopathy, ventricular arrhythmias, and premature death. In contrast, OGA transgenic hearts had lower O-GlcNAcylation but identical cardiac function to wild-type littermate controls. OGA transgenic hearts were resistant to pathologic stress induced by pressure overload with attenuated myocardial O-GlcNAcylation levels after stress and decreased pathologic hypertrophy compared with wild-type controls. Interbreeding OGT with OGA transgenic mice rescued cardiomyopathy and premature death, despite persistent elevation of myocardial OGT. Transcriptomic and functional studies revealed disrupted mitochondrial energetics with impairment of complex I activity in hearts from OGT transgenic mice. Complex I activity was rescued by OGA transgenic interbreeding, suggesting an important role for mitochondrial complex I in O-GlcNAc-mediated cardiac pathology.
Conclusions
Our data provide evidence that excessive O-GlcNAcylation causes cardiomyopathy, at least in part, attributable to defective energetics. Enhanced OGA activity is well tolerated and attenuation of O-GlcNAcylation is beneficial against pressure overload-induced pathologic remodeling and heart failure. These findings suggest that attenuation of excessive O-GlcNAcylation may represent a novel therapeutic approach for cardiomyopathy.



Circulation: 26 Apr 2021; 143:1687-1703
Umapathi P, Mesubi OO, Banerjee PS, Abrol N, ... Zachara NE, Anderson ME
Circulation: 26 Apr 2021; 143:1687-1703 | PMID: 33593071
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Abstract

Invasive Management of Acute Myocardial Infarction Complicated by Cardiogenic Shock: A Scientific Statement From the American Heart Association.

Henry TD, Tomey MI, Tamis-Holland JE, Thiele H, ... American Heart Association Interventional Cardiovascular Care Committee of the Council on Clinical Cardiology; Council on Arteriosclerosis, Thrombosis and Vascular Biology; and Council on Cardiovascular and Stroke Nursing
Cardiogenic shock (CS) remains the most common cause of mortality in patients with acute myocardial infarction. The SHOCK trial (Should We Emergently Revascularize Occluded Coronaries for Cardiogenic Shock) demonstrated a survival benefit with early revascularization in patients with CS complicating acute myocardial infarction (AMICS) 20 years ago. After an initial improvement in mortality related to revascularization, mortality rates have plateaued. A recent Society of Coronary Angiography and Interventions classification scheme was developed to address the wide range of CS presentations. In addition, a recent scientific statement from the American Heart Association recommended the development of CS centers using standardized protocols for diagnosis and management of CS, including mechanical circulatory support devices (MCS). A number of CS programs have implemented various protocols for treating patients with AMICS, including the use of MCS, and have published promising results using such protocols. Despite this, practice patterns in the cardiac catheterization laboratory vary across health systems, and there are inconsistencies in the use or timing of MCS for AMICS. Furthermore, mortality benefit from MCS devices in AMICS has yet to be established in randomized clinical trials. In this article, we outline the best practices for the contemporary interventional management of AMICS, including coronary revascularization, the use of MCS, and special considerations such as the treatment of patients with AMICS with cardiac arrest.



Circulation: 12 Apr 2021; 143:e815-e829
Henry TD, Tomey MI, Tamis-Holland JE, Thiele H, ... American Heart Association Interventional Cardiovascular Care Committee of the Council on Clinical Cardiology; Council on Arteriosclerosis, Thrombosis and Vascular Biology; and Council on Cardiovascular and Stroke Nursing
Circulation: 12 Apr 2021; 143:e815-e829 | PMID: 33657830
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Abstract

Spontaneous Cervical Artery Dissection in Vascular Ehlers-Danlos Syndrome: A Cohort Study.

Adham S, Billon C, Legrand A, Domigo V, ... Jeunemaitre X, Frank M
Background:
and purpose
Vascular Ehlers-Danlos syndrome is a rare inherited connective tissue disorder because of pathogenic variants in the COL3A1 gene. Arterial complications can affect all anatomic areas and about 25% involve supra-aortic trunks (SATs) but no systematic assessment of cervical artery lesions has been made. The primary objective was to determine an accurate prevalence of spontaneous SAT lesions in a large series of patients with vascular Ehlers-Danlos syndrome at diagnosis and during follow-up. Secondary objectives were to study their neurological consequences (transient ischemic attack or stroke) and the possible relationships with sex, genotype, ascertainment status.
Methods
A retrospective review of a monocentric cohort of patients with molecularly proven vascular Ehlers-Danlos syndrome followed in a tertiary referral center from 2000 to 2017.
Results
One hundred forty-four patients were analyzed, 56.9% (n=82) had SAT lesions: 64.6% females, 74.4% index-case patients. Most lesions were identified in early arterial assessment (48% at first work-up, mean age of 35.7±13.0 years). Cumulative incidence of a first identification of a SAT lesion was 41.7% at 40 years old. On the complete period of survey, 183 SAT lesions (with 132 dissections and 33 aneurysms) were identified, mainly in internal carotid arteries (56.3%) and vertebral arteries (28.9%), more rarely in patients with COL3A1 null mutations (P=0.008). Transient ischemic attack or stroke were reported in n=16 (19.5%) of the 82 patients with SAT lesions without relation with age, sex, treatment, or hypertension.
Conclusions
Cervical artery lesions are frequent and mostly asymptomatic in patients with vascular Ehlers-Danlos syndrome. Local dissections and aneurysms are the most frequent type of lesions, but transient ischemic attack or stroke seem rare.



Stroke: 29 Apr 2021; 52:1628-1635
Adham S, Billon C, Legrand A, Domigo V, ... Jeunemaitre X, Frank M
Stroke: 29 Apr 2021; 52:1628-1635 | PMID: 33641388
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Abstract

Current Therapeutic Options in Aortic Stenosis.

Boskovski MT, Gleason TG
Aortic stenosis is the most common valvular disease requiring valve replacement. Valve replacement therapies have undergone progressive evolution since the 1960s. Over the last 20 years, transcatheter aortic valve replacement has radically transformed the care of aortic stenosis, such that it is now the treatment of choice for many, particularly elderly, patients. This review provides an overview of the pathophysiology, presentation, diagnosis, indications for intervention, and current therapeutic options for aortic stenosis.



Circ Res: 29 Apr 2021; 128:1398-1417
Boskovski MT, Gleason TG
Circ Res: 29 Apr 2021; 128:1398-1417 | PMID: 33914604
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Abstract

Transcatheter Closure of Atrial Septal Defect Associated With Pulmonary Artery Hypertension using Fenestrated Devices.

Wang JK, Chiu SN, Lin MT, Chen CA, Lu CW, Wu MH
In patients with pulmonary artery hypertension (PAH) associated with atrial septal defect (ASD), closure of ASD may carry significant risks. We aimed to evaluate the safety and efficacy of transcatheter closure of ASD in selected patients with PAH using a fenestrated device followed by pulmonary vasodilator therapy. During the 14.8-year period, 51 ASD patients (10 males, age 46 ± 18 years) with a mean pulmonary artery pressure (PAP) ≥ 35 mm Hg and/or systolic PAP ≥ 60 mm Hg, underwent closure with a fenestrated device. Of them, mean Qp/Qs ratio, systolic PAP and mean PAP were 2.6 ± 1.2, 73 ± 14 mm Hg, and 44 ± 8 mm Hg, respectively. A total of 35 patients received pulmonary vasodilator therapy. The New York Heart Association (NYHA) functional class improved at 3 to 6 months follow-up. (p < 0.001) Nineteen patients underwent repeated catheterization. A comparison of the hemodynamic parameters between baseline and repeated catheterization revealed significant decreases in both systolic and mean PAP (77 ± 11 vs 55 ± 14 mm Hg, p < 0.0001 & 48 ± 7 vs 37 ± 8 mm Hg, p = 0.001, respectively), pulmonary vascular resistance (PVR) (5.1 ± 2.3 vs 4.0 ± 1.7 WU, p = 0.011) and PVRi (7.7 ± 3.3 vs 6.2 ± 2.4 WU*m2, p = 0.024). After a follow-up period of 84 ± 45 months, 6 mortalities were noted in which 2 were due to cardiac causes. In conclusion, catheter closure of ASD in patients with PAH using a fenestrated device followed by vasodilator therapy is safe and effective.

Copyright © 2021. Published by Elsevier Inc.

Am J Cardiol: 14 May 2021; 147:122-128
Wang JK, Chiu SN, Lin MT, Chen CA, Lu CW, Wu MH
Am J Cardiol: 14 May 2021; 147:122-128 | PMID: 33667439
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This program is still in alpha version.