Topic: Journal Club Selection

Abstract

Multisystem Inflammatory Syndrome in Children - Initial Therapy and Outcomes.

Son MBF, Murray N, Friedman K, Young CC, ... Randolph AG, Overcoming COVID-19 Investigators
Background
The assessment of real-world effectiveness of immunomodulatory medications for multisystem inflammatory syndrome in children (MIS-C) may guide therapy.
Methods
We analyzed surveillance data on inpatients younger than 21 years of age who had MIS-C and were admitted to 1 of 58 U.S. hospitals between March 15 and October 31, 2020. The effectiveness of initial immunomodulatory therapy (day 0, indicating the first day any such therapy for MIS-C was given) with intravenous immune globulin (IVIG) plus glucocorticoids, as compared with IVIG alone, was evaluated with propensity-score matching and inverse probability weighting, with adjustment for baseline MIS-C severity and demographic characteristics. The primary outcome was cardiovascular dysfunction (a composite of left ventricular dysfunction or shock resulting in the use of vasopressors) on or after day 2. Secondary outcomes included the components of the primary outcome, the receipt of adjunctive treatment (glucocorticoids in patients not already receiving glucocorticoids on day 0, a biologic, or a second dose of IVIG) on or after day 1, and persistent or recurrent fever on or after day 2.
Results
A total of 518 patients with MIS-C (median age, 8.7 years) received at least one immunomodulatory therapy; 75% had been previously healthy, and 9 died. In the propensity-score-matched analysis, initial treatment with IVIG plus glucocorticoids (103 patients) was associated with a lower risk of cardiovascular dysfunction on or after day 2 than IVIG alone (103 patients) (17% vs. 31%; risk ratio, 0.56; 95% confidence interval [CI], 0.34 to 0.94). The risks of the components of the composite outcome were also lower among those who received IVIG plus glucocorticoids: left ventricular dysfunction occurred in 8% and 17% of the patients, respectively (risk ratio, 0.46; 95% CI, 0.19 to 1.15), and shock resulting in vasopressor use in 13% and 24% (risk ratio, 0.54; 95% CI, 0.29 to 1.00). The use of adjunctive therapy was lower among patients who received IVIG plus glucocorticoids than among those who received IVIG alone (34% vs. 70%; risk ratio, 0.49; 95% CI, 0.36 to 0.65), but the risk of fever was unaffected (31% and 40%, respectively; risk ratio, 0.78; 95% CI, 0.53 to 1.13). The inverse-probability-weighted analysis confirmed the results of the propensity-score-matched analysis.
Conclusions
Among children and adolescents with MIS-C, initial treatment with IVIG plus glucocorticoids was associated with a lower risk of new or persistent cardiovascular dysfunction than IVIG alone. (Funded by the Centers for Disease Control and Prevention.).

Copyright © 2021 Massachusetts Medical Society.

N Engl J Med: 30 Jun 2021; 385:23-34
Son MBF, Murray N, Friedman K, Young CC, ... Randolph AG, Overcoming COVID-19 Investigators
N Engl J Med: 30 Jun 2021; 385:23-34 | PMID: 34133855
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Abstract

Cardiovascular and Renal Outcomes with Efpeglenatide in Type 2 Diabetes.

Gerstein HC, Sattar N, Rosenstock J, Ramasundarahettige C, ... Branch K, AMPLITUDE-O Trial Investigators
Background
Four glucagon-like peptide-1 (GLP-1) receptor agonists that are structurally similar to human GLP-1 have been shown to reduce the risk of adverse cardiovascular events among persons with type 2 diabetes. The effect of an exendin-based GLP-1 receptor agonist, efpeglenatide, on cardiovascular and renal outcomes in patients with type 2 diabetes who are also at high risk for adverse cardiovascular events is uncertain.
Methods
In this randomized, placebo-controlled trial conducted at 344 sites across 28 countries, we evaluated efpeglenatide in participants with type 2 diabetes and either a history of cardiovascular disease or current kidney disease (defined as an estimated glomerular filtration rate of 25.0 to 59.9 ml per minute per 1.73 m2 of body-surface area) plus at least one other cardiovascular risk factor. Participants were randomly assigned in a 1:1:1 ratio to receive weekly subcutaneous injections of efpeglenatide at a dose of 4 or 6 mg or placebo. Randomization was stratified according to use of sodium-glucose cotransporter 2 inhibitors. The primary outcome was the first major adverse cardiovascular event (MACE; a composite of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular or undetermined causes).
Results
A total of 4076 participants were enrolled; 2717 were assigned to receive efpeglenatide and 1359 to receive placebo. During a median follow-up of 1.81 years, an incident MACE occurred in 189 participants (7.0%) assigned to receive efpeglenatide (3.9 events per 100 person-years) and 125 participants (9.2%) assigned to receive placebo (5.3 events per 100 person-years) (hazard ratio, 0.73; 95% confidence interval [CI], 0.58 to 0.92; P<0.001 for noninferiority; P = 0.007 for superiority). A composite renal outcome event (a decrease in kidney function or macroalbuminuria) occurred in 353 participants (13.0%) assigned to receive efpeglenatide and in 250 participants (18.4%) assigned to receive placebo (hazard ratio, 0.68; 95% CI, 0.57 to 0.79; P<0.001). Diarrhea, constipation, nausea, vomiting, or bloating occurred more frequently with efpeglenatide than with placebo.
Conclusions
In this trial involving participants with type 2 diabetes who had either a history of cardiovascular disease or current kidney disease plus at least one other cardiovascular risk factor, the risk of cardiovascular events was lower among those who received weekly subcutaneous injections of efpeglenatide at a dose of 4 or 6 mg than among those who received placebo. (Funded by Sanofi; AMPLITUDE-O ClinicalTrials.gov number, NCT03496298.).

Copyright © 2021 Massachusetts Medical Society.

N Engl J Med: 27 Jun 2021; epub ahead of print
Gerstein HC, Sattar N, Rosenstock J, Ramasundarahettige C, ... Branch K, AMPLITUDE-O Trial Investigators
N Engl J Med: 27 Jun 2021; epub ahead of print | PMID: 34215025
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Abstract

Tofacitinib in Patients Hospitalized with Covid-19 Pneumonia.

Guimarães PO, Quirk D, Furtado RH, Maia LN, ... Berwanger O, STOP-COVID Trial Investigators
Background
The efficacy and safety of tofacitinib, a Janus kinase inhibitor, in patients who are hospitalized with coronavirus disease 2019 (Covid-19) pneumonia are unclear.
Methods
We randomly assigned, in a 1:1 ratio, hospitalized adults with Covid-19 pneumonia to receive either tofacitinib at a dose of 10 mg or placebo twice daily for up to 14 days or until hospital discharge. The primary outcome was the occurrence of death or respiratory failure through day 28 as assessed with the use of an eight-level ordinal scale (with scores ranging from 1 to 8 and higher scores indicating a worse condition). All-cause mortality and safety were also assessed.
Results
A total of 289 patients underwent randomization at 15 sites in Brazil. Overall, 89.3% of the patients received glucocorticoids during hospitalization. The cumulative incidence of death or respiratory failure through day 28 was 18.1% in the tofacitinib group and 29.0% in the placebo group (risk ratio, 0.63; 95% confidence interval [CI], 0.41 to 0.97; P = 0.04). Death from any cause through day 28 occurred in 2.8% of the patients in the tofacitinib group and in 5.5% of those in the placebo group (hazard ratio, 0.49; 95% CI, 0.15 to 1.63). The proportional odds of having a worse score on the eight-level ordinal scale with tofacitinib, as compared with placebo, was 0.60 (95% CI, 0.36 to 1.00) at day 14 and 0.54 (95% CI, 0.27 to 1.06) at day 28. Serious adverse events occurred in 20 patients (14.1%) in the tofacitinib group and in 17 (12.0%) in the placebo group.
Conclusions
Among patients hospitalized with Covid-19 pneumonia, tofacitinib led to a lower risk of death or respiratory failure through day 28 than placebo. (Funded by Pfizer; STOP-COVID ClinicalTrials.gov number, NCT04469114.).

Copyright © 2021 Massachusetts Medical Society.

N Engl J Med: 15 Jun 2021; epub ahead of print
Guimarães PO, Quirk D, Furtado RH, Maia LN, ... Berwanger O, STOP-COVID Trial Investigators
N Engl J Med: 15 Jun 2021; epub ahead of print | PMID: 34133856
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Abstract

Classification of Heart Failure According to Ejection Fraction: JACC Review Topic of the Week.

Lam CSP, Solomon SD
The recent U.S. Food and Drug Administration expanded indication for sacubitril/valsartan introduces a new potential taxonomy for heart failure, with no reference to \"preserved\" ejection fraction but referring to \"below normal\" ejection fraction as those most likely to benefit. This review summarizes the evolution of nomenclature in heart failure and examines evidence showing that patients with ejection fraction in the \"mid range\" may benefit from neurohormonal blockade similar to those with more severely reduced (<40%) ejection fraction. Furthermore, prominent sex differences have been observed wherein the benefit of neurohormonal blockade appears to extend to a higher ejection fraction range in women compared to men. Based on emerging evidence, revised nomenclature is proposed defining heart failure with \"reduced\" (<40%), \"mildly reduced,\" and \"normal\" (≥55% in men, ≥60% in women) ejection fraction. Such nomenclature signals consideration of potentially beneficial therapies in the largest group of patients with reduced or mildly reduced ejection fraction.

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

J Am Coll Cardiol: 28 Jun 2021; 77:3217-3225
Lam CSP, Solomon SD
J Am Coll Cardiol: 28 Jun 2021; 77:3217-3225 | PMID: 34167646
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Abstract

Systematic Coronary Risk Evaluation (SCORE): JACC Focus Seminar 4/8.

Graham IM, Di Angelantonio E, Visseren F, De Bacquer D, ... Cooney MT, European Society of Cardiology Cardiovascular Risk Collaboration
Clinical estimation of the combined effect of several risk factors is unreliable and this resulted in the development of a number of risk estimation systems to guide clinical practice. Here, after defining general principles of risk estimation, the authors describe the evolution of the European Society of Cardiology\'s (ESC) Systematic COronary Risk Evaluation (SCORE) risk estimation system and some learnings from the data. They move on to describe the establishment of the ESC\'s Cardiovascular Risk Collaboration and outline its proposed research directions. First among these is the evolution of SCORE 2, which provides updated, calibrated risk estimates for total cardiovascular events for low, moderate, high, and very high-risk regions of Europe. The authors conclude by considering that the future of risk estimation may be to express risk as years of exposure to a cardiovascular risk factor profile rather than risk over a fixed time period, such as 10 years, and how advances in genetics may permit individualized lifetime risk estimation from childhood on.

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

J Am Coll Cardiol: 21 Jun 2021; 77:3046-3057
Graham IM, Di Angelantonio E, Visseren F, De Bacquer D, ... Cooney MT, European Society of Cardiology Cardiovascular Risk Collaboration
J Am Coll Cardiol: 21 Jun 2021; 77:3046-3057 | PMID: 34140109
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Abstract

Statin associated lower cancer risk and related mortality in patients with heart failure.

Ren QW, Yu SY, Teng TK, Li X, ... Lam CSP, Yiu KH
Aims
Patients with heart failure (HF) have an increased risk of incident cancer. Data relating to the association of statin use with cancer risk and cancer-related mortality among patients with HF are sparse.
Methods and results
Using a previously validated territory-wide clinical information registry, statin use was ascertained among all eligible patients with HF (n = 87 102) from 2003 to 2015. Inverse probability of treatment weighting was used to balance baseline covariates between statin nonusers (n = 50 926) with statin users (n = 36 176). Competing risk regression with Cox proportional-hazard models was performed to estimate the risk of cancer and cancer-related mortality associated with statin use. Of all eligible subjects, the mean age was 76.5 ± 12.8 years, and 47.8% was male. Over a median follow-up of 4.1 years (interquartile range: 1.6-6.8), 11 052 (12.7%) were diagnosed with cancer. Statin use (vs. none) was associated with a 16% lower risk of cancer incidence [multivariable adjusted subdistribution hazard ratio (SHR) = 0.84; 95% confidence interval (CI), 0.80-0.89]. This inverse association with risk of cancer was duration dependent; as compared with short-term statin use (3 months to <2 years), the adjusted SHR was 0.99 (95% CI, 0.87-1.13) for 2 to <4 years of use, 0.82 (95% CI, 0.70-0.97) for 4 to <6 years of use, and 0.78 (95% CI, 0.65-0.93) for ≥6 years of use. Ten-year cancer-related mortality was 3.8% among statin users and 5.2% among nonusers (absolute risk difference, -1.4 percentage points [95% CI, -1.6% to -1.2%]; adjusted SHR = 0.74; 95% CI, 0.67-0.81).
Conclusion
Our study suggests that statin use is associated with a significantly lower risk of incident cancer and cancer-related mortality in HF, an association that appears to be duration dependent.

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

Eur Heart J: 21 Jun 2021; epub ahead of print
Ren QW, Yu SY, Teng TK, Li X, ... Lam CSP, Yiu KH
Eur Heart J: 21 Jun 2021; epub ahead of print | PMID: 34157723
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Abstract

STING, a cytosolic DNA sensor, plays a critical role in atherogenesis: a link between innate immunity and chronic inflammation caused by lifestyle-related diseases.

Pham PT, Fukuda D, Nishimoto S, Kim-Kaneyama JR, ... Barber GN, Sata M
Aims 
Lifestyle-related diseases promote atherosclerosis, a chronic inflammatory disease; however, the molecular mechanism remains largely unknown. Endogenous DNA fragments released under over-nutrient condition provoke sterile inflammation through the recognition by DNA sensors. Here, we investigated the role of stimulator of interferon genes (STING), a cytosolic DNA sensor, in atherogenesis.
Methods and results 
Apolipoprotein E-deficient (Apoe-/-) mice fed a western-type diet (WTD), a hypercholesterolaemic mouse model, showed higher STING expression and markers for DNA damage such as γH2AX, p53, and single-stranded DNA (ssDNA) accumulation in macrophages in the aorta compared with wild-type (WT) mice. The level of cGAMP, a STING agonist, in the aorta was higher in Apoe-/- mice. Genetic deletion of Sting in Apoe-/- mice reduced atherosclerotic lesions in the aortic arch, lipid, and macrophage accumulation in plaques, and inflammatory molecule expression in the aorta compared with the control. Pharmacological blockade of STING using a specific inhibitor, C-176, ameliorated atherogenesis in Apoe-/- mice. In contrast, bone marrow-specific STING expression in Apoe-/- mice stimulated atherogenesis. Expression or deletion of STING did not affect metabolic parameters and blood pressure. In vitro studies revealed that STING activation by cGAMP or mitochondrial DNA accelerated inflammatory molecule expression (e.g. TNF-α or IFN-β) in mouse and human macrophages. Activation of nuclear factor-κB and TANK binding kinase 1 was involved in STING-associated vascular inflammation and macrophage activation. Furthermore, human atherosclerotic lesions in the carotid arteries expressed STING and cGAMP.
Conclusion 
Stimulator of interferon genes stimulates pro-inflammatory activation of macrophages, leading to the development of atherosclerosis. Stimulator of interferon genes signalling may serve as a potential therapeutic target for atherosclerosis.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: [email protected]

Eur Heart J: 05 Jul 2021; epub ahead of print
Pham PT, Fukuda D, Nishimoto S, Kim-Kaneyama JR, ... Barber GN, Sata M
Eur Heart J: 05 Jul 2021; epub ahead of print | PMID: 34226923
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Abstract

Eight-year outcomes for patients with aortic valve stenosis at low surgical risk randomized to transcatheter vs. surgical aortic valve replacement.

Jørgensen TH, Thyregod HGH, Ihlemann N, Nissen H, ... Olsen PS, Søndergaard L
Aims
The aims of the study were to compare clinical outcomes and valve durability after 8 years of follow-up in patients with symptomatic severe aortic valve stenosis at low surgical risk treated with either transcatheter aortic valve implantation (TAVI) or surgical aortic valve replacement (SAVR).
Methods and results
In the NOTION trial, patients with symptomatic severe aortic valve stenosis were randomized to TAVI or SAVR. Clinical status, echocardiography, structural valve deterioration, and failure were assessed using standardized definitions. In total, 280 patients were randomized to TAVI (n = 145) or SAVR (n = 135). Baseline characteristics were similar, including mean age of 79.1 ± 4.8 years and a mean STS score of 3.0 ± 1.7%. At 8-year follow-up, the estimated risk of the composite outcome of all-cause mortality, stroke, or myocardial infarction was 54.5% after TAVI and 54.8% after SAVR (P = 0.94). The estimated risks for all-cause mortality (51.8% vs. 52.6%; P = 0.90), stroke (8.3% vs. 9.1%; P = 0.90), or myocardial infarction (6.2% vs. 3.8%; P = 0.33) were similar after TAVI and SAVR. The risk of structural valve deterioration was lower after TAVI than after SAVR (13.9% vs. 28.3%; P = 0.0017), whereas the risk of bioprosthetic valve failure was similar (8.7% vs. 10.5%; P = 0.61).
Conclusions
In patients with severe aortic valve stenosis at low surgical risk randomized to TAVI or SAVR, there were no significant differences in the risk for all-cause mortality, stroke, or myocardial infarction, as well as the risk of bioprosthetic valve failure after 8 years of follow-up.
Clinical trial registration
URL: http://www.ClinicalTrials.gov. Unique identifier: NCT01057173.

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

Eur Heart J: 27 Jun 2021; epub ahead of print
Jørgensen TH, Thyregod HGH, Ihlemann N, Nissen H, ... Olsen PS, Søndergaard L
Eur Heart J: 27 Jun 2021; epub ahead of print | PMID: 34179981
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Abstract

Tubulin-folding cofactor E deficiency promotes vascular dysfunction by increased endoplasmic reticulum stress.

Efentakis P, Molitor M, Kossmann S, Bochenek ML, ... Münzel T, Wenzel P
Aims
Assessment of endothelial function in humans by measuring flow-mediated dilation (FMD) risk-stratifies individuals with established cardiovascular disease, whereas its predictive value is limited in primary prevention. We therefore aimed to establish and evaluate novel markers of FMD at the population level.
Methods and results
In order to identify novel targets that were negatively correlated with FMD and investigate their contribution to vascular function, we performed a genome-wide association study (GWAS) of 4175 participants of the population based Gutenberg Health Study. Subsequently, conditional knockout mouse models deleting the gene of interest were generated and characterized. GWAS analysis revealed that single-nucleotide polymorphisms (SNPs) in the tubulin-folding cofactor E (TBCE) gene were negatively correlated with endothelial function and TBCE expression. Vascular smooth muscle cell (VSMC)-targeted TBCE deficiency was associated with endothelial dysfunction, aortic wall hypertrophy, and endoplasmic reticulum (ER) stress-mediated VSMC hyperproliferation in mice, paralleled by calnexin up-regulation and exacerbated by the blood pressure hormone angiotensin II. Treating SMMHC-ERT2-Cre+/-TBCEfl/fl mice with the ER stress modulator tauroursodeoxycholic acid amplified Raptor/Beclin-1-dependent autophagy and reversed vascular dysfunction.
Conclusion
TBCE and tubulin homeostasis seem to be novel predictors of vascular function and offer a new drug target to ameliorate ER stress-dependent vascular dysfunction.

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

Eur Heart J: 15 Jun 2021; epub ahead of print
Efentakis P, Molitor M, Kossmann S, Bochenek ML, ... Münzel T, Wenzel P
Eur Heart J: 15 Jun 2021; epub ahead of print | PMID: 34132336
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Abstract

Systems Approach to Discovery of Therapeutic Targets for Vein Graft Disease: PPARα Pivotally Regulates Metabolism, Activation, and Heterogeneity of Macrophages and Lesion Development.

Decano JL, Singh SA, Gasparotto Bueno C, Ho Lee L, ... Aikawa E, Aikawa M
Background
Vein graft failure remains a common clinical challenge. We applied a systems approach in mouse experiments to discover therapeutic targets for vein graft failure.
Methods
Global proteomics and high-dimensional clustering on multiple vein graft tissues were used to identify potential pathogenic mechanisms. The PPARs (peroxisome proliferator-activated receptors) pathway served as an example to substantiate our discovery platform. In vivo mouse experiments with macrophage-targeted PPARα small interfering RNA, or the novel, selective activator pemafibrate demonstrate the role of PPARα in the development and inflammation of vein graft lesions. In vitro experiments further included metabolomic profiling, quantitative polymerase chain reaction, flow cytometry, metabolic assays, and single-cell RNA sequencing on primary human and mouse macrophages.
Results
We identified changes in the vein graft proteome associated with immune responses, lipid metabolism regulated by the PPARs, fatty acid metabolism, matrix remodeling, and hematopoietic cell mobilization. PPARα agonism by pemafibrate retarded the development and inflammation of vein graft lesions in mice, whereas gene silencing worsened plaque formation. Pemafibrate also suppressed arteriovenous fistula lesion development. Metabolomics/lipidomics, functional metabolic assays, and single-cell analysis of cultured human macrophages revealed that PPARα modulates macrophage glycolysis, citrate metabolism, mitochondrial membrane sphingolipid metabolism, and heterogeneity.
Conclusions
This study explored potential drivers of vein graft inflammation and identified PPARα as a novel potential pharmacological treatment for this unmet medical need.



Circulation: 21 Jun 2021; 143:2454-2470
Decano JL, Singh SA, Gasparotto Bueno C, Ho Lee L, ... Aikawa E, Aikawa M
Circulation: 21 Jun 2021; 143:2454-2470 | PMID: 33821665
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Abstract

Evidence-Based Assessment of Genes in Dilated Cardiomyopathy.

Jordan E, Peterson L, Ai T, Asatryan B, ... Ware J, Hershberger RE
Background
Each of the cardiomyopathies, classically categorized as hypertrophic cardiomyopathy, dilated cardiomyopathy (DCM), and arrhythmogenic right ventricular cardiomyopathy, has a signature genetic theme. Hypertrophic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy are largely understood as genetic diseases of sarcomere or desmosome proteins, respectively. In contrast, >250 genes spanning >10 gene ontologies have been implicated in DCM, representing a complex and diverse genetic architecture. To clarify this, a systematic curation of evidence to establish the relationship of genes with DCM was conducted.
Methods
An international panel with clinical and scientific expertise in DCM genetics evaluated evidence supporting monogenic relationships of genes with idiopathic DCM. The panel used the Clinical Genome Resource semiquantitative gene-disease clinical validity classification framework with modifications for DCM genetics to classify genes into categories on the basis of the strength of currently available evidence. Representation of DCM genes on clinically available genetic testing panels was evaluated.
Results
Fifty-one genes with human genetic evidence were curated. Twelve genes (23%) from 8 gene ontologies were classified as having definitive (BAG3, DES, FLNC, LMNA, MYH7, PLN, RBM20, SCN5A, TNNC1, TNNT2, TTN) or strong (DSP) evidence. Seven genes (14%; ACTC1, ACTN2, JPH2, NEXN, TNNI3, TPM1, VCL) including 2 additional ontologies were classified as moderate evidence; these genes are likely to emerge as strong or definitive with additional evidence. Of these 19 genes, 6 were similarly classified for hypertrophic cardiomyopathy and 3 for arrhythmogenic right ventricular cardiomyopathy. Of the remaining 32 genes (63%), 25 (49%) had limited evidence, 4 (8%) were disputed, 2 (4%) had no disease relationship, and 1 (2%) was supported by animal model data only. Of the 16 evaluated clinical genetic testing panels, most definitive genes were included, but panels also included numerous genes with minimal human evidence.
Conclusions
In the curation of 51 genes, 19 had high evidence (12 definitive/strong, 7 moderate). It is notable that these 19 genes explain only a minority of cases, leaving the remainder of DCM genetic architecture incompletely addressed. Clinical genetic testing panels include most high-evidence genes; however, genes lacking robust evidence are also commonly included. We recommend that high-evidence DCM genes be used for clinical practice and that caution be exercised in the interpretation of variants in variable-evidence DCM genes.



Circulation: 05 Jul 2021; 144:7-19
Jordan E, Peterson L, Ai T, Asatryan B, ... Ware J, Hershberger RE
Circulation: 05 Jul 2021; 144:7-19 | PMID: 33947203
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Abstract

Single Nuclei Sequencing Reveals Novel Insights Into the Regulation of Cellular Signatures in Children With Dilated Cardiomyopathy.

Nicin L, Abplanalp WT, Schänzer A, Sprengel A, ... Rupp S, Dimmeler S
Background
Dilated cardiomyopathy (DCM) is a leading cause of death in children with heart failure. The outcome of pediatric heart failure treatment is inconsistent, and large cohort studies are lacking. Progress may be achieved through personalized therapy that takes age- and disease-related pathophysiology, pathology, and molecular fingerprints into account. We present single nuclei RNA sequencing from pediatric patients with DCM as the next step in identifying cellular signatures.
Methods
We performed single nuclei RNA sequencing with heart tissues from 6 children with DCM with an age of 0.5, 0.75, 5, 6, 12, and 13 years. Unsupervised clustering of 18 211 nuclei led to the identification of 14 distinct clusters with 6 major cell types.
Results
The number of nuclei in fibroblast clusters increased with age in patients with DCM, a finding that was confirmed by histological analysis and was consistent with an age-related increase in cardiac fibrosis quantified by cardiac magnetic resonance imaging. Fibroblasts of patients with DCM >6 years of age showed a profoundly altered gene expression pattern with enrichment of genes encoding fibrillary collagens, modulation of proteoglycans, switch in thrombospondin isoforms, and signatures of fibroblast activation. In addition, a population of cardiomyocytes with a high proregenerative profile was identified in infant patients with DCM but was absent in children >6 years of age. This cluster showed high expression of cell cycle activators such as cyclin D family members, increased glycolytic metabolism and antioxidative genes, and alterations in ß-adrenergic signaling genes.
Conclusions
Novel insights into the cellular transcriptomes of hearts from pediatric patients with DCM provide remarkable age-dependent changes in the expression patterns of fibroblast and cardiomyocyte genes with less fibrotic but enriched proregenerative signatures in infants.



Circulation: 26 Apr 2021; 143:1704-1719
Nicin L, Abplanalp WT, Schänzer A, Sprengel A, ... Rupp S, Dimmeler S
Circulation: 26 Apr 2021; 143:1704-1719 | PMID: 33618539
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Abstract

Replacement Myocardial Fibrosis in Patients With Mitral Valve Prolapse: Relation to Mitral Regurgitation, Ventricular Remodeling, and Arrhythmia.

Constant Dit Beaufils AL, Huttin O, Jobbe-Duval A, Senage T, ... Selton-Suty C, Le Tourneau T
Background
Mitral valve prolapse (MVP) is a frequent disease that can be complicated by mitral regurgitation (MR), heart failure, arterial embolism, rhythm disorders, and death. Left ventricular (LV) replacement myocardial fibrosis, a marker of maladaptive remodeling, has been described in patients with MVP, but the implications of this finding remain scarcely explored. We aimed at assessing the prevalence, pathophysiological and prognostic significance of LV replacement myocardial fibrosis through late gadolinium enhancement (LGE) by cardiac magnetic resonance in patients with MVP.
Methods
Four hundred patients (53±15 years of age, 55% male) with MVP (trace to severe MR by echocardiography) from 2 centers, who underwent a comprehensive echocardiography and LGE cardiac magnetic resonance, were included. Correlates of replacement myocardial fibrosis (LGE+), influence of MR degree, and ventricular arrhythmia were assessed. The primary outcome was a composite of cardiovascular events (cardiac death, heart failure, new-onset atrial fibrillation, arterial embolism, and life-threatening ventricular arrhythmia).
Results
Replacement myocardial fibrosis (LGE+) was observed in 110 patients (28%; 91 with myocardial wall including 71 with basal inferolateral wall, 29 with papillary muscle). LGE+ prevalence was 13% in trace-mild MR, 28% in moderate MR, and 37% in severe MR, and was associated with specific features of mitral valve apparatus, more dilated LV and more frequent ventricular arrhythmias (45% versus 26%, P<0.0001). In trace-mild MR, despite the absence of significant volume overload, abnormal LV dilatation was observed in 16% of patients and ventricular arrhythmia in 25%. Correlates of LGE+ in multivariable analysis were LV mass (odds ratio, 1.01 [95% CI, 1.002-1.017], P=0.009) and moderate-severe MR (odds ratio, 2.28 [95% CI, 1.21-4.31], P=0.011). LGE+ was associated with worse 4-year cardiovascular event-free survival (49.6±11.7 in LGE+ versus 73.3±6.5% in LGE-, P<0.0001). In a stepwise multivariable Cox model, MR volume and LGE+ (hazard ratio, 2.6 [1.4-4.9], P=0.002) were associated with poor outcome.
Conclusions
LV replacement myocardial fibrosis is frequent in patients with MVP; is associated with mitral valve apparatus alteration, more dilated LV, MR grade, and ventricular arrhythmia; and is independently associated with cardiovascular events. These findings suggest an MVP-related myocardial disease. Last, cardiac magnetic resonance provides additional information to echocardiography in MVP.



Circulation: 03 May 2021; 143:1763-1774
Constant Dit Beaufils AL, Huttin O, Jobbe-Duval A, Senage T, ... Selton-Suty C, Le Tourneau T
Circulation: 03 May 2021; 143:1763-1774 | PMID: 33706538
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Abstract

Cardiovascular magnetic resonance imaging: emerging techniques and applications.

Chowdhary A, Garg P, Das A, Nazir MS, Plein S
This review gives examples of emerging cardiovascular magnetic resonance (CMR) techniques and applications that have the potential to transition from research to clinical application in the near future. Four-dimensional flow CMR (4D-flow CMR) allows time-resolved three-directional, three-dimensional (3D) velocity-encoded phase-contrast imaging for 3D visualisation and quantification of valvular or intracavity flow. Acquisition times of under 10 min are achievable for a whole heart multidirectional data set and commercial software packages are now available for data analysis, making 4D-flow CMR feasible for inclusion in clinical imaging protocols. Diffusion tensor imaging (DTI) is based on the measurement of molecular water diffusion and uses contrasting behaviour in the presence and absence of boundaries to infer tissue structure. Cardiac DTI is capable of non-invasively phenotyping the 3D micro-architecture within a few minutes, facilitating transition of the method to clinical protocols. Hybrid positron emission tomography-magnetic resonance (PET-MR) provides quantitative PET measures of biological and pathological processes of the heart combined with anatomical, morphological and functional CMR imaging. Cardiac PET-MR offers opportunities in ischaemic, inflammatory and infiltrative heart disease.

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

Heart: 29 Apr 2021; 107:697-704
Chowdhary A, Garg P, Das A, Nazir MS, Plein S
Heart: 29 Apr 2021; 107:697-704 | PMID: 33402364
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Abstract

Aging athlete\'s heart: An echocardiographic evaluation of competitive sprint- vs endurance-trained master athletes.

Kusy K, Błażejewski J, Gilewski W, Karasek D, ... Sinkiewicz W, Grześk G
Background
Sports training triggers exercise-induced cardiac remodeling (EICR). Sprint- and endurance-trained master athletes are exposed to different hemodynamic stimuli accompanied by aging. We aimed to compare EICR types in light of the Morganroth hypothesis, frequency of abnormalities, and relationships between cardiac traits and age.
Methods
In our observational cross-sectional study, we performed echocardiographic examinations in 142 sprint-trained (36‒83 years) and 114 endurance-trained (38‒85 years) competitive master athletes. We compared structural and functional characteristics to population reference values and identified EICR types. Athletic groups were compared using t-test and chi-squared test. Relationships with age were assessed using linear regression.
Results
In the sprint group, 51.0% of athletes had normal cardiac geometry (non-hypertrophic heart), 4.2% eccentric hypertrophy, 36.4% concentric remodeling, and 8.4% concentric hypertrophy. In their endurance peers, the proportions were 22.8%, 16.7%, 36.8%, and 23.7%, respectively. Many athletes in both groups had structural abnormalities as assessed using population norms (up to ∼81% for septal thickness) but their resting cardiac function was normal. The relationships of structural and functional cardiac characteristics with age were mostly weak to moderate and did not differ between training modalities.
Conclusions
Even though many endurance- and sprint-oriented master athletes exceed population norms for cardiac structure, they do not go beyond the \'gray zone\' and preserve normal cardiac function. Therefore, physiological adaptations, rather than pathological abnormalities, are expected in aging but still active athletes. Inconsistent with the Morganroth hypothesis, EICR is shifted toward normal geometry in sprinters and concentric remodeling/hypertrophy in endurance runners. A better understanding of the mechanisms behind cardiac remodeling during aging is needed to adequately predict EICR types in master athletes.

Copyright © 2021. Published by Elsevier Inc.

J Am Soc Echocardiogr: 23 Jun 2021; epub ahead of print
Kusy K, Błażejewski J, Gilewski W, Karasek D, ... Sinkiewicz W, Grześk G
J Am Soc Echocardiogr: 23 Jun 2021; epub ahead of print | PMID: 34175421
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Abstract

Move more - be happier? Physical Activity and Health-Related Quality of Life in Children with Congenital Heart Disease.

Brudy L, Meyer M, Oberhoffer R, Ewert P, Müller J
Objective
This cross-sectional study aimed to determine whether there is an association between objectively assessed physical activity (PA) and health-related quality of life (HRQoL) in children with CHD.
Patients and methods
From September 2017 to January 2021, 343 children with CHD (12.1 ± 3.3 years, 135 girls) provided valid PA data after a 7-day objective PA assessment. PA was evaluated as average daily steps and moderate-to-vigorous physical activity (MVPA) minutes assessed via wearable bracelet Garmin vivofit® Jr. These children also completed the KINDL® - a 24 Likert-scaled item questionnaire assessing HRQoL in the six dimensions physical well-being, emotional well-being, self-esteem, family, friends and everyday functioning.
Results
Daily Steps (r=.166, p=.003) and daily MVPA minutes (r=.134, p=.017,) were both correlated to total KINDL® score. Furthermore, both steps and MVPA were associated with the subscales physical well-being (steps: r=.165 p=.003; MVPA: r=.129, p=.022), friends (steps: r=.210, p<.001, MVPA: r=.179, p=.001), and steps also to everyday functioning (r=.142, p=.012). Logistic regression showed each MVPA minute increase conferred to a 1% increase in reporting better HRQoL (OR: 1.009 [95% CI: 1.002 - 1.017], p=.019).
Conclusions
PA was positively associated with HRQoL in children with CHD. Patients who move more are more likely to report better HRQoL. While the magnitude of this association needs to be further understood, continuous encouragement towards more PA seems to be crucial in a holistic approach to medical aftercare in children with CHD.

Copyright © 2021. Published by Elsevier Inc.

Am Heart J: 17 Jul 2021; epub ahead of print
Brudy L, Meyer M, Oberhoffer R, Ewert P, Müller J
Am Heart J: 17 Jul 2021; epub ahead of print | PMID: 34289343
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Abstract

Tricuspid valve tethering is associated with residual regurgitation after valve repair in hypoplastic left heart syndrome: a three-dimensional echocardiography study.

Shigemitsu S, Mah K, Thompson RB, Grenier J, ... Khoo NS, Colen T
Background
Tricuspid regurgitation (TR) is a risk factor for morbidity and mortality in children with hypoplastic left heart syndrome (HLHS). Surgical tricuspid valve (TV) repair is common but durable repair remains challenging. This study examines mechanisms of TR requiring surgery, features associated with unsuccessful repair, and TV changes after surgical repair.
Methods
We assessed 36 patients with HLHS requiring TV repair (TVR) and 36 matched HLHS controls using two-dimensional and three-dimensional echocardiography (2DE and 3DE). Using 3DE, TV coordinates from annulus, leaflet and ventricle were used to measure annulus, leaflet, prolapse and tethering values, and anterior papillary muscle (APM) angle. TR grade, ventricle size, function and shape were assessed with 2DE.
Results
Patients requiring TVR had greater total leaflet prolapse, larger TV annular and leaflet areas, and flatter annulus, with no difference in tethering, coaptation index or APM angle. HLHS patients with successful TVR at follow-up (58%) was associated with preoperative total leaflet prolapse (especially posterior). Unsuccessful repair was associated with preoperative tethering of septal leaflet. TVR in HLHS patients caused a reduction of total annulus and leaflets size, reduced prolapse and tethering of posterior leaflet, but did not affect anterior leaflet prolapse or septal leaflet tethering.
Conclusion
Features associated with TVR include a flattened and dilated TV annulus with leaflet prolapse. The additional presence of a tethered septal leaflet prior to TVR is associated with significant post-operative TR. Current surgical techniques, predominantly posterior annuloplasty and commissuroplasty, adequately address annulus size and posterior leaflet pathology, but not septal leaflet tethering. Individualized and innovative surgical techniques are vital to improve surgical repair success.

Copyright © 2021. Published by Elsevier Inc.

J Am Soc Echocardiogr: 16 Jun 2021; epub ahead of print
Shigemitsu S, Mah K, Thompson RB, Grenier J, ... Khoo NS, Colen T
J Am Soc Echocardiogr: 16 Jun 2021; epub ahead of print | PMID: 34147648
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This program is still in alpha version.