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

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

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

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

Regional and ethnic influences on the response to empagliflozin in patients with heart failure and a reduced ejection fraction: the EMPEROR-Reduced trial.

Lam CSP, Ferreira JP, Pfarr E, Sim D, ... Zannad F, Packer M
Aims
The aim of this article is to explore the influence of region and race/ethnicity on the effects of empagliflozin in the Empagliflozin Outcome Trial in Patients with Chronic Heart Failure and a Reduced Ejection Fraction (EMPEROR-Reduced) trial.
Methods and results
Of 3730 patients, 1353 (36.3%) were enrolled in Europe, 1286 (34.5%) in Latin America, 425 (11.4%) in North America, and 493 (13.2%) in Asia; 2629 (70.5%) were White, 257 (6.9%) Black, and 672 (18.0%) Asian. Placebo event rates (per 100 patient-years) for cardiovascular death or heart failure (HF) hospitalization varied by region (Asia 27.7, North America 26.4, Latin America 21.4, and Europe 17.5) and race/ethnicity (Black 34.4, Asian 24.3, and White 18.7); driven by differences in HF hospitalization. The ratio of total HF hospitalization to cardiovascular death varied from 5.4 in Asia and 4.8 in North America to 2.1 in Europe; and from 4.8 in Black and 4.2 in Asian to 2.2 in White patients. Groups with the highest ratio had the greatest reduction in the primary outcome with empagliflozin. Inclusion of outpatient worsening HF episodes added more events in Europe vs. other regions; enhanced the placebo event rates in Europe vs. other regions; and increased the relative risk reduction with empagliflozin in Europe from 6% to 26%.
Conclusions
There were notable differences in the placebo event rates for major HF events across diverse regions and race/ethnic groups. The benefit of empagliflozin was most pronounced in groups with the highest ratio of HF hospitalization to cardiovascular death. Regional differences were attenuated when the definition of HF events was expanded to include outpatient worsening HF events.

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

Eur Heart J: 28 Jun 2021; epub ahead of print
Lam CSP, Ferreira JP, Pfarr E, Sim D, ... Zannad F, Packer M
Eur Heart J: 28 Jun 2021; epub ahead of print | PMID: 34184057
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Abstract

HIV infection is associated with thoracic and abdominal aortic aneurysms: a prospective matched cohort study.

Høgh J, Pham MHC, Knudsen AD, Thudium RF, ... Kofoed KF, Nielsen SD
Aims
Little is known about the prevalence of aortic aneurysms among people living with HIV (PLWH). We investigated whether HIV status is independently associated with having aortic aneurysms. Furthermore, we determined risk factors associated with aortic aneurysms in PLWH.
Methods and results
PLWH aged ≥40 years (n = 594) were recruited from the Copenhagen Comorbidity in HIV Infection study and matched for age and sex with uninfected controls (n = 1188) from the Copenhagen General Population Study. Aortic dimensions were assessed using contrast enhanced computed tomography. Aortic aneurysms were defined according to the European Society of Cardiology guidelines, i.e. an aortic dilation of ≥50% or an infrarenal aortic diameter of ≥30 mm. Among PLWH and uninfected controls, the median (interquartile range) age was 52 (47-60) and 52 (48-61) and 88% and 90% were male, respectively. We found 46 aneurysms in 42 (7.1%) PLWH and 31 aneurysms in 29 (2.4%) uninfected controls (P < 0.001). PLWH had a significantly higher prevalence of ascending aortic aneurysms and infrarenal aortic aneurysms. In an adjusted model, HIV was independently associated with aortic aneurysms (adjusted odds ratio; 4.51 [95% confidence interval 2.56-8.08], P < 0.001). Within PLWH, obesity and hepatitis B co-infection were associated with aortic aneurysms.
Conclusion
PLWH had four-fold higher odds of aortic aneurysms compared to uninfected controls, and HIV status was independently associated with aortic aneurysms. Among PLWH, age, obesity and hepatitis B co-infection were associated with higher odds of aortic aneurysms. Our findings suggest that increased attention to aortic aneurysms in PLWH may be beneficial.

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: 07 Jul 2021; epub ahead of print
Høgh J, Pham MHC, Knudsen AD, Thudium RF, ... Kofoed KF, Nielsen SD
Eur Heart J: 07 Jul 2021; epub ahead of print | PMID: 34240121
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Abstract

Regulation of the Methylation and Expression Levels of the BMPR2 Gene by SIN3a as a Novel Therapeutic Mechanism in Pulmonary Arterial Hypertension.

Bisserier M, Mathiyalagan P, Zhang S, Elmastour F, ... Sahoo S, Hadri L
Background
Epigenetic mechanisms are critical in the pathogenesis of pulmonary arterial hypertension (PAH). Previous studies have suggested that hypermethylation of the BMPR2 (bone morphogenetic protein receptor type 2) promoter is associated with BMPR2 downregulation and progression of PAH. Here, we investigated for the first time the role of SIN3a (switch-independent 3a), a transcriptional regulator, in the epigenetic mechanisms underlying hypermethylation of BMPR2 in the pathogenesis of PAH.
Methods
We used lung samples from PAH patients and non-PAH controls, preclinical mouse and rat PAH models, and human pulmonary arterial smooth muscle cells. Expression of SIN3a was modulated using a lentiviral vector or a siRNA in vitro and a specific adeno-associated virus serotype 1 or a lentivirus encoding for human SIN3a in vivo.
Results
SIN3a is a known transcriptional regulator; however, its role in cardiovascular diseases, especially PAH, is unknown. It is interesting that we detected a dysregulation of SIN3 expression in patients and in rodent models, which is strongly associated with decreased BMPR2 expression. SIN3a is known to regulate epigenetic changes. Therefore, we tested its role in the regulation of BMPR2 and found that BMPR2 is regulated by SIN3a. It is interesting that SIN3a overexpression inhibited human pulmonary arterial smooth muscle cells proliferation and upregulated BMPR2 expression by preventing the methylation of the BMPR2 promoter region. RNA-sequencing analysis suggested that SIN3a downregulated the expression of DNA and histone methyltransferases such as DNMT1 (DNA methyltransferase 1) and EZH2 (enhancer of zeste 2 polycomb repressive complex 2) while promoting the expression of the DNA demethylase TET1 (ten-eleven translocation methylcytosine dioxygenase 1). Mechanistically, SIN3a promoted BMPR2 expression by decreasing CTCF (CCCTC-binding factor) binding to the BMPR2 promoter. Last, we identified intratracheal delivery of adeno-associated virus serotype human SIN3a to be a beneficial therapeutic approach in PAH by attenuating pulmonary vascular and right ventricle remodeling, decreasing right ventricle systolic pressure and mean pulmonary arterial pressure, and restoring BMPR2 expression in rodent models of PAH.
Conclusions
All together, our study unveiled the protective and beneficial role of SIN3a in pulmonary hypertension. We also identified a novel and distinct molecular mechanism by which SIN3a regulates BMPR2 in human pulmonary arterial smooth muscle cells. Our study also identified lung-targeted SIN3a gene therapy using adeno-associated virus serotype 1 as a new promising therapeutic strategy for treating patients with PAH.



Circulation: 05 Jul 2021; 144:52-73
Bisserier M, Mathiyalagan P, Zhang S, Elmastour F, ... Sahoo S, Hadri L
Circulation: 05 Jul 2021; 144:52-73 | PMID: 34078089
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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

Cooperative Binding of ETS2 and NFAT Links Erk1/2 and Calcineurin Signaling in the Pathogenesis of Cardiac Hypertrophy.

Luo Y, Jiang N, May HI, Luo X, ... Gillette TG, Hill JA
Background
Cardiac hypertrophy is an independent risk factor for heart failure, a leading cause of morbidity and mortality globally. The calcineurin/NFAT (nuclear factor of activated T cells) pathway and the MAPK (mitogen-activated protein kinase)/Erk (extracellular signal-regulated kinase) pathway contribute to the pathogenesis of cardiac hypertrophy as an interdependent network of signaling cascades. How these pathways interact remains unclear and few direct targets responsible for the prohypertrophic role of NFAT have been described.
Methods
By engineering cardiomyocyte-specific ETS2 (a member of the E26 transformation-specific sequence [ETS] domain family) knockout mice, we investigated the role of ETS2 in cardiac hypertrophy. Primary cardiomyocytes were used to evaluate ETS2 function in cell growth.
Results
ETS2 is phosphorylated and activated by Erk1/2 on hypertrophic stimulation in both mouse (n=3) and human heart samples (n=8 to 19). Conditional deletion of ETS2 in mouse cardiomyocytes protects against pressure overload-induced cardiac hypertrophy (n=6 to 11). Silencing of ETS2 in the hearts of calcineurin transgenic mice significantly attenuates hypertrophic growth and contractile dysfunction (n=8). As a transcription factor, ETS2 is capable of binding to the promoters of hypertrophic marker genes, such as ANP, BNP, and Rcan1.4 (n=4). We report that ETS2 forms a complex with NFAT to stimulate transcriptional activity through increased NFAT binding to the promoters of at least 2 hypertrophy-stimulated genes: Rcan1.4 and microRNA-223 (=n4 to 6). Suppression of microRNA-223 in cardiomyocytes inhibits calcineurin-mediated cardiac hypertrophy (n=6), revealing microRNA-223 as a novel prohypertrophic target of the calcineurin/NFAT and Erk1/2-ETS2 pathways.
Conclusions
Our findings point to a critical role for ETS2 in calcineurin/NFAT pathway-driven cardiac hypertrophy and unveil a previously unknown molecular connection between the Erk1/2 activation of ETS2 and expression of NFAT/ETS2 target genes.



Circulation: 05 Jul 2021; 144:34-51
Luo Y, Jiang N, May HI, Luo X, ... Gillette TG, Hill JA
Circulation: 05 Jul 2021; 144:34-51 | PMID: 33821668
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Abstract

Usefulness of Alcohol Septal Ablation in the Left Ventricular Outflow Tract Obstruction in Fabry Disease Cardiomyopathy.

Zemánek D, Marek J, Dostálová G, Magage S, ... Kovárník T, Linhart A
Fabry disease (FD) is an X-linked linked genetic disorder caused by α-galactosidase A deficiency. The typical clinical manifestation is left ventricular hypertrophy, often mimicking hypertrophic cardiomyopathy (HC). In contrast to sarcomeric HC, left ventricular outflow tract obstruction (LVOTO) is less frequent. We describe 6 male patients with genetically confirmed FD and symptomatic LVOTO. All of them underwent a transcatheter alcohol septal ablation with an immediate effect on the obstruction in all cases and without any serious complications. The median LVOT maximal pressure gradient was 85 (60 to 170) mm Hg. The hemodynamic effect persisted during subsequent follow-up (ranging from 6 months to 16 years). Five patients reported substantial symptomatic improvement. Four patients were receiving specific FD therapy before the interventional procedure. In conclusion, alcohol septal ablation appears to be effective in the treatment of LVOTO in patients with FD and appears to be comparable to the limited published experience with surgical septal myectomy. Despite some important differences between FD HC and sarcomeric HC, the recommendation for treating LVOTO should be similar.

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

Am J Cardiol: 30 Jun 2021; 150:110-113
Zemánek D, Marek J, Dostálová G, Magage S, ... Kovárník T, Linhart A
Am J Cardiol: 30 Jun 2021; 150:110-113 | PMID: 34011439
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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

Venous Flow Variation Predicts Preoperative Pulmonary Venous Obstruction in Children with Total Anomalous Pulmonary Venous Connection.

White BR, Faerber JA, Katcoff H, Glatz AC, Mascio CE, Cohen MS
Background
Identifying preoperative pulmonary venous obstruction in total anomalous pulmonary venous connection is important to guide treatment planning and risk prognostication. No standardized echocardiographic definition of obstruction exists in the literature. Definitions based on absolute velocities are affected by technical limitations and variations in pulmonary venous return. The authors developed a metric to quantify pulmonary venous blood flow variation: pulmonary venous variability index (PVVI). The aim of this study was to demonstrate its accuracy in defining obstruction.
Methods
All patients with total anomalous pulmonary venous connection at a single institution were identified. Echocardiograms were reviewed, and maximum (Vmax), mean (Vmean), and minimum (Vmin) velocities along the pulmonary venous pathway were measured. PVVI was defined as (Vmax - Vmin)/Vmean. These metrics were compared with pressures measured on cardiac catheterization. Echocardiographic measures were then compared between patients with and without clinical preoperative obstruction (defined as a need for preoperative intubation, catheter-based intervention, or surgery within 1 day of diagnosis), as well as pulmonary edema by chest radiography and markers of lactic acidosis. One hundred thirty-seven patients were included, with 22 having catheterization pressure recordings.
Results
Vmax and Vmean were not different between patients with catheter gradients ≥ 4 and < 4 mm Hg, while PVVI was significantly lower and Vmin higher in those with gradients ≥ 4 mm Hg. The composite outcome of preoperative obstruction occurred in 51 patients (37%). Absolute velocities were not different between patients with and without clinical obstruction, while PVVI was significantly lower in patients with obstruction. All metrics except Vmax were associated with pulmonary edema; none were associated with blood gas metrics.
Conclusions
The authors developed a novel quantitative metric of pulmonary venous flow, which was superior to traditional echocardiographic metrics. Decreased PVVI was highly associated with elevated gradients measured by catheterization and clinical preoperative obstruction. These results should aid risk assessment and diagnosis preoperatively in patients with total anomalous pulmonary venous connection.

Copyright © 2021 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.

J Am Soc Echocardiogr: 29 Jun 2021; 34:775-785
White BR, Faerber JA, Katcoff H, Glatz AC, Mascio CE, Cohen MS
J Am Soc Echocardiogr: 29 Jun 2021; 34:775-785 | PMID: 33600926
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Abstract

Cardiac Resynchronization Therapy Response Assessment with Electromechanical Activation Mapping within 24 Hours of Device Implantation: A Pilot Study.

Melki L, Wang DY, Grubb CS, Weber R, ... Garan H, Konofagou EE
Background
Cardiac resynchronization therapy (CRT) response assessment relies on the QRS complex narrowing criterion. Yet one third of patients do not improve despite narrowed QRS after implantation. Electromechanical wave imaging (EWI) is a quantitative echocardiography-based technique capable of noninvasively mapping cardiac electromechanical activation in three dimensions. The aim of this exploratory study was to investigate the EWI technique, sensitive to ventricular dyssynchrony, for informing CRT response on the day of implantation.
Methods
Forty-four patients with heart failure with left bundle branch block or right ventricular (RV) paced rhythm and decreased left ventricular ejection fraction (LVEF; mean, 25.3 ± 9.6%) underwent EWI without and with CRT within 24 hours of device implantation. Of those, 16 were also scanned while in left ventricular (LV) pacing. Improvement in LVEF at 3-, 6-, or 9-month follow-up defined (1) super-responders (ΔLVEF ≥ 20%), (2) responders (10% ≤ ΔLVEF < 20%), and (3) nonresponders (ΔLVEF ≤ 5%). Three-dimensionally rendered electromechanical maps were obtained under RV, LV, and biventricular CRT pacing conditions. Mean RV free wall and LV lateral wall activation times were computed. The percentage of resynchronized myocardium was measured by quantifying the percentage of the left ventricle activated within 120 msec of QRS onset. Correlations between percentage of resynchronized myocardium and type of CRT response were assessed.
Results
LV lateral wall activation time was significantly different (P ≤ .05) among all three pacing conditions in the 16 patients: LV lateral wall activation time with CRT in biventricular pacing (73.1 ± 17.6 msec) was lower compared with LV pacing (89.5 ± 21.5 msec) and RV pacing (120.3 ± 17.8 msec). Retrospective analysis showed that the percentage of resynchronized myocardium with CRT was a reliable response predictor within 24 hours of implantation for significantly (P ≤ .05) identifying super-responders (n = 7; 97.7 ± 1.9%) from nonresponders (n = 17; 89.9 ± 9.9%).
Conclusion
Electromechanical activation mapping constitutes a valuable three-dimensional visualization tool within 24 hours of implantation and could potentially aid in the timely assessment of CRT response rates, including during implantation for adjustment of lead placement and pacing outcomes.

Copyright © 2021 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.

J Am Soc Echocardiogr: 29 Jun 2021; 34:757-766.e8
Melki L, Wang DY, Grubb CS, Weber R, ... Garan H, Konofagou EE
J Am Soc Echocardiogr: 29 Jun 2021; 34:757-766.e8 | PMID: 33675941
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Abstract

Hypertrabeculation; a phenotype with heterogenous etiology.

Adabifirouzjaei F, Sachiyo I, DeMaria AN
Left ventricular hypertrabeculation (LVHT) is a phenotype with multiple etiologies and variable clinical presentation and significance. It is characterized by a 2-layer myocardium with an enlarged trabecular layer and a thinner compacted layer. The prevalence has been increasing due to advances in cardiac imaging. Initial attention was focused on the congenital noncompaction syndrome, and the presence of LVHT was always attributed to this etiology. However, due to the lack of consensus diagnostic criteria, LVHT has now been reported in a broad spectrum of cardiomyopathies, congenital heart diseases, monogenetic disorders, neuromuscular diseases, and even healthy individuals. LVHT is often associated with systolic dysfunction, arrhythmias, and thromboembolic events. Given the etiologic heterogeneity, the prognosis and outcomes are primarily determined by comorbidities, and treatment is dictated by known guidelines. We present hypertrabeculation (HT) as a phenotype and discuss the varied landscape in the classification, etiology, diagnosis, and management of the condition.

Copyright © 2018. Published by Elsevier Inc.

Prog Cardiovasc Dis: 11 Jul 2021; epub ahead of print
Adabifirouzjaei F, Sachiyo I, DeMaria AN
Prog Cardiovasc Dis: 11 Jul 2021; epub ahead of print | PMID: 34265334
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This program is still in alpha version.