Topic: Journal Club Selection

Abstract

Smooth Muscle Cell-Enriched Long Noncoding RNA Regulates Cell Plasticity and Atherosclerosis by Interacting With Serum Response Factor.

Ni H, Haemmig S, Deng Y, Chen J, ... Dai Q, Feinberg MW
Objective
Vascular smooth muscle cell (VSMC) plasticity plays a critical role in the development of atherosclerosis. Long noncoding RNAs (lncRNAs) are emerging as important regulators in the vessel wall and impact cellular function through diverse interactors. However, the role of lncRNAs in regulating VSMCs plasticity and atherosclerosis remains unclear. Approach and
Results:
We identified a VSMC-enriched lncRNA cardiac mesoderm enhancer-associated noncoding RNA (CARMN) that is dynamically regulated with progression of atherosclerosis. In both mouse and human atherosclerotic plaques, CARMN colocalized with VSMCs and was expressed in the nucleus. Knockdown of CARMN using antisense oligonucleotides in Ldlr-/- mice significantly reduced atherosclerotic lesion formation by 38% and suppressed VSMCs proliferation by 45% without affecting apoptosis. In vitro CARMN gain- and loss-of-function studies verified effects on VSMC proliferation, migration, and differentiation. TGF-β1 (transforming growth factor-beta) induced CARMN expression in a Smad2/3-dependent manner. CARMN regulated VSMC plasticity independent of the miR143/145 cluster, which is located in close proximity to the CARMN locus. Mechanistically, lncRNA pulldown in combination with mass spectrometry analysis showed that the nuclear-localized CARMN interacted with SRF (serum response factor) through a specific 600-1197 nucleotide domain. CARMN enhanced SRF occupancy on the promoter regions of its downstream VSMC targets. Finally, knockdown of SRF abolished the regulatory role of CARMN in VSMC plasticity.
Conclusions
The lncRNA CARMN is a critical regulator of VSMC plasticity and atherosclerosis. These findings highlight the role of a lncRNA in SRF-dependent signaling and provide implications for a range of chronic vascular occlusive disease states.



Arterioscler Thromb Vasc Biol: 21 Jul 2021:ATVBAHA120315911; epub ahead of print
Ni H, Haemmig S, Deng Y, Chen J, ... Dai Q, Feinberg MW
Arterioscler Thromb Vasc Biol: 21 Jul 2021:ATVBAHA120315911; epub ahead of print | PMID: 34289702
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Abstract

Analysis of F-Sodium Fluoride Positron Emission Tomography Signal Sources in Atherosclerotic Minipigs Shows Specific Binding of F-Sodium Fluoride to Plaque Calcifications.

Nogales P, Velasco C, Mota-Cobián A, González-Cintado L, ... Mateo J, Bentzon JF
Objective
18F-sodium fluoride (18F-NaF) positron emission tomography (PET) imaging is thought to visualize active atherosclerotic plaque calcification. This is supported by the binding of 18F-NaF to plaque calcification ex vivo, but no prior studies have examined binding of 18F-NaF to human-like plaque in vivo. Our aim was to validate the specificity of 18F-NaF PET for plaque calcifications in atherosclerotic minipigs. Approach and
Results:
Gain-of-function PCSK9D374Y (proprotein convertase/subtilisin kexin type 9) transgenic Yucatan minipigs (n=4) were fed high-fat diet for 2.5 years to develop atherosclerosis and then subjected to 18F-NaF PET/computed tomography imaging. The heart, aorta, and iliac arteries were immediately re-scanned ex vivo after surgical extraction. Lesions from the abdominal aorta, iliac arteries, and coronary arteries were cryo-sectioned for autoradiography. Histological plaque characteristics, PET/computed tomography signal, and autoradiography were linked through regression and co-localization analysis. Arterial 18F-NaF PET signal had intensities comparable to clinical scans and colocalized moderately with calcification detected by computed tomography. Histological analysis showed calcification spanning from microcalcifications near lipid pools and necrotic core to more homogenous macrocalcifications. Comparison with arteries from autopsy cases confirmed the resemblance in localization and appearance with early human plaque calcification. Regression analysis in the abdominal aorta showed correlations with calcified plaque but could not rule out contributions from noncalcified plaque. This was resolved by autoradiography, which showed specific accumulation in plaque calcifications in all examined arteries. In the context of porcine abdominal aorta, 18F-NaF PET imaging was, however, less accurate than computed tomography for detecting small calcifications.
Conclusions
18F-NaF accumulates specifically in calcifications of atherosclerotic plaques in vivo.



Arterioscler Thromb Vasc Biol: 21 Jul 2021:ATVBAHA121316075; epub ahead of print
Nogales P, Velasco C, Mota-Cobián A, González-Cintado L, ... Mateo J, Bentzon JF
Arterioscler Thromb Vasc Biol: 21 Jul 2021:ATVBAHA121316075; epub ahead of print | PMID: 34289703
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Abstract

Clinical features and outcomes in patients with cardiogenic shock complicating acute myocardial infarction: early vs recent experience with impella.

Singh H, Mehta RH, O\'Neill W, Kapur NK, ... Rosman H, Kaki A
Objectives
To compare clinical features and outcomes in patients with acute myocardial infarction complicated by cardiogenic shock (AMICS) treated in the early experience with Impella percutaneous ventricular assist device and patients treated recently.
Background
Since pre-market approval (PMA) of Impella device as treatment for AMICS, use of the device has grown considerably.
Methods
We retrospectively analyzed 649 AMICS patients treated with perioperative Impella, with 291 patients treated from 2008 to 2014 comprising the early experience cohort and 358 patients treated from 2017 to 2019 comprising the recent experience cohort. The primary end point was risk adjusted in-hospital mortality.
Results
Mean age and gender distribution of patients was similar in the two cohorts. The recent cohort had more invasive hemodynamic monitoring (64% vs 46%; P < .001) and less use of an intra-aortic balloon pump prior to Impella (15% vs 41%; P < .001). Recently treated patients were significantly more likely to receive Impella support prior to PCI (58% vs 44%; P = .005). In-hospital mortality was lower in the recent cohort (48% vs 56%; P = .043). This difference was however no longer significant after risk adjustment (adjusted OR 0.89, 95% CI 0.59-1.34, P = .59). Rates of acute kidney injury, major bleeding, and vascular complications requiring surgery were also significantly lower in the recent cohort.
Conclusions
Use of Impella for AMICS during recent years is associated with lower unadjusted in-hospital mortality, which may reflect better patient selection, earlier device implantation, and improved management algorithms. In-depth understanding of these factors may inform the development of future treatment protocols.

Copyright © 2021 Elsevier Inc. All rights reserved.

Am Heart J: 30 Jul 2021; 238:66-74
Singh H, Mehta RH, O'Neill W, Kapur NK, ... Rosman H, Kaki A
Am Heart J: 30 Jul 2021; 238:66-74 | PMID: 33848505
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Abstract

Severe Mitral Paravalvular Leak Treated with Percutaneous Paravalvular Leak Closure with Underlying Severe Mitral Annular Calcium.

Sudhakaran S, Tandon A, Rafael AE, Choi JW
Standard operative mitral valve replacement for mitral stenosis in the setting of severe mitral annular calcium has been associated with increased morbidity and mortality. Inability to ensure a well seated prosthesis may lead to periprosthetic leak. We present a case of severe paravalvular leak, causing significant hemolysis, after mitral valve replacement with underling severe mitral annular calcium. The leak was successfully repaired using a transseptal percutaneous approach, with subsequent resolution of hemolysis.

Published by Elsevier Inc.

Am J Cardiol: 31 Jul 2021; 152:165-167
Sudhakaran S, Tandon A, Rafael AE, Choi JW
Am J Cardiol: 31 Jul 2021; 152:165-167 | PMID: 34162483
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Abstract

Prognostic Value of Multilayer Left Ventricular Global Longitudinal Strain in Patients with ST-segment Elevation Myocardial Infarction with Mildly Reduced Left Ventricular Ejection Fractions.

Abou R, Goedemans L, Montero-Cabezas JM, Prihadi EA, ... Bax JJ, Delgado V
Multilayer (epi-, mid- and endocardium) left ventricular (LV) global longitudinal strain (GLS) reflects the extent of myocardial damage after ST-segment myocardial infarction (STEMI). However, the prognostic implications of multilayer LV GLS remain unclear. We studied the association between multilayer LV GLS and prognosis in patients with mildly reduced or preserved LV ejection fraction (EF) after STEMI. Patients with first STEMI and LVEF>45% were evaluated retrospectively. Baseline multilayer (endocardial, mid-myocardial and epicardial) LV GLS were measured on 2-dimensional speckle tracking echocardiography. Patients were followed up for of all-cause mortality. A total of 569 patients (77% male, 60 ± 11 years) were included. After a median follow-up of 117 (interquartile range 106-132) months, 95 (17%) patients died. We observed no differences in baseline LVEF and peak troponin levels between survivors and non-survivors. However, non-survivors showed more impaired GLS at all layers (epicardium: -11.9 ± 2.8% vs. -13.4 ± 2.8%; mid-myocardium: -14.2 ± 3.2% vs. -15.6 ± 3.2%; endocardium: -16.5 ± 3.7% vs. -17.7 ± 3.6%, p <0.05, for all). On multivariable analysis, increasing age (hazard ratio 1.095; p<0.001) and impaired LV GLS of the epicardial layer (hazard ratio 1.085; p = 0.047) were independently associated with higher risk of all-cause mortality. In addition, LV GLS at the epicardium had incremental prognostic value for all-cause mortality (χ2 = 114, p = 0.044). In conclusion, in contemporary STEMI patients with mildly reduced or preserved LVEF, ageing and reduced LV GLS of the epicardium (reflecting transmural scar formation) were independently associated with all-cause mortality after adjusting for clinical and echocardiographic variables.

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

Am J Cardiol: 31 Jul 2021; 152:11-18
Abou R, Goedemans L, Montero-Cabezas JM, Prihadi EA, ... Bax JJ, Delgado V
Am J Cardiol: 31 Jul 2021; 152:11-18 | PMID: 34162486
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Abstract

Usefulness of Left Ventricular Myocardial Deformation in Children Hospitalized for Acute Myocarditis who Develop Arrhythmias.

Pruitt CR, Menon S, Lal AK, Eckhauser AW, ... Miller T, Niu M
Cardiac arrhythmias occur in 3-40% of patients with acute myocarditis and cause significant morbidity and mortality. Myocardial injury also results in abnormal myocardial deformation. The relationship between left ventricular (LV) deformation, measured by two-dimensional speckle tracking echocardiography (2D-STE), and arrhythmia in pediatric myocarditis is unknown. We evaluated the association between 2D-STE and arrhythmias in children hospitalized with acute myocarditis. We reviewed patients ≤ 18 years hospitalized for acute myocarditis from 2008 to 2018. Arrhythmias were defined as 1) non-sustained or sustained ventricular tachycardia or ventricular fibrillation, 2) sustained supraventricular tachycardia (SVT), 3) high-grade or complete heart block, and 4) any arrhythmia treated with an antiarrhythmic medication. Systolic LV strain values (including LV global longitudinal strain (GLS), global circumferential strain (GCS), and six segments of LV regional long axis strain) were obtained from initial echocardiograms during hospitalization. Of 66 patients hospitalized, 23 (35%) had arrhythmias. SVT was the predominant arrhythmia (74%). Global and regional strain indices were reduced in the arrhythmia group: LV GLS [-8.9 (IQR -13.6, -6.1) vs. -13.7 (IQR -16.9, -9.7), p = 0.038]; basal inferior/septal [-10.7 (IQR -15.5, -7.8) vs. -16.4 (IQR -18, -11.8), p = 0.009]; basal anterior/lateral [-7.1 (IQR -12.8, -4.7) vs. -9.4 (IQR -16.7, -7.4), p = 0.025]; and mid inferior/septal segments [-9 (IQR -13, -7.7) vs. -14.1 (IQR -22.5, -10.7), p = 0.007]. After controlling for age, reductions in GLS and segmental strain in the two basal and two mid-segments were associated with increased arrhythmia occurrence (p <0.05). Our findings suggest that echocardiographic LV deformation by 2D-STE may be useful in identifying pediatric patients with acute myocarditis at risk for arrhythmias.

Copyright © 2021 Elsevier Inc. All rights reserved.

Am J Cardiol: 31 Jul 2021; 152:113-119
Pruitt CR, Menon S, Lal AK, Eckhauser AW, ... Miller T, Niu M
Am J Cardiol: 31 Jul 2021; 152:113-119 | PMID: 34148631
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Abstract

Incidence, Predictors, and Prognostic Impact of Immediate Improvement in Left Ventricular Systolic Function After Transcatheter Aortic Valve Implantation.

Jeong YJ, Ahn JM, Kang DY, Park H, ... Kim DH, Park DW
Immediate improvement in left ventricular ejection fraction (LVEF) following transcatheter aortic valve implantation (TAVI) is common; however, data on the pattern and prognostic value of this improvement are limited. To evaluate the incidence, predictors, and clinical impact of immediate improvement in LVEF, we studied 694 consecutive patient who had underwent successful TAVI for severe aortic stenosis (AS) between March 2010 and December 2019. We defined immediate improvement of LVEF as an absolute increase of ≥5% in LVEF at post-procedure echocardiogram. The primary outcome was major adverse cardiac or cerebrovascular event (MACCE), defined as a composite of death from cardiovascular cause, myocardial infarction, stroke, or rehospitalization from cardiovascular cause. Among them, 160 patients showed immediate improvement in LVEF. The independent predictors of immediate LVEF improvement were absence of hypertension and baseline significant aortic regurgitation, and greater baseline LV mass index. Immediate improvement in LVEF was significantly associated with a lower risk of MACCE (adjusted hazard ratio, 0.48; 95% confidence interval, 0.28-0.81; p = 0.01). In conclusion, approximately one-fourth of patients with severe AS who underwent TAVI showed immediate improvement in LVEF during index hospitalization. Immediate LVEF recovery was associated with a lower risk of MACCE during follow-up.

Copyright © 2021 Elsevier Inc. All rights reserved.

Am J Cardiol: 31 Jul 2021; 152:99-105
Jeong YJ, Ahn JM, Kang DY, Park H, ... Kim DH, Park DW
Am J Cardiol: 31 Jul 2021; 152:99-105 | PMID: 34127247
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Abstract

Safety and Efficacy of Intravenous Ferric Derisomaltose Compared to Iron Sucrose for Iron Deficiency Anemia in Patients with Chronic Kidney Disease With and Without Heart Failure.

Ambrosy AP, von Haehling S, Kalra PR, Court E, ... McDonagh T, Cleland JGF
Ferric derisomaltose (FDI) is an intravenous (IV) high-dose iron formulation approved in the US for the treatment of iron deficiency anemia in adults who are intolerant of/have had an unsatisfactory response to oral iron, or who have non-dialysis-dependent chronic kidney disease (NDD-CKD). FERWON-NEPHRO was a randomized, open-label, multicenter clinical trial evaluating the safety and efficacy of a single infusion of FDI 1,000 mg versus up to 5 doses of iron sucrose (IS) 200 mg (recommended cumulative dose, 1,000 mg) over 8 weeks in patients with NDD-CKD and iron deficiency anemia. Of 1,525 patients included in the safety analysis, 244 (16%) had a history of heart failure (HF). Overall, the rate of serious or severe hypersensitivity reactions was low and did not differ between treatment groups. Cardiovascular adverse events (AEs) were reported for 9.4% of patients who had HF and 4.2% who did not. Time to first cardiovascular AE was longer following administration of FDI compared with IS (hazard ratio: 0.59 [95% CI: 0.37, 0.92]; p=0.0185), a difference that was similar in patients with or without HF (p=0.908 for interaction). Patients achieved a faster hematological response (assessed by changes in hemoglobin and ferritin concentrations, and increase in transferrin saturation) with FDI versus IS. In conclusion, in patients with NDD-CKD, a single infusion of FDI was safe, well tolerated, and was associated with fewer cardiovascular AEs and a faster hematological response, compared to multiple doses of IS. These effects were similar for patients with and without HF.

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

Am J Cardiol: 31 Jul 2021; 152:138-145
Ambrosy AP, von Haehling S, Kalra PR, Court E, ... McDonagh T, Cleland JGF
Am J Cardiol: 31 Jul 2021; 152:138-145 | PMID: 34162484
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Impact:

This program is still in alpha version.