bluuebunny/crossref_metadata_2025_split huggingface dataset:
Untargeted Lipidomics Reveals a Specific Enrichment in Plasmalogens in Epicardial Adipose Tissue and a Specific Signature in Coronary Artery Disease
Authors: Barchuk Magali , Dutour Anne , Ancel Patricia , Svilar Ljubica , Miksztowicz Veronica , Lopez Graciela , Rubio Miguel , Schreier Laura , Nogueira Juan Patricio , Valéro René , Béliard Sophie , Martin Jean Charles , Berg Gabriela , Gaborit Bénédicte 
Published: March 2020

Objective:
Epicardial adipose tissue (EAT) is an active endocrine organ that could contribute to the pathophysiology of coronary artery disease (CAD) through the paracrine release of proatherogenic mediators. Numerous works have analyzed the inflammatory signature of EAT, but scarce informations on its lipidome are available. Our objective was first to study the differences between EAT and subcutaneous adipose tissue (SAT) lipidomes and second to identify the specific untargeted lipidomic signatures of EAT and SAT in CAD.

Approach and Results:

Subcutaneous and EAT untargeted lipidomic analysis was performed in 25 patients with CAD and 14 patients without CAD and compared with paired plasma lipidomic analysis of isolated VLDL (very low-density lipoprotein) and HDL (high-density lipoprotein). Lipidomics was performed on a C18 column hyphenated to a Q-Exactive plus mass spectrometer, using both positive and negative ionization mode. EAT and SAT had independent lipidomic profile, with 95 lipid species differentially expressed and phosphatidylethanolamine 18:1p/22:6 twenty-fold more expressed in EAT compared with SAT false discovery rate =3×10
−4
). Patients with CAD exhibited more ceramides (
P
=0.01), diglycerides (
P
=0.004; saturated and nonsaturated), monoglycerides (
P
=0.013) in their EAT than patients without CAD. Conversely, they had lesser unsaturated TG (triglycerides;
P
=0.02). No difference was observed in the 295 lipid species found in SAT between patients with and without CAD. Fifty-one lipid species were found in common between EAT and plasma lipoproteins. TG 18:0/18:0/18:1 was found positively correlated (
r
=0.45,
P
=0.019) in EAT and HDL and in EAT and VLDL (
r
=0.46,
P
=0.02).

Conclusions:
CAD is associated with specific lipidomic signature of EAT, unlike SAT. Plasma lipoprotein lipidome only partially reflected EAT lipidome.
Hypokalemia Promotes Arrhythmia by Distinct Mechanisms in Atrial and Ventricular Myocytes
Authors: Tazmini Kiarash , Frisk Michael , Lewalle Alexandre , Laasmaa Martin , Morotti Stefano , Lipsett David B. , Manfra Ornella , Skogestad Jonas , Aronsen Jan M. , Sejersted Ole M. , Sjaastad Ivar , Edwards Andrew G. , Grandi Eleonora , Niederer Steven A. , Øie Erik , Louch William E. 
Published: March 2020

Rationale:
Hypokalemia occurs in up to 20% of hospitalized patients and is associated with increased incidence of ventricular and atrial fibrillation. It is unclear whether these differing types of arrhythmia result from direct and perhaps distinct effects of hypokalemia on cardiomyocytes.

Objective:
To investigate proarrhythmic mechanisms of hypokalemia in ventricular and atrial myocytes.

Methods and Results:

Experiments were performed in isolated rat myocytes exposed to simulated hypokalemia conditions (reduction of extracellular [K
+
] from 5.0 to 2.7 mmol/L) and supported by mathematical modeling studies. Ventricular cells subjected to hypokalemia exhibited Ca
2+
overload and increased generation of both spontaneous Ca
2+
waves and delayed afterdepolarizations. However, similar Ca
2+
-dependent spontaneous activity during hypokalemia was only observed in a minority of atrial cells that were observed to contain t-tubules. This effect was attributed to close functional pairing of the Na
+
-K
+
ATPase and Na
+
-Ca
2+
exchanger proteins within these structures, as reduction in Na
+
pump activity locally inhibited Ca
2+
extrusion. Ventricular myocytes and tubulated atrial myocytes additionally exhibited early afterdepolarizations during hypokalemia, associated with Ca
2+
overload. However, early afterdepolarizations also occurred in untubulated atrial cells, despite Ca
2+
quiescence. These phase-3 early afterdepolarizations were rather linked to reactivation of nonequilibrium Na
+
current, as they were rapidly blocked by tetrodotoxin. Na
+
current-driven early afterdepolarizations in untubulated atrial cells were enabled by membrane hyperpolarization during hypokalemia and short action potential configurations. Brief action potentials were in turn maintained by ultra-rapid K
+
current (I
Kur
); a current which was found to be absent in tubulated atrial myocytes and ventricular myocytes.

Conclusions:
Distinct mechanisms underlie hypokalemia-induced arrhythmia in the ventricle and atrium but also vary between atrial myocytes depending on subcellular structure and electrophysiology.
Celastrol Attenuates Angiotensin II–Induced Cardiac Remodeling by Targeting STAT3
Authors: Ye Shiju , Luo Wu , Khan Zia A. , Wu Gaojun , Xuan Lina , Shan Peiren , Lin Ke , Chen Taiwei , Wang Jingying , Hu Xiang , Wang Shengjie , Huang Weijian , Liang Guang 
Published: March 2020

Rationale:
Excessive Ang II (angiotensin II) levels lead to a profibrotic and hypertrophic milieu that produces deleterious remodeling and dysfunction in hypertension-associated heart failure. Agents that disrupt Ang II–induced cardiac dysfunction may have clinical utility in the treatment of hypertension-associated heart failure.

Objective:
We have examined the potential effect of celastrol—a bioactive compound derived from the Celastraceae family—on Ang II–induced cardiac dysfunction.

Methods and Results:
In rat primary cardiomyocytes and H9C2 (rat cardiomyocyte-like H9C2) cells, celastrol attenuates Ang II–induced cellular hypertrophy and fibrotic responses. Proteome microarrays, surface plasmon resonance, competitive binding assays, and molecular simulation were used to identify the molecular target of celastrol. Our data showed that celastrol directly binds to and inhibits STAT (signal transducer and activator of transcription)-3 phosphorylation and nuclear translocation. Functional tests demonstrated that the protection of celastrol is afforded through targeting STAT3. Overexpression of STAT3 dampens the effect of celastrol by partially rescuing STAT3 activity. Finally, we investigated the in vivo effect of celastrol treatment in mice challenged with Ang II and in the transverse aortic constriction model. We show that celastrol administration protected heart function in Ang II–challenged and transverse aortic constriction–challenged mice by inhibiting cardiac fibrosis and hypertrophy.

Conclusions:
Our studies show that celastrol inhibits Ang II–induced cardiac dysfunction by inhibiting STAT3 activity.
Nfatc1 Promotes Interstitial Cell Formation During Cardiac Valve Development in Zebrafish
Authors: Gunawan Felix , Gentile Alessandra , Gauvrit Sébastien , Stainier Didier Y.R. , Bensimon-Brito Anabela 
Published: March 2020

Rationale:
The transcription factor NFATC1 (nuclear factor of activated T-cell 1) has been implicated in cardiac valve formation in humans and mice, but we know little about the underlying mechanisms. To gain mechanistic understanding of cardiac valve formation at single-cell resolution and insights into the role of NFATC1 in this process, we used the zebrafish model as it offers unique attributes for live imaging and facile genetics.

Objective:
To understand the role of Nfatc1 in cardiac valve formation.

Methods and Results:

Using the zebrafish atrioventricular valve, we focus on the valve interstitial cells (VICs), which confer biomechanical strength to the cardiac valve leaflets. We find that initially atrioventricular endocardial cells migrate collectively into the cardiac jelly to form a bilayered structure; subsequently, the cells that led this migration invade the ECM (extracellular matrix) between the 2 endocardial cell monolayers, undergo endothelial-to-mesenchymal transition as marked by loss of intercellular adhesion, and differentiate into VICs. These cells proliferate and are joined by a few neural crest–derived cells. VIC expansion and a switch from a promigratory to an elastic ECM drive valve leaflet elongation. Functional analysis of Nfatc1 reveals its requirement during VIC development. Zebrafish
nfatc1
mutants form significantly fewer VICs due to reduced proliferation and impaired recruitment of endocardial and neural crest cells during the early stages of VIC development. With high-speed microscopy and echocardiography, we show that reduced VIC formation correlates with valvular dysfunction and severe retrograde blood flow that persist into adulthood. Analysis of downstream effectors reveals that Nfatc1 promotes the expression of
twist1b
—a well-known regulator of epithelial-to-mesenchymal transition.

Conclusions:
Our study sheds light on the function of Nfatc1 in zebrafish cardiac valve development and reveals its role in VIC formation. It also further establishes the zebrafish as a powerful model to carry out longitudinal studies of valve formation and function.
Phosphoproteomic Analysis of Neonatal Regenerative Myocardium Revealed Important Roles of Checkpoint Kinase 1 via Activating Mammalian Target of Rapamycin C1/Ribosomal Protein S6 Kinase b-1 Pathway
Authors: Fan Yi , Cheng Yiwei , Li Yafei , Chen Bingrui , Wang Zimu , Wei Tianwen , Zhang Hao , Guo Yueshuai , Wang Qiming , Wei Yongyue , Chen Feng , Sha Jiahao , Guo Xuejiang , Wang Liansheng 
Published: March 2020

Background:
In mammals, regenerative therapy after myocardial infarction is hampered by the limited regenerative capacity of adult heart, whereas a transient regenerative capacity is maintained in the neonatal heart. Systemic phosphorylation signaling analysis on ischemic neonatal myocardium might be helpful to identify key pathways involved in heart regeneration. Our aim was to define the kinase-substrate network in ischemic neonatal myocardium and to identify key pathways involved in heart regeneration after ischemic insult.

Methods:
Quantitative phosphoproteomics profiling was performed on infarct border zone of neonatal myocardium, and kinase-substrate network analysis revealed 11 kinases with enriched substrates and upregulated phosphorylation levels, including checkpoint kinase 1 (CHK1) kinase. The effect of CHK1 on cardiac regeneration was tested on Institute of Cancer Research CD1 neonatal and adult mice that underwent apical resection or myocardial infarction.

Results:
In vitro, CHK1 overexpression promoted whereas CHK1 knockdown blunted cardiomyocyte proliferation. In vivo, inhibition of CHK1 hindered myocardial regeneration on resection border zone in neonatal mice. In adult myocardial infarction mice, CHK1 overexpression on infarct border zone upregulated mammalian target of rapamycin C1/ribosomal protein S6 kinase b-1 pathway, promoted cardiomyocyte proliferation, and improved cardiac function. Inhibiting mammalian target of rapamycin activity by rapamycin blunted the neonatal cardiomyocyte proliferation induced by CHK1 overexpression in vitro.

Conclusions:
Our study indicates that phosphoproteome of neonatal regenerative myocardium could help identify important signaling pathways involved in myocardial regeneration. CHK1 is found to be a key signaling responsible for neonatal regeneration. Myocardial overexpression of CHK1 could improve cardiac regeneration in adult hearts by activating the mammalian target of rapamycin C1/ribosomal protein S6 kinase b-1 pathway. Thus, CHK1 might serve as a potential novel target in myocardial repair after myocardial infarction.
Evidence From Family Studies for Autoimmunity in Arrhythmogenic Right Ventricular Cardiomyopathy
Authors: Caforio Alida L.P. , Re Federica , Avella Andrea , Marcolongo Renzo , Baratta Pasquale , Seguso Mara , Gallo Nicoletta , Plebani Mario , Izquierdo-Bajo Alvaro , Cheng Chun-Yan , Syrris Petros , Elliott Perry M. , d’Amati Giulia , Thiene Gaetano , Basso Cristina , Gregori Dario , Iliceto Sabino , Zachara Elisabetta 
Published: March 2020

Background:
Serum anti-heart autoantibodies (AHAs) and anti-intercalated disk autoantibodies (AIDAs) are autoimmune markers in myocarditis. Myocarditis has been reported in arrhythmogenic right ventricular cardiomyopathy (ARVC). To provide evidence for autoimmunity, we searched for AHAs and AIDAs in ARVC.

Methods:
We studied: 42 ARVC probands, 23 male, aged 42, interquartile range 33–49, 20 from familial and 22 nonfamilial pedigrees; 37 clinically affected relatives (ARs), 24 male aged 35, interquartile range 18–46; and 96 healthy relatives, 49 male, aged 27, interquartile range 17–45. Serum AHAs and AIDAs were tested by indirect immunofluorescence on human myocardium and skeletal muscle in 171 of the 175 ARVC individuals and in controls with noninflammatory cardiac disease (n=160), ischemic heart failure (n=141), and healthy blood donors (n=270). Screening of 5 desmosomal genes was performed in probands; when a sequence variant was identified, cascade family screening followed, blind to immunologic results.

Results:

AHA frequency was higher (36.8%) in probands, ARs (37.8%), and healthy relatives (25%) than in noninflammatory cardiac disease (1%), ischemic heart failure (1%), or healthy blood donors (2.5%;
P
=0.0001). AIDA frequency was higher in probands (8%,
P
=0.006), in ARs (21.6%,
P
=0.00001), and in healthy relatives (14.6%,
P
=0.00001) than in noninflammatory cardiac disease (3.75%), ischemic heart failure (2%), or healthy blood donors (0.3%). AHA-positive status was associated with higher frequency of palpitation (
P
=0.004), implantable cardioverter defibrillator implantation (
P
=0.021), lower left ventricular ejection fraction (
P
=0.004), AIDA-positive status with both lower right ventricular and left ventricular ejection fractions (
P
=0.027 and
P
=0.027, respectively). AHA- and/or AIDA-positive status in the proband and at least one of the respective relatives was more common in familial (17/20, 85%) than in sporadic (10/22, 45%) pedigrees (
P
=0.007).

Conclusions:
The presence of AHAs and AIDAs provides evidence of autoimmunity in the majority of familial and in almost half of sporadic ARVC. In probands and in ARs, these antibodies were associated with features of disease severity. Longitudinal studies are needed to clarify whether they may predict ARVC development in healthy relatives or if they be a result of manifest ARVC.
Low-Attenuation Noncalcified Plaque on Coronary Computed Tomography Angiography Predicts Myocardial Infarction
Authors: Williams Michelle C. , Kwiecinski Jacek , Doris Mhairi , McElhinney Priscilla , D’Souza Michelle S. , Cadet Sebastien , Adamson Philip D. , Moss Alastair J. , Alam Shirjel , Hunter Amanda , Shah Anoop S.V. , Mills Nicholas L. , Pawade Tania , Wang Chengjia , Weir McCall Jonathan , Bonnici-Mallia Michael , Murrills Christopher , Roditi Giles , van Beek Edwin J.R. , Shaw Leslee J. , Nicol Edward D. , Berman Daniel S. , Slomka Piotr J. , Newby David E. , Dweck Marc R. , Dey Damini 
Published: March 2020

Background:
The future risk of myocardial infarction is commonly assessed using cardiovascular risk scores, coronary artery calcium score, or coronary artery stenosis severity. We assessed whether noncalcified low-attenuation plaque burden on coronary CT angiography (CCTA) might be a better predictor of the future risk of myocardial infarction.

Methods:
In a post hoc analysis of a multicenter randomized controlled trial of CCTA in patients with stable chest pain, we investigated the association between the future risk of fatal or nonfatal myocardial infarction and low-attenuation plaque burden (% plaque to vessel volume), cardiovascular risk score, coronary artery calcium score or obstructive coronary artery stenoses.

Results:

In 1769 patients (56% male; 58±10 years) followed up for a median 4.7 (interquartile interval, 4.0–5.7) years, low-attenuation plaque burden correlated weakly with cardiovascular risk score (
r
=0.34;
P
<0.001), strongly with coronary artery calcium score (
r
=0.62;
P
<0.001), and very strongly with the severity of luminal coronary stenosis (area stenosis,
r
=0.83;
P
<0.001). Low-attenuation plaque burden (7.5% [4.8–9.2] versus 4.1% [0–6.8];
P
<0.001), coronary artery calcium score (336 [62–1064] versus 19 [0–217] Agatston units;
P
<0.001), and the presence of obstructive coronary artery disease (54% versus 25%;
P
<0.001) were all higher in the 41 patients who had fatal or nonfatal myocardial infarction. Low-attenuation plaque burden was the strongest predictor of myocardial infarction (adjusted hazard ratio, 1.60 (95% CI, 1.10–2.34) per doubling;
P
=0.014), irrespective of cardiovascular risk score, coronary artery calcium score, or coronary artery area stenosis. Patients with low-attenuation plaque burden greater than 4% were nearly 5 times more likely to have subsequent myocardial infarction (hazard ratio, 4.65; 95% CI, 2.06–10.5;
P
<0.001).

Conclusions:
In patients presenting with stable chest pain, low-attenuation plaque burden is the strongest predictor of fatal or nonfatal myocardial infarction. These findings challenge the current perception of the supremacy of current classical risk predictors for myocardial infarction, including stenosis severity.

Registration:

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT01149590.
Association of Intensive Lifestyle Intervention, Fitness, and Body Mass Index With Risk of Heart Failure in Overweight or Obese Adults With Type 2 Diabetes Mellitus
Authors: Pandey Ambarish , Patel Kershaw V. , Bahnson Judy L. , Gaussoin Sarah A. , Martin Corby K. , Balasubramanyam Ashok , Johnson Karen C. , McGuire Darren K. , Bertoni Alain G. , Kitzman Dalane , Berry Jarett D. ,   Look AHEAD Research Group
Published: March 2020

Background:
Type 2 diabetes mellitus (T2DM) is associated with a higher risk for heart failure (HF). The impact of a lifestyle intervention and changes in cardiorespiratory fitness (CRF) and body mass index on risk for HF is not well established.

Methods:
Participants from the Look AHEAD trial (Action for Health in Diabetes) without prevalent HF were included. Time-to-event analyses were used to compare the risk of incident HF between the intensive lifestyle intervention and diabetes support and education groups. The associations of baseline measures of CRF estimated from a maximal treadmill test, body mass index, and longitudinal changes in these parameters with risk of HF were evaluated with multivariable adjusted Cox models.

Results:
Among the 5109 trial participants, there was no significant difference in the risk of incident HF (n=257) between the intensive lifestyle intervention and the diabetes support and education groups (hazard ratio, 0.96 [95% CI, 0.75–1.23]) over a median follow-up of 12.4 years. In the most adjusted Cox models, the risk of HF was 39% and 62% lower among moderate fit (tertile 2: hazard ratio, 0.61 [95% CI, 0.44–0.83]) and high fit (tertile 3: hazard ratio, 0.38 [95% CI, 0.24–0.59]) groups, respectively (referent group: low fit, tertile 1). Among HF subtypes, after adjustment for traditional cardiovascular risk factors and interval incidence of myocardial infarction, baseline CRF was not significantly associated with risk of incident HF with reduced ejection fraction. In contrast, the risk of incident HF with preserved ejection fraction was 40% lower in the moderate fit group and 77% lower in the high fit group. Baseline body mass index also was not associated with risk of incident HF, HF with preserved ejection fraction, or HF with reduced ejection fraction after adjustment for CRF and traditional cardiovascular risk factors. Among participants with repeat CRF assessments (n=3902), improvements in CRF and weight loss over a 4-year follow-up were significantly associated with lower risk of HF (hazard ratio per 10% increase in CRF, 0.90 [95% CI, 0.82–0.99]; per 10% decrease in body mass index, 0.80 [95% CI, 0.69–0.94]).

Conclusions:
Among participants with type 2 diabetes mellitus in the Look AHEAD trial, the intensive lifestyle intervention did not appear to modify the risk of HF. Higher baseline CRF and sustained improvements in CRF and weight loss were associated with lower risk of HF.

Registration:

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT00017953.
Redefined Measure of Early Neurological Improvement Shows Treatment Benefit of Alteplase Over Placebo
Authors: Agarwal Shashank , Scher Erica , Lord Aaron , Frontera Jennifer , Ishida Koto , Torres Jose , Rostanski Sara , Mistry Eva , Mac Grory Brian , Cutting Shawna , Burton Tina , Silver Brian , Liberman Ava L. , Lerario Mackenzie P. , Furie Karen , Grotta James , Khatri Pooja , Saver Jeffrey , Yaghi Shadi 
Published: March 2020

Background and Purpose—
The first of the 2 NINDS (National Institute of Neurological Disorders and Stroke) Study trials did not show a significant increase in early neurological improvement, defined as National Institutes of Health Stroke Scale (NIHSS) improvement by ≥4, with alteplase treatment. We hypothesized that early neurological improvement defined as a percentage change in NIHSS (percent change NIHSS) at 24 hours is superior to other definitions in predicting 3-month functional outcomes and using this definition there would be treatment benefit of alteplase over placebo at 24 hours.

Methods—
We analyzed the NINDS rt-PA Stroke Study (Parts 1 and 2) trial data. Percent change NIHSS was defined as ([admission NIHSS score−24-hour NIHSS score]×100/admission NIHSS score] and delta NIHSS as (admission NIHSS score−24-hour NIHSS score). We compared early neurological improvement using these definitions between alteplase versus placebo patients. We also used receiver operating characteristic curve to determine the predictive association of early neurological improvement with excellent 3-month functional outcomes (Barthel Index score of 95–100 and modified Rankin Scale score of 0–1), good 3-month functional outcome (modified Rankin Scale score of 0–2), and 3-month infarct volume.

Results—

There was a significantly greater improvement in the 24-hour median percent change NIHSS among patients treated with alteplase compared with the placebo group (28% versus 15%;
P
=0.045) but not median delta NIHSS (3 versus 2;
P
=0.471). Receiver operating characteristic curve comparison showed that percent change NIHSS (ROC
percent
) was better than delta NIHSS (ROC
delta
) and admission NIHSS (ROC
admission
) with regards to excellent 3-month Barthel Index (ROC
percent
, 0.83; ROC
delta
, 0.76; ROC
admission
, 0.75), excellent 3-month modified Rankin Scale (ROC
percent
, 0.83; ROC
delta
, 0.74; ROC
admission
, 0.78), and good 3-month modified Rankin Scale (ROC
percent
, 0.83; ROC
delta
, 0.76; ROC
admission
, 0.78).

Conclusions—
In the NINDS rt-PA trial, alteplase was associated with a significant percent change improvement in NIHSS at 24 hours. Percent change in NIHSS may be a better surrogate marker of thrombolytic activity and 3-month outcomes.