bluuebunny/crossref_metadata_2025_split huggingface dataset:
3046High levels of MMP-cleaved mimecan is associated to carotid plaque stability and less future cardiovascular events
Authors: Goncalves I , Tengryd C , Nielsen S H , Genovese F , Bengtsson E , Karsdal M , Leeming D J , Nilsson J , Edsfeldt A 
Published: October 2019

Abstract

Introduction
The clinical consequences of atherosclerosis, myocardial infarction and stroke are the most common causes of death globally. Mimecan, a small leucine rich-repeat proteoglycan (SLRP), is cleaved by matrix metalloproteinases (MMPs) and known to be involved in collagen fibrillogenesis and angiogenesis. Circulating levels of MMP-cleaved mimecan (cMIM) has previously been identified as a marker of extracellular matrix remodelling in ApoE−/− knockout mice. The role of mimecan and its degradation in human atherosclerotic plaques has not been explored.

Purpose
We explored whether full-length mimecan and cleaved mimecan (cMIM) are associated to plaque composition and evaluated if they can predict future cardiovascular events.

Methods
Two hundred and eighteen human atherosclerotic plaques were stained for mimecan using immunohistochemistry. cMIM was measured in 202 plaque tissue homogenates using a competitive ELISA assay. Histological components (α-actin, CD68 and glycophorin A) were assessed using immunohistochemistry, neutral lipids were measured using Oil Red O and visible areas of calcium deposits were quantified. Matrix metalloproteinases (MMP-1, -2, -3, -9, -10 and -12), tissue inhibitors of matrix metalloproteinases (TIMP-1 and -2) were analysed in plaque tissue homogenates using ELISA assays and a proximity extension assay. ECM components (glycosaminoglycans, collagen and elastin) were detected with colorimetric assays and the TGF-β1, β2 and β3 were measured by a multiplex assay. Cardiovascular events were registered using national registers, patient records and telephone calls during a follow-up period of 59 months IQR (34–73).

Results
Mimecan was expressed in human atherosclerotic plaques. The expression correlated positively with neutral lipids and intraplaque hemorrhage and inversely with α-actin. In contrast cMIM correlated with α-actin and inversely with neutral lipids. cMIM correlated also with stabilizing extracellular matrix proteins elastin, collagen as well as TGF-β1, β2 and β3. Mimecan correlated to MMP-9 and cMIM correlated to MMP-2 and TIMP-2. Patient with high levels of cMIM had a lower risk of future cardiovascular events which remained significant after adjusting for risk factors (age, gender, diabetes and symptoms) in a multivariate Cox regression

Conclusion(s)
Mimecan was associated with vulnerable plaque features, whereas cMIM was related to stable plaque features. Low levels of cMIM predicted future cardiovascular events, independently of known risk factors. Taken together this suggests a possible role for mimecan and its cleavage in atherosclerosis that needs to be further explored.

Acknowledgement/Funding
Danish Research Foundation, Swedish Research Council, Swedish Heart and Lung Foundation, Skåne University Hospital and more.
3074Analyzing the regulation of a catecholamine-dependent altered cAMP signaling in a patient-specific induced pluripotent stem cell takotsubo-model
Authors: Huebscher D , Borchert T , Hasenfuss G , Nikolaev V , Streckfuss-Boemeke K 
Published: October 2019

Abstract

Background/Purpose
Takotsubo syndrome (TTS) is characterized by acute transient left ventricular dysfunction in the absence of obstructive coronary lesions. Although, we identified an enhanced β-adrenergic signaling and higher sensitivity to catecholamine-induced stress toxicity as mechanisms associated with the TTS phenotype in our former study, the pathogenesis of TTS is still not completely understood. Here, we aimed to prove the hypothesis of a phosphodiesterase (PDE)-dependent regulation of 3',5'-cyclic adenosine monophosphate (cAMP) signaling in TTS under catecholamine stress.

Methods and results
We generated functional TTS induced pluripotent stem cell-derived cardiomyocytes (TTS-iPSC-CMs) from 6 patients and treated the cells with catecholamines to mimic a TTS-phenotype. Using a cytosolic Förster resonance energy transfer (FRET) based cAMP sensor, we could observe that β-adrenergic receptor (β-AR) stimulations led to stronger FRET responses in the cytosol of TTS-CMs as compared to controls. Besides β-ARs, PDEs are main players involved in cAMP signaling in CMs. At basal level TTS-CM show a significantly higher PDE3A and a reduced PDE4D protein expression in the TTS-CMs compared to control. In addition, FRET experiments show that after β-AR stimulation, the strong effects of the PDE4 family in the cytosol of control cells were significantly decreased in TTS-CMs. This is in line with previously described reduced PDE4 activity in failing mouse hearts. By analyzing PDE-dependent cAMP downstream effects as PKA-dependent phosphorylation, we could show an additional increase of PLN phosphorylation (PLN-S16), especially in control, when treating iPSC-CMs with a combination of iso and PDE4 inhibitor. In contrast, in TTS-iPSC-CMs the contribution of the PDE-families PDE2, 3 or 4 to phosphorylation of PLN-S16 was increased over iso alone. This suggests that different PDEs in TTS and control are involved in functional segregation of the SERCA2a microdomain from the cytosol in terms of cAMP downstream effects. To directly address the hypothesis that local cAMP dynamics might be altered in TTS, we used a SERCA micro domain targeted FRET based cAMP sensor. In contrast to the cytosolic cAMP regulation, the PDE4 inhibitor effects in the SERCA2 micro domain were only slightly decreased in TTS. Instead, the contribution of PDE2 to local cAMP degradation was slightly increased.

Conclusion
Our data show for the first time alterations of local cAMP signaling in healthy and diseased TTS-iPSC-CMs. TTS leads to changes in PDE composition in the cytosol but not significantly in SERCA microdomain. Our results uncover a PDE-dependent altered β-adrenergic signaling as a potential disease cause. This data highlight that TTS-iPSC-CMs can be used to provide a versatile tool for evaluating new treatment options for TTS as therapeutic targets.
3076Individual patient meta-analysis of global longitudinal strain: is one normal range enough?
Authors: D'Elia N , Caselli S , Van Den Bosch A E , Kosmala W , Lancellotti P , Morris D , Muraru D , Takeuchi M , Van Grootel R W J , Villarraga H R , Marwick T H 
Published: October 2019

Abstract

Background
Despite over a decade of evidence, uptake of GLS into guidelines and practice has been slow. Age, BP, and software have been reported to influence GLS, and have led to uncertainty about defining the normal range (NR). As there have been software changes since the last meta-analysis, we sought to define NR in the current era.

Methods
Pubmed, Cochrane, and EMBASE were searched using the keywords “Left Ventricle”, “Normal global longitudinal strain”, and “Speckle tracking Echocardiography” and relevant synonyms from 2011. Studies were included if they reported GLS based on speckle tracking techniques, included at least 20 healthy individuals, and had up to date contact details available. Healthy was defined as lack of known disease. Platforms used included General Electric, Philips, Canon and Tomtec. The authors of 8 of the 12 studies (67% response) provided individual patient data. Linear regression was used to determine predictors of GLS.

Results
There were 2396 pts, mean age 42 years (range 18–92), weight 66±12kg, height 169±9cm, BSA 1.7±0.2m2, and SBP 120±13 mmHg. Normal range for GLS was 21.0±2.6%. In multivariable analysis age (β=-0.02, p<0.01), weight (β=-0.03, p<0.01), SBP (β=-0.01, p<0.01) and platform were associated with GLS. GLS tends to vary with extremes of age and BP (see Figure 1 and Figure 2).
GLS vs Age group

Conclusion
Extremes of age and BP may lead to low GLS, but generally, GLS is <16% is abnormal.

Acknowledgement/Funding
None
3254Manifestations of myocardial fibrosis in the standard 12-lead electrocardiogram
Authors: Holmstrom L , Kentta T , Haukilahti A , Pakanen L , Huikuri H , Junttila M J 
Published: October 2019

Abstract

Background
Myocardial fibrosis has substantial role in sudden cardiac deaths (SCD). Major challenge in preventing SCDs is early recognition of vulnerable patients with fibrotic cardiomyopathy. Our aim was to find manifestations of myocardial fibrosis in 12-lead electrocardiogram (ECG).

Methods
Study population is based on the Fingesture study, which has gathered data from 5,869 consecutive autopsied SCD victims between 1998 and 2017 in Finland. The degree of fibrosis was determined based on the histological samples taken from the heart during autopsy and was categorized into four groups; 1) no fibrosis, 2) scattered mild fibrosis, 3) moderate patchy fibrosis and 4) substantial fibrosis. We were able to collect pre-mortem 12-lead ECGs from 1,100 SCD victims. Ischemic cardiomyopathy was the cause of death in 689 cases and 411 had nonischemic cardiomyopathy at autopsy in the group where ECG was available.

Results
Mean age of the study subjects was 66±13 years and 75% were male. At least some amount of myocardial fibrosis was present in 92% of the victims. QRS duration in ECG correlated with the degree of fibrosis in autopsy as follows; 96±21ms in group 1 (n=93), 97±20ms in group 2 (n=357), 103±26ms in group 3 (n=506) and 108±27ms in group 4 (n=144; p<0.001, β=0.153). Prevalence of fragmented QRS complex was higher among victims with severe fibrosis (40% in group 1, 43% in group 2, 60% in group 3 and 65% in group 4; p<0.001). Additionally, inferolateral T-wave inversions were more common in groups with increasing amount of myocardial fibrosis (5.4% in group 1, 13.2% in group 2, 20.4% in group 3 and 31.9% in group 4; p<0.001). Associations were visible in both ischemic and nonischemic SCDs but reached statistical significance only among ischemic SCD victims. Heart rate corrected JT interval and Sokolow-Lyon index had no linear correlation with the degree of fibrosis.

Conclusions
Myocardial fibrosis was associated with QRS prolongation, T-wave inversions and QRS fragmentation among SCD victims. Fibrosis did not manifest as clearly in ECG among patients with nonischemic cardiomyopathies as among ischemic SCD victims. The results may explain the increased risk for SCD in patients with abnormal QRS complex or inverted T waves providing means for recognizing patients with underlying fibrotic cardiomyopathy.

Acknowledgement/Funding
Sigrid Juselius Foundation, Foundation of Cardiac Research, Paavo Nurmi Foundation and Paulo foundation, Finland
3293Atherothrombotic risk and outcomes following guided de-escalation of antiplatelet treatment in patients with acute coronary syndrome:a post-hoc analysis of the TROPICAL-ACS trial
Authors: Rizas K , Farhan S , Huczek Z , Merkely B , Hein-Rothweiler R , Vogel B , Massberg S , Huber K , Aradi D , Sibbing D 
Published: October 2019

Abstract

Background
A de-escalation of P2Y12-inhibitor treatment guided by platelet function testing (PFT) has been identified as a safe and alternative treatment strategy in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI). However, no specific data are available on the efficacy of such strategy in patients with high atherothrombotic risk (ATR).

Purpose
To investigate the safety and efficacy of guided de-escalation of P2Y12-inhibitor treatment in patients with low- vs. high-ATR.

Methods
The TROPICAL-ACS trial randomized 2,610 biomarker-positive ACS patients 1:1 to either conventional treatment with prasugrel for 12 months (control group) or to a PFT guided de-escalation treatment strategy (guided de-escalation group). The primary endpoint was defined as the composite of cardiovascular mortality (CVM), myocardial infarction (MI), stroke, and clinically overt bleeding (bleeding ≥ grade 2 according to the BARC criteria). The ischemic endpoint was defined as the composite of CVM, MI or stroke. We used semi-parametric Cox regression analysis and interaction testing to assess the effect of low- vs. high-ATR on the primary and ischemic endpoints. High-ATR was defined as one of the following: (i) age ≥65 years or (ii) age <65 and either history of peripheral artery disease or at least two of the following risk-factors: diabetes mellitus, current smoking or renal dysfunction.

Results
Patients with high- (n=990) versus low-ATR (n=1,620) exhibited a higher risk for the primary endpoint (11.0% vs. 6.7%; HR 1.67; 95% CI 1.28–2.18; p<0.001). Guided de-escalation was non-inferior to conventional treatment for the primary endpoint in both patients with high- (10.5% vs. 11.5%; pnon-inferiority = 0.029; Figure 1A) and low-ATR (5.6% vs. 7.7%; pnon-inferiority=0.001; Figure 1B). Moreover, there was no significant interaction in the prognostic value of guided de-escalation between high- and low-ATR groups for both the primary (HR 0.90 [0.61–1.32]; p=0.586 in patients with high-ART vs. 0.71 [0.48–1.04; p=0.082 in patients with low-ATR; pinteraction= 0.394) and combined ischemic endpoints (HR 0.83 [0.44–1.56]; p=0.567 in patients with high-ATR vs. 0.68 [0.35–1.34]; p=0.262 in patients with low-ATR; pinteraction =0.666).
Kaplan-Meier curves

Conclusion
A guided DAPT de-escalation strategy appears to be safe and effective in ACS patients regardless of the atherothrombotic risk. Further studies are needed for refining antiplatelet treatment strategies in ACS patients with varying levels of atherothrombotic risk.

Acknowledgement/Funding
Klinikum der Universität München, Roche Diagnostics, Eli Lilly, and Daiichi Sankyo.
3301A novel high-sensitivity cardiac troponin i assay for early diagnosis of acute myocardial infarction
Authors: Boeddinghaus J , Nestelberger T , Twerenbold R , Koechlin L , Wussler D , Badertscher P , Puelacher C , Du Fay De Lavallaz J , Rubini Gimenez M , Zimmermann T , Miro O , Martin-Sanchez F J , Keller D I , Reichlin T , Mueller C 
Published: October 2019

Abstract

Background
Lately, the novel high-sensitivity cardiac troponin I (hs-cTnI) Access assay was developed. Its clinical performance in patients presenting with chest pain to the emergency department (ED) is unknown.

Purpose
To clinically validate the novel hs-cTnI-Access assay and to derive and validate an assay specific 0/1h-algorithm accordingly to the European Society of Cardiology (ESC) recommendations.

Methods
In a prospective international multicentre study we enrolled patients presenting to the emergency department with symptoms suggestive of acute myocardial infarction (AMI). Final diagnoses were centrally adjudicated by two independent cardiologists including all clinical information including cardiac imaging twice: first, using serial hs-cTnT (Elecsys, primary analysis) and second, using hs-cTnI (Architect, secondary analysis) measurements in addition to the clinically used (hs)-cTn. Hs-cTnI-Access was measured at presentation and at 1h. Primary objective was a direct comparison of diagnostic accuracy as quantified by the area under the receiver-operating-characteristic curve (AUC) of hs-cTnI-Access versus the two established hs-cTn assays (hs-cTnT-Elecsys, hs-cTnI-Architect). Secondary objectives included the derivation and internal validation of an hs-cTnI-Access specific 0/1h-algorithm.

Results
AMI was the adjudicated final diagnosis in 243/1579 (15.4%) patients. The AUC at presentation for hs-cTnI-Access was 0.95 (95% CI, 0.94–0.96), significantly higher as hs-cTnI-Architect (0.92 [95% CI, 0.91–0.94; p<0.001]), and comparable to hs-cTnT-Elecsys (0.94 [95% CI, 0.93–0.95; p=0.12]) Applying the derived hs-cTnI-Access 0/1h-algorithm (derivation cohort n=686) to the internal validation cohort (n=680), 60% of patients were ruled-out (sensitivity 98.9% [95% CI, 94.3–99.8]), and 15% of patients were ruled-in (specificity 95.9% [95% CI, 94.0–97.2]). Patients ruled-out by the 0/1h-algorithm had a survival rate of of 100% after 30-days and 98.4% after two years of follow up. Findings were confirmed in the secondary analyses using the adjudication including serial measurements of hs-cTnI (Architect).
Performance of the 0/1h-algorithm

Conclusions
Diagnostic accuracy of the novel hs-cTnI-Access assay is excellent and at least comparable to the two established hs-cTn assays. The assay-specific 0/1h-algorithm allows a safe rule-out and accurate rule-in of MI in about 75% of patients within 1-hour after presentation to the ED. Survival of patients ruled-out by the 0/1h-algorithm was very high.

Acknowledgement/Funding
Swiss National Science Foundation, the Swiss Heart Foundation, the KTI, the European Union, the Stiftung für kardiovaskuläre Forschung Basel
3308The critical roles of coagulation factors in inducing brown adipose tissue dysfunction and systemic metabolic disorder in obesity
Authors: Hayashi Y , Shimizu I S , Yoshida Y Y , Ikegami R I , Katsuumi G K , Suda M S , Fujiki S F , Minamino T M 
Published: October 2019

Abstract
Obese individuals are predisposed to cardio-metabolic disorders. Brown adipose tissue (BAT) is an active metabolic organ abundant with mitochondria, and studies suggest a potential role of BAT in the maintenance of metabolic health in rodents and humans. Metabolic stress causes BAT dysfunction, but the underlying mechanisms are largely unknown. Coagulation factor Xa (FXa) is critically involved in a coagulation cascade, and it is also known to mediate biological effects by the activation of protease-activated receptor (PAR)-signaling. Accumulating evidence shows that PAR1 contributes to tissue remodeling in cardiovascular system. Here we show a previously unknown role of FXa-PAR signaling in promoting BAT dysfunction and systemic metabolic disorder in a murine dietary obese model. Imposing a high fat diet (HFD) on C57BL/6NCr mice led to a marked increase in tissue factor (TF), coagulation factor VII and FXa in BAT. TF-FVIIa (activated form of FVII)-FXa complex is known to activate PAR1, and we found a significant increase in PAR1 expression in BAT upon metabolic stress. Administration of a FXa inhibitor ameliorated BAT whitening, improved thermogenic response and systemic glucose intolerance upon dietary obesity. In contrast, administration of warfarin did not show any phenotype in BAT. BAT specific TF and PAR1 over-expression model showed significant whitening of this tissue, which was associated with systemic glucose intolerance. BAT specific PAR1 KO mice improved glucose intolerance and thermogenic response under a metabolically stressed condition. In differentiated brown adipocytes, FXa markedly increased mitochondrial reactive oxygen species (ROS) and reduced mitochondrial membrane potential. Inhibition of PAR1 ameliorated FXa-induced mitochondrial ROS production and reduction in membrane potential. We also found that plasma FXa level did not increase in obese mice as well as in obese individuals. These results suggest the previously unknown role of coagulation systems in promoting BAT dysfunction, leading to systemic metabolic disorders. Maintenance of BAT homeostasis through the suppression of FXa-PAR1 signaling would become a new therapeutic target for obesity and diabetes.
3327Increasing incidence of cardiac device related endocarditis over the past ten years: a single center analysis
Authors: Vervaecke A , Van De Vyver G , Scott B , Vermeersch P 
Published: October 2019

Abstract

Background
Cardiac device related infective endocarditis (CDIE) is an increasing problem in the current cardiology practice, related to high mortality and morbidity. Recent trends have shown an increase in cardiac device placement, which remains a risk factor for developing CDIE. We performed a retrospective analysis of all patients admitted to our hospital. The aim of our study was to identify a possible correlation between the amount of device placements and the incidence of CDIE.

Methods
All patients, aged 18 years or above, diagnosed and treated for IE in our hospital in the 11 years between January 1st 2007 and December 31st 2017 were retrospectively identified. The amount of cardiac device placements was meticulously kept up to date by the administrative department. Due to the retrospective nature of our study no approval of the local ethics committee was required.

Results
A total of 33 patients with proven CDIE were identified There were no CDIE documented in 2007,2009 and 2010. 2008 showed 2 CDIE (16.7%) whereas the last 4 years of the study showed a mean incidence of 5.75 IE per year. Our population was predominantly male (84.8%) and nearly a third of the population died during hospital stay. The mean age of the population was 73.9 years old. Three quarters of the population underwent surgery and 24 patients out of these underwent device removal, the remaining 2 patients underwent valve replacement or catheter removal.
Half of the patients had early-onset or procedure-related IE (<12 months post procedure). The remaining cases were defined as late onset IE. Overall, 80% of CDIE developed within 3 years after the procedure.
The most prevalent causative organisms in our CDIE population were Staphylococci (68%) followed by Streptococci (20%). Eight out of 33 cases appeared to be culture negative (24.2%).
We sought to correlate these findings to the amount of cardiac device procedures (de novo implantations and replacements) as of 2004 (to compensate for the possible 3-year delay). The number of CD procedures increased by nearly 400% over the course of these 14 years.
Patient demographics

Conclusions
The incidence of CDIE has increased in our population over the past 11 years. This increase runs parallel with the expansion of the number of devices implanted. About half of CDIE occur within 1 year of the procedure defined as early onset CDIE, but the presence of a cardiac device remains a risk factor for IE even thereafter. Causative organisms in our study for CDIE specifically appear to coincide with the results from other studies done in more general populations, with Staphylococci remaining the most prevalent organisms. As patients with cardiac devices implanted appear to be at increased risk for IE, one might add these to the group of patients requiring IE-prophylaxis, especially because of the high mortality rate of IE, which appears to be even higher for CDIE.