bluuebunny/crossref_metadata_2025_split huggingface dataset:
3073Leveraging transcriptome sequencing for detecting novel disease-related pathways using human cardiac sarcoidosis myocardium biopsies
Authors: Yoshida S , Nomura A , Tada H , Sakata K , Nakanishi C , Fujino N , Hosomichi K , Tajima A , Takamura M 
Published: October 2019

Abstract

Background/Introduction
Cardiac sarcoidosis (CS) is one of the main causes of poor outcomes in patients with sarcoidosis, a systemic granulomatous disorder of complex etiology including a genetically susceptible host and specific exposure to disease-triggering antigens. Recently, transcriptome analysis using sarcoidosis peripheral monocytes was reported to be useful for exploring genetic susceptibility and novel disease-causing pathways. However, transcriptome sequencing has not been used to explore disease-related genes and pathways directly using human CS myocardial biopsies.

Purpose
This study aimed to identify transcriptome profiles and novel disease-related pathways of CS by comparing human CS myocardial biopsies with control samples using ribonucleic acid (RNA) sequencing (RNA-Seq).

Methods
We assessed 30 patients with suspected myocardial disorders who underwent transcatheter endomyocardial biopsies at our University Hospital, Japan. Of those, 7 were clinically diagnosed with CS, 9 with hypertrophic cardiomyopathy (HCM), and 14 with dilated cardiomyopathy (DCM). Messenger RNAs were extracted from cardiac muscle biopsies using the Ovation SoLo RNA-Seq System (NuGEN Technologies), according to the manufacturer's instructions. Sequencing was performed with coverage of approximately 20 million reads per sample using Illumina HiSeq 2000. Sequencing reads were mapped using the STAR 2-pass method with GRCh37 as the reference. The DESeq2 R package (version 3.8) was used for further analyses. Principal component analysis (PCA) on gene expression was conducted for detecting outliers such as non-muscular samples. Differential gene expression analysis was performed between the 7 patients with CS and 23 patients with cardiomyopathy (HCM and DCM, non-CS). Gene Ontology (GO) enrichment analysis was conducted to estimate possible disease-related pathways.

Results
We successfully sequenced 60 myocardial biopsy samples (original and biological duplicates) from 30 CS patients. Of these, 2 outlier samples shown by the PCA plot were removed, and 58 were used for further analyses. We found 243 genes that were differentially expressed between CS patients and non-CS patients. Top-rated genes were RP11–366M4.8, RELN, S100A6, WASF3and UCHL1. Pathway analysis using GO demonstrated enrichment oflymphocyte activation (P=4.8x10–16), organelle fission (P=6.1x10–14), the M phase of the mitotic cell cycle (P=2.2x10–13), nuclear division (P=2.4x10–13), mitosis (P=2.4x10–13) and T-cell activation pathways (P=1.2x10–12).

Conclusions
Our differential gene expression and pathway analysis results using human CS myocardial biopsies suggested that lymphocyte activation, specifically the T-cell activation pathway, is linked to CS pathogenesis. Further studies are needed to decipher the role of specific genes related to genetic susceptibility and/or pathways associated with CS occurrence.
3151The prognostic meaning of a reduced reserve of left ventricular force during exercise in hypertrophic cardiomyopathy
Authors: D'Alfonso M G , Peteiro J , De Azevedo Bellagamba C C , Torres M A R , Re F , Tesic M , Monserrat L , Djordjevic-Dikic A , Beleslin B , Fernandez X , Cotrim C , Olivotto J , Ciampi Q , Mori F , Picano E 
Published: October 2019

Abstract

Background
Hypertrophic cardiomyopathy (HCM) patients with blunted force-frequency relationship assessed with pacing during cardiac catheterization are at greater risk of adverse events. Left ventricular contractile reserve (LVCR) based on force can be obtained noninvasively during exercise stress echocardiography (ESE).

Purpose
To evaluate the prognostic correlates of force-based LVCR during ESE in HCM.

Methods
We enrolled 332 HCM patients (age 51±15 years, 193 males, New York Heart Association, NYHA, Class I-III, EF 68±9%, maximal wall thickness 20±5 mm, left ventricular outflow tract gradient, LVOTG, present at rest in 34 pts, 10%) referred for ESE in 7 quality-controlled labs. SE assessment included LVOTG (mm Hg), LV Force (systolic blood pressure by cuff sphygmomanometer + LVOTG/LV end-systolic volume assessed with 2-D, mmHg/ml) and LVCR (peak/rest ratio of LV Force). LV volumes were measured from apical biplane (4- and 2-chamber) views with Simpson method when feasible (n=290) or with linear Teichholz (T) method from parasternal (long- or short-axis) view (n=42). All patients were followed-up.

Results
Force values were 8.5±6.7 at rest and 15.0±13.7 mmHg/mL at peak stress (P<0.001). During a median follow-up time of 58 months, 50 patients experienced at least one event: 19 deaths (10 cardiac), 9 hospitalizations for acute heart failure, 16 myotomy/myectomy and 22 atrial fibrillations. The event-free survival was lower in the 195 patients with LVCR <1.77 (identified with Receiver-Operator Characteristic analysis) compared to the 137 with LVCR ≥1.77: see figure. Multivariate analysis identified LVCR (Hazard ratio, HR, 2.032, 95% confidence intervals, CI, 1.042–3.964, P=0.037), age (HR, 1.033, 95% CI 1.009–1.058, P=0.007) and NYHA class (HR 2.204, 95% CI 1.161–4.185, P<0.016) as independent predictors of events.
Figure 1. HCM-LVCR

Conclusion
A non-invasive evaluation of LVOTG, systolic blood pressure and LV end-systolic volume during ESE allows to assess force-based LVCR in HCM. Lower LVCR is associated with greater risk of events at follow-up.
3226The impact of cardiovascular risk factors on global longitudinal strain over a ten-year period in the general population: The Copenhagen City Heart Study
Authors: Skaarup K G , Lassen M C H L , Biering-Soerensen S R B S , Joergensen P G J , Appleyard M A , Berning J B , Hoest N H , Jensen G B J , Schnohr P S , Soegaard P S , Gislason G H G , Moegelvang R M , Biering-Soerensen T B S 
Published: October 2019

Abstract

Background
Global longitudinal strain (GLS) of the left ventricle (LV) has proved to be a strong predictor of cardiovascular morbidity and mortality. GLS declines throughout adult-life as the LV remodels and adapts. Information on the impact of cardiac risk factors such as male sex, obesity, smoking status, hypertension, hypercholesterolemia, and diabetes on GLS through time has not yet been investigated.

Purpose
The aim of the present study was to investigate the impact of age, sex, body mass index (BMI), smoking status (current and previous vs never), mean arterial blood pressure (MAP), total plasma cholesterol (TPC), and HbA1c on GLS in the general population over a 10-year period.

Method
A total of 689 citizens recruited from the general population participated in the 4th and 5th Copenhagen City Heart Study (CCHS4 and CCHS5) a prospective longitudinal study. At CCHS4 the mean age was 51 years and 45% were male. The average decline in GLS during the follow-up period was −0.65%. All participants underwent two echocardiographic examinations median 10.4 [IQR: 10.2, 10.9] years apart along with thorough health examinations. All analyses were adjusted for baseline GLS value (CCHS4 value).

Results
In regression models, increasing age, male sex, increasing BMI, MAP, hypertension, increasing HbA1c, and diabetes proved to be significantly associated with increased decline in GLS. Relationship between significant continuous cardiovascular risk factors and ΔGLS are displayed in restricted spline curves (Figure 1). In a multivariable regression model including all the investigated cardiovascular risk factors, estimated glomerular filtration rate, plasma pro B-type natriuretic peptide, heart rate, and previous ischemic heart disease, age (standardized β-coef. = −0.10, P=0.005), male sex (standardized β-coef. = −0.16, P<0.001), and MAP (standardized β-coef. = −0.07, P=0.009) remained independent predictors of an accelerated decline in GLS during a 10-year period.
Restricted cubic spline curves

Conclusion
In the general population increasing age, male sex, and increasing MAP are all independently associated with an accelerated decline in GLS over a 10-year period.
3255Characterization of the arrhythmogenic substrate with multimodality imaging in ischemic patients undergoing VT ablation: relationship between cardiac computed tomography and magnetic resonance
Authors: Zucchelli G , Soto Iglesias D , Jauregui B , Teres C , Penela D , Barletta V , Bongiorni M G , Berruezo A 
Published: October 2019

Abstract

Background
Cardiac magnetic resonance (CMR)-aided ventricular tachycardia (VT) substrate ablation has shown to improve VT recurrence-free survival, through a better identification of the arrhythmogenic substrate. However, the access to CMR may be limited in certain centers or sometimes Its use can be contraindicated in patients with cardiac implantable electronic device. Cardiac computed tomography (CT) has shown to improve the results of substrate ablation, correlating with low-voltage areas and local abnormal ventricular activity, and identifying ridges of myocardial tissue (CT-channels) that may be appropriate target sites for ablation.

Purpose
To evaluate the correlation between CT and CMR imaging in identifying anatomical heterogeneous tissue channels (CMR-channels) or CT-channels in ischemic patients undergoing VT substrate ablation.

Methods
The study included 30 post-myocardial infarction (MI) patients (mean age 69±10; 94% male, left ventricular ejection fraction 35±10%), who underwent both CMR and cardiac CT before VT substrate ablation. Using a dedicated post-processing software, the myocardium was segmented in 10 layers from endocardium to epicardium both for the CMR and CT, characterizing the presence of CMR-channels and CT-channels, respectively, by two blinded operators, assigned either to CMR or CT analysis. CMR-channels were classified as endocardial (CMR-channels in layer <50%), epicardial (CMR-channels in layers ≥50%) or transmural (in both endo and epicardial layers). Presence and location of CT and CMR-channels were compared.

Results
In 26/30 patients (86.7%) 91 CT-channels (mean 3.0±1.9 per patient) were identified while 30/30 (100%) showed CMR-channels (n=76; mean 2.4±1.2 per patient). We found 190 CT-channel entrances (mean 6.3±4.1 per patient), and 275 CMR-channel entrances (mean 8.9±4.9 per patient) on cardiac CT and CMR, respectively. There were 47/91 (51.6%) true positive CT-channels. On the contrary, 44/91 (48.4%) CT-channels were considered false positives [19/91 (20.9%) identified out of CMR scar], and 29/76 (38.2%) CMR-channels could not be identified on CT. Thirty-six out of 76 (47.4%) CMR-channels were considered as non-endocardial (epi- or transmural). Twenty-nine out of 36 (80.5%) non-endocardial CMR-channels were coincident with CT-channels.
CT and CMR Channels

Conclusion
CT shows a modest sensitivity in identifying CMR-channels and fails in ascertain their complexity, underestimating the number of entrances; however, channels location at CT fit well with CMR for those classified as transmural or epicardial.
3259Next-generation sequencing to confirm clinical FH in The Netherlands
Authors: Reeskamp L , Zuurbier L C , Hovingh G K , Defesche J C 
Published: October 2019

Abstract

Background
Pathogenic variants in the genes encoding the low-density lipoprotein receptor (LDLR), apolipoprotein B100 (APOB) and proprotein convertase subtilisin/kexin type 9 (PCSK9)) are known to cause familial hypercholesterolemia (FH), a disease characterized by high LDL-C levels. We set out to investigate which proportion of patients with extremely elevated LDL-C levels, who were referred for molecular analysis, carry a mutation in any of the three FH genes or other, putative FH genes.

Methods
Targeted next-generation sequencing of 28 genes involved in lipid metabolism was performed in 1475 clinical FH patients with LDL-C levels >5mmol/L (corresponding with possible, probable and definite FH score according to the Dutch Lipid Clinic Network criteria) and triglyceride levels <4.5 mmol/L. Genetic variants and copy number variants were curated consecutively using specialist analysis software. (Likely) pathogenic variants in LDLR, APOB, or PCSK9 were annotated as FH-causing variants.

Results
14.3% of the 1475 patients with clinical FH were heterozygous carriers of a mutation in LDLR, APOB, or PCSK9. This number ranged from 8% in the lowest LDL-C group (5–5.99 mmol/L) to 56% in patients with the highest LDL-C levels (>8 mmol/L). Patients with LDLR, APOB, or PCSK9 variants had median LDL-C levels of 6.8 [5.7–7.9], 6.2 [5.1–7.0], and 6.4 [5.7–6.8] mmol/L [interquartile range], respectively. Mutation-negative FH patients had median LDL-C levels of 5.8 [5.2–6.5] mmol/L. Of the FH mutation-negative patients 7.4% had a (likely) pathogenic variant in the gene encoding lipoprotein lipase (LPL) and 1.3% in the apolipoprotein E (APOE) gene. The proportion of FH mutation-negative patients carrying an APOE variant increased from 1.2% in the lowest LDL-C group to 7.5% in patients with LDL-C >8 mmol/L. Mutation-positive FH patients were significantly younger (41.61±17.53 years vs 52.62±13.28 years P<0.001) and had a significant lower BMI (25.86±4.87 vs 26.55±4.07kg/m2, P=0.02) compared to mutation negative patients.
Figure 1

Conclusions
A genetic defect in LDLR, APOB or PCSK9 is identified in only 14.3% of the patients with a clinical FH phenotype (defined as LDL-C >5 mmol/L) referred for molecular testing in the Netherlands. Mutations in LPL and APOE were found in a minor proportion of the FH mutation-negative patients. Our finding that a mutation is only found 56% of patients who present with LDL-C levels above 8 mmol/L indicates that either misclassification of FH and/or other genetic defects may be present in this group.

Acknowledgement/Funding
Grant [016.156.445] from The Netherlands Organisation for Scientific Research (NWO)
3296Clinical application of the fourth universal definition of myocardial infarction
Authors: Hartikainen T , Soerensen N A , Haller P M , Gossling A , Blankenberg S , Westermann D , Neumann J T 
Published: October 2019

Abstract

Background
The recently released fourth version of the Universal Definition of Myocardial Infarction (UDMI) introduced substantial changes such as the implementation of the categories acute and chronic myocardial injury. It further recommends the use of sex-specific troponin cut-offs and consideration of absolute rather than relative changes of troponin concentrations for diagnosis of myocardial infarction (MI). Our aim was to apply the updated UDMI in patients with suspected MI to investigate its effect on diagnosis and prognosis.

Methods
We included 2'304 patients presenting to the emergency department with suspected MI. The final diagnosis was first adjudicated according to the 3rd UDMI by two physicians in a blinded fashion using all available medical records, laboratory findings including high-sensitivity troponin T results as well as clinical and imaging findings. Thereafter all patients were re-adjudicated based on the 4th UDMI, again all available information was used. Included patients were followed up to 4 years to assess all-cause mortality, incident nonfatal MI, revascularization and rehospitalization. Hazard ratios (HR) were calculated to investigate the effect of the diagnoses based on the 4th UDMI on prognosis.

Results
Out of 2'304 included patients, 708 got reclassified by the 4th UDMI. 442 (19.2%) were diagnosed as having MI compared to 504 (21.9%) based on the 3rd UDMI. Out of 1'862 non-MI patients, 74 (3.97%) patients had acute and 583 (31.3%) chronic myocardial injury (Figure 1). Patients with acute or chronic injury were older, more often female and had worse renal function than other non-MI patients. The most common causes for acute myocardial injury were heart failure, pulmonary embolism and takotsubo cardiomyopathy. For chronic myocardial injury hypertension, heart failure and non-obstructive coronary artery disease were the most frequent reasons. In cox regression analyses unadjusted HR for all-cause mortality in patients with acute or chronic myocardial injury was considerably higher when compared to patients with non-cardiac chest pain (HR 13.2 (confidence interval (CI) 6.7–26.3) (p<0.001) for acute myocardial injury and 7.2 (CI 4.2–12.5) (p<0.001) for chronic myocardial injury). After adjustment for age and gender, acute and chronic myocardial injury still strongly predicted a poorer outcome and higher rate of cardiovascular events compared to other non-MI patients. Patients with acute or chronic myocardial injury showed equally poor outcome as patients with MI.
Figure 1. Re-adjudication

Conclusion
By introducing the categories of acute and chronic myocardial injury the 4th UDMI succeeds to identify non-MI patients with higher risk for cardiovascular events and poorer outcome and thus seems to improve risk assessment in this heterogeneous population. Prevention strategies for this specific population are yet to be investigated.
3304High sensitive cardiac troponin i at admission and 30 minutes later to rule-in or rule-out acute myocardial infarction - Preliminary results from the RACING-MI trial
Authors: Bang C , Hansen C , Glerup Lauridsen K , Alcaraz Frederiksen C , Schmidt M , Jensen T , Hornung N , Loefgren B 
Published: October 2019

Abstract

Introduction
Current ESC guidelines have introduced a 0h/1h algorithm for accelerated rule-in or rule-out of acute myocardial infarction (MI) when using assay specific high-sensitive cardiac troponin I (hs-cTnI). Several studies have investigated the diagnostic performance and safety of this approach using different hs-cTnI assays. However, little is known of the diagnostic performance of a 0h/30min algorithm.

Purpose
To evaluate the diagnostic accuracy of early rule-in or rule-out of MI after 30 minutes by applying assay specific hs-cTnI cut-off values from a recently validated 0h/1h algorithm.

Methods
We prospectively enrolled chest pain patients suggestive of MI admitted to the Emergency Department. Patients underwent serial hs-cTnI measurements at admission (0 hour) and after 3 hours according to clinical practice. In addition, hs-cTnI measurements were performed after 30 minutes. The assay specific cut-off values from the 0h/1h algorithm were applied to the 30 minute cohort (figure 1). Final diagnosis was adjudicated independently by two physicians.

Results
In total, 943 patients were included. MI was the final diagnosis in 67 (7.1%) patients. Overall, absolute hs-cTnI values after 30 minutes were significantly higher in the MI group than in the non-MI group (19.2 (Q1:Q3) 2.7–75.3) ng/L versus 0.1 (0.2–0.7) ng/L, p<0.001). When applying the assay-specific hs-cTnI cut-off valuesfor the 0h/1h algorithmto the 30 minute patient cohort, 52.4% of patients were classified as rule-out with a negative predictive value of 100% (95% CI: 99.2–100). In total, 8.5% were classified as rule-in with a positive predictive value of 83.8% (95% CI: 74.2–90.3). Sensitivity was 100% (95% CI: 94.6–100) and specificity was 97.4% (95% CI: 95.7–98.6). Overall, 39.1% were assigned to the observational zone with a 3.5% prevalence of MI.

Conclusions
The use of assay specific hs-cTnI measurement at admission (0h) and 30 min later can be used to safely rule-out MI. This indicates that it might be safe to develop a 0h/30min algorithm and hereby reduce time to diagnosis even further. NCT03634384.

Acknowledgement/Funding
Randers Regional Hospital, A.P Møller Foundation, Boserup Foundation, Korning Foundation, Højmosegård Grant, Siemens Healthcare (TNIH assays), etc.
4036The knowledge as the determinant of the adherence to antihypertensive treatment
Authors: Swiatoniowska N , Bartosiak E , Szymanska-Chabowska A , Mazur G , Jankowska-Polanska B 
Published: October 2019

Abstract

Introduction
The education of the patients with cardio-vascular diseases aims to modify the present risk factors and to increase the aware participation in the therapy. Arterial hypertension is one of the most common modifiable risk factors of cardio-vascular diseases. However, the knowledge of the self-care and adherence to therapeutic recommendations are highly disappointing. Understanding people's levels of knowledge on cardiovascular risk factors and its relation to level of adherence in antihypertensive treatment might contribute effectively to medical staff efforts to prevent, treat and control the disease.
The aim of the study was analysis of the knowledge of the cardio-vascular risk factors and the adherence to therapeutic recommendations.

Material and methods
101 patients (mean age 57.5±13.2) with arterial hypertension (stage I and II according to ESC) were enrolled into the study. The following questionnaires were used: Morisky's Self-Reported Measure of Medication Adherence (MMAS-8-Item), Hill-Bone Compliance to High Blood Pressure Therapy Scale (Hill-Bone Scale) and The Cardiovascular Disease Risk Factors Knowledge Level Scale (CARRF).

Results
41% of the patients had worse knowledge of the cardio-vascular risk factors. In comparative analysis there were the significant differences in adherence to treatment with regards to the knowledge according to CRRRF questionnaire. The patients with better knowledge had the best adherence, which diminished along with worsening the knowledge (19.0±3.5 vs 18.3±3.7 vs 16.6±4.1). The increase of the knowledge by one point in scale CARRF-KL was accompanied by the increase of the adherence by 0.14 point (mean). The relations between knowledge and adherence was observed in terms of the treatment (8.3±2.0 vs 10.1±5.0 vs 8.9±3.5; p=0.003) and the global results of Hill-Bone questionnaire (19.5±4.4 vs 22.7±7.3). The relation between the knowledge and the adherence in terms of salt intake or control check-ups was not proved. In multiple regression analysis the knowledge was significant independent determinant, which influenced the adherence in terms of the treatment MMAS (b= 0.253; p=0.0004)

Conclusions
Adherence to therapeutic recommendations is related to the knowledge of the cardio-vascular risk factors, i.e. the better knowledge, the better adherence. The knowledge is the independent predictor of adherence to treatment in patients with arterial hypertension. The identification of knowledge deficits as a factor contributing to lack of adherence and poor hypertension control remains a key challenge for clinicians caring for patients with hypertension.