bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 12008: Nos1 Adapter Protein Nos1ap Overexpression Alters Qtc Intervals in Transgenic Mice
Authors: Williams Tatjana , Arias-Loza Anahi P , Abeßer Marco , Schmitt Joachim , Schuh Kai , Ritter Oliver 
Published: July 2021

Background:
Congenital long- or short-QT syndrome may lead to life-threatening ventricular tachycardia and sudden cardiac death. Apart from rare disease-causing mutations in ion channels, common genetic variations in the neuronal nitric oxide synthase (NOS1) regulator NOS1AP, have recently been associated with QT interval variations in a human whole-genome association study. In fact, NOS1AP SNPs have been linked to increases in QTc intervals and sudden cardiac death. We therefore speculate that myocardial NOS1AP overexpression may lead to a decrease of the QTc interval and an increased susceptibility to rhythm disorders.

Methods and Results:
We generated transgenic mice (TG) with a conditional myocardial NOS1AP overexpression and focused on electrical alterations. Conditional overexpression of NOS1AP resulted in a 147% ventricular increase in TG mice compared to WT littermates. NOS1AP was mainly located at the sarcolemma where it interacted with NOS1 and the L-type Ca2+- channel. HW/BW ratio, ventricular ANP expression, ventricular cross-sectional area and collagen deposition were not altered in NOS1AP mice under baseline conditions.

However, NOS1AP overexpressing mice showed a clear decrease of QTc intervals (33 vs. 48 ms). They were more prone to bradycardia (resting heart rate 467 bpm vs. 666 bpm). Atrial programmed stimulation repeatedly caused atrial tachycardia. Ventricular programmed stimulation caused VT in some mice with NOS1AP overexpression.
We also investigated the functional effect of the human rs16847548 (T/C). We found that this SNP decreased NOS1AP promoter activity in a viral NOS1AP luciferase assay, suggesting that this SNP downregulates NOS1AP expression in humans.

Conclusion:
Myocardial overexpression of NOS1AP leads to a significant shortening of the QTc interval with an increased susceptibility to atrial and ventricular rhythm disorders. SNP rs16847548 in NOS1AP resulted in downregulation of NOS1AP expression which provides an explanation for elongation of QTc intervals. In summary, not only a mutation in ion channels itself but also genetic alterations in expression of ion channel modifiers, such as NOS1AP, have an impact on QTc intervals.
Abstract 13672: High Frequency Echocardiography and Speckle Tracking Based Strain Analysis Revealed Delayed Functional Recovery After Myocardial Cryoinjury in Adult Zebrafish
Authors: Hein Selina , Lehmann Lorenz , Katus Hugo A , Hassel David 
Published: July 2021

Zebrafish is a widespread used model in cardiovascular research, and recently adult zebrafish, as a more human relevant model compared to larval stages, became particularly valuable to study heart regeneration. While cardiac performance in larval stages can be easily assessed using transillumination microscopy, methods to reliably assess cardiac function in adult zebrafish are largely missing.
Here, we developed the first standardized protocol to reliably assess cardiac function in adult zebrafish using high frequency echocardiography and speckle-tracking algorithms. Respecting distinct anatomic characteristics in zebrafish, we defined three examination planes according to standards in human echocardiography. Further, by combining conventional echocardiographic measurements with modern speckle tracking based strain analysis we are able to measure myocardial performance in extremely high spatial and temporal resolution. Thereby we were able to attain high quality B-Mode imaging and PW-Doppler signals allowing distinct detection of changes in chronotropy, inotropy and, for the first time in adult zebrafish, in dromotropy in response to treatment with Atenolol and Isoproterenol. Additionally, we employed zebrafish that underwent cardiac cryoinjury to longitudinally follow functional cardiac regeneration. High-resolution speckle-tracking strain analysis allowed us to demarcate injured myocardial regions and demonstrate that functional healing extends beyond 30-45 days post injury (dpi) as previously implied by conventional methodologies. Specifically, we found delayed restitution of cardiac displacement and re-synchronization of injured and non-injured myocardium beyond 60 dpi until 120 dpi. In summary, our protocol enables highly reproducible and high throughput measurements of cardiac performance in adult zebrafish in a high spatio-temporal resolution. Thereby, our protocol represents a valuable novel tool for functional cardiac assessment and to detect changes in cardiac function in response to gene mutation or myocardial injury and might lead to further insights into cardiac physiology and disease.
Abstract 15113: A Novel Purification Method for Cardiomyocytes and Endothelial Cells Derived From Human Pluripotent Stem Cells Using Microrna-responsive Messenger Rna
Authors: Miki Kenji , Takahashi Seiya , Funakoshi Shunsuke , Yamanaka Shinya , Saito Hirohide , Yoshida Yoshinori 
Published: July 2021

MicroRNAs (miRNAs) are small non-coding RNA that controls gene expression through translational regulation or mRNA cleavage. Recent progress in synthetic biology demonstrated that synthetic “RNA switches” enable to regulate gene expression depending on the intracellular environment. Here we show that synthetic mRNA technologies that modulate reporter protein expression by sensing miRNA activities enable purification of target cells in a safe and effective manner.
To select cardiac-specific miRNA candidates, we performed miRNA microarray analyses using human induced pluripotent stem cell (hiPSC) line integrated MYH6 promoter driven EGFP cassette. We found 14 candidates, and synthesized individually these 14 miRNA-responsive OFF switch mRNAs (miR-switches) containing the sequence of blue fluorescent protein (TagBFP). We individually transfected them with EGFP mRNA into differentiated cells including cardiomyocytes derived from human pluripotent stem cell (hPSCs). We found that several cells transfected with miR-1- or miR-208-switches diminished TagBFP intensity, and sorting of these cells yielded high populations of troponin T-positive cardiomyocytes reproducibly and significantly (e.g., up to >98% in five hPSC lines). In addition, we developed a non-sorting system for purification of cardiomyocytes using miR-switch that code apoptosis-inducible protein (up to >97%). These cardiomyocytes purified by miR-switches were successfully engrafted in mouse heart and did not form tumor even when injected into testes of SCID mice. We next examined whether the system can be applied to purify endothelial cells, and confirmed that several miR-switches enabled high purification of CD31+ cells from differentiated derivatives of hPSCs (up to >98%), which have the function of tube formation like HUVEC. Moreover, the use of multiple miRNA-responsive mRNAs enabled simultaneous and high purification of cardiomyocytes and endothelial cells from heterogeneous population derived from hPSCs induced by single differentiation method (up to >98%).
Our results suggest that miR-switch technology can be used for a variety of purposes including purification in any type of cells.
Abstract 15675: Bone Marrow Derived Ixmyelocel-T From Patients With Severe Ischemic Dilated Cardiomyopathy Display Robust Anti-Inflammatory and Pro-Angiogenic Properties
Authors: Ledford Kelly J , Remmers Ann E , Tubo Ross 
Published: July 2021

Ixmyelocel-T, an expanded autologous multicellular therapy cultured from BMMNCs consisting of regenerative MSCs and M2-like macrophages, has shown clinical promise in the treatment of ischemic DCM. However the quality of BM-derived cell therapies from patients with severe heart failure is unclear as reports suggest they are dysfunctional due to advanced age and the systemic disease state. We hypothesized that ixmyelocel-T generated from ischemic DCM patients BMMNCs would consist of expanded MSCs and M2 macrophages, and produce anti-inflammatory and angiogenic factors useful for cardiac repair.
BMMNCs were obtained from 55-80 year old ischemic DCM patients, with LVEF < 35% and NYHA Class III or IV, enrolled in the phase 2b clinical IXCELL-DCM trial. The BMMNCs were either used in experiments or expanded in a closed bioreactor system for 12 days to generate ixmyelocel-T (n = 13). FACS revealed a 50 ± 5% fold expansion in CD90+ MSC and a 96 ± 39% fold expansion in CD14+ M2-like macrophages in ixmyelocel-T. Cytokine arrays revealed ixmyelocel-T secreted more regulatory and trophic factors compared to BMMNCs. Specifically, ixmyelocel-T secreted significantly more Flt-3L, GM-CSF, IL-10, IL-13, IL-1ra, IL-2, IL-3, IL-5, MCP-1, CCL18, TGF-β, angiopoietin-2, IL-8, TIMP-1, TIMP-2, and VEGF compared to BMMNCs. ELISA analysis confirmed that ixmyelocel-T secreted significantly higher levels of IL-10 (2092 ± 183 vs 130 ± 17 pg/mL, p < 0.001) and IL-1ra (12241 ± 2806 vs 1857 ± 564, p < 0.001) after LPS challenge. Ixmyelocel-T had higher gene expression of the anti-inflammatory and pro-angiogenic markers HMOX1, CCL18, FGF2, IGF1, PGF, SDF-1α, Ang-1, Ang-2 and lower levels of the pro-inflammatory markers TNFα, IL-1β, IFN[[Unable to Display Character: &#611;]], IL-12 compared to BMMNCs after LPS challenge. Additionally, co-culture of ixmyelocel-T with HUVECs resulted in significant wound healing in an in vitro scratch assay compared to BMMNCs (56 ± 4 vs 39 ± 8%, p < 0.001).
This data suggests that the process used to generate ixmyelocel-T is ideal for the therapeutic expansion of BMMNCs from patients with severe cardiac diseases. Ixmyelocel-T retains a regenerative, anti-inflammatory, and pro-angiogenic profile which holds promise for treatment in advanced cardiac diseases where treatment options are limited.
Abstract 17474: Management State of Low-Density Lipoprotein Cholesterol has a Favorable Effect on Left Ventricular Reverse Remodeling in Patients With ST-Segment Elevation Acute Myocardial Infarction
Authors: Makino Akihiro , Matsunaga Atsuhiko , Yamaoka-Tojo Minako , Kameda Ryo , Masuda Takashi , Ako Junya 
Published: July 2021

Left ventricular remodeling following ST elevation acute myocardial infarction (STEMI) is still an issue in the primary percutaneous coronary intervention (PCI) era. This study aimed to examine whether control of cholesterol levels is predictive of reverse remodeling in patients with STEMI.
Subjects were 56 patients with first STEMI successfully and completely reperfused. Single photon emission computed tomography (SPECT) was used to measure LV function at 1 and 6 months after onset. Reverse remodeling was defined as a >10% reduction in LV end-systolic volume at 6-month follow-up compared with baseline SPECT. Patients were divided into reverse remodeling (n=15) and non-reverse remodeling (n=41) groups, and clinical characteristics including age, sex, body mass index, peak serum creatine kinase, number of coronary artery lesions, coronary risk factors and medications, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), LDL-C/HDL-C ratio, and triglycerides were compared between the groups. We examined the proportions of patients with target LDL-C (<70 mg/dL), HDL-C (≥40 mg/dL), and TG (<150 mg/dL) levels, and LDL-C/HDL-C ratio of <1.5. Multivariate stepwise logistic regression analyses were performed to evaluate the relationship between occurrence of reverse remodeling and clinical characteristics.
In baseline clinical characteristics, there were significant differences between the two groups regarding to management states of LDL-C levels and the LDL/HDL ratio. The proportions of patients achieving target LDL-C levels and LDL-C/HDL-C ratio were higher in the reverse remodeling group than in the non-reverse remodeling group (80% and 17%, p<0.0001; 60% and 10%, p<0.0001, respectively). Logistic regression analysis revealed that patients with target LDL-C levels were significantly more likely to show reverse remodeling (odds ratio 19.429, 95% confidence interval 4.317-87.432, p<0.0001).
The present study showed that the good control of LDL-C independently predicts reverse remodeling in patients with first STEMI. This finding underscores the need for achieving and maintaining target LDL-C levels through secondary prevention for reverse remodeling.
Abstract 17810: Spectral Analysis-Based Risk Score to Early Predict Mortality and Cerebral Performance in Patients Undergoing Therapeutic Hypothermia for Ventricular Fibrillation and Comatose Status
Authors: Filgueiras-Rama David , J. Calvo Conrado , Salvador- Montañés Óscar , Cádenas Rosalía , Ruiz-Cantador Jose , Armada Eduardo , Rey Juan Ramón , Merino JL , Peinado Rafael , Pérez-Castellano Nicasio , Pérez-Villacastín Julián , G. Quintanilla Jorge , Jiménez Santiago , Castells Francisco , J. Chorro Francisco , López-Sendón JL , Berenfeld Omer , Jalife José , López de Sá Esteban , Millet José 
Published: July 2021

Introduction:
Early reliable prognostication in comatose survivors after cardiac arrest due to ventricular fibrillation (VF) is very limited, especially in patients undergoing mild hypothermia.

Hypothesis:
Spectral analysis of VF before a DC shock will reflect the degree of acute cerebral injury as a consequence of time in VF and concomitant myocardial ischemia.

Methods:
We included consecutive patients undergoing mild hypothermia after cardiac arrest due to VF, eventually with return of spontaneous circulation (ROSC), and a comatose status on admission. Background clinical variables, VF time and frequency domain fundamental variables were considered in the analysis. The primary and secondary outcomes were a favorable neurological performance (FNP) during hospitalization and survival to hospital discharge, respectively. The predictive model was developed in a retrospective cohort (September 2006 to September 2011) and further validated in a prospective cohort (October 2011 to July 2013). The model was also tested at follow-up.

Results:
Sixty-one patients out of 239 who underwent mild hypothermia fulfilled the inclusion criteria. FNP was present in 16 (50.0%) and 21 patients (72.4%) in the retrospective and prospective cohorts, respectively. Seventeen (53.1%) and 21 patients (72.4%), respectively, survived to hospital discharge. Both outcomes were significantly associated (p<0.001). Multivariate analysis on the retrospective cohort

provided a prediction model (sensitivity=0.94, specificity=1) including dominant frequency, ratio between number of peaks in high and low frequency bands, power spectral density ratio between high and low frequency bands and the number of shocks delivered before ROSC. Validation on the prospective cohort showed sensitivity=0.88 and specificity=0.91 for both primary and secondary outcomes. A
model-derived risk score properly predicted 93% of FNP. The model showed cstatistic ≥0.89 after a median follow-up of 48.5±10.5 and 5±1.8 months in the retrospective and prospective cohorts, respectively.

Conclusions:
A spectral analysis-based model reliably correlates time-dependent VF spectral changes with acute cerebral injury in comatose survivors after cardiac arrest undergoing mild hypothermia.
Abstract 18574: Empagliflozin Reduces Systolic Blood Pressure in Dipper and Non-Dipper Patients with Type 2 Diabetes and Hypertension
Authors: Chilton Robert , Tikkanen Ilkka , Crowe Susanne , Johansen Odd Erik , Broedl Uli C , Woerle Hans J , Hach Thomas 
Published: July 2021

In a Phase III randomized trial (EMPA-REG BP™), patients with type 2 diabetes (T2DM) and hypertension (defined as mean seated office systolic blood pressure [SBP] 130-159 mmHg and diastolic BP [DBP] 80-99 mmHg at screening) received empagliflozin (EMPA) 10 mg (n=276), EMPA 25 mg (n=276) or placebo (PBO; n=271) once daily in the morning for 12 weeks (mean [SD] age 60.2 [9.0] yrs, HbA1c 7.90 [0.74] %, 24-h SBP 131.4 [12.3] mmHg, 24-h DBP 75.0 [7.8] mmHg). We assessed changes from baseline in SBP (mean 24-h, awake-time, sleep-time) via ambulatory BP monitoring at week 12 in patients categorized as dippers (sleep-time mean SBP ≤90% of awake-time mean; n=417) or non-dippers (sleep-time mean SBP >90% of awake-time mean; n=350).
Baseline mean (SD) 24-h SBP (mmHg) was 129.9 (11.6) in dippers and 133.1 (12.4) in non-dippers. Adjusted mean (SE) changes from baseline in mean 24-h SBP (mmHg) in dippers were -0.2 (0.7) with PBO vs -3.8 (0.6) and -3.9 (0.7) with EMPA 10 and 25 mg, respectively (both p<0.001), and in non dippers were 1.0 (0.7) with PBO vs -1.6 (0.7) with EMPA 10 mg (p=0.013) and -3.8 (0.7) with EMPA 25 mg (p<0.001). Hourly mean SBP patterns over 24 h for dippers and non-dippers were maintained with EMPA 25 mg (Figure) and 10 mg. Adjusted mean (SE) changes from baseline in awake-time SBP (mmHg) in dippers were -0.5 (0.7) with PBO vs -4.6 (0.7) with EMPA 10 and 25 mg (both p<0.001), and in non dippers were 1.3 (0.8) with PBO vs -2.2 (0.8) with EMPA 10 mg (p=0.002) and -4.2 (0.7) with EMPA 25 mg (p<0.001). Adjusted mean (SE) changes from baseline in sleep-time SBP (mmHg) in dippers were 0.4 (0.8) with PBO vs -2.6 (0.8) with EMPA 10 mg (p=0.007) and -2.2 (0.8) with EMPA 25 mg (p=0.022), and in non-dippers were 0.1 (0.9) with PBO vs -0.5 (0.9) with EMPA 10 mg (p=0.603) and -3.2 (0.8) with EMPA 25 mg (p=0.006). There were no apparent differences in heart rate with EMPA vs PBO in dippers or non-dippers.
In patients with T2DM and hypertension, EMPA 10 mg and 25 mg significantly reduced SBP vs PBO in dippers and non-dippers.
Abstract 203: Long-term Outcome Of Kawasaki Disease With Giant Coronary Aneurysms Which Waste Cardiac Follow-up; A Case Report
Authors: Mizuno Masanori , Chikada Masahide , Tsuzuki Yoshimitsu , Ono Hirokuni , Arima Masaki , Goto Kenjiro , Aso Kentaro 
Published: July 2021

We report 2 cases of Kawasaki disease (KD) which required surgical interventions long after initial diagnosis. Case 1: Twenty-one years-old male. He was diagnosed as KD at the age of 1. Despite he received intravenous gamma-globulin therapy, bilateral giant coronary aneurysms were formed. In addition, multiple aneurysms include abdominal, iliac and axillary arteries were formed simultaneously. Coronary angiography (CAG) was thought to be dangerous because of iliac artery aneurysm formation. He received medical follow-up with aspirin administration only. He referred to our department at the age of 13. Ischemic changes were confirmed on both treadmill exercise test and cardiac scintigraphy. CAG showed 75% right coronary artery (RCA) stenosis and 99% left main trunk stenosis. Coronary artery bypass grafting (CABG) was performed and his postoperative course has been uneventful. Case 2: Thirty-seven years-old male. He was diagnosed as KD at the age of 1. Left giant coronary aneurysms were formed and subsequently aneurysm was occluded. Aspirin was administrated, but he interrupted medication and follow-up for himself. He referred to our institution due to cardiopulmonary arrest during exercise. After successful resuscitation, CAG revealed total occlusion of RCA and 99% left coronary artery stenosis. Emergent CABG was performed and no postoperative sequel has occurred. Both cases didn’t receive sufficient assessment during the follow-up period. As a result, fatal cardiac event was occurred in case 2. Coronary aneurysm tends to change into combine aneurysmal and stenotic lesion. Long time follow up is necessary even if patients have no symptom.
In addition, to decrease lost follow up patients, we should explain the risk of sudden cardiac death repeatedly and emphasis necessity of long term follow-up and medication.
Abstract 23: Trends in Kawasaki Disease Incidence - 2004-2014
Authors: Sexson Tejtel Sara K , Ramirez Andrea A , Liou Amy , Seery Thomas , Canter Debra , DeGuzman Marietta , Altman Carolyn 
Published: July 2021

Background:
Kawasaki disease is the leading cause of acquired heart disease in children in the US. While it remains a rare disease, the purpose of this study is to evaluate the incidence of KD

Methods:
To evaluate our hypothesis we used the Pediatric Health Information Systems (PHIS), 2004-2013, including all discharges at 44 of the largest freestanding children’s hospitals in the US.

Results:
Between 2004-2013, there were 16,417 hospitalizations for KD, 10,388 (61%) were male. The race of patients admitted with KD showed 5276 (31%) Caucasian, 2370 (14%) African American, 1586 (9.3%) Other, and 941 (5.5%) Asian. The average length of stay 3.9 days. The number of patients with KD increased annually for the past decade, Figure 1.

The largest proportion of the increase was from those children between 1 and 5 years of age, Figure 2.
Most children were only hospitalized once (14,231, 84%) however some children required subsequent hospitalization (1,291,8%).

Conclusions:
There has been a steady increase in the number of admissions per year for Kawasaki disease predominately for those patients ages 1-5 years.
Abstract 74: Coronary Artery Lesions in Children with Kawasaki’s Disease: A 10-Year Follow-up in Moscow
Authors: Bockeria Olga , Lyskina Galina , Shirinskaya Olga , Satyukova Anna , Gagarina Nina 
Published: July 2021

Background:
Kawasaki’s disease (KD) is an acute systemic vasculitis in childhood. Lesion in the coronary arteries (CA) causes an acute or chronic ischemia, myocardial infarction and sudden death.

Materials and Methods:
The study included 189 children with KD for the period of 9 years (2004 - 2013). The age of the patients at the time of the acute stage of the disease was 1 month - 12 years 8 months . Boys and girls ratio was 1.8:1. 92% of the children were ill at the age of up to 5 years. Mean follow-up period was 15,8 months. We performed coronary angiography by CT scan in 14 children and by catheter in 9 children in CCVS. Echo was done in all 189 children.

Results:
Aneurysms of CA were found in 59 (31.2%) patients according to echocardiography data. The frequency of aneurysm formation in children first year of life was higher than in children older than 1 year (41.3% and 29.3%). Thirty eight (20%) patients had multiple aneurysms. Small aneurysms with a diameter less than 5 mm were found in 16.4% of patients, average (5 - 8 mm) - in 9%, giant (greater than 8 mm) - in 5.8% of patients. Transient CA ectasia was diagnosed in 13.2% of children.

Sensitivity of echocardiography in diagnosis of CA aneurysms was 88.5% in comparison with MSCT coronary angiography, specificity - 92.3%. Mean aneurysms' diameter measured by ECHO was 7,1 ± 3,3 mm, while CT contrast study revealed 7,3 ± 3,1 mm (p> 0.05).
We found an involution of 40.2% of aneurysms during follow-up.
Thrombi were found in 8 of 11 patients with giant aneurysms by echocardiography. Five thrombi disappeared after conservative therapy, 2 increased and occluded the RCA. CA stenosis greater than 75% was revealed in 2 patients with giant aneurysms in 2 years 7 months and in 3.5 months after manifestation of KD by using coronary arteriography.

Conclusion:
Kawasaki’s disease is a frequent cause of aneurysms, thrombosis and stenosis in coronary arteries in early childhood. Giant aneurysms often predispose to occlusion of the CA. Echocardiography is a highly specific and sensitive method for the visualization of CA aneurysms and thrombi. Other methods are useful when distinguishing stenosis and thrombosis in small CA is required.