bluuebunny/crossref_metadata_2025_split huggingface dataset:
P4477Editing of myosin phosphatase as a novel approach for sensitization of vascular smooth muscle to vasodilators (NO/cGMP/ROS) and lowering of blood pressure in hypertension
Authors: Fisher S , Reho J J , Meddeb M , Ursitti J , Htet M 
Published: October 2019

Abstract

Background
Despite the many drugs for treatment of hypertension, it remains inadequately treated in >50% of patients and the number one contributor to cardiovascular mortality world-wide. Thus new targets and treatment strategies are badly needed. Myosin Phosphatase (MP) is a viable target: it is the primary effector of vascular smooth muscle relaxation and a critical mediator of signaling pathways regulating vessel tone.

Purpose
We are using complementary/ translatable approaches to test the hypothesis: editing of the Myosin Phosphatase Regulatory (Targeting) subunit (MYPT1), by shifting the expression of naturally occurring isoforms, will sensitize vascular smooth muscle to NO/cGMP/ROS mediated vasorelaxation and thereby lower BP in models of hypertension. A further goal is to determine mechanisms by which these signals activate MP thereby causing vasorelaxation.

Methods
LoxP sites were inserted in introns flanking alternative Exon24 (E24) of Mypt1. Mice were crossed with smMHCCreER mice and treated with Tamoxifen for smooth muscle specific deletion of E24 (SMcKO E24).Skipping E24 codes for a Mypt1 isoform that contains a C-terminal leucine zipper (LZ) motif required for cGMP-dependent protein kinase (cGK1) binding and NO/cGMP/ROS activation of MP. Second, we developed and tested guide RNAs for the purpose of AAV-CRISPR/CAS9 editing of Mypt1 E24 as a treatment for hypertension. Effect of editing is tested in otherwise normal mice and in the AngII sub-pressor model of hypertension.

Results
SMcKO E24 mice had mean BP that was 15+3 mmHg lower than control (n=5; p<0.05). Mesenteric arteries from these mice were significantly more sensitive to DEA/NO mediated relaxation (EC50: 2.1+0.5 nM vs 18.2+5.6 mM; n=5–6, p<0.05). Experiments testing response to AngII infusion are in progress and will be presented at the meeting. Preliminary biochemical assays support a 2-pool model, in which NO/cGMP/ROS activates the LZ+ pool, while contractile agonists inhibit the LZ- pool of MP, in the control of BP/ blood flow. We have generated a number of AAV Crispr/Cas9 gRNAs and validated their efficacy of editing of Mypt1 E24 in vitro. Experiments are in progress to test their efficacy and effect on BP in vivo.

Conclusion
These studies support that editing of Mypt1 E24 could be a novel strategy for vasodilator sensitization and effective lowering of blood pressure in humans with hypertension, thereby having a substantial impact on CV mortality world-wide.

Acknowledgement/Funding
NIH
P4479The association of LEPR rs1137101 polymorphism with the incidence of left ventricular hypertrophy in patients with obstructive sleep apnea and hypertension
Authors: Sobieraj P , Bielicki P , Plywaczewski R , Brzoska K , Barnas M , Kumor M , Jonczak L , Stepkowski T , Piechuta A , Chazan R , Sliwinski P , Kruszewski M 
Published: October 2019

Abstract

Background/Introduction
Obstructive sleep apnea (OSA) is one of the most common respiratory disease which is considered as a risk factor for cardiovascular disease and death. Although coexistence of OSA and arterial hypertension may be attributed to well-known common environmental risk factors for both diseases, a genetic background should be considered. LEPR rs1137101 polymorphism was reported to be associated with coronary artery disease and heart failure. Left ventricular hypertrophy is a part of hypertension-mediated organ damage assessment and an independent risk factor for adverse outcome in patients with hypertension.

Purpose
This study is aimed to establish the relationship between LEPR rs1137101 polymorphism and left ventricular hypertrophy in patients with OSA and arterial hypertension.

Methods
Consecutive patients with newly diagnosed OSA confirmed by polysomnography underwent genotyping for the single nucleotide polymorphisms of LEPR (rs1137101).
LVH was diagnosed using standard 12-lead electrocardiogram according to the current European Society of Cardiology guidelines. Logistic regression was used to assess the relationship between LEPR rs1137101 polymorphisms and LVH.

Results
From 600 subjects diagnosed with OSA, 427 subjects with hypertension were included for further analysis (25.1% women, 74.9% men). In analyzed subpopulation mean age was 58.5±9.4 years, body mass index 33.7±6.6 kg/m2, apnea-hypopnea index 43.1±23.6/hour. In 34 (8.0%) subjects LVH was diagnosed. Genotyping revealed, that 123 (28.8%) subjects were LEPR rs1137101 AA homozygotes, 202 (47.3%) LEPR rs1137101 A/G heterozygotes and 102 (23.9) LEPR rs1137101 G/G homozygotes.
Logistic regression showed, that LEPR rs1137101 A/A polymorphism vs A/G and G/G was associated with increased risk of LVH (odds ratio: 2.08, 95% confidence interval: 1.02–4.25, p=0.03). The relationship was significant also after adjustment for age, sex, apnea-hypopnea index and current smoking status (odds ratio: 2.28, 95% confidence interval: 1.08–4.83, p=0.03).

Conclusions
Our study shows a possible link between the polymorphism of the LEPR rs1137101 polymorphism and LVH in patients with OSA and arterial hypertension.

Acknowledgement/Funding
The study received financial support from the Polish National Science Centre (710/N-COST/2010/0)
P4488Organotypic culture of the epicardium: a new tool for cardiovascular research
Authors: Maselli D , Johnson R D , Szilveszter Matos R , Chiappini C , Camelliti P , Campagnolo P 
Published: October 2019

Abstract

Background
The epicardium, the most external layer of the heart, is composed of a layer of epithelial cells and underlying connective tissue. Following myocardial infarction, epicardial cells are activated and provide a source of paracrine factors and progenitor cells. In the border zone of the ischaemic tissue, the activated epicardial cells support cardiac and vascular regeneration by releasing pro-angiogenic and pro-survival factors, and by differentiating towards multiple cell lineages. During this process, activated epicardial cells migrate to the site of injury where they contribute to both post-ischemic remodelling and fibrosis. There is limited knowledge of the cellular and molecular regulation of these processes in large animals and humans, in part due to the lack of robust and representative models.

Purpose
In this project, we developed an ex vivo 3D organotypic model derived from porcine hearts, amenable to culture, which enables structural, molecular and cellular studies of the epicardium.

Methods
Thin epicardial/cardiac tissue slices (EpCardio-TS) were obtained by using a vibratome to cut the first layer of tissue from the epicardial side of porcine heart cubes. Slices were cultured for up to 72h in a bioreactor that uses a 3D printed chamber connected to a control system that allows maintenance and adjustment of culture conditions, and ensures continuous media flow. Local intracellular delivery of fluorescent quantum-dots (Qdots) was performed using nanoneedle chips to track epicardial cells, whilst cell fate is visualised in 3D by performing immunofluorescence on decolourised slices.

Results
Intact EpCardio-TS obtained from porcine heart included a viable epicardium, expressing typical epicardial markers (wt-1, mesothelin, uroplakin), and an electrically active myocardium. Live/dead staining showed epicardial (67.8±16.2%, N=5) and myocardial (40.8±28.6%, N=3) viability, and TUNEL assay confirmed low levels of apoptosis (6.3±5.1% of wt-1+ epicardial cells N=1). Moreover, the presence of proliferating epicardial cells (PCNA+), the increase in wt-1+ cells, and the increase in epicardial gene expression (Tbx18 and TCF21) suggested that cells maintain their progenitor phenotype and undergo activation in culture. Nanoinjection of fluorescent Qdots to EpCardio-TS localized them to the wt-1+ cells on the slice surface, presenting a strategy to mark the epicardial layer. This, combined with the successful decolourisation of the slices, provides an in vitro platform to track the role of epicardial cells in cardiac remodelling and fibrosis.

Conclusions
EpCardio-TS represents a robust ex vivo model merging the complexity of a 3D organotypic culture with the simplicity of the in vitro culture. EpCardio-TS are amenable to culture and cell tracking, and can therefore find application in toxicology and gene therapy screening for the modulation of epicardial interactions with myocardial and non-myocardial cells of the heart.
P4517Heart failure in elderly and very elderly hospitalized patients: an epidemiological analysis from the REPOSI registry
Authors: Proietti M , Marra A M , Salzano A , Romiti G F , Mannucci P M , Nobili A , Cittadini A 
Published: October 2019

Abstract

Introduction
Epidemiological data about heart failure (HF) in the elderly and, in particular, very elderly patients are lacking.

Purpose
To provide the epidemiological profile of elderly and very elderly HF patients in terms of prevalence, associated clinical factors, burden of multimorbidity and functional status.

Methods
Overall cohort of the REgistro POliterapie SIMI (REPOSI) was used to assess study aims. REPOSI is an Italian Nationwide Registry of elderly hospitalized patients in Internal Medicine and Geriatric wards. HF diagnosis was assessed at hospital admission according to ICD-9 code 428.XX.

Results
Among the 7003 patients originally enrolled, a total of 1095 (15.6%) patients reported a diagnosis of HF at hospital admission. Prevalence of HF progressively increased according to age strata, up to 26.8% in patients ≥90 [Figure]. A logistic regression analysis found that increasing age, body mass index and total cumulative illness rating scale (CIRS) were associated with HF (Table). Moreover, atrial fibrillation, chronic kidney disease, chronic obstructive pulmonary disease and polypharmacy (≥5 drugs) were associated with HF, while liver disease and neoplasm were inversely associated (Table). According to CIRS severity index and comorbidity index quartile, HF patients reported more likely values in the highest quartile than those without HF (47.4% vs. 26.6%, p<0.001 and 34.4% vs. 18.5%, p<0.001 respectively). According to short blessed test, geriatric depression scale and Barthel index, patients with HF had significantly more cognitive impairment and dementia, depression and dependent from others in daily activities than those without HF (all p<0.001).
Prevalence of HF according to Age Strata

Conclusions
In a cohort of elderly patients hospitalized in Internal Medicine and Geriatric wards HF was highly prevalent, in particular in those very elderly. HF was associated with several clinical factors, emphasizing a stronger clinical complexity. HF patients were more burdened with multimorbidity and showed an impaired functional status.

Acknowledgement/Funding
None
P4523Impact of comorbiditity on the predictive value of acute kidney injury in patients admitted for acute decompensated heart failure: a prospective study
Authors: Kayama K , Yamada T , Morita T , Furukawa Y , Tamaki S , Iwasaki Y , Kawasaki M , Kikuchi A , Kawai T , Seo M , Abe M , Nakamura J , Fukunami M 
Published: October 2019

Abstract

Background
Comorbidities are associated with poor clinical outcome in patients with chronic heart failure, and acute kidney injury (AKI) also provides prognostic information in patients with heart failure. However, there is no information available on the impact of comorbidities on the prognostic value of AKI in patients admitted for acute decompensated heart failure (ADHF).

Methods
We prospectively studied 357 consecutive ADHF patients with survival discharge. Patients with hemodialysis were excluded. Comorbidity was measured with the Age-adjusted Charlson comorbidity index (ACCI) which is commonly used for the evaluation of the comorbid condition which is weighted and scored, with additional points added for age. AKI was defined as an absolute increase in serum creatinine of 0.3mg/dl or more during hospitalization. The endpoint was all-cause death (ACD).

Results
During a follow-up period of 2.2±1.4 years, 97 patients had ACD. At multivariate Cox analysis, ACCI (p<0.0001) and AKI (p=0.0061) were significantly and independently associated with ACD. Patients with high ACCI (≥5: determined by ROC analysis) had a significantly greater risk of ACD (39% vs 16%). In the subgroup of high ACCI, patients with AKI had a significantly higher risk of ACD (60% vs 35%), whereas there was no significant difference in the risk of ACD between with and without AKI (15% vs 16%) in the subgroup of low ACCI.

Conclusions
The presence of AKI was associated with the increased risk of mortality in ADHF patients with higher comorbidity burden but not in those without them.
P4524His bundle pacing in patients pacemaker indication and with mildly reduced ejection fraction
Authors: Gardas R , Jarosinki G , Sznjader R , Biernat J , Goscinska-Bis K , Golba K S 
Published: October 2019

Abstract

Background
Right ventricular pacing (RVP) can be harmful and in a number of patients leads to deterioration of left ventricle function. The deleterious effect of RVP is particularly visible in patients with reduced ejection fraction. His bundle pacing (HBP) allows ventricular stimulation without electrical and mechanical dyssynchrony and should not be associated with deterioration of left ventricle function. In some patients HBP restores electrical and mechanical synchrony.

Objective
The aim of the study is to evaluate effect of HBP on left ventricle function in patient with reduced left ventricle ejection fraction (LVEF.

Methods
Twenty-one patients with indication for permanent pacing and with (LVEF) between 35 and 50% were included into the study. Age 71,9±10,44. Men 76,2%. 13 (61,9%) patients with permanent atrial fibrillation. In 33,3% of patients there were intraventricular conduction delay (IVCD), 3 (14,3%) with LBBB, 3 (14,3%) with RBBB and 1 (4,8%) with nonspecific IVCD. 6 patients were upgraded from previously implanted pacemaker. Mean QRS duration 133,6±37,85. Baseline ejection fraction (EF) 42,6±3,21%. Clinical and echocardiographic evaluation were performed at baseline and after 6–12 months of follow up.

Results
QRS duration narrowed from 133,6±37,85ms to 114,3±16,90ms (p=0,033) with HBP. HBP was associated with reduction of end systolic left ventricular volume (LVES) from 91,5±31,10ml to 75,9±38,56ml (p=0,0058). EF improved from 42,6±3,21% to 48,3±7,39% (p=0,0006). Improvement in EF in patients without myocardial infarction (MI) was better (42,6±3,23% to 49,5±8,04%, p=0,0053) than in patients with MI (42,6±3,37% to 47,0±6,79%, p=0,062). Increase in EF was also better in patients with atrial fibrillation (42,7±3,19% to 49,9±8,20%, p=0,0017) than int patients with sinus rhythm (42,4±3,46% to 45,6±5,28%, p=0,17). Functional capacity assessed by NYHA class improved significantly from 2,4±0,59 to 1,7±0,58.
Ejection Fraction

Conclusion
His bundle pacing is associated with th significant clinical and echocardiographic improvement in patients with mildly reduced left ventricular ejection fraction and indication for permanent pacing. After 6–12 moths of HBP pacing the improvement in EF is greater in patients with atrial fibrillation and without myocardial infarction.
P4526Implant procedure and lead handling characteristics of a novel active fixation quadripolar lead: Results from the Attain Stability Quad clinical trial
Authors: Faerestrand S , Crossley G H , Philippon F , Yee R , Kong M H , Kloppe A , Bongiorni M G , Delnoy P P H M , Shelby L , Van Ginneken M M E , Jackson K P 
Published: October 2019

Abstract

Background
Dislodgements of left ventricular (LV) leads are still a challenging problem in cardiac resynchronization therapy (CRT). The Attain Stability Quad (ASQuad) MRI SureScan 4798 steroid-eluting, quadripolar LV lead has a side-helix to enable the lead to be actively fixated to the vessel wall. The uniquely designed active fixation can be advantageous in vessels that are wide or have short take-offs. Further, the helix easily elongates to allow for future extraction.

Purpose
To report on the handling, performance and safety of ASQuad LV lead in a large clinical study.

Methods
The ASQuad clinical study is a prospective clinical trial from 50 centers in 10 countries enrolling CRT candidates implanted with the ASQuad LV lead. Aside from evaluating safety and effectiveness of the LV lead, the trial specifically collected data on parameters related to lead stability during and post implant.

Results
Of 440 enrolled patients (74.8% male, average age 70±11 years) that underwent an implant attempt, 426 (96.8%) were successfully implanted. The helix was mostly affixed in the mid to basal lateral position (62%), followed by mid to basal posterior position (29%). The lead tip placement was most often mid lateral or mid posterior (77%), and in a vein with diameter greater than the pacing electrode diameter (>5.1 French) in the majority (60%) of procedures. Among all subjects (n=421) who underwent pacing capture thresholds (PCT) tests before and immediate after guide catheter slitting, 98% reported ≤1 V difference in PCT, and 86% were within 0.5 V. The interquartile range for the difference in PCT was −0.1 to 0.1 V. The mean PCT at implant for all subjects at the final selected LV pacing vector was 1.15±0.70 V at 0.5 ms pulse width. The average LV lead implant time was 16±21 minutes. Targeted pacing location was achieved in 97% of successful implants, and 98% of implanters reported good or fair stability after guidewire removal. The overall handling of the LV lead was rated as acceptable by implanters in 99% of cases. Three patients (0.7%) experienced LV lead dislodgement post implant, and these complications were resolved by repositioning of the lead (0 and 1-day post implant) in two and by lead replacement when noted at 90 days follow-up in one.

Conclusions
The ASQuad LV lead was implanted with a high rate of success and ability to achieve the targeted pacing location. Lead handling and stability following guidewire removal were rated as acceptable by nearly all implanters. The side-helix likely improved LV lead stability since 98% of the subjects had ≤1 V difference in PCT before and after catheter slitting during implant procedures, and by demonstrating a low post implant lead dislodgement rate.

Acknowledgement/Funding
Sponsored by Medtronic
P4531Early and late superresponse to cardiac resynchronization therapy
Authors: Kuznetsov V A , Enina T N , Soldatova A M , Petelina T I , Shirokov N E , Salamova L A 
Published: October 2019

Abstract

Background
Superresponders to cardiac resynchronization therapy (CRT) demonstrate significant reverse remodeling, improvement in cardiac function, decrease in inflammatory mediators and markers of cardiac fibrosis. It is not clear if superresponse (SR) can be early or late and if the time of SR to CRT is associated with different degree of biochemical improvement.

Aim
To assess structural and functional heart parameters, sympathetic activity, levels of biomarkers of myocardial fibrosis, inflammatory and neurohormonal mediators in patients with various time of SR to CRT.

Methods
The study enrolled 82 superresponders to CRT (decrease in left ventricular end-systolic volume (LVESV) >30%) (mean age 60.4±9.3 years; 80.5% men, 19.5% women; 54.9% with ischemic etiology of heart failure). Patients were divided into two groups: group 1 (n=19) – SR was achieved within 24 months (14.0 [8.0; 21.0] months); group 2 (n=63) - SR was achieved after 24 months (59 [43.0; 84.0] months). Echocardiographic parameters, plasma levels of epinephrine, norepinephrine, NT-proBNP, interleukin (IL) 1β, IL-6, IL-10, tumor necrosis factor alpha (TNF-α), metalloproteinase (MMP) 9, tissue inhibitors of metalloproteinase (TIMP) 1 and 4 were evaluated.

Results
At baseline there were no differences in demographic, clinical and echocardiographic characteristics between the groups. Levels of epinephrine (1.1 [0.1; 2.2] ng/ml vs 2.1 [0.7; 3.4] ng/ml; p=0.049) and IL-10 (1.8 [1.5; 3.5] pg/ml vs 3.9 [2.7; 5.1] pg/ml; p=0.019) were significantly higher in group 2. Both groups demonstrated significant improvement in echocardiographic parameters. On follow-up left ventricular (LV) end-systolic dimension (p=0.041), LV end-diastolic dimension (p=0.049), LVESV (p=0.014), LV end-diastolic volume (p=0.045) were lower in group 2. In group 1 IL-6 (p=0.047), TNF-α (p=0.047) decreased significantly and there was a tendency for IL-1β (p=0.064) and norepinephrine (p=0.069) levels to increase. In group 2 levels of IL-1β (p<0.001), IL-6 (p=0.030), IL-10 (p=0.003), TNF-α (p<0.001), TIMP-1 (p=0.010) and epinephrine (p=0.024) decreased significantly while MMP-9/TIMP-1 (p=0.023) increased as compared to baseline levels. Additionally there was a tendency for NT-proBNP level to decrease in group 2 (p=0.069). Follow-up level of norepinephrine (7.8 [2.9; 17.2] ng/ml vs 1.1 [0.2; 8.7] ng/ml; p=0.011 was lower and MMP-9/TIMP-4 level was higher (0.058 [0.044; 0.091] vs 0.092 [0.064; 0.111]; p=0.013) in group 2. Diverse trends were observed in IL-10 (0.4 [−0.6; 1.2] pg/ml in group 1 vs −2.3 [−3.4; −0.5] pg/ml in group 2; p=0.007) and norepinephrine (4.0 [−5.2; 14.3] ng/ml in the group 1 vs −1.2 [−11.6; 4.0] ng/ml in the group 2; p=0.015) between the groups.

Conclusion
CRT modulates sympathetic, neurohumoral, immune and fibrotic activity. Late SR to CRT is associated with decrease of sympathetic and inflammatory activity and more pronounced LV reverse remodeling.
P4533Duration of heart failure and effect of defibrillator implantation in patients with non-ischemic systolic heart failure
Authors: Elming M B , Thoegersen A M , Videbaek L , Bruun N E , Eiskjaer H , Haarbo J , Egstrup K , Gustafsson F , Svendsen J H , Hoefsten D E , Pehrson S , Nielsen J C , Koeber L V , Thune J J 
Published: October 2019

Abstract

Introduction
Patients with non-ischemic systolic heart failure have increased risk of sudden cardiac death (SCD) and death from progressive pump failure. Whether the risk of SCD changes over time is unknown. We seek to investigate the relationship between duration of heart failure, mode of death, and effect of implantable cardioverter defibrillator (ICD) implantation.

Methods
We examined the risk of all-cause death and SCD according to the duration of heart failure among patients with non-ischemic systolic heart failure enrolled in the Danish Study to Assess the Efficacy of ICDs in Patients with Non-ischemic Systolic Heart Failure on Mortality (DANISH) trial. Patients were divided according to quartiles of heart failure duration (Q1 ≤8 months, Q2 9 ≤18 months, Q3 19 ≤65 months, Q4 ≥66 months).

Results
A total number of 1116 patients were included. Patients with the longest duration of heart failure were older, more often men, had more comorbidity, and more often received cardiac resynchronizing therapy device. Doubling of heart failure duration was an independent predictor of both all-cause mortality (HR 1.26 95% CI 1.17–1.37, p<0.0001), and SCD (HR 1.29 95% CI 1.11–1.49, p=0.0009). The proportion of deaths caused by SCD was not different between heart failure quartiles (p=0.91), and the effect of ICD implantation on all-cause mortality was not modified by the duration of heart failure (p=0.59).
Duration of heart failure and death

Conclusions
Duration of heart failure predicted both all-cause mortality and risk of SCD independently of other risk indicators. However, the proportion of death caused by SCD did not change with longer duration of heart failure and the effect of ICD was not modified by the duration of heart failure.

Acknowledgement/Funding
The work was sponsored by The Danish Heart Foundation (Hjerteforeningen) and the Lundbeck Foundation (Lundbeckfonden). The DANISH trial was supported