bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 18968: Bromocriptine-QR: A Potential Novel Strategy for Cardiovascular Risk Reduction in Type 2 Diabetes
Authors: Chamarthi Bindu , Ezrokhi Michael , Cincotta Anthony H
Published: April 2024

Type 2 diabetes (T2D) is associated with a substantially increased risk of cardiovascular disease (CVD). Of the available therapies for T2D, none have been conclusively shown to reduce CVD risk. Metformin has long been considered the only agent with some evidence, albeit limited, of a potential CVD benefit. Bromocriptine-QR (BQR), a quick release sympatholytic dopamine agonist, is a newer FDA-approved therapy for T2D. Based on preclinical and clinical study findings, it is postulated that BQR restores the normal circadian peak in central dopaminergic tone diminished in insulin resistant states, which in turn reduces hyperactive sympathetic tone and improves central fuel sensing thereby reducing postprandial hepatic glucose and lipid output as well as reduces vascular resistance, oxidative stress, and inflammation. In a one-year randomized trial of BQR vs. placebo added to standard therapy (diet and/or ≤ 2 diabetes medications including sulfonylureas, TZD, metformin, or insulin) in 3070 T2D subjects (average duration of T2D: 7.9 years), including individuals with pre-existing CVD, BQR therapy resulted in a 40% hazard rate reduction (HRR) in major CVD events, pre-specified as a composite of time to first myocardial infarction, stroke, coronary revascularization, hospitalization for angina or congestive heart failure. In the present study, this CVD effect of BQR was evaluated in a subset of this original study population on metformin +/- another anti-diabetes therapy at baseline (N = 1791). The composite CVD end point occurred in 16/1208 BQR-treated (1.3%) and 18/583 placebo-treated (3.1%) subjects resulting in a 53% CVD HRR (ITT group, Cox regression analysis; HR 0.47, 95% CI 0.24, 0.92, P = 0.028) adjusted by age (HR 1.08, 95% C.I. 1.04, 1.12, P = 0.0003) and pre-existing CVD (HR 2.27, 95% C.I. 1.02, 5.07, P = 0.041). Kaplan-Meier Curves of the cumulative incidence rate yielded a CVD HRR of 58% (HR 0.42, 95% C.I. 0.21, 0.85, Log-Rank = 0.017). These findings reaffirm prior observations of CVD risk reduction with BQR therapy and further demonstrate the potential for a marked additive effect of BQR above any derived from metformin, suggesting a potential novel strategy for CVD risk reduction in T2D.
Abstract 19011: Is It Necessary to Pre-Stent Right Ventricular Outflow Tract Prior to Percutaneous Pulmonary Valve Implantation in All Patients?
Authors: Turner Daniel R , Thatte Nikhil M , Gupta Pooja , Aggarwal Sanjeev , Singh Harinder , Forbes Thomas J , Gowda Srinath T
Published: April 2024

Background:
Bare metal stent placement prior to Melody valve insertion (MVI) is common. We analyzed acute and short-term outcome following MVI with and without pre-stenting (PS) the conduit.

Methods:
This is a retrospective single-center study. Patients (pts) were divided into two groups, with and without PS. The conduits were divided into homograft (HG) and valve with supporting ring (VSR) groups.

Results:
From June 2010 to May 2013, 49 pts underwent MVI. Conduits were HG in 24 (49%) and VSR in 25 (51%). Primary indication was stenosis in 20 and regurgitation in 29 pts. PS was performed in 16 (33%) vs. no PS in 33 (67%) pts. Major procedural complication included conduit (HG) rupture requiring covered stent placement in 1 pt. In the entire cohort, baseline peak RVOT gradient at cath was 27.14 ± 14.55 vs. 14.82 ± 9.83 mmHg post-implantation (p < 0.0001). Baseline pulmonary regurgitation (PR) was moderate to severe in 36/40 (90%). Only 2 had moderate or greater PR post-implant. Freedom from Melody stent fracture was 95.83% (in 23/24) at 9.85 months and freedom from melody valve dysfunction was 93.7% (45/48) at median 16.5 months of follow up. The pre- and immediate post-implantation RVOT gradient (12.81 ± 14.14 mmHg vs. 12.09 ± 11.88 mmHg, p=0.852) and degree of PR were not significantly different between the PS and no PS group. At follow-up, Melody valve dysfunction and freedom from stent fracture were not significantly different between the groups. In pts with VSR, RVOT gradient post-implant was not significantly different between the PS and no PS groups; however pts with no PS showed a trend towards lower post-implant RVOT gradient (20.38 ± 10.72 vs. 12.76 ± 10.23, p=0.059). There were no VSR pts with stent fracture and only 1 had moderate PR on follow-up.

Conclusion:
We demonstrated excellent procedural and short term success in all pts despite absence of pre-stenting in the majority of pts. Patients with VSR and no pre-stenting had better or comparable hemodynamic results and no stent fractures at short term follow-up. Pts with VSR may not require pre-stenting prior to MVI.
Abstract 19037: Impact of Stress Hyperglycemia on Coronary Flow Reserve Following Successfully Recanalized Primary Acute Myocardial Infarction in Non-Diabetic Patients
Authors: Imamura Sari , Hirata Kumiko , Teraguchi Ikuko , Yamano takashi , tanimoto takashi , Ino Yasushi , Yamaguchi Tomoyuki , Kubo Takashi , Imanishi Toshio , Akasaka Takashi
Published: April 2024

Background:
Stress hyperglycemia (SH) is associated with adverse outcome and reduction in myocardial salvage after acute myocardial infarction (AMI), especially in non-diabetic patients. However, no relationship has been identified between admission blood glucose level and coronary flow reserve (CFR) as an index of microvascular function in non-diabetic patients with AMI.

Methods:
This study assessed 73 consecutive patients with a first anterior AMI who underwent successful percutaneous coronary intervention within 24 h from onset of symptoms. Plasma blood glucose was measured on admission. SH was defined as blood glucose ≥10 mmol/L (180 mg/dl). We excluded the patients with a previous or current diagnosis of diabetes or an abnormal oral glucose tolerance test (OGTT, 75-g) 5 days after admission. CFR was calculated as the ratio of hyperemic, which was induced by intravenous adenosine administration, to baseline diastolic coronary flow velocity of the left anterior descending artery using transthoracic echocardiography 7 days after AMI.

Results:
In 73 non-diabetic patients (mean age: 65 years, 48 males), 14 patients showed SH (218±48mg/dl).

Baseline diastolic coronary flow velocity in patients with SH (24±11cm/s) was higher than those without SH(19±6 cm/s, p=0.04), while there was no significant difference in hyperemic coronary flow velocity between the patients with (50±26 cm/s) and without SH (48±20 cm/s). Calculated CFR of the patients with stress hyperglycemia (2.0±0.4) was significantly lower than those without stress hyperglycemia (2.4±0.6, p=0.02).

Conclusions:
CFR was impaired in non-diabetic patients with hyperglycemia on admission. Impaired coronary microcirculation may partly contribute to reduced myocardial salvage and adverse outcome in patients with SH.
Abstract 19057: Macrophage SR-BI Deletion Promotes Defective Efferocytosis via Src/Akt/Rac1 Signaling Pathway Resulting in Increased Atherosclerotic Lesion Necrosis
Authors: Tao Huan , Yancey Patricia G , Babaev Vladimir R , Blakemore John , Zhang Youmin , Ding Lei , Fazio Sergio , Linton MacRae F
Published: April 2024

Apolipoprotein E (ApoE) and scavenger receptor class B type I (SR-BI) double knockout (DKO) mice exhibit accelerated coronary atherosclerosis and premature death, but the underlying mechanisms have not been fully elucidated. Defective phagocytosis of apoptotic cells (efferocytosis) is an important mechanism behind increased necrosis and inflammation in atherosclerosis. We performed bone marrow transplantation studies in apoE
-/-
mice to examine the impact of macrophage deficiency of SR-BI on atherosclerotic lesion cell death, efferocytosis, and inflammation. DKO→ApoE
-/-
mice developed 2.1-fold more atherosclerotic lesion area (P<0.01) with 6.7-fold more apoptotic cells (P<0.01), and 5.2-fold higher necrotic core content (P<0.01), compared to ApoE
-/-
SRBI
+/+
→ApoE
-/-
mice. Efferocytosis was dramatically defective as shown by a 17-fold higher ratio of free to macrophage associated apoptotic nuclei/bodies in atherosclerotic lesions of DKO→ApoE
-/-
mice(P<0.01). Deletion of macrophage SR-BI resulted in 64.3% (P<0.01) and 64.2 % (P<0.01) decreases in efferocytosis of apoptotic WT thymocytes compared to WT macrophages in vitro and in vivo, respectively. Deletion of macrophage SR-BI elicited maladaptive inflammation with significantly higher expression of pro-inflammation genes (IL-1β, IL-6, TNF-α) and lower expression of anti-inflammation genes (IL-10 and TGF-β). Moreover, SR-BI bound phosphatidylserine in vitro and on the surface of apoptotic cells. SR-BI directly interacted with Src in macrophages. SR-BI deficiency caused significant decreases in Src/Akt/Rac1 activities during macrophage efferocytosis of apoptotic cells. Pharmacological activation of Rac1 rescued SR-BI deficiency-mediated defective efferocytosis, and inhibition of Src reduced macrophage efferocytosis. In conclusion, macrophage SR-BI deficiency promotes defective efferocytosis resulting in increased atherosclerotic lesion necrosis and maladaptive inflammation. Thus, macrophage SR-BI functions as a receptor for apoptotic cells and mediator of efferocytosis via the Src/Rac1 signaling pathway, supporting macrophage SR-BI expression and signaling as a potential target for the prevention and treatment of atherosclerosis.
Abstract 19078: Pre-Existing Left Atrial Fibrosis and Diastolic Dysfunction is Associated With Deterioration in Diastolic Function Following Left Atrial Ablation In Patients With Recurrent Atrial Fibrillation
Authors: Khurram Irfan , Maqbool Farhan , Dewire Jane , Beinart Roy , Berger Ronald D , Marine Joseph , Spragg David D , Ashikaga Hiroshi , Calkins Hugh , Nazarian Saman
Published: April 2024

Background:
Radiofrequency (RF) ablation for treatment of atrial fibrillation (AF) is known to induce left atrial (LA) fibrosis. LA diastolic dysfunction has been associated with AF and has shown predictive value for AF recurrence post ablation. This study is designed to evaluate the pattern of change in LA diastolic function following RF ablation.

Methods:
A total of 127 consecutive AF patients were enrolled in the AF Ablation MRI cohort. Fourteen underwent a repeat ablation for recurrent AF and were selected. During routine ablation procedure, LA pressures were acquired in sinus rhythm following trans-septal puncture and prior to ablation. LA diastolic function was evaluated by measuring the slope of the passive LA filling curve and was quantified using diastolic function scores defined by the ratio of change of LA pressure (as defined by invasive pressure measurements) to volume (as defined by MRI) during passive filling of LA (ΔP/ΔV) mmHg/ml and was measured prior to both ablations. The change in LA diastolic function was considered significant if >25% change from baseline was observed. Percent left atrial fibrosis was quantified by using the image intensity ratio as previously described.

Results:
The mean diastolic function score for the 14 AF patients (62±7yrs, 79% male) was 0.76±0.28 mmHg/ml (Paroxysmal AF 0.58±0.18 and persistent AF 0.90±0.28, p=0.031). Of these, 4 (28.6%) patients had no substantial change >25% in their diastolic function score (grp A) at repeat imaging. Six had improvement, 4 remained stable, grp B and 4 had deterioration-grp C. When compared with group A, group C had worse baseline LA diastolic function (0.6±0.2 v 1.1±0.3, p0.019) and greater baseline fibrosis (8.0±2.4% v 15.3±7.0, p0.042).

Conclusion:
Deterioration of diastolic function in patients with AF recurrence after LA ablation is associated with more extensive baseline fibrosis and worse baseline LA diastolic function.
Abstract 19093: Paradoxical Improvement of Tricuspid Valve Incompetence Severity Following Implantation of Ventricular Leads
Authors: Baquero Giselle A , Banchs Javier E , Yadav Pradeep , Samii Soraya M , Penny-Peterson Erica , Wolbrette Deborah L , Naccarelli Gerald V , Gonzalez Mario D
Published: April 2024

Background:
Cardiac rhythm management devices (CRMD) require an endocardial ventricular lead to be placed across the tricuspid valve. Worsening tricuspid regurgitation (TR) with implantation of CRMD has been described. We report the incidence of improvement in TR after CRMD placement, which is an unexpected finding.

Methods:
We retrospectively reviewed 148 patients (age 68±15) that received a CRMD. TR, ejection fraction (EF) and pulmonary artery systolic pressure (PASP) measured by Doppler echocardiography before and after CRMD implantation were analyzed. The TR was graded according to the degree of severity as mild, moderate and severe. A scale of 0-4 according to the grade of severity was used. Improvement in the severity of TR was classified corresponding with the reduction in grades of severity of TR as follows: minimal (<1grade), slight (1), and significant reduction (≥2).

Results:
Mean follow-up time was 30±12 months. Thirty-nine (26%) patients experienced improvement in the severity of TR (from 1.7±0.8 to 0.9±0.7; p=0.0001-5) after placement of a CRMD. The remaining 109 patients had an increase in the severity of TR (from 0.1±0.5 to 1.4±0.9; p=0.0005-10). Reduction in TR was associated with improvement in EF (from 41±19 to 47±14%; p=0.01) and PASP (from 45±15 to 36±14mmHg; p=0.002-2). Patients that had increase in TR did not have a significant change in their EF (from 40±17 to 42±15%; p=0.07) and had worsening of their PASP (from 38±14 to 42±16mmHg; p=0.002). Evaluation of improvement in TR per type of device implanted revealed no difference between patients who received pacemakers (PPM), defibrillators (ICD) or cardiac resynchronization therapy devices (CRT) (ICD/CRT vs PPM p=0.12; ICD vs PPM p=0.22; ICD vs CRT p=0.29 and CRT vs PPM p=0.07).

Conclusion:
Severity of TR may improve in some patients after CRMD placement. This could be attributed to diuresis and optimization of medical therapy at the time of CRM implant or restoration of AV synchrony with pacing, as evidenced by the reduction in PASP and improved EF among those patients.
Abstract 19099: Epicarial Progenitors Contribute to Neonatal Mammalian Heart Regeneration
Authors: Kimura Wataru , Muralidhar Shalini A , Sadek Hesham O
Published: April 2024

Heart failure is a costly and deadly disease affecting over 5 million Americans. At the core of the pathophysiology of heart failure is the inability of the adult mammalian heart to regenerate following injury. In sharp contrast to the adult mammalian heart, we recently showed that the neonatal mammalian heart is capable of complete regeneration, including re-vascularization of the myocardium, following resection of the ventricular apex or myocardial infarction (MI). However, this remarkable regenerative capacity is lost by 7 days post natally. The regenerative response of the neonatal mouse heart is mediated mostly by proliferation of pre-existing cardiomyocytes, which is in line with the mechanism of zebrafish heart regeneration. We also have shown that neonatal heart injury is associated with epicardial activation, which is also a hallmark of zebrafish heart regeneration. However, the lineage contribution of epicardial cells during neonatal mouse heart regeneration remains to be determined.

We performed genetic lineage tracing data using Capsulin (Cap)MerCreMer knock-in mouse crossed with Rosa26/tdTomato reporter mouse, in which epicardial cells are specifically and irreversibly labeled by tamoxifen pulse at postnatal day 0, revealed the contribution of neonatal epicardium to multiple lineages of the heart, including the majority of interstitial fibroblasts, vascular endothelial and smooth muscle cells both during normal post natal growth and after injury.. Considering that embryonic epicardial cells contribute to fibroblasts, vascular endothelial/smooth muscle cells and in contrast adult epicardium only contribute to interstitial fibroblasts and very rarely to vascular smooth muscle cells after the injury, it appears that lineage contribution of epicardial cells is highly correlated with the capacity for neovascularization following cardiac injury. These findings uncover a novel and important role of Capsulin positive epicardium derived cells in vasculogenesis during neonatal heart development and regeneration, and opens the door for future studies to better understand the dynamics of Capsulin expression and function in the post-natal mammalian heart.
Abstract 19128: Quantitative Spatial Cardiac Localization of PVCs Using the 12 Lead ECG
Authors: van Dam Peter , Tung Roderick , Shivkumar Kalyanam , Laks Michael
Published: April 2024

Introduction:
The precise localization of the site of origin of a PVC or VT prior to ablation would facilitate the planning and execution of the electrophysiological procedure. Current electrocardiographic imaging (ECGI) techniques uses body surface mapping that is costly, complex, and requires as many as 256 leads to localize the PVC origin. We developed and tested a novel myocardial activation based ECGI technique utilizing the readily available 12 lead ECG to localize the PVC origin.

Method:
The myocardial activation based ECGI requires a patient specific model of the heart and thorax. For the PVC or VT origin localization, the fastest route algorithm is used on patient specific models created by newly developed morphing software.

Result:
Eight patients that underwent electrophysiological mapping and ablation of PVCs were studied. The PVCs origins were localized on the endocardium of the mid left lateral wall, the anterior RVOT, the LV superior septum, septal RVOT and mid wall of the RVOT. In one patient the PVC origin was located on the epicardial RVOT. PVC localization by the 12-lead ECGI was correlated to the site of successful ablation. All patients (8/8) had accurate prediction of the PVC origin. However, in two patients without patient specific models the localization was reversed between the RV free wall and septum of the RVOT. With patient specific models, these latter two cases would likely be localized correctly.

Conclusion:
This feasibility study of the modified myocardial activation based ECGI shows ability to localize the PVC origin based on only the standard 12 lead ECG. This ECGI method yields activation estimates of isochrones on both ventricles from which the PVC origin location is derived. This new ECGI technique can localize the PVC from any part of the ventricular endocardium, intra-myocardium or epicardium.
Abstract 19140: Prediction of Inotrope Initiation in Patients With Advanced Heart Failure
Authors: Jorde Ulrich P , Nahumi Nadav , Han Jason , Duong Jimmy , Lee Shing , Morrison Kerry A , Thomas Sunu S , Colombo Paolo , Yuzefpolskaya Melana , Garan Arthur R , Uriel Nir
Published: April 2024

Introduction:
It is now widely accepted that the need for inotropic therapy initiation in advanced heart failure (INTERMACS Class 3) in otherwise suitable patients constitutes the closing point of the ideal time window to initiate long term mechanical circulatory support. In this study, we sought to predict this time point.

Hypothesis:
Maximal exercise testing in conjunction with echocardiographic parameters can be used to objectively stratify a pts risk for inotrope dependence.

Methods:
We conducted a prospective study of pts in various stages of HF. Cardiopulmonary exercise testing and echocardiograms were performed at baseline, and the pts were followed for 48 months. The primary endpoint was inotrope initiation; secondary endpoints included LVAD implantation, heart transplantation, and death.

Results:
One hundred and thirty-five pts were enrolled. The mean pt age was 53 ± 13 years, 74% were male, and 34% had ischemic cardiomyopathy. The cohort was 15%, 40%, 45%, and NYHA Class I, II, and III respectively. Pts were followed for a median duration of 31 months (IQR: 16-46). Since enrollment, 19 pts (14.1%) have been initiated on inotrope therapy. Univariate predictors of inotrope dependence that were entered into the multivariable Cox model are: left ventricular ejection fraction, peak oxygen consumption, and heart rate reserve >45%. The derived score predicts inotrope initiation within one year with a sensitivity of 78.6% and specificity of 73.7% (ROC curve AUC=0.82). Probability of inotrope initiation was well stratified by scoring quartiles.

Conclusion:
A simple score comprised of left ventricular ejection fraction, peak oxygen consumption, and heart rate reserve >45% can help predict HF deterioration. Validation of a successful model which predicts time to inotrope use would be beneficial for appropriate timing of mechanical circulatory support.
Abstract 19143: Atrio-Esophageal Fistula After Atrial Fibrillation Ablation: A Pooled Analysis of 33 Cases
Authors: Reddy Madhu Y , Yarlagadda Vivek , Vallakati Ajay , Ponnaganti Gopi Manohar , Janga Pramod , Pillai Anand , Atkins Donita , Lakkireddy Dhanunjaya
Published: April 2024

Introduction:
Atrio-esophageal fistula (AEF) is one of the most devastating complications of percutaneous atrial fibrillation (AF) ablation. Despite its high case fatality, clinical predictors, presentation and outcomes of the complication are not well studied due to the rarity of the complication. We intended to perform a pooled analysis of all cases of atrio-esophageal fistula reported in the literature.

Methods:
We reviewed Medline for all cases of AEF as a complication after percutaneous AF ablation. Patient demographics, procedural characteristics, clinical presentation, management and outcomes all these patients were collected and analyzed. Predictors of mortality were assessed using univariate analyses.

Results:
A total of 33 cases of AEF post-AF ablation were reported in the literature till May of 2013. Mean age of the patients was 54 ± 13 years of which 30 (91%) were males. Majority of them had non-paroxysmal AF (18; 66%). Mean time to presentation after the procedure was 21 ±14 days. Most patients presented with fever (26; 79%). Other common presenting symptoms were chest pain (12; 36%), stroke 8 (26%), seizures (6; 19%) and hematemesis 4 (13%). Of the 33 patients 15 (45%) patients died during the immediate follow-up directly related to the AEF. In 22 (66%) patients surgery was attempted as the primary mode of therapy, 4 (18%) patients had a stent placed and the rest underwent palliative care. In univariate analyses, the only predictor of mortality was age. Patients who died were older than those who survived (61 ±13 vs 49 ±13; p = 0.004).

Conclusion:
Atrio-esophageal fistula is a devastating complication of AF ablation with a case fatality rate of 45%. Older patients are more likely to die of the complication.
Abstract 19146: Disruption of TRAF2-TAK1-IKKB Signaling Triggers Mitochondrial Perturbations and Necrotic Cell Death in Doxorubicin Cardiotoxicity
Authors: Kirshenbaum Lorrie A. , Dhingra Rimpy , Margulets Victoria
Published: April 2024

The anthracycline doxorubicin (dox) is a highly effective anti-tumour agent, however, its use is limited by its severe cardiotoxic effects that manifests as heart failure. The decline in cardiac performance induced by doxorubicin remains poorly defined. A critical survival role for the canonical IKKβ -NF-κB signaling pathway has been demonstrated in ventricular myocytes. In this report, we demonstrate that, dox impairs IKKβ- NF-κB signaling in ventricular myocytes accompanied by mitochondrial perturbations including mPTP, loss of membrane potential and ROS production. IKKβ- NF-κB signaling involves TRAF 2 mediated ligation of K63 ubiquitin chains to RIP1 (Receptor Interacting Protein 1) which serves as scaffold for recruitment of ubiquitylated Tak1 complex and phosphorylation-dependent activation of IKKβ -NF-kB signaling. Interestingly, ventricular myocytes treated with dox demonstrated reduction in expression levels of TRAF2 and TAK1. This was accompanied by a decline in K63- ubiquitylation chains and concomitant increase in K-48 polyubiquitination of RIP1, impaired NF-kB activation and necrotic cell death. Interestingly, inhibiting the kinase activity of RIP1 with Necrostatin-1, (Nec1) suppressed necrotic cell injury induced by dox but not NF-kB activation. Concordant with these findings was a marked increase in necrotic cell death in cardiac myocytes defective for IKKB signaling or MEF cells deficient for p65 treated with dox. Notably, mitochondrial perturbations, including PT-pore opening , ROS production, calcium uptake, LDH, Tn(T) and HMGB-1 release and necrotic cell injury induced by dox were completely abrogated by restoring IKKB-NF-kB signaling in cardiac myocytes or Nec-1. Herein, we provide novel evidence that K-48 ubiquitylation of RIP1 by doxorubicin provides a functional switch that signals necrotic cell death in cells defective for IKKβ-NF-kB signaling. Hence, interventions that modulate IKKB- NF-kB activation may prove beneficial in mitigating the cardiotoxic effects of dox.
Abstract 19152: Lamin A/C-Deficient Bone Marrow-Derived Mesenchymal Stem Cells Exhibit Spontaneous Pre-Adipogenic Conversion
Authors: Jaalouk Diana E , Ho Chin Yee , Loffredo Francesco S , Isermann Philipp , Lammerding Jan
Published: April 2024

Laminopathies are disorders that affect multiple tissues including skeletal muscle as in Emery-Dreifuss muscular dystrophy (EDMD) and cardiac as in dilated cardiomyopathy (DCM). They arise from mutations in the
LMNA
gene that encodes the nuclear envelope proteins lamins A/C. To date, the underlying mechanisms are poorly understood. Recently, several studies established a link between lamin A and dysfunction of adult stem cells. Considering that muscular laminopathies adversely affect tissues of mesenchymal origin, we rationalized that this may be in part attributed to altered differentiation of MSCs. Our aim is to characterize the differentiation of MSCs isolated from an EDMD (
Lmna
-/-
) mouse model which also develops DCM. Marrow aspirates from age- and gender- matched
Lmna
+/-
and
Lmna
+/+
littermates were used as controls. After limited passages in tissue culture, we noted that a large proportion of the
Lmna
-/-
MSCs readily differentiated into fat-containing cells without pre-stimulation with adipogenic supplements. Grown under similar conditions, we did not observe any changes in the control groups. Absorbance measurements of Oil Red O stain alcohol extracts showed significantly higher quantities of fat-containing droplets in
Lmna
-/-
MSCs (2.209 ± 0.039) compared to wild-type (0.095 ± 0.019) and heterozygous controls (0.062 ± 0.001); (mean OD
520
± SEM);
p<0.01
. Likewise, we observed similar PPAR-gamma -dependent pre-adipogenic conversion in
Lmna
-/-
mouse embryo fibroblasts (MEFs) grown to over-confluence in monolayers
in vitro.
Real-Time PCR quantification showed no significant induction in the expression of the transcriptional regulators SREBP-1 and FAS post adipogenic stimulation in MEFs, but both had higher baseline expression in
Lmna
-/-
compared to controls. IHC staining of paraffin-embedded tissue sections of de-calcified bone marrow showed elevated expression of FABP-4 in
Lmna
-/-
mice compared to controls, suggesting an
in vivo
predisposition of Lamin A/C - deficient marrow - derived MSCs to spontaneous adipogenic conversion. Research is underway to characterize the expression of other transcriptional regulators in MSCs and in bone marrow sections from Lamin A/C - deficient mice.
Abstract 19155: Multiple Arterial Grafting Confers Survival Advantage Compared to Percutaneous Intervention With Drug-Eluting Stents in Multivessel Coronary Artery Disease. A Propensity Score Adjusted Analysis
Authors: Raja Shahzad , Benedetto Umberto , Chudasama Dimple , Daley Siobhan , De Robertis Fabio , lsley Charles I , Amrani Mohamed
Published: April 2024

Background:
Despite increasing recognition that coronary artery bypass grafting (CABG) compared to percutaneous coronary intervention (PCI) significantly reduces the need for repeat revascularization in multivessel coronary disease (MVD), overall late mortality has been shown comparable for the two strategies. This perception supports PCI as an acceptable alternative to conventional CABG particularly when drug eluting stents (DES) are used. On the other hand, multiple arterial grafting (MAG) confers improved patency and survival benefits compared with conventional CABG utilizing single internal mammary artery. We aimed to investigate whether MAG offers survival benefit over DES-PCI in MVD.

Methods and Results:
A total of 5686 patients with MVD (≥2 vessel) underwent CABG (n=4256) or PCI (n=1430) at a single institution. MAG was performed in 1264 CABG cases and DES where implanted in 1180 PCI cases. Propensity score adjusted analysis was performed to investigate the potential survival advantage of MAG over PCI. Mean follow-up was 4.6±2.9 years. Risk for late death was comparable after DES-PCI versus conventional CABG in the overall population (adjusted HR 1.11; 95%CI 0.9 to 1.33; P=0.25). However DES-PCI was associated with an increased risk for late death when compared to MAG (HR 1.86; 95% CI 1.45 to 2.40; P<0.0001) and this advantage persisted when elective cases only where included (HR 1.67; 95%CI 1.23 to 2.26, Figure). DES-PCI was associated with a 3.35 fold increased risk for repeat revascularization over MAG (95%CI 2.38 to 4.71; P<0.0001) and 2.94 fold increased risk for repeat revascularization over conventional CABG (95%2.27 to 3.81; P<0.0001).

Conclusions:
Compared to conventional CABG, MAG improved late survival when compared to DES-PCI. When feasible, MAG should be strongly recommended in patients with MVD.
Abstract 19170: Coronary Artery Calcium Score in Patients With Heterozygous Familial Hypercholesterolemia is Proportional to Lifetime LDL Burden After up to 28 Years of Treatment
Authors: Duell P. Barton
Published: April 2024

Heterozygous familial hypercholesterolemia (FH) is associated with severe hypercholesterolemia and early onset of CVD. Prior studies have demonstrated elevated coronary artery calcium deposition in FH. Initiation of treatment as early as age 8-12 years is presumed to help prevent cardiovascular complications.

Hypothesis:
Long-term LDL-lowering treatment will reduce accumulation of coronary artery calcium (CAC) in FH.

Methods:
Cross-sectional analysis of data from 28 patients with heterozygous FH and no prior diagnosis of CVD who had a CAC score measurement.

Results:
Twenty-eight subjects treated in our University Lipid Disorders Clinic for 0-28 years were studied (current age 58 +/- 11 years, 18 women, pre-treatment LDL cholesterol (C) 245 +/- 93, lipoprotein(a) 72 +/- 104, current CAC score 210 +/- 464, CAC percentile 55 +/- 38). The cumulative lifetime LDL burden was proportional to the age treatment was initiated (r=0.47, P=0.013). The CAC score was proportional to age (r=0.52, P=0.026) and cumulative LDL burden (r=0.71, r=0.0016), and was higher in men vs women (442 +/- 721 vs 81 +/- 129, P=0.046). HDL-C, triglycerides, and lp(a) were not correlated with CAC scores. Nine patients treated > 15 years had an achieved LDL-C 105 +/- 40 compared to 202 +/- in 11 patients treated < 1 year. The long term group initiated aggressive treatment at an average age 21 years younger than the short term group (mean age 38 +/- 15 [range 20-67] vs 59 +/- 11 [range 43-71]; P=0.024). Despite these differences, many long-term patients had elevated CAC scores (33% > 400) after up to 28 years of treatment.

Summary:
CAC scores, which are a marker for atherosclerotic plaque accumulation (but calcium may be absent in about 50% of plaques in patients with FH) are proportional to age and lifetime LDL burden in patients with FH, but elevated CAC scores are prevalent even after long-term aggressive LDL-lowering therapy beginning at a mean age of 38 years.

Conclusions:
These findings indicate that patients with heterozygous familial hypercholesterolemia warrant aggressive LDL lowering initiated at a young age.
Abstract 19187: Impact of a Tailored Behavioral Intervention on Lowering Sodium Intake in Adults With Uncontrolled Hypertension
Authors: Stadler Gertraud , Yeh Ming-Chin , Wang Binhuan , Friedberg Jennifer , Natarajan Sundar
Published: April 2024

Introduction:
:
Sodium is related to elevated blood pressure (BP) and reducing sodium intake is a key non-pharmacological approach to lowering BP. We conducted a randomized controlled trial testing whether a tailored or non-tailored behavioral intervention would lead to lower BP. Sodium intake was one of the key dietary behaviors targeted.

METHODS:
This 3-arm randomized controlled trial evaluated the effectiveness of two active interventions, each compared to the usual care (UC) control group. Participants in the active intervention groups received either a tailored stage-matched intervention (SMI) based on the transtheoretical model (TTM) or a non-tailored health education intervention (HEI) to lower BP through six monthly telephone calls targeting diet, exercise and medication adherence. Participants were adult patients with repeated uncontrolled blood pressure. Urinary sodium levels were measured at baseline and post-intervention (6 months). We indexed sodium intake using urinary sodium-to-creatinine ratio to standardize for time and urine volume since last urination. To compare the two intervention groups with the usual care group at the 6-month follow-up we conducted planned contrasts comparing SMI and HEI with UC in a robust regression model adjusting for baseline sodium-to-creatinine ratio.

RESULTS:
At baseline, there were no differences between the groups with the median sodium-to-creatinine ratios being 9.28 for SMI, 10.08 for HEI and 8.99 for UC. At the 6-month follow-up, the median sodium-to-creatinine ratio was 7.99 for SMI, 8.76 for HEI and 9.39 for UC. Participants in the SMI group showed on average lower sodium-to-creatinine ratio than participants in the usual care group (SMI-UC contrast:
p
= .04). Participants in the HEI group did not differ from participants in the usual care group (HEI-UC contrast:
p
= .45).

CONCLUSIONS:
A TTM-based tailored behavioral intervention leads to lower sodium intake. Such an intervention shows promise for lowering sodium intake in adults with uncontrolled hypertension.
Abstract 19248: Endothelial Overexpression of LOX-1 Protects From in vivo Arterial Thrombosis and Modulates Oct-1 and SIRT1 Expression
Authors: Akhmedov Alexander , Camici Giovani G , Stivala Simona , Holy Erik W , Breitenstein Alexander , Lohmann Christine , Paneni Francesco , Beer Juerg-Hans , Tanner Felix C , Matter Christian M , Luescher Thomas F
Published: April 2024

Background:
The hallmark of the initiation of atherosclerotic lesion is foam cell formation, and oxidized LDL (oxLDL) is believed to play a key role in the initiation of the atherosclerotic process. OxLDL is internalized by several receptors, such as SR-AI/II, SR-BI, CD36, and CD68. OxLDL is also internalized by EC, but this uptake depends on receptors other than the classic scavenger receptors. In 1997, a lectin-like oxidized LDL receptor-1 (LOX-1, OLR1) was identified in bovine aortic endothelial cells. LOX-1 is a type II membrane glycoprotein with an apparent molecular weight of 50 kDa. It has a C-terminal extracellular C-type lectin-like domain. This lectin-like domain is essential for binding to oxLDL. Binding of oxLDL to LOX-1 induces several cellular events in endothelial cells, such as activation of transcription factor NF-kB, upregulation of MCP-1, and reduction in intracellular NO, which may trigger the onset of cardiovascular events.

Methods and Results:
We generated endothelial-specific
LOX-1
transgenic mice using the Tie2 promoter (
LOX-1TG
). 12-wk-old male
LOX-1TG
and wild-type (WT) mice were applied for carotid artery thrombosis model.
LOX-1TG
mice developed carotid artery thrombosis within a mean occlusion time of 36.96±4.83 min, while WT mice occluded within a mean time period of 22.75±3.87 min (n=10,
P
< 0.05). Initial blood flow in carotid artery did not differ between both groups. Decreased occlusion time in
LOX-1TG
mice was further associated with decreased tissue factor expression and surface activity as shown by qPCR and ELISA. Furthermore,
LOX-1TG
mice showed increased mRNA and protein expression of transcription factor Oct-1 and histone deacetylase SIRT1 in carotid artery, pointing out that Oct-1 and SIRT1 both may be involved in the observed downregulation of tissue factor through its known target NF-kB. Indeed,
in vivo
knockdown of either Oct-1 or SIRT1 by siRNA further confirmed their role in arterial thrombosis.

Conclusions:
Thus, our data suggest that LOX-1 plays a protective role in the arterial thrombosis and that both Oct-1 and SIRT1 are involved representing new LOX-1-mediating signaling pathway. Hence, modulation of LOX-1 may represent novel therapeutic options for targeting arterial thrombosis.
Abstract 19281: Chemokine-Coupled β2 Integrin-Dependent mRNA Stabilization in Macrophages Modulates VEGF-A Protein Levels During Ischemia-Induced Arteriogenesis
Authors: Morrison Alan R , Yarovinsky Timur O , Young Bryan D , Moraes Filipa , Ross Tyler , Ceneri Nicolle , Zhang Jiasheng , Zhuang Zhen W , Sinusas Albert J , Schwartz Martin A , Simons Michael , Bender Jeffrey R
Published: April 2024

VEGF-A directs both developmental and inducible arteriogenesis through the maturation of smaller vessels and the recruitment of collateral networks. Our lab has demonstrated that integrin-induced mRNA stability plays an important role in macrophage production of VEGF-A protein through translocation and activation of the mRNA stabilizing protein, HuR. It is well known that macrophages may serve as a source of VEGF-A; however, it remains unclear whether macrophages are the principle source of VEGF-A during ischemia-induced arteriogenesis and whether this integrin signaling mechanism modulates VEGF-A protein levels in ischemic muscle tissue in vivo. Here we demonstrate that chemokine-coupled β2 integrin adhesion signaling results in the formation of a complex between the low molecular weight G-protein, Rac2, and the heavy chain of Nonmuscle Myosin IIA (MyH9), leading to translocation of the message stabilizing protein, HuR, and the subsequent prolongation of VEGF-A mRNA half-life. Macrophage-specific gene deletion of MyH9 reduces chemokine-coupled β2 integrin adhesion-stimulated HuR translocation and consequent stabilization of VEGF-A message. Moreover, during hindlimb ischemia, there is global loss of VEGF-A protein in the arteriogenic muscle tissue along with decreased perfusion recovery secondary to decreased small vessel arteriogenesis in the macrophage-specific MyH9-/- mice. These defects appear specific to the induced inflammatory response as these mice demonstrate adequate capillary angiogenic, arteriogenic and arteriolar collateral development at baseline. This chemokine-coupled, adhesion-based signaling pathway provides a unique, rapid molecular switch in gene expression whereby inflammatory monocyte-derived macrophages become the key in vivo source of VEGF-A protein during ischemia-induced arteriogenesis. We anticipate this pathway to be a novel target for the therapeutic induction or inhibition of VEGF-A-mediated arteriogenesis where clinically relevant.
Abstract 221: Pharmacokinetics and Brain Bioavailability of Nitrite Therapy After Ventricular Fibrillation Cardiac Arrest in Rats
Authors: Uray Thomas , Empey Phil E , Drabek Tomas , Jackson Travis , Stezoski Jason P , Tisherman Samuel A , Kochanek Patrick M , Dezfulian Cameron
Published: April 2024

Introduction:
Nitrite (NO
2-
) reduces neurological damage and myocardial dysfunction after cardiac arrest (CA), likely through a nitric oxide (NO) or S-nitrosothiol mechanism. The pharmacokinetics (PK) and blood brain barrier (BBB) penetration and elimination of nitrite therapy after CA are unknown but have important implications for clinical translation. Prior reports support optimal cytoprotection at blood levels of 10-20 μM. We tested the hypothesis that exogenous nitrite rapidly crosses the BBB and is taken up by tissues, increasing levels in cerebrospinal fluid (CSF), brain and heart.

Methods:
Rats (total n=23) were subjected to 5 min VF CA followed by 1.5 min CPR/defibrillation. Rats received either 1 ml placebo or nitrite (8μM) intravenously between 5-10 min resuscitation time (RT). Shams (n=6) with or without nitrite treatment were also analyzed. Nitrite blood levels were measured at various times up to 60 min. At 16 min RT (n=13), CSF was obtained, animals perfused with nitrite-free saline and brain, and heart removed. Separate placebo-controlled experiments (n=6) measured blood nitrite clearance during the initial hour RT. Tissue nitrite concentrations were calculated based on wet tissue weight.

Results:
Blood nitrite levels were 57.14±10.82 μM at 11 min RT in the nitrite groups, respectively, vs. 0.94±0.58 μM in placebo (p<0.001). Blood nitrite rapidly declined in the initial 2 min after dosing (distribution) reaching 73% of peak values with a more gradual elimination (beta t
½
= 25 min) subsequently. Nitrite rapidly crossed the BBB and was present in CSF at 17.1±1.1 min RT in levels comparable to plasma. Heart and brain had more modest 2-3 fold increases.

Conclusions:
Nitrite given after CA rapidly crosses the BBB and the PK data suggest significant tissue uptake. These data provide a biological basis for potential cytoprotection including the brain and will inform clinical trials regarding optimal dosing.
Abstract 227: The Association of Body Mass Index with End-Tidal Carbon Dioxide and Return of Spontaneous Circulation Following Cardiac Arrest
Authors: Leary Marion , Cinousis Marisa , Sheak Kelsey , Li Jiaqi , Abella Benjamin S
Published: April 2024

Background:
End-tidal carbon dioxide (ETCO
2
) has been shown to correlate with return of spontaneous circulation (ROSC) during cardiac arrest. However, ETCO2 is confounded by a number of factors such as patient physiologic parameters and CPR quality.The relationship of patient Body Mass Index (BMI) to mean intra-arrest ETCO
2
and subsequent ROSC is unknown.

Objective:
To measure the association of BMI with intra-arrest ETCO
2
and ROSC.

Methods:
In a single-center cohort of cardiac arrest patients between 7/2007 - 6/2012, we measured ETCO
2
using side-stream capnography during resuscitation efforts, and calculated patient BMI from clinical records. Student’s t-tests were used to compare outcomes.

Results:
Of the 345 cardiac arrest cases that were recorded, 48 had both BMI and ETCO
2
data available. The mean age of the cohort was 63.1±16.5 yrs, 12/48 (25%) were female and 10/48 (21%) had VF/VT as the initial rhythm, 18/48 (38%) obtained ROSC. When we examined those who obtained ROSC versus those who did not, BMI was significantly less in the cohort that obtained ROSC (23.8±5.9 v 32.0±10.8, p=0.002) and ETCO
2
was higher (34.3±8.9 v 22.4±13.7, p=0.001). There were no statistically significant differences in patient demographics, compression rate or depth between the two groups. Overall, there were no significant interaction between BMI and ETCO
2
(p-value=0.921).

Conclusions:
BMI was significantly lower and ETCO
2
higher in those patients who had ROSC, though there was not a relationship between BMI and ETCO2, suggesting that ETCO2 can be clinically utilized and interpreted independent of patient habitus.
Abstract 230: Targeted Temperature Management: Exploring the Association Between Processes of Care and Outcomes After Out-of-Hospital Cardiac Arrest
Authors: Lin Steve , Scales Damon C , Dorian Paul , Kiss Alex , Common Matthew R , Brooks Steven C , Goodman Shaun G , Morrison Laurie J
Published: April 2024

Introduction:
Randomized trials have demonstrated that Targeted Temperature Management (TTM) improves functional survival in patients after out-of-hospital cardiac arrest (OHCA). However, the optimal process of implementation and delivery remains unclear, specifically how fast, how cold or how long to cool. The objective of this study was to evaluate the association of these processes of care with survival and neurological function in patients after OHCA.

METHODS:
We conducted a retrospective cohort study on consecutive adult (≥18 years) non-traumatic OHCA patients from November 1, 2007 to January 31, 2012. Eligible patients who were treated with TTM after return of spontaneous circulation were included. The primary and secondary outcomes were in-hospital survival and good neurological status (Modified Rankin Scale of 0-3) at hospital discharge, respectively. Bivariate and generalized estimating equation analyses were used to evaluate the associations between processes of care variables and patient outcomes.

Results:
There were 5770 consecutive OHCA patients, of whom 747 (12.9%) patients were eligible and received TTM; 365 (48.9%) patients survived to hospital discharge, of whom 241 (66.0%) patients had good neurological outcomes. After adjusting for the Utstein variables, a higher temperature prior to cooling was associated with improved survival [OR 1.26 per °C, 95% CI 1.09-1.46, p=0.002] and neurological outcomes [OR 1.27 per °C, 95% CI 1.08-1.50, p=0.004]. Moreover, a slower rate of cooling was associated with improved survival [OR 0.73 per °C/hr, 95% CI 0.54-1.00, p=0.05] and neurological outcomes [OR 0.74 per °C/hr, 95% CI 0.57-0.97, p=0.03]. The location of cooling initiation, coldest temperature, and cold duration ≤34°C were not associated with outcomes.

CONCLUSION:
A higher baseline temperature prior to cooling and a slower rate of cooling were associated with both improved survival and neurological outcomes. This may reflect the complex relationship between the extent of brain injury causing hypothalamic dysfunction and impaired thermoregulation, and the cooling techniques used in patients after cardiac arrest.
Abstract 235: More Than Doubled Survival in Out-of-Hospital Cardiac Arrest After the Implementation of a Dual Dispatch System is Attributable to Pre-Hospital Rather Than In-Hospital Factors
Authors: Nordberg Per , Hollenberg Jacob , Rosenqvist Mårten , Herlitz Johan , Jonsson Martin , Järnbert-Pettersson Hans , Forsberg Sune , Dahlqvist Tobias , Ringh Mattias , Svensson Leif
Published: April 2024

Introduction:
In 2005, a dual dispatch system using fire fighters as first responders in addition to emergency medical service in out-of-hospital cardiac arrest (OHCA) was implemented in Stockholm, Sweden. A pilot study from 2006 showed doubled survival in witnessed OHCA compared to historical controls. The aim of this study was to determine the short and long term impact of the intervention and to investigate the additional effect on survival of in-hospital interventions such as therapeutic hypothermia and acute catheterization.

Methods and Results:
OHCA from 2004 (historical controls, n=620) and 2006-2009 (intervention period, n=2863). Fire fighters performed CPR in 90 % of the patients. They were first on scene and connected an automated external defibrillator in 41% of the cases. The median time from dispatch to arrival of first responder shortened from 7.7 minutes in the control period to 6.7 minutes (p<0.001). Survival to 1 month improved from 3.9 % to 7.4 % (p=0.002). Logistic regression (adjustments for: sex, age, place, etiology, witnessed status, bystander-CPR, first rhythm) gave adjusted OR 2.7 (CI 1.5-4.6). Survival to 3 years increased from 2.4% to 6.2% (p<0.001), adjusted OR 3.5 (CI 1.8-7.0). In the logistic regression analysis including in-hospital factors we found no additional outcome benefit of therapeutic hypothermia, adjusted OR 1.5 (CI 0.7-3.2) and acute catheterization/thrombolysis, adjusted OR 1.7 (CI 0.9-3.1).

Conclusions:
The implementation of a dual dispatch system using fire-fighters has significantly increased survival after 1 month and 3 year in OHCA. Only pre-hospital factors had an impact on outcome.