bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 16913: Cardiac Magnetic Resonance Versus Routine Catheterization Prior to Bidirectional Glenn Operation: Long-Term Follow-Up of a Randomized Clinical Trial
Authors: Brown David W , Gauvreau Kimberlee , Powell Andrew J , Lang Peter , Colan Steven D , del Nido Pedro J , Odegard Kirsten C , Geva Tal
Published: April 2024

Background:
A previously published randomized clinical trial of cardiac magnetic resonance (CMR) versus routine catheterization in patients with functional single ventricle (SV) prior to Glenn operation (BDG) demonstrated similar short-term post-operative outcomes. We sought to evaluate late outcomes in this cohort to ascertain any long-term effects of this management strategy.

Methods:
Retrospective review of enrolled patients through most recent follow-up.

Results:
Follow-up was available on all 82 patients in the original cohort, median age 6.5 years at most recent follow-up. Of these, 76 (93%) underwent Fontan operation; 2 died prior to Fontan. Baseline demographics, anatomic factors, and age at BDG did not differ between those randomized to CMR versus catheterization. Although CMR patients were slightly younger at Fontan operation (2.4 vs 2.7 years, p=0.02), baseline weight, body surface area, and oxygen saturation at time of Fontan were similar. Echocardiographic data prior to Fontan were similar, with 2 patients in each group having ≥ moderate ventricular dysfunction, and only 1 patient with ≥ moderate atrioventricular valve regurgitation. Catheterizations were performed in all patients prior to Fontan (n=76). Although age at catheterization was younger in the CMR group (2.3 vs 2.7 years, p=0.003), hemodynamic parameters were not significantly different, including pulmonary vascular resistance, mean pulmonary artery, atrial, and ventricular end-diastolic pressures. Prevalence of coarctation and pulmonary artery stenoses were similar. Patients in the CMR group had a similar rates of transcatheter interventions (71 vs. 79%, p=0.6) including similar rate of coil occlusion of aorto-pulmonary collaterals (66 vs. 61%, p=0.29). At time of Fontan, short-term complications, hospital length of stay, and the percent of patients meeting a 5-part definition of a successful Fontan operation were not significantly different (71 vs 55%, p=0.23).

Conclusions:
The CMR and catheterization groups had equivalent clinical and hemodynamic profiles prior to Fontan, and similar post-Fontan outcomes at a median follow-up of 6 years post BDG. For selected patients, a pre-BDG evaluation with CMR is an acceptable alternative to catheterization.
Abstract 16914: Expression of Lamin Mutation p.R644C, The Most Common Known Cause of Cardiolaminopathies, Causes Cardiac Fibroblasts Senescence
Authors: Song Hwang-Hwan , Jin Un-Ho , Tsai Ju-Yun , Marian Ali J
Published: April 2024

Background:
Mutations in LMNA, encoding lamin A/C (LMNA), cause a diverse array of distinct phenotypes, including progeroid syndromes. The phenotype in the heart, referred to as cardiolaminopathies, typically manifests as early onset and progressive dilated cardiomyopathy (DCM), atrial bradyarrhythmias and conduction defects. The most commonly reported mutation in cardiolaminopathies is the p.R644C, which is located in the C-terminus. The domain is involved in progeroid syndromes. We posit that cardiolaminopathies caused by the p.R644C mutation represent non-syndromic premature cardiac aging.

Methods and Results:
We expressed wild type and mutant LMNA (LMNA-WT and LMNA-R644C, respectively) in cardiac fibroblasts isolated from adult mouse hearts using recombinant adenoviruses. Expression of LMNA-R644C was associated with blebbing of the nuclear membrane, a characteristic of progeroid syndromes. Co-immunopreciptation studies showed reduced binding of LMNA-R644C to its interactome proteins, namely retinoblastoma (Rb), lamin-associated protein 2α and protein phosphatase 2A, leading to reduced inactivation of Rb by hyperphosphorylation. Consequently, levels of Cdkn1a (P19) and Cdkn2d (P21), well-established inhibitors of cell cycle progression were increased and levels of Cyclin A2 and Cyclin B1, markers of cell cycle progression to mitosis, were reduced. In accord with cell cycle inhibition, proliferation rate of cardiac fibroblasts was decreased, as indicated by increased cell doubling time and reduced BrdU incorporation, while expression level of senescence-associated β-galactosidase, a marker for cell senescence was increased.

Conclusions:
Expression of LMNA-R644C mutation, the most common mutation found in cardiolaminopathies, impairs interactions among constituents of the LMNA/Rb/LAP2α/PP2A complex leading to hypophosphorylation of Rb, suppression of cell cycle progression and senescence of cardiac fibroblasts. We conclude that cardiolaminopathies represent non-syndromic premature cardiac senescence.
Abstract 16976: Respiratory Muscle Trainings Started in Acute Period of Complicated Myocardial Infarction in Patients with Pulmonary Hypertension
Authors: Kolesnikova Elena , Arutyunov Grigory , Rylova Anna , Rylova Natalia
Published: April 2024

Background:
Positive effects of physical exercises as a part of comprehensive rehabilitation after acute myocardial infarction (MI) are well known. Patients with MI and concomitant heart failure (HF) with pulmonary hypertension (PH) often can't take part in physical trainings. Purpose: To study the effect of respiratory muscles trainings (RMT) in patients with acute MI and concomitant HF and PH.

Methods:
87 MI patients 68,1±4,3 years old were randomized to either an exercise training group (EG) or to a control group (CG). Patients were on their 3-5 day of MI and had NYHA III-IV class . The EG participated in a RMT with gradual increase of inspire and expire resistance. RMT were started at the hospital on the 3-5 day after MI and were continued for 12 months at home by patients themselves. Trainings were held for 20-30 minutes 1-2 times every day.

Results:
In 1 year the distance of 6 minute walk test increased significantly in EG (262,2±9,22 m in EG vs 277,1±9,1 m in CG at baseline, p>0,05; in 1 year 285±8,7m vs 275,3±9,28 m p<0,01). Peak VO2 also increased significantly in EG (3,95±1,71 ml/kg/min in EG vs 3,96±1,72 ml/kg/min in CG at baseline, p>0,05; in 1 year 6,84±1,55 vs 4,61±1,16 ml/kg/min, p<0,01). RMT helped to stabilize mean pulmonary pressure (56,1±10,3 mm Hg in TG vs 56,8±7,7 mm Hg in CG at baseline, p>0,05 and 54,4±7,7 mm Hg in TG vs 79,7±9,2mm Hg in CG in 12 months,p<0,01). There was a statistically significant increase in the maximal inspiratory mouth pressure in most of patients, from 4,23 kPa ± 1,12 vs 4,19 kPa ± 1,11,p>0,05 at baseline to 5,6 kPa ± 0,8 vs 4,1 kPa ± 1,1; p < 0,01 in 12 months). Health related quality of life measured by SF-36 increased in both groups, but results in physical functioning, bodily pain, vitality, role emotional scales were significantly higher in EG patients. In a year there was 3 lethal outcomes in EG vs 8 inCG. EG patients had significantly less hospitalizations because of HF progression (7,8% in EG vs 14,6% in CG) and pneumonias (2,1% vs 15,3%).

Conclusion:
RMT in patients with MI and HF with PH can be started at their acute period. It improves physical capacity, stabilize pulmonary pressure, increase health-related quality of life and decrease number of hospitalizations during first year after MI.
Abstract 16979: Impact of ICD Shock Testing and Non-Testing on Arrhythmia Therapy Efficacy
Authors: Nordbeck Peter , Warmuth Marcus , Bauer Wolfgang R , Ertl Georg , Ritter Oliver
Published: April 2024

Background:
Defibrillation testing is often performed during implantation of implantable cardioverter defibrillators (ICD) to confirm therapy efficacy, even though there are no prospective data suggesting that outcome is improved by this procedure when modern ICDs are implanted. The aim of the study was to investigate whether shock testing during ICD implantation is feasible for predicting future effectiveness of ICD therapy.

Methods:
The retrospective analysis included a cohort of consecutive patients who received an ICD device with telemedicine capacity in our clinic, with each tachycardia episode monitored and evaluated online. All devices were implanted by means of standard surgical techniques, and shock testing was conducted or desisted due to the attending cardiologist's and surgeon's discretion.

Results:
357 patients who received either an ICD or CRT-ICD with home monitoring capacity could be enclosed in the study. From 219 patients, in which ICD shock testing was performed during implantation, initial shock testing revealed satisfactory results in 210 cases; otherwise, additional surgical measures led to shock testing success. 138 patients were not tested. Compared to the shock testing group, implantation for primary prevention was more common in the non-testing group. In the shock testing group, 124 patients had VT/VF requiring ICD shock therapy. First shock efficacy was 99% for the first VT event in this group, with only one patient undergoing an ineffective first shock delivery. In this patient, the VT could be terminated with the second shock. However, in the long run 7 patients had at least one documented episode with an ineffective shock, despite the fact that previous shocks had been successful. In the non-testing group, 76 patients required ICD shock therapy and first shock efficacy was 100% for the first VT event in this group. Accordingly, there was no significant difference regarding first shock efficacy between patients with ICD for primary or secondary prevention.

Conclusions:
Shock efficacy for treatment of the first ventricular tachycardia was generally high, regardless whether shock testing was performed during implantation or not. This result challenges the current paradigm of ICD shock testing during implantation.
Abstract 17: A Noninvasive Method for Measuring the Physiologic Quality of CPR Through Application of Quantitative Waveform Analysis of the Ventricular Fibrillation Electrocardiogram
Authors: Salcido David D , Housler Greggory , Menegazzi James J
Published: April 2024

Background:
Parameters by which the quality of cardiopulmonary resuscitation (CPR) is commonly gauged, include rate, depth, and chest compression fraction. These measure the process of delivering CPR but give no insight into its physiologic effect. Analysis of electrophysiologic changes during CPR may provide a direct assessment of the impact of CPR that transcends CPR process parameters.

Objective:
Assess the relationship between coronary perfusion delivered over time (i.e., dose) during CPR and a quantitative measure of the ventricular fibrillation ECG, amplitude spectrum area (AMSA).

Methods:
Data were pooled retrospectively from 3 swine resuscitation experiments, comprising 63 placebo study arm animals. Swine were sedated, anesthetized, and instrumented with micromanometer-tipped pressure catheters. Coronary perfusion pressure (CPP) was calculated as the difference between the aortic and right atrial pressures at the end of the diastolic phase. Ventricular fibrillation was induced with a transthoracic shock and left untreated for 5 or 8 minutes. CPR was then initiated and continued for 90 seconds (n = 14), 3 minutes (n=25), or 5 minutes (n=24), and was accompanied in 2 series by the administration of epinephrine, vasopressin, propranolol, and sodium bicarbonate. Coronary perfusion dosage was calculated as the area under the CPP curve (CPP-AUC), and AMSA measurements were taken from 5-second periods immediately prior to and immediately following CPR. Delta AMSA was calculated as the difference between the log of the ending and starting AMSA values. Linear regression was used to assess the association between CPP-AUC and Delta AMSA.

Results:
In univariate models CPP-AUC was significantly inversely associated with Delta AMSA when duration of CPR was 3 minutes (p = 0.02) or 5 minutes (p = 0.002), but not 90 seconds (p = 0.119). In a multivariate linear regression model containing CPP-AUC, duration of CPR, and series, the CPP-AUC was significantly inversely related to Delta AMSA (p < 0.001).

Conclusion:
The change in the VF waveform during CPR correlates strongly with the dose of perfusion provided over a period of CPR and thus may be a useful measure for estimating CPR quality independent of process measures.
Abstract 17018: Plasma Concentrations of Galectin-3 in Patients with Suspected and Confirmed Heart Failure: Distribution, Associations and Prognostic Significance
Authors: Sherwi Nasser S , Goode Kevin M , Zhang Jufen , Nicholls Rachel , Yassin Ashraf , Wong Kennth , Clark Andrew , Cleland John
Published: April 2024

Background:
Plasma concentrations of galectin-3 predict outcome in patients with acute heart failure but have not been studied in a large epidemiologically-representative out-patient population.

Aims:
To explore the distribution, associations and prognostic significance of plasma concentrations of galectin-3 in patients with suspected heart failure of varied phenotypes.

Methods:
Patients referred to a heart failure clinic from the local population were invited to participate. Symptoms, signs and routine investigations, including spirometry, electro- and echo-cardiograms and blood tests, including NT-proBNP were systematically recorded. Patients were followed for four or more years.

Results:
Of 1,047 patients evaluated, 403 had no structural heart disease on echo, 508 had left ventricular (LV) systolic dysfunction, 76 had substantial valve disease and 108 had evidence only of ‘diastolic’ LV dysfunction. Plasma galectin-3 ranged (median IQR) from 14.8 (11.0 to 18.3)ng/ml in patients without overt disease to 19.5 (15.1-24.6)ng/ml in patients with LV systolic dysfunction and elevated NT-proBNP. Greater age, serum creatinine and white blood cell count, lower systolic blood pressure and female sex, but not LV function, predicted plasma galectin-3 but explained little of its variability (R
2
= 0.0300; p<0.0001). During follow-up, 266 patients (25%) died, of which 145 were primarily for cardiovascular reasons. On univariate analysis and after correction for age and sex differences, the plasma concentration of galectin-3 was a strong predictor of all-cause mortality.

Conclusions:
Plasma galectin-3 is commonly increased in patients with heart failure but appears better related to renal function and NT-proBNP than LV ejection fraction. Plasma galectin-3 is strongly related to an adverse prognosis, which may be due, in part, to its relationship to renal function. Whether galectin-3 is a marker or mediator of cardiac and renal dysfunction remains to be determined.
Abstract 17025: Dimethylarginine Dimethylaminohydrolase-1 Slows Progression of Fibrocalcific Aortic Valve Disease
Authors: Zhang Bin , Oehler Elise A , Roos Carolyn M , Arghami Arman , Miller Jordan D
Published: April 2024

Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthases (NOS), and is degraded primarily by dimethylarginine dimethylaminohydrolase-1 (DDAH1). While ADMA is elevated in patients with fibrocalcific aortic valve stenosis (FCAVD), is it unknown whether tissue levels of DDAH1 are altered in FCAVD, and whether systemic elevations in ADMA levels accelerate initiation and/or progression of FCAVD. In the present study, we measured expression of DDAH1 in normal and stenotic human aortic valves, and tested the hypothesis that increases in ADMA worsen hypertension and endothelial dysfunction and accelerate the initiation and progression of FCAVD in hypercholesterolemic mice. In tissue from humans with FCAVD, expression of DDAH1 was significantly increased compared to normal valve tissue (normal = 1.0 ± 0.1, FCAVD = 1.3 ± 0.1, ⋔⋔Ct method; p < 0.05). To experimentally alter DDAH1 levels, we used low density lipoprotein receptor-deficient, apolipoprotein B100-only (LA) mice that were either wild-type (D
+/+
) or heterozygous (D
+/-
) for DDAH1. Blood pressure (tail cuff), aortic endothelial function (isolated organ bath), and aortic valve function (echocardiography), were measured at 3 and 6 month time points in these mice. Compared to LA-D
+/+
mice, systolic arterial pressure was significantly increased in LA-D
+/-
mice at both 3 month (121±4 mmHg and 144±4 mmHg) and 6 months (138±6 mmHg and 148±4 mmHg). Aortic endothelial function progressively declined with prolonged hypercholesterolemia, but maximum relaxation to acetylcholine did not differ between LA-D
+/+
and LA-D
+/-
mice at 3 or 6 months. While aortic valve function was similar between LA-D
+/+
and LA-D
+/-
mice at 3 months (peak transvalvular velocity: 1.98±0.07 m/sec versus 1.94±0.06 m/s, respectively), aortic valve function was significantly worse in LA-D
+/-
(2.41±0.11 m/sec) compared to LA-D
+/+
mice (2.20±0.09 m/sec) at 6 months (p < 0.05). In conclusion, our data support a working model in which increases in valvular DDAH1 levels protect against progression of FCAVD. Importantly, loss of DDAH1 in mice does not alter aortic valve function during early stages of FCAVD, but accelerates progression of FCAVD independently of changes in endothelial function.
Abstract 17031: Epigenetic Modifications at
VEGFR1
Locus in Response to Angiogenic Signal
Authors: Dutta Debasree , Paul Soumen
Published: April 2024

Vascular endothelial growth factor (VEGF) and its receptors (VEGFR1/VEGFR2) are primary regulators of angiogenesis. Among them, VEGFR1 has a dual role of either stimulating or suppressing angiogenesis. So, it is highly important to understand the molecular mechanism underlying its regulation. Earlier we found that angiogenic signal-ETS1-HIF2α regulatory axis is involved in the activation of
Vegfr1
chromatin domain in endothelial cells. However, the dynamic nucleoprotein structure that assembles at the
Vegfr1
chromatin locus is poorly understood. Here, we report that dynamic alteration in
Vegfr1
transcription is associated with epigenetic marks that facilitate or repress transcriptional activation. The rapid induction of
Vegfr1
transcription in response to angiogenic signal FGF2/EGF in yolk sac endothelial cells (YSECs) is associated with rapid increase in acetylated histone H3 at lysine 9 (H3acK9), 56 (H3acK56) and 27 (H3acK27), levels at the
Vegfr1
chromatin domain. A time course analysis revealed that these acetylation levels are gradually reduced with time and is correlated with transcriptional repression of
Vegfr1
. The increase in acetylation is associated with the induction in expression of histone acetyl transferase, Creb Binding Protein (CBP) in YSECs. Knockdown of CBP by RNA interference inhibited FGF2/EGF induced VEGFR1 expression with loss in histone acetylation marks. Level of repressive modification of histone H3 methylated at lysine27 (H3me3K27) at the
Vegfr1
locus correlated with transcriptional repression of
Vegfr1
. Member of the polycomb group family might regulate the transcriptional repression of
Vegfr1
in endothelial cells as well as during differentiation of embryonic stem cells towards endothelial progenitors. This approach will provide important insights about molecular mechanisms of gene regulation in angiogenic signal-activated vs. repressed endothelial cells and will lead to therapeutic modalities for controlling angiogenesis.
Abstract 17034: The Novel Extracellular Matrix Protein Podocan Shows a Distinct Expression Pattern in Human Primary versus Restenotic Atherosclerotic Coronary Lesions and its Lack of Extra-Cellular Expression in Restenotic Tissue is Associated with Increased Wnt-Pathway Activation
Authors: Hutter Randolph , Huang Li , Fuster Valentin , Klotman Paul , Badimon Juan Jose
Published: April 2024

Background:
Vascular smooth muscle cell (VSMC) migration and proliferation are associated with restenosis post percutaneous intervention. Podocan is a novel member of the small leucin rich repeat protein family. We recently have described podocan as an inhbitor of VSMC migration and proliferation via the Wnt-pathway. Now we are reporting the expression of podocan and Wnt-pathway related molecules in human primary stable coronary atherosclerosis compared to restenosis.

Methods and Results:
The expression of podocan and non-phospho-beta catenin (NPBC) an indicator of Wnt-pathway activation was evaluated by immunohistochemistry in coronary atherectomy samples (n=32) (data presented as mean % cells positive for NPBC, ± SEM). The antibody against the human form of podocan was generated in our lab whereas antibodies for NPBC, Wnt 1 and LRP-6 were obtained commercially. In atherectomy samples from patients with primary stable atherosclerosis (n=20) podocan expression was abundant in extra-cellular as well as intra-cellular location. Podocan deposits were seen especially in plaque areas surrounding neovessels. Out of 20 coronary primary lesions 16 showed podocan expression. In contrast, restenotic lesions showed a paucity of podocan with only 5 out of 12 lesions staining positive for podocan. Of note, extra-cellular podocan deposition was completely absent in all restenosis samples and podocan present was restricted to an intra-cellular/cytoplasmic staining pattern. The expression of NPBC was strongly increased in restenotic compared to primary lesions (35 ± 6 % vs. 4 ± 2 %, P<0.05). Importantly, nuclear staining of NPBC indicative of nuclear translocation of beta catenin was observed only in restenotic lesions. Immuno-fluorescence double labeling showed a strong co-localization of Wnt-1 and LRP-6 on VSMC in areas of hyperplasia in restenotic lesions.

Conclusions:
We are reporting for the first time the expression of podocan in human coronary atheroma. The paucity of podocan and the absence of extra-cellular podocan in restenotic tissue were associated with a strong increase in NPBC expression in VSMC indicating increased Wnt-pathway activation. This points to podocan and the Wnt-pathway as possible key regulators of VSMC in human atherosclerosis.
Abstract 17035: Identification of Novel Circulating Multipotent Stem Cells in Human Peripheral Blood, Which Originate From Human Heart
Authors: Yang Han-Mo , Kim Ju-Young , Lee Joo-Eun , Cho Hyun-Jai , Lee Hae-Young , Kang Hyun-Jae , Oh Byung-Hee , Park Young-Bae , Kim Hyo-Soo
Published: April 2024

Background:
There has been only one study showing the presence of multipotent stem cells in bone marrow, called multipotent adult progenitor cells (MAPCs). These cells can be differentiated not only into mesenchymal lineage cells, but also into cells with neuroectoderm or endoderm features. Until recently, however, there has been no report isolating and characterizing these cells from human peripheral blood. Here, we hypothesized that there might be circulating multipotent stem cells in human peripheral blood. In addition, we tried to find the origin of these cells.

Methods and Results:
From human peripheral blood mononuclear cells adherent on non-coated dishes, we could identify new population of cells, which are quite distinct from previously reported other stem cells. Newly identified cells have the gene profiles such as Oct3/4, KLF4, and c-Myc, suggesting multipotent stemness. Moreover, FACS analysis demonstrated that these stem cells have the property of mesenchymal stem cells. With diverse differentiation media, we could differentiate these cells into endothelial-like cells or vascular smooth muscle-like cells. These stem cells have the properties of osteogenic, adipogenic, and myogenic differentiation. Moreover, these cells can be differentiated into ectodermal lineage cells such as neuron-like cells as well as endodermal lineage cells such as hepatocyte-like cells. When injected into the mouse heart
in vivo
, these newly identified stem cells could be differentiated into endothelial cells, smooth muscle cells, and cardiomyocytes. To investigate the origin of these cells, we collected peripheral mononuclear cells from patients receiving the transplantation of bone marrow, liver, heart, or kidney. After culturing these cells and identifying HLA type of each cells, we could confirm that these stem cells are derived from human heart.

Conclusion:
This study showed the presence of novel circulating multipotent stem cells in human peripheral blood. Interestingly, these cells are derived from human heart. These findings suggest that these cells can be easily obtained from human peripheral blood and used for regenerative medicine in real world.
Abstract 17049: Upregulation of the Matricellular Protein Thrombospondin (TSP)-1 in the db/db Heart Regulates Matrix Remodeling and Induces Vascular Rarefaction
Authors: Gonzalez-Quesada Carlos , Biernacka Anna , Lee Dong-Wook , Li Na , Dobaczewski Marcin , Frangogiannis Nikolaos G
Published: April 2024

The matricellular protein Thrombospondin (TSP)-1, a potent angiostatic agent and crucial TGF-β activator, is markedly upregulated in animal models of obesity and diabetes and in tissues from diabetic patients; however, its role in the pathogenesis of diabetic complications is unknown. Leptin resistant db/db mice rapidly develop obesity and diabetes and exhibit cardiac hypertrophy, fibrosis and diastolic dysfunction as they age. We hypothesized that TSP-1 induction in the db/db heart may regulate cardiac remodeling and fibrosis. TSP-1 expression was markedly upregulated in db/db hearts. In order to dissect the role of TSP-1 in diabetic cardiomyopathy we generated db/db TSP-1 -/- (dbTSP-1) mice and we studied the effects of TSP-1 absence on the metabolic and cardiac dysfunction associated with central leptin resistance. TSP-1 absence did not affect weight gain and fat content in db/db mice. Mortality was comparable between db/db and dbTSP-1 mice. dbTSP-1 mice had significant alterations in chamber geometry exhibiting increased left ventricular dilation (LVEDV, db/db:73.36+2.03 vs. dbTSP1:90.14+5.85 p<0.01) associated with a modest deterioration in systolic function (FS, db/db: 41.82+1.07 vs. dbTSP1:31.02+1.59 p<0.01). In order to dissect the mechanisms responsible for chamber dilation in dbTSP-1 mice, we examined the effects of TSP-1 absence on matrix remodeling. Using a hydroxyproline assay, we found that TSP-1 loss reduced collagen deposition in db/db animals. Decreased cardiac fibrosis in dbTSP-1 mice was associated with diminished TGF-β/Smad3 signaling and attenuated MMP activity in the myocardium. Moreover, db/db hearts exhibited an aging-associated vascular rarefaction in the myocardium that was attenuated in dbTSP-1 animals (capillary density, WT: 4311.6+313.17 vs. db/db: 2994+133 vs. dbTSP1 3659.1+60.9 p<0.01). Our findings demonstrate that, while inducing TGF-β activation and cardiac fibrosis, TSP-1 induction in obese diabetic hearts plays a role in maintaining matrix homeostasis, thus protecting the myocardium from dilative remodeling. Moreover, TSP-1 upregulation is, at least in part, responsible for reduced angiogenesis in the hypertrophied diabetic heart, leading to formation of a rarefied capillary network.
Abstract 17091: High Saturated Fat Intake Improves Survival in Genetic Cardiomyopathy Compared to a High Polyunsaturated Fat Diet or a Low Fat Diet
Authors: Galvao Tatiana , Hecker Peter , Brown Bethany , O'Connell Kelly , O'Shea Karen , Stanley William
Published: April 2024

Surprisingly, a high fat diet comprised mainly of saturated fatty acids improves LV function and survival in rat models of heart failure induced by hypertension or myocardial infarction. The mechanism for this effect is not clear, nor is it known if a similar effect occurs with a high fat diet composed of plant derived polyunsaturated fatty acids (PUFA), or in genetic cardiomyopathies. We determined if survival in cardiomyopathic hamsters (Bio TO-2 strain) is prolonged by a high fat diet compared to a low fat diet (see table). Further, we compared the effect of high fat diets enriched with either saturated fat (palmitate and stearate), or PUFAs from plant sources(primarily linoleic and α-linolenic acids). Cardiomyopathic hamsters (6 wks old) were fed either a Low Fat diet; a High PUFA diet, or a High Saturated Fat diet. Survival was assessed (n=30/group), and subgroups were evaluated at 30 wks of age (n=12/group) for LV and mitochondrial function. The diet has no effect on LV function as assessed by echocardiography, and there was no difference in body weight or LV mass. Since there is impaired mitochondrial function in heart failure and dietary lipid composition might positively impact mitochondrial function, isolated mitochondria were assessed. Respiration and Ca
2+
-induced mitochondrial permeability transition were unaffected by diet. On the other hand, the high PUFA diet increased fat pad mass compared with the two other cardiomyopathic groups and elevated plasma free fatty acid concentration (p<0.05). Importantly, there was a significant increase in survival in the high saturated sat group compared to the either the low fat or the high PUFA groups after 16 months of treatment (p<0.0001). These results show that a high fat diet comprised largely of long chain saturated fatty acids increase survival in cardiomyopathic hamsters compared to either a low fat diet or a high fat diet comprised of PUFA from plant sources. The effect was independent of improved mitochondrial function.
Abstract 17094: “Trojan Horse” Monocytes: a New Approach for Gene Delivery to Angioplastied Arteries
Authors: Fishbein Ilia , Adamo Richard F , Corrales Ricardo , Chorny Michael , Forbes Scott , Levy Robert J
Published: April 2024

Introduction:
Monocyte-derived macrophages are implicated in sustained inflammation typical of atherosclerotic and restenotic arteries. Since the role of macrophage-mediated inflammatory reactions in the progression of atherosclerosis and post-angioplasty restenosis is firmly established, multiple approaches have been devised to decrease the number and/or functionality of mononuclear phagocytic cells residing in atherosclerotic and stented arteries. However, no prior research has exploited the capability of monocytes to target sites of vascular injury in order to introduce pro-healing “therapeutic” genes into diseased vasculature. Here we report preliminary results demonstrating feasibility of this concept.

Methods and Results:
Monocytes were isolated from heparinized rat blood by sequential Ficoll and Percoll gradient centrifugation. The cells labeled with CM-DiI dye (5x10
5
cells/ml) were suspended in complete RPMI1640 medium and administered via tail vein to rats that underwent balloon denudation injury of carotid arteries 4 days prior to cell therapy. The animals were euthanized on day 8 after balloon injury (day 4 after monocyte delivery). The CM-DiI-labeled cells were found in the nascent neointima and adventitia of balloon-injured arteries (373±90 and 77±37 per mm
2
of tissue, respectively). Comparison of CM-DiI labeling with immunohistochemical staining results (CD 68) has demonstrated that up to 30% of all macrophages in the neointimal tissue of rats treated with ex vivo modified monocytes derive from the delivered cells. To verify functional competence of delivered cells, monocytes isolated as above were transduced with adenovectors driving synthesis of firefly luciferase and administered to rats that underwent Fogarty balloon injury 4 days prior to the cell delivery. One day later, luciferase expression in balloon injured arteries was confirmed by bioluminescence imaging.

Conclusions:
These pilot studies demonstrate the feasibility of using ex vivo transfected autologous or syngeneic monocytes as a means to introduce prohealing factors to diseased vasculature.
Abstract 17102: Atherosclerotic Plaques in Mice Experience Greatest Biomechanical Stress Remote From the Fibrous Cap
Authors: Campbell Ian C , Weiss Daiana , Oshinski John N , Taylor W. Robert
Published: April 2024

Introduction:
Although the atherosclerosis-prone mouse model is widely studied and has contributed much to the current understanding of atherogenesis, rupture of plaques in mice has not been conclusively observed. Consequently, uncertainty of the utility of the mouse model for studying endpoints like plaque rupture pervades in the field. In this study, we investigated the biomechanical likelihood of plaque rupture in mice.

Hypothesis:
The highest stresses are located away from the fibrous cap of lesions in mice.

Methods:
We studied acute models of atherosclerosis (15 ApoE-/- and 15 LDLr-/- mice, high-fat diet 8 weeks with simultaneous Angiotensin II osmotic pumps) and a chronic model (15 ApoE-/- mice aged 1 year, regular chow diet). The ascending and descending aortas and brachiocephalic artery were harvested for histological staining of morphology. To preserve in vivo anatomy as accurately as possible, vessels were perfused with a vascular casting compound at each mouse's measured diastolic blood pressure and then embedded in methyl methacrylate resin blocks, which minimize sectioning artifacts. Histology sections were the input geometry for a lesion-specific finite element analysis (FEA) computer model of solid mechanics within the vessel wall. For comparison, we performed similar FEA simulation on 15 human coronary plaques of the thin-cap fibroatheroma (TCFA) phenotype.

Results:
In human lesions, highest stresses tended to be located on the fibrous cap or shoulders of the plaque, consistent with current understanding of plaque rupture. However, in mouse plaque simulations, the highest stresses and strains were located away from the lesions on the thin plaque-free wall.

Conclusion:
The characteristic difference in peak stress location explains the lack of plaque rupture in mice. This study demonstrates that local mechanical strains in the fibrous cap of murine atherosclerotic lesions are insufficient to cause plaque rupture, in contrast to human lesions.
Abstract 17123: Correlation Between Ethnicity and Extent of Coronary Artery Disease on Coronary CT Angiography: Results From the Advanced Cardiovascular Imaging Consortium
Authors: Chinnaiyan Kavitha M , Poopat Chad , Share David , Raff Gilbert , Kazerooni Ella , Ananthasubramaniam Karthik , Goraya Tauqir , Girard Steven , Gallagher Michael J , Peyser Patricia
Published: April 2024

Background:
Although racial differences in prevalence of coronary artery disease (CAD) are well-known, race is not included in widely used risk assessment algorithms. The purpose of this study was to establish if race was an independent predictor of significant CAD (>50% stenosis) on coronary CT angiography (CCTA).

Methods:
Patients with no known CAD undergoing CCTA at 41 institutions and enrolled in a large statewide registry, the Advanced Cardiovascular Imaging Consortium (ACIC) between July 2007 and April 2011 were included. Demographics, risk factors, Framingham Risk Scores (FRS), pre-test CAD likelihood and extent of CAD on CCTA were compared between racial groups. Multivariable models were constructed adjusting for FRS, gender, pre-test likelihood and race to predict >50% stenosis.

Results:
Of the 19,105 patients studied, 86.8% were self-identified as Caucasian, 11.7% African and 1.5% Asian. Caucasians were older, more often asymptomatic, had history of peripheral vascular disease and atrial fibrillation while Africans were more often obese with history of diabetes, hypertension, stroke, congestive heart failure and chronic kidney disease (p<0.0001). On CCTA, Caucasians more often had a stenosis >50% compared to Africans and Asians (16.5% vs. 9% and 12.8%, respectively, p<0.0001). On multivariate analysis, Caucasian race remained a significant and independent predictor of >50% stenosis on CCTA in men and women, with incremental value over FRS and pre-test likelihood (Table).

Conclusions:
Risk factors and extent of CAD differ significantly among ethnicities. In this large population, race/ethnicity was an independent predictor of significant CAD on CCTA, suggesting that it should be considered in risk assessment schemes.
Abstract 17133: Cardiac Steatosis Detected in Hypertrophic Cardiomyopathy, Dilated Cardiomyopathy and Aortic Stenosis
Authors: Suttie Joseph J , Dass Sairia , Bull Sacha , Holloway Cameron , Banerjee Rajarshi , Cox Pete , Pitcher Alex , Franco Belen Rial , Francis Jane , Schneider Jurgen , Robson Matthew , Watkins Hugh , Myerson Saul , Neubauer Stefan
Published: April 2024

BACKGROUND
The failing heart is characterised by impaired myocardial energetics and a compensatory shift from fatty acid to glucose metabolism. Cardiac steatosis has been implicated in ventricular contractile dysfunction, hypertrophy, inflammation and arrhythmias.Therefore we assessed cardiac steatosis using 1H magnetic resonance spectroscopy in hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM, EF35 mmHg, LVEF>45%).

METHODS
75 prospectively enrolled subjects (15 DCM, LVEF34±15%; 17 HCM, LV mass 165±42g; 14 AS, gradient 44±2 mmHg and 29 normal volunteers) were scanned at 3T.1H magnetic resonance spectroscopy (MRS) was used to quantify myocardial lipid/water content(%) and 31P MRS to measure the phosphocreatine/adenosine triphosphate (PCr/ATP) ratio in the same region of the mid-ventricular septum. LVEF was assessed using cine imaging and tagging was used to assess global circumferential strain (% deformation normal -19±2; reduced contraction between -16 and 0%).

RESULTS
All subjects were well matched between cohorts for BMI, fasting glucose and total cholesterol (26±4 kg/m2, 5.0±0.6mmol/l, 5.1±1.2 mmol/l, p<0.05). Cardiac lipid content was elevated in all patientcohorts compared with normal volunteers (HCM 0.7±0.4; DCM 0.7±0.3; AS 0.7±0.6 vs normals 0.33±0.2% lipid/water, p<0.01 for all). PCr/ATP ratios were also impaired in all patientgroups (HCM 1.6±0.2; DCM 1.7±0.2; AS 1.7±0.2 vs normals 2.1±0.2, p<0.01 for all).Peak systolic circumferential strain was impaired in HCM (-16±2%, p<0.01) and DCM (-14±3%, p<0.01) compared to normals (-19±2%) but unchanged in AS (-18±2%).

CONCLUSION
Cardiac steatosis occurs in HCM and DCM in the presence of impaired energetics and abnormal contractile function andin patients with AS in the presence of preserved global contractile function. This suggests a potential role for cardiac steatosis as a novel biomarker and mechanism inboth early and advanced non-ischemic cardiac disease.
Abstract 17145: Ventricular-Specific Deletion of Liver Kinase B1 Fails to Produce Cardiomyopathy and Atrial Fibrillation Associated with Pan-Cardiac Deletion of Liver Kinase B1
Authors: Ross Jenna L , Palmeri Monica , Zaha Vlad G , Young Lawrence H
Published: April 2024

Liver kinase B1 (LKB1) is a serine/threonine kinase that is the major upstream kinase for AMP-activated protein kinase, but also appears to have additional actions regulating cardiac growth and development. In order to assess the functional consequences of LKB1 deletion on ventricular structure and function, we compared pan-cardiac LKB1 knockout (MHC Cre-LKB1flox/flox) with ventricular-specific LKB1 knockout (MLC2v Cre-LKB1flox/flox) and control mice (LKB1flox/flox). LKB1 mRNA was reduced by 91% in MHC Cre-LKB1flox/flox ventricles and 84% in MLC2v Cre-LKB1flox/flox ventricles; LKB1 protein was reduced by 95% in both RV and LV from MHC Cre-LKB1flox/flox mice and by 87% in MLC2v Cre-LKB1flox/flox mice. LKB1 expression in left atrial (LA) was normal in MLC2v Cre-LKB1flox/flox, but was reduced by 85% in MHC Cre-LKB1flox/flox. MHC Cre- LKB1flox/flox mice developed early onset atrial fibrillation (2 weeks) in contrast to MLC2v Cre-LKB1flox/flox and control hearts, which showed no arrhythmia. MHC Cre-LKB1flox/flox hearts had LA enlargement vs. MLC2v Cre-LKB1flox/flox vs. LKB1flox/flox (2.53±0.13 mm vs. 1.59±0.21 mm vs.1.61±0.12 mm, n=5-11, p<0.05). In addition, left ventricular (LV) wall thickness was greater (p<0.05) in MHC Cre-LKB1flox/flox (0.91±0.03 mm) vs. MLC2v Cre-LKB1flox/flox (0.71±0.02 mm) vs. LKB1flox/flox (0.69±0.02 mm, p<0.05). MHC Cre-LKB1flox/flox also had decreased LV ejection fraction (LVEF) of 30.9±1.5% vs. MLC2v Cre-LKB1flox/flox (48.5±2.7%) vs. LKB1flox/flox (46.8±3.1%, p<0.05). Electron micrographs of MHC Cre-LKB1flox/flox ventricles showed alterations in gap junction formation and a loss of mitochondrial integrity; however, both MHC Cre-LKB1flox/flox and MLC2v Cre-LKB1flox/flox hearts appeared normal. Thus, pan-cardiac deletion of LKB1 leads to atrial fibrillation, LV hypertrophy and LV dysfunction, which do not occur with ventricular specific LKB1 deletion.
Abstract 17152: Prophylactic Left Cardiac Sympathetic Denervation for Patients with Long QT Syndrome and Beta Blocker Intolerance
Authors: Harris Katy M , Moir Christopher , Ackerman Michael J
Published: April 2024

Introduction:
Long QT Syndrome (LQTS) is a potentially lethal, but highly treatable cardiac channelopathy. Current treatment options include pharmacotherapy (mostly beta blockers), device therapy (mostly implantable cardioverter defibrillators (ICDs)), and/or left cardiac sympathetic denervation (LCSD) with the majority of patients requiring only beta blocker therapy. However, beta blockers are not without side effects and beta blocker intolerance can have a profoundly negative effect on a patient's quality of life. Heretofore, a prophylactic ICD has been utilized for the patient with LQTS who can not tolerate high dose beta blocker therapy. Here we examined the role of a prophylactic LCSD rather than an ICD for the LQTS patient with beta blocker intolerance.

Methods:
In this IRB-approved study, we retrospectively reviewed the electronic medical record for 58 patients (28 male (48%), mean age at diagnosis 9.6 ± 9 years (yrs), mean baseline QTc 524 ± 73 ms, 93% genotype positive) with LQTS who underwent LCSD at our institution from November 2005 through May 2011 (mean age at LCSD 14.0 ± 9.8 yrs).

Results:
Out of 58, 19 patients (33%; 15 female (79%) had LCSD as primary prevention because of beta blocker intolerance and were older at LQTS diagnosis (15.1 ± 8 vs 7.0 ± 9 yrs;.p=0.001), older at LCSD (20.5 ± 8 vs 10.9 ± 9 yrs; p<0.001), and had a shorter baseline QTc (493 ± 32 vs 539 ± 82 ms; p = 0.004) compared to the other 38 patients. Post-LCSD, 5/19 (26 %) had QTc-shortening of >30ms. With an average follow-up of 1.3 ± 0.8 yrs, none of these patients have experienced a post-LCSD cardiac event even though 7/19 (37%) had at least 1 LQTS-associated cardiac event. Qualitatively, there has been a dramatic improvement in quality of life following LCSD with subsequent decrease in beta blocker dose in 13 or discontinuation of beta blockers altogether in 5.

Conclusions:
Prophylactic LCSD may provide a beta blocker-reducing or even sparing strategy without increasing risk in carefully selected patients. However, LCSD should not be viewed as curative or an ICD-alternative for high-risk patients. Among appropriately selected patients who are failing to tolerate beta blocker therapy, LCSD may be an acceptable, quality of life improving alternative to an ICD and its associated comorbidities.
Abstract 17161: Bradycardia Elicits a Secondary Cai Elevation During the Action Potential (AP) Plateau Which is Spatially Heterogeneous, Prolongs AP Durations (APD) Further, Enhances Dispersion of Repolarization (DOR) and May Explain the Arrhythmogenic Properties of Bradycardia
Authors: Kim Jong , Nemec Jan , Papp Rita , Salama Guy
Published: April 2024

Introduction:
Bradycardia is known to prolong APD and DOR and is a factor that promotes arrhythmia in long QT type 2. In numerous conditions, spontaneous Ca
2+
release from sarcoplasmic reticulum has been shown to trigger early afterdepolarizations, ectopic activity that initiate arrhythmias, but the interplay between secondary Ca
2+
elevation (SCE) and membrane excitability has not been demonstrated in bradycardia.

Objectives:
To correlate voltage-depolarization during the AP plateau to SCE during bradycardia.

Methods:
Dual optical mapping of intracellular calcium transient (CaT) and AP was performed in Langendorff perfused rabbit hearts. After AV node ablation, CaT and AP dynamics were investigated at physiological (120 beats per minute (bpm)) and slow heart rate (50 bpm).

Results:
Upon changing HR from 120 to 50 bpm, APD gradually increased with a time-constant of 53.8±8.9 s, consistent with clinical QT measurements. The shift from 120 to 50 bpm elicited SCE during the AP plateau that was a) regionally heterogeneous, b) associated with enhanced depolarization of the AP plateau and was reversed by pacing at 120 bpm. Regional differences of SCE at 50 bpm were significantly increased (P<0.01, n=7) and were correlated with dispersion of APD (r=0.9277±0.03, n=7). SCE and APD prolongation were more pronounced at the base of right ventricles than the apex of left ventricles (P<0.01, n=7) (Figure). Suppression of SCE with K201 (1 µM/L) (to stabilize RyR2) reduced APD (P<0.01, n=5) and DOR (P<0.02, n=5). The molecular basis of the spatial distribution of SCE is currently being correlated to the intrinsic distributions of Ca
2+
handling channels and transporters (Cav1.2α, RyR2, NCX and SERCA2a)

Conclusion:
These data show for the first time that bradycardia elicits SCE which contributes to AP prolongation and its spatial heterogeneity increases DOR. These changes explain why bradycardia is a critical factor to trigger Torsade de Pointes in LQT2.
Abstract 17203: Prevalence of Low Levels of High-Density Lipoprotein Cholesterol (HDL-C) at Presentation in Acute Coronary Syndromes (ACS) and its Relation to In-Hospital Mortality: Results from the NCDR®
Authors: Acharjee Subroto , Roe Matthew T , Amsterdam Ezra A , Holmes DaJuanicia , Boden William E
Published: April 2024

Background:
Despite profound advances in medical and procedural therapy, significant residual risk persists for in-hospital mortality among patients admitted with ACS. Low HDL-C, a known independent risk predictor for increased cardiovascular events, may modulate risk in ACS patients.

Methods:
We evaluated baseline HDL-C levels among 98,276 non-ST-elevation MI patients from the NCDR ACTION-GWTG registry enrolled from 490 U.S. hospitals between January 2007 and December 2010. Clinical characteristics, treatments, and in-hospital outcomes were analyzed by quartiles of HDL-C measured during hospitalization. Using the highest quartile as referent, hazard ratios were obtained for in-hospital mortality using multivariable risk adjustment.

Results:
Almost half of the patients in the examined cohort had presentation HDL-C levels lower than or equal to the median (36.9 mg/dL). Patients in lower HDL-C quartiles were younger, more often male, white, smokers, obese, diabetic and had greater rates of prior MI, PCI, CABG and revascularization (P <0.0001) compared to those in higher HDL-C quartiles. Use of medical therapy (aspirin, clopidogrel, beta-blockers, ACE inhibitors or ARBs, statins and other lipid-lowering agents) at home was greater among patients with lower HDL-C (P = 0.0002 for statins, <0.0001 for others). Significantly greater in-hospital mortality was noted with decreasing HDL-C quartiles in the overall cohort. Among patients in the lowest HDL-C quartile, a 16% greater risk of in-hospital death was noted compared to their counterparts in the highest HDL-C quartile (P = 0.0073) (Figure 1).

Conclusion:
Low levels of HDL-C at presentation was common among this national contemporary “real-world” cohort of patients admitted with non-ST-elevation ACS. Very low HDL-C levels (≤ 30 mg/dL) at presentation represented an adverse prognostic factor and was associated with higher in-hospital mortality.