bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 17057: Long Term Outcomes in Coronary Artery Disease Patients With Acetylsalicylic Acid Sensitivity Undergoing a Novel Desensitization Protocol
Authors: Rossini Roberta , Musumeci Giuseppe , Mihalcsik Laurian , Nijaradze Tamar , Sirbu Vasile , Fiocca Luigi , Baroni Matteo , Inashvili Ana , Valsecchi Orazio , Guagliumi Giulio , Gavazzi Antonello , Angiolillo Dominick J
Published: April 2024

Purpose:
Aspirin therapy is the cornerstone of treatment in patients (pts) with coronary artery disease, particularly those undergoing percutaneous coronary intervention (PCI). The aim of this study was to test the safety and efficacy of a new standard desensitization procedure, using escalating low doses of aspirin in pts with acetylsalicylic acid sensitivity.

Methods:
Out of 3080 pts undergoing coronary angiography, seventy-seven had a history of aspirin sensitivity (2.5%). A history of cutaneous reactions (urticaria and/or angioedema) was reported in 76% of pts, respiratory sensitivity (asthma and/or rhinitis) in 21.5%, whereas 2.5% had a history of anaphylactic shock. All pts underwent the desensitization procedure: six sequential doses of aspirin (1, 5, 10, 20, 40, and 100 mg) administered orally at predefined intervals, with the procedure lasting 5.5 hours. None received pretreatment with antihistamines or corticosteroids. Blood pressure, pulse, cutaneous, nasoocular, or pulmonary reactions were monitored until 4 hours after the procedure. Pts were followed-up for 18.1± 6.3 months. Major adverse cardiac events (MACE), defined as death, repeat revascularization and stroke were recorded.

Results:
The desensitization procedure was successful in 71 pts (92.2%). No serious adverse reactions occurred: 3 pts with history of idiopathic urticaria developed cutaneous reaction, 2 pts (with frequent asthma attacks) experienced shortness of breath associated with bronchospasm, and 1 pt had shortness of breath without bronchospasm. All reactions were immediately resolved with corticosteroids and antihistamines. All pts but 15 (19.4%) underwent PCI (1.8 stent/pt, DES 75.5%, multivessel PCI 31.4%) and were discharged on dual antiplatelet therapy. At follow-up, aspirin was maintained in 92.9% pts. None of the discontinuations were due to allergic reaction. The incidence of MACE was 6.5% (1 non-cardiac death and 4 repeat revascularizations). None of the pts experienced stent thrombosis.

Conclusions:
This novel desensitization procedure seems to be safe and effective. Complex PCI procedures can be performed also in such pts, without increasing the risk of stent thrombosis.
Abstract 17098: Blood Pressure Response to Controlled Diesel Exhaust Inhalation in Human Subjects is Modified by Functional Variation in TRPV1
Authors: Cosselman Kristen , Krishnan Ranjini M , Oron Assaf P , Peretz Alon , Larson Tim V , Kaufman Joel D , Jansen Karen
Published: April 2024

Background:
Exposure to traffic-related air pollution is associated with increased risk of cardiovascular disease and mortality. Diesel exhaust (DE) inhalation is a model exposure, and we hypothesize that pollutants trigger acute cardiovascular events via neurogenic processes. We evaluated blood pressure (BP) response to DE and whether the effect was modified by genotype for the transient receptor potential receptor, vanilloid type 1 (TRPV1), a non-selective cation channel expressed in the lung and activated by noxious chemical stimuli. The t allele for the TRPV1 single nucleotide polymorphism rs8065080 at position 585 results in Ile substituting for Val, and has been associated with reduced nociception.

Methods:
Forty-seven non-smokers, age 18-49 with no prior cardiovascular or pulmonary disease, underwent controlled exposures to each condition [DE at 200 μ g/m
3
PM
2.5
and filtered air (FA)] for 120 minutes in a crossover experiment. Exposures were double-blind, randomized to order, and separated by at least 2 weeks. We measured BP pre-exposure, at 5 time points during exposure, and 3, 5, 7 and 24 hours from exposure start. We analyzed pressure change (from pre-exposure values) for each exposure to determine the difference between DE and FA.

Results:
Compared with FA, systolic blood pressure (SBP) increased at all time points measured during and after DE exposure (p=0.004); mean effect peaked 30 to 90 minutes after exposure began (3.9 mmHg, p=0.01). No effects were observed for heart rate or diastolic BP. SBP response varied by
TRPV1
Ile585Val genotype, with t/t subjects showing the lowest SBP response to DE (see Figure).

Conclusion:
DE exposure was associated with a rapid increase in SBP, with a reduced response in subjects with the Ile-Ile variation of TRPV1. This suggests that TRPV1 activation by a component of DE may be a key step explaining observed vascular effects of air pollution, perhaps by initiating autonomic signaling or neurogenic inflammation.
Abstract 17101: Mitochondrial Ros Activates Golgi Resident eNOS in the Vascular Endothelium Following Hypoxia-Reoxygenation (h/r): Role of Oxygen Sensing in Cellular Adaptation
Authors: Varadharaj Saradhadevi , Druhan Lawrence J , Zweier Joe R , Chen Chun-An , Velayutham Murugesan , Wang Tse-Yao , Liu Xiaoping , Soorappan Rajasekaran N , Zweier Jay L
Published: April 2024

Adaptation to hypoxia (H) is achieved by the cell's ability to sense alterations in O
2
and respond accordingly. Changes in cellular oxygenation trigger signaling pathways with reactive oxygen species (ROS) and nitric oxide (NO) playing critical roles. ROS and NO also regulate the tissue inflammation and injury associated with ischemia/reperfusion as occurs in unstable coronary syndromes. While moderate periods of H followed by reoxygenation (R) can induce vascular protection, questions remain regarding how this occurs. Therefore, studies were performed to elucidate the mechanisms responsible for protection of vascular endothelium following H/R with particular focus on ROS-induced NO production and its downstream targets, in endothelial cells (BAECs). We hypothesize that mitochondrial ROS-mediated activation of Golgi eNOS-NO is integral in inducing the vasculoprotective mechanisms critical for cellular adaptation to H/R. BAECs were subjected to H (2 hr) and R (10 - 60 min). H triggered clustering of mitochondria toward nuclei and upon R perinuclear ROS production was seen (Fig). This was associated with activation of Golgi resident ser/thr kinase (Akt) as evidenced by the presence of pAkt in the Golgi fraction that in turn activates Golgi resident eNOS. The H/R-induced activation of Golgi eNOS was attenuated by pretreatment with complex III inhibitor, myxothiazol confirming the role of mitochondrial ROS. NO produced at the vicinity of the Golgi inhibited vWF release. Thus, in response to R, eNOS in endothelial cells is activated due to serine 1179 phosphorylation within the Golgi by mitochondrial ROS-induced activation of PI3K/Akt. A discrete intracellular NOS pool is activated by H/R that serves to inhibit exocytosis of WPB that in turn can decrease inflammation and thrombosis. This knowledge of how cells sense and adapt following hypoxia provides a framework to understand the role of H/R in cardiovascular diseases that can be ultimately used toward treatment.
Abstract 17115: Bayesian Analysis of Risk Stratification Strategies in Non-ST Elevation Acute Coronary Syndromes
Authors: Lang Christopher , Arora Rohit
Published: April 2024

Background:
Early stratification of patients with acute coronary syndromes is a critical aspect of contemporary cardiology. Risk scores are often used to help identify patients likely to benefit from early interventional strategies, based on expected short term prognosis. Additionally, understanding long term benefit from utilization of risk scores to guide intervention, as well as differential benefit of particular risk scoring strategies can help guide clinical application and management. To investigate this, we compared the PURSUIT, GRACE and TIMI risk scores for NSTEMI, evaluating mortality and non-fatal MI at one year, using Bayesian statistical methods.

Methods
: Using published retrospective data of 460 patients, Bayesian posterior probabilities were calculated. Risk scoring systems were stratified into high and low risk groups, based on either PURSUIT score of 14, TIMI score of 3, or a GRACE score of 133. Within these groups, early revascularization or conservative management was compared based on mortality or non-fatal MI events at 1 year. Posterior probabilities as well as probabilities of greater than 20% benefit of using a risk scoring system were calculated.

Results:
Based on the study results, the Bayesian posterior probability for the primary combined endpoint of death and nonfatal MI for the low risk group are 59.3% for PURSUIT, 68.8% for TIMI, and 70.1% for GRACE. The Bayesian posterior probabilities for the high risk group are 73.1% for PURSUIT, 58.6% for TIMI, and 74.0% for GRACE. Probabilities of >20% predictive benefit and sensitivity analysis was calculated, and have similar trends to the posterior probabilities.

Conclusions:
Bayesian analysis suggests that the using low GRACE and TIMI scores for conservative management have a greater likelihood of clinical benefit than the PURSUIT risk scale. The GRACE and PURSUIT scores have a clinically relevant benefit in predicting patients deemed to be high risk undergoing early revascularization compared to the TIMI score. Overall, the GRACE score was demonstrated to be the most robust scoring system for guiding both interventional and conservative management strategies for 1 year outcomes, and should be applied more widely.
Abstract 17117: In Vitro Monitoring of Microbubble Mediated Clot Dissolution Using Optical Coherence Tomography (OCT)
Authors: Leeman Jonathan E , Kim Jong S , Kagemann Larry , Yu Francois , Chen Xucai , Pacella John J , Schuman Joel S , Villanueva Flordeliza S , Kim Kang
Published: April 2024

Background:
Thrombolysis using ultrasound (US) induced destruction of systemically injected microbubbles (MBs) is a potential targeted treatment for acute myocardial infarction or ischemic stroke. The physical mechanisms underlying MB mediated clot lysis are incompletely elucidated, partly due to limitations in methods to characterize morphologic and volumetric changes in a thrombus resulting from MB destruction. Here, we explore possibilities for 3D quantitative assessment of sonothrombolysis using optical coherence tomography (OCT), a high resolution imaging modality.

Methods:
Thrombi were formed in polyethylene tubing (1.67 mm i.d.) from recalcified porcine blood using silk suture as a nidus for thrombosis. Lipid shell MBs suspended in saline and tissue plasminogen activator (rt-PA, 3 μ g/ml) were perfused through the tube (22 μ l/min, 2x107 MBs/ml) using a syringe pump while US pulses (1 MHz, 1.0 MPa, 100 cycles) were delivered over 30 min to the clot from a single element transducer every 5 sec to ensure MB replenishment between destructive pulses. 3D OCT images of clots were obtained before and after US treatment, rt-PA alone, or saline alone (n=3/condition). Clot volume was measured using clot boundary determination by thresholding pixel intensity of each cross-sectional OCT image.

Results:
Thrombi treated with US + MBs + rt-PA decreased in volume by 55.7% (0.02 mm3; p=0.02). rt-PA alone resulted in a 25.6% (0.009 mm3; p=0.39) decrease in volume and treatment with saline alone did not change clot volume (0.003 mm3; p=0.94). OCT images qualitatively showed greatest change in clot shape and volume in regions closest to the source of US (Fig 1).

Conclusion:
3D OCT can quantify thrombolysis. As expected, the addition of US and MBs enhanced the lytic effect of rt-PA. OCT imaging may reveal the physical effects of contrast US on thrombus structure, thereby yielding insights into mechanisms of sonothrombolysis that can be used to optimize treatment regimens.
Abstract 17160: Vagolytic Therapy Prevents CPVT Induction in Casq2-KO Mice
Authors: Faggioni Michela , Hwang Hyun Seok , van der Werf Christian , Knollmann Bjorn C
Published: April 2024

Background:
Cathecolaminergic polymorphic ventricular (CPVT) is characterized by an increase in the ventricular arrhythmia burden with a gradual rise in the heart rate. However it has been observed that in young patients reaching maximum heart rate during exercise test CPVT may paradoxically be abolished. In addition, we previously reported that in isolated Casq2-/- hearts, a CPVT mouse model, an increase in heart rate can prevent the induction of CPVT. Here we hypothesize that increasing heart rate by vagolytic therapy can prevent CPVT in vivo.

Methods:
Surface ECGs were recorded from 11 anaesthetized Casq2-/- mice (4 males and 7 females; 24±2 month of age). Vagolytic therapy was performed with an i.p. injection of 0.5mg/kg of atropine. After the heart rate increase had reached its plateau (~10 min post atropine), catecholamine challenge was carried out with 1.5mg/kg isoproterenol (Atr/ISO group). The incidence of PVC and VT was analyzed and compared with that obtained in the same mice after injection of only 1.5mg/kg of isoproterenol (ISO group).

Results:
Administration of atropine in Casq2-/- mice increased the heart rate by 23% (±4%) but did not induce any arrhythmia (Fig. A). On the other hand, ISO alone, as expected, caused PVCs in all mice and VT episodes in 4/11 mice. Pretreatment with atropin significantly reduced PVC incidence during ISO challenge (Atr/ISO: 1.13±0.46 PVC/min vs. ISO: 4.93±1.74 PVC/min, p<0.05) (Fig. B) and completely prevented VT induction. Conversely, slowing the sinus heart by infusion of the muscarinic agonist carbachol significantly increased the incidence of ISO-induced CPVT in isolated perfused Casq2-/- hearts (n = 20 hearts, p<0.01).

Conclusions:
A catecholamine-independent increase in the sinus heart rate, obtained by muscarinic receptor block with atropine, is sufficient to protect Casq2-KO mice from CPVT during catecholamine challenge in vivo.
Abstract 17183: Cardiac Magnetic Resonance with Late Gadolinium Enhancement is a Marker of Active Inflammation in Constrictive Pericarditis Patients: Imaging and Biochemical Correlation
Authors: Alraies M Chadi , AlJaroudi Wael , Zurick Andrew O , Shabrang Cyrus , To Andrew C , Yarmohammadi Hirad , Dahiya Arun , Flamm Scott D , Klein Allan L
Published: April 2024

Background:
The diagnosis of constrictive pericarditis (CP) is problematic and there is limited data on the role of cardiac magnetic resonance imaging (CMR) with late gadolinium enhancement (LGE) and inflammatory markers in the diagnosis and management of CP.

Hypothesis:
We sought to study the correlation of CMR LGE and inflammatory markers with disease activity of CP and response to treatment.

Methods:
We identified 59 patients (mean age 52±10 years, 64% female) with confirmed medically managed CP between 2007 and 2010 who had serial CMR and high sensitivity C-reactive protein (hs-CRP) at baseline and follow-up (26±16 weeks).

Results:
At baseline, LGE was absent in 9 patients (18%) (Group 1) and present in 50 (84%) (Group 2). Patients in Group 2 had worse heart failure symptoms, higher baseline hs-CRP levels, and were more likely to be treated with prednisone and colchicine (Table 1). On follow-up CMR, none of the patients in Group 1 demonstrated LGE while the patients in Group 2 showed reduction. There was a significant decrease in heart failure symptoms and hs-CRP in Group 2 (P=0.01).

Conclusion:
In patients with CP, CMR can be used as a measure of ongoing inflammation and its presence correlates with disease activity. It can be performed serially in CP patients to follow disease progression and resolution with medical management, thus avoiding unwanted referrals to surgery.
Abstract 17216: Aquaporin-1 is Required for Vascular Differentiation of Human Induced Pluripotent Stem Cells Following Exposure to Glucose-Induced Hyperosmolarity
Authors: Madonna Rosalinda , Shelat Harnath , De Caterina Raffaele , Geng Yong-Jian
Published: April 2024

Background and objective:
Diabetic hyperglycemia increases plasma osmolarity, leading to adaptive cell reponses. Aquaporin-1 (AQP1) is induced by hyperosmolarity and plays a role in the vascular permeability. Induced pluripotent stem (iPS) cells offer a disease-relevant cellular model for the interplay of risk factors in the vascular complications of diabetes. We tested the hypothesis that glucose-induced hyperosmolarity promotes angiogenesis in human iPS cells through activation of AQP1 and downstream osmosignaling pathway, thus orchestrating cell sprouting and migration.

Methods and results:
Human iPS cells were generated from skin fibroblasts by lentiviral transduction of four reprogramming factors (Oct4, SOX2, Klf4 and c-Myc). Following 3 weeks compact refractive embryonic stem cell-like colonies emerged. All the iPS cell colonies expressed OCT4, SSEA3, SSEA4 and SOX2, characteristic of successful dedifferentiation. After reprogramming, iPS cells were transfected with siRNA-AQP1 or scrambled controls, and exposed to 5.5 mmol/L glucose (normoglycemia), high glucose (HG) at 12.5, 25 and 45 mmol/L or with high mannitol (HM) at 12.5, 25 and 45 mmol/L for 24-72 hours. Exposure to either HG or HM increased expression of AQP1 and tonicity enhancer binding protein (TonEBP) while decreasing the iPS cell numbers. In iPS cells, AQP1 could be co-immunoprecipitated with β-catenin. HG and HM strongly induced the expression of β-catenin (n=3, p<0.001 vs normal glucose by ANOVA). Under these conditions, proteins co-immunoprecipitated with anti-AQP1 and β-catenin showed increased ratio of F-actin vs G-actin (n=3, p<0.01 vs normal glucose by ANOVA). iPS cells formed bundles in methylcellulose matrix and tubing networks in matrigel, especially when they were exposed to HG and HM (HG 2.8±0.2 fold; HM 3.3±0.5 fold; n=3, p<0.01 by ANOVA. SiRNA to AQP1 reverted the inducing effects of HG and HM on β-catenin expression, actin polymerization and angiogenic activities.

Conclusions:
The hyperosmolarity serves as a biophysical factor that promotes angiogenesis in human iPS cells. This effect may occur through an AQP1-associated cytoskeleton remodeling. Targeting the osmosignaling pathway offers a novel strategy to reduce vascular complications of diabetes.
Abstract 17239: Mechanisms of Vascular Oxidative Stress Induction of Obesity
Authors: Youn Ji- Youn , Lob Henrich , Siu Kin L , Oak Jeong-Ho , Harrison David G , Cai Hua L
Published: April 2024

The present study investigates whether and how vascular reactive oxygen species (ROS) induce obesity and insulin resistance/metabolic syndrome. Epidemiologically, pathological conditions like hypertension and hypercholesterolemia associated with obesity, and these diseases promote vascular ROS production. It has been thought that obesity is causal in these conditions. We instead propose that vascular ROS may play a causal role in obesity by promoting inflammation, adipogenesis and exercise intolerance. Wild-type (WT) mice and mice having excessive vascular ROS production (smooth muscle-specific overexpression of p22phox, a key component of NADPH oxidase, tg
sm/p22phox
, body weight (BW) elevated modestly but significantly at baseline) were fed high-fat diet for 6 weeks. Intriguingly, tg
sm/p22phox
mice developed exaggerated obesity. The BW increased from 32.16±2.34 g in the 6 mo old tg
sm/p22phox
mice to 43.03±1.44 g (vs. 30.81±0.71 g to 37.89±1.16 g in the WT mice). The percentage of increase is 34±3.35% vs. 23±3.08% respectively (p<0.01). Fat mass was also significantly further increased. Glucose tolerance tests indicate a more severe insulin resistance phenotype in the tg
sm/p22phox
mice, which was associated with reduced HDL cholesterol and increased leptin levels. These animals also had impaired spontaneous activity, increased ROS production and mitochondrial dysfunction in skeletal muscle. Oral administration with antioxidant ebselen prevented weight gain and insulin resistance in high-fat fed tg
sm/p22phox
mice. In mice having deficient vascular ROS production however (p22phox
loxp/loxp
crossed with mice expressing Cre recombinase driven by the tamoxifen-inducible smooth muscle myosin heavy chain promoter, tg
smmhc/cre
mice), high-fat feeding failed to induce weight gain and leptin resistance. These vascular p22phox knockout mice also had reduced T cell infiltration of perivascular fat. In conclusion, these data seem to provocatively implicate that vascular NADPH oxidase-derived ROS induce obesity and insulin resistance/metabolic syndrome. To our knowledge this represents the first evidence that vascular ROS play a causal role in the development of obesity and insulin resistance/metabolic syndrome.
Abstract 17271: An Alternatively Spliced Kcnh2 Variant Restores Cardiac Repolarization in a Model of Long QT Syndrome: Implications for Phenotypic Variation in Human Long QT Syndrome
Authors: Jou Chuanchau J , Bian Jiantao , Lopez Angelica , Su Zhi , Tristani-Firouzi Martin
Published: April 2024

Introduction:
Mutations in
KCNH2
(
HERG1
, LQT-2) are a common cause of Long QT Syndrome (LQTS). Despite sharing the same mutation, affected family members often display marked differences in disease severity, including risk of sudden cardiac death. The genetic basis of this phenotypic variation is not known. We previously validated a zebrafish model of human LQT-2. Here, we use a repolarization-deficient zebrafish mutant (
breakdance
,
bre
) to probe the molecular basis of phenotypic variation.

Methods:
Bre
is due to a recessive
kchn2
mutation (I59S) within the cytoplasmic N-terminal domain. 5’-RACE and qPCR were used to clone and quantify novel N-terminal variants from zebrafish and human heart. Biophysical properties of zebrafish and human variants were characterized using voltage- and patch-clamp techniques.
In vivo
functional effects were determined by over-expressing the variants in knch2-null zebrafish embryos, and assaying for ability to restore ventricular repolarization by characterizing phenotypes of the embryonic heart at 48 hour-post-fertilization.

Results:
We identified a novel, alternatively spliced N-terminal variant,
kcnh2 1c
, with in-frame deletion of Exon 2-6. The
1c
variant constitutes ~40% of the
kcnh2
transcript, and is expressed 4X greater in atrium than ventricle. The
1c
variant deletes the disease-causing mutation, I59S. Activation of kcnh2 1c channels is similar to WT, but deactivation is accelerated.
In vivo
,
kcnh2 1c
functions similar to WT, and is able to partially restore ventricular repolarization in knch2-null zebrafish. We identified 2 novel N-terminal variants in human heart that are also differentially expressed between the atrium and ventricle. Biophysical function of the human variants is similar to zebrafish 1c.

Conclusion:
Kcnh2 1c
modulates cardiac repolarization in the
bre
mutant by excising the disease-causing mutation. Approximately 30% of LQT-2 mutations localize to the N-terminus, and are subject to alternative splicing. By excising N-terminal mutations human 1c variants may modulate repolarization and influence phenotypic expression in LQTS.
Abstract 17295: Predictors of Adverse Events in Patients with Postpericardiotomy Syndrome Following Cardiac Surgery
Authors: Alraies M Chadi , Tamarappoo Balaji , AlJaroudi Wael , Shabrang Cyrus , Klein Allan L
Published: April 2024

Background:
Post-pericardiotomy syndrome (PPS) is relatively common and troublesome complication following cardiac surgery. Criteria for the diagnosis of PPS have been suggested in previous studies. It can occur a few days to several weeks following cardiac surgery and patients who fail medical therapy with anti-inflammatory medications are at risk for future adverse events.

Hypothesis:
To identify clinical risk factors that may predict which patients with PPS may have a high likelihood of experiencing adverse events which include: recurrent pericarditis, pericardial effusion, and need for pericardiocentesis, pericardial window, or pericardiectomy.

Methods:
We examined 239 consecutive patients who developed PPS after cardiac surgery from 2007-2010 (table). Logistic regression was used to examine univariate predictors of adverse events. Significant univariate predictors were added to the multivariable model in a step-wise fashion to identify the most significant predictors of adverse events among individuals with PPS.

Results:
Out of 239 patients (mean age, 58±16, 72% male) with PPS (mean time to diagnosis 27±18 days), 75 (31.1%) patients experienced significant adverse events. Younger age, pericardial effusion size, and post-operative NYHA class III-IV were significant univariate predictors (p<0.05). The combined use of NSAIDs, colchicine, and corticosteroids (triple-therapy) was associated with a reduced risk of adverse events. In a multivariable model, triple-therapy was a negative predictor but younger age, effusion size, and pericardial constriction were associated with increased risk of developing adverse events (p<0.05).

Conclusions:
This study identifies younger age, post-operative constriction, and failure to use triple-therapy as predictors of increased risk of adverse events and pericardial intervention among patients with PPS following cardiac surgery.
Abstract 173: Cardiogenic Shock in Cardiac Arrest No Longer a Contraindication for Therapeutic Hypothermia
Authors: Kebed Kalie Y , Sharkey Scott W , Unger Barbara T , Feldman David S , Schwartz Robert S , Poulose Anil K , Burke M Nicholas , Mooney Michael R
Published: April 2024

Introduction:
Therapeutic hypothermia (TH) is neuroprotective and increases survival in cardiac arrest patients. Cardiac arrest is often seen in the setting of acute myocardial infarction (MI), and cardiogenic shock is a known poor prognostic factor.

Methods:
“Cool It” is a comprehensive TH protocol integrated into a regional STEMI network. From Feb 2006 to July 2010, 192 consecutive cardiac arrest patients who remained unresponsive following return of spontaneous circulation were enrolled in the Cool It protocol, regardless of initial rhythm or hemodynamic status. We hypothesize patients in cardiogenic shock secondary to MI treated with primary PCI will have greater survival and neurologic outcome than those without concurrent MI.

Results:
Of the 192 patients, 77 (40.1%) were in cardiogenic shock. Survival with favorable neurologic outcome (CPC 1 or 2) was poorer in cardiogenic shock patients than non-cardiogenic shock patients, 34/77 (44.2%) vs. 60/115 (52.2%) p=0.28, but not statistically significantly. Of those in cardiogenic shock, 32 (41.6%) had ST elevation on EKG, and a total of 42 (54.6%) were found to have an acute occlusion by angiography. Culprit arteries were: LAD n=19 (45.2%), RCA n=14 (33.3%), CMX n=5 (11.9%), L main n=4 (9.5%), and 39/42 (92.9%) and were successfully reperfused and stented. For patients with cardiogenic shock, survival with favorable neurologic outcome (CPC 1 or 2) was greater in patients with concurrent MI than without MI, 21/42 (50.0%) vs. 9/35 (25.7%) p=0.03. Cardiogenic shock with LAD lesions had the greatest favorable neurologic survival compared to other lesions, 13/19 (68.4%) vs. 8/23 (34.8%) p=0.03. Non-LAD lesion cardiogenic shock had no statistically significant survival or neurologic benefit over cardiogenic shock without concurrent MI, 8/23 (34.8%) vs. 9/35 (25.7%) p=0.46.

Conclusion:
TH should be the standard of care for unresponsive cardiac arrest patients in cardiogenic shock. Patients with cardiogenic shock and concurrent LAD STEMI have improved survival and neurologic outcomes than those cardiogenic shock patients without concurrent STEMI. Cardiogenic shock should no longer be considered a contraindication to TH, especially with concurrent STEMI.
Abstract 17307: Endothelial Nitric Oxide Synthase Promotes a Shift in Adipocyte Phenotype in Diet-Induced Obesity
Authors: Sansbury Brian , Hellmann Jason , Tang Yunan , Nichol Kathie , Spite Matthew , Bhatnagar Aruni , Hill Bradford G
Published: April 2024

Obesity and diabetes are the most pressing health issues of our time. Current CDC estimates show that over two-thirds of American adults are overweight or obese and nearly 10% display frank type 2 diabetes. Although a decrease in nitric oxide (NO) bioavailability has been linked to insulin resistance, it is not known how increasing NO affects diet-induced obesity and diabetes. We hypothesized that overexpression of endothelial nitric oxide synthase (eNOS) would mitigate diet-induced obesity and insulin resistance. Mice overexpressing eNOS (eNOS
TG
) and wild-type C57BL/6 mice (WT) were placed on either 60% high fat or 10% low fat diet for six weeks. The eNOS
TG
mice showed a striking resistance to diet-induced obesity compared with WT mice, as evidenced by decreased weight gain (4.29±1.04g vs. 9.00±1.52g; n=13, p<0.05), despite nearly identical increases in plasma cholesterol and similar glucose and insulin intolerance. This resistance to obesity was further supported by the differences evident in adipocyte morphology. The mean adipocyte area of the high fat-fed eNOS
TG
mice was decreased compared with WT mice (1949±461µm
2
vs. 4022±249µm
2
n=7, p<0.05). Adipose tissue of eNOS
TG
mice also showed increased mitochondrial content compared with WT mice. Protein levels of the mitochondrial proteins cytochrome c oxidase subunit 1 and aldehyde dehydrogenase 2, as well as PGC1α and Sirt3 were increased by two fold or greater (p<0.05). However, no increase in UCP-1 levels was detected. Extracellular flux analysis of differentiated 3T3 adipocytes treated with an NO donor (DETA-NONOate) showed increases in oxidative phosphorylation, glycolysis, and fatty acid oxidation compared with untreated adipocytes (n=5, p<0.05). The triglyceride content of differentiated 3T3 adipocytes was decreased by nearly half after incubation with NO in culture. These data suggest that overexpression of eNOS prevents diet-induced obesity and promotes a shift in the adipocytes to a previously un-described phenotype characterized by increased mitochondria and fat oxidation capacity.
Abstract 17314: Free Radical-Dependent Sod2 Promoter Demethylation is Associated with Healthy Vascular Aging
Authors: Nguyen Albert , Geoffroy Steve , Phillips Michael , Thorin Eric
Published: April 2024

BACKGROUND:
Free radicals are important signaling molecules but whether they contribute to epigenetic-dependent regulation of vascular function during aging is unknown. We hypothesized that the normal metabolism-derived free radical production induces epigenetic regulations at the promoter region of antioxidant enzymes, promoting their up-regulation and thus, delays healthy age-associated vascular damage and endothelial dysfunction.

METHODS:
Mice were treated (n=12) or not (control; CTL, n=12) with the antioxidant catechin (CAT; 30mg/kg/d) from weaning to the age of 9 months (9m); 6 mice from each group were then kept untreated until the age of 12 months (12m). At sacrifice (9 or 12m), femoral arteries were isolated to study endothelial function characterized by acetylcholine (Ach)-induced dilation in pressurized (100 mm Hg) vessels, and for DNA extraction to quantify Sod2 gene promoter methylation (EpiTYPER, Sequenom). The abdominal aorta was isolated to measure mRNA Sod2 levels (qPCR). Results are mean±SEM.

RESULTS:
At 9m, Ach-induced dilation was similar in CTL (87±5%) and CAT-treated (94±2%) mice. After inhibition of NO synthase (NOS), however, Ach-induced NO-independent dilatation was reduced (P<0.05) in CTL mice (33±16%) but not in CAT-treated mice (81±9%). These differences were maintained at 12m. These functional changes suggest that normal oxidative stress impairs NO-independent compensatory dilation at 9m without further degradation at 12m. In CTL mice, Sod2 promoter methylation decreased from the age of 9 to 12m (from 16±2% to 7±1%; P<0.05); this was prevented by CAT (15±3% and 14±3%, at 9 and 12m, respectively) suggesting that free radicals lead to an epigenetic-dependent up-regulation of Sod2 expression. Accordingly, Sod2 mRNA expression was similar at 9m but greater at 12m in CTL (1.39±0.12 a.u.; P<0.05) compared to CAT-treated (0.31±0.06) mice. Hence, scavenging free radicals with CAT prevented the epigenetic-dependent up-regulation of compensatory Sod2 expression.

CONCLUSION:
Free radical-dependent Sod2 promoter demethylation is associated with healthy vascular aging; this could contribute to minimizing the rise in oxidative stress-dependant damage and delay endothelial dysfunction.
Abstract 17338: Effect of Symptom Awareness Training on Heart Failure Self-Care and Symptom Burden
Authors: Jurgens Corrine , Riegel Barbara
Published: April 2024

Symptom severity is associated with timely care-seeking among heart failure (HF) patients. Delay in responding to symptoms frequently results in escalating symptom severity by the time patients seek care. The study purpose was to test the effect of an interactive symptom training protocol on self-care, symptom burden and health provider contact.

Method:
Using a randomized controlled trial design, 46 HF patients were randomized to a symptom training protocol or usual HF education. All received a weight scale and self-care booklet. Intervention patients received interactive training on symptom recognition and use of a daily symptom graph. HF self-care was measured using the Self-Care of HF Index (SCHFI) at baseline, 3 and 6 months, higher scores indicate better self-care. HF symptom severity was measured with the HF Somatic Perception Scale (HFSPS). Scores range 0-90 with higher scores indicating higher symptom burden. Emergent calls to providers were documented by telephone interview at 1, 3 and 6 months. Self-care and symptom severity were analyzed with repeated measures ANOVA.

Results:
The sample mean age was 71.4 years,
SD
10.9, 39% female, 87% White and functionally compromised (78% NYHA III-IV). Both groups had clinically relevant improvement in SCHFI maintenance and management scores at 3 months and some further improvement in maintenance scores at 6 months, but no significant differences between groups. Despite similar SCHFI scores at 6 months, the mean HFSPS score was 50% lower in the intervention group (10.6 vs 20.4, p=.03). The intervention group initiated more contacts with health providers than the usual care group (10 vs 8).

Implications:
Patients receiving symptom training demonstrated improvement in symptom recognition ability although self-care scores were no different than those of the control group. Better symptom recognition may be responsible for increased contact with health providers by those in the intervention group.
Abstract 17407: Right Ventricular Systolic Function in Subjects with HFpEF: A Community Based Study
Authors: Mohammed Selma F , Roger Veronique L , Abou Ezzeddine Omar F , Redfield Margaret M
Published: April 2024

Background:
Pulmonary hypertension is common in HFpEF and is associated with increased mortality. Pulmonary hypertension can lead to right ventricular systolic dysfunction. However, the magnitude and prognostic significance of RV dysfunction in the HFpEF population are unclear.

Hypothesis:
RV systolic dysfunction is common in HFpEF and is associated with increased mortality.

Methods:
RV size and systolic function were assessed qualitatively (as normal or abnormal) and pulmonary artery systolic pressure (PASP) was estimated using echocardiography in 548 consecutive HFpEF subjects (Framingham criteria and EF ≥50%) from a prospective population based study (Olmsted County, Minnesota). Control group was a retrospectively identified random sample of age and sex matched hypertensive (N=360) and normotensive subjects (N=168) from Olmsted County. HFpEF group was followed for up to 5 years (median follow up 4.4 years).

Results:
See table and figure. RV enlargement and systolic dysfunction were more prevalent in HFpEF compared with age and sex matched hypertensive and normotensive controls. In HFpEF subjects with PASP above the median, RV systolic dysfunction was associated with poor survival compared with normal RV function. RV systolic dysfunction was a significant predictor of mortality even after adjustment for age and PASP in a Cox regression model (Hazard Ratio=1.4, p=0.02).

Conclusions:
In the community, RV systolic dysfunction is common in HFpEF and is associated with higher mortality. Although quantitative assessment of RV function is difficult owing to its complex geometry, qualitative assessment is feasible on the majority of subjects and provides significant prognostic information.
Abstract 17432: Influence of Smoking on Arterial Stiffness - A Racial Comparison
Authors: Menon Vivek , Poole Joseph , Veledar Emir , Morris Alanna , Patel Riyaz S , Din-Dzietham Rebecca , Coverson Dorothy , Gibbons Gary , Vaccarino Viola , Quyyumi Arshed
Published: April 2024

BACKGROUND:
Although an association between smoking and arterial stiffness has been well established, whether this varies by ethnicity remains a subject of controversy. We hypothesized that the association between smoking and increased arterial stiffness is race-specific.

METHODS:
White (n=285, 36 smokers) and black (n=317, 91 smokers) participants (mean age 50±9, 57% female) from the Morehouse-Emory Partnership to Eliminate Cardiovascular Health Disparities (META-Health) study underwent measurement of central augmentation index (CAIx), a composite measure of arterial wave reflections and stiffness using applanation tonometry (SphygmoCor, AtCor). Mixed statistical models were used to determine whether race, age, gender, glucose, lipid parameters, systolic blood pressure (SBP), triglycerides and waist circumference (WC) were predictors of change in CAIx caused by smoking.

RESULTS:
Age, gender, race, SBP, WC and smoking were found to be independent predictors of CAIx (all P<0.05). The two-way interaction (adjusted for all risk factors) between race and smoking on CAIx was statistically significant. Moreover, CAIx (corrected for heart rate at 75 beats per minute) were similar in white and black non-smokers (20.3 and 21.0, respectively), but significantly higher in black compared to white smokers (21.3 vs.26.4, p=0.027, respectively).

CONCLUSIONS:
Race is a strong predictor of the degree of change in arterial stiffness in conjunction with smoking, with black smokers having higher CAIx. There were no racial differences in non-smokers. The mechanisms by which smoking predisposes blacks to developing arterial stiffness need to be investigated.
Abstract 17457: Radiation Exposure is Incresead Through the Last Ten Years
Authors: Morrone Doralisa , Kolm Paul G , Xu Xin , Jurkovitz Claudine , Ehrenthal Deborah , Ehsanur Rahman , Weintraub William S
Published: April 2024

BACKGROUND:
Since the first percutaneous coronary intervention (PCI) numerous efforts have been made to reduce the exposure time to radiation and protect the operator against the radiation damage. Our purpose is to compare two periods of time and determine if the exposure time has changed over the years.

METHODS:
We collected all myocardial infarction (MI) procedures entered into the Cath/PCI Registry from 2006 to 2011. Our population was divided in two groups according to years of PCI (2006-2008) and (2009-2011). We used interrupted time series analysis to compare mean time of exposure between the groups. The results were adjusted according to the complications in cath lab using linear regression. Complications included tamponade, vessel dissection and bleeding at the entry site during the procedure.

RESULTS:
1403 consecutive percutaneous coronary intervention (PCI) were recorded. Among the complication we had 0.1% vessel dissection; 0.6% bleeding in the entry site, and 0.1% tamponade. The mean time of fluoro exposure was 11 minutes ± 7.1 (SD) in the first group and 14 minutes ± 8.5 in the second group. The results of the linear regression showed that the p value for the comparison between the means was highly significant (=0.000) Figure

CONCLUSION:
In the era of new technologies and emphasis on prevention, fluoro exposure for the operators has increased through the years. This finding suggests that efforts should be made to identify the reasons and establish the best approaches to avoid unnecessary exposure.
Abstract 17470: NF-κB Activation Down Stream of Tuber Sclerosis Complex -mTOR Signaling pathway is Suppressed in Doxorubicin-Induced Cardiotoxicity
Authors: Dhingra Rimpy , Gordon Joseph W , Gang Hongying , Kirshenbaum Lorrie A
Published: April 2024

The signaling networks that coordinate cell survival and cell death are poorly defined in the heart. The mammalian target of rapamycin (mTOR) is a highly conserved serine threonine kinase centrally involved in vital processes including growth, proliferation, and gene transcription. However, mTOR's role in regulating cell survival under normal or disease conditions has not been undetermined. Previously we established a cytoprotective role for the cellular factor NF-κB in ventricular myocytes. Notably, we demonstrated that NF-κB activation was necessary and sufficient for basal cell survival and suppressing mitochondrial perturbations during hypoxic injury. Herein, we provide new compelling evidence that activation of IKK-NF-κB signaling pathway down-stream of mTOR suppresses mitochondrial perturbations and cell death during metabolic stress imposed by nutrient deprivation or hypoxia. In contrast to wild type cells, constitutive activation of mTOR in tuber sclerosis complex (TSC) 2
-/-
cells displayed marked increased mTOR targets p-P70S6, p-4EBP-1 and S6 protein. Interestingly, a significant increase in nuclear NF-κB activity and NF-κB gene transcription was also observed in TSC 2
-/-
cells. Interestingly, in
in vivo
and
in vitro
models of Doxorubicin (Dox) -induced cardiotoxicity we observed a marked reduction in mTOR and NF-κB activity. However, basal NF-κB activity and cell viability were significantly reduced upon mTOR inactivation following metabolic stress or hypoxia. Moreover, basal Bnip3 gene transcription and cell death were significantly increased in cells treated with DOX and defective for mTOR activity. IKKβ- mediated activation of NF-κB restored mTOR activity and suppressed cell death induced by Bnip3 in DOX treated cells. To our knowledge our data provide the first direct evidence that operationally links mTOR and cell survival via IKKβ-NF-κB mediated repression of Bnip3.
Abstract 17498: PKA is the Canonical Mediator of “Fight-or-flight” Response of the Heart
Authors: Zhang Xiaoying , Tang Mingxin , Ai Xiaojie , Szeto Christopher , Hua Xiang , Chen Xiongwen
Published: April 2024

β-adrenergic system is the major system regulating cardiac function under “fight-or-flight” situations. Recently it has been reported that PKA-independent mechanisms such as exchange protein directly activated by cAMP (EPAC) and PKA-independent activation of Ca/calmodulin dependent kinase II (CaMK II) also play a role in the “fight-or-flight” response (FFR). To study the relative contribution of PKA, CaMK II and EPAC to the FFR, transgenic mice (4m) with specific inhibition of PKA (PKI) and myocytes were used to determine cardiac or myocyte responses to β-adrenergic stimulation.

Results:

1

. PKI was fully expressed at the age of 4 months and did not interfere with the production of cAMP induced by β-AR stimulation and the activation of CaMK II by high extracellular Ca, indicating no alteration of the components of β-AR/Gs/AC signaling pathway;

2

. ECHO showed that at baseline, the fractional shortening (FS: PKI: 38.7±1.5%; ctr: 39.0±2.1%) and ejection fraction (EF: PKI: 66.8±3.2%; ctr: 68.9.0±4.1%) were not significantly different between groups; ISO increased heart rate (HR: ctr: from 412±11bpm to 613±23bpm; PKI: from 425±13bpm to 430±21bpm), EF (ctr: 85.6±3.3%; PKI: 70.8±2.9%) and FS (ctr: 57.0±4.5%; PKI: 39.5±2.7%) in ctr but not in PKI mice.

3

. At baseline, maximal dp/dt (ctr: 6980±197mmHg/s; PKI: 7204±200mmHg/s) and minimum -dp/dt (ctr: -6248±214mmHg/s; PKI: 6587±304mmHg/s) were not different; ISO increased the HR, dp/dt (ctr: 1298±246mmHg/s; PKI: 7264±156mmHg/s) and -dp/dt (ctr: 7588±390mmHg; PKI: -5607±414mmHg) in ctr but not in TG mice.

4

. ISO increased Ca current, contraction, Ca transient and SR Ca content in ctr myocytes but not in TG myocytes.

5

. The phosphorylation of phospholamban at the PKA site (ser16) and CaMK II site (thr17) induced by ISO was blocked by PKI but not in ctr hearts, indicating that CaMK II is downstream to PKA.

6

. An EPAC activator, 8-cp-TOME-AM, could not increase cardiac performance of Langendorff perfused PKI hearts although it did slightly enhance cardiac function of ctr hearts, maybe due to its inhibitory effects on phosphodiesterases.

Conclusion:
PKA and its downstream CaMK II are the mediators of the “fight-or-flight” responses. Other PKA-independent pathways may not play a significant role.
Abstract 17503: Role of Blood Coagulation Factor V Expressed by Vascular Smooth Muscle Cells in vascular Remodeling
Authors: Karuparthi Poorna R , Strawn Tammy , Zhang Qiong , Fay William , Sun Hongmin
Published: April 2024

Introduction
- Blood coagulation factor V (fV) is synthesized in liver and present in blood, where it plays a central role in blood coagulation. FV is also expressed by cultured vascular smooth muscle cells (VSMC), and fV antigen has been detected in atherosclerotic plaque, suggesting that extrahepatic expression of fV plays an important role in vascular wall function and disease. However, very little is known about the functional impact of fV expression by VSMC, and it is unknown if fV is expressed locally within the arterial wall in vivo.

Methods
- We generated transgenic (Tg) mice with liver-specific fV transgene expression and crossed them to mice carrying a null fV mutation (fV
+/-
mice) to generate Tg rescue mice lacking native expression of fV (Tg+ fV
-/-
). We isolated, cultured, and characterized aortic VSMC from Tg
+
fV
-/-
mice and compared results to control Tg
+
fV
+/+
or wild-type (C57BL/6J) mouse VSMC. We studied the effect of fV expression on VSMC proliferation in vitro, and used reverse transcriptase (RT) PCR to assess fV expression in murine aorta.

Results
VSMC from Tg
+
fV
+/+
mice proliferated faster than Tg
+
fV
-/-
VSMC, at time points ranging from 24-96 hrs (Absorbance values, as noted with MTT assay, at all time points were statistically significant; at 48 hrs, Tg
+
fV
+/+
vs Tg
+
fV
-/-
, n = 4; P <0.001). Cell cycle analysis with flowcytometry suggested that there were fewer cells in active division phases at different time points in the Tg
+
fV
-/-
VSMC. The difference in VSMC proliferation rates between groups persisted in the presence of hirudin, a potent and highly specific thrombin inhibitor (P < 0.05). RT-PCR demonstrated that fV was expressed in both WT mouse cultured VSMC and aortic tissue in vivo.

Conclusions
- Expression of fV by VSMC promotes cell proliferation. This effect appears to be partly mediated not only by downstream thrombin, which activates VSMC, but also by a thrombin independent mechanism. fV is expressed in vivo in vascular tissue. These results offer important insights into the biological effects of fV and suggest that it has vascular functions distinct from its role in blood coagulation.