bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 9944: Temporal Relationship Between Major Hemorrhagic Events and Mortality among Patients with Recent Acute Coronary Syndrome: Insights from ATLAS ACS 2-TIMI 51
Authors: Pride Yuri , Mohanavelu Satishkumar , Mega Jessica , Braunwald Eugene , Gibson C. Michael 
Published: April 2024

Background: Multiple studies have demonstrated an association between hemorrhagic events and long-term mortality among patients with ACS. The goals of this analysis were to (1) describe risk factors associated with non-CABG-related TIMI major bleeding and (2) determine whether there was a temporal relationship in the association between hemorrhagic events and mortality.
Methods and results: ATLAS ACS-TIMI 51 enrolled patients with recent ACS and followed them for clinical outcomes for a median of 13 months. Multivariable Cox regression analyses adjusting for treatment and baseline characteristics were used to determine independent risk factors for non-CABG-related TIMI major bleeding. To analyze the hazard ratio and time dependency of bleeding on mortality, we used iterative day-to-day landmark analyses after the hemorrhagic event. Of the 15,526 patients enrolled, 196 (1.26%) had a non-CABG-related TIMI major bleed. Independent predictors of non-CABG-related TIMI major bleeding (p<0.10) included assignment to rivaroxaban, increasing age, male sex, diabetes mellitus, revascularization for the index event and region of enrollment. Non-CABG-related TIMI major bleeding was associated with a significantly increased risk of mortality, even after adjusting for baseline differences (HRadj 5.94, 95% CI 4.2-8.5, p<0.001). However, in the iterative landmark analysis, the hazard ratio did not differ statistically from baseline risk by 12 days after the bleeding event (Figure). Furthermore, in a landmark analysis, there was no difference in mortality among 30-day survivors of major bleeding compared with propensity-matched controls (3.9% vs. 4.1%, p=NS).
Conclusions: Among patients with recent ACS, major bleeding is associated with higher mortality, even after adjusting for differences in baseline characteristics. However, the relationship between major bleeding and mortality is no longer significant 12 days after the bleeding event.
Abstract 18068: Basis for a Major Genetic Alteration in Essential Hypertension: Inherited Defect in RBC-K Function and Oxygen Transport
Authors: Delgado-Almeida Antonio R , Delgado-Lelievre Maria C 
Published: April 2024

For decades, the pathogenesis and management of hypertension have been focused on dietary salt consumption, low potassium (K) intake, or hormonal factors triggering elevation of BP.
In this context, our description of an inherited defect in RBC-K transport serially recorded in hypertensive subjects and in 52% of their normotensive adolescents offspring implies a genetic defect from erythropoietic cells and a biochemistry abnormalities in the circulating RBC as K-dependent pyruvate kinase activity for ATP synthesis, or allosteric K-O2 binding by hemoglobin, recently described by our Laboratory.

Methods:
A pedigree analysis was performed in randomized hypertensive patients (HT, aged ≥30-years) with essential hypertension (BP>140/90 mmHg), confirmed in the last 3-years, and having low RBC K content (<92 mmol/l of cell). Normotensive (NT) group were healthy subjects matched for sex-age-race and having normal BP and higher RBC-K. Family data includes sex-age-race of parents, siblings, spouses, children and presence of hypertension, diabetes (D), coronary heart diseases (CHD) and Stroke. For each family the number of deceased, age and cause of death were accurately obtained.

Results:
Fifty two hypertensive subjects disclosed family data (104 parents, 219 siblings, 24 spouses and 64 children= 411 cases) with large number of HT and CV disease: a) Parents: 63 hypertensive and 15 diabetic HT (75% incidence) with 3 AMI, 3 Stroke, 1 CRF and 21 CV deaths at age 58±7; b) Siblings: 142 out of 219 were HT (64.8 %; range 33-90%), 7 of them Stroke, 4 DM, CAD 15, 25 CV deaths at age 58±10 year; c) spouse 8 HT 33 %, children: <30 years (9, 14% HT), ≥30 years, 15 HT, 23%), the remaining being NT. From 104 HT parents were born 142 HT (17 CV deaths, 125 alive, aged 52±6).

In contrast, from 24 NT subjects there were: 48 parents, 153 siblings, 16 spouses and 48 children (total 265): a) Parents: 12 HT (25%), 2 AMI, 5 CAD, 3 DM, 13 no CV deaths at age 73±7 years; Siblings: 14 HT (9.2%) 7 DM, CV, no deaths, all alive aged 52±7; c) spouses HT 29%, children 7 HT, 14.5%. From 48 NT parents were born only 14 HT subjects.

In Conclusion:
This study strongly suggests the presence of a major hereditary defect in essential hypertension, involving defective RBC-K transport and function.
Abstract 18497: Attenuated Endothelial Cd39 Activity Mediates Vascular Remodeling in Pulmonary Arterial Hypertension
Authors: Helenius Mikko , Vattulainen Sanna , Komulainen Anne , Taimen Pekka , Koskenvuo Juha , Alastalo Tero-Pekka 
Published: April 2024

Occlusive intimal hyperplasia in pulmonary arterial hypertension (PAH) leads to devastating consequences in pulmonary circulation and increased mortality. A phenotypic switch in endothelial cells (EC) has been suggested to play a role in the pathobiology of occlusive vasculopathy. We hypothesized that alterations in extracellular purinergic signaling could play a role in regulating EC fate during PAH progression. Purine signaling is regulated by cell surface ecto-enzymes such as CD39 and CD73. These enzymes are powerful mediators of cellular signaling since their activity adjusts the level of extracellular purine nucleotides that are potent cell signaling molecules.
By using our unique magnet bead-based ex vivo EC profiling strategy in the rat monocrotaline model of PAH we identified a major ~50% decrease (p<0.001) in adenosinetriphosphate (ATP) -hydrolyzing CD39 activity at early stages of the disease. The activity of AMP-hydrolyzing CD73 was not changed during the disease course. Similar ~50% (p<0.05) decrease in specific CD39 activity, leading to accumulation of ATP niche, was observed in cultured pulmonary ECs from end-stage human idiopathic PAH patients. This attenuated enzyme activity was, at least partly, mediated through down-regulation of CD39 expression on RNA (~70%, p<0.05) and protein level. Immunohistochemistry on human iPAH patient lung revealed that CD39 was significantly down-regulated in arteries with intimal disease compared to arteries with normal appearance. We then showed that suppression of CD39 through RNAi or excess 2 μM ATP niche initiates an EC phenotypic switch with apoptosis resistant and hyperproliferative phenotype, identical to iPAH ECs. We also show that increased ATP niche stimulates synthesis of extracellular matrix components associated with intimal disease, such as versican. In addition, increased 2 μM ATP concentration and co culture with CD39-deficient ECs induce pulmonary artery smooth muscle cell (PASMC) proliferation (~50%, p<0.005) and migration (~50%, p<0.05) and, thus, could contribute to SMC pathology in PAH. We show evidence, both in rat and human, that attenuation of CD39 activity is tightly linked to vascular remodeling, EC phenotypic switch and could represent a novel target for PAH therapy.
Abstract 18726: Thrombin-Inhibiting Nanoparticles Prevent Growth of Fibrin Clots by Inhibiting and Adhering to Clot-Bound Thrombin
Authors: Myerson Jacob W , Palekar Rohun U , Wickline Samuel A 
Published: April 2024

Introduction:
Sustained and localized prevention of clotting via thrombin inhibition could provide efficient care without significant bleeding effects for clinical scenarios including angioplasty, myocardial infarction, microangiopathy, and acute kidney injury. Thrombin-inhibiting perfluorocarbon nanoparticles (PFC NPs) carrying the direct inhibitors bivalirudin (BVR) and PPACK have demonstrated minimal bleeding effects with inhibition of and binding at sites of acute thrombosis in mouse and rabbit models. Here, we demonstrate that thrombin-inhibiting PFC NPs inhibit clot-bound thrombin and seal clots against further growth when exposed to plasma.

Methods and Results:
In solution, BVR, PPACK, BVR NPs, and PPACK NPs demonstrated concentration-dependent inhibition of Fibrinopeptide A (FPA) production by thrombin, as evaluated by ELISA. FPA ELISA for human plasma exposed to human fibrin clots demonstrated that BVR, PPACK, BVR NPs, and PPACK NPs inhibited thrombin bound in fibrin clots to the same extent as in solution.

Fibrin clots were incubated with non-targeted NPs, BVR NPs, or PPACK NPs. 19F MRI at 12T demonstrated that BVR and PPACK NPs specifically bind to clots (figure 1A).
Clots treated with BVR, PPACK, BVR NPs, PPACK NPs, or saline, were submerged in human plasma and imaged sequentially over one hour in T2-weighted 1H MRI at 12T. Clots treated with saline, BVR, or PPACK grew in volume when exposed to plasma, adding loose fibrin gel. Clots treated with BVR or PPACK NPs did not grow significantly (figure 1B-E).

Conclusions:
Thrombin-inhibiting PFC NPs have previously been shown to specifically bind to sites of acute thrombotic injury. Data presented herein show that PPACK and BVR NPs inhibit activity of clot-bound thrombin and specifically bind to fibrin clots derived from human plasma. PPACK and BVR NPs bound on the surface of fibrin clots prevent further clot growth on exposure to plasma.
Abstract 18735: Worsening Right Ventricular Structural Mechanics in Constrictive Pericarditis; Pericardiectomy Didn’t Fix the Problem!
Authors: Tariq Muhammad U , Alraies M C , Kusunose Kenya , Klein Allan 
Published: April 2024

Introduction:
Constrictive pericarditis (CP) is the result of scarring and consequent loss of the normal elasticity of the pericardial sac. Pericardiectomy is the definitive treatment for most cases of constriction. However it is believed structural changes in the right ventricle (RV) may result in tricuspid regurgitation (TR) after total pericardiectomy in patients with CP.

Case report This is the case of a 55-year-old man who had a history of viral pericarditis, HTN and heart failure. He was evaluated for progressive pedal edema and ascites, found to have CP with equalization of RV and LV diastolic pressures and respiratory discordance of systolic pressures, consistent with CP on right heart catheterization. He underwent pericardiectomy and was found to have extensive pericardial adhesions and severe calcifications. Seven weeks later, he presented with complaints of fluid overload and was noted to have newly decreased RV systolic function accompanied by increase in RV volume with tricuspid annular dilation and 2-3+TR (Table and Figure). Diuretics were reinitiated and he is followed for potential tricuspid valve surgery.
Discussion TR may develop post pericardiectomy in patients with CP. This is commonly noted with persistent RV failure symptoms post operatively. It may be caused by RV dilation and worsening TR, which results in increased RV strain, signifying poor status of longitudinal RV function. Tricuspid regurgitation is explained by RV and tricuspid annular dilatation. It is important to have a detailed evaluation perioperatively in patients with CP undergoing pericardiectomy.
Abstract 18748: High Resolution Structure Determination and Small Molecule Inhibitor Identification of NPP4, a Procoagulant Enzyme Localized to Brain Vascular Endothelium
Authors: Braddock Demetrios 
Published: April 2024

We recently identified the enzyme NPP4, an uncharacterized member of the nucleotide pyrophosphatase/phosphodiesterase family, as present at high concentrations on the vascular surface of the brain and promotes platelet aggregation in a dose dependent manner at physiologic concentrations of AP3A. AP3A is a small molecule stored at high concentrations in platelet dense core granules and is released upon platelet activation at high concentrations in the vicinity of the growing thrombus. Ap3A has a significantly longer lifespan in whole blood than ADP and has long been thought to promote stable thrombus formation by serving as a ‘chemically masked’ source of ADP. The goal of the present study was to determine the high-resolution three-dimensional structure of NPP4, and to identify small molecule inhibitors of NPP4 useful for the in vitro and in vivo validation of the physiologic role of the enzyme. We used X-ray crystallography to determine the high-resolution structure of the enzyme, and high-throughput small molecule screening to identify lead small molecules as lead inhibitors.
The three-dimensional structure of the enzyme was determined to1.5Å resolution in the presence and absence of its enzymatic product (AMP), and high-affinity (nM) small molecule inhibitors of NPP4 were identified as lead inhibitors in high throughput small molecule screens. Structure-activity relationships (SAR) of the lead compound were explored via chemical derivatization, and three-dimensional structures of the lead compounds were obtained to assist a structure-guided approach to lead optimization. Our combined studies lay the foundation for the validation of the biological role of NPP4 in hemostasis and establishes the necessary tools and reagents for the translational application of our preliminary findings into the clinic.
Abstract 18830: Mitochondrial Suppression Due to Loss of Sirt3 Deacetylase Activity Causes Pulmonary Arterial Hypertension
Authors: PAULIN Roxane , Dromparis Peter , Sutendra Gopinath , Provencher Steeve , Bonnet Sebastien , Michelakis Evangelos D 
Published: April 2024

Pulmonary arterial hypertension (PAH) is characterized by suppressed apoptosis in the pulmonary artery (PA) wall, leading to an obstructive vascular remodeling and premature death. The suppressed apoptosis is partly due to suppressed mitochondrial function. Recently PAH patients have been shown to have clinical evidence of insulin resistance. Sirtuin 3 (Sirt3), is a mitochondria-localized deacetylase that regulates mitochondrial function. Loss of Sirt3 activity promotes acetylation and inhibition of many mitochondrial enzymes, resulting in mitochondrial suppression. Loss-of-function polymorphisms in the SIRT3 gene have been associated with metabolic syndrome. We hypothesized that loss of SIRT3 promotes PAH.
In vitro, we used resistance PA smooth muscle cells (PASMC) isolated from WT and KO SIRT3 mice. Normoxic-KO-PASMCs had a global decrease in Kreb’s cycle intermediates (mass spectrometry) and respiration, increased mitochondrial membrane potential and decreased mitochondrial reactive oxygen species compared to WT-PASMCs, mimicking the profile of WT-PASMC exposed to hypoxia. They also had activation of Hif-1a (luciferase activity assays), confirming a “pseudohypoxic” state, increased proliferation (%Ki67) and suppressed apoptosis (%TUNEL). In vivo, compared to WT, Sirt3 KO normoxic mice developed spontaneous PAH (mPAP, 30.9±3.13mmHg vs 14±1.41mmHg) which did not worsen by chronic-hypoxia CH (10% for 3 weeks), associated with right ventricle hypertrophy and significant vascular remodeling. Systemic blood pressures did not differ between groups. In the monocrotaline MCT rat model, intra-tracheal nebulization of Sirt3 adenovirus at day 21-post MCT injection, improved mPAP and vascular remodeling compared to the GFP-only adenovirus treated rats.
We showed for the first time a critical role of SIRT3 in PAH. In a parallel abstract submission (Gurtu et al) we describe increased frequency of a characterized loss-of-function SIRT3 single nucleotide polymorphism in PAH patients. The loss of SIRT3 function causes a mitochondrial suppression perhaps explaining both the anti-apoptotic diathesis in PAH vessels and the extra-pulmonary metabolic abnormalities recently described in these patients.
Abstract 18991: A Mir-208-mef2 Axis Drives the Decompensation of Right Ventricular Function in Pulmonary Hypertension
Authors: Paulin Roxane , Sutendra Gopinath , Gurtu Vikram , Dromparis Peter , Michelakis Evangelos D 
Published: April 2024

Right Ventricular Failure (RVF) is the major cause of morbidity and mortality in PHT but remains understudied compared to left ventricular failure. The transition from a compensated to decompensated RV occurs much earlier in the RV for unknown reasons. RV and LV have different embryology; the Islet1/Mef2/Hand2 axis is specific for RV formation. Mef2 regulates metabolic, contractile and angiogenic genes critical for RV adaptation to pressure overload. MicroRNAs (miRNAs) have emerged as important determinants of LV development and disease, but little is known about RV miRNAs. We hypothesized that a miRNA-Mef2 axis is important in RV decompensation.
We modeled RVF in the rat monocrotaline (MCT) PAH model in a clinical manner, establishing 3 sequential stages of RV response to PAH (n=6/group): a) normal RV at baseline (NRV, RVSP=38±2mmHg, CO=102±2ml/min and RV/LV+Septum=22±1); b) compensated RV (CRV) 3-4weeks post-MCT when mortality is minimal and cardiac output is stable (RVSP=66±8 mmHg, CO=80±13ml/min, RV/LV+Septum=48±3); c) decompensated RV (DRV) 4-6weeks post-MCT when contractility and cardiac output declines while RV size, ascites and mortality increase rapidly (RVSP=52±2mmHg, CO=67±10ml/min, RV/LV+Septum=58±2).
Using unbiased miRNA arrays (n=9), we found that the levels of the cardiac-specific miRNA miR-208 progressively decreased in CRV and DRV, correlating with RV size increase (r=-0.68, n=20, p<0.001); whereas its expression is known to remain stable in models of LV hypertrophy. The level of the miR-208 target, MED13, increased in DRV. MED13, a subunit of the complex mediator of transcription, activates the repressor NCoR1, which deacetylates Mef2 family members, decreasing their transcriptional activity. NCoR1 expression was increased in DRV, while Mef2 expression was decreased. We infected adult cardiomyocytes isolated from CRV free walls with an adenovirus expressing an anti-miR-208. This was associated with increased MED13 and NCoR1 levels, and decreased Mef2 expression, mimicking the transition to DRV in vivo.
We identified an RV-specific miR-208-Mef2 axis characterizing the transition from CRV to DRV, which may lead to the discovery of much-needed biomarkers and treatments of RVF, for which there are currently no treatments.
Abstract 288: Predicting Return of Spontaneous Circulation Using Cerebral Oximetry and End Tidal CO2
Authors: Engel Thomas , Thomas Craig J , Medado Patrick , Reed Brian , Millis Scott , O’Neil Brian J 
Published: April 2024

Background:
Previous literature has identified ETCO2 as a good predictor of ROSC. Cerebral Oximetry (CerOx) utilizes near infrared spectroscopy to non-invasively measure regional O2 saturation of the frontal lobes of the brain.

Objectives:
The objective of this study is to compare the predictive value of simultaneously measured ETCO2 and CerOx for ROSC during CPR.

Methods:
We conducted an IRB approved, prospective study on a convenience sample of subjects suffering cardiac arrest. Subjects were monitored with ETCO2 and CerOx simultaneously during CPR performed in the ED. We analyzed the data using logistic regression modeling and ROC curve analysis.

Results:
We analyzed 135 events. Mean age was 64.5±15.6 years. 90 (66.7%) were witnessed arrests with 78 (57.8%) receiving bystander CPR. Average downtime was 24.9±15.0 minutes. ROSC was achieved in 39 (28.9%) of these subjects. Initial rhythm presented as 58 (43.0%) asystole, 52 (38.5%) PEA and 25 (18.5%) VF/VT.

A series of binary logistic regression models were run in which various derivations of ETCO2 and CerOx were simultaneously entered into the model to predict ROSC. CerOx, but not ETCO2, proved to be a significant predictor in determining ROSC for the following variables: regression slope during the full code [CerOx p<0.000, ETCO2 p<0.386], regression slope during the last 5 minutes of the resuscitation [CerOx p<0.000, ETCO2 p<0.749], maximum value recorded during resuscitation [CerOx p<0.000, ETCO2 p<0.858]. Both CerOx and ETCO2 proved to be significant predictors of ROSC for the following variables: last value recorded during resuscitation [CerOx p<0.000, ETCO2 p<0.009], the change from first value recorded to last value recorded [CerOx p<0.000, ETCO2 p<0.000].
CerOx also proved to be a better predictor of ROSC than ETCO2 when utilizing a ROC curve analysis: last values recorded [CerOx, AUC=0.856; ETCO2, AUC=0.761] and maximum values recorded [CerOx, AUC=0.802; ETCO2, AUC=0.630].

Conclusions:
CerOx is a better predictor of ROSC than ETCO2 when analyzed by the whole resuscitation effort, the last five minutes, the maximum value, the last value recorded, and the change in values from first to last recordings during CPR. The maximum and last values of CerOx are good diagnostic tests for predicting ROSC.
The Regression of Atherosclerosis: The Journey From the Liver to the Plaque and Back
Authors: Fisher Edward 
Published: April 2024

The Duff Memorial Award Lecture will consist of 3 short stories. In the first, new developments will be presented on how the production of very low density lipoproteins (VLDL, which become LDL) by the liver is controlled by the degradation of their apolipoprotein B (apoB) component. In particular, our recent results have shown that insulin and niacin, two medically relevant regulators of the plasma levels of VLDL, utilize a process called autophagy to accomplish this. In the second, recent studies on the regression of atherosclerosis in novel mouse models will be presented. Specifically, I will show that to get rid of the cholesterol-filled disease-causing cells from the arterial plaques, new, healthy, monocytes need to be recruited from the circulation. In the third story, the use of natural and synthetic nanoparticles to carry imaging and therapeutic agents directly to atherosclerotic plaques will be presented.
Abstract 9257: Atrial Fibrillation is Associated With Worse Outcomes in Patients With Diastolic Heart Failure than Patients With Systolic Heart Failure
Authors: Smith Sakima A , Hite Arnold J , Ishola Abiodun , Hasan Ayesha K 
Published: April 2024

Introduction:
Atrial fibrillation (AF) is prevalent and is associated with heart failure (HF). HF causes changes in atrial structure and physiology that predispose to AF. Our goal was assess the impact of AF on HF patients with either preserved (HFpEF) or reduced (HFrEF) left ventricular ejection fraction (LVEF).

Hypothesis:
We hypothesized that patients with HFrEF would likely have more adverse events and worse outcomes.

Methods:
This was a retrospective review of 763 patients with HF at baseline who developed AF. We analyzed the CHADS and CHADS-Vasc scores and time to death, time to AF development, time to death from AF development, time to adverse events (figure 1), and length of stay (LOS).

Results:
Patients with HFpEF had significantly longer LOS for AF or HF hospitalizations. While patients with HFrEF on average developed AF four months sooner than patients with HFpEF, those with HFpEF died six months earlier (table 1).

Using multiple linear regression only age was a significant predictor for time to AF development.
There were no significant differences between HFrEF vs HFpEF patients with respect to time to an adverse event. When patients were stratified into younger vs older cohorts (< or ≥ 50 years of age) there was a significant difference for the waiting time to an adverse event between the younger and older patients (figure 1).

Conclusion:
Patients with HFpEF and AF represent a cohort of patients that have a significant burden of disease and poor outcomes. Their increased LOS is likely a product of their multiple co-morbid conditions complicating their underlying HF. Our data also suggests that the most important factor for time to an adverse event for HF patients with AF is age, not the LVEF.