bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 18594: Plasma Volume Status Calculated Instantaneously from Weight and Hematocrit Relates to Objectively Measured Plasma Volumes and Powerfully Predicts Death and First Morbid Events in Chronic Heart Failure
Authors: Ling Hua Zen , Aung Nay , Cheng Adrian , Flint Julia , Aggarwal Suneil , Mendonca Michelle , Rashid Mohammad , Kang Swan , Papalia Francesco , Cotton Charles , Kalra Paul , Thomas Martin , Kuskowski Michael , Cohn Jay N , Woldman Simon , Anand Inder S , Okonko Darlington O
Published: April 2024

Background:
Plasma volume (PV) expansion hallmarks worsening chronic heart failure (CHF) but no non-invasive means of quantifying volume status exists. Because weight and hematocrit are intimately related to PV, we derived an index of relative PV status (PVS) using validated equations based on these simple indices. We tested the validity and prognostic utility of our index in a logical sequence of analyses.

Methods:
First, we correlated current PV measured using
125
Iodine-human serum albumin to calculated values ([1-hematocrit] x [a + (b x weight)]). Second, we subtracted calculated current PV from ideal PV (c x weight) to derive PVS ([(current-ideal)/ideal] x 100%) in CHF patients (pts). Third, we assessed the prognostic implications of PVS in 5002 pts in the Val-HeFT trial (age 62±11y, LVEF 27±7%, 37% NYHA≥3) and validated this in an accrued ‘real world’ sample of 246 CHF pts (age 67±13y, LVEF 28±8%).

Results:
Calculated and measured PV correlated at baseline in normal subjects (n=119, r=0.68) with a bias of 78mL, and at baseline (n=22, r=0.44) and over time (r=0.60) in hospitalized CHF pts. In the Val-HeFT cohort, PVS was -10±11% (median [±IQR]) and related to volume biomarkers such as NT-BNP, urea, eGFR, albumin, and sodium (all P<0.01). Over 2 years, 977 (20%) pts died. PVS was associated with death (Fig
A
) and first morbid events in a ‘J-shaped’ fashion with the highest and lowest risks seen with a PVS> - 4% and between -12% to -14%, respectively. Stratification into quartiles confirmed this with a PVS> - 4% (versus ≤ - 4%) prognostic (unadjusted HR 1.65, 95% CI 1.44-1.88, χ
2
54, P<0.001, Fig
B
) even after adjustment for 22 variables including NT-BNP. These results were mirrored in the validation cohort.

Conclusions:
PVS calculated from simple clinical indices reliably reflects the degree to which patients have deviated from their ideal PV and independently relates to outcomes. Titrating CHF therapy to keep PVS below - 4% and ideally between -12% to -14% might increment survival.
Abstract 18628: Aortic Arch Dissection: Does it Matter in the Current Management of Type B?
Authors: Tolenaar Jip , Tsai Thomas T , Evangelista Arturo , O'Gara Patrick , Pape Linda , Fattori Rossella , Braverman Alan C , Desai Nimesh D , Appoo Jehangir , Bossone Eduardo , Montgomery Daniel G , Isselbacher Eric M , Nienaber Christoph A , Eagle Kim A , Trimarchi Santi
Published: April 2024

Introduction: Current guidelines report that arch involvement in aortic dissection requires open surgical repair. However, arch dissections are frequently managed with less invasive treatment when ascending aorta involvement is absent. The aim of this project is to clarify the importance of aortic arch involvement in such conditions,

Methods: Patients with aortic arch dissection enrolled in IRAD from January 1, 1996 to May 1, 2012 were included in this analysis. Patient groups were defined based on the location of the entry tear and aortic extension: entry tear in the aortic arch with extension confined to the arch (group 1; n = 8), entry tear in the aortic arch with antegrade extension (group 2; n = 55) and entry tear in de descending or abdominal aorta with retrograde extension into the arch (group 3; n = 55). For this abstract, we analyzed the difference in therapies and outcome for these groups.

Results: Compared with the other groups, isolated arch patients presented more frequent with syncope, an abrupt onset of pain and less frequent with posterior pain. Treatment differed among groups and most of the isolated arch patients were treated medically. One third of the Group 3 patients was managed endovascular, with excellent outcomes, with a total in-hospital mortality of 7.3% (p = .062). No differences in mortality were observed during follow-up. (p = .193)

Conclusion: Aortic arch involvement in aortic dissection is diverse and our observations emphasize that open surgical repair may be not always indicated in all patients. Selective patients, based on entry tear and aortic extension, might benefit from less invasive treatment options, such as endovascular repair and medical therapy
Abstract 18646: The Dynamic Relationship Between GRK2 and NOS/NO Critically Determines Cardiac Ischemia/Reperfusion Injury
Authors: Huang Z. Maggie , Gao Erhe , Shang Xiying , Tian Xufan , Qiu Gang , Chuprun J Kurt , Hayashi Hiroki , Hess Douglas T , Lefer David J , Stamler Jonathan S , Koch Walter J
Published: April 2024

Background and Aim
s: G protein-coupled receptor kinase 2 (GRK2) and endothelial nitric oxide synthase (eNOS) play key roles in cardiac signaling and function. Increased GRK2, seen in injured myocardium, causes increased cell death and injury after ischemia while reciprocally, eNOS/NO exerts protection. A link between these two systems occurs as GRK2 can be regulated via S-nitrosylation (SNO) at Cys340, which inhibits its activity. Alternatively, increased GRK2 activity inhibits NO in the heart. The aim of this study was to determine whether there is a dynamic interaction between cardiac GRK2 and eNOS/NO.

Methods: We investigated a direct interaction between GRK2 and eNOS in cultured myocytes and hearts. Cardiac-specific transgenic mice overexpressing GRK2 (Tg-GRK2) and mice with expression of the GRK2 inhibitor βARKct (Tg-βARKct) were used to create hybrid mice with concurrent modulation of eNOS. Finally, we created novel knock-in mice where all endogenous GRK2 was a mutant form (Cys340Ser) resistant to SNO regulation. All mice were characterized basally and subjected to ischemia/reperfusion (I/R) injury and infarct size and cardiac phenotypes determined.

Results: 1). Co-immunoprecipitation discovered an interaction between GRK2 and eNOS in cardiac tissue, which was significantly increased in the ischemic heart. 2). TgGRK2/TgeNOS hybrid mice showed significantly reduced infarct size and improved function post I/R compared to Tg-GRK2 mice. Protection offered by βARKct was reversed in mice without eNOS. 3). SNO-GRK2 was increased by isoproterenol and GSNO in WT mice but was not observed in GRK2-C340S mice. 4). Interestingly, GRK2-C340S mice exhibited significantly larger injury post I/R compared to WT mice with decreased cardiac dysfunction. GSNO treatment reduced infarct size in WT mice but had no effects in GRK2-C340S mice. Also, pre-treatment with the NOS inhibitor L-NAME increased infarct size in WT mice but not in GRK2-C340S mice.

Conclusions:
Our data demonstrates a unique relationship between GRK2 and NO signaling in the heart, which has direct implications for mechanisms of cardiac injury. This includes the demonstration that GRK2 is a nodal pro-death kinase after I/R injury and its SNO is a requirement for NO-mediated cardioprotection.
Abstract 18667: Anti-atherosclerotic Effect of CER-001, an Engineered HDL-mimetic, in the High-fat Diet-fed LDLr Knockout Mice
Authors: Goffinet Marine , Tardy Claudine , Bluteau Alice , Boubekeur Nadia , Baron Rudi , Keyserling Constance , Barbaras Ronald , Lalwani Narendra , Dasseux Jean-Louis
Published: April 2024

CER-001 is an engineered HDL-mimetic, comprised of recombinant human ApoA I and phospholipid, exhibiting properties of nascent pre-ß HDL. Intravenous infusion of CER-001 promotes reverse lipid transport by causing rapid mobilization of cholesterol in animals, including in man. Previous studies have shown that CER-001 induced cholesterol efflux from macrophages similar to HDL3 in vitro, enhanced LCAT activity, and exhibited anti-inflammatory response similar to natural HDL. The aim of this study was to evaluate the effect of CER-001 on atherosclerotic plaques in high-fat diet-fed LDL-receptor -/- mice. Mice on high-fat diet for 10 weeks were given CER-001, 10 mg/Kg, intravenously. Aortic plaques were evaluated by immunohistochemistry following 5 or 10 doses given every second day. CER-001 caused 22.5% (p=0.02) and 32% (p= 0.009) reductions in plaque size, and 14% (p=0.08) and 23% (p=0.03) reductions in lipid content following a treatment regimen of 5 and 10 doses, respectively. Also, there was an 80% reduction in macrophage content in the plaque following 5 doses, as shown by F4/80 staining (p=0.0001), suggesting decreased inflammation. These data suggest that CER-001, an HDL-mimetic, could be a suitable therapeutic for the treatment of atherosclerosis and associated vascular complications, including in familial hypercholesterolemia patients.
Abstract 18673: Fluoroscopy and High Voltage Testing - A Paradigm Shift in evaluation of Insulation Failure of Riata Lead
Authors: Lakshmanadoss Umashankar , Kulkarni Abhishek , Lahoda David , Young Angie , Romanyshyn Mary , Deshmukh Pramod
Published: April 2024

Introduction:
Current HRS guidelines for management of Riata lead recall are limited to close follow up. We have observed and reported high voltage testing (HVT) failure of Riata leads despite normal high resolution fluoroscopy (HRF) appearance and low voltage evaluation. We sought to assess the role of HRF and HVT to identify lead insulation defect.

Methods:
Patients with Riata leads were evaluated clinically and informed about the lead insulation issues. In addition to device interrogation, HRF examination and HVT testing were performed.

Results:
Out of 331 patients with Riata leads, 180 patients were seen in office. A total of 90 were screened with HRF and HVT. Separation of conductors was seen in 51% (46/90) and 9 % (8 patients) failed HVT (failed to induce/sense/shock VF). Out of 8 patients who failed HVT, 5 had normal HRF examinations. Retrospectively, additional 17 patients underwent lead extraction due to lead malfunction consistent with insulation failure. Lead extraction due to insulation defects were done in 36 /331 total pts and 19/90 screened patients (8 failed HVT, 8 patients for secondary prevention and externalized cables, 3 with externalized cables and on patient request). With 543 years of combined follow up(average 6 +1.3 years), prevalence of HRF detected insulation defect is 51% (46/90), 8.5%/year and malfunction consistent with insulation failure is 7.5% (25/331), 1.25%/year. Clinical examination, device interrogation, HRF and HVT has provided additional information and resulted in lead extractions in 19 patients (5 with normal and 14 with abnormal fluoroscopic appearance) despite of having normal low voltage parameters.

Conclusions:
Close follow up as suggested by HRS guidelines failed to identify high voltage integrity in 9% of patients. Additionally, 21% screened patients underwent lead extraction. These findings suggests the need of a larger prospective study incorporating the HRF and HVT to evaluate the integrity of Riata leads.
Abstract 18703: Novel MicroRNA 874 is a Unique Angiogenic Modulator of Stem Cell Paracrine Factor Epidermacan
Authors: Zhang Ying , Liu Yangfan , Pow-anpongkul Pete , Naidoo Vinogran , Payne J.Alan , Mu Hui , Katsanis Nicholas , Mirotsou Maria , Dzau Victor
Published: April 2024

Introduction:
We have previously shown that treatment with epidermacan a novel stem cell derived paracrine factor promoted angiogenesis
in vitro
accompanied with an increase in angiogenic miRNA expression. Here, we identified novel microRNAs regulated by epidermacan and validated their importance in modulating the epidermacan angiogenic effects
in vitro
and
in vivo
.

Methods and Results:
Increased levels of pro-angiogenic miRNAs such as miR-10b, miR-21 and miR-424 were discovered in MicroRNA profiling of HUVEC cells treated with epidermacan and then confirmed by qRT-PCR. We also identified miR-874, a relatively unknown miRNA but for its role as a tumor suppressor. Investigation of the downstream microRNA/gene networks revealed that epidermacan regulated known angiogenic genes such as VEGFC, TBX1, HIF-1a and NRP1
.
Importantly, treatment with epidermacan decreased the levels of HoxD10, a known target of miR-10b in thrombin induced angiogenesis. Inhibition of miR-10b or miR-874 via anti-miR transfection repressed the effects of epidermacan in HUVEC tube formation on matrigel. Interestingly inhibition of miR-10b also reversed the angiogenic effects of VEGF; however inhibition of mir-874 only suppressed the effects of epidermacan, suggesting miR-874 as an epidermacan specific target. The
fli:GFP
transgenic zebrafish model was used to study the role of epidermacan in angiogenesis
in vivo
. Morpholino against zebrafish epidermacan gene was injected into the yolk of
fli:GFP
transgenic zebrafish embryos at 1-4 cell stage, and larvae were collected at 4 days post fertilization to monitor vessel development. The trunk vascular network was disorganized in larvae injected with the morpholino of epidermacan compared to uninjected control. The vascular defects were rescued by co-injection of 100 pg mRNA of human NDNF (epidermacan homolog), suggesting that vessel malformation is specifically due to knockdown of epidermacan.

Conclusion:
Our data confirm the role of epidermacan as an angiogenic factor and identify the novel miR-874 as specific modulator of epidermacan’s angiogenic effect. Further analysis to elucidate the microRNA/gene networks downstream of epidermacan will provide new insights on the regulatory networks of angiogenesis.
Abstract 18739: Autophagy Regulates Vascular Smooth Muscle Cell Synthetic Phenotype Transition and Resistance to Oxidative Stress
Authors: Salabei Joshua K , Cummins Timothy D , Bhatnagar Aruni , Hill Bradford G
Published: April 2024

Arterial lesions due to atherosclerosis and restenosis are characterized by heightened oxidative stress and the transformation of vascular smooth muscle cells (VSMCs) to a synthetic phenotype. However, it is not known how synthetic VSMCs (sVSMCs) respond to the stress encountered in advanced vascular lesions. Our previous studies show that electrophilic stress caused by lipid peroxidation products promotes autophagy and endoplasmic reticulum stress. In this study, we tested the hypothesis that conversion to the synthetic phenotype primes VSMCs to survive under conditions of high oxidative stress. Synthetic VSMCs, elicited by exposure to platelet-derived growth factor-BB (PDGF-BB), maintained lower levels of endogenous protein-aldehyde adducts and demonstrated a heightened ability (2.5-fold; p<0.05) to remove proteins modified by the lipid peroxidation product 4-hydroxy-
trans
-2-nonenal (HNE) than contractile VSMC (cVSMC). Moreover, HNE detoxification in sVSMCs was enhanced; the primary pathway of HNE detoxification—aldehyde dehydrogenase-mediated oxidation to 4-hydroxynonenoic acid—was increased by 30% and glutathione conjugation was increased by 50% (p<0.05). The sVSMCs showed a 20% increase in viability compared with cVSMCs when challenged with HNE (p<0.05). This resistance to stress in sVSMCs was found to be due primarily to robust induction of the autophagic program. PDGF-BB exposure increased autophagic flux (>2-fold vs. untreated cells; p<0.05), as assessed by quantifying GFP-microtubule-associated protein 1 light chain 3 (LC3) puncta as well as electron microscopy and LC3II abundance. Blockade of autophagy by spautin-1 or 3-methyladenine prevented the PDGF-BB-induced decreases in expression and abundance of calponin and α-SM-actin, suggesting that autophagy is required for VSMC phenotype conversion. Inhibiting autophagy also prevented removal of HNE-damaged proteins and prevented PDGF-induced increases in NAD
+
- and glutathione-linked HNE detoxification (p<0.05). Collectively, these results show that PDGF-BB induces autophagy in VSMCs, which is required for conversion of VSMCs to the synthetic phenotype and for resistance to the oxidative stress characteristic of vascular lesions.
Abstract 18743: Bayesian Comparative Analysis for Prevention of Stroke and Net Clinical Benefit of Novel Oral Anticoagulants in Non-Valvular Atrial Fibrillation
Authors: Lang Christopher , Arora Rohit
Published: April 2024

Background:
The recent emergence of novel oral anticoagulants dabigatran, rivaroxaban and apixaban for prevention of stroke and systemic embolization in atrial fibrillation are attractive alternatives to warfarin. Despite this, the differences in efficacy and bleeding events between these medications remains unclear. To compare differential benefit, we performed a Bayesian analysis comparing the efficacy and safety parameters of the 3 novel agents.

Methods:
Using data from the 3 major trials investigating the novel oral anticoagulants, we conducted a Bayesian analysis using null prior probabilities, which is particularly suited to indirect comparisons. The primary endpoints of stroke and systemic embolization were assessed, along with safety endpoints of major bleeding. A Bayesian analysis was performed on each group, defining probabilities of benefit for the posterior probability. From this data, net clinical benefit calculations were performed and posterior probabilities were obtained.

Results:
Posterior probabilities for stroke and systemic embolization indicate the apixaban, rivaroxaban and dabigatran have an 87.3%, 88.7%, and 66.3% probability of benefit over warfarin, respectively. Major bleeding events were found to have a 98.6%, 88.0% and 55.0% probability of benefit over warfarin. Net clinical benefit analysis indicates benefit with apixaban and rivaroxaban that was greater than dabigatran.

Conclusions:
Using Bayesian analytic techniques, all of the novel oral anticoagulants were found to be non-inferior to warfarin. However, the effectiveness in prevention of stroke suggests that both apixaban and rivaroxaban significantly outperform dabigatran. Net clinic benefit and safety endpoints support the use of apixaban as opposed to rivaroxaban and dabigatran. While more data emerges investigating the differential benefit of these new medications, Bayesian techniques offer novel comparative statistics which can guide clinical decision making.
Abstract 18746: Variation in Intravenous Inotrope Use for Patients Hospitalized with Heart Failure: Data from Get withthe Guidelines
Authors: Allen Larry A , Fonarow Gregg C , Grau-Sepulveda Maria V , Hernandez Adrian F , Peterson Pamela N , Partovian Chohreh , Heidenrich Paul A , Bhatt Deepak L , Peterson Eric D , Krumholz Harlan M
Published: April 2024

Background:
Data guiding the use of intravenous inotrope agents for patients hospitalized with heart failure (HF) are sparse. Guidelines crudely recommend inotrope use for highly selected patients with decompensated HF, hypotension, and evidence of end-organ hypoperfusion. Real-world patterns of inotrope use are not well characterized.

Methods:
We examined inotrope use for patients hospitalized with HF from 2005-2011 and enrolled in the Get With The Guidelines (GWTG-HF) registry. We used hierarchical logistic regression models to estimate risk-standardized hospital-level utilization rates of dobutamine, dopamine and milrinone, adjusting for clinical and demographic factors.

Results:
Overall, 7,909 of 130,224 (6.1%) of HF patients hospitalized at 240 GWTG participating centers received inotrope administration (dobutamine 44%, dopamine 24%, milrinone 17%, combination 15%). Rates of inotrope use were constant from 2005 to 2011. At the hospital level, risk-standardized institutional rates of inotrope rates use ranged from 0-34% (median 5.1%, 25th-75th percentile 2.0-9.9%, Figure). Hospital region, rural location, size, and academic status were not significantly associated with the use of an inotropic agent.

Conclusion:
Inotrope use during hospitalization varied markedly across participating hospitals. This degree of institutional variation, even after accounting for measured differences in case mix, suggests use patterns that are based to a greater degree on individual site propensity than by patient factors. The implications of these markedly different patterns of care are worthy of further investigation .
Abstract 18777: Glucagon-like Peptide-1 Inhibits Thrombin-induced Human Platelet Aggregation
Authors: Cameron-Vendrig Alison , Reheman Adili , Afroze Talat , Noyan-Ashraf Hossein , Ni Heyu , Husain Mansoor
Published: April 2024

Background:
Studies of glycemic control in diabetics receiving glucagon-like peptide-1 (GLP-1)-targeted drugs have suggested reduced incidences of cardiovascular events over 6-12 months. Mechanisms underlying this surprisingly rapid effect are not known.

Methods
&

Results:
To investigate potential anti-thrombotic effects of GLP-1 and related analogs, we tested GLP-1(7-36)NH2, the most abundant endogenous GLP-1, and the commercially available GLP-1 analog exenatide in thrombin-induced platelet aggregation assays using freshly isolated gel-filtered human platelets (3x108/ml) in normoglycemic conditions (5.5mM glucose). Incubation with GLP-1 (10-10 to 10-6 M) or exenatide (5x10-10 to 10-8 M) for 15 min at 37°C delayed and reduced platelet aggregation as compared to PBS-treated controls. GLP-1 (10^-9M) resulted in a 60% decrease in aggregation 1 min after thrombin stimulation. To investigate whether this effect may be mediated by a GLP-1 receptor (R), whole cell lysates (40 µg) from gel-filtered human platelets and the human megakaryocyte (MGK) cell line MEG-01 were probed with a polyclonal anti- GLP-1R Ab (1:1250; Santa Cruz). Although Western blot showed bands (∼56 kD) consistent with the known GLP-1R in both platelets and MEG-01 cells, GAPDH-normalized expression levels of GLP-1R were ∼13 and ∼45 fold lower in these cells than in human pancreas. Given the limited specificity of Abs raised against GPCRs, RT-PCR was performed on RNA from MEG-01 cells with primers designed to yield full-length human GLP-1R cDNA. PCR products were cloned and sequenced, revealing inserts identical to GLP-1R. As this receptor is known to be adenylate cyclase-coupled, cAMP assays were also performed (EIA kit, Cayman Chemicals). MEG-01 cells incubated for 15 min with 10-7 M GLP-1 showed a ∼60% increase in intracellular cAMP, an inhibitor of platelet activation, as compared to untreated controls; while the cAMP response to prostacyclin PGI2 was much greater (positive control; 16 fold).

Conclusion:
Human platelets and MGK express low levels of GLP-1R. While GLP-1 induced only small increases in cAMP in MGK, both GLP-1 and exenatide inhibited thrombin-induced platelet aggregation. These data suggest that GLP-1-targeted drugs may possess anti-platelet effects.
Abstract 18778: Myocardial Gene Therapy by Adeno-HSPA12B Administration Induces Angiogenesis and Prevents Ventricular Dysfunction Following Acute Myocardial Infarction in Type I Diabetic Rats
Authors: Thirunavukkarasu Mahesh , Suresh Sumanth C , Selvaraju Vaithinathan , Sanchez Juan A , Maulik Nilanjana
Published: April 2024

Introduction:
Molecular chaperones/heat shock proteins (HSPs) are important regulators of angiogenesis. HSPA12B, a member of HSP70 sub-family 12 predominantly expressed in endothelial cells is required for angiogenesis. In the present study we examined the effects of overexpressing HSPA12B on angiogenesis and myocardial function by intramyocardial administration of adenovirus encoding HSPA12B (Ad. HSPA12B) in a myocardial infarction (MI) model in streptozotocin induced Type I diabetic rats.

Methods:
The rats were divided into 6 groups. 1) Control Sham (CS), 2) CMI+Ad.LacZ (CLZMI), 3) CMI+Ad.HSPA12B (CMI-HSPA12B), 4) Diabetic Sham (DS), 5) DMI+Ad.LacZ (DLZMI), 6) DMI+Ad.HSPA12B (DMI-HSPA12B). Following left anterior descending coronary artery ligation Ad.LacZ or Ad.HSPA12B was injected at 4 border zone sites to either CLZMI/DLZMI or CMI-HSPA12B /DMI-HSPA12B group.

Results:
We observed increases in capillary (2245±37.2 (n=4) vs 1732±102.5 (n=3); p<0.05) & arteriolar (19±0.5 (n=3) vs 14±0.5 (n=6); p<0.05) density (counts/mm2) in the DMI-HSPA12B compared to the DLZMI group. Formalin-fixed mid-ventricular tissue sections stained with Picrosirius red, exhibited a 44% decrease in collagen deposition in DMI-HSPA12B compared to DLZMI hearts. Echocardiography at 30 days revealed decreased left ventricular inner diameter (systole) (6.3±0.3 vs. 8.5±0.3 (n=6); p<0.05) & increased ejection fraction (51±0.6 vs. 32±0.9 (n=6); p<0.05) & fractional shortening (27±0.4 6 vs. 16±0.5 6 (n=6); p<0.05) in the DMI-HSPA12B compared to DLMI group. Western blot analysis showed increased expression of HSPA12B (1.4 fold) and VEGF (1.4 fold) 4 days after HSPA12B gene delivery in the DMI-HSPA12B group compared to the DLZMI group.

Conclusion:
Targeted delivery of HSPA12B induced angiogenesis and improved hemodynamic function in a rat model. Our novel approach may be a viable therapeutic modality in the treatment of diabetes related cardiac failure by stabilizing the myocardium, promoting neovascularization & augmenting protective as well as regenerative responses in ischemic rat myocardium.
Abstract 18799: Association of Long-term Risk Factor Levels with Coronary Artery Wall Remodeling Indices: The Chicago Healthy Aging Low-RISk Magnetic Resonance Angiography (CHARISMA) Study
Authors: Lloyd-Jones Donald M , Berry Jarett D , Ning Hongyan , Lin Kai , Daviglus Martha , Liu Kiang , Li Debiao , Walsh Joseph A , Carr James
Published: April 2024

Background:
Coronary artery wall remodeling (CAR) has recently been recognized as an important feature of atherosclerosis development. Long-term associations of risk factor (RF) burden with remodeling indices have not been described.

Methods:
In 2009-11, we performed MR angiography in 440 randomly-selected participants (ppts) of the Chicago Healthy Aging Study, whose RFs had been measured in 1967-73. We examined association of aggregate burden of RFs with CAR indices measured by 1.5T MR imaging. Cross-sectional images of the proximal portions of the left main (LMCA, 1 slice), left anterior descending (LAD, 3 slices) and right (RCA, 3 slices) coronary arteries prescribed using coronary landmarks were acquired using a breath-hold, black-blood, ECG-gated, turbo spin echo sequence. RF burden at baseline was stratified into “Low Risk” (untreated cholesterol <200 mg/dL, untreated blood pressure <120/<80 mm Hg, not smoking and no diabetes) and “Not Low Risk,” including all others. Individual RF associations were also examined.

Results:
Among 422 ppts with evaluable images, the mean age was 32±5 y at baseline and 71±5 y at follow-up; 65% were male and 84% white. By design, 154/422 (36.5%) had the Low Risk profile at baseline, but only 5.5% maintained it at follow up. The Table shows the CAR indices, stratified by Low Risk status at baseline. Mean and maximal wall thickness measures were significantly lower for ppts with Low Risk status at baseline in the LMCA and LAD, as was overall coronary wall area in the LAD. Associations were generally as expected for individual RFs and were particularly significant for baseline obesity.

Conclusions:
These are the first data to examine long-term associations of RF burden with indices of coronary artery wall remodeling. These associations may explain part of the mechanism of the decades-long protection against development of clinical coronary events observed in individuals with the Low Risk profile in younger adulthood.
Abstract 18805: Vorapaxar, A Platelet Thrombin-Receptor Antagonist, in Patients with Non-ST-Segment Elevation Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention: Results from the TRACER Trial
Authors: Valgimigli Marco , Tricoci Pierluigi , Huang Zhen , Aylward Philip , Armstrong Paul , White Harvey , Widimsky Petr , Harrington Robert , Cequier Angel , Ziada Khaled , Chen Ming-Fong , Chen Edmond , Lokhnygina Yuliya , Wallentin Lars , Strony John , Mahaffey Kenneth , Moliterno David
Published: April 2024

Objectives: Evaluate the effects of protease-activated-receptor 1 antagonist vorapaxar in NSTE ACS pts undergoing PCI during index hospitalization.

Methods: This prespecified analysis of a post-randomization subgroup evaluated the effects of vorapaxar compared with placebo among TRACER pts undergoing PCI, focusing on implanted stent type (drug-eluting stent [DES] vs bare metal stent [BMS]).

Results: Among 12,944 TRACER pts, 7479 (58%) underwent PCI during index hospitalization; 1576 (44.4%) of vorapaxar pts and 1484 (42.1%) of placebo pts received exclusively BMS implantation. During the treatment period with vorapaxar, the median duration of thienopyridine therapy was 133 (47-246) days with BMS and 221 (88-341) days with DES. At 1 yr, the primary endpoint (CV death, MI, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization) occurred in 10.4% of pts with vorapaxar vs 10.6% of pts with placebo (HR 0.96; 95% CI 0.83-1.10). The key secondary endpoint (CV death, MI, stroke) occurred in 6.8% with vorapaxar and 7.3% with placebo (HR 0.89; 95% CI 0.75-1.05). A trend of interaction was noted on CV death, MI, and stroke between treatment and type of implanted stent, with pts receiving BMS showing a relatively greater effect from vorapaxar (Figure). GUSTO moderate/severe bleeding was overall increased with vorapaxar with no statistical interaction, although the relative increase appeared less with BMS (HR 1.27; 95% CI 0.85-1.90) than with DES (HR 1.70; 95% CI 1.14-2.53).

Conclusions: In this post-randomization subgroup analysis, the efficacy of vorapaxar among PCI pts is consistent with the overall TRACER results. The duration of dual antiplatelet therapy was shorter with BMS than with DES, and a noteworthy signal of increased efficacy and less bleeding liability was noted in BMS pts. These results point to further research opportunities to evaluate the potential clinical role of vorapaxar.
Abstract 18867: Multiple Biomarkers Predict Risk of Incident Heart Failure in Population Free of Cardiovascular Disease: The Multi-Ethnic Study of Atherosclerosis
Authors: Balfour Pelbreton C , Bertoni Alain G , Chen Haiying , Chahal Harjit , Lima Joao A , Herrington David M
Published: April 2024

Background:
Heart Failure is a complex syndrome with numerous patho-physiological mechanisms and altered biomarker profiles. Biomarkers that indicate risk for incident HF are less well established. Objective: To evaluate the predictive role of biomarkers reflecting different patho-physiological pathways for prediction of HF in the Multi-Ethnic Study of Atherosclerosis (MESA), a large multi-ethnic community based cohort.

Methods:
We evaluated 6,814 Caucasian, African-American, Hispanic, and Chinese participants with mean age 62.3 ± 10.3 (51.4% female). We examined individual and joint associations of CRP, fibrinogen, NT-proBNP, homocysteine, and urine albumin to creatinine ratio (UACR) with incident HF using Cox proportional-hazard models adjusting for age, sex, ethnicity, systolic BP, antihypertensive therapy, smoking, diabetes, total cholesterol, BMI, left ventricular hypertrophy by ECG, and estimated glomerular filtration rate. Hazard ratios (HR) were calculated per 1-SD change in log (biomarker). A multivariable-adjusted stepwise procedure (p for retention < 0.05) was used to determine the independent contributions of the biomarkers for prediction of HF. We examined the increased model discriminative value with calculation of the C-statistic. Net reclassification index (NRI) was calculated with participants stratified in 3 risk categories; low (10%).

Results:
During median follow-up of 7.6 years, 176 participants developed HF. In multivariable-adjusted models, 3 of 5 biomarkers were individually associated with HF; NT-proBNP, CRP, and UACR [HRs: 2.46, (95% CI 2.11-2.87), 1.28 (1.09-1.50), and 1.29 (1.14-1.45), respectively]. After stepwise selection only NT-proBNP [HR: 2.56 (95% CI 2.17-3.03)] and CRP [HR: 1.20 (95% CI 1.03-1.41)] remained statistically significant. The C-statistic significantly increased when NT-proBNP and CRP were added to the model (0.864 vs. 0.808). The addition of biomarkers improved NRI (NRI 0.29, p <0.0001).

Conclusions:
CRP and NT-proBNP are significant independent predictors and substantially improve risk classification for incident heart failure. More research is warranted to determine the clinical utility of measuring these biomarkers in subjects at risk for incident heart failure.
Abstract 18896: Preliminary Analysis of the National Child Death Review Database for Cardiovascular Deaths
Authors: Vetter Victoria L , Covington Theresa M , Dykstra Heather , Overpeck Mary , Iyer V. Ramesh , Dugan Noreen P , Haley Danielle M , Hammond Rachel , Shults Justine
Published: April 2024

Background:
The National Center for the Review and Prevention of Child Deaths (NCRPCD) maintains a unique multistate database supported by the US Maternal and Child Health Bureau to record circumstances of child deaths with data submitted by state Child Death Review teams.

Methods:
We aim to describe circumstances of child cardiovascular deaths (CVD) in the NCRPCD database and to identify modifiable risk factors, potential disparities, and their contribution to sudden cardiac death (SCD) and non-sudden CVD. An analytical dataset involving 16 states was developed for analysis of CVD cases occurring in 2005-2009. We developed algorithms to identify SCD and non-sudden CVD cases. Logistic regression was used to identify correlates of SCD among all CVD cases.

Results:
CVD cases (1099) were 0.6 (0.1, 9.6) yrs median (IQR) with 55% ≤1 yr and 22% ≥12 yrs; Male 58%; White 70%, Black 22%, Asian 2%, Other 5%; Hispanic ethnicity 19%. Prior conditions, present in 47%, included congenital heart defects (CHD), 23%; cardiomyopathy (CM), 4%; arrhythmia (AR), 2%. Most deaths occurred at home/school, 30% or in the hospital, 40%. Common causes of death were CHD 21%; AR 17%; and CM 8%. Reclassification indicated 59.1% (649/1099) of CVD were SCD and 33.8% (371/1099) were non-sudden CVD. Differences in SCD (versus non-sudden death) were noted by race with SCD in 73.2% blacks vs. 60.9% whites (p=0.02). More SCD occurred in the suburban (84.9%) than in urban sites (57.6%) p<0.0005. Among SCD, 911 was called in 92.6% of suburban and 78.6% of urban SCD (p=0.006). In a multivariable logistic regression model (Table) being black, older (>6 months), Hispanic, and living in the suburbs were significantly associated with SCD.

Conclusions:
The NCRPCD database contains valuable information to help understand and prevent SCD. Evaluation of risk factors for SCD indicated a higher risk by race, age, ethnicity, and location.
Abstract 18917: High Overweight and Obesity Rates in Fontan Patients: a Twenty-Year History
Authors: Chung Stephanie T , Hong Borah J , Patterson Lance W , Petit Christopher J , Ham Jee-Young N
Published: April 2024

Background:
Elevated body mass index (BMI) is a major independent risk factor for cardiovascular disease. The prevalence of obesity in patients with Fontan physiology is unknown and the added disease burden is unclear. There are no longitudinal studies on weight trends in Fontan patients. Objective: To determine the prevalence of overweight (OW) and obesity (OB) and to track longitudinal changes in BMI in children and adults treated with Fontan palliative surgery at a major tertiary care center. Design and

Methods:
We performed a retrospective chart review of all patients who underwent the Fontan operation between 1992 - 2012. Subjects were categorized by age as outlined by the NHANES database (2-5 y, 6-11 y, 12-19 y, adults) and growth records were reviewed. BMI percentiles were calculated for children using the US Centers for Disease Control (CDC) growth charts. CDC definitions of OW and OB were used.

Results:
Anthropometric data were available for 701 subjects (n=401, age 2-5 y; n= 333, age 6-11 y; n=217, age 12-19 y; and n=128, adult). Among adults, 38% (n=49) were OW or OB at last clinic visit, with 21.1% (n=27) OW and 17.2% (n=22) OB. Longitudinal data were available for 83 adult subjects. Of this subset, 14.5% (n=12) were OW or OB in childhood, 85.5% (n=71) had BMI < 85th percentile. Forty seven percent of OB adults were OW or OB in childhood (n=9/19). The likelihood of being OW/OB as an adult was 2.5 times higher if there was OW/OB present during childhood (CI 1.8-3.6, p =<0.001). Within children, the total rates of OW and OB in age groups 2-5 y, 6-11 y and 12-19 y were 24.7% (n=99), 26.4% (n=88) and 13.3% (n=29), respectively. Childhood OB rates were 13.4 % (n=54), 12% (n=40), and 4.6% (n=10), respectively, compared to national obesity rates of 10.4%, 19.6%, and 18.1% (NHANES 2007-2008).

Conclusion:
In this high-risk population, obesity rates for adults are nearly as high as those reported in national data, and are higher than national rates for children ages 2-5y. Longitudinal data in adult Fontan patients show that increased weight begins in childhood. The impact of early-onset obesity especially in young children with complex congenital heart disease is unknown. Assessment of the additional disease burden of obesity in this population requires additional study.
Abstract 18947: Circulating esRAGE is Associated with a Pro-Inflammatory/Pro-Atherothrombotic Profile in Familial Combined Hyperlipidemia Patients with Non-alcoholic Fatty Liver Disease
Authors: Santilli Francesca , Scarpini Francesca , Bocchia Monica , Fabbri Alberto , Lunghetti Stefano , Navarri Romina , Puccetti Luca
Published: April 2024

Familial Combined Hyperlipidemia (FCHL) is the most common atherogenic lipid disorder, with FCHL patients representing 10-20% of premature myocardial infarction survivors. A significant overlap with non-alcoholic fatty liver disease (NAFLD) and metabolic syndrome (MS) may suggest a common pathogenesis and explain the increased cardiovascular burden. Plasma levels of endogenous secretory receptor for advanced glycation-end-products (esRAGE), have been inversely associated with components of the MS, and may counteract RAGE-mediated pathogenesis, by acting as a decoy. We hypothesized that a ligand-RAGE pathway hyperactivity and inadequate endogenous protective response by esRAGE, as well as a number of pro-inflammatory and pro-atherothrombotic biochemical abnormalities, may be associated with the occurrence of NAFLD in a fraction of FCHL patients, even before and regardless of the diagnosis of MS. We performed a cross-sectional comparison among 72 patients with vs. 72 without NAFLD. Each group included FCHL alone, MS alone, and FCHL plus MS (n=24 each group). Regardless of the underlying biochemical abnormality (FCHL or MS), circulating esRAGE was significantly lower in patients with NAFLD as compared to their counterpart, in association with higher levels of CD40 ligand (CD40L), endogenous thrombin potential (ETP) and oxidized LDL and lower levels of IL-10 and adiponectin. MS and FCHL have additive effects on the above mentioned abnormalities. esRAGE was inversely related to CD40L and oxLDL and directly related to IL10 and adiponectin only in the groups with MS and NAFLD. Among patients with FCHL, those with the lowest esRAGE and highest degree of pro-inflammatory and atherothrombotic abnormalities coincide with the clinical diagnosis of NAFLD, regardless of MS, suggesting an interplay between adipokine secretion, oxidative stress and platelet/coagulative activation accelerating NAFLD occurrence as a proxy for cardiovascular disease.
Abstract 18968: Correlation Between Myocardial Perfusion and Contractility by SPECT and MRI, and Electromechanical Mapping Parameters in Patients with Advanced Coronary Artery Disease. A PRECISE Substudy
Authors: Sanz-Ruiz Ricardo , Gutierrez Ibañes Enrique , Perez David Esther , Alonso Farto Juan Carlos , Elizaga Corrales Jaime , Fernández Santos Maria Eugenia , Sanchez Fernandez Pedro Luis , Fernández Avilés Francisco
Published: April 2024

Introduction:
electromechanical mapping (EMM) of the left ventricle (LV) is a new technique that provides us with voltage (unipolar and bipolar voltage) and contractility (lineal local shortening) information of the LV. The objective of this study was to assess the correlation between EMM parameters and myocardial perfusion and contractility by SPECT/MRI, in patients with advanced chronic coronary artery disease (CAD).

Methods:
the PRECISE clinical trial of freshly isolated adipose-derived stem cells for angiogenesis included pts with chronic stable CAD, reversible perfusion defects detectable by SPECT and not amenable for revascularization. Wall motion score index was assessed with MRI imaging in all patients (normal=1; hypokinetic=2; akinetic=3). Perfusion was studied with SPECT Tc-99m sestamibi (normal=grade 0; most impaired=grade 4) and EMM was performed with the NOGA XP system, all using the same 17-segment polar map of the LV. All studies were performed and analyzed by independent observers blinded to the results of the other techniques.

Results:
27 consecutive pts were included (62±8 years and 77% male). A total of 865 SPECT and MRI segments were correlated with the corresponding EMM data. Segments with better perfusion at rest and stress (fig.1), and segments with better WMSI by MRI (fig.2) had better voltage and local shortening parameters.

Conclusions:
EMM is a useful technique for assessing myocardial health status in terms of perfusion and contractility in chronic CAD pts, and can be used for a precise delivery of stem cell therapy.
Abstract 18970: Angiotensin-(1-7) Enhances the Regenerative Capacity of Cardiac Progenitor Cells (CPCs, Islet-1
+
) in Ischemia-induced Cardiac Injury Model
Authors: Qi Yanfei , Bruce Erin , Vinayak Shenoy , Jeffrey Colleen , Liu Meng , Lin Fan , Yuan Wei , Abbatematteo, Joseph , Katovich Michael , Raizada Mohan
Published: April 2024

Stem cell therapy has achieved limited success to provide sufficient exogenous reparative support in ischemic heart diseases (IHD). We evaluated the hypothesis that transduction of CPCs with Ang-(1-7) would improve their regenerative capacity, as this peptide has been shown to improve hematopoietic progenitor cell functions. First, we determined if Ang-(1-7) improves CPC functions
in vitro
. Angiogenesis and migratory potential of CPCs, lenti-Ang-(1-7) transduced CPCs and CPCs treated with 1µM Ang-(1-7) were evaluated. Ang-(1-7) enhanced the CPC capability to form tubes; protected CPCs from hypoxia (H) induced inhibition of migration (CPC 688.7 ± 52.8, H treated CPC 124.5 ± 187.7, H+lenti-Ang-(1-7) 617.2 ± 45.4, H+1µM Ang-(1-7) 878.8 ± 303.9; RFU); reduced ACE mRNA level in the CPCs and shifted the balance to the vasoprotective axis of the RAS. Next,
in vivo
studies were carried out by injecting CPCs or lenti-Ang-(1-7) transduced CPCs (4 × 10
6
), into the jugular vein three days after permanent left anterior descending coronary artery ligation. Echocardiography, hemodynamic, histological parameters, and capillary vessel density were measured to assess cardiac function and the effects of cell transplantation four weeks thereafter. Results from the
in vivo
studies demonstrated that myocardial infarction (MI) significantly reduced fractional shortening (FS, 33.0% ± 1.5 vs 59.5% ± 1.9 for control), increased ventricular hypertrophy (VH, 3.6 ± 0.1 vs 2.7 ± 0.1for control, (g/kg)), and decreased dP/dt
max
(7235 ± 271.9 vs 10394 ± 326.3 for control, mmHg/sec). In comparison to MI, CPCs alone restored FS by 22%, reversed VH by 11%, and improved dP/dt
max
by 23%. Remarkably, Ang-(1-7) expressing CPCs further improved FS by 44%, decreased VH by 15%, and attenuated the reduction in dP/dt
max
by 42%. Finally, capillary density in the peri-infarct myocardium was increased by 59% with CPCs alone and this capillary density was further increased by 139% with Ang-(1-7) expressing CPCs. In conclusion, these observations, for the first time, demonstrate that Ang-(1-7) enhances the regenerative capacity of CPCs and promotes angiogenesis to improve cardiac hemodynamic following MI. They suggest that Ang-(1-7) transduced CPC could have therapeutic potential in IHD.
Abstract 18993: High Prevalence of Cognitive Impairment in Older Heart Failure Patients at Hospital Discharge
Authors: Demers Catherine , Harkness Karen , Heckman George A , Prior Peter , McKelvie Robert S , Thabane Lehana , Dafoe Nancy , Foster Gary , Pizzacalla Anne , Virk Sindy , Morris Cara , Teo Koon K , Patterson Christopher
Published: April 2024

Background:
Evidence suggests that HF patients do not consistently engage in self-care. One possible reason may be the presence of undetected mild cognitive deficits (MCD). The primary objective of this study was to prospectively evaluate whether MCD measured with the Montreal Cognitive Assessment (MoCA) test in HF patients aged ≥60 years at hospital discharge is associated with impaired ability to self-care (measured with the Self-Care Heart Failure Index (SCHFI), patient is considered adequate if score ≥70/100).

Methods
/

Results:
We prospectively recruited HF patients within 48 hours from hospital discharge. In addition to the assessment of cognitive function, we measured baseline intelligence (NAART35), depression (Geriatric Depression Scale,
GDS15
), caregiver burden (modified Oberst Caregiver Burden Scale), activities of daily living (Barthel index), and frailty (Clinical Frailty Scale, CFS). We have recruited 51 patients (mean age 78, SD 7 years, 51% male) in this study. Sixty eight percent of patients have a high school education or less, 45% are married, 42% widowed, and 64% of patients have a total household income of <$40,000. Fifty three percent of patients have a left ventricular ejection fraction >45%. The mean number of medications at hospital discharge is 10 (SD 4). The mean MoCA score at baseline was 22 (SD 4) and 87% of patients had a MoCA score <26 (indicating cognitive impairment). The SCHFI at baseline was 64 for self-maintenance, 46 for self-management, and 63 for self-confidence. Caregiver burden was low for the 2 subscales (Demand: 1.9, Difficulty: 1.3). The mean score for the
GDS15
was 4/15 (no depression: 0-4/15), Barthel index was 82/100 indicating that the patients are not fully independent for ADLs. The mean CFS score was 4/7 indicating that these individuals are limited by symptoms during their activities.

Conclusion:
To our knowledge, this is the first prospective study at hospital discharge indicating a high prevalence of cognitive impairment. These results suggest that older HF patients have significant undetected cognitive deficits which may impact on their ability to self-care, which may in turn potentially lead to re-hospitalization early after hospital discharge.