bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 18372: Platelet Reactivity Measurements Before and After Percutaneous Coronary Intervention Among Patients Undergoing Early Invasive Management for Acute Coronary Syndrome
Authors: Carvalho Leonardo , Tang Chin Chee , Long Teo Zhen , Yan Bryan , Huang Xu-Rui , Troughton Richard , Fong Alan , Mejin Melissa , Ting Chloe , Jing Mingxue , Kong Kylie , Lee Chi Hang Ronald , Chia Boon Lock , Tang Huay Cheem , Richards Arthur Mark , Chan Mark
Published: April 2024

Introduction:
There are conflicting data on the optimal timing of platelet reactivity (PR) measurements to identify patients at risk of major adverse cardiovascular events (MACE) and bleeding.

Hypothesis:
We hypothesized that significant changes in PR occur peri-PCI

Methods:
We studied 395 patients undergoing PCI for NSTEMI/UA. Patients received, in the emergency room, aspirin (300 mg loading dose followed by 100 mg maintenance dose) and one of two P2Y
12
antagonists: clopidogrel (300 mg/ 75 mg OM) or ticagrelor (180 mg/ 90 mg BD). Adenosine diphosphate-induced multiple electrode aggregometry (Multiplate
®)
was performed to analyze PR at the time of PCI and post-PCI (24 hours). In-hospital and 30-day MACE, defined as cardiovascular death, recurrent MI, stroke or stent thrombosis, and bleeding, defined as bleeding academic research consortium (BARC) type 2 or greater bleeding, were assessed in all patients.

Results:
Patients were treated with clopidogrel [N=356 (89%)] or ticagrelor [N=39 (11%)] (Table1). The mean pre and post PCI PR was consistently higher with clopidogrel than ticagrelor. However, the mean reduction in pre-post PCI PR was 3-fold greater for clopidogrel than ticagrelor (P<0.01 by Kruskall-Wallis test). In-hospital and 30-day post-discharge MACE and bleeding events corresponded closely with the frequency of pre and post PCI hyporesponders, defined as PR >468 AU*min, and hyperresponders, defined as PR > 300 AU* min, respectively.

Conclusion:
Large differential reductions in PR were observed within 24 hours post-PCI. PR measurements tracked well with inhospital and post-discharge MACE and bleeding events. Among patients with only pre-PCI measurement, consideration should be given to repeating PR measurements within 24 hours post-PCI.
Abstract 18390: Aortic Pulse Wave Velocity Measurement by Doppler Technique During Transesophageal Echocardiography Examination: A Feasible and Reproducible Method
Authors: Plamondon Isabelle , Somma Jacques , Arsenault Jean , Saint-Pierre André
Published: April 2024

Introduction:
Aortic pulse wave velocity (aPWV) is the gold-standard measure of arterial stiffness. In daily practice, the carotid-femoral PWV (cfPWV) is widely used for arterial stiffness assessment. PWV is calculated by dividing traveled distance by transit time. But, the inaccuracy of distance measurement and the approximation of the true aortic length which change with age may influence the absolute value of cfPWV.

Making the assumption that the flow wave of continuous spectral Doppler corresponds to the real pulse wave, aPWV can be directly measured in the aorta by transesophageal echography (TEE). The aim of this study is to evaluate whether aPWV measured by Doppler technique during TEE is easily feasible and to analyse the reproducibility of the technique.

Methods:
Doppler images were obtained from the TEE examination of the thoracic aorta in 44 patients undergoing elective cardiac surgery. From a random choice of 194 acquisitions, a total of 100 images were analyzed offline by two different investigators in two separated periods to measure the transit time according to the two tangents method.

Results:
The Bland-Altman plots illustrate that there is no significant difference nor bias between the two readings made by one observer and neither for the mean of the observations made by separated observers. Intra-observer reproducibility of the Doppler measurements was high ( Intra Class Correlation (ICC) = 0.98 and 0.96). Agreement between observer was also good (ICC=0.98).

Conclusions:
These data demonstrate that Doppler technique during TEE is a feasible and reproducible method to calculate aPWV.
Abstract 18396: Peroxisome Proliferator-Activated Receptor Gamma- Deficiency in Endothelial Cells Leads to Impaired Angiogenesis
Authors: Vattulainen Sanna , Koskenvuo Minna M , Li Caiyun Grace , Li Molong , de Jesus Perez Vinicio , Alvira Cristina , Sawada Hirofumi , Koskenvuo Juha W , Rabinovitch Marlene , Alastalo Tero-Pekka
Published: April 2024

Rationale:
TIE2 promoter mediated loss-of peroxisome proliferator-activated receptor gamma (PPARγ) in mice (TIE2CrePPARγflox/flox) (KO) leads to endothelial cell (EC) dysfunction, pulmonary arterial hypertension and osteopetrosis through loss-of osteoclasts. Although some of the functions and mechanisms of PPARγ-mediated regulation of vascular homeostasis have been revealed, the exact role of PPARγ in angiogenesis is obscure.

Methods:
The role of PPARγ in angiogenesis was evaluated in vivo in KO and wild type (WT) mice by matrigel plug assays. As the level of endothelial progenitor cells (EPC) (CD34+/VEGFR2+/CD45-) especially in circulation can reflect angiogenic capacity, their levels were assessed in peripheral blood, spleen and bone marrow (BM) in both mouse models by flow cytometry. BM transplantations were used to switch EPC phenotypes. Magnetic beads were used to isolate mouse pulmonary ECs (PEC) for functional studies. In human ECs (HMVEC) PPARγ-deficiency was studied using siRNA strategy.

Results:
In vivo angiogenesis assay showed a significant attenuation of angiogenic capacity in KO mice when compared to WT. In contrast to WT, KO mice implanted with matrigel plugs showed no significant angiogenic response to BMP2. Interestingly, KO mice had significantly (>50%) reduced EPC levels in spleen and circulation when compared to WT but their levels in bone marrow (BM) were 3-fold in KO mice suggesting a mobilization defect from the BM. WT BM transplantation rescued the mobilization defect in KO mice and normalized the EPC levels but did not rescue the angiogenesis defect. In vitro studies with mature PECs isolated from KO mice showed a 40% decrease in tube-formation and migration after VEGF and BMP2 stimulation when compared to WT cells. In line with this, PPARy-deficient HMVECs showed a similar angiogenic defect in vitro (P<0.001, N=9).

Conclusion:
PPARγ plays an important role in sustaining angiogenic potential in mature ECs both in mice and humans. Osteoclasts are essential for mobilization of EPCs from the BM.
Abstract 184: Inhibition of Nitric Oxide Synthase Attenuate Hemorrhage Induced Inflammatory Response and Protect Against Multiple Organ Injury in a Rat Model
Authors: Soliman Mona , Arafah Maha
Published: April 2024

Hemorrhagic shock activates inflammatory pathways and results in upregulation of cytokine synthesis. Nitric oxide has been implicated in the pathophysiology of hemorrhagic shock.

Objectives:
We have investigated the protective effects of inhibition of inducible nitric oxide synthase (iNOS) using N
G
- nitro-L-arginine methyl ester (L-NAME) on preventing organ injury in a rat model of hemorrhagic shock and resuscitation.

Methods:
Male Sprague Dawley rats (300-350 gm) were assigned to 3 experimental groups (n= 6 per group): 1) Normotensive rats (N), 2) Hemorrhagic shock rats (HS) and 3) Hemorrhagic shock rats treated with L-NAME (HS-L-NAME). Rats were hemorrhaged over 60 min to reach a mean arterial blood pressure of 40 mmHg. Rats were treated with 1 ml of 8 mg/Kg L-NAME intra-arterially after 60 min hemorrhagic shock. Resuscitation was performed in vivo by the reinfusion of the shed blood for 30 min to restore normo-tension. Arterial blood samples were collected from all groups at the end of the experimental period for measurement of tumor necrosis factor α (TNF-α). Biopsy samples were taken for light microscopy. Histological examination of hemorrhagic shocked untreated rats revealed structural damage. Less histological damage was observed in multiple organs in L-NAME- treated rats. L-NAME-treatment decreased the number of inflammatory cells and mitochondrial swollen in myocardial cells. Treatment with L-NAME decreased the inflammatory response to hemorrhagic shock by lowering the levels of TNF-α. L-NAME treatment reduced microscopic damage and injury in multiple organs and reduced the inflammatory response to hemorrhagic shock by inhibiting iNOS in a hemorrhagic shock model in rats.
Abstract 18410: Gastrointestinal Bleeding in Recipients of the HeartWare Ventricular Assist System
Authors: Goldstein Daniel J , Aaronson Keith D , Tatooles Antoine , Silvestry Scott C , Jeevanandam Valluvan , Gordon Robert A , Hathaway David R , Najarian Kevin B , Slaughter Mark S
Published: April 2024

Purpose:
Gastrointestinal bleeding (GIB) is a significant problem with continuous flow left ventricular assist devices. The HeartWare HVAD was recently approved for bridge to transplantation (BTT). GIB in patients supported with the HVAD as part of the pivotal BTT trial and the Continued Access Protocol (CAP) is reviewed.

Methods:
GIB events from 332 HeartWare recipients (140 BTT, 192 CAP patients) having at least 6 months of follow up (306 patient-years) were analyzed. Post implant anticoagulation consisted of heparin followed by Coumadin at a target INR of 2-3. Aspirin was recommended at 81-325 mg. Statistical analysis was performed using Fisher’s exact test for the comparison of proportions and Poisson regression for the comparison of event rates.

Results:
Forty-two (12.7%) patients (78.6% men) age 55.3 ± 11.4 yrs experienced a GIB. Overall, the 42 patients had 82 GIB events that resulted in 0.27 events PPY (range 1-7 events) with 38% experiencing a recurrent GIB. Median time to first GIB was 89 days. GIB was more frequent in patients receiving 81mg aspirin vs. 325mg (0.14 vs. 0.09 PPY, P=0.018). Patients with GIB were more likely to have ischemic CHF etiology (54.8% vs. 34.1%
P
=0.016), and diabetes (47.6% vs. 33.1%, P=0.083). Most GIB events (71/82, 86.6%) occurred >30 days post implant and 94% required transfusions. Seventeen percent of events occurred in setting of INR >3. GIB resulted in 65 rehospitalizations in 32 patients with a median length of stay of 8 days. Source of bleeding was ascribed to a definite or suspected AVM in 28% of patients while in 29% of patients, no source was identified. Location was 22% upper GI, 32% small bowel, 11% lower GI and 33% unknown. Forty-six percent of patients with GIB had an intervention such as cautery or clipping. None required surgery. There were no deaths related to GIB.

Conclusion:
GIB occurred in 12.7% of HVAD recipients followed for at least 6 months postop. GIB events were often recurrent, led to transfusions and were rarely associated with supratherapeutic INRs. Most occurred outside the perioperative window and AVMs were the predominant culprit lesion. Rehospitalizations were frequent and prolonged. Efforts to reduce the incidence of and readmissions for GIB are warranted.
Abstract 18436: Systems Biology Identifies a Gene Driving Expression of Metabolic Syndrome in Lyon Rats
Authors: Kwitek Anne E , Wang Jinkai , Ma MC John , Mennie Amanda , Pettus Janette , Xing Yi
Published: April 2024

The metabolic syndrome (MetS) is a collection of co-occurring complex disorders including obesity, hypertension, dyslipidemia, and insulin resistance. The Lyon Hypertensive (LH) and Lyon Normotensive (LN) rats are models of MetS sensitivity and resistance, respectively. To identify genetic loci influencing phenotypes underlying MetS, an F2 intercross between LH and LN was studied to identify physiological quantitative trait loci (pQTL) contributing to plasma lipid and leptin levels, blood pressure, and body weight/adiposity. We performed mRNA-seq in F2 rats to identify the loci regulating gene expression, or expression (e)QTL, followed by gene expression network analyses. Systems biology methods were applied to identify candidate MetS genes, including genes previously shown to be MetS-related. We found an eQTL hotspot on RNO17, which was also located within pQTLs for MetS-related traits. The genes regulated by this eQTL hotspot were mainly in two co-expression network modules (a mitochondria related module and a gene regulation related module) and causally affect many MetS-related traits. Multiple evidences strongly and consistently support
RGD1562963,
a gene regulated
in cis
by this eQTL hotspot as the eQTL driver gene directly affected by genetic variation between LH and LN rats. Our study sheds light on the intricate pathogenesis of MetS and that systems biology with high-throughput sequencing is a powerful method to study the etiology of complex multifactorial diseases.
Abstract 18442: Long-Term Prognostic Value of Cardiac Magnetic Resonance and Echocardiography After Reperfusion Therapy in ST-Segment Elevation Myocardial Infarction
Authors: Kwon Susan H , Lee Kwang J , Mohammed Selma F , Barsness Gregory W , Bell Malcolm R , Larsen David , Glockner James , Oh Jae K
Published: April 2024

Background:
The aim of this study was to determine whether adding DE-CMR and/or TTE based parameters beyond known clinical factors provides incremental improvement of predicting long-term outcomes in STEMI patients who undergo acute reperfusion therapy.

Methods and Results:
One hundred twenty patients with first time STEMI who underwent PCI (74%), fibrinolysis (3%), and both (19%), were studied by both delayed enhancement cardiac magnetic resonance (DE-CMR) and transthoracic echocardiogram (TTE) during the acute phase of myocardial infarction. The primary endpoint was major adverse cardiac events (MACE). There were 28 events (6 deaths, 13 recurrent ischemia, and 9 heart failure) over a median follow-up of 4 years. We defined incremental increase in prognostic value by increase in Cox proportional hazards global chi square (χ
2
) and/or increase in c-index with the addition of TTE and/or CMR parameters after adjusting for clinical variables. Among the clinical data, heart rate (HR: 1.02, p=0.047) and troponin (HR: 1.13, p=0.013) predicted MACE (χ
2
: 12.4, P=0.002; C index 0.69). After adjusting for these clinical factors, adding TTE parameters (left ventricular end systolic volume index [HR: 1.05, p<0.0001] and mitral valve deceleration time [HR: 0.99, p=0.036]), increased the global χ
2
to 24.6 and C index to 0.74 (p<0.0001). When CMR parameter (infarct size [HR: 2.92, p<0.0001]) was added to the clinical data alone, there was greater increase in global χ
2
to 36.8 and C index to 0.83 (p<0.0001). Addition of DE- CMR to clinical data combined with TTE measures showed significant incremental value with increased χ
2
difference of 17.6 (p<0.0001). There was no significant incremental value of adding TTE to clinical data combined with DE-CMR (p>0.05).

Conclusion:
DE-CMR provides significant incremental value for prognosticating adverse cardiac events over clinical data alone (or when in combination with TTE) in STEMI patients who undergo reperfusion therapy.
Abstract 18445: Embryonic Origins of Vascular Progenitors in the Adult Murine Aorta
Authors: Steinbach Sarah K , Carruthers Martha H , Smyth David , Miller Freda D , Robbins Clinton S , Husain Mansoor
Published: April 2024

Background:
The vasculature is derived from many different sources during embryonic development, including neural crest, and mesoderm of splanchnic, pharyngeal and somitic origin. Vascular smooth muscle cells (VSMC) of the aorta are similarly derived from several embryonic sources, however the developmental and phenotypic heterogeneity of their progenitors is poorly understood.

Methods & Results:
Using specialized Cre mice which irreversibly mark cells of specific embryonic origin, we isolated distinct subsets of progenitors from the aorta that are derived from neural crest (Wnt1), somite (Myf5) and another (Brachyury; T) mesoderm source. Intriguingly, a population of lineage-marked cells that express high levels of the reporter tdTomato (tdT-hi) is uniquely expressed in the aorta, and not found in blood, bone marrow or spleen. In Myf5- and T-marked lineages, this tdT-hi population gave rise to clonally-derived spheres that differentiated into VSMC, adipocytes, S100β-positive neural cell and macrophage in vitro. Consistent with the observed progenitor activity of the tdT-hi population, a subset of these cells co-express Sox2 and Sca1, known adult stem/progenitor cell markers. Further evidence of progenitor activity was demonstrated in an in vitro CFU assay where tdT-hi cells gave rise to Mac3+Ly6C+ macrophage and Ly6G+ neutrophils. As experimental cell culture is prone to artifact, and differentiated cell types may not be represented in vivo, we conducted complementary analyses in mice. Leukocytes such as macrophage, B-cells and T-cells from Myf5-Cre mice were found to be lineage-marked cells with lower levels of tdT expression (tdT-lo), suggesting derivation from somitic mesoderm and differentiation from the tdT-hi aortic progenitor. Indeed, somite-derived leukocytes were enriched over 6-fold in the arch of the aorta vs. the blood, bone marrow and spleen of these mice.

Summary:
These data support the existence of an aorta-resident Myf5 lineage-marked (i.e. somitic mesoderm-derived) progenitor capable of contributing to both VSMC and blood compartments. How these neural crest vs. somite- and other mesoderm-derived aortic-resident progenitors and their progeny participate in vascular pathogenesis is not yet known.
Abstract 18448: Ckit Marks Cardiac Neural Crest Progenitors in the Developing Mouse Heart
Authors: Chatzistergos Konstantinos , Takeuchi Lauro M , Saur Dieter , Seidler Barbara , Balkan Wayne , Kanashiro-Takeuchi Rosemeire O , Hare Joshua M
Published: April 2024

Introduction:
Cardiac stem cells expressing the receptor tyrosine kinase c-Kit are a promising cell-based therapy for heart regeneration. However, there is ongoing controversy regarding the embryogenic origins and identity of these cells. We addressed this issue by using a tamoxifen-inducible cKitCreERT2/+ allele to establish the genetic fate-map of c-Kit in the developing mouse heart.

Hypothesis:
c-Kit marks an embryonic myocardial progenitor cell population which contributes extensively to mammalian cardiogenesis.

Methods:
cKitCreERT2/+ mice were crossed with R26RLacZ or IRG Cre-reporter mice. To induce recombination in c-Kit expressing cells, females pregnant with cKitCreERT2/R26RLacZ or cKitCreERT2/IRG fetuses were administered intraperitoneal injections of tamoxifen (100μl of 20mg/ml) from 7.5-8.5 (n=10) or 9.5-12.5 (n=15) days post coitum (dpc). Embryos were analyzed at 18.5dpc.

Results:
Confocal analysis, as well as x-gal staining, revealed that during 7.5-8.5dpc (the period which first and second heart field myocardial progenitors contribute to cardiogenesis) few to no labeled cells were seen in the heart, indicating that c-Kit does not mark progenitors of the cardiogenic mesoderm. In contrast, there was extensive cardiomyogenic contribution from cells expressing c-Kit during 9.5-12.5dpc. A mean of 171.4±21 c-Kit derivatives/field were detected throughout the myocardium [cells/field: 15.2±5.5 in outflow tract (OFT); 5.8±1.0 in left atrium; 16.1±4.7 in right atrium; 39.4±6.3 in right ventricle; 30.1±3.8 in left ventricle; 72.6±11.0 in interventricular septum], ~30% of which were cardiomyocytes (48.1±5.8 per field). Importantly, c-Kit contributed to all expected cardiac neural crest derivatives, including OFT, cardiac and aortic valves, cardiac conduction system, epicardium, endocardium and myocardium. Consistent with a neural crest origins, contribution to endothelium and smooth muscle of the OFT was documented, although coronary vascular cell differentiation was not observed

Conclusions:
Collectively, our findings strongly support that adult c-Kit+ CSCs are postnatal derivatives of c-Kit+ cardioblasts of neural crest origin, an original source of cardiomyocytes during cardiogenesis.
Abstract 18477: Left Ventricular Ejection Fraction is Not Sensitive Enough to Accurately Determine Timing of Surgical Referral for Asymptomatic Patients With Chronic Mitral Regurgitation
Authors: Maniar Hersh S , Brady Beckah D , Lee Urvi , Cupps Brian P , Kar Julia , Pasque Michael K
Published: April 2024

The current clinical guidelines for
asymptomatic
patients with chronic MR, utilize EF to trigger surgical referral. We hypothesize that
1)
EF is not sensitive enough to detect the earliest contractile injury in chronic MR and
2)
injury associated with chronic MR is not global but rather heterogeneous, occurring regionally and predictably, and prior to the onset of global left ventricular (LV) dysfunction.

Asymptomatic:
patients with chronic MR and
normal
left ventricular EF by echocardiography (n=14) underwent cardiac MRI with tissue tagging. The point-specific comparison (at 15,300 LV grid points) of multiple strain parameters to a 60-patient normal human strain database allowed
normalization
of patient-specific regional contractile function. Data was color-contour mapped over patient-specific 3D geometry, then further averaged across six LV regions (anterior, anterolateral, posterolateral, posterior, posteroseptal, anteroseptal).

Global:
LV function by multiparametric strain analysis was normal for all 14 MR patients when compared to normal controls. Despite overall preserved global LV function, the LV septum demonstrated significantly worse

normalized

contractile function when compared to other regions of the LV (
0.07
± 0.42 vs
-0.40
± 0.54,
p=0.009
). Hyper-contractile regions (lateral walls) appeared to compensate (p=0.002) for the reduced septal contractile function thereby masking injury detection by

global

indices. In asymptomatic MR patients with normal global LV function, contractile injury is heterogeneous, with a consistent distribution pattern identifying the LV septum as being injured earliest with contractile compensation by other regions. Rather than relying upon global LV contractile metrics, which does not detect early onset of injury, asymptomatic chronic MR patients should be followed with surveillance of early injury (or “sentinel”) LV regions (LV septum) with high-resolution metrics of regional contractile function.
Abstract 18487: Characteristics and Outcomes of Patients With Severe Aortic Stenosis (Peak Gradients > 125 mm Hg)
Authors: Sodhi Nishtha , Poddar Kanhaiya Lal , Goel Sachin , Modi Dhruv , Bajaj Navkaranbir , Rahim Shiraz , Tuzcu E. Murat , Svensson Lars G , Griffin Brian P , Kapadia Samir R
Published: April 2024

Background:
Limited data exists about the unique echocardiographic characteristics of patients with very high gradient severe aortic stenosis (VHG-SAS). We sought to determine if there are differences in left ventricular hypertrophy severity, ejection fraction (EF), and coronary artery disease (CAD) status in patients with VHG-SAS compared to severe AS patients with lower gradients.

Methods:
We identified patients with greater than 125 mm Hg peak gradients defined as VHG-SAS and patients with peak gradients between 64-125 mm Hg defined as high gradient severe AS (HG-SAS) evaluated between 1994 and 2011from our echocardiographic database. We then propensity matched these patients based on age and gender and compared their echocardiographic characteristics.

Results:
340 patients with HG-SAS and 212 patients with VHG-SAS were identified. Matched pairs of 212 patients were analyzed for a variety of baseline comorbidities and echocardiographic parameters (Table).

Conclusions:
Patients with VHG-SAS have fewer cardiac comorbidities (CAD, Mitral regurgitation, Depressed EF, Diabetes, Hypertension) compared to HG-SAS patients. Furthermore, patients with VHG-SAS have a smaller LV Size and greater wall thickness suggesting an adequate compensatory response to pressure overload.
Abstract 18492: Effectiveness of Lifestyle Intervention by Obesity Status: Does One Size Fit All?
Authors: Azar Kristen M , Xiao Lan , Ma Jun
Published: April 2024

Most U.S. adults are overweight or obese with severe obesity projected to increase 130% within 2 decades. Little is known about the effectiveness of efficacious lifestyle intervention by severity of obesity once adapted to real-world settings. This study compared by baseline body mass index (BMI) category (25-≤30, 30-≤35, or 35+) the effects of 2 primary care-based lifestyle interventions among overweight or obese adults with pre-diabetes and/or metabolic syndrome randomized to receive usual care alone (n = 81) or usual care plus a coach-led (n = 79) or self-directed (n = 81) behavioral weight-loss intervention.

Each used a Diabetes Prevention Program-based 12-week core curriculum plus technology-mediated coach contact and self-monitoring for a total of 15 months. Between-group differences at 15 months were evaluated by intention-to-treat and tests of group by baseline BMI category interactions in repeated-measures (3, 6 and 15 months) mixed models (SAS, version 9.2). Compared to usual care, the coach-led intervention resulted in significantly greater reductions from baseline to 15 months in BMI (primary outcome) and weight for all categories, in waist circumference (WC) for BMI 25≤30 and 35+, and in fasting plasma glucose levels for BMI 30≤35 and 35+ (largest
P
= .02). In contrast, self-directed intervention led to greater improvements than did usual care in BMI (
P
= .03) and weight (
P
= .02) only for BMI 25≤30, in WC for BMI 30≤35 (
P
= .03), and in glucose levels for BMI 35+ (
P
= .02). Moreover, BMI and weight (
P
= .01) and WC (
P
= .04) reductions for BMI 35+ were significantly greater in the coach-led vs. self-directed intervention.

Overweight participants (BMI 25 ≤ 30) responded comparably to interventions, both of which were more effective than usual care.

In conclusion, baseline BMI may influence treatment effectiveness. Clinicians and researchers should take an individual’s baseline BMI into account when developing or recommending a weight-loss treatment strategy.
Abstract 18498: Regulator of Calcineurin 1 (RCAN1): A New Factor in the Control of Mitochondrial Dynamics, Metabolism, and Cardiomyocyte Survival
Authors: Parra Valentina , Rotter David , Pedrozo Zully , Rothermel Beverly A
Published: April 2024

Dysregulation of calcium handling and mitochondrial function are hallmarks of heart disease. Furthermore, mitochondrial dynamics and metabolism influence the susceptibility of the heart to ischemia reperfusion (I/R). Regulator of Calcineurin 1 (RCAN1) is an endogenous feedback inhibitor of calcineurin, a calcium-activated phosphatase involved in pathological cardiac remodeling. The hearts of mice with a targeted disruption of Rcan1 are more susceptible to damage from I/R in vivo. Here we have used an in vitro model of simulated I/R (sim-I/R) and advanced mitochondrial imaging techniques to dissect RCAN1’s cardiomyocyte-autonomous role in mitochondrial dynamics and cell survival. SiRNA was used to deplete the RCAN1.4 and RCAN1.1 isoforms from neonatal rat ventricular myocytes (NRVMs). Cultures were subjected to 6 hours of sim-I/R followed by 12 hours of reperfusion. Death, measured as LDH release, was significantly greater in the siRCAN1-depeleted cultures than in si-controls. Si-depleted NRVMs were dyed with Mitotracker-green and three-dimensional images obtained by confocal microscopy. Z-stacks of thresholded images were volume-reconstituted. Our results show that siRCAN1-depleted NRVMs have a decrease in the mean volume of mitochondrial particles and an increase in the total number of these organelles. Consistent with increased mitochondrial fission, the rate of ATP production and the mitochondrial membrane potential were lower in siRCAN1-depleted NRVMs compared to control siRNA treated cells. There was also a profound redistribution of the mitochondrial network, decreasing the functional coupling between mitochondria and endoplasmic reticulum, assayed as a decrease in mitochondrial calcium uptake capacity. In vivo and in vitro ultraestructural EM studies showed increased mitochondrial fragmentation and a loss of the cristae structure. Finally, there was evidence of sarcomeric hypertrophy in NRVMs depleted of RCAN1, correlating with a switch to a more glycolytic metabolism. These studies suggest that RCAN1 helps preserve a functional mitochondrial network, providing new insights into the role of mitochondrial dynamics and calcineurin/RCAN1 regulation in adaptive and pathological cardiac remodeling.
Abstract 18536: Performance of Framingham Risk Function With Coronary Artery Calcium in Predicting Major Coronary Events in an Asian Cohort
Authors: Onuma Oyere K , Chun Eun Ju , Pencina Karol , Massaro Joseph M , O’Donnell Christopher J , Hoffmann Udo
Published: April 2024

Background:
In non-White populations, the original Framingham risk functions (FRF) overestimates coronary heart disease (CHD) risk and requires recalibration. We tested whether the inclusion of coronary artery calcium (CAC) can improve the performance of the FRF in CHD prediction in an asymptomatic Asian cohort.

Methods:
We determined risk factors, CAC burden and CV outcomes in a sample of 4502 asymptomatic South Koreans (from the registry-based ESCORT Study) and in 3141 asymptomatic Caucasian participants from the Framingham Heart Study (FHS). Primary endpoint was a composite of cardiovascular death, myocardial infarction, and unstable angina with revascularization. We assessed both the discriminatory value of the original FRF before and after the addition of CAC using area under the receiver operator characteristic (AUC) and the calibration/predictive ability using the D’Agostino-Nam Chi squared test for survival data, where a chi-square statistic > 20 indicates poor calibration.

Results:
There were 95 hard CHD events (45 ESCORT, 50 FHS) over a 55 month (ESCORT) and 60 month (FHS) follow-up period. For the FRF, the AUROC was 0.82, and the D’Agostino-Nam chi-squared statistic was 22.59 (p = 0.007) for predicting MACE in the ESCORT cohort. After the addition of CAC, the AUC improved to 0.85 and the D’Agostino-Nam chi-squared statistic improved to 16.14 (p = 0.064). The Caucasian-derived FRF model had poor predictive ability/calibration and consistently overestimated event rates in the Asian ESCORT cohort over all risk categories. For instance, in the 10th decile of risk, the predicted event rate using the FRF was 6% compared to an actual rate of 3.5% in the ESCORT cohort (Figure 1a)

Conclusion:
Addition of CAC to the classic Framingham risk functions significantly improves its performance in terms of discrimination and calibration in the prediction of major adverse CHD events in an Asian (South Korean) population.
Abstract 18538: Subclinical Left Ventricular Dysfunction, Adverse Myocardial and Aortic Remodeling in Patients With Tetralogy of Fallot Late After Surgical Repair
Authors: Rickers Carsten , Andrade Ana , Jerosch-Herold Michael , Voges Inga , Pham Minh H , Shah Ravi , Hart Christopher , Wegner Philip , Gabbert Dominik , Kramer Hans Heiner
Published: April 2024

Introduction:
In patients after repair of tetralogy of Fallot (ToF) there is increasing evidence that left ventricular dysfunction and dilation may be present even in younger patients, which could potentially accelerate the occurrence of left heart failure. We examined by cardiac magnetic resonance (CMR) imaging if impaired LV function, diffuse myocardial fibrosis, and increased aortic stiffness is prevalent in asymptomatic ToF.

Methods:
CMR at 3T was performed in 109 asymptomatic ToF patients (age, 19.3±12.8 years) after surgical correction (16.6±10.0 years post operation) and 64 age-matched controls. Parameters of aortic distensibility (at 4 different aortic locations) and ventricular volumes were obtained from cine CMR. In a subset (n=50), myocardial extracellular volume fraction (ECV) was calculated from pre- and post-gadolinium contrast T1 measurements of blood and myocardium accounting for hematocrit.

Results:
Compared to control subjects, ToF patients had increased indexed LV endsystolic volumes resulting in a lower ejection fraction (LVEF; 50.7 ± 8.8 versus 59.0 ± 5.4; p<0.01). The RV enddiastolic and endsystolic volumes were also increased (p<0.01). Patients with TOF had a higher LV mass-to-volume ratio and increased aortic distensibility, reflecting alterations in ventricular-vascular coupling. Left atrial passive and total ejection fraction were decreased, and were associated with age (p<0.01) suggesting early onset of diastolic dysfunction. ECV was elevated in patients with ToF (0.32 ± 0.05 versus 0.26 ± 0.01 in controls (p<0.01), more so in females (p<0.05), and was inversely associated with indexed LV mass (p<0.05).

Conclusion:
Asymptomatic repaired ToF patients have subclinical alterations in LV geometry, function, aortic distensibility, and tissue architecture (by ECV). These findings indicate an early adverse cardiovascular phenotype that may reinforce a long-term risk burden of incipient LV failure in addition to effects on the RV.
Abstract 18544: The Association of Kidney Disease Measures With Left-Sided Cardiac Structure and Function: The Atherosclerosis Risk in Communities (ARIC) Study
Authors: Matsushita Kunihiro , Sang Yingying , Shah Amil M , Skali Hicham , Coresh Josef , Solomon Scott D
Published: April 2024

Introduction:
Small studies with selected population such as hypertensives or diabetics reported the association of kidney disease with cardiac structure and function. A more comprehensive examination for glomerular filtration rate (GFR) and albuminuria regarding their relationships to cardiac structure and function in a large sample from the general population is needed.

Hypothesis:
Both estimated GFR (eGFR) and albuminuria (urinary albuinu-cratinine ratio [ACR]) are associated with left-sided cardiac structure (left atrial volume index [LAVI], left ventricular end-diastolic diameter [LVEDD], and left ventricular mass index [LVMI]) and function (left ventricular ejection fraction [LVEF]).

Methods:
We studied 4041 participants (mean age 75±5 years) of the ARIC Study who did not have prior coronary heart disease or heart failure at visit 5 (2011-13) and underwent transthoracic echocardiography. The association between the kidney measures and cardiac echo parameters was assessed using regression models incorporating spline terms of kidney measures (knots at their clinical cutpoints) with the adjustment for potential confounders.

Results:
There were 1051 and 725 participants with reduced eGFR (<60 ml/min/1.73m
2
) and elevated ACR (≥30 mg/g), respectively. Reduced eGFR was associated with LAVI and LVMI only when it reached <30 ml/min/1,73m
2
(Figure). In contrast, higher ACR was steadily associated with high LAVI, LVMI, and LVEDD and low LVEF (all
P
<0.001).

Conclusions:
Elevated albuminuria was consistently associated with altered left-sided cardiac structure and function, whereas the alteration was restricted to some indices at moderate to severe stage for low eGFR. These findings suggest that kidney damage or its precedent conditions, e.g., endothelial dysfunction, are more involved in the pathophysiology of cardiac structural and functional alteration compared to kidney dysfunction.
Abstract 18556: S100A1 Released From Ischemic Cardiomyocytes Signals Myocardial Damage and Functions as Cardiac Alarmin
Authors: Rohde David , Schön Christoph , Boerries Melanie , Tsoporis James N , Parker Thomas G , Peppel Karsten , Katus Hugo A , Most Patrick
Published: April 2024

Rationale:
S100 proteins released from necrotic cells function as danger signals, referred to as alarmins, which play an active role in tissue inflammation and repair via recognition of molecular pattern receptors such as Toll-like receptors (TLRs).

Objective:
To investigate whether S100A1, the S100 isoform with the highest abundance in cardiomyocytes, acts as an alarmin in response to ischemic myocardial injury.

Methods and Results:
Patients with acute ST-elevation myocardial infarction (MI) revealed a significant increase in circulating S100A1 protein serum levels assessed by enzyme-linked immunosorbent assay. Experimental MI in C57Bl/6 mice induced comparable S100A1 release, and immunofluorescence uncovered S100A1 internalization in cardiac fibroblasts (CFs) adjacent to damaged cardiomyocytes
in vivo
. Further
in vitro
analyses using genetic, biochemical and imaging techniques demonstrated exclusive and rapid endocytosis of S100A1 by CFs, followed by endosomal TLR4-dependent transient activation of mitogen- and stress-activated protein kinases (MAPK/SAPK) and nuclear factor kappaB component p65. CFs exposed to S100A1 assumed an anti-fibrotic and immunomodulatory phenotype exemplified by decreased collagen and smooth muscle actin and enhanced intercellular adhesion molecule 1 and interleukin 10 mRNA and protein levels downstream of MAPK/SAPK and p65. In C57Bl/6 mice, intramyocardial S100A1 injection recapitulated the specific transcriptional changes
in vivo
. Subsequently, antibody-mediated neutralization of MI-released S100A1 enlarged infarct size and enhanced pro-fibrotic marker expression.

Conclusion:
Our study identifies cardiomyocyte damage-released S100A1 as cardiac alarmin and uncovers the molecular mechanisms conveying anti-fibrotic and immunomodulatory actions. The beneficial impact of the S100A1-mediated TLR4-dependent cardiac fibroblast phenotype conversion warrants continued investigation of its role in myocardial infarct healing.
Abstract 18557: Lipid Phenotypes at the Extremes of HDL Cholesterol: Very Large Database of Lipids Study 9
Authors: Al-hijji Mohammed , Martin Seth S , Blaha Michael , Joshi Parag H , Blumenthal Roger S , Toth Peter P , Jones Steven R
Published: April 2024

Background:
Patients with extreme levels of HDL-C may inform contemporary controversies in HDL metabolism and therapies.

Aim:
To characterize lipid phenotypes at extremes of HDL-C.

Methods:
We examined 136,746 U.S. adults and children from the Very Large Database of Lipids (Baltimore, MD;
NCT01698489
) who were clinically referred for a Vertical Auto Profile test (Birmingham, AL) of cholesterol subfractions from 2009 to 2011. We categorized patients at extreme levels of HDL-C into percentile categories (<0.1
th
, 0.1
th
to <1
st
, 1
st
to 5
th
, 95
th
to 99
th
, >99
th
to 99.9
th
, and >99.9
th
). Within these groups, we examined HDL-C subclasses 2 and 3, LDL-C, LDL density, non-HDL-C, triglycerides, VLDL-C, and remnant lipoprotein cholesterol.

Results:
Patients had a mean age of 59±15 years and 52% were women. With increasing HDL-C percentile, there was monotonically rising HDL
2
-C/HDL
3
-C ratio, consistent with more cholesterol loaded HDL particles (Table, P<0.0001). Triglycerides, VLDL-C, and remnant lipoprotein cholesterol levels decreased monotonically with rising HDL-C levels (P<0.0001). LDL-C increased proportionally with VLDL-C decrease resulting in constant median non-HDL-C levels. There is a progressive increase in LDL density with decreasing HDL-C. In addition to these broad trends, there was within-group heterogeneity.

Conclusion:
Across a broad range of HDL-C, these findings illustrate the extensive interaction between HDL and triglyceride rich remnant lipoproteins, and LDL density, possibly mediating residual cardiovascular risk. Careful phenotyping will be crucial in selecting clinical trial populations for novel HDL-targeted therapies as patients with low and high HDL-C are not all one in the same.
Abstract 18567: Enhancement of Collaterals by Resveratrol in a Rabbit Model of Hind Limb Ischemia
Authors: El Eter Eman A , Al Zamil Hana , Deif Maha
Published: April 2024

Background:
Resveratrol, a naturally occurring phytoalexin induced cardio angiogenic effects. It is not recognized to induce collaterals in limb ischemia.

Methods:
Rabbits were assigned into:1) ischemic , 2) ischemic + Resveratrol. (Loading s.c dose 2.5 mg/kg, followed by 2.5 mg/day/orally x 28 days) and 3) ischemic + LY294002 (3-phosphatidyl inositol (PI3) kinase inhibitor) + Resveratrol. Limb ischemia was induced as described [2].

Results/conclusions:
Resveratrol produced an increase in limb blood pressure ratio by 40% and angiographic score. Angiogenesis detected by CD31 immunostaining and upregulation of eNOS protein expression.
LY294002
, attenuated collaterals and angiogenesis.

Conclusions:
reveratrol enhanced micro and macrocollateral development in ischemic limbs via Akt/PI3-kinase pathway and eNOS providing a possible therapeutic potential for ischemic limbs. References:[1] Bradamante S, Barenghi L, Villa A. Cardiovasc Drug Rev 2004; 22: 169-188.[2] Takeshita S, Rossow ST, Kearney M, et al. J Clin Invest 1994; 93: 662-670.
Abstract 18572: Left Ventricle Reverse Remodeling After Acute Myocardial Infarction Predicted by MVO (CE-CMR). A Meta-Analysis of Prospective Trials
Authors: Romero Jorge , Lupercio Lopez Florentino , Husain Syed Arman , Chavez Patricia , Garcia Mario J
Published: April 2024

Background:
Microvascular obstruction (MVO) is a predictor for reverse remodeling as evidenced by an increase in left ventricle end diastolic volume index (LVEDVi) and left end systolic volume index (LVESVi) in patients following acute myocardial infarction (AMI). Contrast Enhanced CMR (CE-CMR) is the leading diagnostic modality to access the presence and extent of MVO.

Objective:
To determine the predictive value of MVO detected by CE-CMR as a predictor for Reverse remodeling in patients with AMI

Methods:
A systemic review of Medline, Cochrane, and Embase for all the clinical trials using CMR to detect MVO and assessing its association reverse remodeling was performed. Given the high heterogeneity (i.e. I
2
> 25), we used a random effect model.

Results:
A total of 6 studies with 423 patients (male: 83%, mean age 61 years (SD=+/-4) and average EF of 40% (SD+/-3) fulfilled the inclusion criteria. The overall incidence for MVO was 57% (230) (SD= +/- 7). Head to head comparison of patients with and without evidence of MVO on initial CMR with in 1 week for AMI showed a higher incidence of reverse remodeling on the follow up CMR at a mean time of 6 months (SD+/-1). Patients with evidence of MVO had significantly higher volumes. The mean difference in LVEDVi and LVESVi between the initial and follow up MRI was 8.11 (95% CI 4.49-11.73) and 9.10 (95% CI 6.21-12.18) respectively.

Conclusion:
MVO detected by CE-CMR is a strong predictor for LV reverse remodeling in patients suffering from acute myocardial infarction.
Abstract 18573: Genetic Variation of the Alpha-Subunit of the Epithelial Sodium Channel Influences the Lung Fluid Response to Hypoxia in Healthy Humans
Authors: Baker Sarah , Wheatley Courtney , Taylor Bryan , Keller Manda , Johnson Bruce , Snyder Eric M
Published: April 2024

Cardiogenic pulmonary edema is a life-threatening complication in patients with heart failure (HF) resulting from increased alveolar Cl- secretion and inhibition of alveolar epithelial Na+ channels (ENaC). Not all HF patients develop pulmonary edema, despite similar clinical characteristics, suggesting a genetic component to edema formation in response to cardiac failure. The ENaC are crucial for alveolar fluid clearance, with the alpha subunit demonstrating particular importance. We have previously found that genetic variation of the alpha subunit (SCNN1A) of ENaC, an alanine (A) to threonine (T) substitution, influences ion regulation during exercise and in response to albuterol. In the present study, we sought to determine the influence of the threonine variant (T663; AT/TT group) on lung fluid regulation in response to normobaric hypoxia, an environmental condition known to increase pulmonary capillary hydrostatic stress in healthy humans. Lung ion and fluid changes were assessed using exhaled Na+ (ENa+) and the lung diffusing capacity for carbon monoxide and nitric oxide (DLCO and DLNO, respectively) to determine alveolar-capillary membrane conductance (DM). 19 healthy subjects (n=8 vs. 11, %female=50 vs. 62%, age=27±1 vs. 28±2yrs., ht=171±3 vs. 173±2cm, wt=69±6 vs.72±3kg , BMI=23±1 vs.24±1kg/m2 , for AA and AT/TT, respectively) completed two overnight visits in a hypoxic tent simulating just over 5,400m. The visits were randomized to inhaled placebo (P) or inhaled amiloride (Aml, 1.5mg in 5ml normal saline, used to inhibit ENaC activity) with ENa+, DLCO, and DM assessed at baseline and following 12 hours of hypoxic exposure. There was an effect of genotype on the ENa+ response to hypoxia with placebo that was abolished with amiloride, but no effect of genotype on the diffusing capacity of the lung (Table). These results suggest that genetic variation of SCNN1A may influence ion regulation in the lung under conditions of elevated hydrostatic stress.
Abstract 18608: Serial Quantitative Coronary Analyses for the Evaluation of One-Year Changes in Grafts and Native Vessels After a Coronary Artery Bypass Surgery: Insights From the Cardiac Catheterization for Bypass Graft Patency Rate Optimization (CABG-PRO) Study
Authors: Kotsia Anna P , Michael Tesfaldet T , Rangan Bavana V , Michalis Lampros K , Fotiadis Dimitris I , Papafaklis Michail I , Abdullah Shuaib A , Hastings Jeffrey , Grodin Jerold M , Banerjee Subhash , Brilakis Emmanouil S
Published: April 2024

Background:
Left internal mammary arteries (LIMAs) and saphenous vein grafts (SVGs) are widely used for coronary artery bypass surgery (CABG), but there is limited information on the post-CABG remodeling of these vessels, as well as the bypassed native coronary arteries. We aimed to investigate the serial changes in lumen dimensions of SVGs, LIMAs and the bypassed native arteries in humans.

Methods:
Thirteen consecutive patients with recent CABG enrolled in our study and underwent angiography immediately after the surgery and one year later. Quantitative coronary analysis (using CAAS Workstation 5.11 software) was performed in 12 LIMAs, 26 SVGs and 59 native coronary arteries that were bypassed.

Results:
Mean age was 60.8±5.8 years and all the study patients were men while the initial clinical presentation was stable angina (76.9%). Compared to immediately post CABG, at 12 month follow-up angiography the minimal, maximal and mean SVG lumen diameters of the SVGs significantly decreased: (2.83±0.87mm vs 1.99±0.79mm, p<0.0001; 5.10±1.52mm vs 3.82±1.20mm, p<0.0001; 3.96±1.22mm vs 2.75±0.97mm, p<0.0001; respectively). No significant differences were observed in the baseline and follow-up measurements of LIMA grafts (minimal lumen diameter 1.31± 0.78mm vs 0.86±0.72mm, p=0.17; maximal lumen diameter 2.74±1.25mm vs 2.28mm±1.52, p=0.31; mean lumen diameter 0.62±0.45mm vs 1.02±1.12mm, p=0.24) and the native coronary vessels (minimal lumen diameter 0.76±0.40mm vs 0.82±0.46mm, p=0.31; maximal lumen diameter 2.88±0.99mm vs 3.07±1.18mm, p=0.09; mean lumen diameter 1.84±0.65mm vs 1.86±0.76mm, p=0.74).

Conclusions:
During the first year post CABG SVGs undergo significant negative remodeling, inferred by lumen constriction, which is not observed in LIMA grafts and the grafted native coronary arteries. The impact of this negative remodeling on clinical outcomes remains to be determined.