bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 14109: Ischemic and Bleeding Outcomes of Potent P2y12 Inhibitor Antiplatelet Agents versus Clopidogrel in Elderly Patients With Acute Coronary Syndrome: A Meta-Analysis of Randomized Trials
Authors: Abusnina Waiel , Al-abdouh Ahmad , Bizanti Anas , Gill Gauravpal S , Abdelrazeg Houssien Abdelrazeg , Alshebani Yazeid , Kanmanthareddy Arun K , Dahal Khagendra B
Published: April 2024

Introduction:
Potent oral P2Y12 inhibitors (prasugrel or ticagrelor) are recommended in patients who present with acute coronary syndrome (ACS) compared to clopidogrel on the basis of landmark trials. However, there is no clear recommendation for such agents in elderly patients (>65 years) with ACS.

Methods:
We queried the electronic databases of PubMed, Cochrane Central Register of Clinical Trials, EMBASE and ClinicalTrial.gov since inception through February 25, 2021 for randomized studies evaluating potent oral P2Y12 inhibitors vs. clopidogrel in elderly patients who present with ACS. Hazard ratios (HR) with 95% confidence interval (CI) were computed and p<0.05 was considered statistically significant.

Results:
Eight randomized studies including a total of 10,081 patients were included in this analysis. At mean follow-up of 26 months, there was no significant difference between potent oral P2Y12 inhibitors and clopidogrel in terms of MACE [HR 0.97, 95% CI 0.82-1.15; P 0.73] (Figure), all-cause mortality [HR 0.91, 95% CI; 0.75-1.10: P 1.00], myocardial infarction [HR 0.95, 95% CI; 0.78-1.17: P 0.64], and stroke [HR 1.24, 95% CI; 0.82-1.86: P 0.31]. There was significant increase in major bleeding with potent oral P2Y12 inhibitors in elderly compared to clopidogrel [HR 1.32, 95% CI; 1.09-1.59: P 0.004](Figure) while the cardiovascular mortality was significantly decreased in the elderly treated with potent oral P2Y12 inhibitors compared to clopidogrel [HR 0.82, 95% CI; 0.68-0.98: P 0.03].

Conclusions:
This meta-analysis suggests that using potent oral P2Y12 inhibitors in elderly patients with ACS is associated with a reduction in the risk of cardiovascular mortality with increased risk of bleeding compared to clopidogrel with no significant change in terms of MACE.
Abstract 14116: Exercise and Specialized Proresolving Lipid Mediators Stimulate Mitochondrial Metabolism in Macrophages
Authors: Pena Calderin Ernesto H , Hill Bradford G , Hellmann Jason
Published: April 2024

Exercise may prevent the development and progression of chronic inflammatory diseases through alterations in immune cell function. We find that macrophages isolated from mice subjected to 4 weeks of voluntary wheel exercise display enhanced basal and maximal mitochondrial respiration. We have previously shown that exercise also increases the production of specialized proresolving mediators (SPMs), macrophage phagocytosis, and resolution of acute inflammation; however, whether exercise-induced SPM formation directly alters macrophage metabolism remains unknown. SPMs stimulate resolution through actions on specific G-protein coupled receptors (GPCRs) in macrophages (
e.g.
, RvD1=> Fpr2). Therefore, we treated macrophages for 1 h with SPMs that act through distinct GPCRs (
e.g.
, RvD1, RvD2, RvE1, and MaR1) and found enhanced basal (vehicle vs 1nM SPM; 6.11±0.1 vs RvD1 7.76±0.6 vs RvD2 9.48±0.9 vs RvE1 7.20±0.5 vs MaR1 8.73±0.9 pmol/min/μg protein; P<0.05;
n
=3), maximal (vehicle vs 0.1nM SPM; 9.06±1.1 vs RvD1 14.37±1.1 vs RvD2 16.54±2.7 vs RvE1 12.32±1.5 vs MaR1 13.28±1.3 pmol/min/μg protein; P<0.05;
n
=3), and ATP-linked respiration (vehicle vs 1nM SPM; 2.83±0.2 vs RvD1 4.50±0.3 vs RvD2 4.39±0.2 vs RvE1 4.71±0.3 vs MaR1 4.20±0.2 pmol/min/μg protein; P<0.05;
n
=3). Stimulation of mitochondrial metabolism with RvD1 was receptor mediated as
Fpr2
-deficient macrophages displayed no significant changes in mitochondrial respiration following treatment (vehicle vs 1nM RvD1; basal 6.74±0.6 vs 6.52±0.2; maximal 11.54±1.2 vs 13.26±1.0; ATP-linked 5.84±0.8 vs 5.33±0.2 pmol/min/μg protein). Collectively, these data suggest that exercise-induced production of SPMs stimulates mitochondrial metabolism in macrophages, which could underlie their common proresolving properties and the exercise-induced amelioration of chronic inflammatory diseases.
Abstract 14119: Aortic Stiffness is Associated With Cognitive Decline and Cardiovascular Disease Manifestation in Cancer Survivors
Authors: White Zach J , Parr Shannon K , Turpin Vanessa-Rose G , Hammond Stephen T , Ade Carl
Published: April 2024

Introduction:
Cancer survivors experience a high prevalence of cognitive deficits and risk of CVD. Aortic stiffening, which increases following cancer diagnosis, inhibits pulsatile flow damping and potentiates microvascular damage within the cerebral circulation, which may contribute to associations observed between stiffness, cognitive decline, and mild cognitive impairment (MCI) in the general population. However, there is a paucity of evidence on the association between arterial stiffness and cognitive decline among cancer survivors.

Methods:
We evaluated dementia-free cancer survivors in the Framingham Original and Offspring Cohorts (n=277, 80±12.3 years old, 56.7% women, 9.3±8.8 years from first diagnosis) with carotid-femoral pulse wave velocity (cfPWV) measurements. Over a mean follow-up of 7.7±3.9 years, the Mini-Mental State Examination (MMSE; global cognitive function) and neuropsychological exams (NP; executive function, learning and memory) were completed. We noted cognitive decline and incident MCI per clinically relevant standards. We used linear and logistic regression models to determine the relationship between cfPWV and cognitive decline/MCI. Cox Regression related cfPWV and cognitive function to the risk of CVD. Multivariate models were adjusted for age, sex, depressive symptoms, and traditional CVD risk factors.

Results:
cfPWV was significantly associated with the rate of decline for global cognitive function (ΔMMSE). Higher cfPWV was significantly associated with clinically defined MCI, denoted by an impaired MMSE (OR(95%CI): 9.2(2.5-33.5)) and NP score (4.3 (1.4-13.0)) in univariate logistic models. We observed a 3.4 times higher risk of CVD in cancer survivors with high cfPWV (HR(95%CI): 3.45 (1.04-11.66)) in the final model. Changes in cognitive function were not associated with CVD.

Conclusion:
Our findings suggests an association between aortic stiffness, future cognitive decline, and an increased risk of CVD in a diverse cohort of cancer survivors. Our findings support the potential adverse consequences of a stiffening arterial vasculature following cancer diagnosis; specifically those related to cognitive function and long-term CVD outcomes.
Abstract 14132: The Crystal Structures Of Human Cytochrome P450 2C9 Provide Insights Into The Effect Of Genetic Variation And The Binding Of Losartan
Authors: Shah Manish
Published: April 2024

The human cytochrome P450 2C9 (CYP2C9) enzyme metabolizes many of the currently available medications that include anti-coagulant warfarin, anti-hypertensive losartan, anti-diabetics tolbutamide and glimepiride. Genetic variations in CYP2C9 that include the common alleles *2 and *3 have resulted in reduced enzyme activity leading to altered metabolism of various drug substrates compared with the wild-type (WT). The CYP2C9*2 genetic variant represent an amino acid change from arginine to cysteine at position 144. The crystal structure of CYP2C9 WT and the *2 variant complexed with losartan were recently published. However, the structure of these enzymes in the absence of any ligand or losartan is not available. Thus, the aim was to determine the ligand free structure of these enzymes and assess the hypothesis that the drug binding orchestrates the conformational change and leads to reorientation of amino acid sidechains to interact with losartan in the active site. The data for the CYP2C9 WT and the CYP2C9*2 crystals in the absence of any ligands was collected remotely at the Stanford Synchrotron Radiation Light Source and the structures were solved using x-ray crystallography. The ligand-free structure of the *2 variant revealed markedly different conformation compared to the recently published structure in complex with losartan. The changes in the F, F’, G and G’ helices indicate an open conformation in the absence of losartan compared to the losartan complex. Whereas the ligand-free structure of the WT illustrated similarity in the overall conformation to the previously published structures with losartan bound. Comparison of the ligand free structure of the CYP2C9 WT or the *2 variant with the losartan bound structure identified the amino acid sidechains important for interaction with the drug in the active site. Furthermore, the structure of the *2 variant in the absence or presence of losartan provided a useful framework to investigate the effect of amino acid substitution that leads to altered binding of the drug. In conclusion, the structural characterization of the CYP2C9 WT and the *2 variant yield insights into the conformational changes that occur upon binding of losartan and help understand the effect of genetic polymorphisms on drug metabolism.
Abstract 14134: Relationship Between Blood Pressure and Thoracic Aortic Diameter
Authors: DePaolo John , Levin Michael , Tcheandjieu, Catherine , Priest James , Dipender Gill , Burgess Stephen , Damrauer Scott , Chirinos Julio A
Published: April 2024

Introduction:
The impact of blood pressure (BP) traits, including systolic/diastolic blood pressure (SBP/DBP), pulse pressure (PP) and mean arterial pressure (MAP), on thoracic aorta (TA) diameter remains poorly understood.

Hypothesis:
We hypothesize that genetic predisposition to elevated SBP, DBP, MAP and PP is related to risk of TA dilation suggesting enhanced primary and secondary prevention strategies for thoracic aortic aneurysm (TAA).

Methods:
We performed two-sample Mendelian randomization to investigate the effect of BP traits on TA diameter. We considered SBP, DBP, MAP, and PP in 479,103 participants of diverse ancestry from UK Biobank. We considered 32,215 participants from UK Biobank who underwent cardiac MRI for TA diameter. Genetic instruments were constructed from uncorrelated (r
2
< 0.001) genetic variants associated with each BP trait at genome-wide significance (p < 5 x 10
-8
) in a pan-UK Biobank GWAS of BP traits.

Results:
Each of genetically-predicted MAP (beta = 0.017, 95% CI 0.013 to 0.021, p = 2 x 10
18
), SBP (beta = 4.1 x 10
-3
, 95% CI 8.4 x 10
-4
to 7.4 x 10
-3
, p = 0.01) and DBP (beta = 0.27, 95% CI 0.022 to 0.032, p = 9 x 10
-29
) were positively associated with increased TA diameter. PP was inversely associated with TA dimension (beta = -0.015, 95% CI -0.021 to -0.010, p = 2.4 x 10
-7
). When considered jointly in multivariable Mendelian randomization, both genetically-predicted PP (beta = -0.037 mm/mmHg increase, 95% CI -0.045 to -0.029, p = 2 x 10
-20
) and MAP (beta = 0.038mm/mmHg increase, 95% CI 0.031 to 0.046, p = 3 x 10
-23
) were independently associated with TA diameter. In bi-directional analyses, increased TA diameter was associated with decreased PP and SBP, and increased DBP. Results were robust to MR methods that make different assumptions about the presence of pleiotropic variants, and using alternative genetic variants to proxy BP traits.

Conclusions:
These data suggest elevated BP contributes to TA diameter. Multivariable analysis suggests both steady pressure (proxied by MAP) and pulsatility (proxied by PP) directly contribute to aortic size. These findings suggest societal-level intervention to lower blood pressure to prevent TAA development and related morbidity and mortality.
Abstract 14138: Effect of Nicotine Exposure to Induced Pluripotent Stem Cell Derived Endothelial Cell Therapy in a Murine Model of Peripheral Artery Disease
Authors: Chan Alex Ho Pang , Hu Caroline , Huang Ngan F
Published: April 2024

Introduction:
Clinical solutions for peripheral artery disease (PAD) remain elusive due to the many challenges of surgical intervention. Stem cell therapy offer a promising option, but barriers exist to their clinical translatability. Among these include lifestyle choices like tobacco use that may influence the efficacy of stem cell therapy. The objective of this study aims to examine the potential effects of nicotine on human induced pluripotent stem cell derived endothelial cells (iPSC-ECs) therapy in the context of PAD.

Hypothesis:
Chronic nicotine exposure negatively affects the therapeutic potential of implanted iPSC-ECs in a murine model of PAD.

Methods:
Mice were implanted with an osmotic pump for controlled exposed to nicotine or saline (control) for 28 days. Plasma cotinine was measured to confirm nicotine exposure. After 28 days of nicotine or saline exposure, the mice underwent induction of hindlimb ischemia and before receiving an injection of 10
6
iPSC-ECs. A second dose of cells were injected to the ischemic limb on day 7 post-surgery. All mice were monitored for blood perfusion recovery using laser Doppler spectroscopy imaging. Survival of the transplanted cells in vivo were tracked by bioluminescence imaging. The mice receiving iPSC-ECs were also imaged for cell survival using bioluminescence imaging. At day 14 post-surgery, mice were euthanized, and the gastrocnemius muscle and thigh muscle were harvested for histological analysis.

Results:
The average cotinine concentration in sera was ~200 ng/mL, which is within physiological range for a tobacco user. Blood perfusion recovery at day 14 showed trends of nicotine treated groups have hindered perfusion recovery, compared to those treated with saline. Importantly, nicotine exposure trended with poorer perfusion recovery after cell therapy. Bioluminescent imaging showed iPSC-ECs persisted in vivo for all groups without significant difference.

Conclusion:
Nicotine exposure was associated with poorer blood perfusion recovery after iPSC-EC therapy, compared to control saline exposure, suggesting that nicotine may have adverse effects on iPSC-EC therapy for treatment of PAD.
Abstract 14147: Septal Native T1 is Higher in Patients With Pre-Capillary Pulmonary Hypertension Compared to Post-Capillary Pulmonary Hypertension
Authors: Cerne John W , Pathrose Ashitha , Sarnari Roberto , Gordon Daniel , Devabhaktuni Bhargav , Chow Kelvin , Allen Bradley D , Avery Ryan , Markl Michael , Carr James C
Published: April 2024

Introduction:
Right heart catheterization (RHC) is used to diagnose and classify pulmonary hypertension (PH). Because RHC is invasive, there is growing interest in non-invasive PH evaluation techniques, such as cardiac magnetic resonance (CMR).

Hypothesis:
CMR-derived fibrosis indices [native T1 (NT1) and extracellular volume (ECV)] differ between pre-capillary PH (PRE-PH), post-capillary PH (POST-PH) and controls.

Methods:
RHC-defined PH patients and healthy controls (N=25, age=52+/-13 years) underwent CMR. A cardiologist classified patients into PRE-PH (N=29, age=55+/-8 years) and POST-PH (N=19, age=66+/-13 years) based on RHC measurements and clinical history. T1 maps of the left ventricle were acquired using a Modified Look-Locker Inversion Recovery sequence before and after administration of gadolinium contrast. T1 maps were manually segmented using the AHA 16 segment model to obtain segmental native and post-contrast T1. Segmental ECV was calculated using NT1, post-contrast T1, and hematocrit. Global ECV and NT1 were calculated by averaging all segments.

Results:
PRE-PH had higher NT1 than POST-PH in segments 8 (1077+/-39 vs 1046+/-36 ms, p=.01), 9 (1082+/-47 vs 1051+/-44 ms, p=.03), and 14 (1080+/-74 vs 1028+/-53 ms, p=.01). Global ECV and NT1 were higher in PRE-PH (31+/-4% and 1056+/-36 ms) than controls (28+/-4% and 1013+/-29 ms) (p=.017 and p=.000, respectively).

Conclusions:
NT1 was different between PRE-PH and POST-PH in mid- and apical-septal segments, however segmental ECV and global measures were not. NT1 may reflect more than just ECV expansion, providing additional insight into the myocardium. Regional NT1 may complement RHC for classifying PH.
Abstract 14165: Ultrasound-Accelerated Thrombolysis May Be the Preferred Catheter-Based Lytic Therapy for Pulmonary Embolism
Authors: Potkonjak Mary , Golemi Lolita , Madan Nidhi , Attanasio Steve
Published: April 2024

Introduction:
Pulmonary embolism (PE) is estimated to cause 100,000 deaths annually in the US. Systemic use of fibrinolytic drugs carries risks of significant bleeding. Catheter directed thrombolysis (CDT) delivers thrombolytic drugs directly to the site of the clot and in lower doses which may improve its safety profile. We aimed to investigate the safety and efficacy of CDT in intermediate risk PE and contemporary trends of follow-up cardiac testing in these patients.

Methods:
75 patients who underwent CDT for intermediate risk PE at a single center from 2014-2021 were studied retrospectively. Outcomes included procedure related complications and mortality. Continuous variables are presented as mean±SD, categorical variables as percentages. Logistic regression and survival analysis was used. Data was analyzed in Stata/BE 17.0.

Results:
Demographics (Table 1), lab and imaging data (Table 2) were assessed for 75 patients. Troponin and BNP were elevated in 63.5% and 60% respectively. RV dilation was present in 86.7%. Ultrasound accelerated thrombolysis (EKOS) was performed in 80% and standard CDT in 20%. One procedural complication occurred, a patient undergoing standard CDT suffered a cardiac arrest and died. Major bleeding occurred in four patients but did not contribute to mortality. Mortality at 30 days and one year were 6.8% (5/73) and 13% (9/69) respectively. Only three deaths were attributed to cardiovascular causes. Those who underwent EKOS had 85.6% lower odds of death in 30 days (OR 0.14 (0.03-0.79), p=0.02) compared to CDT; however, our results are limited by a small sample size. Follow up imaging was assessed at 1 year (Table 3). Echo was most frequently performed in 45.3% of patients.

Conclusions:
EKOS for intermediate risk PE is a safe procedure with no procedural mortalities in our study. As follow up was poor, with less than 50% of the cohort receiving imaging, future directions should be aimed at ensuring these patients are monitored for long-term sequelae of PE.
Abstract 14167: Cardiac Electrophysiologists' Perspectives on Sleep Apnea
Authors: Dong Michael Q , Liu Linda , Bilchick Kenneth C , Mehta Nishaki , Koene Ryan , Adabag Selcuk , Bunch Jared , Baranchuk Adrian M , Kwon Younghoon
Published: April 2024

Introduction:
Sleep apnea (SA) is a well-recognized and potentially modifiable factor in the pathophysiology of arrhythmias including atrial fibrillation (AF). The purpose of the study was to evaluate cardiac electrophysiologists’ (EP)’s perception about SA and opinions on management.

Methods:
Based on semi-structured interviews among conveniently sampled EP (N=4) to narrow preliminary areas of interest for investigation, we created a 27-item online Likert scale-based survey instrument entailing several domains using: 1) the relevance of SA in EP practice and familiarity with it, 2) the practice patterns for SA screening and diagnosis, 3) perception on treatments for SA, 4) opinion on the SA care model. The survey was distributed to 89 academic EP programs in the United States and Canada.

Results:
A total of 105 cardiologists from 49 institutions responded over a 9-month period, including 63% attending EP and 37% EP fellows in training. The majority of respondents agreed that SA is a major concern in their practice (94%) and that they frequently discussed the connection between SA and the risk of arrhythmia with patients (95%). However, nearly half of respondents (42%) indicated insufficient education on SA during training. In addition, many of them (58%) agreed that they would be comfortable managing SA themselves with proper training and education. Many EPs (53%) were not satisfied with the referral process to a sleep specialist in the area where they practice. The majority (66%) of EP physicians agreed that cardiologists should become more involved in the management of SA than they are now. Additionally, majority (86%) agreed that trained advanced practice providers should be able to assess and manage SA. Many identified time constraints, lack of knowledge, and referral process as major barriers to cardiologists becoming more involved in SA care.

Conclusions:
There is wide recognition by EP of the importance of SA and its relationship with arrhythmia and AF. However, education and incorporation into cardiology practice appears to lag. Future studies examining the impact of integrating SA care delivery in EP practice on patient outcomes, satisfaction of both patients and EP and healthcare cost are needed.
Abstract 14169: Implications of Elevated Troponin on Time-to-Surgery in Non-ST Elevation Myocardial Infarction (NIHR Health Informatics Collaborative: Trop-CABG Study)
Authors: Sinha Shubhra , Benedetto Umberto , Mulla Abdulrahim , Glampson Ben , Panoulas Vasileios F. , Gautama Sanjay , Davies Jim , Papadimitriou Dimitri , Woods Kerrie , Elliott Paul , Hemmingway Harry , Williams Bryan , Asselbergs Folkert W , Melikian Narbeh , Krasopoulos George , Sayeed Rana , Wendler Olaf , Baig Kamran , Chukwuemeka Andrew , angelini gianni , Sterne Jonathan , Johnson Tom , Shah Ajay M , Perera Divaka , Patel Riyaz , Kharbanda Rajesh , Channon Keith M , Mayet Jamil , Kaura Amit
Published: April 2024

Background:
The optimal timing of coronary artery bypass grafting(CABG) in patients with non-ST elevation myocardial infarction (NSTEMI) and the utility of pre-operative troponin levels in decision-making remains unclear. We investigated (a)the association between peak pre-operative troponin and survival post-CABG in a large cohort of NSTEMI patients and (b)the interaction between troponin and time-to-surgery.

Methods:
Our cohort consisted of 1746 NSTEMI patients(mean age 69±11 years, 21% female) with recorded troponins that had CABG at five United Kingdom centers between 2010 and 2017. Time-segmented Cox regression was used to investigate the interaction of peak troponin and time-to-surgery on early(within 30 days) and late(beyond 30 days) survival.

Results:
Average interval from peak troponin to surgery was 9±15 days, with 1466(84.0%) patients having CABG during the same admission. Sixty patients died within 30-days and another 211 died after a mean follow-up of 4±2years(30-day survival 0.97±0.004 and 5-year survival 0.83±0.01). Peak troponin was a strong predictor of early survival(adjusted P=0.002) with a significant interaction with time-to-surgery(P interaction=0.007). For peak troponin levels <100 times the upper limit of normal, there was no improvement in early survival with longer time-to-surgery. However, in patients with higher troponins, early survival increased progressively with a longer time-to-surgery, till day 10. Peak troponin did not influence survival beyond 30 days(adjusted P=0.64).

Conclusions:
Peak troponin in NSTEMI patients undergoing CABG was a significant predictor of early mortality, strongly influenced the time-to-surgery and may prove to be a clinically useful biomarker in the management of these patients.
Abstract 14188: Medication Opportunities Among Patients Admitted for Heart Failure With Reduced Ejection Fraction
Authors: Swat Stanley , Allen Larry A , Greene Stephen J , Devore Adam D , Xu Haolin , Matsouaka Roland , Goyal Parag , Peterson Pamela , Hernandez Adrian F , Krumholz Harlan M , Yancy Clyde W , Fonarow Gregg C , Hess Paul
Published: April 2024

Introduction:
Patients hospitalized with heart failure with reduced ejection fraction (HFrEF) are eligible for multiple medical therapies prior to discharge. The number of new medication opportunities for HFrEF patients by the time of hospital discharge has not been recently characterized.

Methods:
We identified 47,277 patients hospitalized for HFrEF between 2017 and 2020 across 160 sites in the Get With The Guidelines-Heart Failure Registry and eligible for medical therapy. Accounting for collected contraindications for each medication class, we calculated the differences between both admission and discharge medications based on professional guideline eligibility.

Results:
The mean number of guideline-eligible medications for HFrEF patients was 3.51 ± 0.96 while the number of medications used on admission was lower at 2.06 ± 1.33. Among those eligible for each medication class, the proportion of use before admission to discharge increased for all classes: ACEi/ARB/ARNI from 60% to 93%, beta blocker from 70% to 98%, MRA from 26% to 56%, hydralazine/isosorbide among African Americans from 15% to 27%, anticoagulation for atrial fibrillation from 69% to 89%, and diuretics for signs/symptoms of congestion from 63% to 86%. Cumulatively, 29% of patients were eligible for 1 new medication, 30% for 2-3 new medications, and 10% for ≥ 4 new medications. The proportion of patients on all guideline eligible medications increased from 29% on admission to 60% on discharge. Of all new medication opportunities (mean, 1.44 ± 1.32), 66% were addressed by discharge (
Figure 1
).

Conclusions:
Among patients hospitalized for HFrEF in the US, two-thirds of all new guideline indicated medication opportunities are addressed by discharge. Nonetheless, continued efforts toward initiating guideline medications for HFrEF are needed, integrating inpatient with post discharge opportunities for medication use.
Abstract 14193: Bmp-7 Ameliorates Lipid Accumulation Induced, Hmgb1 Initiated Pyroptosis Leading To Sarcopenia, Muscle Deterioration And Adverse Muscle Remodeling In Diabetes
Authors: Aluganti Narasimhulu Chandrakala A , Singla Dinender K
Published: April 2024

Introduction:
Diabetic muscle myopathy involves hyperglycemia and inflammation that causes skeletal muscle dysfunction. However, the potential cellular mechanisms that occur during hyperglycemia and inflammation, which induces sarcopenia, muscle deterioration and muscle dysfunction remains unknown.

Hypothesis:
We hypothesize that, Bone morphogenetic protein-7 (BMP-7) ameliorates hyperlipidemia induced inflammation and pyroptosis in the development and progression of diabetic myopathy.

Methods:
C57BL6 mice were treated with saline, streptozotocin (STZ), or STZ+BMP-7 to generate diabetic muscle myopathy. Diabetes was established by increased fasting glucose levels and GTT. Gastrocnemius muscle and blood samples were collected. Blood was used to determine the lipid levels. Skeletal muscle was used to investigate lipid accumulation, pyroptosis, muscle deterioration, atrophy, and adverse structural remodeling using histology, immunohistochemistry, western blot, and RT-PCR.

Results:
We observed a significant (
p
<0.05) increase in blood glucose and serum lipid levels in diabetic animals. A significant (
p
<0.05) increase in hyperglycemia lead an increase in lipid accumulation, inflammasome formation and further an up-regulation of the downstream pyroptotic markers as well as signaling markers [TGFβ, Smad2 and Smad3] in diabetic muscle cells. Structural analysis showed the significant (
p
<0.05) loss of muscle weight, decreased myofibrillar area, increased muscle deterioration and fibrosis leading to muscle dysfunction. Whereas, BMP-7 attenuated hyperglycemia, hyperlipidemia, lipid accumulation, inflammation, pyroptosis, signaling markers and diabetic adverse structural modifications resulting in significantly (
p
<0.05) improved muscle function.

Conclusion:
We report for the first time that increased hyperlipidemia aggravates inflammation involved cellular pyroptosis that induces significant muscle cell loss and adverse remodeling in diabetic muscle myopathy. Targeting pyroptosis and lipid accumulation in muscle cells, with BMP-7 improves diabetic muscle pathophysiology and muscle function. These findings shows BMP-7 as a potential therapeutic option to treat diabetic myopathy.
Abstract 14194: Dynamic Metabolite Profiles of Heart Failure and Central Hemodynamics
Authors: Lejonberg Carl , Egerstedt Anna , Gidlöf Olof , Czuba Tomasz , Smith Gustav
Published: April 2024

Aim:
Large-scale plasma metabolite profiling is garnering considerable interest for the discovery of therapeutic targets and facilitation of precision medicine across a range of conditions. Heart failure (HF) represents a particularly promising application of metabolite profiling for precision medicine. Here, we performed untargeted metabolite profiling of heart failure cases and healthy controls, and studied transplant dynamics and central hemodynamic correlates of identified metabolites.

Methods and Results:
Metabolite profiling was conducted with liquid chromatography-tandem mass spectrometry methods in two independent case-control samples: one sample with advanced HF patients undergoing right-heart catheterization (RHC, n=248) and healthy controls of matching age and sex (n=30), and one sample with HF outpatients (n=83) and controls from a population-based cohort (n=583). Metabolites associated with HF were identified based on multivariable-adjusted logistic regression models. In total, 93 of 1370 studied metabolites were significantly associated with HF in both cohorts with concordant directionality, after Bonferroni correction. A subset of the advanced HF patients underwent heart transplantation (n=28), after which a second sample was obtained at the routine 6 month follow up exam. In linear mixed-effects regression models, 17 metabolites (18%) returned significantly towards healthy control levels. Of these, 13 (76%) were associated with at least one of 14 central hemodynamic parameters. Most associations were with right atrial pressure (RAP, 10 metabolites), mixed venous oxygen saturation (12 metabolites) and left-ventricular stroke work index (9 metabolites). For example, vanillylmandelate, a catecholamine metabolite, was associated with stroke volume and cardiac index, while kynurenine, an immunomodulatory tryptophan metabolite mainly produced in the liver and previously associated with kidney function, was associated with higher left-sided (pulmonary arterial wedge pressure) and right sided (RAP) filling pressures.

Conclusions:
Here, we comprehensively identified metabolites associated with HF and describe the hemodynamic correlates and metabolite dynamics upon HF reversal by transplantation.
Abstract 14198: Peptide-siRNA Nanoparticles Targeting NF-kB Subunit P50 Suppress Experimental Abdominal Aortic Aneurysm Progression and Prevent Rupture
Authors: Yan Huimin , Hu Ying , Akk Antonina , Pan Hua , Wickline Samuel , Pham Christine
Published: April 2024

Rationale:
Abdominal aortic aneurysm (AAA) is a progressive vascular condition associated with high risk of mortality due to rupture if left untreated. AAA is an inflammatory process with excessive local production of extracellular matrix degrading enzymes, leading to dilatation, and rupture of the abdominal aorta. We posit that targeting NF-κB, a signaling pathway that controls inflammation, will halt AAA progression and prevent rupture.

Methods and Results:
In an elastase-induced AAA model we observe that NF-κB activation increases progressively post-elastase perfusion. Unexpectedly, we found that AAA progression is marked by predominant nuclear localization of the NF-κB p50 subunit at the exclusion of p65. Using the amphipathic peptide p5RHH to form nanocomplexes with siRNA, we show that NF-κB p50, but not p65 knockdown mitigates small AAA progression. Since elastase-induced AAA is self-limiting, we turn to an AAA model by topical application of elastase combined with TGF-β inhibition, which leads to rapid aortic diameter expansion and rupture in 50% of experimental animals. Systemic delivery of p5RHH-siRNA nanoparticles suppressing p50 protect 100% of male mice from rupture (and sudden death) in this model but does not significantly mitigate aneurysm expansion. In both models, knockdown of p50 is accompanied by significant decrease in inflammatory infiltrate, release of various cytokines, inducible nitric oxide synthase expression, and cell apoptosis.

Conclusions:
These results identify NF-κB pathway p50 subunit as a critical key modulator of the inflammatory process in AAA and p50 represents a potential therapeutic target in the medical management of AAA to prevents expansion and rupture.

Figure 1. (A) Elastase + anti-TGF-β AAA model. (B) Aortic rupture with hematoma (arrow). (C) Survival curve (n = 6-10 mice per treatment group). p50 knockdown prevents rupture and death (C) but not AAA expansion (D). *
P
< 0.05, **
P
< 0.01, ***
P
< 0.001. inact.=inactive.
Abstract 14215: Mortality and Readmission Among Medicare Beneficiaries Hospitalized for Heart Failure Who Are Treatment Candidates for SGLT-2 Inhibitors
Authors: Vaduganathan Muthiah , Greene Stephen J , Zhang Shuaiqi , Chiswell Karen , Devore Adam D , Butler Javed , Heidenreich Paul A , Huang Joanna , Kittleson Michelle M , Joynt Maddox Karen E , McDermott James J , Owens Anjali T , Peterson Pamela , Solomon Scott , Vardeny Orly , Yancy Clyde W , Fonarow Gregg C
Published: April 2024

Background:
SGLT2i form the latest pillar in the management of HFrEF and appear effective across a range of patient profiles. There is increasing interest around initiation of SGLT2i during hospitalization, yet little is known about the putative benefits of this implementation strategy.

Methods:
We evaluated Medicare beneficiaries with HFrEF (≤40%) hospitalized at 228 sites in the GWTG-HF Registry in 2016 who had linked claims data for ≥1 year post-discharge. We identified those eligible for a SGLT2i under the FDA label for dapagliflozin (excluding eGFR<30 mL/min per 1.73 m
2
, dialysis, or type 1 diabetes). We evaluated 1-year outcomes overall and among key subgroups (age≥75y, sex, race, hospital region, eGFR, diabetes status, triple therapy).

Results:
Among 7,767 patients hospitalized for HFrEF, 6,218 (80%) would be SGLT2i candidates (mean age 79±8y, 38% women, 12% Black). Among eligible candidates, discharge use of β-blockers, ACEi/ARB, MRA, ARNI, and triple therapy (ACEi/ARB/ARNI+β-blocker+MRA) was in 86%, 65%, 30%, 3%, and 21%, respectively. Treatment candidates faced a 1-year incidence [95% CI] of mortality and HF readmission of 38% [36-39%] and 32% [31-33%], respectively, and each exceeded 25% across all key subgroups. Among 1,301 beneficiaries eligible for already on triple therapy, 1-year incidence of mortality was 26% [24-28%] and 1-year HF readmission was 30% [27-32%].

Conclusions:
Medicare beneficiaries eligible for SGLT2i after HF hospitalization, including those well-treated with other disease-modifying therapies, face high risks of mortality and HF readmission by 1 year. Whether these heightened risks can be modified with implementation of SGLT2i at time of a worsening HF event is the subject of ongoing clinical trials.
Abstract 14224: JAK2V617F Red Blood Cells Promote Atherosclerosis and Thrombosis
Authors: Liu Wenli
Published: April 2024

Elevated hematocrit is associated with cardiovascular risk; however, the causality and mechanisms are unclear. The JAK2V617F (JAK2VF) mutation markedly increases cardiovascular risk both in myeloproliferative disorders with elevated blood cell counts and in the much more prevalent clonal hematopoiesis of indeterminate potential with normal blood cell counts. Jak2VF mouse models with elevated white blood cells (WBC), platelets and red blood cells (RBCs) display accelerated atherosclerosis. However, whether Jak2VF RBCs promote atherogenesis and thrombosis independently from increased WBC and platelets remains uncertain. We used Erythropoietin Receptor (EpoR) Cre recombinase to generate a conditional knock-in of murine Jak2VF (VFEpoR) in the RBC lineage. Hyperlipidemic VFEpoR mice without elevated blood cell counts showed accelerated arterial thrombosis and increased atherosclerotic plaque necrosis. Induction of erythrocytosis with low dose erythropoietin (EPO) without concomitant leukocytosis or thrombocytosis further worsened thrombosis and atherosclerosis. VFEpoR atherosclerotic lesions featured endothelial barrier breakdown, RBC infiltration, iron deposition, lipid peroxidation, macrophage erythrophagocytosis and macrophage ferroptosis. VFEpoR RBCs had reduced antioxidant defenses and contained increased ROS and lipid hydroperoxides. Phagocytosis of murine or human WT or Jak2 VF RBCs by WT macrophages induced lipid peroxidation and ferroptotic death that was prevented by the ferroptosis inhibitor Liproxstatin-1. Ferroptosis inhibition reversed increased atherosclerosis and necrotic core formation in VFEpoR mice but had no impact in controls. These studies demonstrate that both qualitative and quantitative defects in Jak2VF RBCs accelerate atherosclerosis and thrombosis. Phagocytosis of WT or Jak2VF RBCs by macrophages leads to ferroptotic cell death, suggesting ferroptosis as a new therapeutic target to reduce RBC-mediated cardiovascular risk.
Abstract 14231: The Role of Altered Notch-Sox9-Hapln1 Signaling in the Pathogenesis of Bicuspid Aortic Valve
Authors: Ghazizadeh Zaniar , Liu Ya , Ugwu Nelson , Adeniran Adebowale , Neogi Arpita , Mani Arya
Published: April 2024

Bicuspid aortic valve (BAV) is a common congenital valve disorder with a prevalence close to 1%. Genetic studies on familial forms of BAV had previously identified NOTCH1 receptor as key mediator in the disease pathogenesis. However, the role of different Notch ligands in valve development in health and disease has remained elusive. Here we sequenced a total of 158 individuals with BAV and identified a list of 12 genes significantly enriched in the patients. Among the identified genes, there were various mutations in NOTCH1 receptor and Notch ligands. To further dissect the role of various Notch ligands in valve development, we generated knock-out models of Jag1a, Jag2b, Dll4, and Dld in Zebrafish and explored their effect on the heart outflow tract. Interestingly, Jag1a and Jag2b had opposite effects on valve diameter. Using single cell RNA and bulk RNA seq, and chip sequencing techniques on murine knock-out models of the corresponding genes, we identified a novel Notch-Sox9-Hapln1 signaling pathway dysregulated in the genetic models of Notch mutation that could underlie the changes in endocardial cells. Finally, we observed alterations in this pathway in aortic valve specimens from patients with bicuspid versus tricuspid aortic valves. In conclusion, our study identifies an association between mutations in Notch ligands and BAV and highlights the role of Notch-Sox9-Hapln1 pathway in aortic valve development and implicates its altered function as a novel pathway for the pathogenesis of BAV.
Abstract 14232: Performance Of Cardiac Magnetic Resonance Fingerprinting Mapping - Evaluation By Comparison With Standard Techniques In A Large Patient Population
Authors: Rajagopalan Varun , Siva Kumar Shruti , Madabhushi Anant , Al-Kindi Sadeer , Walker Jonathan R , Hamilton Jesse , Seiberlich Nicole , Rashid Imran , Rajagopalan Sanjay
Published: April 2024

Background:
Parametric mapping is now widely used as a part of cardiac MRI protocols. Cardiac Magnetic Resonance Fingerprinting (cMRF) techniques for parametric mapping allow for simultaneous evaluation of T1 and T2 within a single acquisition. In this study, we evaluate the performance of cMRF through comparison with clinically utilized pulse sequences for T1 and T2 in a large heterogeneous population.

Hypothesis:
cMRF T1 and T2 measurements agree with clinically available mapping sequences in a heterogeneous patient cohort.

Methods:
We obtained myocardial T1 and T2 values across the whole mid short axis slice of the left ventricle in 175 patients using cMRF (T1/T2), Modified Look-Locker Inversion Recovery (MOLLI, T1), and T
2
-prepared balanced steady-state free precession (bSSFP). Patients were classified into the groups “Ischemic cardiomyopathy (ICM)”, “Nonischemic Cardiomyopathy (NICM)”, “Normal”, and “Other”. The group classified as “Other” was not analyzed separately.

Results:
cMRF had similar T1 compared with MOLLI (1036 vs 1046 ms, p=0.06, r=0.76) and slightly lower T2 compared with bSSFP (46.1 vs 49.6 ms, p<0.01, r=0.5) in the entire cohort. Mean T1 was higher in ICM compared to Normal when measured by both MRF (1074 vs 997, p<0.01) and MOLLI (1073 vs 1015, p<0.01). The same was true when comparing NICM and Normal for both MRF and MOLLI (p<0.01). T1 was more concordant in NICM (r=0.82) vs ICM (r=0.46) and Normal (r=0.54) while T2 had similar concordance across the spectrum of pathologies. Bland-Altman plots showed good agreement between cMRF and MOLLI (Bias: -9.86, 95% CI: -98.58, 78.86)/bSSFP (Bias: -3.55, 95% CI: -11.68, 4.57). The concordance was stable across a range of heart rates.

Conclusions:
cMRF is an emerging technique for simultaneous T1/T2 mapping in the myocardium. In a large heterogeneous population, cMRF T1 and T2 values showed good agreement with clinically-utilized pulse sequences. Further work is needed to identify sources of discrepancies.
Abstract 14248: Obesity-Induced Abnormal Epigenetic Response in Macrophages Deteriorates Wound Healing
Authors: Takahashi Kentaro , Liu Jinghua , Urao Norifumi
Published: April 2024

Background:
Macrophages play key roles in the normal wound healing process, and their dysregulation is linked with impaired wound healing in disease conditions such as diabetes and obesity. Epigenetic mechanism such as histone modification involves in macrophage dysregulation. Epigenetic response to hypoxic environment has implications in macrophage functions in inflammation. Whether obesity influences histone modification under hypoxia is unknown.

Methods and Results:
Wild-type mice were fed normal diet (ND) or high-fat diet (HFD) for 4-5 months to induce obesity. Bone marrow-derived macrophages (BMDMs) were obtained from both groups. BMDMs were treated in hypoxic condition (1% O
2
) for 1 hour, and the enrichment of histone 3 lysine 4 tri-methylation (H3K4me3) in BMDMs was assessed with western blotting and high-content imaging analysis. We found that hypoxia increases total H3K4me3 levels in BMDMs from ND, whereas this hypoxia-induced H3K4me3 upregulation was abolished in BMDMs from HFD. ChIP-seq was performed to investigate detailed H3K4me3 landscape and revealed hypoxia-induced H3K4me4 enrichment in promoter regions targeted by a H3K4 demethylase Kdm5a, including Hoxb9 and Sart3 in BMDMs from ND but not from HFD. This is aligned with the role of Kdm5a as a rapid hypoxia sensor and indicates impaired pro-healing activity of macrophages in HFD. Mechanistically, paralleled western blot of phospho-Akt showed a linear correlation with H3K4me3 levels, supporting the previous finding that p-Akt negatively regulates nuclear translocation of Kdm5a.

Conclusion:
Obesity impairs the wound healing response of macrophages by modifying epigenetics via p-Akt/Kdm5a axis.
Abstract 14253: Combining History Of Present Illness With Risk Stratification Scores To Predict Intensive Care Admission For Suspicious Acute Coronary Syndrome Patients In The Emergency Department
Authors: Xue Diyang , Frisch Stephanie O , Frisch Adam N , Wang Zhendong , Luo Zhimeng , Daqing He
Published: April 2024

Introduction:
Patient symptom data are recorded in free text notes in the electronic health records and are difficult to extract. Natural language processing (NLP) is a technique that can be used to mine key patient symptoms that can be combined with risk stratification tools to improve patient outcomes.

Hypothesis:
Adding symptom data to the National Early Warning Score (NEWS) and quick sequential organ failure assessment score (qSOFA) will improve the area under the receiver operating curve (AUC) performance.

Methods:
NEWS scores and qSOFA scores were calculated with assistance from an emergency medicine physician for each patient with suspicion of acute coronary syndrome at initial emergency department (ED) assessment. Independent reviewers annotated the outcome of admission to the intensive care unit as a binary outcome (yes/no). The Apache clinical Text Analysis Knowledge Extraction System (cTAKES), an open access NLP platform, was used to preprocess and run analysis on patient free text ED history of present illness notes. Patient symptom data were extracted and used as patient features/input variables and combined with variables from the NEWS and qSOFA scores. Logistic regression model was used to do prediction. We used DeLong’s test to determine the statistical difference between each scores’ AUC.

Results:
70 patients out of 1195 had an intensive care admission. The AUC for the NEWS and qSOFA scores were 0.75 and 0.67, respectively. After adding symptoms features, the AUCs improved to 0.81 and 0.79, respectively. There were statistical differences between the AUCs between each score.

Conclusion:
Adding patient symptom data improves performance of both the NEWS and qSOFA risk stratification scores. Enhanced risk stratification scores with symptom data could identify those at high risk for clinical deterioration and could help augment accurate decision making at ED disposition.
Abstract 14272: Whole Exome Sequence Analysis of Pulmonary Hypertension in the UK Biobank
Authors: Clapham Katharine , Pampana Akhil , Choi Seung H , Honigberg Michael , Peloso Gina , Ellinor Patrick T , Natarajan Pradeep
Published: April 2024

Introduction:
Pulmonary hypertension (PH) is a progressive disease characterized by adverse remodeling of the lung vasculature and right ventricular failure. While
BMPR2
mutations account for the majority of familial pulmonary arterial hypertension (PAH), the predisposing genetic factors in non-familial PH are not well understood. Whole exome sequencing (WES) data from individuals in the UK Biobank (UKB) provides a unique opportunity to interrogate the genetic factors underlying this rare disease.

Hypothesis:
Rare disruptive coding variants associated with sporadic PH will provide novel mechanistic insights.

Methods:
Exome sequences were aligned to the GRCh38 reference genome and variants annotated using Variant Effect Predictor. We identified rare (minor allele frequency <1%) high confidence loss-of-function variants using LOFTEE and deleterious missense variants using MetaSVM. We then performed a rare variant burden association study using logistic regression in REGENIE adjusting for age, sex, array, smoking status, and principal components 1-10. These analyses were performed on unrelated individuals identified based on kinship (kinship > 0.0884). We secondarily curated a list of 58 candidate PAH genes based on recent publications of rare variants identified in PAH, as well as the ClinVar database. PH was defined utilizing ICD codes 416.0 (ICD-9), I27.0, I27.2 (ICD-10).

Results:
185,586 UKB participants were included; 665 with PH (age 62 years (+/-6), 46% female) and 184,921 controls (age 56 years (+/-8), 55% female). Rare variant association testing did not identify exome-significantly associated genes (p<2.5x10
-7
), nor nominal associations in candidate PAH genes. Four novel genes with p<0.01 were identified, which included genes important in mitochondrial function (
ACADM
), nicotinic acetylcholine receptor signaling (
MYO18A
), pulmonary surfactant metabolism (
SFTPA1
) and smooth muscle function (
BEST2
).

Conclusions:
We identified putative genes associated with PH in the population which have not been previously implicated in familial PAH. If additional evidence supports the roles of these genes in PH, these findings may provide new therapeutic insights.