bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 4147197: Deletion of PKM2 in macrophages fosters stabilization but not regression of atherosclerotic plaques
Authors: Dionisio Flavio , Prica Filip , Zhu Yeqian , Gisslinger Anna , Andersson Linda , Bengtsson Eva , Bjoerkbacka Harry , Massberg Steffen , Schulz Christian , Tomas Lukas
Published: November 2024

High-risk human atherosclerotic plaques show a metabolic profile characterized by a high glycolytic flux. Pyruvate kinase M2 is an important regulator of increased glycolytic activity and deletion of PKM2 in macrophages induces a reparatory macrophage phenotype. Given these results, we hypothesized that inhbiting glycolysis in macrophages by deleting PKM2 might induce atherosclerotic regression and present a viable therapeutic target. For this, we employed LDL receptor antisense oligonucleotides in
LysM
Cre
PKM2
flox
, allowing us temporal control of the LDL receptor knockdown and thus the induction of atherosclerosis regression by normocholesterolemia after a period of atherosclerotic development. After 16 weeks of Western Diet and ASO treatment, we found no difference in plaque size between
PKM2
cKO
and littermate
PKM2
WT
controls. We verified these results in a second centre in Sweden by transplanting either
PKM2
cKO
or
PKM2
WT
bone marrow into LDL receptor knockout mice and analysing the plaque area over the entire aortic root after 16 weeks of Western Diet. Despite similar plaque sizes between the two genotypes, we found that plaque collagen content was increased in
PKM2
cKO
compared to
PKM2
WT
mice (58±11 vs. 46±9%, p<0.05) whereas CD68 area was significantly decreased (39±10 vs. 23±9%, p<0.05) - mirroring previous results from another group. In line with these results, we found a trend towards more effective efferocytosis in vitro in
PKM2
cKO
compared to
PKM2
WT
macrophages. In order to test the effect of PKM2 knockout on plaque regression, we treated
PKM2
cKO
and
PKM2
WT
mice with Western Diet and ASOs for 16 weeks, after which we stopped ASO injections and fed them a chow diet for another 4 weeks to induce normocholesterolemia and plaque regression. After 20 weeks of treatment, we did not see a difference in plaque size or markers of plaque stability (lipid/collagen/macrophage content). These findings confirm previous results that PKM2 knockout in macrophages leads to a more stable phenotype in progressing plaques. Nonetheless, after a short period of normocholesterolemia - comparable to initiated statin treatment in patients - this advantage of non-functional PKM2 is lost. We conclude that PKM2 does not appear to be a promising therapeutic target to ameliorate atherosclerosis progression and initiate regression.
Abstract 4147205: Characterization of plasma proteome perturbations to distinguish thrombotic myocardial infarction from non-thrombotic myocardial injury and chronic coronary artery disease.
Authors: Tomar Shubham , Trainor Patrick , Lidani Karita , Mousavi Hossein , DeFilippis Andrew
Published: November 2024

Background:
The distinction between thrombotic myocardial infarction (TMI) and non-thrombotic myocardial injury (nTMi) is crucial, given their varied etiologies, unique treatment approaches, and higher misclassification in clinical setting. In this study, we compared plasma proteome among individuals with TMI, nTMi, and chronic coronary artery disease (cCAD).

Methods:
Mass spectrometry-based proteomic analysis was conducted in 173 patients (84 with TMI, 36 with nTMi, and 51 with cCAD) who underwent coronary angiography (T
0 -
acute time) and had an average 3-month post-procedure follow-up (T
fu,
quiescent state). Initially, we assessed temporal change from T
0
to T
fu
in proteomic profile in TMI group to identify proteins elevated during acute thrombosis. Subsequently, we compared these proteins’ levels at the acute phase across all groups to find differentially expressed proteins. We used hierarchical Bayesian models to analyze protein abundances, considering study group, time-point, and their interaction, with random effects for individual variability. Statistical significance was determined using Bayesian factor analysis with a threshold of BF > 150.

Results:
Proteomic profiling of plasma samples quantified 1,756 proteins. In TMI, 141 proteins varied significantly between T
0
and T
fu
. Proteins related to platelet activation, hemostasis, cell adhesion, and tissue remodeling were elevated. In contrast, proteins associated with extracellular matrix remodeling, cell adhesion, receptor signaling, and growth factor binding were reduced. Notably, six proteins showed differences when comparing TMI to nTMi. Specifically, Decorin, Myoglobin, and C-reactive protein levels were elevated during T
0
, while the others were decreased in TMI group. Comparing TMI to cCAD, 47 proteins differed significantly (
Figure 1A
).

Conclusion:
Our unique study design, using patients as their own controls, helped us in identifying distinct proteomic signature that can offers a promising set of noninvasive biomarkers for differentiating between TMI from other myocardial injury events.
Abstract 4147208: Life’s Essential 8 and Association with Adverse Cardiovascular Disease Events: Is Inflammation the Missing 9
th
Factor?
Authors: Pollack Ian , Swanson Justin , Bambs Claudia , Reis Steven , Saeed Anum
Published: November 2024

Background:
Recent data show that inflammation leads to residual atherosclerotic cardiovascular disease (ASCVD) risk. The recently revised AHA’s Life’s Essential 8 (LE8) optimal cardiovascular health advisory does not include inflammation as a modifiable risk factor for optimal cardiovascular health. We investigated the role of inflammation as a ninth component of LE8.

Methods:
Measures of cardiovascular health and inflammation biomarkers data were evaluated among 1,869 patients (age 59.0±7.45 years, 65.7% female, 41.9% self-identified as Black) enrolled in the Heart Strategies Concentrating on Risk Evaluation (Heart SCORE) study. Multivariable adjusted regression models were used to examine the association of LE8 quartiles with incident ASCVD events and all-cause mortality. We then tested the association of inflammatory markers (interleukin-6 [IL-6] and C-reactive protein [hs-CRP]).

Results:
Over a median of ~12 years, ideal level of blood glucose was associated with significantly lower risk of ASCVD (HR 0.26, CI 95% [0.12-0.58]; p=0.001). A similar trend was seen for ideal BP (HR 0.45, [0.18-1.12]; p=0.086). For all-cause mortality, no smoking emerged as the main protective factor (HR 0.29 CI95% 0.16-0.53, p<0.001).

Overall, highest quartile of LE8 Score was significantly associated with lower risk of ASCVD events and all-cause mortality (HR 0.14, [0.04-0.48];p<0.01) (
Table
). In stratified analysis, age and IL-6 levels (HR 1.54 (1.05-2.25); p=0.03) were independently associated with a higher risk of ASCVD events despite higher LE8 scores.

Conclusion:
Despite optimal health parameters, as identified by optimal Life’s Essential 8 scores, high IL-6 levels are independently associated with residual risk of ASCVD events. Utility of adding IL-6 as a ‘necessary ninth’ modifiable parameter needs to be explored further.
Abstract 4147249: Estimating Effects of Magnesium Supplement Use on Preventing Heart Failure in Diabetic Patients via Target Trial Emulation
Authors: Cheng Yan , Zullo Andrew , Yin Ying , Shao Yijun , Ahmed Ali , Liu Simin , Zeng Qing , Wu Wen-Chih
Published: November 2024

Introduction:
Magnesium (Mg) deficiency may increase the risk of heart failure (HF) in diabetic patients. Less is known about whether the use of Mg supplements is associated with a lower risk of HF in these patients.

Research Questions:
We emulated target trials to estimate the effects of Mg supplement use on preventing HF in diabetic patients.

Methods:
We analyzed data from the US Veterans Health Administration to identify eligible diabetic patients for a Mg supplement target trial from 01/01/2006 to 12/31/2020. Eligibility was checked at an outpatient visit with following criteria: 1) aged 40+ years, 2) free of outcomes, 3) had a HbA1C test in the past year, and 4) no prior Mg use. Mg supplement use was obtained by natural language processing of electronic health record. Mg supplement use was defined as use within 30 days of the eligible outpatient clinic visit. HF diagnosis was the primary outcome; Major adverse cardiac events (MACE), including death and HF hospitalization, was secondary outcome. Patients were followed up to 10 years until the outcome, censored due to no further Mg supplement use for Mg users or starting Mg supplement use for non-users, or receipt of a new Mg prescription.

We used Inverse probability weighting to account for differences in baseline characteristics between Mg user and non-users. We conducted a Cox regression model on the weighted cohort to compare the effect of Mg Supplement use on outcomes.

Results:
A total of 94,239 patients were enrolled in the target trials (17,619 Mg users; mean age, 67.3 years; 4.9% females, 18.5% Blacks). The mean duration of Mg supplement use was 3.7±3.3 yrs. The incidence of HF was slightly lower in Mg users compared to non-users (16.9 vs. 17.9 events per 1000 person-years). Mg supplement use was associated with a lower risk of HF and MACE (Figure 1).

Conclusion:
Our study showed that long-term Mg supplementation was associated with a lower risk of HF and MACE in diabetic patients. The potential benefits of Mg supplement use should be further confirmed in a randomized-controlled trial.
Abstract 4147265: Title: Immortalization of human cardiac fibroblasts using a combination of SV40 large T antigen and hTERT.
Authors: Semaan Josiane , Stratton Matthew
Published: November 2024

Background:
Fibroblasts are critical regulators of health and disease. Unfortunately, primary isolated fibroblasts retain limited proliferation potential. To enable robust biochemical experimentation in cardiac fibroblasts we immortalized human cardiac fibroblasts using lentiviral delivered SV40 large T antigen (SV40), human telomerase reverse transcriptase (hTERT), or both tools in combination.

Methods:
Following virus treatment with immortalization genes and hygromycin selection, we characterized subsequent immortalized cell lines for proliferative capacity and ability to become activated in response to TGF-β1 treatment. Expression of Periostin (POSTN), alpha smooth muscle actin (αSMA) and Sertad4 was measured via qPCR after 48hrs of vehicle or TGF-β1 (10ng/ml) treatment. Western Blot analysis was performed to detect the phosphorylation of SMAD2, AKT and P38 in response to TGF-β1 and cell doubling time was calculated at each passage through passage 20.

Results:
Fibroblasts immortalized with SV40 did not proliferate past passage 18 while those immortalized with hTERT quiesced at passage 19. Only the combination treatment resulted in fibroblasts that proliferated through passage 20 (last measured doubling time of 3.25 days – shortest doubling time of 1.23 days at passage 11). Early passage fibroblasts (passage 7) from each immortalization strategy showed increased mRNA expression of Sertad4, POSTN and αSMA following TFG-β1 treatment. However, only the combination strategy resulted increased Sertad4 and POSTN expression in higher passage cells upon stimulation. All immortalization strategies resulted in decreased αSMA expression upon TGF-β1 treatment in fibroblasts beyond passage 10. All cell lines tested retained the ability to increase AKT and SMAD2 phosphorylation in response TGF-β1 treatment.

Conclusions:
These results indicate that fibroblast immortalization through a combined SV40 large T antigen and hTERT expression approach is superior to individual manipulation. The combination strategy resulted in increased proliferative capacity and more robust TGF-β responsiveness. These cells may be a useful tool for investigating molecular mechanisms of fibroblast activation when the inability to expand primary cultures would be limiting
Abstract 4147275: A Longitudinal 20-year Analysis Indicates Acceleration of Cardiometabolic Comorbidities on Dementia Risk
Authors: Huang Lihua , Danish Muhammad , AuYeung Tung Wai , Lee Jenny , Kwok Timothy , Abrigo Jill , Wei Yingying , Lo Cecilia , Fung Erik
Published: November 2024

Background:
Dementia often seen in people aged ≥65y years is a major public health burden in Hong Kong, as its men and women have one of the longest lifespan worldwide. Using territory wide electronic health records (EHRs) spanning >20 years, we investigated the impact of cardiometabolic comorbidities on dementia risk.

Methods:
EHRs of public hospitals provided by Hong Kong’s Hospital Authority (HADCL) were examined for patient visits from 01/01/2000 to 12/31/2020. Included were individuals born in 1920,1930,1940,1950 with ICD-10 codes for all-cause dementia, or use of dementia and/or psychotropic drugs. Atrial fibrillation, stroke, hypertension, myocardial infarction, diabetes mellitus, chronic kidney disease, and hyperlipidemia identified by ICD codes or dispensed diabetic drug(s) or dihydropyridine calcium channel blocker (for hypertension) were investigated for age-dependent association with dementia using landmark analysis with multivariate Cox models.

Results:
A total of 222,418 patients (49% female) in four birth cohorts were examined with landmark analysis, which showed similar incidences for dementia. Adjusted for multiple testing, increased risk of all-cause dementia stratified by birth cohorts were significantly associated with hypertension and stroke from age 65, diabetes from age 50, and chronic kidney disease among men from age 58–64 (Figure). Earlier onset of these comorbidities except for hypertension were associated with increased dementia risk. Moreover, while the risk of dementia declined with old age in patients with diabetes, the risk for dementia markedly increased with hypertension after age 80. Surprisingly, the most recent birth cohorts, especially males, showed dementia risk elevation with diabetes, stroke and chronic kidney disease.

Conclusion:
We showed hypertension is a major risk for dementia in men/women >80 years, indicating hypertension management is critical for dementia risk reduction in the aged. The increase in dementia risk with stroke, diabetes, and chronic renal disease in the recent birth cohorts indicates disease burden acceleration predicting increase in economic burden. Further studies are warranted to investigate possible epigenetic mechanisms modulating dementia risk.
Abstract 4147290: The association between alcohol intake and pericarditis and myocarditis: The "All of Us” Research Program
Authors: Ndakotsu Andrew , Bene-alhasan Yakoub , Mensah Samuel , Acquah Isaac , Devkota Amrit , Osei Albert
Published: November 2024

Introduction:
Alcohol consumption is associated with an increase in pro-inflammatory cytokines. Acute non-infectious pericarditis may be a consequence of the alcohol-related inflammatory process. This study investigates the association between excessive alcohol consumption and the risk of acute pericarditis and myocarditis.

Hypothesis:
Alcohol use may be associated with myocarditis and pericarditis through oxidative stress, immunological dysfunction, and direct toxicity to the heart muscle.

Methods:
This is a cross-sectional study of participants in the All of Us study at the time of enrollment. Alcohol use, our primary exposure was measured using the Alcohol Use Disorder Identification Test-Consumption (AUDIT-C) score. Participants were stratified based on their AUDIT scores into Low risk-(males with Audit less than 4, females with Audit less than 3),moderate risk (AUDIT 4-5 in males, 3-5 in females), high risk (AUDIT 6-7 in both males and females) severe risk (AUDIT 8-12 in both males and females). The diagnosis of pericarditis and myocarditis was identified using electronic health records at the time of enrollment. The study adjusted baseline age, sex, race, educational status, income, health insurance, and smoking status. Logistic regression models were used to evaluate the association between alcohol intake and myocarditis/pericarditis. Models were adjusted for age, sex, race, educational status, income, health insurance, and smoking status.

Results:
Out of 135,010 eligible participants at baseline, 220 cases of myocarditis and pericarditis were detected. People with severe alcohol intake were (n=4825) more likely to be male (n, 3125, 64.8%%), less likely to be insured (n, %=4320, 89.5%) and less likely current cigarette smokers (n, %= 1007, 9.3%). The odds of developing myocarditis or pericarditis were not statistically significantly different with increasing AUDIT-C categories as compared to never- after adjusting for confounders. (table 1)

Conclusion:
There was no significant association found between higher AUDIT scores and an elevated risk of myocarditis and pericarditis.
Abstract 4147314: Contemporary Diagnosis, Management, and Outcomes of Patients With Low-Gradient Severe Aortic Stenosis: A Multi-Center Analysis
Authors: Vemulapalli Sreekanth , Lindman Brian , Elmariah Sammy , Pibarot Philippe , Peterson Benjamin , Rodriguez Evelio , Leon Martin , Mack Michael , Eberst Kyle , Genereux Philippe
Published: November 2024

Background:
The American College of Cardiology/American Heart Association guidelines recommend assessing aortic stenosis (AS) using American Society of Echocardiography-endorsed parameters and referring patients with severe symptomatic AS for treatment. Yet, multi-site real-world assessment of guideline adherence is lacking.

Methods:
We assessed consecutive echocardiographic reports for patients >18 years of age from 30 US institutions with appropriate permissions between January 2018–March 2024 (egnite Database; egnite, Inc.). Completeness of echocardiographic evaluation of AS was assessed. Patients with severe AS were stratified into high- and low-gradient (HG, mean aortic gradient [MG] ≥40 mm Hg; LG, MG <40 mm Hg). Rates of Heart Team evaluation within 60 days and aortic valve replacement (AVR) within 6 months were assessed via the Kaplan-Meier method.

Results:
Of 2,829,095 echocardiographic reports, V
max
, MG, aortic valve area (AVA), stroke volume index, left ventricular ejection fraction (LVEF), and AS severity were missing in 25%, 30%, 35%, 83%, 5%, and 36%, respectively. Of 1,189,382 patients with available AS severity assessment, 45,967 had an AVA ≤1.0 cm
2
and/or V
max
≥4.0 m/s with only 52% being diagnosed with severe AS and 20% being diagnosed as <moderate AS. Of 26,903 patients (2.3%) diagnosed with severe AS, there was a greater proportion of LG cases (LG: 52%, HG: 48%). Regardless of LVEF or symptoms, a lower proportion of severe LG AS patients were evaluated by a Heart Team within 60 days (LG: 37%, HG: 53%) and received an AVR within 6 months (LG: 35%, HG: 61%). Patients not evaluated by the Heart Team were older and more likely to be female and non-White than those who were evaluated, despite a comparable history of heart failure. A greater number of mortality events was observed among LG vs HG patients seen (877/10,241 vs. 381/9304) and not seen (2679/10,121 vs. 914 / 3453) by the Heart Team.

Conclusions:
Key parameters needed to diagnose the severity of AS are often missing in echocardiographic reports. Compared to HG, severe LG AS patients have lower Heart Team evaluation rates, with racial, sex, and age disparities, as well as lower AVR rates and more observed mortality events. Further work is needed to enhance guideline adherence for the diagnosis and management of patients with severe LG AS.
Abstract 4147316: Utilization of Palliative Care for Patients Living with Long-Term (LT) LVAD Therapy
Authors: El Khoury Marc , Creechan Patrick , Gupta Richa , Hockstein Michael , Avila-Quintero Victor , Flores Jose , Balsara Keki , Anderson Kelley , Groninger Hunter , Sheikh Farooq , Rao Anirudh
Published: November 2024

Background:
Outpatient palliative care has been associated with improved health-related quality-of-life (HRQoL) in patients with heart failure. However, there is limited understanding of its utilization among patients with long-term left ventricular assist device (LT-LVAD) therapy. The prevalence of LVAD implantation as long-term therapy has increased over the past decade; these patients may particularly benefit from outpatient palliative care.

Objective:
To identify the predictors of outpatient palliative care utilization in a sample of LT-LVAD patients from a high-volume LVAD center.

Methods:
This retrospective chart review analyzed data from 270 patients who received LVAD as long-term therapy between January 1, 2017, and December 30, 2021, and were supported on LVAD therapy for at least two years. Patients who received heart transplantation prior to the study end-date were excluded. Logistic regression models were used to estimate the odds of receiving outpatient palliative care (with or without inpatient palliative care) versus receiving inpatient palliative care alone.

Results:
Among 270 patients, the mean age was 62 years (+/- 12), 74.2% were male, 79.0% Black and 17.3% White. By device: 77.4% received HeartMate 3™ (HM3), 19.6% HVAD™ LVAD, 3.0% HeartMate II™. Patients lived an average of 4 years (+/- 1) post-implantation. The mean number of hospitalizations from implantation to death or end-of-study was 7.85 (+/- 7.04). 180 patients received inpatient palliative care consultation alone; 90 patients received at least one outpatient palliative care visit. Black patients had increased odds of receiving outpatient palliative care compared to White patients (OR 2.27, P=0.040). For each additional hospitalization a patient experienced, the odds of receiving outpatient palliative care increased (OR 1.06, P=0.002). Patients with HVAD™ LVAD were less likely to receive outpatient palliative care than those with HM3 (OR 0.45, P=0.029).

Conclusion:
In this large cohort of patients supported on LT-LVAD therapy, Black patients were more likely to receive outpatient palliative care than White patients. More frequent hospitalizations and LVAD type were associated with an increased likelihood of outpatient palliative care visits. Future studies should explore the factors contributing to these differences to better understand and enhance palliative care utilization for all patients on LT-LVAD therapy.
Abstract 4147323: The Effects of Illicit Drug Use on Congestive Heart Failure Patients and Hospital Readmission Rates at Harlem Hospital Center
Authors: Majdalani Rosemarie , Magdits Mariel , Alshammari Asmaa , Hughes Anna , McCann Lily , Devarajan Sriraman , Thu Myint , Jameel Ihab , Mangeshkar Shaunak , Kwentoh Ifeoma , Roy Pooja , Dulal Subash , Jha Sapana , Shou Jialu , Rijhwani Simran , Ionescu Natalia , Kakade Meghana , Kurian Damian , Raiszadeh Farbod
Published: November 2024

Introduction:
CHF is defined as a chronic disease that impacts more than 5 million adults in the United States with significant population-wide impact on morbidity, mortality and hospitalization burden, especially amonth high-risk and vulnerable populations. Although the intricacies of CHF and readmission risk have been well documented, there have been fewer studies investigating the effect of illicit drug use on CHF patients and readmission outcomes especially in a population at high risk of health disparities.

Objective:
The purpose of this study was to examine the effects of illicit drug use on CHF patients and hospital readmission rates at Harlem Hospital Center with a high density of patients with health disparities.

Methods:
We included all patients admitted during a 2 year period (2019-2020) with a primary diagnosis of heart failure to Harlem Hospital Center and conducted in depth assessment of drug use history including patient history, available laboratory analysis, and collateral EMR information. Rehospitalization was assessed by review of EMR by trained medical professionals. Our results were analyzed using standard statistical methods between the two groups with and without history of drug use.

Results:
Our study population included 380 admitted CHF patients. The overall prevalence of illicit drug use in CHF patients was 32.89%, with the most common drug used being cocaine. CHF patients who used illicit drugs had a 22.58% 30-day readmission rate in comparison to 13.78% among CHF patients who didn’t use illicit drugs. In addition, CHF patients who used illicit drugs had higher all-time hospitalizations and were more likely to be admitted than non-illicit drug users in terms of heart failure hospitalizations. Overall, CHF patients who used any type of illicit drug were twice as likely to be readmitted after index hospitalization compared to CHF patients who didn’t use illicit drugs. We also found that CHF patients who used illicit drugs were slightly younger, more likely to be male, and more likely to smoke cigarettes. Lastly, we observed that at least 50% of CHF patients who used illicit drugs were on government assistance, lacked family support, and were unemployed.

Conclusion:
Drug use is a common problem among patients with CHF in this vulnerable population and is associated with significant adverse outcomes such as increased rehospitalization. Systemic efforts to address this at the patient and community level are justified.
Abstract 4147332: Echocardiographic Risk Prediction of Outcomes in Acutely Ill Pulmonary Arterial Hypertension Patients
Authors: Malhi Jasmine , Mombeini Hoda , Jani Vivek , Naranjo Mario , Mercurio Valentina , Osgueritchian Ryan , Hassan Hussein , Hsu Steven , Simpson Catherine , Damico Rachel , Kolb Todd , Mathai Stephen , Hassoun Paul , Mukherjee Monica
Published: November 2024

Background:
Despite advancements in pulmonary arterial hypertension (PAH) management both in-hospital and long-term mortality remain high for those admitted to the ICU.

Aims:
We sought to identify echocardiographic predictors of outcomes and to develop a straightforward risk prediction score to predict one-year mortality in ICU-admitted PAH patients.

Methods:
This single-center, retrospective study examines adult PAH patients hospitalized in the JHH ICU from January 2010 to December 2020. Echocardiographic indices were collected and associated with outcomes using Cox proportional hazards (CPH) modeling to predict one-year mortality. Using these indices as well as clinical and lab data, a machine learning (ML) prediction model, Random Survival Forest (RSF), was trained and evaluated with a time-varying area under the curve (AUC).

Results:
Out of 102 PAH patients, 77 had complete echocardiograms at index hospitalization. Baseline characteristics are presented in Table 1. Right ventricular (RV) dilatation, RV contractile dysfunction (impaired TAPSE, FAC, and RVFWLS), more positive RA conduit strain, and RV-pulmonary artery (PA) uncoupling were associated with increased one-year mortality after adjusting for age, sex, race, and functional class (Figure1A). Kaplan-Meier survival curves revealed that TAPSE, TAPSE/PASP, RVFWLS, and RVFWLS/PASP have significant prognostic discriminative ability at optimal thresholds of 13 mm, 15 mm/mmHg, -9.5%, and 15%/mmHg, respectively. Our best ML RSF model achieved a mean time-varying AUC of 0.73 (Figure1B), with the top five predictors being estimated 4-chamber LV end-diastolic volume, FAC, echo-derived PASP, RVFWLS, and echo-estimated pulmonary vascular resistance (Figure1C-D).

Conclusion:
Echocardiographic right heart functional indices are associated with one-year mortality in ICU-admitted PAH patients. Employing these parameters in an ML model was predictive of adverse clinical outcomes.
Abstract 4147342: Beat-to-beat Blood Pressure Variability, Cerebrovascular Reactivity, and White Matter Lesion Volume In Older Adults
Authors: Lohman Trevor , Sible Isabel , Engstrom Allie , Kapoor Arunima , Shenasa Fatemah , Alitin John Paul , Gaubert Aimée , Nguyen Amy , Shao Xingfeng , Wang Danny , Nation Daniel
Published: November 2024

Introduction:
Brain health is dependent upon maintenance of stable cerebral blood flow in part through the interplay of blood pressure variability (BPV) and cerebrovascular reactivity (CVR). Consistent with this conceptualization, both BPV and CVR have been separately implicated in cerebral hypoperfusion and white matter lesion (WML) burden. However, the interactive effect of BPV and CVR on WML burden has yet to be investigated.

Hypothesis:
Older adults with elevated BPV and deficient CVR will exhibit greater WML volume.

Aims:
Determine the relationship between elevated beat-to-beat BPV and WML volume across varying levels of whole brain CVR.

Methods:
Independently living older adults without history of major neurological/psychiatric history were recruited from the community and underwent continuous blood pressure monitoring and pseudo-continuous arterial spin labeling MRI. Whole brain perfusion was quantified during 5 minutes of rest with simultaneous monitoring of end-tidal CO
2
(
ET
CO
2
) levels. BPV was quantified as beat-to-beat systolic average real variability and spontaneous CVR was quantified as %change in CBF/change in
ET
CO
2
at rest. WML volume was quantified from T1-weighted fluid attenuated inversion recovery and segmented with the lesion growth algorithm implemented in the LST toolbox version 3.0.0 for SPM12.

Results:
Eighty-five older adults were studied (mean age = 69.3 years; SD = 6.56; age range 55–89 years; 61.4% female). Resting whole brain CVR moderated the relationship between BPV and WML volume
(
B= -
.12
, P=
.01). Specifically, in individuals with impaired whole brain CVR, elevated BPV was independently associated with increased white matter lesion volume (
Fig. 1
).

Conclusion:
The present findings show that the relationship between BPV and WML volume is dependent upon whole brain CVR. This suggests that the cerebral vasculature’s ability to respond to vasoactive stimuli determines whether elevated BPV is associated with white matter lesions. Future studies of blood pressure variability and cerebral small vessel disease should account for this interactive effect.
Abstract 4147345: Sex differences in cardiac allograft rejection states using Tissue gene-expression profiling (MMDx)
Authors: Fernandez Valledor Andrea , Moeller Cathrine , Oren Daniel , Rahman Salwa , Baranowska Julia , lotan dor , Rahman Afsana , Elad Boaz , DeFilippis Ersilia , Regan Matthew , Yunis Adil , Salazar Ruben , Hennecken Carolyn , Fried Justin , Raikhelkar Jayant , Clerkin Kevin , Latif Farhana , Sayer Gabriel , Uriel Nir
Published: November 2024

Introduction:
Limited knowledge exists regarding the influence of sex on rejection-related gene-expression profiling using the Molecular Microscope (MMDx).

Methods:
We prospectively included all heart transplant recipients who underwent endomyocardial biopsy for clinical indication from November 2022 to May 2024 at New York Presbyterian. During the biopsy procedure, four samples were sent for histologic evaluation, and two for molecular analysis. Donor-derived cell-free DNA levels (dd-cfDNA%), peripheral gene-expression profiling (pGEP) scores, MMDx rejection scores, and rejection rates on histology and MMDx were compared based on sex.

Results:
A total of 414 samples were included, 130 (31.4%) were from female recipients. dd-cfDNA levels were higher in females compared to male recipients (
0.30%
[0.15-0.80] vs.
0.22%
[0.11-0.45]; p=0.02). Despite similar rates of pGEP scores (32 [28-34] vs. 32 [29-35]; p=0.70) or pGEP positivity (14.6% vs 17.0%; p=0.18), there was a trend towards a higher prevalence of donor-specific antibodies in female recipients (51.5% vs. 44.4%; p=0.20). Overall, rejection rates on MMDx (30.8% vs. 19.1%; p=0.01) and MMDx rejection scores (
0.40
[0.17-0.63] vs.
0.27
[0.11-0.55]; p=0.005) were higher in female recipients (
Figure 1
), primarily due to increased rates of antibody-mediated rejection (
ABMR
) diagnosis in this group (
21.5%
vs.
10.8%
; p=0.003). No differences in rejection rates were noted when assessed by histology (6.9% vs 8.0%; p=0.37).

Conclusion:
In a cohort of heart transplant recipients biopsied due to suspected rejection, female recipients were associated with increased MMDX-rejection scores and higher rejection rates, primarily driven by a twofold higher frequency of ABMR detection by MMDx compared to males.
Abstract 4147347: The value of Coronary Artery Disease Polygenic Risk Score (CAD PRS) and Coronary Artery Calcium Score (CACS) in the prediction of Atherosclerotic Cardiovascular Diseases (ASCVD)
Authors: Wasef Natale , Biskupski Patrick , Alsaiqali Mahmoud , Stys Krystina , Hajek Catherine , Bartaria Shubhi , GU SHAOPENG , Guo Xiuqing , Rotter Jerome , Larson Eric , Stys Adam , Rajpurohit Naveen , Petrasko Marian , Stys Tom
Published: November 2024

Introduction:
Atherosclerotic cardiovascular disease (ASCVD) is a complex disease process, and an early diagnosis of high-risk patients will decrease morbidity and mortality. In our study, we evaluated Coronary Artery Disease Polygenic Risk Score (CAD PRS) and Coronary Artery Calcium Score (CACS) and their combination in the prediction of ASCVD, represented by peripheral vascular disease, aortic sclerosis, severe aortic stenosis, and stroke.

Method:
Our population was individuals enrolled in the Sanford Heart Screening Program and genotyped using the Illumina Global Screening Array version 1. CAD PRS was calculated using a literature-derived list of 180 single nucleotide polymorphisms (SNP). Patients were classified into two groups based on CAD PRS: High PRS (>=85
th
percentile) or low/intermediate PRS (<85
th
percentile). CACS was classified as high risk with a value of ≥ 300 and a non-high score when <300. We used hierarchical logistic regression to assess CAD PRS, CACS, and their combination in predicting ASCVD.

Results:
In a sample of 689 patients, CACS was associated with sclerosis (OR=2.29 [1.18, 4.30], p<.05), aortic stenosis (OR=10.0 [2.14, 70.6], p<.01), PVD (OR=2.52 [1.23, 4.97], p<.01) but not a stroke (OR=1.63 [0.62, 3.87], p=.3). A high PRS was shown not to be significantly associated with aortic sclerosis (OR=1.23 [0.52, 2.60], p=.60), PVD (OR=1.09 [0.40, 2.52], p=.8), or stroke (OR=1.5 [0.49, 3.84], p=.4), but was marginally associated with aortic stenosis (OR=4.31 [0.84, 19.8], p=.058). When holding a high CACS constant, a high PRS failed to show any significant hierarchical utility in predicting aortic stenosis (OR=3.10 [0.59, 14.7], p=.20).

Conclusion:
The combination of high CAD PRS to high CACS was not clinically significant in improving predictive value for atherosclerotic cardiovascular diseases, although was noted to be marginally significant for aortic stenosis. Increasing sample size might increase the power and show clinical significance in future assessment
Abstract 4147354: Life’s Essential 8 among adults living with cardiovascular-kidney-metabolic (CKM) syndrome: 2013-2020 National Health and Nutrition Examination Survey
Authors: Adeleye Khadijat , Akubo Chelsea , Tomiwa Tosin , Dugbartey Janice , Olusola-Bello Mojisola , Sullivan Valerie , Ogungbe Bunmi
Published: November 2024

Introduction:
Cardiovascular-kidney-metabolic (CKM) syndrome is a multifaceted condition impacting cardiovascular, kidney, and metabolic health. Life’s Essential 8 (LE8), key measures for improving and maintaining cardiovascular health, may predict health outcomes, but its relationship with CKM syndrome is unclear.

Objectives:
This study aimed to examine LE8 scores within CKM stages 1-4 among the US adult population.

Methods:
Data from the National Health and Nutrition Examination Survey (NHANES, 2013-2020) were analyzed. CKM was categorized into 4: presence of excess adiposity, prediabetes (stage 1), metabolic risk factors, CKM or CVD risk factors, high-risk kidney disease (stages 2-3), clinical CVD with CKM risk factors (stage 4). Each LE8 factor was scored between 0 and 100 points and categorized into quartiles Q1 (low): 0-38, Q2 (moderate): >38–50.65, Q3 (high): >50.65–63, and Q4 (very high): >72.86. We fitted a weighted generalized linear model adjusting for race/ethnicity, age, gender, education, poverty income ratio, insurance, and employment.

Result:
We include 9,019 adults with CKM; mean age 50.7(±15) years, 49% female. For stage 1 CKM, high (β =0.98 (95% CI: 0.97–0.99) and very high (β =0.95(95% CI:0.93- 0.97) LE8 quartile were significantly associated with lower risk of CKM, compared to low LE8 quartile (figure). Also, Increasing LE8 scores progressively showed reductions in the risk of stage 2 CKM in high (β =0.96 (95% CI: 0.97–0.99) and very high (β =0.91, 95% CI: 0.97–0.99) LE8 quartiles. Similar to stage 2, increasing LE8 scores significantly reduced the risk of stage 3 CKM in the high (β =0.96 (95% CI: 0.97–0.99) and very high (β =0.91, 95% CI: 0.97–0.99) LE8 quartiles. Greater reduction in CKM stage 4 risk was observed for moderate (β = 0.98, 95% CI: 0.97–0.99), p=0.009; high (β =0.92 (95% CI: 0.89–0.95), and very high (β -0.82, 95%CI:0.75- 0.89), LE8 quartiles.

Conclusion:
The association between LE8 scores and CKM stages suggests that improving LE8 scores may reduce the prevalence and severity of CKM syndrome among adults. These findings contribute to the importance of early intervention strategies targeting cardiovascular and metabolic health.
Abstract 4147358: Outcomes of ECMO vs. Impella as a Bridge to Heart Transplant: A Nationwide Analysis in the United States
Authors: Ghimire Manoj , Poudel Sajana , Ghimire Kalpana , Shrestha Karun , Subedi Prakriti , Chamay Salomon , Nikollari Redi , Kadariya Dinesh , Celaj Sulejman
Published: November 2024

Introduction:
Heart transplantation (HT) is the gold standard for end-stage heart failure, but limited donor availability and increasing disease prevalence have necessitated the use of mechanical circulatory support (MCS) devices. There is a rising trend of MCS devices used as a bridge to transplant with variable outcomes. This study examines trends and outcomes of MCS devices, specifically Extracorporeal Membrane Oxygenation (ECMO) and Impella, used as bridges to HT.

Hypothesis:
Impella support leads to better survival and post-transplant outcomes than ECMO.

Methods:
A retrospective cross-sectional study was conducted using National Inpatient Sample data from 2016-2021. Trends in utilization and patient outcomes were compared for those who received ECMO and Impella as bridges to HT. International classification of disease (ICD-10) codes were used to extract the data.

Results:
During the study period, 17,570 HTs were performed, with a rising trend in using MCS devices as a bridge to transplant, especially Impella. ECMO was used in 1,635 patients and Impella in 755 patients. The mean age of the study population was 52.5 years and 610 (25.5%) were female. Cardiogenic shock was more common among patients with Impella (94.04% vs. 67.28%, p<0.001). Severe sepsis (9.27% vs. 23.24%, p<0.001) and transplant failure (0% vs. 13.15%, p<0.001) were higher with ECMO use. Mortality was lower with Impella (1.99% vs. 27.22%, p<0.001). Hospital stay and costs were similar for both groups.

Conclusion:
In patients undergoing HT, the use of the Impella device was associated with lower in-hospital mortality, severe sepsis, and transplant failure compared to ECMO.
Abstract 4147380: Cardiomyocyte Contractile Phenotype as a Marker of Cardiomyopathy Risk
Authors: Campbell Stuart , Rasheed Yusuf , Halder Saiti , Ng Kaiquan Kenneth , Young Samuel , Kim Lynne , Li Xia , Brueckner Martina , Stendahl John , Rupert Cassady
Published: November 2024

Introduction:
Cascade genetic screening for risk stratification is standard practice in the family of a patient diagnosed with hypertrophic cardiomyopathy (HCM), provided that a pathogenic mutation is present. We sought an alternative to genetic testing for cases where the patient lacks any suspicious variants (genotype-negative).

Hypothesis:
Induced pluripotent stem cell (iPSC)-derived cardiomyocytes from HCM patients with pathogenic mutations exhibit one or more altered contractile parameters when formed into engineered heart tissues (EHTs). These include elevated peak force, delayed relaxation, or blunted length-dependent activation (LDA). We hypothesized that EHTs derived from genotype-negative HCM patients would show similar contractile aberrations. If so, aberrant contractile phenotype could serve as a marker of HCM risk in screening family members when genetic testing is inconclusive.

Methods:
A total of 18 iPSC lines were obtained from a combination of public biobanks, institutional sources, and blood samples from consenting patients. These included lines from apparently healthy individuals (n=11) and from genotype-unknown or genotype-negative HCM patients (n=7). Four of the healthy lines were randomly selected as reference controls and the remaining 14 lines formed a blinded cohort. iPSCs were differentiated into cardiomyocytes and formed into EHTs using MyoPod tissue scaffolds. Following three weeks of culture, EHT contractility and LDA were assessed. Bootstrapping analysis was used to compare blinded EHT behavior against the reference group to mimic a diagnostic test.

Results:
None of the genotype-negative EHT groups showed statistically significant contractile differences compared to reference panels. One apparently healthy control EHT showed a significant (p<0.05) increase in contractile force; exome sequencing revealed a rare
FHOD3
mutation (D284N). Only one HCM patient line showed statistically significant change in contractility relative to reference (31% drop in normalized LDA, p<0.05). Sequencing revealed a known pathogenic HCM mutation (
MYH7
K351E) in that patient.

Conclusions:
EHTs derived from genotype-negative HCM patients do not exhibit detectable alterations in contractile behavior, but patient EHTs harboring suspected or known pathogenic variants reliably do. This method has the potential to determine mutation penetrance in specific patients or pathogenicity of novel variants.
Abstract 4147384: P66ShcK81-sumoylation mediates hyperlipidemia-induced endothelial dysfunction in mice
Authors: Uppulapu Shravan Kumar , KUMAR JITENDRA , Kumari Sujata , Sharma Kanika , Paradee William , Yadav Ravi Prakash , Kumar Vikas , Kumar Santosh
Published: November 2024

Introduction:
Hyperlipidemia promotes atherosclerosis, a leading cause of myocardial infarction and stroke. Atherosclerosis is commonly associated with endothelial dysfunction. Elevated levels of p66Shc and sumoylated proteins have been implicated in hyperlipidemia-induced endothelial dysfunction. Recently, we discovered that SUMO2 modifies p66Shc at lysine-81, regulating its function. However, the role of endogenous p66ShcK81 sumoylation remains unclear.

Methods:
We used LDLr-/- mice and p66ShcK81R knock-in mice on an LDLr-/- background (p66ShcK81R-KI x LDLr-/-). Hyperlipidemia was induced by feeding the mice a high-fat diet for 4 weeks. We monitored body weight gain and measured serum total cholesterol levels. Endothelial function, oxidative stress, and sumoylation were assessed in the aortas. Additionally, we performed global mass spectrometry to identify the molecular signaling pathways regulated by p66ShcK81-SUMO2ylation in endothelial cells.

Results and Discussion:
To determine the contribution of SUMO2 to this sumoylated pool of proteins, we treated human umbilical vein endothelial cells with oxidized LDL and knocked down SUMO2 with siRNA. The majority of the sumoylated proteins were found to be SUMO2-conjugated, suggesting that SUMO2 is primarily affected in hyperlipidemia. In LDLr-/- mice on a high-fat diet, we observed increased expression of SUMO2/3-conjugated proteins compared to controls. Feeding a high-fat diet induced a similar increase in serum cholesterol levels as well as weight gain in both LDLr-/- and p66ShcK81R-KI x LDLr-/- mice. Vascular reactivity revealed significant impairment of endothelium-dependent vasorelaxation of aortic rings in LDLr-/- mice. However, aortic rings from p66ShcK81R-KI x LDLr-/- mice displayed vasorelaxation similar to control p66ShcK81R-KI mice. We also noted increased oxidative stress (8-OHdG levels) in LDLr-/- mice, which was significantly reduced in p66ShcK81R-KI x LDLr-/- mice. Lastly, mass spectrometry data indicated that p66ShcK81-SUMO2ylation promotes mitochondrial dysfunction and impairs Rho-GTPase signaling in endothelial cells.

Conclusion:
Our findings demonstrate that p66ShcK81 mediates hyperlipidemia-induced endothelial dysfunction and oxidative stress. Investigating the role of specific molecules regulated by p66ShcK81-SUMO2ylation may lead to the discovery of novel tools to manage endothelial dysfunction caused by hyperlipidemia.
Abstract 4147397: The Impact of Frailty on In-Hospital Outcomes of Percutaneous Coronary Intervention Performed for Stable Ischemic Heart Disease
Authors: Akunor Harriet , Singh Nikita
Published: November 2024

Background:
Ischemic heart disease (IHD) is a prevalent cardiovascular disease (CVD) associated with high morbidity and mortality. Over 600,000 percutaneous coronary interventions (PCI) are performed each year for IHD. Frailty and CVD are often interrelated, affecting disease and treatment outcomes. Frailty is a syndrome of physiological decline, characterized by marked vulnerability to adverse health outcomes. Frailty is prevalent in adults with IHD requiring PCI. However, the relationship between frailty and PCI outcomes is not well described.

Methods:
We analyzed the 2020 National Inpatient Sample (NIS) to identify index hospitalizations in which PCI was performed for patients >18 years with stable ischemic heart disease (SIHD), defined as PCI discharges without acute coronary syndromes (ACS), such as STEMI, NSTEMI, or unstable angina. Patients were categorized as frail if they had a hospital frailty risk score (HFRS) of 5 or higher, and non-frail if their score was below 5. We assessed in-hospital mortality, intracranial hemorrhage, gastrointestinal (GI) hemorrhage, anemia requiring blood transfusion, acute kidney injury (AKI), and hospital length of stay (LOS) between both groups. Hospital-level discharge weights were applied during statistical analyses to derive national estimates.

Results:
A total of 116,620 patients underwent inpatient PCI for SIHD, of whom 33,875 were frail adults. Frail patients had higher odds of in-hospital mortality (adjusted odds ratio [AOR] = 8.72, 95% confidence interval [CI]: 7.44-10.23), intracranial hemorrhage (AOR = 4.65, 95% CI: 2.18-10.82), GI hemorrhage (AOR = 2.03, 95% CI: 1.63-2.53), anemia requiring blood transfusion (AOR = 1.65, 95% CI: 1.32-2.06), and AKI (AOR = 2.12, 95% CI: 1.93-2.32) during the index hospitalization, as well as a longer LOS (median 5 days, interquartile range [IQR] 3-10 days, vs. median 2 days, IQR 2-3 days).

Conclusion:
Frail adults undergoing inpatient PCI for SIHD are at increased risk for in-hospital mortality and periprocedural complications, with longer LOS. Frailty is common among patients undergoing PCI for SIHD; understanding these outcomes may improve shared decision-making for patients considering PCI.