bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 4139912: Inflammatory biomarkers in people treated with tirzepatide living with overweight or obesity, without and with T2D: a post-hoc analysis from SURMOUNT-1 and SURMOUNT-2
Authors: Sattar Naveed , Verma Subodh , Sourij Harald , Wilson Jonathan , Stefanski Adam , zhang xiaotian , Griffin Ryan , Ruotolo Giacomo , Linetzky Bruno
Published: November 2024

Background:
Tirzepatide (TZP) is a once weekly GIP and GLP-1 receptor agonist approved for the treatment of type 2 diabetes (T2D) and obesity. This post hoc analysis examined biomarkers of inflammation in people living with obesity, or overweight, without and with T2D, from SURMOUNT-1 and SURMOUNT-2. Furthermore, we evaluated the contribution of weight reduction- associated and - unassociated effects on biomarkers of inflammation.

Methods:
A total of 700 participants were randomly selected from SURMOUNT-1 and SURMOUNT-2 (100 participants from each treatment arm: placebo, 5, 10, and 15 mg in SURMOUNT-1 and placebo, 10 and 15 mg in SURMOUNT-2). The association of treatment with change from baseline in the inflammation biomarkers interleukin-6 (IL-6) and high sensitivity C-reactive protein (hsCRP) at 24 and 72 weeks was assessed along with the estimated percentages of the association attributable to weight loss through a mediation analysis.

Results:
In SURMOUNT-1, following 72 weeks of treatment with TZP without T2D, TZP was associated with significantly decreased IL-6 (-26% to -31%) and hsCRP (-51% to -65%), compared to placebo in all dose groups. In SURMOUNT-2, following 72 weeks of treatment with TZP in participants with T2D, changes of -16% to -23% in IL-6 and -55% to -56% in hsCRP were observed (significance seen for all groups except for TZP 15mg on IL-6). At 24 weeks, only 18% and 31% of hsCRP changes were associated with weight reduction in SURMOUNT-1 and -2, respectively. In SURMOUNT-1, 77% of IL-6 changes and 87% of hsCRP changes at 72 weeks were associated with weight reduction. In SURMOUNT-2, 78% of IL-6 changes and 57% of hsCRP changes at 72 weeks were associated with body weight reduction.

Conclusions:
In this post hoc analysis of SURMOUNT-1 and -2, early changes in hsCRP (week 24) were weight reduction-unassociated, while at week 72, changes in the inflammation biomarkers IL-6 and hsCRP observed in TZP-treated participants were mainly weight reduction-associated. The relative contribution of weight reduction-dependent effects was more prominent in participants without T2D, compared to those with T2D. Collectively, these data suggest TZP was associated with reduced inflammation in people with overweight/obesity and/or T2D.
Abstract 4139930: Low Ventricular Stiffness is Associated with Suboptimal Outcomes in Single Right Ventricle Patients after the Fontan Operation: A Novel Phenotype
Authors: Chowdhury Shahryar , Atz Andrew , Graham Eric , Bandisode Varsha , Rhodes John , Nutting Arni , taylor carolyn , Savage Andrew , Hassid Marc , Kavarana Minoo , Menick Donald
Published: November 2024

Introduction:
Despite a rigorous screening process, including cardiac catheterization, a subset of single right ventricle (SRV) patients demonstrate suboptimal short-term outcomes after the Fontan operation. The goal of this study was to perform a comprehensive assessment of diastolic function in pre-Fontan SRV patients using invasive reference-standard measures and determine their associations with post-Fontan outcomes.

Methods:
Children 2-6 years old with SRV physiology undergoing pre-Fontan heart catheterization were recruited prospectively. SRV patients were divided into those who had an optimal or suboptimal outcome. A suboptimal outcome was defined as length of stay ≥14 days or heart transplant/cardiac death in first year after Fontan. Patients with hemodynamically insignificant patent ductus arteriosus referred for catheterization closure were recruited as controls. Patients underwent pressure-volume loop analysis using reference-standard methods. The measure of ventricular stiffness, β, was obtained via preload reduction. Cardiac magnetic resonance imaging for extracellular volume (ECV) and serum draws for matrix metalloproteinase (MMP) activity were performed.

Results:
Of 19 SRV patients, 9 (47%) had a suboptimal outcome. 15 controls were included. Demographic and catheterizations are shown in Table 1. Echocardiographic and MRI data are shown in Table 2. Patients with suboptimal outcomes had lower ventricular stiffness, lower ECV, and lower MMP-2 compared to patients with optimal outcomes (Figure 1). Patients with suboptimal outcomes had similar stiffness to biventricular controls. Patients with optimal outcome had less total fluid in the first 24 hours than the suboptimal group (1107 (IQR 953, 1303) vs. 1482 (IQR 1305, 1598) mL, p = 0.03). The only invasive measure that had an association with suboptimal outcome was β, p=0.038.

Conclusion:
SRV patients with suboptimal outcome after Fontan had lower ventricular stiffness compared to patients with optimal outcome. Lower stiffness led to an increased need for fluid resuscitation and higher chest tube output after Fontan. The usual response in chronically increased RV afterload is for the RV to hypertrophy and stiffen over time in order to maintain cardiac output. This is not seen in low SRV stiffness patients and may represent a maladaptive extracellular matrix response to chronic afterload elevation. This novel phenotype that may have important clinical implications and requires further study.
Abstract 4139932: Glucagon-like peptide-1 Receptor Agonists reduce the Incidence of Echocardiographic Pulmonary Hypertension
Authors: Garry Jonah , Kundu Suman , Eden Svetlana , Alcorn Charles , Freiberg Matthew , Brittain Evan
Published: November 2024

Introduction:
No interventions decrease the risk of developing pulmonary hypertension (PH). We hypothesize Glucagon-like peptide-1 receptor agonists (GLP-1) reduce risk of PH through salutary changes in metabolism, weight, and the pulmonary vasculature. We examined GLP-1 exposure and development of PH among pts with diabetes (DM) in a national healthcare system.

Methods:
Pulmonary artery systolic pressure (PASP) estimates were extracted from TTEs in the Veterans Affairs system. PH (primary outcome) was defined as PASP >35 mmHg. Individuals free of PH on or after 1/2007 (baseline) were followed through the development of PH, death, or censored on 12/2020. The primary exposure was GLP-1 prescription modeled as: 1) Baseline exposure 2) Time-updated exposure and 3) Cumulative days of exposure (among exposed). We used multivariable cox models adjusted for demographics, comorbidities, and clinical characteristics in
Table 1
.

Results:
We identified 147,619 patients with DM (63 years [IQR 59-67], 95% Male, 21% Black) with a baseline TTE free of PH. Median follow up was 4.5 years (2.3-7.3 IQR). Of these, 2,621 pts were exposed to GLP-1 at baseline and 5,699 pts after baseline. Median time on drug (among exposed) was 296 days (120-570 IQR). Characteristics of exposed vs unexposed at baseline are displayed in
Table 1
with Age-adjusted Kaplan Meier curve in
Figure 1A
. GLP-1 exposure associated with decreased risk of incident PH when modeled as baseline exposure (HR 0.76; 95% CI 0.67-0.87), time-varying exposure (HR 0.82; 95% CI 0.76-0.89), and time-varying exposure restricted to pts without baseline exposure (HR 0.85; 95% CI 0.78-0.94). Risk of PH decreased as days on GLP-1 increased (
Figure 1B
). At 90 days on drug, we observed decreased risk of PH (HR 0.94; 95%CI 0.92-0.96).

Conclusions:
GLP-1 exposure at baseline or de novo during follow up is associated with decreased incidence of PH in pts with DM. The benefit from GLP-1 starts near 90 days and increases with time on drug.
Abstract 4139978: Multi-Modality Imaging Characteristics and Survivals By Aortic Stenosis Subtypes In Patients Undergoing Transcatheter Aortic Valve Replacement
Authors: Haroun Elio , Arockiam Aro Daniela , Dong Tiffany , Agrawal Ankit , Khurana Rishabh , El Dahdah Joseph , Alamer Mohammad , Kassab Joseph , Bhalla Jaideep Singh , Bodi Kashyap , Harb Serge , Popovic Zoran , Rodriguez L , Puri Rishi , Reed Grant , Krishnaswamy Amar , Griffin Brian , Kapadia Samir , Wang Tom Kai Ming
Published: November 2024

Background:
Discrepant transthoracic echocardiography (TTE) parameters are not infrequently observed in patients with significant aortic stenosis (AS), however, there is limited literature regarding their computed tomography (CT) characteristics and prognostic implications.

Aims:
We compared the multi-modality imaging characteristics and outcomes in patients undergoing transcatheter aortic valve replacement (TAVR) by AS subtype.

Methods:
Patients with severe AS (defined as aortic valve area <1.0 cm2 on TTE, n=906, age 79±9 years, 41.5% women) undergoing TAVR during 2019-2020 were classified by TTE as high-gradient (HG-AS, n=446, LVEF 61 ±8%), classical low-flow low-gradient (CLFLG-AS, n=121, LVEF 37 ±9%), paradoxical low-flow low-gradient (PLFLG-AS, n=261, LVEF 61 ±6%) and normal-flow low-gradient (NFLG-AS, n=78, LVEF 62 ±6%) AS. TTE and CT characteristics and all-cause mortality during follow-up were compared.

Results:
Aortic valve area by TTE (continuity equation) and CT (planimetry) were lowest for HG-AS patients (means 0.70cm
2
and 1.04cm
2
), and highest for NFLG-AS patients (0.86cm
2
and 1.18cm
2
), while aortic valve calcium score (AVCa) on CT was higher for HG-AS patients than other groups (2471HU versus 2009-2180 HU). Kaplan-Meier survival curves by AS subgroup are shown in the figure. Low-gradient AS subgroups (compared with HG-AS) remained independently associated with worse survival with hazards ratio 2.04 (95% confidence interval 1.50-2.77) even after adjusting for other clinical and AS imaging parameters.

Conclusion:
Characteristic TTE and CT features by AS subtypes are reported. TAVR patients with low-gradient AS (CLFLG-AS, PLFLG-AS and NFLG-AS) continue to have worse prognosis than HG-AS, highlighting the need for further research in these patients to improve their management and outcomes.
Abstract 4140001: Impact of White Matter Hyperintensity in the Corpus Callosum on Parahippocampal Atrophy and Prognosis in Heart Failure Patients Without Dementia
Authors: Meguro Tomomi , Meguro Yuko , Funabashi Nobusada
Published: November 2024

Background:
Aged heart failure (HF) patients without dementia have a risk of cognitive impairment (CI) that attenuates the effect of treatment for HF. White Matter Hyperintensity (WMH) and gray matter atrophy in parahippocampal gyrus (PHG) are a potential risk of CI. However, it is not clear whether location and volume of local WMH is associated with atrophy in PHG and predicts prognosis of HF patients.

Hypothesis:
In HF patients without dementia, local WMH volume is associated with brain atrophy of PHG and predicts prognosis.

Methods:
We enrolled sixty-one HF patients (age 76±11 years, NYHA class II, EF47±17 %) in the study. We excluded patients with dementia using mini-mental state examination. We took 3D-T1 weighted images and Fluid Attenuated Inversion Recovery (FLAIR) images of whole brain using 1.5T magnetic resonance imaging (MRI). We performed image analysis using 2mm voxel-based morphometry with Statistical Parametric Mapping to evaluate the local WMH volume in the frontal, temporal, parietal, and occipital lobes, as well as the corpus callosum (
CC
), and to assess the severity of PHG atrophy. We quantified the severity of PHG atrophy using Z-scores. We constructed receiver operating characteristic (ROC) curves to determine the cut-off point of the each local WMH volume for estimating cardiac death and admission due to HF. We constructed Kaplan-Meier Curves adjusted with age, sex, presence of atrial fibrillation, diabetes, dyslipidemia, and blood pressure using inverse probability weighting method.

Results:
Local WMH volume of CC demonstrated the highest prognostic accuracy (area under the ROC curve 0.73). We divided patients into High-WMH group (n=36, volume of WMH in CC 0.65±37 mL) and Low-WMH group (n=25, volume of WMH in CC 0.14±0.07 mL) according to the cut-off value (0.24 mL) of local WMH volume in CC. As shown in representative cases in Figure1, the Z-score value in PHG (pink circle) was higher in High-WMH group (1.43±0.77) compared to Low-WMH group (0.93±0.63, P=0.01). Adjusted Kaplan-Meier curves showed poor prognosis of High-WMH group (Figure 2).

Conclusions:
In HF patients without dementia, local WMH in corpus callosum is a potential risk of CI and predicts poor prognosis.
Abstract 4140002: Health Literacy Exacerbates Neighborhood Social Vulnerability in Older Black and Hispanic Adults with Heart Failure: Results from the SCAN-MP Study
Authors: Islam Shabatun , Teruya Sergio , Fine Denise , Sabogal Natalia , Fils Sergylensky , Ullah Ikram , Sanchorawala Anya , Miller Edward , Gallegos Cesia , de Freitas Cinthia , Kurian Damian , Ionescu Natalia , Janvier Ivrose , Raiszadeh Farbod , Magnani Jared , Maurer Mathew , Ruberg Frederick
Published: November 2024

Introduction:
Neighborhood residence and health literacy are associated with cardiovascular outcomes, however their interactions in minoritized populations are unknown. We evaluated the association between neighborhood social vulnerability, heart failure hospitalization (HFH), and all cause mortality in a cohort of older Black and Hispanic individuals with prior diagnosis of HF in the northeastern US.

Hypothesis:
Individuals living in the most socially vulnerable neighborhoods have the highest HFH and 12-month mortality, and having limited health literacy will exacerbate these effects.

Methods:
We recruited individuals >60 years self-identified as Black race or Hispanic ethnicity with heart failure as part of the Screening for Cardiac Amyloidosis with Nuclear Imaging in Minority Population
(
SCAN-MP) study. We assessed their social vulnerability index (SVI) at the census-tract level; health literacy (HL) with the Newest Vital Sign; and symptom burden with the Kansas City Cardiomyopathy Questionnaire (KCCQ). Cox proportional hazards ratio models evaluated the association between participants’ SVI and HFH (with death as competing risk) and 12-month mortality. We assessed interaction of HL with SVI. Outcomes were stratified for those with limited health literacy.

Results:
Of 619 participants (mean age 73y, 51% women, 85% Black race), 50% lived in neighborhoods of extreme vulnerability (>89
th
percentile national ranking of SVI). Individuals in the highest quartile (versus lowest) of SVI had increased HF symptoms (KCCQ Overall Score 64.8 vs. 70.6) and lower adequate health literacy (10% vs. 19%). After adjusting for age, sex, ethnicity, and gait speed, the highest quartile of SVI (vs. lowest) experienced higher HFH with death as competing risk (HR 1.71 [1.06, 2.76], p=0.03) and higher 12-month mortality (HR [95% CI] 5.17 [1.13, 23.69], p=0.03). Formal test of interaction for health literacy was significant for HFH (p=0.04), but not mortality (p=0.99). In stratified analysis of those with limited health literacy, living in the most vulnerable neighborhood was especially associated with higher HFH (HR 2.69 [1.48, 4.88], p=0.001).

Conclusion:
Older Black or Hispanic individuals with HF residing in neighborhoods with higher SVI had increased HFH and 12-month mortality. HL modified the association with HFH. These results suggest that addressing health literacy may impact the risk of HFH among those in the most vulnerable neighborhoods.
Abstract 4140007: Potent P2Y12 inhibitors versus Clopidogrel in Cancer Patients undergoing Percutaneous Coronary Intervention
Authors: Gitto Mauro , Sartori Samantha , Vogel Birgit , Leone Pier Pasquale , Smith Kenneth , Bay Benjamin , Krishnan Prakash , Sweeny Joseph , OLIVA ANGELO , Moreno Pedro , Di Muro Francesca , Krishnamoorthy Parasuram , Kini Annapoorna , Dangas George , Mehran Roxana , Sharma Samin
Published: November 2024

Background:
Although cancer is one of the major high bleeding risk criteria, patients with cancer undergoing percutaneous coronary intervention (PCI) experience a heightened risk of both ischemic and bleeding events.

Hypothesis:
Potent P2Y12 inhibitors (P2Y12i; prasugrel and ticagrelor), as compared to clopidogrel, might reduce the risk of thrombotic complications in patients with cancer undergoing PCI.

Aims:
To evaluate the safety and efficacy of potent P2Y12 inhibitors, compared to clopidogrel, in cancer patients undergoing PCI.

Methods:
Consecutive cancer patients undergoing PCI at a tertiary center between 2012 and 2022 who were discharged on potent P2Y12i were compared with those on clopidogrel. Patients on chronic anticoagulant therapy were excluded. The primary composite efficacy endpoint was major adverse cardiac and cerebrovascular events (MACCE), including death, myocardial infarction or stroke, while bleeding was the key safety endpoint.

Results:
Of the 1,702 patients included in the study, 373 (21.9%) were treated with potent P2Y12i and 1,329 (78.1%) with clopidogrel. The prevalence of P2Y12i use was 12.3% in patients with active cancer and 23.1% in those with cancer in remission. Factors associated with potent P2Y12i use were acute coronary syndrome presentation and lesion length, while clopidogrel at discharge was associated with active cancer status, thrombocytopenia, older age and femoral access. MACCE at 1 year occurred in 3.5% of patients in the potent P2Y12i group vs. 6.8% in the clopidogrel group (p=0.038; adj. HR: 0.53, 95% CI: 0.26-1.10), while no differences in terms of bleeding were detected (5.5 vs. 7%, adj. HR: 0.92, 95% CI: 0.53 - 1.60). At subgroup analysis, the reduction in MACCE was significant in patients with remission but not active cancer (p for interaction = 0.011).

Conclusions:
Potent P2Y12i appear to be safe in terms of bleeding and potentially associated with greater ischemic risk reduction compared to clopidogrel among patients with cancer undergoing PCI, particularly in case of cancer in remission.
Abstract 4140013: Sleep Disparities Across Demographics and Cardiometabolic Disorders in the NIH All of Us Fitbit Database
Authors: Kulkarni Adeep , Upadhyay Dhairya , Grams Morgan , Barua Souptik
Published: November 2024

Background:
Prior research has noted disparities in sleep duration among demographic groups and those with cardiometabolic disorders. However, these are mostly based on self-reported data. The NIH All of Us Fitbit database offers a new method for objective and reliable sleep assessment.

Goals:
The study aimed to objectively assess sleep duration using the All of Us Fitbit database across various demographic variables and cardiometabolic disorders.

Methods:
All of Us participants with at least one year of Fitbit data were identified. Fitbit’s "minutes asleep" parameter was extracted daily over the first year of Fitbit use and averaged. The average total minutes asleep (TMA) was compared across self-reported age, sex and race groups. For those individuals who also shared their electronic health record (EHR) data, TMA was compared between those with and without hypertension, diabetes, and sleep apnea. T-test and ANOVA were used for comparisons.

Results:
The first year of Fitbit data for 13,039 participants (51 [16]* years, 69% female, 82% White) was analyzed, with sleep information available for 330 [104] days (90% complete data). TMA decreased with age, with the 18-44, 45-64, and 65+ groups averaging 366 [64], 348 [72], and 339 [85] minutes respectively (p<0.0001). Men and women had a small difference in TMA (342 [74] vs 351 [77] mins respectively, p<0.0001). Individuals who self-reported as Black or African-American had significantly lower TMA (304 [68] mins) compared to other groups (White: 353 [76] mins, Asian: 334 [67] mins, Other: 344 [69] mins; p<0.0001). Among 8587 individuals who also shared their EHR data, lower TMA was observed in those with, compared to those without, prevalent hypertension (332 [83] vs 353 [76] mins), diabetes (320 [82] vs 349 [78] mins), and sleep apnea (328 [77] vs 350 [79] mins) respectively (all p<0.0001).

*mean [SD]

Conclusion:
Fitbit data analysis identified variations in sleep duration across age, race, and presence of cardiometabolic disorders. Objective sleep assessment using wearables could provide more reliable insights into sleep disparities and their associations with cardiometabolic outcomes.
Abstract 4140020: Sex-Based Disparities in Cardiopulmonary Exercise Testing Response Among Patients with Postural Orthostatic Tachycardia Syndrome
Authors: Sharif Salaheddin , Olson Thomas
Published: November 2024

Introduction:
Postural orthostatic tachycardia syndrome (POTS) is a chronic syndrome with symptoms of orthostatic intolerance, tachycardia, and exercise intolerance. POTS predominately affects young females, with notable variations in incidence and manifestations between females and males. Limited data exist on sex differences in the response to cardiopulmonary exercise test (CPET) in patients diagnosed with POTS.

Methods:
Retrospective analysis of 307 POTS patients who underwent CPET between 2000 and 2023 at Mayo Clinic. Diagnosis of POTS was confirmed by tilt-table testing with a sustained increase in heart rate (HR)≥ 30 bpm or HR>120 bpm 10-min post-tilt and without orthostatic hypotension. Patients were grouped by sex (male: n=48 and female: n=259). Predicted peak values were calculated and independent t-tests were used to compare between-group differences.

Results:
There were no significant differences between males and females for age (28±8 vs 27±7, years) or body mass index (24±5 vs 24±5, kg/m
2
) (both p>0.05). The time between diagnosis and CPET was not significantly different between males and females (21±113 vs 44±280 days, p>0.05). Resting HR was lower in male patients (76±17 vs 85±18 bpm, p<0.05). At peak exercise, there was no difference in respiratory exchange ratio (1.18±.2 vs 1.17±0.1, p>0.05). Males had significantly lower peak HR (171±22 vs 176±19 bpm) and lower percent (%) predicted peak HR (88±12 vs 93±13 %) (both p<0.05) compared to females. Peak oxygen consumption (VO
2
peak) was significantly higher in males (29.2±8 vs 24.9±7 mL/kg/min), however; % predicted VO
2
peak was lower in males (65±17 vs 71±18 %) (both p<0.05). Peak oxygen (O
2
) pulse was higher in males (14±4 vs 9±2 mL/beat, p<0.05) with no difference in % predicted peak O
2
pulse (73±17 vs 78±17 %, p>0.05).

Conclusion:
These data suggest male patients achieved a lower peak HR, % predicted peak HR, and % predicted VO
2
peak than female patients. Both male and female patients utilized a similar % predicted peak O
2
pulse. These findings suggest male POTS patients demonstrate more impaired exercise tolerance compared to female patients. Additional research is needed to fully elucidate the underpinning physiologic mechanisms responsible for impaired exercise tolerance in POTS and the apparent sex differences in exercise capacity.
Abstract 4140021: Metabolic crisis and TRPM4 activation cause QT prolongation in TANGO2 deficiency disease
Authors: Wang Lili , KIM Kyungsoo , Kannankeril Prince , Brookes Paul , Knollmann Bjorn
Published: November 2024

Background:
TANGO2 deficiency disease (TDD), caused by a homozygous large deletion in the
Tango2
gene, is associated with impaired fatty acid oxidation-triggered metabolic crises, which can include severe QT prolongation and ventricular arrhythmias. The mechanism of transient QT prolongation and arrhythmias is unknown. Here we test the hypothesis that activation of the nonselective cation channel TRPM4, regulated by intracellular ATP and Ca, contributes mechanistically to arrhythmia risk in TDD.

Methods:
CRISPR/Cas9 was used to generate a human induced pluripotent stem cell cardiomyocyte (hiPSC-CM) model with a
Tango
2 exon 3 to 9 deletion (
Tango2
-/-
). Mitochondrial oxygen consumption rate (OCR), intracellular ATP/ADP ratios, and action potentials (APs) were evaluated in

Tango2
-/-

hiPSC-CMs under metabolic conditions fueled by either 5.6 mmol/L glucose or 0.1 mmol/L palmitate.

Results:
Analogous to clinical TDD,

Tango2
-/-

hiPSC-CMs showed a significant decrease in palmitate-dependent OCR and a profound reduction in intracellular ATP production when palmitate was the sole substrate, worsened after 24-hour fasting. In contrast, when glucose was the only energy source,

Tango2
-/-

hiPSC-CMs demonstrated OCR and ATP production rates comparable to control. These observations suggest dysfunction in mitochondrial palmitate oxidation leading to energy deficiency in

Tango2
-/-

hiPSC-CMs, which subsequently result in prolongation of AP duration. Intracellular delivery of Mg-ATP normalized palmitate-induced AP prolongation in

Tango2
-/-

hiPSC-CMs post fasting. Additionally, although no alterations in L-type Ca current were found, L-type Ca channel inhibition with verapamil alleviated palmitate-induced AP prolongation in

Tango2
-/-

hiPSC-CMs post fasting by stabilizing ATP/ADP ratios and ameliorating intracellular calcium dysregulation. We found post-fasting exposure to palmitate upregulated
Trpm4
gene expression in

Tango2
-/-

hiPSC-CMs. Targeted genetic knockdown or pharmacological blockade of TRPM4 channels normalized AP prolongation in

Tango2
-/-

hiPSC-CMs.

Conclusion:
Our findings established a mechanistic link between myocardial energy deficiency, TRPM4 activation and the development of AP prolongation in TDD, emphasizing the energetic basis of arrhythmias. Targeting TRPM4 is a promising new therapeutic strategy to prevent QT prolongation and arrhythmia in TDD.
Abstract 4140045: Association of non-invasive liver fibrosis scores with disease severity and long-term adverse outcomes in patients with pulmonary arterial hypertension
Authors: Gao Luyang , zhang sicheng , Li Xin , Li Sicong , zhao qing , Zhao Zhihui , Duan Anqi , Huang Zhihua , Wang Yijia , Luo Qin , Liu Zhihong
Published: November 2024

Background:
Mounting evidence indicates that non-invasive liver fibrosis scores (LFs) are associated with various cardiovascular diseases, but their role in pulmonary arterial hypertension (PAH) is not yet clear. This study aims to explore the relationship between LFs and PAH.

Methods:
The study enrolled 1048 patients with PAH from January 2017 to January 2021, comprising individuals with idiopathic PAH and PAH related to congenital heart disease. Fibrosis-5 score (FIB-5), fibrosis-4 score (FIB-4), aspartate aminotransferase to alanine aminotransferase ratio (AAR), aspartate aminotransferase to platelet ratio index (APRI) and Forns score (FC) were used to evaluate the degree of liver fibrosis in patients with PAH. The association of ILs with European Society of Cardiology (ESC) risk stratification was evaluated using one-way ANOVA. The correlation between LFs and long-term adverse outcomes was determined using multivariate Cox regression models and restricted cubic splines. Subgroup analyses, predicated on age, sex, World Health Organization functional class and body mass index, were carried out to evaluated interaction effects.

Results:
During a mean of 40.8 months’ follow-up, 283 participants experienced all-cause death or worsening condition. With higher ESC risk stratification, PAH patients had significantly lower FIB-5 (4.563±4.118 vs. 3.475±10.693 vs. 2.444±5.454 vs. 0.924±4.10, P=0.003) and higher FC (5.661±1.762 vs. 5.983±1.897 vs. 6.506±1.919 vs. 7.230±1.900，P<0.001). After adjusting for confounding factors, multivariable Cox regression models indicated that FIB-5 (hazard ratio [HR] 0.968, 95% confidence interval [CI] 0.949-0.988, P = 0.005) and FIB-4 (HR 1.905, 95% CI 1.388-2.614, P＜0.001) independently predicted adverse outcomes. The highest predictive performance was observed for FIB-5 compared to other LFSs. No significant interaction effect was observed in the subgroup analysis.

Conclusions:
Liver fibrosis was associated with disease severity and long-term prognosis in patients with PAH. The markers FIB-5 and FIB-4 serve as independent predictors of clinical deterioration in patients with PAH.
Abstract 4140064: Income and Mobility Loss in Peripheral Artery Disease
Authors: Whipple Mary , Xu Shujun , Zhang Dongxue , Tian Lu , Zhao Lihui , McDermott Mary
Published: November 2024

Introduction:
Lower income is associated with a higher prevalence of peripheral artery disease (PAD). However, whether lower income is associated with faster rates of mobility loss among people with PAD is unknown. This study describes associations of income with mobility loss in people with PAD.

Methods:
Data from four longitudinal studies of participants with PAD conducted in Chicago were combined (the Walking and Leg Circulation Study [WALCS] I, II, and III and the Biomarker Risk Assessment in Vulnerable Outpatients [BRAVO] study). Participants with an ankle brachial index (ABI) <0.90 were categorized at baseline into quartiles of median income derived from their residence zip code. Mobility loss was assessed via participant report and a 6-minute walk test at baseline and annually. Among participants able to walk up one flight of stairs or walk ¼ mile without assistance at baseline, self-reported mobility loss was defined as becoming newly unable to climb one flight of stairs or walk ¼ mile without assistance. Objectively measured mobility loss was defined as becoming unable to complete the 6-minute walk without stopping among participants who completed the 6-minute walk without rest at baseline. Cox regression was used to evaluate relationships between income and mobility loss, adjusting for age, sex, race, cohort, BMI, smoking, and comorbidities.

Results:
A total of 1133 participants (n=451 [40%] women, n=288 [25%] Black, mean [SD] ABI 0.65 [0.15]) were included. Mean follow-up was 4.5 years. Rates of becoming unable to walk for 6 minutes without stopping were significantly higher among people with lower income, defined by zip code (P trend = 0.001).

Conclusions:
Among people with PAD, lower income defined by zip code of residence was associated with a significantly higher rate of mobility loss. Future studies should identify the factors that explain the associations reported here and identify interventions to overcome them.
Abstract 4140066: In ACS patients within 4 hours of pain to balloon time, the impact of no-reflow after PCI and ultrasound attenuation as detected by intravascular ultrasound on the incidence of no-reflow.
Authors: Iidaka Kazunobu
Published: November 2024

Background:
The no-reflow has been reported to be associated with larger infarct size and mortality after acute myocardial infarction (AMI). A pathological classification of no-reflow was proposed: structural no-reflow—microvessels within the necrotic myocardium exhibit loss of capillary integrity (it is usually irreversible)—and functional no reflow—patency of microvasculature is compromised due to distal embolization, spasm, ischemic injury, reperfusion injury. It may be reversible. After about 6 hours of AMI, myocardial necrosis occurs, which leads to the coronary microcirculation to injury which contribute to no-reflow. The rate of no-reflow was lower in patients presented with AMI, who had reperfusion in less than 4 hours. In AMI within 4 hours of pain-to-balloon time, the proportion of reversible causes of no-reflow may be higher compared to irreversible causes. The incidence of no-reflow was higher in patients with attenuated plaque ≥5 mm in length as evaluated by intravascular ultrasound (IVUS).

Objective:
The aim of this study was to evaluate the effects of no-reflow after PCI and the association between attenuation plaque as detected by IVUS and no-reflow in ACS patients within 4 hours of pain-to-balloon time.

Methods and Results:
We retrospectively evaluated 77 ACS patients within 4 hours of pain-to-balloon time between December 2020 and March 2022. Patients were divided into the reflow group (final TIMI 3) (n = 58) and the no-reflow group (final TIMI < 3) (n = 19). The median peak creatine kinase (CK) level was significantly higher in the no-reflow group compared to the reflow group (3754 IU/L [IQR: 4155] vs. 1712 IU/L [IQR: 2849]). Blood pressure decrease during PCI was significantly more pronounced in the no-reflow group (47.4% vs. 8.6%, p < 0.001). The proportion of low attenuation plaque observed by IVUS with a length of ≥5 mm was significantly higher in the no-reflow group compared to the reflow group (52.6% vs. 25.5%, p = 0.032). The proportion of low attenuation plaque with an angle of ≥180 degrees was significantly higher in the no-reflow group compared to the reflow group (68.4% vs. 41.2%, p=0.043).

Conclusion:
In ACS patients within 4 hours of pain-to-balloon time, the peak CK and the decrease in blood pressure during PCI were significantly greater and the proportion of low attenuation plaque with a length of ≥5 mm and an angle of ≥180 degrees were significantly higher in the no-reflow group.
Abstract 4140096: CCN2 Correlates with Early Markers of Right Ventricular Dysfunction in Adults with Pulmonary Arterial Hypertension
Authors: Schramm Jennifer , Byrd Carly , Ambade Anjira , Rosen Darin , Cubero Salazar Ilton , Simpson Catherine , Tedford Ryan , Hsu Steven , Hassoun Paul , Everett Allen , Damico Rachel
Published: November 2024

Introduction:
Cellular Communication Network 2 (CCN2, also known as CTGF and IGFBP8) is a cysteine-rich secreted matrix protein with four tandem modules and is an upstream regulator of TGFß, a key pathogenic molecule in pulmonary arterial hypertension (PAH). Altered right ventricular-pulmonary artery (RV-PA) coupling has been shown to be an early marker of right ventricular (RV) dysfunction associated with adverse outcomes in PAH.

Research Question:
We studied the relationship between CCN2 and the diagnosis, disease severity, hemodynamics, and metrics of pathologic RV structure and function in a deeply-phenotyped cohort of patients with suspected and established PAH.

Methods:
Adult PAH patients (N=38, median age 62 years, 79% female) and controls (N=8, median age 64.5 years, 100% female) had CCN2 levels measured from samples obtained the same day as simultaneous right heart catheterization, multi-beat pressure volume loop assessment, cardiac MRI and functional outcome assessment. CCN2 levels were log-transformed and adjusted for age and sex using linear and logistic regression to allow for comparison with clinical and hemodynamic variable. Analysis of composite outcome (death or transplant) was conducted using a Cox proportional hazard model and Kaplan Meier analysis.

Results:
CCN2 levels were associated with lower RV stroke volume (p<0.05), lower RV end-systolic elastance (RV Ees, p<0.02), and impaired RV-pulmonary arterial coupling (RV Ees/Ea, p<0.05) by Spearman correlation. In linear regression models adjusted for age and sex, log(CCN2) was significantly associated with RV Ees and RV Ees/Ea (p<0.001 and p = 0.04, respectively). CCN2 levels were not significantly correlated with other hemodynamics or functional status (p >0.1 for all). Finally, higher log(CCN2) levels were correlated with lower transplant free survival with Cox Hazard Ratio of 3.99 (p<0.04) in patients with PAH. Kaplan-Meier demonstrates patients with CCN2 level above a Youden cutoff of 43 ng/mL had increased mortality with median survival less than 7.5 years (Figure 1).

Conclusions:
CCN2 levels correlate with more impaired RV-PA coupling and worse outcomes for adults with PAH. This patient cohort were diagnosed early in the disease course with mild symptoms. There was an association between CCN2 levels with early markers of RV dysfunction, RV-PA uncoupling, RV stroke volume, and adverse outcomes. This implicates CCN2 as a potential biomarker of early RV dysfunction of PAH.
Abstract 4140175: Association of Non-Cardiac Comorbidities With Long-Term Re-Hospitalization for Heart Failure: Contemporary Analysis of 88,528 Consecutive Cases
Authors: Ambrosio Giuseppe , Tagliabue Elena , Pellicori Pierpaolo , Lund Lars , Pontiroli Antonio
Published: November 2024

Background:
Heart failure (HF) may coexist with non-cardiac comorbidities. Yet, while relevant, the impact of non-cardiac comorbidities on long-term HF re-hospitalizations (Re-Hosp) is is not well established. Previous studies do not reflect modern HF management, often report just all-cause Re-Hosp, or are based on selected populations from randomizd trials.

We investigated the association of non-cardiac comorbidities with long-term Re-Hosp for HFafter discharge for HF in a large, contemporary setting.

Methods:
Administrative hospital discharge data for HF (primary diagnosis) (Jan 1st 2015-Dec 31st 2019) of all >10 Million residents of Lombardy (Italy); follow up through June 30th 2021. Comorbidities assessed from discharge information and/or administrative codes for chronic diseases. Re-Hosp risk for HF (primary diagnosis) after HF discharge as a function of non-cardiac comorbidities was assessed by Cox proportional-hazard models (age- and sex-adjusted). Kaplan Meier curves for HFRe-Hosp were stratified for number of non-cardiac comorbidities.

Results:
88,528 consecutive patients received a HF primary discharge; over 42.8±18.3 months of follow-up, 79,533 HF Re-Hosp occurred (32.44/100 patient/year). Risk of HF Re-Hosp increased with increasing number of non-cardiac comorbidities. Adjusted by age, females with >4 comorbidities had a 3.08 (CI 2.73-3.47) greater risk of Re-Hosp compared with females without comorbidities; males with >4 comorbidities had a 2.62 (CI 2.39-2.87) greater risk compared with males without comorbidities. By multivariable analysis, number of comorbidities, age, and male sex, remained significantly associated with Re-Hosp risk (Figs 1, 2).

Risk of all-cause death also increased with increasing number of non-cardiac comorbidities, from 1.42 for HF patients with 1-2 comorbidities to 2.20 for HF patients with >4 comorbidities.

Also the number of days spent in hospital because of HF after index HF discharge significantly increased with increasing number of non-cardiac comorbidities, from 19.9±19.3 days in patients without non-cardiac comorbidities to 45.4±33.0 days for patients with >4 non-cardiac comorbidities (p<0.0001).

Conclusion:
In a large, contemporary real-world series of patients hospitalized with HF, HF re-hospitalizations, all-cause mortality, and life-time spent in hospital due to worsening HF increased with number of non-cardiac comorbidities. Non-cardiac comorbidities substantially impact the clinical trajectory of HF patients.
Abstract 4140222: Oxytocin treatment for spinal neuraxial modulation of ventricular excitability
Authors: Hellman Abigail , Callenberger Sydney , Kuwabara Yuki , Salavatian Siamak , mahajan aman , Howard-Quijano Kimberly
Published: November 2024

Introduction:
Cardiac sympathoexcitation is a major contributor to the pathogenesis of ventricular tachyarrhymias (VTs) during ischemia reperfusion (I/R) and chronic myocardial infarction (MI). Afferent network connections in the spinal cord control sympathetic output to the heart. Our team reported spinal cord stimulation (SCS) decreased cardiac sympathoexcitation and reduced VTs during ischemia. RNAsequencing data revealed that oxytocin (OXT) receptor is significantly upregulated with SCS; however, whether OXT alone can modulate the cardiospinal neural network to reduce sympathoexcitation and VTs is unknown.

Hypothesis:
Both intranasal (IN) and intrathecal (IT) administration of oxytocin agonist reduce sympathoexcitation, VTs, and cellular activation.

Methods:
Two models of cardiac ischemia were used in Yorkshire domestic swine. In acute I/R, a suture was placed around the left anterior descending (LAD) coronary artery, after sternotomy. Chronic infarction (MI) was created by polystyrene microspheres (1ml) injected via a 3mm angioplasty balloon catheter to the left circumflex under fluoroscopy guidance. Animals recovered post-MI for 6-8wk. Intrathecally, OXT agonist (TGOTFisher Scientific, 90ug) was delivered via catheter placed at T1-T4 level. Intranasally, OXT Pitocin (20U) was administered. The therapeutic doses were chosen based on dose response curve experiments, determining lowest effective dose based on activation recovery interval (ARI) change. We compared ventricular excitability, and arrhythmic substrate between experimental groups by measuring ARI, a validated marker for action potential duration. ARI changes signify the functional density and regional myocardial responses to interventions. After, T2-T4 spinal cord was collected postmortem for molecular analysis. Fluorescence
in situ
hybridization protocol for RNAscope Fluorescent v2 Assay (ACD) was followed. Cell counts represented as 3 puncta or more centered around DAPI.

Results:
We report that both ARI and VTs significantly increased as a result of I/R and MI and returned to baseline with administration of both IN and IT OXT (p<0.05, two-way ANOVA n=6-8 animals) Additionally, FOS, a marker of cellular activation, increased with I/R and MI and decreased as a result of both IT and IN OXT in the spinal cord.

Conclusions:
By evaluating the role of OXT in reducing cardiac sympathoexcitation at the level of the spinal cord, we provide insights into developing new pharmacologic therapies.
Abstract 4140236: Development and Accuracy of Natural Language Processing-based Expression Matching to Identify and Classify Cardiomyopathy from Cardiovascular Magnetic Resonance Reports
Authors: Shenoy Ujwala , Zhang Lu , Jha Mawra , Kwong Raymond , Manning Warren , Nezafat Reza , Tsao Connie
Published: November 2024

Background:
Cardiovascular magnetic resonance (CMR) is the gold standard non-invasive assessment of cardiomyopathy (CM); however, interpretation and CM classification from reports by clinicians and researchers at scale can be unclear and time-consuming.

Research Question:
Can a large language model accurately classify CM from clinical CMR reports, to improve diagnostic accuracy?

Aims:
To establish a novel natural language processing (NLP) model employing expression matching for CM detection and differentiation, and to compare its effectiveness with established methods.

Methods:
In our study, an unsupervised rule-based NLP model was developed on 3561 consecutive text impressions from clinical CMR reports at Beth Israel Deaconess Medical Center and compared against physician adjudicated diagnosis (gold-standard labels) of 6 broad groups of CM (
Figure 1
). A semi-supervised biomedical bidirectional encoder representation from transformers (BioBERT) model was fine-tuned (80% training/20% validation) using NLP labels to improve generalization. The models’ performance was compared with comprehensive keyword search and ChatGPT4. We performed external validation by testing 1202 clinical CMR text impressions from Brigham and Women’s Hospital.

Results:
The stepwise classification of our NLP model is shown in
Figure 2
. NLP and NLP-based BioBERT outperformed other methods (
Table 1
). In external validation, the mean AUC of NLP (0.92) and NLP-based BioBERT (0.93) had better performance compared to keyword search (0.71) and ChatGPT4 (0.73).

Conclusion:
Our rule-based NLP and NLP-based BioBERT models accurately identify CM from CMR reports, enabling applications in widespread CMR report comprehension and large dataset research of cardiomyopathies.
Abstract 4140245: Electronic Clinical Decision Support Tool Increases Oral Anticoagulant Prescription in the Emergency Department: Initial Findings From a Multi-Phase, Multi-Center Stepped-Wedge Cluster Randomized Trial
Authors: Bhadra Sombuddha , Hopkins Bradley , Elman Miriam , Nguyen Thuan , Kinney Erin , Kim Joy , Anwar Mariam , Obando Kaye Ann , Prychyna Diana , Schnittke Nikolai , Neth Matthew , Sun Benjamin , Kea Bory
Published: November 2024

INTRODUCTION:
Atrial fibrillation (AF), often diagnosed in the Emergency Department (ED), increases the risk of stroke by 64% but can be mitigated by guideline-directed oral anticoagulant (OAC) treatment.

RESEARCH QUESTION:
Does clinician education of an AF clinical decision support (CDS) tool increase OAC prescription rates for patients with new-onset AF or paroxysmal AF (pAF)?

GOALS:
To increase guideline recommended care practice of OAC prescribing for appropriate candidates in the ED.

Methods:
This multi-center, multi-phase, stepped-wedge cluster-randomized clinical trial includes a retrospective phase (Phase 0) and implementation of an external browser link to the CDS in the EHR (Phase 1) which included patient-specific stroke and bleeding risk stratification scores with recommendation for OAC based on professional society guidelines, along with targeted provider education on how to use the resource. Data was collected from ED visits of patients aged > 18 with a primary AF/pAF diagnosis from Jan 1, 2020–May 25, 2024. The three sites, one academic and two community hospitals, implemented Phase 1 in January ‘22, April ‘22, and April ‘23. Eligibility for OAC treatment was based on clinical judgment weighing the benefit of stroke prevention against the risk of bleeding. A logistic GEE model assessed the intervention's impact on OAC prescribing and treated ED providers as a random effect to account for clustering. The model included the CDS intervention and covariates for site, cardiology consultation, guideline citation, and patient factors such as sex, race, ethnicity, and age.

Results:
Of 4397 patients analyzed, 655 met inclusion criteria, among which 296 (45.19%, median age 68) were prescribed OAC, 175 in Phase 0, and 121 in Phase 1. The odds ratio estimates and their corresponding 95% confidence intervals are as follows: CDS intervention 1.75 [1.20, 2.54], sex female vs male 2.31 [1.57, 3.38], age 0.27 [0.12, 0.61], site 0.55 [0.29, 1.04] and 0.45 [0.25, 0.83] for each community site vs academic, cardiology consultation 4.56 [2.80, 7.42], and guideline citation 2.23 [1.44, 3.43]. Race and ethnicity did not show significant associations.

CONCLUSION(S):
We demonstrated that clinician education and limited CDS tool integration into the EHR are linked to an almost two-fold increase in OAC prescribing for suitable AF/pAF patients. Future studies should evaluate the influence of further CDS integration on OAC prescribing, long-term adherence, patient outcomes.
Abstract 4140250: A Case Series of Papillary Fibroelastomas on the Coumadin ridge
Authors: Aboukhatwa Omar , Akiki Elias , Kurmann Reto , Larson Kathryn , Keeney Michael , Bois Melanie , Klarich Kyle
Published: November 2024

Background:
Papillary fibroelastomas (PFE) arising between the left upper pulmonary vein and left atrial appendage, commonly referred to as the coumadin ridge or Q-tip, are extremely rare and best detected by transesophageal echocardiography (TEE). Although PFEs are benign, they have been associated with a range of serious embolic events.

Objective:
To analyze the characteristics, clinical findings, and diagnostic techniques of PFEs originating from the coumadin ridge.

Methods:
We describe 13 cases of pathology proven papillary fibroelastomas uniquely attached to the Q-tip. Patient data, including demographics, mass characteristics and diagnostic imaging were collected and analyzed.

Results:
Thirteen patients with pathology-proven PFEs attached to the coumadin ridge were included in the study. The median age of the cohort is 73 (IQR 67-77), and 54% of the patients were male. Tumor sizes ranged from 2mm to 20mm with a median of 5mm (IQR 3.5-8.5). Twelve (92%) of the PFEs were initially visualized on TEE, and one case was diagnosed postoperatively by pathologists after the excision of the left atrial appendage. The majority of cases were incidental diagnoses, with 46% of cases incidentally discovered intraoperatively by routine TEE, and 30% visualized on TEE done for diverse reasons including valvular assessment, exclusion of infective endocarditis, and coronary artery disease (CAD) assessment. One case was incidentally detected on CMR performed as part of a metastatic tumor workup. Four (30%) patients presented with symptoms of stroke/TIA, of which 2 had a previous history of stroke. One patient had symptoms of both TIA and angina pectoris. Cardiovascular disease risk factors were prevalent: 69% had hyperlipidemia, 46% had atrial fibrillation (Afib), 31% had CAD, 54% had hypertension, and 46% were former smokers.

Conclusions:
Masses on the Q-tip are rare but significant intracardiac sources of embolism. Accurate identification and categorization of these masses are challenging, yet critical, to guide appropriate surgical intervention and improve patient outcomes. Further studies are needed to establish standardized diagnostic and treatment protocols for this unique presentation of PFEs.