bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 4147781: ADMET-AI enables interpretable predictions of drug-induced cardiotoxicity
Authors: Swanson Kyle , Mukherjee Souhrid , Walther Parker , Lai Celine , Yan Christopher , Shivnaraine Rabindra , Leitz Jeremy , Pang Paul , Zou James , Wu Joseph
Published: November 2024

Background:
Drug-induced cardiotoxicity (DICT) is a severe adverse drug reaction that contributes to clinical trial failures and drug withdrawals. Forecasting DICT is challenging due to the property’s complex nature, and experimental assays are cumbersome and poorly correlate with human outcomes. Machine learning trained on clinical DICT data can quickly and accurately predict cardiotoxicity, pre-empting clinical failure and providing insight.

Methods:
We used our previously developed ADMET-AI machine learning platform to predict DICT and its sources. ADMET-AI is a freely available web tool (admet.ai.greenstonebio.com) that predicts 41 absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of a given molecule. We coupled ADMET-AI’s 41 ADMET property predictions with an Extreme Gradient Boosting (XGB) model to output a probability of cardiotoxicity. This XGB model was trained on 555 drugs from the published DICTrank dataset that have been labeled as having either no cardiotoxicity (262 drugs) or severe cardiotoxicity (293 drugs). Notably, over 67% of the DICTrank drugs are not in any of the 41 ADMET-AI training datasets.

Results:
The ADMET-AI-based cardiotoxicity XGB model, evaluated with 10-fold cross-validation, achieved an average area under the precision-recall curve (PR-AUC) of 0.75. Our model outperformed an XGB model trained on SwissADME predictions (PR-AUC=0.69). Shapley values identified CYP2D6 Substrate and Nrf2-Antioxidant Responsive Element as key predictors of severe cardiotoxicity, while CYP2D6 inhibition and Aromatase were linked to non-cardiotoxicity. t-SNE analysis of the DICTrank chemical space using the five most predictive ADMET-AI properties showed clear clustering of toxicity. Case studies of cisapride and lactulose illustrated the model’s ability to distinguish between cardiotoxic and non-cardiotoxic drugs based on predictions. Compared to publicly available models, ADMET-AI is currently the fastest and most accurate tool for ADMET and DICT prediction.

Conclusions:
ADMET-AI effectively predicts DICT with insight into potential causes, surpassing the current standard of public tools. The ADMET-AI-based cardiotoxicity prediction models are freely available to enable DICT prediction, with the potential to prevent late-phase clinical failures. While this study focuses on DICT, a similar workflow can adapt ADMET-AI to make predictions for other key properties in drug discovery.
Abstract 4147807: Peak Oxygen Uptake Changes as a Function of Lean Mass After Cardiac Rehabilitation
Authors: Elkhatib Wiaam , Olson Thomas
Published: November 2024

Introduction:
Peak oxygen uptake (VO
2
peak), standardized to total body mass (ml/kg/min) is a predictor of morbidity and mortality in cardiovascular disease patients. However, subsets of individuals undergoing exercise based cardiac rehabilitation (CR) show no improvement or reduction in VO
2
peak despite improvement in other functional measures.

Hypothesis:
Change in peak VO
2
post-CR, adjusted for lean mass rather than total mass better reflects peak VO
2
improvements.

Aim
: To assess the influence of CR on lean mass and the effect of lean mass compared to total body mass changes on peak VO
2
following CR.

Methods:
This observational cohort study included adults >18 years old who completed CR between 2015-2022 at Mayo Clinic, Rochester. All patients completed both dual energy X-ray absorptiometry (DXA) and cardiopulmonary exercise testing (CPET) for measurement of body composition (total mass and lean mass) and VO
2
peak pre- and post-CR. Improvement in VO
2
peak was defined as >% increase. Paired t-tests, one-way ANOVA, and descriptive statistics were performed.

Results:
Of 145 subjects, 81% were male and 63% Caucasian with a mean (SD) age of 62.8±12.6 years, BMI of 30.3±5.7, and 33.4±8.2 of 36 prescribed (92.8%) CR sessions completed. Pre-CR, patients demonstrated absolute VO
2
peak of 1,997.0±693.5 mL/min, relative of 22.1±6.2 mL/kg/min, and relative to lean mass of 35.2±9.6 mL/kg lean/min. After CR, patients demonstrated 1.2±3.1 kg reduction in total mass (p<0.05) and 0.4±1.7 kg increase in lean mass (p<0.05). Post-CR VO
2
peak increased by 17.1±117.0% absolute units (mL/min) (p<0.05), 9.0±16.1 % relative units (mL/kg/min) (p<0.05), and 15.9±111.9% units relative to lean mass (mL/kg lean/min) (p<0.05). Absolute and relative to lean mass units demonstrated greater improvements in VO
2
peak compared to relative units (p<0.05). Dependent on units, 70.3% of patients demonstrated an improvement in absolute VO
2
, 75.2% patients improved relative VO
2
, and 62.8% patients improved VO
2
relative to lean mass.

Conclusions:
These data demonstrate significant increases in lean mass and VO
2
following CR, with larger improvements reflected in units adjusted for lean mass compared to traditional relative units. In contrast, the largest proportion of patients showed positive improvements in VO
2
peak relative units with the smallest proportion relative to lean mass. These data suggest the reporting methodology for change in VO
2
following CR may impact overall findings.
Abstract 4147821: Physical Activity Impacts Cardiac Tissue Mitochondrial Respiration During Anthracycline Chemotherapy
Authors: Riojas Angelica , Harbert Shona , Lacy Jessica , Piloso Jemima , Kramer Philip , Weis Jared , Melendez Giselle
Published: November 2024

Background:
Increasing physical activity (PA) mitigates left ventricular (LV) declines in breast cancer patients undergoing Anthracycline (Anth) treatment. There is evidence that Anth induces mitochondrial dysfunction in cardiac and skeletal muscle (SM), contributing to LV dysfunction. However, the underlying mechanisms by which PA may be an effective therapy remain elusive.

Objective:
To evaluate the association between cardiac and SM mitochondrial function with LV function of mice treated with Anth. We hypothesize exercise improves mitochondrial function which ameliorates Anth-induced tissue injury.

Methods:
Twenty 12-week-old female mice treated with 5 mg/kg of doxorubicin (Dox, IP once a week for 4 weeks) were randomized to low-intensity treadmill exercise (Dox+Ex) or no exercise (Dox+no-Ex). In a blinded analysis, we measured LV function by echocardiography (LV ejection fraction, LVEF) before and after Dox treatment. At the experimental endpoint, tissues were collected to measure LV collagen volume fraction (CVF) and high-resolution respirometry (Oroboros, O
2
flux per mass pmol/(s*mg)) of LV and SM. An additional cohort of mice injected with saline that did not exercise (Saline-no-Ex, n=5) were used as controls for respirometry experiments.

Results:
Animals that did not exercise during Dox treatment experienced LV dysfunction (Pre-Dox: 66.6±2.9% vs. Post-Dox: 57.4±7.2%,
p
=0.01), while exercise ameliorated such declines (Pre-Dox: 67.2±3.8% vs. Post-Dox: 66.5±7.8%,
p
=0.43). Mice that exercised experienced lower levels of CVF (Dox+Ex: 0.9±0.1 % vs. Dox-no-Ex: 1.5±0.5%;
p
<0.02). Importantly, mice treated with Dox that did not exercise exhibited lower complex I maximal respiratory capacity (CI-Max) compared to controls (Dox+no-Ex: 29.4±25.5 vs. Saline-no-Ex: 92.3±56.1,
p
= 0.04) and exercise during Dox treatment prevented such declines (Dox+no-Ex: 29.37±25.45 vs. Dox+Ex: 139.6±66.3
p
=0.01). There were no changes in CI-Max in SM between groups (
p>
0.05). Cardiac tissue CI-Max was significantly correlated with post-Dox LVEF (r=0.82,
p
=0.03). No associations were observed between LVEF and SM CI-max (
p
=0.66).

Conclusions:
Exercise mitigated LV dysfunction, cardiac fibrosis, and cardiac CI-linked respiration declines after Dox treatment. Our results add to the evidence suggesting that exercise may be an effective therapy to prevent Anth-induced LV dysfunction in patients undergoing Anth therapies. Mitochondrial complex I represents a promising therapeutic target.
Abstract 4147830: Association Between Subcutaneous versus Visceral Adiposity and Type 2 Diabetes in United States Adults
Authors: Visaria Aayush
Published: November 2024

Introduction:
Visceral abdominal (VA) fat is an established risk factor for type 2 diabetes. It is still unclear, however, whether subcutaneous abdominal (SA) fat independently also increases diabetes risk.

Aims:
We aimed to 1) describe the distribution of abdominal fat composition by sex, and 2) determine the independent association between SA fat and diabetes.

Methods:
We included U.S. adults 20-59 years from the 2011-2018 National Health and Nutrition Examination Survey (NHANES) with whole body DEXA scans. DEXA scans were performed using Hologic Discovery model A densitometers. Visceral&subcutaneous fat mass (in lbs) were estimated via Hologic software (APEX v4.0) at the L4-L5 interspace. We used multivariable logistic regression to determine the association between SA, VA,&SA-to-VA fat ratio and diabetes (A1c ≥6.5%, fasting glucose ≥126 mg/dl or known diabetes diagnosis). All analyses were stratified by sex, accounted for the complex survey design to obtain nationally representative estimates, and were adjusted for potential confounders.

Results:
Among 7,125 adults (48% female, 61% non-Hispanic White), 33% had BMI ≥30, 49% had high waist circumference (>88cm for female, >102cm for male), and 7% had diabetes. Females had a median 0.9 lbs (IQR, 0.5-1.3) of VA fat, median 3.9 lbs (2.9-5.2) of SA fat, and a SA-to-VA ratio of 4.6 (3.5-6.2). Males had a median 1.0 lbs (IQR, 0.7-1.5) of VA fat, median 2.7 lbs (1.8-3.5) of SA fat, and a SA-to-VA ratio of 2.3 (1.8-3.0). After adjusting for VA and confounders, every 1 lb increase in SA fat was associated with a lower, albeit insignificant, odds of diabetes in females and males (OR [95% CI]; female: 0.84 [0.65,1.08], male: 0.87 [0.71,1.07]). In contrast, every 1 lb increase in VA fat was associated with a >2.5x higher odds of diabetes (female: 3.36 [2.26,4.99], male: 2.58 [1.69,3.98]). Every 1 unit increase in SA-to-VA ratio was associated with a significant 33-35% lower odds of diabetes (female: 0.67 [0.57,0.78], male: 0.65 [0.53,0.80]).

Conclusion:
U.S. females typically have four-to-sixfold more SA than VA fat, whereas males have one-to-threefold more SA than VA fat. In both females and males, SA was independently associated with lower likelihood of diabetes, suggesting subcutaneous abdominal adiposity may not contribute to, and potentially protect against, diabetes risk, akin to appendicular (arm/leg) adiposity.
Abstract 4147833: Parachute to the Rescue: The Mysterious Right Heart Mass
Authors: Trivedi Rishi , Madaan Prateek , gheyath bashaer , Friedman Oren , Singh Siddharth
Published: November 2024

Case Presentation:
A 27-year-old female with a history of Crohn’s disease and prior pulmonary nocardiosis presented with fever of unknown origin (FUO) and lung infiltrate. CT pulmonary angiogram revealed a segmental pulmonary embolism and a sessile mass with mobile components in the right atrium (RA). A band-like mass extending from the interventricular septum to the body of the right ventricle (RV) was also noted. Transthoracic echocardiogram confirmed these findings and showed moderate to severe tricuspid regurgitation. Lab testing was notable for white blood cell count elevation and positive lupus anticoagulant with unremarkable antibody panel. Based on initial testing, the differential diagnosis included RV thrombus, malignancy, or endocarditis. The patient was started on antibiotics, anticoagulation, and transferred to our hospital.

Decision Making:
The patient underwent a transesophageal echocardiogram that demonstrated a layered RA thrombus with mobile components, patent foramen ovale, and a congenitally dysplastic ‘parachute’ tricuspid valve (TV) with apical displacement of septal leaflet (Figure 1). It was noted that TV chordae tendinae attached to a single papillary muscle which was contiguous with the moderator band. Cardiac MRI confirmed these findings and that the RA mass was a thrombus. Despite anticoagulation and antibiotics, the patient continued to have intermittent fevers. PET CT demonstrated hypermetabolism of the RA thrombus and therefore suction thrombectomy was performed. Pathology revealed thrombus with purulent debris; however, no organisms were identified. With antibiotics and anticoagulation, the patient improved clinically and was discharged with plans for outpatient follow up.

Discussion:
Parachute deformity of the atrioventricular valves is characterized by unifocal attachment of chordae tendinae to a single papillary muscle. Parachute deformity of the TV has been very rarely reported (<20 published cases) and it is associated with other congenital anomalies. This case of parachute TV deformity with FUO highlights the importance of multi-modality imaging in the workup of structural heart abnormalities and the importance of pattern recognition in diagnosing rare cardiac abnormalities.
Abstract 4147845: Valsartan and Cardiac Remodeling in Early-Stage Hypertrophic Cardiomyopathy: The VANISH Trial Cardiac Magnetic Resonance Substudy
Authors: Ostrominski John , Claggett Brian , Jerosch-Herold Michael , Axelsson Anna , Day Sharlene , Russell Mark , Zahka Kenneth , Pereira Alexandre , Colan Steven , Murphy Anne , Canter Charles , Bach Richard , Wheeler Matthew , Rossano Joseph , Owens Anjali , Mestroni Luisa , Taylor Matthew , Patel Amit , Wilmot Ivan , Soslow Jonathan , Becker Jason , Lakdawala Neal , Bundgaard Henning , Vargas Jose , Ho Carolyn
Published: November 2024

Background:
Valsartan has previously been shown to attenuate cardiac remodeling among individuals with early-stage sarcomeric hypertrophic cardiomyopathy (HCM), a condition characterized, in part, by increased cardiomyocyte size. Cardiac magnetic resonance (CMR) imaging parameters, such as late gadolinium enhancement (LGE), are associated with disease progression and outcomes in HCM, but whether valsartan influences these parameters remains uncertain.

Methods:
In this prespecified CMR substudy of the international, multicenter, phase 2 VANISH (Valsartan for Attenuating Disease Evolution in Early Sarcomeric HCM) trial, we evaluated treatment effects of valsartan versus placebo on cardiac structure and function, including indexed extracellular volume (iECV), indexed intracellular volume (iICV; reflecting cell size or number), and LGE. Between-group differences in CMR parameters from baseline to 2 years were evaluated using multivariable mixed effects models.

Results:
Overall, 137 (77%) VANISH participants (mean age 23±10 years; 37% female; 97% White) had CMR imaging available at baseline and 2 years. Baseline characteristics and CMR parameters were well-balanced between the treatment arms. Baseline non-indexed ECV and ICV (available at baseline and year 2 in 52 participants) were 32±7% and 68±7%, respectively. Among those with detectable LGE (n=37; 27%), the median [IQR] global LGE mass was 10 [2-28] grams. Between baseline and 2 years, iICV was significantly reduced with valsartan vs. placebo (between-group difference, -5.0 mL/m
2
, 95% CI -9.7 to -0.4;
P
=0.032) (
Figure
). Valsartan was also associated with improved left ventricular end-diastolic volume index vs. placebo (between-group difference, +3.3 mL/m
2
, 95% CI 0.4 to 6.2;
P
=0.027); no significant between-group differences were observed for other CMR parameters, including iECV and global LGE mass.

Conclusions:
These findings provide important mechanistic insights into the effect of valsartan in early-stage HCM, showing potential benefits on myocardial intracellular volume. These findings support and extend those of the primary VANISH trial, stressing the need for further research efforts to identify cellular mechanisms of valsartan on HCM progression.
Abstract 4147889: Nationwide Temporal Trends in Aortic Valve Replacement for Bicuspid and Tricuspid Aortic Valve Stenosis
Authors: Barghout Mohamed , Elkaryoni Ahmed , Imran Hafiz , Ehsan Afshin , Sodha Neel , Abbott J Dawn , Sharaf Barry , Gordon Paul , Saad Marwan
Published: November 2024

Background:
Recent data demonstrated a temporal increase in adoption of transcatheter aortic valve replacement (TAVR) for treating aortic stenosis (AS) across all age groups. Whether there is a differential trend in adoption of TAVR vs. surgical AVR (SAVR) according to valve type, i.e., bicuspid (BAV) vs tricuspid aortic valve (TAV), is unknown.

Methods:
The Vizient Clinical Database was queried to identify patients who underwent TAVR vs SAVR between October 2015 and November 2023. Patients who underwent AVR for aortic regurgitation or underwent concomitant surgery during SAVR were excluded. The final cohort was divided according to the valve type into BAV and TAV cohorts. National trends in TAVR vs SAVR were examined overall and across BAV and TAV cohorts stratified by different age groups (<65, 65-80, >80 years) using linear regression analysis. Logistic regression analyses were performed to examine if age and valve type are predictors of TAVR use.

Results:
Among 365,985 patients who underwent isolated AVR for AS, 248,697 (67.95%) underwent TAVR. BAV was present in 42,754 (11.7%) of the final cohort and was treated with SAVR in 85% of patients. Across all age groups, there was an uptrend in the overall use of TAVR and among both BAV and TAV cohorts. The relative rise in all TAVR use was highest in patients <65 years (157%) and in TAVR for BAV was highest in patients 65-80 years (493.93%). In 2023, SAVR was the main AVR modality in all patients <65 years (76.80%), while TAVR was the main modality in patients >80 years (97.84%). In the BAV cohort, SAVR remained the main AVR modality in patients < 65 years (92.65%) and 65-80 years (69.47%), while TAVR was the main modality in patients >80 years (82.83%). In logistic regression analysis, patients 65-80 years and >80 years were more likely to receive TAVR than younger patients <65 years, and BAV patients were less likely to receive TAVR compared to TAV patients (p < 0.05 for all).

Conclusion:
TAVR is increasingly adopted across all age group and is more commonly performed for tricuspid vs bicuspid AS. Per these contemporary national trends, SAVR remains the main AVR modality in all patients <65 years, and in BAV patients <80 years, while TAVR remains the main AVR modality in all patients > 80 years.
Abstract 4147892: Outcomes with AngioVac Debulking of Tricuspid Valve Endocarditis with Stratification of Vegetation Size
Authors: Palatnic Leonard , Sheppard John , Zlotnick David
Published: November 2024

Background:
The AngioVac mechanical aspiration system has recently emerged in the literature for its use in the percutaneous debulking of intracardiac vegetations and masses. However, description of its efficacy in the setting of vegetation size stratification has remained sparse. We present our unique experience with the AngioVac system in patients with tricuspid valve infective endocarditis (TVIE) and high or prohibitive operative risk with a vegetation size ≥ 2cm compared to a vegetation size of < 2cm.

Methods:
We performed a retrospective, in-hospital, comparative analysis on all patients who underwent percutaneous AngioVac vegetation debulking in the setting of TVIE with a vegetation size ≥ 2cm compared to a vegetation size < 2cm from January 2017 to December 2023 at a large academic tertiary care hospital.

Results:
Of the 62 patients who underwent AngioVac debulking, 56 patients had the size of the vegetation described on echocardiography and were included. 35 patients had a vegetation size ≥ 2cm and underwent AngioVac debulking. 17 (48.6%) were women and mean age was 39.192 +/- 12.186 years. 21 patients had a vegetation size < 2cm and underwent AngioVac debulking. 10 (47.6%) were women and mean age was 38.508 +/- 12.056 years. During their index admission, between patients with a vegetation size < 2cm compared to ≥ 2cm, there was no difference in time (days) from procedure to blood culture clearance (P-value: 0.171, 95% CI: -1.178 – 6.360). There was no difference in the risk of stroke (P-value: 0.517, 95% CI: 0.000-8.792), or blood transfusion requirement (P-value 0.011, 95% CI: 0.039 – 0.757). There was no difference in the risk of experiencing worsening tricuspid regurgitation post-procedure (OR: 0.211, 95% CI: 0.004 – 1.884) or risk of recurrent endocarditis (OR: 0.778, 95% CI: 0.104 – 4.634). Finally, there was no difference in the length of hospital stay (days) between both groups (P-value: 0.234, 95% CI -4.966 – 19.758), and there was no difference in in-hospital mortality post-procedure (P-value: 0.626, 95% CI: 0.116 – 25.524). Notably, neither of the two groups required surgical or percutaneous tricuspid valve replacement.

Conclusion:
This retrospective, comparative analysis adds to the growing literature that Angiovac debulking may be a safe and effective long-term alternative to cardiac surgery in patients with TVIE and elevated perioperative risk, irrespective of vegetation size.
Abstract 4147898: Bromodomain-containing protein 4 Mediates TGF-β-induced Smooth Muscle Cell Differentiation
Authors: Guo Xia , Olajuyin Ayobami , Mandlem Venkatakirankumar , Sunil Christudas , Hou Yunzhuan , Adeyanju Oluwaseun , Petkar Sana , Qian Guoqing
Published: November 2024

Vascular smooth muscle cell (VSMC) differentiation is an essential component of vascular development. VSMCs are not terminally differentiated cells. They switch their phenotypes between proliferative and differentiated states, which is a major factor contributing to vascular diseases like atherosclerosis, aneurysms, hypertension, etc. Transforming growth factor-β (TGF-β) plays an essential role in VSMC differentiation. However, the detailed mechanisms remain incompletely understood. Bromodomain-containing protein 4 (BRD4) belongs to the family of bromodomain and extra-terminal domain (BET) proteins. It is an epigenetic modulator that has been implicated in different human diseases including cancer and tissue fibrosis. However, whether BRD4 mediates TGF-β-induced SMC differentiation remains unclear and was explored in this study. We found that TGF-β induced 10T1/2 cells (a mesenchymal stem cell line) to express markers of SMCs in a time dependent manner. Interestingly, the BRD4 inhibitor JQ1 and degrader ARV-825 effectively blocked the differentiation of 10T1/2 cells towards SMCs induced by TGF-β, as indicated by decreased induction of SMC markers such as SM22α and α-SMA. Knockdown of BRD4 using siRNA also significantly decreased TGF-β-induced differentiation of 10T1/2 cells towards SMCs. TAZ is a mediator of TGF-β-induced SMC maker gene expression. BRD4 inhibition attenuated TGF-β-induced TAZ expression, suggesting that BRD4 may regulate SMC differentiation through TAZ expression. In addition, BRD4 mediates the binding between TAZ and Smad3 to regulate the SMC marker gene transcription. Take together, our findings suggest that BRD4 modulates TGF-β-induced SMC differentiation and might play a role in SMC differentiation-related vascular diseases.
Abstract 4147899: Clinical Usefulness of Pulmonary Embolism Response Team (PERT) among Pulmonary Embolism Patients: A Systematic Review and Meta-analysis
Authors: Oli Prakash , Dawadi Sagun , Shrestha Dhan , Shtembari Jurgen , Bhandari Amit , Katz Daniel
Published: November 2024

Background:
Despite the advancement in management, pulmonary embolism has challenges in its early diagnosis and initiation of the therapies. To counter this situation, the concept of a Pulmonary Embolism Response Team (PERT), a multidisciplinary team comprised of different healthcare providers, emerged in 2012 as an initiative to optimize care for pulmonary embolism patients. This approach shown to be effective in improving the early and effective management of PE patients, thus improving the clinical recovery in some studies yet remain inclusive in other studies. Given the trending PERT acceptance situation in PE management, we performed this systematic review and meta-analysis to analyze the clinical impact of the PERT approach on PE patient management.

Methods:
We conducted a systematic review and meta-analysis from pertinent studies published until May 2024 using PubMed, Embase, and Scopus databases comparing PERT vs standard approach for PE management. This study is registered with PROSPERO and data analysis was performed using the RevMan Web.

Results:
In this analysis, 15,621 PE patients who managed via the PERT or standard approach were included in 23 studies. The use of PERT was associated with significantly lower odds of short-term mortality (OR: 0.76, CI 0.59 to 0.99), and higher odds of utilization of advanced treatment strategy (OR: 3.45, CI 1.95 to 6.09). Additionally, PERT was associated with favorably lower odds of major bleeding (OR: 0.60, CI 0.34 to 1.05) and early achievement of therapeutic anticoagulation (MD: -1.39, CI -5.32 to 2.54). Despite higher odds of ICU admission, the length of stay in ICU was significantly lower in the PERT group (MD: -0.67, CI -1.28 to -0.05).

Conclusion:
Based on this meta-analysis, the PERT approach for PE management significantly increases the chances of utilization of advanced PE management strategies, thus shortening the ICU stays, and reducing mortality risk. Additionally, it could potentially reduce the major bleeding risk. PERT should be in the focus as one of the standards of care for area PE management.
Abstract 4147904: Chronotropic Incompetence in Amyloid Cardiac Disease: A Marker of Severity?
Authors: Santos Patarroyo Sebastian , Ortega Aviles Laura , Grogan Martha , Allison Thomas
Published: November 2024

Background:
Cardiac amyloidosis is a rapidly progressing and severe condition leading to heart failure and reduced quality of life. Amyloid deposits impair both chronotropic and pumping functions of the heart. The Cardiopulmonary Exercise Test (CPET) is a vital tool in assessing the severity and progression of this disease.

Aims:
This study aims to investigate the differences in chronotropic function associated with the stages of heart failure in patients with cardiac amyloidosis and outcomes.

Methods:
A retrospective cohort study was conducted involving 194 patients diagnosed with cardiac amyloidosis who underwent at least one CPET from February 2010 to February 2024. Medical records were reviewed for data on the type of amyloidosis, comorbidities, and CPET results. The cohort was divided into two groups according to the Weber Classification: Weber Class A/B and Weber Class C/D. Patients who had CPET studies post-heart transplant were excluded. Statistical analyses, including Fisher’s exact test and chi-square test, were used. Cox regression model analysis, proportional hazards model for time to event. Adjustment for beta-blocker use was made to assess chronotropic incompetence. A p-value <0.05 was considered significant.

Results:
Among the 194 patients, 94 were classified as Weber A/B and 100 as Weber C/D. The average age at the time of the stress test was similar between the groups: 62.9 ± 11.7 years for Weber A/B and 62.3 ± 10.7 years for Weber C/D (p=0.087)
Table 1
. Chronotropic function, evaluated through CPET, showed significant differences. Heart rate reserve was significantly lower in the Weber C-D group compared to the A-B group (p<0.001). The chronotropic index was also significantly lower in the Weber C-D group
Figure 2.
Chronotropic incompetence was observed in 43.9% of the Weber A and increased progressively, being significantly more prevalent in the Weber D group (100%) (p<0.001). Additionally, Chronotropic incompetence was strongly associated with the composite outcome of (hospitalization for heart failure and death) HR 1.932 (1.126 -3.313) p =0.0167
(Table 2).

Conclusion:
CPET assessment of chronotropic function correlates with VO2 parameter evaluated in Weber classification. Patients with higher Weber stages of heart failure in amyloidosis exhibited a higher prevalence of chronotropic incompetence, indicating it could serve as a marker of cardiac function.
Abstract 4147924: An intensive longitudinal study of daily minority stressors and home blood pressure among sexual minority and heterosexual siblings
Authors: Xu Zidu , Lopez Veneros David , Caceres Billy
Published: November 2024

Background:
Sexual minority (e.g., gay/lesbian, bisexual) adults are at a higher risk of hypertension than heterosexual adults. Minority stressors, which are chronic psychosocial stressors related to one’s sexual minority identity, are hypothesized to influence these hypertension disparities among sexual minorities. However, these associations have not been formally tested.

Aims:
We sought to examine sexual identity differences in daily minority stressors (i.e., experienced and anticipated discrimination) and blood pressure (BP) between sexual minority and heterosexual siblings of the same sex.

Hypothesis:
We hypothesized that: 1) participants who reported greater daily minority stressors would have higher systolic BP (SBP), and 2) the associations of daily minority stressors with SBP would be stronger among sexual minority siblings.

Methods:
We conducted a 14-day daily diary study to examine the associations of personally experienced and anticipated (i.e., expectations of experiencing discrimination) discrimination with SBP among sexual minority adults and their heterosexual siblings with no history of hypertension or cardiovascular disease. Home SBP was assessed each morning and evening for 14 consecutive days following AHA guidelines. Daily minority stressors were assessed via structured diaries. We used multilevel linear models to estimate associations between daily minority stressors with same-day morning and evening SBPs. We then included interaction terms between each minority stressor and sexual identity.

Results:
The sample included 40 participants (20 sibling pairs) with a mean age of 26.7 (±5.35) years. Approximately 75% were assigned female sex at birth, 68% were White (68%), and 15% were Latinx. Sexual minority adults reported had higher same-day evening SBPs (
B=
2.16,
p
=0.03) than their heterosexual siblings. Participants who reported higher anticipated discrimination had higher same-day evening SBP (
B
=0.68,
p
<0.001) and next-morning SBP (
B
=2.16,
p
=0.03). Daily experienced discrimination was not associated with SBP. Sexual identity did not moderate the associations between minority stressors with SBP.

Conclusions:
This is the first study to document that daily anticipated discrimination and having a sexual minority identity are linked with elevations in home SBP. Findings suggest there is a need for larger studies to investigate mechanisms linking anticipated discrimination with elevations in SBP and potential differences by sexual identity.
Abstract 4147927: Gut Microbiome Clusters and Their Clinical Correlates in Cardiovascular Disease Risk Assessment
Authors: Mahmoudi Hamidabad Negin , Lewis Brad , Lerman Lilach , Lerman Amir
Published: November 2024

Background:
Recent studies have reported associations between alterations in gut microbiome composition (GMC) and cardiovascular disease risk factors (CVR). However, data regarding the use of GMC as a biomarker of CVR is scarce.

Aims:
The current study was designed to assess the distinct patterns in GMC among patients with varying degrees of CVR and/or atherosclerotic cardiovascular disease (ASCVD).

Methods:
Patients with a range of CVR including hypertension (HTN), hyperlipidemia (HLD), diabetes (DM), and/or ASCVD referring to Mayo Clinic from 2013 to 2018 were prospectively enrolled. DNA extracted from stool samples was analyzed using the V3-V5 region of the 16s data. Microbial α-diversity was assessed by the observed taxonomic units, Shannon, and Chao1 indices. β-diversity was assessed using Bray-Curtis dissimilarity and plotted using principal coordinates analysis. Hierarchical clustering was used to identify patterns in the GMC samples. Random Forest analysis was used to identify the most important clinical factors differentiating the clusters.

Results:
A total of 211 patients with a median age of 60 [IQR: 50,70] years and with 90 (42.7%) males were included. Two clusters of GMC were identified
(Figure 1A)
. Cluster 1 and 2 had 104 (49.3%) and 107 (50.7%) patients, respectively. Among CVRs, age and body mass index were the most prominent factors contributing to the difference in GMC among clusters (
Figure 1B
). Cluster 2 had a better α diversity profile than Cluster 1
(Figure 1C-E)
. There was no significant difference in TMAO between clusters (P=0.6). Cluster 2 patients were younger (P<0.001), leaner (P=0.007), more physically active (P<0.001), less male (P=0.009), and had a lower prevalence of ASCVD (P=0.003), HTN (P=0.010), and HLD (P=0.005). There was no significant difference in the prevalence of DM (P=0.063), smoking (P=0.446), and alcohol intake (P=0.134) between the clusters.

Conclusion:
This study suggests the potential of GMC profiling as a valuable biomarker for assessing CVRs, with age and BMI as the most prominent factors associated with GMC clustering.
Abstract 4147972: Trends In Racial and Demographic Disparities In Cardiovascular Disease-Related Mortality In Prostate Cancer Patients In The United States From 1999-2022
Authors: Amin Emaan , Memon Muhammad , Kalra Ankur
Published: November 2024

Introduction:
Recent studies have highlighted the cardiotoxic effects of novel androgen deprivation therapy for prostate cancer. The association of demographic and geographic background on cardiovascular disease (CVD)-related mortality in patients with prostate cancer is unclear.

Goals:
We aimed to analyze the trends in CVD mortality among patients with prostate cancer in the United States (US) from 1999-2022, with stratification by age, race, census region, rural-urban status, place of death, and specific CVD types.

Methods:
The age-adjusted mortality rates (AAMR) per 100,000 people were extracted using the Centers for Disease Control and Prevention WONDER database from 1999-2022. Joinpoint regression was utilized to calculate annual percentage change (APC) with 95% confidence intervals to assess for significant differences in change in AAMR over time.

Results:
A total of 440,318 deaths occurred due to CVD in patients with prostate cancer in the US in the last 20 years. The AAMR declined from 1999 to 2016 (APC -3.0 [-3.3, -2.8]) and rose till 2022 (APC 4.6 [3.4, 6.2]). AAMRs were stable in recent years for Non-Hispanic (NH) Asian or Pacific Islanders (2018-2020; APC (11.7 [-0.9, 17.9]) and NH American Indian or Alaska Native men (1999-2022, APC (-0.6 [-1.6, 0.3]). NH Black, NH White, and Hispanic men had a significant increase in AAMR from 2017 (APC 4.9), 2016 (APC 5.1), and 2018 (APC 7.0) to 2022, respectively, after an initial decline. NH Black men had the highest AAMR across all census regions. Mississippi, the District of Columbia, Nebraska, and California had the greatest overall AAMRs. The AAMRs were higher in rural than urban areas (5.9 vs 5.3/100000 people). Most deaths occurred in the decedent's home (35.3%) and in men aged >85 years. Ischemic heart disease (AAMR 2.0), hypertensive disease (AAMR 1.7), and cardiac arrest (AAMR 1.4) were the top 3 causes of CVD-related mortality among patients with prostate cancer.

Conclusion:
CVD mortality in prostate cancer patients has increased in recent years with the greatest AAMR in NH Black and elderly men, and those living in rural areas. Identifying the causes and creating policies to reduce disparities requires further research.
Abstract 4148007: Cardiovascular outcomes with Glucagon-like Peptide-1 receptor agonists and Sodium-glucose Cotransporter-2 Inhibitors in patients with ischemic stroke in the community
Authors: Sheffeh Mohammad Ali , Estrada Magana Andres , Medina-Inojosa Jose , Ortega Aviles Laura , Bianchettin Rosana , Medina-Inojosa Betsy , Klaas James , Brown Robert , Lopez-Jimenez Francisco
Published: November 2024

Background:
Sodium-glucose cotransporter-2 inhibitors (SGLT-2i) and glucagon-like peptide-1 receptor agonists (GLP1-RA) have known cardiovascular benefits. We aimed to assess the efficacy of GLP1-RA or SGLT2i initiation in reducing mortality or cardiovascular events in a community-based cohort of adults with ischemic stroke.

Methods:
Patients ≥18 years old admitted for acute ischemic stroke between Jan 2000 and June 2022 were identified using the Rochester Epidemiology Project. Subjects were considered exposed to SGLT-2i or GLP1-RA if they were treated with either medication after the index stroke and before the primary (all-cause mortality) or secondary outcomes (MI, recurrent ischemic stroke or composite). Kaplan-Meier curves and Cox models are shown in the
Figures
.

Results:
We included 7044 subjects, mean age 72±14 yr, 52% male, 94% white, over a median follow-up of 3 [1-7] years, 416 subjects (6%) had a second stroke, 426 (6%) had an incident MI and 3738 (53%) died. Those on SGLT2i/GLP1-RA had a decreased risk for mortality, incident MI, and composite in the univariate analysis. These associations remained significant after multivariable adjustment and were not affected by minimum time of exposure
Figure 1&2
. SGLT2i/GLP1-RA use was associated with recurrent ischemic stroke in the multivariate analysis
Figure 2C
. All associations remained significant in most sub-analyses of individual medications except for the association between GLP1-RA and recurrent stroke
Figure 3

Conclusions:
SGLT2i or GLP-1 RA use was associated with decreased mortality and risk of myocardial infarction and recurrent stroke in patients with ischemic stroke.
Abstract 4148102: Trends in the Burden of Ischemic Stroke and Kidney Dysfunction; An analysis of Global Burden of Disease 1990-2021
Authors: Shaukat Muhammad Talha , Rehman Wania , Hayat Malik Saad , Sohail Sara , Ali Muhammad Khan Bahadur , Shahzaib Muhammad , Rahman Saad Ur
Published: November 2024

Introduction:
Ischemic stroke and renal failure frequently coexist, impairing patient outcomes. Comprehending this association is imperative in formulating a multidisciplinary methodology to augment patient outcomes and quality of life.

Objective:
We offer estimates showing the evolution of kidney dysfunction related ischemic stroke from 1990 to 2021. It will utilize disability-adjusted life years (DALYs), years of life lost (YLLs) and age-standardized death rates (ASDR) to find discrepancies overall survival outcomes in both sexes.

Methods:
Data on ASDR, DALY, and YLL were extracted from the GBD database. After examining global trends, we analyzed continents, socio-demographic index (SDI) and World Bank income level classification of countries. Using Joinpoint regression, the average annual percentage changes (AAPC) were determined.

Results:
The ASDR for kidney dysfunction related ischemic stroke showed a declining trend globally between 1990 and 2021. The ASDR was 7.29(95%UI: 4.68-10.07) in 1990 and dropped to 4.24 (AAPC: -1.73; 95% CI: -1.76 to -1.69) in 2021. DALYs dropped from 130.3(95%UI: 90.36-172.67) in 1990 to 82.1 (AAPC: -1.47; 95% CI: -1.50 to -1.44) in 2021. YLL had a consistent decline from 1980 to 2021, with an AAPC of -1.66 (95% CI: -1.69 to -1.62). High-middle and middle SDI region had higher death rates throughout the study period.

Asia and America had lower ASDRs, whereas Europe and Africa had higher ASDRs across the board. Africa's AAPC was -0.37 (95% CI: -0.4 to -0.32) between 1990 and 2021. Similarly, Europe's AAPC of -2.85 (95% CI: -2.93 to -2.77) showed a decline from 1990 to 2021. Asia's AAPC showed a drop, coming in at -1.19 (95% CI: -1.22 to -1.15). America's AAPC was -1.97 (95% CI: -2.02 to -1.91).

According to world bank income levels, upper-middle and lower-middle income countries had higher ASDRs.

Conclusion:
Due to similar risk factors and bidirectional effects, the combination of ischemic stroke and renal failure worsens patient outcomes. In order to effectively address the intricate interactions between various illnesses and enhance patient prognosis, an in-depth investigation of the reasons behind stark disparities in death rates is necessary.
Abstract 4148170: Impact of cancer on healthcare utilization in patients with heart failure
Authors: Mathew Don
Published: November 2024

Background:
Cardiovascular disease is an important cause for mortality in cancer patients and cancer is a primary cause of non- cardiac mortality in patients with heart failure. With an estimated 17 million cancer survivors in the US, with numbers only expected to increase and a projected 8 million heart failure patients by 2030, these diseases have a tremendous impact on healthcare costs. The aim of this study is to determine the hospital resource utilization in patients with heart failure and cancer.

Methods:
This is a retrospective cohort study using the Agency of Healthcare Research and Quality’s National Readmission Database (NRD) for the year 2019. Patients with a principal discharge diagnosis of heart failure were stratified into two groups based on presence of cancer. Weighting of patient level observations was implemented to obtain national level estimates. The primary outcome was 30-day all-cause hospital readmission. The secondary outcomes analyzed were 30- day mortality rate, mean length of stay and mean cost of hospitalization. The five most common causes of readmission were also determined.

Results:
53, 219 weighted heart failure hospitalizations had cancer, while 996,566 did not have cancer. Patients with cancer had a significantly higher rate of 30-day readmission rate (25.6 % vs 22.1%; OR: 1.22; p <0.05). Patients with cancer also had a higher 30-day mortality rate (5.7% vs 3.1%; OR: 1.6; p <0.05), longer length of stay (6.14 vs 5.6 days; p <0.05) and higher hospitalization costs ($ 15,191 vs $14,013; p < 0.05). More than one third of readmissions were due to heart failure.

Conclusion:
Among patients with heart failure, a co-existing diagnosis of cancer is associated with increased 30-day readmission rate, increased 30-day mortality, longer length of stay and higher hospitalization costs.
Abstract Or107: Sulfatide-specific natural killer T cells regulate early inflammation and ameliorate post-cardiac arrest brain injury
Authors: Tamura Tomoyoshi , Cheng Changde , Villasenor-Altamiran Ana , Yamada Kohei , Hayashida Kei , Ikeda Kohei , A. Menon Jaivardhan , Chen Xi , Chung Hattie , Chen Jiani , Lawler Patrick , Baron Rebecca , Bohula Erin , Morrow David , Chen Fei , Merriam Louis , Weissman Alexandra , Brenner Michael , Chen Xiang , Ichinose Fumito , Kim Edy
Published: November 2024

Background:
Innate T cells have both deleterious and protective roles in a range of diseases. Natural killer T (NKT) cells are a major type of innate T cell, but their role and clinical relevance after cardiac arrest (CA) are undefined.

Hypothesis:
In patients after CA, an early increase in diverse NKT (dNKT) cells correlates with good neurological outcomes. dNKT cells improve outcomes after CA by reducing inflammatory responses in the brain.

Aims:
To investigate the clinical relevance of dNKT cells after out-of-hospital CA (OHCA) and their roles in a murine CA model.

Methods:
A clinical retrospective cohort study of complete blood cell counts with differentials after OHCA. Single-cell RNA-seq and flow cytometry of circulating T cells in OHCA patients. Good neurological outcomes were defined as a Cerebral Performance Category of 1 or 2 at 30 days post-CA. Single-nucleus RNA-sequencing(-seq) of hippocampal cells (50,332 nuclei), RT-PCR, and flow cytometry of the brain 24 hours post-CA in mice.

Results:
In a large OHCA patient cohort (N=1,955), the percentage of lymphocytes early (less than 12 hours) after CA was independently associated with good neurological outcomes (adjusted odds ratio [95%CI], 1.08 [1.03-1.14], P=0.005). Transcriptional profiling of T cells in OHCA patients at single-cell resolution showed an increase in an innate T cell-like NCAM1
+
subset in patients with good neurological outcomes. This subset expressed cytotoxic, cytokine, and chemokine genes. Flow cytometry identified an early increase in circulating dNKT cells in patients with good neurological outcomes post-CA. In a murine model of CA, type II dNKT cells migrated to the brain after CA. NKT cell-deficient mice (Cd1d
-/-
) had increased neuronal injury and mortality after CA. Cd1d
-/-
mice had increased molecular and cellular inflammation compared to wild-type mice 24 hours post-CA. Global transcriptomic analysis of murine brain at single-nucleus resolution indicated NKT cells suppressed inflammatory axes post-CA in multiple cell types, including astrocytes, microglia, and inhibitory neurons. Treatment with sulfatide (a lipid antigen for dNKT cells) improved neurological function after CA.

Conclusions:
Early abundance of dNKT cells was associated with good neurological outcomes after OHCA. dNKT cells are neuroprotective after CA by suppressing inflammatory axes in the brain. Immunomodulation of dNKT cells via endogenous lipids is a potential treatment approach after CA.
Abstract Or108: Optimizing Post-resuscitation Care after Resuscitative Endovascular Balloon Occlusion of the Aorta and Automated Head-up Position Cardiopulmonary Resuscitation.
Authors: Segond Nicolas , Pourzand Pouria , Moore Johanna , Metzger Anja , Salverda Bayert , Suresh Mithun , bachista kerry , Debaty Guillaume , Lurie Keith
Published: November 2024

Background:
Addition of resuscitative endovascular balloon occlusion of the aorta (REBOA) to automated head-up position (AHUP) cardiopulmonary resuscitation (CPR), the combination of active compression decompression CPR, an impedance threshold device, and controlled gradual elevation of the head and thorax, increases cerebral perfusion pressure. Optimal management of REBOA deflation after prolonged AHUP-CPR and ROSC is unknown.

Hypothesis:
We hypothesized that partial deflation of REBOA, rather than full deflation after ROSC, would result in better hemodynamic parameters.

Aims:
To compare hemodynamic parameters 1 minute before and 1 minute after complete (100%) versus partial (50%) REBOA deflation after prolonged AHUP-CPR and ROSC.

Methods:
Yorkshire pigs weighing ∼40 kg were anesthetized and ventilated. After 10 minutes of untreated ventricular fibrillation, AHUP-CPR was started and continued for a median time of 44 minutes. After ROSC, REBOA deflation was initiated in two ways: complete (100%) or partial (50%) deflation over 5 seconds. The following hemodynamic parameters were measured 1 minute before and 1 minute after deflation: mean aortic pressure (MAP), cerebral perfusion pressure (CerPP), and coronary perfusion pressure (CorPP). Data, in mmHg, are presented as mean ± SD, and compared using a paired t-test.

Results:
13 pigs were included, with 8 pigs in the 100% deflation group and 5 in the 50% deflation group. After ROSC in the 100% deflation group, MAP was 81.5±36.0 before deflation vs. 43.0±14.4 after (p=0.01), whereas in the 50% deflation group, MAP was 90.5±33.0 vs. 83.4±33.3 (p=0.02). CerPP was 72.3±34.4 before deflation vs. 35.9±14.6 (p=0.01) in the 100% deflation group, and 84.6±31.2 vs. 77.6±31.8 (p=0.02) with 50% deflation. Similarly, CorPP was 74.1±37.3 before deflation vs. 36.1±15.8 (p=0.01) after in the 100% deflation group, and 83.0±32.7 vs. 76.1±33.0 (p=0.02) in the 50% deflation group. The differences from before to after deflation were markedly less in the 50% deflation group versus the 100% deflation group: MAP (7.0±4.3 vs. 38.5±25.7, p=0.02), CerPP (7.1±4.4 vs. 36.3±24.4, p=0.02), and CorPP (6.0±4.2 vs. 39.8±25.2, p=0.02), respectively.

Conclusion:
In this porcine model of prolonged cardiac arrest, partial deflation of the REBOA balloon post ROSC resulted in strikingly higher hemodynamics compared with complete deflation. These findings highlight the need to develop a post-ROSC REBOA deflation strategy when used during AHUP-CPR.