bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 17374: Epigenetic Age Acceleration in Adult Congenital Heart Disease
Authors: Jain Parag N , Zhuang Beryl C , Whitehead Joanne , Kobor Michael , Checchia Paul
Published: December 2023

Introduction:
DNA methylation (DNAm) changes reflect alterations in the immune response to cardiac surgery in older adults. However, whether adults with congenital heart disease (ACHD) who underwent palliative cardiac surgery during childhood experience epigenetic age acceleration (EAA) is unknown.

Hypothesis:
ACHD patients with Fontan(F) procedures would have advanced EAA compared to healthy adults.

Methods:
A case-control study in young adults (aged 20-30 years) with Fontan circulation at a tertiary ACHD hospital with age-matched healthy adults. DNAm were measured by the EPIC Array. EAAs were calculated by extracting residuals by regressing epigenetic ages on chronological age in linear regression models for four epigenetic clocks. DNAm-based cell type proportions and EAA differences between the two groups were tested by robust linear models (rlm) adjusted for age, sex, and self-reported ethnicity.

Results:
Thirteen Fontan patients (6 female: 7 male) were compared with 20 age-matched controls (15 female). The median age of the F group was 23 years, compared to 27 years in control. Both subgroups had a predominant white race and non-Hispanic ethnicity. The F group has lower B memory cells and naïve CD4+ cells than controls (adjusted p<0.05). The F group has statistically significant higher Grimage and Phenoage EAA than the controls (p<0.01).

Conclusions:
Patients who underwent the Fontan procedure experience advanced EAA at a young age. Future studies evaluating the key predictors that drive EAA difference is needed to understand the impact of chronic alteration of physiology.
Abstract 17395: Effect of ION904, an Antisense Inhibitor of Angiotensinogen Production: Results of Phase 1 and Phase 2 Pilot Studies
Authors: Morgan Erin , Duran Jason M , Weinland Julia , Lin Tao , Mullick Adam E , Geary Richard , Tsimikas Sotirios
Published: December 2023

Background:
Drugs that inhibit the renin-angiotensin-aldosterone system (RAAS) act within the kidney and disturb tubuloglomerular feedback leading to renal dysfunction and hyperkalemia. We previously published that inhibiting angiotensinogen (
AGT
) mRNA in hepatocytes with GalNAc-modified antisense oligonucleotide (ASO)-IONIS-AGT-L
Rx
given subcutaneously (SC) weekly is effective in significantly reducing plasma angiotensinogen (AGT) with no on-target or off-target effects.

Objective:
We aimed to develop a more potent and durable ASO targeting
AGT
. ION904 is a GalNAc-conjugated ASO that specifically reduces hepatic
AGT
production with minimal activity in the kidneys.

Methods:
In a phase 1 study (PH1), healthy volunteers were treated with placebo saline (PBO) or ION904 SC with single ascending doses (PBO or 10-120 mg, n=56). A phase 2 (PH2) pilot study (n=48) in patients with uncontrolled hypertension (SBP > 130 - ≤ 170 mmHg) on at least 1 antihypertensive medication were randomized to PBO or 30, 60, or 90 mg of ION904 SC every 4 weeks for 3 months (3:1 randomization). The primary endpoint was plasma AGT reduction at Week 15. The study was not powered for SBP reduction.

Results:
ION904 resulted in a significant mean percent reduction in plasma AGT levels compared to pooled PBO at Day 15 (-12% v. -76%, PBO v. 120 mg, p ≤ 0.001) in PH1. In PH2, the mean percent reduction in AGT levels were significantly greater in the ION904 group compared to PBO at the primary endpoint, Week 15, (-6% v. -79%, PBO v. 90 mg, p=0.001). Robust median AGT reductions were observed at the primary endpoint (-5% v. -86%, PBO v. 90 mg). A larger proportion of subjects (11/26, 42%) in the ION904 group achieved ≥ 10 mmHg reductions compared to PBO (3/10, 30%) at Week 15. No signals for hyperkalemia, renal dysfunction, hypotension (on target effect) or liver dysfunction or thrombocytopenia (off target effects) were noted. No drug-related serious adverse events occurred.

Conclusions:
Monthly administration of ION904 demonstrated significant plasma AGT reductions with a favorable safety and tolerability profile supporting development in heart failure and hypertension.
Abstract 17400: Effects of Concurrent Extracellular Vesicle and Metformin Therapy in Porcine Model of Chronic Myocardial Ischemia and Metabolic Syndrome
Authors: Sabe Sharif A , Harris Dwight D , Broadwin Mark , Sabra Mohamed , Xu Cynthia , Abid Ruhul , Sellke Frank W
Published: December 2023

Introduction:
We previously demonstrated using a swine model of chronic myocardial ischemia (CMI) that extracellular vesicle (EV) therapy improves cardiac function, perfusion, and angiogenic signaling, but these benefits were blunted in the setting of metabolic syndrome (MS).

Hypothesis:
We hypothesized that concurrent treatment with metformin may augment the cardiac effects of EV therapy in a swine model of CMI and MS.

Methods:
Twenty-nine Yorkshire swine were fed a high fat diet for four weeks to induce MS, then underwent placement of an ameroid constrictor to the left circumflex artery to induce CMI. Two weeks later, pigs receiving either oral placebo or 500mg metformin (MET) BID underwent intramyocardial injection of either vehicle or mesenchymal stem cell-derived EVs. This resulted in four groups: placebo+vehicle (CON, n=6), placebo+EV (EV, n=8), MET+vehicle (MET, n=7), and MET+EV (METEV, n=8). Five weeks after injection, pigs underwent functional measurements and harvest of ischemic myocardium. Perfusion, capillary density, and protein expression were measured by microspheres, immunofluorescence, and immunoblotting respectively.

Results:
Cardiac function was improved in EV compared to CON (SV p=0.02, SW p=0.01, CO p=0.03), and in MET compared to CON (SV p=0.03, SW p=0.09, CO p=0.2), though there were no differences between MET and METEV groups (p>0.5 for all). Contractility as measured by slope of PRSW relationship was improved with METEV compared to CON (p=0.04), with a trend towards improvement in MET compared to CON (p=0.21), but not with EV alone. During pacing, there was increased perfusion in MET (p=0.04) and METEV (p=0.04) groups compared to CON. At rest, there was increased perfusion in MET (p=0.05) group, with a trend towards increased perfusion in METEV group (p=0.29) compared to CON, without differences between MET and METEV (p>0.5). Capillary density was unchanged in METEV compared to CON (p>0.5). The MET and METEV groups had decreased expression of p-Akt (p=0.01, p=0.06) and p-ERK (p=0.09, p=0.03) compared to CON, without changes in p-eNOS (p>0.5), and all without differences between MET and METEV (p>0.5).

Conclusions:
In the setting of CMI and MS, the blunted effects of EVs are not augmented by concurrent metformin therapy.
Abstract 17405: Biodistribution, Dosimetry, and Specificity of A
99m
Tc-Labeled Matrix Metalloproteinase Targeted Radiotracer (
99m
Tc-RP805) for Myocardial Infarct Imaging
Authors: Thorn Stephanie L , Freeburg Lisa A , Spinale Francis G , Sinusas Albert J
Published: December 2023

Introduction:
Activation of matrix metalloproteinase (MMPs) post myocardial infarction (MI) predicts post-MI remodeling. MMP activation in the heart can be detected using 99mTc-RP805 a radiolabel peptidomimetic that binds to the catalytic site. The purpose of this study was to evaluate the biodistribution, dosimetry, and specificity of clinical grade 99mTc-RP805 for first-in-human studies.

Methods:
Male and female rats (n=24) were injected with
99m
Tc-RP805 and euthanized at 1, 3, 7 or 12 hr post injection to determine biodistribution and estimate human dosimetry. Organ activity (%ID/g) was used to estimate whole body and organ effective dose using OLINDA. MI was induced in rats by LAD ligation (n=19) and injected with
99m
Tc-RP805 3 days post MI, and rats were euthanized 3 hr after injection in absence (n=9) or presence (n=10) of a 100 x blocking dose of RP805 (257 ug/kg) 30 min prior to radiotracer injection to establish specificity. In vivo SPECT/CT imaging was performed with GMP grade
99m
Tc-RP805 in rats post-MI (n=4).

Results:
The %ID/g for each organ is presented per time point (Fig 1 A). The highest radiation dose was found in male kidneys at 3 hr (%ID/g: 6.11 ± 0.54), female kidneys at 1hr (%ID/g: 6.31 ± 0.88). The estimated total body dose for human males was calculated at 0.172 mSv/mCi and 0.283 mSv/mCi for females, equaling a dose of 3.4 mSv and 5.7 mSv for a 30 mCi injection in males and females, respectively. There is 4 fold increase 99mTc-RP805 uptake in the infarct area compared to the normal LV (Fig 1B) and uptake was blocked with cold compound (ANOVA, p<0.001). In vivo SPECT/CT imaging with a newly synthesized GMP compound demonstrates uptake in the anterior LV (Fig 1C).

Conclusions:
We have developed and evaluated clinical grade
99m
Tc-RP805 for targeted MMP imaging post-MI and demonstrated favorable dosimetry, biodistribution, and specificity for first-in-human imaging.
Abstract 17425: Matricellular Protein CCN1 Modulates Post-Infarct Scar Integrity and Structure
Authors: Fischer Annalara G , Elliott Erin M , Brittian Kenneth R , Aebersold Julia W , Tong Nicholas C , Nong Yibing , Jones Steven P , Moore Joseph B
Published: December 2023

Introduction:
Collagen deposition is required for repair of the heart following myocardial infarction (MI). As collagen abundance increases, so does its alignment, potentially influencing scar integrity. Because cell-matrix interactions regulate fibroblast behavior and matrix dynamics, adhesive factors, like cellular communication network (CCN) proteins, may contribute to post-MI scar formation. CCN1's role in skin collagen modulation and its recent emergence as a heart failure biomarker indicate its potential contribution to post-MI matrix remodeling. Consequently, we focused on CCN1 as a potential regulator of collagen organization.

Hypothesis:
CCN1 guides collagen alignment to support scar integrity via enhancing fibroblast-matrix interactions.

Methods & Results:
Tamoxifen (TAM)-inducible
Ccn1
fibroblast-specific KO (

Ccn1
-/-

) and control (

Ccn1
fl/fl

) mice (16-20 wk old) received TAM 3 wk prior to permanent coronary artery ligation. Cardiac function, heart mass, and scar structure were evaluated 1 wk post-MI using echocardiography, gravimetrics, and imaging techniques (picrosirius red, second harmonic generation, and transmission electron microscopy).

Ccn1
-/-

mice exhibited decreased survival (A) and an increased incidence of cardiac rupture compared to

Ccn1
fl/fl

(B-C). There were no differences in cardiac function or scar size among the groups. Macro- (E-F) and micro- (G) level structural analyses uncovered significant reductions in collagen organization in

Ccn1
-/-

mice. RNAi-mediated CCN1 depletion in fibroblasts resulted in reduced focal adhesion (FA) formation in culture (43.0 FA/cell ± 5.6 vs. 89.3 FA/cell ± 9.6; Mean ± SEM, p=0.0013, n=7), highlighting its role in facilitating fibroblast-ECM interactions.

Conclusions:
CCN1 is required for post-MI scar integrity. CCN1 may regulate fibroblast-ECM interactions to alter collagen organization.
Abstract 17431: A Rare Cause of Constrictive Pericarditis in a Case of Adult T-cell Lymphoma
Authors: Mounir Abdulghani , Essien Ekow , Masood Faisal , Galazka Patrycja , Jan M F
Published: December 2023

Introduction:
Adult T-cell lymphoma (ATCL) is a rare T cell lymphoproliferative malignancy that typically presents with lymphadenopathy, hepatosplenomegaly, lytic lesions, hypercalcemia or skin lesions. Cardiac involvement is rare.

Case presentation:
A 66-year-old male with a history of chronic kidney disease and hypertension presented with dyspnea. Transthoracic echocardiography revealed a moderate pericardial effusion and a left ventricular ejection fraction of 45%. Further workup with MRI and transesophageal echocardiography found extensive circumferential pericardial thickening with enhancement and extensive mediastinal and hilar lymphadenopathy along with a mass along the course of the superior vena cava with extension of disease into the right atrium along the right atrial wall (Figure 1). Endobronchial biopsy of the mediastinal lymph nodes was positive for T-cell lymphoma. Chemotherapy was initiated; however, the patient decided to focus on comfort measures only.

Discussion:
Cardiac involvement in ATCL is rare and usually detected in postmortem autopsies. Incidence is unknown, and experience is limited to case reports. The largest case series to date found 16 patients who had antemortem diagnosis of symptomatic cardiac involvement of ATCL. The characteristic features included infiltration of the myocardium, pericardial effusion, valvular lesions, and masses in the atrium, similar to what was seen in our patient. To our knowledge, there have been no reported cases of ATCL causing constriction. Prognosis is poor, with median survival of 5 months after development of symptoms (n = 15, range 0-120 months).

Conclusion:
The incidence of cardiac ATCL is unknown, but it is an extremely rare occurrence. It can present with a wide variety of cardiac involvement, including constriction. The prognosis of cardiac ATCL remains poor.
Abstract 17444: Racial and Ethnic Disparities in Anthracycline Cardiotoxicity
Authors: Zhang Lili , Song Justin , Hanif Waqas , Clark Rachel , Haroun Magued , Fernandez Hazim Carol , McNaughton Caroline , Slipczuk Leandro , Garcia Mario J , Pu Min , Neilan Tomas G , Makower Della , Sica Roberto Alejandro , Chambers Earle C , Rodriguez Carlos J
Published: December 2023

Introduction:
There are limited data on anthracycline cardiotoxicity in racially and ethnically diverse populations.

Aims:
Our study sought to examine the incidence of cardiotoxicity and the changes in left ventricular ejection fraction (LVEF) in cancer survivors treated with anthracycline in a multiracial/ethnic community.

Methods:
We included consecutive adult patients who underwent anthracycline-based chemotherapy from 2016 to 2019 for any type of cancer. Patients with preexisting heart failure were excluded. The endpoint was the development of cardiotoxicity (defined as clinical HF or drop in LVEF≥10% to LVEF<53%).

Results:
Our retrospective cohort included 925 patients (22% Non-Hispanic White (NHW), 25% Non-Hispanic Black (NHB), 31% Hispanic, and 2% Asian). Hypertension, diabetes, and hyperlipidemia were more prevalent in NHB, Hispanic, and Asian patients than in NHW patients. The mean cumulative anthracycline dose was 197±99 mg/m
2
and the mean LVEF was 64±5.7%, both similar across racial and ethnic groups. During a median follow-up of 21 months, 116 patients (13%) developed cardiotoxicity. The incidence of cardiotoxicity was significantly higher in NHB (16%), Hispanic (15%), and Asian (18%) patients compared to NHW patients (7%) (p=0.045). Of the 116 patients with cardiotoxicity, 21 patients had reduced ejection fraction (LVEF<50%) and 81 had preserved ejection fraction (LVEF≥50%). Significantly more Hispanic patients developed cardiotoxicity with reduced ejection fraction (33.3%) compared to NHW (14.3%) and NHB (6.1%) patients (p=0.014). The mean decline in LVEF was higher in NHB patients (4% ± 9%) and Hispanic patients (6% ± 10%) than in NHW patients (3% ± 7%).

Conclusions:
In a large racially and ethnically diverse cohort of cancer survivors treated with anthracycline-based chemotherapy, NHB and Hispanic patients had an increased risk of cardiotoxicity and a greater decline in LVEF compared to their White counterparts.
Abstract 17462: Angiotensin II-Mediated Suppression of Skeletal Muscle Autophagy via mTOR and FoxO3a Pathways
Authors: Sindi Fareed , Delafontaine Patrice , Yoshida Tadashi
Published: December 2023

Background:
Chronic skeletal muscle (SK.M) atrophy, cachexia, occurs in diseases such as congestive heart failure (CHF), which is associated with high levels of angiotensin II (Ang-II). We have shown that Ang-II infusion reproduces major aspects of CHF-induced SK.M atrophy and causes mitochondrial (MT) damage and dysfunction in SK.M. Ang-II also inhibits autophagy/mitophagy, and a combination of these effects likely causes accumulation of damaged MT, leading to SK.M atrophy.

Hypothesis:
Ang-II infusion suppresses autophagy in SK.M via activation of mTOR and inhibition of FoxO3a.
Aim:
To understand the molecular mechanisms whereby Ang-II inhibits autophagy/mitophagy in SK.M.

Methods:
12 weeks old male FVB mice were infused with Ang-II (1.0 μg·kg
-1
·min
-1
) or saline via osmotic minipumps (ALZET 1007D) for 7 days (N=6). Expression of autophagic markers and FoxO3a target genes were analyzed in tibialis anterior muscles by western blotting (at d1 & d7) and qPCR (at d4), respectively. Colchicine treatment was included in the analyses to assess autophagic flux
in vivo
. For statistical analysis Two-way ANOVA and t-test were used.

Results:
In the presence of colchicine, LC3 lipidation was decreased in Ang-II infused mice, indicating that Ang-II inhibits autophagy at the autophagosome formation step. Furthermore, Ang-II increased p62 and PINK1 and decreased BNIP3, suggesting that Ang-II-mediated reduction of autophagy causes disruption of damaged MT clearance via mitophagy. Mechanistically, Ang-II likely inhibits autophagosome formation via two pathways, mTOR and FoxO3a: Ang-II increased phosphorylation of mTOR at Ser2448 (p<0.005) and its downstream target 4E-BP1 at Thr37/46 (p<0.0005). Lastly, Ang-II increased phosphorylation of FoxO3a at Thr32 (p<0.0005), associated with reduced mRNA expression of FoxO3a target genes, such as LC3B and BNIP3 (24% and 46% reductions, respectively).

Conclusion:
Ang-II inhibits autophagosome formation in SK.M via mTOR activation and FoxO3a inhibition. Suppression of autophagy via these pathways likely disrupts clearance of damaged MT, leading to SK.M atrophy. These results provide insights for future development of therapies for CHF-induced cachexia by targeting mTOR and FoxO3a pathways to restore autophagy.
Abstract 17482: Association of Ankle-Brachial Index with Coronary Artery Calcium Scoring for Coronary Vascular Disease Risk Stratification
Authors: Gaballa Andrew , Hajj Ali Adel , Feinleib Steven , Schoenhagen Paul , Seballos Raul J , Wang Tom Kai Ming K , Fendrikova Mahlay Natalia , Desai Milind Y
Published: December 2023

Introduction:
The Ankle-Brachial Index (ABI) and coronary artery calcium scoring (CACS) are important tools for cardiovascular disease risk stratification. This study aimed to investigate the association between ABI index in combination with CACS for risk stratification of coronary vascular disease.

Hypothesis:
Given that both the ABI and the Coronary Artery Calcium Scoring are predictors of cardiovascular events, we hypothesize that an association between the Multiethnic Study on Subclinical Atherosclerosis Coronary Artery Calcium Scoring (MESA-CACS) and ABI exists.

Methods:
A total of 2655 patients (mean age 59±6 years, 72% male, and 87% white) who underwent CACS screening and ABI as part of a primary prevention screening program at the Cleveland Clinic between March 2016 and October 2021 were included in this study. ABI measurements were obtained by dividing the ankle systolic blood pressure by the brachial systolic blood pressure. The 10-year risk score based on MESA-CACS was calculated and categorized into 4 groups (<1%, 1-4.99%, 5-9.99% and ≥10%). ABI was categorized into normal (1-1.4), non-compressible (≥ 1.4) and abnormal (< 1).

Results:
Among the total of 2655 patients, 164 (6%) had a MESA-CAC score of <1%, 1566 (59%) had a score of 1-4.99%, 501 (19%) had a score of 5-9.99%, and 424 (16%) had a score of ≥10%. The median ABI was 1.17 (range 0.79-1.77) on the left and 1.17 (0.50-1.78) on the right. Tabulating the patients based on their ABI index across the MESA-CACS categories showed no significant difference among the groups with a p-value of 0.830 (Fig 1), with the majority of the patients (> 98% of patients) in all 4 groups having a normal ABI index of 1-1.4.

Conclusion:
The ABI did not demonstrate a significant association with the MESA-CACS, suggesting its potential use as a synergistic marker for coronary vascular disease risk stratification. Long-term cohort studies are needed to validate this result.
Abstract 17489: Bupropion Poisoning: Extracorporeal Membrane Oxygenation as a Rescue Strategy
Authors: Kochiashvili Avtandil , Yabut Jevin , Kwarta Bethany , Gluck Jason A
Published: December 2023

Introduction:
Bupropion is a commonly prescribed antidepressant. Although generally well-tolerated, bupropion overdose can lead to severe cardiovascular and neurological toxicity. We present a case of cardiogenic shock and status epilepticus as a result of bupropion intoxication.

Case Presentation:
A 29-year-old female with history of depression and borderline personality disorder presented to the emergency department unresponsive after ingesting large quantities of bupropion, alprazolam and lisdexamfetamine. Vital signs were unremarkable and physical exam revealed pupil asymmetry. CT head was unremarkable. Urine toxicology was positive for amphetamines and benzodiazepines, with a blood alcohol level of 104. QTc was 522. Patient received versed for status epilepticus and was placed on mechanical ventilation. She developed sustained ventricular tachycardia and hypotension, unresponsive to bicarbonate and amiodarone. The patient was placed on venoarterial extracorporeal membrane oxygenation (VA ECMO) to provide hemodynamic support while eliminating bupropion from circulation. Following repeated episodes of VT, the patient was successfully cardioverted and started on amiodarone. TTE demonstrated left ventricular ejection fraction (LVEF) of <30%. Notably, lipid emulsion therapy was not administered as patient stabilized with ECMO support. After 48 hours of electrical stability, she was weaned off ECMO and inotropes and transitioned to guideline-directed medical therapy. Repeat TTE demonstrated LVEF of 60% on day 12. Mental status improved and patient was admitted to psychiatry with outpatient cardiology follow-up.

Discussion:
Bupropion overdose can cause prolonged QTc, ventricular arrhythmias, and seizures. Cardiotoxicity results from inhibition of gap junction ion channels, compromising conduction and contractility. Various approaches, including ECMO and lipid emulsion therapy, have been effectively employed in such cases. This case demonstrates that ECMO can serve as a hemodynamic bridge during the elimination of bupropion while augmenting its clearance via increased flow, underscoring the benefits of mechanical circulatory support in cases of intoxication affecting cardiac contractility and conduction.
Abstract 17490: Impaired Cerebrovascular Oxygen Delivery, Reserve, and Metabolism in Adult Fontan Patients
Authors: Suriany Silvie , Xu Botian , Gonzalez-Zaccarias Clio , Shen Jian , O'Neil Sharon , Panigrahy Ashok , Peterson Bradley , Detterich Jon , Wood John C
Published: December 2023

Introduction:
Patients with univentricular hearts undergo a three-stage surgical palliation, culminating in total caval-pulmonary connection (Fontan procedure), maximizing delivery of oxygenated blood to the systemic circulation. Prior brain research in this population has highlighted genetic predisposition, in-utero oxygen delivery, surgical insults, and pre-Fontan cyanosis as possible mechanisms of brain injury, but none have examined the impact of the Fontan repair on brain hemodynamics.

Study Purpose:
To determine the sufficiency of brain O
2
delivery, cerebrovascular reserve (CVR), brain O
2
extraction fraction (OEF), and cerebral metabolic rate of O
2
(CMRO
2
) in adult Fontan patients, compared to permeability-surface area (PS) of blood brain barrier (BBB) integrity to water, and endothelin levels.

Hypothesis:
We hypothesized that brain O
2
delivery, CVR, PS, and CMRO
2
would be decreased in Fontan patients, proportional to endothelin levels, an established surrogate for low cardiac output.

Methods:
We have enrolled 35 Fontan patients (age 20.8 ± 2.5 years, 21M) and 24 control subjects (age 23.4 ± 4.8 years, 9M) to undergo brain MRI, excluding all subjects with known stroke, seizure, or genetic abnormalities. We collected total cerebral blood flow (CBF), OEF, CVR, and PS using 3T MRI.

Results:
Table 1 summarizes differences in O
2
delivery, CBF, OEF, CMRO
2
, CVR, PS, and endothelin levels in the study cohort. O
2
delivery, CBF, CVR, and CMRO
2
were decreased in Fontan patients; OEF and PS were not different. Endothelin was increased but uncorrelated with the brain metrics. CMRO
2
was correlated with PS (r
2
= 0.19, p<0.001).

Conclusion:
Adult survivors of Fontan palliation have decreased brain O
2
delivery and reserve, without compensatory OEF increases, leading to lower CMRO
2
. Decreased CMRO
2
was associated with decreased PS, but not endothelin, suggesting microvascular dysfunction rather than low cardiac output as the fundamental etiology.
Abstract 17497: Natural History of the Left Ventricular Ejection Fraction in Heart Failure and Sudden Cardiac Death
Authors: Chugh Sumeet S , Uy-Evanado Audrey , Chugh Harpriya , Aziz Habiba , Nakamura Kotoka , Sargsyan Arayik S , Jui Jonathan , Reinier Kyndaron
Published: December 2023

Background:
A clinical diagnosis of heart failure (HF) is associated with increased risk of sudden cardiac death (SCD), but only HF with severely reduced LV ejection fraction (HFrEF, EF ≤35%) is utilized for risk stratification. Guideline-directed medical therapy and heart disease processes may improve or reduce the LVEF.

Hypothesis:
There is significant variation of LVEF over time among HF patients with SCD.

Methods:
From a large, prospective population-based study of SCD in the Northwest US (catchment population 1 million, 2002-2018), we identified all consecutive patients with a diagnosis of HF and prior assessment of LVEF. The sub-group of patients with at least 2 prior LVEF evaluations (earliest and latest in relation to SCD) was determined.

Results:
A total of 1622 individuals suffered SCD with a known diagnosis of HF (65% male, age 72±14) of which 434 had 2 LVEF evaluations at least 1 yr apart prior to their SCD. At earliest evaluation, 100 (23%) had HFrEF (73% male, age 67±13), 88 (20%) had HF with moderately reduced EF (HFmrEF, 35<ef<50) (71% male, age 72±12), and 246 (57%) had hf with preserved ef (hfpef, ef≥50) (57% 72±12). comparing the earliest latest assessment of lvef, mean lvef in hfref increased by 9±14 percentage points (p<0.001) from 27±6 to 36±14; hfmref decreased over time -4±14 (p="0.003)" 43±4 39±14; hfpef -8±13, 62±7 54±14. each subtype changed substantially (mean 2.9±1.5 yrs), sizeable proportions re-classified into different subtypes (Figure). Overall, the HF LVEF subtype was unchanged in 58% and altered in 42% (p<0.001).

Conclusions:
Based on the LVEF, at least 40% of HF sub-types were re-classified prior to SCD and risk assessment would be variable depending on when LVEF was measured. These findings highlight the limitations of using the LVEF as the only risk predictor of SCD.
Abstract 17518: Aortic Dissection Repair of Both Stanford Type A and Stanford Type B Aortic Dissection in Teaching Hospitals is Associated With Lower Mortality
Authors: Li Renxi , Luo Qianyun , Green Derrick L , Huddleston Stephen
Published: December 2023

Introduction:
Aortic dissection (AD) repair is a high-risk procedure. Hospital teaching status may impact postoperative outcomes after AD repair. This study aimed to compare mortality after AD repair for both Stanford Type A (TAAD) and Stanford Type B (TBAD) in urban private practice (UPP) versus teaching hospitals (TH).
Method:
Patients who underwent TAAD and TBAD repair were identified in the National Inpatient Sample (NIS) from Q4 2015-2020 by ICD10-CM/PCS. Comparison of postoperative mortality between UPP versus TH among TAAD and TBAD were examined separately. In addition, mortality after open surgery and Thoracic Endovascular Aneurysm Repair (TEVAR) in TBAD were compared. Significant preoperative differences were present between cohorts, so multivariable logistic regressions were performed. Adjusted preoperative variables included sex, age, race, socioeconomic status, comorbidity, primary payer status, and hospital characteristics.
Result:
There were 316 patients in UPP and 4,494 patients in TH who underwent TAAD repair. In TBAD, 247 patients were treated in UPP and 3,845 patients were treated in TH. Of patients with TBAD, 114 UPP and 1,533 TH had open repair, whereas 133 UPP and 2,312 TH had TEVAR. Compared to TH, mortality was higher in both TAAD (aOR 1.37, p<0.01) and TBAD (aOR 1.89, p<0.01) in UPP. Within TBAD, UPP had higher mortality in both open repair (aOR 1.80, p<0.02) and TEVAR (aOR 1.88, p<0.05). At UPP, length of stay>7 days was less common than in TH (aOR 0.50, p<0.01) among patients who had TBAD open repair. Post-operative major adverse cardiac events, myocardial infarction, or stroke were not different in all AD groups when comparing patients in UPP to TH.

Conclusion:
Treatment of both TAAD and TBAD at UPP is associated with significantly higher in-hospital mortality. Emergent transfer to teaching hospitals might be considered to achieve lower mortality of AD.
Abstract 17538: The Weekend Effect on In-Hospital Outcomes of Elderly Patients With Acute Ischemic Stroke and Concurrent COVID-19 Infection: A Nationwide Multicenter Study
Authors: Mohammed Adil S , Manne Suvidha , Ahmed Hafeezuddin , Polamarasetty Harshavardhan , Siddiqui Muneeb , Arastu Azeem , Vanukuru Sravya Gayatri , Devarala Bhagya Lakshmi , Ganampet Narendranath Reddy , Jayaprakash Sanmayi , Singh Sandeep , Desai Rupak
Published: December 2023

Background:
Acute ischemic stroke (AIS) and COVID-19 are individually associated with poor outcomes. The impact of the pandemic on the US healthcare system, including staff shortages and disparities, may have delayed timely interventions and adherence to guidelines. We investigated the Weekend Effect on outcomes in elderly patients with AIS and COVID-19 to better understand its relationship during the challenging pandemic period.

Methods:
Using ICD-10-CM codes, we analyzed AIS and COVID-19 hospitalizations among the elderly (>65 years) from the 2020 National Inpatient Sample. Weekday and weekend admissions were compared for baseline characteristics, comorbidities, and outcomes. The multivariable analysis was adjusted for confounding variables. A two-tailed p<0.05 was considered significant.

Results:
Of 14,070 total AIS and concurrent COVID-19 admissions among the elderly, 10,425 were on weekdays, and 3645 were on weekends. While both cohorts exhibited comparable age distributions, the weekend admissions had a higher percentage of females (47.1% vs. 45.2%) and whites (59.5% vs. 58.1%). They had a higher prevalence of hypertension (82.2% vs. 78.6%), hyperlipidemia (52.9% vs. 50.1%), chronic pulmonary disease (19.1% vs. 17%), obesity (15% vs. 13.6%), depression (10.2% vs. 8.2%). Additionally, all-cause mortality (33.5% vs. 32.5%) and cardiogenic shock (1.9% vs. 1.7%) were slightly higher among weekend admissions. Upon adjusting for confounding factors, the overall mortality rate among weekend admissions showed no significant association, aOR-1.15 [95%CI:0.42-0.96; p-0.169].

Conclusion:
Although there is a higher prevalence of comorbidities and overall mortality among weekend admissions, no significant association between the Weekend Effect and poor in-hospital outcomes in elderly COVID-19 patients with AIS was noted. However, ensuring adequate staffing and resource availability during weekends may enhance the quality of care provided.
Abstract 17565: Sympathetic Neural Overactivity, Endothelial Dysfunction, Aortic Stiffening, and Diminished Exercise Capacity in Breast Cancer Survivors Treated With Doxorubicin and Trastuzumab-Based Chemotherapy
Authors: Izaias Joao , Bernardes Renata , Ono Bruna , Faria Diego , Sales Artur , Testa Laura , Moniz Camila , Mota Mauricio , Salemi Vera M , Rossman Matthew , Craighead Daniel , Clayton Zachary , Bortolotto Luiz , Irigoyen Maria C , Colombo Fernanda , Seals Douglas , Kluser Allan
Published: December 2023

Introduction:
Previous evidence demonstrates that breast cancer (BC) survivors who were treated with doxorubicin and trastuzumab-based chemotherapy have an increased risk of developing cardiovascular (CV) disease at least 7 years after completion of cancer treatment. The reasons for the increased CV disease risk are not completely understood, a constellation of physiological changes may contribute. We hypothesized that BC survivors compared with age- and body mass index (BMI), sex -matched healthy controls, exhibit sympathetic neural overactivity, vascular endothelial dysfunction, aortic stiffening, and diminished exercise capacity.

Methods:
Twelve women BC survivors, treated with doxorubicin and trastuzumab (age=48±2 years and BMI=28±2 Kg/m
2
) and fourteen women control subjects (age=46±1 years and BMI=27±1 Kg/m
2
) were studied. Muscle sympathetic nerve activity (MSNA, Microneurography), endothelium-dependent dilation (brachial artery flow-mediated dilation, BAFMD), aortic stiffness (carotid-femoral pulse wave velocity, CFPWV), blood pressure (BP, Finometer), heart rate (HR, Electrocardiogram), and peak oxygen uptake (V˙O
2
peak, Cardiopulmonary exercise testing) were measured.

Results:
BC survivors were evaluated 8±2 years after the completion of cancer treatment. Burst frequency and burst incidence of MSNA were higher and BAFMD and V˙O
2
peak were lower in BC survivors than in controls (
p
<0.001). There were not differences between the groups in CFPWV, BP, and HR (
p
>0.05). MSNA burst frequency and burst incidence were inversely associated with V˙O
2
peak or BAFMD (
p
<0.05).

Conclusion:
Our findings demonstrate that BC survivors have an augmented sympathetic neural activity, endothelial dysfunction, and attenuated exercise capacity, which may help to explain, at least in part, the increased CV risk in this population. Therefore, it is urgent to establish therapeutic strategies (e.g., physical exercise rehabilitation) to restore or alleviate these cardiovascular changes in BC survivors.
Abstract 17580: "Healthy Smile for a Healthy Heart": A National Study on the Correlation Between Periodontal Diseases and Coronary Artery Disease
Authors: Alshami Abbas , Udongwo Ndausung , Heaton Joseph , Donley Timothy , Sealove Brett
Published: December 2023

Introduction:
Chronic inflammatory periodontal disease (CIPD) is a common disease of the supporting tissues of the teeth that manifest as swelling, bleeding, pain, and clinical attachment loss (CAL) upon periodontal examination. CIPD has been associated with a chronic inflammatory state, also a known risk factor for coronary artery disease (CAD).

Hypothesis:
There is a possible correlation between CIPD and CAD.

Methods:
We utilized the 2013-2014 National Health and Nutrition Examination Survey database. We included participants aged 30 years and above who reported having gum disease and had undergone a periodontal examination. CAL measured in millimeters, was reported at six different locations around 28 teeth. To obtain national estimates, we conducted complex survey sample analyses, accounting for weights, clustering, and strata. Furthermore, we adjusted for well-known CAD risk factors in multivariate analyses.

Results:
Our study included 184,010,722 participants; 7.3% had CAD (n=13,461,796), and 17.1% reported CIPD (n=31,425,382). Baseline Characteristics are presented in Table 1. The unadjusted rate of CAD was higher in patients with CIPD than those without CIPD [10.3% (n=3,238,995) vs 6.7% (n=10,222,801), p=0.018]. Similarly, average CAL was higher in patients with CAD (2.04 vs 1.62 mm, p<0.001). After adjusting for confounders listed in Table 1, CIPD was a significant predictor of CAD (OR 1.744, 95% CI 1.088-2.796, p=0.012). The average CAL of all the teeth also predicted CAD (OR 1.195, 95% CI 1.025-1.394, p=0.026).

Conclusions:
Our data suggest that patients with reported CIPD had a 1.7 times higher risk of developing CAD. Similarly, each 1 mm increase in CAL leads to a 20% increased CAD risk (OR 1.2). Further prospective studies are needed to confirm these findings and to explore whether treatment of CIPD mitigates the increased CAD risk. These findings underscore the significance of optimizing dental health in patients with CAD.
Abstract 17586: Physical Activity Associates With a Greater Reduction in Heart Failure Risk Among Individuals With Depression and/or Anxiety
Authors: Al-Hamam Abdulaziz , Abohashem Shady , Gharios Charbel , Zureigat Hadil , GOUDOT Guillaume , Grewal Simran , Aldosoky Wesam , Alani Omar , Osborne Michael , Tawakol Ahmed A
Published: December 2023

Introduction:
Physical activity (PA) has shown a dose-dependent reduction in the incidence of heart failure (HF) by mitigating stress-related neural activity (SNA). Accordingly, we postulated that the impact of PA on HF incidence may be more pronounced in individuals with chronic stress conditions (e.g., depression and/or anxiety) that associate with heightened baseline SNA.

Objective:
To test whether PA confers a greater reduction in HF incidence among individuals with (vs. without) pre-existing depression and/or anxiety.

Methods:
Among 48,673 participants (median age 60 years, 40% male) in the Mass General Brigham Biobank, self-reported PA data were collected through a health survey and converted to metabolic equivalent of task minutes per week. Data on incident HF, its subtypes, depression, anxiety, and cardiovascular risk factors were obtained using the International Classification of Disease Codes. Cox regression was employed to assess the association between PA and ten-year HF risk and to examine potential interactions.

Results:
PA (per each standard deviation) is independently associated with greater reductions in all HF risk among individuals with depression and/or anxiety (standardized hazard ratio [HR] [95% confidence interval (CI)]: 0.735 [0.648, 0.834], p<0.001) compared to those without depression and/or anxiety (0.821 [0.781, 0.864], p<0.001, p-interaction=0.038*). Similar associations were observed between PA and the risk of HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF) among those in whom HF could be classified, Fig1.

Conclusions:
PA is associated with greater reductions in risk of incident HF, including HFpEF and HFrEF, with the greatest reductions in those with pre-existing depression and/or anxiety. These findings highlight the potential for improved cardiovascular benefits linked to PA in individuals with elevated baseline SNA.
Abstract 17590: Association of Intensive vs Standard Blood Pressure Lowering With 1-year and 2-year Changes in Cardiac Biomarker Levels: Findings From SPRINT
Authors: Shastid Spencer L , Dalmacy Djhenne , Ascher Simon , Ballantyne Christie M , NAMBI VIJAY , de Lemos James A , Berry Jarett D
Published: December 2023

Background:
The Systolic Blood Pressure Intervention Trial (SPRINT) demonstrated that intensive systolic blood pressure (SBP) lowering was associated with marked reductions in cardiovascular disease (CVD) endpoints. We recently reported that intensive SBP lowering was also associated with a small increase in high-sensitivity cardiac troponin T (hs-cTnT) and a large decrease in N-terminal pro-B-type natiuretic peptide (NT-proBNP) over 1-year. However, data on longer term biomarker changes with intensive versus standard SBP lowering have not been previously reported.

Methods:
hs-cTnT and NT-proBNP were measured at baseline, 1 year, and 2 years from stored specimens in SPRINT participants. Changes in biomarkers were evaluated continuously on the log scale with interval censoring of participants with CVD events. The effect of intensive SBP lowering on biomarker changes was assessed using linear regression models with treatment effects reported as geometric mean ratios.

Results:
Of 9,361 SPRINT participants, hs-cTnT and NT-proBNP were measured in 8,828 (baseline), 7,887 (Year 1), and 7,463 (Year 2) free of CVD events. Intensive SBP lowering led to a 3% increase in log-transformed hs-cTnT from baseline to Year 1, but there was no significant change observed from baseline to Year 2. In contrast, intensive SBP lowering led to a consistent 10% decrease in NT-proBNP from baseline to Year 1 and to Year 2. NT-proBNP levels increased slightly from Year 1 to Year 2 in both treatment arms such that the 1-Year treatment effect for intensive SBP lowering was maintained to Year 2 (see Table).

Conclusions:
Intensive SBP lowering was associated with a transient, modest increase in hscTnT at Year 1 that was no longer present at Year 2. In contrast, intensive SBP lowering was associated with a persistent reduction in NT-proBNP at both 1 and 2 years follow-up. These findings highlight the complex responses of cardiac biomarkers to intensive SBP lowering.
Abstract 17610: A Novel Approach Using Deep Neural Networks on Clinical Cardiac MRIs Can Identify Patients With Clonal Hematopoiesis of Indeterminate Potential With High Accuracy
Authors: Ryu Allen , Christofides Anthos , Matute Martinez Carlos , Jayakrishnan Ritujith , Ahn Shawn , Ferrigno Guajardo Ana , Espinoza Jeacy , Chen Nathan , Jha Alokkumar , Im Yunju , Halene Stephanie , VanOudenhove Jennifer , MOJIBIAN HAMID , Duncan James , Dvornek Nicha , Kwan Jennifer M
Published: December 2023

Background:
Clonal hematopoiesis of indeterminate potential (CHIP) has been shown to be an independent risk factor for heart disease and heart failure. DNA sequencing is the gold standard to diagnose CHIP. It is unclear if deep learning techniques using routine clinical imaging can aid in identifying those who are likely to have CHIP and thus likely at increased risk for heart disease and heart failure.

Hypothesis:
We hypothesized that deep learning models trained on routine cardiac MRI (CMR) would be able to help predict who has CHIP

Methods:
We enrolled patients into an IRB approved study to evaluate for CHIP and associated imaging findings. Whole exome sequencing and our somatic variant pipeline was used to identify those who had CHIP. Various machine learning techniques were employed for training and testing, including SVM, random forest and convolutional neural networks (CNN) to predict who had CHIP from CMR imaging.

Results:
We enrolled 98 unique patients with CMR and found that 40 (41%) had CHIP. Majority were female 65 (66%) and there was no significant difference in median age between CHIP vs no CHIP (69, IQR 62-78 vs 65, IQR 54-72). There were no significant differences between CHIP vs no CHIP patients in co-morbidities such as CAD, DM, HTN, HF. Compared to SVM and random forest, the best performing model with high sensitivity, specificity and accuracy was derived from CNN (AUC 0.64 vs 0.71 vs 0.85 respectively). We found that multi-view MRI inputs were more accurate than single view MRI inputs for the CNN model. Using an unsupervised approach with CNN and multi-view input, we were able to predict CHIP with 82% accuracy.

Conclusions:
CNN is a promising deep learning technique that can accurately classify CHIP and thus those at higher cardiovascular disease risk. Ongoing analyses are underway to validate these findings using the UK Biobank and TOPMED datasets and predict who will develop cardiomyopathy with CHIP.
Abstract 17613: Discharge Planning and Resource Utilization for Minimizing Readmissions in Acute Exacerbation of Chronic Heart Failure: Insights From an Observational Study in a Community Hospital
Authors: Abouzid Mohamed R , Siddiqi Muhammad , Eldahtoury Samar , Ali Karim , Ghanim Mohammed , Mofleh Dania
Published: December 2023

Introduction:
This cross-sectional study aimed to analyze the discharge disposition distribution among readmitted patients in a large community facility due to acute exacerbation of chronic heart failure (AECHF) and to examine the association between sex and age and discharge disposition.

Methods:
A total of 1,584 patients aged 65 years or older with AECHF were readmitted to a large community hospital in the Southeast Texas area from April 2021-April 2022. Descriptive analysis was used to examine discharge disposition among AECHF-readmitted patients. A multinomial logistic regression model was used to assess the association between age groups (65-74, 75-85, and 85 or older) and sex (male, female) and discharge disposition. We used SAS version 9.4 to perform all analyses. We report odds ratios (ORs) and 95% confidence intervals (CIs).

Results:
Overall, 55.6% of patients had a discharge disposition to home with self-care, while 27.3% had a discharged disposition to home with external home health support and 17.1% to skilled nursing facilities. The logistic regression analysis showed no significant differences in disposition discharge when comparing the 75-85 age group (OR=0.93, 95% CI, 0.72-1.20) and the 85 or older age group (OR=1.28, 95% CI, 0.92-1.78) to 65-75 age group. Additionally, no statistically significant differences were observed by sex when comparing males to females (OR 0.99, CI 0.79-1.24).

Conclusion:
This study highlights the importance of effective discharge planning in reducing readmissions for AECHF. Gender did not significantly influence disposition distribution, suggesting that other factors play a more prominent role. Comprehensive optimal discharge planning and appropriate resource allocation, including transfer to home with home health support, skilled nursing facilities, long-term acute care, or rehabilitation, based on the patient's condition at discharge are recommended to improve patient outcomes and reduce the burden of readmissions due to AECHF.
Abstract 17627: The Relationship Between Physical Activity, Extracellular Vesicles, and Diabetes Risk in African American Women at Risk for Cardiovascular Disease: Data From a Pilot Study of the Step It Up Physical Activity Intervention
Authors: Dobrian Anca , Miller Noel , Bavuso Matthew , Vijayakumar Nithya , Neally Sam , Collins Billy , Potharaju Kameswari , Ceasar Joniqua , Curlin Kaveri , Andrews Marcus , Turner Briana , Gutierrez-Huerta Cristhian , Troendle James , Mitchell Valerie , Sampson Maureen , Remaley Alan , Baumer Yvonne , Powell-Wiley Tiffany M
Published: December 2023

Background:
Diabetes and cardiovascular disease (CVD) disproportionally affect African American (AA) women. Prior studies suggest extracellular vesicles (EV) are involved in atherogenesis, but little is known about relationships between PA and EVs in AA women. Thus, we examined associations between diabetes risk markers, EV, and PA in a community-based cohort of AA women at risk for CVD from resource-limited Washington, D.C. neighborhoods.

Methods:
Participants were enrolled in pilot testing of Step It Up, a place-tailored mobile app designed to increase PA. Baseline daily step counts for PA were measured by Fitbit® (Charge 2) and fasting baseline blood samples were cryopreserved. NMR (Nuclear magnetic resonance) spectroscopy was used to measure Lipoprotein Insulin Resistance Index (LP-IR), a diabetes risk marker. EV were isolated from heparinized plasma using size exclusion chromatography with size and numbers determined by nanoparticle tracking analysis. Associations between LP-IR, EVs, and daily step count were analyzed using multivariable regressions adjusted for BMI and ASCVD 10-year risk score.

Results:
The study cohort was a convenience sample of AA women with overweight/obesity (N=24, Age: 57±12, BMI: 35±6, ASCVD: 9±5). Smaller EV size associated with higher LP-IR (β=-0.45, p=0.04) with EV concentration trending to a positive association with LP-IR (β=0.38, p=0.08). Higher daily step count associated with larger EV particle size (β=0.48, p=0.02) but not with EV concentration. Additionally, higher daily step count associated with lower LP-IR (β=-0.42, p=0.04).

Conclusions:
Our data show that reduced EV size and increased EV concentration associate with higher LP-IR, a diabetes index among a community-based cohort of AA women. Additionally, our findings suggest that PA might help mitigate these associations. More research is needed to understand the potential impact of PA on EV, diabetes risk and subsequent CVD. Future PA interventions in at-risk patients may reduce existing diabetes and CVD-related health disparities and EVs may emerge as a mechanistic link.