bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 13130: Impact of Midregional N-Terminal Pro-Atrial Natriuretic Peptide, Soluble Suppression of Tumorigenicity 2 and Brain Natriuretic Peptide Levels on Heart Rhythm in Persistent Atrial Fibrillation Treated by Electrical Cardioversion: The Biorhythm 2 Study
Authors: Badoz Marc , Serzian Guillaume , Favoulet Baptiste , SELLAL Jean-Marc , de CHILLOU Christian , Laurent Gabriel , Ecarnot Fiona , Karine Bardonnet , SERONDE Marie France , Schiele Francois , Meneveau Nicolas
Published: June 2023

Introduction:
We assessed the impact of plasma levels of MRproANP, sST2 and BNP on the maintenance of sinus rhythm at one year after a successful electrical cardioversion of atrial fibrillation.

Methods:
Prospective, multicenter, observational study including patients undergoing electrical cardioversion of persistent AF. MRproANP, sST2 and BNP were measured in peripheral venous blood before cardioversion. Primary endpoint was recurrent AF detected during the 12 month follow-up, defined as ECG showing AF, or any AF episode lasting >30 seconds on 24 hour Holter monitoring.

Results:
We included 61 patients from 12/2017 to 03/2019. Average was 67.4±7.8 years, 46 were males (75.4%). Sinus rhythm was restored in 51 patients (83.6%). In these 51 patients, plasma concentrations of MRproANP were significantly higher among patients with recurrent AF at 12 months than among those in sinus rhythm (314.45 [210.90-342.50] vs 214.50 [138.97-264.72] pmol/L, p<0.01). There was no difference between groups in terms of sST2 and BNP concentrations. ROC curve analysis identified an MRproANP threshold of 311.5pmol/L as having the best predictive value for recurrent AF at 12 months. By multivariable analysis, MRproANP >311.5 pmol/L was found to be the sole predictor of AF recurrence (odds ratio 13.57; 95% CI, 2.01-91.54), and identified subjects at very high risk of recurrence (positive predictive value=83.3%).

Conclusion:
Elevated MRproANP level independently predicts recurrent AF, whereas sST2 and BNP levels do not appear to have any prognostic value in assessing the risk of recurrence of AF at one year after successful electrical cardioversion.
Abstract 13133: Effect of Ocedurenone in Patients With Uncontrolled Hypertension and Stage 3b/4 Chronic Kidney Disease - Subgroup Analysis of a Phase 2b Clinical Trial
Authors: Ye June , McCabe James , Benn Vincent , YANG Y Fred F , Tan Judy , Liu Jinrong , Bakris George L , Pitt Bertram
Published: June 2023

Introduction:
BLOCK-CKD is a Phase 2b, multicenter, randomized, double-blind, placebo-controlled study evaluating the safety, efficacy, and pharmacokinetics of the nonsteroidal MRA Ocedurenone (KBP-5074) in patients with stage 3b/4 CKD and uncontrolled hypertension while taking 2 or more antihypertensive medications.

Hypothesis:
Although the study is not powered for subgroup analysis, it is of interest to examine the consistency of results across various subgroups.

Methods:
Of 162 patients randomized, 138 (85.2%) completed the study. Effect of Ocedurenone on SBP reduction and serum potassium levels by baseline eGFR < 30, eGFR ≥ 30, and diabetic status was explored.

Results:
Consistent and clinically meaningful SBP reduction at Day 84 was observed in the subgroups analyzed. SBP mean (SE) change from baseline to day 84 in the eGFR < 30 group were 0.2 (3.03), -12.7 (5.45), and -15.4 (5.01) for placebo, 0.25mg, and 0.5mg doses respectively. In the ≥ 30 group, the changes were -9.7 (3.38), -10.8 (3.29), and -16.1 (4.08), respectively. In the diabetic patient group, the changes were -4.2 (4.22), -11.8 (5.91), and -13.0 (6.5) respectively. In the non-diabetic patient group, the changes were -6.0 (2.93), -11.4 (3.34), and -17.1 (3.51) respectively. Similar small dose-dependent increases in serum potassium were observed in nearly all subpopulations. Changes from baseline to day 84 in SBP by baseline eGFR and diabetic status and the corresponding changes in serum potassium and eGFR by baseline eGFR and diabetic status are shown in Figure 1.

Conclusions:
In this Phase 2 trial, the effect of Ocedurenone on SBP reduction and serum potassium levels was consistent among clinically important subgroups. Due to the relatively small number of patients these conclusions need to be confirmed in the larger ongoing Phase 3 trial.
Abstract 13134: Weight Neutral Intervention Improves Metabolic Syndrome Status in Family Caregivers
Authors: Frediani Jennifer K , Higgins Melinda K , Butts Brittany N , Gary Rebecca , Hepburn Kenneth , Dunbar Sandra B
Published: June 2023

Introduction:
Weight neutral approaches to obesity management may be more effective than traditional weight loss programs. Weight neutral approaches include self-esteem improvement, intuitive eating, and sustainable physical activity (PA) and can reduce cardiometabolic markers without significant weight loss.

Hypothesis:
We hypothesize that psychoeducation plus exercise intervention will improve cardiometabolic biomarkers related to metabolic syndrome (MetS).

Methods:
This secondary data analysis from a randomized controlled intervention trial of sedentary family care givers aimed to improve perceptions of caregiving and physical function. A subgroup of the original trial was studied: the psychoeducation group (PE) and psychoeducation plus exercise (PE+EX) groups and those that had blood glucose above 90 ng/dL. The PE group received printed and video instructions of stretching and a 4-week self-care intervention. The PE+EX group received the same plus a 12-week aerobic and resistance PA program. Measurements were at baseline (BL) and 6 months. Univariate comparisons between treatment groups at 6 months were reported.

Results:
Participants (n=74) had a mean age of 57 years, 87% female, 74% Black, 69% were college educated, mean body mass index (BMI) of 32.3 kg/m2 at BL which did not change significantly by 6m (BMI 32.1, paired t-test p=0.186). Of the 23 that had MetS at baseline in the PE group, 13 (57%) no longer had MetS at 6 months and 2 (13%) worsened. In the PE+Ex group, 12 of the 18 (68%) no longer had MetS at 6 months and 3 (17%) worsened. Overall, there was a positive change in MetS status between BL and 6 months (McNemar’s p<0.001). Of all MetS components, waist circumference (WC) showed significant improvement (14.8% with at risk waist circumference improved, p=0.021). Overall, 39 of 74 (53%) decreased their MetS risk by 1-3 factors from BL to 6 months (Wilcoxon, p<0.001). There was no significant difference between the groups (p=0.358).

Conclusions:
We conclude that a psychoeducation intervention either alone or with an exercise component showed improvement in MetS status. Future studies should design weight neutral interventions with the intent on changing behavior around diet and exercise combined.
Abstract 13146: Cardioprotective Effects of Mtss1 Reduction in Dilated Cardiomyopathy
Authors: Choe Dongwook , Brandimarto Jeffrey A , Petrenko Nataliya , Marti-Pamies Ingrid , Burke Megan , Lv Wenjian , Day Sharlene , Musunuru Kiran , Wang Xiao , Cappola Thomas P
Published: June 2023

Introduction:
MTSS1 is an I-BAR protein that interacts with the actin cytoskeleton and the cell membrane and is speculated to play a role in cell motility, tumor metastasis, and cardiogenesis. Enhancer variants that reduce the expression of MTSS1 in the human left ventricle have been associated with cardioprotective traits in genome-wide association studies. However, the effect of MTSS1 downregulation on the development of heart disease has not been studied in experimental models. Here we tested the hypothesis that reduction of MTSS1 protects against dilated cardiomyopathy (DCM) in vitro and in vivo.

Methods:
We used CRISPR-Cas9 to knock out MTSS1 in induced pluripotent stem cells (iPSCs) harboring pathogenic variants from patients with severe DCM. DCM iPSC lines with and without MTSS1 were then differentiated into cardiomyocytes and phenotyped in vitro. A DCM mouse model containing a TPM1 D230N transgene was crossed with a mouse model heterozygous for Mtss1 knockout. Progeny from this F1 cross were assessed for differences in cardiac structure and function via echocardiography.

Results:
MTSS1 deletion restored the beta-adrenergic response in DCM iPSC cardiomyocytes. In parallel, Mtss1 deletion partially rescued DCM-associated phenotypes including left ventricular dilation and reduced ejection fraction in mice.

Conclusions:
Our initial results suggest a causal link between MTSS1 reduction and cardioprotection in DCM. Inhibiting cardiac MTSS1 may hold therapeutic potential for DCM, though the cellular mechanisms through which MTSS1 affects cardiac phenotypes remain under investigation.
Abstract 13198: Cardiac TRPC6 N338S is a Gain-of-Function Mutation Associated With Doxorubicin-Induced Cardiomyopathy
Authors: Lu Tong , Norton Nadine , Lee Hon-chi
Published: June 2023

Introduction:
Doxorubicin (DOX) is widely used for chemotherapy, but cardiotoxicity and cardiomyopathy are major adverse effects. The canonical transient receptor potential 6 gene (
TRPC6)
is a putative risk gene for cardiomyopathy. Recently, a TRPC6 N338S mutation was found in a patient with DOX-induced heart failure. However, the TRPC6 N338S mutant has not been characterized, and how it affects cardiac function is unknown.

Hypothesis:
We hypothesized that TRPC6 N338S is a gain-of-function mutation producing intracellular Ca
2+
overload in cardiomyocytes.

Methods:
Using patch clamp recording, molecular biological and molecular docking analyses, we assessed the function of TRPC6 N338S heterologously expressed in HL-1 cardiac cells.

Results:
TRPC6 N338S significantly increased the current densities of TRPC6 (defined as 1 μM BI-749327 sensitive components, a highly selective TRPC6 inhibitor) in HL-1 cells at baseline and after exposure to 50 μM 1-oleoyl 2-acetyl-sn-glycerol (OAG, an activator of TRPC6), compared to cells expressing TRPC6 WT. Moreover, a 24-h pretreatment with 0.5 μM DOX further potentiated the OAG effects on TRPC6 WT currents with a significantly greater response in the N338S currents. Ca
2+
imaging also showed enhanced intracellular Ca
2+
levels in cells expressing the N338S mutant with OAG and DOX treatment. Biological studies found that the cytoplasmic and surface expression of TRPC6 WT and N338S mutant were identical in HL-1 cells, but those of TRPC6 N338S were markedly upregulated after treatment with 0.5 μM DOX, compared to TRPC6 WT. Molecular docking and dynamics simulation analysis unraveled that OAG binds to a pocket constituted by the pore-helix, S5 and S6 domains of TRPC6 through polar interactions. OAG binds to the same site in TRPC6 N338S with shortened interfacial distances due to additional polar and hydrogen bonding between OAG and the N338S mutant.

Conclusions:
TRPC6 N338S mutation strengthens the interaction with OAG, stabilizes the OAG-TRPC6 N338S complex, and enhances the OAG effects. Treatment with DOX significantly increases the expression and function of TRPC6 N338S in HL-1 cells. Hence, the TRPC6 N338S is a gain-of-function mutation and may contribute to cardiotoxicity in patients with anthracycline treatment.
Abstract 13235: Ischemic Preconditioning and Lazaroid (u-74389g) Administration Similarly Attenuate Ischemia-Reperfusion-Induced Spinal Cord Inflammatory and Apoptotic Responses by Targeting the S100-Receptor for Advanced Glycation End Product Pathway
Authors: Tsoporis James N , Ektesabi Amin , Izhar Shehla , dos Santos Claudia , Parker Thomas G , Leong-Poi Howard , Rizos Ioannis K , Apapalois Apostolos E , Toumpoulis Stavros K , Toumpoulis Ioannis K
Published: June 2023

Introduction:
Spinal cord injury and subsequent paraplegia represents a devastating complication of thoracoabdominal aortic surgery. Pro-inflammatory cytokine expression and spinal cord neuronal apoptosis have been implicated in inflammation and neurodegeneration respectively after ischemia.

Hypothesis:
We investigated the neuroprotective effects of the steroid antioxidant Lazaroid U-74389G versus conventional ischemic preconditioning (IPC) in a pig model of spinal cord ischemia-reperfusion injury by examining the expression of pro-inflammatory and pro-apoptotic S100 members and the receptor for advanced glycation end products (RAGE).

Methods:
Spinal cord ischemia was induced by thoracoabdominal aortic occlusion (TAO). A total of 27 pigs were randomized in four groups. Group I (n=5) sham operation, group II (n=7) TAO for 45min and received placebo, group III (n=8) received 3 doses of Lazaroid (3 mg/kg) 60min and 30min before and at 30min during TAO (duration 45min), and group IV (n=6) TAO for 20min followed by additional TAO for 45min and 80 minutes later. Neurologic evaluation was performed according to Tarlov score (0-4, 4=normal). The lumbar spinal cords were harvested at 7th postoperative day for the expression of inflammatory and apoptotic markers by real-time RT-PCR.

Results:
Group III and IV had better neurologic outcome postoperatively compared to group II where all animals developed paraplegia (Tarlov scores: 3.5 versus 3.6 versus 0.33, respectively, P<0.001). Group II showed marked pro-inflammatory responses as quantified by 2-4-fold increases in the mRNA of pro-inflammatory S100A6, S100A8 and high-mobility group box 1, and RAGE, compared to group I. Additionally, group II, exhibited apoptosis as quantified by a 40-60% decrease in the mRNA of anti-apoptotic BCL2 and BIRC2, and 2-3-fold increases in pro-apoptotic BAX mRNA and caspase 3 activity. Compared to group II, inflammatory and apoptotic responses were highly attenuated albeit to a similar degree in groups III and IV.

Conclusions:
In a large animal model very close to the clinical setting, we demonstrated that in addition to IPC, Lazaroid represents an alternative yet effective pharmacologic intervention in reducing spinal cord ischemia-reperfusion injury following TAO.
Abstract 13277: Hiv and Race Are Independently Associated With Endothelial Dysfunction
Authors: Mouchati Christian , Durieux Jared , Zisis Sokratis N , McComsey Grace A
Published: June 2023

Objective:
Assessing the vascular function in HIV
+
compared to HIV
-
with assessment of body composition, inflammation, and gut integrity markers.

Introduction:
HIV and ART are associated with an increased risk of CVD. Thus, the need for a non-invasive test to detect increased risk or early signs of CVD.

Hypothesis:
HIV and non-white race are independently associated with vascular dysfunction. High viral load, BMI, and inflammation damage endothelial function.

Methods:
We included participants ≥18 years, with peripheral arterial tonometry testing (EndoPAT2000) between 2014-2022. HIV
+
had a stable ART regimen, and a VL ≤400 c/mL. We measured the vessel’s adaptability with Reactive Hyperemia Index (RHI) (normal>1.67) and elasticity with Augmentation Index (AI) (normal<-10). We assessed markers of systemic inflammation, immune activation, and gut integrity. We used linear mixed models to estimate endothelial dysfunction with a significant p-value<0.05.

Results:
Overall, 511 participants (296 HIV+ and 215 HIV-) were included. The estimated RHI among HIV+ was 13% lower (p=0.01) compared to HIV-. In Non-White, the estimated RHI was 9% lower (p=0.001) than in White. Every 1% increase in BMI we would expect RHI to increase 0.17% (p=0.01). At the time of EndoPAT, the estimated RHI was 8% lower (p=0.04) among PI antiretroviral therapy use compared to HIV+ who were taking NRTI or NNRTIs. The estimated odds of having endothelial dysfunction (RHI ≤ 1.67) is 1.56 times greater (95% CI: 1.05, 2.31) in Non-White compared to White, independent of HIV status [OR=1.4 (95% CI: 0.94, 2.13)]. There was not enough evidence to suggest that inflammation, gut, or monocyte markers, current or nadir CD4, duration of HIV, or current treatment with NRTI or NNRTIs at the time of EndoPat was associated with endothelial dysfunction.

Conclusions:
HIV and non-white race are independently associated with endothelial dysfunction. PI use was associated with vascular dysfunction in all racial groups.
Abstract 13280: Proteomic Indicators of Cardiovascular Health Relate to Brain Volume and Dementia Risk
Authors: Dark Heather E , Paterson Clare , Peng Zhongsheng , Duggan Michael R , Daya Gulzar N , Bilgel Murat , An Yang , Moghekar Abhay , Davatzikos Christos , Resnick Susan , Loupy Kelsey , Simpson Missy , Mosley Thomas , Coresh Josef , Williams Stephen A , Walker Keenan A
Published: June 2023

Introduction:
Several studies demonstrate that cardiovascular (CV) health - even among individuals without overt CV disease - is associated with brain function and may influence Alzheimer’s disease (AD) and dementia progression. Using a proteomic score to quantify the full spectrum of CV health, the current study examined the association of protein-based indicators of CV risk and CV-related mortality with brain structure and dementia risk among older adults.

Methods:
The SomaScan platform was used for plasma proteomic phenotyping in the Baltimore Longitudinal Study of Aging (BLSA) (n=984) and the Atherosclerosis Risk in Communities (ARIC) study (n=7901). SomaSignal Test measures of risk for CV events, and heart failure-related mortality were derived from the proteome. Concurrent with blood-draw for proteomic assessments, BLSA participants received 3T brain MRI scans, which quantified AD-relevant brain atrophy (SPARE-AD) and total brain volume (TBV). Following protein measurement at Visit 3, ARIC participants were followed for 20+ years, during which time incident dementia was assessed. We used demographic-, intracranial volume, and
APOE
ε4-adjusted linear regression and Cox models to relate proteomic indicators of CV health to brain volume and dementia risk, respectively.

Results:
Protein-based risk for CV events and heart-failure mortality were each associated with greater brain atrophy in regions vulnerable to AD and lower total brain volume (
Figure 1
). Higher risk scores for CV events and both preserved and reduced ejection fraction heart failure mortality were associated with incident dementia (HR per z-score increase (95% CI): 1.26 (1.20-1.33), 1.18 (1.12-1.23) and 1.27 (1.22-1.32), respectively, all p < 0.001).

Conclusions:
Proteomic indicators of risk for CV disease/mortality are associated with neurodegeneration and future dementia risk. Proteomic indicators of CV health may aid in monitoring and prediction of neurodegenerative disease.
Abstract 13294: Role of Retrospective Cardiac Computed Tomography Angiography in the Detection of Prosthetic Valve Endocarditis
Authors: Alonso Mileydis , Neicheril Radhika , Seijo De Armas Yelenis , Perez Eduardo , Navia Jose L , Lopez David
Published: June 2023

Case presentation
A 47-year-old man was readmitted for evaluation of recurrent fevers, night sweats, and weight loss over a 3 month period. He had a history of bioprosthetic aortic and mitral valve replacements for rheumatic valve disease and heart failure with reduced ejection fraction due to non-ischemic cardiomyopathy. Physical examination was remarkable for a[LMD1] grade II/VI systolic murmur. Laboratory notable for neutrophilic leukocytosis elevated C-reactive protein and erythrocyte sedimentation rate. Blood cultures demonstrated
Staphylococcus epidermidis
. On transthoracic echocardiogram (TTE) performed in the current admission and transesophageal echocardiogram (TEE) done 2 months prior the prosthetic valves were not clearly visualized, but there was no regurgitation, stenosis or vegetation noted. Due to a high index of suspicion for prosthetic valve endocarditis (PVE), a retrospectively gated cardiac computed tomography angiography (CCTA) of the entire cardiac cycle was performed. It revealed a 13 mm mobile vegetation attached to the ventricular side of the left coronary cusp (Figure 1). Subsequently, the patient underwent a redo aortic valve replacement. Blood cultures cleared and the patient was discharged on hospital day 16 to complete 6 weeks of Cefazolin and Rifampin.

Discussion:
The modified Duke criteria play an important role in the diagnosis of native valve infective endocarditis (IE) (~ 80% sensitive), but it carries a lower diagnostic yield in the detection of PVE. While TEE carries high accuracy in the diagnosis of native valve endocarditis, approximately 30% of patients with PVE and/or intra-cardiac devices have inconclusive or normal echocardiographic findings. Inability to recognize IE in a timely fashion (<4 days) leads to greater embolic events. We showed how CCTA can be used to expedite the diagnosis of PVE.
Abstract 13324: Impact of Chronic Electronic Cigarette Vapor Exposure on the Recovery of Cardiovascular Function in Experimental Rat Myocardial Ischemia/Reperfusion Model
Authors: Dai Wangde , Shi Jianru , Zhao Lifu , Carreno Juan , Kleinman Michael T , Herman David , Arechavala Rebecca J , Renusch Samantha , Hasen Irene , Ting Amanda , Kloner Robert A
Published: June 2023

Background:
The impact of long-term electronic cigarettes (E-cig) vaping on cardiovascular function in rats were investigated.

Methods:
Sprague Dawley rats (both sex, 6 weeks old) were randomly exposed to filtered air (n=32), E-cig with nicotine (E-cig Nic
+
, n=26), E-cig without nicotine (E-cig Nic
-
, n=26), or standard cigarette smoke (n=31). After exposure to inhalation exposure for 8 weeks, the rats were subjected to 30 minutes of left coronary artery occlusion followed by 3 hours of reperfusion. Cardiovascular function was measured with intracavitary Millar catheters and echocardiography during the surgical procedure.

Results:
As the data shown in the Table, at 2.5 hours after coronary artery reperfusion, heart rate, cardiac output and positive/negative LV dp/dt were lower in the E-cig Nic
+
group compared to the air and/or cigarette group. LVFS in the cigarette group was higher than compared to E-cig Nic
+
or air group. There was a significantly higher systemic arterial resistance in the E-cig Nic
+
group compared to the cigarette group.

Conclusions:
Chronic E-cig Nic
+
exposure impairs the cardiovascular function recovery during the phase of coronary artery reperfusion after heart attack, indicated by reductions of heart rate, cardiac output, LV positive and negative dp/dt (suggesting a reduction in contractility and relaxation); and increase in systemic arterial resistance in the setting of experimental acute myocardial infarction compared to air and/or standard cigarette smoke.
Abstract 13329: Intralipid Protects the Heart in Late Pregnancy Against Ischemia/Reperfusion Injury via Inducing Mir122 by Targeting Pkm2
Authors: Aryan Laila , Medzikovic Lejla , Li Min , Ruffenach Gregoire , Rahman Shadie , Bastanhagh Ehsan , Esdin Leana , Sun Wasila , Eghbali Mansoureh
Published: June 2023

INTRODUCTION:
We have shown hearts of late-pregnant (LP) rats have higher vulnerability to ischemia-reperfusion injury (IRI) compared to non-pregnant (NP) rats, and administration of intralipid (ITLD), a clinically safe fat emulsion, at the onset of reperfusion protects the LP rat heart against IRI. Our goal is to decipher the mechanisms for the ITLD-mediated cardioprotection in LP against IRI.

Methods:
We occluded the left anterior descending coronary artery of female Sprague-Dawley rats (2-3 months old NP and LP, 20-21 days pregnant) for 45 minutes followed by 3 hours reperfusion. The ITLD group was given ITLD at the onset of reperfusion (5mg/kg of 20%). We assessed myocardial necrosis via TTC staining and sent the hearts for microRNA-microarray profiling (Ocean Ridge Biosciences). In vitro, female cardiomyocytes were transfected either miR122 mimic, miR122 inhibitor, or scramble control (40uM), followed by 3 hours hypoxia and 6 hours reoxygenation. We collected human blood samples from NP, LP, and LP coronary heart disease (CHD) patients. P<0.05 was considered statistically significant. Values are expressed as mean±SEM.

Results:
MicroRNA-microarray profiling showed microRNA-122-5p (miR122) is downregulated 4-fold in the heart of LP rats subjected to IRI compared to healthy pregnant rats and upregulated 10-fold in the heart of LP rats that received ITLD at reperfusion, which we confirmed with qPCR (0.32±0.12, 90.2±10.3, n=5 animals/group). miR122 is significantly decreased in the plasma of healthy LP women compared to healthy NP women (0.6±0.16, LP n=9, NP n=7) and decreased in LP women with CHD compared to healthy LP (0.43±0.13, CHD n=5). TargetScan showed PKM2 to be a target of miR122. We confirmed significantly increased PKM2 in LP IRI rat myocardium compared to NP IRI (1.88±0.32) and significantly decreased in LP IRI rat administered ITLD (0.32±0.18). MiR122 overexpression in female cardiomyocytes subjected to hypoxia/reoxygenation (H/R) significantly decreased PKM2 (0.35±0.12), apoptosis (0.77±0.12) and oxidative stress (0.51±0.12), while miR122 knockdown expressed the opposite effect (n=4).

Conclusions:
Intralipid protects the heart in late pregnancy against ischemia/reperfusion injury by upregulating miR122, which targets PKM2.
Abstract 13334: Whole Blood Multi-Omic Characterization of the ISCHEMIA Cohort Reveals Vulnerable and Resilient Subtypes of Chronic Coronary Disease
Authors: Cornwell Macintosh G , Chen Ze , Kullo Iftikhar J , McManus Bruce M , Newby L Kristin K , Held Claes , Bangalore Sripal , Maron David J , Hochman Judith S , Reynolds Harmony R , Berger Jeffrey S , Newman Jonathan D , Ruggles Kelly V
Published: June 2023

Introduction:
Chronic coronary disease (CCD) is a leading cause of death worldwide. Whole blood (WB) transcriptomic (RNA-seq) and methylation ‘omics’ data can discern molecular underpinnings of CCD and create molecular subtypes to aid risk prediction.

Methods:
Of 1,064 participants with moderate-severe ischemia (Age: 67.1±6.2, 19.4% Female, 17% non-White) from the ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) biorepository, 646 participants had available WB RNA-seq and 737 had WB methylation data (
Fig 1A
). Unsupervised clustering and differential analyses identified omics-derived molecular subtypes. We identified co-regulated gene modules of each subtype, performed subtype-level enrichment of clinical variables, and performed Kaplan-Meier analyses for time to cardiovascular (CV) death or myocardial infarction (MI).

Results:
Multi-omic analysis revealed 4 RNA-seq-derived subtypes (RS) and 3 methylation-derived subtypes (MS). RNA-seq Subtype 1 (RS1) was enriched for molecular drivers indicative of an adaptive immune response, had clinical enrichment of female sex, statin use, and greater ischemia, and had decreased risk of CV death or MI (
Fig 1B
). RNA-seq Subtype 2 (RS2) was enriched for innate immune response pathway, and patients who were older and White, and was associated with increased risk of CV death or MI. Similarly, methylation subtypes also yielded a high-risk subtype (MS3) and a low-risk subtype (MS2) (
Fig 1C
). Integration of transcriptomic and methylomic subtypes led to further distinction of resilient and vulnerable subgroups.

Conclusions:
WB RNA-seq and methylation data identified molecularly-defined subtypes that informed the underlying disease pathology of CCD patients in ISCHEMIA. These subgroups were differentially enriched for clinical characteristics and event outcomes, demonstrating the potential use for blood-based omics tests to aid in the prognosis of CCD.
Abstract 13353: Association of Plasma Metabolites With Inflammatory Markers CRP and GlycA and Their Responses to Exercise Training
Authors: Hoffmann William G , Barber Jacob L , Dev Prasun , Clarkson William A , Cai Guoshuai , Rao Prashant , Mi Michael , Katz Daniel H , Ghosh Sujoy , Clish Clary , Robbins Jeremy M , Bouchard Claude , Gerszten Robert E , Sarzynski Mark A
Published: June 2023

Introduction.
C-reactive protein (CRP) and GlycA are established biomarkers of inflammation. Regular exercise tends to decrease CRP and GlycA levels. However, the spectrum of molecules associated with the anti-inflammatory effects of regular exercise are less well understood.
Hypothesis.
We hypothesized that distinct metabolite signatures exist for both baseline levels and exercise responsiveness of CRP and GlycA.
Methods.
Measures were performed before and after 20 weeks of endurance exercise training in 652 Black and White adults from the HERITAGE Family Study. A total of 300 targeted plasma metabolites were measured using LC-MS. High-sensitivity CRP and GlycA were measured using automated assays and NMR spectroscopy (LabCorp), respectively. Linear mixed models were used to test: 1) Association of
baseline
metabolites with
baseline
hsCRP and GlycA and 2) Association of
changes
in metabolite with
changes
in hsCRP and GlycA. Models were adjusted for age, sex, race, BMI, with family membership as a random variable, with change models also adjusting for baseline trait value. Significance was determined as FDR<0.05.
Results.
Baseline levels and changes of hsCRP and GlycA were moderately correlated (r=0.51 and 0.31, p<0.0001 for both, respectively). At baseline, 40 and 94 metabolites were associated with hsCRP and GlycA, respectively, with 30 metabolites associated with both phenotypes. The top baseline associations for both traits included multiple species of lysophosphatidylcholine (LPC) and phosphatidylethanolamine (PE), while cortisol, biliverdin, and bilirubin were among the metabolites associated with GlycA only. The changes in only one metabolite were associated with concomitant changes in CRP, while no associations were found for change in GlycA.
Conclusions.
Plasma metabolite associations with baseline hsCRP overlapped with those associated with baseline GlycA levels. Several unique metabolite associations with baseline GlycA were identified, including molecules in established inflammatory pathways. Metabolite changes with exercise were not associated with changes in either measure. These findings have implications for the use of metabolites as signatures of systemic inflammation vs as targets of lifestyle interventions.
Abstract 13369: Takotsubo Cardiomyopathy Following Electroconvulsive Therapy
Authors: Girard Andrew A , Hammock James , Ives Christopher , Camacho Roberto
Published: June 2023

Case Presentation:
A 71-year-old woman presented to our institution for treatment-refractory depression requiring electroconvulsive therapy (ECT). She underwent a transthoracic echocardiogram (TTE) during a pre-ECT evaluation, which demonstrated no regional wall motion abnormalities and a left ventricular ejection fraction (LVEF) of 60 - 65%. The patient subsequently underwent ECT. During the procedure, sinus tachycardia with associated ST-segment changes were noted on telemetry. Esmolol was administered with subsequent improvement in her tachycardia, however ST-segment changes persisted. A twelve-lead electrocardiogram was obtained and was notable for new T-wave inversions in leads V1-V4 and Q-waves in leads III and aVF. However, STEMI criteria was not met. A TTE obtained shortly after her ECT demonstrated ballooning of the LV apex and an LVEF of 35%, consistent with takotsubo cardiomyopathy. Laboratory evaluation was notable for a high sensitivity troponin peak of 130 ng/L and a brain natriuretic peptide level of 746 pg/mL. Cardiac catheterization was not performed as the patient had a negative stress test prior to admission. The patient’s symptoms improved over the next two days, and she was discharged with close outpatient follow-up.

Discussion:
Takotsubo cardiomyopathy occurs following physical or psychological stress. Greater than half of patients with takotsubo cardiomyopathy have neurologic or psychiatric disorders. Takotsubo cardiomyopathy is an increasingly recognized serious complication of ECT and can be seen in post-menopausal women with depression. The introduction of beta blocker therapy has been used to prevent recurrent episodes of post-ECT takotsubo cardiomyopathy. Despite this, there are reports of post-ECT takotsubo cardiomyopathy in patients on chronic beta blocker therapy. Thus, the risks and benefits of proceeding with additional ECT treatments must be weighed after an initial episode of takotsubo cardiomyopathy.
Abstract 13377: Modulating Mitochondrial Phosphate Transport Shapes Intracellular Ca Signaling to Impact Arrhythmogenesis
Authors: Deb Arpita , Knollmann Bjorn C , Liu Bin
Published: June 2023

Introduction:
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a stress-induced arrhythmic syndrome due to genetic defects of the sarcoplasmic reticulum (SR) Ca release channel complex of ryanodine receptor 2 (RyR2). Our recent study suggests that mitochondria function as a Ca buffer to absorb RyR2-mediated aberrant Ca release and thus mitigate its detrimental consequences in CPVT. Mitochondrial phosphate (Pi) transport has been shown to play a role in both mitochondrial Ca uptake and buffering.

Hypothesis:
We hypothesize that modulating mitochondrial Pi transport impacts arrhythmogenesis in CPVT by altering mitochondrial Ca uptake and buffering.

Methods:
Ventricular myocytes were isolated from a genetic CPVT model of CASQ2 knockout (Cnull) mouse. Fluorescent imaging experiments were performed with live cells to examine intracellular Ca dynamics and cellular arrhythmic burden. Mitochondrial Pi transport was modulated by a pharmacological inhibitor or manipulating cytosolic Pi concentration.

Results:
In the presence of β agonist isoproterenol, an inhibitor of mitochondrial Pi carrier N-ethylmaleimide (NEM) significantly exacerbated Ca handling of intact Cnull cells, resulting in more than 60% of cells displaying pacing-independent Ca oscillations. The NEM treatment also significantly increased the amplitude of cytosolic Ca transient and SR Ca content. Consistent with results obtained in intact cells, NEM treatment exacerbated arrhythmogenic Ca waves and reduced mitochondrial Ca uptake in permeabilized Cnull cells. Moreover, inhibiting mitochondrial Pi transport by lowering cytosolic Pi concentration also increased the frequency of Ca waves and reduced mitochondria Ca uptake in permeabilized Cnull cells. On the contrary, increasing cytosolic Pi concentration reduced the frequency of Ca waves and increased mitochondrial Ca uptake in permeabilized Cnull cells.

Conclusions:
Modulating mitochondrial Pi transport impacts arrhythmogenesis in CPVT cells through altering mitochondrial Ca uptake and buffering. Enhancing mitochondrial Pi transport may represent a promising therapeutic strategy to reduce arrhythmogenic Ca waves and cardiac arrhythmias in CPVT.
Abstract 13378: Association Between Social Connection and Biological Age as Determined by Artificial Intelligence-Enabled Electrocardiography
Authors: Rajai Nazanin , Medina-Inojosa Jose R , Sheffeh Mohammad Ali , Baez Suarez Abraham , Nyman Mark A , Attia Zachi , Lerman Lilach O , Medina-Inojosa Betsy , Lopez-Jimenez Francisco , Lerman Amir
Published: June 2023

Introduction:
Increasing evidence unravels the role of loneliness and social connection in cardiovascular diseases potentially mediating accelerated biological aging. The present study aims to explore the association between social connection and biological aging as determinate by artificial intelligence-enabled electrocardiography (ECG).

Methods:
This is an observational retrospective cohort of adults aged ≥18 seen at Mayo Clinic from 2019-2022 who completed the social determinants of health questionnaire and had a 12-lead ECG within one year of completing the questionnaire. Five questions were asked to understand each patient’s
social connection
. The answers were scored to assess their level of social connection from socially isolated (score of 0) to socially connected (score of 4). The biological age was predicted from ECGs using the previously developed convolutional neural network (AI-ECG age). Delta age (Δage) was defined as AI-ECG age minus chronological age, where positive values reflect an older than expected age.

Results:
We included 280,323 subjects (chronological age 59.7±16.4 years, 51% female). The average AI-ECG age was 59.5±13.5 year. Better social connection status correlated with lower delta age (β=-0.33 (95%CI, -0.38 and -0.28, p<0.001, adjusted to chronological age and sex). Conversely, individuals reporting the least social connection were an average of 2 years older than expected whereas those with the most social connection were 2 years younger than expected by AI-ECG (Figure 1).

Conclusions:
Social connection is strongly associated with slower biological aging compared to chronological aging, independent of the conventional cardiovascular risk factors. This observation underscores the need to address social connection as a healthcare determinant.
Abstract 13388: Age-Stratified Sex Differences in COVID-19 Hospital Outcomes
Authors: Chu Jian , Brandon Margaret , Wang Sven , Shah Manali , Du-Fay-de-Lavallaz Jeanne , Volgman Annabelle S , suboc tisha , Williams Kim A
Published: June 2023

Introduction:
Sex differences in COVID-19 outcomes are well-known and have been ascribed to numerous factors including age-dependent sex hormones. We hypothesize that the protective effect of female sex in hospitalized COVID-19 patients attenuates with age.

Methods:
We retrospectively analyzed patients who were hospitalized for COVID-19 infection at three hospitals of the Rush University System for Health (RUSH) (Chicago, IL) between March to December 2020. The primary endpoints were in-hospital mortality and major adverse cardiovascular events (MACE), defined as a composite of acute myocardial infarction, cardiac arrest, acute heart failure, and stroke. Stratified logistic regression was performed to estimate the odds ratios of these endpoints in male compared to female patients by age group (<45, 45-55, 55-65, 65-75, and ≥75 years).

Results:
Of 1705 patients (age 58.1±16.9 years, 54.3% male, 24.6% White) who were hospitalized for COVID-19 infection, 179 (10.5%) patients experienced in-hospital mortality and 290 (17.0%) patients experienced MACE, respectively. The incidence of these outcomes progressively increased with age in both sexes. In patients <45 years of age, there was a trend towards increased risk for in-hospital mortality (aOR 4.47; 95% CI: 0.54 - 42.38) and MACE (aOR 2.43; 95% CI: 0.97 - 6.10) in men compared to women. However, this trend attenuated with increasing age strata and there was a slight decrease in risk for in-hospital mortality (aOR 0.79; 95% CI: 0.39 - 1.58) and MACE (aOR 0.70; 95% CI: 0.38 - 1.28) among middle-aged (55-65 years of age) men compared to women.

Conclusions:
In this multi-hospital registry of COVID-19 patients, there was a reverse J-shaped trend in odds of in-hospital mortality and MACE in men compared to women. Female sex appeared to be an independent protective factor for adverse hospital outcomes among patients <55 years of age but not among older patients, suggesting a protective role of premenopausal sex hormones.
Abstract 13415: Coronary Calcium Score on Standard of Care Oncologic CT Scans for the Prediction of Adverse Cardiovascular Events in Patients With Non-Small Cell Lung Cancer Treated With Concurrent Chemoradiotherapy
Authors: Koutroumpakis Efstratios , XU TING , Lopez-Mattei Juan , Gilchrist Susan , Corrigan Kelsey , Pan Tinsu , Lu Yang , Mohan Radhe , Zhang Xiaodong , Meng Qing , Lin Ruitao , Xu Tianlin , Deswal Anita M , Liao Zhongxing
Published: June 2023

Introduction:
Chemoradiotherapy (CRT) has been associated with increased incidence of cardiovascular (CV) adverse events (CAE) including coronary events. Coronary calcium scoring (CAC) has shown to predict coronary events beyond the traditional CV risk factors. This study examines whether CAC, measured on standard, non-gated, non-contrast chest CT (NCCT) imaging, predicts the development of CAE in patients with non-small cell lung cancer (NSCLC) treated with CRT.

Methods:
Patients with NSCLC who were treated with CRT at MD Anderson Cancer Center from 7/2009 until 4/2014 and who had at least one NCCT scan within 6 months from their first CRT were identified. CAC scoring was performed on NCCT scans by an expert cardiologist and a cardiac radiologist following the 2016 SCCT/STR guidelines (software: Syngo.Via, Siemens Healthcare). CAE were graded based on the most recent Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. CAE were also grouped into i. coronary/vascular events ii. arrhythmias iii. heart failure or iv. pericardial disease. All CAE were adjudicated by a board-certified cardiologist.

Results:
Out of a total of 193 patients, 45% were female and 91% were white. Median age was 65 years (IQR: 58-72) and median BMI was 27 kg/m
2
(24-32). Of 193 patients, 142 (74%) had CAC > 0 Agatston units (AU), 93 (48%) had CAC
>
100 AU and 36 (49%) CAC
>
300 AU. Twenty-nine patients (15%) developed a grade
>
2 CAE during a median follow up of 26.2 months (12.7-53.5). Of those, 11 (38%) were coronary/vascular events. In the multivariate cox regression analysis, controlling for mean heart dose and pre-existing heart disease, higher CAC was independently associated with development of a grade
>
2 CAE (HR: 1.04, 95% CI: 1.01-1.08, p=0.022) and with worse OS (CAC
>
100 AU, HR: 1.64, 95% CI: 1.11-2.44, p=0.013). In a sub-analysis evaluating the type of the CAE, it was the coronary/vascular events that were significantly associated with higher baseline CAC (median: 676 AU vs 73 AU, p=0.035).

Conclusions:
CAEs are frequent in patients with NSCLC treated with CRT. CAC calculated on “standard of care” NCCT can predict the development of CAEs and specifically coronary/vascular events, as well as OS, independently from other traditional risk factors and radiation mean heart dose.
Abstract 13427: Bleeding in Morbidly Obese Patients Treated With Direct Oral Anticoagulants Compared to Warfarin: The Michigan Anticoagulation Quality Improvement Initiative Experience
Authors: Ardeshna Nelish , Feldeisen Thane , Kong Xiaowen , Haymart Brian , Ali Mona , Shah Vinay , Barnes Geoffrey , Froehlich James B
Published: June 2023

Introduction:
Direct Oral Anticoagulants (DOACs) have overtaken warfarin in the treatment of non-valvular Atrial Fibrillation (AF) and venous thromboembolism (VTE). However, there is very limited data that explores the safety of DOACs for patients that are morbidly obese (BMI >40).

Methods:
In this multi-center retrospective study, we sought to use the Michigan Anticoagulation Quality Improvement registry (MAQI) to see how treatment of non-valvular AF or VTE with DOAC vs. warfarin affects bleeding in morbidly obese patients. Specifically, we compared average major, clinically relevant non-major (CRNM), and minor bleeding events per 100 patient years that were adjusted for statistically significant baseline characteristics (p<0.05).

Results:
There were a total of 1028 patients with BMI >40 included in the registry between June 2015 and September 2019. 434 patients were treated with DOACs, while 594 patients were treated with warfarin. Baseline characteristics between the two groups included age (61.5 vs 57.8, p<0.001), gender (63.6% vs 61.1% female, p=0.42), race (76.5% vs 64.3% white, p<0.001), and HAS-BLED score (2.3 vs 2.3, p=0.96). The DOAC treated group had a higher event rate of major (4.3 vs 3.7, p=0.006), CRNM (10.7 vs. 7.4, p=0.002), and minor bleeding (19.1 vs. 13.2 p<0.001) compared to the warfarin treated group.

Conclusions:
There is a higher rate of major, CRNM, and minor bleeding in morbidly obese patients treated with DOAC compared to warfarin. Further studies to compare the two anticoagulants and understand bleeding drivers in this population are needed.
Abstract 13435: Utilization of Primary Prevention Implantable Cardioverter Defibrillator (ICD) Among Older Patients With Hypertrophic Cardiomyopathy (HCM): A Real World Analysis
Authors: Goldstein Sarah A , kennedy kevin , Friedman Daniel , Al-Khatib Sana M , Wang Andrew
Published: June 2023

Introduction:
Guidelines differ for the use of primary prevention ICDs among patients with HCM, with particular ambiguity among older patients (age
>
65). This analysis examined the utilization of primary prevention ICDs among older patients with HCM.
Methods:
NCDR ICD was queried to identify patients with HCM who received a primary prevention ICD between 2010-2016. Patient characteristics were reported overall and by age category. Trends in ICD utilization and relevant patient characteristics were assessed over time.
Results:
Of 5571 patients with HCM who were included, 1511 (27.1%) were
>
65 years old. In comparison with younger HCM patients, those
>
65 had higher NYHA class (III-IV 18.9% vs 12.3%, p<0.001), and more frequently had cardiovascular and non-cardiovascular co-morbidities (atrial fibrillation (40.6% vs 19.8%, p<0.001), ischemic heart disease (24.3% vs 8.3%, p<0.001), valvular disease (12.5% vs 7.2%, p<0.001), hypertension (79.2% vs 49.5%, p<0.001), cerebrovascular disease (12.3% vs 6.5%, p<0.001), chronic lung disease (15.0% vs 7.6%, p<0.001) and diabetes mellitus (23.2% vs 12.5%, p<0.001). Analyzing risk factors for sudden cardiac death (SCD), older patients had a lower prevalence of family history of SCD (20.3% vs. 30.1%), but a higher prevalence of syncope (34.3% vs 31%, p=0.019), NSVT (50.7% vs. 38.6%) and reduced LVEF (23.1% vs. 15.3%) (p<0.001 for all). ICD utilization increased over time in all age groups, but represented a similar percentage of the overall HCM cohort irrespective of age. There were no changes in the prevalence of risk factors for SCD over time (Figure).
Conclusions:
Older patients who received a primary prevention ICD had more cardiovascular and non-cardiovascular comorbidities and higher rates of certain SCD risk factors compared with younger patients with HCM. ICD utilization among older patients with HCM increased over time at a similar rate as observed among younger patients despite stable a prevalence of SCD risk factors.
Abstract 13442: Right Ventricular Outflow Tract Doppler Notching: A Sensitive Non-Invasive Discriminator of Pulmonary Vascular Disease in Patients With Heart Failure With Preserved Ejection Fraction
Authors: Troutman Gregory S , Bhattacharya Priyanka T , Birati Edo Y , Zamani Payman L , Prenner Stuart B , Grandin E. Wilson , Menachem Jonathan N , Kawut Steven M , Smith K. Akaya , Forfia Paul R , Vaidya Anjali , Mazurek Jeremy A
Published: June 2023

Introduction:
Pulmonary hypertension (PH) in the setting of heart failure with preserved ejection fraction (PH-HFpEF) is further characterized as isolated post-capillary PH (IpcPH) or combined pre- & post-capillary PH (CpcPH). This is distinguished by pulmonary vascular resistance (PVR) cut-off of 3 WU. Prior definitions used a diastolic pulmonary gradient (DPG) cut-off of 7mmHg to distinguish PH subtype. Studies have examined echocardiographic right ventricular outflow tract Doppler notching (RVOT-notch) as a correlate for pulmonary vascular disease, though its role in distinguishing PH-HFpEF subtype by current vs. prior definition has never been described.

Hypothesis:
Our study explores the ability of RVOT-notch to distinguish CpcPH from IpcPH in patients with PH-HFpEF, in the context of current PVR & prior DPG cutpoints.

Methods:
We retrospectively reviewed patients with PH-HFpEF referred to our PH program who underwent right heart catheterization and echo (later reviewed independently by blinded cardiologists to assess RVOT-notch).

Results:
86 patients with PH-HFpEF were reviewed with a mean age of 66 and female predominance. Patients with RVOT-notch had signs of worsening right heart function both via echocardiography (higher estimated PASP, more severe TR, lower TAPSE) & hemodynamically (higher DPG, higher PVR, and lower pulmonary arterial compliance). RVOT-notch was able to distinguish CpcPH from IpcPH, with current PVR cut-off ≥3 WU (sensitivity 91%, specificity 68%, PPV 76%, NPV 88%) and prior DPG cut-off ≥7mmHg (sensitivity of 94%, specificity 58%, PPV 57%, NPV 94%).

Conclusions:
In PH-HFpEF, RVOT-notch is a sensitive marker of CpcPH, and notably better reflects the current PVR-based definition (PVR≥3) with better specificity than prior DPG-based definition. This could have implications as non-invasive screening for CpcPH in patients with PH-HFpEF. Further work is needed to validate this marker in larger cohorts.