bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 16624: Association of Subclinical Atherosclerosis and Echocardiographic Indices of Cardiac Remodeling: The Framingham Study
Authors: Castro-Diehl Cecilia , Song Rebecca J , Xanthakis Vanessa , Mitchell Gary F , Cheng Susan , Vasan Ramachandran S
Published: April 2024

Subclinical atherosclerosis, a marker of myocardial ischemia, may impact cardiac remodeling indices; yet this association has not been evaluated. We hypothesized that higher coronary artery calcium (CAC) burden is associated with alterations of cardiac remodeling in individuals free of congestive heart failure (CHF) and myocardial infarct (MI).

We related CT-based CAC score to echocardiographic (echo) indices in 2,650 Framingham Study participants (mean age 52 yrs, 48% women; 39% had CAC>0). We examined the following echo indices (log-transformed dependent variables): left ventricular (LV) mass index (LVMi), LV ejection fraction (LVEF), E/e’, global longitudinal strain (GLS), left atrial ejection fraction (LAEF) and aortic root diameter (AoR). Using multivariable-adjusted generalized linear models to account for relatedness, we modeled CAC score (independent variable) as a log-transformed continuous [ln(CAC+1)] or categorical (0, 1-100, and ≥101) variable. Adjusting for standard risk factors, higher CAC burden was associated with higher LVMi, E/e’ and AoR, and with lower LAEF. Those with CAC score≥101 had lower LAEF and higher E/e’ and AoR compared to those with CAC=0 (
P
<0.05 for all, Figure). We observed effect modification by sex and age (interaction
P
<0.05) for the association of CAC score with LAEF and with AoR, respectively. In stratified analysis, higher CAC values were associated with lower LAEF values only in women (
P
<0.003), and with higher AoR in older participants (>median age of 58 yrs;
P
<0.007).

Conclusions:
Subclinical atherosclerosis is associated with cardiac remodeling indices, consistent with the potential adverse impact of subclinical ischemia on myocardial and aortic remodeling in individuals free of CHF and MI. The prognostic significance of these associations warrant evaluation in future studies.
Abstract 16625: Electrical Activity in the Blind Spot of Lasso Guided PVI
Authors: Stix Guenter , Gwechenberger Marianne , Stix Laura
Published: April 2024

Introduction:
The primary goal of AF ablation are complete and durable lesions in a circumferential line around all ipsilateral pulmonary veins. But there is a highly complex and multilayered arrangement of myocardial fibers around the orifice of the pulmonary veins, allowing for unpredictable ways of electrical conduction in this area.

Hypothesis:
The Lasso-catheter records signals at least one or more millimeters inside the pulmonary veins, but PVI usually is intended by a circumferential line at least several millimeters outside the veins. High density mapping was used to determine whether electrical activity can be detected in the blind spot between the circumferential ablation line on the atrial side and the site of the Lasso-catheter in the pulmonary veins.

Methods:
Patients scheduled for their first PVI underwent a circumferential radiofrequency ablation of the ipsilateral pulmonary veins. The PVI was verified by 1) an exit- and entryblock via all 20 electrodes of the Lasso 2515 variable, 2) a negative adenosine test and 3) unexcitability along the ablation line. After successfully completing all 3 tests an additional high density mapping with was performed.

Results:
We included 34 consecutive patients (61 +/- 10 years, 9 females), 28 patients had paroxysmal and persistent AF, 6 patients longstanding persistent AF. Complete PVI was achieved in all patients, verified by all 3 tests. Additional high density mapping with 7023 +/- 645 EGMs per left atrium revealed no electrical activity within the circumferential ablation line in 13 patients (38%), but in a majority of 21 patients (62%) electrical activity beyond the circumferential ablation line could be detected: in 12 of these patients (57%) in one region and in further 9 patients (43%) in several regions. The carina between the right pulmonary veins was the region were residual electrical activity was detected most frequently (15 patients, 71%). The pulmonary veins themselves appeared isolated in all 34 patients (100%) in the high density mapping.

Conclusions:
High density mapping appeared to detect electrical activity in a hitherto blind spot of Lasso-controlled PVI. Ablation of this discrete electrical activity beyond the circumferential lines might be of additional importance for durable PVI.
Abstract 16634: Preoperative Biomarkers of Inflammation and Oxidative Stress Predict Early Outcomes and Only Modestly Decline After Left Ventricular Assist Device Implantation: A Prospective Study
Authors: Yuzefpolskaya Melana , Nasiri Mojdeh , Pinsino Alberto , Onat Hatice D , Zuver Amelia M , Nwokocha Joseph K , Royzman Eugene A , Mabasa Melissa , Clemons Autumn M , Castagna Francesco , Garan Arthur R , Brunjes Danielle L , Takeda Koji , Takayama Hiroo , Naka Yoshifumi , Uhlemann Anne-Catrin , Colombo Paolo C , Demmer Ryan T
Published: April 2024

Background:
Inflammation and oxidative stress play a pivotal role in pathogenesis of heart failure (HF). Left ventricular assist device (LVAD) is a durable option for treatment of advanced HF, however i) trends of inflammatory and oxidative biomarkers over time are unknown and ii) complications such as right ventricular failure (RVF), stroke and renal failure remain high. The aims of this study were to: i) study longitudinal patterns of inflammation and oxidative stress in LVAD pts and ii) create a biomarker score to identify pts at risk for early adverse events.

Methods:
We prospectively studied 67 pts (166 samples): pre-LVAD n=56; LVAD (1mo; n=45); LVAD (3-6mo; n=39); LVAD (9-12mo; n=18) and LVAD (18mo; n=8). Inflammatory/oxidative biomarkers: adiponectin, C-reactive protein (CRP), endothelin-1(ET1), interleukin-6 (IL6), tumor necrosis factor- α (TNF α), isoprostane(IsoP), soluble (sCD14), trimethylamine N-oxide (TMAO) were measured in blood. Adverse events including death, stroke, RV failure, and renal replacement therapy (RRT) during implant admission were collected. A pre-LVAD biomarker score was calculated accounting for the number of biomarkers greater than median. Composite event was combination of death, stroke, RV failure and RRT. The RV failure and composite event rates were tested against the biomarker score (<median vs ≥median).

Results:
Pts were 58±14 yo, 87% male. TMAO and IsoP decreased at 1 mo, then rebounded modestly. ET1, CRP, and IL6 increased at 1 mo and subsequently declined (Table). Adverse event rates were higher in the biomarker score ≥median vs <median: RV failure occurred in 14 (47%) vs 4 (19%) (p=0.042); composite event rate occurred in 14 (47%) vs 5 (24%) (p=0.097).

Conclusion:
LVADs reduce the degree of inflammation and oxidative stress in advanced HF within the first 3mo, however reductions are modest and biomarkers do not normalize. Pre LVAD elevation of biomarkers can identify pts at risk for early adverse events.
Abstract 16653: Coronary Artery Calcium, SPRINT Eligibility and Role of Risk Prediction for Intensive Blood Pressure Therapy: The Coronary Artery Calcium Consortium
Authors: Uddin S M Iftekhar , Mirbolouk Mohammadhassan , Kianoush Sina , Orimoloye Olusola A , Dardari Zeina , Graham Garth , Whelton Seamus P , Miedema Michael D , Nasir Khurram , Rumberger John , Shaw Leslee J , Berman Daniel S , Budoff Mathew J , McEvoy John W , Matsushita Kunihiro , Blaha Michael J
Published: April 2024

Introduction:
Coronary artery calcium (CAC) is a strong predictor of future cardiovascular events. We assessed whether CAC scoring could be used to identify hypertensive adults aged >50 years who have cardiovascular disease (CVD) mortality rates similar to those observed in the Systolic Blood Pressure Intervention Trial (SPRINT) and who therefore might benefit from intensive blood pressure therapy. In addition, we examined the ability of CAC to stratify CVD risk among hypertensive adults, including those who are eligible for SPRINT.

Methods:
We studied 16,167 hypertensive adults from the CAC Consortium, among whom 5,163 were SPRINT-eligible (age >50 years, Framingham Risk Score >15%, and no diabetes mellitus). In order to determine what CAC scores were associated with CVD mortality rate observed in the standard-treatment group of SPRINT (0.43%/year), this rate was first age-standardized to the population structure of the CAC Consortium (age-standardized annual CVD mortality rate = 0.35%/year). A CAC-CVD mortality plot was then generated. A y-axis line was placed at the age-standardized CVD mortality rate, and its intersection with the CAC-CVD mortality plot was interpreted as the CAC-score equivalent of SPRINT-level risk. We also compared multivariable-adjusted hazard ratios of coronary heart disease (CHD) and CVD deaths by CAC category (0, 1-100, 100-400, >400).

Results:
Mean age of the study population was 58.1±10.6 years. Over a mean follow-up of 11.6±3.6 years, there were 409 CVD and 207 CHD deaths. A CAC score of 220 (confidence range 165-270) was associated with the age-standardized CVD mortality rate observed in SPRINT. Additionally, increasing CAC scores were associated with increased CHD and CVD mortality in the overall study population [CHD
-
CAC 100-400: Hazard ratio (95% confidence interval) 1.9 (1.0-3.4), CAC>400: 4.2 (2.3-7.4); CVD - CAC 100-400: 1.9 (1.3, 2.8), CAC>400: 3.5 (2.4, 5.1)]. A similar pattern was observed in the SPRINT-eligible population.

Conclusions:
CAC risk stratifies adults with hypertension, including SPRINT-eligible adults. A CAC score of around 220 can identify hypertensive adults aged >50 years with CVD risk similar to SPRINT and may therefore help identify candidates for more intensive blood pressure therapy.
Abstract 16657: Role of Exercise Induced Mitral Regurgitation and Its Prevalence in Functional Limitation of Heart Failure Patients With Preserved Ejection Fraction
Authors: Barletta Marta , Bandera Francesco , Giammarresi Andrea , Labate Valentina , Losito Maurizio , Caracciolo Maria M , Rovida Marina , Guazzi Marco
Published: April 2024

Background:
Functional limitation in heart failure (HF) patients recognize multiple mechanisms. Exercise-induced mitral regurgitation (Ex-MR) has been extensively studied in HF population with reduced ejection fraction (HFrEF, EF < 40%), as responsible of right ventricle (RV) to pulmonary circulation (PC) uncoupling phenomenon. The relative role of this hemodynamic determinant has not been investigated so far in HF patients with preserved (HFpEF, EF > 50%) and mid-range EF (HFmrEF, EF 40 - 49%).

Aim:
To describe functional phenotypes and cardiac response to exercise in HF patients, with respect to the development of Ex-MR.

Methods:
179 HF patients and 23 controls were tested with cardiopulmonary exercise test (CPET) combined with exercise-echocardiography. Based on current guidelines, we identified 114 HFrEF, 34 HFmrEF and 31 HFpEF, further divided according with the presence of at least moderate (>2+/4+) Ex-MR.

Results:
Ex-MR rate was 58%, 41% and 42% in HFrEF, HFmrEF and HFpEF, respectively. Ex-MR was associated with echocardiographic signs of RV-PC uncoupling (TAPSE/PASP ratio), particularly enhanced by the exercise in HFpEF patients. HFpEF with Ex-MR showed a distinct phenotype with chronotropic competence and increased peripheral oxygen extraction, compared to Ex-MR - cohort, possible expression of a compensatory mechanism to significant reduction in contractile reverse. The Ex-MR was associated with lower peak VO2 and workload in HFrEF and HFmrEF, while there were no differences related to HFpEF. The presence of Ex-MR significantly compromised also ventilatory efficiency (VE/VCO2) in all HF classes.

Conclusion:
Ex-MR emerged as a new mechanism of functional limitation in HFpEF, sharing a common pathophysiological basis with other HF patients. The RV-PC uncoupling is the best haemodynamic correlate of Ex-MR.
Abstract 16669: Left Atrial Function After Closure of Atrial Septal Defect in Adults: Comparison Between Transcatheter Closure and Surgical Closure
Authors: Toyono Manatomo , Yamada Shunsuke , Aoki-Okazaki Mieko , Takahashi Tsutomu
Published: April 2024

Introduction:
Transcatheter closure is offered as an alternative to surgery for the majority of patients with secundum atrial septal defect (ASD). However, little is known about the effect of a mechanical device on left atrial (LA) function.

Hypothesis:
Transcatheter closure of secundum ASD preferably preserves LA function compared with surgical closure in adult patients.

Methods:
We examined adult patients who underwent transcatheter (n = 58) and surgical ASD closure (n = 17) and controls (n = 20). Patients with greater than mild mitral or tricuspid regurgitation and those with a history of atrial fibrillation were not included. All the devices employed were the Amplatzer
TM
Septal Occluders. LA volumes were measured by the biplane area-length method using 2-dimensional transthoracic echocardiography at the onset of mitral opening (Vmax), the beginning of LA systole (Va) and the onset of mitral closure (Vmin) before and 15 ± 11 months after ASD closure. LA reservoir, conduit and booster pump functions were assessed by (Vmax-Vmin)/Vmax, (Vmax-Va)/Vmax and (Va-Vmin)/Va, respectively. Left ventricular (LV) ejection fraction was obtained to estimate LV systolic function. For the estimation of LV diastolic function, the ratio of transmitral early to late flow velocity (E/A), deceleration time of early mitral flow velocity (DT) and the ratio of systolic to diastolic pulmonary venous flow velocity (S/D) were obtained by conventional Doppler echocardiography.

Results:
In transcatheter closure, employed device size indexed to body surface area was 12 ± 3 mm/m
2
. Before ASD closure, there was no significant difference in all the LA parameters between the 2 groups, whereas LV ejection fraction was significantly decreased in the surgical group as compared with the transcatheter group. After ASD closure, Vmax index was significantly increased in the surgical group. LV end-diastolic volume index were significantly increased both after transcatheter and surgical ASD closure. After ASD closure, the surgery group showed significantly decreased LA reservoir and conduit functions as compared with the transcatheter group and controls.

Conclusions:
The transcatheter group, not surgical group, showed preserved LA function at mid-term follow-up after ASD closure.
Abstract 16672: Determining the Diagnostic Yield for Atrial Fibrillation Using Continuous Smartwatch Monitoring
Authors: Genicot Matthieu , Vanvinckenroye Amaury , Proesmans Tine , Vranken Julie , Vandervoort Pieter
Published: April 2024

Introduction:
Smartwatch technologies become ubiquitous in our daily life and can contribute to better health. The optical sensing element (photoplethysmography or PPG) enables continuous heart rate and heart rhythm monitoring. However, signal quality is a major challenge to overcome to improve the diagnostic yield.

Hypothesis:
To compare the diagnostic yield of AF detection between traditional 24h Holter and continuous wearable monitoring.

Methods:
In this study, patients receiving a diagnostic 24h ECG Holter monitor were parallel provided with a wearable smartwatch device capable of continuous PPG logging. Data was recorded up to 24 hours and the ECG and PPG signals were synchronized. The PPG signals were analyzed by the FibriCheck algorithms and compared towards the Holter analysis results.

Results:
In total, 100 patients participated in the study with a mean age of 60±13 years and 53.8% was male. Over 142,560 minutes of data have been collected from both Holter and wearable device. On average, 45% of the data was labeled as insufficient quality. There was a significant (P<0.001) difference in presence of bad quality between day (47.5%) and night (10.6%). In total, on Holter, 9.6% of the data was labelled as atrial fibrillation, while on the PPG signal only 6.5% AF was found. Missing AF occurred during episodes of insufficient quality, impacting the diagnostic yield. Without a quality detection system, a over-diagnostic rate of 48.1% AF was observed.

Conclusions:
Initial results indicate the feasibility of continuous heart rhythm monitoring using wearable systems. However, optimizing the diagnostic yield remains a challenge. Diagnostic results obtained during the night are in high agreement between Holter and wearable.
Abstract 16676: A-mhc MitoTimer Mouse Reveals Metabolic Heterogeneity in the Heart
Authors: Stotland Aleksandr B , Stasna Miroslava , Parker Sarah J , van Eyk Jennifer , Gottlieb Roberta A
Published: April 2024

Introduction and hypothesis:
To study mitochondrial turnover in the heart, we developed MitoTimer, a fluorescent protein targeted to the mitochondrial matrix that matures from green to red fluorescence over time. We generated a mouse line where MitoTimer is expressed under the cardiac-restricted promoter and were able to observe newly-synthesized and quiescent mitochondria in cardiomyocytes. Surprisingly, the hearts exhibit considerable heterogeneity in green-to-red MitoTimer fluorescence at the level of cardiomyocytes as well as between the mitochondria within individual cells. We hypothesized that these discrete subpopulations of cells represent fibers engaged in specialized functions.

Methods:
To isolate cells from the heart for proteomic and biochemical analysis, we developed an isolation strategy utilizing flow-cytometry followed by sequential processing to separate cytosolic, myofilament and insoluble protein fractions for liquid chromatography/mass spectrometry. Results of the analysis were validated by biochemical techniques.

Results:
Analysis of cardiomyocyte sub-populations revealed substantial differences in their protein compositions. Green cells display a profile consistent with an upregulation of PPARA and KLF15 signaling pathways and a downregulation of insulin receptor signaling, suggesting a preference for fatty acid oxidation (FAO). Consistent with this analysis, Western blots revealed that green cells express higher levels of CD36 and Cpt1b proteins compared to red cells. Interestingly, maturation of Timer protein fluorescence to red is sensitive to changes in molecular oxygen concentration. Cells that exhibit higher utilization of FAO and thus a lower oxygen tension will have a decrease in MitoTimer protein maturation, resulting in a greater green fluorescence. These results suggest MitoTimer may be a useful not only as a marker of mitochondrial age, but also as a marker of metabolic substrate preference.

Conclusion:
Cardiomyocytes in the heart present a highly heterogeneous population, arranged in discrete fibers that have a higher preference for one metabolic substrate over another. We are currently investigating the physiological roles these fibers play in the heart.
Abstract 16677: Protein Kinase G I Alpha Attenuates Inducible Ventricular Tachycardia and QRS/T Wave Alternans in the Type II Diabetic Heart
Authors: Blanton Robert M , Jin Hongwei , Madias Chris , Zhang Yali , Wang Bo , Aronovitz Mark J , Richards Daniel A , Galper Jonas B
Published: April 2024

Introduction:
Diabetes increases ventricular tachycardia (VT) and sudden cardiac death risk in humans. We previously found the type I diabetic (DMI) heart displays: reduced responsiveness to parasympathetic stimulation; increased QRS/T Wave alternans (marker of proarrhythmic calcium dyshomeostasis); and hyperactive GSK3beta. Cardiac parasympathetic stimulation promotes production of intracellular cyclic GMP (cGMP). The effects of cGMP and its downstream effector PKG, on these indices of VT in type II diabetes (DMII) remain poorly understood.

Hypothesis:
PKGIa modulates inducibility of VT and QRS/TWA in the DMII heart and mediates the cGMP effect on VT through inhibition of myocardial GSK3beta.

Methods:
Using an established protocol of programmed ventricular stimulation we measured: VT incidence, duration, and QRS/T Wave alternans. We studied the following mice: wild type; Db/Db model of DMII; high fat high sucrose (HFHS) model of insulin resistance; and the PKGIa leucine zipper mutant (LZM) mouse, which has no DM but has PKGIa disrupting mutations. Mice were treated with or without the cGMP-augmenting phosphodiesterase inhibitor sildenafil 10 mg/kg, or the GSK3b inhibitor TWS119 20 mg/kg.

Results:
LVs of HFHS mice displayed 30 ± 8% reduction of cGMP compared with control (p<0.05, n=3 per group), while myocardial cGMP in LZM mice did not differ from control. In failing LVs from humans, there was also a 46% reduction in myocardial cGMP in DM compared with nondiabetic (p= .058, n=3 per group). Db/Db and HFHS mice had increased inducible VT (0.25 +/- 0.1 s in Db/Db, 2.2 +/- 1 s HFHS, vs 0 s in WT control, p <0.05), as well as TWA. Treatment with sildenafil reduced VT incidence, duration, and TWA in Db/Db and HFHS mice. LZM mice also had increased VT duration and TWA incidence (0 of 4 in WT vs 5 of 6 in LZM, p<0.05). Inhibition of GSK3β rescued inducibility of VT in Db/Db, HFHS, and in LZM mice.

Conclusions:
These findings support that in the DMII heart reduced cGMP promotes VT, whereas pharmacological augmentation of cGMP inhibits VT. Inducible VT and TWA in the PKG LZM mouse provides direct support that PKGIa opposes VT in the DMII heart. These support that cGMP activation of PKG inhibits GSK3beta, leading to reduced incidence of inducible VT.
Abstract 16682: Abnormal Left Ventricular Deformation in Mitral Valve Prolapse
Authors: Romero Daza Angelica , Chokshi Aalap , Pardo Martinez Patricia , Maneiro Melon Nicolas , LaRocca Gina , Cham Matthew , Jacobi Adam H , Chung Michael S , Fernández Friera Leticia , Solis Martin Jorge , Sanz Javier
Published: April 2024

Background:
Mitral valve (MV) prolapse (MVP) is usually considered a primary valvular abnormality. We hypothesized that there are concomitant abnormalities in regional left ventricular (LV) function in this syndrome.

Objective:
To characterize LV global and regional strain in MVP with and without significant mitral regurgitation (MR), defined as regurgitant fraction >15%, in comparison with controls using cardiac magnetic resonance (CMR).

Methods:
A total of 109 MVP patients (median age 51 years, 40% males) with normal LV ejection fraction, and a control group of 45 patients (47 years, 53% males) without structural heart disease by CMR were retrospectively included. From standard cine images we quantified LV volumes and ejection fraction and, using feature tracking, global and segmental longitudinal and circumferential peak systolic strains.

Results:
Significant MR was found in 49 (44%) of MVP patients. Compared with controls, MVP patients had significantly higher LV end-diastolic and end-systolic volumes without differences in ejection fraction (Table). While there were no differences in global strains, regional longitudinal and circumferential peak systolic strains were increased in the basal anterior and anterolateral segments, and reduced in the mid inferior segment (Table). When comparing only patients without significant MR with controls, these differences remained significant (Table).

Conclusions:
In patients with MVP and normal LV ejection fraction there is LV dilatation and increased basal anterior and anterolateral deformation in comparison with controls, even in the absence of significant MR. These findings suggest that MVP may be a disease not only of the MV but also of the adjacent myocardium.
Abstract 16683: Subcellular Changes in NF-κB p50-Dependent iNOS Regulation in Doxorubicin-Induced Cardiomyopathy (DIC)
Authors: Bagchi Ashim K , Zimmer Alexsandra , Akolkar Gauri , Ludke Ana R , Singal Pawan K
Published: April 2024

A repeat use of doxorubicin (Dox), an anti-cancer drug, can cause heart failure in cancer patients. Dox-induced cardiac mitochondrial as well as ER damage due to oxidative and nitrosative stress (O/NS) has been widely studied. However, mechanism by which Dox exerts iNOS changes via mitochondrial damage and/or ER stress is yet to be elucidated. We investigated whether iNOS induced inflammatory changes in Dox exposed hearts involve mitochondrial and/or endoplasmic reticulum (ER) damage. A cumulative dose of Dox (15mg/kg B.W., ip) was given to Male Wistar rats. We noted an increase in cytC release in the cytoplasm due to O/NS indicating mitochondrial injury. Dox induced linking of chaperone binding immunoglobulin protein (Bip) to activating transcription factor 6 (ATF6) suggested an increased unfolded protein response (UPR) contributing to ER stress which was independent of upstream transcription factors inositol requiring enzyme 1 (IRE1) and protein kinase RNA-like ER kinase (PERK). ATF6-induced ER stress promoted NFκBp105/p50-induced expression of iNOS and NO production in the myocardium. The latter was associated with increased expression of TLR2 and TRAF2 together with NFκB105/50 expression suggesting that ER-stress promoted the inflammatory response in the myocardium. Co-localization of iNOS or TLR2 together with calnexin/grp78 (ER markers) but not with Tom20 (mitochondria marker) suggested that only ER stress promoted inflammatory response. The study suggests that inhibition of Bip binding to ATF6 may modulate ER-stress-mediated inflammation in DIC and presents a novel avenue for a development of the therapeutics for treatment of DIC.
Abstract 16684: Cardiovascular Responses of Persons With ABI to Computerized Motor-Cognitive Assessments
Authors: Gobert Denise , Edmiston Sarah
Published: April 2024

Introduction:
Recent evidence suggests that a traumatic brain injury is associated with a higher risk for cardiovascular pathology and impaired responses to activities of daily living. However, limited standardized testing is available to document cardiovascular responses during motor-cognitive function after acquired brain injury (ABI). Our study aimed to compare cardiovascular responses in persons with and without ABI during motor-cognitive assessments in virtual-reality gaming environments.

Hypothesis:
We hypothesized that there would be a significant difference in participant effort as defined by cardiovascular response specific to each activity.

Methods:
50 participants (M/F = 16/34) age 29.31 (+/-11.667) years with and without ABI (9/41) performed a timed, 4-square stepping task to test dynamic balance (4SST) and the standardized Montreal Cognitive Assessment (MoCA).Testing included polar heart monitoring of participant effort via heart rate (HR) while performing five standardized, virtual-reality games to test motor-cognitive skills. Variables included HR, 4SST time, MoCA score, and computerized Cognitive Scores (ICOG). Descriptive statistics explored group performance using SPSS 24.0 (IBM) and an alpha level of 0.05.

Results:
results Indicated similar performance in MoCA and ICOG scores (26.78 +/- 2.188, 28.043 +/- 2.230 respectively) but ICOG effort ratings were significantly higher in the ABI group compared to without ABI (2.60 +/- 1.140 vs. 1.60 +/- 1.095 respectively). Also, the ABI group took significantly longer to complete each ICOG activity (34.056 +/- 24.461 vs. 29.964 +/- 25.727 respectively) with significantly delayed reaction times (3.598+/- 1.542 vs. 2.825 +/- 1.630 respectively). Significant relationships occurred between the ICOG activity score and the associated HR (r = - 0.512, p = 0.030) and 4SST and AGE (r = 0.526, p = 0.025). Multiple regression analysis indicated history of concussion, previous night hours of sleep, MoCA scores, gender, and HR significantly explained 61.2% of the ICOG variance (p = 0. 005).

Discussion:
Results indicate significant differences in cardiovascular responses to motor-cognitive activities however similar performance in MoCA and ICOG scores. There was also a significant difference in effort and reaction time scores. This trend appeared to explain overall ICOG performance as presented by the regression analysis.

Conclusions:
Preliminary findings warrant further research of cardiovascular responses during specific motor-cognitive tasks common to ADL’s.
Abstract 16687: Aging-Related Klotho Deficiency in Human Aortic Valve Interstitial Cells Exaggerates the Inflammatory Response Through Down-Regulation of Autophagy Activity
Authors: Yao Qingzhou , Deng Xinsheng , Ao Lihua , Cleveland Joseph , Furllerton David , Meng Xianzhong
Published: April 2024

Calcific aortic valve disease (CAVD) is prevalent in the elderly. The inflammatory response of aortic valve interstitial cells (AVICs) contributes to the mechanism of CAVD progression. Our previous work demonstrated that the innate immunity mediated by Toll-like receptors (TLRs) in human AVICs up-regulates the production of inflammatory mediators and pro-osteogenic activity and that human AVICs express anti-aging protein Klotho, and Klotho deficiency is responsible for the enhanced osteogenic activity in diseased AVICs. Autophagy plays an important role in modulating cellular inflammatory response. Currently, the effect of Klotho on AVIC autophagy function and inflammatory response is unknown. We
hypothesis
that Klotho suppresses AVIC inflammatory response through maintaining cellular autophagy activity.

Methods:
Levels of autophagy proteins (LC3-I, and LC3-II), Klotho and ICAM-1 were determined in AVICs of normal valves from young (25.3±2.7 years) and older (61.5±4.3 years) donors by immunoblotting. Autophagy modulators (rapamycin, 2.0 μM; Autophinib, 100 nM and Bafilomysin A1, 10 nM) and recombinant Klotho (5.0 μg/ml) were applied to AVICs to assess their impact on inflammatory responses.

Results:
AVICs from older donors have lower levels of Klotho and autophagy activity, but produce higher levels of ICAM-1. TLR4 stimulation in AVICs from young donors reduces cellular levels of Klotho and autophagy activity, and increases ICAM-1 production. Further, recombinant Klotho enhances autophagy activity in AVICs from older donors through induction of PTEN and inhibition the Akt-mToR-p70S6K pathway, and it suppresses the inflammatory response in unstimulated AVICs from older donors and stimulated cells from young donors. Down-regulation of autophagy enhances, while up-regulation of autophagy reduces, the inflammatory response in AVICs.

Conclusions:
Autophagy plays an important role in suppression of human AVIC inflammatory response. Klotho deficiency in AVICs associated with aging exaggerates the inflammatory response through down-regulation of autophagy activity. Recombinant Klotho may have the therapeutic potential for suppression of valvular inflammation associated with CAVD progression.
Abstract 16697: Predictive Value of Cardiopulmonary Exercise Testing Parameters for 1-Year Adverse Outcomes in Ambulatory Advanced Heart Failure
Authors: Lala Anuradha , Mancini Donna M , Shahim Angiza , Shah Keyur , Lanfear David Lanfear, M.D. , Thibodeau Jennifer , Palardy Maryse , Ambardekar, M.D. Amrut , McNamara Dennis , Baldwin J.Timonthy , Jeffries Neal , Stevenson Lynne W , Khalatbari Shokoufeh , Spino Catherine A , Richards Blair , Mann Douglas L , Stewart Garrick C , Aaronson Keith D
Published: April 2024

Introduction:
Maximal and submaximal cardiopulmonary exercise (CPX) parameters predict heart failure (HF) outcomes, yet the best predictors in advanced ambulatory HF are not known.

Hypothesis:
We examined the discriminative value of maximal CPX parameters including peak oxygen consumption (peak VO2), VO2 pulse, circulatory power (CP, peak systolic BP x peak VO2), and end tidal pressure CO2 (PetCO2), as well as submaximal parameters of ventilatory efficiency (VE/VCO2 slope), VO2 at anaerobic threshold (VO2AT) and oxygen uptake efficiency slope (OUES) on the combined outcome of LVAD, UNOS 1 transplant or death at 1 year.

Methods:
REVIVAL enrolled systolic HF pts in INTERMACS profiles 4-7 despite optimal medical therapy and CRT, of whom 273 performed CPX; 64 did not exercise (26 too ill, 38 for non-cardiac issues). ROC curves display the discriminative power of each parameter using censored c-statistics. The best multivariable model was identified by Cox regression.

Results:
At 1 year, there were 53 events (10 transplants,19 deaths; 24 LVADs). Pts with and without events were comparable for age (61 vs 60 yrs), LVEF (27 vs 29%), and BMI (31 vs 32 kg/m
2
).) Peak VO2, VO2AT, OUES, PetCO2, and CP were higher in the no event group (all p <0.001), whereas VE/VCO2 slope was lower (p<0.0001); respiratory exchange ratio was not different. Among the 26 pts too sick for exercise, the event rate was 15/26 (58%) compared to 38/273 (14%) in those exercising (HR=6.7, p<0.0001). Figure displays ROC curves and c-indices for CPX parameters. VO2 pulse (HR 1.18, p=0.017), CP (HR 0.86, p=0.005) and VE/VCO2 slope (HR 1.1, p=0.0001) were significant predictors in the multivariable analysis (model c-statistic=0.80).

Conclusions:
In ambulatory advanced HF, the inability to perform exercise due to being too ill predicts adverse outcome and for those who can exercise, VE/VCO2 slope is the most robust submaximal CPX parameter, while CP was the strongest maximal parameter to predict death, transplant or LVAD at 1 year.
Abstract 16708: Inhibition of Alpha-Ketoglutarate Dehydrogenase Activates Autophagy
Authors: Karlstaedt Anja , Vitrac Heidi , Raedschelders Koen , Spivia Weston , Schiffer Walter , McNavish Daniel , VanEyk Jennifer , Taegtmeyer Heinrich
Published: April 2024

Introduction:
Metabolic reprogramming is a hallmark of cancer and heart failure. In isocitrate dehydrogenase 1 and 2 mutant tumors, increased plasma levels of the oncometabolite D-2-hydroxyglutarate (D2-HG) inhibit α-ketoglutarate dehydrogenase (α-KGDH) in the heart. This inhibition is associated with muscle atrophy and reduced ATP and NADH provision. The connection between metabolic changes and proteome remodeling are still poorly understood.

Hypothesis:
Inhibition of α-KGDH promotes autophagy activation through the sirtuin family of NAD
+
-dependent deacetylases.

Methods:
We treated both male and female wild-type C57BL/J6 mice (n=12) with D2-HG in vivo, and cultured L6 myocytes (L6Ms) and adult mouse ventricular cardiomyocytes (AMVMs) with D2-HG. We constructed LC3 mutants with a lysine-to-arginine (GFP-LC3K49R-K51R) and lysine-to-glutamine (GFP-LC3K49Q-K51Q) replacement at Lys49 and Lys51 mimicking deacetylated and acetylated LC3, respectively.

Results:
Inhibition of α-KGDH by D2-HG is accompanied by heart and skeletal muscle atrophy, as well as increased LC3 and p62 expression in mice treated over 30-days.
In vivo
and
in vitro
treatment with D2-HG for 24h, increases phosphorylation and activation of AMPK, while phosphorylation of mTOR and p70S6K decreases. Thus, acute α-KGDH inhibition impacts protein turnover. Autophagy activation is highly dependent on D2-HG concentration and duration. ATP levels significantly decrease in differentiated L6Ms and AMVMs when treated with D2-HG levels above 0.13 mM over 24 to 96 h. GFP-tagged LC3 co-localizes with lysosomes labeled with LysoTracker Blue dye and mitochondria labeled with MitoTracker Red CMXRos dye upon α-KGDH inhibition, which indicates the presence of autophagosomes and mitophagosomes. We show that upon α-KGDH inhibition and subsequent NAD
+
increase, Sirt1 forms a molecular complex with LC3 and activates autophagy through deacetylation of LC3. In these conditions, LC3K49R-K51R mutants show puncta formation in the cytoplasm indicating that in addition to NAD
+
increase other factors are driving autophagy activation. Mass spectrometry-based proteomics and metabolomics revealed that α-KGDH inhibition induces upregulation of tropomyosin, NADH dehydrogenase and proteins involved in glycolysis and pentose phosphate pathway.

Conclusions:
Inhibition of α-KGDH promotes autophagy activation through deacetylation of LC3 by Sirt1 and culminates in proteome remodeling.
Abstract 16725: A Novel Role for MAGI1 in Disturbed Flow-Induced Endoplasmic Reticulum Stress in Endothelial Cells
Authors: Paez-Mayorga Jesus , Wang Yin , Kotla Sivareddy , Abe Junichi , Le Nhat-Tu
Published: April 2024

Introduction:
Atherosclerotic plaque predominantly develops in areas where endothelial cells (ECs) are exposed to disturbed flow (d-flow). Endoplasmic reticulum (ER) stress, characterized by the activation of ER transmembrane sensor ATF6 and transcription factor XBP-1, has been implicated in d-flow-induced atherogenesis. At d-flow regions, expression of both total and spliced XBP-1 and activation of ATF6 are increased, resulting in EC apoptosis. Additionally, over-expression of XBP-1 accelerates atherosclerotic formation. A recent genome-wide association study revealed a strong correlation between membrane-associated guanylate kinase with inverted domain structure-1 (MAGI1), a scaffold protein that associates with the tight and adherens junctions, and chronic inflammatory diseases.

Hypothesis:
We hypothesize that MAGI1 is crucial in d-flow-induced EC inflammation, apoptosis, and atherogenesis via regulating ER stress signaling.

Methods and Results:
Microarray analysis revealed that MAGI1 depletion inhibits ER-stress related genes, including XBP-1. qRT-PCR results confirmed that MAGI1 depletion abolished d-flow-mediated expression of spliced and full-length XBP-1 which correlated with reduced d-flow-induced apoptosis. To examine the mechanism by which MAGI1 regulates ER stress signaling, we found that MAGI1 is associated with ATF6, and that MAGI1-ATF6 complex formation is increased by inflammatory stimuli including d-flow and thrombin. Because the cleaved form of ATF6 can translocate from ER and Golgi to the nucleus, where it binds to ER-stress response elements and upregulates XBP-1 expression, we asked if MAGI1 facilitates ATF6 nuclear translocation. We found that thrombin-mediated ATF6 nuclear translation is significantly inhibited by MAGI1 depletion.

Conclusions:
Our results indicate that d-flow elicits the formation and translocation of a MAGI1-ATF6 complex from the cytosol to the nucleus that leads to ER stress via XBP1 induction and EC apoptosis. Our study suggests a novel role for endothelial MAGI1 as a link between d-flow and ER stress, both of which are fundamental constituents of atherogenesis.
Abstract 16731: Novel CMR Anatomical Predictors of Mitral Regurgitation Presence and Severity in Mitral Valve Prolapse
Authors: Chokshi Aalap , Romero Daza Angelica , Pardo Marinez Patricia , Maneiro Melon Nicolas , Jacobi Adam , Chung Michael , Cham Matthew , LaRocca Gina , Solis Martin Jorge , Fernández Friera Leticia , Sanz Javier
Published: April 2024

Introduction:
Mitral valve (MV) prolapse (MVP) is often associated with mitral regurgitation (MR). The determinants of MR in MVP are incompletely understood.

Methods:
We retrospectively identified 86 consecutive patients with MVP and preserved ejection fraction undergoing CMR with velocity encoding for MR quantification between 2005 and 2017. On 3-chamber cine images we measured, in end-diastole (Figure), end-systole, and their percentage change during the cardiac cycle, the following parameters: basal and mid inferolateral wall thickness, posterior papillary muscle length, annulus diameter, LV diameter and distance from the posterior papillary muscle to anterior and posterior annulus. In addition, we measured anterior and posterior leaflet thickness in diastole and maximal prolapse distance in end-systole. We explored the associations between these parameters and mitral regurgitant fraction (RF) using multivariate linear regression.

Results:
Median age was 52.6 years and 48% were males. There was posterior MVP in 49 (57%), bileaflet MVP in 35 (41%) patients, and isolated anterior MVP in 2 (2%) patients. MR was present in 73 (85%) and, in these, median RF was 23% (IQR 13-33%). In multivariate analyses, diastolic papillary muscle to posterior annulus distance, maximal prolapse distance, maximal posterior leaflet thickness, and LV basal inferolateral diastolic thickness were independent predictors of mitral RF (p<0.05 for all).

Conclusions:
Beyond known determinants of MR in MVP such as maximal prolapse and leaflet thickness, we identified novel anatomical predictors of MR severity, namely increased diastolic papillary muscle to posterior annulus distance and LV basal inferolateral thickness. Whether these abnormalities represent secondary changes to MVP (i.e. basal inferolateral “stretch” and compensatory regional LV hypertrophy, respectively) or primary phenotypic features of the MVP syndrome is uncertain.
Abstract 16734: Coronary Artery Calcium as a Predictor of All-Cause, Cardiovascular and Coronary Heart Disease Mortality in Asian Americans: The Coronary Artery Calcium Consortium
Authors: Orimoloye Olusola A , Banga Sandeep , Dardari Zeina , Uddin S M Iftekhar , Berman Daniel S , Miedema Michael D , Rumberger John A , Nasir Khurram , Budoff Matthew J , Blaha Michael J , Mirbolouk Mohammadhassan
Published: April 2024

Introduction:
Although coronary artery calcium (CAC) has been shown in multiple populations to be predictive of risk, very few studies have assessed its predictive value in Asian-Americans. We therefore assessed the value of CAC for cardiovascular and all-cause mortality risk prediction in Asian-Americans using data from the CAC Consortium, the largest observational cohort of clinical CAC scoring yet assembled.

Methods:
We included 1,621 Asian Americans from the CAC consortium. CAC was modeled in categorical (CAC 0; CAC 1 - 99; CAC 100 - 399; CAC ≥ 400) and continuous forms. Participants were followed over a median of 12 ± 4 years for all-cause mortality, cardiovascular disease (CVD) mortality and coronary heart disease (CHD) mortality. The predictive value of CAC for individual outcomes was assessed using multivariable-adjusted Cox proportional hazards regression models adjusted for traditional cardiovascular risk factors. Results were reported as hazard ratios (95% confidence intervals). Additionally, cubic spline graphs centered at CAC = 100 were generated for graphical presentations of CHD and CVD mortality hazards with increasing CAC score.

Results:
Mean (SD) age of the population was 54 (11.2) years and 64% were men. Approximately 49% had a CAC score=0. A total of 59 deaths, 16 CVD-specific deaths and 8 CHD-specific deaths were recorded over the duration of follow-up. Of a total of 794 participants in the CAC=0 group, only 9 deaths were recorded (0.93 per thousand person-years). There were no CVD or CHD deaths in the CAC=0 group over the duration of follow-up. Individuals with CAC ≥ 400 had approximately 3 times the multivariable-adjusted hazards of all-cause mortality compared against a reference of CAC=0. (Hazard ratio 3.3 (1.3 - 8.6)). Similarly, we noted statistically significant increases in risk of CHD (HR 2.6 (1.5 - 4.3)) and CVD (HR 2.3 (1.8 - 2.9)) mortality per unit increase in log (CAC + 1).

Conclusion:
Similar to more extensively studied race/ethnic groups, CAC is strongly predictive of all-cause and cardiovascular mortality in Asian Americans. These findings may help address the existing knowledge gaps for cardiovascular risk prediction in Asian Americans as recent guidelines have little data-driven advice for risk prediction in this population.
Abstract 16742: Early Recurrence of Ventricular Tachycardia is Associated With Greater One-Year Mortality Among Patients With Severe Heart Failure
Authors: Beck Natalie M , Sauer Peter J , Tumolo Alexis Z , Sandhu Amneet , Zipse Matthew M , Borne Ryan T , Nguyen Duy T , Schuller Joseph L , Aleong Ryan G , Tompkins Christine , Varosy Paul D , Rosenberg Michael , Khazanie Prateeti , Altman Natasha , Brieke Andreas , Cornwell William , Wolfel Eugene , Ambardekar Amrut , Allen Larry , Tzou Wendy S
Published: April 2024

Background:
Ventricular tachycardia (VT) is common in patients with severe heart failure (HF).
Objective:
We sought to determine whether early recurrence of VT is associated with worse survival.

Methods:
We performed retrospective analysis of patients presenting to a tertiary referral hospital between 2006-2017 with VT and severe HF (defined as New York Heart Association functional Class IV or any Interagency Registry for Mechanically Assisted Circulatory Support score) for whom electrophysiology consultation was requested. A comparison was made in baseline characteristics and outcomes between those with early VT recurrence (within 30 days of initial consult) and those without early VT recurrence.

Results:
Of 129 patients, 47% underwent ablation while 53% were managed medically. Mean age was 60±12 years, 84% were males, ischemic cardiomyopathy was present in 55%, mean LVEF was 24±12%, and 77% had a preexisting ICD. Early recurrence of VT was observed in 25 patients (19%). Those with early recurrence had lower mean LVEF (20±7% vs 25±12%,
p
=0.032), were less likely to have an ICD prior to presentation (56% vs 82%,
p
=0.015), were more likely to have been treated with only medications (80% vs 20%,
p
=0.003), had greater in-hospital mortality (28% vs 5%,
p
=0.002) and experienced a longer hospitalization (23±19 vs 17±16 days), compared to those without early recurrence. There was no significant difference in other baseline characteristics between groups. Patients with early recurrence had significantly worse 1-year survival 56% vs 82% (Figure), with OR 3.5, 95% CI [1.3,8.9].

Conclusion:
Early VT recurrence among patients with severe heart failure is associated with increased mortality within the year following presentation. VT ablation should be considered to help mitigate risk of early recurrence and associated morbidity in such patients.
Abstract 16744: Advanced Glycation End Products and the Pathophysiology of Bioprosthetic Heart Valve Structural Degeneration
Authors: Frasca Antonio , Keeney Samuel , Lee Suengwon , Bavaria Joseph E , Gorman Robert C , Levy Robert J , Ferrari Giovanni
Published: April 2024

Introduction:
Bioprosthetic heart valves (BHV) are widely used to treat severe heart valve disease. BHV function deteriorates after 10-15 years due to structural degeneration (SVD) often involving calcification. SVD occurs regardless of biomaterial, requiring prosthesis replacement. Advanced glycation end products (AGEs) are post-translational, non-enzymatic protein modifications associated with diabetic complications and cardiovascular disease. Serum proteins, such as albumin, are also AGE modified.

Hypothesis:
AGEs, exacerbated by serum protein infiltration, play a role in SVD.

Methods:
Clinical BHV explants (n = 45) of glutaraldehyde-crosslinked bovine pericardium (BP, n = 35) or porcine aortic valve (PAV, n = 10) and equivalent unimplanted BHV were probed by immunostaining per semi-quantitative scoring (range 0-4) for generalized AGE, N-carboxymethyllysine (CML, an AGE-receptor ligand), and human serum albumin (HSA), the most abundant serum protein. Demographics comprise ages 34 to 86 (mean: 64.95), 28 males and 17 females, 8 diabetics, and 15 previous and concomitant coronary artery bypass patients (both conditions associated with SVD). BHV calcification was quantified by atomic absorption spectroscopy. BHV glycation was modeled by exposing BP to 50mM glyoxal +/- 5% albumin for 24hr, followed by either immunostaining for CML and albumin or
14
C glyoxal scintillation. Albumin incorporation was verified by mass uptake.

Results:
All explants showed positive immunostaining for AGE (mean ± SE = 3.52 ± 0.10); most showed HSA (2.30 ± 0.18) and less intense CML (1.55 ± 0.16) staining; unimplanted BHV staining was negative. Score comparisons showed no significant differences for BP vs PAV, coronary bypass or diabetic patients vs all patients. BHV Ca levels (122.01 ± 18.01ug/mg, binned as <30 vs >100ug/mL) did not correlate with AGE immunostaining. In vitro, glyoxal-generated CML and infiltrated albumin were evident throughout BP per immunostaining.
14
C glyoxal uptake by BP was 12.01 ± 0.50nmol/mg after 28 days and was increased 57.2 ± 7.5% by albumin co-incubation. Albumin co-incubation increased BP mass by 4.10 ± 0.19%.

Conclusions:
AGEs are associated with SVD regardless of BHV type and SVD risk factors. Albumin exacerbates AGE accumulation.