bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 12674: LDL Transcytosis by SR-BI Requires Signaling That is Distinct From Reverse Cholesterol Transport
Authors: Sugiyama Michael , Neculai Dante , Zyla Roman , Bredow Clara , Nyegaard Steffen , Lee Warren L
Published: April 2024

Introduction:
How LDL crosses an intact endothelial layer to initiate atherosclerosis is poorly understood, although it is postulated to involve LDL transcytosis. To date, technical limitations have greatly limited the study of its molecular mechanisms. We have recently devised an assay for quantifying LDL transcytosis by primary human coronary artery endothelial cells and have reported an unexpected role for the scavenger receptor SR-BI. SR-BI is best known as the HDL receptor and mediates reverse cholesterol transport; its downstream signaling involves the adaptor PDZK1 and endothelial nitric oxide synthase (eNOS). However, whether SR-BI internalization and its canonical signaling pathway are required for LDL transcytosis is unknown.

Hypothesis:
We hypothesized that LDL transcytosis and reverse cholesterol transport require different signaling pathways.

Methods:
Transcytosis of DiI-labeled LDL by primary human coronary artery endothelial cells was studied by total internal reflection fluorescence microscopy. The role of lipid rafts, PDZK1, eNOS and MAP kinases was studied by siRNA and pharmacological inhibitors.

Results:
Incubation with LDL induced the internalization of SR-BI, which was enriched in lipid rafts. Knockdown of caveolin-1 significantly attenuated LDL transcytosis. Coronary endothelial cells expressed low levels of PDZK1 and knockdown by siRNA had no effect on transcytosis. Similarly, inhibition of eNOS or addition of exogenous nitric oxide (NO) by NO-donors did not affect LDL transcytosis. Over-expression of G420H-SR-BI, a mutant receptor which does not perform reverse cholesterol transport, actually induced LDL transcytosis while the SR-BI inhibitor BLT-1, which prevents reverse cholesterol transport, had no effect on LDL transcytosis. Finally, inhibition of c-Jun N-terminal kinase (JNK) significantly attenuated LDL transcytosis.

Conclusions:
SR-BI is internalized during LDL transcytosis but PDZK1 and nitric oxide are not required. Instead, JNK kinase is involved. These data raise the possibility that reverse cholesterol transport and LDL transcytosis by SR-BI are regulated separately. These findings suggest that LDL transcytosis by SR-BI may constitute a novel therapeutic target for atherosclerosis.
Abstract 12718: Better Than Bazett: Accounting for Recent Heart Rate History Improves QT Correction in Atrial Fibrillation
Authors: Riad Fady S , Razak Eathar , Saba Samir , Shalaby Alaa , Nemec Jan
Published: April 2024

Introduction:
QT interval prolongation is associated with a risk of polymorphic ventricular tachycardia. The QT interval shortens with increasing heart rate and correction for this effect is necessary for meaningful QT interval assessment. The best way to correct the QT interval during atrial fibrillation (AF) is uncertain.

Methods:
Digitized Holter recordings were analyzed from patients with AF. Models of QT interval dependence on RR intervals were tested by sorting the beats into 20 bins based on corrected RR interval and assessing ST-T variability within the bins. Less variability indicated better model performance. Signal-averaging within bins was then performed to determine QT/RR dependence. Finally, standard deviation of QTc estimates was calculated for each model as a measure of real world utility.

Results:
Data from 30 patients (29 men, 69.3±7.3 years) were evaluated. QT behavior in AF is well described by a linear function (slope ~0.19) of steady-state corrected RR interval, which combines an “immediate response” component (weight ~ 0.18) with an exponential weight function (time-constant 120 s) over the preceding 3 minutes. This model performs significantly (p<0.0001) better than models based on instantaneous RR interval only, provides better QT/RRc correlation, and results in more consistent QTc estimates. It also outperforms models based on shorter time-constants and other previously proposed models on all parameters.

Conclusions:
QT interval accommodation during AF is well described by a formula combining a small “immediate response” to instantaneous RR interval change and an exponentially weighted “history” of RR intervals over the preceding 3 minutes. This model may improve detection of repolarization delay in AF. QT response to heart rate changes in AF is similar to previously published QT dynamics during atrial pacing and in sinus rhythm.
Abstract 12723: Referral to Cardiac Rehabilitation After Percutaneous Coronary Intervention, Coronary Artery Bypass Surgery, and Valve Surgery: Data From the Clinical Outcomes Assessment Program
Authors: Beatty Alexis L , Bradley Steven M , Maynard Charles , McCabe James M
Published: April 2024

Introduction:
Despite guideline recommendations that all patients undergoing percutaneous coronary intervention (PCI), coronary artery bypass surgery (CABG), or valve surgery be referred to cardiac rehabilitation, cardiac rehabilitation is underused. The objective of this study was to identify predictors of cardiac rehabilitation referral after PCI, CABG, and valve surgery.

Methods:
We analyzed data from the Clinical Outcomes Assessment Program (COAP), a registry of all non-federal hospitals performing PCI and cardiac surgery in Washington State. We included eligible PCI, CABG, and valve surgery patients from 2010 to 2015 who were discharged alive. We analyzed PCI and cardiac surgery separately by performing multivariate hierarchical logistic regression for the outcome of cardiac rehabilitation referral at discharge, clustered by hospital. Candidate predictors included age, gender, race/ethnicity, and comorbidities.

Results:
Cardiac rehabilitation referral was reported in 47% (32,049/67,556) of eligible PCI patients from 36 hospitals and 91% (19,320/21,329) of eligible cardiac surgery patients from 20 hospitals. The hospital in which the procedure was performed was a stronger multivariate predictor of referral than any individual patient characteristic for both PCI (hospital referral range 2% to 97%; median odds ratio 6.29; 95% confidence interval 4.27, 10.24) and cardiac surgery (hospital referral range 49% to 100%; median odds ratio 5.92; 95% confidence interval 3.48, 12.60)(Figure).

Conclusions:
Cardiac rehabilitation referral at discharge was less prevalent after PCI than cardiac surgery. The strongest predictor of cardiac rehabilitation referral was hospital in which the procedure was performed. Efforts to improve cardiac rehabilitation referral should focus on increasing referral after PCI, especially in hospitals with low referral.
Abstract 12738: Elevated Sympathetic Activity, Impaired Endothelial Function, and Late Hypertension After Repair of Coarctation of the Aorta
Authors: Lee Melissa G , Mynard Jonathan P , Lambert Elisabeth , Cheung Michael M , Lambert Gavin , d’Udekem Yves
Published: April 2024

Introduction:
There is a high prevalence of hypertension late after repair of coarctation of the aorta but its exact mechanism is unknown. Elevated sympathetic tone may contribute to the development of late hypertension. This study aims to investigate the neural profile of coarctation patients including the use of muscle sympathetic nerve activity (MSNA) testing, a direct method of measuring sympathetic activity.

Methods:
Twenty-three patients aged ≥18 years with a coarctation repair underwent transthoracic echocardiography (TTE) and measurements of resting and 24-hour ambulatory blood pressures (BP), MSNA, sympathetic and cardiac baroreflex functions, digital endothelial function, and pulse wave velocity (PWV). Median age at repair was 1.2 months (interquartile range: 0-9 months). Patients were compared to 18 healthy controls matched for age, gender, weight, and waist/hip circumference ratio.

Results:
After a follow-up of 26 ± 5 years, 6% (1/18) and 44% (8/18) had clinic resting hypertension and prehypertension, respectively. On 24-hour BP monitoring, 15% (3/20) and 20% (4/20) had hypertension and prehypertension, respectively. Left ventricular hypertrophy on TTE was present in 43% (6/14), and was more prevalent in patients with prehypertension/hypertension on 24-hour BP monitoring compared to those with normal 24-hour BP (75% [3/4] vs. 30% [3/10], p=0.2). Coarctation patients had elevated MSNA compared with controls (50 ± 25 vs. 29 ± 14 bursts/100 heartbeats, p=0.01), decreased sympathetic baroreflex function (-2.2 ± 2.1 vs. -7.0 ± 5.6 bursts/100 heartbeats·mmHg
-1
, p=0.007), normal cardiac baroreflex function (41.9 ± 30.4 vs. 35.7 ± 21.1 ms·mmHg
-1
, p=0.6), decreased endothelial function (pulse amplitude tonometry ratio: 0.4 ± 0.3 vs. 0.8 ± 0.5, p=0.004), and normal PWV (5.8 ± 1.1 vs. 5.5 ± 0.4 m/s, p=0.7).

Conclusions:
After coarctation repair patients have increased MSNA, impaired sympathetic baroreflex response, and impaired endothelial function, all of which may contribute to the development of late hypertension. Agents targeting sympathetic activity and endothelial function may be the ideal antihypertensive therapies after coarctation repair. Regular monitoring for late hypertension after coarctation repair is warranted.
Abstract 12746: A Case of Biopsy-Proven Erdheim-Chester Disease Manifesting With Pan-Aortitis, Coronary Artery Encasement, a Large Pericardial Effusion, Orbital Pseudotumors, and a Right Heart Mass
Authors: Blumenthal Daniel M , Perugino Cory , Ghoshhajra Brian B , Hutter Adolph M
Published: April 2024

A 72 year-old woman with a distant history of a cryptogenic right middle cerebral artery stroke presented with three days of fatigue, confusion, and recrudescence of old stroke symptoms. . Head and neck imaging demonstrated a small subarachnoid hemorrhage, orbital pseudotumors, cerebellar lesions, and circumferential thickening of the aortic arch and great vessels. Additional imaging of the chest, abdomen, pelvis, and legs revealed a large pericardial effusion, pan-aortitis, and sclerotic intramedullary lesions in both femurs. An electrocardiogram showed sinus rhythm, RBBB, and low voltage. Pulsus paradoxus was 10 mmHg. Laboratory analysis was notable for elevated serum inflammatory markers. Echocardiogram showed brief right ventricular diastolic inversion and a right atrioventricular groove mass. Diagnostic and therapeutic pericardiocentesis yielded 350cc of serosanguinous fluid, and evaluation for rheumatologic, infectious, and neoplastic etiologies was unremarkable. Cardiac magnetic resonance imaging (MRI) confirmed the presence of a right atrioventricular groove pseudotumor with avid late gadolinium enhancement and non-obstructive fibrotic encasement of the right and left anterior descending coronary arteries. The combination of pan-aortitis, orbital pseudotumors, pericardial effusion, coronary encasement, and right heart pseudotumor raised suspicion for Erdheim-Chester disease. Femoral bone biopsy revealed infiltration by CD68 (+), CD1a (-) histiocytes, confirming this diagnosis. Genetic testing identified a mutation in the gene for B-type RAF Kinase (BRAF) protein. Treatment with vemurafenib, a BRAF inhibitor, was initiated, and the patient’s disease has not progressed in the eighteen months since starting this treatment. Erdheim-Chester disease is a rare systemic illness caused by proliferation of non-Langerhans cell histiocytes. Cardiovascular manifestations—such as those seen in this case—complicate a majority of cases, and are the predominant cause of death. At least 50% of cases have mutations in the BRAF gene. While Erdheim-Chester disease has no known cure, vemurafenib represents a promising new therapy for BRAF mutation (+) cases.
Abstract 12749: Aortic Valve Replacement in Mixed Aortic Valve Disease-Beyond Ejection Fraction
Authors: EGBE Alexander , Warnes Carole
Published: April 2024

Introduction:
There are limited data about outcomes after aortic valve replacement (AVR) in mixed aortic valve disease (MAVD) population

Hypothesis/objectives:
To determine the risk factors for cardiovascular adverse event (CAE) after AVR in patients wit moderate-severe MAVD

Methods:
Review of patients with moderate-severe MAVD (combination of ≥moderate aortic stenosis and ≥moderate aortic regurgitation) who underwent AVR at Mayo Clinic, 1994-2014. CAE was defined as stroke, heart failure hospitalization, severe left ventricular (LV) dysfunction or cardiac death.

Results:
AVR was performed in 283 patients, age 67±5 years, follow-up 9±3 years, men 206 (73%). A bioprosthetic valve was implanted in 151 (57%), aorta replacement in 75 (27%) and coronary artery bypass grafting in 89 (31%). There were 5 perioperative deaths (2%).

CAE occurred in 69 (24%) (stroke 22, heart failure hospitalization 28, severe LV dysfunction 46, and cardiac death 26). Only one event was counted per patient. The multivariable predictors of CAE were relative wall thickness >0.46 (hazard ratio [HR] 3.24, 95% confidence interval [CI] 1.25-5.33,
P
=.001), LV mass index >180 g/m
2
(HR 1.79, 95% CI 1.32-2.63,
P
=.02), and LV ejection fraction <50% (HR 1.48, 95% CI 1.11-2.59,
P
=.04). The presence of RWT > 0.46 reliably predicted postoperative CAE with sensitivity of 78% and specificity of 88%.

Conclusions:
Preoperative LV hypertrophy was the strongest predictor of CAE after AVR in patients with MAVD. Perhaps it should be taken into consideration when determining the timing of AVR.

Legends
Kaplan-Meier curves showing cardiovascular adverse event (CAE) occurrence

(A) CAE rates in the entire cohort; (B) CAE rates in patients with RWT >0.46 (blue) vs RWT ≤0.46 (red); (C) CAE rates in patients with LVMI >180 g/m
2
(green) vs RWT ≤180 g/m
2
(yellow); (D) CAE rates in patients with LVEF < 50% (purple) vs RWT ≥50% (light blue).
Abstract 12750: Ascorbate Prevents Hypertension, Proteinuria and Concentric Hypertrophy by Balancing the Nitroso-redox System in a Model of Preeclampsia, the S-nitrosoglutathione Reductase (gsnor) Deficient Mice
Authors: Kulandavelu Shathiyah , Dulce Raul A , Takeuchi Rosemeire K , Balkan Wayne , Hare Joshua M
Published: April 2024

Introduction:
Preeclampsia (PE), a leading cause of maternal and fetal mortality and morbidity, is characterized by increased levels of reactive oxygen species (ROS) and S-nitrosylated protein, and decreased levels of the antioxidant, ascorbate (Asc). Mice lacking S-nitrosoglutathione reductase (GSNOR
–/–
), a denitrosylase that regulates protein S-nitrosylation, exhibit a PE-like phenotype including maternal hypertension, proteinuria, cardiac concentric hypertrophy and impaired placental vascularization. We hypothesize that the PE-like phenotype is mediated by nitroso-redox imbalance and nitrosative stress and can be rescued by ascorbate treatment.

Methods:
Pregnant GSNOR
–/–
and control (WT) mice (n=5-7) were provided drinking water ± Asc beginning on day 0.5 of gestation (E0.5). We determined blood pressure using a Millar catheter, relative wall thickness by echocardiography, and placental vascularization by isolectin staining. Cardiomyocytes (CM) were isolated at late stage pregnancy (E17.5) and levels of ROS (2’7’-dichlorofluorescein), nitric oxide (NO, diaminofluorescin) and peroxynitrite (dihydrorhodamine 123) were determined by fluorescence (ΔF/F
0
).

Results:
CMs isolated from pregnant GSNOR
–/–
hearts, exhibited elevated levels of ROS (2.48±0.39 vs. 1.58±0.18 in WT, P<0.05), free nitric oxide (6.65±0.43 vs. 5.59±0.26 in WT, P<0.05) and peroxynitrite (0.75±0.04 vs. 0.39±0.03 in WT, P<0.05). These increases were prevented with Asc treatment (P<0.01), which completely rescued the PE phenotype in GSNOR
–/–
mothers, including hypertension (105±2 mmHg vs. 95± mmHg in Asc-treated, P<0.05), proteinuria (P<0.05) and relative wall thickness (0.56±0.04 vs. 0.45±0.03 in Asc-treated (P<0.05). Placental vascularization was also significantly improved with Asc treatment in GSNOR
–/–
mothers. Asc had no effect on these parameters in WT mice.

Conclusions:
Our findings indicate that nitroso-redox imbalance and nitrosative stress contribute to PE in mice. Asc treatment balanced the nitroso-redox system and rescued the pathological phenotypes in GSNOR
–/–
mice, suggesting that it can be used therapeutically to treat or prevent preeclampsia.
Abstract 12768: Right Ventricular Mechanical Dyssynchrony in Pulmonary Hypertension is Associated With Right Ventricular Performance and Pulmonary Hemodynamics
Authors: Igata Sachiyo , Tahara Nobuhiro , Tahara Atsuko , Honda Akihiro , Nitta Yoshikazu , Sugiyama Yoichi , Munehisa Bekki , Nakamura Tomohisa , Kumanomido Jun , Kumagai Eita , Fukumoto Yoshihiro
Published: April 2024

Background:
Right ventricular mechanical dyssynchrony (RVD) in pulmonary hypertension (PH) is prevalent and correlates with the extent of RV dysfunction and clinical worsening, but is not fully investigated. The aim of this study is to investigate clinical factors associated with RVD in patients with PH.

Methods:
The study involved 24 patients (23 females; mean age of 62.2±17.5) with pre-capillary PH diagnosed by right heart catheterization, without electrocardiographic intraventricular conduction delay. They underwent determination of blood chemistry, magnetic resonance imaging and echocardiography including 2-dimensional speckle tracking. RVD was evaluated by 2-dimensional speckle-tracking echocardiography calculating the coefficient of variance of the times to peak-systolic strain for the 4 mid-basal RV segments (RV-CV4).

Results:
Mean pulmonary artery pressure (mPAP), pulmonary vascular resistance (PVR) and RV-CV4 were 33.4±11.7 mmHg, 7.3±4.4 wood unit and 10.5±7.3,respectively. In univariate analyses, mPAP, PVR, RV-fractional area change (inversely), RV-ejection fraction (inversely) and uric acid were significant correlated with RV-CV4. Multivariate stepwise analysis revealed that uric acid was independently associated with RV-CV4 (R
2
=0.593).

Conclusion:
The present study demonstrated that high uric acid level was a sole independent associate of RV dyssynchrony in PH patients, suggesting a predictor of heart failure and mortality.
Abstract 12793: Anemia and the Risk of Sudden Cardiac Arrest in General Population
Authors: Kim In-Jung , Yang Pil-Sung , Kim Tae-Hoon , Uhm Jae-Sun , Pak Hui-Nam , Lee Moon-Hyoung , Joung Boyoung
Published: April 2024

Introduction:
Anemia might be associated with increased sudden cardiac arrest (SCA) in several cardiovascular diseases. However, the relationship between anemia and SCA is still unclear in general population.

Hypothesis:
This study assessed the effect of anemia on SCA in general population.

Methods:
From the Korean National Health Insurance Database Cohort (NHID-Cohort), we studied 494,948 subjects (mean age, 47.8 [SD, 14.2] years; 245,333 men [49.6%]) with national health check-up. Hemoglobin (Hb, g/dl) was evaluated as both a continuous and a categorical variable (mild anemia, 11 to < 13 for men and 11 to < 12 for women; moderate anemia, 8 to < 11; and severe anemia < 8).

Results:
During a mean follow up period of 5.4 years, SCA occurred in 989 participants (352 women). Incidence rates for SCA increased across the 4 anemia groups in men (0.5, 2.6, 8.8, and 8.9 per 1000 person-years) and women (0.3, 0.7, 0.9, and 1.9 per 1000 person-years), respectively. In multivariable models adjusted for cardiovascular factors and interim myocardial infarction, a 26 and 28% increased in SCA risk per 1-unit decrease in Hb was observed in men (95% confidence interval [CI], 20-33%; P<.001) and in women (95% CI, 19-39%; P<.001). Adjusted hazard ratios for SCA associated with anemia were 2.08 (95% CI, 1.71-2.53; P<.001) and 1.88 (95% CI, 1.50-2.35; P<.001) for men and women, respectively, compared with individuals without anemia. Adjusted hazard ratios of SCA also increased as severity of anemia. (Severe anemia; 7.58 [95% CI, 2.82-20.35; P<.001] and 7.81 [95% CI, 3.45-17.67; P<.001)] in men and women, respectively)

Conclusions:
Anemia was associated with increased risk of SCA in general population. Anemia should, therefore, be considered as a useful prognosticator, and therapeutic strategies aimed to increase hemoglobin levels in general population should be investigated.
Abstract 12818: First Experience of Three-dimensional Rotational Angiography Image Integration With Electroanatomical Mapping System to Guide Catheter Ablation of Atrial Fibrillation
Authors: Fujita Satoshi , Fujii Eitaro , Kagawa Yoshihiko , Inoue Katsuhiro , Yamada Tsuyoshi , Yamada Norikazu , Ito Masaaki
Published: April 2024

Introduction:
Rotational angiography of the left atrium with three-dimensional (3D) reconstruction (3D-ATG) represents a modern method enabling to create computed tomography (CT) like 3D images on a standard X-ray machine. Recently, electroanatomical mapping system can import 3D images reconstructed by 3D-ATG.

Hypothesis:
We assessed the hypothesis that atrial fibrillation (AF) ablation using 3D-ATG would be feasible with a significant reduction in effective dose without compromising image quality compared with 3D CT image.

Methods:
3D-ATG was performed by using the Philips Allura Xper FD 10 system operated at a low-frame pulsed fluoroscopy (7.5 frames per second). Effective radiation dose was calculated from dose area product (DAP) measurements in 103 patients (mean age of 65 years, 71% men) undergoing AF ablation guided by 3D-ATG. Organ dose was measured at 37 points with a radiophotoluminescence glass dosimeter inserted in the position of an anthropomorphic Rando Phantom. Effective dose was calculated by multiplying organ dose by tissue weighting factor. The DAP to effective dose conversion factor was calculated by measurement of DAP at the same time of radiation exposure. Effective dose at CT examination was estimated from dose length product and conversion factor of 0.014. Left atrial dimensions and vertical ostial pulmonary vein (PV) diameters for each imaging method were compared.

Results:
The DAP to effective dose conversion factor of 3D-ATG was 2.4x10
-4
mSv/mGy•cm
2
by using the Philips Allura Xper FD 10 system in our hospital. Mean DAP for all patients was 7777±1488mGy•cm
2
for rotational angiography of the left atrium. The corresponding effective radiation doses for 3D-ATG were 1.9±0.4mSv. The effective doses for CT examinations were 13.6±4.2mSv (p<0.001). The correlations of left atrial dimension were r=0.73 for sagittal plane, 0.76 for coronal, and 0.80 for vertical (p<0.005). The correlation coefficient between 3D-ATG and 3D-CT for the ostial PV diameters was r=0.72 for left superior PV, 0.88 for left inferior PV, 0.60 for right superior PV, and 0.65 for right inferior PV (p<0.005).

Conclusions:
AF ablation using 3D-ATG is possible with a significant reduction in effective dose without compromising image quality.
Abstract 12825: Feasibility of Amplitude Spectrum Area Estimation in Ventilation Pauses During Cardiopulmonary Resuscitation
Authors: Wei Liang , Dai Chenxi , Gao Peng , Quan Weilun , Li Yongqin
Published: April 2024

Introduction:
Amplitude spectral area (AMSA) calculated from ventricular fibrillation (VF) waveform not only predicts defibrillation outcome, but may also reflect effectiveness of chest compressions. However, reliable VF waveform analysis usually requires rescuers to stop compressions. In the present study, we investigated whether AMSA could be accurately estimated in ventilation pauses during cardiopulmonary resuscitation (CPR).

Methods:
A total of 40 out-of-hospital cardiac arrest patients with VF as the initial rhythm were included in this study. All patients received resuscitation with a 30:2 compressions to ventilation ratio. ECG data and chest compression waveforms before first defibrillation were extracted. Each episode included at least one full resuscitation cycle consisting of 30 compressions followed by a ventilation pause, further compressions, and a pre-shock pause with artifact-free VF signal. AMSA was continuously calculated using a sliding window of 2 seconds duration with sliding step size of 1 sampling point. Ventilation pauses were identified by the chest compression waveforms. Mean AMSA value during chest compression (AMSA_c) and minimal AMSA value during ventilation pause (AMSA_p) were compared with the AMSA value measured in noise-free VF (AMSA_nf) during the pre-shock pause.

Results:
Twenty patients received mechanical CPR and other 20 patients received manual chest compressions. The ventilation pause was 3.19±0.62 sec for mechanical CPR and 5.96±2.06 for manual CPR. AMSA_c was significantly higher than AMSA_p (32.4±30.0 mVHz vs. 6.6±3.9 mVHz,
p
<0.01) and AMSA_nf (32.4±30.0 mVHz vs. 6.0±3.5 mVHz,
p
<0.01). As shown in Figure 1, AMSA_nf was strongly correlated with AMSA_p (r=0.90,
p
<0.01) but not with AMSA_c (r=0.50,
p
=0.11).

Conclusions:
AMSA could be reliably determined in ventilation pauses during CPR but not during chest compressions.
Abstract 12872: The Association of Second Hand Tobacco Smoke With Obstructive and Nonobstructive Atherosclerosis as Assessed by Coronary Computed Tomographic Angiography
Authors: Hecht Harvey , Yankelevitz David , Cham Matthew , Yip Rowena , Narula Jagat , Henschke Claudia
Published: April 2024

Introduction:
A dose-related association between secondhand tobacco smoke (SHTS) and coronary artery calcium (CAC) has been reported, but the total extent of atherosclerosis has not been investigated.

Objective:
To assess the relationship of the extent of atherosclerosis on coronary computed tomographic angiography (CTA) to the extent of secondhand tobacco smoke (SHTS) exposure in asymptomatic never smokers.

Methods:
Two hundred sixty eight never smokers, aged 40-80, completed a risk factor and extent of lifetime SHTS exposure questionnaire providing a total SHTS exposure score. Analyses of the prevalence, extent and plaque characteristics of atherosclerosis on CTA were performed and the independent contribution of SHTS was determined.

Results:
Coronary atherosclerosis was noted in 48% and was more frequent with low/moderate and high versus minimal SHTS exposure (48% and 69% vs. 25%, P < 0.0001). >50% stenosis, 1-49% stenosis and no stenosis were noted in 6%, 42% and 52% respectively. Adjusted ORs for any atherosclerosis were: 2.1 (95% CI: 1.0-4.4, P=0.05) for low-moderate and 3.5 (95% CI: 1.4-8.5, P=0.01) for high versus minimal SHTS exposure and were not significant for diabetes (P=0.45), hyperlipidemia (P=0.11), hypertension (P=0.65), and renal disease (P=0.24). With increasing SHTS exposure, the number of major vessels (P=0.0013), and the number of segments with any atherosclerosis (p=0.0001) significantly increased as did the number of involved segments with any plaque or stenosis (P < 0.0001), with calcified plaques alone (P <0.0001), with calcified and mixed plaques (P < 0.001) but not noncalcified plaques alone (P = 0.11).

Conclusions:
The presence and extent of atherosclerosis were associated with the extent of SHTS exposure even when adjusted for other risk factors, further demonstrating the causal relationship of SHTS exposure and coronary disease.
Abstract 12893: Design and cGMP-Generating Actions of a Novel Selective and Non-Selective Particulate Guanylyl Cyclase B Activator Targeting Cardiorenal Fibrotic Remodeling
Authors: Sangaralingham S. J , Huntley Brenda K , Ichiki Tomoko , Burnett John C
Published: April 2024

Introduction:
Cardiorenal fibrotic remodeling (CFR), often in the setting of heart failure (HF) and kidney disease (CKD), is a major cause for increased risk in mortality, for which there are no effective drugs. C-type natriuretic peptide (CNP) is a 22 amino acid (AA) ligand for the particulate guanylyl cyclase receptor-B (GC-B) and exerts anti-fibrotic actions, with little effect on blood pressure (BP) or renal function, via its second messenger cGMP. To overcome CNP’s limited efficacy with its short half-life, we designed 2 novel CNP-based peptides (C53 and CU32). C53 consists of CNP plus a 31 AA N-terminus extension, while CU32 is the CNP ring fused with the N- and C-termini of urodilatin (GC-A agonist). Here we investigated the cGMP generating actions of C53 and CU32, with the goal of advancing novel GC-B/cGMP therapeutics for CFR.
Hypotheses:
We hypothesized that C53 and CU32 would have cGMP activating actions in vivo, however only C53 would generate cGMP production selectively via GC-B in vitro. We also hypothesize that the addition of the C-termini to CU32 would form a non-selective GC-B/cGMP agonist with renal and BP lowering actions.

Methods:
HEK293 cells expressing human GC-B or -A and human fibroblasts (hFs), where GC-B is abundant, were stimulated with C53 or CU32 (10-8M) for 10 min. Two groups of normal rats (n=8) received a 75 min equimolar IV infusion of C53 or CU32. Change in mean arterial pressure (ΔMAP), sodium (Na) excretion and plasma and urinary cGMP were assessed. *p<0.05.

Results:
C53 and CU32 activated cGMP in GC-B cells (C53: 75±9, CU32: 24±2 pmol/well*), while only CU32 activated cGMP in GC-A cells (C53: 0±0, CU32: 50±3 pmol/well*). In hFs, both C53 and CU32 generated cGMP. In vivo, plasma cGMP (C53: 91±4, CU32: 94±6 pmol/ml) and urinary cGMP excretion (C53: 177±28, CU32: 227±28 pmol/min) were similar with both peptides. Yet, CU32 induced a greater reduction in ΔMAP (C53: -7±1, CU32: -16±3 mmHg*) and increased Na excretion (C53: 1.4±0.2, CU32: 2.4±0.2 uEq/m*) compared to C53.

Conclusions:
We report the engineering of a selective (C53) and non-selective (CU32) GC-B agonist that has favorable cGMP generating action in hFs and in vivo. Thus, C53 and CU32 may represent novel GC-B therapeutics that could be tailored to specific phases of HF or CKD to prevent CFR.
Abstract 12900: β-Adrenergic Receptor Kinase-1 is Strongly Associated With Physical Heart Failure Symptoms
Authors: Denfeld Quin E , Mudd James O , Hasan Wohaib , Winters-Stone Kerri , Hiatt Shirin O , Gelow Jill M , Chien Christopher V , Lee Christopher S
Published: April 2024

Introduction:
Heart failure (HF) is associated with significant physical symptom burden, but exactly how symptoms are related to pathophysiological mechanisms in HF is unclear. To date, no studies have examined the role of metabolic senescence in explaining HF symptoms.

Hypothesis:
There is a significant relationship between metabolic senescence and physical symptoms among adults with HF.

Methods:
This was a secondary analysis of data collected from a sample of adults with symptomatic HF. Metabolic senescence was measured with β-adrenergic receptor kinase-1 (βARK1; picograms/milliliter (pg/mL)). Physical symptoms were measured with the HF Somatic Perception Scale (HFSPS; range 0-90, higher = worse). The Seattle HF Model (SHFM) was used as a composite of traditional clinical variables (range roughly 0-4, higher = worse). Generalized linear modeling was used to quantify the relationship between βARK1 and HFSPS scores, adjusting for SHFM scores.

Results:
The average age of the sample (
n
= 96) was 54.3±13.5 years, 77.1% were male, and a majority (83.3%) of the sample had Class III or IV HF. Median raw value of βARK1 was 10.7 (IQR [4.2-28.9]) pg/mL. βARK1 (β = 1.42 ± 0.31,
p
<0.001) and SHFM scores (β = 12.40 ± 1.58,
p
< 0.001) were significantly related to HFSPS scores, and there was a significant interaction effect of βARK1 and SHFM scores in predicting HFSPS scores (Figure; interaction effect: β = -0.42 ± 0.09,
p
< 0.001; model:
F
(3,88) = 87.00,
p
< 0.001). In stepwise modeling, βARK1 was significantly associated with HFSPS scores (β = 0.22±0.1,
p
= 0.038) after controlling for other predictors of physical symptoms (model R
2
= 0.250,
F
(7, 70) = 3.34,
p
= 0.004).

Conclusions:
Worse metabolic senescence is associated with worse physical symptoms in HF, providing preliminary evidence of alternative pathophysiologic mechanisms underlying physical symptoms in HF.
Abstract 12918: Comparison between Standard and Reduced Doses of Direct Oral Anticoagulants for Periprocedural Anticoagulation in Truly Low Thromboembolic Risk Patients Undergoing Catheter Ablation of Atrial Fibrillation
Authors: Nakamura Kohki , Naito Shigeto , Minami Kentaro , Sasaki Takehito , Kumagai Koji , Funabashi Nobusada , Kobayashi Yoshio , Oshima Shigeru
Published: April 2024

Introduction:
Direct oral anticoagulants (DOACs) are generally administered in truly low thromboembolic risk patients undergoing atrial fibrillation (AF) ablation. All DOACs have two dose settings, but reduced doses are commonly used in patients for whom a DOAC dose reduction is not necessary according to the dose reduction criteria in the real world.

Purpose:
This study aimed to evaluate the safety and efficacy of periprocedural DOACs in AF patients with a CHA
2
DS
2
-VASc score of 0 (male) or 1 (female), and compare that between standard and reduced DOAC doses.

Methods:
We retrospectively enrolled 1013 consecutive patients receiving periprocedural DOACs, and 232 patients (median, 54 years) with a CHA
2
DS
2
-VASc score of 0 (190 males) or 1 (42 females) were analyzed (dabigatran, n=36; rivaroxaban, n=121; apixaban, n=59; edoxaban, n=16). Standard and reduced doses were administered in 149 and 83 patients, respectively, but essentially a dose reduction was not necessary in 95.2% of the reduced dose patients. All DOACs were discontinued on the day of the procedure and no pre-ablation heparin bridging was performed.

Results:
The standard and reduced dose patients required a similar heparin dosage (median, 13630 vs. 13330 units, P=0.671), and the mean and maximum activated clotting times were 303 and 329 seconds with the standard doses, and 310 and 333 seconds with the reduced doses, respectively (P=0.012 and 0.076). No symptomatic thromboembolisms occurred. The incidence of major and minor bleeding and silent cerebral ischemic lesions on magnetic resonance imaging was 0.7%, 5.4%, and 10.0% with the standard doses and 0%, 1.2%, and 12.5% with the reduced doses, respectively (P=0.642, 0.107, and 0.558). The standard and reduced doses revealed a similar bleeding risk (2 with minor bleeding vs. 0; P=0.305) during the post-ablation oral anticoagulation (median, 106 days vs. 92 days; P=0.627).

Conclusions:
Standard and reduced DOAC doses for periprocedural anticoagulation revealed a similar thromboembolic and hemorrhagic risk in CHA
2
DS
2
-VASc low-risk patients undergoing AF ablation. A reduced dose use, if not according to the dose reduction criteria, may not contribute to either a reduction in bleeding or an increase in thromboembolisms associated with AF ablation.
Abstract 12935: Age Related Cardiac Dysfunction and Pancreatic β-cell Function in Diabetes Were Improved by P53 Inhibition Through Parkin-mediated Mitophagy
Authors: Ariyoshi Makoto , Hoshino Atsushi , Okawa Yoshifumi , Tateishi Syuhei , Hato Daichi , Yamanaka Ryoetsu , Honda Sakiko , Fushimura Yohei , Iwai-Kanai Eri , Matoba Satoaki
Published: April 2024

Previous studies have demonstrated mitochondrial dysfunction has roles in the progression of several diseases and tumor suppressor p53 has a boarder role that extends to the modulation of mitochondrial homeostasis. Here we show that cytosolic p53 impairs autophagic degradation of damaged mitochondria and facilitates mitochondrial dysfunction during the development of heart failure and diabetes, and that cytosolic p53 binds to
Parkin
and disturbs its translocation to damaged mitochondria and their subsequent clearance by mitophagy. In heart, prevalence and induction of mitochondrial autophagy is attenuated by senescence or doxorubicin (DOX) treatment. And p53-deficient mice show less decline of mitochondrial integrity and cardiac function reserve with increasing age or after treatment with DOX. And, overexpression of
Parkin
improves the functional decline in aged heart, and is accompanied by decreased senescence-associated β-galactosidase activity and proinflammatory phenotypes. Furthermore, regarding diabetes, p53 deficiency protects against the development of diabetes in streptozotocin (STZ)-induced type 1 and
db/db
mouse models of type 2 diabetes. Glucolipotoxicity stimulates NADPH oxidase via RAGE and TLR4. This oxidative stress induces the accumulation of p53 in the cytosolic compartment of pancreatic β cells in concert with ER stress. The occurrence of mitophagy is maintained in STZ-treated
p53–/–
mice that exhibit preserved glucose oxidation capacity and subsequent insulin secretion signaling, leading to better glucose tolerance. These protective effects are not observed when
Parkin
is deleted. Besides, pifithrin-α improves mitochondrial dysfunction and glucose intolerance in both STZ-treated and
db/db
mice. Thus, p53-mediated inhibition of mitophagy modulates dysfunction of heart and islet, raising the possibility that therapeutic activation of mitophagy by inhibiting cytosolic p53 may ameliorate heart failure and diabetes.
Abstract 12981: Long-term Efficacy of Balloon Pulmonary Angioplasty in Patients With Inoperable Chronic Thromboembolic Pulmonary Hypertension
Authors: Tatebe Shunsuke , Sugimura Koichiro , Aoki Tatsuo , Yamamoto Saori , Yaoita Nobuhiro , Kozu Katsuya , Sato Haruka , Satoh Kimio , Shimokawa Hiroaki
Published: April 2024

Background:
Balloon pulmonary angioplasty (BPA) has been shown to markedly improve both exercise capacity and pulmonary hemodynamics in patients with inoperable chronic thromboembolic pulmonary hypertension (CETPH). Since 2009, we have adopted BPA as a first-line treatment strategy for inoperable CTEPH. The aim of this study was to evaluate the long-term efficacy of BPA in patients with inoperable CTEPH.

Methods and Results:
From 1992 to 2014, we treated a total of 110 patients with inoperable CTEPH at our Hospital. Among them, we excluded 11 patients from the present analysis due to advanced cancer or multiple organ failure at admission. We divided the remaining 99 patients into 2 groups; the historical control (HC) group (N=35; mean age, 62 years; M/F = 30/5) who were admitted from 1992 to 2008 and the BPA group (N= 64; mean age, 64 years; M/F= 49/15) who were admitted from 2009 to 2014. We compared baseline characteristics, hemodynamics and long-term survival between the 2 groups. There was no significant difference in baseline parameters, including age, sex, WHO functional class or serum BNP levels between the 2 groups. Regarding hemodynamic parameters, the BPA group had significantly higher pulmonary capillary wedge pressure compared with the HC group (9±0.4 vs. 7±0.6 mmHg, P<0.01). The median follow-up period was 53 months (IQR 26-80 months) for the HC group and 23 months (IQR 13-39 months) for the BPA group. Kaplan-Meier analysis showed that the survival rate was significantly better in the BPA group compared with the HC group (log-rank P=0.02), with the estimated 5-year survival probability of 98% for the BPA group and 73% for the HC group (
Figure
). The multiple Cox hazard analysis showed that both age (hazard ratio 1.07, P=0.02) and the HC group (hazard ratio 9.2, P=0.01) were independent predictor of mortality.

Conclusions:
These results indicate that BPA has a beneficial impact on long-term survival in patients with inoperable CTEPH.
Abstract 12989: Attenuation of Renal Fibrosis and Inflammation in
Npr1
Haplotype Mice by Retinoic Acid and Sodium Butyrate via Interactive Modulation of STAT1, HDACs and NF-κB
Authors: Kumar Prerna , Periyasamy Ramu , Gogulamudi Venkateswara R , Pandey Kailash N
Published: April 2024

Introduction:
Mice lacking functional guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA) gene (
Npr1
) exhibit hypertension, kidney disease, and heart failure. In this study, we investigated the effect of butyric acid, a histone deacetylase (HDAC) inhibitor and all-trans retinoic acid (ATRA) hybrid drug (ATRA-BA) on the attenuation of renal inflammation and fibrosis in
Npr1
haplotype mice.

Methods and results:
Adult (18-20 week old) male
Npr1
haplotype (1-copy;
Npr1
+/-;
n=10), wild-type (2-copy;
Npr1
+/+
; n=10), and gene-duplicated (3-copy;
Npr1
++/+
; n=10) mice were treated with ATRA-BA (1.0 mg/kg/day) by intraperitoneal injections for 2-weeks. A significant decrease in systolic blood pressure was observed in ATRA-BA-treated
Npr1
+/-
mice (treated, 113.3 ± 1.5 vs. control, 130.4 ± 1.9; p < 0.01; n=10). Treatments with ATRA-BA showed a marked reduction in tubulo-interstitial fibrosis (50%, p < 0.001) and a decrease in renal col 1α levels (treated, 25.9 ± 1.2 vs. control, 57.2 ± 2.9, p < 0.001) in
Npr1
+/-
mice. Significant reduction was observed in renal IL-6 (55%, p < 0.001) and MCP-1 (61%, p < 0.01) protein levels in ATRA-BA-treated
Npr1
+/-
mice compared with untreated controls. There was significantly increased renal NF-κB (p65) protein expression and activity in
Npr1
+/-
mice; however, reduced levels were observed in
Npr1
+/++
mice compared with wild-type mice. Renal NF-κB (p65) activity decreased (52%, p < 0.01) in drug-treated
Npr1
+/-
mice compared with controls. Treatment with ATRA-BA facilitated dissociation of HDAC1/2 from STAT1 protein complex and enhanced STAT1 acetylation. Furthermore, acetylated STAT1 formed complex with NF-κB (p65), thereby inhibiting its activity. Higher urinary albumin creatinine ratio and urinary protein was detected in
Npr1
+/-
mice compared with
Npr1
+/+
mice and a complete reversal was observed in drug-treated
Npr1
+/-
animals.

Conclusions:
The present results demonstrate that ATRA-BA reduces blood pressure and repairs the abnormal renal pathology in haplotype
Npr1
+/-
mice by modulating STAT1, HDAC1/2, NF-κB (p65) interactions. The findings will be important in developing the strategies for treating the hypertension and renal pathological conditions.
Abstract 13029: Longitudinal Association of Cardiorespiratory Fitness and Physical Activity With Left Ventricular Structure and Function: The Coronary Artery Risk Development In Young Adults (CARDIA) Study
Authors: Markman Timothy M , Blaha Michael , Venkatesh Bharath A , Shah Ravi , Colangelo Laura , Lloyd-Jones Donald M , Murthy Venkatesh L , Lima Joao A , Desai Chintan
Published: April 2024

Introduction:
Physical activity (PA) and cardiorespiratory fitness (CRF) are related but distinct markers of cardiovascular risk. We aim to characterize the association of PA and CRF with left ventricular (LV) structure and function.

Methods:
CARDIA enrolled adults age 18 to 30 years in 1985-86 (Year 0). We assessed the relationship between PA (exercise units, {EU}) and CRF (treadmill minutes) from Year 0 with LV structure and function by echocardiography at Year 25. For PA, 200 EU represents a 70-kilogram man expending 300 kilocalories in three 50-minute walks. We used multivariable linear regression to determine if change in PA and CRF were independent predictors of LV structure and function at Year-25.

Results:
We included 3,339 participants (44% male, 46% black) stratified by the median of PA and CRF. As shown in the Table, participants with CRF above the median had more favorable LV structure and function, including lower LV mass (LVM), higher septal and lateral mitral annular velocity (e’), and more negative global longitudinal strain (GLS). Participants with PA above the median also had more negative GLS and greater septal e’ than those below the median, but the association was not significant in multivariable regression with CRF in the model. CRF remained significantly associated with more negative GLS even when PA was included (β = -0.09, P < 0.001). Compared to participants who remained below the median CRF from Year 0 to Year 20, those who moved from below the median in CRF at Year 0 to above the median at Year 20 had more favorable Year 25 GLS (-14.9% and -15.4%, P = 0.01) and Year 25 LVM (160 gm and 167 gm, P = 0.01). Those who moved above the median in PA also had favorable LV remodeling; however, the association was attenuated with multivariable adjustment.

Conclusions:
CRF in young adulthood is more closely associated with favorable parameters of LV structure and function 25 years later than PA. Improvement in CRF was associated with more favorable GLS and LV mass 20 years later.
Abstract 13031: Ultrasound Molecular Imaging of Inflammation in Mouse Abdominal Aorta With Modulated Acoustic Radiation Force
Authors: Wang Shiying , Herbst Elizabeth B , Unnikrishnan Sunil , Klibanov Alexander L , Mauldin F W , Hossack John A
Published: April 2024

Introduction:
Ultrasound molecular imaging has demonstrated the ability to detect the molecular signature of early vascular inflammation. Consequently, it may enable more timely detection of atherosclerosis. Unfortunately, existing methods face substantial challenges in large blood vessels. Recently, a new modulated acoustic radiation force (ARF)-based imaging method has demonstrated rapid and quantitative measurements of biomarkers in large vessels.

Hypothesis:
We hypothesized that a clinically translatable method could be tested pre-clinically for non-invasive rapid detection of vascular cell adhesion molecule (VCAM)-1 in the mouse abdominal aorta.

Methods:
C57BL/6 mice fed with a high-fat diet were used as a diet-induced obesity model (M
DIO
). Normal mice were used as controls (M
Normal
). Anti-VCAM-1 and isotype control antibodies were conjugated to microbubbles to form the VCAM-1 targeted (MB
VCAM-1
) and control (MB
Control
) microbubbles, respectively. Constant infusions of microbubbles were performed, during imaging, for 180 s (
A
). A parameter, residual-to-saturation ratio (RSR), was extracted and used to assess VCAM-1 expression. Four groups of mice were studied (5 mice per group): M
Normal
+ MB
Control
, M
DIO
+ MB
Control
, M
Normal
+ MB
VCAM-1
, and M
DIO
+ MB
VCAM-1
.

Results:
RSR of the M
DIO
+ MB
VCAM-1
group was 56.0%, significantly higher (
p
< 0.0005) than that of any other group (-94.9% for M
Normal
+ MB
Control
, -13.9% for M
DIO
+ MB
Control
, and -37.4% for M
Normal
+ MB
VCAM-1
) (
B
). Immunohistochemistry confirmed M
Normal
exhibited minimal VCAM-1 staining while M
DIO
exhibited VCAM-1 staining localized to the endothelium (
C
).

Conclusions:
In conclusion, a statistically significant assessment of VCAM-1 in mouse abdominal aorta was achieved using the modulated ARF-based method. This technique yields progress towards rapid targeted molecular imaging in large blood vessels, and thus has long-term potential for early diagnosis of atherosclerosis.