bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 4143707: Subclinical Coronary Plaque and Atherosclerotic Cardiovascular Disease Events among Overweight Men and Women: A Multi-Cohort Study
Authors: Tizon-Marcos Helena , Al Rifai Mahmoud , Pappalettere Carolina , Blaha Michael , Marrugat Jaume , Castaner Olga , Nasir Khurram , Al-Mallah Mouaz , Erbel Raimund , Stang Andreas , Jöckel Karl , Lehmann Nils , Schramm Sara , Schmidt Boerge , Poirier Paul , Cainzos Achirica Miguel
Published: November 2024

Introduction:
The population of men and women who are overweight (defined as a BMI 25-29.9 kg/m
2
) continues to grow at fast pace. The prevalence and prognostic implications of a high coronary artery calcium (CAC) score in this group are poorly defined.

Aims:
Using a multiethnic cohort of men and women, we compared the ASCVD event-risk at follow up in normal weight, overweight, and obese individuals, overall and further stratified by CAC scores.

Methods:
Individual-level pooled analysis of participants from MESA, JHS, HNR, and FHS free of ASCVD at baseline and in whom CAC and BMI data were available. Participants with BMI <18.5 kg/m
2
were excluded. CAC was categorized as =0, 1-99, and ≥100 Agatston Units. The primary outcome was ASCVD events during follow-up, comprising fatal and non-fatal coronary heart disease and stroke events.

Results:
A total of 14,740 participants were included. The BMI was distributed as follows: BMI <25 kg/m
2
: 27.4%, BMI 25-29.9 kg/m
2
: 40.0%, BMI 30-34.9 kg/m
2
: 20.8%, BMI >=35 kg/m
2
: 11.8%. Among overweight participants, 52% had CAC>0, and 22% had CAC≥100 (17% prevalence among individuals with normal weight). The distribution of CAC by BMI categories is presented in the Figure. The incidence of ASCVD events among overweight participants was: 3.8 per 1000 person-years for those with CAC=0, 8.1 for CAC>0 - <=99, and 20.7 for CAC≥100. In regression analyses, compared to BMI 18.5-25 kg/m
2
individuals (reference group), the adjusted HR of ASCVD events for overweight participants with CAC≥100 was higher than that for unselected obese participants (Figure). A sub-analysis restricted to participants free of prediabetes and diabetes yielded similar trends, with the combination overweight+high CAC score being associated with a higher ASCVD risk than those with obesity.

Conclusions:
The ASCVD risk of overweight people with CAC≥100 is higher than that observed among individuals with BMI≥30 kg/m
2
. Overweight individuals with high CAC scores comprise relatively frequent and high-risk group, which may benefit from systematic detection and aggressive risk-reduction interventions.
Abstract 4143745: Short- and Long-Term Outcomes of Antegrade versus Retrograde Approaches in Patients Undergoing Percutaneous Coronary Intervention for Chronic Total Occlusion: A Meta-Analysis
Authors: Goyal Aman , Khan Rozi , Tariq Muhammad Daoud , Abbasi Haleema Qayyum , Jain Hritvik , Sulaiman Samia , Kadam Esha , AlJaroudi Wael
Published: November 2024

Background:
Chronic total occlusion (CTO) percutaneous coronary intervention (PCI) is a complex procedure to restore blood flow in completely occluded coronary arteries with the aim of improving symptoms and quality of life. While CTO-PCI success rates have increased owing to advancements in antegrade and retrograde techniques, the choice of approach remains crucial. The antegrade approach is often the initial method chosen because of its relative simplicity, whereas the retrograde approach is considered in more complex cases or when the antegrade approach fails.

Aims:
The data suggest that the retrograde approach is associated with higher periprocedural complications, although the reports are conflicting. Our meta-analysis aimed to compare the efficacy and safety of the antegrade and retrograde approaches for CTO-PCI.

Methods:
A comprehensive literature search was conducted on PubMed, Embase, Google Scholar, and Scopus from inception until June 5, 2024. Pooled risk ratios (RR) with 95% confidence intervals (CI) were calculated using Review Manager, with a p-value of <0.05 considered significant. Random-effects models were used for all statistical analyses.

Results:
Twenty-two observational studies involving 49,152 CTO-PCI patients, with 35,844 and 13, 308 patients in the antegrade and retrograde arms, respectively, were included. The antegrade approach was associated with a significantly lower risk of in-hospital outcomes than the retrograde approach, including reduced mortality (RR=0.45, 95% CI: 0.28-0.72, p=0.0008), myocardial infarction (RR=0.37, 95% CI: 0.28-0.50, p<0.00001), major adverse cardiovascular events (RR=0.34, 95% CI: 0.25-0.46, p<0.00001), and cerebrovascular events (RR=0.50, 95% CI: 0.29-0.85, p=0.01) (Figure 1). In terms of long-term outcomes, both approaches had comparable risks for all-cause mortality (RR=0.71, 95% CI: 0.44-1.14, p=0.16) and myocardial infarction (RR=0.76, 95% CI: 0.38-1.52, p=0.44) (Figure 2).

Conclusion:
The antegrade approach is associated with significantly reduced risks of several in-hospital outcomes, but both approaches have comparable risks for long-term outcomes. Skillful and judicious use of the retrograde approach for CTO-PCI is recommended.
Abstract 4143871: Effect of Continuous Estrogen on Peripheral Microvascular Function in Women of Trans Experience
Authors: Jaramillo-Torres Maria , O'Connell Emily , SenthilKumar Gopika , Durand Matthew , Freed Julie
Published: November 2024

We have previously shown that chronic exposure to 17β-estradiol promotes microvascular endothelial dysfunction in isolated human arterioles from healthy adult individuals assigned male at birth (IAMB). Microvascular dysfunction is a strong predictor of future cardiac events and women of transgender experience have a higher risk of cardiovascular death, however the effects of continuous gender affirming hormone therapy on
in vivo
microvascular function remain unknown. We hypothesized that
in vivo
endothelial-derived, nitric oxide (NO)-mediated vasodilation is impaired within the peripheral microvasculature in IAMB who have been exposed to continuous gender affirming hormone therapy compared to age-matched controls. Inclusion criteria for this prospective, cross-sectional study included healthy IAMB, age 18-60 years, no past medical history of cardiovascular disease, and a minimum 1-year exposure to gender affirming hormone therapy (estrogen; E2). Peripheral microvascular function was assessed using Laser Doppler Flowmetry with microdialysis (LDF-MD). Two microdialysis fibers were placed in the ventral forearm of eleven subjects (3 IAMB, 8 IAMB+E2) with sites randomized to serve as 1) control (lactated Ringer’s) and 2) infusion with the nitric oxide synthase inhibitor L-NAME. After baseline measurement, vehicle and L-NAME were administered followed by infusion of two doses of acetylcholine (Ach; 1mM, 10mM). Following a rest period, a local heating protocol was then implemented to assess NO-mediated dilation and maximal vasodilation (39°C and 42°C + sodium nitroprusside, respectively). Compared to controls, a reduced trend in dilation to Ach was observed in IAMB+E2 (1mM Ach max dilation (%): 57.2±13.0 vs 80.2±8.7,
p
=0.33; 10mM Ach max dilation (%): 70.4±7.0 vs 93.7±3.1,
p
=0.08, IAMB+E2 and IAMB, respectively). A reduced trend in dilation was also observed in IAMB+E2 compared to controls in response to local heating (32.9±8.9 % vs 60.7±6.2 %, respectively,
p
=0.10). The degree to which dilation was inhibited in the presence of L-NAME was higher with the local heating protocol for the control group (46.6%) vs the estrogen group (22.2%). Together, this pilot study suggests that
in vivo
microvascular function may be impaired by chronic estrogen therapy in women of trans experience.
Abstract 4143917: Novel Precision Cardiology Treatment for PRKAG2 Cardiomyopathy, a Subset of Patients with Wolff-Parkinson-White Syndrome
Authors: Missinato Maria Azzurra , Lemoine Kellie , Ho Giang , Fong Joshua , Wang Jie , Abdulkadir Sami , Yu Aaron , Jordan Maryam , Kasmer Sydney , Delos Santos Nathaniel , Meng Qingying , Hedlund Maria , Lam Son , Zhu Yiming , Paige Sharon , Blasi Eileen , Karamanlidis Georgios
Published: November 2024

Background:
PRKAG2 syndrome is an inherited disease caused by mutations in the
PRKAG2
gene, which encodes the γ2 regulatory subunit of AMP-activated protein kinase (AMPK). These mutations result in increased AMPK activity leading to aberrant myocardial glycogen deposition. Patients with PRKAG2 syndrome can develop cardiac hypertrophy, ventricular pre-excitation, supraventricular arrhythmias and conduction system disease, all of which increase the risk of sudden cardiac death. Some patients develop progressive heart failure necessitating heart transplantation. Current treatments include standard medications for heart failure and pacemaker/ICD implantation for arrhythmias. However, there is a significant need to treat the underlying causes of PRKAG2 syndrome. Small interfering RNA (siRNA) oligonucleotides present a promising therapeutic approach by reducing mutant
PRKAG2
mRNA levels, thereby lowering AMPK activity.

Hypothesis:
Antibody oligonucleotide conjugates (AOCs) can be designed to target
PRKAG2
mRNA to treat PRKAG2 syndrome.

Aims:
To investigate the tolerability and efficacy of an AOC targeting
PRKAG2
mRNA in mice and non-human primates (NHPs).

Methods:
iPSC-derived cardiomyocytes were used to screen and identify a potent siRNA against
PRKAG2
. The lead siRNA was conjugated to an anti-TfR1 monoclonal antibody to create AOC 1072 for targeted cardiac delivery and was subsequently administered to mice and NHPs.

Results:
In vitro
screening identified an siRNA with an EC50 <10 pM and a maximum
PRKAG2
mRNA reduction >90%. A single, IV injection of the mouse surrogate of AOC 1072 at 1 mg/kg (siRNA component) resulted in a potent and durable myocardial
Prkag2
mRNA reduction in mice, with about 75% and 50% reduction observed at 2 and 6 months, respectively. AOC treatment reduced glycogen accumulation in the skeletal muscle of mice expressing the
Prkag2
-R528G disease variant. A single IV administration of AOC 1072 at 3 mg/kg (siRNA component) resulted in about 85% reduction of cardiac
PRKAG2
mRNA in NHPs at 28 days, with no adverse effects (ECG or heart weight).

Conclusions:
Our data suggests AOC technology can be used efficiently to deliver siRNA to the heart. This precision cardiology treatment can significantly reduce
PRKAG2
mRNA expression, offering a promising therapeutic approach for PRKAG2 syndrome, a currently incurable genetic condition with very limited treatment options.
Abstract 4143933: Body size relations of ascending aorta dimensions: An analysis of 49,193 adults in the UK Biobank reveals an optimal normalization method
Authors: Tavolinejad Hamed , Beeche Cameron , Dib Marie-Joe , Salman Oday , Azzo Joe David , Witschey Walter , Maynard Hannah , Chirinos Julio
Published: November 2024

Background:
Organ size and body size relations are often non-linear (allometric). However, allometric relations for thoracic aorta are poorly understood and current practice is based on linear (ratiometric) indexation of aortic dimensions, which can provide misleading information in individual patients. Assessing allometric relationships can have important implications for the detection of aneurysms, particularly at the extremes of body size.

Methods:
A U-Net convolutional neural network (CNN) segmentation architecture was trained, validated, and used to segment the ascending aorta (AA) and derive its maximum cross-sectional dimensions using MRI scans obtained from 49,193 UK Biobank participants. Sex-adjusted allometric (log-log) models were used to derive allometric exponents describing the relationship of AA size (diameter and cross-sectional area) to body size (height and BSA) in a healthy reference subgroup (n=3,972). Prognostic associations with all-cause mortality and aneurysm complications were then assessed in the entire population over a median follow-up of 66 months.

Results:
Relationships between AA diameter or area and BSA were highly non-linear (
Table 1
) and exhibited significant differences between males and females (P for interaction=0.013), precluding the use of a single exponent for both sexes. In contrast, a quasi-linear relationship was found for aortic area and body height (exponent=0.98), making simple ratiometric indexation allometrically adequate. Moreover, no differences in this allometric relation were found between men and women (P for interaction=0.32), indicating its suitability regardless of sex. In contrast, ratiometric diameter/height, diameter/BSA, or area/BSA indexation provided markedly and systematically biased prevalence estimates for aortic dilation, misclassifying many individuals at the extremes of body size (
Figure
). Finally, the use of the linear area/height ratio was consistently predictive of death and aneurysm complications in the overall population and provided the highest C-index for aneurysm complications regardless of body size (
Table 2
).

Conclusions:
In contrast to all other indexation methods, the linear AA area/height ratio is a practical, allometrically correct, and most informative aortic size index, and can be utilized equally in men and women. This should guide strategies for aneurysm detection and decision making in clinical practice and future studies.
Abstract 4143939: A large-scale multi-view deep learning-based assessment of left ventricular ejection fraction in echocardiography
Authors: Jing Linyuan , Long Aaron , vanMaanen David , Rocha Daniel , Hartzel Dustin , Kelsey Christopher , Ruhl Jeffrey , Beecy Ashley , Elnabawi Youssef , Metser Gil , Mawson Thomas , Tat Emily , Jiang Nona , Duffy Eamon , Hahn Rebecca , Homma Shunichi , Haggerty Christopher , Poterucha Timothy , Elias Pierre
Published: November 2024

Introduction:
Recent studies using deep learning techniques have demonstrated promising left ventricular ejection fraction (LVEF) assessment from transthoracic echocardiograms (TTEs). However, most prior studies have focused on videos from a single apical view, a technique known to be subject to limitations given the regionality of LV systolic function. We hypothesized that a deep learning model trained to include echocardiographic video clips from multiple views from a large dataset will improve accuracy in LVEF assessment.

Methods:
We identified all adult TTEs with a clinically reported LVEF at Columbia University between 2019-2024. A view classification model was trained to identify apical 4 and 2-chamber and parasternal long and short-axis views for LVEF assessment. The internal dataset was split into train, validation and test sets to train spatiotemporal convolutional models for each of the 4 views to assess LVEF for each video clip. The median clip-level LVEF within a study was used to derive a study-level LVEF. The model was evaluated on an internal test set and a large external test set, which included all available adult TTEs from Weill Cornell Medical Center since 2011. As benchmark comparison, the previously published EchoNet-Dynamic model was also evaluated on the external test set.

Results:
The model was trained and validated on 97,566 internal studies, comprising 1,424,265 videos from 60,741 unique patients. The model achieved state of the art performance on the internal test set (16,396 studies), with mean absolute error (MAE) of 3.4% and root mean squared error (RMSE) of 4.6%. Multi-view results were superior to all single-view models. Model showed robust predictions on external test set (179,298 studies), with MAE of 5.6% and RMSE of 7.1% and outperformed EchoNet-Dynamic (Table).

Conclusions:
We developed a deep learning model trained on multiple echocardiographic views using the largest dataset to date. Our model achieved state-of-the-art accuracy in assessing LVEF with a level of agreement between the AI and cardiologist LVEF assessments comparable to cardiologist interobserver variability. Further studies are underway to study the implementation of these models within clinical systems.
Abstract 4143955: Prevalence and Burden of Coronary Artery Calcium Across the Pooled Cohort Equation versus the American Heart Association PREVENT Risk Calculator
Authors: Gershon Gabrielle , Razavi Alexander , Yang Yan , Dzaye Omar , Whelton Seamus , Blaha Michael , Blumenthal Roger , Sperling Laurence , De Cecco Carlo , van Assen Marly
Published: November 2024

Background:
The 2013 Pooled Cohort Equation (PCE) has been a useful starting point to assess atherosclerotic cardiovascular disease (ASCVD) risk. In 2023, the PREVENT risk calculator was developed and validated as a contemporary calculator considering the cardiovascular-kidney-metabolic health paradigm. Coronary artery calcium (CAC), measured on non-contrast cardiac computed tomography (CT), improves ASCVD risk stratification beyond traditional risk factors. However, the prevalence of CAC burden across PCE versus PREVENT risk groups is unknown.

Hypothesis:
We hypothesized that there would be a higher CAC burden for PREVENT vs PCE calculated risk across low, borderline-intermediate, and high-risk groups.

Methods:
This retrospective study included 6,003 asymptomatic individuals who underwent CAC scoring for ASCVD risk stratification from 2010-2023 at Emory. The 10-year risk for ASCVD according to PCE and base PREVENT were retrospectively calculated. CAC was quantified using the Agatston method. CAC scores across PREVENT and PCE groups were compared using Chi-square tests, using CAC (0, 1-99, 100-299, ≥300) and PCE/PREVENT (low<5, borderline-intermediate 5-19, high≥20%) 10-year risk categories. Concordant/discordant groups were created according to agreement between PCE and PREVENT (
>
7.5 PCE/PREVENT <7.5).

Results:
The mean age 57(9), 41% were women, and 11% were Black people. PCE classified 51.8% (n=3112) low, 41.5% (n=2490) borderline-intermediate, and 6.7% (n=401) high-risk participants, whereas PREVENT classified 72.1% (n=4329) low, 27.3% (n=1641) borderline-intermediate, and 0.6% (n=33) high-risk participants. Among participants, 41.2% (n= 2474) had CAC=0, 36.5% (n=2189) had 1-99, 11.4% (n=687) had 100-299, and 10.9% (n=653) had ≥300 CAC. For both PCE and PREVENT, higher risk groups had higher median CAC. CAC distribution was heterogeneous across risk categories within both PCE and PREVENT, and between PCE and PREVENT (p<0.001). CAC prevalence was 72% and 81% for individuals with borderline-intermediate risk according to PCE and PREVENT, respectively. Median CAC scores were similar across discordant PCE/PREVENT risk groups (33 (1-201) vs 29 (1-201)).

Conclusion:
The prevalence of CAC was similar across calculated PCE and PREVENT risk groups, including individuals with borderline-intermediate risk. These results underline the continued utility of CAC at improving risk stratification beyond PCE and PREVENT.
Abstract 4143989: Differences in Patient-Centered Outcomes Between Patients with Heart Failure and With and Without Renal Dysfunction
Authors: AWAL ISSAHAKU , Cha Geunyeong , Thapa Ashmita , Kang JungHee , Chung Misook , Biddle Martha , Wu Jia-Rong , Latimer Abigail , Thompson Jessica , Moser Debra
Published: November 2024

Background:
Heart failure (HF) is not a homogeneous condition, and comorbidities, such as renal dysfunction, commonly complicate the clinical picture. However, differences in patient-centered outcomes (PCO), such as depressive symptoms, health-related quality of life, functional status, adherence, and self-care behaviors, have not been explored in patients with HF with and without renal dysfunction.

Hypothesis:
We hypothesized that there is a significant difference in PCO between patients diagnosed with heart failure with renal dysfunction and those without renal dysfunction.

Methods:
A secondary data analysis was conducted using the RICH Heart Program Heart Failure Database. We included 517 patients (61 ± 13 years old, 66% male, 66% NYHA class III/IV) with HF with (22%) and without (78%) renal dysfunction. Depressive symptoms were measured using the Patient Health Questionnaire-9, health-related quality of life using the Minnesota Living with Heart Failure Questionnaire, functional status using the Duke Activity Status Index, adherence using the Medical Outcomes Study Specific Adherence Scale, and Self-care using the Self-care of Heart Failure Index. Independent samples t-tests were conducted to compare PCO between the two groups.

Results:
All PCO were significantly different between the two groups. Compared to patients without renal dysfunction, those with renal dysfunction had worse depressive symptoms (8.1 ± 5.9 vs 10.0 ± 6.0, respectively, p = 0.001), poorer health-related quality of life (50.5 ± 24.9 vs 58.0 ± 25.6, p = 0.005, respectively), and lower functional status (11.7 ± 11.7 vs 77.0 ± 7.1, p < 0.001, respectively). Patients with renal dysfunction had better scores on self-reported adherence (29.2 ± 6.0 vs 25.6 ± 7.7, p < 0.001), self-care maintenance (61.6 ± 21.1 vs 54.3 ± 23.2, p = 0.03), and self-care management (60.9 ± 23.0 vs 53.8 ± 22.9, p = 0.04) than those without.

Conclusions:
Even though patients with HF and renal dysfunction reported better adherence and self-care behaviors, they still had higher levels of depressive symptoms, worse health-related quality of life, and lower functional status. This suggests that knowledge of their comorbidity prompted better self-care, but other PCO remained poor. Increased attention to promoting specific self-care behaviors that focus on renal dysfunction in the context of HF should be tested to determine if PCO can be improved in this patient population.
Abstract 4143995: Association of left ventricular summit arrhythmias with pathogenic gene variants
Authors: Kondamudi Nitin , Bevan Graham , Nazer Babak , Stergachis Andrew , Hisama Fuki , Chatterjee Neal
Published: November 2024

Background:
Genetic cardiomyopathies (CM) are increasingly diagnosed among patients with ventricular arrhythmias (VA). There is increasing recognition of the regional nature of potential arrhythmic substrate in genetic CM, including involvement of the basal left ventricular (LV) septum and LV summit. Whether anatomically constrained ventricular arrhythmias predict genetic CM is not known.

Research question:
Are LV summit arrhythmias associated with pathogenic/likely pathogenic (P/LP) gene variants?

Aims:
To examine whether LV summit VA is associated with P/LP gene variants in patients referred for ventricular tachycardia (VT) or premature ventricular complex (PVC) ablation.

Methods:
The cohort included patients with arrhythmia and cardiomyopathy panel genetic testing (Invitae) between 2018 and 2024 who also underwent VT/PVC ablation at the University of Washington. VA location (summit vs. non-summit) was defined using electroanatomic voltage and activation mapping. The prevalence of P/LP gene variants in those with and without LV summit VA were compared using Fisher’s exact testing. Logistic regression was used to examine the association of LV summit VA with P/LP gene variants with multivariable adjustment for anti-rhythm drugs and standard risk factors including age, sex, and LV ejection fraction (LVEF).

Results:
The study included 57 patients (mean age 55±16 years, 82% male, LVEF 44±13%, n=22/35 PVC/VT ablation). LV summit VA was identified in 10 patients and P/LP gene variants were found in 22 patients. The prevalence of P/LP genetic variants was significantly higher in LV summit vs. non-summit patients (70% vs. 32%, p=0.04). Those with LV summit arrhythmias had a 7-fold higher odds of P/LP genetic variants compared to non-LV summit arrhythmias (adj OR [95% CI]: 6.6 [1.1-39.6]. P/LP variants in LV summit VA individuals were either TTN (n=3 [2 truncating variant, 1 splice site]) or LMNA (n=4 [3 missense, 1 deletion]).

Conclusion:
LV summit VA are associated with P/LP genetic variants with known tropism for basal septal pathology. This preliminary work supports efforts to expand the paradigm that anatomically-specific VA may represent the electrical manifestation of genetic CM.
Abstract 4144021: The Sodium-Potassium Pump Activations and the Sex-Specific Antiarrhythmic Action of Mirabegron
Authors: Liu Xiao , Zhang Liyang , Kote Anxhela , Tisdale James , Chen Zhenhui , Chen Peng-Sheng
Published: November 2024

Background:
β-3 adrenoceptor (AR) activation is antiarrhythmic in a canine model of ventricular arrhythmia. Na-K ATPase (NKA) expression is higher in female than male rats and is stimulated by β-3 agonist due to an inhibitory oxidative modification.

Objective:
To test the hypothesis that mirabegron, a β-3 agonist approved by the FDA for treating overactive bladder, has more anti-fibrillatory effects in females than in male rabbit ventricles due to NKA stimulation.

Methods:
We performed optical mapping studies in 6 male and 6 female Langendorff-perfused rabbit hearts at baseline, then sequentially after adding mirabegron (500 and 1000 nM), followed by ouabain (500 nM), a specific NKA blocker. All hearts underwent 10 attempts of ventricular fibrillation (VF) induction with a ventricular burst pacing (20 Hz for 10 s) at each stage of the experiment.

Results:
A
shows phase maps during VF. Triangles indicate PSs. Mirabegron 1000 nM significantly decreased VF inducibility (number of VF induced in the 10 attempts) from 4.8±3.2 to 2.2±2.9 (p=0.034) in females but not in males (from 4.5±2.6 to 5.0±2.8, p=0.656) (
B
). Consistent with our previous reports, Mirabegron 1000 nM decreased PSs/VF (number of phase singularity per VF episode) in females (from 10.5±2.7 to 2.9±3.3, p=0.010) but not in males (from 11.3±2.3 to 9.7±2.6, p=0.167). Adding ouabain did not reverse mirabegron’s effects on PSs/VF (2.4±3.9, p=0.706) in females. However, it decreased PSs/VF significantly in males (3.4±4.0, p=0.038). Mirabegron decreased conduction velocity (CV, activation time
-1
, /s) in both males (from 40.3±6.5 to 30.4±5.3, p<0.001) and females (from 38.8±7.2 to 30.0±4.9, p=0.010). Adding ouabain did not further change CV in both males (31.6±8.2, p=0.434) and females (28.1± 5.3, p=0.066). Ouabain decreased APD
25
after mirabegron significantly (54.6±6.6 ms vs 68.4±3.4 ms in males, p=0.019; 51.4±6.9 ms vs 65.6±6.5 ms in females, p=0.049, 200 ms pacing cycle length), but did not change the APD
80
.

Conclusion:
Mirabegron reduced PSs/VF and VF inducibility more in females than males. These sex-specific antiarrhythmic effects were not affected by NKA blockade with ouabain.
Abstract 4144037: Association Between Imaging Follow Up and 1-Year Reintervention Risk After Peripheral Vascular Intervention for Claudicatio
Authors: Romain Gaelle , Smolderen Kim , Cleman Jacob , Callegari Santiago , Rahman Mufti , Knight Derek , Mena-Hurtado Carlos
Published: November 2024

Background:
One-third of patients undergoing peripheral vascular intervention (PVI) for refractory claudication undergo a reintervention within 1 year. It is unknown whether receiving follow up imaging after PVI for claudication is associated with 1-year reintervention risk.

Aim:
To assess the association between receiving imaging follow-up within 3 months after PVI for claudication and 1-year reintervention risk before occurrence of major amputation.

Method:
We studied patients with claudication undergoing PVI who were alive and without reintervention at 3 months (2015-2018) in the Vascular Quality registry. Reintervention and imaging data were defined from Medicare data. Imaging follow-up included ankle brachial index (ABI), duplex ultrasound (DU), computed tomography angiography (CTA), and magnetic resonance angiogram (MRA) within 3 months post-PVI. We propensity-matched 1:1 for imaging follow-up status (No vs. Yes). The Aalen-Johansen method and Fine-Gray model assessed the 1-year cumulative incidence and reintervention risk (sub-hazard ratio, sHR) in patients without vs. with imaging follow-up, accounting for the competing mortality risk. Sensitivity analysis excluded ABI from imaging follow-up.

Results:
Each imaging follow-up status included 2,208 patients. Mean age was 71.3±8.4 years and 39.0% female. In patients with imaging, 47.1% received 1 imaging test, of which 75.1% were ABIs. Over 50% received ≥2 imaging tests within 3 months post-PVI, with 5% receiving ≥1 per month. The 1-year cumulative incidence and reintervention risk was similar in patients without vs. with imaging (17.5% 95%CI 15.9-19.2 vs. 18.8% 95%CI 17.1-19.2 and sHR 0.92 95%CI 0.80-1.06,
P
=0.259). When excluding ABI, the 1-year cumulative incidence and reintervention risk was lower in those without vs. with imaging (18.3% 95%CI 16.6-20.2 vs. 21.1% 95%CI 19.2-23.0 and sHR 0.86 95%CI 0.74-0.99,
P
=0.039) (
Figure
).

Conclusion:
Although over half of patients received multiple imaging tests within 3 months post-PVI for claudication, extensive imaging beyond ABI follow-up, was not associated with reintervention risk, which remained high with 1-year rates around 20%. Future efforts should study optimal imaging strategies and cost-benefit ratios.
Abstract 4144043: Automated Left Ventricular Volumetry using Artificial Intelligence in Coronary Calcium Scans (AI-CAC) Predicts Heart Failure Comparably to Cardiac MRI and Outperforms NT-proBNP: The Multi-Ethnic Study of Atherosclerosis (MESA)
Authors: Naghavi Morteza , Reeves Anthony , Atlas Kyle , Zhang Chenyu , Atlas Thomas , Budoff Matthew , Roy Sion , Henschke Claudia , Yankelevitz David , Wong Nathan , Levy Daniel
Published: November 2024

Introduction:
Artificial intelligence-powered coronary artery calcium scan (AI-CAC) provides more actionable information than currently reported. We have previously shown in the Multi-Ethnic Study of Atherosclerosis (MESA) that AI-enabled left atrial (LA) volumetry in CAC scans (AI-CAC) enabled prediction of atrial fibrillation (AF) as early as one year. Furthermore, we have shown adding AI-CAC LA volumetry to CHA
2
DS
2
-VASc risk score improved stroke prediction in MESA. We have recently reported that AI-CAC left ventricular (LV) volumetry and mass significantly predicted incident heart failure (HF) and outperformed NT-proBNP. In this study, we compared LV volume measured by AI-CAC versus cardiac magnetic resonance (CMR) imaging and NT-proBNP for predicting HF. Additionally, we compared AI-CAC vs. NT-proBNP for detection of left ventricular hypertrophy (LVH) defined by the 95th percentile of CMR LV mass.

Methods:
We used 15-year outcomes data for incident HF from 3078 asymptomatic MESA participants (52.3% women, age 62.2±10.3 years) who underwent both CAC scans and CMR at the baseline examination. We applied the AutoChamber
TM
(HeartLung.AI, Houston, TX) component of AI-CAC to 3078 CAC scans.Data on CMR semi-automated LV volume, NT-proBNP, and Agatston CAC score were obtained from MESA. Discrimination was assessed using the time-dependent area under the curve (AUC) for incident HF.

Results:
Over 15 years of follow up, 133 cases of HF were diagnosed. The AUC for AI-CAC (0.789) and CMR (0.793) were not significantly different (p=0.67) but were significantly higher than NT-proBNP (0.719) and Agatston score (0.664) (p<.0001) for prediction of incident HF. AI-CAC and CMR significantly improved the continuous Net Reclassification Index of NT-proBNP (0.37) and Agatston score (0.45) for HF prediction (p<0.001 for all). The AUC for AI-CAC vs. NT-proBNP for LVH was 0.871 vs. 0.600 for males and 0.854 vs. 0.600 for females.

Conclusion:
In this multi-ethnic asymptomatic population, AI-CAC automated LV volumetry and CMR semi-automated LV volumetry similarly predicted incident HF over 15 years and outperformed NT-proBNP. AI-CAC significantly outperformed NT-proBNP for detection of LVH. Both AI-CAC and CMR significantly improved on NT-proBNP and Agatston CAC score for predicting incident HF.
Abstract 4144057: AI-enabled Cardiac Chambers Volumetry in Non-Contrast Cardiac CT scans (AI-CAC) Detects HFrEF vs. HFpEF
Authors: Naghavi Morteza , Atlas Kyle , Zhang Chenyu , Reeves Anthony , Jaalouk Emily , Henschke Claudia , Yankelevitz David , Roy Sion , Budoff Matthew
Published: November 2024

Introduction:
Coronary artery calcium (CAC) scans contain more information than is currently reported. We have previously shown in the Multi-Ethnic Study of Atherosclerosis (MESA) that AI-enabled left atrial (LA) volumetry in CAC scans (AI-CAC) enabled prediction of atrial fibrillation (AF) as early as one year. Furthermore, we have shown adding AI-CAC LA volumetry to CHA
2
DS
2
-VASc risk score improved stroke prediction in MESA. We have recently reported that AI-CAC left ventricular (LV) volumetry and mass significantly predicted incident heart failure (HF) and outperformed NT-proBNP. In this report, we examined whether AI-CAC can distinguish heart failure with reduced ejection fraction (HFrEF) versus heart failure with preserved ejection fraction (HFpEF).

Methods:
We applied the AutoChamber
TM
(HeartLung.AI, Houston, TX) component AI-CAC to data from 75 patients who underwent both a cardiac CT scan and echocardiography at Harbor UCLA medical center. AI-CAC took on average 21 seconds per scan and reported estimated volume for left atrium (LA), left ventricle (LV), right atrium (RA), and right ventricle (RV). LV volume was indexed (LVVI) by dividing LV volume by body surface area (BSA) to allow a more accurate assessment of the size of the left ventricle relative to the size of the individual. The average BSA for males and female were 1.59 ± 0.3 and 1.29 ± 0.2, respectively. HFrEF and HFpEF were defined as EF<40% and EF>50% respectively.

Results:
Average EF was 57.5 ± 7.0 in males and 59.7 ± 8.1 in females, respectively. AutoChamber volume for HFpEF vs HFrEF were LA (84.8+35.3 vs 113.2+32.8 p=0.002), LV (109.9+36.7 vs 170.7+65.9 p=0.0007), RA (97.5+58.3 vs 117.2+51.1 p=0.18), RV (135.6+52.1 vs 176.2+70.8 p=0.008), LVW (116.1+39.1 vs 170.6+56.9 p=0.0005). Density plots in the figure show a clear distinction between HFpEF and HFrEF using AI measured LVVI and comparable results.

Conclusion:
AI-enabled automated cardiac chambers volumetry in CAC scans correlates well with echocardiography-based LVVI and detects HFrEF vs. HFpEF. Further studies are needed to evaluate the clinical utility of AI-CAC and the ability of AutoChamber for prospective detection of patients at risk of HFrEF vs. HFpEF.
Abstract 4144061: BubR1 Insufficiency Recapitulates Changes Associated with Age-Related Cardiac Pathologies
Authors: Pun Renju , Thapa Aradhana , Takafuji Sylar , Kay Gabrielle , Suzuki Rexton , Haas Aliya , Kim Michael , North Brian
Published: November 2024

Cardiovascular diseases (CVDs) continue to be the leading cause of mortality worldwide, surpassing all other conditions in annual fatalities. Aging is a significant risk factor for CVDs, as it induces structural and functional alterations in the cardiovascular system. BubR1, a serine/threonine protein kinase, plays a crucial role in regulating the spindle assembly checkpoint during mitosis. Previous studies have shown that BubR1 insufficiency results in premature aging phenotypes, including kyphosis, cataracts, and reduced lifespan. BubR1 hypomorphic mice, which express approximately 10% of normal BubR1 protein levels, display conduction abnormalities such as a prolonged QTc interval, and suffer from sudden cardiac death. Given that BubR1 protein levels decline with age, we hypothesize that BubR1 is essential for maintaining adult cardiac structure and function, and its loss may drive age-related cardiac pathophysiology. In this study, we characterized the tissue, cellular, and molecular phenotypes present in hearts isolated from BubR1 hypomorphic mice. Structural analysis revealed that these mice exhibit cardiac hypertrophy, as shown by increased heart weight and ventricular cardiomyocyte size. Masson’s trichrome staining indicated elevated fibrosis in both the ventricular and perivascular regions of BubR1 hypomorphic hearts. At the molecular level, these hearts showed increased levels of p21 and phospho-γH2AX, markers of cellular senescence and DNA damage. Transcriptomic profiling further indicated that BubR1 insufficiency leads to dysregulation of pathways critical to cardiac function, including those related to voltage-gated ion channel activity, contractile fiber organization, and extracellular matrix organization. A comparative analysis between BubR1 hypomorphic hearts and aged hearts revealed a set of common dysregulated genes, suggesting shared mechanisms underlying BubR1 insufficiency and cardiac aging. Since the risk of heart failure increases with age, we conducted additional comparison between BubR1 hypomorphic mice and end-stage heart failure patients which suggested that BubR1 insufficiency mimics the transcriptomic changes associated with heart failure, such as increased expression of
Nppa
and
Nppb
genes. Overall, our findings suggest that BubR1 is a key regulator of age-related cardiac pathologies and represents a potential therapeutic target for CVDs.
Abstract 4144064: AI-enabled bone mineral density (AutoBMD AI) measurement in coronary artery calcium (CAC) scans associated with high CAC score independently of conventional risk factors: Multi-Ethnic Study of Atherosclerosis (MESA)
Authors: Naghavi Morteza , Atlas Kyle , Zhang Chenyu , Reeves Anthony , Atlas Thomas , Henschke Claudia , Yankelevitz David , Roy Sion , Budoff Matthew
Published: November 2024

Background:
The association between low bone mineral density (BMD) and coronary artery calcium (CAC) has been reported before using manual measurement of thoracic BMD. Such manual measurements are time-consuming and subject to operator errors. We therefore used an AI-enabled BMD measurement tool to explore the relationship between CAC and BMD independent of traditional risk factors.

Methods:
The validation of AutoBMD AI (HeartLung.AI, Houston TX) has been reported previously. We applied AutoBMD to CAC scans of 6043 individuals (53.3% female, age 61.9±10.2 years) from the baseline examination (2000-2002) of MESA. Thoracic BMD was measured in T7-T9 vertebrae. Osteoporosis was defined as a T-Score below -2.5. Cox proportional hazards regression was used to calculate hazard ratios (HR) per unit change for 10-year coronary heart disease (CHD) prediction.

Results:
Average BMD in men and women were 164.4 ± 45.1 and 163.1 ± 50.0 g/cm
3
respectively (P=0.3467). Average CAC score for men and women were 223.4 ± 544.0 and 76.2 ± 241.3 cm
3
respectively (P<0.0001). A total of 1672 cases were classified as osteoporotic, which included 986 (58.0%) men and 714 (42.0%) women. After adjusting for age, gender and conventional CVD risk factors, average CAC score in osteoporotic cases versus normal BMD was 170.1 ± 531.1 vs. 130.4 ± 272.8 respectively (P = 0.004). Decreased BMD was associated with CHD independently of CAC score and CVD risk factors (HR=0.997, p=0.0143).

Conclusion:
Low BMD and high CAC are associated independently of age, gender, and traditional risk factors of cardiovascular diseases. Further studies are warranted to evaluate the potential added value of BMD to CAC for prediction of adverse events.
Abstract 4144067: AI-enabled Cardiac Chambers Volumetry in Coronary Artery Calcium Scans (AI-CAC) vs. ASCVD Pooled Cohorts Equation and PREVENT Risk Scores: The Multi-Ethnic Study of Atherosclerosis
Authors: Naghavi Morteza , Reeves Anthony , Atlas Kyle , Zhang Chenyu , Atlas Thomas , Henschke Claudia , Yankelevitz David , Budoff Matthew , FAN WENJUN , Yu Ruilin , Branch Andrea , Ma Ning , Roy Sion , Nasir Khurram , Molloi Sabee , Fayad Zahi , McConnell Michael , Kakadiaris Ioannis , Zulueta Javier , Maron David , Narula Jagat , Shah Prediman , Williams Kim , Abela george , Levy Daniel , Wong Nathan
Published: November 2024

Background:
Coronary artery calcium (CAC) scans contain valuable information beyond the Agatston score which is used for coronary artery disease prediction only. We have previously reported AI-enabled cardiac chambers volumetry in CAC scans (AI-CAC) predicts incident atrial fibrillation (AF), heart failure (HF), and stroke in the Multi-Ethnic Study of Atherosclerosis (MESA). Here we compare the distribution of cardiac chambers volumes vs. risk categories of ASCVD pooled cohorts’ equation (PCE) and PREVENT
TM
risk scores.

Methods:
We applied the AutoChamber
TM
component of AI-CAC to 5830 individuals (52.2% women, age 61.7±10.2 years) without known CVD that were previously obtained for CAC scoring at the baseline examination of MESA. We calculated 10-year estimated risk from the PCE and PREVENT Risk Scores based on 4 categories of risk: <5%, 5-7.5%, 7.5-20%, >20% using baseline risk factors. The PREVENT total CVD base model was used in analysis, which excludes urinary albumin to creatinine ratio and social depravity index. We compared the distribution of the quartiles of left atrial (LA) and left ventricle (LV) volumes to categories of both risk scores. We defined enlarged cardiac chambers as the top quartile of LA (>82.7 cc) and LV (>136.5 cc) volume, which corresponded to 33% and 21.1% incidence of all-CVD events over 10 years (CHD, HF, AF, stroke, CVD deaths), respectively. LA and LV volumes were standardized by adjusting for body surface area (BSA).

Results:
A substantial portion of cases categorized by PREVENT as low risk (10-year risk <5%) had enlarged cardiac chambers (Figure 1). In females the lowest category of PREVENT had 10.6% enlarged LA cases and 26.6% enlarged LV volume cases. In males, the lowest category of PREVENT had 13.7% enlarged LA cases and 29.4% enlarged LV volume cases. Similarly, in low risk PCE, females had 12.8% enlarged LA and 24.9% enlarged LV, and males had 12.8% enlarged LA and 24.6% enlarged LV.

Conclusion:
In this multi-ethnic longitudinal population study, a substantial portion of cases classified as low-risk by PCE and PREVENT risk scores had enlarged LA and LV volumes detected by AI-CAC, putting them at risk for future HF, AF, and stroke.
Abstract 4144092: Dysregulation of DSCAM and Sclerostin Signaling in Down Syndrome Associated Congenital Heart Disease and Other Phenotypes
Authors: Tang Vi , Zhang Qi , Morton Sarah , McKean David , Narayan Priyanka , Layton Olivia , Sharma Ananya , Seidman Jonathan , Seidman Christine
Published: November 2024

Introduction:
Trisomy 21 (T21) is the most common genetic cause of congenital heart disease (CHD) with a preponderance of atrioventricular canal defects (AVCD), a type of malformation that is uncommon in euploid CHD patients. Mechanisms that cause CHD and AVCD in T21 are unknown. We recently reported an 11-fold increase in levels of
SOST
which resides on chromosome 17 and encodes sclerostin, a secreted Wnt inhibitor, in T21 CHD tissues compared to euploid CHD controls. Further investigations revealed that
SOST
is primarily expressed in cardiac endothelial cells and genetic inactivation of
DSCAM
on chromosome 21 in T21 endothelial cells derived from human induced pluripotent stem cells (iPSC-ECs) diminishes sclerostin secretion.

Methods and Results:
DSCAM is a transmembrane cell adhesion molecule that is involved in neuronal synapse formation. Recent studies suggest that the DSCAM intracellular domain (ICD) can translocate to the cell nucleus to regulate gene expression in HEK293 cells. To test whether the DSCAM ICD can function as a transcription regulator in endothelial cells, we overexpressed DSCAM-ICD-GFP fusion protein in T21 iPSC-ECs and euploid human aortic endothelial cells (HAECs) using lentiviral vectors. We observed a discrete nuclear localization pattern of DSCAM-ICD-GFP compared to a more diffused cytoplasmic localization of GFP alone. Overexpression of DSCAM-ICD-GFP also resulted in a modest increase in sclerostin secretion in HAECs as compared to GFP controls. Ongoing experiments will measure sclerostin secretion in T21 iPSC-ECs that overexpress DSCAM-ICD-GFP. To test whether increased sclerostin secretion can lead to CHD, we obtained mice carrying a human
SOST
transgene (

SOST
Tg

) that exhibit osteopenia, consistent with Wnt inhibition by sclerostin. As cardiac phenotype has not been assessed, we will report cardiac structure and function using echocardiography and histology to determine the consequences of
SOST
overexpression.

Conclusions:
An increase in
DSCAM
gene dosage in T21 leads to increased sclerostin secretion in endothelial cells. The localization of DSCAM ICD in the cell nucleus indicates potential direct or indirect regulatory activities on
SOST
and other genes. Defining these effects and the consequences of sclerostin-inhibition of Wnt signaling may indicate the mechanisms for CHD in approximately half of patients with T21.
Abstract 4144106: Markers of Abdominal Aortic Stenoses in Williams Syndrome
Authors: McCarthy Elisa , Kaplinski Michelle , Adamson Gregory , MacMillen Kirstie , Zucker Evan , Chaudhuri Abanti , Algaze Claudia , Collins Ronnie
Published: November 2024

Background:
Renal artery stenosis (RAS) is common in Williams syndrome (WS). Gold standard advanced cardiovascular (CV) imaging (aCVI) required to confirm RAS (CT, catheter angiography, or MRI) often requires anesthesia, which is associated with sudden CV events in WS. We sought to identify echocardiographic CV measures associated with abdominal arteriopathy in WS that might be used to determine which patients require aCVI.

Methods:
We retrospectively reviewed all patients with WS treated at our center with aCVI from 2015 to 2022. From aCVI obtained, we measured the diameter of the abdominal aorta (Ao) at the hiatus (AoH), right renal artery (AoRRA), and celiac trunk (AoCA), and the origin, proximal aspect (4mm from the origin), and midpoint of the RRA, left renal artery (LLA), celiac artery (CA), superior mesenteric (SMA) and inferior mesenteric (IMA) arteries. For all aortic measurements, we calculated Z-scores using published formulae (Hegde, 2015). To our knowledge, there are no Z-scores available for pediatric SMA, IMA, or renal arteries, so we used a ratio reflecting the most severe area of narrowing (either origin:midpoint or proximal:midpoint). From the echo closest in absolute time to aCVI, we measured the ascending Ao wall thickness in the suprasternal sagittal echocardiographic view and compared it to the same measurement in age- and height-matched controls.

Results:
There were 48 patients with WS and aCVI included in the study (26 CT, 17 cath, 5 MRI). In 44 (92%), the abdominal Ao was diffusely stenotic (Z-scores <-2 at AoH, AoCA, or AoRRA). There was strong correlation between AoH and AoCA (r
2
=0.76), AoH and AoRRA (r
2
=0.79), and AoCA and AoRRA (r
2
=0.69) (all Z-score comparisons). There was moderate correlation between AoH Z-score and worst narrowing ratio of CA (r
2
=0.40), and between the worst narrowing ratios of the RRA and LRA (r
2
=0.53). Ascending Ao from 47 patients with WS (obtained at a median 44 days from aCVI) was thicker in WS compared to 47 controls (22 vs 17mm, p<0.001), but did not correlate with any abdominal arterial measures.

Conclusion:
Though often a marker of severe cardiac disease in WS, ascending Ao thickness does not predict abdominal arterial stenoses in WS. However, stenosis of AoH on aCVI is correlated with other abdominal stenoses in WS. Since AoH can be measured by echo, more work is necessary to determine whether this could serve in WS as an indicator of further abdominal stenoses and need for subsequent aCVI.