bluuebunny/crossref_metadata_2025 huggingface dataset:
Figure 5 from Mathematical Modeling Unveils Optimization Strategies for Targeted Radionuclide Therapy of Blood Cancers
Authors: Kuznetsov Maxim , Adhikarla Vikram , Caserta Enrico , Wang Xiuli , Shively John E. , Pichiorri Flavia , Rockne Russell C.
Published: November 2024

Survival curves for the test set of virtual mice, grouped by relative significance of self-damage, ks: (A) low ks; (B) intermediate ks; and (C) high ks. Personalized schedules based on cancer-binding capacity, γN0, yield robust treatment optimization via initial saturation of cancer-binding capacity with the first dose, enabling redistribution of further injected small doses toward still viable cells that continue expressing specific receptors. Coefficient of drug impurity, η, corresponds to the labeling ratio of 1.85 kBq/μg.
Figure 4 from Mathematical Modeling Unveils Optimization Strategies for Targeted Radionuclide Therapy of Blood Cancers
Authors: Kuznetsov Maxim , Adhikarla Vikram , Caserta Enrico , Wang Xiuli , Shively John E. , Pichiorri Flavia , Rockne Russell C.
Published: November 2024

A, Scatter plot of cancer-binding capacity, i.e., total amount of specific receptors on cancer cells at the moment of drug injection, and minimal single curative dose produced by the global parameter sweep within the training set of 1,000 virtual mice. Cancer-binding capacity represents the product of the number of specific receptors on each cancer cell, γ, and the initial number of cancer cells, N0. Maximal safe dose is based on the exact value of only one parameter, cancer-binding capacity, and on physiologic ranges of other parameters. Coefficient of drug impurity, η, corresponds to the labeling ratio of 1.85 kBq/μg. B, Survival curves and (C) toxicity curves for a single test set of 1,000 virtual mice, treated by different approaches.
Genotype-phenotype correlation and feminizing surgery in Danish children with congenital adrenal hyperplasia
Authors: Lind-Holst Marie , Berglund Agnethe , Duno Morten , Hvistendahl Gitte , Fossum Magdalena , Juul Anders , Jørgensen Niels , Main Katharina M. , Gravholt Claus H. , Hansen Dorte
Published: November 2024

Introduction: Congenital adrenal hyperplasia (CAH) is characterized by a broad spectrum of symptoms.
This study aims to describe genotype-phenotype correlations, clinical manifestations at diagnosis, and the frequency of feminizing surgery in childhood.

Methods: A nationwide retrospective cohort study of patients diagnosed with CAH, aged ≤18, between 1943 and 2018. CAH was identified in national registries and validated through medical record reviews and phenotypically classified as salt-wasting (SW), simple virilizing (SV), or non-classic (NC) CAH. In a sub-cohort (diagnosed between 1999 and 2018) clinical data and feminizing surgery data were investigated. CYP21A2 variants were grouped as Null, A, B, C, and D.

Results: The cohort comprised 379 patients with CAH. Genotype-phenotype correlations were as follows: Null and SW (100%), A and SW (94%), B and SV (51%), and C and NC (75%). In the subcohort (n=159, females=99) the female-to-male ratios were: SW=1.5, SV=1.1, and NC=2.3. Symptoms of precocious pseudopuberty dominated at diagnosis (39%). Males presented with significantly advanced bone age by the time of diagnosis (p=0.0009). In 53% of females (n=53), virilization of the external genitalia was present at the time of diagnosis, and in 46% (n=46) this developed already prenatally. Of the prenatal virilized females 85% underwent early feminizing genitoplasty. Virilization was identified in both mild and severe genotypes.

Conclusion: Milder genotypes do not accurately predict CAH phenotype or prenatally reject serious outcomes such as virilization. The frequency of early genitoplasty is high among females with prenatal virilization. The delayed diagnosis and non-diagnosis of especially males with mild CAH advocate for a more prominent role of genetic testing in the diagnostic and screening for CAH.
Conjunctival Phlyctenule and Nodular Scleritis in a Patient with Previous Herpes Simplex Virus-2 Exposure: Causative Agent or Innocent Bystander?
Authors: Khan Shawn , Saigal Khushi , Maleki Arash
Published: November 2024

Introduction: Phlyctenular keratoconjunctivitis is an inflammatory condition arising from a type IV hypersensitivity reaction, presenting with inflamed nodules on the conjunctiva and cornea. Scleritis is a severe ocular inflammation linked to systemic diseases, potentially vision threatening, and involving immune responses similar to phlyctenular keratoconjunctivitis. This case report discusses a patient with a history of herpes simplex virus (HSV)-2 infection who primarily developed phlyctenular conjunctivitis and later progressed to nodular scleritis. Case Presentation: A 66-year-old female presented with pain, redness, and a foreign body sensation in her left eye for 2 days. Initial treatment for epidemic keratoconjunctivitis with tobramycin-dexamethasone improved her symptoms. However, 3 weeks later, she developed a conjunctival phlyctenule. Diagnostic tests, including blood work and conjunctival swabs, were conducted. While most tests were negative, HSV-2 IgG was positive. The patient failed topical corticosteroid monotherapy; however, she responded to oral valacyclovir. Follow-up examinations showed significant improvement, with resolution of the conjunctival phlyctenule and nodular scleritis, and her best-corrected visual acuity returned to 20/20. Conclusion: This case highlights the importance of considering HSV-2 in atypical presentations of phlyctenular conjunctivitis and scleritis. The patient’s response to antiviral therapy underscores the potential role of HSV-2 in such ocular inflammation. Thorough infectious workups and alternative treatment approaches are crucial in managing unconventional cases. Experimental treatments based on laboratory findings can be valuable for patients preferring conservative management, emphasizing the need for close follow-up and personalized care in ocular inflammatory diseases.
Missense Variant Met119Val in ACTB in a Patient with Baraitser-Winter Syndrome Type 1 and Mild Intellectual Disability
Authors: Zechi-Ceide Roseli Maria , Serigatto Henrique Regonaschi , Galvanin Ana Laura , Rafacho Marina Bigeli , Kokitsu-Nakata Nancy Mizue , Guion-Almeida Maria Leine , Di Donato Nataliya
Published: November 2024

Introduction: The Baraitser-Winter syndrome (BRWS) is a rare condition characterized by multiple congenital anomalies and developmental delay. Most cases present moderate to severe global delay and intellectual disability. The etiology of BRWS is heterogeneous, caused by heterozygous gain-of-function variants in ACTB or ACTG1 genes. Case Report: Here we report on a Brazilian female patient with dysmorphic craniofacial features of the BRWS, oligodontia, partial agenesis of the corpus callosum, pineal cyst, cervical cystic hygroma, pterygium colli, axillary pterygium, duplicated left hallux, seizures, and mild developmental delay. Sanger sequencing of the ACTB gene showed the heterozygous missense variation NM_001101.5 (ACTB):c.355A>G (p.Met119Val). Conclusion: The clinical findings are compatible with the diagnosis of BRWS type 1. Our case includes oligodontia as a new feature of the BRWS type 1 phenotype. Functional study of the variant here described could contribute to elucidate the pathogenetic pathway that results in the severe craniofacial phenotype associated with mild developmental delay.
Abstract 4138053: Chronic Kidney Disease Prevalence and Outcomes in Patients with Type 2 Diabetes or Prediabetes at High Cardiovascular Risk: Results from the CINEMA Program
Authors: Datla Sanjana , Albar Zainab , Eaton Elke , Porges Jodie , Nennstiel Matthew , Sullivan Claire , greene lloyd , Al-Kindi Sadeer , Padiyar Aparna , Rahman Mahboob , Rajagopalan Sanjay , Neeland Ian
Published: November 2024

Introduction:
Chronic kidney disease (CKD) is a global health concern, particularly among patients with type 2 diabetes mellitus (T2DM) and prediabetes, who are at high risk of cardiovascular disease (CVD). The Center for Integrated and Novel Approaches in Vascular-Metabolic Disease (CINEMA) program at University Hospitals Cleveland Medical Center aims to address these challenges through a multidisciplinary, patient-centered intervention. This study evaluates CKD prevalence, outcomes, and guideline-directed treatments within the CINEMA program.

Methods:
Patients with T2DM or prediabetes at high-risk for cardiovascular events, including those with established atherosclerotic CVD, elevated coronary artery calcium score ≥100, chronic heart failure, ischemic stroke, peripheral arterial disease, CKD (defined as eGFR<60mL/min/1.73m
2
and/or by the presence of albuminuria, UACR ≥30 mg/g) and obesity with metabolic syndrome were included.

Results:
From May 2020 to September 2022, 454 patients were enrolled in the CINEMA program with 45% having a diagnosis of CKD. Among those with CKD, the median age was 64 years, 48% were women, and 47% were Black. 93% had T2DM, 82% had HTN, 52% had established coronary artery disease, and 39% had heart failure. Median eGFR was 49 mL/min/1.73m
2
and median UACR was 42 mg/g. Over two-thirds of those with CKD were stage G3 or greater and 50% were stage A2 or greater. Persons with CKD were more likely to be older, Black, have diabetes and heart failure (p<0.05 for all). UACR screening increased ~8-fold with the CINEMA program. The CINEMA intervention was associated with statistically significant improvements in cardiometabolic risk factors with reductions in body weight (-3.49 lbs), BMI (-0.54 kg/m2), systolic blood pressure (-2.65 mmHg), Hb A1c (-0.63%), total cholesterol (-9.01 mg/dL) and LDL cholesterol (-8.29 mg/dL) with p<0.05 for all. No significant changes were seen in eGFR (p=0.58) or UACR (p=0.41). Notably, there was significant increase in prescription rates of SGLT2i (25% to 55%) and GLP-1RA (14% to 38%) in the CKD population from baseline to follow-up visit (p<0.05).

Conclusions:
The CINEMA program demonstrates effectiveness in improving ASCVD risk factors and shows promise in addressing CKD outcomes among high-risk patients with T2DM or prediabetes. Enhanced screening for CKD, proper risk stratification, and aggressive implementation of guideline directed medical therapies in patients with CKD can lead to improved outcomes.
Abstract 4138081: Neighborhood Level Social Determinants of Health and Loss of Blood Pressure Control
Authors: Le Jonathan , Nguyen Andrew , Huang Tzu Yu , Botting Patrick , Navarrette Jesse , Cheng Susan , Ebinger Joseph
Published: November 2024

Introduction:
Uncontrolled hypertension is a potent cardiovascular risk factor, with a higher prevalence in adults with disadvantaged social determinants of health (SDoH). While prior work has shown an association with uncontrolled blood pressure (BP) and adverse SDoH in general, less is known about specific SDoH domain drivers of this association, knowledge of which may inform interventions to improve health and reduce disparities.

Methods:
We examined health records in all adults with ≥2 outpatient visits/year in at least 2 consecutive years from 2017-2023. BP level was determined by the first 2 visits in the first year and last 2 readings in the second year; BP control was based on contemporary thresholds (<130/80 mmHg). Loss of BP control (controlled in first year and uncontrolled in second year) was determined year over year. Neighborhood SDoH was assessed by linking patients’ zip codes to the Healthy Places Index (HPI), including 8 domains (economic, education, transportation, social, housing, health insurance, clean environment, and neighborhood). Multivariable regression analyses were used to examine associations of demographics, clinical, and SDoH characteristics.

Results:
A total of 145,318 patients were identified, of whom 94,276 (64.9%) lost BP control at some point during the study period. In analyses adjusting for demographic, clinical, and SDoH factors (Figure 1A), risk of losing BP control was associated with living in a neighborhood with a HPI score in the worst quartile (OR 1.12, 95% CI 1.08-1.15). Evaluation of SDoH domain identified the economic (1.15 [1.12-1.18], P = 0.012) and education (1.15 [1.12-1.18], P < 0.001) as the only SDoH domains associated with loss of BP control, though positive association trends were also appreciated for transportation (1.09 [1.06-1.12], P = 0.079) and health insurance (1.1 [1.07-1.13], P = 0.097) domains (Figure 1B).

Conclusions:
In over 140,000 adults with controlled BP, almost two-thirds lost BP control in the subsequent year. This loss of BP control was associated with many neighborhood level SDoH factors, specifically economic and educational domains. These results inform potential targets to help reduce disparities and improve BP related health outcomes.
Abstract 4138217: A Machine Learning-Based Novel Risk Score Model for Spontaneous Coronary Artery Dissection
Authors: Agrawal Ankit , Arockiam Aro Daniela , bhagat umesh , Haroun Elio , Majid Muhammad , Wang Tom Kai Ming
Published: November 2024

Background:
Spontaneous coronary artery dissection (SCAD) remains a poorly understood differential diagnosis of acute coronary syndrome (ACS). We aimed to develop a machine learning-based risk score model to predict in-hospital mortality in patients with SCAD.

Methods:
The National Inpatient Sample (NIS) 2016-2020 database was used to identify all adult patients (≥18 years of age) with SCAD, identified using ICD-10 code I25.42. Relevant clinical characteristics and outcomes were extracted. The primary endpoint was in-hospital all-cause mortality. The dataset was randomly split into 3 subsets: training, validation, and testing, with a ratio of 0.7, 0.2, and 0.1, respectively. The risk score was generated using R software’s Autoscore package, which is a machine learning-based automatic clinical score generator, and performance was evaluated using the area under receiver-operative characteristics curve (AUC) with 95% confidence intervals (95%CI).

Results:
Among the 8,260 SCAD patients identified [age 60.9±14.4 years, female 4,708 (57%)], there were 480 (5.8%) primary outcome events. Out of the top 20 covariates seen in the Parsimony plot, we used six for our risk score (0–100): age, comorbidity burden, cardiogenic shock, balloon pump, extracorporeal membrane oxygenation, and race (Figure 1A). The AUC for the derivation and validation cohorts was 0.862 (0.817–0.907) and 0.833 (0.788–0.879), respectively (Figures 1B and 1C).

Conclusion:
We developed and internally validated a machine learning-based risk score model to predict outcomes in patients with SCAD with a high AUC of 0.833 (0.788–0.879). Risk score models guide decision-making, and future studies are needed for external validation of our findings.
Abstract 4138218: Meeting Physical Activity Recommendations Among Wearable Device Users: Insights from the 2022 Health Information National Trends Survey
Authors: Lee Minjung , Nam Soohyun
Published: November 2024

Background:
The benefits of physical activity for health and well-being are well documented. Promoting physical activity is crucial for enhancing population health. Wearable devices play a significant role in tracking health-related activities and have been shown to enhance engagement in physical activities. While studies have identified sociodemographic patterns in wearable device usage, little is known about their impact on real-world outcomes, such as increased physical activity.

Research Question:
Is there a variation in achieving the recommended level of physical activity among wearable device users?

Aim:
To examine factors associated with achieving the recommended weekly minimum of 150 minutes of moderate-intensity physical activity among wearable device users.

Methods:
Data from the 2022 Health Information National Trends Survey (HINTS 6) of wearable device users (n = 1,718) were analyzed. We reported adjusted odds ratios from multivariable logistic regression of meeting recommended levels of physical activity.

Results:
Among the 1,718 participants who utilized wearable devices, 64.3% were female with a mean (M) age of 48.2 ± 0.36 years. The majority were White (58.1%), followed by Asian (18.4%). Among the wearable users, 54.8% met the recommended weekly minimum of 150 minutes of moderate-intensity physical activity. The age group of 65 to 74 years (OR, 1.96; 95% CI, 1.04, 3.69; p=0.04) was more likely to achieve 150 minutes of physical activity per week. However, Asian wearable users were less likely to achieve physical activity goals compared to other racial and ethnic wearable users (OR, 0.55; 95% CI, 0.31, 0.96; p=0.04). Additionally, individuals with a body mass index ≥30 kg/m
2
(OR, 0.54; 95% CI, 0.36, 0.79; P<0.01) and those with high blood pressure (OR, 0.62; 95% CI, 0.41, 0.94; p=0.03) were less likely to meet physical activity recommendations.

Conclusions:
This study highlights variations in physical activity outcomes among wearable device users and underscores the importance of enhancing the public's ability to use these devices to increase physical activity. Future efforts should include exploring facilitators of effective wearable use, in various sociodemographic groups, especially for those at risk of obesity or hypertension.
Abstract 4138237: Clinical Utility of T2 Mapping for the Assessment of Myocardial Inflammation in Patients With Cardiac Sarcoidosis
Authors: Uno Mio , Kosuge Hisanori , Fujita Yasuhiro , Hida Satoshi , Satomi Kazuhiro
Published: November 2024

Introduction:
18
F-FDG PET has been used for the evaluation of active inflammatory lesions in cardiac sarcoidosis (CS), but it is burdensome for patients to perform as a routine follow-up. Late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) that can detect myocardial fibrosis is limited in its ability to assess active inflammation. T2 mapping has been shown to detect myocardial inflammation in myocardial diseases without radiation exposure and contrast agents (Figure). However, the ability of T2 mapping for discriminating inflammatory myocardium has not been fully clarified in patients with CS.

Hypothesis:
We assessed the hypothesis that T2 mapping has potential for the discrimination of inflammatory myocardium in patients with CS.

Methods:
Twenty-seven subjects who underwent CMR at 3T and
18
F-FDG PET to diagnose CS were enrolled. Fourteen subjects were diagnosed as CS due to LGE and myocardial FDG uptake on
18
F-FDG PET (PET-positive group). Thirteen subjects showed no myocardial FDG uptake (PET-negative group). NativeT1, T2, and extracellular volume fraction (ECV) were measured using a 16-segment model. Receiver-operating characteristic (ROC) curve analysis was performed to evaluate T1 and T2 mapping in discriminating between active and inactive inflammatory segments in the PET-positive group.

Results:
Mean native T1, native T2 and ECV showed no significant differences between the PET-positive and the PET-negative groups. However, maximum T2 values, which were highest ones in the 16 segments, were significantly higher in the PET-positive group than the PET-negative group (51.3 ± 7.7 ms vs 45.7 ± 3.6 ms, p = 0.014). In the PET-positive group, ROC analysis showed AUC of 0.72 in native T2, 0.61 in native T1, and 0.68 in ECV for discriminating inflammatory myocardium. The optimal cutoff value of native T2 was 45.7 ms, and the diagnostic performance had a sensitivity of 44.4 %, specificity of 93.3 %
,
positive predictive value of 88.1 %, and negative predictive value of 60.1 %.

Conclusion:
T2 mapping is a promising approach for the discrimination of inflammatory myocardium without radiation exposure and contrast agents in patients with cardiac sarcoidosis.
Abstract 4138246: Differences in Major Adverse Cardiovascular and Lower Limb Events and Guideline-Directed Medical Therapy Among Males and Females Within an Integrated Healthcare System
Authors: Le Viet , Knight Stacey , Bair Tami , Bride Daniel , May Heidi , Sadik Kay , Brunisholz Kimberly , GALT SPENCER , Knowlton Kirk , Anderson Jeffrey
Published: November 2024

Background:
Health disparities based on gender have been recognized as having a detrimental impact on care delivery and early identification of disease processes. Peripheral arterial disease (PAD) is the third leading cause of atherosclerotic disease mortality. It is unclear what role, if any, gender plays in the diagnosis, treatment, and outcomes of PAD.

Hypotheses:
Females are less likely to have guideline-directed medical therapy (GDMT) and more likely to have major adverse cardiovascular events (MACE) and major adverse lower limb events (MALE) than males.

Methods:
The Intermountain Health electronic database was queried for patients meeting the following criteria: ≥18-years of age, PAD diagnosis between Jan 2006 to Dec 2021, seen at least once within the 18-months following initial PAD diagnosis, and had a symptom of PAD (see table). Follow-up GDMT, based on the 2016 AHA/ACC PAD guidelines, was determined by medication and procedures. Time to outcomes of MACE (all-cause death, MI, stroke, or unstable angina hospitalization) and MALE (limb ischemia, limb revascularization, or limb amputation) were examined using Cox-proportional hazard adjusted for GDMT, age, and prior CAD.

Results:
A total of 7522 patients had a symptomatic PAD diagnosis, with 38% female and 62% male. Females tended to be older (70.1±13.0 vs 68.6±11.7), more likely to be obese (25% v 21%), and less likely to have Afib (21% v. 24%), CAD (30% v 41%), MI (11% v 16%), renal failure (19% v 22%) but more likely to have a bleeding history (30% v 26%) (all p<0.01). Females were slightly less likely to have all the GDMT and yet had similar rates of referrals to specialists but higher rates to primary care providers (Table). After adjustment, females were less likely to have MACE (HR=0.94; 95% CI: 0.88, 0.99) and MALE (HR=0.85; 95% CI: 0.80, 0.92).

Conclusion:
Females had lower rates of MALE, driven by lower limb revascularization or amputation rates, and slightly lower rates, after adjustment, for MACE. This was observed despite the high rates of GDMT for both females and males (~80% in any category), with females having slightly less GDMT.
Abstract 4138253: Reintervention Burden of Single and Biventricular Palliation of Pulmonary Atresia with Intact Ventricular Septum
Authors: Nitsche Lindsay , Devlin Paul , Sukhavasi Amrita , McHugh-Grant Sara , Bontrager Colleen , Burnham Nancy , Gaynor J , Glatz Andrew , Fuller Stephanie
Published: November 2024

Introduction:
Pulmonary atresia with intact ventricular septum (PAIVS) patients may proceed down a single (SV) or biventricular (BV) pathway. We evaluated the total interventional burden of both pathways including after either end-state was reached.

Hypothesis:
SV patients will have more interventions in comparison to BV patients.

Goals:
Assess the nature of interventions in PAIVS.

Methods:
Retrospective review of PAIVS patients from 1995-2020 who achieved SV (Fontan completion) or BV (normal saturations with no significant shunts) end-state. Demographic, procedural, and follow-up details were collected. Descriptive statistics were used and Kaplan-Meier analysis of freedom from reintervention was performed.

Results:
Of 79 patients who reached end-state, 40 (51%) were SV and 39 (49%) were BV. Total median in-hospital time was 48 [31-78] days and 18 [12-35] days for SV and BV (p<0.01). The ratio of in-hospital days to total follow-up was a median of 1.7% [0.9-2.7] for SV and 0.4% [0.3-0.8] for BV (p<0.01). SV and BV cohorts had an overall median of 4 [3-5] and 3 [2-4] interventions, respectively (p<0.01). Interventions and their relationship to end-state are shown in
Table 1
. The SV and BV groups achieved end-state at a median of 2.9 [2.3-3.6] and 2.1 [0.2-8.8] years (p=0.01) (
Figure 1A
). Median follow up in years after achieving end-state was similar between groups {7 [2.7-15.8] in SV and 7.4 [4.2-13.4] for BV (p=0.11)}. After end-state, there was no difference in the proportion of patients requiring reinterventions (17 (43%) SV and 12 (31%) BV, p>0.05). Freedom from reintervention at 15-years was 44.1% in the SV group and 64.3% in the BV group (p=0.11) (
Figure 1B)
with one late SV death.

Conclusions:
PAIVS therapy requires multiple interventions to achieve both SV and BV repair. While SV patients undergo more interventions and spend more days in the hospital, reinterventions and 15-year freedom from reintervention were comparable between groups with equivalent follow up.
Abstract 4138275: Demographic, Regional, and State-level Trends of Mortality in patients with Atrial fibrillation in the United States, 1999 to 2020
Authors: Jaiswal Vikash , Latif Fakhar , Mashkoor Yusra , Danisha FNU , Jaiswal Akash , Hanif Muhammad , Amara Richard , Dickfeld Timm , Biswas Monodeep
Published: November 2024

Background:
There exists a paucity of data regarding mortality trends among individuals with atrial fibrillation (AF) based on age, gender, race and ethnicity, and geographic regions.

Objective:
To investigate the trends in mortality in the United States (US) associated with AF among individuals aged ≥45 years.

Methods:
We reviewed the death certificate data from the Centers for Disease Control and Prevention (CDC) Wide-ranging Online Data for Epidemiologic Research (WONDER) database to examine atrial fibrillation–related mortality trends from 1999 to 2020 in individuals ≥45 years of age. We calculated crude and age adjusted mortality rates (AAMRs) per 100 000 patients and annual percentage change (APC) with 95% CIs.

Results:
Between 1999 and 2020, 2,576,839 AF-related deaths were identified among US adults over 45 years of age. The age adjusted mortality rate (AAMR) for AF-related deaths rose significantly from 70.6 in 1999 to 149.1 in 2020. Initially, the AAMR remained stable from 1999 to 2009 (APC): 2.31; 95% CI: -0.57 to 5.84), then increased significantly from 2009 to 2018 (APC: 3.60; 95% CI: 2.12 to 4.75), and saw a sharp rise from 2018 to

2020 (APC: 8.46; 95% CI: 4.76 to 10.44). There were notable disparities among demographic groups. Men consistently had higher AAMRs than women from 1999 (men: 79.9, women: 64.4) to 2020 (men: 180.5, women: 125.3). Non-Hispanic (NH) White adults had the highest AAMR (108.6), followed by NH American Indian/Alaska Native (73.4), NH Black (66.7), Hispanic or Latino (55.5), and NH Asian or Pacific Islander adults (51.2). The age group 85+ consistently showed the highest mortality rates throughout the study period. Regional differences were also evident, with the residents of western region (109.5) and nonmetropolitan areas (109.6) having the higher AAMRs when compared to other regions (Midwest: 104.3, Northeast: 95.1, and South: 95.0) and metropolitan areas (98.3), respectively. State-level variations were also significant.

Conclusion:
Our study found a rise in AF-related mortality in the US from 1999 to 2020, with significant disparities among demographic and geographic subgroups. Higher AAMRs were noted in males, non-Hispanic Whites, adults over 85, and residents of the western and nonmetropolitan US. Addressing disparities in access to quality care, timely diagnosis, insurance maintenance, and implementing targeted health policies can help reduce AF-related mortality.
Abstract 4138278: A Titin Missense Variant Causes Atrial Fibrillation
Authors: Arif Mahmud , Chen Hanna , Hill Michael , Barney Miles , Sridhar Arvind , Owais Asia , DeSantiago Jaime , Darbar Dawood
Published: November 2024

Background:
Rare loss-of-function variants in
TTN
, the gene encoding the sarcomeric protein titin, have been causally associated with atrial fibrillation (AF). Missense
TTN
variants (
TTN
mv) are generally regarded as benign in relation to dilated cardiomyopathy, but their role in AF is unknown.

Hypothesis:
TTN
mv are associated with clinical outcomes and AF pathogenesis.

Aims:
We aimed to determine if
TTN
mv are associated with AF/heart failure (HF) hospitalizations and investigate if a rare missense variant (
TTN
-T32756I) caused AF using human induced pluripotent stem cell-derived atrial cardiomyocytes (iPSC-aCMs).

Methods:
Whole exome sequencing was performed in 131 adults at an urban academic healthcare system who identified as non-Hispanic Black (NHB) or Hispanic/Latinx (HL). Multivariable Cox proportional hazard models were used to assess cumulative risk of AF/HF hospitalization. Isogenic
TTN
-T32756I iPSC-aCM mutants were generated using the CRISPR-Cas9 technique. We used confocal microscopy to assess sarcomeric integrity, MuscleMotion to assess contractility, and optical voltage mapping and patch-clamping to assess the electrophysiological (EP) properties.

Results:
We identified 137
TTN
mvs in 76/131 (58.0%) of subjects, which were most commonly in the
TTN
A-band. 64 AF-related and 110 HF-related hospitalizations occurred after a median follow-up time of 4.16 years. Hospitalization risk was higher in
TTN
mv carriers (HR 1.81,
Fig. 1A
). We also identified three patients with early-onset AF who shared a rare missense variant T32756I.
TTN-T32756I
-iPSC-aCMs displayed aberrant contractility (
Fig. 1B-D
), shortened action potential duration (
Fig. 1G-H
), increased activity of cardiac K
+
channel (
Fig. 1I
), and dysregulated Ca
2+
homeostasis (
Fig. 1J
) without compromising sarcomeric integrity (
Fig. 1E-F
). The titin-binding protein, Four-and-a-Half Lim domains 2 (FHL2), also has increased binding with KCNQ1 and its modulatory subunit KNCE1 in
TTN-T32756I
-iPSC-aCMs, which may enhance the slow delayed rectifier K
+
current (
I
ks
). Suppression of FHL2 normalized
I
ks
, supporting FHL2 as a mediator of the increased
I
ks
(
Fig. 1K)
.

Conclusion:
In a single-center multi-ethnic AF cohort,
TTN
mv were associated with increased AF/HF hospitalization, and the T32756I-
TTN
mv causes ion channel remodeling and an AF-like EP phenotype. These findings establish a mechanistic link between
TTN
mv, K
+
ion channels, and sarcomeric regulatory proteins that may represent a novel therapeutic target.
Abstract 4138301: Burden of Hyperlipidemia, Cardiovascular Mortality, and COVID-19: A Retrospective-Cohort Analysis of US Data
Authors: Pham Hoang Nhat , Sainbayar Enkhtsogt , Ramzi Ibrahim , Olson April , Alabagi Abdulla , Soin Sabrina , Aiti Danny , Tran Phillip , Lee Justin , Khanji Mohammed , Chahal Anwar , Mamas Mamas
Published: November 2024

Background:
Hyperlipidemia (HLD) is a major risk factor for cardiovascular disease (CVD). Little is known regarding temporal variation in CVD mortality related to HLD. The COVID-19 pandemic added complexity to factors influencing CVD mortality.

Question:
What are the yearly trends and impact of the COVID-19 pandemic on HLD-related CVD mortality in the United States?

Methods:
Mortality and demographic data for adults were obtained from CDC repository from 1999-2020, using ICD-10 codes HLD (E78.0-E78.5) and CVD (I00-I99). Age adjusted mortality rates (AAMR) per 1,000,000 population was standardized to the 2000 US population. Log-linear regression models evaluated mortality shifts. Average annual percentage change (AAPC) from 1999-2019 was used to calculate projected AAMR in 2020, subsequently compared to actual 2020 death rates to estimate pandemic-attributed excess deaths.

Results:
A total of 483,155 HLD-related CVD deaths were recorded between 1999-2020. Despite the CVD mortality decline in general population, HLD-related CVD AAMR rose from 36.33 [95% CI, 35.52-37.13] in 1999 to 99.77 [98.67-100.87] in 2019. Ischemic heart diseases (AAMR 49.39) were the most common causes of death while hypertension had the highest annual mortality increase (AAPC +10.23%) in populations with HLD. Higher HLD-related CVD mortality was observed in males (AAMR 104.87) than females (AAMR 61.93), in those ≥75 years (AAMR 646.45) than 35-75 years (AAMR 54.11), in non-Hispanic (NH) (AAMR 82.49) than Hispanic (AAMR 58.98) populations, and in rural (AAMR 89.98) than urban (AAMR 78.94) regions. NH Black populations (AAMR 84.35) and Western US regions (AAMR 96.88) had the highest HLD-related CVD. The first year of COVID-19 pandemic resulted in 10.55% excess HLD-related CVD death, with the most prominent increase in the 35-75 years age group (14.23%), Hispanic (17.96%), Black (14.82%), and urban (11.68%) populations.

Conclusions:
Our study revealed an increase in HLD-related CVD mortality which was exacerbated by the COVID-19 pandemic. Higher CVD mortality disproportionately affected males, Black, elderly (≥75 years), and rural populations with HLD. Further research is needed to validate our findings and identify contributing factors.
Abstract 4138303: Stress Hyperglycemia Ratio Predicts MACE and All-cause Mortality in Acute Coronary Syndrome Patients: A Meta-Analysis Comparing Patient with Diabetes Mellitus and Non-Diabetes Mellitus
Authors: Kanagala Ramya S D , Kanthala Neha , Mathew Joanne , Mylavarapu Maneeth , Singh Sachin , Vala Lovekumar , Dhadhal Riya , Danish Ali , Damarlapally Nanush , Mohammed Adil , Ahmed Hafeezuddin , alsulami meshal , Desai Rupak
Published: November 2024

Background:
A higher stress hyperglycemic ratio (SHR) has been reported to be associated with adverse cardiac outcomes. However, the role of SHR in predicting clinical outcomes by comparing patients with and without diabetes mellitus is yet to be explored.

Objective:
To evaluate the prognostic value of the SHR for predicting major adverse cardiovascular (MACE) and all-cause mortality in ACS patients with and without diabetes mellitus.

Methods:
Per PRISMA guidelines, we comprehensively reviewed PubMed, Google Scholar, and SCOPUS for eligible studies reporting on SHR and its association with MACE (8 studies) and all-cause mortality (7 studies) in ACS patients. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a binary random-effects model, with results displayed as forest plots. Heterogeneity was assessed using I2 statistics, and a leave-one-out sensitivity analysis was performed. P<0.05 was considered significant.

Results:
A total of 15 studies with 45,774 patients with ACS were included in the analysis. The majority of patients were males (72.6%) with a mean age of 62.8 years. High SHR was associated with higher odds of MACE (1.93 [1.54–2.42]) and all-cause mortality (1.91 [1.58–2.31]) (Fig. 1). Subgroup analysis revealed increased odds of all-cause mortality (1.69 [1.34–2.11] for patients with diabetes vs 2.12 [1.65–2.71] for patients without diabetes) and MACE (1.60 [1.30–1.97] for patients with diabetes vs 1.44 [1.28–1.62] for patients without diabetes), all p<0.01. (Fig. 2). Additionally, the leave-one-out sensitivity analysis demonstrated that excluding any particular study did not significantly affect outcomes (p<0.05).

Conclusions:
In patients with ACS, SHR is an independent predictor of MACE and all-cause mortality, irrespective of diabetes status. Strict glycemic control strategies may improve outcomes in this high-risk population. These findings underscore the importance of early recognition and management of stress hyperglycemia in ACS patients.
Abstract 4138304: Macrophage ZIP8 Enhances Efferocytosis and Mitigates Atherosclerosis by Modulating cellular Manganese (Mn) Homeostasis
Authors: Yi Ting , Huang Zhijie , Chen Ji , Qin Donglu , Wang Fengjiao , Li Chenyu , Yu Bilian , Wang Mi
Published: November 2024

Introduction:
ZIP8, also known as SLC39A8, is a transmembrane transporter responsible for the movement of various divalent metal ions. Multiple genome-wide association studies (GWAS) have revealed a significant association between a mutation in ZIP8 (rs13107325; Ala391Thr) and cardiovascular diseases. While its physiologic role is incompletely understood, recent studies implicate that Zn2+ influx into monocytes regulated by ZIP8 is a novel factor determining their adhesion and recruitment to atherosclerotic lesions. The potential role of ZIP8 in modulating macrophage function and thereby influencing the development of atherosclerosis warrants further investigation.

Methods and Results:
Using an ApoE
-/-
ZIP8 A393T missense mutation mouse model, we quantified atherosclerotic plaque burden and lipid profiles following induction of atherosclerosis. The presence of the ZIP8 A393T missense mutation resulted in increased necrotic regions and plaque load in the atherosclerosis mouse model, while having no impact on total cholesterol (TC) or low-density lipoprotein cholesterol (LDL-C) levels. Confocal microscopy and flow cytometry to investigate how reduced ZIP8 expression affects macrophage efferocytosis. When siRNA was used to knock down ZIP8 in vitro, macrophage efferocytosis was reduced. Subsequently, Macrophage-specific ZIP8 knockout mice (ZIP8
LysM
) demonstrated a decrease in the efferocytosis index in primary macrophage. Additionally, in vivo thymic and peritoneal efferocytosis assays showed an impaired efferocytosis phenotype in ZIP8
LysM
mice. Confocal microscopy showed ZIP8
LysM
mice have no effect on macrophage binding to apoptotic cells. The lack of or incompleteness of the F-ACTIN ring formed by macrophages surrounding apoptosis in the ZIP8
LysM
mice, and the prolonged duration of phagocytosis ring formation suggests that the internalization process is compromised. The role of ZIP8 ion transport in the efferocytosis impairment mechanism was also investigated.The regulation of macrophage efferocytosis via the metabolism of D-galactose, glutamine, glutamate, and Zn
2+
is unaffected by ZIP8. Mn
2+
was identified as a vital regulatory factor in the efferocytosis function of ZIP8 in macrophages.

Conclusions:
ZIP8 influences the efferocytotic capacity of macrophages and regulates the clearance of apoptotic cells through Mn
2+
, suggesting that ZIP8 and Mn
2+
hold promise as a key therapeutic targets for the treatment of atherosclerotic cardiovascular diseases.
Abstract 4138310: Successful Endovascular Closure of Ascending Aortic Pseudoaneurysm Using Atrial Septal Defect Occluder
Authors: Khan Wahab Jahangir , Asif Muhammad , Paa Christopher , Bacharach Michael , Wagener John
Published: November 2024

Introduction:
Ascending aortic pseudoaneurysms are mostly related to either surgery or non-surgical trauma. Any pseudoaneurysm arising from graft anastomoses, regardless of size or location, must be repaired due to the potential for catastrophic rupture. Traditional surgical intervention has a high mortality rate, but percutaneous treatment has emerged as an alternative. We present such a case of pseudoaneurysm treated by percutaneous intervention using a 6-mm Amplatzer device.

Case:
A 77-year-old female with a history of type A aortic dissection s/p emergent repair with a 32 mm tube graft one year ago presented with chest pain radiating to her back. Initial vital signs showed a BP of 185/105, SaO2 98% on RA, 98.3 F, HR 98 bpm, and RR 24/min. A chest CT scan suggested a pseudoaneurysm at the proximal anastomotic site of the aortic graft (Figs. 1A and B). Serial troponin and EKGs were unremarkable for acute ischemia. Multiple quaternary centers declined intervention due to the high risk of redo sternotomy for open repair and patient frailty. After multidisciplinary discussions, it was felt that percutaneous closure with an Amplatzer device was possible without coronary obstruction. In the catheterization lab, a TEE probe was placed to visualize the pseudoaneurysm of the ascending aorta (Fig. 1C). Angiography showed the aneurysm coming off the posterior aorta just above the noncoronary cusp, with the neck measuring ~6 mm (Fig. 1D). The aneurysm was successfully engaged using an 8-French sheath and an 8-French AL1. Based on measurements from the TEE and the angiogram, a 6 mm ASO device was used. After device deployment and release, aortograms showed that the pseudoaneurysm was excluded (Fig. 1H). Assessment with TEE and CTA showed no residual flow in the pseudoaneurysm (Fig. 1 E–G).

Conclusion:
Using an atrial septal occluder, endovascular intervention may be a safe and effective alternative to surgery for treating the ascending aortic pseudoaneurysm, especially in patients with a high prohibitive surgical risk. Longitudinal follow-ups are needed to comment on long-term mortality benefits for these individuals.
Abstract 4138322: Do branched stent grafts for dissecting aortic aneurysms really improve long-term outcomes?
Authors: Kawatou Masahide , Matsuo Takehiko , Yamamoto Erika , Tazaki Junichi , Takeda Takahide , Takai Fumie , Osada Hiroaki , Takatoku Kazuhiro , Kira Hiromasa , Fujimoto Yasuyuki , Fujimoto Haruka , Nakanishi Ryo , Kanno Kazuyoshi , Ikeda Tadashi , Ono Koh , Minatoya Kenji
Published: November 2024

Backgrounds:
We have previously used a handmade branched stent graft (SG) to treat thoracic aortic aneurysms. In this study, we examined the long-term results of treatment for dissecting thoracic aortic aneurysms.

Methods:
Between 2004 and 2014, we treated 28 patients with dissecting thoracic aneurysms using the branched SGs.

Results:
The mean age was 65 ± 14 years; 17 were over 70, and 22 were male. The mean time from the onset of dissection was 5.7 ± 6.3 years; 6 were operated within one year. The mean aneurysm diameter was 59 ± 8 mm. All dissecting aneurysms were located after zone 3. SG branches were one in 24 cases, two in 2, and three in 2. Twenty-two were treated for entry closure and distal landing in the true lumen. Six with limited dissecting aneurysms were treated for entry closure and distal landing in a non-dissected lumen. The cause of perioperative death was pneumonia in 1. The mean follow-up was 8.3 ± 5.3 years. Entry closure was achieved at 86%, branch patency was 94%, and aneurysm diameter was reduced by an average of 5 ± 14%. There were 6 aneurysm-related deaths. Two were aneurysm ruptures, and each of the 4 was additional operative death, sudden death, SMA occlusion, and type A dissection. The aneurysm-related mortality was 26% at eight years; there was no difference between under 70 and over 70 years old. The cumulative risk of additional procedures was 57% at eight years, and the risk was higher in those over 70 than those under 70 (p<0.05). Thirteen required additional procedures, and 5 required multiple. In detail, re-TEVAR to distal SINE was in 7, re-TEVAR for aneurysm enlargement due to residual false lumen was in 1, re-TEVAR for type 1a endoleak (EL) was in 4, open repair was in 3, stenting for stenosis of true lumen in iliac artery was in 1, stenting for SG branches were in 2, and embolization of the left subclavian artery after re-TEVAR was in 1. Details of open repair were partial arch and thoracic descending replacement for type 1a EL in 1, ascending and partial arch replacement for type 1a EL followed by partial arch and thoracoabdominal replacement in 1, partial arch and thoracoabdominal replacement for distal SINE and aneurysm enlargement in 1.

Conclusion:
The branched SG for dissecting thoracic aneurysms successfully achieved the initial goal of entry closure, which concept is promising, but requires careful observation for appropriate additional procedures.
Abstract 4138330: Clinical outcomes in rheumatic mitral stenosis and the novel Yeo’s index
Authors: Leow Ryan , Li Tony , Chiu Jackie , Chan Meei-Wah , Kong William , Poh Kian-Keong , Kuntjoro Ivandito , Sia Ching-Hui , Yeo Tiong-Cheng
Published: November 2024

Introduction:
Yeo’s index, the product of the mitral leaflet separation index and dimensionless index of mitral valve, was recently described to accurately identify severe rheumatic mitral stenosis (MS). We aimed to study the association between Yeo’s index and clinical outcomes in patients with rheumatic MS.

Methods:
We studied 297 patients with rheumatic MS. Clinical and echocardiographic data were obtained from the electronic medical record and Yeo’s index was measured in all cases. The outcome studied was a composite of all cause death, heart failure (HF) hospitalisation, mitral valve intervention and stroke or transient ischaemic attack. We also performed subgroup analysis of patients without pre-existing atrial fibrillation (AF) to assess for association with new onset AF.

Results:
After a median follow up of 6.3 years, 145 patients (48.8%) developed the composite outcome. Yeo’s index (
p
<0.001), mitral valve area (MVA) by pressure half-time (PHT) (
p=
0.028) and planimetry (
p
<0.001), age (
p
=0.016), history of diabetes mellitus (
p
=0.029), previous HF (
p
=0.021), left ventricular ejection fraction (
p
=0.022), and pulmonary artery systolic pressure (
p
=0.007) were univariately associated with the composite outcome. Yeo’s index remained independently associated (
p
<0.001, HR 0.094, 95% CI 0.260-0.340) with the composite outcome in multivariate analysis. In subgroup analysis of patients without pre-existing AF, Yeo’s index was independently associated (
p
=0.024, HR 0.354, 95% CI 0.143-0.874) with new onset AF. MVA by PHT and planimetry were not associated with new onset AF.

Conclusion:
Yeo’s index was independently associated with clinical outcomes in patients with rheumatic MS.
Abstract 4138332: Lipoprotein (a), Triglyceride-Glucose Index and Incident Atherosclerotic Cardiovascular Disease (ASCVD): Analysis of the UK Biobank
Authors: Kazibwe Richard , Schaich Christopher , Chevli Parag , Kingsley Jeffrey , Rikhi Rishi , Ahmad Muhammad , Mirzai Saeid , Namutebi Juliana , Mehta Anurag , Bhatia Harpreet , Michos Erin , Shapiro Michael
Published: November 2024

Background:
The triglyceride-glucose index (TyG), an inexpensive novel surrogate marker for insulin resistance, and lipoprotein (a) [Lp(a)] are both risk factors for atherosclerotic cardiovascular disease (ASCVD). However, it is uncertain whether TyG modifies the relationship of Lp(a) with incident ASCVD.

Objective:
To investigate the relationship of Lp(a) and TyG with the risk of incident ASCVD.

Methods:
We included UK Biobank participants without ASCVD at enrollment. Baseline TyG was calculated as ln[fasting triglycerides (mg/dL) × fasting plasma glucose (mg/dL)/2]. We classified TyG values as high (≥75th percentile) or low (<75th percentile), and Lp(a) levels, in nmol/L, as <125 or ≥125. Participants were then stratified into four groups: Group-1: Low TyG with Lp(a), <125, Group-2: Low TyG with Lp(a) ≥125, Group-3: High TyG with Lp(a) <125, and Group-4: High TyG with Lp(a) ≥125. We used multivariable Cox regression to estimate the risk of ASCVD (a composite of peripheral arterial disease, coronary artery disease, myocardial infarction, ischemic stroke, and cardiovascular mortality) of TyG and Lp(a) adjusted for the other, and in the four combination groups.

Results:
Eligible participants (N=254,377) had a mean (SD) age of 56.0 (8.1) years, and 53.2% were female. The median follow-up was 14.6 years. In separate models additionally adjusted for cardiovascular risk factors (see Figure legend), the hazard ratio (HR [95% CI]) for ASCVD was 1.18(1.13–1.23) for Lp(a) ≥125 nmol/L (vs. <125 nmol/L), adjusted for TyG, and 1.09(1.05–1.13) for high TyG (vs. low), adjusted for Lp(a). A statistically significant interaction between TyG and Lp(a) was observed in the fully adjusted model (p <0.001). Compared to Group-1 (low TyG with Lp(a) <125nmol/L), the adjusted HR (95% CI) of incident ASCVD in Group-2, -3 and -4 were: 1.07(1.04–1.13), 1.15 (1.09–1.21) and 1.34(1.25–1.44), respectively
(Figure).

Conclusions:
These findings demonstrate that TyG and Lp(a) are associated with incident ASCVD risk independently of each other. Moreover, TyG modified the effect of Lp(a) on ASCVD, suggesting that insulin resistance may amplify the atherogenic, inflammatory, and/or thrombotic effects of Lp(a), thereby further increasing ASCVD risk.