bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 4141104: Safety and Therapeutic Potential of Allogeneic Adipose-Derived Stem Cell Spray Transplantation in Ischemic Cardiomyopathy: A Phase I Clinical Trial
Authors: Kawamura Takuji , Yoshioka Daisuke , Kawamura Ai , Misumi Yusuke , Taguchi Takura , Saito Shunsuke , Yamauchi Takashi , Miyagawa Shigeru
Published: November 2024

Background:
Ischemic cardiomyopathy, characterized by an imbalance in myocardial blood supply due to coronary artery atherosclerosis, presents a formidable health challenge. Although coronary artery bypass grafting (CABG) can enhance long-term survival, a subset of patients does not exhibit significant improvement in cardiac function post-surgery. This study investigated the safety and therapeutic potential of allogeneic adipose-derived stem cell (ADSC) spray transplantation combined with CABG in ischemic cardiomyopathy.

Methods:
This single-center, double-blind, randomized clinical trial included six eligible patients with ischemic cardiomyopathy who underwent CABG. The ADSCs, suspended in fibrin glue, were sprayed directly onto the heart during surgery. Primary endpoints encompassed adverse events, late gadolinium-enhanced magnetic resonance imaging (LGE-MRI) volume changes, and feasibility. Secondary endpoints included alterations in left ventricular function, exercise tolerance, and heart failure symptoms.

Results:
All patients underwent surgery successfully without complications. ADSC spray transplantation, evidenced by a reduced LGE-MRI volume, exhibited potential therapeutic benefits by improving left ventricular function and exercise tolerance in the ADSC group compared to the placebo group (Figures 1 and 2). Adverse events were minimal and primarily associated with the CABG procedure.

Conclusions:
This study establishes the safety and feasibility of ADSC spray transplantation combined with CABG for the treatment of ischemic cardiomyopathy. The observed improvements in LGE-MRI volume and cardiac function suggest a potential therapeutic effect, warranting further investigation in larger phase II and III clinical trials. This novel approach holds promise as a clinically viable treatment strategy to enhance revascularization outcomes in patients with ischemic cardiomyopathy.

Registration:

https://clinicaltrials.gov/study/NCT04695522

https://jrct.niph.go.jp/en-latest-detail/jRCT2053190103
Abstract 4141106: AIR-TELTEC-HF Medical Expert System: a new rule-based tool of Intelligent Telemedicine for Chronic Heart Failure
Authors: Vianello Annamaria , Olivelli Martina , Donati Massimiliano , Fanucci Luca , Bechini Alessio , Petrucci Ilaria , MASI STEFANO
Published: November 2024

Background:
Medical expert systems (MES) proceed on a “knowledge base” of clinical variables linked together by a set of rules written by medical experts. The
main
goal of our multidisciplinary team of medical experts and knowledge, information engineers was to create an “intelligent telemedicine” able to improve outcomes through early detection of clinical instability in patients with chronic heart failure (CHF) and multimorbidity.

Methods:
General Practitioners (GP) and Internal Medicine Specialists designed the "knowledge base" including 30 variables and 283 IF/THEN rules. Variables were: vital signs and symptoms, antropometric, age, sex, pharmacological, clinical and instrumental values of heart and renal failure, indices of cardiovascular comorbidities and other comorbidities determining cardiac and/or renal deterioration. A set of hierarchically organized rules identify: 1) the risk class at the time of enrollment, 2) the global risk, continuously updated from self-measurement data and clinical surveys, 3) the most appropriate monitoring plan (Fig.1).

Medical experts provided 8 plans (Fig.2a) for CHF patients, according to their global risk of worsening heart failure (WHF). The higher intensity of monitoring was assigned to all cases the MES was not able to handle.

Results:
AIR-TELTEC-HF MES underwent a first validation on 66 clinical cases, comparing its output vs the expected monitoring defined by medical experts. All cases with clinical instability and WHF (n° 18) were correctly assigned by the MES to the highest intensive monitoring plan. Overall, in 56 cases there was agreement between human expert and MES, leading to an F1-Score of 84% (Fig.2b).

Conclusions:
Our AIR-TELTEC-HF MES prototype for “intelligent telemedicine” reproduces the work of an expert medical team in telemonitoring settings. This prototype can be further improved involving other leading HF experts to enhance the clinical rules for many other cases of CHF and multimorbidity.

It is easy-of-use and explainable enough to assist GP in clinical practice, and to facilitate multidisciplinary clinical discussion on complex patient with CHF and multimorbidity. Using MES for student training would increase the future accuracy in following CHF patients.

Thanks to an appropriate monitoring of the initial phase of WHF, we would have a sensible decrease in hospitalizations. Moreover AIR-TELTEC-HF MES could be integrated with other MES, clinical records, and information systems to exchange data.
Abstract 4141117: Semaglutide and cardiovascular outcomes by blood pressure in the SELECT trial
Authors: Verma Subodh , Deanfield John , Arbel Yaron , Cariou Bertrand , Matos Ana Laura S.A. , Hovingh G. Kees , Jeppesen Ole Kleist , Kahn Steven , Latkovskis Gustavs , Lingvay Ildiko , Maeng Michael , Maher Vincent , Parkhomenko Oleksandr , Poulter Neil , van de Borne Philippe , Kure Peter , Lincoff Abraham
Published: November 2024

Introduction:
Although glucagon-like peptide-1 receptor agonists have been shown to reduce BP and major cardiovascular adverse events (MACE), little is known about whether the benefits of these therapies vary in individuals with hypertension (HT) or across the spectrum of BP categories.

Research Question and Aim:
To evaluate the effect of once-weekly semaglutide 2.4 mg vs placebo on cardiovascular (CV) outcomes by baseline BP categories in SELECT.

Methods:
SELECT was a double-blind, randomized, placebo-controlled trial that included patients aged ≥45 years with preexisting CV disease and BMI ≥27 kg/m
2
without diabetes. Patients received once-weekly semaglutide 2.4 mg or placebo; the primary endpoint was time to first MACE analyzed with a Cox proportional hazards model with semaglutide and placebo as fixed factors according to baseline BP categories.

Results:
Among 17,604 randomized patients, 14,392 (82%) had a history of HT. Patients with history of HT were older and more likely female, with a higher BMI, lower eGFR, and higher UACR. A higher proportion presented with atrial fibrillation, obstructive sleep apnea, and heart failure NYHA class II/III, but fewer underwent coronary revascularization (Table). Patients with HT who received placebo had a higher incidence rate of MACE vs semaglutide (2.6 vs 2.1 per 100 patient-years, respectively). Semaglutide generally exhibited consistent benefits for CV outcomes regardless of history of HT or baseline BP categories (Figure). Compared with placebo, semaglutide significantly and consistently reduced systolic BP (SBP) across BP categories (normal, −2.9 [95% CI−4.0; −1.9]; elevated BP, −2.8 [−4.0; −1.6]; stage 1, −3.4: [−4.1; −2.6]; stage 2, −3.7 [− 4.4; −2.9]).

Conclusions:
HT is highly prevalent in people with overweight or obesity and atherosclerotic CV disease without diabetes and is associated with increased MACE. Semaglutide led to consistent reductions in MACE and lowered SBP irrespective of baseline BP category.
Abstract 4141123: Utility of Comprehensive Profiling of Blood Amino Acid in the Identification and Clinical Characterization of High-Risk Populations for Developing Future Adverse Events in Patients with Cardiovascular Disease
Authors: Moribayashi Kohei , Matsuura Yunosuke , Yamamoto Kinuko , Tanaka Hiroki , Komaki Soichi , Yamaguchi Masashi , Ideguchi Takeshi , Tsuruda Toshihiro , Kaikita Koichi
Published: November 2024

Background:
The associations of specific blood amino acid (AA) metabolite levels with frailty and heart failure have been reported. However, the utility of comprehensive AA profiling in cardiovascular disease (CVD) patients remains unknown.

Aims:
This study aimed to determine whether plasma AA profiling through hierarchical clustering analysis (HCA) can identify and clinically define a high-risk population prone to future adverse events.

Methods:
We enrolled 267 patients (mean age 74 years, 60% male) with CVD (118 with ischemic heart disease, 85 with valvular heart disease, 33 with cardiomyopathy, and 31 with other CVD). In fasting plasma samples, 39 AA metabolite levels were measured using liquid chromatography-mass spectrometry. Hierarchical clustering was used for data analysis. Major adverse cardiovascular events (MACE) were defined as a composite of all-cause mortality, nonfatal myocardial infarction, ischemic stroke, and rehospitalization for worsening heart failure. During a one-year follow-up, MACE incidence was compared across HCA-based patient clusters using Kaplan-Meier (KM) curve analysis. The cluster with the worst prognosis was characterized clinically compared to other clusters.

Results:
HCA enabled patients to be categorized into four clusters (Figure 1A). KM curves showed that Cluster 2 had a significantly worse prognosis than other clusters (log-rank test; p=0.0018) (Figure 1B). AA metabolism in Cluster 2 was characterized by the lowest values of total AA, non-essential AA (NEAA), essential AA (EAA), branched-chain AA (BCAA), BCAA/total AA ratio, and NEAA/EAA ratio. Compared to non-Cluster 2 patients, those in Cluster 2 were older (p=0.004), had lower body weight (p=0.02), a higher prevalence of chronic kidney disease (p<0.0001), higher levels of brain natriuretic peptide (p<0.0001) despite similar left ventricular ejection fraction, lower albumin levels (p=0.001), and more frailty indicators, such as muscle weakness (p=0.002), slower walking speed (p=0.0003), and lower scores on the Short Physical Performance Battery (p=0.002).

Conclusion:
Comprehensive blood AA profiling can effectively identify high-risk CVD patient groups and provide relevant clinical characterization for prognosis.
Abstract 4141125: Lower Limit of Normal for Left Atrial Strain: An updated Systematic Review with Bayesian Meta-Analysis from 10,533 Healthy Subjects
Authors: Katayama Yosuke , Nirthanakumaran Deva , Ozawa Koya , Jeyaprakash Prajith , Pathan Faraz , Negishi Tomoko , Low Gary , Negishi Kazuaki
Published: November 2024

Background:
Left atrial (LA) strain is an established marker of LA function. Our previous meta-analysis (Pathan, 2017) from 2,542 healthy subjects reported 39.4% with lower limit of normal (LLN) at 38.0%. However, subsequent original studies revealed much lower LLN, ranging from 15.1% to 28.2% (Figure). The LLN is critically important for clinical practice to distinguish abnormal LA function from normal. Thus, we hypothesised that a Bayesian meta-analysis to pool LLN from healthy individuals would determine a clinically meaningful cut-off threshold for LA strain.

Aim:
As there has been a large number of recent studies reporting normal LA strain since 2017, we aimed to update our systematic review and run Bayesian analysis for LLN of LA strain.

Methods:
Following PRISMA Guidelines, an updated systematic review was conducted by searching PubMed, Embase, and Scopus databases. Studies of LA strain were included if they involved >20 healthy patients without cardiac disease or risk factors between 2016 and September 2022. Mean LA reservoir strain with 95% confidence intervals were extracted from eligible studies. We use Bayesian meta-analysis to pool the lower 95% confidence interval of the LA reservoir strain from included studies. Prior to pooling the result, we standardised the data with log transformation. The priori used in this model was based on weak informative prior with N (0,1) as the prior distribution. The posterior mean was then exponentiated to obtain the lower reference value and its 95% credible interval (CI).

Results:
Sixty-three studies (10,533 healthy patients) satisfied inclusion criteria. Our updated Bayesian Meta-analysis demonstrated a pooled mean of 37.8% [95% CI: 36.1, 39.4] with LLN at 22.4% [20.6, 24.3], which is more concordant with recent original studies (Figure).

Conclusions:
The normal mean LA strain has been updated by pooling >10,000 subjects. The updated LLN of 22.5% may represent a better clinical cut-off for normal LA strain to identify individuals with abnormal LA strain.
Abstract 4141139: Decreased CD34
+
Peripheral Cell Count is Associated with Worse Left Ventricular Function in Patients with Takotsubo Cardiomyopathy
Authors: Poglajen Gregor , Jovanovic Mark , Frljak Sabina , Zorz Neza , Vrtovec Bojan
Published: November 2024

Background:
The underlying mechanisms of microvascular dysfunction in Takotsubo cardiomyopathy (TCM) remain incompletely understood.

Aim:
As CD34
+
cells are central to coronary microvascular homeostasis we investigated the potential association between CD34
+
cell count and changes in left ventricular function in patients with TCM.

Methods:
In a single-center prospective pilot cohort study we included 19 consecutive patients with TCM treated at our center between January 1
st
, 2022, and December 31
st
,2023. Patients with a history of malignancy were not considered for this analysis. TCM diagnosis was established per InterTac Registry criteria. Patients were enrolled within 24h of admission and underwent comprehensive clinical examination, blood biochemical and hematological analysis, and echocardiography at baseline and 6-month follow-up. CD34
+
cell count was measured using Beckman-Coulter Navios EX flow cytometry with standard antibodies according to ISAGE protocol.

Results:
Patient average age was 66±7 years, all patients were female, and hypertension and diabetes were present in 11 (57%) and 16 (84%) patients, respectively. The initial clinical presentation of TCM was acute chest pain in 15 (79%) patients and 16 (84%) patients displayed symptoms and signs of acute heart failure. Physical or psychological stress was identified in 17 (89%) of patients. Mean baseline left ventricular ejection fraction (LVEF) was 53±11% with apical dyskinesia being present in all patients. A peak mean troponin and NT-proBNP serum levels were 2353±2917 pg/mL and 3273±3196 pg/mL, respectively. The average baseline CD34+ cell count was 1.26±1.0x10
6
/L. We established a significant positive correlation between baseline LVEF (r=0.54; P=0.03) and LVOT VTI (r=0.61; P=0.01) and CD34+ cell count. When stratifying patients on LVEF, patients with LVEF≥50% displayed significantly higher CD34+ cell count than patients with LVEF<50% (1.7±0.9x10
6
/L vs. 0.7±0.0.8x10
6
/L; P=0.04). In the latter group, we also established a positive correlation between CD 34+ cell count and improvement in LVEF at 6-month follow-up (r=0.6; P=0.02).

Conclusion:
In patients with Takotsubo cardiomyopathy CD34+ peripheral cell count appears to correlate with the magnitude of left ventricular functional impairment and with the dynamics of left ventricular recovery. Further studies are needed to confirm our preliminary data and to explore CD34+ cells as a potential therapeutic target in this patient cohort.
Abstract 4141163: Blood Pressure in Adolescence and Stroke at a Young Age in 1.9 Million Males and Females
Authors: Fishman Boris , Vinograd Adi , Tsur Avishai M , Bardugo Aya , Bendor Cole , Libruder Carmit , Zucker Inbar , Lutski Miri , Ram Amit , Hershkovitz Yael , Orr Omri , Furer Ariel , Perelman Maxim , Chodick Gabriel , Yaniv Gal , Tanne David , Derazne Estela , Tzur Dorit , Afek Arnon , Coresh Josef , Grossman Ehud , twig gilad
Published: November 2024

Background:
The rising incidence of stroke among young adults is partly explained by underdiagnosis of risk factors such as hypertension. Current blood pressure cutoff values for hypertension diagnosis in adolescence are not based on cardiovascular outcomes and lack specificity for sex, even though female adolescents have lower blood pressure values.

Methods:
A nationwide, population-based, retrospective cohort study including data of all Israeli adolescents (16-19 years) who were evaluated prior to mandatory military service in 1985 through 2013. The medical evaluation included routine measurements of height, weight, and blood pressure. The primary outcome was the first occurrence of a stroke at a young age (≤52 years) as documented in the National Stroke Registry. Cox proportional hazard models were applied separately for males and females and adjusted for adolescent body mass index and sociodemographic variables. Diabetes status in adulthood, as documented in the National Diabetes Registry, was also accounted. Several sensitivity analyses were conducted, including the evaluation of ischemic stroke cases only as the outcome and stroke occurrence at a very young age (≤45 years).

Results:
The cohort comprised 1,897,048 adolescents (42.4% females). During 11,355,476 person-years of follow-up, there were 1,470 first stroke events, 1,233 (83.8%) cases were of ischemic etiology. In male adolescents, a diastolic blood pressure of ≥80 mmHg was associated with an adjusted hazard ratio (aHR) for stroke at a young age of 1.28 (95% confidence interval 1.05-1.58) (Image 1). In male adolescents with blood pressure of 70-79 mmHg, the aHR was comparable to that of the reference group (<70 mmHg). The aHRs of female adolescents with a blood pressure of 70-79 mmHg and ≥80 mmHg were 1.40 (1.09-1.80) and 1.39 (1.03-1.88), respectively (Image 2). In the sub-analysis of ischemic stroke cases as the outcome, the aHRs were 1.63 (1.23-2.16) and 1.59 (1.14-2.22) for females with blood pressure of 70-79 mmHg and ≥80 mmHg, respectively. The results persisted in extensive sensitivity analysis (Image 1, Image 2).

Adolescent systolic blood pressure of 120-129 mmHg or ≥130 mmHg compared to <120 mmHg was not associated with the outcome in adolescents of both sexes.

Conclusions:
Diastolic blood pressure in adolescence was associated with stroke at a young age, with a lower cutoff level among females.
Abstract 4141166: Identification of Clinical Phenotypes and Heterogeneous Treatment Effects of Surgical Revascularization in Ischemic Cardiomyopathy: A Machine Learning Consensus Clustering Analysis
Authors: Chu Tongxin , Zhou Zhuoming , Liang Mengya , Wu Zhong-kai
Published: November 2024

Introduction:
The Surgical Treatment for Ischemic Heart Failure (STICH) trial confirmed the survival benefits of surgical revascularization compared to medical therapy alone in patients with ischemic cardiomyopathy (ICM). However, the complexities of clinical characteristics in this population may lead to distinct clinical phenotypes with heterogeneity in risk stratification and therapeutic responses to medical therapy or surgical revascularization.

Aims:
To identify ICM patients with different clinical phenotypes for evaluating their outcomes and heterogeneous treatment effects (HTEs) of coronary artery bypass grafting (CABG).

Methods:
We applied a machine learning-based consensus, K-Medoids clustering analysis to the STICH trial dataset. A total of 20 clinically available variables were utilized to distinguish the phenotypes. We compared the risk of all-cause mortality and cardiovascular mortality among different phenotypes. Then, the survival benefits of CABG compared with medical therapy alone were assessed in the identified phenotypes for evaluating HTEs.

Results:
From July 2002 to May 2007, 1212 patients with ICM were enrolled in the STICH trial, with a median follow-up time of 9.7 years. Consensus clustering analysis identified four distinct clinical phenotypes. Specifically, phenotype 1 (n=415) was characterized by higher hemoglobin (14.4 ± 1.4 g/dL) and hyperlipidemia rate (75.2%). Phenotype 2 (n=263) was younger (56.9 ± 8.5 years) and tended to be male (92.4%), with lower LVESVI (69.2 ± 25.2 mL/m
2
). Phenotype 3 (n=280) was older (62.3 ± 9.5 years), with higher creatinine (1.3 ± 0.7 mg/dL) and lower LVEF (24.0 ± 7.8 %). Phenotype 4 (n=254) had higher LVEF (31.4 ± 8.7 %), and higher rates of diabetes mellitus (62.2%) and hypertension (72.8%). Compared with other phenotypes, phenotype 3 had the highest risk of all-cause mortality (HR 1.69, 95% CI 1.41-2.02;
P
<0.001) and cardiovascular mortality (HR 1.80, 95% CI 1.45-2.22;
P
<0.001). Among phenotype 2, CABG was associated with a significantly lower risk of all-cause mortality (HR 0.70, 95% CI 0.50–0.98;
P
=0.033) and cardiovascular mortality (HR 0.63, 95% CI 0.43–0.92;
P
=0.015) compared with medical therapy alone.

Conclusions:
We identified four clinical phenotypes with distinct outcomes and HTEs among ICM patients. Phenotype 3 (older, higher creatinine, lower LVEF) had the poorest clinical outcomes. Phenotype 2 (younger, male, lower LVESVI) was more likely to derive greater survival benefits from CABG.
Abstract 4141176:

Trends in 30-day readmission rate, mortality outcome, and resource utilization among patients admitted for ST-Segment Elevation Myocardial Infarction
Authors: Fatuyi Michael , Eze Stella , Akinti Oluwasegun , Oluwadamisi Jeremiah , Udongwo Ndausung , Olu-Lawal Tolulope , Amoah Joseph , Ramratnam Mohun , Jacobson Kurt
Published: November 2024

BACKGROUND:
With limited data on recent outcomes, ST-segment elevation myocardial infarction (STEMI) continues to be a significant public health issue in the modern day. This study aims to evaluate the most recent trends in 30-day readmission rate (30-dRr), mortality, and resource utilization associated with STEMI.

METHODOLOGY:
We utilized the Nationwide Readmission Database to analyze data from 2016 to 2021. Patients aged ≥ 18 years with STEMI identified using ICD-10 codes. The primary aim was trends in 30-day readmission rates (30-dRr). Secondary objectives included investigating mortality rates, resource utilization measured by LOS, and mean hospital costs adjusted for inflation&identifying readmission most common diagnosis (R-MCD) readmission. The study employed predictive marginal effects over years®ression analyses.

RESULTS:
In recent years, we noticed a decrease in the total number of Index Admissions for STEMI, declining from 508,179 (203 per 100,000 person-year) in 2016 to 457,790 (177 per 100,000 person-year) in 2021 (p trend = 0.001). The median age at index admission was 74.2 years (SD ± 13), with males accounting for 58.8%. Among readmitted patients, the average age was 69.4 years (SD ± 13.7), with males at 58.6%. The 30-day readmission rate has consistently decreased from 9.84% in 2016 to 7.97% in 2021 (p trend = 0.001). The mortality rates for both index admission and readmission have remained stable over the years at 3.14% and 3.15%, respectively, in 2016, and 3.0% and 2.9%, respectively, in 2021 (p trend = 0.4 and 0.1, respectively). The mean LOS for index admission has decreased from 3.8 days in 2016 to 3.5 days in 2021 (p trend = 0.001), with readmission LOS showing a similar decrease from 4.0 days in 2016 to 3.8 days in 2021 (p trend = 0.001). Additionally, the inflation-adjusted mean hospital costs have risen over the years, increasing from $23,758.4 in 2016 to $26,038 in 2021 for index admission (p trend = 0.001) and from $15,335.5 in 2016 to $17,662 in 2021 for readmission (p trend = 0.001). The R-MCD was acute coronary syndrome (25%) and heart failure (23%)

CONCLUSION:
We observed a decrease in the prevalence of STEMI, accompanied by a reduction in the 30-dRr during the study year. Despite stable index and readmission trend mortality outcomes, the LOS has progressively decreased with a rise in hospitalization costs. Further prospective studies are crucial for risk stratification to effectively guide mortality outcomes&cost.
Abstract 4141200: Association of Increased AST/ALT Ratio with Future Cardiovascular Events in Diabetic Patients without Prior Cardiovascular Disease
Authors: Ono Yoshiyasu , Ikeda Shota , Shinohara Keisuke , Matsumoto Sho , Yoshida Daisuke , Nakashima Ryosuke , Nakashima Hiroka , Miyamoto Ryohei , Abe Kohtaro
Published: November 2024

Introduction:
Increased aspartate aminotransferase to alanine aminotransferase ratio (AST/ALT ratio) has recently been reported to be associated with all-cause and cardiovascular disease (CVD) mortality; however, its association with CVD events remains unclear.

Research Question:
Can the AST/ALT ratio predict CVD events in diabetic patients without a history of CVD?

Aim:
To investigate if the AST/ALT ratio is associated with future CVD in diabetic patients without known CVD but at high risk for it.

Methods:
Data form the EMPATHY study, which compared intensive and standard statin therapy in patients with type 2 diabetes mellitus (T2DM), diabetic retinopathy, and hyperlipidemia without known CVD, were used. Patients were divided into two groups based on a baseline AST/ALT ratio cut-off of 1.0, in accordance with previous reports, and the association with CVD events was analyzed.

Results:
A total of 4871 patients were divided into high (>1.0, n=2414) and low (≤1.0, n=2457) AST/ALT ratio groups. During a median follow-up of 36.7 months, 261 CVD events occurred. The cumulative incidence of CVD was significantly higher in the high AST/ALT group compared to the low AST/ALT group (P=0.008, log-rank test) (
Fig. A
). Multivariate Cox regression analysis showed that a high AST/ALT ratio was significantly associated with increased risk of CVD compared to a low AST/ALT ratio (HR, 1.36 [95% CI, 1.04–1.79], P=0.002). This significant association was also observed when analyzing the AST/ALT ratio as a continuous variable, consistent with the restricted cubic spline curve analysis (
Fig. B
). The association of a high AST/ALT with CVD events was similar in subgroups stratified by sex, age, body mass index, and hemoglobin A1c (
Fig. C
).

Conclusion:
Increased AST/ALT ratio was significantly associated with the risk of CVD in patients with T2DM, diabetic retinopathy, and hyperlipidemia without a history of CVD, suggesting its usefulness as a predictor of CVD events in these patients.
Abstract 4141210: Renal outcomes in transthyretin cardiac amyloidosis
Authors: Ioannou Adam , Razvi Yousuf , Porcari Aldostefano , Rauf Muhammad , Martinez-Naharro Ana , Venneri Lucia , Hawkins Philip , Gillmore Julian , Fontana Marianna
Published: November 2024

Background:
Transthyretin cardiac amyloidosis (ATTR-CA) is a progressive cardiomyopathy that commonly presents with concomitant chronic kidney disease. Impaired renal function is associated with worse outcomes, but the prognostic value of changes in renal function over time are yet to be defined.

Objectives:
This study aimed to assess the prognostic importance of a decline in estimated glomerular filtration rate (eGFR) as a marker of renal progression in a large cohort of patients with ATTR-CA.

Methods:
A retrospective analysis of 2001 patients diagnosed with ATTR-CA at the National Amyloidosis Centre (NAC) who underwent a baseline and follow-up eGFR assessment at 1-year between 2000-2024.

Results:
Between baseline and 1-year visits, 208(10.4%) patients experienced renal progression (defined as a decrease in eGFR of >30%). Renal progression was associated with a 2.4-fold higher risk of mortality (HR=2.37,95%CI[1.91-2.94],P<0.001) and the risk was similar across the 3 genotypes (interaction P=0.972) and the 3 NAC disease stages (interaction P=0.172). Deterioration of the cardiorenal axis is tracked through a biomarker progression score composed of NT-proBNP progression (defined as an increase of >700ng/L and >30%) and renal progression. When compared with patients with a stable NT-proBNP and eGFR, a higher risk of mortality was observed in patients experiencing either NT-proBNP or renal progression (HR=2.02,95%CI[1.70-2.40],P<0.001) and those experiencing both NT-proBNP and renal progression (HR=3.77,95%CI[2.84-5.00],P<0.001).

Conclusions:
Renal progression is frequent and consistently associated with an increased risk of mortality. Combining renal and NT-proBNP progression produces a biomarker progression score that reflects worsening of the cardiorenal axis and identifies patients at the highest risk.
Abstract 4141212: Cardiovascular And Obstetrical Outcomes In Women With Premature Coronary Artery Disease
Authors: MIKOU Meryem , PROCOPI Niki , CHARLEUX Pierre , Rahoual Ghilas , Kerneis Mathieu , Silvain Johanne , Legrand Lise , Nizard Jacky , Montalescot Gilles , Zeitouni Michel
Published: November 2024

Background:
Premature coronary artery disease (CAD) is increasing, especially in young women. There is currently no data regarding the cardiovascular and obstetrical risk of pregnancy in patients with premature CAD.

Objective:
This study aims to describe the cardiovascular, obstetrical and fetal outcomes in pregnant patients with premature CAD.

Methods:
Using the AFIJI cohort of individuals with premature CAD (Appraisal of risk Factors in young Ischemic patients Justifying aggressive Intervention), we compared the cardiovascular outcomes of women aged < 40 years-old who experienced pregnancy versus those who did not. Major adverse cardiovascular events (MACE) including death, myocardial infarction, ischemic stroke, or unplanned revascularization were analyzed using a Cox model with pregnancy as a time-dependent variable. A secondary analysis described obstetrical and fetal outcomes in pregnant women with premature CAD vs. pregnant women of the French National maternal and fetal cohort (n=11992).

Results:
Among women with premature CAD in the AFIJI cohort (N = 120), 50 were aged < 40 years among whom 24 experienced pregnancy. Aspirin was the only treatment continued during pregnancy. We observed an association between pregnancy and an increased risk of cardiovascular events (aHR 3.87, IC95% 1.41-10.63, p < 0.01) adjusted for age and tobacco use. When comparing with the French National database, pregnant women with premature CAD had higher rates of preeclampsia (20.8% vs. 2.3%), pregnancy-induced hypertension (37.5% vs. 2%), threat of premature birth (20.8% vs. 4.8%), postpartum hemorrhage (12.5% vs. 3%) and fetal death (8.7% vs. 0.8%).

Conclusion:
Pregnancy in women with premature coronary artery disease is associated with a higher risk of major adverse cardiovascular events and significant more obstetrical complications. These findings highlight the need for careful monitoring and management of pregnant patients with a prior history of CAD to mitigate these risks.
Abstract 4141217: Lipid Profiles and Prognosis in Heart Failure: A Participant-Level Pooled Analysis of the PARADIGM-HF and PARAGON-HF Trials
Authors: Siqueira Sara , Pabon Maria , Claggett Brian , Packer Milton , Lam Carolyn , Rouleau Jean , Zile Michael , Lefkowitz Marty , Desai Akshay , Jhund Pardeep , McMurray John , Vaduganathan Muthiah , Solomon Scott
Published: November 2024

BACKGROUND:
Higher total cholesterol (TC) and LDL-C levels may improve outcomes in heart failure (HF) patients. Elevated remnant cholesterol (RC) is a novel potential atherosclerosis risk factor, but its role in HF is underexplored.

AIM:
To investigate classical (TC, LDL-C, triglycerides (TG), and HDL-C) and novel (RC) lipid parameters (LP) as risk determinants for CV events in HF patients across the LVEF spectrum.

METHODS:
We pooled participant-level data from the PARADIGM-HF (LVEF ≤40%) and PARAGON-HF (LVEF ≥45%) trials to assess the association of LP with CV outcomes. RC was calculated as TC minus the sum of HDL-C and LDL-C. Lipid levels were classified per the National Lipid Association and RC by quartiles. The associations with time to first HF hospitalization and myocardial infarction (MI) were evaluated by adjusted Cox proportional hazards models stratified by trial. Restricted cubic splines accounted for potentially non-linear relationships.

RESULTS:
Of 12,819 participants with available lipid data, 1,967 (15.3%) experienced HF hospitalization and 442 (3.4%) had an MI. Over a median follow-up of 2.6 years, various LP were not consistently or significantly associated with risk of HF hospitalization, while higher RC and TC were linked to increased risk of MI
(Table 1)
. When evaluating LP continuously, there was a significant non-linear association between RC and risk of HF hospitalization, with a nadir in risk at ~ 20-30 mg/dL
(Figure 1)
. In contrast, higher levels of RC, LDL-C, and TC were linearly and significantly associated with risk of MI. None of the results were modified by LVEF.

CONCLUSION:
In a global HF population, higher RC levels were consistently associated with increased risk of MI, while the relationship between RC and the more frequent endpoint of HF hospitalization appeared to be more complex and inconsistent. These data might explain why previous interventional lipid lowering trials have not modified disease course in HF.
Abstract 4141252: Transcatheter versus Surgical Tricuspid Repair among Medicare Beneficiaries: One-Year Results
Authors: Shimoda Tomonari , Ueyama Hiroki , Miyamoto Yoshihisa , Watanabe Atsuyuki , Gotanda Hiroshi , Tsugawa Yusuke , Kuno Toshiki
Published: November 2024

Background:
Mid-term comparative evidence on transcatheter versus surgical tricuspid valve repair is limited at the national level.

Objective:
We aimed to evaluate the in-hospital and 1-year outcomes of transcatheter edge-to-edge repair (TV-TEER) versus surgical repair among Medicare beneficiaries.

Methods:
We analyzed the national data on Medicare beneficiaries aged ≥65 who underwent TV-TEER or isolated surgical tricuspid repair between January 2016 and December 2021. The outcomes of interest included in-hospital mortality, permanent pacemaker implantation rates, and 1-year all-cause mortality and major adverse cardiovascular events (MACE). MACE comprised all-cause mortality, heart failure hospitalization, stroke, and tricuspid reinterventions. We computed propensity scores for undergoing TV-TEER or surgical repair and a matching weight analysis was conducted to compare the two groups.

Results:
A total of 2,257 patients were included (TV-TEER= 1,063 patients, surgical repair = 1,194 patients). The annual volume of TV-TEER cases increased from 20 in 2016 to 307 in 2021 while the annual volume of surgical cases decreased from 233 cases to 156 cases (Figure A). In the unadjusted cohort, TV-TEER was associated with lower in-hospital and 1-year mortality rates (hazard ratio [HR], 0.83; 95% confidence interval [CI], 0.70-0.99; P=0.03). Adjusted in-hospital mortality was also significantly lower in the TV-TEER group compared to the surgical repair group (2.2% vs. 14.2%, P<0.001). Additionally, TV-TEER was associated with lower 1-year all-cause mortality compared to surgical repair (adjusted HR, 0.75; 95% CI, 0.61-0.92; P=0.007) (Figure B). MACE was also lower in the TV-TEER group at 1 year (adjusted HR, 0.73; 95% CI, 0.60-0.88; P<0.001). TV-TEER also resulted in fewer post-treatment permanent pacemaker implantations (0.5% vs. 14.0%, P<0.001) after adjustment.

Conclusions:
Among Medicare beneficiaries undergoing TV-TEER or surgical repair, TV-TEER was associated with more favorable in-hospital and 1-year outcomes compared to surgical repair. While a rapid increase in TV-TEER cases was observed, further validation of mid-term outcomes is essential to ensure proper patient selection.
Abstract 4141277: Continuous nitric oxide inhalation in a murine model of bronchopulmonary dysplasia and pulmonary hypertension
Authors: Zazzeron Luca , Marutani Eizo , Lichtenegger Paul , Ichinose Fumito
Published: November 2024

Introduction:
Abnormal lung development is associated with respiratory disease and pulmonary hypertension (PH) in children. PH associated with bronchopulmonary dysplasia (BPD) carries significantly morbidity and mortality due to right ventricular (RV) failure.

Aim:
to develop an animal model of BPD and PH and examine the effects of chronic nitric oxide (NO) inhalation.

Methods:
We exposed C57bl/6J mouse pups to 11% FiO
2
starting on post-natal day 2-4 with (11%-NO) or without (11%) continuous inhalation of 10 ppm NO for 8 weeks. Control mice breathed air (21%). At age 8 weeks we evaluated the degree of lung injury by measuring arterial PO
2
while breathing 11% FiO
2
, by obtaining lung pressure-volume curves and by pathological evaluation; on transthoracic echocardiography we evaluated the degree of PH by assessing the ratio between the pulmonary artery acceleration time and the ejection time (PAAT/ET), and the RV function by assessing the tricuspid annular plane systolic excursion (TAPSE). We measured RV systolic pressure (RVSP) and RV hypertrophy with the Fulton’s ratio.

Results:
11% and 11%-NO mice compared to controls had lower PaO
2
(42.5±5.1 vs. 42.3±5.4 vs. 51.8±1.4 mmHg, p<0.01), increased lung compliance (51.3±9.6 vs. 46.9±3.2 vs. 35.0±3.3 mL/cmH
2
O, p<0.001), reduced alveolarization, severe small vessel muscularization and vascular rarefaction (Fig. 1 and 2). Treatment with NO ameliorated the reduction in PAAT/ET and TAPSE that was observed in 11% mice compared to controls (11%-NO vs. 11% vs. 21%: PAAT/ET 0.27±0.03 vs. 0.22±0.04 vs. 0.32±0.04, p<0.0001, TAPSE: (0.85±0.16vs. 0.67±0.10 vs.1.1±0.2 mm, p<0.0001). Similarly, the RVSP of 11% mice was significantly elevated compared to control mice and diminished by NO treatment (11% vs. 21% vs. 11%-NO: 84±7 vs. 28±4 vs. 66±7 mmHg p<0.0001). RV hypertrophy in 11% mice was more severe than in 11%-NO mice compared to controls (Fulton’s ratio: 52±8% vs. 42±6% vs. 22±2%, p<0.0001). The median RV cardiomyocytes cross-sectional area significantly increased in both 11% and 11%-NO mice compared to controls but at a lesser extent in the 11%-NO mice (198[194-201 vs.181[178-183] vs.149[87-240] mm
2
, p<0.0001) (Fig. 3).

Conclusions:
we developed a new mouse model of BPD with associated severe PH and RV dysfunction. Continuous inhaled NO did not improve neonatal hypoxia-induced lung injury but ameliorated PH, RV hypertrophy and function. Translation of this therapy to children with BPD and PH may improve clinical outcomes.
Abstract 4141282: Cystamine/Pentagalloylglucose-based versatile modification strategy of decellularized porcine pericardium for transcatheter tissue engineered heart valves
Authors: Liu Yuqi , Xu Yin , Fan Pengning , Xu Li , Qian Xingyu , Zheng Yidan , Chen Ming , Li Fei , Qiao Weihua , Dong Nianguo
Published: November 2024

Transcatheter valve replacement has become the preferred treatment for high-risk elderly patients considering the advantages of less invasive surgical trauma and faster postoperative recovery. Transcatheter heart valves (THVs) primarily made of glutaraldehyde-crosslinked pericardial materials pose a risk of thrombosis and calcification, and are subjected to additional stress during catheter delivery, which leads to poor durability. Herein, we constructed a novel transcatheter tissue engineered heart valve for in situ regeneration through functional modification of cystamine (CySA) and pentagalloylglucose (PGG) on decellularized porcine pericardium (DPP), referred to as CySA/PGG-PP. A dynamically reversible fiber network structure was formed by the modification of CySA and PGG, resulting in excellent resistance to enzymatic degradation and crimping stability of CySA/PGG-PP. The distinctive capability of CySA to catalyze the production of endogenous nitric oxide (NO) provided CySA/PGG-PP with a long-term NO release system that inhibited platelet adhesion and activation to improve hemocompatibility. Proteomics analysis revealed that the improvement of hemocompatibility might be mediated by protein phosphorylation and arachidonic acid metabolism-related pathways. Furthermore, we found that CySA/PGG-PP exhibited significant recellularization and tissue remodeling in a rat abdominal aortic implantation model, accompanied by a mild inflammatory response and no calcification. The positive results in vivo might be regulated by genes associated with cell adhesion and differentiation, extracellular matrix organization, and TGF-β signaling pathway, as revealed by RNA sequencing. Consequently, the instructive transcatheter tissue-engineered valve overcomes the limitations of existing THVs with the aim of significantly improving valve durability for clinical therapy.
Abstract 4141288: ETX-291: A GalOmic™ siRNA for the Treatment of Cardiometabolic Disease
Authors: Fischer Alexander , Pursell Natalie , Whitmore Alan
Published: November 2024

Introduction:
Cardiometabolic diseases significantly increase the risk of stroke and heart attack, leading causes of death worldwide. Due to the multifactorial nature of cardiometabolic diseases, residual cardiovascular risk remains with current monotherapies, highlighting the need for treatments with pleiotropic effects in at-risk populations. e-therapeutics (ETX) uniquely combines computation and RNAi to discover life-transforming medicines. ETX’s RNAi platform, GalOmic™, enables generation of specific, potent, and long-acting siRNA therapies that effectively silence novel gene targets in hepatocytes. HepNet™, ETX’s computational platform, identified the
B4GALT1
gene as a key factor in metabolic disease. This link was supported by genetic evidence that individuals with
B4GALT1
missense mutations have pronounced cardiovascular risk reduction. Together, this indicates that a GalOmic™ siRNA targeting
B4GALT1
could be a potential treatment for cardiometabolic diseases.

Methods:
Potent siRNAs against
B4GALT1
were designed
in silico.
siRNAs were screened
in vitro
in Huh7 cells, primary mouse and human hepatocytes, and
in vivo
in C57BL/6 mice for selection of the lead GalOmic™ siRNA, ETX-291. ApoE3*L.CETP mice on high-fat diet and fructose water were subcutaneously injected weekly with ETX-291 for 12 weeks. After 10 weeks, glucose tolerance tests were performed. Plasma fasting insulin, glucose, lipids, and fibrinogen were measured every 4 weeks and at study termination. Terminal cholesterol profiling and measurement of free fatty acids and liver mRNA expression were also performed.

Results:
ETX-291 displayed high potency
in vitro
and
in vivo
with long duration of action. Treatment of ApoE3*L.CETP mice with ETX-291 significantly reduced the cardiometabolic risk factors LDL and VLDL cholesterol, triglycerides, free fatty acids, and fibrinogen. ETX-291 significantly improved insulin resistance markers and normalized glucose tolerance tests.

Conclusions:
ETX-291, a GalOmic™ siRNA targeting
B4GALT1
, positively affects multiple cardiometabolic risk factors in a humanized mouse model of metabolic disease. The pleiotropic mechanism of action beyond LDL-C lowering, combined with the validated risk reduction observed in individuals with
B4GALT1
missense mutations, makes ETX-291 a promising candidate for clinical development. ETX-291 shows potential for therapeutic and preventative treatment in at-risk populations due to its favorable safety profile and prolonged duration of action.
Abstract 4141302: Endothelial Cell-derived Exosome Regulates the Proliferation and Migration of Smooth Muscle Cells and Aggravate Recurrent In-stent Restenosis
Authors: jiang yu , Tan Fangshun , yu miao , Yang WeiXian , Qian Hai-Yan
Published: November 2024

Background:
After percutaneous coronary intervention (PCI), 5-10% of patients experience in-stent restenosis (ISR), and among these, 10-20% develop recurrent in-stent restenosis (RISR). Proteins could be encapsulated into exosomes and participate in intercellular signaling, affecting various progression of cardiovascular diseases. However, the effect of exosome-derived proteins on RISR progression needs further exploration.

Aims:
Vascular endothelial injury initiates restenosis post-PCI, with the excessive proliferation and migration of vascular smooth muscle cells (VSMCs) playing a central role. To elucidate the mechanisms by which exosomes derived from endothelial cells influence the proliferation and migration of VSMCs, thereby contributing to the exacerbation of RISR.

Methods:
Firstly, coronary plasma was collected from 8 RISR patients and 8 healthy controls. Exosomes were isolated using ultracentrifugation techniques. Protein components in exosomes were sequenced by four-dimensional data-independent acquisition (4D-DIA) quantitative proteomics. Exosomes with high TGF-β1 were co-cultured with primary VSMCs to assess their functional impact on cell behavior. After 24 hours of serum starvation to synchronize cell cycles, the cells were treated with PKH67-labeled exosomes. Subsequent confocal microscopy analysis to evalulate the presence of PKH67-labeled exosomes in VSMCs. Next, we performed cell proliferation assays (CCK-8) and migration assays (wound healing and transwell migration) to evaluate the effects of exosomal transfer on VSMC activity. The expression of TGF-β1, MYH9 and Smad2/3 pathway with their phosphorylation status in exosome-treated VSMCs were tested using WB assays.

Results:
Exosomes from RISR patients, with high TGF-β1 expression, were originated from endothelial cells and could be internalized by VSMCs. TGF-β1 activated Smad2/3 pathway and then promoted MYH9 expression. In addition, overexpression of TGF-β1 boosted the expression of MYH9, while the knockdown of TGF-β1 has the opposite effect. The functional rescue experiment validated that TGF-β1 can regulate downstream MYH9, and participates in the proliferation and migration of VSMCs via Smad2/3 pathway.

Conclusion:
Our study suggests that exosome-derived, endothelial cell-originated TGF-β1 is essential to VSMCs proliferation and migration. This process is mediated via TGF-β1- Smad2/3-MYH9 axis.
Abstract 4141311: The Association Between Oxidative Balance Score and Hypertension: A Cross-Sectional Study
Authors: Wang Kang , Chen Pengfei , Tan Bohao , Wei Cheng , Tang Jianjun , Fang Zhen-fei , Liu Qiming , Chen Zhangling , Zhou Shenghua
Published: November 2024

Background:
The association between oxidative stress score (OBS) and hypertension remains unclear in the US population.

Hypothesis:
We hypothesized that higher OBS was associated with a lower risk of hypertension.

Methods:
A total of 22,938 adults (mean age: 47.2 years) were enrolled from 8 survey cycles of NHANES (2003-2004, 2005-2006, 2007-2008, 2009-2010, 2011-2012, 2013-2014, 2015-2016 and 2017-2018). The total OBS consisted of the dietary OBS and the lifestyle OBS, based on 16 dietary components (including dietary iron, zinc, total fat, copper, selenium, magnesium, calcium, vitamin C, E, B6 and B12, total folate, carotene, niacin, riboflavin, and fiber) and 4 lifestyle components (including body mass index, alcohol, smoking, and physical activity). Weighted multivariate logistic regression was used to investigate the association between OBS and hypertension, and restricted cubic spline (RCS) assessed the nonlinear relationship.

Results:
In the multivariate-adjusted model, a substantially inverse association was observed between total OBS and risk of hypertension. Comparing the extreme quartile groups, the OR and 95% CI were 0.62 (0.52-0.73). Furthermore, higher dietary OBS and lifestyle OBS were similarly associated with a lower risk of hypertension (OR (95%CI): 0.78(0.66,0.93); 0.38(0.33,0.44), respectively). The RCS exhibited a nonlinear dose-response association between total OBS and hypertension (
P
non-linearity
< 0.001).

Conclusion:
These findings support the potential beneficial role of OBS for the prevention of hypertension in adults.