bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 4137278: Efficacy and Safety of Left Atrial Appendage Closure Devices in Patients Aged Above 80 Years: A Systematic Review and Meta-Analysis
Authors: Barrera Nelson I , Jimenez Yomary , Gallegos Koyner Francisco , Jou Katerina , Cerrud-Rodriguez Roberto , Ammirati Giuseppe , Di biase Luigi
Published: November 2024

Background:
Limited single-center and observational studies suggest that left atrial appendage occlusion (LAAO) may be a safe alternative in selected elderly patients with AFib.

Hypothesis:
We hypothesize that patients aged over 80 will have similar rates of complications and the same level of efficacy in stroke prevention as young patients.

Aims:
This review aims to establish the safety and efficacy of LAAO in octogenarians and nonagenarian patients with AFib.

Methods:
A systematic search of PubMed, Science Direct, and CENTRAL was performed for studies that reported outcomes comparing octogenarian and nonagenarian patients who underwent LAAo with their younger counterparts. The Review Manager 5.4 software was utilized to conduct a meta-analysis of the outcomes.

Results:
Seven observational studies consisting of 6,126 patients were included, of whom 1,879 (31%) were ≥80 years old and 4247 (69%) <80 years old. The mean age of the octogenarian and older cohort ranged from 82.3 to 84.5 years, while that of the younger cohort ranged from 68.2 to 75.9 years. The mean follow-up across the studies ranged from one month to five years post-LAAO. Our pooled analysis showed no significant difference in the odds of mortality (OR 1.30; 95% CI [0.49, 3.47]; p = 0.60), all causes of stroke (OR 1.22; 95% CI [0.61, 2.43]; p= 0.57), vascular complications (OR 1.70; 95% CI [0.61,4.73]; p=0.31), and pericardial complications (OR 1.45; 95% CI [0.69, 3.05]; p = 0.33) but a significant difference in the odds of major bleeding events (OR 1.88; 95% CI [1.51, 2.34]; p<0.00001)occurred in patients aged >80 compared to their younger counterparts.

Conclusion:
This meta-analysis suggests that LAAO in patients aged 80 years and above demonstrates comparable mortality rates, post-procedural complications, and efficacy to those seen in younger patients. The findings support the safety and effectiveness of LAAO as a viable alternative for stroke prevention in very elderly patients, with additional consideration needed for those with increased susceptibility to bleeding events.
Abstract 4137306: Percutaneous Coronary Intervention Versus Optimal Medical Therapy for Vulnerable Atherosclerotic Coronary Plaques: A Pilot Meta-Analysis of Randomized Controlled Trials
Authors: Jain Hritvik , Odat Ramez , Goyal Aman , Rathore Sawai Singh , Jha Mayank , Jain Jyoti , Yadav Ashish , Passey Siddhant , Saleem Maryam , Suleiman Hassan
Published: November 2024

Background:
Vulnerable coronary plaques are identified as thin-capped fibroatheromas with substantial plaque and a lipid-enriched necrotic core. These plaques are often non-flow-limiting on assessment; however, they have been associated with future adverse clinical outcomes, such as unstable angina, myocardial infarction, and sudden cardiac death. Current guidelines do not recommend revascularization of such coronary plaques; however, percutaneous coronary intervention (PCI) can theoretically slow atherosclerotic progression and potentially reduce future adverse events.

Methods:
Major electronic databases were searched for randomized controlled trials (RCTs) that compared PCI to optimal medical therapy (OMT) for vulnerable coronary plaques. The outcomes were pooled using a random-effects model, and the results were expressed as risk ratios (RR) with corresponding 95% confidence intervals (CI).

Results:
3 RCTs with 1811 patients (909: PCI and 902: OMT) were included. PCI demonstrated a statistically insignificant trend towards a decreased risk of all-cause mortality [RR: 0.40; 95% CI: 0.13, 1.27; p=0.12], cardiovascular mortality [RR: 0.17; 95% CI: 0.02, 1.38; p=0.10], myocardial infarction [RR: 0.78; 95% CI: 0.35, 1.72; p=0.53], target vessel-related myocardial infarction [RR: 0.68; 95% CI: 0.04, 11.27; p=0.79], ischemia-driven target vessel revascularization [RR: 0.22; 95% CI: 0.04, 1.22; p=0.08], and major adverse cardiovascular events [RR: 0.41; 95% CI: 0.14, 1.18; p=0.10] compared to OMT.

Conclusion:
This study concluded that PCI was comparable to OMT in patients with vulnerable atherosclerotic coronary plaques. Further large-scale RCTs with longer follow-up durations are required to confirm these findings.
Abstract 4137309: Superior Ventricular Longitudinal Strain Is Linked To Metabolic Adaptations, Protective Ventricular Remodeling Among Older Women And Clinical Outcomes.
Authors: WONG JIE JUN , Leng Shuang , ZHAO XIAODAN , Tan Glades , Zhang Hongzhou , Kovalik Jean Paul , Gao Fei , Wee Hai Ning , Chua Kee Voon , Ching Jianhong , Tan Ru , Zhong Liang , Koh Angela
Published: November 2024

Background:
Superior left ventricular (LV) systolic function among older women over men has been linked to differences in aging-related ventricular remodeling. Global longitudinal strain (LVGLS) is particularly susceptible to early aging perturbations and may precede systolic failure. Combining cardiovascular magnetic resonance (CMR) with metabolomics, we investigated LVGLS in parallel with markers of myocardial biosynthesis and metabolism pathways to explore the mechanisms and sex dimorphisms of cardiac aging.

Methods:
Community adults without cardiovascular disease (CVD) underwent serum metabolomics profiling and simultaneous CMR. Prospective clinical outcomes were tracked from 2014 to 2021. Multiple logistic regression adjusted for significant baseline variables.

Results:
Among 202 participants (46% women, 70.2±8.8 years), participants with better LVGLS were characterized by smaller LV chambers (LVESVi 30.0±14.2 vs 22.0±5.6ml/m
2
, adj. p <0.001; LVEDVi 70.9±19.9 vs 64.0±10.2ml/m
2
, p=0.001 adj. p=0.054) and mass (LVMi 51.5±14.5 vs 43.9±8.8g/m
2
, adj. p=0.008) accompanied by lower levels of several long-chain acylcarnitines species (C12:2-OH/C10:2-DC, C12:1-OH, C12-OH/C10-DC, C14, C16:3-OH/C14:3-DC) independent of sex, diastolic blood pressure, smoking history, and body habitus. Compared to men of similar age, women had superior LVGLS (-21.9±2.6 vs -20.1±2.8%, adj. p=0.024) in tandem with smaller ventricles and less hypertrophy despite similar adjusted LVEF. Higher anaplerotic (methionine, arginine) and proteogenic (phenylalanine, tyrosine) amino acids (AA), together with lower acylcarnitines, distinguished women with better over poorer LVGLS while no AA differences were observed among men. During follow-up, poorer baseline LVGLS was associated with incident composite mortality and hospitalizations (OR=1.12 95%CI 1.01-1.24, p=0.026 adj. p=0.049).

Conclusion:
Preserved ventricular systolic function among older women was linked to superior LVGLS and favorable remodeling than men. Better LVGLS was accompanied by biomarkers of better mitochondrial oxidation, anaplerosis, and proteogenesis, suggesting enhanced myocardial fuel energetics and biosynthesis with better strain. LVGLS represents a promising quantifiable marker of early systolic aging among older adults without CVD linked to prospective clinical outcomes. Biological insights into the aging-adaptive mechanisms of strain conservation may reveal targets in preventing aging susceptibilities to myocardial dysfunction.
Abstract 4137311: Inhibition of IL-33 by tozorakimab in patients with diabetic kidney disease: Cardiovascular insights from FRONTIER-1
Authors: Selvarajah Viknesh , Maki-Petaja Kaisa , Bartesaghi Stefano , Surkova Elena , Vavere Andrea , Arya Deepa , Brooks Dennis , Grice Daniel , Zhu Yan , Pecoits-Filho Roberto , Lambers Heerspink Hiddo , Hofherr Alexis
Published: November 2024

Introduction:
Interleukin-33 (IL-33) is a potent mediator of injury-induced local inflammation. Soluble ST2 (sST2), a decoy receptor of IL-33, is a prognostic serum biomarker for heart failure (HF). Here, we evaluated the impact of tozorakimab, an IL-33-neutralizing monoclonal antibody, on sST2-related secondary cardiac endpoints.

Methods:
FRONTIER-1 was a 24-week phase 2B study (NCT04170543) in patients with diabetic kidney disease (DKD). Key cardiac exclusion criteria were: 1) NYHA Class 3/4; 2) Left ventricular ejection fraction (LVEF) < 40%; 3) B-type natriuretic peptide (BNP) > 200 pg/mL. Local echocardiography (LVEF) was performed at Screening and Week 24. For exploratory analysis, echocardiography recordings were evaluated by a core laboratory. Throughout the study, BNP and sST2 were assessed and adverse events (AE) recorded. Safety and tolerability were evaluated for all dosed participants (Safety Analysis Population, SAP).

Results:
573 participants were included in the SAP (139 = placebo / 434 = tozorakimab). Baseline characteristics were balanced across treatment groups. Tozorakimab was generally well tolerated and the incidences of AE, serious AE (SAEs), discontinuations, and death were similar to placebo. In the placebo group, cardiac disorder AE were reported in 6.5%, and SAE in 2.2%. Decline in LVEF of > 10% was seen in 5 participants (4.3%). None developed BNP > 200 pg/mL or clinical signs of HF. 1 participant (0.7%) presented with clinical symptoms of HF (SAE) without significant changes in LVEF or BNP. On tozorakimab, cardiac disorder AE/SAE were less frequent (3.7%/1.8%). Decline in LVEF of > 10% was observed in 31 participants (8.3%), with 3 showing BNP elevation to 200–308 pg/mL. Two of these participants (0.5%) developed clinical signs of HF with LVEF 55%/30% and BNP < 200 pg/mL. No further AE related to HF were reported for tozorakimab. Central analysis of LVEF revealed a substantial variability of site-based measurements indicating LVEF reductions > 10 % in 2 (3.7%) participants on placebo and 6 (2.9%) on tozorakimab. Furthermore, central exploratory analysis demonstrated a slight increase in LVEF from baseline (1.62%, 95% CI: 0.22, 3.03) and a reduction in average E/e' (-0.47, 95% CI: -0.93, -0.01) for tozorakimab, but not placebo. Trends in BNP and sST2 over time were comparable.

Conclusion:
This study suggests a favorable cardiac safety profile for tozorakimab in patients with DKD. IL-33 inhibition did not elevate serum sST2 significantly.
Abstract 4137342: Prolonged Bazett’s corrected QT interval is associated with cardiovascular events and sudden death in Japanese patients with cardiovascular risk
Authors: Hirata Yuki , Kabutoya Tomoyuki , Hoshide Satoshi , Kario Kazuomi
Published: November 2024

Background:
QT durations are sex-dependent, with women having longer QT durations than men. In addition to congenital long-QT syndrome, prominent QTc prolongation is a risk for sudden death. There are several correction formulas for the QTc interval, but the association between the QTc interval and cardiovascular events by type of correction in patients at cardiovascular risk remains unclear.

Hypothesis:
Prolonged QTc duration is associated with cardiovascular events and sudden death in patients at high cardiovascular risk.

Methods:
We enrolled 4,654 subjects from the Cardiovascular Prognostic Coupling Study in Japan (Coupling Registry), who had one or more cardiovascular risk factors. We used two different definitions of QT prolongation: Bazett’s corrected QT interval (QTcB) and Fridericia’s corrected QT interval (QTcF). QTc was divided into quartiles by gender, and quartile associations with the primary endpoint (composite cardiovascular events: cardiovascular death, nonfatal myocardial infarction/stroke) and secondary endpoint (sudden death) were compared.

Results:
QTc duration in females (QTcB: median 428 [IQR 414–444] ms, QTcF 422 [IQR 409–436] ms) was slightly longer than that in males (QTcB: median 419 [IQR 405–435] ms and QTcF 415 [IQR 402–430], both p<0.001). The mean follow-up period was 53 ± 17 months, during which 159 primary endpoints and 14 secondary endpoints occurred.

The longest QTcB group (Q4: ≥ 435 ms in men, ≥ 444 ms in women) had significantly more cardiovascular events than the other quartiles (vs. Q1: p=0.016, vs. Q2: p=0.037, and vs. Q3 p=0.141), and sudden death was more common than in Q2 and Q3 (vs. Q2 0.003, vs. Q3: p=0.032).

On the other hand, the longest QTcF group (Q4) (≥430 ms for men, 436 ms for women) had significantly more cardiovascular events than the Q1 and Q2 groups but not the Q3 group (vs. Q1: p=0.016, vs. Q2: p=0.037, and vs. Q3: p=0.141); sudden death was not significantly different among quartiles (all P>0.05).

Conclusions:
In Japanese patients at cardiovascular risk, prolonged QTcB was associated with cardiovascular events as well as sudden death.
Abstract 4137349: Cardiomyocyte resilience to Doxorubicin with NAD
+
supplementation in cardiotoxicity
Authors: Gorica Era , costantino sarah , El khal Abdala , Ruschitzka Frank , Dzemali Omer , Paneni Francesco , Rodriguez Cetina Biefer Hector
Published: November 2024

Introduction:
Doxorubicin (DOX) is a potent chemotherapy drug that carries a significant risk of cardiotoxicity leading tso heart failure by presenting a notable challenge in cancer treatment. Despite being characterized by oxidative stress and inflammation, fully understanding Doxorubicin-induced cardiotoxicity (DIC) mechanisms remains elusive. Ongoing research emphasizes the promising role of nicotinamide adenine dinucleotide (NAD
+
) and its precursors in cardiovascular health. Therefore, we sought to evaluate the effectiveness of NAD
+
in preventing or reducing DIC.

Methods:
H9c2 rat cardiomyocytes were pre-treated with NAD
+
100uM for 48 hours, subsequently exposed to DOX 500nM for 24 hours, and received a follow-up NAD
+
100uM treatment for an additional 48 hours. Cell viability was evaluated via the MTT assay. Mitochondrial reactive oxygen species (ROS) production was measured using the MitoSOX assay. The expression of genes crucial for cardiac cell development and function was analyzed through quantitative polymerase chain reaction (qPCR). Furthermore, Western blotting (WB) was conducted to detect changes in the expression of proteins associated with oxidative stress and apoptosis, thus providing an in-depth assessment of NAD
+
's potential therapeutic effects against anthracycline-induced cardiac complications.

Results:
NAD
+
treatment maintained myocardial cell viability in the presence of DOX and modulated gene expression beneficial for cardiac function, including downregulation of pro-inflammatory cytokines such as IL1b and TNF-a. Furthermore, it reduced oxidative stress markers, decreased levels of pro-apoptotic Caspase 3, and increased levels of the antioxidant SOD2 via Sirt1 pathway regulation.

Conclusion:
Our findings highlight the critical importance of a multidisciplinary research approach to elucidate the cardioprotective capacity of NAD
+
against DIC, potentially paving the way for new targeted strategies in oncological therapies.
Abstract 4137350: Temporal Trends and Effect of Superior Vena Cava Isolation Plus Pulmonary Vein Isolation for Paroxysmal Atrial Fibrillation Ablation: A Systematic Meta-Analysis with Trial Sequential Analysis
Authors: Guan Wenchi , Liu Jun , Li Xiaofeng , Chen Keping , yao yan
Published: November 2024

Objectives:
To assess the efficacy and safety of Superior Vena Cava Isolation (SVCI) plus Pulmonary Vein Isolation (PVI) compared to PVI alone in patients with drug-refractory paroxysmal atrial fibrillation (PAF).

Methods:
We utilized PubMed, EMBASE, Cochrane Library (CENTRAL) and Web of Science to identify the published randomized controlled trials (RCTs) involving patients undergoing SVCI+PVI ablation compared to PVI alone therapy. The search, conducted until February 17, 2024, used the terms "Superior Vena Cava," "Pulmonary Vein," "Radiofrequency Ablation," and "Atrial Fibrillation." Two reviewers screened records, extracted outcomes, and evaluated risk bias. The analysis employed Revman 5.4 and Trial Sequential Analysis (TSA 0.9.5.10 Beta).

Results:
The results included 4 RCTs involving 532 patients. Recurrence of atrial fibrillation significantly reduced in the SVCI+PVI group compared to the PVI alone group (RR 0.42, 95% CI 0.26–0.69, P = 0.0005; I
2
= 16%, P
heterogeneity
= 0.04) during a mean 12-month follow-up. Trial Sequential Analysis (TSA) supported these findings. Procedural complications did not show significant differences (RR 1.72, 95% CI 0.52–5.75, P = 0.38; I
2
= 0%, P
heterogeneity
= 0.56).

Conclusion:
In conclusion, the meta-analysis of RCTs suggests that SVCI in addition to PVI is superior to PVI alone for PAF, with no increase in procedural complications. TSA demonstrated consistent results with an adequate sample size, indicating no need for further RCTs on this matter.
Abstract 4137441: Online Cognitive Behavioral Therapy Targeting Psychological Distress Following Open Heart Surgery: An Uncontrolled Pilot Study
Authors: Sarnholm Josefin , Wahlund Tove , Kronish Ian , BERGMAN MAJA , Sartipy Ulrik , Stenman Malin
Published: November 2024

Background:
Cardiac surgery is a significant procedure that reduces mortality and alleviates symptom burden in individuals with cardiovascular diseases. However, many patients develop depression and cardiac-related anxiety postoperatively, which negatively affects long-term prognosis and rehabilitation. There is a clinical need to develop scalable psychological treatments to mitigate these negative health effects.

Objective:
To investigate the feasibility and potential efficacy of a brief internet-delivered cognitive behavioral therapy (internet-CBT) intervention to reduce psychological distress in patients following cardiac surgery.

Methods:
The pilot study included 32 cardiac surgery patients (i.e., CABG, heart valve repair/replacement, aortic repair, or combined CABG and valve repair/replacement) with endorsed postoperative psychological distress and/or interference with daily life who underwent surgery from eight weeks to nine months prior to enrollment. Exclusion criteria included prior cardiac surgery with a ventricular assist device or heart transplant and severe medical or psychiatric illness. The internet-CBT targeted cardiac anxiety and depressive inactivity, lasted for five weeks, and was guided by clinical psychologists via text-based interactive online treatment modules. It included interoceptive exposure, in-vivo exposure, and behavioral activation. Self-assessments were completed at pre-treatment, post-treatment, and at 6-month follow-up.

Results:
Preliminary analyses post-treatment showed substantial pre-post improvements across multiple domains. Notable findings included significant reductions in depressive symptoms (Cohen’s d = 0.70; p = 0.04), cardiac anxiety (Cohen’s d = 1.53; p < 0.001), and perceived severity of post-operative symptoms (Cohen’s d = 1.06; p = 0.006). Participants demonstrated high adherence to the treatment, with the large majority of participants completing all five treatment modules (83.3%). Satisfaction with the treatment was also high (25.5 points out of 32), as measured by the Client Satisfaction Questionnaire, and no adverse events were reported.

Conclusion:
This novel internet-CBT intervention post-cardiac surgery appears to be feasible, acceptable, and clinically promising in reducing postoperative psychological distress. It could be used as a viable adjunct treatment to enhance recovery post-cardiac surgery. These preliminary findings warrant further testing in a randomized controlled trial.
Abstract 4137447: Length of WACA line Affects 1
st
Pass Success rates in PVI
Authors: Belden Elizabeth , Phalunas Caitlin , Bailey Grace , Lathia Minesh , Thosani Amit , Belden William , Silverstein Joshua , Shaw George , Friehling Mati , Cherian Tharian , Duan Chaojing , Liu Emerson
Published: November 2024

Background:
Standard ablation for atrial fibrillation consists of wide antral pulmonary vein isolation, efficacy for which depends on a contiguous series of ablation lesions. The larger a circumference ablated around the pulmonary veins, the more challenging it may be to ensure durable isolation, due to technical and anatomic factors, which may in turn contribute to higher rates of atrial fibrillation (AF) recurrence. The relationship between WACA size and success rates may inform procedural methods and optimize outcomes.

Objective:
To examine the relationship between length of WACA lines and ablation success in patients that have undergone a PVI ablation.

Methods:
We performed a single-center, retrospective analysis of a consecutive series of 258 patients who underwent 1
st
pulmonary vein isolation (PVI) for the treatment of atrial fibrillation, between 1/1/2022 and 6/30/2023. Radiofrequency ablation (RFA) was performed using 50 W with a contact-force sensing irrigated catheter. Information on acute 1
st
pass success for left and right vein was recorded. The length of each WACA line was traced out manually, following the center of the ablated lesions. Follow up information consisted of AF recurrence at three, six, and twelve months. Student t-test was used for comparison of means and Chi-square test was used for categorical variables.

Results:
All veins were successfully isolated in all patients. WACA 1
st
pass success rates were 87% in the left veins, and 83% in the right veins. Right WACA lines were generally longer. In patients with Left WACA 1
st
pass success, the average length of the WACA line was 94.8cm, compared to 100.1cm in the group without 1
st
pass success (p=0.025). In patients with right WACA 1
st
pass success, the average length of the WACA line was 105.8cm, compared to 110.6cm in the group without 1
st
pass success (p=0.07). When evaluating post PVI patients for recurrence of AF at 1year, there was a non-statistically significant association of AF recurrence with longer combined L+R WACA lines during index PVI (205.5cm vs 197.0cm, p=0.065).

Conclusion:
Longer WACA lines during index PVI are associated with failure of 1
st
pass isolation. Further study is needed to address the mechanism by which longer WACA lines affect ablation efficacy, whether due to technical factors reflecting something intrinsic to underlying substrate.
Abstract 4137449: Diagnostic Yield and Testing Characteristics of an Invasive Coronary Function Testing Program
Authors: Bitar Fouad , Abou-Karam Roukoz , Cheng Fangzhou , Gady Shoshana , Sakhuja Rahul , Jaffer Farouc , Fahed Akl
Published: November 2024

Background:
Angina, ischemia, or myocardial infarction in the absence of obstructive coronary artery disease (ANOCA, INOCA, or MINOCA) is common and underdiagnosed. Invasive coronary function testing (CFT) for microvascular disease through coronary thermodilution and for coronary vasospasm through coronary reactivity testing can provide definitive diagnoses and improve patient quality of life. Here, we describe a single site experience launching a CFT program and present the diagnostic yield and test characteristics of the first 66 patients.

Methods:
The first 66 patients who underwent invasive CFT at Mass General Hospital after the launch of the program in 2022 were included. Invasive CFT data and clinical characteristics before and after were entered into a registry. We used descriptive statistics to summarize patient characteristics, diagnostic yield and change in management with invasive CFT. We describe the dose-response and safety of incremental doses of acetylcholine.

Results:
Among 66 patients (mean age 61.73±11.02 years, 56% female), 17 patients underwent testing at the time of an index angiogram and 49 were scheduled after knowledge of coronary anatomy. Reasons for invasive coronary function testing were post-revascularization angina (n=30, 45.5%), ANOCA (n=21, 31.8%), INOCA (n=9, 13.6%), MINOCA (n=4, 6.1%), and heart transplant patients (n=2, 3%). 24 (36.3%) patients underwent coronary thermodilution only, 6 (9.1%) coronary reactivity testing only , and 36 (54.5%) both. CFT resulted in a definitive diagnosis in 45 (68.1%) of participants – 37.9% with coronary vasospasm only, 13.6% with microvascular dysfunction only, and 16.7% with both. There were 21 (31.8%) patients who remained negative after invasive CFT. Invasive CFT led to a change in management in 46 (70%) patients. For example, nitrate, calcium channel blocker and beta blocker prescriptions were modified in 47%, 50%, and 52.3% of patients, respectively. Among 42 patients who underwent coronary reactivity testing by provocation with intracoronary acetylcholine doses of 20, 100, and 200 mcg, there was a dose-response to angina (18.5%, 70.2%, and 95.2%), ischemic ECG changes (11.1%, 75.7%, and 95.2%), and vessel spasm of greater than 90% (3.7%, 27%, and 57.1%). There was only one safety event(PTCA to re-establish flow after spasm).

Conclusions:
We demonstrate the safe implementation of an invasive coronary function testing program with very high diagnostic yield and impact on management.
Abstract 4137457: Cross-sectional Investigation of Proteomic Signatures of Blood Pressure Traits.
Authors: Aggarwal Mohit , Huan Tianxiao , Courchesne Paul , Joehanes Roby , Dupuis Josee , O'Connor George , Levy Daniel
Published: November 2024

Background:
Hypertension is a major risk factor for cardiovascular disease affecting one third of the adult population worldwide. Over 90% cases of hypertension are without a distinct etiology. Identification of protein biomarkers of hypertension may provide insight into disease pathophysiology and highlight novel therapeutic targets.

Methods:
We conducted association analyses between 2922 plasma proteins (exposure) and blood pressure (BP) traits (outcome) in 45,926 UK Biobank participants (aged 57 ± 8 years; 54% women). We employed linear mixed models to study protein associations with systolic and diastolic BP and logistic mixed models to test abundance of proteins in hypertensive vs. normal individuals. The associations were adjusted for age, sex, body mass index, estimated glomerular filtration rate, smoking and alcohol drinking status, and batch effects. Hypertension was defined as systolic BP ≥140 mmHg or diastolic BP ≥90 mmHg) or current use of anti-hypertensive medication. Sensitivity analysis excluded individuals taking BP medication (n=10,229). Functional enrichment analysis was performed to elucidate biological functions and tissue specificity of significant protein signatures (
P
< 0.00017). We further performed Mendelian randomization (MR) to infer causal relations of protein biomarkers and BP.

Results:
We identified 1469 proteins associated with systolic BP and 1638 with diastolic BP. The corresponding numbers were 1410 and 1566 after excluding treated individuals. Plasma levels of 1215 proteins (1105 upregulated, 110 downregulated) differed in individuals with hypertension (N=24,724) compared to normal (N= 21,202). Most of these proteins were specific to liver, adipose tissue, renal cortex and coronary artery. Protein signatures of hypertension showed enrichment in pathways involved in inflammatory response, cholesterol homeostasis, complement and coagulation cascades, and hemostasis. Putatively causal associations were observed for 141 proteins with SBP and 142 with DBP.

Discussion:
This study elucidates protein signatures associated with BP and hypertension. Systemic inflammation and cholesterol homeostasis play important roles in the pathophysiology of hypertension.
Abstract 4137479: Integrating Ambulatory Care Pharmacists into Value-Based Primary Care: A Scalable Model for Addressing Cardiometabolic Disease
Authors: Blood Alexander , Saag Harry , Chesler Adam , Ameripour Dalia , Gutierrez Max , Nguyen Van , Richardson Cassandra , Fields Clive , Clair Jen , Yao Aaron , Moodley Sashidaran
Published: November 2024

Background:
Chronic disease is common, costly, and complicated. In the shift to value-based payment models, interventions to engage patients and improve disease control are necessary to reduce morbidity, mortality, and cost. The use of ambulatory pharmacists has demonstrated improved management of chronic diseases. Traditionally, ambulatory pharmacists are employed by healthcare systems. In this study, we test if integrating ambulatory pharmacists hired, trained, and managed by a retail pharmacy into value-based primary care (VBPC) clinics improves care.

Hypothesis:
Integrating a Walgreens pharmacist empowered by collaborative drug therapy management agreements (CDTM) into Village Medical (VMD) clinics will improve indicators of chronic disease control.

Aims:
Improve hemoglobin A1c (HbA1c) in patients with type 2 diabetes (T2D) and systolic blood pressure (SBP) and diastolic blood pressure (DBP) measurements in patients with hypertension (HTN).

Methods:
An ambulatory pharmacist was embedded into VMD clinics in Phoenix, Arizona under the supervision of VMD primary care providers via a CDTM. The pharmacist provided education, coaching, and medication management by prescribing and titrating therapies for treating T2D and HTN - enabled by access to pharmacy dispensing data. β was generated from difference-in-differences (DID) analyses with propensity score matched controls.

Results:
125 patients had T2D, and 43 patients had HTN in the intervention group with 250 and 86 in the matched control group, respectively. The mean age was 65 years, 54% were female, 2% non-English speaking, and 29% racial/ethnic minorities. The average baseline HbA1c was 9% in the intervention group and 10% in the matched cohort. The average baseline SBP was 146 mmHg in the intervention group and 142 mmHg in the matched cohort. The β in the T2D group was -1.61% (p<0.001) while the β in the HTN group was -10.2 mmHg (p<0.01) for SBP and -2.0 mmHg (p=0.42) for DBP.

Conclusion:
We saw significant reductions in SBP and HbA1c in the pharmacist-managed group compared with matched controls. These results demonstrate that pharmacist integration into VBPC clinics may improve measures of chronic disease known to be associated with morbidity and mortality.
Abstract 4137488: Mild elevation of [K
+
]
0
reduces atrial fibrillation burden and enhances the efficacy of flecainide to suppress the arrhythmia: an experimental study.
Authors: Burashnikov Alexander , Antzelevitch Charles
Published: November 2024

Background:
It is desirable to improve rhythm control management of atrial fibrillation (AF). Extracellular potassium ([K
+
]
0
) may affect AF generation and anti-AF efficacy of the sodium channel blockers.

Methods:
AF burden (i.e., percentage of time spent in AF) was determined in Langendorff-perfused guinea pig hearts in the range of [K
+
]
0
of 3-6 mM in the presence and absence of flecainide (1.0 µM). Spontaneous and single premature beat-induced AF were monitored for 30 min in the presence of acetylcholine (0.3 µM).

Results:
Spontaneous AF episodes were consistently recorded at 3 mM [K
+
]
0
but not at 4-6 mM [K
+
]
0
either with or without flecainide. AF burden was progressively reduced with elevation of [K
+
]
0
and anti-AF efficacy of flecainide progressively increased at the higher [K
+
]
0
(Figure). * p<0.05 vs. 3 mM [K
+
]
0
with no flecainide; ** p<0.05 vs. 3 mM [K
+
]
0
with flecainide; # - p<0.05 vs. respective no flecainide. n=5-6 per group.

Conclusion:
Our findings indicate that mild elevation of [K
+
]
0
significantly reduces AF burden and enhances the efficacy of flecainide to decrease AF burden.
Abstract 4137518: The implications of polygenic versus phenotypic characterization of obesity for cardiovascular-kidney-metabolic health
Authors: Dikilitas Ozan , Naderian Mohammadreza , Kosel Matt , Hamed Marwan , Schaid Daniel , Kullo Iftikhar
Published: November 2024

Introduction:
The overall amount and the distribution of body fat, proxied by body-mass index (BMI) and waist-to-hip ratio (WHR), are two important measures of obesity and have significant polygenic heritability. We aimed to investigate whether polygenic scores (PGS) for these traits have additional predictive utility, beyond phenotypic characterization of obesity, for cardiovascular-kidney-metabolic (CKM) health.

Methods:
We derived PGS for BMI (PGS
BMI
) and WHR adjusted for BMI (PGS
WHRadjBMI
) using PRS-CS-auto on summary statistics from ~700k individuals of European ancestry (EA) in the GIANT consortium and selecting ~1M common variants for each score. We conducted association analyses in the Atherosclerosis Risk in Communities study, a prospective cohort including 8,631 EA individuals with ascertainment of incident diabetes, hypertension, chronic kidney disease, atrial fibrillation, coronary heart disease, ischemic stroke, and heart failure. We used nested Cox models to measure the added predictive utility of PGS to BMI and WHR for incident CKM phenotypes.

Results:
The study cohort (age 54.4±5.7 years, 52.4% women, follow-up 24.5±7.6 years) had a baseline BMI of 26.4 kg/m
2
(median [IQR]; 21.6-29.6) and WHR of 0.94 (0.88-0.98). PGS
BMI
and PGS
WHRadjBMI
were associated with their phenotypes (partial

R
2

; BMI 0.11 and WHR 0.04,
p
<0.001), although with a large phenotypic variability across the distribution of PGS (IQR for 1
st
and 10
th
deciles of PGS; BMI 19.6-28.3 and 22.6-35.9, WHR 0.79-1.03 and 0.87-1.05). Anthropometric measures of obesity were associated with a wider gradient of risk compared to PGS for obesity–most notable for diabetes and cardiovascular phenotypes (Table 1a). Addition of PGS
BMI
and PGS
WHRadjBMI
to BMI and WHR resulted in limited improvement in risk discrimination across incident CKM phenotypes (Table 1b).

Conclusions:
Observed anthropometric measures of obesity are sufficient, and for certain conditions far superior, to capture the risk of incident CKM phenotypes. These findings suggest PGS for adiposity traits likely have limited clinical utility to refine risk stratification for CKM syndrome among middle aged adults.
Abstract 4137559: Assessing Veterans’ Risk of Cardiovascular Disease by Gender Identity
Authors: Streed Carl , Heier Kory , Oleary John , Jasuja Guneet , Goulet Joseph , Duncan Meredith
Published: November 2024

Background:
Extant literature suggests that transgender and gender diverse (TGD) individuals experience a higher burden of CVD risk factors and psychosocial stressors than their cisgender (cis) peers. However, prior studies have been limited by self-reported outcomes or small samples.

Aim:
To determine whether TGD veterans have greater CVD (MI, ischemic stroke, cardiac revascularization) incidence than cis veterans using large, nationwide data.

Methods:
We used EHR data from the Veterans Healthcare Administration to identify veterans with >2 outpatient encounters in fiscal years 2010-2019. Veterans’ gender identity was classified using natural language processing in combination with gender-affirming hormone therapy (GAHT) and a previously validated algorithm for identifying TGD individuals using ICD codes and VHA data. Of 1,105,082 veterans without prior CVD, 42,149 were classified as TGD. We examined sample characteristics by gender identity and used Cox regression to assess the association of gender identity with incident CVD.

Results:
TGD veterans’ mean age (years) was 46 (cis females=40; cis males=53). Cis females had the fewest CVD risk factors, followed by TGD veterans and cis males. Adjusting for age, race, and Hispanic ethnicity, TGD veterans had 1.49 [1.42-1.56] and 0.93 [0.90-0.97] times the risk of CVD compared to cis females and cis males, respectively. Upon additional adjustment for other CVD risk factors, renal function, alcohol use disorder, depression, anxiety, and sexual minority status, results remained statistically significant. Significance also held in sensitivity analyses which matched each TGD veteran to cis female and male veterans on age within 2 years. In analyses stratified by gender identity, trans feminine (HR [95% CI]: 1.26 [1.14-1.40]) and uncategorized TGD veterans (HR [95% CI]: 1.29 [1.22-1.37]) were at higher CVD risk than cis female veterans; trans masculine (HR [95% CI]: 0.85 [0.77-0.93]) and trans feminine veterans (HR [95% CI]: 0.90 [0.82-0.99]) were at lower CVD risk than cis male veterans. Among TGD veterans, GAHT receipt was associated with an 11% decrease in CVD risk.

Conclusion:
TGD veterans’, particularly trans feminine and uncategorized TGD veterans’, CVD risk was greater than that of cis females. Contrary to prior findings, GAHT was associated with decreased CVD risk. These results invite further study into the mechanisms by which GAHT and other factors impact CV health across and within gender identities.
Abstract 4137646: Transcriptomic Profiling of Human Myocardium at Sudden Death to Define Vulnerable Substrate for Lethal Arrhythmias
Authors: Caudal Arianne , Liu Yu , Pang Paul , Maison David , Nakasuka Kosuke , Feng Jean , Schwarzer-Sperber Hannah Sabeth , Schwarzer Roland , Moffatt Ellen , Henrich Timothy , Padmanabhan Arun , Connolly Andrew , Wu Joseph , Tseng, MD Zian
Published: November 2024

Background:
While some chronic pathological substrates for sudden cardiac death (SCD) are well-known (e.g., coronary disease and left ventricular [LV] dysfunction), the vulnerable myocardial state predisposing to fatal arrhythmia remains a critical barrier to near-term SCD prevention.

Hypothesis:
Myocardium of autopsy-defined SCDs exhibit distinct expression profiles vs. non-cardiac sudden deaths and trauma deaths that reflect its acute vulnerable state in the hours to days before SCD, as expression arrests upon death.

Goals/Aims:
Define the vulnerable myocardial substrate for lethal arrhythmia by targeted RNA profiling.

Methods:
We used autopsy to adjudicate arrhythmic from non-arrhythmic causes in 1,265 sudden deaths in San Francisco from 2011-2018. We performed a transcriptomic evaluation of LV sampled at the time of SCD from 245 consented cases using a curated panel of 448 genes with known or hypothesized association with SCD.

Results:
Comparison between Arrhythmic (n=129) and Non-Arrhythmic (n=116) cohorts revealed 31 differentially upregulated and 36 downregulated genes (p-adj<0.05), related to collagen-containing extracellular matrix (upregulation of
FAP
,
FMOD
,
LTBP2
), ion transport (upregulation of
KCNA5
and
KCNN3
, and downregulation of
KCNJ8, KCNK1, KCNJ5
), and contraction (downregulation of
MYH6
). Fibrosis-related genes showed the highest magnitude increased expression in Arrhythmic vs. Non-arrhythmic deaths and vs. published transcriptomes from end-stage heart failure. After molecular stratification by known markers for mature (
COL1A1, COL1A2, COL3A1)
and active (
POSTN
,
MEOX1
) fibrosis, cases with highest expression of both had the highest proportion of arrhythmic cause of death (27/36 [75%]) vs. cases with low expression of both (87/181 [38%], p=0.006) or vs. mature only (10/14 [71%]) or active only (5/14 [36%]). Activated fibroblast gene expression was enriched in Arrhythmic female vs. Arrhythmic male cases, among other sex-specific differences in ion channel and myosin (upregulation of
SCN4B
,
SCN8A
,
KCNAB1
in females,
KCNJ4
and
MYH7B
in males) expression.

Conclusions:
RNA profiling of myocardium at SCD identifies active fibrosis, undetectable by conventional clinical methods, in the presence of fixed scar and selected ion channel dysregulation (more pronounced among female cases) as an acute vulnerable substrate for fatal arrhythmias, and may identify patients at elevated near-term risk for SCD and novel pathways for intervention.
Abstract 4137695: Bundle Branch Block(BBB) is Independently Associated With Adverse Cardiovascular Outcomes in Patients With Heart Failure With Preserved Ejectionfraction(HFPEF): A Propensity Score Matched Analysis
Authors: Slee April , Saksena Sanjeev
Published: November 2024

Background:
Ventricular dyssynchrony due to BBB can cause adverse cardiovascular(CV) outcomes in HF with reduced EF and is known to occur in HFpEF but its independent impact on is unclear.

Objective:
To determine if BBB is an independent risk factor for adverse HF outcomes in HFpEF and the impact of atrial fibrillation (AF)..

Methods:
We studied the impact of BBB in HFpEF utilizing propensity score(PS) matched cohorts without and with BBB from the TOPCAT Americas trial to account for confounding by other co-morbidities. Outcomes analyzed included the TOPCAT primary outcome, CV death&hospitalization (CVH), sudden death, pump failure death (PFD), HF hospitalizations(H), and progression of HF. The impact of concomitant AF ( defined as any AF or AF on ECG) on these outcomes with and without BBB was analyzed.

Results:
329 pts with HFpEF&BBB were PS matched for 24 demographic&disease state variables, BNP strata and AF status with a cohort of 329 pts with HFpEF without BBB. BBB was associated with increased risk of the TOPCAT primary outcome (Hazard ratio{HR} 1.44, 95% confidence intervals {CI} 1.10-1.89, p=0.008), increased risk of HF hospitalizations by 41%(HR 1.41 95% CI 1.04-1.91 p=0.0248) but not CVH (HR 1.18, 95% CI 0.93-1.49, p=..169), but not sudden death (HR 1.40, 95% CI 0.70-2.82, p=0.342) or CV death (HR 1.26, 95% CI 0.84-1.89, p=0.257). Risk of pump failure death (PFD) with BBB was significantly higher in HFpEF subjects without a history of AF (Figure left panel .Kaplan Meier Log rank p=0.0478, HR: 4.22, 95% CI: 0.89 to 19.87, p=0.0689) but not in AF (p=0.138). PFD risk was markedly higher in AF subjects without BBB ( Figure right, Kaplan Meier Log rank p=.0012, HR:7.99, 95% CI:1.80 to 35.41,p = 0.0063) than those with BBB (p=0.91)

Conclusion:
Ventricular dysynchrony induced by BBB independently worsens HFH risk in HFpEF. Its adverse impact on PFD iis seen in the absence of AF. Increase in PFD risk with AF in HFpEF subjects is most prominent in those with normal intraventricular conduction. Mechanical dyssynchrony induced by BBB may have a role in HFpEF subgroups with preserved atrioventricular filling, leading to these adverse HF outcomes
Abstract 4137713: Epsin-Mediated PCSK9-LDLR Interaction: A New Therapeutic Target for Atherosclerosis
Authors: Gupta Krishan , Zhu Bo , Chen Kaifu , Chen Hong
Published: November 2024

Introduction:
Atherosclerosis, a leading cause of cardiovascular diseases, causes about 17.9 million deaths annually. It is driven by high levels of LDL cholesterol (LDL-C). The liver's LDL receptor (LDLR) removes LDL-C from the bloodstream, but its degradation by PCSK9 exacerbates the condition. Epsin, an endocytic adaptor protein crucial for clathrin-mediated endocytosis, plays a significant role in atherosclerosis, particularly lipid metabolism.

Hypothesis:
We propose that hepatic epsins significantly contribute to atherosclerosis by facilitating the PCSK9-induced degradation of LDLR, thus impeding LDL-C clearance.

Objectives:
This study aims to investigate hepatic epsins' role in PCSK9-mediated LDLR degradation and its effects on LDL-C levels and atherosclerosis development. Using bioinformatics, we will analyze enriched pathways and networks to study epsins modulation, which will be validated through biochemical assays and in vivo experiments.

Methods:
Liver-specific double knockout (DKO) mice lacking epsin1 and epsin2 were created on an ApoE
-/-
background. Atherosclerosis was induced using a Western diet (WD), and blood cholesterol and triglyceride levels were monitored. We employed high-resolution single-cell RNA sequencing (scRNA-seq) to analyze cellular transitions, intercellular interactions, and Gene Ontology pathway enrichment within hepatocyte-derived data.

Results:
RNA velocity reveals the transition from lipogenic Alb
hi
Hepatocytes to glucogenic Hnf4a
hi
Hepatocytes in Liver-DKO mice on an ApoE
-/-
background on a WD. Liver-DKO mice on an ApoE
-/-
background on a WD exhibited significantly reduced atherogenesis and lower blood cholesterol and triglyceride levels compared with wild-type on an ApoE
-/-
background on a WD. Gene Ontology enrichment analysis showed elevated pathways for LDL particle clearance and enhanced LDLR-cholesterol communication scores in Liver-DKO mice, suggesting improved LDL-C clearance. Nanoparticle-encapsulated siRNAs targeting liver epsins effectively inhibited atherosclerosis.

Conclusion:
Epsin depletion in the liver upregulated LDLR protein levels, and PCSK9-triggered LDLR degradation was abolished, preventing atheroma progression. Targeting liver epsins presents a novel therapeutic strategy for atherosclerosis, supported by network analysis and predictive modeling for effective interventions.
Abstract 4137717: Atrial Fibrillation in Valvular Heart Disease: Assessing the Impact of Genetics in the UK Biobank
Authors: Cristin Luca , Tang Janet , Tastet Lionel , Marcus Gregory , Delling Francesca
Published: November 2024

Background:
Atrial fibrillation (AF) in valvular heart disease (VHD) is typically linked to pressure or volume overload resulting in atrial remodeling. However, the independent contribution of genetics to AF in VHD beyond abnormal hemodynamics and other risk factors remains unclear.

Objective:
To study the role of a previously developed Polygenic Risk Score (PRS) for AF in predicting AF across different VHDs in the UK Biobank cohort.

Methods:
We analyzed UK Biobank data between 2000 and 2022. ICD codes were used to define incident AF and VHD status, including mitral valve (MV) disease [prolapse (MVP), regurgitation (MR) and stenosis (MS)] and aortic (AV) disease [stenosis (AS) and regurgitation (AR)]. Prior AF was excluded. Participants were divided into quintiles based on the PRS: the top quintile was defined as high genetic AF risk, second through fourth as intermediate genetic risk, and bottom quintile as low genetic risk.

Results:
Among 452841 participants with available PRS, 2238 had at least one VHD (385 MVP, 1058 MR, 81 MS, 421 AR, and 509 AS). AF incidence was 9.9%, 13.6%, and 19% in the low, intermediate and high genetic risk groups respectively, compared to 1.4%, 2.8%, and 5.7% in the general population (all p<0.05) -
Figure 1A
. Cox regression models adjusted for cardiovascular risk factors showed different genetic effects on AF across VHD types. Censoring patients at death, including valve intervention as a time-dependent variable, and excluding AF within 30 days post-intervention, PRS independently predicted AF in MV disease (hazard ratio [HR] 1.7, p=0.03 for the intermediate risk/mid PRS; HR 2.3, p=0.002 for the high risk PRS), particularly in those with MVP (HR 3.1, p=0.03 for the high PRS). However, in those with AV disease, PRS was not significantly associated with AF (p=0.93 and p=0.07) -
Figure 1B.

Conclusion:
In patients with VHD, AF PRS is significantly associated with an increased risk of developing AF. However, the genetic impact varies across different VHD. In AV disease, there is a minimal genetic contribution, and the elevated AF risk may be predominantly due to pressure or volume overload. In contrast, in MV disease, particularly in MVP, there is a substantial genetic influence on AF risk.