bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 4140265: Single Cell Transcriptomics Unveils Novel Lung Capillary Endothelial Cell Populations and Their Crucial Roles
Authors: James Joel , Dekan Aleksandr , Bharti Dinesh , Valuparampil Varghese Mathews , Kacar Sedat , Niihori Maki , Rafikova Olga , Rafikov Ruslan
Published: November 2024

Background:
Understanding the intricate dynamics of lung microcirculation and capillary endothelial cells (ECs) is crucial for shedding light on both normal physiological processes and the pathogenesis of pulmonary diseases. Recent advancements in single-cell transcriptomics (scRNA-seq) have unveiled distinct lung EC populations, including aerocytes and general capillary cells (gCaps).

Hypothesis:
We hypothesized that gCaps demonstrate more extensive diversity than previously understood, marked by distinct molecular and functional profiles.

Methods:
We utilized scRNA-seq and computational analysis on enriched populations of lung ECs. The mitostress Seahorse assay was conducted to study metabolic function. Electric cell-substrate impedance sensing (ECIS) assessed cell growth, and the Matrigel assay evaluated angiogenic potential of isolated ECs.

Results:
scRNA-seq analysis identified five novel gCap populations, each with unique molecular signatures and functions. Notably, two populations characterized by the expression of ion transporters Scn7a (Na+) and Clic4 (Cl−) are crucial for establishing arterial-to-vein zonation and enhancing the capillary barrier. We identified "root" cells (Flot1+), exhibiting the highest G2M and S scores, essential for the mitotic regeneration and repair of neighboring ECs. Depletion of Flot1+ cells significantly impaired EC proliferation, highlighting their critical role in cell repair. Furthermore, we discovered that gCaps aiding in the venous transition were characterized by the expression of Lingo2. Additionally, we identified a population of detached gCaps marked by an elevated expression of Fabp4, metabolically active genes, and tip-cell markers, suggesting a key role in regulating angiogenesis. The Matrigel sprouting assay confirmed that Fabp4+ gCaps significantly contribute to angiogenesis. Metabolic assays indicated that both Clic4+ and Fabp4+ cells exhibited increased mitochondrial function. Finally, western blot analysis across various EC junction and signaling proteins in isolated gCaps showed significant heterogeneity, further illustrating the complex nature of these cell populations.

Conclusion:
Our study highlights the diverse roles and molecular signatures of lung capillary ECs, enhancing our understanding of their contributions to both normal lung function and pulmonary diseases. These insights also offer valuable direction for developing therapeutic strategies aimed at addressing cardiovascular disorders.
Abstract 4140281: Redefining atrial fibrillation treatment success: Institutional results of atrial fibrillation care using patient-defined pragmatic goals
Authors: Kolomaya Alexander , Zenger Brian , Torre Michael , Lyons Ann , Bunch Thomas , Hess Rachel , Piccini Jonathan , Lobban Trudie , Miller Morgan , Redd Andrew , Spertus John , Zhang yue , Steinberg Benjamin
Published: November 2024

Background:
While atrial fibrillation (AF) clinical trials define treatment success by time to first AF episode > 30 seconds, our previous survey identified patient-defined success as a Toronto AF Severity Score (AFSS) of ≤ 5 (no-mild symptoms, 80% of participants) and an AF episode lasting ≤ 1 hour (60% of respondents). Our objective is to better understand patterns of AF treatment success and failure when defined by patient priorities.

Methods:
Using an institutional retrospective cohort of AF patients with either AFSS scores (53.8%) and/or ambulatory ECG (AECG) data (59.4%), we describe the proportion of patients failing to achieve an AFSS ≤ 5 or AF episodes ≤ 1 hour (
Figure 1
).

Results:
Between 2019 and May 2024, 2087 patients with an AFSS symptom score, and 2305 with AECG monitoring were included, of whom 862 (41%) had AFSS scores ≤5 and 1130 (49%) had AF episodes ≤1 hour. Compared to patients with AFSS ≤ 5, 1225 patients (59%) with AFSS > 5 were younger, more likely to be female, and have more comorbid conditions (hypertension, diabetes mellitus, obstructive sleep apnea, and heart failure) without significant differences in treatment, including rhythm control strategies
(Table 1)
. Compared to patients with AF episodes ≤ 1 hour, 1175 patients (51%) with AF episodes > 1 hour were more likely to have received prior ablation, prior cardioversion, and anti-arrhythmic medications.

Conclusion:
Less than half of AF patients in clinical practice have AF symptom scores or arrhythmia burdens meeting patient-defined goals, with significant differences in both success measures by patient characteristics. Pursuing goal-oriented treatment in AF research and care may help clinicians identify uncontrolled patients, align treatment to patient priorities, and direct future medical intervention at an individual level.
Abstract 4140287: Comparison of Coronary Artery Calcium and Measures of Renal Dysfunction in Reclassifying Cardiovascular Risk Among Individuals with Diabetes
Authors: Kianoush Sina , Bishay Rachelle , Ichikawa Keishi , Krishnan Srikanth , Benzing Travis , Aldana Jairo , Ghanem Ahmed , Hamidi Hossein , Bagheri Marziyeh , Deljavanghodrati Mina , Kinninger April , Malik Shaista , Wong Nathan , Budoff Matthew
Published: November 2024

Background:
The risk of cardiovascular disease (CVD) varies among patients with diabetes. Evidence is insufficient for comparing coronary artery calcium (CAC) and measures of renal dysfunction in reclassifying CVD risk among these patients.

Hypothesis:
This study assesses whether CAC enhances discrimination and net reclassification improvement (NRI) compared to measures of renal dysfunction in persons with diabetes.

Methods:
We used Cox proportional hazard models to compare the performance of CAC and measures of renal dysfunction in predicting CVD in the Multi-Ethnic Study of Atherosclerosis (MESA). Models adjusted for age, sex, race, ever smoking, body mass index, systolic blood pressure, total cholesterol, high-density cholesterol, triglycerides, A1c, fasting blood sugar, hypertension medication use, and insulin use. Measures of renal dysfunction included estimated glomerular filtration rate (eGFR) and urine albumin-creatinine ratio (UACR), assessed individually or as composite variables (eGFR <60 mL/min/1.73 m
2
or UACR >30 mg/g). Improvements in c-statistics and the 10-year area under the curve (AUC) were calculated.

Results:
A total of 839 participants, with a mean age of 64.5 ± 9 years, 396 female (47.2%), 155 White (18.4%), 321 Black (38%), 260 Hispanic (31%), and 103 Chinese (12%), were included. Of the total, 528 (63%) had CAC >0, 139 (17%) had eGFR <60 mL/min/1.73 m
2
, and 232 (28%) had UACR >30 mg/g. Patients were followed up for a mean of 13.4 years. CAC, eGFR, and UACR were associated with an increased risk of CVD in all predefined models. CVD risk increased incrementally with the increase in CAC category (Table). The addition of CAC significantly increased AUC in Model 1 with baseline variables (0.680 vs. 0.726, p=0.002), Model 2 with individual measures of renal dysfunction (0.702 vs. 0.745 p=0.003), and Model 3 with composite measures of renal dysfunction (0.706 vs. 0.746, p=0.004).

Conclusion:
CAC reclassifies CVD risk beyond measures of renal dysfunction and may be used to identify higher-risk patients among those with diabetes.
Abstract 4140310: B cell-mediated antigen presentation promotes adverse cardiac remodeling in chronic heart failure
Authors: Lovell Jana , Duque Carolina , Rousseau Sylvie , Bhalodia Aashik , Bermea Kevin , Cohen Charles , Adamo Luigi
Published: November 2024

Introduction:
Acute myocardial infarction (MI) induces splenic remodeling and rapid mobilization of immune cells from the spleen to the injured myocardium. Activation of this “cardio-splenic” axis contributes to adverse cardiac remodeling and the development of chronic heart failure. B cells account for the majority of splenic immune cells, but their potential role within the cardio-splenic axis of heart failure remains incompletely explored. In this study, we provide evidence indicating that B cells play an essential role within the cardio-splenic axis via MHC II-mediated antigen presentation.

Methods and Results:
MI was induced in mice via permanent ligation of the left anterior descending coronary artery. Four weeks following MI or sham surgery, splenic B cells were isolated and transferred into healthy wild-type mice. Eight weeks after adoptive transfer, we assessed cardiac remodeling of recipient mice using echocardiography, gravimetric analysis, and histology. We found that the adoptive transfer of splenic B cells from post-MI mice was sufficient to induce adverse cardiac remodeling in recipient mice (Figure 1). Adoptively transferred splenic B cells were identified in the blood, spleen, and heart of recipient mice 8 weeks post-adoptive transfer. Single cell RNA sequencing (scRNAseq) of splenic B cells was then performed in mice following MI. Biological pathway analyses revealed dysregulation of signaling pathways related to antigen processing and presentation in post-MI mice, suggesting splenic B cells were modulating adverse cardiac remodeling via major histocompatibility complex class II (MHC II)-mediated antigen presentation (Figure 2). Therefore, we developed transgenic mice with B cell-specific MHC II deletion and repeated our adoptive transfer studies. The adoptive transfer of splenic B cells deficient in MHC II from post-MI mice did not induce adverse cardiac remodeling in naïve recipients (Figure 3). Transcriptomic analyses of peripheral blood B cells were also performed in post-MI human patients and healthy control patients, and showed similar dysregulation of antigen processing and presentation in B cells in both acute and chronic phases of MI.

Conclusions:
Following MI, splenic B cells recirculate along the cardio-splenic axis and contribute to adverse cardiac remodeling via MHC II-mediated antigen presentation. Our results thus point towards MHC II-mediated signaling in B cells as a novel and specific therapeutic target in heart failure.
Abstract 4140326: Predictors of Developing Ischemia-Reperfusion Injury Immediately after Heart Transplantation
Authors: Manla Yosef , Patel Jignesh , Kittleson Michelle , Nikolova Andriana , Chang David , Kransdorf Evan , Stern Lily , Czer Lawrence , Kobashigawa Jon
Published: November 2024

Introduction:
Post-heart Transplant (HTx) ischemia-reperfusion injury (IRI) is not uncommon and has been associated with an increased risk of rejection and cardiac allograft vasculopathy. IRI may occur due to long ischemia time, high dose inotropes, and technical surgical reasons. Identifying other recipient and donor characteristics that might set patients at higher risk for developing IRI might help inform decision-making and improve patient outcomes. Therefore, we aim to investigate predictors of developing IRI immediately after HTx.

Methods:
Between 2010 and 2020, we assessed 893 patients undergoing HTx at our center. Recipient and donor characteristics were collected and compared between patients who were noted to have immediate post-HTx (within 30 days) IRI on their endomyocardial biopsy (n=241) vs. those who did not (n=652). Multivariable logistic regression was used to determine predictors of IRI development and included all univariate significant variables with (P<0.1). Outcomes were represented as odds ratios with corresponding 95% confidence intervals.

Results:
Among 893 patients undergoing HTx, 241 (27%) had IRI within 30 days post-HTx (time to IRI was 14.4 ± 7.3 days). Compared to patients without IRI, those who developed IRI trended towards being older (57 ± 12 vs. 55 ±13 years, P=0.07), were less likely to receive induction therapy with anti-thymocyte globulin (ATG) (43.6 vs. 52.9%, P=0.01), and less likely to be listed with an urgent status at the time of HTx (62.7% vs. 71.9%, P=0.008). Patients listed with an urgent status were on optimal hemodynamic support. No other significant differences were recorded in other pre-transplant or peri-operative recipient characteristics among patients who developed IRI vs. those who did not. In regard to donor characteristics, those who developed IRI received hearts from older donors (37 ± 13.5 vs. 34.9 ± 12.2, P=0.03) and showed a trend toward a higher likelihood of donor-recipient sex mismatch (29.9% vs. 23.6%, P=0.059), regardless of recipient sex. On multivariable logistic regression, only ATG-induction [OR:0.69, 95%CI [0.51-0.93], P=0.015) therapy and urgent status at transplantation [OR:07, 95%CI [0.51-0.96], P=0.028) were significant predictors of IRI development

Conclusion:
Optimal prioritization of HTx candidates on the waitlist and use of ATG induction therapy seem to protect against immediate IRI post-HTx.
Abstract 4140343: Role of a novel protein phosphatase 2A activating drug in the regulation of late sodium current.
Authors: Malhotra Nipun , Wallace Michael , Musa Hassan , Takenaka Sarah , Han Mei , xu Xianyao , Hund Thomas , Muthusamy Natarajan , Mohler Peter , El Refaey Mona
Published: November 2024

Introduction:
The voltage-gated Na
+
channel, Na
v
1.5, plays a leading role in the regulation of myocyte excitability and cardiac function. However, a small “late” component of Na
v
current
I
Na
(
I
Na,L
) increases in response to enhanced adrenergic conditions and is linked to fatal arrhythmias.
I
Na,L
regulation is controlled by a host of proteins, in physiological and pathological states. However, little is known regarding pathways that negatively regulate
I
Na,L.
Our previous work showed that protein phosphatase 2A (PP2A) modulation regulates Na
v
1.5 activity but the field still needs molecules that selectively target PP2A
in vivo.

Hypothesis:
Our newly identified PP2A activating drug will negatively modulate
I
Na,L
via regulation of Na
v
1.5 Ser571 phosphorylation.

Methods:
We isolated and cultured ventricular myocytes (VMs) from 3 months old C57Bl/6 mice. First, we treated the VMs with 2µM of drug for 1, 2, 3 and 4 hours to determine PP2A activity (n=4/group), later PP1 activity was assessed 3-hour post treatment of drug/DMSO in the presence of 5nM okadaic acid (n=4/group). Further, protein expression was evaluated after addition of drug/DMSO to the VMs for 3 hours, followed by 10 min treatment with 1 or 2µM Isoproterenol (Iso) (2µM Iso: n=3-7, 1µM Iso: n=4-5). Furthermore,
I
Na
current-voltage relationship and
I
Na,L
recordings comparing drug and DMSO treated mouse VMs were performed at baseline and after Iso (DMSO: N=8; n=15, drug: N=5; n=10, N: mouse, n: cell). Lastly, immunoblots were performed using heart lysates from control and post transverse aortic constriction surgery mice (n=4/group).

Results:
We observed an increase in PP2A activity 3 hours post drug treatment (p=0.0326), however no change in PP1 activity was observed in drug/DMSO treated VMs. We further confirmed a reduction in Na
v
1.5pSer571 (2µM Iso: p=0.02, 1µM Iso: p=0.0398) levels with no changes in Ca
v
1.2pSer1927 and total Na
v
1.5 expression in drug treated VMs vs. DMSO. Patch clamp recordings revealed no significant changes in
I
Na
current-voltage relationship, instead an increase in
I
Na,L
was seen in DMSO treated VMs post Iso (p<0.05). Drug treated VMs displayed a resistance to Iso-induced
I
Na,L
prolongation at -35, -30, -25, -20, -15 and -10 mV voltage. Finally, increased expression of the PP2A inhibitor (I2PP2A/SET) was observed in failing heart vs non-failing control heart lysates (p=0.04).

Conclusion:
Our new compound activates PP2A via SET and specifically targets
I
Na,L
in VMs.
Abstract 4140348: Characterization of Isolated Right Ventricular Congestion in Cardiogenic Shock
Authors: Kaur Gurleen , Berg David , Van Diepen Sean , Katz Jason , Guo Jianping , Morrow David , Bohula Erin
Published: November 2024

Introduction:
Right ventricular (RV) congestion has been associated with poor outcomes in cardiogenic shock (CS); however, the clinical profile of pts with CS&isolated RV congestion has been less well characterized. We aimed to describe the severity of illness, resource utilization&mortality in pts with isolated RV congestion compared to other congestive profiles.

Methods:
The Critical Care Cardiology Trials Network is a multicenter registry of CICUs coordinated by the TIMI Study Group (Boston, MA). Pts with CS with invasive hemodynamic assessment within 24h of CICU admission (2018-2023)¬ on mechanical circulatory support (MCS) at the time were included. Congestive profiles were defined by right atrial pressure (RAP)&pulmonary capillary wedge pressure (PCWP): isolated RV (RAP≥12&PCWP<18); isolated left ventricular (LV: RAP<12&PCWP≥18); biventricular (BiV: RAP≥12&PCWP≥18), and non-congested (NC: RAP<12&PCWP<18).

Results:
Of 2121 pts with CS, 1186 (56%) met the inclusion criteria with 7.1% classified as RV congestion, 61.6% as BiV, 18.5% as LV&12.7% as NC. The RV group was more likely to be female&have pulmonary disease than others&less likely to have prior HF or severe valve disease than LV&BiV. The RV congestion group had lower pulmonary artery pulsatility index&higher pulmonary vascular resistance than LV&NC (p<0.05 for all); MAP&CI were similar across groups. PE was a contributor to CS in 1.2% and pHTN in 13.1% of RV cases. The RV group more often presented with
de novo
HF-CS, where BiV&LV more often had acute on chronic HF-CS. The RV group tended to have worse shock severity by SOFA score, lactate, vasoactive-inotropic score (global p<0.05 for all)&SCAI stage (panel A) and was more likely to have a cardiac arrest (p=0.010). The RV group had greater use of mechanical ventilation&renal replacement, but lower use of MCS (panel B). CICU mortality was significantly higher in the RV group compared to other profiles (panel C), including after adjustment for cardiac arrest&CS etiology.

Conclusion:
In pts with CS, isolated RV congestion was associated with the highest presenting illness severity, resource utilization&mortality when compared to other congestive profiles.
Abstract 4140358: Predictors Of The Need For Powered Extraction Sheaths During Transvenous Lead Extraction
Authors: Mekary Wissam , El-Chami Mikhael , Bhatia Neal , Lloyd Michael , Westerman Stacy , Shah Anand , Leal Miguel , Delurgio David , Patel Anshul , Tompkins Christine , Merchant Faisal
Published: November 2024

Introduction:
The need for powered sheaths, either laser or mechanically-powered, may increase risk during transvenous lead extraction (TLE). Tools to better predict the need for powered sheaths may facilitate procedural risk stratification.

Methods:
We identified all TLE procedures at Emory Healthcare from 2007-2023. Clinical characteristics and procedural details were collected from medical records. Although the specific details of the extraction procedure were at the discretion of the operator, extraction of targeted leads typically followed a stepwise approach of simple traction, with or without a locking stylet, followed by use of powered sheaths, if needed.

Results:
Out of 1,717 TLE procedures, 849 (49.4%) used powered sheaths. The dwell time of the oldest lead targeted for extraction was significantly longer in cases requiring powered sheaths: 8.7 ± 5.6 vs. 2.3 ± 2.6 years, p<0.001. Powered sheath use as a function of lead dwell time is presented in Figure 1A. Even among leads with dwell times of <1 year, 6% of pacing and 7% of defibrillator leads necessitated powered sheaths. The number of leads targeted for extraction was also higher in cases requiring powered sheaths: 1.8 ± 0.9 vs. 1.6 ± 0.7 leads, p<0.001. In a multivariate model (Figure 1B), increased lead dwell time, increased number of leads, presence of a defibrillator and renal dysfunction were associated with increased likelihood of needing powered sheaths. In contrast, infectious indication for extraction and the presence of a coronary sinus lead were associated with lower likelihood of needing powered sheaths. Major procedural complications (1.8 vs. 0.9%, p=0.13) and procedural deaths (0.8 vs. 0.2%, p=0.09) were numerically higher with powered sheaths.

Conclusion:
A significant minority of leads with dwell time <1 year require powered sheaths for extraction. Longer lead dwell time, increased lead number, presence of a defibrillator and renal dysfunction are associated with increased likelihood of needing powered sheaths. These data may guide pre-operative risk stratification and facilitate tailored use of resources for TLE, such as cardiac surgical back-up.
Abstract 4140361: Evaluating Inflammatory Tone Following Consumption of Full-fat or Non-fat Yogurt: Peripheral Blood Mononuclear Cell Inflammatory Response
Authors: Taormina Victoria , Eisenhardt Simonne , Gilbert Matthew , Kien C , Poynter Matthew , Kraft Jana
Published: November 2024

Inflammation is vital to maintaining homeostasis and immune defense, yet chronic, low-grade inflammation is a hallmark of many cardiometabolic diseases. Due to the high saturated fatty acid content in full-fat dairy foods, national dietary guidance recommends consuming low- or non-fat dairy foods to decrease cardiometabolic disease risk. However, many unique fatty acids found in dairy fat may elicit beneficial effects on chronic low-grade inflammation and the effect of dairy fat within its food matrix remains unclear. Thus, our research question centered on the effect of full-fat dairy foods on inflammatory tone. We hypothesized that short-term consumption of three daily servings of full-fat yogurt would beneficially affect inflammatory tone. The aim of the project was to compare the inflammatory response of individuals with prediabetes after a diet with and without dairy fat. An eight-week randomized controlled clinical trial was conducted comprising two, three-week experimental diet periods, differentiated by the daily consumption of either full-fat yogurt (3.25% fat) or non-fat yogurt. Each experimental diet was preceded by a one-week control diet. Following each diet period, peripheral blood mononuclear cells were isolated from whole blood and incubated in media with or without lipopolysaccharide stimulus. After a 24-hour incubation, cell supernatants were analyzed for interleukin (IL)-1β, IL-6, IL-8, IL-10, and tumor necrosis factor-α concentrations. Under unstimulated conditions, the concentration of IL-1β present in the cell supernatant was lower as a result of the full-fat yogurt diet, compared to the non-fat yogurt diet (0.1 pg/mL compared to 24 pg/mL, respectively;
P
< 0.01), but there were no differences between diets in IL-1β concentrations at 1, 10, or 100 ng/mL lipopolysaccharide stimulation. Diet did not affect supernatant concentrations of IL-6, IL-8, IL-10, or tumor necrosis factor-α in the unstimulated and stimulated conditions. In conclusion, only minimal differences were observed between diets with three daily servings of full-fat or non-fat yogurt indicating that short-term consumption of dairy fat may not impact inflammation via peripheral blood mononuclear cell cytokine secretion.

Funding for this project was provided by the National Dairy Council, Vermont Dairy Promotion Board, USDA National Institute of Food and Agriculture, and UVM Food Systems Research Center.
Abstract 4140382: Does pain predict physical function, cognitive function, activities of daily living, or health-related quality life among adults with heart failure?
Authors: Smith Asa , Jung Miyeon , Pressler Susan
Published: November 2024

Introduction:
Although an estimated 54% of patients with heart failure (HF) and chronic pain report high symptom-associated distress, it is unclear whether pain predicts reduced physical function, cognitive function, independent activities of daily living (IADL) or health-related quality of life (HRQL) over time. The aims were to evaluate baseline pain presence as a predictor of physical function, cognitive function, IADL, and HRQL at baseline, 10 weeks, 4 months, and 8 months after baseline.

Methods:
In a retrospective longitudinal secondary analysis, data were analyzed from 237 participants with HF enrolled in the Cognitive Intervention to Improve Memory in Heart Failure Patients study. Pain presence was measured with the Health Utilities Index Mark-3 Questionnaire (HUI-3), physical function was measured by the Timed Up and Go (TUG), cognitive function was measured with the Montreal Cognitive Assessment (MoCA), IADL was measured by the Everyday Problems Test (EPT), and HRQL was measured by the Minnesota Living with Heart Failure Questionnaire (LHFQ). Descriptive statistics, independent t-tests, and linear mixed models were used to achieve the aims while controlling for gender.

Results:
The demographics were mean age 66.31 ± 12.02 years, gender 46% men, 54% women, race 13.5% Black, 85.7% White, 0.8% Other, NYHA class I: 9.7% II: 37.6% III: 52.7%, average LVEF: 48.9%. A total of 160 (67.51%) reported pain.

In independent t-tests, patients with pain experienced significantly longer (i.e., worse) TUG scores at all timepoints except 10 weeks, and significantly higher (i.e., worse) LHFQ scores at all timepoints (see Table 1). However, in linear mixed models, pain at baseline did not predict TUG scores (F = 1.239, p = .298), MoCA scores (F = 0.148, p = .931), EPT scores, (F = 0.522, p = .668), or LHFQ scores (F = 0.364, p = .779) over time – see Table 1.

Conclusions:
Patients with HF and pain experienced significantly worse LHFQ and TUG scores at multiple timepoints. However, pain did not significantly predict cognitive function, physical function, IADL, or HRQL over time. Future prospective studies are needed to examine other outcomes associated with pain in this population and utilize more robust pain instruments.
Abstract 4140394: Substantial cardiovascular risk reduction with icosapent ethyl in patients with prior cardiovascular events regardless of coronary artery disease history: REDUCE-IT CAD
Authors: Aggarwal Rahul , Bhatt Deepak , Ballantyne Christie , Miller Michael , Brinton Eliot , Jacobson Terry , Ketchum Steven , Lira Pineda Armando , Doyle Ralph , Tardif Jean-Claude , Steg Philippe
Published: November 2024

BACKGROUND:
REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial) was a multinational, double-blind trial that randomized 8,179 statin-treated patients with controlled low-density lipoprotein cholesterol, elevated triglycerides, and cardiovascular (CV) risk, to icosapent ethyl (IPE) 4 g daily or placebo. Randomization was stratified by established CV history (70.7%), or diabetes and other risk factors (29.3%).

METHODS/RESULTS:
We evaluated IPE in patients with CV history, further characterized as having a documented history of coronary artery disease (CAD), or not. Primary (CV death, nonfatal myocardial infarction [MI], nonfatal stroke, coronary revascularization, hospitalization for unstable angina) and key secondary (CV death, nonfatal MI, nonfatal stroke) CV endpoints were evaluated. Of the 5,785 (70.7%) REDUCE-IT patients with established CV disease, 4,532 patients had a history of CAD (multi vessel CAD, prior MI, hospitalization for high-risk non-ST-segment elevation acute coronary syndrome) and 1,253 patients did not. IPE reduced primary and key secondary first and total (first plus recurrent) events in patients with and without a history of CAD. In patients with CAD, IPE demonstrated a 25% relative risk reduction in first (HR 0.75; 95% CI 0.66, 0.84;
P
<0.0001; NNT 17) and 32% reduction in total primary endpoint events (RR 0.68; 95% CI 0.59, 0.78;
P
<0.0001) compared with placebo (
Figure 1A
). In patients without CAD, IPE demonstrated a 34% relative risk reduction in first (HR 0.66; 95% CI 0.51, 0.85;
P
=0.0012; NNT 13) and 47% reduction in total primary endpoint events (RR 0.53; 95% CI 0.40, 0.70;
P
<0.0001) (
Figure 1B
). In patients with and without CAD, similar robust reductions were observed for key secondary endpoint events. CV risk reductions were generally consistent across subgroup analyses by CAD history. Safety findings in patients with or without CAD were generally consistent with the overall study findings and did not differ substantially in patients with or without CAD.

CONCLUSION:
IPE demonstrated robust CV benefit in statin-treated patients with CV disease. Patients with and without CAD experienced large reductions in absolute and relative risk of CV events.
Abstract 4140407: The Importance Of The Atrium For Cardiac Performance In Athletes: A Sample Of Athletes Monitored At The Heart Institute, University Of Sao Paulo Medical School (InCor-HCFMUSP).
Authors: Galvao de Oliveira Oldra Leonardo , Sevilhano Milanesi Gabriele , Fonseca Guilherme Wesley Peixoto da , Souza Francis , Alves Maria-Janieire , Kalil Filho Roberto
Published: November 2024

Background:
Long-term high physical performance athletes are more susceptible to major cardiac adaptations. However, the onset and variations in these adaptations within specific populations, such as Brazilians, remain unclear.

Research Questions:
Which significant cardiac adaptations do high-performance athletes (HPA) exhibit compared to non-competitive regular practitioners (NCRP), and if these adaptations are still physiological.

Aims:
To evaluate the anatomical adaptations of cardiac chambers resulting from physical exercise in Brazilian HPA.

Methods:
This retrospective study analyzed exams conducted from October 2014 to May 2024. We enrolled 28 HPA and 185 NCRP who regularly exercised recreationally. Echocardiograms were performed using a two-dimensional echocardiogram with color Doppler, including atrial measurement by the Teichholz method. Maximum oxygen consumption (VO2max) was assessed by cardiopulmonary exercise testing (CPET).

Results:
There was no difference between groups for age (49±15 vs. 53±14 years; p=0.094), body weight (69.3±10.0 vs. 70.0±11.7 kg; p=0.094) and resting heart rate (63±8 vs. 60±13 bpm/min; p=0.684). VO2max (57.6±13.9 vs. 47.3±9.4 ml/kg/min; p<0.001), interventricular septum (9.2±1.2 vs. 9.0±1.2 mm; p=0.094), left atrium (37.6±2.9 vs. 35.1±3.6 mm; p<0.001) and left ventricular end-systolic diameter (34.2±5.1 vs. 31.2±3.3 ml; p<0.001) were higher in HPA, while mass index (91.7±13.9 vs. 83.3±17.6; p=0.051) and left ventricular wall (9.1±1.2 vs. 8.6±1.1 mm; p=0.056) showed a tendency to be higher in HPA compared to NCRP. Left ventricular ejection fraction (LVEF) was lower in HPA in comparison to NCRP (63±6 vs. 66±4; p=0.004). There were correlations between VO2max and diastolic volume (r=-0.17; p=0.031), systolic volume (r=-0.30; p<0.001) and LVEF (r=0.73; p=0.016). In a stepwise backward regression using the median value of 48.7 ml/kg/min for VO2max, right ventricle (OR, 1.208; 95% CI, 1.051-1.389; p=0.07), body mass index (OR, 0.625; 95% CI, 0.466-0.837; p=0.002), and systolic volume (OR, 0.723; 95% CI, 0.542-0.965; p=0.028) were independently associated.

Conclusion:
HPA shows echocardiogram-assessed heart changes within clinical range. Increased atrial size and end-diastolic volume, despite proper systole, may affect cardiac filling and function by impairing cardiac output and performance, suggesting early atrial function screening to prevent future diseases in high-performance athletes.
Abstract 4140416: Impact of reduced right ventricular function on prognosis or heart failure hospitalization in wild-type transthyretin cardiac amyloidosis
Authors: Omuro Ayumi , Okuda Shinichi , TAMITANI MASAKI , Nawata Junya , Nakashima Yusuke , Miho Fujita , Murakawa Kaori , Uno Moe , Masamune Uchida , Okamura Takayuki , Sano Motoaki
Published: November 2024

Background：
Wild-type transthyretin cardiac amyloidosis (ATTRwt-CA) is a disease that is increasingly diagnosed through non-invasive diagnostic procedures, including echocardiography and 99mTc-pyrophosphate scintigraphy, and advances in medical treatment. However, echocardiographic prognostic markers of ATTRwt-CA have not been fully clarified.

Aims:
The aim of this study was to evaluate physical findings, biomarkers, and echocardiographic parameters related to prognosis and heart failure (HF) in patients with ATTRwt-CA.

Methods:
Thirty-two consecutive patients diagnosed with ATTRwt-CA by myocardial biopsy at Yamaguchi University Hospital from April 2021 to March 2023 were included. Echocardiographic parameters associated with composite adverse outcomes including all-cause mortality or hospitalization for HF were examined.

Results:
During an average follow-up period of 542 days,３patients died and 3 patients were hospitalized for HF. The proportion of male was 91%, the mean NYHA was 1.9, and 44% had a history of HF hospitalization. The average of left ventricular ejection fraction (LVEF) was 44.5%, and wall thickness averaged 13.5mm at interventricular septum. At univariate analysis, systolic blood pressure（systolic BP: 121mmHg vs. 99mmHg, p<0.01）, diastolic BP (68mmHg vs. 56mmHg, P<0.05), NT-pro BNP (2304pg/ml vs. 5875pg/ml, p<0.01), right ventricular (RV) basal diameter (37mm vs. 41mm, p<0.05), tricuspid annular plane systolic excursion (16.5mm vs. 14.5mm, p<0.05), right ventricular fractional area change (38% vs. 28%, p<0.01), right atrial volume index (37.2ml/m2 vs. 55.2ml/m2, p<0.05) were significantly associated with the composite adverse outcome. Left-sided echocardiographic parameters including LV diameter, LVEF, stroke volume index, E/E’, global longitudinal strain, and left atrial reservoir strain were not associated with outcome.

Conclusion:
In ATTRwt-CA, in addition to NT-pro BNP and BP, the presence of decreased RV function may correlate with prognosis or HF admission.
Abstract 4140422: Molecular and Functional Characterization of DENND3 as a Novel Regulator of Ion Channel Trafficking
Authors: Gao Shan , Ye Dan , Neves Raquel , Kim Changsung , Tester David , Zhou Wei , Giudicessi John , Ackerman Michael
Published: November 2024

Background:
We identified a novel, ultra-rare missense variant (p.R534S) in
DENND3
as a potential disease-susceptibility variant in a multi-generational pedigree of familial idiopathic ventricular fibrillation (IVF). DENND3 is a guanine nucleotide exchange factor and activator for small GTPase Rab proteins involved in endosome and ion channel membrane trafficking. However, the role of DENND3 in the heart and its potential involvement in cardiac arrhythmias are unknown.

Objective:
To functionally characterize DENND3-p.R534S and determine its impact on channel trafficking.

Methods:
Heterologous co-expression studies in TSA201 cells were performed with DENND3-WT or DENND3-p.R534S and ion channels: KCNQ1 (Kv7.1, IKs), KCNH2 (Kv11.1, IKr), SCN5A (Nav1.5, INa), or CACNA1C (Cav1.2, ICa) as well as Rab proteins (Rab4, Rab5, Rab6, Rab7, Rab11, Rab12). Patient-specific DENND3-p.R534S iPSC-derived cardiomyocytes (iPSC-CMs) and isogenic controls (IC) were created. Localization and expression of ion channel and Rab proteins was assessed using immunofluorescence (IF) by super resolution AiryScan microscopy. GTPase-Glo assays measured Rab protein activity. Electrophysiology studies using patch-clamp and FluoVolt were performed on iPSC-CM models.

Results:
IF imaging showed significant increases in membrane expression of KCNQ1 (11714±157to 21929±378, p<0.05), KCNH2 (11378±160 to 31965±544, p<0.05), , SCN5A (10339±8 to 11225±23, p<0.05), and CACNA1C (11879±83 to 13749±138, p<0.05) in DENND3-p.R534S compared to DENND3-WT expressing TSA201 cells. Rab5 distribution was altered significantly by the DENND3-p.R534S variant, with increased dispersion away from the nucleus (0.23±0.01 vs. 0.17±0.01, p<0.05) and increased proximity to the plasma membrane (0.16±0.02 vs. 0.23±0.01, p<0.05). Additionally, Rab5 activity was enhanced significantly (57% increase) by p.R534S versus WT (p<0.05). iPSC-CMs revealed similar increases in channel membrane accumulation and irregular arrhythmic activity including frequent action potential duration alternans and afterdepolarizations in 78% of p.R534S iPSC-CMs versus none in IC cells (p<0.05).

Conclusion:
DENND3 is a novel ion channel trafficking protein in the heart. The DENND3-p.R534S variant disrupts cardiac ion channel trafficking. These findings highlight DENND3’s role in cardiac ion channel distribution, cellular function, and potential association with arrhythmogenic risk.
Abstract 4140423: Advanced maternal age and association with major adverse cardiovascular events from NHANES from 1999 to 2018
Authors: Mehta Adhya , Agboola Olayinka , Satti Danish Iltaf , Harrington Colleen , Scott Nandita , Sarma Amy , Saad Antonio , Sullivan Scott , Epps Kelly , Honigberg Michael , Kennedy Jamie , Spitz Jared , Sharma Garima
Published: November 2024

Introduction:
Pregnancy at an advanced age is becoming increasingly common in developed countries. The relationship between advanced maternal age (AMA) (≥ 35 years) and major cardiovascular events (MACE) is not well studied. Therefore, we evaluated the association of AMA at the time of last childbirth with MACE in a large nationally representative sample.

Methods:
We analyzed data from the 1999–2018 National Health and Nutrition Examination Survey. Females aged ≥45 years with no missing pregnancy record were included in the analysis. Based on the age of their last childbirth, they were divided into 4 groups- those who delivered at <35 years (GROUP 1), 35-40 years (GROUP 2), >40 years (GROUP 3), and nulliparous (GROUP 4). MACE was defined as a composite of a history of congestive heart failure, coronary artery disease, stroke, or all-cause death. We assessed the association between these groups and MACE using univariate and multivariate logistic regression models.

Results:
Among 13,180 (weighted frequency = 53,636,595) females included in this analysis, 20% had a history of AMA (groups 2 and 3), 70.6% had no history of AMA (group 1), and 9.4% were nulliparous. Compared to nulliparous women, women with no history of AMA had an 83% higher odd of MACE with an OR 1.83 (95% CI 1.45 – 2.31), while those with history of childbirth between ages 35 – 40 years had a 84% higher odd of MACE with OR of 1.84 (95% CI 1.37 - 2.46), and women with childbirth >40 had 2.7 higher odds of MACE (2.73, (1.87 - 4.00)). However, after adjusting for demographic characteristics and surrogates for social determinants of health such as income, food insecurity, and insurance status, as well as cardiovascular (CV) risk factors like alcohol use, smoking, and comorbidities such as diabetes, dyslipidemia, and hypertension, this association was attenuated. (Table 1)

Conclusion:
Our study did not find a significant independent association between the maternal age of last childbirth and MACE. This suggests that maternal age alone may not be the primary risk factor; the effect of AMA might be mediated by other CV, social risk factors, and parity. This warrants further investigation to better risk stratify women with AMA as a documented risk factor.
Abstract 4140442: Hidden in Plain Sight: Mavacamten’s Role in Unmasking Structural Abnormalities in Obstructive Hypertrophic Cardiomyopathy
Authors: Bhuiya Tanzim , Hsieh Ji-Cheng , Gilman Joshua , Makaryus John , Wharton Ronald
Published: November 2024

Goals:
Mavacamten not only promotes favorable cardiac remodeling in obstructive hypertrophic cardiomyopathy but can also unmask additional underlying structural abnormalities.

Description of Case:
An 80-year-old man with atrial fibrillation and basal septal hypertrophy with an intracardiac defibrillator, presented due to six months of exertional dyspnea.

Transthoracic echocardiography (TTE) revealed severe basal septal hypertrophy (1.7cm) and systolic anterior motion (SAM) of the anterior mitral valve leaflet (peak LVOT gradient 104 mm Hg;
Figure 1)
. The patient was treated with metoprolol but presented again one month later with recurrent postural syncope. The metoprolol dosage was increased, and the patient was initiated on mavacamten.

12 weeks after initiation of mavacamten, surveillance TTE demonstrated a LVOT gradient of 7 mmHg at rest and 11 mmHg during Valsalva maneuver, and a basal septal wall thickness of 1.0 cm
.
Severe mitral regurgitation was noted with the mechanism identified as both Carpentier type I and II. The primary etiology of the regurgitation was determined to be P3 prolapse
(Figure 2)
. There was no longer evidence of SAM.

The patient remained symptomatic and was referred to cardiothoracic surgery for mitral transcatheter edge-to-edge repair (mTEER). Post procedure, the patient’s dyspnea resolved. TTE showed the implanted Mitraclip with trace intra-valvular mitral regurgitation
(Figure 3).

Discussion:
This patient likely had a multifactorial cause of dyspnea. Mavacamten improved the patient’s basal septal hypertrophy and SAM. Subsequent TTE revealed a previously undetected mitral regurgitation jet which was only apparent after the use of mavacamten. This finding led to resolution of symptoms with mTEER.
Abstract 4140448: Pericardiocentesis Outcomes in Patients With Chronic Kidney Disease : A Nationwide Analysis from the United States
Authors: Ghimire Manoj , Poudel Sajana , Shrestha Karun , Ghimire Kalpana , Chamay Salomon , Subedi Prakriti , Nassar Sameh , Pandey Oshna , Sherpa Ninda , Kadariya Dinesh , Baghdadi Salim
Published: November 2024

Introduction:
Pericardial effusions are common among patients with renal disease, especially those with advanced chronic kidney disease (CKD). This population frequently experiences uremic pericarditis, dialysis-associated pericarditis, and pericardial effusion. The natural history of pericardial effusions in the context of renal disease is highly variable. Aggressive hemodialysis can lead to resolution in some cases, whereas others may require immediate drainage for optimal management. Despite these clinical observations, there is a paucity of comprehensive literature evaluating the outcomes of pericardiocentesis in patients with CKD.

Hypothesis:
We hypothesize that pericardiocentesis in CKD patients associated with poor outcomes compared to patients without CKD.

Methods:
A retrospective observational study was conducted utilizing a national patient sample database from 2016-2021. Patients who underwent pericardiocentesis were identified using ICD-10 PCS codes. The study compared various demographics and clinical characteristics between patients with or without CKD.

Results:
A total of 126,834 adults who underwent pericardiocentesis were included, of which 34780(27.4%) patients had CKD, 10, 956 (8.66%) patients had ESRD and 7145 (5.6%) patients were dialysis dependent. Patients with CKD were relatively older and had higher prevalence of comorbidities as shown in the below table.

Complications such as cardiac arrest (6.6% vs. 4.35%, p<0.01), cardiogenic shock (13.8% vs. 9.21%, p<0.01), ventricular arrhythmia (7.95% vs. 6.37%, p<0.01), acute kidney injury (41.45% vs. 24.55%, p<0.01), and mortality (12.57% vs. 9.56%, p<0.01) were significantly higher in CKD patients. The length of stay (11.3 vs. 8.6 days, p<0.01) and total hospital charges ($189,799 vs. $153,831, p<0.01) were also greater for CKD patients.

Conclusions:
Patients with CKD who underwent pericardiocentesis for pericardial effusion has significantly higher rates complications, and mortality, along with longer hospital stays and increased healthcare costs . Further research with evaluation of etiology of pericarditis, current medical management, and stratifying patients based on CKD severity and dialysis dependence is required to assess the better outcomes.
Abstract 4140468: Tet Methylcytosine Dioxygenase 2 mutation drives a global hypermethylation signature in patients with pulmonary arterial hypertension resulting in a common T cell phenotype.
Authors: Hindmarch Charles , Potus Francois , Al-Qazazi Ruaa , Nichols William , Pauciulo Michael , Rauh Michael , Archer Stephen
Published: November 2024

Background:
Epigenetic changes in gene expression due to DNA methylation regulate pulmonary vascular structure and function. Genetic or acquired alterations in DNA methylation or demethylation promote development of pulmonary arterial hypertension (PAH). However, the DNA methylome signature of human PAH and its transcriptomic consequences are unknown.

Methods:
Reduced Representation Bisulfite Sequencing was used for epigenome-wide mapping of DNA methylation in whole peripheral blood of 10 healthy people and 20 age/sex matched PAH patients from the PAH Biobank. We used whole-exome sequencing to identify two PAH cohorts, one free of mutations of know PAH-associated gene variants, and a second with mutations of
TET2
, a newly identified PAH gene that encodes TET2, which mediates DNA demethylation.

Results:
Patients carrying
TET2
mutations had greater DNA CpG methylation compared to mutation-free PAH patients, who themselves had increased methylation compared to controls. Differentially Methylated Regions (DMR) were more common in patients with PAH with
TET2
mutations (1,135 DMR) than without mutations (260 DMR). In a public, blood-derived, PAH transcriptomic dataset, we assayed for transcript downregulation of genes that were hypermethylated in our cohort. 161 TET2 DMRs (38 of which were common to PAH without
TET2
mutation) corresponded to downregulated transcripts. Functional analysis of the hypermethylated genes in TET2 patients revealed similar conserved functions, related to T cell differentiation and metabolism. Functional comparison of the 38 hypermethylated genes found in both PAH cohorts and the 161 hypermethylated genes unique to TET2 mutation also revealed regulation of T cell pathways. The most hypermethylated and downregulated genes was transcription factor 7 (TCF7), a regulator of T cell differentiation, which would be predicted to promote inflammation.

Conclusion:
Pan-chromosomal hypermethylation in PAH is greatest in patients with TET2 mutations. Gene hypermethylation may contribute to hallmarks of PAH, including alterations in immune function, T cell differentiation, and metabolism.
Abstract 4140471: Deleting Tissue B-Cell Dynamics Prevents Angiotensin II-Induced Hypertension in Mice
Authors: Monga Jasmeen Kaur , Zhou Annie , Wang Tao , Momen Abdul , Siraj M. Ahsan , Husain Mansoor
Published: November 2024

Background:
Hypomorphic
c-myb
mice (with reduced B cells) manifest low baseline blood pressure [BP], increased 24-h urinary sodium and water excretion, and protection from DOCA salt-induced hypertension [HTN]. Here we study B cell dynamics and their role in angiotensin [Ang]-II-induced HTN using tissue flow cytometry [FC] and diphtheria toxin [DT]-induced B cell depletion in CD19-Cre/R26-iDTR mice.

Methods&Results:
To investigate B cell dynamics in HTN, wild-type [WT] C57BL/6J male mice aged 10-12 wk were implanted with either (a) 500 ng/kg/min x 28-d (low-dose) or (b) 1000 ng/kg/min x 28-d (high-dose) Ang-II, or (c) saline for FC of all B cell subsets in aorta, spleen, and bone marrow. CD19
+
B cells in aorta increased 9.3-fold with low-dose (1.5±0.9E
2
vs. 1.4E
4
cells/aorta; N=1-4/group; p<0.01) and 8-fold with high-dose of Ang-II (1.5±0.9E
2
vs. 1.2±0.4E
4
; N=2-4/group; p<0.01). In spleen, CD138
+
plasma cells increased 3.4-fold with low-dose- (2.1±0.3E
5
vs. 7.2E
5
cells/spleen; N=1-4/group; p<0.001) but not with high-dose Ang-II (2.1±0.3E
5
vs. 1.3±0.1E
5
; N=2-4/group; p=0.14). In bone marrow, plasma cells decreased 4-fold with low-dose (2.3±0.3E
6
vs. 0.59±0.6E
6
cells/bone marrow; N=2-4/group; p<0.05) but increased 2.2-fold with high-dose-Ang-II (2.3±0.3E
6
vs. 5.2±0.9E
6
cells/bone marrow; N=2-4/group; p<0.01). Then, 10-12-wk old male CD19-Cre/R26-iDTR mice and R26-iDTR controls were implanted with osmotic minipumps to deliver Ang-II (500 ng/kg/min) over 28-d. Intraperitoneal DT (25 ng/g) was injected weekly x 4 to both groups. Flow cytometry [FC] of blood and spleen at d-28 confirmed successful depletion of all B cell subsets in CD19-Cre/R26-iDTR but not R26-iDTR controls. BP measurements at d-28 showed attenuated HTN in B cell-depleted mice compared to non-depleted controls (94±15 vs. 134±12 mmHg; N=5/group; p<0.05). Metabolic studies revealed only
non
-B cell depleted mice to have increased 24-h Na
+
and urine excretion in response to Ang-II (N=4/group).

Conclusion:
CD19
+
B cells infiltrate aorta during Ang-II-induced HTN. Ang-II levels regulate peripheral plasma cell homeostasis possibly through migration from/to or expansion within bone marrow and spleen. B cell depletion in the CD19-Cre/R26-iDTR model demonstrates the importance of B cell subtypes in the pathogenesis of Ang-II-induced HTN, suggesting a potential therapeutic strategy for HTN.