bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 12772: Regulation of Blood Pressure by Smooth Muscle TRPV4 Channels Under Normal and Hypertensive Conditions
Authors: Chen Yen , Daneva Zdravka , Kuppusamy Maniselvan , Ottolini Matteo , Klimentova Eliska , Sonkusare Swapnil K
Published: April 2024

Introduction:
Recent studies suggest that transient receptor potential vanilloid 4 (TRPV4) channel is a functionally important Ca
2+
influx pathway in arterial smooth muscle cells (SMCs).

Hypothesis:
We hypothesized that SMC TRPV4 (TRPV4
SMC
) channels regulate blood pressure under normal conditions and in hypertension.

Results:
Radiotelemetric recordings showed lower blood pressures in the SMC-specific TRPV4
-/-
(TRPV4
SMC
-/-
) mice than the control mice. Phenylephrine (PE, α1 adrenergic receptor or α1AR agonist)-induced constriction was blunted in small mesenteric arteries (MAs) from TRPV4
SMC
-/-
mice, whereas intraluminal pressure-induced constriction was increased. These data demonstrated that TRPV4
SMC
channels contribute to α1AR-induced vasoconstriction but oppose pressure-induced vasoconstriction. Both PE and intraluminal pressure increased the activity of elementary Ca
2+
influx signals through TRPV4
SMC
channels (TRPV4
SMC
sparklets). TRPV4 agonist GSK1016790A (30 nM) activated the currents through large-conductance, Ca
2+
-sensitive K
+
(BK) channels in SMCs, whereas phenylephrine had no effect on BK channel currents. These data implied the presence of two functionally distinct pools of TRPV4
SMC
channels: 1) α1AR-activated, constrictor TRPV4
SMC
channels; and 2) pressure-activated, dilator TRPV4
SMC
channels. Next, direct STORM imaging demonstrated that ~30% TRPV4
SMC
channels co-localize with α1ARs and ~10% TRPV4
SMC
channels co-localize with BK channels. Importantly, only ~3% TRPV4
SMC
channels co-localized with both α1ARs and BK channels, supporting the concept of spatially distinct constrictor and dilator TRPV4
SMC
channels. Angiotensin II (Ang II, 7-14 days) infusion resulted in a lower increase in blood pressure in TRPV4
SMC
-/-
mice than the control mice, demonstrating a crucial role of TRPV4
SMC
channels in blood pressure elevation in hypertension. Moreover, Ang II infusion in C57BL6 mice increased α1AR-TRPV4
SMC
signaling; reduced pressure-activation of TRPV4
SMC
channels; and reduced TRPV4
SMC
-BK channel signaling.

Conclusions:
Our results show that increased constrictor TRPV4
SMC
channel activity and reduced dilator TRPV4
SMC
channel activity combine to elevate blood pressure in hypertension.
Abstract 12774: Effects of Interleukin-1β on Cardiac Reserve and Exercise Capacity in the Mouse
Authors: Vohra Habeebah Z , MEZZAROMA Eleonora , Abbate Antonio , Toldo Stefano
Published: April 2024

Introduction:
Heart failure (HF) is characterized by dyspnea, fatigue, and exercise intolerance. Clinical evidence points to increased interleukin-1β (IL-1β) activity in patients with HF, with IL-1 blockade improving the exercise capacity in HF patients. In healthy mice, recombinant-mouse IL-1β (rmIL-1β) induces acute systolic dysfunction, peaking 4 hours after administration. However, the direct effects of rmIL-1β on exercise capacity are unknown.

Hypothesis:
rmIL-1β diminishes the exercise capacity in the mouse.

Methods:
Adult mice were trained to run on a treadmill and exercise capacity was assessed before, 4, and 96 hours after intraperitoneal rmIL-1β (3 μg/kg) or vehicle (0.9% NaCl) administration (N=7-10/group). In separate groups of mice, left ventricular ejection fraction (LVEF) was assessed at baseline, 4, and 96 hours after stimulation using transthoracic echocardiography. The ultrasound operator was blind to treatments. The cardiac reserve was measured by calculating the difference in LVEF before and after β-adrenergic stimulation using isoproterenol (10 ng/mouse) in IL-1β or vehicle-treated mice (N=5-11/group).

Results:
Treatment with rmIL-1β significantly reduced exercise capacity measured at 4 and 96 hours (32% reduction at 4 hours and 33% reduction at 96 hours, P<0.01 vs baseline for both time points), whereas no effect was observed in the vehicle-treated group (P<0.05 for IL-1β vs vehicle). LVEF was significantly reduced 4 hours after treatment with rmIL-1β (29% reduction, P<0.01 vs baseline at 4 hours), without any significant changes after vehicle. After 96 hours, LVEF had recovered to pre-treatment values. Cardiac reserve was significantly reduced at 4 and at 96 hours after IL-1β group (7% LVEF change at 4 hours and 2% at 96 hours P<0.05 vs baseline for both time points) and not after vehicle (P<0.05 for IL-1β vs vehicle).

Conclusions:
Administration of exogenous IL-1β reduces exercise capacity through an impairment in cardiac reserve.
Abstract 12775: Supervised Exercise Therapy Adherence and Six-Minute Walk Improvement in Peripheral Artery Disease. Findings From Two Randomized Clinical Trials
Authors: Hammond Michael M , Tian Lu , Zhao Lihui , Zhang Dongxue , McDermott Mary M
Published: April 2024

Introduction:
Supervised exercise therapy (SET) is first line therapy for improving walking ability in people with peripheral artery disease (PAD), but adherence to SET is poor. The association of SET adherence with change in six-minute walk distance in PAD is unclear.

Methods:
Data were combined from two randomized clinical trials of SET for PAD. In both trials, participants with PAD were randomized to exercise or a control group for six months. Those randomized to SET were asked to attend 72 exercise treadmill exercise sessions over six months in the presence of an exercise physiologist. Those randomized to attention control were asked to attend up to 24 educational sessions once weekly for six months. Adherence rates were defined as the number of attended intervention or control sessions divided by the number of expected sessions. Participants randomized to SET were categorized into tertiles of adherence, according to the proportion of exercise sessions attended. Six-minute walk was measured at baseline and at 6-month follow-up.

Results:
281 randomized participants (mean age: 68±9 years; 43% female; 61% African American) were included. The mean adherence rate was 75±18 % in the SET group. The adherence rates for the three SET tertiles were: ≤ 69%, 69 – 85%, and ≥ 85% respectively. Baseline characteristics, within group 6-month changes in six-minute walk distance by intervention group, and pairwise comparisons results are shown in table.

Conclusion:
While greater adherence to SET was associated with greater six-minute walk distance improvement, even participants with PAD in the lowest tertile of adherence had significantly greater six-minute walk improvement, compared to control. These data suggest that even intermittent exercise activity significantly improves six-minute walk in people with PAD.
Abstract 12776: Neighborhood Walkability is Not Associated With Attaining Recommended Physical Activity in a Behavioral Weight Loss Trial Testing Remotely Delivered Feedback Messages
Authors: Kariuki Jacob K , Bizhanova Zhadyra , Sereika Susan M , Conroy Margaret B , Parmanto Bambang , Beatrice Britney , Loar India , Cheng Jessica , Pulantara I Wayan , Wang Yuhan , Cedillo Maribel , Singh Anmol , Burke Lora E
Published: April 2024

Background:
Adding feedback messages (FB) to self-monitoring (SM) can help reinforce behavior change. However, socio-environmental barriers such as limited access to parks and sidewalks (i.e., low walkability) may limit one’s ability to respond to FB focused on physical activity (PA).

Hypothesis:
Residents of high walkability neighborhoods receiving FB will have higher PA levels than those not receiving FB.

Methods:
Secondary analysis of a 12-month behavioral weight loss intervention (SMARTER trial) in which participants were randomized to either SM+FB (n=251) or SM alone (n=251) groups. The SM+FB group received a smartphone pop-up message every other day that was tailored to their PA patterns. Neighborhood walkability was assessed via Walk Score (0-100), PA via Fitbit Charge 2 tracker, and weight via Tanita scale. Key study variables included the walkability of neighborhoods (Walk Score: low [<50] vs. high [≥50]), and recommended PA (moderate-to-vigorous PA (MVPA) ≥150 min/week or step count ≥7500/day). Generalized linear mixed model results are reported as adjusted odds ratios (AOR) with 95% confidence intervals (CI).

Results:
The sample with complete PA data (n=297) was white (87.9%), female (78.1%), well educated (82% with ≥4 years of college), and on average 48.9±13.7 years of age. Compared to high walkability neighborhoods, low walkability neighborhoods had a higher proportion of the sample who were non-white (18.1% vs 8.3%, p=.011), <45 years of age (45.7% vs 31.5%, p=.013), and with household income <$60,000 (p<.0001) at baseline. After adjusting for these baseline differences and exercise self-efficacy, on average neighborhood walkability did not moderate the effect of FB on the attainment of the recommended MVPA (AOR=1.48, 95% CI: 0.72 - 3.06) or step count (AOR=1.05, 95% CI: 0.48 - 2.29) goal at 12 months. Furthermore, there were no significant treatment or time main effects or interactions observed (p≥0.05), suggesting that there was no significant change in PA over 12 months for both treatment groups.

Conclusion:
Our findings suggest that FB and neighborhood walkability did not have significant impact on attaining PA goals in the SMARTER weight loss trial. More studies are needed to replicate our work in a more diverse sample.
Abstract 12781: Network Medicine-Based Multimodal Omics Discovery and iPSC-Based Validation of Metformin for Potential Treatment of Atrial Fibrillation
Authors: Lal Jessica C , Zhou Yadi , Rennison Julie H , Van Wagoner David R , Barnard John , Cheng Feixiong , Chung Mina K
Published: April 2024

Introduction:
Atrial Fibrillation (AF) is the most prevalent cardiac arrhythmia in the United States. Effective, safe, and durable therapeutic interventions are lacking. Thus, it is imperative to improve clinical management by utilizing novel approaches for drug repurposing. To date, multimodal omics analysis of genomics, transcriptomics, and protein-protein interactions [PPIs] have not been fully exploited for AF drug repurposing.

Hypothesis:
We hypothesize that using Network Medicine-based multimodal omics analysis for drug prioritization and functional observations using induced pluripotent stem cell (iPSC) models can help us identify effective therapeutic strategies and elucidate drug’s mechanisms-of-action for restoring normal sinus rhythm.

Methods:
Here, we used RNA-sequencing data from a biobank of left atrial tissues obtained from cardiac surgery patients to identify testable AF disease modules under the human protein-protein interactome network model. We systematically prioritized repurposable drug candidates for AF using both network proximity and gene-set enrichment analysis approaches by leveraging AF disease module findings, drug-target network, and drug-induced gene signatures in human cell lines. RNAseq was used to assess the transcriptomic impact of a top drug candidate, metformin, on gene expression of atrial myocytes differentiated from human iPSCs (a-iCMs).

Results:
Via network-based screening of 2,891 FDA-approved or clinical drugs, we found nine putative drug candidates (including Metformin, Furosemide, and Rofecoxib) using both network proximity z-score and GSEA-based enrichment scores. RNA-seq analysis of metformin-treated a-iCMs identified 238 differentially expressed genes following multiple test correction (P< 2.96E-06). Several key cardiovascular or drug-related markers were differentially expressed in Metformin treated a-EHTs. Of note NMRK2 and PCK2 were upregulated, and TGFB1 and TXNIP were downregulated, suggesting an improved energy utilization following metformin treatment.

Conclusions:
In summary, this study presented state-of-the-art network medicine methodologies for AF drug repurposing and identified metformin as a candidate treatment for AF patients.
Abstract 12796: Fasting and Post-Load Glucose and Non-Esterified Fatty Acids and Risk of Heart Failure and Its Subtypes in Older Adults
Authors: Oesterle Adam , Buzkova Petra , Pellegrini Cara , IX Joachim H , Hirsch Calvin , Tracy Russell , Siscovick David S , Djousse Luc , Mukamal Ken J , Kizer Jorge R
Published: April 2024

Introduction:
Glucose and non-esterified fatty acids (NEFA) are myocardial fuels whose fasting and postprandial levels are under different homeostatic regulation. The relationships of fasting and postload glucose and NEFA with incident HF and its subtypes remain incompletely defined.

Methods:
We hypothesized that fasting and postload glucose and NEFA are positively associated with incident HF in older adults, with postload levels bearing stronger associations. Serum glucose and NEFA levels were measured during fasting and 2 hours post oral glucose tolerance test in the Cardiovascular Health Study. HF with preserved (HFpEF) and reduced ejection fraction (HFrEF) were examined secondarily.

Results:
Among 2238 people (age 78±4) with median follow-up of 9.9 years, there were 737 HF events (257 classifiable as HFpEF, 197 as HFrEF). After adjustment for demographic and lifestyle factors (main model), both fasting (HR per SD 1.11 [95% CI 1.01-1.23]) and postload (HR per SD 1.14 [1.05-1.24]) glucose was significantly associated with incident HF. No association was seen for fasting or postload NEFA. When adjusted for each other, only postload glucose (HR 1.11 [1.003-1.22]), but not fasting glucose (HR 1.06 [0.94-1.20]), remained associated with HF. Further adjustment for prevalent atherosclerotic cardiovascular disease, atrial fibrillation and other risk factors in the causal pathway did not affect the association for postload glucose, but eliminated that for fasting glucose. There was no interaction by sex, but associations for fasting and postload glucose appeared stronger with higher BMI (p<0.025). Assessment of HF subtypes showed no associations for glucose or NEFA with HFpEF. Both fasting glucose (HR 1.23 [1.03-1.48]) and postload glucose (HR 1.24 [1.07-1.45]) were significantly associated with HFrEF, but relationships disappeared on mutual adjustment.

Conclusions:
Fasting and postload glucose, but not NEFA, were associated with incident HF, particularly HFrEF. The association proved especially robust for postload glucose, which reflects pancreatic β-cell insufficiency and skeletal muscle decline. Our findings suggest that targeting relevant pathways in these two organ-tissues could offer new approaches for HF prevention in elders.
Abstract 13000: Quality of Care and In-Hospital Outcomes of Patients Hospitalized for Heart Failure With Reduced Ejection Fraction During the COVID-19 Pandemic: Findings From the Get With the Guidelines-Heart Failure Registry
Authors: Keshvani Neil , Mehta Anurag , Alger Heather , Rutan Christine , Williams Joseph H , Zhang Shuaiqi , Young Rebecca , Alhanti Brooke , Chiswell Karen , Greene Stephen J , Devore Adam D , Fonarow Gregg C , Pandey Ambarish
Published: April 2024

Introduction:
COVID-19’s impact on in-hospital care quality and outcomes of patients hospitalized with acute heart failure (HF) has not been systematically evaluated nationally.

Methods:
Patients hospitalized with HF with ejection fraction (EF) <40% in the AHA GWTG-HF registry during the pandemic (3/1/2020 - 4/1/ 2021) and pre-pandemic (2/1/2019 - 2/29/2020) periods were included. Adherence to HF process of care measures, in-hospital mortality, and length of stay (LOS) were compared in the pre-pandemic vs pandemic period and among hospitalized HF patients with vs without COVID-19 across both periods.

Results:
40,005 pre-pandemic and 35,561 pandemic period patients admitted across 346 centers (median age 68, 33% women, 58% White) were included. There were no differences in clinical characteristics, comorbidities, presentation vital signs, or EF during the pandemic vs pre-pandemic periods. Among process of care measures, utilization of guideline-directed medical therapy at discharge was comparable across both periods. In contrast, rates of ICD placement or prescription and blood pressure control at discharge were lower during the pandemic (vs pre-pandemic period) (
Table
). In-hospital death (2.5% vs. 3.0%, p<0.001) and LOS (mean 5.4 vs. 5.7 days, p=0.008) were higher during the pandemic vs pre-pandemic. Substantial geographic variation was seen in the in-hospital death rates during the pandemic, with highest rates among patients hospitalized in the Northeast region (3.36%). Among HF patients hospitalized during the pandemic with COVID-19 (N = 527 [1.5%]), adherence to ICD placement or prescription at discharge and prescription of aldosterone antagonist or ACE/ARB/ARNi were lower, and risk of in-hospital death and length of stay were significantly higher than those without COVID-19.

Conclusion:
In-hospital mortality and adherence to certain quality measures worsened during COVID-19 pandemic among patients admitted for acute decompensated HFrEF.
Abstract 13011: RNA-Seq Analysis Of Human Abdominal Aorta Samples Identifies Putative Markers For Early Stage Atherosclerosis
Authors: Mao Chunhong , Hixson James , Kim Do-Kyun , Jackson Fannie , Vander Heide Richard , Wang Yue , Van Eyk Jennifer E , Herrington David M
Published: April 2024

Introduction:
Atherosclerosis can be defined as an assembly of hundreds of intra- and extra-cellular expressed genes that jointly alter cellular processes and produce characteristic remodeling of the local tissue environment. To improve early detection, and to interrupt the disease process before clinical consequences occur, it is necessary to recognize and understand the specific patterns of expressed genes that constitute the molecular signature of early atherosclerosis. To study this, we used RNA-Seq to identify expressed genes that are differentially abundant across normal and diseased human aortic tissues.

Methods:
Pairs of diseased (fatty streak (fs), fibrous plaque (fp), complex fibrous plaque (fc)) and adjacent normal (nl) grossly identified aortic samples were collected from coroner’s autopsies at the Louisiana State University (n=59). Each aortic specimen (100 mg tissue) was homogenized for total RNA extraction and generation of cDNA libraries which were sequenced by the Ion Proton™ System (Life Technology). RNA-Seq reads (avg. read length = 125) were evaluated using FASTQC for sequencing quality and aligned to the human reference genome using HISAT2. The RNA transcripts were assembled and quantified using StringTie. DESeq2 was used to compare expression levels for 16,827 genes passing QC across diseased and non-diseased samples.

Results:
Diseased samples had a large number of differentially expressed genes (DEGs) (fc:1731> fp:380 > fs:80) when compared with paired nl samples (Benjamin-Hochberg adjusted p-value
<
0.05), including 70 genes expressed in mitochondria. GO enrichment analysis of the fs, fp and fc DEGs showed the top enriched biological processes for the advanced lesions (fp, fc) were mostly immune response related pathways while the top enriched processes in fs samples were mainly lipoprotein metabolism. A group of 42 genes were differentially expressed in all the diseased samples compared with their adjacent nl control samples.

Conclusions:
The differentially expressed genes identified here provide greater resolution concerning molecular dysregulation of lipoprotein and immune function pathways and reinforce emerging data concerning abnormal mitochondrial function in early atherosclerosis.
Abstract 13025: The Inferior Vena Cava Plethora Is A Predictor Of Bleeding Events In Patients With Heart Failure With Reduced Ejection Fraction And Atrial Fibrillation
Authors: Lee Kyuho , Roh Seung-young , Park Soohyung , Back Seungmin , Lee Jieun , Kang Dong O , Kim Ji Bak , Choi Jah , Na Jin O , Choi Cheol Ung , Kim Jin W , Rha Seung Woon W , Park Chang Gyu , Seo Hong-Seog , Kim Eung Ju
Published: April 2024

Introduction:
In patients have heart failure with reduced ejection fraction (HFrEF) and atrial fibrillation (AF), anticoagulation therapy to prevent thromboembolic events was essential but occurs often bleeding complication. We explored echocardiographic markers to predict clinical outcome.

Method:
In-hospitalized 282 patients with HFrEF and AF between 2000 and 2021 were retrospectively analyzed. The presence of inferior vena cava plethora (IVCP) was confirmed by echocardiography at the time of admission. Eighty-five patients who had IVCP (IVCP group) was compared to 197 patients (70%) who did not have IVCP (control group)

Result:
IVCP group had more CKD (24% vs 13%, p=0.036), lower platelet (171k±63 vs 192k±64, p=0.007) and lower left ventricular ejection fraction (30±9 vs 34±11 p=0.001) than control group. Major bleeding event during 5 years follow up occurs significantly higher in IVCP group (Kaplan Meier Method, Log rank p=0.042) (figure). Gastrointestinal (GI) bleeding was 73% of major bleeding. In multivariable analysis, the IVCP was independent predictor of major bleeding (HR, 2.17; 95% CI 1.06-4.44).

Conclusion:
In patients with HFrEF and AF requiring antithrombotic treatment, IVCP was a predictor of major bleeding, especailly GI bleeding.
Abstract 13026: What Causes Speedy Growth (Within 3 to 6 Months) of Vulnerable Plaques in Acute Coronary Syndrome: An Angiographic and Machine Learning Analysis
Authors: Nguyen Thach N , Le Thoa , Le Minh H , Vuong Ngoc H , LE DO H , Nguyen Nguyet T , Le Trang T , Nguyen Thoai H , Cao Thinh , Rigatelli Gianluca , Zuin Marco , Pham Hung N , Ho Dung T , Talarico Ernest , Nguyen Thuong Nghia T
Published: April 2024

Introduction:
Based on damages by flow abnormalities seen in pipes, our research is built on the hypothesis that the flow disturbances start and grow atherosclerotic plaques. Our strategy is to use knowledge and practice of fluid mechanics to identify the different types of abnormal coronary flows and correlate them with the appearance and growth of lesions.

Hypothesis:
In patient with fast tract ACS when a normal segment becomes severely stenotic in a matter of 3 to 6 months, what kind of abnormal flow could trigger this speedy growth of a plaque ?

Methods:
Patients were selected if there was a near normal segment in the first angiogram and severe lesion in the 2nd angiogram 3 to 6 months later. LDL cholesterol level and HbA1c were also measured. In our cardiac catheterization laboratories, in the past 5 years, all patients underwent a special new dynamic coronary angiogram protocol. The contrast was injected until the coronary artery was completely opacified. As the injection of contrast stopped, the blood in white color moved in and displaced the contrast in black. The morphologies, movements and interactions of the blood flow in white color above a black background were reviewed frame by frame by investigators. The main measurements were the types of flow, their durations and direction at the index segment of the 1rst angiogram. At the same time, an artificial intelligence (AI) program (mainly Machine Learning (ML) algorithm) searched by 2 models built on Python. Model 1 was based on U-net and Densenet-121 for vessel segmentation. Model 2 was used for classification of flow (laminar, turbulent, antegrade, retrograde or stagnant). Model 2 was trained based on the convolutional neural network.

Results:
Ten dual angiograms were selected. At the index segment of the 1st angiogram, 80% showed turbulent and retrograde flow. The duration of this turbulent flow lasted 80% of one cardiac cycle (diastole and systole). The duration of retrograde flow lasted 90% of one systolic phase. A high level of LDL cholesterol (120mg%) was statistically significant while the HbA1c was not.

Conclusions:
In patient with fast tract ACS when a near normal segment became severely stenotic in a matter of 3 to 6 months, prolonged turbulent and retrograde flow with high LDL cholesterol were the culprits.
Abstract 13030: Hyperglycemia Drives In-Stent Restenosis in STEMI Patients
Authors: Mone Pasquale , Gambardella Jessica , Pansini Antonella , Minicucci Fabio , Mauro Ciro , Santulli Gaetano
Published: April 2024

Introduction:
Hyperglycemia (HG) has been shown to adversely affect the outcome of ST-elevation myocardial infarction (STEMI).

Hypothesis:
We hypothesized that HG at hospital admission could increase the risk of in-stent restenosis after primary percutaneous coronary intervention (PCI) for STEMI.

Methods:
We enrolled consecutive STEMI patients referred to the division of Cardiology of "Antonio Cardarelli" Hospital in Naples, comparing normoglycemic subjects (
NG
), patients without diabetes mellitus but with HG (
HG-non-DM
), and patients with both HG and DM (
HG-DM
).

Results:
A total of 336 propensity score matched patients were included in the study: 112 NG, 112 HG-non-DM, and 112 HG-DM. At 1-year follow-up, 6.5% of NG patients, 14.0% of HG-non-DM, and 18.5% of HG-DM had been re-hospitalized for restenosis; Kaplan-Meier curves (
p
: 0.009) are depicted in the
Figure
.

We then examined these findings applying a multivariate analysis with Cox regression in HG-non-DM patients, observing a significant association with restenosis for glycemia at hospital admission, total and LDL-cholesterol.

Conclusions:
The present study is the first to evaluate the effects of HG on the risk of restenosis in STEMI patients without DM, comparing the results to both HG-DM and NG subjects. Taken together, our data indicate that HG is associated with adverse outcomes in STEMI patients independently of DM. These findings emphasize the importance of glycemic control in all STEMI patients in order to reduce the risk of complications.
Abstract 13054: Longitudinal Strain-Derived Myocardial Work to Reflect the Systolic Performance of Athlete’s Heart
Authors: Tokodi Marton , Oláh Attila , Fabian Alexandra , Lakatos Balint K , Hizoh István , Ruppert Mihály , Sayour Alex A , Barta Balint A , Kiss Orsolya , Sydó Nóra , Csulak Emese , Ladanyi Zsuzsanna , Merkely Béla , Kovacs Attila , Radovits Tamás
Published: April 2024

Introduction:
In athletes, the exercise training-induced enhancement of myocardial contractility is challenging to be captured using conventional echocardiographic parameters due to their load-dependency.

Hypothesis:
As speckle-tracking echocardiography (STE)-derived myocardial work (MW) is considered to be less dependent on loading conditions than global longitudinal strain (GLS), we hypothesized that it reflects cardiac contractility more reliably, and thus, it represents a robust resting marker of the athlete's heart. Accordingly, we investigated whether MW can capture the supernormal LV systolic performance of swim-trained rats and elite human swimmers even during resting conditions.

Methods:
Sixteen rats underwent a 12-week swim training program and were compared to controls (n=16). STE was performed to assess GLS, which was followed by invasive pressure-volume (P-V) analysis to measure contractility (slope of end-systolic P-V relationship [ESPVR]). Global MW index (GMWI) was calculated from GLS curves and LV pressure recordings. In the human investigations, 20 elite swimmers and 20 healthy sedentary controls were enrolled. GMWI was calculated through the simultaneous evaluation of GLS and non-invasively approximated LV pressure curves at rest. All subjects underwent cardiopulmonary exercise testing to determine peak oxygen uptake (VO
2
/kg).

Results:
Exercised rats exhibited higher values of GLS, GMWI, and ESPVR than controls (-20.9±1.7 vs. -17.6±1.9 %, 2745±280 vs. 2119±272 mmHg·%, 3.72±0.72 vs. 2.61±0.40 mmHg/μL, all p<0.001). Ordinary least squares modeling revealed that GLS was predominantly determined by sex and afterload, whereas the major determinants of GMWI were contractility and exercise. In humans, regular exercise training was associated with decreased GLS (-17.6±1.5 vs. -18.8±0.9 %, p=0.002) but increased GMWI at rest (1899±136 vs. 1755±234 mmHg·%, p=0.025). GMWI correlated positively with VO
2
/kg (r=0.53, p<0.001).

Conclusions:
GMWI precisely reflected LV contractility in a rat model of exercise-induced LV hypertrophy and captured the supernormal systolic performance in human athletes even at rest. Our findings endorse the utilization of MW analysis in the evaluation of the athlete's heart.
Abstract 13055: Endotrophin is Significantly Associated With Risk of Mortality in HFpEF Patients Irrespective of Underlying Atrial Fibrillation
Authors: Reese-petersen Alexander L , Gonzalez Arantxa , LOPEZ BEGONA , Ravassa Susana , Karsdal Morten , Genovese Federica , Díez Javier
Published: April 2024

Introduction:
The global burden of heart failure with preserved ejection fraction (HFpEF) is increasing. HFpEF is projected to become the dominant type of HF, and atrial fibrillation (AF) is known to contribute to pathogenesis by aggravating fibrosis. Endotrophin is a bioactive molecule released from collagen type VI during its maturation, and it is a marker of fibroblast activity. The aim of this post-hoc analysis was to confirm the previously observed prognostic potential of endotrophin (measured by PRO-C6) for adverse outcome in HFpEF and to investigate the potential influence in risk stratification by AF.

Methods:
166 patients with hypertensive HFpEF were included for analysis. 48.2% were NYHA Class II, 49.4% NYHA Class III and 1.2% NYHA Class IV. 50.6% of patients had a previous history of AF. Cardiac function was assessed by echocardiography and standard clinical measures. Circulating endotrophin was quantified at baseline in serum by means of an enzyme-linked immunosorbent assay, PRO-C6.

Results:
PRO-C6 levels increased significantly with disease severity in HFpEF patients (NYHA Class III vs II, p=0.0003), and in HFpEF patients with AF (p=0.023). PRO-C6 was able to discriminate between patients at risk of all-cause mortality (AUC=0.73, p<0.001), but no improvement in this association was observed when factoring in AF (AUC=0.72, p=0.001). When looking at patients stratified in PRO-C6 tertiles, patients in the upper tertile had a significantly higher risk of mortality (p<0.0001, hazard ratios 3 vs 1=4.1, 3 vs 2=3.5, respectively) and HF hospitalization (p<0.0001, hazard ratio 3 vs 1=4.4, 3 vs 2=1.6, respectively) compared to tertiles 1 and 2.

Conclusions:
In this population of hypertensive HFpEF patients, circulating endotrophin, measured by PRO-C6, was increased with increasing disease severity, and associated with a higher risk of adverse outcome in HFpEF, regardless of underlying AF. The data presented here suggest a potential role of endotrophin in HFpEF pathophysiology, associated to disease progression in HFpEF patients with or without AF. These data confirm previous observations, and strengthen the usefulness of endotrophin, measured by the PRO-C6 biomarker, as a prognostic tool aiding in assessment of HFpEF patients.
Abstract 13056: The Novel Cardiokine GDF3 Predicts Fibrotic Remodeling Post-Myocardial Infarction
Authors: masurkar nihar , Bouvet Marion , Logeart Damien , DELACROIX Clement , Mercadier Jean Jacq , sirol marc , Gellen Barnabas , Trégouët David-Alexandre , Marazzi Giovanna , Sassoon David , Valente Mariana , Hulot Jean S
Published: April 2024

Introduction:
Myocardial infarction (MI) induces a repair response that ultimately generates a stable fibrotic scar. Although the scar prevents cardiac rupture, an excessive profibrotic response impairs optimal recovery.

Hypothesis:
To explore the regulation of fibroblasts proliferation through a paracrine action of cardiac stromal cells post-MI

Methods:
We carried out a bioinformatic secretome analysis of cardiac stromal PW1
+
cells isolated from normal and post-MI mouse hearts to identify novel secreted proteins. Functional assays were used to screen secreted proteins that promote fibroblast proliferation. The expressions of secreted proteins candidates were subsequently analyzed in mouse and human hearts and plasmas. The relation between levels of circulating protein candidates and adverse post-MI cardiac remodeling was examined in a cohort of 80 patients with a first ST-elevation MI and serial cardiac magnetic resonance imaging (MRI) evaluations.

Results:
Cardiac stromal PW1
+
cells undergo a change in paracrine behavior post-MI and secrete factors that promote fibroblast proliferation. Among these factors, growth differentiation factor 3 (GDF3), a member of the transforming growth factor-β family, was markedly upregulated in the ischemic hearts and induced fibroblast proliferation at high level. In humans, GDF3 was detected in the plasma at day 4 post-MI and GDF3 circulating levels were significantly associated with an increased risk of adverse remodeling 6-month post-MI (adjusted Odds Ratio (OR) = 1.76 [1.03 - 3.00], p = 0.037).

Conclusions:
Our findings define a mechanism for the pro-fibrotic action of cardiac stromal cells through secreted cardiokines, such as GDF3, a candidate marker of adverse fibrotic remodeling following MI.
Abstract 13069: Baseline QRS Duration ≫ for >140 msec is Associated With Poor In-Hospital Prognosis of Patients With Acute Myocarditis
Authors: Yoshida Ayano , Takada Takuma , Jujo Kentaro , Shibahashi Eiji , Kawamoto Takanori , Kametani Motoko , SATOMI Natsuko , KAMISHIMA KAZUHO , Saito Takashi , Tomari Erina , Honda Atsushi , Takagi Atsushi , Ashihara Kyomi , Hagiwara Nobuhisa
Published: April 2024

Introduction:
The clinical manifestation of acute myocarditis (AM) is highly variable, and the mechanisms of this diversity have not been fully elucidated. Hence, it is hard to precisely predict their prognosis, and some cases with AM rapidly progress into cardiogenic shock, resulting in the increased in-hospital mortality.

Hypothesis:
There are some parameters in the initial presentations to predict the prognosis of patients with AM.

Methods:
This is a multicenter observational study including hospitalized AM patients between 2007 and 2019. We set the primary endpoint of this study as a composite of in-hospital death from any cause and implantation of ventricular assist devices during the index hospitalization.

Results:
Of 76 enrolled patients [average age: 42 years; male: 79%; mean left ventricular ejection fraction (LVEF): 41%], 13 patients (17%) developed the composite endpoint, and 8 (11%) died within 10 days after the admission. Patients who experienced the composite endpoint were more likely to be older, and have diabetes, anemia, impaired renal functions, higher creatine kinase-MB, lower LVEF, and longer QRS duration on ECG at admission. In the multivariable logistic regression analysis, QRS duration on ECG at admission was independently associated with the composite endpoint, even after adjusting for confounding factors such as age, sex, and LVEF at admission [OR: 1.31, 95% CI: 1.01-1.72]. The ROC curves for the primary endpoint revealed that the cut-off value of QRS duration at admission were 140 msec (sensitivity: 100%, specificity: 90%, AUC: 0.97). Kaplan-Meier analysis showed that patients with baseline QRS duration > for >140 msec had a significantly higher rate of the primary endpoint than those with QRS duration <140 msec (p<0.001,
Figure
).

Conclusions:
Prolonged QRS duration at admission could predict in-hospital prognosis in patients with AM. We should consider the intensive care and close observation in such a high-risk population with AM.
Abstract 13070: The Probiotic
Bifidobacterium breve
, Bif195, Supports the Defense Against Aspirin-Induced Gastrointestinal Mucosal Damage
Authors: DAMHOLT ANDERS B , Loen Nina , Engel Sara , Haaber Anne , Wellejus Anja , Knop Filip K
Published: April 2024

Introduction:
Low-dose aspirin (50-325 mg daily) is widely recommended for the prevention of cardiovascular disease. However, daily use of aspirin is associated with an increased risk of gastrointestinal mucosal damage including gastric and duodenal ulcers. We have recently published data on the ability of the probiotic
Bifidobacterium breve
, Bif195, to reduce aspirin-induced epithelial damage in the small intestine, as evaluated by capsule endoscopy. However, it remains undetermined whether Bif195 alters aspirin-induced mucosa damage in the gastric ventricle, representing a more aspirin-exposed area and hostile environment for probiotics.

Methods:
In a 2x4 week double-blinded, placebo-controlled, randomized, crossover clinical trial, 25 healthy men and women were asked to take a daily oral dose of 300 mg aspirin during both intervention periods, and randomized to a sequence of daily oral intake of
Bifidobacterium breve
, Bif195≥ 10
11
colony forming units) capsules and placebo capsules, separated by a 6 weeks washout period. Participants were subjected to a gastroduodenoscopy immediately before and in the end of each intervention period. All gastroduodenoscopies were performed by the same gastroenterologist. The primary endpoint was change in Lanza score (0-5). Furthermore, mucosal biopsies, luminal fluids and blood samples were collected.

Results:
Gastrointestinal damage was absent in all subjects at baseline (Lanza score 0). The score was significantly reduced with Bif195 compared to placebo, in the Gastric ventricle. Values after treatment, see the table.

Conclusion:
Aspirin-induced gastric mucosa damage is significantly ameliorated by intake of Bif195 resulting in a 3 times lower Lanza score compared to placebo, whereas no statistically significant difference was observed in the duodenum. Bif195 may represent a beneficial supplement to continuous aspirin treatment reducing risk of aspirin-induced upper GI mucosa damage and ulcer formation.
Abstract 13074: Impact of Adrenergic Receptor Polymorphisms on Incident Ventricular Fibrillation During Acute Myocardial Ischemia: The MAP-MI Study
Authors: Chevalier Philippe , Roy Pascal , Ankou Benedicte , Morel Elodie , MILLAT Gilles , Morgan Gina , Holder Indrani , London Barry , Minobe Wayne , Slavov Dobromir , Deliniere Antoine , Carroll Ian , Bristow Michael R ,   MAP-MI Investigators
Published: April 2024

Rationale:
During acute coronary syndromes (ACS) adrenergic receptor (AR) signaling may have major effects on cardiac arrhythmias including VF. AR gene products are highly polymorphic, and minor variants exhibit potentially important pharmacologic differences compared to receptors encoded by major allele homozygotes (
mah
).

Objective:
We tested the general hypothesis that polymorphic variants in the
ADRB1
,
ADRB2
or
ADRA2C
genes affect incident VF during ACS.

Methods and Results:
We recruited 953 subjects with a proven MI and no previous history of AC. In a case-control design 477 VF patients were compared to 476 controls without VF who did not differ in baseline characteristics. DNA collection and subsequent genotyping for
ADRB1
389/49,
ADRB2
27/16 and
ADRA2C
322-325 Ins/Del were available in 718-779 patients. Results were expressed as Odds Ratios (OR) for VF vs. No-VF subjects by comparing each
mah
to minor allele monotype genotypes, genotype combinations or haplotypes. The entire cohort OR (95% CI) for patients receiving (41%) vs. not receiving beta-blockade (BB) was (0.70 (0.53, 0.93), P=0.014), dictating a BB adjustment in the genotype-VF analyses. No minor allele genotype was associated with increased incident VF. Monotypes with statistically significant ORs and their
mah
comparators were:
ADRB2
monotypes and
ADRB1
or
ADRB2
haplotypes were not associated with VF reduction. Two of 3
ADRB1
and 3 of 4
ADRB2
monotypes or genotype combinations associated with VF reduction encoded ARs that exhibit increased agonist-induced internalization.

Conclusions:
In acute MI AR variants associated with reduced incident VF are those that mediate increased adrenergic drive (
ADRA2
C Del) and beta-AR internalization. This combination would be predicted to redirect beta-AR signaling from canonical pathways to "biased" EGFR and ERK1/2 mediated cardioprotection.
Abstract 13083: Circulating Androgen Levels and Risk of Incident Heart Failure in Older Men: The Cardiovascular Health Study (CHS)
Authors: Njoroge Joyce N , Tressel William , Biggs Mary Lou , Matsumoto Alvin , Smith Nicholas L , Rosenberg Emily , Hirsch Calvin , Gottdiener John S , Mukamal Ken J , Kizer Jorge R
Published: April 2024

Introduction:
Circulating androgen levels in men decline with advancing age and have been linked to diabetes and atherosclerotic cardiovascular disease (ASCVD). A similar relationship has been reported for low total testosterone (T) and incident heart failure (HF), but whether this differs for free T or the more potent androgen, dihydrotestosterone (DHT), remains unknown.

Methods:
We hypothesized that total and free T are inversely related and SHBG positively related to incident HF in older men, whereas, based on earlier data on ASCVD in CHS, total DHT bears a U-shaped relationship with this outcome. In a male sample from CHS without prevalent ASCVD or HF, serum T and DHT concentration were measured by liquid chromatography tandem mass spectrometry, and sex hormone-binding globulin (SHBG) by immunoassay. Free T was calculated from total T, SHBG and albumin. We used Cox regression to estimate relative risks of HF, adjusting for age, race, BMI, smoking, alcohol, physical activity, systolic BP, antihypertensive use, total and HDL cholesterol, and eGFR.

Results:
In 1061 men (age 76±5) followed for a median of 9.6 years, there were 368 HF events. Restricted cubic splines showed no meaningful departure from linearity, and relationships were expressed per SD decrement in androgen levels. After adjustment, lower free T was significantly associated with higher risk of HF (HR 1.14 [95% CI 1.01, 1.28]), p=0.03). Risk estimates for total T (HR 1.12 [0.99, 1.26], p=0.07), DHT (HR 1.10 [0.97, 1.24], p=0.14) and SHBG (HR 1.07 [0.95, 1.21], p=0.25) were directionally similar, but not statistically significant. The association of lower free T and HF was not altered after further adjustment for diabetes or atrial fibrillation. In a sensitivity analysis excluding participants with history of prostate cancer, findings were similar.

Conclusion:
Total T, free T, DHT and SHBG were inversely associated with incident HF, but only the association of free T was statistically significant. These findings suggest a contribution of androgen deficiency to HF incidence among men late in life, the segment of the population at highest risk of both conditions. Additional research is needed to determine whether androgen replacement therapy is an effective strategy to lower HF risk in older men.
Abstract 13104: L-carnitine Supplementation Improves Right Ventricular Function in Two Models of Right Ventricular Failure
Authors: Agrawal Vineet , Hemnes Anna R , Shelburne Nicholas J , Fortune Niki , Fuentes Julio , Colvin Daniel C , Calcutt Marion W , Talati Megha H , Poovey Emily A , West James , Brittain Evan
Published: April 2024

Introduction:
Previous studies have shown that right ventricular (RV) failure in pulmonary arterial hypertension is characterized by diminished fatty acid oxidation and ultimate lipotoxicity due to accumulation of toxic lipid intermediates. Whether or not augmenting fatty acid oxidation can reverse lipotoxic RV failure in PAH is not known.

Hypothesis:
In this study, we tested the hypothesis that augmentation of fatty acid oxidation through L-carnitine supplementation reverses RV failure in two models of RV failure.

Methods:
BMPR2 (R899X) mice were allowed to develop PAH for 10 weeks prior to supplementation of L-carnitine or control in their water for 8 weeks. In a second model, wild type C57/BL6 mice underwent pulmonary artery banding and were treated with L-carnitine or control 2 weeks after banding surgery. Finally, L-carnitine supplementation was also tested on H9C2 cardiomyocyte-like cells transfected with mutant BMPR2. Lipid accumulation was measured by Oil Red O or BODIPY stain. Fatty acid-mediated mitochondrial respiration was measured by Oroboros Oxygraph or Seahorse analysis.

Results:
In vivo
, L-carnitine in BMPR2 mice and pulmonary artery banded mice increased RV cardiac output, RV ejection fraction, and mitochondrial respiration of long-chain fatty acids. Hemodynamic improvement in RV cardiac output was confirmed in pulmonary artery banded mice.
In vitro
, L-carnitine reduced lipid accumulation and increased fatty acid oxidation in BMPR2 mutant H9C2 cells through a Cpt1-dependent mechanism.

Conclusions:
In summary, augmentation of fatty acid oxidation in right ventricular failure through L-carnitine supplementation improves RV function, increases fatty acid oxidation, and decreases lipid accumulation.
Abstract 13106: Modulation of Mitochondrial Respiration During Early Reperfusion Using Amobarbital Decreases Cardiac Injury in Donation After Circulatory Death Hearts
Authors: Akande Oluwatoyin E , Chen Qun , Cholyway Renee , Toldo Stefano , Lesnefsky Edward J , Quader Mohammed
Published: April 2024

Introduction:
Hearts from donation after circulatory death (DCD) donors are becoming an important source for heart transplantation (HTx). However, DCD hearts undergo ischemia reperfusion injury (IRI) and manifest impaired cardiac function. Blockage of electron transport chain (ETC) with the reversible inhibitor amobarbital (AMO) may mitigate IRI. Since pretreatment is not allowed in the DCD donors, therapeutic interventions at reperfusion are critical to limit injury in DCD hearts.

Hypothesis:
Transient blockade of ETC using AMO at reperfusion can decrease IRI in the DCD heart.

Methods:
Sprague Dawley rat hearts were subjected to 25 min.
in-vivo
ischemia. Hearts were then treated with 2mM AMO or vehicle for the first 5 min. of reperfusion, followed by Krebs-Henseleit buffer perfusion at 37
0
C on a Langendorff setup for 55 or 85 minutes. Infarct size was measured in hearts reperfused for a total of 90 min. Subsarcolemmal mitochondria (SSM) and interfibrillar mitochondria (IFM) were isolated from a separate set of hearts reperfused for a total of 60 min. to assess calcium retention capacity (CRC), a measurement of mitochondrial permeability transition pore (MPTP) susceptibility to opening, and H
2
O
2
generation. Control beating donor (CBD) hearts underwent similar evaluation except for the ischemia.

Results:
AMO treatment caused a significant 19% decrease in infarct size (Figure A) compared to vehicle treated DCD hearts (25±2 vs.31±2 % of the Left Ventricle; mean± SEM, p<0.05). CRC was improved with AMO compared to vehicle treated DCD hearts (360±17 vs. 269±17nmol/mg in SSM; 485±19 vs. 388±26nmol/mg in IFM; p<0.05. Figure B). H
2
O
2
generation was reduced in AMO treated DCD hearts, especially in SSM (37±4 vs.59± 5pmol/mg/min; p<0.05. Figure C).

Conclusions:
Brief inhibition of mitochondrial respiration with AMO during early reperfusion decreases injury in DCD hearts. AMO is a promising approach to protect myocardium in DCD hearts.