bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 4141762: Multi-omics analysis of host transcriptomics and gut microbiota reveals altered tumor necrosis factor alpha signaling in older adults with heart failure
Authors: Chen Jie , Wang Zequan , Kuang Huan , Dungan Jennifer , Liu Tingting , McCauley Paula , Chen Ming-Hui , Starkweather Angela , Cong Xiaomei
Published: November 2024

Introduction:
Chronic heart failure (HF) is linked to elevated serum TNF-α levels and affects multiple signaling pathways in non-cardiomyocytes, such as immune cells, intestinal epithelial cells, lymphatic endothelial cells, vascular cells, and their interactions. The combined dysbiosis of host transcriptomics and gut microbiota concerning altered TNF-α signaling in older adults with HF remains unknown.

Methods:
We recruited 10 older adults with heart failure (HF) (6 females) and 16 healthy controls (HCs) (10 females) from the Northeastern U.S. Non-fasting peripheral blood and stool samples were collected. Serum TNF-α was assayed using Enzyme-linked Immunosorbent Assay (ELISA) kits. Differentially expressed genes (DEGs) between HF and HCs were investigated using the R package "DESeq2" after aligning the raw blood RNA sequence data to the reference database and undergoing quality control. The QIAGEN Ingenuity Pathway Analysis (IPA) was used to analyze the canonical pathways associated with the DEGs. The 16S rRNA V4 gene regions of stool samples were sequenced and processed using the Mothur 1.42.3 pipeline. The Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) was used to predict the metagenomic functions of different gut microbiota compositions.

Results:
The mean ages of the HF and HC subjects were 73.50 (SD = 8.33) and 63.19 (SD = 7.75), respectively. HF subjects had significantly higher serum TNF-α levels than HCs (p < 0.05). Among the DEGs, HF subjects had 18 downregulated genes (e.g.,
AK5
,
FAM167A
,
RGCC
, and
SARDH
) and 3 upregulated genes (
SMPD3
,
TMIGD3
, and
FRRS1
) compared with HCs. TNF signaling (p < 0.01) was one of the significantly different canonical pathways in the DEGs between HF and HCs. HF subjects had significantly enriched
Mogibacterium
and diminished
Sutterella
than HCs (p < 0.05) and lower P53 signaling pathway activity than HCs (p < 0.05) among the predicted functions in stool samples.

Conclusions:
By analyzing serum TNF-α, whole transcriptomics, and gut microbiota, we identified higher serum TNF-α, differentially expressed genes (DEGs) and their canonical pathways, and distinct compositions and predicted functions of gut microbiota in older adults with HF compared to healthy controls. These findings suggest that TNF-α signaling may be a potential target for developing precise HF interventions and highlight the need for further large-scale multi-omics analysis in understanding and treating HF.
Abstract 4141798: Empagliflozin dramatically reduced stroke size and cerebral edema in a rat model
Authors: Dai Wangde , Carreno Juan , Pahlevan Niema , Alavi Rashid , Kloner Robert
Published: November 2024

Background:
Ischemic stroke is associated with high mortality, morbidity and disability that significantly affects the quality of life of patients even in the current thrombolytic/thrombectomy era. The effect of empagliflozin (EMPA), a sodium glucose co-transporter 2 inhibitor on stroke is unknown.

Methods:
Male SD rats were randomized into three groups (n = 10 in each group): (1) Control group: rats received regular diet alone (without EMPA); (2) Acute treatment group: EMPA (10 mg/kg, IV) given at 10 minutes prior to middle cerebral artery occlusion (MCAO) and one minute prior to reperfusion; (3) Chronic treatment group: EMPA given by food (20 mg/kg) for 7 days before MCAO. A standard intraluminal filament MCAO was performed for one hour of MCA occlusion followed by 3 hours of reperfusion. The brain was harvested and sliced for 2,3,5-triphenyltetrazolium chloride (TTC) staining to measure the volume of cerebral infarction and edema using the technique of Regoldi.

Results:
The size of the cerebral infarction, expressed as percentage (%) of the infarct volume to the whole brain volume, was significantly smaller in the acute EMPA treatment group (2.8 ± 1.2%) and chronic EMPA group (7.3 ± 2.7%) compared with the control group (16.7 ± 3.2%; p = 0.002) (Figure). The edema of the ipsilateral hemisphere, expressed as percentage of the edema volume to the contralateral hemisphere volume (%), was significantly reduced in the acute EMPA group (4.6 ± 0.9%) and chronic EMPA group (5.2 ± 0.7%) compared to the control group (11.2 ± 1.5%; p = 0.001).

Conclusion:
Our data indicates that EMPA significantly reduced cerebral infarction and edema in a stroke model in rats. Acute IV EMPA reduced stroke size by 83%.
Abstract 4141803: noise-induced sleep disruption reduces myocardial perfusion and impairs cardiac function in mice
Authors: Gouwens Kara , Nong Yibing , Hill Bradford , Nystoriak Matthew
Published: November 2024

Sleep is essential for heart health throughout the lifespan. Although poor sleep is linked to cardiovascular disease and all-cause mortality, there is little known about how chronic sleep disruption affects the heart. Because adequate oxygen delivery is necessary to sustain cardiac function, we hypothesized that sleep disruption suppresses myocardial perfusion, which over time, could impair mechanical performance. To test this, we examined how environmental noise, a major contributor to human sleep disruption, applied during the murine inactive/light phase (noise-induced sleep disruption; NISD) impacts sleep patterns and myocardial perfusion in C57BL/6N male mice. We surgically implanted EEG/EMG transmitters to quantify wake and sleep periods. After recovery and a baseline period (2d), mice were exposed to randomized noise (2,382–4,000 kHz; ≤103 db; ≤39 sec) between 6:00–18:00 (NISD group). Control mice underwent the same procedure, but without noise application. Sleep durations were measured at baseline, 1 d, 2 wk, and 4 wk. Relative to control mice, NISD showed fragmented sleep patterns with reduced sleep bout length (~17%; p=0.02) and increased sleep bout number (~26%; p=0.09) when normalized to respective baseline data, yet similar 24 hr total sleep duration (control: 11.6 ± 0.3 h, NISD: 11.4 ± 0.9 h; n=3–4/group, p=0.82). After 4 wk of NISD, myocardial perfusion and cardiac function were measured using contrast echocardiography and left ventricular pressure-volume recordings at baseline and following norepinephrine-mediated increases in cardiac work. In control mice, myocardial perfusion increased in proportion to increases in cardiac work; however, in the NISD group, the slope of the relationship between myocardial perfusion and cardiac work was significantly blunted (control: 0.0058 ± 0.002; NISD: 0.0002 ± 0.001; n=4–5/group, p=0.01). Echocardiography revealed increased left ventricular diameter (LVID
s
, control: 2.2±0.2 mm, NISD: 2.6±0.2 mm; p=0.01), and two-dimensional speckle tracking showed a significant reduction in global longitudinal left ventricular strain (control: 19.5±2.5%, NISD: 16.4±0.8%; p=0.02) in NISD mice compared with controls, consistent with moderate systolic impairment following prolonged sleep disruption. Taken together, these data support the concept that environmental factors, via effects on sleep quality, can impact the regulation of blood flow to the heart and cardiovascular health.
Abstract 4141821: Genotype and Family History as Risk Markers of Sudden Cardiac Death in Hypertrophic Cardiomyopathy
Authors: Sakhnini Ali , Montazeri Mahdi , Chow Cindy , Silver Josh , Saha Sudipta , Chan Raymond , Gollob Michael , Fan Steve , Rowin Ethan , maron Martin , Rakowski Harry , Adler Arnon
Published: November 2024

Introduction:
The role of genotype in sudden cardiac death (SCD) risk stratification in hypertrophic cardiomyopathy (HCM) patients is unclear. Whether family history of SCD (FHxSCD) is independently associated with SCD after correction for genotype has never been investigated.

Methods:
This observational cohort study included HCM patients who had genetic testing at Toronto General Hospital or Tufts Medical Center. FHxSCD was defined as unexplained SCD before the age of 40 or due to HCM in a first-degree family member. SARC+ was defined as the identification of a (likely) pathogenic variant in a sarcomeric gene. The combined SCD outcome included SCD, resuscitated cardiac arrest (rCA), or appropriate ICD therapy.

Results:
The study included 3258 patients [2142 (65.7%) male, 896 (27.5%) SARC+]. Over a median follow-up of 5 years (IQR 1.9–9.6), 114 (3.5%) experienced a SCD outcome (10 SCD, 27 rCA, and 77 ICD therapies).

Both FHxSCD and SARC+ were independently associated with SCD, with hazard ratios of 1.97 [1.26-3.10, P = 0.003] and 1.73 [1.15-2.59, P = 0.008], respectively (Fig. 1). Among patients with FHxSCD but no other risk markers, the cumulative proportion of SCD was 7.8% and 9.8% at 5 and 10 years in SARC+ patients, but only 2.6% and 4.6% in SARC- patients (Fig. 2).

Adding genotype to the HCM SCD risk calculator resulted in a net reclassification index of 0.162 (0.046–0.285). Compared with the original model and using a 6%/5-year cutoff, the new model identified 8 more patients with events as high-risk but also an additional 4 patients without events.

Conclusion:
In our cohort, both FHxSCD and genotype were independently associated with SCD outcomes. In patients with FHxSCD as the sole risk marker, the risk of SCD is significant (>6%/5 years) in SARC+ patients but not in SARC- patients. Adding genotype to the HCM SCD risk calculator improves its ability to discriminate between patients at high and low risk.
Abstract 4141843: Cardiovascular Disease and Cancer Mortality by Cardiovascular Health: Life's Essential 8 in the REasons for Geographic and Racial Differences in Stroke (REGARDS) Study
Authors: Huether Katherine , Pinheiro Laura , Judd Suzanne , Long Leann , Safford Monika , Lloyd-Jones Donald , Plante Tim
Published: November 2024

Introduction:
Cardiovascular disease (CVD) and cancer are the top 2 causes of death among US adults. Life’s Essential 8 (LE8) is an updated cardiovascular health (CVH) metric that includes many factors known to reduce cancer risk. It is unclear how LE8-quantified CVH relates to CVD and cancer mortality in a competing risk framework.

Methods:
REGARDS recruited 30,239 Black and White adults from the 48 contiguous US states in 2003-07. We excluded individuals with prevalent CVD or cancer, missing LE8, or no follow-up. Baseline total LE8 scores were categorized as low (<50), moderate (50-79), or high CVH (≥80). Cause-specific hazard models estimated relative hazard of CVD and cancer mortality as competing risks, adjusting for age, sex, race, level of education, and region.

Results:
Among 11,385 REGARDS participants who were free of CVD and cancer (mean [SD] age 65 [9] years, 52% women, 44% Black adults), 24%, 66%, and 10% had low, moderate, and high CVH, respectively. Over a median (IQR) follow-up of 14 (8-18) years, 8% died from CVD, 7% from cancer, and 17% from other causes. Moderate and high CVH were significantly associated with graded lower risk of CVD and cancer mortality after adjusting for potential confounders (
Table
). CVD mortality was lower across better physical activity, blood pressure, diet, sleep, smoking, and glucose CVH groupings. Cancer mortality was lower across better diet and smoking groupings.

Conclusion:
LE8-quantified CVH was independently associated with lower CVD and cancer mortality in a competing risk framework and in graded fashion. These findings underscore the significance of lifestyle modifications in mortality risk reduction for the top 2 causes of death in the US, advocating for their incorporation into clinical guidelines and preventive counseling.
Abstract 4141868: Circulating immune cells, inflammatory risk, and atherosclerotic cardiovascular disease: an analysis across 5 cohorts of 17,971 diverse adults
Authors: Goonewardena Sascha , Murthy Venkatesh
Published: November 2024

Introduction:
Inflammation is pivotal in initiating and accelerating atherosclerotic cardiovascular disease (ASCVD). Inflammatory responses result from coordinated actions of circulating molecular mediators and circulating immune cells (CIC). The complete blood count (CBC) is the standard approach to profile CIC. In an analysis across 5 cohorts, we sought to define the relationships between CBC features and ASCVD.

Hypothesis:
We hypothesized that CBC features are associated with ASCVD endpoints, including stroke, myocardial infarction (MI), revascularization, and mortality.

Methods:
We examined the relationships between CBC features, traditional risk factors, and mortality in NHANES (n=6162). We then examined individual CBC features and ASCVD endpoints using adjusted Cox proportional hazards models to compute hazard ratios (HR) standardized in each cohort and combined with random effects meta-analysis across four longitudinal cohorts (n=11,809 subjects from Framingham Offspring, Framingham 3
rd
Gen, MESA, and CARDIA cohorts).

Results:
We first examined the prognostic value of CBC features compared with laboratory assessments (lipid panel, HbA1c, hs-CRP, and basic metabolic panel) in NHANES and found that CBC features were significantly associated with all-cause and CV mortality (data not shown). Next, we validated and extended these findings in a meta-analysis across four additional longitudinal cohorts, evaluating the association of individual CBC features with ASCVD endpoints. In the fully adjusted and fully adjusted + hs-CRP models, CBC features (e.g., neutrophils, monocytes, and lymphocytes) were associated with ASCVD endpoints (
Figure 1A
). The meta-analyzed standardized hazard ratio of WBC for MACE3 (stroke, MI, all-cause mortality) was 1.07 (1.01 - 1.14; p=0.02) (
Figure 1B
).

Conclusions:
To our knowledge, this is the first study to examine the association of CIC features with ASCVD across a large, diverse sample of adults. CIC features are associated with ASCVD endpoints and mortality even after adjustment for traditional risk factors and laboratory values, including hs-CRP. Taken together, our data reveal unexpected insights into the interplay of CIC, inflammatory risk, and ASCVD.
Abstract 4141869: Effects of Compliant Chest Compression Rate on Return of Spontaneous Circulation in In-Hospital-Cardiac-Arrest
Authors: Atkins Janel , Reynolds Julia , Pearson David
Published: November 2024

Introduction:
Over 290,000 in-hospital cardiac arrests occur annually in the United States. Survival is about 25% with significant variation across the country. Evidence supports high-quality chest compressions as a vital factor to achieving return of spontaneous circulation (ROSC) and improving outcomes after cardiac arrest. Research illustrates a propensity for healthcare professionals to provide chest compressions at a rate outside the American Heart Association guideline of 100-120 compressions/minute.

Goal/Hypothesis:
The team hypothesized greater compliance with chest compression rate guidelines would increase ROSC. The goal of this initiative was to increase CC rate compliance from a facility baseline of 15-64% toward the published benchmark of 80%, and to positively impact ROSC.

Method:
An interdisciplinary team focused on optimizing CC rate compliance. The Plan, Do, Study, Act methodology provided structure and a systematic approach to data informed improvements. Rate data was collected, then shared on a Power BI dashboard and in a facility specific report. The impact of the awareness campaign was assessed at the end of each quarterly cycle for 9 facilities.

Results/Outcomes:
Data for 2023 included 487 code events and 6,315 minutes of CPR. At year end, improvements were found at 5 facilities (12, 12, 14, 17,&7%) over baseline, and 2 facilities achieved the benchmark. Statistical analysis was conducted to evaluate CC rate compliance in correlation with ROSC. Cases were sorted into 2 groups: Group 1 (compliance 80% or greater) or Group 2 (compliance less than 31.6% - calculated first quartile). Three hundred two cases met inclusion criteria. Cochran’s formula was used (95% CI) to calculate sample size (Group 1:111 cases; Group 2:107cases). A Chi-squared test showed a significant difference in achieving ROSC between the groups (p=0.0223). Group 1 achieved ROSC 20% more frequently than Group 2.

Conclusions:
Chest compression rate compliance was positively associated with improved rate of ROSC in this project. Project findings prompted the system resuscitation committee to require facilities to set a goal for CC rate compliance improvement. Improvement can be achieved without financial or educational burden. Other performance-based quality metrics to improve clinical outcomes should be included in future research with consideration of co-morbidities.
Abstract 4141873: Estrogen Activates Endothelial Neutral Sphingomyelinase in a Sex-Dependent Manner
Authors: Limpert Rachel , SenthilKumar Gopika , Lindemer Brian , Freed Julie
Published: November 2024

Microvascular endothelial dysfunction is a strong predictor of future adverse cardiac events. We have previously shown that exposure to chronic estrogen induces microvascular endothelial dysfunction in isolated microvessels from otherwise healthy adults, with more extensive dysfunction exhibited in vessels from males. Further, we have demonstrated sex-specific, estrogen-induced increases in endothelial ceramide, a sphingolipid that when accumulated promotes microvascular endothelial dysfunction. The source of ceramide in response to estrogen remains unknown. Here we hypothesized that exogenous estrogen activates the ceramide-forming enzyme neutral sphingomyelinase (NSmase) in a sex-dependent manner. Sex-specific human umbilical vein endothelial cells (HUVECs) were cultured to passage 3 and treated with 17β-estradiol (E2, 100nM) or vehicle for 0, 1, and 2 minutes prior to collection and lysis of cells. NSmase activity was measured by the Neutral Sphingomyelinase Activity Assay Kit (Echelon Biosciences) according to manufacturer instructions. NSmase activity was greater in female compared to male HUVECs after 1 minute of treatment with E2 (normalized %change from control±SE; Untreated Control vs. 1 min E2; female:0.00±9.4% vs. 42.33±9.4%, n=6 vs. n=3, respectively,
p
=0.0174; male:-0.17±4.45 vs. 27.33±6.36, n=6 vs. n=3, respectively,
p
=0.1507; one-way ANOVA). Interestingly, NSmase activity was also significantly increased following 2 minutes of E2 treatment, an effect not observed in cells from females (normalized %change from control±SE; Untreated Control vs. 2 min E2; female:0.00±9.4% vs. 19.0±4.7%, respectively, n=6,
p
=0.26; male:-0.17±4.4 vs. 38.3±6.9, respectively, n=6,
p
=0.004). These data suggest that estrogen activates NSmase in a sex-dependent manner with an earlier, transient activation observed in females and a more sustained response in males. Collectively, this may further explain the sexually dimorphic response to estrogen and provide a potential therapeutic avenue to prevent microvascular damage in individuals chronically exposed to estrogen.
Abstract 4141912: Targeting NEK2 to Induce Senescence and DNA Damage in Pulmonary Arterial Hypertension
Authors: Martineau Sandra , Yamamoto Keiko , Bourgeois Alice , Lemay Sarah-Eve , Sauvaget Melanie , Breuils Bonnet Sandra , Potus Francois , Provencher Steeve , Boucherat Olivier , Bonnet Sebastien
Published: November 2024

Introduction:
Pulmonary arterial hypertension (PAH) is characterized by vasoconstriction and vascular remodeling of the distal pulmonary arteries (PAs) leading to progressive elevation of PA pressure, right heart failure and death. Extensive proliferation and resistance to apoptosis of PA smooth muscle cells (PASMCs) is perhaps the most prominent feature of PAH accounting for the histopathological changes seen in this disease. With the recognition of this, direct targeting of vascular remodeling may represent a promising strategy.

Goal:
To illuminate new actionable targets involved in pulmonary vascular remodeling in PAH.

Methods:
Molecular, biochemical and pharmacological approaches were used to identify Never In Mitosis A-Related Kinase 2 (NEK2) and study its role in pulmonary vascular remodeling in PAH

Results:
We performed a comparative RNA-sequencing analysis between control and PAH-PASMCs and then integrated our dataset with publicly available datasets conducted on comparable samples. Among the genes that were concordantly up-regulated in PAH-PASMCs, we identified NEK2, a kinase and druggable target implicated in the progression of mitosis. Using Western blot (WB) and immunofluorescence (IF), we confirmed that NEK2 is upregulated in PASMCs and distal PAs of PAH patients and animal models (Sugen/Hypoxia- and monocrotaline-exposed rats). Pharmacological (NCL0017509) and molecular (siNEK2) inhibition of NEK2 reduced PAH-PASMCs proliferation, as assessed by IF (Ki67 labeling, EdU incorporation, p<0.05) and qPCR (MCM2, PLK1 and Survivin , p<0.05). Further analysis revealed that pharmacological inhibition of NEK2 blocks cell cycle progression in the G2/M phase (flow cytometry, p<0.01) and increases DNA damage (comet assay p<0.001, WB of pDNAPK/DNAPK and RAD51, p<0.05). Moreover, we found that PAH-PASMCs subjected to NEK2 inhibition acquire a senescent phenotype (WB of p16, p21 and p53, p<0.05).

Conclusion:
Our results suggest that NEK2 contributes to the pro-proliferative phenotype of PAH-PASMC and may represent a new target in PAH.
Abstract 4141914: Fragmentation Analysis of Heart Rate Variability after Ischemic Stroke in Rats: A New Indicator of Heart-Brain Connection
Authors: Alavi Rashid , Dai Wangde , Pahlevan Niema , Arakaki Xianghong , Gharib Morteza , Kloner Robert
Published: November 2024

Introduction:
Fluctuations of heart rate, or heart rate variability (HRV), contain important information about autonomic functions and regulations of the cardiovascular system. Heart rate fragmentation (HRF) is an inter-beat interval dynamics approach (Front Physiol, 2017 PMID: 29184505) that enhances analysis of short-term HRV. HRF has shown consistency with breakdown of neuroautonomic-electrophysiologic control system of the sino-atrial node. Here, we evaluate alterations of HRF metrics prior to, during the ischemic stroke and after reperfusion.

Methods:
We used the standard ischemic stroke model (intraluminal suture middle cerebral artery (MCA) occlusion) in adult male/female Sprague Dawley rats (n=11, 2-3 months old, weight: 296 ± 47 g, 27% female). The common carotid artery (CCA) was temporarily occluded while a suture was introduced to the internal carotid artery and advanced until it interrupted blood supply to MCA. We occluded the MCA for 1 hour followed by 3 hours of reperfusion (Fig.1). Electrocardiogram (ECG) was continuously measured throughout the surgeries. Post-surgery, the presence of cerebral infarction was confirmed by incubating brain slices in triphenyl tetrazolium chloride (TTC staining). HRF metrics were computed using 1-minute recordings of ECG at 3 time-points: a) baseline; b) 1 hour after MCA occlusion (pre-reperfusion); and c) 3 hours after reperfusion.

Results:
Significant differences (p<0.05) were found between the baseline and 3 hours after reperfusion (Fig.2) for two HRF metrics: PIP% (percentage of inflection points i.e., changes in heart rate acceleration sign) and W1% (percentage of only 1 inflection point in sequences of five consecutive heart rate intervals).

Conclusions:
Our results suggest that there are specific HRF metrics that alter significantly after ischemic stroke in rats. This study shows the possibility of developing noninvasive HRF-based techniques for detection or monitoring of ischemic stroke and treatment in future.
Abstract 4141925: Impact of Chemotherapy Exposure on New-Onset Cardiovascular Disease Risk in Cancer Survivors
Authors: Raab Gabriel , Underwood Whitney , Ma Xiaoyue , Wallins Joseph , Scott Jessica , Liu Jennifer , Jones Lee , Yu Anthony
Published: November 2024

Background:
Five-year survivors of cancer are at excess risk of non-cancer competing morbidity and mortality including cardiovascular disease (CVD). However, whether excess risk differs based on exposure to specific chemotherapy treatments is unclear. We compared risk of CVD among 5-year cancer survivors with or without prior chemotherapy exposure.

Methods:
Using a retrospective cohort design, we identified 25,535 pan-cancer survivors with ≥5 years follow-up at MSKCC. New onset CVD events (i.e., heart failure [HF], myocardial infarction [MI], stroke) were ascertained based upon administrative billing codes. Cumulative incidence rates (CIR) were estimated, accounting for the competing risk of death, and differences between groups with and without chemotherapy treatment were evaluated using Gray’s test. Multivariable Fine and Gray proportional hazard models estimated sub-distribution hazard ratios (sHR) and 95%CIs for survivors treated with versus without chemotherapy. Subgroups of survivors treated with an individual class of chemotherapy were also examined.

Results:
Median follow-up was 116.2 (IQR, 80.6-162.0) months (Table). Compared to survivors with no chemotherapy exposure, survivors with prior chemotherapy treatment had higher CIR of HF (7.62% vs. 2.77%, P<0.01) and stroke (5.44% vs. 3.06%, P<0.01), but not MI (3.92% vs 3.49%, P=0.20). In multivariable models, survivors who received chemotherapy had higher risk of HF (sHR: 4.08; 95% CI: 3.47-4.80), MI (sHR: 1.61; 95% CI: 1.36-1.91), and stroke (sHR: 2.64; 95% CI: 2.20-3.15). Risks of CVD varied based upon type of chemotherapy received (Figure 1).

Conclusion:
Cancer survivors who received chemotherapy had higher risks of CVD compared with survivors without chemotherapy exposure, with variation based upon type of chemotherapy. These findings underscore the need for aggressive CVD risk factor modification and prevention in cancer survivors, especially those who received chemotherapy associated with increased CVD risk.
Abstract 4141931: Effect of Storage Temperature on Myocardial Tissue Preservation in Rat Hearts
Authors: Kiernan Zachary , Labate Gina Marie , Chen Qun , Quader Mohammed
Published: November 2024

Background:
Cold static storage of the heart in ice for transportation is thought to cause post-transplantation graft dysfunction secondary to freeze injury. No basic science or randomized clinical trial has objectively evaluated this concern.

Hypothesis:
Hearts stored at 0°C for four hours do not sustain freeze injury.

Aim:
To quantify the myocardial damage and resulting function in hearts stored at 0
o
C, 4
o
C and 8
o
C for four hours.

Methods:
Male Sprague-Dawley rat hearts were procured under general anesthesia and immediately stored in University of Wisconsin solution at 0
o
C, 4
o
C and 8
o
C for four hours (n = 6-8/group). Hearts were then re-perfused on a Langendorff apparatus for 90 minutes using oxygenated Krebs-Henseleit buffer (37
o
C) at a perfusion pressure of 73 mmHg. Functional parameters were recorded via a balloon tip catheter in the left ventricle. Coronary flow rate was monitored with timed collection of effluent. At the end, hearts were collected for infarct size quantification using triphenyltetrazolium chloride staining.

Results:
Infarct size in hearts stored at 0°C, 4°C, and 8°C were 28±1%, 32±2%, and 39.7±2%, respectively. There was no significant difference in infarct size between hearts stored at 0°C and 4°C. Hearts stored at 8°C had a significantly larger infarct size compared to both 0°C and 4°C (
P
= 0.0004 and 0.0178, respectively). Left ventricle developed pressure in hearts stored at 0°C, 4°C, and 8°C were 55±4 mmHg, 51±3 mmHg, and 55±2 mmHg, respectively (all
P
> 0.05). Negative dP/dt in hearts stored at 0°C, 4°C, and 8°C were -2505±274 mmHg/sec, -1969±186 mmHg/sec, and -1861±175 mmHg/sec, respectively (all
P
> 0.05). Coronary flow at 4°C (22 mL/min) was higher compared to 0°C (19 mL/min) and 8°C (16 mL/min) (
P=
0.0371 and
P
=0.0003, respectively). Cardiac troponin I levels in the coronary effluent from hearts stored at 0°C, 4°C, and 8°C were 0.88±0.1 ng/ml, 0.86±0.1 ng/ml, and 1.24±0.2 ng/ml, respectively (all
P
> 0.05).

Conclusion:
Hearts stored at 0°C for four hours showed no signs of freezing, they showed similar functional parameters and comparable levels of biochemical markers for injury compared to hearts stored at 4°C. Hearts stored at 8°C had a larger infarct size compared to 0°C or 4°C.
Abstract 4141936: Neurocognitive and vascular dysfunction in a murine model of atrial fibrillation is attenuated by mitochondrial catalase
Authors: Guttipatti Pavithran , Ji Ruiping , Saadallah Najla , Avula Uma Mahesh , Dasrat Parmanand , Parsons Samantha , Wan Elaine
Published: November 2024

Background:
Atrial fibrillation (AF) increases the risk of cognitive decline and dementia independent of stroke or comorbidities. However, the mechanism is poorly understood and there is no animal model studying the effects of persistent AF on the brain.

Objectives:
We studied a genetic mouse model with spontaneous and persistent AF to assess cognitive performance, brain structure, and vascular function and to investigate if expression of mitochondrial catalase can improve these deficits in AF mice.

Methods:
We have previously established a double transgenic mouse model expressing modified human Na
+
channel
SCN5A
with spontaneous prolonged AF (DTG-AF mice). We have shown DTG-AF-mCAT mice expressing mitochondrial catalase (mCAT) have greatly reduced AF burden. We used the automated touchscreen test to assess visual discrimination and learning. Selection of the correct stimulus between two screens results in a reward. Number of trials and time to achieve a performance criterion of 80% correct was compared between control (n=15), DTG-AF (n=18), and DTG-AF-mCAT mice (n=12) via one-way ANOVA and Mantel-Cox test respectively. Brain imaging was performed with T2-weighted MRI on control (n=7) and DTG-AF (n=7) mice. Vascular function was assessed by measuring myogenic tone of cannulated third order mesenteric arteries ex-vivo (n = 9, 9, 9 vessels). * p<0.05, *** p< 0.001.

Results:
DTG-AF mice show significantly impaired visual learning on the touchscreen test, requiring greater trials to reach performance criterion than control mice (mean difference 133.6 ± 53.8). Brain MRI did not reveal microinfarcts but demonstrated increased lateral ventricle size in DTG-AF mice suggestive of ventriculomegaly (1.83 ± 0.19 vs 1.27 ± 0.17). Mesenteric resistance arteries in DTG-AF mice demonstrated loss of myogenic tone with increasing intraluminal pressure. Importantly, reducing AF burden with mitochondrial catalase significantly improved touchscreen test performance and restored myogenic tone.

Conclusion:
DTG-AF mice model the neurocognitive dysfunction seen in AF and display loss of myogenic tone and vascular dysfunction which may be the cause of altered cerebral autoregulation. Reducing mitochondrial ROS is sufficient to improve cognitive performance and reverse vascular dysfunction.
Abstract 4141953: Genetic deficiency of flavin containing monooxygenase 3 (
Fmo3
) lowers circulating trimethylamine N-oxide level and protects against atherosclerosis
Authors: Han Maggie , Charugundla Sarada , Wang Zeneng , SINHA Satyesh , Zhou Zhiqiang , Allayee Hooman , Hazen Stanley , Lusis Aldons , Shih Diana
Published: November 2024

Introduction:
Our groups have previously identified trimethylamine N-oxide (TMAO) as a risk factor for cardiovascular diseases (CVD). In humans, elevated plasma TMAO levels are associated with a ~2.5-fold increased risk for major adverse cardiac events, such as death, myocardial infarction, and stroke. Bacterial metabolism of dietary choline (and L-carnitine) in the intestine leads to an intermediate, trimethylamine (TMA), which is absorbed from the gut and oxidized primarily by the hepatic flavin-containing monooxygenase 3 (FMO3) to generate TMAO.

Hypothesis:
We hypothesize that decreased TMAO generation caused by FMO3 deficiency in mice leads to decreased circulating TMAO levels and atherosclerosis.

Approach and Results:
We generated FMO3 knockout (KO) mouse on a C57BL/6J background via CRISPR/Cas9 technology. We then crossed the FMO3KO mice with LDL receptor knockout (LDLRKO) mice to generate FMO3 heterozygous (FMO3Het)/LDLRKO mice and FMO3KO/LDLRKO mice for the study. Female FMO3Het/LDLRKO and FMO3KO/LDLRKO mice were fed a 1% choline, a TMAO precursor, and 0.5% cholesterol diet for 3 months to increase circulating TMAO and total cholesterol levels. After diet feeding, FMO3KO/LDLRKO mice had 51% lower TMAO levels compared to FMO3Het/LDLRKO mice (18.3 μM vs. 38.3 μM, p < 0.0001), but no effects on plasma lipids, glucose, or insulin levels. Most notably, atherosclerotic lesion at the aortic root was decreased by 24% (p < 0.01) in the FMO3KO/LDLRKO mice as compared to the FMO3Het/LDLRKO mice. The mRNA levels of inflammatory genes, such as Cox2 and E-selectin, in the aorta were significantly decreased by more than 50% in FMO3KO/LDLRKO mice when compared to the control mice. Western blot analysis revealed decreased NF-κB activation in the aorta samples of the FMO3KO/LDLRKO mice as compared to those of the controls, suggesting reduced inflammation in the former. We also measured circulating IL-6 and TNF-α levels but did not observe any differences in plasma levels of these inflammatory biomarkers.

Conclusions:
Taken together, our data demonstrate that Fmo3 deficiency reduces TMAO levels and aortic lesion development in the context of an appropriate pro-atherogenic diet that contains also high levels of a TMAO precursor. These results also suggest that one mechanism for the pro-atherogenic effects of TMAO is through localized upregulation of inflammatory pathways at the level of the vessel wall, which do not necessarily manifest systemically.
Abstract 4141995: Impact of myocardial infarction on aortic and mitral bioprosthetic valve degeneration
Authors: Rouabhia Dounia , Desroches Florence , Paquin Amelie , Mohammadi Siamak , Clavel Marie-Annick , Pibarot Philippe , Beaudoin Jonathan
Published: November 2024

Background:
Studies have previously suggested that myocardial infarction (MI) have an impact on native aortic valve stenosis progression as well as inducing pathobiological changes in native mitral and tricuspid native valve leaflets. Inflammation, renal failure, and hypertension have been identified as potential factors accelerating structural valve degeneration (SVD). However, the impact of MI on bioprosthetic valve and SVD is unknown.

Hypothesis:
MI accelerates the progression of bioprosthetic valve degeneration.

Methods:
A retrospective cohort analysis of patients who underwent a bioprosthetic aortic or mitral valve replacement at Quebec Heart and lung Institute was done. Patients were identified through a keyword search in institutional medical records and through the local cardiac surgical database (n = 158). Inclusion required a bioprosthetic valve in aortic (n = 146) or mitral (n = 12) position, with or without history of MI after surgery and at least two echocardiograms within 5 years post-MI, along with available echocardiograms performed ≥6 months prior to the MI. Patients were matched for baseline and prosthetic valve characteristics and divided into two groups 1) No MI (controls, n= 79), 2) MI (cases, n= 79). Echocardiograms were reviewed for valve mean and maximal gradient as well as valve area derived from the continuity equation.

Results:
At baseline, the two matched groups had comparable characteristics and echocardiographic data. The annualized progression of prosthetic valve area was higher in the MI group (-0.04 ± 0.16 cm
2
/y vs 0.00 ± 0.11, p = 0.039). This was mostly driven by patients with aortic valve replacement (aortic valve area -0.05 ± 0.14 cm
2
/y vs 0.01 ± 0.11, p = 0.0077). Using a mixed linear model, the presence of MI had a significant interaction with the decline of aortic valve area and indexed aortic valve area (p = 0.0057, p = 0.0041). There was no difference in mean or maximal gradient between the two matched group. Annual progression rate of indexed bioprosthetic aortic valve area was faster in men compared to women in the whole population (-0.061 ± 0.01 cm
2
/m
2/
y vs -0.01 ± 0.02 cm
2
/m
2/
y for men and women, respectively; p = 0.009).

Conclusion:
This study suggests that bioprosthetic valve stenosis may be accelerated following a myocardial infarction. These findings could be explained by the same fibrotic mechanisms observed in native valves. More studies are needed to understand the underlying mechanisms and clinical impact.
Abstract 4142045: Costs and Healthcare Resource Utilization in Transthyretin Amyloid Cardiomyopathy Exceeds That of Non-amyloid Heart Failure
Authors: Grodin Justin , Masri Ahmad , Wright Richard , Tamby Jean-Francois , Falvey Heather , Hennum Liana , Badwe Chaitanya , Allison Melissa , Ramesh Rakesh , Sanghi Shradha , Dev Sandesh , Nativi-Nicolau Jose
Published: November 2024

Background:
Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive, fatal condition characterized by worsening heart failure (HF), exercise intolerance, cardiac arrhythmias, aortic stenosis, and orthopedic manifestations. Recent analyses have shown ATTR-CM presents a significant burden to the healthcare system, but data on healthcare resource utilization (HCRU) comparing ATTR-CM to non-ATTR HF in the US are lacking.

Aim:
To compare HCRU and costs in patients (pts) with ATTR-CM to that of pts with non-ATTR HF using medical and pharmacy claims.

Methods:
Using the Optum Clinformatics Data Mart (Jan 2016-Sep 2023), pts with ATTR-CM were identified based on presence of HF and/or cardiomyopathy (CM) occurring within 2 years of first amyloidosis diagnosis (excluding light-chain amyloidosis) and followed for at least 12 months after first HF/CM diagnosis. ATTR-CM pts were matched 1:1 to non-ATTR HF pts using propensity score matching. After index diagnosis, both groups were assessed for HCRU, including inpatient acute cardiovascular (CV) hospitalizations (CVH), length of stay, and cost. Hospitalizations were considered CV if a pt received a CV diagnosis during the hospitalization period.

Results:
There were 4581 pts with ATTR-CM (mean [±SD] age: 76 [9.13] years; 56.2% male) who met inclusion criteria and were matched to 4581 non-ATTR HF pts (mean [±SD] age: 76 [8.86] years; 56.0% male) for comparison (Table). ATTR-CM pts had a higher trend of CVH and a higher number of total CVHs and mean hospitalizations per pt compared to non-ATTR HF pts (p<0.001). The mean cost per hospitalization (p=0.00463) and mean cost per annual hospitalizations per pt (p<0.001) were higher for ATTR-CM compared to non-ATTR HF. ATTR-CM pts were also hospitalized for more mean days annually for CV-related reasons compared to non-ATTR HF pts (p<0.001). On average, pts with ATTR-CM spent 2.3 days more than matched non-ATTR HF pts in the hospital each year.

Conclusion:
Compared to non-ATTR HF, ATTR-CM is associated with a greater burden on the healthcare system as evaluated by hospitalization rate, costs per hospitalization, annual hospitalization costs, and days hospitalized annually.
Abstract 4142056: Impact of Obstructive Sleep Apnea on In-Hospital Outcomes of Adults with Hypertrophic Cardiomyopathy
Authors: Roma Nicholas , Desai Spandan , Pattoli Megan , Magid Lindsey , Yellapu Vikas , Shirani Jamshid
Published: November 2024

Background:
Obstructive sleep apnea (OSA) has been reported in a sizable proportion of adults with hypertrophic cardiomyopathy (HCM) and has been associated with higher incidence of adverse outcomes including arrhythmias (atrial fibrillation, non-sustained ventricular tachycardia) and sudden cardiac death when untreated. We aimed to evaluate the impact of OSA on in-hospital outcomes of patients with HCM.

Methods:
National Inpatient Sample 2016-2020 was queried to identify admissions for HCM patients with (HCM+OSA) and without (HCM-OSA) OSA. In-hospital outcomes were compared with use of logistic regression.

Results:
From 2016-2020, 271,085 adults with HCM were admitted to hospital of whom 45,135 (16.6%) were identified to also have OSA. Age was similar between both groups. (Table) Comorbidities (diabetes, coronary artery disease, hyperlipidemia, and chronic kidney disease) were more prevalent among HCM+OSA [Table]. Additionally, HCM+OSA more often had the obstructive phenotype (43.8 vs. 42.87%, p<0.001), heart Failure with preserved ejection fraction (37.75 vs. 27.01%, p<0.001), and paroxysmal atrial fibrillation (24.65 vs. 19.76%, p<0.001) and more frequently underwent septal reduction therapy [surgical myectomy (2.61 vs. 2.09%) or alcohol septal ablation (0.94 vs. 0.76%), both p<0.001)]. In-hospital outcomes such as overall mortality, need for intensive care unit admission, mechanical ventilation, mechanical circulatory support and use of vasopressors did not differ among patients with HCM and with or without SH [Table].

Conclusion:
In this study, 1 in ~6 adults with HCM admitted to hospital also had OSA. OSA in HCM was associated with higher prevalence of comorbid conditions and the obstructive phenotype and thus higher rates of septal reduction therapy. However, presence of OSA did not impact in-hospital outcomes of HCM in this study.
Abstract 4142133: Variant-enhancer-gene mapping at the 9p21 locus in smooth muscle cells reveals new enhancer-gene pairs and mechanistic insights for coronary artery disease
Authors: Ramste Markus , Weldy Chad , Zhao Quanyi , Ranta Amanda , Li Daniel , Sharma Disha , Monteiro Joao , Worssam Matthew , Amgalan Dulguun , Qin Guyu , Nguyen Trieu , Kim Juyong , Engreitz Jesse , Assimes Themistocles , Park Chong , Quertermous Thomas
Published: November 2024

The majority of variants identified by genome-wide association studies (GWAS) that influence coronary artery disease (CAD) risk reside in noncoding regions of the genome, making it challenging to link them with the genes they regulate. The 9p21.3 locus is the most impactful genetic risk locus for CAD. Due to the complexity of this locus, the causal genes and molecular mechanisms are poorly understood. Enhancers are cell type specific, and vascular smooth muscle cells (SMC) are known to have the highest heritable risk for CAD and play a major role in the atherosclerotic plaque formation. Here, we report efforts to systematically map SMC specific enhancers to neighboring genes within the 9p21.3 locus by implementing single cell CRISPRi enhancer screens and validating single causal variants in these enhancers. First, we intersected CAD GWAS loci with human coronary artery SMC (HCASMC) ATAC-seq and H3K27ac ChIP-seq datasets to focus on the disease relevant SNPs. This analysis identified 27 SNPs in 11 enhancers, that we targeted with CRISPRi machinery and analyzed at 5- and 10-days post transduction. As target genes in the locus are lowly expressed, we employed the targeted Perturb-seq (TAP-seq) approach for library generation and sequencing. We identified several enhancer-gene -pairs, including a strong enhancer-gene connection to both
CDKN2A
and
CDKN2B
. Additionally, we identified multiple enhancer regions that control
MTAP
expression, with smaller but significant effects. We followed up with individual validation of enhancer-gene pairs through qPCR. Furthermore, these results are consistent with chromosomal interaction data obtained from our previous HiChIP. Notably, enhancers 5 and 6 were strong regulators of CDNK2B and CDKN2A expression, so we investigated how variants in these enhancers might directly disrupt transcription factor (TF) binding. By using luciferase enhancer assays, CHIPseq and phenotypic in vitro assays we linked this variation with TFs that drive vascular calcification in SMCs. Our results identify new variant to gene links and suggest how the genetic risk in 9p21 is mediated in the vascular wall, providing mechanistic understanding of vascular calcification and genetic risk of CAD and suggesting a novel mechanism of how 9p21.3 mediates disease risk.
Abstract 4142145: The Usefulness of Left Atrial Strain for Successful Weaning from Venoarterial Extracorporeal Membrane Oxygenator
Authors: Shin Heayoung , Kim Darae , Bak Minjung , Cho Yang Hyun , Choi Jin-Oh , YANG JEONGHOON
Published: November 2024

Backgrounds:
Echocardiographic predictors of successful weaning from venoarterial extracorporeal membrane oxygenator (VA-ECMO) have been fully elucidated although previous studies reported echocardiographic parameters of left ventricular systolic function as a weaning indicator. Therefore, we investigated whether left atrial (LA) strain was associated with successful weaning from VA-ECMO.

Methods:
A total of 144 patients with profound cardiogenic shock who received VA-ECMO between March 2016 and March 2024 were enrolled from a single-center prospective registry. The ECMO flow study assessed cardiac recovery before the weaning trial. The flow was decreased by around 30% of the initial flow for 15 minutes. We assessed conventional echocardiographic parameters, LA strain, and left ventricular global longitudinal strain (LV GLS) both at baseline and after flow reduction, respectively. The primary outcome was successful ECMO weaning.

Results:
After excluding 24 patients with poor image quality, 120 patients were finally analyzed. Among them, 70 patients (58.3%) had successful weaning from VA-ECMO. During the ECMO flow study, aortic velocity time integral (13.1±7.1cm vs 9.7±4.0cm, p=0.002), left ventricular ejection fraction (35.4±12.3% vs 25.2±10.7%, p, and mitral s’ velocity (7.5±2.7 vs 5.4±2.0 cm/sec, pechocardiographic parameters for ECMO weaning, were higher in the weaning success group compared to the weaning failure group at ECMO minimal flow. The increase of LA strain (p in the successful weaning group was significantly higher than in the failed group according to the reduction of flow contrast to left ventricular ejection fraction (p=0.264) and mitral s’ velocity (p=0.001). LA strain (AUROC=0.789, 95% CI 0.705-0.872, pat minimal flow had a predictive performance for successful ECMO weaning comparable to that of LVEF(AUROC=0.750, 95% CI 0.660-0.839, p at minimal flow.

Conclusions:
LA strain at minimal ECMO flow might be useful as an indicator of successful weaning from VA ECMO along with conventional echocardiographic parameters.

Keyword: extracorporeal membrane oxygenator; weaning; left atrial strain