bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P377: Insulin Resistance is Associated With Carotid Intima-media Thickness in Non-diabetic Subjects: the ELSA-Brasil Cohort Baseline
Authors: Santos Itamar S , Bittencourt Márcio S , Goulart Alessandra C , Schmidt Maria I , Diniz Maria F , Lotufo Paulo A , Bensenor Isabela M
Published: March 2022

Background:
Epidemiological studies have analyzed the association between carotid intima-media thickness (CIMT) and insulin resistance, glucose levels or glycated hemoglobin with mixed results.

Objective:
To evaluate the association between CIMT and homeostasis model assessment - insulin resistance (HOMA-IR), fasting and post-load plasma glucose and glycated hemoglobin in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) baseline.

Methods:
We included 8,028 participants (aged 35-74 years) without diabetes or overt cardiovascular disease who had complete CIMT data at baseline. We built crude and adjusted linear and binary logistic models to evaluate the association between CIMT and (a) HOMA-IR; (b) fasting plasma glucose; (c) post-load plasma glucose; and (d) glycated hemoglobin. We also built
post-hoc
models, stratified by sex.

Results:
In the fully-adjusted linear models, only the association between CIMT (in mm) and HOMA-IR remained significant (table). Consistent with these results, only the association between the highest age- sex- and race-specific CIMT quartile and HOMA-IR was significant in the adjusted model (odds ratio [OR]: 1.10; 95% CI: 1.04 - 1.17). The association between HOMA-IR and the highest CIMT quartile remained significant in sex-specific analyses (OR: 1.10; 95% CI: 1.02 - 1.20 for men and OR: 1.10; 95% CI: 1.02 - 1.20 for women). We did not find an independent association between CIMT and glucose or glycated hemoglobin levels.

Conclusion:
We found a direct, independent association between HOMA-IR and CIMT in a large sample of non-diabetic men and women. Mechanisms unrelated to glucose homeostasis, as a direct effect of insulin on atherosclerosis or medial hypertrophy, may be involved in this association.
Abstract P381: Vascular Inflammation as a Subclinical Marker of Atherosclerosis Demonstrates High Cardiometabolic Risk in a Resource-limited, Community-based Population
Authors: Rivers Joshua P , Mitchell Valerie , Peters-Lawrence Marlene , Joshi Aditya A , Dey Amit K , Mehta Nehal N , Powell-Wiley Tiffany M
Published: March 2022

Background:
Vascular inflammation (VI) is associated with increased cardiovascular (CV) events among populations with inflammatory disease. Less is known about VI among populations in communities characterized by lower neighborhood-level socioeconomic status and limited resources for physical activity and dietary intake, particularly those identified as having CV risk factors through community-based (CB) efforts. Specifically, no comparisons exist of VI between CB cohorts and populations with known inflammatory disease associated with CV risk, such as psoriasis (PSO).

Hypothesis:
We hypothesized that VI by 18-FDG PET/CT would be similar in a resource limited CB cohort compared to a matched mild/moderate PSO cohort.

Methods:
In the Washington, DC CV Health and Needs Assessment, we evaluated CV risk factors among participants of a day-long, CB event in resource-limited Washington, DC areas (NCT01927783). Those having at least one CV risk factor (obesity, hypertension, hyperlipidemia, or diabetes) underwent 18-FDG PET/CT to measure VI for cardiometabolic phenotyping. Cardiometabolic markers were compared between the CB cohort and PSO cohort; VI between the cohorts was also compared using linear regression modeling.

Results:
The CB cohort was African-American, middle-aged, and predominantly female, and the PSO cohort was half female and mostly Caucasian. Both cohorts were obese and pre-hypertensive with elevated lipid levels. There was no significant difference in VI between the CB cohort and the PSO cohort in both unadjusted (beta 0.25, p 0.15) and adjusted models including age, BMI, and race (beta 0.21, p 0.14).

Conclusion:
Populations with CV risk factors in resource-limited communities have comparable VI to those with known inflammatory PSO. These findings highlight a need for 1) CB efforts to identify individuals at high CV risk who might not otherwise be seen in a clinical setting and 2) targeted CB interventions to reduce CV risk for these populations. However, larger studies are needed to confirm our findings.
Abstract 20919: Manipulation-Free Particle Image Velocimetry Method of Screening Drugs Using Human iPSC-Derived Cardiomyocytes
Authors: Rajasingh Sheeja , Czirok Andras , Isai Dona G , Samanta Saheli , Zhou Zhigang , Barani Bahar , Drosos Nicholas , Dawn Buddhadeb , Rajasingh Johnson
Published: March 2022

Introduction:
Currently available drug screening models are not efficient in detecting cardiac toxicity. Here we demonstrate the in vitro Particle Image Velocimetry (PIV) assays followed by fourier spectrum and heatmap analyses for measuring the impact of different cardiac drugs on the spontaneous beat frequency (SBF) and spontaneous beat amplitude (SBA) of beating cardiomyocytes (CMCs).

Hypothesis:
Our PIV method of measuring CMCs contractility could be beneficial for drug testing and preclinical screening to detect cardio-toxicity.

Methods and Results:
The novelty of our system is that we can record the spatiotemporal maturation of human iPSC-derived CMCs at specific positions. We have evaluated the contractility of CMCs with the response to various chemical compounds such as Verapamil (Ca2+ blocker), Isoproterenol (Ca2+ activator), E-4031 (K+ inhibitor) and NS-1643 (K+ activator). Our optically recorded beat patterns were in good agreement with the calcium-imaging signal (
Fig 1
). Our data also show that Isoproterenol, the β adrenergic agonist influencing intracellular Ca2+ dynamics, induced a substantial and sustained increase in SBF without triggering arrhythmias
(Fig 2A, B)
. Fourier analysis clearly indicates a shift in the SBF
(Fig. 2C
, dotted line). Power spectra of consecutive recordings are shown as heat maps (
Fig. 2D
). The reversibility of the Isoproterenol effect is indicated by the SBF returning to the baseline value after drug removal (Fig
2B, E
).

Conclusions:
We report for the first time the applications of PIV assays for prospective cardiac drug efficacy screening by measuring the contractility of CMCs from the video image without jeopardizing the biology of cells.
Abstract 20920: Does Provider Gender Matter? Guideline Concordance in Post-Cardiac Arrest Care
Authors: McDaniel Kyle T , Nelson Jessica L , Daugherty Stacie L , Havranek Edward P , Perman Sarah M
Published: March 2022

Introduction:
Recent studies have suggested that female physicians are more likely to adhere to clinical practice guidelines in medical care. When clinical guidelines for post-cardiac arrest care are adhered to patients have better outcomes.

Hypothesis:
We hypothesize that gender of the attending provider may affect guideline concordance in post-cardiac arrest care.

Methods:
We identified 139 out-of-hospital cardiac arrest patients treated at an academic tertiary care facility between 12/2013 and12/2016. Patients were over 18 years of age, suffered a medical cardiac arrest and were comatose at hospital admission. Demographic data and arrest characteristics were collected. The gender of the admitting provider and the provider who lead the first documented family meeting were abstracted. To assess for evidence based practice, we utilized 4 previously cited guidelines that are associated with improved survival; a.) was coronary angiography completed within 24 hours of admission, b.) was targeted temperature management initiated, c.) was target temperature achieved, and d.) did withdrawal of life sustaining therapy occur before 72 hours from return of spontaneous circulation?

Results:
Of the total cohort, 61.9% were male, mean age was 57.5 ±16.2 years, 36.6% had an initial shockable rhythm and 41.7% received bystander CPR. Fifty-six (40.3%) individuals survived to hospital discharge. Approximately 28.8% of the cohort was admitted to the hospital by a female attending physician. Guideline adherence by provider gender is described in the Table. No statistically significant differences were appreciated when examining the frequency of guideline concordant care and attending physician gender.

Conclusions:
In this small cohort of post-cardiac arrest patients, provider gender does not appear to affect post-arrest care guideline adherence. Further study in a large, multi-center cohort may yield different findings.
Abstract 20931: Therapeutic Hypothermia in In Hospital Cardiac Arrest
Authors: Arora Shilpkumar , Kumar Varun , Tripathi Byomesh , Lahewala Sopan , Kundoor Vishwa , Dave Mihir , Patel Smit , Bhatia Subir , Shah Harshil , Gidwani Umesh , Gopalan Radha
Published: March 2022

Introduction:
Role of therapeutic hypothermia in out of hospital cardiac arrest is well studied but data is sparse for in-hospital cardiac arrest (IHCA).

Methods:
Nationwide Inpatient Sample (NIS) database from 2011-2014 was utilized to identify ICHA using the ICD-9-CM procedural codes 99.60(CPR) and 99.63(closed cardiac massage) in any procedural fields. Therapeutic hypothermia was identified by 99.81 in any procedural field. Patient with age<18 years and missing information on age, gender and mortality was removed. Primary outcome was hospitalization survival. We used Greedy’s algorithm for propensity score match (1:20) to adjust for extensive list of clinically important confounders. We used simple logistic regression to generate odds ratio on matched cohort.

Results:
86,593 patients (Age>65 years: 58.48%, female: 44.12%) with In hospital cardiac arrest was identified,of which 1777 (2.05 %) received therapeutic hypothermia. Overall survival was 30%- with or without hypothermia. After propensity score matching (1:20) we identified 1537 matched pairs (32,277 patients) without any statically significant difference in baseline characteristics between two groups. C- index for the model was 0.714. Worse survival was observed in patients with hypothermia in matched cohort [Survival: (31.82% without hypothermia vs. 28.1% with hypothermia with p-value- 0.002) (OR:0.84, 95% CI:0.75-0.94, p-0.002)]. About a quarter of in-hospital cardiac arrest were Vfib/Vtach arrest and Subgroup propensity score match analysis in Vfib/Vtach arrest showed better survival without hypothermia, similar results were observed in PEA/asystole cardiac arrest.

Conclusion:
Worst survival was observed with hypothermia in hospital cardiac arrest patients. Risk of hypothermia complications outweighs the benefit of preserving brain in patients who received almost immediate resuscitation. Future clinical trials and prospective studies will be needed to concur our results.
Abstract 20932: Dynamic Regulation of Myocardial Long Noncoding RNAs in Human Heart Failure and Reverse Remodeling With Left Ventricular Assist Device Support
Authors: Liao Xianghai , Lu Rong , Clemons Autumn , Blum Raia , Truby Lauren , Garan Arthur R , Yuzefpolskaya Melana , Colombo Paolo , Vunjak-Novakovic Gordana , Topkara Veli K
Published: March 2022

Introduction:
Long noncoding RNAs (lncRNAs) have emerged as critical regulators of gene expression and have been implicated in various biological processes. Modulating lncRNA levels could be a plausible strategy for the treatment of heart failure (HF), however the specific lncRNAs responsible for cardiac reverse remodeling remain largely unknown.

Hypothesis:
Myocardial lncRNAs mediate reverse remodeling through
cis
-regulation of the neighboring mRNAs

Methods:
RNA sequencing was performed using total RNA isolated from failing human myocardium before (n=21) and after (n=12) left ventricular assist device (LVAD) implantation as well as from non-failing controls (n=5). Mapped reads for all GENCODE v26 lncRNAs were calculated. Differentially regulated mRNAs and lncRNAs were identified using a fold-change cut-off of 2 and a false discovery rate of 5%. Pearson correlation coefficient was used to determine the relationship between lncRNA and neighboring mRNAs.

Results:
81 incident HF and 47 reverse remodeling lncRNAs were identified (Figure 1A). 46 HF lncRNAs (56.8%) were normalized following LVAD support and showed reciprocal regulation in the pre- vs. post-LVAD myocardium (Figure 1B). Recovery lncRNAs included recently described Myheart (originating in the MYH7 locus) as well as novel lncRNAs (NPPA-AS1, RORB-AS1, lnc-TECRL). Majority of the antisense, intergenic, and intronic myocardial lncRNAs demonstrated a positive correlation with neighboring genes suggesting
cis
-regulation by lncRNAs during cardiac reverse remodeling (Figure 1C).

Conclusions:
Myocardial lncRNAs are dynamically regulated during myocardial remodeling (HF) and reverse remodeling with LVAD support. Mechanical unloading is accompanied by partial normalization of the pathological lncRNA signature. Further studies will determine mechanisms by which neighboring protein coding genes are regulated by lncRNAs in the failing human heart.
Abstract 20934: Chronic Polarization of Inflammatory Monocytes by Super-Low Grade Endotoxin Aggravates the Pathogenesis of Atherosclerosis
Authors: Geng Shuo , Yuan Ruoxi , Li Liwu
Published: March 2022

The subclinical levels of Gram negative bacterial endotoxin, LPS, circulating in the blood are prevalent in the individuals with adverse health conditions or lifestyles. LPS is a potent agent in the dynamic programming of monocytes, and altered innate immune homeostasis mediated by non-resolving inflammatory monocytes has long been suspected in the pathogenesis of atherosclerosis. However, the mechanisms responsible for the sustainment of inflammatory monocytes during atherosclerosis are poorly understood. We hypothesized that the selective modulation of molecular switches in monocytes by super-low dose LPS may facilitate the establishment of non-resolving inflammation during atherosclerosis. We challenged high-fat-diet (HFD) fed ApoE deficient mice with chronic LPS administration, and observed that LPS effectively induced expansion of Ly6C
high
pro-inflammatory monocytes with elevated levels of CCR5, MCP-1, and reduced SR-B1. Compare to PBS administration, chronic injection of super-low dose LPS significantly elevated the lipid deposition within the atherosclerotic plaques in HFD fed ApoE deficient mice, while induced remarkable reduction in collagen content of the plaques. To test whether the LPS reprogrammed monocytes, instead of systemic effects of LPS, may contribute the exacerbation of atherosclerosis, we performed adoptive transfer experiment. Bone-marrow monocytes harvested from ApoE deficient mice were primed in vitro with super-low dose LPS for 5 days, and then intravenously injected into HFD fed ApoE once weekly for 1 month. We observed significant increases of the plaque sizes as well as lipid deposition in atherosclerotic lesions, indicating that programmed monocytes directly aggravated atherosclerosis progression. At the molecular level, we observed that monocytes programmed by super-low dose LPS maintained higher levels of transcription factor IRF5 and reduced levels of a critical inflammatory repressor, Blimp-1. Intriguingly, the inflammatory monocyte priming by super-low dose LPS was dependent upon TRAM/TRIF but not MyD88. In conclusion, our data suggest super-low grade LPS may program sustained low-grade inflammatory monocytes that are conducive for the chronic pathogenesis of atherosclerosis.
Abstract 20947: Dnmt and Hdac Inhibitors Together Inhibits Lps Induced Cell Death by Modulating Stat3 Jmjd3 Signaling Axis
Authors: Ganguly Samanta Saheli , Zhou Zhigang , Rajasingh Sheeja , Barani Bahar , Drosos Nicholas , Dawn Buddhadeb , Rajasingh Johnson
Published: March 2022

Introduction:
Inflammation associated with acute lung injury (ALI) is caused by direct insult to the lungs or by sepsis, which is responsible for tissue damage and cell death. Although the therapeutic effectiveness of epigenetic modifiers can potentially limit lung inflammation, few studies have examined the combinatorial (Aza+TSA) use of a DNA methyl transferase (DNMT) inhibitor, Aza (5-Aza 2-deoxycytidine), and histone deacetylase (HDAC) inhibitor, TSA (Trichostatin A), on the recovery of cell death mechanisms in macrophages.

Hypothesis:
Therapy with Aza+TSA will reduce cell death by interfering with phosphorylation of JNK and ERK and thereby inhibit JMJD3 expression.

Methods and Results:
In an LPS-induced ALI mouse model, a single dose of Aza+TSA prevented lung inflammation and injury with significant reduction in mortality as compared with mice treated with either Aza or TSA alone (Thangavel J 2014). DNA ladder analysis shows a decrease in the DNA breaks in LPS-induced bone marrow derived macrophages (BMDMs) treated with Aza+TSA when compared to untreated LPS control
(Fig. A)
. There is also a reduction in phosphorylation of JNK and ERK in LPS-induced BMDMs when treated together compared to untreated or treated with either Aza or TSA alone. This reduction is caused by the decrease in JMJD3 expression when STAT3 was pulled down after the combined treatment of Aza+TSA, emphasizing the involvement of STAT3-JMJD3 signaling in inflammation associated cell death mechanism
(Fig. B)
.

Conclusions:
LPS acts on macrophages through activation of the MAPK pathway followed by the modulation of STAT3-JMJD3 associated with cell death. Administration of DNMT and HDAC inhibitor together interrupts STAT3-mediated decrease in the JMJD3 signaling pathway and cell death in BMDM. !--[endif]-->
Abstract 20949: Impact of Renal Denervation on Autonomic Nerve Activity
Authors: Cho Youngjin , Choi Eue-Keun , Oh Il-Young , Cha Myung-Jin , Oh Seil
Published: March 2022

Introduction:
Recent studies reported potential antiarrhythmic effect of catheter-based renal denervation (RDN). We sought to evaluate impacts of RDN on cardiac autonomic nerve activity in ambulatory canine model.

Methods:
Telemetry devices (D70-EEE, DSI) were implanted in 17 mongrel dogs to record ambulatory nerve activity simultaneously from left stellate ganglion (SG), superior left ganglionated plexus (SLGP), and left renal nerve. After 1 week of baseline nerve activity recording, RDN was performed at both renal arteries using a specialized catheter (Symplicity
TM
, Medtronic) (n=10). A control animals underwent autonomic nerve recording operation but with sham procedure (n=3). Bilateral surgical stripping of the renal nerve adventitia was performed in 4 dogs (n=4, surgical RDN). One-minute integrated nerve activities were quantified and compared among groups up to 2 weeks.

Results:
Renal nerve acvitivity (RNA) decreased after catheter RDN (-6.7±13.4% from baseline), while RNA increased after sham operation by 7.4±9.5% (p=0.103). After surgical RDN, no RNA was observed. In contrast to the increased SG nerve activity (SGNA) after sham operation (+2.2±11.4%), SGNA decreased after catheter RDN (-2.1±10.8%, p=0.073) and surgical RDN (-10.6±13.1%, p=0.061 vs. control). SLGP nerve activity (SLGPNA) also increased by 7.1±3.1% after sham operation, while SLGPNA decreased after catheter-based (-8.1±13.9%, p=0.008), and surgical RDN (-6.3±10.2%, p=0.073 vs. control). Immunohistochemistry showed increment of TH (tyrosine hydroxylase)-negative cells in SG after RDN (% of TH-negative cells: control=1.8%, catheter RDN=5.5% [p=0.058 vs. control], surgical RDN=7.35% [p=0.039, vs. control]).

Conclusions:
The response of renal nerve and cardiac autonomic nerve activity to catheter based RDN was diverse. Renal denervation decreased SGNA and SLGPNA, with neural remodeling at SG. These results may support anti-arrhythmic effects of RDN.
Abstract 20953: M1 and M2 Specific Purinergic Receptor Repertoire Alters Response to Damage Associated Molecular Patterns
Authors: Merz Julian , Nettesheim Alina , von Garlen Sunaina , Zirlik Andreas , Stachon Peter
Published: March 2022

Introduction:
Dying cells release damage associated molecular patterns (DAMPs) like nucleotides into the extracellular fluid, orchestrating a profound immune response. Purinergic receptors decrypt the composition of extracellular nucleotides and translate it to distinct cellular reactions. M1 and M2 macrophages are immune cells involved in many diseases which react in a completely different way. Nevertheless, how the microenvironment exactly triggers their behavior is not fully understood.

Hypothesis:
We hypothesize a distinct expression pattern of purinergic receptors on M1 and M2 macrophages which leads to an unique microenvironment recognition and behavior.

Methods:
Macrophages were generated by bone marrow isolation and cultivation with macrophage colony stimulating factor (M-CSF). Bone marrow derived macrophages (BMDMs) were differentiated to M1 via addition of IFNγ and LPS. M2 differentiation was initiated by the addition of IL-4. Gene transcription quantification was assessed by real-time PCR. Intracellular Ca
2+
signaling was quantified by Fluo-4 AM.

Results:
Differentiation of BMDMs with either IFNγ/LPS or IL-4 leads to the upregulation of M1 or M2 specific gene transcription. Subsequent real-time PCR analysis of purinergic receptors revealed a strong relationship between the expression pattern and the differentiation to M1 or M2 macrophages. Whereas M1 macrophages upregulate predominantly G
αi
coupled metabotropic P2Y receptors, M2 macrophages preferentially upregulate G
αq
coupled P2Y receptors. Comparison of the two ADP-dependent P2Y receptors (P2Y
1
and P2Y
13
) showed a M1 and M2 specific expression pattern with M1 macrophages solely expressing the G
αi
coupled P2Y
13
and M2 macrophages exclusively expressing the G
αq
coupled P2Y
1
receptor. In agreement with the specific expression pattern, ADP stimulation evokes a significant Ca
2+
flux in M2 macrophages but failed to induce it in M1 macrophages.

Conclusion:
Our experiments revealed for the first time that M1 and M2 macrophages express a unique purinergic receptor repertoire and sense the nucleotide based microenvironment differently. With this knowledge we could interfere with one macorphage subtype without disturbing the others.
Abstract 20954: Abnormal Liver Function Tests Are Association With Adverse Outcomes in Acute Decompensated Heart Failure in the CARRESS Trial
Authors: Solanki Jigna , Bilchick Kenneth , Wynter Javelle , Parker Alex , Mwansa Hunter , Kennedy Jamie , Abuannadi Mohammad , Bergin James , Mazimba Sula
Published: March 2022

Introduction:
Hepatic congestion with abnormal liver function tests (LFTs), including aspartate aminotransferase (AST), alanine aminotransferase (ALT) and total bilirubin (TBL) complicates acute decompensated heart failure (ADHF). The prognostic implication of abnormal LFTs in ADHF is less studied.

Hypothesis:
We hypothesized that abnormal LFTs would be associated with unfavorable outcomes in the Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS) trial.

Methods:
Cox proportional hazards analysis was performed to assess the association between LFTs (AST, ALT and TBL) at baseline in the CARRESS trial with adverse clinical outcomes, including death, death or HF rehospitalization, and death or any rehospitalization. Correlation analysis was used to assess the relationship between baseline LFTs and BNP, a surrogate of cardiac filling pressures.

Results:
Among 188 patients (67.9 ± 12.8 years, 25% female), 15.4% died, 35.5% died or had a HF rehospitalization, and 53.8% died or were rehospitalized for any reason. Elevated TBL at baseline was associated with an increased risk of death or rehospitalization for any reason (HR 1.65 per each mg/dL increase in total TBL, 95% CI 1.15-2.38, P=0.007), and a TBL in the upper quartile (> 1.2 mg/dL) was associated with an increased risk of death or HF hospitalization (HR 1.96, 95% CI 1.11-3.45, P=0.02) (Figure). Total bilirubin and BNP at baseline were moderately correlated (r=0.34, P=0.007). There were also no significant associations for AST or ALT with any of the clinical outcomes (P>0.20 for all).

Conclusion:
Total bilirubin was independently associated with adverse events in ADHF and was also correlated with BNP, a marker of increased cardiac filling pressures. More studies are needed to better define the implications of abnormal LFTs in other HF phenotypes.
Abstract 20955: Synergistic Effects of Rivaroxaban With Direct-Acting Anti-Platelet Agents on Platelet Reactivity and Thrombin Generation
Authors: Kotha Jayaprakash , Cardenas Juan M , Roe Matthew T , Ohman Erik M , Gibson Charles M , Jennings Lisa K
Published: March 2022

Introduction:
Direct-acting oral anticoagulants (DOACs) are increasingly evaluated for the secondary prevention of thrombosis-related events; however, DOAC dose-related effects on platelet function, particularly with anti-platelet agents, are unknown.

Hypothesis:
Factor Xa inhibitors do not have direct anti-platelet activity; however, by their capacity to inhibit thrombin generation (TG), they indirectly regulate thrombin-dependent platelet activation. This indirect mode of action may have additive effects with anti-platelet agents such as aspirin or P2Y12 antagonists.

Methods:
Platelet-rich plasma (PRP) from healthy individuals (n=6) was incubated with increasing amounts, and combinations of rivaroxaban (Riva), aspirin (ASA) and/or ticagrelor(T). The impact on platelet function was studied using light transmission aggregometry (LTA) and fluorogenic TG assays (TGA). For LTA, maximal aggregation (MA) was measured after initiation of tissue factor (TF)-induced TG. Similarly, for TG assays in platelet-poor plasma (PPP) and PRP low TF concentrations were used to initiate TG.

Results and Conclusions:
Riva treatment alone decreased % MA by TF-generated thrombin by 24% (15 ng/ml; akin to 2.5 mg bid dosing) and 71% (120 ng/ml; akin to 10 - 20 mg bid dosing). Riva, in combination with both anti-platelet agents, decreased MA substantially by 69% at 15 ng/ml and significantly by 89% at 120 ng/ml (p<0.05). However, when PRP is treated only with ASA or T (sans Riva), thrombin-mediated MA decreased by 12% and 25%, respectively. In TGA, Riva alone in PPP caused significant inhibition of TG (p <0.05). At 15 ng/ml, ~40% inhibition of peak TG was noted in PPP, though in PRP, inhibition was only 22% with donor variability observed. At 120 ng/ml Riva, peak TG inhibition was 90% and 64% for PPP or PRP, respectively. Though evident at higher Riva doses, the 15 ng/ml dose showed no synergy with ASA or T or the ASA/T combination in inhibiting TG in PRP. These results demonstrate that Riva provides an additive effect in reducing platelet reactivity, and its impact is highly dose-dependent and influenced by anti-platelet therapies. Such findings should be taken into consideration for anti-FXa dosing, either when anti-platelet therapies are or are not part of a treatment regimen.
Abstract 20970: Atrial Fibrillation and Intra-Arterial Treatment of Acute Ischemic Stroke: Is the Romance Deeper Than Embolism?
Authors: Saleem Muhammad A , Shaikh Suhail , Khan Safi U
Published: March 2022

Introduction:
Recent evidence remains inconclusive about the impact of atrial fibrillation (AF) on prognosis after intravenous thrombolysis and/or intra-arterial (IA) acute stroke treatment (AIS).

Hypothesis:
AF (either first episode or chronic) adversely affects stroke outcomes in patients undergoing IA treatment for AIS.

Methods:
We analyzed data from the 434 subjects in the IA treatment arm of Interventional Management of Stroke (IMS) III trial. The trial included AIS patients who were eligible for IV rtPA infusion within three hours after stroke onset. The subjects that were randomized to the IA treatment arm later received a protocol approved endovascular treatment. Demographics, vascular risk factors, and outcome measures were compared between patients with and without atrial fibrillation. The main outcomes considered were early neurological deterioration and hemorrhagic complications, excellent (mRS: scores of 0-2) functional outcome at 3 months, and good quality of life (EQ-5D index 0.5-1.0) at one year from randomization. Adjusted logistic regression analysis was performed to compare these outcomes.

Results:
Of the 434 patients who were studied (mean ± SD age, 66.3 ± 12.3 years, with 50.2% of patients being men), 153 had AF either chronic or diagnosed at baseline EKG and 281 had no AF. The patients with AF were significantly older (age 71.2±8.2 vs. 63.6±13.3 years), had more severe strokes (NIHSS>=20) at baseline assessment (40.5% vs. 24.9%). The subjects with AF had higher adjusted odds of early neurological deterioration (OR 1.3, 95%CI 0.6-1.9, p=0.81), symptomatic intracranial hemorrhage (OR 1.7; 95% CI 0.7-3.8; p=0.27), and subarachnoid hemorrhage (OR 1.4; 95% CI 0.7-2.7; p=0.31). The subjects with AF had lower odds of having good functional outcome 3 months after randomization (OR 0.8; 95% CI 0.4-1.1; p=0.06). The two groups did not differ in their adjusted odds of symptomatic ICH, parenchymal hematomas, 90 days mortality, and quality of life after one year.

Conclusions:
In the patients undergoing IA treatment for AIS, AF may adversely impact early recovery in neurological function and long-term functional outcomes but not the rates of hemorrhagic complications, mortality, or good quality of life.
Abstract 20985: CHA2DS2-VASc Score Predicts Risk of Incident Stroke in Patients Without Atrial Fibrillation/ Flutter in a Referral Population
Authors: Hussain Nasir , Gersh Bernard J , Kopecky Stephen L , Thomas Randal J , Allison Thomas G
Published: March 2022

Background:
CHA2DS2-VASc score has been shown to predict occurrences of incident stroke in patients with history of atrial fibrillation (A-Fib)/ Flutter. However, data on whether if CHA2DS2-VASc score would predict incidence of stroke in patients without A-Fib/ Flutter is less clear.

Methods:
From 1993 through 2010, all patients undergoing a clinically indicated treadmill exercise test (TMET) at the Mayo Clinic, Rochester, MN were identified (N= 76,857). From this, Olmsted and neighboring counties residents were selected (N=14,095). From this, patients with age <18 years; prior history of valvular heart disease or A-Fib/ Flutter were excluded. Patient undergoing only Bruce or accelerated Naughton protocols on TMET were considered. Patients were stratified into 4 groups at baseline based on CHA2DS2-VASc score as determined at the time of TMET; group-0 score=0; group-I=1; group-2=2; group-3≥3. Patients were prospectively followed from the date of TMET until end of January 2016 for occurrence of incident stroke (ischemic and hemorrhagic). Stroke diagnosis was ascertained through retrospective chart review. Traumatic intracranial bleed was not considered. Proportional hazard regression modeling was done to assess relationship of CHA2DS2-VASc score with the stroke outcome while adjusting for METs achieved, sex, obesity, smoking status, and other relevant risk factors.

Results:
Final study population comprised of 12,624 patients with female comprising 37% of the cohort. Mean age in our study group was 52.2 ± 12.8 years. During an overall median follow-up of 14 (8 to 17) years, 1,255 (9.9%) patients developed incident stroke. While using CHA2DS2-VASc group-3 as referent, patients in CHA2DS2-VASc group-0 [0.18(0.14-0.23, p<.001)], group-1[0.33 (0.28-0.39, p<.001)], and group-2 [0.50 (0.43-0.58, p<.001)] were at significantly lower risk of developing stroke. Each increase of one point on the CHA2DS2-VASc scale was associated with a 51% [1.51(1.45-1.58, p<.001)] increase in incidence of stroke.

Conclusion:
CHA2DS2-VASc score predicts incidence of stroke in patients without history of A-Fib/ Flutter.
Abstract 20987: Pulmonary Blood Volume Evaluated by Dual-Energy CT is a New Maker for the Management of Chronic Thromboembolic Pulmonary Hypertension
Authors: Onishi Hiroyuki , Nakayama Kazuhiko , Yanaka Ken-ichi , Tamada Naoki , Shinkura Yuto , Tuboi Yasunori , Shimoyama Shinsuke , Nishii Tatsuya , Kono Atushi , Negi Noriyuki , Mori Shumpei , Otake Hiromasa , Satomi-Kobayashi Seimi , Shinke Toshiro , Emoto Noriaki , Hirata Ken-ichi
Published: March 2022

Background:
Chronic thromboembolic pulmonary hypertension (CTEPH) is pulmonary obstructive vascular disease. But there were few methods to quantify lung blood perfusion. In dual-energy CT (DECT), two image datasets are acquired in the same anatomic location using two different tube potentials. DECT can produce a more sensitive iodine distribution map image than conventional CT, which enable us to quantify blood perfusion in lung fields. There were few reports showing the clinical significance of DECT in CTEPH.

Methods:
We enrolled 59 consecutive CTEPH patients who underwent DECT from Jan. 2015 to Feb. 2017. We evaluated the relations between DECT parameter as lung pulmonary blood volume (PBV) and clinical parameters from 6-min walk distance (6MWD), respiratory function test, cardiopulmonary exercise test (CPX), and right heart catheterization (RHC).

Results:
In 59 patients (female 41, mean age 60.0±13.6 years old), two patients were WHO functional class (WHO-Fc) IV, 28 were WHO-Fc III, 23 were WHO-Fc II, six were WHO-Fc I. 28 patients were evaluated at pre-treatment, nine at post pulmonary endarterectomy (PEA), 18 at post balloon pulmonary angioplasty (BPA), and four at post hybrid therapy (PEA and BPA). The average of PBV were 25.4±7.4 Hounsfield Unit. Mean pulmonary arterial pressure (mPAP) were 29.5±12.9 mmHg, pulmonary vascular resistance (PVR) were 553±404 dyne*sec/cm5, cardiac index were 2.3±0.7 l/min/m2. The value of PBV was well reflected with WHO-Fc classification. (I/II/III/IV=31.8±6.4/27.1±7.4/22.8±6.2/23.5±13.4; ANOVA p=0.019), and was significantly correlated with mPAP (r = -0.57, p < 0.01), PVR (r = -0.60, p < 0.01), VE/VCO2 slope (r =- 0.47, p < 0.01), BNP level (r = -0.60, p < 0.01).

Conclusion:
PBV was positively correlated with symptom, hemodynamics, exercise capacity, and BNP level in the patients of CTEPH, suggesting that PBV by DCET can work as a new management index from a perspective of pulmonary blood perfusion.
Abstract 21004: Relation Between Optimal Medical Therapy Trends on Outcomes in Patients With Peripheral Arterial Disease and Coronary Artery Disease Undergoing Cardiac Catheterization
Authors: Cohoon Kevin P , Herrmann Joerg , Lennon Ryan J , Gulati Rajiv , Wennberg Paul W
Published: March 2022

Introduction:
Peripheral arterial disease (PAD) is a strong predictor of systemic atherosclerosis with substantial morbidity and mortality. Medical management in PAD and coronary artery disease (CAD) has changed in recent eras with the use of high intensity statin and dual antiplatelet therapies.

Hypothesis:
Test whether mortality and major adverse cardiovascular events (MACE) (death and MI) has decreased over eras among PAD patients undergoning revascularization with percutaneous coronary intervention (PCI).

Methods:
Longitudinal cohort study of 549 patients who underwent PCI and non-invasive lower arterial study between 1997 and 2008 as identified in the Mayo Clinic PCI registry were stratified into 2 time eras: 1997-2003 (era1), and 2004-2008 (era2). PAD was assessed using the highest resting ABI and stratified according to established categories; < 0.90 (definite PAD); 1.00-1.39 (normal); and ≥ 1.40 defined a non-compressible artery. Kaplan-Meier methods were used to analyze follow-up survival.

Results:
Stratified by ABI over both time eras, 225 patients had PAD, 94 were non-compressible, and 142 were normal. Overall mortality rates were higher in era2 non-compressible and PAD patients than in non-PAD patients when compared to era1 (58%, 33%, 26%, vs 49% 32%, 19%, p<0.001 for all within-era comparisons) (Figure 1). MACE-free survival were higher in era2 non-compressible and PAD patients than in non-PAD patients when compared to the era1 (64%, 41%, 29% vs 59% 39%, 25%, p≤0.005 for all within-era comparisons). There were significant differences in medical therapy between era2 vs. era1 with higher discharge use of aspirin (98%; 94%), beta-blockers (88%; 66%), any lipid lowering drugs (86%; 76%), ACE inhibitors (67%; 56%), and diuretics (52%; 40%).

Conclusions:
Over the past two eras, the overall mortality has increased among patients with PAD and non-compressible vessels in era2 vs. era1 despite higher utilization of statin and antiplatelet therapies.
Abstract 21011: Crispr/ndcas9 Adenoviral Vector System as a Tool for Promoting Mitochondrial Biogenesis in Cardiomyocytes
Authors: Ashok Deepthi , Sidor Agnieszka , O'Rourke Brian
Published: March 2022

Mitochondrial dysfunction contributes to heart failure. Our recent work revealed that genes in mitochondrial biogenesis and quality control, such as the peroxisome proliferator activated receptor gamma coactivator-1α(PGC-1α) and mitochondrial transcription factor A(TFAM), are downregulated in a rodent model of heart failure. Here, we apply CRISPR/Cas9 technology as a transcriptional activator to target sequences upstream of the start site to promote transcription of PGC-1α or TFAM. Since cardiomyocytes are difficult to transduce, we developed an adenoviral gene delivery system for expression of the CRISPR/Cas9 activating complex and a targeting gRNA to modulate expression of any gene of interest in differentiated cardiomyocytes, with our initial focus on activating the metabolic gene program. We use nuclease-dead Cas9 (ndCas9) fused to an activation domain VP64 and guide RNAs for activation of target genes. Proof-of-principle evidence was obtained by activating a cyclic AMP response element (CRE)-driven luciferase reporter gene and activation of endogenous CRE-regulable genes (PCK1 and PGC-1α). Next, we constructed ndCas9-gRNA adenoviral vectors to target PGC-1α and TFAM in the rat genome to determine if transcription of these genes can be increased. Functional effects of viral gene transduction in H9C2 cells and neonatal rat ventricular myocytes are assessed by determining mitochondrial DNA copy number (mtDNA)/genomic DNA ratio, and mtDNA quantity by picogreen labeling.

Results:
We have successfully upregulated the luciferase gene and endogenous CRE-regulated gene PCK1 in the same reporter cell line with ndCas9-VP64, as evidenced by significant increases in mRNA and protein expression levels. We have constructed and delivered adenoviral vectors with ndCas9 that are efficiently expressed by the host cells (NRVMs and H9c2 cells) and showed increased expression of PGC1a and TFAM in H9c2 cells. Importantly, an increase in mtDNA copy number was evoked by TFAM activation. For the first time, we show that the CRISPR/ndCas9 system can be used as a powerful tool for modulating transcription of native genes involved in mitochondrial biogenesis in cardiac cells, opening the door to developing novel therapeutic approaches for heart failure
Abstract 21013: Impaired Postischemic Neovascularization in Sickle Cell Disease
Authors: Okwan-Duodu Derick , Hansen Laura , Lyle Alicia , Joseph Gigi , Archer David , Taylor W Robert
Published: March 2022

Objectives:
The adaptive response to vascular injury is the formation of collateral vessels to maintain organ function. Many of the clinical complications associated with sickle cell disease (SCD), such as strokes, retinopathy, sudden cardiac death and recalcitrant leg ulcers, can be attributed to repeated bouts of vascular insufficiency, yet the detailed mechanisms of collateral vessel formation following injury are largely unknown in SCD. Here, we characterize post-ischemic neovascularization in SCD, with a focus on the cellular source and contribution of H
2
O
2
, given our previous work showing the critical importance of this reactive oxygen species (ROS) in collateral vessel formation.

Methods and Results:
To evaluate post-ischemic neovascularization, we performed hind limb ischemia (HLI) by ligation of the femoral artery in the humanized Townes sickle cell (SS) mice, and compared them to their wildtype (AA) mice. Our results showed significant diminution in functional collateral vessel formation in SS mice following HLI as evaluated by LASER Doppler perfusion imaging (76 ±13 % recovery in AA vs 34±10 % recovery in SS by day 28, p < 0.001 n=8 per group). The rate of amputation after HLI was significantly increased in the SS compared to AA mice (25% vs 5%), as was the rate of foot necrosis (80% vs 15%, P <0.001, 8 mice per group). Spontaneous motor function recovery evaluation by the running wheel assay was also significantly impaired in SS mice (36% vs 97% at 28 days post HLI, p < 0.001, n=6 mice per group). The phenotype was associated with persistent neutrophils in the hind limb muscle for up to 28 days in the SS, a time point by which all neutrophils were cleared in AA mice. Consequently, there was a 2.45 fold increased production of H
2
O
2
in SS mice at day 28, compared to AA mice (p< 0.05). Importantly, both
in vivo
depletion of neutrophils and treatment with the anti-oxidant N-acetylcysteine (NAC) significantly reduced oxidative stress and improved functional collateral formation in the SS mice.

Conclusions:
Our data suggest dysfunctional collateral vessel formation in SS mice after vascular injury, and provide mechanistic basis for the multiple vascular complications of SCD. Targeting neutrophils and excessive ROS may improve vascular dysfunction in SCD.
Abstract 21014: Respiratory-Gated Auricular Vagal Nerve Stimulation Lowers Blood Pressure in Hypertensive Patients
Authors: Garcia Ronald G , Sclocco Roberta , Gabriel Aileen , Napadow Vitaly , Barbieri Riccardo
Published: March 2022

Introduction:
Despite the benefits of existing blood pressure lowering drugs, approximately 50% of hypertensive patients are inadequately controlled while taking medications. Autonomic nervous system dysfunction is associated with the development and progression of hypertension, and neurostimulation devices that target sympathetic or vagal modulation have been suggested as potential novel treatments for this disorder.

Hypothesis:
In this study, we assessed the hypothesis that respiratory gated transcutaneous vagus nerve stimulation (RAVANS tVNS) reduces blood pressure in hypertensive patients.

Methods:
Twelve hypertensive subjects (53.2 ± 5.8 years, 7 males) with persistent high blood pressure levels despite current antihypertensive treatment were enrolled in the study. Participants underwent two experimental sessions on non-consecutive days. In each session subjects were evaluated during an initial rest period followed by RAVANS or sham tVNS stimulation. Electrodes were placed over vagal innervated regions in the ear (cymba concha). RAVANS tVNS was delivered for 15 minutes at 25 Hz (pulse width: 15 ms), and gated in real time to exhalation. Sham stimulation was delivered with the current generator shut off, without the subjects’ knowledge. Measurement of blood pressure levels by continuous beat-to-beat recordings were performed with a Finometer device (Finapress Medical System, the Netherlands). Mean arterial pressure (MAP) levels were computed over the rest and stimulation periods and were compared between groups.

Results:
No significant baseline differences in MAP levels were found between groups (104.9 ± 7.6 mmHg vs 103.6 ± 6.1 mmHg, p=0.6). Administration of exhalatory-gated RAVANS tVNS resulted in a significant reduction of MAP values compared to Sham tVNS (-4.1 ± 7.0 mmHG vs 2.6 ± 5.6 mmHg, p=0.02), whereas no significant effects in heart rate or respiratory frequency were observed.

Conclusions:
Our findings reveal that exhalatory-gated RAVANS tVNS has a significant effect in the acute reduction of blood pressure levels in hypertensive patients. These promising results support a potential role of this intervention in the treatment of hypertension, however further longitudinal studies will be required to test this hypothesis.
Abstract 21017: A Systematic Review and Meta-Analysis on Success and Complications of Epicardial Access
Authors: Turagam Mohit K , Koerber Scott , Vuddanda Venkat , Balla Sudarshan , Atkins Donita , Di Biase Luigi , Natale Andrea , Lakkireddy Dhanunjaya
Published: March 2022

Background:
Epicardial access (EA) is increasingly used in various electrophysiological procedures with wide variation in EA success and complications.

Methods:
A comprehensive search was performed in PubMed, EBSCO and Google Scholar databases for studies reporting success and complications with EA. Meta-analysis was done using MedCalc software with random effects-model. Procedural success was defined as successful pericardial access. Pericardial tamponade was defined as pericardial effusion requiring drainage. Success and complications were adjusted and calculated per 100 procedures.

Results:
A total of 6 studies [retrospective - 5, prospective - 1] including 1,122 patients [large bore (LB) - 878, micropuncture (MP) - 219 and EpiAcces- 25 patients] undergoing EA for ventricular tachycardia ablation and Lariat procedure.
Table 1,2
demonstrates rates of procedural success and complications of EA. Acute procedural success was 94.9% [95% CI (93.1 - 96.1)]. Pericardial tamponade, pericardial effusion, emergency heart surgery and RV puncture were seen in 1.7%, 2.8%, 0.7% and 6.5% respectively.

Conclusion:
EA is feasible with a 95% procedural success and acceptable rate of major complications. Use of MP needle and advancement in other EA technology will further improve procedure safety.
Abstract 21026: Macrophages Preferentially Endocytose Systemically-Delivered Exosomes at Steady State or During Acute Inflammation
Authors: de Couto Geoffrey , Jaghatspanyan Ervin , Makkar Nupur , Marbán Eduardo
Published: March 2022

Introduction:
Cardiosphere-derived cells (CDCs), which are in advanced clinical testing for heart failure, Duchenne muscular dystrophy and pulmonary hypertension, secrete exosomes (CDC
exo
) which are highly anti-inflammatory. CDC
exo
, but not fibroblast (FB) exosomes, lead to cardioprotection through polarization of macrophages (Mφ) following ischemia/reperfusion injury (de Couto et al.,
Circulation,
2017). Here we demonstrate that intravenous delivery of CDC
exo
in mice (healthy or acutely inflamed) leads to preferential uptake by resident Mφ via phagocytosis.

Methods & Results:
To assess biodistribution, we labeled CDC
exo
with the fluorescent liposomal dye DiD (Invitrogen). Healthy mice (C57Bl6; 8-12 weeks) were treated with an intraperitoneal injection of either LPS (5mg/kg) or saline prior to intravenous infusion of DiD-labeled CDC
exo
(in 100μL saline). Four hours later, organs were collected for
ex vivo
analysis. Biofluorescence imaging (Xenogen) revealed strong DiD signal in Mφ-rich organs including the liver, spleen, and lung, while immunohistochemistry and flow cytometry resolved preferential uptake of CDC
exo
by tissue Mφ within the liver (60-80% DiD
+
CD11b
+
), spleen (70-80% DiD
+
F4/80
+
), lung (60-90% DiD
+
F4/80
+
), and peritoneal cavity (40-60% DiD
+
CD11b
+
). The heart also exhibited measurable fluorescence signals. To determine how avidly distinct cardiovascular cell types preferentially take up CDC
exo
in vitro
, Mφ, FB, endothelial cells (EC), and cardiomyocytes (CM) were exposed to DiD-labeled CDC
exo
and examined over time. Within one hour, Mφ demonstrated the greatest uptake of CDC
exo
(Mφ: 81%; FB: 60%; EC: 65%; CM: 51%; p<0.05). The addition of both phagocytosis (Cytochalasin D) and clathrin (Pitstop 2) inhibitors completely blocked CDC
exo
uptake by Mφ.

Conclusions:
Intravenous delivery of CDC
exo
in mice (healthy or acutely inflamed) leads to preferential uptake by Mφ within organs that are rich in such cells (i.e., liver, spleen, lung, and peritoneal cavity).
In vitro
, Mφ take up CDC
exo
via phagocytosis and endocytosis more readily than other cardiac cell types. These data suggest the potential utility of CDC
exo
treatment in cardiovascular diseases where Mφ infiltration is prominent (e.g., atherosclerosis).