bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 18952: A Novel Engineered Neuregulin-hydrogel System Regenerates Mammalian Heart Muscle and Enhances Ventricular Function in a Preclinical Ovine Model of Ischemic Cardiomyopathy
Authors: Cohen Jeffrey E , Goldstone Andrew B , Purcell Brendan P , Shudo Yasuhiro , MacArthur, Jr. John W , Edwards Bryan B , Patel Jay B , Hopkins Michael S , Eskandari Anahita , Steele Amanda N , Cheung Nicholas C , Aribeana Chiaka N , Burdick Jason A , Woo Y. Joseph
Published: March 2022

Objective:
The clinical efficacy of neuregulin (NRG), a ligand of the Her family receptors, is hindered by off-target exposure and requisite daily systemic infusions. We recently encapsulated NRG in a hydrogel (HG) for targeted and sustained myocardial delivery; beneficial results in a murine model of ischemic cardiomyopathy were clear. Here, we evaluate NRG-HG’s translational potential for myocardial regeneration and functional improvement in the clinical realm using a preclinical ovine model of ischemic cardiomyopathy.

Methods:
Male Dorset sheep (n=30) underwent baseline cardiac assessment with MRI and pressure-volume (PV) catheterization. Myocardial infarction (MI) was induced by ligating the 2
nd
and 3
rd
diagonal artery branches, and sheep were randomized to receive myocardial borderzone injection of 1mL saline, HG alone, NRG alone, or NRG-HG. Eight weeks post-infarction, repeat hemodynamic assessment was performed followed by tissue acquisition. A subset underwent sacrifice at 1 week for molecular analyses.

Results:
Analysis of myocardial borderzone 1-week post-infarction revealed NRG-HG augmented phosphorylated ErbB4, ErbB2, ERK, and histone h3 compared with all other groups. This marker activation suggests receptor activation, downstream signaling, and cardiac cell-cycle entry. At 8 weeks, NRG-HG significantly reduced scar size and augmented ventricular function (Table). There was no evidence of off-target NRG at 1 and 8 weeks, and no evidence of gel embolization or neurologic insult (by brain MRI) from intramyocardial hydrogel delivery.

Conclusion:
Targeted and sustained intramyocardial delivery of NRG with an engineered hydrogel platform triggers regeneration of mammalian heart muscle and augments ventricular function in a large animal model of ischemic cardiomyopathy. This novel, engineered delivery system realizes the true potential of NRG and its translation to clinical regenerative therapeutics.
Abstract 18955: Detection of Chest Compressions Using Transthoracic Impedance
Authors: Ramachandran A. R , Coult Jason , Kudenchuk Peter , Blackwood Jennifer , Sherman Lawrence , Rea Thomas
Published: March 2022

Objective:
Real-time detection of chest compressions during resuscitation can provide essential feedback to rescuers about CPR quality. Accelerometer technology can accurately detect compressions, but requires added equipment and expense. Conversely, the transthoracic chest impedance signal is recorded by nearly all defibrillators, and offers a more available means to characterize chest compressions. This work aims to develop and test an algorithm to accurately detect chest compressions using frequency characteristics of the impedance signal.

Methods:
To train the chest compression detection algorithm, 6-second impedance clips were taken from a convenience sample of 82 out-of-hospital cardiac arrest patients. Data from a separate group of 173 patients were used as a validation set to determine performance, using concurrently collected accelerometer data as the reference for true chest compressions. Clips were collected randomly during either compressions or pauses. Clips with transitions between compressions and pauses were excluded. The detection algorithm used bandpass filtering to eliminate ventilations and artifact outside normal chest compression frequencies. Spectral peak analysis between 1-4 Hz was employed to eliminate harmonics of the fundamental chest compression frequency and detect true compressions.

Results:
Of 1258 6-second clips from the 173 patients in the validation dataset (846 with chest compressions and 412 without), the sensitivity and specificity of the impedance-based compression detection algorithm were 98.7% [97.7, 99.4] and 96.4% [94.1, 98.0], respectively.

Conclusion:
An impedance-based algorithm can detect chest compressions with high accuracy using frequency analysis, and provides a potentially valuable tool for assessing resuscitation quality.
Abstract 18972: Safety and Efficacy of Vorapaxar in Secondary Prevention of Atherosclerotic Disease: A Meta-analysis of Randomized Control Trials
Authors: Garg Aakash , Sharma Abhishek , Chatterjee Saurav , Bagae Solomon , Stefanini Giulio G
Published: March 2022

Background:
A substantial risk of residual cardiovascular events remains despite the current standard antiplatelet therapy in patients with atherosclerotic disease. Protease activating receptor (PAR-1) antagonist Vorapaxar is a novel antiplatelet agent acting by inhibition of thrombin-induced platelet aggregation. Recently, FDA has approved vorapaxar for long term secondary prevention of vascular events in stable patients with a prior MI or PAD, and without history of stroke or transient ischemic attack. However, these recommendations are largely based on a single phase 3 randomized control trial (TRA 2P TIMI-50).

Objective:
To study the cumulative evidence for vorapaxar use in patients with atherosclerotic cardiovascular disease.

Methods:
A systematic review of randomized control trials in MEDLINE, EMBASE, EBSCO, CINAHL, Web of Science and Cochrane databases comparing vorapaxar with placebo was performed. Pre-specified efficacy endpoints were all-cause mortality, CV mortality, myocardial infarction, stroke and repeat revascularization. The pre-specified safety endpoint was the composite of TIMI major and minor bleeding. Risk ratios were used as the metric of choice by applying random effects models..

Results:
A total of 5 RCTs with 40,630 patients were included. Compared with placebo, vorapaxar led to a significant risk reduction in terms of myocardial infarction [RR 0.93; 95% CI 0.80-0.92] and stroke [RR 0.84; 95% CI 0.72-0.97]. No differences were observed between vorapaxar and placebo with respect to all-cause mortality [RR 0.99; 95% CI 0.90-1.07], cardiovascular mortality [RR 0.93; 95% CI 0.84-1.02], and repeat revascularization [RR 0.96; 95% CI 0.85-1.08]. Vorapaxar was associated with a higher risk of TIMI major and minor bleeding [RR 1.30; 95% CI 1.02-1.65] compared with placebo. There was insignificant (I-squared) heterogeneity between studies.

Conclusion:
Vorapaxar reduces the risk of ischemic events in patients with atherosclerotic disease at the cost of an increased bleeding risk.
Abstract 18986: Unopposed TNF/TNFR1 Signaling Prevents Therapeutic Benefit From Cardiac Stem Cell Therapy After Reperfused Myocardial Infarction in Mice
Authors: Hamid Tariq , Xu Yuanyuan , Ismahil Mohammad A , Goel Mehak , Patel Bindiya , Michaud Amy M , Li Qianghong , Bhatnagar Aruni , Bolli Roberto , Prabhu Sumanth D
Published: March 2022

Despite expansion of resident cardiac stem cells (CSCs) after myocardial infarction (MI), the heart is unable to regenerate, suggesting that local factors inhibit CSC function. Tumor necrosis factor-α (TNF), increased in infarcted and failing hearts, is one candidate inhibitory factor; its effects are specific to its two receptors (TNFRs). We hypothesized that TNF/TNFR signaling in CSCs modulates the efficacy of CSC therapy after reperfused MI in mice. Magnetically sorted, c-kit enriched, Lin– CSCs were isolated from wild-type (WT), TNFR1-/-, and TNFR2-/- mice, expanded, and 1 x 105 CSCs were administered via intramyocardial injection in the border zone 48 h after 60 min ischemia in WT C57BL/6 mice (n = 13-18/group). Five weeks after CSC therapy, as compared with PBS-injected MI mice, WT CSC transplantation significantly (p<0.05) improved LV systolic function (ESV 50 ± 14 vs 63 ± 23 μL; EF 31 ± 11 vs 24 ± 9%). Analogous to WT CSCs, TNFR1-/- CSCs also significantly improved LV systolic function (ESV 44 ± 5 uL; EF 35 ± 3%). In contrast, TNFR2-/- CSC transplanted MI hearts exhibited greater LV systolic dysfunction (ESV 62 ± 5 uL; EF 29 ± 4%) as compared with both WT and TNFR1-/- CSC injected hearts, and were comparable to PBS-injected MI hearts. There was signficantly reduced border zone (BZ) fibrosis in both WT (7.6 ± 3.2%) and TNFR1-/- CSC (7.2 ± 1.9%) injected hearts as compared with either PBS-injected MI hearts (11.6 ± 2.8%), or TNFR2-/- CSC injected MI hearts (15.7 ± 4.0%). Analogous to fibrotic change, cardiomyocyte hypertrophy in post-MI hearts was significantly decreased after cell transplantation with either WT CSCs (322 ± 56 μm2) or TNFR1-/- CSCs (244 ± 29 μm2), as compared with PBS-injected MI hearts (423 ± 56 μm2), with more robust improvements in hypertrophy in the TNFR1-/- CSC MI hearts. In contrast, cardiomyocyte size after TNFR2-/- CSC transplantation (389 ± 58 μm2) was comparable to PBS injected hearts, and significantly greater than either WT or TNFR1-/- CSC injected MI hearts. We conclude that myocardial TNF diminishes the efficacy of CSC therapy via TNFR1 signaling, especially when unopposed by concomitant TNFR2 signaling. Selective TNFR1 blockade, or TNFR2 agonism, at the time of cell transplantation may improve the functional outcomes of CSC therapy after MI.
Abstract 18993: Statins Reduce Thoracic Aortic Aneurysm Growth in Marfan Syndrome Mice via Inhibition of the RAS Induced ERK Signaling Pathway
Authors: Arakawa Mamoru , Koyano Tiffany K , Sato Tetsuya , Youn Young-Nam , Penov Kiril , Pedroza Albert J , Connoly Andrew J , Adachi Hideo , Fischbein Michael
Published: March 2022

Rationale:
Aortic root aneurysm formation and subsequent dissection remain the major cause of death in patients with Marfan syndrome (MFS). HMG-CoA reductase inhibitors (statins) have been reported to reduce aneurysm growth in MFS mouse models, although the mechanism is unknown. In addition to reducing cholesterol, statins block both farneslyation and geranylgeranylation, which participate in membrane bound G-protein signaling, including Ras. The Ras signaling pathway (via ERK) has been shown to be important in MFS aneurysm formation.

Objective:
Systematically dissect the prenylation pathway to better define the mechanism behind the beneficial effect of statins on aneurysm reduction in MFS and anticipate this will help elucidate the pathophysiology of aneurysm formation.

Method and results:
Fbn1
C1039G/+
mice (4 week old) were treated subcutaneously with either (a) Pravastatin (PS) (HMG-Co Reductase inhibitor) (100 mg/kg per day); (b) Manumycin A (MA) (FPT inhibitor) (2.5 mg/kg/every other day); (c) Perillyl Alcohol (PA) (GGPT-1 and -2 inhibitor) (5.0 mg/kg/every other day); or (d) vehicle control Fbn1
C1039G/+
mice from age 4-8 weeks. PS and MA significantly reduced aneurysm growth compared to vehicle control (PS:1.57 ± 0.03 mm; MA: 1.55 ± 0.06 mm; vehicle: 1.77 ± 0.05 mm, respectively: p < 0.05). There was no significant difference between PS and MA treated groups. In contrast, PA did not significantly decrease aneurysm size (PA: 1.81 ± 0.06 mm). Elastin staining illustrated reduced elastin breakdown in MA treated mice compared to vehicle control treated groups (MA: 2.2 ± 0.3, vehicle: 4.2 ± 0.6, respectively: p < 0.05). After identifying that the Ras pathway is important, we measured the relative expression of pRaf-1 and pErk1/2, downstream enzymes in transforming growth factor- β (TGF-β) signaling pathway with Western blot. Although elevated in control Marfan mice, both pRaf-1 and pErk 1/2 were significantly reduced in MA treated mice, corresponding with a reduction in aneurysm growth (pRaf-1: MA: 5.1 ± 1.3, vehicle: 8.8 ± 0.8, p = 0.08, pErk1/2: MA: 2.3 ± 0.1, vehicle: 3.2 ± 0.1, p < 0.05, respectively).

Conclusion:
Statins reduce aortic aneurysm growth in Fbn1
C1039G/+
Marfan mice by decreasing both Ras activation and downstream ERK signaling.
Abstract 19003: Extracellular ATP Induces Vascular Inflammation and Atherosclerosis via P2Y2 in Mice
Authors: Stachon Peter , Geis Serjosha , Heidenreich Adrian , Hoppe Natalie , Dufner Bianca , Idzko Marco , Zirlik Andreas
Published: March 2022

Introduction:
A solid body of evidence supports a role of extracellular ATP and ist P2-receptors in innate and adaptive immunity. It promotes inflammation as a danger signal in various chronic inflammatory diseases. Hypothesis: We hypothesize contribution of extracellular ATP and its receptor P2Y2 in vascular inflammation and atherosclerosis.Methods: Leukocyte rolling and adhesion after stimulation with ATP was determined with intravitalmicroscopy in P2Y2-competent and P2Y2-deficient mice. Migration was analyzed with peritonitis model. To test the role of extracellular ATP in atherosclerosis, ATP or saline as control was injected intraperitoneally three times a week in LDLR-/- mice consuming high cholesterol diet (HCD). Furthermore, P2Y2-competent or P2Y2-deficient mice consumed a HCD for 16 weeks. Atherosclerosis was determined with immunhistochemistry and lesional expression of inflammatory molecules was measured with realtime PCR.

Results:
Extracellular ATP induced leukocyte rolling, adhesion, and migration as assessed by intravital microscopy and in sterile peritonitis. Atherosclerosis significantly increased after 16 weeks in ATP-treated mice (n=13; control group 0.26mm2; ATP group 0.33mm2, p=0.01). To gain into the role of ATP-receptor P2Y2 in ATP induced leukocyte recruitment, ATP was administered systemically in P2Y2-deficient or -competent mice. In P2Y2-deficient mice the ATP induced leukocyte adhesion was significantly reduced. P2Y2 expression in atherosclerosis was measured by real-time PCR and immunohistochemistry and demonstrates an increased expression s mainly due to influx of P2Y2-expressing macrophages. To investigate the functional role of P2Y2 in atherogenesis, P2Y2-deficient LDLR-/- mice consumed HCD. After 16 weeks P2Y2-deficient mice showed significantly reduced atherosclerotic lesions with decreased macrophages compared to P2Y2-competent mice (n=11; aortic arch: control group 0.25mm2; P2Y2-deficient 0.14mm2, p=0.04). Mechanistically,atherosclerotic lesions from P2Y2-deficient mice expressed less lesional VCAM-1 and ICAM-1 RNA .

Conclusion:
We show for the first time that extracellular ATP induces vascular inflammation and atherosclerosis via activation of P2Y2.
Abstract 19086: Pulsatile Shear Stress-mediated Fatty Acid Metabolites Promote Anti-oxidant Effects
Authors: Jen Nelson , Tang Jonathan , Gau Jonathan , Ajijola Olujimi A , Li Rongsong , Hsiai Tzung K
Published: March 2022

Temporal and spatial variations in shear stress are intimately linked with vascular metabolic effects. While oscillatory shear stress (OSS) preferentially develops at the lateral wall of arterial bifurcations and induces oxidative stress and inflammatory states, pulsatile shear stress (PSS) develops in the straight portions of the vasculature to oppose the effects and promote “athero-protection”. In this context, we hypothesize that PSS activates PPAR-γ to produce athero-protective fatty acid metabolites to attenuate oxidative stress. Metabolomic analysis performed for 155 metabolites from human aortic endothelial cells exposed to PSS (τ
avg
= 23±8 dyne/cm
2
at 1 Hz for 4 hrs) revealed a significant increase in anti-inflammatory metabolites, including fatty acids such as oleic acid (OA) and dicarboxylic acids such as azelaic acid (AzA) (1.43±0.73-fold, 2.03±0.54-fold vs. control, respectively,
p
< 0.05, n=6), and up-regulated metabolism-related genes including SCD1 and PPAR-γ (1.42±0.14-fold, 1.53±0.32-fold vs. control, respectively,
p
< 0.001, n=6). SCD1 produces oleic acid, and SCD1 mRNA expression was down-regulated by siPPAR-γ (0.66±0.17-fold, vs. PSS,
p
< 0.05, n=4). AzA, a known PPAR-γ agonist and a breakdown product of oleic acid, down-regulated VCAM and ICAM (0.31±.09-fold, 0.18±.01-fold vs. control, respectively,
p
<0.05, n=4) when treated with AzA alone. AzA attenuated H
2
O
2
-induced VCAM and ICAM mRNA expression (0.36±0.10-fold, 0.38±0.20-fold, respectively,
p
<0.05, n=4). The role PSS on PPAR- γ activation was further recapitulated in a model for paroxysmal atrial fibrillation (Afib) in New Zealand White rabbits. The right atrium was paced at 800 bpm (cycle length (CL) = 75 ms) to produce an irregular ventricular response of a mean rate of 200 bpm (CL = 300 ms) to simulate atrial fibrillation for 4 hours. p-PPAR- γ staining in the athero-prone aortic arches vs. athero-protective descending aortas was decreased in response to a reduction in time-averaged shear stress (from τ
avg
= 32.0±2.4 dyne/cm
2
to τ
avg
= 22.7±3.5 dyne/cm
2
). Overall, pulsatile shear stress-induced fatty acid metabolites impart anti-oxidant effects to maintain endothelial homeostasis, implicating the role of PPAR-γ-SCD1-OA-AzA pathway.
Abstract 19103: Tolvaptan Increases Urine Output Without Hemodynamic Impairment in Heart Failure Patients With Renal Dysfunction
Authors: Ikeda Yuki , Inomata Takayuki , Shinagawa Hisahito , Kida Keisuke , Shibagaki Yugo , Sato Naoki , Izumi Tohru , Ako Junya
Published: March 2022

Introduction:
There has been scant clinical evidence on whether the aquaretic effect of tolvaptan (TLV) contributes to decongestion without further renal impairment compared with furosemide (FUR).

Methods:
The Kanagawa Aquaresis Investigators Trial of TLV on Heart Failure Patients with Renal Impairment (K-STAR) is a multicenter, open-labeled, randomized, controlled prospective clinical study of 81 patients with heart failure (HF) in Japan. Patients with residual signs of congestion despite treatment with oral FUR at a dose of ≥40 mg/day with baseline estimated glomerular filtration rates of <45 mL/min were randomly assigned to two groups for 7-day treatments with either ≤15 mg/day of additive TLV or ≤40 mg/day of FUR.

Results:
During the treatment period, a more significant increase from baseline in urine volume (%ΔUV) was seen in the TLV group than in the FUR group (+42 ± 43% in the TLV group vs. +15 ± 39% in the FUR group, p < 0.01). Renal function was better preserved in the TLV group than in the FUR group [increase in serum creatinine (%ΔCr): +3 ± 13% in the TLV group vs. +10 ± 14% in the FUR group, p = 0.015]. Increases in the ratio of blood urea nitrogen to %ΔCr and %ΔUV were positively correlated in the FUR group (r = 0.33, p = 0.03) but were not significantly correlated in the TLV group (r = -0.15, p = 0.34). Moreover, an increase in pulse rate (%ΔPR: r = 0.31, p = 0.04) and decrease in stroke volume (%ΔSV: r = –0.35, p = 0.04) were positively correlated to the %ΔUV in the FUR group but not in the TLV group (%ΔPR: r = 0.10, p = 0.51; %ΔSV: r = –0.08, p = 0.65; respectively).

Conclusions:
TLV increases UV with less hemodynamic and renal impairment by maintaining adequate intravascular volume compared with FUR in HF patients with renal dysfunction.
Abstract 19138: Thirty-day Readmission Following Transcatheter Aortic Valve Replacement is Common, Most Often Associated With Heart Failure and Infection, and Consumes Substantial Resources
Authors: Lerner Daniel J
Published: March 2022

Introduction:
Readmission within 30 days of hospitalization (30dRA) is increasingly used as a metric for quality of care. Transcatheter aortic valve replacement (TAVR) is also increasing, but 30dRA following TAVR is not well-understood.

Hypothesis:
The purpose of this study is to define the incidence, etiology, and resource utilization of 30dRA following TAVR.

Methods:
We used the ICD-9-CM code for TAVR (35.05) to identify patients who underwent TAVR and survived to discharge in 2012, in the Agency for Healthcare Research and Quality’s Healthcare Cost and Utilization Project’s State Independent Databases for 4 geographically distinct states: Florida, Massachusetts, New York, and Washington. The patients were divided into 2 groups: those with and without a 30dRA. Patients with a 30dRA for rehabilitation on the day of discharge were excluded. Approximately 8% of 30dRA were not captured because they occurred in the following year.

Results:
The incidence of 30dRA following TAVR was 20.2% (244/1210). The most common principal diagnoses for readmission were heart failure (21%), infection (17%), bleeding (11%), and dysrhythmia (7%). A total of 4.2% of patients died during the 30dRA. More than 60% required skilled care following discharge, and only 20% had a routine discharge to home or self-care. The Centers for Medicare and Medicaid Services (CMS) were the primary payer for 93.4% of 30dRA following TAVR. The mean length of stay for a 30dRA was 7.0 +/- 6.6 days. The mean charges for a 30dRA were $61,657 +/- $73,000. On univariate analysis, the number of chronic comorbidities (9.9 +/- 2.8 vs. 9.3+/- 2.8; P=0.002), length of index hospitalization (10.3 +/- 7.4 vs. 8.9 +/- 6.9; P=0.01), and non-routine discharge (83.1% vs. 72.6% P<0.001) were associated with 30dRA. There was no significant difference in the mean age (83 years), gender makeup (50% female), racial makeup (19% non-White), and primary payer between patients who did and did not have a 30dRA.

Conclusions:
More than one in five patients undergoing TAVR is readmitted within 30 days of the procedure, most commonly for heart failure and infection. Future research should be directed toward identifying patients at risk for post-TAVR heart failure and infection prior to discharge, to reduce 30dRA.
Abstract 19166: Transportation Time Does Not Affect Mortality in Patients With Type A Aortic Dissection in a Hospital Without Cardiothoracic Surgery
Authors: Susawa Hitoshi , Mikami Shinsuke , Takemoto Hajime , Nakao Yuki , Kobayashi Kengo , Tanaka Haruki , Tanaka Kouichi , Kihara Yasuki
Published: March 2022

Introduction:
Acute aortic dissection (AD) is a rare case, but if it occurs rapid diagnosis and treatment are needed. It is currently crucial for AD patients to be transferred to a specialized hospital in a safe and timely manner. However, transportation time does not fully access to affect mortality in these patients.

Methods:
We evaluated fifty-one subjects who were suspected aortic dissection between 2010 and 2014 in a hospital without cardiothoracic surgery. Thirty cases of AD confirmed with 64-slice computed tomography (20 cases of Stanford type A and 10 cases of type B) were divided into a high-risk group (eight cases, 8 Stanford type A and zero type B) and a low-risk group (22 cases, 12 Stanford type A and 10 type B) according to the hypotension (systolic blood pressure<90 mmHg). The transportation time and mortality were compared between the high-risk group and the low-risk group, and the correlation between the measured transportation time and mortality was analyzed.

Results:
The transportation time and mortality were compared between Stanford type A and type B, and statistically significant differences were found. The transportation time and mortality were compared between the high-risk group and low-risk group, revealing a statistically significant difference (p < 0.05). Moreover, a significant correlation was not found between the transportation time and mortality (r = 0.287; p = 0.367). CONCLUSIONS: The hypotensive patients are the greater transportation risk for AD patients with type A dissection. Transportation time does not affect mortality in patients with low-risk type A aortic dissection.
Abstract 19199: The Effects of Self Efficacy and Social Support on Quality of Life of Patients and Family Caregivers After Coronary Artery Bypass Grafting
Authors: Thomson Patricia , Howie Catherine A , Chung Missok L
Published: March 2022

Introduction:
Personal and social resources are critical factors in patient recovery after coronary artery bypass grafting (CABG). Family members are an importance source of support for the patient. Because of the importance of interdependent relationships, it is vital to examine associations between self efficacy, social support and quality of life at the dyadic level. No known studies have explored patient’s cardiac self efficacy and family caregiver’s perceptions of patient self efficacy and social support as influences on quality of life in CABG

Aims:
To examine the effects of patient’s pre-operative cardiac self efficacy and family caregiver’s perceptions of patient self efficacy on their own and their partner’s quality of life after CABG; to examine the effects of patient’s and family caregiver’s preoperative social support on their own and their partner’s quality of life after surgery.

Methods:
A total of 80 dyads completed questionnaires before and 4 months after CABG. Self-efficacy was assessed using the Cardiac Self Efficacy, social support was assessed using the MOS Social Support Survey, and quality of life assessed using the Short-Form 12 Health Survey. Longitudinal data were analysed using Multilevel modelling regression, the Actor-Partner Interdependence Model with distinguishable dyad regression.

Results:
Of the 80 dyads, 75 were patient-spouse dyads. Patients were 80% males, aged 64.5 years and family caregivers were 90% females, aged 61.05 years. Patients’ tangible support exhibited an
actor e
ffect on their mental health,indicating low tangible support pre-operatively predicted their poorer mental health 4 months after CABG (β = .087, t = 2.059, p = 0.042). Patients’ self efficacy for maintaining function (SE-MF) exhibited a
partner
effect (β = -.768, t = 3.275, p = 0.002) on family caregivers physical health, indicating patient’s pre-operative SE-MF influenced the family caregivers health in a negative way.

Conclusions:
Patient’s post-operative mental health was affected by their low pre-operative tangible support. The family caregivers physical health was negatively affected by patients self efficacy for maintaining function.
Abstract 19250: Urinary Homocysteine Thiolactone Predicts Acute Myocardial Infarction in a Randomized Controlled Homocysteine-lowering B-vitamin Trial
Authors: Jakubowski Hieronim , Borowczyk Kamila , Glowacki Rafal , Nygård Ottar
Published: March 2022

Introduction:
Elevated plasma total homocysteine (tHcy) is associated with increased risk of coronary artery disease (CAD) and stroke. However, tHcy-lowering by B-vitamin therapy has no effect on cardiovascular disease (CVD), suggesting that tHcy is not causally related to CVD. One Hcy metabolite, Hcy-thiolactone (HTL), not accounted for in clinical tHcy assays, has been independently implicated in CVD. HTL is generated in the human body by methionyl-tRNA synthetase during protein biosynthesis and is cleared by the kidney.

Hypothesis:
Our objective was to test the predictive value of urinary HTL as risk marker of incident acute myocardial infarction (AMI) and to evaluate potential effect modification by B vitamin treatment and status.

Methods and Results:
We analyzed urinary HTL in samples from 2048 patients (20.5% female, mean age 61.7 years) who underwent coronary angiography for stable angina pectoris and were recruited to the Western Norway B Vitamin Intervention Trial. Linear regression was used to study determinants of baseline urinary HTL/creatinine and no association was observed with established risk factors such as age, gender, hypertension, body mass index, diabetes, apolipoprotein B and A1. Cox regression was used to study its association with subsequent risk of AMI. During median 4.7-years follow-up, 183 patients (8.9%) suffered from AMI. After adjustment for age, gender, diabetes, smoking, extent of CAD at angiography and left ventricular ejection fraction, per tertile increment in HTL/creatinine was significantly associated with AMI (RR 1.23; 95% CI 1.025-1.474; P=0.026). No significant effect-modification by folate/B12 or B6 treatment was observed. The association was entirely confined to patients with low (below median) levels of the inactive B6 metabolite pyridoxic acid (P-interaction 0.020), and identified patients with low risk. The risk association of plasma tHcy was confined to patients with elevated pyridoxic acid (P-interaction 0.001), and identified patients with high risk.

Conclusions:
Urinary HTL is a risk predictor of AMI in patients with CAD independent from established risk factors and plasma tHcy, but related to vitamin B6 metabolism. These surprising results should encourage further research into HTL and CVD.
Abstract 19303: Cognitive Dysfunction and Patients’ Attitudes Toward Generator Replacement and Deactivation of Their Implantable Cardioverter Defibrillator at the End-of-life
Authors: Hammash Muna , Thylen Ingela , Biddle Martha , Bailey Alison , Miller Jennifer , Moser Debra
Published: March 2022

Background:
Despite its life saving benefits, Cardioverter Defibrillator (ICD) implantation is associated with increased risk of cognitive dysfunction. Studies examining the association between cognitive status and attitudes toward withdrawing ICD therapy [i.e., generator replacement at end-of-service and ICD deactivation at End-of-Life (EOL)] in the long term are scarce.

Objective:
The specific aims of this study were to: 1) describe patients’ attitudes toward withdrawal of ICD therapy at EOL; and 2) determine the association between cognitive dysfunction and recipients’ attitudes toward generator replacement and toward ICD deactivation at EOL, controlling for age, anxiety and depression.

Methods:
A total of 114 ICD recipients (35% female, age 67 ± 12 years) completed the Montreal Cognitive Assessment, Patient Health Questionnaire-9, and Brief Symptom Anxiety instruments. Data about participants’ attitudes toward withdrawal of therapy were collected by asking participants to answer “Yes/No” or “Not sure” for the following two statement, respectively: “I want to have the battery in my ICD replaced even if I am seriously ill suffering from another disease,” “I want to have the defibrillating shocks in my ICD even if dying of cancer or another serious disease.” The association between cognitive dysfunction and attitudes toward generator replacement and ICD deactivation were tested using logistic regression analysis.

Results:
The majority of participants (68%) would like to replace the generator at end-of-service even if they are seriously ill with another disease; 44% favored to keep shocks even if they are dying from cancer or other serious disease. Ten per cent and 16%, respectively, were indecisive about generator replacement and ICD deactivation at EOL. Cognitive dysfunction significantly predicted recipients’ attitude toward generator replacement (β = 4.12, p = .02), but not their attitudes toward ICD deactivation at EOL.

Conclusion:
Cognitive dysfunction predicted recipients’ attitude toward generator replacement at end of service. This suggests that considering patients’ cognitive function is essential to maximize ICD recipients’ ability to make treatment decisions at EOL.
Abstract 19319: Fasting Glucose, Fasting Insulin, and Insulin Resistance in the Prediction of Myocardial Infarction and Mortality at Long-term Follow-up
Authors: Nielsen Mette L , Pareek Manan , Leósdóttir Margrét , Nilsson Peter M , Olsen Michael H
Published: March 2022

Objective:
To assess the additional prognostic value of fasting blood glucose (FBG), fasting plasma insulin (FPI), and homeostasis model assessment derived insulin resistance (HOMA-IR) for predicting incident myocardial infarction (MI) and all-cause mortality, independently of traditional cardiovascular (CV) risk factors.

Methods:
As part of a population-based cohort study aiming to screen for CV risk factors, 6024 men and 1013 women without known diabetes mellitus (DM) or overt CV disease (CVD defined as previous MI, stroke, or transient ischemic attack), recruited 1974-1992, had both FBG and FPI measured at baseline. Subsequently, HOMA-IR was derived using the computerized HOMA calculator and ranked into quartiles due to the non-normal distribution and presumably non-linear biological effect of insulin resistance. Prognostic values of FBG, FPI, HOMA-IR, and traditional risk factors were tested using Cox proportional hazards regression analysis and likelihood-ratio testing. Follow-up time from inclusion until event (first MI or death) or censoring (emigration or last follow-up date (≤ 20 years)) comprised the underlying time scale.

Results:
Median [IQR] age at inclusion was 47.7 [47.1-48.3] years, whereas median [IQR] HOMA-IR was 0.9 [0.4-1.4]. Over a median follow-up time of 20 years, 1448 events occurred (11.3 per 1000 person-years). The simple prediction model, i.e. the model with traditional CV risk factors only, included age, gender, body mass index, systolic blood pressure, total cholesterol, and smoking status. Addition of FBG, but not FPI or HOMA-IR resulted in significant model improvement (FBG: χ2 = 5.82, p = 0.02; FPI: χ2 = 0.29, p = 0.59; HOMA-IR: χ2 = 0.08, p = 0.78). Moreover, we detected significant interactions between both FBG and FPI (χ2 = 12.52, p < 0.001), FBG and HOMA-IR (χ2 = 6.07, p = 0.01), and FPI and HOMA-IR (χ2 = 13.15, p < 0.001).

Conclusion:
Addition of FBG, but not FPI or HOMA-IR provided additional significant prognostic value on top of traditional CV risk factors in the prediction of MI or death at long-term follow-up in subjects without CVD and/or DM at baseline. Furthermore, interaction analyses revealed that the prognostic values of both FBG and FPI were significantly greater among subjects in the highest HOMA-IR quartile.
Abstract 19331: The Adrenal Vein Sampling International Study-2: Results in 1636 Primary Aldosteronism Patients
Authors: Rossi Gian P , Rossitto Giacomo , Vanderriele Paul E , Amar Laurence , Reincke Martin ,   AVIS2 investigators
Published: March 2022

Background:
Guidelines recommend Adrenal vein sampling (AVS) for the subtyping of primary aldosteronism (PA), the most common curable cause of arterial hypertension. How this recommendation is implemented in practice remains uncertain. Hence, in 2011 upon completion of the AVIS-1 Study we launched the AVIS-2 Study to determine: 1) the success rate of the AVS studies performed in major referral centers worldwide; 2) the impact of AVS results on the clinical decision making and on outcome of the patients at follow-up.

Methods:
All the AVIS-1 Study centers were invited to join the AVIS-2 by entering the individual PA patients AVS and clinical data in an ad hoc predefined web-based database. Data were analyzed according to use of cosyntropin unstimulated or -stimulated protocols.

Results and Conclusions:
Sixteen centers in Europe, North America and Asia recruited a total of 1656 PA patients (age 50 years ± 10; 39.5% females). The AVS success rate was examined as a function of the Selectivity Index (SI) cutoffs. Among unstimulated AVS (n = 1307), the rate of bilaterally selective tests fell from 86% to 53% and 45% with cut off values of 1.10, 2.00 and 3.00, respectively; for adrenalectomized patients (49% of total), the decision was based on bilateral selective AVS in 71%, 56% and 43% of cases, respectively. Among cosyntropin-stimulated AVS, 85%, 80%, 76% and 72% were bilaterally selective, with a cut-off of 2.00, 3.00, 4.00, and 5.00, respectively; the rate of adrenalectomy based on AVS data fell from 47% with a cut-off = 2.00 to 40% with a cut-off = 5.00. The lateralization index value did not improve by comparing those with SI bilaterally > 2.0 (baseline) and > 5.0 after cosyntropin (3.8 [median, 1.6-12.7 IQR] vs 3.7 [1.5-14.0]).

Conclusions:
Only a minority of PA submitted to AVS have bilaterally selective studies if high cutoffs for the SI are used. Moreover, in even less patients AVS eventually led to adrenalectomy. These intriguing results from the largest dataset of AVS studies provide compelling evidence for the need of further prospective studies in this field.
Abstract 19353: Prohibitin: A Potential Circulating Mitokine That May be Involved in Pulmonary Arterial Hypertension
Authors: PAULIN Roxane , Kinnaird Adam , Boukouris Aristeidis , Gurtu Vikram , Haromy Alois , Michelakis Evangelos D
Published: March 2022

Introduction:
In Pulmonary Arterial Hypertension (PAH), a “cancer-like” mitochondrial suppression in pulmonary vascular cells underlies in part the apoptosis resistance that characterizes the proliferative vascular remodeling. There is emerging evidence that a similar mitochondrial suppression is present in extra-pulmonary tissues like the skeletal muscle or circulating cells in PAH. We speculated that this may be due to a circulating factor. In cancer, such factors may underlie muscle wasting (cancer cachexia). In worms, there is evidence that “mitokines” secreted by one organ can “condition” other organs remotely by suppressing mitochondria. We hypothesized that Prohibitin (PHB-1; a protein increased both in the tumor and in the serum of cancer patients) maybe a candidate mitokine in PAH.

Results:
To determine whether the pulmonary circulation responds to endogenously produced PHB-1, we studied a rat tumor xenotransplant model with CRL-2335 breast cancer cells. Rats with tumors exhibited higher PA pressures compared to rats without tumors (mPAP=12±1mmHg vs 20±2mmHg, n=18) and this increase correlated with tumor size. Importantly, this increase in PA pressures was not due to thromboembolism and was associated with increased muscularization of resistance PAs. PHB-1 levels were increased in the PAs and serum of rats with tumors compared to controls and in the culture media of CRL2335 compared to normal cells. PASMCs exposed to Recombinant (Rec)PHB-1 displayed inhibited pyruvate dehydrogenase, increased mitochondrial membrane potential (TMRM live cell imaging 37±0.5AFU vs 53±1.2AFU), decreased mitochondrial respiration and suppressed apoptosis, mimicking the PAH phenotype. Preliminary data suggested that RecPHB-1 activates the plasma membrane receptor ErbB2, which is translocated into the mitochondria (immunoblot on isolated mitochondria and immunostaining) where it acts as a negative regulator of mitochondrial function.

Conclusion:
The pulmonary circulation may be responsive to endogenous circulating mitochondrial inhibitors originating from extra-pulmonary tissues. PHB-1 may be a potential mitokine in PAH.
Abstract 19397: Factors Affecting Exercise Capacity in Diabetic Heart Failure Patients
Authors: Allen Laura N , Jamil Haqeel A , Gierula John , Paton Maria , Garnham Jack , Kearney Mark , Bowen Scott , Witte Klaus K
Published: March 2022

Background:
Exercise intolerance is a key feature of chronic heart failure (CHF). CHF patients with concomitant diabetes (CHF-DM) have heightened exercise intolerance, poorer prognosis and worse symptoms. Causative mechanisms may be impaired ventilatory, cardiac or skeletal muscle function. We prospectively assessed factors affecting exercise capacity in CHF and CHF-DM.

Methods:
Stable CHF (n=33) and CHF-DM (n=33) patients with left ventricular systolic dysfunction (ejection fraction (EF) <50%; NYHA class I-II; optimal device and medical therapy), were matched for age (mean±SD: 76±7 yr), weight (85±13 kg), height (1.72±0.06 m), systolic function (EF: 38±11%) and diastolic function (EA ratio 0.9±0.2). They underwent peak cardiopulmonary exercise testing with breath-by-breath pulmonary gas exchange analysis. Exertional shortness of breath (S) symptoms were recorded using the standardized Borg 0-10 scale. Continuous variables were reported as means (SD) and analysed using ANCOVA, categorical variables were analysed using the chi-squared test. A p-value of < 0.05 was taken as significant.

Results:
CHF-DM had reduced exercise capacity (pVO2 13.9±4.3 v 17.5±5.9 ml/kg/min; p=0.01) and lower exercise time (354±209 v 511±250s; p=0.01). Cardiac and ventilatory responses did not differ: Heart rate rise (44±5 v 46±4 bpm; p=0.21), Ve/VCO2 (37.2±9.4 v 39.5±10.5; p=0.35), peak respiratory frequency (31.7± 6.7 v 31.1± 7.6 breaths/min; p=0.76). Symptoms did not differ at baseline, peak or during exercise (Peak Borg S: 4±2 v 4±2; p= 0.73) The lactate threshold (LT) (9.86±0.27 v 11.26 ±0.32 L/min; p=0.48), time to LT (358 ± 92.58 v 393 ± 203.94 s; p=0.22) and the respiratory compensation point (RCP) (12.77±0.37 v 14.37± 0.45 L/min; p=0.64) did not differ.

Conclusion:
Exercise capacity is reduced in CHF-DM subjects matched for age, BMI and cardiac function. There are no differences in symptoms of breathlessness, Ve/VCO2 slope or respiratory rate. However, LT and time to LT is unchanged, despite lower exercise time overall. Thus, there is an inability to tolerate exercise beyond the LT. This is likely due to altered skeletal mitochondrial function in the context of concomitant diabetes.
Abstract 19423: Rodent Hind Limb Collaterals Develop as Intertwined Strands Accompanied by Veins
Authors: Schwarz Janina C , van Lier Monique G , Oost Elco , Bakker Erik N , Spaan Jos A , Siebes Maria
Published: March 2022

Background:
The process of angiogenesis and collateral remodeling in response to rodent hind limb ischemia has been intensely studied at micro- as well as at macroscopic level. Yet, a detailed investigation of the three-dimensional (3D) collateral vessel architecture in this model is lacking.

Methods:
To stimulate collateral growth in the rat hind limb the femoral artery was ligated. After sacrifice at day 3, 7 or 28, the systemic circulation was flushed via the cannulated abdominal aorta, the vasculature was filled with fluorescent cast material, and the frozen limbs were embedded in black gel. Registered stacks of episcopic fluorescence images, acquired with a custom-built imaging cryomicrotome (24 μm
3
voxel resolution). High-resolution 3D-renderings of the vascular cast were obtained after deblurring. Multiple collateral arteries and veins were identified between the muscular branch of the femoral and the saphenous artery and vein and diameters were assessed in four regions (near the stem and re-entry, at the mid-zone, and just proximal to the re-union of individual collaterals) using a semi-automatic approach based on vesselness filtering.

Results:
The gracilis collaterals form a complex network of intertwined vessels with highly individual architecture. Both pre-existing and new small collateral loops were commonly bundled as pairs of artery and vein. In early arteriogenesis, these bundles exhibited a multitude of small sprouting side branches. Arterial diameter increased with ischemia duration from 108 μm in healthy to 130 μm in 7-days post-ligation legs and 182 μm in 28-days post-FAL limbs (p<0.01) whereas collateral vein remained unchanged. Rather than an increasing number of long bridging collateral arteries over time, we noticed an increased arcade formation of paired arteries and veins.

Conclusions:
We examined 4 stages of neovascularization in 3D in high detail. Initial sprouting gave way to formation of intertwined collateral strands accompanied by veins. The proximity of collateral arteries to veins calls for investigation of the role of veins during arteriogenesis.
Abstract 19425: A Small Molecule Enforcing MEF2 Deacetylation Prevents and Reverses Hypertrophy and Normalizes Cardiac Function in Multiple Stress Models
Authors: Wei Jian Qin , Joshi Shaurya , Gao Yan , Chen Lin , Bishopric Nanette H
Published: March 2022

Background:
Cardiac hypertrophy leads to progressive cardiac dysfunction, and is an independent risk factor for death. Myocyte enhancer factor 2 (MEF2) is silenced by interaction with class IIa histone deacetylases and activated by p300 acetyltransferase during hypertrophy.

Hypothesis:
Targeting the co-regulatory site on MEF2 will prevent and reverse hypertrophy and associated cardiac dysfunction.

Methods:
Transverse aortic coarctation (TAC) and swimming stress models were used to initiate cardiac hypertrophy in male C57Bl/6 mice. Mice swam for 3 hours twice daily; control mice were immersed briefly. 8MI was administered by daily IP injection at a dose of 40 mg/kg beginning either at the time of intervention (TAC, swimming stress) or 4 weeks afterward (TAC) and continued for 4 weeks. N ≥ 5 per group. RT-PCR, immunohistochemistry, and echocardiography were used to assess cardiac structure and function. Neonatal rat ventricular myocytes (NRVM) were treated with 8MI, the histone deacetylase inhibitors MC1568 (class IIa-selective) or trichostatin A (nonselective, TSA).

Results:
Both TAC and forced swimming induced pathological hypertrophy with deterioration in systolic function in mice receiving DMSO (p<0.001 for both). 4 weeks after TAC or the initiation of swimming, 8MI-treated animals had myocardial mass and function similar to those of sham-operated or immersed-control mice. After 8MI treatment was stopped at 4 weeks, hypertrophy developed in mice that continued to swim, similar to DMSO-treated animals. In mice with established hypertrophy 4 weeks after TAC, treatment with 8MI, but not DMSO, reversed systolic dysfunction (n=5 per group, p=0.0018) and reduced myocardial wall thickness to near that of sham-operated animals. No evidence of systemic toxicity was seen. Mechanistically, 8MI, but not MC1568, promoted HDAC4 nuclear retention and maintained MEF2 in a deacetylated state, and unlike TSA, prevented EP300 accumulation.

Conclusions:
Pharmacological targeting of MEF acetylation in vivo prevents and reverses stress-associated hypertrophy in multiple models. Reversal of hypertrophy by this means improves systolic function and does not prevent successful adaptation to increased cardiac work.
Abstract 19429: Trx1 Regulates Nitroso-redox Balance to Stimulate Autophagy and Cell Survival in Cardiomyocytes
Authors: Nagarajan Narayani , Sciarretta Sebastiano , Sadoshima Junichi
Published: March 2022

Thioredoxin-1 (Trx1) is cardioprotective during oxidative stress. In addition to acting as an oxidoreductase, Trx1 also trans-nitrosylates other proteins. However, the role of Trx1-dependent S-nitrosylation in cardiomyocytes (CMs) is unknown. We investigated how Trx1 affects protein S-nitrosylation (SNO) and the nitroso-redox balance to regulate CM survival during glucose deprivation (GD). Mass spectrometry (MS/MS) analysis showed that Trx1 is S-nitrosylated at Cys73. Protein SNO levels were increased after 4 hrs of GD (1.64 fold, p<0.05; biotin switch assay). Overexpression of Trx1WT increased (3.94 fold), whereas knockdown of Trx1 (0.66 fold, p<0.01) or overexpression of Trx1C73S (0.77 fold, p<0.01) decreased, total protein SNO in response to GD, suggesting that Trx1 Cys73 regulates protein SNO in CMs during GD. Overexpression of Trx1 increased CM survival 24 hrs after GD (1.42 fold vs LacZ, p<0.05). Conversely, shTrx1 (2.13 fold vs control, p<0.01) or Trx1C73S (1.73 fold vs LacZ, p<0.01) increased cell death during GD. Either knockdown of Trx1 (LC3-II/Tubulin, 0.55 fold vs control) or overexpression of Trx1C73S (vs LacZ: LC3-II/Tubulin, 0.60 fold; autophagosomes, 0.83 fold, p<0.005; autolysosomes, 0.62 fold, p<0.005) significantly decreased autophagosome formation during GD. Increased interaction between Trx1 and a key autophagy protein, Atg7, was observed during GD and oxidative stress, as evaluated with the Trx1C35S trapping mutant. However, addition of DTT abolished this interaction, suggesting that Trx1 and Atg7 interact with one another via a disulfide linkage. By biotin switch assay and MS/MS analyses, we found that SNO-Trx1 can trans-nitrosylate Atg7 in vitro and that Atg7 is S-nitrosylated during GD in CMs. By labeling reduced and oxidized Cys residues in Atg7 with iodoacetamide and MMTS respectively, we determined that the level of Atg7 oxidation did not increase during oxidative stress in CMs, suggesting that Trx1 trans-nitrosylates Atg7 to prevent irreversible oxidative damage in Atg7. Taken all together, our results indicate that Trx1 promotes trans-nitrosylation of cellular proteins such as Atg7 to regulate the nitroso-redox balance and thus promote cell survival by stimulating autophagy during energy stress in CMs.