bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 16557: Revascularization versus Optimal Medical Therapy for Patients With Prior Coronary Artery Bypass Surgery: An Analysis From the Duke Databank for Cardiovascular Disease
Authors: Harskamp Ralf E , Chiswell Karen , Halim Sharif , Rymer Jennifer , Shaw Linda , Newby L Kristin
Published: March 2022

Objectives:
To describe treatment strategies of patients with prior coronary artery bypass grafting (CABG) who underwent subsequent coronary angiography and to compare clinical outcomes among patients who underwent coronary revascularization (CR) versus optimal medical therapy (OMT).

Methods:
From patients with prior CABG who underwent subsequent non-emergent coronary angiography at Duke University Hospital between January 2003 and October 2012, we identified those with documented stenosis of at least one vessel (native or bypass graft). All patients were followed for subsequent death, MI, or stroke through December 2013. Logistic and Cox-proportional hazards regression models were used for 30-day and 5-year outcomes, respectively.

Results:
A total of 3838 patients were included, of whom 1,672 (43.6%) were treated with CR within 30 days of index catheterization (1615 with PCI and 57 with CABG) and 2,166 (56.4%) received OMT. Median age was 66 (IQR 58-74) years; 26.5% were women. Heart failure was more common in the OMT group (NYHA>II, 11.6% vs. 19.7%); ACS was more common in the CR group (44.7% vs. 36.6%). Rates of death, MI, or stroke were 2.4% in both groups at 30 days and 41.2% and 40.6% for CR and OMT, respectively, at 5-years (Figure 1). Adjusted death, MI or stroke rates were similar between groups at 30 days (OR: 1.05, 95% confidence interval (CI): 0.66-1.65, p=0.85) and 5 years (OR: 1.08, 95%-CI: 0.97-1.20, p=0.18). Five-year death or MI (OR: 1.04, 95% CI: 0.93-1.17, p=0.46) and all-cause mortality (OR: 0.93, 95% CI: 0.82-1.06, p=0.26) were also similar.

Conclusion:
Among patients with prior CABG who undergo subsequent coronary angiography, long-term outcomes are poor. In a non-randomized comparison, clinical outcomes with CR are similar to those for OMT.
Abstract 16575: Arterial Tortuosity is Present in Multiple Genetic Conditions Associated With Aortopathy, a Study From the National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions (GenTAC)
Authors: Morris Shaine A , Kancherla Kalyan , Oda Seitaro , Asch Federico M , Sami Sarah , Payne William A , Dodd Nicholas A , Eagle Kim A , Pedroza Claudia , Pyeritz Reed E , Ravekes William , Roman Mary J , Holmes Kathryn W , Tyson Jon E , Lacro Ron , LeMaire Scott A , Krishnamurthy Rajesh ,   GenTAC Consortium, Milewicz Dianna M
Published: March 2022

Background:
Arterial tortuosity is emerging as an imaging marker of adverse events in aortopathy, but quantification has focused on patients with Marfan and Loeys-Dietz syndromes. Our objective was to characterize vertebral artery tortuosity among a variety of aortopathy phenotypes and genotypes.

Methods:
We performed a retrospective analysis of patients ≤50 years old with at least one of the following: aortic dilation or dissection, bicuspid aortic valve (BAV), or a genotype associated with aortopathy. Patients included were either enrolled in GenTAC or were cared for at our institution, and had undergone a magnetic resonance or computed tomography angiogram that included the vertebral arteries. The disease-causing gene mutation was available for a subset of the patients. The vertebral artery tortuosity index (VTI) was utilized to quantify tortuosity, and was compared among phenotypes and genotypes. Increased tortuosity was defined as ≥2SD above the mean VTI of previously reported controls undergoing evaluation to exclude arrhythmogenic right ventricular dysplasia (mean 4.5±2.5, cutoff=10.5).

Results:
We included 456 patients, of median age 29 years (IQR 15-40 years), and 58% male. The figure shows VTI by phenotype and genotype. VTI was higher in all phenotypic groups than controls (p ≤0.01 for all). All genotypes (for which n>1) had increased VTI compared to controls (p≤0.01 for all). Patients with TGFBR2 mutations had significantly greater VTI (median 59, IQR 20-85) than those with FBN1 mutations (median 25, IQR 13-51, p=0.01); there was no difference in VTI between TGFBR1 (median 19, IQR 12-64) and FBN1 mutations (p=0.79). There was no overall correlation between age and VTI; when evaluated by diagnosis, there was a weak correlation in MFS (Spearman's rho=0.213, p=0.01).

Conclusions:
Increased arterial tortuosity as measured by VTI is present in many phenotypes and genotypes associated with aortopathy, and is not limited to those with mutations in TGFBR1/2.
Abstract 16622: Plasma Metabolomic Profiles Differentiate Hemodynamic Subtypes of Pulmonary Hypertension
Authors: Luo Nancy , Craig Damian M , Ilkayeva Olga , Bain James , Muehlbauer Michael , Kraus William E , Newgard Christopher B , Shah Svati H , Rajagopal Sudarshan
Published: March 2022

Introduction:
Pulmonary hypertension (PH) is defined as a mean pulmonary artery pressures (mPAP) ≥ 25 mmHg. Within PH, there are distinct hemodynamic subgroups based on the presence of hypertension in the precapillary or postcapillary beds of the pulmonary vasculature: pulmonary arterial hypertension (PAH - precapillary PH), passive PH secondary to left heart disease (postcapillary PH) and mixed PH with both precapillary and postcapillary components.

Hypothesis:
As metabolic abnormalities have been noted in PAH and heart failure, we hypothesized that different hemodynamic subtypes of PH would be associated with distinct plasma metabolomic profiles.

Methods:
The CATHGEN biorepository consists of biological samples collected on over 9000 individuals undergoing cardiac catheterization at Duke University Medical Center. Of those subjects who had targeted metabolomics studies performed, 282 were identified with mPAP ≥ 25 mmHg. Of these 282 subjects, 133 met criteria for passive PH (PCWP > 15 mmHg, PVR 15 mmHg, PVR ≥ 3 WU) and 67 for PAH (PCWP ≤ 15 mmHg). Tandem flow injection mass spectrometry (MS) with isotope-labeled internal standards were used for targeted quantitative measurements of ~ 60 metabolites (including free fatty acids, acylcarnitines, amino acids, lipids and ketones). Multivariable logistic regression adjusted for age, presence of coronary artery disease, sex, race, diabetes and ejection fraction were used to determine differences in metabolites between the pulmonary HTN subgroups and with a matched cohort of CATHGEN subjects free from PH (N=280, matched on 282).

Results:
All PH subgroups demonstrated significantly different levels of long chain acylcarnitines from controls (p < 0.01). Compared to controls, subjects with mixed PH also had significant differences in long chain dicarboxyl acylcarnitines (p < 0.01) and C3-C5s (p < 0.028), passive PH had significant differences in ketone related metabolites (p < 0.04), and PAH had significant differences in branched chain amino acids (p < 0.01).

Conclusions:
Passive, mixed and PAH subtypes of PH were associated with distinct plasma metabolomics profiles compared to matched controls. These finding demonstrate that specific metabolic changess develop in the distinct subtypes of PH.
Abstract 16641: Reduction of Phrenic Nerve Injury During Cryoballoon Ablation Using the Proximal Seal Method
Authors: Homer Alexander , Al-Zubaidi Muhanad , Tseng Roger , Dancanay Kelly , Su Wilber
Published: March 2022

Introduction:
Cryoballoon has been effectiveness in treating atrial fibrillation; however it has also been associated with phrenic nerve injury during right-sided pulmonary vein ablation. The use of a proximal seal method would be able to mechanically increase the distance between the cryoballoon and the phrenic nerve and thereby reduce the incidence of phrenic nerve. However, the significance of this maneuver has not been objectively evaluated.

Methods:
Single center experience of cryoballoon ablation using Arctic Front Advance cryoballoon was reviewed. Incidence of phrenic nerve involvement was collected and binned into transient paralysis with recovery during the case, transient paralysis with recovery prior to discharge, or paralysis greater than 24 hours. Results were compared to historical data of phrenic nerve injury in STOP-AF trial where the proximal seal technique was not utilized.

Result:
512 cases of cryoballoon ablation were reviewed from a single center where proximal seal method was used. 14 of 512 patients (2.7%) were identified to have phrenic nerve involvement-- 10 of 14 (71%) patients phrenic nerve recovered during the procedure, 3 of 14 (21%) patients phrenic nerve recovered prior to discharge, and 1 of 14 (7%) patient had prolonged phrenic nerve injury greater than 24 hours. Compared to historic data without proximal seal method, phrenic injury rate of 11.2% was reported in the STOP-AF trial.

Conclusion:
Phrenic nerve injury is a serious complication of cryoballoon ablation and representing a significant adverse outcome in STOP AF Trial. Utilizing the proximal seal method demonstrated significantly less phrenic nerve injury. Further studies are required to better understand the mechanisms of phrenic injury and improve the safety of cryoballoon ablation.
Abstract 16854: An Ungated, Rapid Rest/Stress Myocardial Perfusion Protocol is Useful for Detection of Coronary Artery Disease in Patients With Atrial Fibrillation
Authors: Haider Imran , DiBella Edward V , Shaaban Akram , Adluru Ganesh , Chang Lowell , Suksaranjit Promporn , McGann Christopher J , Likhite Devavrat , Marrouche Nassir F , Sommers Daniel , Jensen Leif , Wilson Brent D
Published: March 2022

Introduction:
In patients with atrial fibrillation, the diagnostic accuracy of standard, gated stress/rest perfusion cardiovascular magnetic resonance (CMR) for detection of coronary artery (CAD) disease remains uncertain. Here we investigated using instead an ungated approach with no ECG gating with a rapid rest/stress perfusion protocol to determine its accuracy for detection of CAD in this patient population. To overcome the potential issue of peri-infarct ischemia with a rest-first sequence, we gave very little time between rest and stress perfusion scans.

Methods:
23 patients with atrial fibrillation (68 ± 13 years, 13 males and 10 females) underwent a very rapid rest/regadenoson stress perfusion imaging protocol and X-Ray angiography in this study. An ungated radial myocardial perfusion sequence was used (TR/TE = 2.2/1.2 msec, 3T, 20 rays/slice, 5 slices after each saturation pulse, ~2х2х8 mm). Rest/stress protocol was performed in the following order: rest image acquisition (0.05 mmol/kg gadoteridol), administration of regadenoson 0.4 mg intravenously (0.4 mg/5 mL) to induce hyperemia, 70 second wait, then stress image acquisition (0.075 mmol/kg gadoteridol). CMR perfusion images were interpreted by a blinded reader as normal or abnormal, without viewing cine or late gadolinium enhanced images, and also evaluated for quality (1 to 5, lowest to highest). Diagnostic accuracy was evaluated by comparison to X-Ray angiography: significant lesions were defined as stenosis >70 % stenosis or functional flow reserve <0.8.

Results:
18 of the scans were negative and 5 were positive by angiography criteria. Sensitivity, specificity and accuracy for detection of CAD were 100%, 89% and 91%, respectively. Average scan time for imaging acquisition was 6.5 ± 4.0 minutes. Average image quality for both rest and stress perfusion images was 3.2 ± 0.9.

Conclusions:
An ungated myocardial perfusion sequence with rapid rest/regadenoson stress perfusion protocol addresses the concern of lingering hyperemia with regadenoson and problematic gating. This study suggests that assessment of myocardial perfusion with an ungated technique is an approach with high accuracy for detection of significant CAD in patients with atrial fibrillation.
Abstract 16933: Targeted Inhibition of Histone Deacetylase 1 Promotes the Activation of a Cardiomyogenic/Vasculogenic Genetic Program in Human Cardiac-derived Mesenchymal Stromal Cells
Authors: Moore Joseph B , Zhao John , Wysoczynski Marcin , Bolli Roberto
Published: March 2022

Alterations in chromatin structure, as mediated by the inhibition of specific HDAC family members, enhance the cardiogenic differentiation capacity of various progenitor cell types; a key property of donor cell populations shown to contribute to the benefits they provide in cardiac cell therapy applications. The influence of HDAC inhibition on cardiac-derived mesenchymal stromal cell (CStC) transdifferentiation or the role of specific HDAC family members in dictating cardiovascular cell lineage specification has not been investigated. In the current study, the consequences of HDAC inhibition on patient-derived CStC proliferation, early induction of cardiac cell lineage commitment markers, and cardiovascular differentiation/cell lineage specification were investigated using the pan-HDAC inhibitor sodium butyrate (NaBu) or shRNA constructs targeting various HDAC family members. CStCs treated with NaBu for 72 hours resulted in a dose-dependent reduction in cell proliferation and a simultaneous induction of cardiogenic transcripts relative to untreated. Further, NaBu treatment stimulated enhanced expression of myocyte- and endothelial-specific markers following dexamethasone-induced differentiation in vitro. shRNA knockdown screens were employed in effort to identify specific HDAC family members responsible for these effects. Accordingly, we revealed the inhibition of HDAC1, but not HDAC4 or HDAC7 (both previously implicated in cardiac differentiation) to promote the activation of a cardiomyogenic/vasculogenic transcriptional program, as well as enhance the expression of early cardiac lineage commitment proteins. Such results identify HDAC1 as a modulator of CStC cardiovascular transdifferentiation and an exploitable target to facilitate CStC-mediated myocardial repair.
Abstract 17001: Reconstituted High-density Lipoprotein (CSL-111) Infusion Improves Post-ischemic Heart Function Through Modulating the Acute Inflammatory Response and Angiogenesis
Authors: Richart Adele , Heywood Sarah , Reddy-luthmoodoo Medini , Natoli Alaina K , Kiriazis Helen , Du Xiao-Jun , Siebel Andrew , Kingwell Bronwyn
Published: March 2022

Aims:
High-density lipoprotein (HDL) has multiple actions which may benefit post-ischemic heart function. We have shown in patients with type 2 diabetes that a single infusion of reconstituted HDL (rHDL, CSL-111) reduces inflammation1 including the number of circulating monocytes, neutrophils and lymphocytes. Whether such effects may contribute to improved heart function after ischemia and reperfusion is unknown. This study aimed to determine the effect of HDL on post-ischemic inflammatory response and heart function in insulin resistant mice.

Methods and Results:
A left coronary artery ligation model was used to study acute ischemia (30min) and reperfusion (I/R) in mice fed a chow (CD) or high fat diet (HFD) for 8 weeks. A single intravenous bolus of rHDL (CSL-111; 80mg/kg) or placebo (saline) was delivered at the time of reperfusion.

At 15 days post I/R, rHDL increased ejection fraction from 40±3% to 48±2% in both diet groups (p=0.004). rHDL also increased stroke volume (p=0.002) and cardiac output in both diet groups (p=0.015). Histological analysis revealed that rHDL increased the myocardial capillary density by 22±4% and 15±4% in CD and HFD mice respectively (p=0.0007; p=0.042). However, rHDL did not alter cardiomyocyte hypertrophy.

Interestingly, rHDL infusion modulated acute post-ischemic inflammatory response by decreasing the total number of circulating leucocytes (p=0.030) and neutrophils (p=0.005) in both diet groups 1 day following I/R. However, rHDL reduced the number of circulating monocytes (p=0.044) and B lymphocytes (p=0.009) only in HFD mice. In both diet groups, at 3 days post-I/R, rHDL reduced recruitment of leukocytes into the heart including monocytes (p=0.038, p=0.014), neutrophils (p=0.005, P=0.020), T lymphocytes (p=0.044, p=0.018) and B lymphocytes (p=0.043, p=0.010). Moreover, rHDL decreased the proportion of B lymphocytes recruited into the heart in HFD mice only (p=0.040), highlighting its strong anti-inflammatory effect particularly in the insulin-resistant state.

Conclusion:
A single infusion of rHDL at time of reperfusion improves post-ischemic heart function through modulation of angiogenesis and acute inflammatory response in insulin-resistant mice.
Abstract 17008: Dipeptidyl peptidase-4 Inhibitor Ameliorates Stress-induced Glucose Metabolism Disorder and Prothrombotic State
Authors: Takeshita Kyosuke , Yisireyili Maimaiti , Murohara Toyoaki
Published: March 2022

Introduction:
Psychological stress evokes lipolytic release of free fatty acid (FFA) and low-grade inflammation in visceral adipose tissue, mediated by increased adipokine secretion, and contributes to glucose metabolism disorder and prothrombotic state via production of coagulation factors (plasminogen activation inhibitor-1 [PAI-1] and tissue factor [TF]) in white adipose tissue (WAT).

Hypothesis:
As accumulating evidence suggests anti-inflammatory potential of dipeptidyl peptidase-4 (DPP4) inhibitors, we investigated the effects of alogliptin on stress-induced adipose tissue inflammation, insulin resistance and prothrombotic state.

Methods:
Mice were subjected to 2-week intermittent restraint stress and orally treated with vehicle, 15 or 45 mg/kg/day alogliptin. Plasma lipids, expression of GLP-1, DPP4 activity, 8OHdG (an oxidant stress marker), monocyte/macrophage markers (CD11b, CD68, and F4/80), proinflammatory cytokines (monocyte chemoattractant protein-1, tumor necrosis factor-α, and interleukin-6), adiponectin, and coagulation factors (PAI-1 and TF) in blood and inguinal WAT was determined using immunohistochemistry, enzyme-linked immunosorbent assay, and RT-PCR, respectively. Glucose metabolism was assessed by glucose tolerance tests (GTTs) and insulin tolerance tests (ITT), and expression of insulin receptor substrate-1 (IRS-1) and glucose transporter 4 (GLUT4) in WAT.

Results:
The stress procedure increased FFA release, 8OHdG-positive cells and monocyte accumulation in WAT, proinflammatory cytokine, and reduced adiponectin and GLP-1, followed by DPP4 activation in plasma. The stress-induced adipose inflammation increased PAI-1 and TF, and worsened insulin sensitivity and decreased IRS-1 and GLUT4 in WAT. The alogliptin administration suppressed stress-induced FFA release, oxidant stress production, adipose inflammation, procoagulant state in a dose dependent manner, and restored glucose metabolism in GTT and ITT.

Conclusions:
The results indicate that alogliptin improves stress-induced prothrombotic state, and glucose metabolism disorder. Our results suggests that alogliptin exerts additive benefits for cardiovascular complication in diabetes patients with mental stress.
Abstract 17026: Serum Adropin Level is Associated With Exercise Training-induced Improvement of Arterial Stiffness in Obese Adults
Authors: Fujie Shumpei , Sato Koji , Hasegawa Natsuki , Fujita Satoshi , Sanada Kiyoshi , Hamaoka Takafumi , Iemitsu Motoyuki
Published: March 2022

Introduction:
Obesity-induced deterioration of arterial stiffness is reduced by habitual exercise, and increased production of nitric oxide (NO) participates in this effect. Adropin is a regulator of endothelial NO synthase and NO release, and circulating adropin level decreases in obese patients. However, the association between exercise-training effects of arterial stiffness and circulating adropin level in obese subjects remains unclear.

Hypothesis:
This study aimed to determine the serum adropin level related to exercise-training effects of arterial stiffness in obese subjects.

Methods:
Eighteen Japanese obese subjects (age: 65.7 ± 1.6 years, % body fat: 34.8 ± 1.6 %) and nine Japanese non-obese subjects (age: 69.1 ± 1.0 years, % body fat: 19.9 ± 2.4 %) participated in this study. Obese subjects completed 8-week of aerobic exercise training (60-70% peak oxygen uptake [VO2peak] for 45 min, 3 days/week). Before and after the intervention, we evaluated plasma nitrite/nitrate (NOx) and serum adropin concentrations, carotid beta-stiffness as an indicator of arterial stiffness, and VO2peak as an index of cardiorespiratory fitness. VO2peak was measured using an incremental cycle exercise test on a cycle ergometer.

Results:
Serum adropin level in the obese subjects was lower than that in the non-obese subjects. After the 8-week intervention, VO2peak was significantly increased and carotid beta-stiffness was significantly decreased (P < 0.05). Moreover, plasma NOx level and serum adropin level was significantly increased after the 8-week intervention (P < 0.05). Additionally, the exercise training-induced reduction in beta-stiffness was negatively correlated with the training-induced changes in serum adropin (r = -0.481, P < 0.05) and plasma NOx levels (r = -0.668, P < 0.01). Furthermore, a significant correlation was observed between the training-induced changes in serum adropin and plasma NOx levels (r = 0.677, P < 0.01).

Conclusions:
These results suggest that the plasma adropin level is increased by aerobic exercise training intervention and is associated with exercise training-induced alternation of arterial stiffness in obese subjects. Thus, the increase in adropin may participate in the exercise-induced reduction of arterial stiffness.
Abstract 17039: Creating Heart Failure-specific Measures From PROMIS®
Authors: Ahmad Faraz S , Kaiser Karen , Schifferdecker Karen E , Adachi-Mejia Anna M , Eisenstein Amy , Greene George J , Yount Susan , Cella David , Kallen Michael , Carluzzo Kathleen L , Fisher Elliott S
Published: March 2022

Background:
National policies call for aligning specific treatments with patients’ goals of care. The impact of heart failure (HF) on health status varies among patients. Although several generic and HF-specific patient-reported outcomes tools have been developed, none explicitly address how to combine generic and disease-targeted items in a coherent and interpretable way. Our goal was to develop a HF tool that identifies and integrates condition-specific items with measures from PROMIS®--a system of reliable and precise self-reported health assessment.

Methods:
We conducted focus groups with HF patients and semi-structured interviews with HF clinicians. We analyzed the transcribed recordings in Dedoose. Using an iterative process, we conducted a content analysis of interview codes to identify relevant PROMIS® domains and items. Codes that did not map to existing PROMIS® tools were used to define gap areas. New items were drafted to reflect the gap areas and then underwent cognitive testing.

Results:
Eight focus groups with a total of 61 patients were conducted. Participants had a mean age of 61, were 39% female, and 90% white. Eleven clinicians (6 MDs, 5 RNs) were interviewed. Sixty-nine items across 12 existing PROMIS® domains were identified. Examples of existing PROMIS® domains were dyspnea, physical function, and depression. Gap analysis and cognitive interviewing produced 22 additional items across 8 domains (3 existing PROMIS® and 5 new domains). The identified new domains were health behavior outcomes, life satisfaction, illness burden, independence, and symptoms.

Conclusions:
We developed a specific process for creating a tool that integrates existing PROMIS® domains with disease-specific outcomes important to patients and clinicians. While our process was specific to HF, it may be applied to other high impact health conditions. Next steps include the assessment of the stability, validity, and responsiveness of these via testing in 800 HF patients.
Abstract 17060: The Effect of Resuscitation Position on Cerebral and Coronary Perfusion Pressure During Mechanical Cardiopulmonary Resuscitation in Porcine Model
Authors: Park Yong-Joo , Kim Taeyun , Shin Sang Do , Song Kyoung Jun , Jang Dayea , Ryu Hyun Ho , DeBaty Guillaume , Lurie Keith
Published: March 2022

Objectives:
Mechanical compression devices can allow us to select a positon during transport with cardiopulmonary resuscitation (CPR) in a small space (like elevator) to reduce the length of stretcher cart. It is unclear, however, whether resuscitation position is associated with cerebral perfusion pressure (CePP) or coronary perfusion pressure (CoPP).

Methods:
This is a randomized crossover experimental trial using female farm pigs (n=12) (42 ± 3kg) sedated, intubated, and paralyzed on a tilt table. After surgical preparation, 6 minutes of untreated ventricular fibrillation was induced followed by 3 minutes in 0° supine position as a stabilization period with mechanical CPR device (M) and an impedance threshold device (ITD). Then, 5 minutes of M-CPR+ITD was performed in a position randomly assigned to either head-up tilt at 30°, 45°, or 60°, supine, or head-down tilt at 30°, 45°, or 60° followed by 5 minutes of M-CPR+ITD in crossover position to the other. We measured and compared the CePPs and CoPPs at the positions using ANOVA with Duncan post-hoc test.

Results:
Baseline hemodynamic parameters among pigs were not different. From head-down to head-up by elevation of angle, mean aortic pressures slightly decreased and intracranial pressure significantly decreased. With 60°, 45°, 30° head-down, 0°(supine), and 30°, 45°, 60° head-up positioning, CePPs increased linearly as follows: 2.4± 3.1, 9.3±3.9, 16.5±5.0, 27.0±2.3, 35.1±1.2, 39.4±12, 39.9±1.5mmHg respectively (p<0.001 by ANOVA and all significant for post-hoc test). CoPPs was peak in head-up 30 °: 12.9± 4.2, 13.3±5.0, 12.8±2.9, 18.1±2.0, 30.3±1.5, 24.1±1.7, 26.5±1.9 mmHg respectively (p<0.001 by ANOVA post-hoc test except between head-down -30° and -65°).

Conclusion:
Mechanical CPR position was associated with different cerebral perfusion pressure by head-up angles. The head-up 30° showed the peak coronary perfusion pressure.
Abstract 17114: The European Registry of Cardiac Arrest - Study One (EuReCa ONE) - Relationship Between Rates of CPR and Rates of Death in European Countries
Authors: Gräsner Jan-Thorsten , Wnent Jan , Masterson Siobhán , Koster Rudolph W , Myrhaugen Tjelmeland Ingvild B , Böttiger Bernd W , Rosell Ortiz Fernando , Maurer Holger , Herlitz Johan , Bossaert Leo ,   EuReCa ONE Study Group
Published: March 2022

Background and Objectives:
EuReCa collects data on out-of-hospital cardiac arrest (OHCA) in Europe. In this study (EuReCa ONE) we hypothesised that a higher rate of death is associated with a higher rate of CPR started. We investigated the relationship between the rate of CPR started and total death rates, and also between the rate of CPR started and death rates from ischaemic heart disease (IHD).

Methods:
We conducted a prospective observational study of EMS attended OHCA from 1
st
- 31
st
October 2014, covering 201 million inhabitants from 27 European countries. The incidence of cases where CPR was started was calculated per 100,000/year for each country. Data on deaths from IHD and all deaths was obtained from health statistics of the European Commission (Eurostat). Correlations between both these death rates and CPR started rates were calculated.

Results:
We found a wide range of rates of CPR started (19 - 104/100,000/year) and differences in all death rates (623 - 1417/100,000/year) and IHD death rates (202 - 766/100,000/year). The figures show the relationships for each country. Correlations between the rates of CPR started and rates of death from IHD and total deaths were Pearson R
2
=0.06 (p=0.25); Pearson R
2
= 0.10 (p=0.12) respectively.

Conclusion:
Correlation is low between the rate of CPR and both the rate of death from all causes and IHD. Differences in mortality rates do not explain the observed variability in the rates of CPR started.
Abstract 17127: RVX-208 a Selective Bromodomain and Extra-terminal BET Protein Inhibitor Acts on Several Pathways to Benefit Cardiovascular Risks
Authors: Wong Norman C , Kulikowski Ewelina , Wasiak Sylwia , Gilham Dean , Halliday Christopher , Lebioda Kenneth , Sweeney Mike , Johansson Jan O
Published: March 2022

The epigenetic modifying compound RVX-208 selectively inhibits the second ligand binding domain in BET proteins to increase ApoA-I/HDL production. In recent trials of CVD patients given standard of care and RVX-208 (200mg/d) there was a 55% relative risk reduction of MACE vs. placebo. This reduction is greater than expected from modest increases in ApoA-I/HDL, thus suggesting benefits of RVX-208 beyond lipid effects. Whether added benefits exist was explored by microarray survey of differential gene expression in primary human hepatocytes (PHH) and whole blood (WB). In PHH, RVX-208 downregulated genes within the complement, fibrin clotting, cholesterol biosynthesis, fatty acid biosynthesis, diabetes and acute phase response (APR) pathways. These data guided more focused analyses on the known HDL proteome encoded by 89 genes of which 30 were affected by RVX-208 and many of these were members of the APR or complement pathways. In support of the microarray data, we used RT-PCR and found RVX-208 lowered mRNA encoding complement 3, 4a/4b and 5 by >50% in Huh-7 and HepG2 cells exposed to RVX-208. Consistent with the mRNA data, secretion of these complement proteins were less from the treated cells. Next the cells were exposed to cytokines in order to mimic an inflammatory state thus inducing complement expression. Treatment with RVX-208 blocked this effect by >50%. Furthermore, in Huh-7 cells, RVX-208 repressed both fibrin clotting factors II (prothrombin) and XI (thromboplastin antecedent) consistent with the PHH microarray data thus suggesting an anti-thrombotic effect for RVX-208. To further extend findings in vitro from hepatoma cells, plasma from patients in our clinical trials who received RVX-208 were assayed and found to have decreased levels of both APR and complement proteins. Lastly, microarray studies of WB from healthy donors treated ex-vivo with RVX-208 uncovered differential regulation of anti- and pro-atherogenic gene sets that were activated and suppressed, respectively by RVX-208. In summary, RVX-208, a selective BET inhibitor, affects several pathways involved in CVD including; reverse cholesterol transport, atherogenesis, complement, thrombosis and vascular inflammation that cumulatively may reduce MACE in high risk CVD patients.
Abstract 17137: Safety and Effectiveness of Dabigatran Relative to Warfarin in Routine Clinical Practice - New Interim Results of Long-term Study Program
Authors: Seeger John D , Bartels Dorothee B , Huybrechts Krista , Gopalakrishnan Chandrasekar , Bykov Katsiaryna , Zint Kristina , Schneeweiss Sebastian
Published: March 2022

Background:
Dabigatran etexilate is a newer oral anticoagulant developed as an alternative to warfarin for stroke prevention in patients with non-valvular atrial fibrillation (NVAF). Although the efficacy and safety of dabigatran were established in a randomized trial, evaluation of its effects in routine clinical practice is ongoing.

Objectives:
Quantification of the comparative safety and effectiveness of dabigatran in routine care within two large US commercial health insurance databases (Truven MarketScan and Optum Clinformatics)

Methods:
Cohort design with propensity score (PS) matching to compare new initiators of dabigatran with warfarin between October 2010 and June 2013. Primary outcomes were stroke and major bleeding. Proportional hazards regression of time to outcome was conducted separately within each data source and results were pooled.

Results:
There were 22,736 PS matched dabigatran and warfarin initiators with NVAF pooled across data sources (MarketScan 18,726; Optum 4,010). The matching resulted in well balanced cohorts with no individual characteristic (including stroke and bleeding risk factors) having a standardized difference of greater than 0.1. The average follow-up for the as-treated analyses was 5 months for dabigatran and 4 months for warfarin. There were 69 strokes amongst dabigatran initiators and 84 strokes amongst warfarin initiators for a pooled HR of 0.71 (95% CI 0.51 – 0.98) (MarketScan HR = 0.65, 95% CI=0.45-0.93, Clinformatics HR = 1.05, 95% CI = 0.50-2.19). For the outcome of major hemorrhage, there were 429 events amongst dabigatran initiators and 480 events amongst warfarin initiators for a pooled HR of 0.77, 95% CI = 0.68 – 0.88) (MarketScan HR = 0.80, 95% CI = 0.70 - 0.92, Clinformatics HR = 0.55, 95% CI = 0.37 - 0.82). Pooled results in the full cohort were fairly consistent across numerous subgroup and sensitivity analyses, however, comparative conclusions within some subgroups are limited by small numbers and limited follow-up time.

Conclusions:
Analyses from this ongoing sequential long-term study program suggest a reduced risk of both stroke and major hemorrhage for dabigatran relative to warfarin. Continued follow-up will increase the sample size, permitting greater precision in effect estimates.
Abstract 17165: Myocardial Iron Depletion In Patients With Heart Failure Is Associated With Mitochondrial Dysfunction And Attenuation Of Citrate Synthase Activity
Authors: Melenovsky Vojtech , Petrak Jiri , Mracek Tomas , Benes Jan , Drahota Zdenek , Pluhacek Tomas , Nuskova Hana , Jana Kovalcikova , Pirk Jan , Houstek Josef
Published: March 2022

Introduction:
Very little is known about the determinants and consequences of abnormal iron (Fe) content in the failing human myocardium.

Hypothesis:
We hypothesized that myocardial Fe deficiency (ID) in heart failure (HF) is associated with impaired mitochondrial function of Fe-regulated enzymes of respiratory chain (RC) and Krebs (TCA) cycle.

Methods:
LV samples were obtained from 90 consecutive patients undergoing transplantation (HF: LVEF 23±8%, age 53±11y, 83% males, 46% CAD, 24 % diabetes) and from 38 HF-free organ donors (CON: LVEF 57±12%, age 42±15y, 50% males, 14% with diabetes). Activities of citrate synthase (CS, Krebs cycle) and RC enzymes NADH-cytochrome c oxidoreductase (NCCR), succinate cytochrome c oxidoreductase (SCCR) and cytochrome c oxidase (COX) were measured in homogenates. Total Fe was measured by ICP-MS after microwave-assisted digestion of lyophilized samples.

Results:
Compared to CON, HF patients had lower total myocardial Fe (156±41 vs 200±38 μg/g dry weight, p<0.001). Myocardial ID (Fe<124.8 μg/g; 2*SD from the mean of CON) was present in 22 % of HF patients. HF+ID patients had more often diabetes (45% vs 18%, p=0.02), but similar age, gender, renal function, haemoglobin concentration, HF aetiology, LVEF or BNP as non-ID HF. Activities of CS, COX, SCCR and NCCR were all reduced in HF vs. CON (-21%, -34%, -28% and -26%, all p<0.001). In HF, Fe correlated with CS (r=0.30, p=0.004) and SCCR activities (r=0.24, p=0.02), but not with COX or NCCR. In pooled cohort, Fe also displayed strongest relation with CS (figure). HF+ID patients displayed reduced CS activity (516±145 vs 613±19, p=0.03), in contrast to preserved RC enzymes.

Conclusions:
Myocardial Fe content is systematically diminished in advanced HF and is associated with mitochondrial dysfunction, in particular with reduced CS activity. These relations may reflect Fe-dependent regulation of aconitase (TCA cycle enzyme) and may influence the utilization of energetic substrates.
Abstract 17210: Cardiorespiratory Fitness and Non Fatal Cardiovascular Events
Authors: Khan Hassan , Rauramaa Rainer , Kurl Sudhir , Savonen Kai , Laukkanen Jari A
Published: March 2022

Introduction:
To examine the relationship between cardiorespiratory fitness (CRF) and risk of non-fatal cardiovascular events.

Methods:
Cardiorespiratory fitness, as measured by maximal oxygen uptake (VO2max), was assessed at baseline in a prospective cohort of 2,089 men aged 42-61 years from the Kuopio Ischaemic Heart Disease Study (KIHD).

Results:
During a mean follow-up of 19.1 years (SD 8.4), 522 non-fatal acute myocardial infarction (MI) events, 198 acute all cause non-fatal stroke events and 221 non-fatal incident heart failure (HF) events were recorded. The hazard ratio (HR) per 1 MET increase in CRF was 0.93(95% CI: 0.88-0.97) for non-fatal MI, 0.94(95% CI: 0.87-1.01) for non-fatal stroke and 0.84(95% CI: 0.78-0.91) for non-fatal HF events after adjustment for established cardiovascular risk factors (age, systolic blood pressure, body mass index, history of cardiovascular disease, diabetes, smoking, alcohol use, serum creatinine, low density lipoprotein levels, physical activity and socioeconomic status). Further adjustment for additional risk factors did not substantially attenuate these associations. In a comparison of extreme quartiles of CRF levels, the corresponding adjusted HRs were 0.74 (95% CI: 0.55-0.99) for non-fatal MI, 0.91(95% CI: 0.58-1.44) non-fatal stroke and 0.49(95% CI: 0.30-0.80) for non-fatal HF respectively, Figures 1& 2.

Conclusions:
In this Finnish population, there is a strong, inverse, and independent association between CRF and non-fatal MI and HF risk, but not for acute non-fatal stroke events. The protective effect of CRF on non-fatal cardiovascular events needs further investigation in larger studies.
Abstract 17353: B Cell Depletion Promotes Aortic Infiltration of Tolerogenic Immune Cells and is Protective of Experimental Aortic Aneurysm
Authors: Schaheen Basil , Downs Emily A , Su Gang , Zhao Yunge , Srikakulapu Prasad , McNamara Coleen A , Butts Cherié , Upchurch Jr. Gilbert R , Meher Akshaya K , Ailawadi Gorav
Published: March 2022

Anti-CD20 antibody-mediated B cell depletion therapy is widely used for the treatment of B cell malignancies and rheumatoid arthritis. Given the observation that B cells are abundant in abdominal aortic aneurysms (AA), we hypothesize that B cell depletion would be protective of experimental AA formation.

C57BL/6j and IL-10 knock-out (KO) mice (male, 8-10 weeks old) were injected intraperitoneal (IP) or intravenous (IV) with mouse monoclonal anti-CD20 IgG2a (or IgG2a control) antibodies at day 7 before and day 7 following induction of AA using the elastase AA perfusion model. AA size was measured at day 14 following perfusion. Depletion of B cell (B1, B2 and IL-10 producing B cells) was confirmed using flow cytometry or immunohistochemistry. IgG and IgM levels were quantified using ELISA. One-way ANOVA was used for data analysis.

B1 cells were prominent in peritoneal cavity, whereas B2 cells were spleen and blood. 85-95% of B1 and B2 cells were depleted at day 7 following both IP and IV treatments. Interestingly, both the treatments strikingly suppressed AA growth (control, 96±8%; IP, 62±5%; and IV, 55±4%, p<0.01, n=8-10). Plasma IgM levels were significantly lower (p<0.01), whereas, IgG levels were similar in the B cell depleted mice compared to control mice. Immunohistology showed IL-10 producing B cells were preserved in spleen of B cell depleted mice. B cell depletion in IL-10 KO mice partially suppressed AA formation (control, 111±6%; anti-CD20, 92±8%; n=4-5) suggesting AA growth was partly dependent on IL-10 producing B cells. Flow cytometry revealed presence of CD19+ with B220+ or CD20+, CD138+ (plasma cells), CD1d+ and IgM+IgD+ cells in AA of control mice, which were absent in B cell depleted mice. Despite the preservation of elastin layers, B220+ cells were found the in the AA of B cell depleted mice, which were CD20- and IDO+ (Indole 2,3-dioxygenase), suggesting they are T cell tolerogenic plasmacytoid dendritic cells (pDC). Correlated with this, the CD4+FoxP3+ regulatory T cell population was higher in the aorta of B cell depleted mice.

The present results suggest B cell depletion protects mice from experimental AA formation partly via preserving IL-10 producing B cells and promoting the presence of tolerogenic pDCs in the aorta.
Abstract 17372: Comparison of Resting Energy Expenditure With Energy Intake in Neonates With Hypoplastic Left Heart Syndrome Following Stage 1 Palliation
Authors: French Christine L , Mills Kimberly I , Walsh Brian K , Kaza Aditya K , Cole Alexis , Baird Catherine , Bond Hilary , Mehta Nilesh M , Duggan Christopher P , Kheir John N
Published: March 2022

Introduction:
Nutrition provision and fluid administration following cardiac surgery in neonates impacts ventilator-dependent days, intensive care unit length of stay and diuretic administration. Resting energy expenditure (REE) in neonates following stage 1 palliation (S1P) for hypoplastic left heart syndrome (HLHS) has been poorly characterized and is essential to the provision of optimal nutrition.

Methods:
We continuously measured REE from postoperative day (POD) 0 through 7 following S1P in n=22 infants using an in-line, indirect calorimetric device (E-COVX moduleTM, GE Healthcare). Artifactual REE values were identified and filtered according to a predefined algorithm. Energy intake (EI) was abstracted from a detailed nutrition record.

Results:
There were no complications related to REE measurement, and 7.4% of measurements were found to be artifactual and excluded. Mean REE was 35.9 ± 10.1 kcal/kg/day on POD 0 and increased by an average of 3.1 ± 0.2 kcal/kg/day each day between POD 0 and 7 (A). Current recommended dietary allowance (RDA) estimates propose energy needs to be 108 kcal/kg/day in these patients.

From POD 0-1, EI was less than REE by 18.5±4.3 kcal/kg/day, as fluid intake was primarily comprised of blood products (46.8±7.4%) and flushes (24.5±1.9%, B). From POD 2-7, EI exceeded REE by 22.6±4.4 kcal/kg/day (cumulative amount of 111 ± 7.7 kcal/kg/day over a 5 day period, C). EI from carbohydrates was disproportionately high (69.1±6.2%), and that from protein remained low (7.6±1.2% of calories, 1.53±0.3 g/kg/day, C).

Conclusions:
Following S1P, EI correlates poorly with measured REE, which is significantly lower than RDA estimates. This may result in excessive fluid and calorie administration in this fluid-sensitive population. Continuous measurement of REE is safe to perform and should be considered in neonates following cardiac surgery. A future trial comparing restricted EI to estimated EI in postoperative neonates is necessary.
Abstract 17429: A Porcine Model of Heart Failure With Preserved Ejection Fraction Induced by Sustained Severe Hypertension
Authors: Zhen Zhe , Zhu Ziyi , Liao Song-Yan , Shuto Chika , Hata Cary , Chen Peter , Tse Hung-Fat
Published: March 2022

Background:
Currently, the lack of well-established large animal models of heart failure with preserved ejection fraction (HFpEF) is one of the major hurdles for developing effective therapies for HFpEF. Here, we describe a large animal model of HFpEF induced by sustained hypertension (HT) that mimics human diseases.

Methods:
We induced sustained severe hypertension in 9 adult pigs using a combination of intravenous Angiotensin-II (Ang-II, 0.015mg/hr) delivery with an osmotic infusion pump and subcutaneous implantation of deoxycorticosterone acetate (DOCA) pellets (100mg/kg) for 10 weeks. All animals underwent invasive blood pressure (BP) telemetry monitoring and serial invasive pressure-volume (PV) loop assessment as well as echocardiographic examination at baseline, 10 weeks and 18 weeks.

Results:
Mean systolic and diastolic BP at baseline was 88/61 mmHg which increased immediately after Ang-II infusion plus DOCA (Week 0,158/105 mmHg) and progressively elevated up to Week 10 (171/126mmHg) that persisted out to Week 18 (183/137mmHg) despite termination of Ang-II infusion. Serial echocardiograms showed the development of left ventricular hypertrophy with significant increase in left ventricular mass with preserved left ventricular ejection fraction (Figure, upper panel). PV loop showed progressive elevation of pulmonary artery capillary wedge pressure (PCWP), left ventricular end-diastolic pressure (LVEDP) and end-diastolic pressure volume relationship (EDPVR) without change in end-systolic pressure volume relationship, suggestive of left ventricular diastolic dysfunction (Figure, lower panel).

Conclusions:
We successfully established a clinically relevant large animal model of HFpEF induced by sustained HT, which can be used for future investigation of new treatments for HFpEF.
Abstract 17443: 3D Printing for Precision Drug Therapy: An Initial Proof of Concept Study
Authors: Yuang Kevin , Pu Shirley , Pu Min
Published: March 2022

Personalized medicine is an emerging approach for disease management. Individuals can vary dramatically in their response to cardiovascular drugs. Personalization of medication dosing is necessary for increasing efficacy and reduction of side-effects based on the patient's race, weight, renal function, liver function or other relevant factors. However, adjustments for oral medications are not easily made due to limited formulations by pharmaceutical companies. We hypothesized it is feasible to produce personalized pills tailored to each individual patient’s clinical and biological characteristics through automated 3D-printing.

Methods:
A prototype computer algorithm was developed in our laboratory. The software includes two databases: 3D volume and dosage-adjustment factors. After inputting clinical and biological factors specific to the patients (age, race, weight, GFR, etc.), the software automatically calculates a personalized dose. Once the appropriate dose is determined, 3 volume datasets are generated and transferred to a STL file of a 4x4 pill board for 3D-printing to test the accuracy and variability of 3D-printed “pills”. Five different doses (80 pills) were created with dosing increments of 25%.

Results:
All pills were successfully printed using a 3D-printer (Figure). Doses of printed pills ranged from 124 mg to 373 mg. There was high reproducibility with standard deviations ranging from 3-5 mg. There were differences of 0.5-6% between the printed pills and computer-generated volumes in 5 different dose ranges indicating pills can be replicated accurately using a volume-concentration equation by the software.

Conclusion:
The study demonstrates that personalized pills based on each individual's clinical and biological characteristics can be produced with high precision through 3D-printing. Further studies are needed to develop 1) a standard adjustment formula for each individual drugs 2) cost-effective 3D drug printing techniques.