bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 16877: High Serum Levels of Trefoil Factor 3 are Associated With an Increased Risk for Cardiovascular Events
Authors: Obendorf Florian , Herz Carsten Thilo , Höbaus Clemens , Pesau Gerfried , Koppensteiner Renate , Schernthaner Gerit
Published: March 2022

Introduction:
Trefoil factor 3 (TFF3), first described in the intestine has general growth but also angiogenic properties. Recently a role in cancer and inflammation was found. Classic cardiovascular risk factors have less predictive power for morbidity and mortality in patients with peripheral arterial disease (PAD) compared to patients with coronary heart disease (CHD).

Hypothesis:
Serum TFF3 levels are able to predict major adverse cardiovascular events (MACE) in patients with PAD.

Methods:
We applied bead array technology to assess the serum levels of TFF3 in 359 patients of a prospective, on-going, long-term follow-up PAD study. First MACE was used as outcome parameter, defined as occurrence of any death, non-fatal myocardial infarction or non-fatal stroke. Statistical analysis were performed including univariate correlations, Receiver Operating Characteristic (ROC) curves, students t-test , ANOVA, Kaplan-Meier (KM)-analysis and Cox-regression.

Results:
Patients with systemic atherosclerosis defined as concomitant PAD, CHD and cerebrovascular disease had significant higher levels of TFF3 (59.38±20.86 ng/ml) at baseline compared to patients with only one (47.22±18.10 ng/ml; p=0.001) or two (49.12±19.43 ng/ml; p=0.006) manifestations of atherosclerosis. KM-analysis demonstrated a significant lower event-free survival for the fourth quartile of TFF3 (71.1%) compared to the other (88.1%) (Log-rank: p<0.001). By using ROC a cut-off for TFF3 of 56.18 ng/ml was defined (sensitivity 56.9%; specifity 72.1%). A multivariable Cox regression model adjusted for age, gender, LDL-Cholesterol, systolic blood pressure, eGFR, diabetes status, smoking status and CRP showed that patients with TFF3 levels higher than 56.18 ng/ml had a hazard ratio of 2.77 (95%Cl: 1.38 - 5.58) for experiencing MACE.

Conclusions:
Our data imply a significant association of serum Trefoil Factor 3 and the occurrence of MACE in patients with atherosclerosis. This association of Trefoil Factor 3 and MACE was unchanged by C-reactive protein. Whether the association of Trefoil Factor 3 is causal, or a consequence of advanced atherosclerosis should be investigated in future trials containing time courses of Trefoil Factor 3 and MACE.
Abstract 16902: Efficacy and Safety of Rivaroxaban versus Warfarin in Patients Taking Non-dihydropyridine Calcium Channel Blockers: Results From the ROCKET AF Trial
Authors: Washam Jeffrey B , Hellkamp Anne S , Lokhnygina Yuliya , Piccini Jonathan P , Berkowitz Scott D , Nessel Christopher C , Becker Richard C , Breithardt Guenter , Fox Keith A , Halperin Jonathan L , Hankey Graeme J , Mahaffey Kenneth W , Singer Daniel E , Patel Manesh R
Published: March 2022

Background:
Non-dihydropyridine calcium channel blockers (non-DHP CCBs) are agents commonly used for ventricular rate control in patients with atrial fibrillation (AF). The agents have the property of combined cytochrome 3A4 and P-glycoprotein (P-gp) inhibition which may lead to increased drug exposure for oral anticoagulants that are substrates for these pathways. We investigated the safety and efficacy of rivaroxaban versus warfarin according to use of these agents.

Objectives:
This post-hoc analysis examined patient characteristics and compared outcomes between rivaroxaban and warfarin using Cox proportional hazards modeling according to the use of non-DHP CCBs at baseline in ROCKET AF (n=14,264).

Methods and Results:
At the time of randomization, 1308 patients (9.2%) were taking a non-DHP CCBs. Patients taking a non-DHP CCB were more likely to be female (45% vs. 39%), have diabetes (43% vs. 40%), and have a medical history of COPD (21% vs. 9%) while they were less likely to have a medical history of heart failure (49% vs. 64%), myocardial infarction (14% vs.18%) and had a lower mean CHADS
2
score (3.3 vs. 3.5). Non-DHP CCB use was not associated with an increased risk of stroke or non-CNS embolism (P=0.11) or the composite outcome of non-major clinically relevant or major bleeding (P=0.087). No significant difference was observed in the primary efficacy (stroke or non-CNS embolism; adjusted interaction P value=0.38) or primary safety outcome (non-major clinically relevant bleeding or major bleeding; adjusted interaction P value=0.14) between rivaroxaban and warfarin with non-DHP CCB use (Table).

Conclusion:
Non-DHP CCBs are commonly used medications for rate control in patients with AF. In spite of having the properties of combined P-gp and moderate CYP3A4 inhibition, use of these agents was not associated with a significant change in the efficacy or safety of rivaroxaban compared with warfarin in the ROCKET AF trial.
Abstract 16903: Prognostic Value of Combined CT Angiography and Myocardial Perfusion Imaging vs. Invasive Coronary Angiography and Nuclear Stress Perfusion Imaging for Predicting Major Adverse Cardiovascular Events - The CORE320 Multicenter Study
Authors: Chen Marcus Y , Rochitte Carlos E , Arbab-Zadeh Armin , Dewey Marc , George Richard T , Miller Julie M , Niinuma Hiroyuki , Yoshioka Kunihiro , Kitagawa Kakuya , Nakamori Shiro , Laham Roger , Vavere Andrea L , Cerci Rodrigo J , Mehra Vishal C , Nomura Cesar , Kofoed Klaus F , Jinzaki Masahiro , Kuribayashi Sachio , de Roos Albert , Laule Michael , Tan Swee Yaw , Hoe John , Paul Narinder , Rybicki Frank J , Brinker Jeffery A , Arai Andrew E , Cox Christopher , Clouse Melvin E , Di Carli Marcelo F , Lima Joao A
Published: March 2022

Background:
Noninvasive risk stratification in patients with suspected coronary artery disease (CAD) is critical for implementing appropriate strategies to prevent major adverse events (MACE). We aim to compare the survival and accuracy of combined CT angiography (CTA) and CT myocardial stress perfusion imaging (CTP) with combined invasive coronary angiography (ICA) and stress SPECT myocardial perfusion imaging for predicting MACE in patients with suspected CAD.

Methods:
The CORE320 prospective multicenter study enrolled 381 patients, between 45-85 years of age, who were clinically referred for ICA. Overall, 379 participants had all imaging including coronary CTA, adenosine stress CTP, SPECT and ICA plus complete 2 year follow-up data. An independent panel adjudicated all adverse events. MACE was defined as late revascularization (beyond 30 days of index ICA), myocardial infarction, cardiac death, hospitalization for chest pain or congestive heart failure, and arrhythmia. Kaplan-Meier survival analysis was performed and area under the receiving operating characteristic curve (AUC) was used to determine test accuracy.

Results:
MACE (45 late revascularizations, 5 myocardial infarctions, 1 cardiac death, 8 hospitalizations for chest pain or congestive heart failure, and 1 arrhythmia) occurred in 51 of 379 patients. The 2 year MACE event free rate for combined CTA/CTP findings was 95% (-) vs. 82% (+) (Figure, p<0.001) and similar to combined ICA/SPECT (p<0.001). Event rates for CTA/CTP vs. ICA/SPECT for either positive or negative results were not significantly different (p=0.126 and p=0.284, respectively). The overall AUC of combined CTA and CTP vs. combined ICA and SPECT for identifying MACE at 2 years was also similar: 68 (95%CI: 62-75) vs. 71 (95%CI: 65-79), respectively, p=0.357.

Conclusion:
Combined CTA and CTP yields similar prediction of 2 year MACE (especially revascularization) and diagnostic accuracy compared to standard ICA and SPECT.
Abstract 16907: A Light-powered Symbiosis With a Primordial Chloroplast Attenuates Myocardial Injury in the Absence of Blood Perfusion
Authors: Goldstone Andrew B , Cohen Jeffrey E , Shudo Yasuhiro , Steele Amanda N , Hopkins Michael S , Patel Jay B , Edwards Bryan B , Patrick William L , Burnett Cassandra E , Paulsen Michael J , Woo Y. Joseph
Published: March 2022

Objective:
The treatment for acute myocardial infarction (MI) is prompt revascularization. Our goal is to develop a novel therapy that mimics perfusion, but is not reliant on restitution of blood flow. We hypothesized that targeted delivery of a photosynthetic agent to the ischemic heart would restore myocardial energetics, attenuate damage, and improve long-term performance.

Methods:
Ten-week old male Wistar rats were used for the ischemia-reperfusion model. The left anterior descending artery (LAD) was temporarily ligated 2mm below the left atrial appendage via a left thoracotomy. Following ligation, animals were randomized to receive direct intramyocardial injection of 200μL PBS (n=7), 10x10
6
photosynthetic
Synechecoccus elongatus
(SE) of equivalent volume (n=10), or sham surgery (n=7). A light source illuminated the ischemic region for 1 hr after injection. The LAD tourniquet was subsequently removed and the heart reperfused. Ventricular function, geometry, and hemodynamics were assessed 4 weeks after surgery with MRI and LV catheterization.

Results:
Myocardial injury was attenuated by the photosynthetic agent: troponin-I concentration in peripheral blood was significantly lower in SE treated animals compared with controls 24 hrs post MI (6.5±4.8 vs. 16.5±10.5 ng/mL,
P
=0.05). Four weeks after MI, the mean LV ejection fraction was significantly greater in SE treated rats compared with controls (36.9±4.7 vs. 48.3±10.5%,
P
=0.02). Similarly, SE treated animals demonstrated a decreased end-systolic volume (327±133 vs. 487±140 μL,
P
=0.03) and a steeper slope of the end-systolic pressure-volume relationship (0.35±0.12 vs. 0.19±0.08,
P
=0.01). Histologic analyses revealed no evidence of intramyocardial abscess formation or persistent SE. Furthermore, the photosynthetic agent prevented upregulation of genes associated with hypoxia (downregulated Hsp-1b 11 fold).

Conclusions:
Delivery of a photosynthetic agent to ischemic myocardium creates a localized symbiotic relationship that safely attenuates myocardial injury and improves long-term ventricular function in a rat model of ischemia-reperfusion. Energizing myocardium with light in the absence of perfusion is a completely novel strategy for treating cardiac ischemia.
Abstract 16912: Molecular Mechanisms Underlying the Beneficial Effects of Inhibition of Soluble Epoxide Hydrolase in the Prevention of Atrial Fibrillation
Authors: Sirish Padmini , Li Ning , Timofeyev Valeriy , Zhang Xiao-Dong , Wang Lianguo , Yang Jun , Lee Kin Sing , Bettaieb Ahmed , Lau Victor , Lopez Javier , Haj Fawaz , Ripplinger Crystal M , Hammock Bruce , Chiamvimonvat Nipavan
Published: March 2022

Introduction:
Atrial fibrillation (AF) represents one of the most common arrhythmias seen clinically and is associated with a significant increase in morbidity and mortality, yet, current treatment paradigms have proven largely inadequate. Inflammation has been shown to play critical roles in the pathophysiology of AF.

Soluble epoxide hydrolase (sEH) catalyzes the hydrolysis of anti-inflammatory epoxyeicosatrienoic acids to corresponding pro-inflammatory diols. We have previously shown beneficial effects of sEH inhibitors (sEHIs) in cardiac failure and in the reduction of atrial arrhythmia inducibility. The objective of this study is to elucidate the molecular mechanisms underlying the prevention of atrial arrhythmia inducibility by sEHIs.

Methods:
In vivo pressure-overload model was used to replicate chronic hypertension. Flow cytometry, electrophysiologic studies and optical mapping were used to determine the mechanistic roles of sEHIs on atrial fibrosis and the reversal of electrical remodeling in atrial myocytes.

Results:
We demonstrate positive effects of sEHI in AF prevention by reducing 1) inflammation, 2) atrial structural remodeling by suppression of atrial fibrosis and hypertrophy (Fig A-D), and 3) electrical remodeling in atrial myocytes (Fig E-G). Mechanistically, inhibition of sEH enzyme results in a more than three-fold decrease in cytokines and chemokines (n=5, p<0.05), inhibition of NF-κB activation, reduction of oxidative and endoplasmic reticulum stress, and a more than five-fold decline in the phosphorylation of key signaling molecules including ERK1/2 and Smad2/3 in atrial myocytes and atrial fibroblasts (n=4, p<0.05).

Conclusions:
This study provides insights into the underlying mechanisms leading to AF by inflammation and represents a paradigm shift from conventional antiarrhythmic drugs, which block downstream molecules to a novel upstream therapeutic target by counteracting the inflammatory processes in AF.
Abstract 16926: Cardiac Ultrasound Has the Potential to Detect Tension Pneumothorax as a Reversible Cause of Cardiac Arrest - An Experimental Porcine Study
Authors: Caap Philip , Aagaard Rasmus , Sloth Erik , Løfgren Bo , Granfeldt Asger
Published: March 2022

Introduction:
Survival from cardiac arrest (CA) with a non-shockable rhythm is unlikely unless a reversible cause is identified and treated. Tension pneumothorax (tPTX) is a potentially reversible cause of CA, however the diagnosis can easily be missed. Cardiac ultrasound has the potential to detect reversible causes of CA. tPTX is believed to compress the heart and great vessels, causing the diameter of the right ventricle (RV) to decrease. In ventricular fibrillation and hypoxia induced CA blood accumulates on the right side of the heart causing RV distension, however the cardiac ultrasonographic characteristics of tPTX before and during CA are unknown.

Hypotheses:
1) In the period up to CA tPTX will decrease RV diameter compared to hypoxia induced CA.

2) At the onset of CA and start of CPR the RV diameter will increase, abolishing group difference.

Methods:
Pigs were randomized to CA induced by either unilateral tPTX (n=9) or hypoxia (n=9). tPTX was induced by injecting increments of air into the intrapleural cavity to a total volume of 50 ml/kg (90% of total lung capacity), while hypoxia was induced by gradually reducing the tidal volume over 30 min. tPTX was decompressed after 7 cycles of CPR. Subcostal 5-chamber ultrasound images of the RV were obtained during induction of CA and CPR. The primary endpoints were RV diameter at the onset CA and after 3 cycles of CPR.

Results:
At baseline the RV diameter was (mean (95%CI)): 24.2 (21.1-27.4) mm in the tPTX group and 24.2 (20.6-27.8) mm in the hypoxia group. Induction of CA, elicited a decrease in RV diameter in the tPTX group to 16.8 (13.0-20.6) mm and an increase in the hypoxia group to 36.2 (32.5-40.0) mm (p-value for comparison to baseline and between groups at CA; p<0.01). After three cycles of CPR RV diameter was significantly smaller in the tPTX group at 11.8 (7.3-16.2) mm when compared to the hypoxia group of 28.2 (24.5-31.9) mm (p<0.01). Immediately after decompression no difference existed between groups: tPTX 28.9 (23.4-34.3) mm vs. hypoxia 29.2 (20.1-38.2) mm (p = 0.94).

Conclusion:
tPTX causes a significantly smaller diameter of the RV compared to hypoxia prior to CA. This difference persisted during CPR, enabling cardiac ultrasound to detect tPTX as a reversible cause of CA. There was no RV difference after tPTX decompression.
Abstract 16954: SCARB1 Gene Variants are Associated With the New Lipid Phenotype of Combined High HDL-C and Lp(a)
Authors: Yang Xiaoping , Sethi Amar , Yanek Lisa R , Mathias Rasika A , Nordestgaard Borge G , Tybjaerg-Hansen Anne , Diane Becker M , Remaley Alan T , Becker Lewis
Published: March 2022

Introduction:
Although lipoprotein(a) (Lp(a)) is atherogenic, little is known about how it is transported from the plasma. Scavenger receptor class B type 1 (SR-B1), encoded by the gene SCARB1, binds high density lipoproteins (HDL). Recently we found that SR-B1 is also a receptor for Lp(a), mediates cellular uptake of Lp(a) in vitro, and promotes clearance of Lp(a) in vivo in mice. Genetic variants in SCARB1 have been associated with HDL level in humans, but no SCARB1 variants affecting Lp(a) have been reported. We hypothesized that loss of function mutations in SCARB1 would be associated with a phenotype of combined high HDL-C and Lp(a). Methods and Results: An index subject was identified in the NIH Lipid Clinic with high levels of both HDL-C and Lp(a). SCARB1 was sequenced and demonstrated a missense mutation at c.386 resulting in an S129L substitution in exon 3. To follow up on this finding, two cohorts of subjects (n=543 in the Genetic Study of Atherosclerosis Risk (GeneSTAR) and n=5907 in the Copenhagen City Heart Study) were screened for combined elevations of HDL-C and Lp(a). Subjects having HDL >80 mg/dl and Lp(a) >100 nmol/L in GeneSTAR, n=8, and >100 mg/dl in CCHS, n=9, underwent sequencing of all SCARB1 exons and splice junctions; 15 from the combined population of 18 were found to have variants predicted or demonstrated to have reduced function of the translated protein. Functional studies showed that 4 of the SCARB1 variants (c.386C>T; c.631-14T>G, c.4G>A and c.631-53mC>T & c.726+55mCG>CA, all heterozygous) had decreased receptor function in vitro, and the latter two were novel and not previously reported. Six of the subjects were homozygous for a common synonymous SCARB1 polymorphism (c.1050C>T) which has been reported to be associated with reduced protein expression.

Conclusion:
Human SCARB1 gene variants are associated with a new lipid phenotype, characterized by increases in both HDL-C and Lp(a). We demonstrate that SCARB1 exonic variants often result in diminished function of the translated SR-B1 lipid receptor with reduced binding/intracellular transport of Lp(a).
Abstract 16959: Interleukin-1 Blockade in Acute Decompensated Systolic Heart Failure: Results of the Anakinra in Decompensated Heart Failure Pilot Study
Authors: Van Tassell Benjamin W , Carbone Salvatore , Oddi Erdle Claudia , Abouzaki Nayef Antar , Melchior Ryan D , Turlington Jeremy S , Trankle Cory R , Christopher Sanah , Thomas Christopher S , Fronk Daniel T , Thurber Clinton , Dinarello Charles A , Biondi-Zoccai Giuseppe , Abbate Antonio
Published: March 2022

Background:
The inflammatory response in acute decompensated heart failure (ADHF) may contribute to the progression of the disease, complication, and re-hospitalization. Interleukin-1 (IL-1) has been identified as a potential therapeutic target in HF. We hypothesized that IL-1 blockade, with Anakinra (Kineret™, Swedish Orphan Biovitrum), would quench the acute inflammatory response in patients with ADHF.

Methods:
We randomized 30 patients with ADHF, reduced left ventricular ejection fraction (LVEF<40%), and elevated C reactive protein (CRP) levels (≥5 mg/l) to either Anakinra 100 mg twice daily for 3 days followed by once daily for 11 days or matching placebo, in a 1:1 double blinded fashion. We measured CRP and IL-6 plasma levels using high-sensitivity assays, daily for 5 days, and then again at 14 days and evaluated the area-under-the-curve (AUC) and interval change (delta).

Results:
Treatment with Anakinra was well tolerated: there were 7 adverse events in 6 patients treated with Anakinra and 12 in 10 patients treated with placebo (OR 0.33 [0.08-1.48, P=0.15). Two patients in the Anakinra group and 5 in the placebo group suspended treatment prematurely (OR 0.31 [0.05-1.93], P=0.21). When compared with placebo, Anakinra did not reduce the CRP-AUC at 4 days (primary endpoint) or at 14 days, while it significantly reduced the IL-6-AUC at 4 and 14 days (Table). Two patients in the Anakinra group and 3 patients in the placebo group experienced worsening HF or readmission for HF (OR 0.61 [0.09-4.34], P=0.62). In patients with paired baseline and day 14 echocardiograms (N=14), Anakinra was associated with a greater recovery in LVEF vs placebo (+10% [+3/+14] vs 0 [-16%/+5%], P=0.020, respectively).

Conclusions:
IL-1 blockade with Anakinra in patients with ADHF appears to be safe and is associated with a blunted inflammatory response. Further studies are warranted to determine whether this anti-inflammatory effect translates into improved clinical outcomes.
Abstract 16999: Analysis of Risk Factors for Mortality and Morbidity of Surgical Aortic Valve Replacement for Aortic Stenosis: Risk Models From a Japanese Database
Authors: Takano Hiroshi , Miyata Hiroaki , Motomura Noboru , Yamauchi Takashi , Shirakawa Yukitoshi , Takamoto Shinichi
Published: March 2022

Background:
Surgical aortic valve replacement (sAVR) is the standard treatment for atherosclerotic aortic stenosis; however, trans-catheter aortic valve replacement (tAVR) is being increasingly used for high risk patients. The risks associated with sAVR have usually been assessed by operative mortality. However, it may be meaningful to assess the risk for operative morbidity.

Purpose:
This study aimed to create risk models associated with sAVR for mortality, as well as for combined mortality and morbidity (M-M), using the Japan Adult Cardiovascular Surgery Database.

Methods:
A total of 14,100 patients who underwent sAVR with/without CABG between 2009 and 2012 were retrospectively evaluated. We excluded patients with contraindications to tAVR, except for chronic dialysis. Multiple logistic regression analysis was used to create a risk model for mortality (30 days postoperative and in-hospital), and for M-M (patient was hospitalized longer than 90 days or patient’s daily activities were disturbed with a modified Rankin scale of 4 or more at discharge).

Results:
Mortality was 3.1%, and rate of M-M was 10.9%. Significant risk factors are listed in the table. Risk factors common to both mortality and M-M were older age, chronic dialysis, atrial fibrillation, higher NYHA class, chronic lung disease, cerebrovascular disease, and congestive heart failure. Risk factors specific to M-M were history of psychoneurotic disorder, diabetes mellitus, obesity, and left ventricular dysfunction.

Conclusions:
Analyzing the risk factors not only for mortality but also for M-M may be useful in identifying appropriate candidates for tAVR.
Abstract 17028: “Worsening Heart Failure” in Chronic Heart Failure With Reduced Ejection Fraction: Definition, Characteristics, and Effects of NT-proBNP Guided Therapy
Authors: Mallick Aditi , Gandhi Parul U , Gaggin Hanna K , Januzzi James L
Published: March 2022

Introduction:
Worsening heart failure (WHF) has been identified as a potentially relevant clinical event in patients with HF syndromes and increasingly used as an endpoint in clinical trials. No standardized definition of WHF exists, nor is it known how WHF relates to risk for other events or how HF therapies may impact it.

Hypothesis:
Using the definition of WHF in the ProBNP Outpatient Tailored Chronic HF (PROTECT) study, we sought to characterize WHF.

Methods:
PROTECT was a randomized trial of 151 symptomatic patients with chronic HF with reduced ejection fraction (HFrEF), comparing standard of care HF management with or without a goal to lower amino-terminal pro-B type natriuretic peptide (NT-proBNP) concentrations <1000 pg/mL. WHF was defined as 1) new or progressive symptoms/signs of decompensated HF, 2) resulting in unplanned intensification of diuretic therapy.

Results:
Over mean follow-up of 10 months, 45 subjects developed WHF, the majority of whom had one or two WHF episodes. At baseline, patients destined to develop WHF had higher EF (31% vs. 25%, p=0.03), were more likely to have jugular venous distension and edema (p<0.02), were less likely to receive angiotensin converting enzyme inhibitors (ACEi), and more likely to receive lower ACEi doses (p<0.04); patients destined for WHF also received higher baseline loop diuretic doses (p<0.001) and had higher concentrations of several HF biomarkers including NT-proBNP, ST2, highly sensitive troponin, and galectin-3 (p <0.001). While numerous baseline factors were univariate predictors of WHF, only ST2 concentrations (p<0.001) and EF (p=0.03) at baseline were independently predictive of future WHF. Occurrence of WHF was strongly associated with subsequent HF hospitalization/CV death (56% vs 6%; p <0.001). Relative to therapies, ACEi use and dose were inversely associated with WHF (p<0.05), while loop diuretic dose was directly associated (P =0.006). Allocation to NT-proBNP-guided care independently predicted fewer WHF in adjusted analyses (HR=0.52, p=0.06) and improved time to first WHF event (log rank p=0.04).

Conclusion:
In chronic HFrEF, WHF is associated with substantial risk for morbidity and mortality. NT-proBNP guided care reduced risk for this important and deleterious outcome.
Abstract 17064: The Accuracy of an Impedance Cardiogram Based Compression Rate Feedback Algorithm Versus Real-time Video Recording of Chest Compression Rate
Authors: Di Maio Rebecca , Crawford Paul , McAlister Olibhear , McReynolds Hannah , Clutton Eddie , Adgey Jennifer
Published: March 2022

Objective:
It is widely known that CPR administered in all settings may be sub-optimal. CPR feedback tools can provide reliable feedback to operators to improve compression rate, depth and fraction. The purpose of this study was to evaluate the use of a CPR rate feedback algorithm incorporated into an automated external defibrillator by comparing the CPR compression rate measured by an Impedance Cardiogram based feedback device, a video recording of real-time CPR and using a commercially available accelerometer

Hypothesis:
ICG based CPR feedback is as effective as accelerometer based feedback.

Methods:
A total of twelve porcine models were used each weighing 29.62±4.2kg. Rate (CPM), End-tidal CO
2
(ETCO
2
), Blood Pressure (BP), SpO2 (%) and Depth (mm) was measured for each model. The Impedance Cardiogram (ICG)/Thoracic Impedance was recorded via 2 standard defibrillation electrodes and as a method of detecting the presence of CPR. Ethical approval was granted by the Northern Ireland Home Office and the Home Office in Scotland. Models were anaesthetised using Propofol and Isoflurane and connected to a Datex Ohmeda
®
monitor for anaesthesia monitoring. A number of physiological measurements were taken every 2 minutes via the carotid and jugular. Rate and depth were measured continuously using Q-CPR
®
, Philips. Recordings from each experiment were acquired using Datex Ohmeda review software for further statistical analysis using SAS 9.2
®
.

Findings:
The proportion of correct audio and visual feedback of the Impedance Cardiogram based feedback device versus the actual CPR compression rate as demonstrated in video recordings was 95.2%. The study also showed that the proportion of “correct” audio and visual feedback of the SAM 450P CPR Rate Feedback algorithm versus the accelerometer rate (CPM) was 87.5% due to underestimation of some measures in the non-ICG based device.

Conclusions:
Therefore it could be concluded that an Impedance Cardiogram based feedback device is highly sensitive to end user chest compression rate over a wide range of rates (40 to 180 compressions-per-minute).
Abstract 17066: Cellular Repressor of E1A-Stimulated Genes Protects From Myocardial Ischemia/Reperfusion Injury by Regulating Myocardial Autophagy and Apoptosis
Authors: Yan Chenghui , Song Haixu , Tian Xiaoxiang , Li Yang , Yang Guitang , Peng Chengfei , Sun Mingyu , Han Yaling
Published: March 2022

Background:
Cellular repressor of E1A-stimulated genes (Creg) is a secreted glycoprotein that regulates tissue and cell homeostasis and has been shown to antagonize heart injury; however, little is known about the role of CREG in ischemia/reperfusion injury (IRI). In this study, we aimed to investigate the role of CREG in cardiac IRI and clarify the mechanism.

Methods:
Myocardial ischemia/reperfusion (MIR) was established by ligation of left descending coronary artery for 30 min in wild type C57 mice (Creg+/+) and heterozygous Creg mice (Creg+/–). Expression of CREG was determined by Western Blot. Infarction size was determined by TTC and Evan’s Blue staining 24 hours after MIR. Cardiac function was evaluated by echocardiography at day 28. Recombinant CREG protein (0.3mg/kg·d) was supplemented through micro-pump embedded subcutaneously in Creg+/+ mice. Cardiac function and infarction size were assessed as mentioned above. Apoptosis, lysosome formation and function were detected in both heart tissue and cardiomyocyte cell line H9C2.

Results:
Level of CREG protein in mouse hearts was downregulated after mice were subjected to MIR, especially in Creg+/– mice. Creg+/– mice had larger infarction sizes after 24 hours of MIR treatment and worse cardiac function at day 28 compared with Creg+/+ mice. However, cardiac function was significantly improved in Creg+/+ mice treated with recombinant CREG protein. In Creg+/– mice, the number of cardiomyocytes undergoing apoptosis was increased, and LC3A and p62 accumulated, suggesting that autophagy was dysfunctional. Upregulation of CREG decreased apoptosis and activated autophagy of cardiomyocytes. Furthermore, we demonstrated that CREG protects cardiomyocytes against apoptosis by activating autophagy both in vivo and in vitro.

Conclusions:
CREG overexpression protects cardiac function against IRI by preventing cardiomyocyte apoptosis. The protective effects of CREG are partly mediated by activation of lysosomal autophagy.
Abstract 17075: Frequency and Predictors of Premature Ventricular Contractions in Young and Healthy Adults
Authors: von Rotz Mirco , Aeschbacher Stefanie , Bossard Matthias , Schoen Tobias , Blum Steffen , Estis Joel , Todd John , Risch Martin , Risch Lorenz , Conen David
Published: March 2022

Background:
Premature ventricular contractions (PVCs) are associated with a higher rate of all-cause mortality and cardiovascular complications in individuals with and without structural heart disease. However, little is known about frequency and predictors of PVCs in the general population.

Methods:
We assembled a population-based sample of individuals aged 25-41 years without prevalent cardiovascular disease. 24-hour electrocardiography (ECG) was performed with a validated device. Rigorous quality control was performed on all ECG studies by a trained physician, in order to adjust PVCs and to remove artefacts. We used multivariable negative binomial regression models to assess the relationship of PVC frequency with a large number of baseline characteristics, lifestyle factors and laboratory parameters.

Results:
Of the 2170 participants recruited for this study, 2065 participants (median age 37 years, 47% men, median BMI 24.1kg/m
2
) qualified for this analysis. During 24 hours of ECG recording, 69% of participants had at least 1 PVC. The median number (interquartile range) of PVCs was 2 (0-5) among men and 2 (0-7) among women, p=0.23. The 95
th
percentile of PVCs over 24 hours was 200 among men and 184 among women. In multivariable models, we found 9 significant predictors for PVC frequency, as displayed in the table.

Conclusion:
This is one of the first studies to systematically assess frequency and risk factors for PVC occurrence in the general population. Our results suggest that PVC occurrence is not uncommon even in healthy low-risk individuals, and that its frequency is determined by several covariates related to cardiovascular risk factors and cardiac structure and function.
Abstract 17077: Nocturnal Intermittent Hypoxia and Short Sleep Duration were Independently Associated With Elevated C-reactive Protein Level in Patients With Coronary Artery Disease
Authors: Fukuoka Ryoma , Kohno Takashi , Kohsaka Shun , Yanagisawa Ryo , Nishiyama Takahiko , Maekawa Yuichiro , Sano Motoaki , Fukuda Keiichi
Published: March 2022

Introduction:
There is growing evidence of a relationship between sleep disorders and cardiovascular diseases including coronary artery disease (CAD). However, the mechanism of these association is not well established. Enhanced vascular inflammation is implicated as a pathophysiologic mechanism in CAD. The aim of this study was to evaluate the relationship among sleep-disordered breathing (SDB), sleep duration, and serum C-reactive protein (CRP) level in patients with CAD.

Methods and Results:
Consecutive 225 patients with CAD who underwent percutaneous coronary intervention were evaluated. We used a nocturnal pulse oximetry as a non-invasive screening method for nocturnal intermittent hypoxia, a surrogate marker of SDB. Nocturnal intermittent hypoxia was evaluated using 3% oxygen desaturation index (3% ODI) which was the number of oxygen desaturation measurement ≤ 3% per hour, and we divided the patients into nocturnal intermittent hypoxia group (3% ODI≥15; n=64) and control group (3% ODI<15; n=161). Sleep quality was assessed using validated questionnaires (Pittsburgh Sleep Quality Index [PSQI]; 5.3±3.4, sleep duration; 385±83 minutes). Nocturnal intermittent hypoxia group had significantly higher BMI compared with control group, but age, gender, other coronary risk factors, sleep disturbance (PSQI≥8), sleep duration, and angiographic findings did not differ between two groups. Laboratory data showed that serum CRP level was significantly higher in patients with nocturnal intermittent hypoxia (0.15 [0.09-0.33] vs 0.06 [0.02-0.21] mg/dl, p=0.003). Short sleep duration (<6 hours) was also associated with increased CRP level (0.22 [0.04-0.40] vs 0.07 [0.03-0.14] mg/dl, p=0.036). In multiple regression analysis adjusted by age, gender, BMI, and acute coronary syndrome, 3% ODI (β=0.25; p=0.016; 95% CI, 0.153 to 1.475) and short sleep duration (β=0.20; p=0.04; 95% CI, 0.022 to 1.299) were independent determinants for log serum CRP level.

Conclusions:
Nocturnal intermittent hypoxia and short sleep duration were independently associated with elevated serum CRP level in CAD patients, suggesting that SDB and sleep duration could be important modifiable factors for the clinical management of patients with CAD.
Abstract 17086: Alirocumab LDL-C-Lowering Efficacy in Patients With Moderate CKD
Authors: Toth Peter P , Cannon Christopher P , Kastelein John J , Colhoun Helen M , Koren Andrew , Louie Michael J , Asset Gaëlle , Rader Daniel J
Published: March 2022

Background:
Patients with chronic kidney disease (CKD) are at increased risk of premature cardiovascular disease. Many of these patients require adjuvant lipid-lowering therapy because of dosing restrictions of some statins in patients with CKD.

Objective:
To determine LDL-C lowering efficacy and safety of the PCSK9 inhibitor alirocumab (ALI) in patients with hypercholesterolemia and with or without moderate CKD.

Methods:
This analysis included data from 10 ODYSSEY Phase 3 trials. Moderate CKD was defined as glomerular filtration rate 30-59 mL/min/1.73m
2
. LONG TERM and HIGH FH (n=2448) compared ALI 150 mg every two wks (Q2W) vs placebo. The remaining 6 trials (n=2535) evaluated ALI 75 mg Q2W vs placebo/ezetimibe, with increase to ALI 150 mg Q2W at wk 12 if LDL-C was ≥70 or ≥100 mg/dL at wk 8 depending on CV risk. Patients received stable background statin ± other LLT, except in ALTERNATIVE and MONO (no statin) and COMBO II (statin but no other LLT).

Results:
Moderate CKD at baseline was present in 481/4983 (9.7%) of patients. Mean baseline LDL-C levels of patients with and without moderate CKD were 109.6 and 127.8 mg/dL, respectively, and 96.9% and 92.7% were receiving a statin. Overall, having moderate CKD did not impact the LDL-C lowering efficacy of ALI (Figure). The smaller LDL-C reduction (vs other studies) seen in alirocumab-treated patients with moderate CKD in the ALTERNATIVE study may be related to low patient number. Adverse events (AEs) were reported by 79.0% ALI vs 81.1% control patients with moderate CKD and 74.7% ALI vs 74.5% control patients without. AEs led to discontinuation in 10.0% ALI vs 8.2% control patients with moderate CKD and 6.0% ALI and 6.6% control patients without.

Conclusions:
ALI consistently lowered LDL-C levels vs control regardless of baseline moderate CKD status. There was no significant difference in % AEs between patients with and without moderate CKD and a numerically higher rate of discontinuations due to AEs in patients with moderate CKD.
Abstract 17093: Long-term Survival After Off-pump Coronary Artery Bypass Graft Surgery: A Cohort Study
Authors: Patel Nishith N , Fiorentino Francesca , Sharabiani Mansour T , Angelini Gianni D
Published: March 2022

Introduction:
Randomised controlled trials demonstrate that Off-Pump Coronary Artery Bypass (OPCAB) is equivalent to On-Pump Coronary artery bypass graft (ONCAB) for in-hospital and short-term outcomes. Recent observational data, however, suggests that OPCAB may be associated with increased mid-term mortality although there are several conflicting studies.

There is little data on long-term survival after OPCAB. The objective of this study was to determine the impact of OPCAB on long-term survival compared to ONCAB.

Methods:
We conducted a retrospective cohort study using the Bristol PATS database of all patients who underwent primary isolated CABG surgery from 1996 to 2011. Mortality data was obtained from the Office of National Statistics. Multivariate regression models were used to estimate the association between OPCAB and long-term survival.

Results:
We evaluated long-term survival in 11,981 patients (mean age 65.5±9.3 years, 2202 females) who underwent CABG (OPCAB, n=6133; ONCAB, n=5848). Survival data was complete in 99.2% of patients, with a median follow-up duration of 8 years (interquartile range: 4.8 to 11.8 years; maximum 17.3 years). Both groups were similar in terms of baseline characteristics and intraoperative variables. Euroscore was 3.7 (0.03) and 3.8 (0.03) and number of distal anastomoses performed were 2.53 (0.81) and 2.92 (0.78) in the OPCAB and ONCAB groups, respectively. Long-term survival was similar between patients undergoing OPCAB and ONCAB (HR for death: 0.94, 95%CI 0.87 - 1.01, p=0.087).

Conclusions:
In patients undergoing coronary revascularisation both ONCAB and OPCAB offer excellent long-term survival.
Abstract 17099: Additional LDL-C Reduction Achieved With Alirocumab Dose Increase on Background Statin
Authors: Kastelein John J , Kereiakes Dean J , Cannon Christopher P , Bays Harold E , Minini Pascal , Lee L. Veronica , Maroni Jaman , Farnier Michel
Published: March 2022

Background:
The majority of ODYSSEY Phase 3 clinical trials of the PCSK9 inhibitor alirocumab (ALI) utilized a dose increase strategy designed to individualize LDL-C lowering therapy.

Objective:
To describe dose response in patients on background statin whose ALI dose was increased from 75 to 150 mg every 2 wks (Q2W) at wk 12.

Methods:
This analysis included 6 Phase 3, randomized, double-blind, double-dummy trials of 24-104 wks duration (N=1291): ALI vs placebo (COMBO I, FH I+II) or vs ezetimibe 10 mg/day (COMBO II, OPTIONS I+II). Patients on background statin with an initial dose of ALI 75 mg Q2W had dose increase to 150 mg SQ Q2W at wk 12, if at wk 8 LDL-C was ≥70 mg/dL (or >100 mg/dl in OPTIONS studies for patients without prior CHD but other risk factors). LDL-C % reductions from baseline were compared at wk 12 (before dose increase) vs wk 24, including only patients receiving study treatment (on-treatment analysis).

Results:
Majority of FH and high-risk patients (73.7%) achieved LDL-C <70 or <100 mg/dL (depending on CV risk) with the 75 mg Q2W dose on background statin. ALI dose was increased in 340 (26.3%) patients at wk 12 (Table). Overall, following dose increase at wk 12, an additional 14.2% reduction in LDL-C was seen at wk 24. Across the Phase 3 program, comparable AE rates were seen in patients who received dose increase vs those who did not: 65.8% vs 66.2% in placebo-controlled trials and 54.5% vs 55.9% in ezetimibe-controlled trials; injection site reactions were reported by 3.9% vs 4.9% in placebo-controlled trials and 0.9% vs 0.8% in ezetimibe-controlled trials.

Conclusions:
The 75 mg Q2W dose is sufficient for most patients to achieve risk-specific LDL-C goals. Increasing ALI dose from 75 to 150 mg Q2W at wk 12 was associated with a 14.2% additional reduction in LDL-C at wk 24, more than double the additional LDL-C reduction achieved by doubling a statin dose. The flexible dosing strategy allows the majority of patients to get to LDL-C goals without affecting the safety profile.
Abstract 17103: SIRT1 in the Cardiomyocyte Counteracts Doxorubicin Cardiotoxicity in vivo
Authors: Tsukamoto Miki , Kuno Atsushi , Hosoda Ryusuke , Sebori Rio , Horio Yoshiyuki
Published: March 2022

Background:
Cardiotoxicity of doxorubicin (DOX) is mediated through mitochondrial perturbations. SIRT1, an NAD
+
-dependent deacetylase, has been reported to promote cellular adaptation to metabolic imbalances in part via mitochondrial biogenesis.

Hypothesis:
SIRT1 in the cardiomyocyte counteracts DOX cardiotoxicity in vivo.

Methods:
Tamoxifen (Tam)-inducible cardiomyocyte-specific SIRT1 knockout mice (SIRT1 cKO) were used. At 2 months of age, mice received Tam to induce knockout, and mice without Cre recombinase served as wild type (WT). Both groups of mice were treated with DOX (4 IP injections of 5 mg/kg/week) starting at 3 months of age. Echocardiography was performed before and after DOX treatment. Cardiac tissues were sampled after the final DOX injection. H9c2 cardiomyocytes were used for in vitro analysis.

Results:
At baseline, there were no differences in left ventricular (LV) dimension, thickness, fractional shortening (FS), and ejection fraction (EF) between the groups. DOX significantly reduced FS, EF, and LV thickness in both groups of mice. However, FS and EF after DOX injections were lower in SIRT1 cKO than in WT (FS, 26% vs. 30%; EF, 59% vs. 65%, P<0.05). ANP and BNP mRNA levels were also higher in SIRT1 cKO (2.4-fold and 2.4-fold, respectively, P<0.05), confirming worsening of cardiac function. Compared with WT, SIRT1 cKO showed reduced cardiac mitochondrial content determined by qPCR analysis of mitochondrial DNA level (-16%, P<0.05). Unexpectedly, mRNA levels of nuclear-encoded mitochondria genes (Cox5b, Atp5a1, and citrate synthase) were not altered in the SIRT1 cKO heart, indicating preserved mitochondrial biogenesis in cKO. Instead, mRNA levels of parkin (+43% P<0.05), PINK1 (+18%), and Bnip3 (+40%) were higher in SIRT1 cKO than in WT, suggesting enhanced mitochondrial degradation via mitophagy. Finally, SIRT1 knockdown in H9c2 cells enhanced DOX (10 μM, 24 h)-induced cell death examined by LDH release compared with control cells (13.2±1.4% vs. 8.6±0.7%, P<0.05).

Conclusions:
The results suggested that SIRT1 in the cardiomyocyte counteracts DOX cardiotoxicity by preserving mitochondrial content in vivo. Enhanced degradation, but not impaired biogenesis, may be involved in mitochondrial depletion in SIRT1 cKO.
Abstract 17106: Nox2-derived Reactive Oxygen Species Impede Vascular Repair in the Context of Endothelium-specific Insulin Resistance
Authors: Ali Noman , Yuldasheva Nadira , Sengupta Anshuman , Smith Jessica , Walker Andrew , Skromna Anna , Makava Natalia , Galloway Stacey , Patel Peysh , Mercer Ben , Wheatcroft Stephen , Kearney Mark , Cubbon Richard
Published: March 2022

Introduction:
Insulin resistance is independently linked to cardiovascular disease, and oxidative stress is recognised as a potential contributor to this relationship. We have previously shown that endothelium-specific insulin resistance promotes endothelial dysfunction, atherosclerosis, and increased vascular NADPH oxidase 2 (NOX2) derived reactive oxygen species (ROS). Oxidative stress may promote vascular disease by impairing endogenous vascular repair.

Hypothesis:
We hypothesise that deletion of NOX2 in mice with endothelial specific insulin resistance can improve vascular repair.

Methods:
Mice with endothelial specific insulin resistance (ESMIRO) were bred with mice deficient in NOX2, in order to produce double-cross ESMIRO x NOX2y/- (ExN) offspring. Phenotypic assessment comprised glucose and insulin tolerance tests and ELISA for plasma insulin concentration. In vivo assessment of vascular repair and angiogenesis were undertaken using femoral artery wire injury and hindlimb ischaemia techniques, respectively, whilst flow cytometry was used to quantify circulating progenitor cells (CPCs). Data are expressed as mean [standard error] and compared using unpaired t-tests; *=p<0.05.

Results:
No significant differences were seen between ExN and ESMIRO in glucose tolerance, insulin sensitivity, or basal insulin level (0.8[0.1]ng/ml vs. 0.8[0.1];p=0.8). ExN mice demonstrated significantly improved vascular regeneration following injury compared to ESMIRO (62%[4%] vs. 46%[3%]*), coupled with a significantly higher number of CPCs (202.6[20.3] per 100000 lymphocytes vs. 134.3[10.6]*). This improvement was not mirrored in ischaemic limb perfusion recovery (Perfusion relative to non-ischaemic limb at 28 days 54%[8%] vs. 53%[4%]).

Conclusions:
Our data demonstrate that targeting NOX2 can augment vascular repair in the setting of endothelial specific insulin resistance, whilst having no detrimental impact on the response to limb ischaemia, and is associated with an increased abundance of CPCs. These findings support a possible role for NOX2 inhibitors to promote recovery from vascular injury in the setting of insulin resistance.
Abstract 17111: Novel Global Ultrasound Imaging and Continuous Dipole Density Mapping: Initial Findings in AF Patients
Authors: Heck Patrick , Neuzil Petr , Reddy Vivek , Grace Andrew
Published: March 2022

Introduction:
Electro-anatomic mapping is standard practice in AF ablation procedures. Virtual anatomies are created to locate structures and navigate catheters and voltage (V) is used to map arrhythmias.

Methods:
A novel non-contact imaging and Dipole Density (DD) mapping system (AcQMap), consisting of a basket catheter (48 Ultrasound (U/S) transducers, 48 electrodes) and console, simultaneously acquires 100,000+ U/S points/min to reconstruct the chamber anatomy and 150,000 intracardiac unipolar V samples/second to map cardiac activity. The 3D surface is algorithmically reconstructed from the U/S point-set with mesh-density comparable to segmented CT (sCT). Inverse and Forward algorithms are applied on intracardiac V to derive and display activation as DD and unipolar V maps, respectively, upon the U/S-constructed 3D anatomy (Figure). Patients listed for AF ablation were consented for U/S and DD mapping. U/S LA anatomy was created from full and sub-sampled point-sets and compared to pre-procedure sCT. DD and V maps were derived for each patient and depolarized surface areas were compared.

Results:
Seven patients (57% Male, Age 61.4 ± 10.3 yrs, AF duration 4.2 ± 2.3 yrs) were enrolled. Complete data sets were collected in 6 subjects. Surface-points must be acquired for at least 30 seconds to achieve a consistent median distance between AcQMap and sCT surfaces. The absolute median distance between surfaces was 2.71 mm. During AF, the mean depolarized area for DD maps was 26.9 cm2, significantly less than for V maps (110.6 cm2, p < 0.001). Overall V:DD ratio was 4.11 for AF.

Conclusions:
Real-time U/S based LA reconstruction was rapid and compared favorably to sCT. DD map provides 4.11 times higher resolution than V maps. The combination of CT-quality anatomy and DD mapping opens the possibility to map AF with more precision to identify areas of interest as potential ablation targets.